FEBRUARY 2011 VOL 2, NO 1 by Value-Based Cancer Care

FEBRUARY 2011 VOL 2 NO 1

www.ValueBasedCancerCare.com

Combination Anti-HER2 Therapies the Wave of the Future

Healthcare Reform Boosted at ASH

A sea change in the approach to management

By Colin Gittens

By Caroline Helwick

Orlando, FL—Healthcare reform offers a chance to correct course from an unsustainable financial path and offers many benefits, said Ezekiel J. Emanuel, MD, PhD, at a policy forum jointly hosted by the American Society of Hematology (ASH) and the European Hematology Association. But for the reforms to produce maximal benefit, there are a number of things physicians need to do, Dr Emanuel said. Dr Emanuel—a special advisor for health policy to the director of the White House Office of Management and Budget until January 2011—first outlined US healthcare spending and outcomes, noting that in 2009, the United States spent $2.53 trillion on healthcare. Despite that number and the alarming growth rate in spending, overall outcomes are not great—for life expectancy at age 65, the United States ranked 12th for men and 16th for women. In cancer care, however, qual-

Continued on page 20

New Cancer Drugs Approved by the FDA, 2000-2010 10

Drugs approved, N

Photo courtesy of the American Society of Hematology

a novel monoclonal antibody akin to trastuzumab. Neil Spector, MD, director of Translational Oncology Research at the Duke Cancer Institute in North Carolina, remarked that, “Combinations of targeted drugs is the future of oncology. This is a very exciting area. We have gone from HER2-overexpressing disease being the most lethal type of breast cancer to a subtype that we are talking about curing.” In the 4-arm NeoSphere trial, triple

Photo by © SABCS/Todd Buchanan 2010

San Antonio, TX—It turns out that for women with HER2-overexpressing breast cancer, treatment with trastuzumab (Herceptin)—which cuts the risk of recurrence by half—may be just the beginning. At the annual San Antonio Breast Cancer Symposium, several key studies evaluated “combined HER2 blockade,” showing impressive outcomes in the preoperative (neoadjuvant) setting. In these studies, rates of pathologic complete response (pCR)—which means that tumors not only shrink but tumor cells become undetectable— exceeded 50%. The studies used various combinations of trastuzumab, lapatinib (Tykerb), and pertuzumab,

Former White House advisor highlights economic benefits

ity is high, with the United States ranked first in prostate cancer, second in breast cancer, and third in colon cancer outcomes worldwide. The passage of healthcare reform is an “historical event,” Dr Emanuel emphasized. To counteract the myths surrounding the bill, he detailed the ways in which costs will be controlled Continued on page 11

Weighing In on the Avastin Decision

Payers’ perspectives from VBCC board members

5 4 3 2 1 0

05 Year

Drugs approved in 2010 (in order of approval) were sipuleucel-T (Provenge), cabazitaxel (Jevtana), odansetron (Zuplenz), eribulin (Halaven), and denosumab (Xgeva). Data adapted from CenterWatch web site. www.centerwatch.com/drug-information/fda-approvals/ drug-areas.aspx?AreaID=12.

An organization you’ll want to be part of.

o assess the potential implications, further questions, and next steps concerning bevacizumab (Avastin) use in patients with metastatic breast cancer, we spoke with a number of key constituents as well as our own editorial board members. One important question evoked by the process has been the discrepancy in voting between the US Food and Drug

VOL. 2

The First Annual Stakeholder Integration Conference March 29-30, 2011 • Philadelphia, PA NO. 5

SPECIAL Turn to page ISSUE

Continued on page 36

INSIDE 10

VALUE PROPOSITIONS . . . . . . . . .

Brachytherapy—what’s the evidence? MEETING COVERAGE . . . . . . . . . . .

A meeting you’ll want to attend.

Administration’s (FDA) Oncologic Drugs Advisory Committee (which voted 12-1 in favor of removing the indication) and the National Comprehensive Cancer Network (NCCN) Breast Cancer Panel, which voted unanimously to affirm its recommendation that Avastin continue to be used for this indication. This has led to

ASH annual meeting SABCS conference ASTRO annual meeting ASHP clinical meeting PATHWAYS IN ONCOLOGY

VBCC PERSPECTIVES . . . . . . . . . .

The essential health benefits provision Decision-support tools to guide value-based care CLINICAL TRIALS . . . . . . . . . . . . . . .

Clinical trials may become nimbler in the future ....

New directions in cancer care

HEALTH POLICY

................

Patients with advanced cancer Healthcare reform repeal

ALOXI provides powerful CINV prevention that can’t be ignored. ®

Proven CINV prevention in a single IV dose s Powerful CINV prevention in the ﬁrst 24 hours and up to 5 days following moderately emetogenic chemotherapy 1,2 s Lasts long against nausea following moderately emetogenic chemotherapy 3 s Powerful acute CINV prevention following highly emetogenic chemotherapy 4 s Eisai offers a variety of support programs and resources

Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.

Important Safety Information s !,/8) IS CONTRAINDICATED IN PATIENTS KNOWN TO HAVE HYPERSENSITIVITY TO THE DRUG OR ANY of its components s -OST COMMONLY REPORTED ADVERSE REACTIONS IN CHEMOTHERAPY INDUCED NAUSEA AND VOMITING include headache (9%) and constipation (5%) Please see the brief summary of the Full Prescribing Information on the adjacent page. References: 1. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 2. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 3. Data on ﬁle. Eisai Inc., Woodcliff Lake, NJ. 4. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-1449.

STARTS STRONG. LASTS LONG.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc. © 2010 Eisai Inc. All rights reserved. Printed in USA. ALO000083A 08/10

FDA UPDATES Rituximab Gains Nod for Maintenance Therapy in Follicular Lymphoma Rituximab (Rituxan) was approved by the FDA as a maintenance treatment for patients with advanced follicular lymphoma (FL) who responded to initial treatment with rituximab plus chemotherapy. ALOXIÂŽ (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: L =23@/B3:G 3;3B=53<71 1/<13@ 163;=B63@/>G K >@3D3<B7=< =4 /1CB3 /<2 23:/G32 </CA3/ /<2 D=;7B7<5 /AA=17/B32 E7B6 7<7B7/: /<2 @3>3/B 1=C@A3A L 756:G 3;3B=53<71 1/<13@ 163;=B63@/>G K >@3D3<B7=< =4 /1CB3 </CA3/ /<2 D=;7B7<5 /AA=17/B32 E7B6 7<7B7/: /<2 @3>3/B 1=C@A3A DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting =A/53 4=@ 2C:BA / A7<5:3 ;5 ) 2=A3 /2;7<7AB3@32 =D3@ A31=<2A =A7<5 A6=C:2 =11C@ />>@=F7;/B3:G ;7<CB3A 034=@3 B63 AB/@B =4 163;=B63@/>G Instructions for I.V. Administration "+ 7A AC>>:732 @3/2G 4=@ 7<B@/D3<=CA 7<831B7=< "+ A6=C:2 <=B 03 ;7F32 E7B6 =B63@ 2@C5A :CA6 B63 7<4CA7=< :7<3 E7B6 <=@;/: A/:7<3 034=@3 /<2 /4B3@ /2;7<7AB@/B7=< =4 "+ #/@3<B3@/: 2@C5 >@=2C1BA A6=C:2 03 7<A>31B32 D7AC/::G 4=@ >/@B71C:/B3 ;/BB3@ /<2 27A1=:=@/B7=< 034=@3 /2;7<7AB@/B7=< E63<3D3@ A=:CB7=< /<2 1=<B/7<3@ >3@;7B CONTRAINDICATIONS "+ 7A 1=<B@/7<271/B32 7< >/B73<BA 9<=E< B= 6/D3 6G>3@A3<A7B7D7BG B= B63 2@C5 =@ /<G =4 7BA 1=;>=<3<BA [see Adverse Reactions (6) 7< 4C:: >@3A1@707<5 7<4=@;/B7=< ] WARNINGS AND PRECAUTIONS Hypersensitivity G>3@A3<A7B7D7BG @3/1B7=<A ;/G =11C@ 7< >/B73<BA E6= 6/D3 3F6707B32 6G>3@A3<A7B7D7BG B= =B63@ '

@313>B=@ /<B/5=<7ABA ADVERSE REACTIONS 31/CA3 1:7<71/: B@7/:A /@3 1=<2C1B32 C<23@ E723:G D/@G7<5 1=<27B7=<A /2D3@A3 @3/1B7=< @/B3A =0A3@D32 7< B63 1:7<71/: B@7/:A =4 / 2@C5 1/<<=B 03 27@31B:G 1=;>/@32 B= @/B3A 7< B63 1:7<71/: B@7/:A =4 /<=B63@ 2@C5 /<2 ;/G <=B @3J 31B B63 @/B3A @3>=@B32 7< >@/1B713 < 1:7<71/: B@7/:A 4=@ B63 >@3D3<B7=< =4 </CA3/ /<2 D=;7B7<5 7<2C132 0G ;=23@/B3:G =@ 6756:G 3;3B=53<71 163;=B63@/>G

/2C:B >/B73<BA @3137D32 >/:=<=A3B@=< 2D3@A3 @3/1B7=<A E3@3 A7;7:/@ 7< 4@3?C3<1G /<2 A3D3@7BG E7B6 "+ /<2 =<2/<A3B@=< =@ 2=:/A3B@=< =::=E7<5 7A / :7AB7<5 =4 /:: /2D3@A3 @3/1B7=<A @3>=@B32 0G â&#x2030;Ľ =4 >/B73<BA 7< B63A3 B@7/:A '/0:3 Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies â&#x2030;Ľ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=194) (N=633) 3/2/163

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The approval was based on data from the phase 3 PRIMA study, an international, multicenter, randomized study that enrolled 1217 patients with previously untreated advanced FL. By continuing rituximab every 2 months for 2 years in patients who responded to initial rituximab plus chemotherapy treatment, progression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ostmarketing Experience '63 4=::=E7<5 /2D3@A3 @3/1B7=<A 6/D3 033< 723<B7I 32 2C@7<5 >=AB/>>@=D/: CA3 =4 "+ 31/CA3 B63A3 @3/1B7=<A /@3 @3>=@B32 D=:C<B/@7:G 4@=; / >=>C:/B7=< =4 C<13@B/7< A7H3 7B 7A <=B /:E/GA >=AA70:3 B= @3:7/0:G 3AB7;/B3 B637@ 4@3?C3<1G =@ 3AB/0:7A6 / 1/CA/: @3:/B7=<A67> B= 2@C5 3F>=AC@3 )3@G @/@3 1/A3A =4 6G>3@A3<A7B7D7BG @3/1B7=<A /<2 7<831B7=< A7B3 @3/1B7=<A 0C@<7<5 7<2C@/B7=< 27A1=;4=@B /<2 >/7< E3@3 @3>=@B32 4@=; >=AB;/@93B7<5 3F>3@73<13 =4 "+ ;5 7< B63 >@3D3<B7=< =4 163;=B63@/>G 7<2C132 </CA3/ /<2 D=;7B7<5 DRUG INTERACTIONS #/:=<=A3B@=< 7A 3:7;7</B32 4@=; B63 0=2G B6@=C56 0=B6 @3</: 3F1@3B7=< /<2 ;3B/0=:71 >/B6E/GA E7B6 B63 :/BB3@ ;327/B32 D7/ ;C:B7>:3 ,# 3<HG;3A C@B63@ 7< D7B@= ABC273A 7<271/B32 B6/B >/:=<=A3B@=< 7A <=B /< 7<6707B=@ =4 ,# ,# ,# ,# ,# ,# /<2 ,# ,# E/A <=B 7<D3AB75/B32 <=@ 2=3A 7B 7<2C13 B63 /1B7D7BG =4 ,# ,# =@ ,# '63@34=@3 B63 >=B3<B7/: 4=@ 1:7<71/::G A75<7I 1//:=<=A3B@=< />>3/@A B= 03 :=E =/2;7<7AB@/B7=< =4 ;5 ) >/:=<=A3B@=< /<2 ;5 ) 23F/;3B6/A=<3 7< 63/:B6G AC0831BA @3D3/:32 <= >6/@;/1=97<3B71 2@C5 7<B3@/1B7=<A 03BE33< >/:=<=A3B@=< /<2 23F/;3B6/A=<3 < /< 7<B3@/1B7=< ABC2G 7< 63/:B6G AC0831BA E63@3 >/:=<=A3B@=< ;5 ) 0=:CA E/A /2;7<7AB3@32 =< 2/G /<2 =@/: />@3>7B/6/@;/1=97<3B71A =4 >/:=<=A3B@=< E3@3 <=B A75<7I 1/<B:G /:B3@32 ( <= 16/<53 ;/F 7<1@3/A3 ABC2G 7< 63/:B6G D=:C<B33@A 7<D=:D7<5 A7<5:3 2=A3 ) >/:=<=A3B@=< ;5 /<2 AB3/2G AB/B3 =@/: ;3B=1:=>@/;723 ;5 4=C@ B7;3A 2/7:G 23;=<AB@/B32 <= A75<7I 1/6/@;/1=97<3B71 7<B3@/1B7=< < 1=<B@=::32 1:7<71/: B@7/:A "+ 7<831B7=< 6/A 033< A/43:G /2;7<7AB3@32 E7B6 1=@B71=AB3@=72A /</:53A71A /<B73;3B71A /<B7</CA3/<BA /<B7A>/A;=271A /<2 /<B716=:7<3@571 /53<BA #/:=<=A3B@=< 272 <=B 7<6707B B63 /<B7BC;=@ /1B7D7BG =4 B63 I D3 163;=B63@/>3CB71 /53<BA B3AB32 17A>:/B7< 1G1:=>6=A>6/;723 1GB/@/07<3 2=F=@C0717< /<2 ;7B=;G17< 7< ;C@7<3 BC;=@ ;=23:A USE IN SPECIFIC POPULATIONS Pregnancy '3@/B=53<71 4431BA /B35=@G '3@/B=:=5G ABC273A 6/D3 033< >3@4=@;32 7< @/BA /B =@/: 2=A3A C> B= ;5 95 2/G B7;3A B63 @31=;;3<232 6C;/< 7<B@/D3<=CA 2=A3 0/A32 =< 0=2G AC@4/13 /@3/ /<2 @/007BA /B =@/: 2=A3A C> B= ;5 95 2/G B7;3A B63 @31=;;3<232 6C;/< 7<B@/D3<=CA 2=A3 0/A32 =< 0=2G AC@4/13 /@3/ /<2 6/D3 @3D3/:32 <= 3D723<13 =4 7;>/7@32 43@B7:7BG =@ 6/@; B= B63 43BCA 2C3 B= >/:=<=A3B@=< '63@3 /@3 6=E3D3@ <= /23?C/B3 /<2 E3:: 1=<B@=::32 ABC273A 7< >@35</@=2C1B7=< ABC273A /@3 <=B /:E/GA >@3271B7D3 =4 6C;/< @3A>=<A3 >/:=<=A3B@=< A6=C:2 03 CA32 2C@7<5 >@35</<1G =<:G 74 1:3/@:G <33232 Labor and Delivery #/:=<=A3B@=< 6/A <=B 033< /2;7<7AB3@32 B= >/B73<BA C<23@5=7<5 :/0=@ /<2 23:7D3@G A= 7BA 34431BA =< B63 ;=B63@ =@ 167:2 /@3 C<9<=E< Nursing Mothers B 7A <=B 9<=E< E63B63@ >/:=<=A3B@=< 7A 3F1@3B32 7< 6C;/< ;7:9 31/CA3 ;/<G 2@C5A /@3 3F1@3B32 7< 6C;/< ;7:9 /<2 031/CA3 =4 B63 >=B3<B7/: 4=@ A3@7=CA /2D3@A3 @3/1B7=<A 7< <C@A7<5 7<4/<BA /<2 B63 >=B3<B7/: 4=@ BC;=@753<717BG A6=E< 4=@ >/:=<=A3B@=< 7< B63 @/B 1/@17<=53<717BG ABC2G / 2317A7=< A6=C:2 03 ;/23 E63B63@ B= 27A1=<B7<C3 <C@A7<5 =@ B= 27A1=<B7<C3 B63 2@C5 B/97<5 7<B= /11=C=@B/<13 =4 B63 2@C5 B= B63 ;=B63@

free survival was nearly doubled compared with those who stopped treatment (P <.001). The safety profile was consistent with those previously reported in pivotal studies of rituximab alone or in combination with chemotherapy. Grade 2 or higher infections were reported more frequently in patients Pediatric Use &/43BG /<2 34431B7D3<3AA 7< >/B73<BA 03:=E B63 /53 =4

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E3@3 â&#x2030;Ľ G3/@A =:2 E67:3 E3@3 â&#x2030;Ľ G3/@A =:2 != =D3@/:: 27443@3<13A 7< A/43BG =@ 34431B7D3<3AA E3@3 =0A3@D32 03BE33< B63A3 AC0831BA /<2 B63 G=C<53@ AC0831BA 0CB 5@3/B3@ A3<A7B7D7BG 7< A=;3 =:23@ 7<27D72C/:A 1/<<=B 03 @C:32 =CB != 2=A3 /28CAB;3317/: ;=<7B=@7<5 /@3 @3?C7@32 4=@ 53@7/B@71 >/B73<BA "4 B63 /2C:B >/B73<BA 7< "+ #"!) 1:7<71/: ABC273A E3@3 â&#x2030;Ľ G3/@A =:2 != =D3@/:: 27443@3<13A 7< A/43BG E3@3 =0A3@D32 03BE33< =:23@ /<2 G=C<53@ AC0831BA 7< B63A3 ABC273A B6=C56 B63 >=AA707:7BG =4 63756B3<32 A3<A7B7D7BG 7< A=;3 =:23@ 7<27D72C/:A 1/<<=B 03 3F1:C232 != 27443@3<13A 7< 34I 1/1G E3@3 =0A3@D32 7< 53@7/B@71 >/B73<BA 4=@ B63 !) 7<271/B7=< /<2 <=<3 /@3 3F>31B32 4=@ 53@7/B@71 #"!) >/B73<BA =E3D3@ "+ 34I 1/1G 7< 53@7/B@71 >/B73<BA 6/A <=B 033< /23?C/B3:G 3D/:C/B32 Renal Impairment 7:2 B= ;=23@/B3 @3</: 7;>/7@;3/:=<=A3B@=< >6/@;/1=97<3B71 >/@/;3B3@A '=B/: AGAB3;71 3F>=AC@3 7<1@3/A32 0G />>@=F7;/B3:G 7< A3D3@3 @3</: 7;>/7@;3/B73<BA E7B6 /<G 235@33 =4 @3</: 7;>/7@;3/B71 7;>/7@;3/:=<=A3B@=< 1=;>/@32 B= B63 63/:B6G AC0831BA =A/53 /28CAB;3/B73<BA E7B6 /<G 235@33 =4 63>/B71 7;>/7@;3/:=<=A3B@=< >6/@;/1=97<3B71A E/A 16/@/1B3@7H32 7< BE3<BG 4=C@ 63/:B6G />/<3A3 AC0831BA =D3@ B63 2=A3 @/<53 =4 K ;15 95 '=B/: 0=2G 1:3/@/<13 E/A 67563@ 7< />/<3A3 AC0831BA 1=;>/@32 B= *67B3A 6=E3D3@ <= 2=A3 /28CAB;36/@;/1=97<3B71A =4 >/:=<=A3B@=< 7< :/19A 6/A <=B 033< /23?C/B3:G 16/@/1B3@7H32 OVERDOSAGE '63@3 7A <= 9<=E< /<B72=B3 B= "+ "D3@2=A3 A6=C:2 03 ;/</532 E7B6 AC>>=@B7D3 1/@3 74BG /2C:B 1/<13@ >/B73<BA E3@3 /2;7<7AB3@32 >/:=<=A3B@=/@B =4 / 2=A3 @/<57<5 ABC2G '67A 7A />>@=F7;/B3:G B7;3A B63 @31=;;3<232 2=A3 =4 ;5 '67A 2=A3 5@=C> 6/2 / A7;7:/@ 7<1723<13 =4 /2D3@A3 3D3<BA 1=;>/@32 B= B63 =B63@ 2=A3 5@=C>A /<2 <= 2=A3 @3A>=<A3 34431BA E3@3 =0A3@D32 7/:GA7A ABC273A 6/D3 <=B 033< >3@4=@;32 6=E3D3@ 2C3 B= B63 :/@53 D=:C;3 =4 27AB@70CB7=< 27/:GA7A 7A C<:793:G B= 03 /< 34431B7D3 B@3/B;3/:=<=A3B@=< =D3@2=A3 A7<5:3 7<B@/D3<=CA 2=A3 =4 >/:=<=A3B@=31B7D3:G 0/A32 =< 0=2G AC@4/13 /@3/ E/A :3B6/: B= @/BA /<2 ;713 '63 ;/8=@ A75<A =4 B=F717BG E3@3 1=<DC:A7=<A 5/A>7<5 >/::=@ 1G/<=A7A /<2 1=::/>A3 PATIENT COUNSELING INFORMATION &33 FDA-Approved Patient Labeling (17.2) in 4C:: >@3A1@707<5 7<4=@;/B7=< Instructions for Patients L #/B73<BA A6=C:2 03 /2D7A32 B= @3>=@B B= B637@ >6GA717/< /:: =4 B637@ ;3271/: 1=<27B7=<A /<G >/7< @32<3AA =@ AE3::7<5 7< /<2 /@=C<2 B63 7<4CA7=< A7B3 -see Adverse Reactions (6) 7< 4C:: >@3A1@707<5 7<4=@;/B7=<. L #/B73<BA A6=C:2 03 7<AB@C1B32 B= @3/2 B63 >/B736/@;/13CB71/:A :0C?C3@?C3 ! (& =@ #73@@3 /0@3 P271/;3<B #@=2C1B7=< 2@=< ?C7B/7<3 @/<13 /<2 3:A7<< 7@3F #6/@;/13CB71/:A C0:7< @3:/<2

ALOXIÂŽ 7A / @357AB3@32 B@/23;/@9 =4 3:A7<< 3/:B61/@3 & &E7BH3@:/<2 CA32 C<23@ :713<A3 7AB@70CB32 /<2 ;/@93B32 0G 7A/7 <1 *==21:744 /93 ! O 7A/7 <1 :: @756BA @3A3@D32 #@7<B32 7< (&

who received rituximab maintenance compared with the observation arm (37% vs 22%) for both. (January 28, 2011)

Transmucosal Opioid for Patients with Cancer Fentanyl (Abstral) transmucosal tablets were approved to manage breakthrough pain for adults with cancer. Abstral is specifically indicated for patients aged â&#x2030;Ľ18 years who are already using opioid pain medication around the clock and who need and are able to safely use high doses of an additional opioid medicine. To reduce potential misuse of the product, Abstral will be available only through a Risk Evaluation and Mitigation Strategy (REMS) program. In addition, only professionals trained in the use of Schedule II opioids for pain should prescribe this product. Transdermally administered medications are placed inside the cheek, gums, tongue, the nasal passages, or throat where they dissolve and are absorbed. Abstral was evaluated in 311 opioidtolerant cancer patients with breakthrough pain. Common adverse reactions included nausea, constipation, drowsiness, and headache; serious events, including death, have been reported in patients using other immediate-release fentanyl products. (January 7, 2011)

FDA Approves Denosumab for Cancer-Related Bone Injury Prevention Data from 3 double-blind, randomized clinical trials have informed the FDAâ&#x20AC;&#x2122;s decision to approve denosumab (Xgeva) for the prevention of skeletal-related events (SREs) including bone fractures and bone pain requiring radiation in patients with metastatic cancer. Denosumab is a monoclonal antibody that targets a protein involved in cancer-related bone destruction called human RANKL and is similar in effect to zoledronic acid (Zometa) and pamidronate disodium (Aredia). Denosumab is not approved for patients with multiple myeloma or other blood cancers. The 3 trials involved 5723 patients with different types of cancer, and compared denosumab and zoledronic acid. SREs were delayed in patients with breast or prostate cancers. The most serious side effects reported with denosumab were hypocalcemia and osteonecrosis of the jaw. (November 19, 2010)

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IN THE LITERATURE: BREAST CANCER Iniparib Raises Hopes in Triple-Negative Breast Cancer A phase 2 study looking at the ad dition of iniparib to gemcitabine (Gemzar) and carboplatin (Paraplatin) in patients with metastatic triplenegative breast cancer has indicated dramatic improvements in progression-free survival (PFS) and overall survival (OS) with this therapy (N Engl J Med. Online ahead of print. January 5, 2011). A total of 123 patients with measurable metastatic breast cancer documented as estrogen receptor–negative, progesterone receptor–negative, and not having overexpression of HER2 were randomized into 2 treatment arms. Primary end points were the rate of clinical benefit (measured by the rate of complete or partial response, plus the rate of stable disease for ≥6 months) and safety. PFS was a secondary end point, and OS was later added as an end point. Adding iniparib to gemcitabine and carboplatin improved the rate of clinical benefit from 34% to 56% and the overall response rate from 32% to 52%. PFS in the therapy arm improved from 3.6 months to 5.9 months and median OS increased from 7.7 months to 12.3 months. Adverse event rates were similar in the 2 arms; the most frequent grade 3 or 4 events included neutropenia, thrombocytopenia, anemia, fatigue or asthenia, or leukopenia. Despite the study’s small size, the authors of an accompanying editorial call the results “exciting...presaging improved therapy for an underserved subgroup of patients with breast cancer.”

sion or death was 3 months in the placebo group and 4 months for those treated with bevacizumab. Mortality rates were similar for both groups up to 210 days after drug discontinuation, and there were similar patterns of disease progression in both groups. The researchers acknowledge the difficulties inherent when analyzing disparate studies, diseases, and small numbers of patients.

Greater Role for Trastuzumab in Smaller HER2-Positive Cancers? A point-of-view essay by 2 English physicians outlines the controversies inherent in treating patients with breast cancer with small (≤1 cm) HER2-positive tumors and the possible benefit that adjuvant trastuzumab (Herceptin) might offer (Lancet Oncol. 2010;11:1193-1199).

Although the combination of trastuzumab and chemotherapy has now been established as a care standard in HER2-positive tumors >1 cm, the lack of randomized, phase 3 trials using this combination in smaller tumors leaves clinicians with the dilemma of balancing possible benefits with toxic effects and potential risks. In addition, the various European and American guidelines for treating

Increased Progression, Mortality Not Apparent After Halting Bevacizumab A retrospective meta-analysis of 5 multicenter, randomized controlled trials of bevacizumab in patients with a variety of cancers showed that the time to disease progression or death was similar in the bevacizumab and the placebo-treated groups after bevacizumab was discontinued (J Clin Oncol. 2011;29:83-88). Some studies have suggested that tumors grow more quickly and metastasize after antiangiogenic agents such as bevacizumab are withdrawn. To test this theory, an international team of investigators analyzed data from 5 double-blind, randomized phase 3 studies of patients with various metastatic cancers. In a pooled analysis, the median time from discontinuation to progres-

VALUE-BASED CANCER CARE

February 2011

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IN THE LITERATURE: BREAST CANCER patients with these tumors are “uncertain and inconsistent,” they write. The number of these small tumors diagnosed has increased as mammography screening has improved. A subset analysis of 1 trastuzumab trial showed that patients with 1-cm to 2-cm tumors derived at least as much clinical benefit from 1 year of adjuvant trastuzumab as did the overall cohort, and this “lends support to the

postulation” that patients with smaller, node-negative cancers “would benefit significantly from adjuvant chemotherapy with trastuzumab,” according to the authors. “We believe that there is now strong circumstantial evidence to justify some form of trastuzumab-based adjuvant therapy in most women with T1b,N0 (>0.5 to ≤1 cm), HER2-positive breast cancers,” the authors conclude.

Targeting Yearly Mammograms to At-Risk Patients Holds Promise Directing yearly mammography efforts to younger women with a familial history of breast cancer will likely prevent deaths, results of a new study show (Lancet Oncol. 2010;11: 1127-1134). English researchers enrolled a cohort of women at intermediate

What happens to the patient caught in the complications of chemotherapy-induced neutropenia? Consider your last patient with neutropenia

Figure. Overall survival by average relative dose intensity (ARDI)

Did your patient experience any consequences from severe or febrile neutropenia? According to a prospective registry study of 2,692 patients encompassing major tumor types, 29.3% overall were impacted by severe or febrile neutropenia in the first 3 cycles of chemotherapy, leaving a large opportunity for risk assessment intervention. This study also showed that the risk of severe or febrile neutropenia was greatest in the first cycle. That risk continued in subsequent cycles.*1

1.0

In a retrospective database analysis (N = 41,779), the inpatient mortality rate for febrile neutropenia–related hospitalization was 9.5%. This inpatient mortality rate was directly related to the number of major comorbidities present at the time of admission. Major comorbidities were defined as any major organ dysfunction requiring diagnostic or therapeutic intervention. Inpatient mortality ranged from 2.6% (556/21,386) for patients with no comorbidities to over 50% (181/358) for those with 4 or more.2

Optimal chemotherapy delivery was shown to improve survival in some tumor types Retrospective studies have shown that dose delays and reductions due to severe or febrile neutropenia may impact treatment plans and result in unfavorable outcomes for some diagnoses.3-7 While there are inherent risks associated with chemotherapy treatment, landmark studies in both non-Hodgkin’s lymphoma (NHL) and early-stage breast cancer have shown that closer adherence to standard doses is one factor that was associated with increased survival rates.8-11 A retrospective analysis demonstrated significantly longer median survival (7.08 years) for patients with NHL who received > 90% average relative dose intensity of CHOP-21 compared with those who received ≤ 90% (N = 210; P = 0.002) (see Figure).12 Multivariate analyses have identified several independent risk factors for reduced relative dose intensity. The risk factors for relative dose intensity < 85% among early-stage breast cancer patients included age, weight, and three-drug regimens (CAF or CMF).3

Estimated survival

Febrile neutropenia–related hospitalization can lead to mortality

0.9 0.8 0.7 ARDI: ≤ 85%

0.6 0.5

ARDI: 86% to ≤ 90%

Value of Tamoxifen, LongTerm Radiotherapy Confirmed in DCIS

0.4 ARDI: > 90%

0.3 0.0 0

4 3 5 Years post-chemotherapy

Retrospective chart data of overall survival in 210 patients treated with CHOP-21 according to average relative dose intensity (ARDI). CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone. Adapted from Bosly A, et al. Ann Hematol. 2008.

For patients with NHL, age > 60 years, advanced disease stage and poor performance status were associated with relative dose intensity < 85%.4

You can intervene for your next patient A comprehensive risk assessment protocol is critical to helping you identify patients at risk for clinically significant febrile neutropenia.

Consider the risk of the chemotherapy regimen ie, chemotherapeutics administered, alone or in combination

Assess patient risk factors

eg, age ≥ 65 years, poor performance status

Risk increases with more comorbidities eg, COPD, cardiovascular disease, diabetes mellitus

Evaluate each patient prior to every cycle To request a febrile neutropenia Risk Assessment Checklist, email: FNchecklist@amgen.com.

Assess the risk.

*Crawford J, et al. J Natl Compr Canc Netw. 2008. Nationwide, prospective registry study conducted in 115 community-based, randomly selected, IRB-approved sites, evaluating the incidence and timing of neutropenia and neutropenic events in the first cycle and in cycles 2–3 across major tumor types. References: 1. Crawford J, et al. J Natl Compr Canc Netw. 2008;6:109-118. 2. Kuderer N, et al. Cancer. 2006;106:2258-2266. 3. Lyman G, et al. J Clin Oncol. 2003;21:4524-4531. 4. Lyman G, et al. J Clin Oncol. 2004;22:4302-4311. 5. Lyman G, et al. J Natl Compr Canc Netw. 2009;7:99-108. 6. Link B, et al. Cancer. 2001;92:1354-1367. 7. Picozzi V, et al. Oncology. 2001;15:1295-1306. 8. Bonadonna G, et al. N Engl J Med. 1995;332:901-906. 9. Bonadonna G, et al. BMJ. 2005;330:217-222. 10. Chirivella I, et al. Breast Cancer Res Treat. 2009;114:479-484. 11. Kwak L, et al. J Clin Oncol. 1990;8:963-977. 12. Bosly A, et al. Ann Hematol. 2008;87:277-283. © 2010 Amgen. All rights reserved.

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familial risk of breast cancer and had them undergo mammography for 4 years, and then compared breast cancer incidence and severity between this group and 2 comparison groups. Of the 6710 women enrolled, 136 women were diagnosed with breast cancer (105 at screening, 28 symptomatically between screening events, and 3 after failing to attend their latest mammogram). Invasive tumors in the study group were significantly smaller, less likely to be node positive, and of more favorable grade than those in the first comparative control group, and were significantly less likely to be node positive than tumors in the second control group. The predicted 10-year mortality rate in the study cohort was significantly lower after risk adjustment. The data suggest that for women at familial risk of breast cancer, “mammographic surveillance could increase cancer detection, reduce the risk of advanced-stage disease, and decrease predicted mortality,” the authors wrote.

Enhanced screening efforts have increased the number of patients diagnosed with ductal carcinoma in situ (DCIS). Of the treatment options available, radiotherapy has previously been shown effective in reducing recurrences of in situ or invasive ipsilateral disease. New long-term results from the United Kingdom, Australia, and New Zealand DCIS trial highlight the role of tamoxifen in this patient population (Cuzick J, et al. Lancet Oncol. 2011;12:21-29). A total of 1701 patients with locally excised DCIS were randomized into a 2x2 factorial trial of radiotherapy, tamoxifen, or both. The primary end points were (1) invasive ipsilateral new events for radiotherapy, and (2) any new breast cancer–related event for tamoxifen. At a median follow-up of 12.7 (range, 10.9-14.7) years, among the 1694 eligible patients (with ipsilateral or contralateral disease), 163 invasive cancers, 197 DCIS, and 16 cases of unknown invasiveness or laterality disease were diagnosed. The incidence of all new breast cancer–related events was significantly reduced with radiotherapy (P <.001) and with tamoxifen (P = .002); radiotherapy reduced ipsilateral invasive disease and ipsilateral DCIS but had no effect on contralateral breast cancer. Tamoxifen significantly reduced recurrent ipsilateral DCIS and contralateral tumors but not ipsilateral invasive disease. ■

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IN THIS ISSUE Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Directors, Client Services John Hennessy john@greenhillhc.com 732-992-1886 Phil Pawelko phil@greenhillhc.com 732-992-1887 Cristopher Pires cris@engagehc.com 732-992-1896 Associate Editor Lara Reiman lara@engagehc.com 732-992-1892 Senior Production Manager Robyn Jacobs Quality Control Director Barbara Marino Business Manager Blanche Marchitto

Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments. This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

ASH ANNUAL MEETING

ASTRO ANNUAL MEETING

Newer Agents Show Promise in CML Physicians Embrace PET Scans Commentary: Key Studies Presented at ASH More...

CMS and FDA Respond to the Evidence Gap The Role of Evidence in Technology Approval Looking Beyond the Pocketbook More...

SABCS CONFERENCE

ASHP CLINICAL MEETING

Ambulatory Care in Metastatic Disease Trastuzumab plus Chemotherapy Improves pCR FISH-Guided Therapy Balances Clinical Benefits, Cost More...

Cost-Effectiveness Comparison: FOLFIRI versus FOLFOX Preventing Emesis Can Save Money Economic Analysis of Chemo-Induced Nausea More...

PATHWAYS IN ONCOLOGY

HEALTH POLICY

Implementing Clinical Pathways Radiation Oncology Pathways Proventys’ Personalized Decision Support

House Votes to Repeal Healthcare Reform Legislation—What Next? Articulating a Better Way for Patients with Advanced Cancer

VBCC PERSPECTIVE What Is Needed in Decision-Support Tools? What the Essential Health Benefits Provision Means for You

BPA Worldwide membership applied for August 2010. Contact Information: For subscription and reprint information please contact: circulation@valuebasedcare.com Telephone: 732-992-1538 Fax: 732-992-1881 Permission requests to reprint all or part of any article published in this magazine should be addressed to PERMISSIONS DEPARTMENT. Fax: 732-992-1881. Address all editorial correspondence to: editor@valuebasedcare.com Telephone: 732-992-1536 Fax: 732-992-1881 Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2011 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

VBCC Editorial Board Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA

David Hom, MBA Solucia Farmington, CT

Denise K. Pierce DK Pierce & Associates Zionsville, IN

Craig Deligdish, MD Florida Comprehensive Cancer Network Melbourne, FL

Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL

Jatin J. Shah, MD M. D. Anderson Cancer Center Houston, TX

Ira Klein, MD, MBA Aetna Hartford, CT

Jayson Slotnik, JD, MPH Foley Hoag Washington, DC

Crystal Kuntz, MPA Astellas Pharma US Washington, DC

Brian K. Solow, MD, FAAFP Prescription Solutions Irvine, CA

Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN

G. Rhys Williams, ScD, MS Amgen Thousand Oaks, CA

Lynn Nishida, RPh Regence BlueCross BlueShield of Oregon Portland, OR

Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD

Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers Pittsburgh, PA Arlene A. Forastiere, MD ITA Partners Philadelphia, PA Tracy Gosselin, RN, MSN Duke University Medical Center Durham, NC Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute New York, NY Section Editor

Naimish Pandya, MD University of Maryland Baltimore, MD

Dawn Holcombe, FACMPE, MBA, ACHE President, DGH Consulting South Windsor, CT

Ed Pezalla, MD, MPH Aetna Pharmacy Management Hartford, CT

VALUE-BASED CANCER CARE

February 2011

Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS BioPharma Partners, LLC New York, NY

VOL. 2

NO. 1

ZOMETA

® (zoledronic acid) Injection Concentrate for Intravenous Infusion Initial U.S. Approval: 2001 BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE 1.1 Hypercalcemia of Malignancy Zometa is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of >12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (mid-range of measured albumin in mg/dL). 1.2 Multiple Myeloma and Bone Metastases of Solid Tumors Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. 1.3 Important Limitation of Use The safety and efficacy of Zometa in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions has not been established. 4 CONTRAINDICATIONS 4.1 Hypersensitivity to Zoledronic Acid or Any Components of Zometa Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported [see Adverse Reactions (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Drugs with Same Active Ingredient Zometa contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treated with Zometa should not be treated with Reclast. 5.2 Hydration and Electrolyte Monitoring Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zometa. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with Zometa in order to avoid hypocalcemia. Zometa should be used with caution with other nephrotoxic drugs. Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zometa. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary. 5.3 Renal Impairment Zometa is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased [see Adverse Reactions (6.1)]. Preexisting renal insufficiency and multiple cycles of Zometa and other bisphosphonates are risk factors for subsequent renal deterioration with Zometa. Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible. Zometa treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine >400 μmol/L or >4.5 mg/dL were excluded. Zometa treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine >265 μmol/L or >3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zometa 4 mg by 15-minute infusion with a baseline creatinine >2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance <30 mL/min [see Clinical Pharmacology (12.3) in the full prescribing information]. 5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.2)]. 5.5 Pregnancy ZOMETA SHOULD NOT BE USED DURING PREGNANCY. Zometa may cause fetal harm when administered to a pregnant woman. In reproductive studies in the pregnant rat, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure (an IV dose of 4 mg based on an AUC comparison) resulted in preand postimplantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use In Specific Populations (8.1)]. 5.6 Musculoskeletal Pain In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes Zometa. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate [see Adverse Reactions (6.2)]. 5.7 Patients with Asthma While not observed in clinical trials with Zometa, there have been reports of bronchoconstriction in aspirin sensitive patients receiving bisphosphonates. 5.8 Hepatic Impairment Only limited clinical data are available for use of Zometa to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zometa in these patients. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Hypercalcemia of Malignancy The safety of Zometa was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zometa 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials. Renal Toxicity Administration of Zometa 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa 4 mg is given as a 15-minute intravenous infusion. Zometa should be administered by intravenous infusion over no less than 15 minutes [see Warnings And Precautions (5) and Dosage And Administration (2) in the full prescribing information]. The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 3). Table 3 provides adverse events that were reported by 10% or more of the 189 patients treated with Zometa 4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug. Table 3. Percentage of Patients with Adverse Events ≥10% Reported in Hypercalcemia of Malignancy Clinical Trials by Body System Zometa Pamidronate 4 mg 90 mg n (%) n (%) Patients Studied Total No. of Patients Studied 86 (100) 103 (100) Total No. of Patients with any AE 81 (94) 95 (92) Body as a Whole Fever 38 (44) 34 (33) Progression of Cancer 14 (16) 21 (20) Cardiovascular Hypotension 9 (11) 2 (2) Digestive Nausea 25 (29) 28 (27) Constipation 23 (27) 13 (13) Diarrhea 15 (17) 17 (17) Abdominal Pain 14 (16) 13 (13) Vomiting 12 (14) 17 (17) Anorexia 8 (9) 14 (14) Hemic and Lymphatic System Anemia 19 (22) 18 (18) Infections Moniliasis 10 (12) 4 (4) Laboratory Abnormalities Hypophosphatemia 11 (13) 2 (2) Hypokalemia 10 (12) 16 (16) Hypomagnesemia 9 (11) 5 (5) Musculoskeletal Skeletal Pain 10 (12) 10 (10) Nervous Insomnia 13 (15) 10 (10) Anxiety 12 (14) 8 (8) Confusion 11 (13) 13 (13) Agitation 11 (13) 8 (8) Respiratory Dyspnea 19 (22) 20 (19) Coughing 10 (12) 12 (12) Urogenital Urinary Tract Infection 12 (14) 15 (15) The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with Zometa 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence. Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zometa. Acute Phase Reaction-like Events Symptoms consistent with acute phase reaction (APR) can occur with intravenous bisphosphonate use. Fever has been the most commonly associated symptom, occurring in 44% of patients treated with Zometa 4 mg and 33% of patients treated with Pamidronate 90 mg. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, flushing, bone pain and/or arthralgias, and myalgias. Mineral and Electrolyte Abnormalities Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, can occur with bisphosphonate use. Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of Zometa in patients with HCM are shown in Table 4 and 5. Table 4. Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM Grade 3 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

2/86 1/86 36/70 0/71

(2%) (1%) (51%) —

n/N

(%)

3/100 2/100 27/81 0/84

(3%) (2%) (33%) —

Table 5. Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM

Table 7. Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases

Grade 4 Laboratory Parameter

Serum Creatinine1 Hypocalcemia2 Hypophosphatemia3 Hypomagnesemia4

Grade 3

Zometa 4 mg

Pamidronate 90 mg

n/N

(%)

n/N

(%)

0/86 0/86 1/70 0/71

— — (1%) —

1/100 0/100 4/81 1/84

(1%) — (5%) (1%)

Laboratory Parameter n/N Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

1Grade

3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) 3 (<7 mg/dL); Grade 4 (<6 mg/dL) 3Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) 4Grade 3 (<0.8 mEq/L); Grade 4 (<0.5 mEq/L) 2Grade

(%)

7/529 6/973 115/973 19/971 1/971

Multiple Myeloma and Bone Metastases of Solid Tumors The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2,042 patients treated with Zometa 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for Zometa 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors. Table 6 describes adverse events that were reported by ≥10% of patients. Adverse events are listed regardless of presumed causality to study drug.

(%)

4/268 4/536 38/537 2/535 0/535

(2%) (<1%) (7%) (<1%) —

n/N

(%)

4/241 0/415 14/415 8/415 1/415

(2%) — (3%) (2%) (<1%)

3 (>3x Upper Limit of Normal); Grade 4 (>6x Upper Limit of Normal) *Serum creatinine data for all patients randomized after the 15-minute infusion amendment 3 (<7 mg/dL); Grade 4 (<6 mg/dL) 3Grade 3 (<2 mg/dL); Grade 4 (<1 mg/dL) 4Grade 3 (>3 mEq/L); Grade 4 (>8 mEq/L) 5Grade 3 (<0.9 mEq/L); Grade 4 (<0.7 mEq/L) Table 8. Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Three Clinical Trials in Patients with Bone Metastases Grade 4 Laboratory Parameter

Serum Creatinine1* Hypocalcemia2 Hypophosphatemia3 Hypermagnesemia4 Hypomagnesemia5

Zometa 4 mg

Pamidronate 90 mg

Placebo

n/N

(%)

n/N

(%)

n/N

(%)

2/529 7/973 5/973 0/971 2/971

(<1%) (<1%) (<1%) — (<1%)

1/268 3/536 0/537 0/535 1/535

(<1%) (<1%) — — (<1%)

0/241 2/415 1/415 2/415 0/415

— (<1%) (<1%) (<1%) —

1Grade

Table 6. Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System Zometa 4 mg n (%)

Pamidronate 90 mg n (%)

Placebo

1031 (100) 1015 (98)

556 (100) 548 (99)

455 (100) 445 (98)

344 (33) 124 (12) 102 (10)

175 83 53

(32) (15) (10)

128 (28) 35 (8) 20 (4)

476 333 320 249 143 105 86 82

(46) (32) (31) (24) (14) (10) (8) (8)

266 183 162 162 81 74 65 61

(48) (33) (29) (29) (15) (13) (12) (11)

171 122 174 83 48 31 14 17

(38) (27) (38) (18) (11) (7) (3) (4)

398 328 252 215 112

(39) (32) (24) (21) (11)

240 172 108 126 62

(43) (31) (19) (23) (11)

130 89 114 84 28

(29) (20) (25) (19) (6)

124 (12) 101 (10)

50 82

(9) (15)

41 30

(9) (7)

231 164 145 130

81 50 60 48

(15) (9) (11) (9)

105 61 59 45

(23) (13) (13) (10)

n (%)

Among the less frequently occurring adverse events (<15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa 4 mg and pamidronate groups) compared to the placebo group. Less common adverse events reported more often with Zometa 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the Zometa 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the Zometa 4 mg group (13%) compared with the pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear. Renal Toxicity In the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (≥1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zometa 4 mg over 15 minutes in these trials (see Table 9). Table 9. Percentage of Patients with Treatment Emergent Renal Function Deterioration by Baseline Serum Creatinine* Patient Population/Baseline Creatinine Multiple Myeloma and Breast Cancer

(55) (23) (21) (15) (14)

316 143 131 106 84

(57) (26) (24) (19) (15)

284 74 73 40 52

Neoplasms Malignant Neoplasm Aggravated

205 (20)

(17)

89 (20)

Nervous Headache Dizziness (excluding vertigo) Insomnia Paresthesia Hypoesthesia

191 180 166 149 127

(19) (18) (16) (15) (12)

149 91 111 85 65

(27) (16) (20) (15) (12)

50 58 73 35 43

Psychiatric Depression Anxiety Confusion

146 (14) 112 (11) 74 (7)

95 73 39

(17) (13) (7)

49 (11) 37 (8) 47 (10)

Respiratory Dyspnea Cough

282 (27) 224 (22)

155 129

(28) (23)

107 (24) 65 (14)

Skin Alopecia Dermatitis

125 (12) 114 (11)

80 74

(14) (13)

36 38

(62) (16) (16) (9) (11)

(11) (13) (16) (8) (10)

(8) (8)

Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of Zometa in patients with bone metastases are shown in Tables 7 and 8.

Zometa 4 mg n/N

Normal Abnormal Total Solid Tumors

569 239 216 156 143

n/N

(1%) (<1%) (12%) (2%) (<1%)

Placebo

2Grade

Ocular Adverse Events Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zometa. No cases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing use [see Adverse Reactions (6.2)].

(22) (16) (14) (13)

Pamidronate 90 mg

1Grade

Injection Site Reactions Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours.

Patients Studied Total No. of Patients Total No. of Patients with any AE Blood and Lymphatic Anemia Neutropenia Thrombocytopenia Gastrointestinal Nausea Vomiting Constipation Diarrhea Abdominal Pain Dyspepsia Stomatitis Sore Throat General Disorders and Administration Site Fatigue Pyrexia Weakness Edema Lower Limb Rigors Infections Urinary Tract Infection Upper Respiratory Tract Infection Metabolism Anorexia Weight Decreased Dehydration Appetite Decreased Musculoskeletal Bone Pain Myalgia Arthralgia Back Pain Pain in Limb

Zometa 4 mg

27/246 (11%) 2/26 (8%) 29/272 (11%) Zometa 4 mg n/N

Normal Abnormal Total Prostate Cancer Normal Abnormal Total

(%)

17/154 (11%) 1/11 (9%) 18/165 (11%) Zometa 4 mg n/N

(%)

12/82 4/10 16/92

(15%) (40%) (17%)

Pamidronate 90 mg n/N

(%)

23/246 (9%) 2/22 (9%) 25/268 (9%) Placebo n/N

(%)

10/143 (7%) 1/20 (5%) 11/163 (7%) Placebo n/N

(%)

8/68 (12%) 2/10 (20%) 10/78 (13%)

*Table includes only patients who were randomized to the trial after a protocol amendment that lengthened the infusion duration of Zometa to 15 minutes. The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zometa (4 mg over 15 minutes), placebo, or pamidronate. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15-minute period. There have been instances of this occurring after the initial Zometa dose. 6.2 Postmarketing Experience The following adverse reactions have been reported during postapproval use of Zometa. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Osteonecrosis of the Jaw Cases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patients treated with intravenous bisphosphonates including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids which may be a risk factor for ONJ. Data suggests a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged [see Warnings And Precautions (5)]. Musculoskeletal Pain Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphosphonate use [see Warnings And Precautions (5)]. Ocular Adverse Events Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.

Hypersensitivity Reactions There have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, and bronchoconstriction. Very rare cases of anaphylactic reaction/shock have also been reported. Additional adverse reactions reported in postmarketing use include:

CNS: taste disturbance, hyperesthesia, tremor; Special Senses: blurred vision; Gastrointestinal: dry mouth; Skin: increased sweating; Musculoskeletal: muscle cramps; Cardiovascular: hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse primarily in patients with underlying risk factors); Respiratory: bronchoconstriction; Renal: hematuria, proteinuria; General Disorders and Administration Site: weight increase; Laboratory Abnormalities: hyperkalemia, hypernatremia. 7 DRUG INTERACTIONS In-vitro studies indicate that zoledronic acid is approximately 22% bound to plasma proteins. In-vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In-vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug. However, no in-vivo drug interaction studies have been performed. 7.1 Aminoglycosides Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zometa clinical trials. 7.2 Loop Diuretics Caution should also be exercised when Zometa is used in combination with loop diuretics due to an increased risk of hypocalcemia. 7.3 Nephrotoxic Drugs Caution is indicated when Zometa is used with other potentially nephrotoxic drugs. 7.4 Thalidomide In multiple myeloma patients, the risk of renal dysfunction may be increased when Zometa is used in combination with thalidomide. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy ZOMETA SHOULD NOT BE USED DURING PREGNANCY. There are no studies in pregnant women using Zometa. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant [see Warnings And Precautions (5.4)]. Pregnancy Category D Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (≥0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (with a systemic exposure of ≥0.07 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality may have been related to drug-induced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonateclass effect. In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse effects included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects observed in the highdose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the lowdose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study. In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (≤0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas), no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatment groups (at doses ≥0.05 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia.

8.3 Nursing Mothers It is not known whether Zometa is excreted in human milk. Because many drugs are excreted in human milk, and because Zometa binds to bone long term, Zometa should not be administered to a nursing woman. 8.4 Pediatric Use Zometa is not indicated for use in children. The safety and effectiveness of zoledronic acid was studied in a one-year active-controlled trial of 152 pediatric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesis imperfecta, aged 1-17 years, 55% male, 84% Caucasian, with a mean lumbar spine BMD of 0.431 gm/cm2, which is 2.7 standard deviations below the mean for age-matched controls (BMD Z-score of -2.7). At one year, increases in BMD were observed in the zoledronic acid treatment group. However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zometa use in children did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemia of malignancy or bone metastases. However, adverse reactions seen more commonly in pediatric patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia, occurred most frequently within 3 days after the first infusion and became less common with repeat dosing. Because of long-term retention in bone, Zometa should only be used in children if the potential benefit outweighs the potential risk. Plasma zoledronic acid concentration data was obtained from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3-8 years and 6 in the age group of 9-17 years) infused with 0.05 mg/kg dose over 30 min. Mean Cmax and AUC(0-last) was 167 ng/mL and 220 ng.h/mL, respectively. The plasma concentration time profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed in adult cancer patients at an approximately equivalent mg/kg dose. 8.5 Geriatric Use Clinical studies of Zometa in hypercalcemia of malignancy included 34 patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zometa as compared to younger patients. Controlled clinical studies of Zometa in the treatment of multiple myeloma and bone metastases of solid tumors in patients over age 65 revealed similar efficacy and safety in older and younger patients. Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function. 10 OVERDOSAGE Clinical experience with acute overdosage of Zometa is limited. Two patients received Zometa 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively. In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose. A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100U/L, each value unknown). The outcome of this case is not known. In controlled clinical trials, administration of Zometa 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, Zometa 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zometa 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [see Dosage And Administration (2.4) in the full prescribing information]. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

REV: OCTOBER 2009 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland for Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

T2009-101

VALUE PROPOSITIONS Brachytherapy Adoption Outstrips Evidence Base The use of brachytherapy instead of external-beam radiation after breast-conserving surgery for breast cancer increased rapidly between 2001 and 2006, despite a lack of mature evidence on the longer-term outcomes resulting with the procedure (J Clin Oncol. Online ahead of print; December 6, 2010). Patients undergoing brachytherapy have shorter courses of therapy, but some experts question the efficacy of the procedure and that it is one of the more costly options for patients with low-risk tumors. The period of increased use correlated with US Food and Drug Administration approval of the first balloon-based brachytherapy device (2002) and Medicare reimbursement for this in 2004. Brachytherapy use was more likely in women with non–health maintenance organization insurance, in areas with higher median income, and with a lower density of radiation oncologists. The authors consider the study hypothesis generating; nevertheless, they conclude that “in an era when new technologies and therapies are advancing rapidly yet, simultaneously, demands are growing to contain costs and establish treatment effectiveness, it is important to analyze available data to understand how decisions are made to use developing treatments.”

The Impact of the Economic Downturn on Patients with Cancer A survey of people with chronic illness, including cancer (N = 506), conducted by researchers from the Harvard School of Public Health between October 27, 2010, and October 31, 2010, illuminates concerns about the impact of the downturn of the economy on patients with cancer.

The economic downturn…

Patients with cancer, %

Has had a negative impact on my health

Will hurt my health in the future

Has forced me to use up most or all of my savings to address medical bills, copayments, and other illness-related fees

Has led to credit card debt

Has led to medical care–associated bankruptcy

The new healthcare reform law will…

Economic Burdens Among Families of Terminally Ill Children The death of a child from cancer inflicts more than pain or grief on families—there are also financial hardships, work disruptions, income loss, and financial coping strategies that impact families and that might be addressed with assistance by the treatment team (J Clin Oncol. Online ahead of print; January 4, 2011). A retrospective survey of 141 American and 89 Australian parents whose children died at 1 of 3 pediatric hospitals brought out the impact of the child’s illness and death—60% of families lost more than 10% of their annual income as a result of work disruptions; 34% of Australian and 19% of American families were likely to lose more than 40% of their income; and after accounting for income loss, 16% of American and 22% of Australian families dropped below the poverty line. The authors propose promoting healthy financial coping mechanisms, adequate provision of available resources to families, and policymaking as means of lessening the financial burdens.

A Coupon for Savings, or Added Costs? “The member is somewhat insulated from the cost of the prescription.... In essence, it drives up the total cost of providing the prescription benefit.” —Kevin Slavik, RPh, MHA, senior director of pharmacy at the Health Care Service Corporation, Chicago, IL, quoted in a New York Times article (Jan 2, 2011:BU1) highlighting the pricing distortions that occur when coupons for branded medications, which reduce a patient’s out-of-pocket cost but increase the costs to insurers, are used.

Low Income + High Deductible = Delayed Care Lower-income families with high-deductible health insurance plans were more likely to delay or forego medical care for reasons of cost than higher-income families with similar coverage (Arch Intern Med. 2010;170:1918-1925). A survey of 141 lower-income families (with incomes ≤300% of the federal poverty level) gathered data on healthcare use in 2009. Of lower-income families, 57% had foregone care (vs 42% of higher-income families), and nearly 20% had put off surgeries or procedures (vs 6% with higher income). When asked about a hypothetical scenario involving a $1000 colonoscopy not covered by their plan, lower-income families were twice as likely to ask their physicians about the need or timeliness of this test. “Policymakers and physicians should consider focused monitoring and benefit design modifications to support lower-income families” in these plans, say the authors.

VALUE-BASED CANCER CARE

February 2011

Leave me better off

Leave me worse off

Not make much difference

Deprived of Reimbursement, ADT Use Shrinks Changes in the Medicare Part B drug reimbursement policy in 2004 and 2005 led to reductions in inappropriate use of androgen-deprivation therapy (ADT) while maintaining use in appropriate cases (N Engl J Med. 2010;363:1822-1832). Inappropriate use was defined when ADT was used as primary therapy for men with localized cancers of low-to-moderate grade, appropriate as adjuvant therapy with radiation therapy for men with locally advanced cancers, and discretionary for men receiving either primary or adjuvant therapy for localized but high-grade tumors. Data from a Medicare database found inappropriate use dropped to 25.7% in 2005 (from 38.7% in 2003), appropriate use remained steady, and discretionary use dropped significantly in 2005 but not in 2004. The findings suggest “that reductions in reimbursement may influence the delivery of care in a potentially beneficial way,” the authors say, but they also caution that “reimbursement policies should be carefully considered to avoid providing incentives for care for which no clear benefit has been established.”

Pharmaceutical Pricing and the Balloon Effect Two recent news items point out the fluidity and unforeseen nature of pharmaceutical pricing. The first, reported in the Guardian on January 2, 2011, describes the efforts of the National Institute for Health and Clinical Excellence to conduct an official appraisal of bevacizumab (Avastin) for use in wet age-related macular degeneration (AMD), despite the opposition of the manufacturers, Genentech and Roche. Genentech has produced a similar but more costly drug intended solely for use in wet AMD (Lucentis), but ophthalmologists have been splitting vials of bevacizumab to treat this condition at a much lower cost. A second story, reported by Dow Jones Newswires on October 29, 2010, details how Genzyme Corporation, the maker of alemtuzumab (Campath), is contemplating providing the cancer drug to patients with B-cell chronic lymphocytic leukemia for free so that it may charge a higher price when used in multiple sclerosis (MS). Alemtuzumab is currently being tested in phase 3 trials for MS; although a lower dose of the drug is used to treat MS, the number of patients who could potentially receive the drug is much higher.

VOL. 2

NO. 1

ASH ANNUAL MEETING

Newer Agents Show Promise in CML By Colin Gittens Orlando, FL—Two early trials of newer drugs that inhibit the BCRABL gene—ponatinib and nilotinib (Tasigna)—for treatment of chronic myelogenous leukemia (CML) demonstrate clinical promise in terms of early or significant clinical response, according to research presented at the 2010 annual meeting of the American Society of Hematology. Ponatinib Leads to Major Cytogenic Response A phase 1 study of the safety, efficacy, and dosing level of the oral agent ponatinib in patients with refractory CML enrolled 74 patients with a median age of 56 years. Most had CML; most had failed several courses of previous therapies, including imatinib (Gleevec), dasatinib (Sprycel), and nilotinib, and 72% had BCR-ABL mutations. Overall, 60 patients with Philadelphia chromosome–positive (Ph+) were evaluable for response. Of 38 evaluable patients with chronic-phase CML, 95% had complete hematologic response, and 66% had major cytogenetic response. All 9 patients with chronic-phase CML plus the T315I mutation have reached complete hematologic response and major cytogenetic response. For 17 evaluable patients with accelerated- or blastphase CML or patients with Ph+ acute lymphoblastic leukemia, 6 (35%) had major hematologic response and 4 (24%) had major cytogenetic response. According to lead author Jorge Cortes, MD, of the Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, “90% of patients achieved a major cytogenetic response by 6 months.” Responses were also observed in

heavily refractory patients with no mutations, and patients with other mutations who are resistant to approved tyrosine kinase inhibitors.

gression-free survival (PFS), failurefree survival (FFS), and event-free survival (EFS) in patients with early chronic-phase Ph+ CML treated with

A remarkable “90% of patients achieved a major cytogenetic response by 6 months.” —Jorge Cortes, MD

Dr Cortes described the drug as being “very pleasantly well tolerated” during the dosing determination phase. The most common drug-related adverse events (≥10% any grade) were thrombocytopenia (23%), rash (22%), arthralgia (15%), headache (15%), increased lipase (14%), nausea (12%), fatigue (11%), and myalgia (11%). The investigators concluded that ponatinib has an acceptable safety profile at clinically effective doses and that emerging major molecular response data demonstrate early responses in patients refractory to second-line agents. Dr Cortes also explained that because in at least 1 laboratory assay ponatinib seems to demonstrate less predisposition to genetic mutations, he is hopeful that this will translate into resistance to the drug developing less frequently in actual practice. Whether ponatinib might be used earlier in the treatment (as second-line therapy) is “very attractive to explore,” Dr Cortes said. A phase 2 study is ongoing. Nilotinib Retains Results at Year 3 The second study focused on 3-year outcomes—overall survival (OS), pro-

nilotinib 400 mg twice daily. Nilotinib has already been approved for first-line therapy of Ph+ CML, and this trial was designed to evaluate cytogenetic and molecular responses and patient outcomes treated for 3 years with nilotinib as frontline therapy. The results were presented by Giantonio Rosti, MD, Department of Hematology/Oncology, University of Bologna, Italy. The multicenter phase 2 trial has enrolled 73 patients so far (median age, 51 years). The cumulative rate of major molecular response was 96%, and none of those patients progressed to the accelerated or blast phase. Only 1 patient has progressed to the blast phase during the 3 years. The cumulative complete molecular response rate was 41%; at 30 months, the OS, PFS, and FFS rates are 99%, and EFS is 92%. Adverse events were mostly grade 1 or 2 and manageable with dose modifications. This trial demonstrates a low failure rate with nilotinib during the first 3 years, with high responses during the first 12 months. Dr Rosti was encouraged that the early promising results had held up at 3 years, because the research team had

Healthcare Reform Boosted at ASH... through its implementation. The legislation does have extensive cost-control aspects, including reduction of overpayments in the Medicare Advantage program and eliminating fraud and abuse. And those cost controls are being implemented through “pay as you go” legislation as components of the bill are phased in. Despite rhetoric to the contrary, healthcare reform does not add to the deficit, Dr Emanuel said. “Healthcare reform is completely paid for through a combination of cuts and assessments,” he said, “unlike Part D Medicare.” And although the effective

VOL. 2

NO. 1

dates from some components of reform are in 2014, hospitals and insur-

Too Early for Clinical Application According to session moderator Peter D. Emanuel, MD, University of Arkansas for Medical Sciences, discovering how these drugs are incorporated into clinical practice remains to be evaluated through further clinical trials. But as newer agents continue to be developed, he suggested that “the burning question is ‘will imatinib eventually become a historical drug?’” Adele Fielding, MD, PhD, University College London, offered a more cautious take, remarking that although

“I’d like to be able to use Dr Cortes’ drug for some of my patients…the reality is that it’s going to be a long time before I can.” —Adele Fielding, MD, PhD

such early-phase studies here are exciting, and “I’d like to be able to use Dr Cortes’ drug for some of my patients… the reality is that it’s going to be a long time before I can.” Longer-term and larger studies of new therapies are needed so that payers who cover them are convinced of the worth of these drugs, she suggested. ■

Continued from cover

care to costly, chronic conditions such as congestive heart failure, coronary

Despite rhetoric to the contrary, healthcare reform does not add to the deficit. “Healthcare reform is completely paid for through a combination of cuts and assessments.” —Ezekiel J. Emanuel, MD, PhD

ers are working ahead to ensure that this can be rolled out smoothly. In terms of patient care, the healthcare reform bill will serve to redirect

feared they might indicate only a delay of “disaster.” “Responses are stable,” he stated.

artery disease, diabetes, hypertension, chronic obstructive pulmonary disease, and asthma. In the United States, 10% of the population incurs 64% of

healthcare spending, he said, and it is essential to focus on that small but costly minority. In addition, reform implements changes of great importance to patients with cancer, including eliminating copays for screening efforts such as mammograms, Pap smears, and colon cancer screening, and elimination of lifetime coverage limits, preexisting conditions, and rescissions. In addition, Dr Emanuel noted, insurers will be required to cover additional routine costs when a patient enrolls in a cancer clinical trial. ■

www.ValueBasedCancerCare.com

BUILD A TREATMENT STRATEGY WITH EXTENDED SURVIVAL ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Important Safety Information for

Pretreatment with dexamethasone or its equivalent has been reported to reduce the incidence and severity of skin rash.

insufﬁciency should avoid taking NSAIDs with short elimination halflives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicities.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

Patients should not begin a new cycle of treatment unless the ANC is *1500 cells/mm3, the platelet count is *100,000 cells/mm3, and creatinine clearance is *45 mL/min.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

Contraindication: ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation. Warnings and Precautions: Patients must be instructed to take folic acid and vitamin B12 with ALIMTA as a prophylaxis to reduce treatmentrelated hematologic and GI toxicities.

Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufﬁciency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal

The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

ALIMTA (pemetrexed for injection) Drug Interactions: Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. See Warnings and Precautions for specific information regarding ibuprofen administration. Use in Specific Patient Populations: It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother. The safety and effectiveness of ALIMTA in pediatric patients have not been established. Dose adjustments may be necessary in patients with hepatic insufficiency. Dosage and Administration Guidelines: Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence): The most severe adverse reactions (grades 3/4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (15 vs 27); leukopenia (5 vs 8); thrombocytopenia (4 vs 13); anemia (6 vs 10); fatigue (7 vs 5); nausea (7 vs 4); vomiting (6 vs 6); anorexia (2 vs 1); and creatinine elevation (1 vs 1). Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56 vs 53); fatigue (43 vs 45); vomiting (40 vs 36); anemia (33 vs 46); neutropenia (29 vs 38); anorexia (27 vs 24); constipation (21 vs 20); leukopenia (18 vs 21); stomatitis/pharyngitis (14 vs 12); alopecia (12 vs 21); diarrhea (12 vs 13); thrombocytopenia (10 vs 27); neuropathy/ sensory (9 vs 12); taste disturbance (8 vs 9); rash/desquamation (7 vs 8); and dyspepsia/heartburn (5 vs 6). For additional safety and dosing guidelines, please see brief summary of Prescribing Information on adjacent page.

insideALIMTA.com

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,>? &:@?30,>? >4,9> ,9/ :?30=> := ,@.,>4,9> ?30 % 1:= :A0=,77 >@=A4A,7 B,> 1:= ,>? &:@?30,>? >4,9> ?30 % B,> ,9/ 1:= :?30=> ?30 % B,> 49 ?30 49?09? ?: ?=0,? ;:;@7,?4:9 $ ! '30=0 3,A0 -009 10B .,>0> :1 !' :A0=/:>0 %0;:=?0/ ?:C4.4?40> 49.7@/0/ 90@?=:;094, ,9084, ?3=:8-:.D?:;094, 8@.:>4?4> ,9/ =,>3 9?4.4;,?0/ .:8;74.,?4:9> :1 :A0=/:>0 49.7@/0 -:90 8,==:B >@;;=0>>4:9 ,> 8,9410>?0/ -D 90@?=:;094, ?3=:8-:.D?:;094, ,9/ ,9084, 9 ,//4?4:9 4910.?4:9 B4?3 := B4?3:@? 10A0= /4,==30, ,9/ 8@.:>4?4> 8,D -0 >009 1 ,9 :A0=/:>0 :..@=> 2090=,7 >@;;:=?4A0 80,>@=0> >3:@7/ -0 49>?4?@?0/ ,> /0080/ 90.0>>,=D -D ?30 ?=0,?492 ;3D>4.4,9 9 .7494.,7 ?=4,7> 70@.:A:=49 B,> ;0=84??0/ 1:= ' =,/0 70@6:;094, 7,>?492 â&#x2030;¥ /,D> ' =,/0 90@?=:;094, 7,>?492 â&#x2030;¥ /,D> ,9/ 4880/4,?07D 1:= ' =,/0 ?3=:8-:.D?:;094, -700/492 ,>>:.4,?0/ B4?3 =,/0 ?3=:8-:.D?:;094, := =,/0 := 8@.:>4?4> '30 1:77:B492 49?=,A09:@> /:>0> ,9/ >.30/@70> :1 70@.:A:=49 B0=0 =0.:8809/0/ 1:= 49?=,A09:@> @>0 82 8 49?=,A09:@>7D :9.0 1:77:B0/ -D 70@.:A:=49 82 8 49?=,A09:@>7D 0A0=D 3:@=> 1:= /,D> '30 ,-474?D :1 !' ?: -0 /4,7DE0/ 4> @969:B9 " % & '4(.12,*1*5.5 76',*1*5.5 03'.40*16 2+ *46./.6; ": .,=.49:2094.4?D >?@/40> 3,A0 -009 .:9/@.?0/ B4?3 ;080?=0C0/ $080?=0C0/ B,> .7,>?:2094. 49 ?30 49 A4A: 84.=:9@.70@> ,>>,D 49 8:@>0 -:90 8,==:B -@? B,> 9:? 8@?,2094. 49 8@7?4;70 49 A4?=: ?0>?> 80> ,>>,D # .077 ,>>,D $080?=0C0/ ,/8494>?0=0/ ,? 4 A /:>0> :1 82 62 /,D := 2=0,?0= ?: 8,70 84.0 ,-:@? ?30 =0.:8809/0/ 3@8,9 /:>0 :9 , 82 8 -,>4> =0>@7?0/ 49 =0/@.0/ 10=?474?D 3D;:>;0=84, ,9/ ?0>?4.@7,= ,?=:;3D " " # ! " &00 ;;=:A0/ $,?409? ,-07492 $,?409?> >3:@7/ -0 49>?=@.?0/ ?: =0,/ ?30 ;,?409? ;,.6,20 49>0=? .,=01@77D

**) +24 2/.( (.) '1) $.6'0.1

$,?409?> ?=0,?0/ B4?3 !' 8@>? -0 49>?=@.?0/ ?: ?,60 1:74. ,.4/ ,9/ A4?,849 ,> , ;=:;3D7,.?4. 80,>@=0 ?: =0/@.0 ?=0,?809? =07,?0/ 308,?:7:24. ,9/ 2,>?=:49?0>?49,7 ?:C4.4?D + (+ ' &"'"+,* ,"(' 29 /22) *// 27165 $,?409?> >3:@7/ -0 ,/0<@,?07D 491:=80/ :1 ?30 =4>6 :1 7:B -7::/ .077 .:@9?> ,9/ 49>?=@.?0/ ?: 4880/4,?07D .:9?,.? ?304= ;3D>4.4,9 >3:@7/ ,9D >429 :1 4910.?4:9 /0A07:; 49.7@/492 10A0= $,?409?> >3:@7/ ,7>: .:9?,.? ?304= ;3D>4.4,9 41 -700/492 := >D8;?:8> :1 ,9084, :..@= '5642.16*56.1'/ ++*(65 $,?409?> >3:@7/ -0 49>?=@.?0/ ?: .:9?,.? ?304= ;3D>4.4,9 41 ;0=>4>?09? A:84?492 /4,==30, := >429> :1 /03D/=,?4:9 ,;;0,= 21(20.6'16 *).('6.215 $,?409?> >3:@7/ -0 49>?=@.?0/ ?: 491:=8 ?30 ;3D>4.4,9 41 ?30D ,=0 ?,6492 ,9D .:9.:84?,9? ;=0>.=4;?4:9 := :A0= ?30 .:@9?0= 80/4.,?4:9> 49.7@/492 ?3:>0 1:= ;,49 := 4917,88,?4:9 >@.3 ,> 9:9 >?0=:4/,7 ,9?4 4917,88,?:=D /=@2> + *- ', * ,"('+ "2 4*3246 !#! " $ ! " ! (216'(6 /. .//; '1) 203'1; '6 .//; : 24 '6 24 999 +)' ,28 0*)9'6(-

!' F ;080?=0C0/ 1:= 4950.?4:9

$) !$

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/. .//; '1) 203'1; 1).'1'32/.5 #! :;D=423? G 74 477D ,9/ :8;,9D 77 =423?> =0>0=A0/ $) !$

$% "' " (& $) !$

ASH ANNUAL MEETING COMMENTARY

Implications of Key Studies Presented at ASH By Craig Deligdish, MD Dr Deligdish is a Hematologist/Oncologist in Melbourne, FL, and an Editorial Board Member of Value-Based Cancer Care

ore than 4300 abstracts were accepted for the 2010 annual meeting of the American Society of Hematology (ASH). As always, there were numerous presentations that enhanced our understanding of hematologic malignancies and contributed to improving current treatment approaches. Several important studies examined the efficacy of treating patients with follicular non-Hodgkin lymphoma (NHL). At the Plenary Scientific Session, an Intergroup Study from England was presented, which compared the preliminary results of patients treated with rituximab versus a watch-and-wait strategy. Asymptomatic adult patients were randomized to either watchful waiting, treatment

with rituximab weekly for 4 weeks, or treatment with rituximab for 4 weeks followed by maintenance therapy. As might have been expected, both treatment groups had significantly prolonged time to initiation of new therapy and significantly prolonged progression-free survival (PFS). However, at the time of the report there was no difference in overall survival (OS) between any of the 3 arms of the trial. Also presented was an update on the results of the PRIMA trial, a multicenter study which confirmed the benefit of 2 years of maintenance rituximab in patients who responded to induction treatment with a combination of rituximab and chemotherapy. These trial results figured in the US Food and Drug Administration’s decision on January 28, 2011, to approve this new indication (see page 3). The consistent theme in both studies was that regardless of the upfront therapy, maintenance therapy with rituximab resulted in significantly improved event-free survival without an improvement in OS. Offering guidance to physicians treating patients with NHL, investigators from Italy led by Umberto Vitolo, MD, suggested that interim positronemission tomography (PET) scanning

does not predict the outcome in patients with diffuse large B-cell lymphomas.

These studies will undoubtedly serve to shift clinical practice as they are further evaluated and incorporated into our body of knowledge. The group looked at the predictive value of PET scans performed after several cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab) chemotherapy and concluded that there was no predictive benefit to a positive interim PET scan, and that the majority of patients with positive interim PET scans still achieved a complete remission as determined by PET scans performed at the conclusion of therapy. Ultimately, the investigators concluded that a larger prospective trial was needed to better assess the prognostic value of interim PET scans in this patient population. Adding to the understanding of the optimal use of PET scanning, the expe-

rience from a single institution in Korea was reported by Deok-Hwan Yang, MD, and colleagues, showing that negative interim PET scans did predict for improved OS and PFS in patients with diffuse large B-cell lymphomas. Reporting on the result of a multicenter phase 2 trial, Robert Chen and colleagues detailed the findings of a study that examined the efficacy and toxicity of brentuximab vedotin (SGN35) in patients with relapsed and refractory Hodgkin lymphoma. All patients had failed prior autologous stem-cell transplant, with 70% of the patients having primary refractory disease. The response rate in 102 patients was impressive, with more than 95% of patients exhibiting some degree of tumor shrinkage. Based on this and other studies demonstrating similar results in patients with anaplastic large-cell lymphoma, Seattle Genetics and Millennium are planning to seek regulatory approval for the indications in both Hodgkin lymphoma and anaplastic large-cell lymphoma. These studies, as well as others presented in this issue, will undoubtedly serve to shift clinical practice as they are further evaluated and incorporated into our body of knowledge. ■

Rituximab Maintenance Can Delay Chemotherapy in Patients with Follicular Lymphoma See also page 3 Orlando, FL—A study designed to compare 2 years of rituximab (Rituxan) therapy versus watchful waiting in patients with asymptomatic, advanced stage follicular lymphoma showed that maintenance therapy delayed the need for chemotherapy and other therapies by up to 3 years. This study was presented by Kirit M. Ardeshna, MD, of University College London Hospitals, United Kingdom. Adult patients were randomized to either watchful waiting (n = 186), rituximab 375 mg/m2 weekly for 4 weeks, or rituximab 375 mg/m2 weekly for 4 weeks (n = 84), followed by rituximab maintenance every 2 months for 2 years (n = 192). As the benefit of rituximab maintenance became clear over the course of the study, the arm

receiving 4 weeks of rituximab was halted. A total of 462 patients were randomized to the 3 arms between September 2004 and May 2009.

short-term rituximab, 80% had not begun any new therapy; and for those on rituximab maintenance, the percentage therapy-free was 91%. Threeyear progression-free survival rates

“Our study has shown that we can defer chemotherapy by a long time in patients who have asymptomatic follicular lymphoma. I imagine this will become the standard of care.” —Kirit M. Ardeshna, MD

At 3 years, 48% of patients in the watch-and-wait group had not initiated any new therapy; for those on

VALUE-BASED CANCER CARE

February 2011

were similarly arrayed—33% in the watchful waiting group; 60% in those receiving 4 weeks of rituximab; and

81% for those on rituximab maintenance. However, there was no difference in overall survival, and 95% of patients remain alive at 3 years. Regarding the effect of rituximab on overall survival, Dr Ardeshna indicated that further work needs to be done in assessing the impact of prior rituximab on response to first new treatment, response duration of this therapy, and time to second new treatment. In addition, although the study was designed to evaluate quality of life, Dr Ardeshna did not present data on this outcome at 2010 ASH. “Our study has shown that we can defer chemotherapy by a long time in patients who have asymptomatic follicular lymphoma,” Dr Ardeshna commented. “I imagine this will become the standard of care.” ■

VOL. 2

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ASH ANNUAL MEETING

Nonmedical Burden of DVT Is High By Debra Wood, RN Orlando, FL—The economic burden associated with deep-vein thrombosis (DVT) during the 2-year period after diagnosis is substantial—$5094 Canadian—with most of the costs occurring in the first 4 months, and postthrombotic syndrome representing a significant predictor of higher cost. “It is important to emphasize that the use of compression stockings could, maybe, decrease the cost of DVT by preventing postthrombotic syndrome,” said Raphael Guanella, MD, with the Division of Angiology and Hemostasis at the Geneva University Hospital, Switzerland, at the 52nd American Society of Hematology Annual Meeting and Exposition.

baseline; unprovoked DVT, occurring in 46% of patients; and postthrombotic syndrome during follow-up, which occurred in 40.8% of patients. “Postthrombotic syndrome was a

significant predictor of cost,” Dr Guanella added. “Postthrombotic syndrome patients had higher costs over time, especially later than 4 months after diagnosis.”

Patients with unprovoked DVT had a higher rate of hospitalization and medical visits. Higher costs in patients with postthrombotic syndrome were associated with more medical visits and the use of drugs. ■

“We were surprised to find more than half of the cost was nonmedical in nature.” —Raphael Guanella, MD Dr Guanella and colleagues conducted a Canadian multicenter, costof-illness study of 355 consecutive patients diagnosed with objectively confirmed acute DVT at 1 of 7 participating hospitals in the province of Quebec from 2001 to 2004. Of the patients, 50% were male, and the median age was 57 years. Of the cohort, 70% were outpatients, 58% had a proximal DVT, and 15% had a pulmonary embolism. The researchers followed patients for 2 years postdiagnosis and tracked medical and nonmedical costs related to DVT using patient-completed cost diaries filled out at baseline and 1, 4, 8, 12, and 24 months and at any DVTrelated clinical event; case report forms completed by nurses; and Quebec provincial administrative healthcare databases containing information on inpatient and outpatient cost. Of the costs associated with DVT, 53% were nonmedical, including an average of 12 lost workdays, representing 58% of the cost; 38.6 hours of assistance needed, 33% of the cost; and 12.7 transportation trips. Hospitalizations accounted for 64% of the medical cost; provider visits, 17%; drugs, 15%; and other, 4%. Patients reported an average of 15 physician visits and 0.7 nonphysician visits. “We were surprised to find more than half of the cost was nonmedical in nature,” Dr Guanella admitted. Three variables were associated with higher costs: pulmonary embolism at

VOL. 2

NO. 1

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www.ValueBasedCancerCare.com

ASH ANNUAL MEETING

Physicians Embrace PET Scans for Follicular Lymphoma Limited evidence leading to use as early therapy By Colin Gittens Orlando, FL—Despite little evidence supporting its use, fluorodeoxyglucose positron-emission tomography (FDG-PET) is often used to initially stage follicular lymphoma (FL), and this may lead to greater use of early therapy for the disease. FL is the most common lymphoma, and between 25% and 33% of patients will be diagnosed with early-stage disease, according to lead author Karim E. Abou-Nassar, MD, of the Division of Hematologic Malignancies, DanaFarber Cancer Institute in Boston. FDG-PET offers improved diagnostic accuracy in several lymphomas, and in FL its use can upstage 18% to 45% of patients and lead to changes in their management. The researchers’ analysis of the National Comprehensive Cancer Net-

work (NCCN)’s Non-Hodgkin’s Lymphoma Outcomes Database included 953 eligible patients (those newly diagnosed with low-grade FL) from among 7 participating NCCN centers. The patients received staging imaging within 6 weeks of diagnosis; 532 underwent FDG-PET as part of initial staging. Of the 189 patients with early-stage follicular lymphoma (ESFL), 120 underwent FDG-PET for initial staging. Use of FDG-PET varied significantly across NCCN centers, ranging from 25% to 78%. Choice of initial treatment strategy for ESFL, however, did not vary significantly by use of FDG-PET. Initial treatment strategy for ESFL also varied significantly according to NCCN centers (P <.001). For all

Systemic Antifungal Drugs Require Close Monitoring By Debra Wood Orlando, FL—The use of costly systemic antifungal drugs requires close monitoring to avoid the negative effects of drug interactions and side effects. Barbara Metzke, a pharmacist in the Department of Hematology and Oncology at the University Medi cal Center in Freiburg, Germany, and colleagues conducted a prospective analysis of the use of systemic antifungal drugs on 2 units at the hospital, an allogeneic stem-cell transplantation ward and one caring for primarily acute leukemia patients, enrolling consecutive patients receiving therapy or prophylaxis. “The project came to light because of the rising cost of antifungals. Since 2004, the cost has more than doubled,” said Ms Metzke. In 2009, systemic antifungal drugs accounted for 20% of the department’s inpatient drug expenses, including chemotherapeutics. Among the 120 patients studied, 70% did not exhibit any signs of fungal infection according to definitions from the European Organisation for Research and Treatment of Cancer/Mycoses Study Group criteria; 3% had a histologically proven invasive fungal infection.

Patients typically are started on empirical therapy if they have a fever or if a computed tomography scan of the lung identifies infiltrate, Ms Metzke said. The 5 drugs used were: liposomal amphotericin B, caspofungin, voriconazole, posaconazole, and fluconazole (which is given prophylactically to transplant patients). Side effects leading to discontinuation of a drug were experienced by 13 patients. Of patients taking voriconazole, 6 developed side effects, including hallucinations/neurotoxicity and elevated liver enzymes. Of patients taking amphotericin B, 5 stopped treatment as a result of skin reactions, declining renal function, and elevated liver enzymes. In addition, amphotericin B had the highest rate of potential drug interactions, with 48 of the 49 patients taking it exposed to at least 1 possible interaction and 35 patients exposed to ≥3 potential drug interactions. “It’s challenging for the physician to select the right drug,” Ms Metzke suggested. She works with them on the units to check interactions. The use and cost of systemic antifungals remains high at the hospital, but the team concluded that the reallife analysis of the drugs’ use is valuable because of the high number of side effects and potential drug interactions in patients receiving these agents. ■

VALUE-BASED CANCER CARE

February 2011

patients diagnosed with ESFL, 55 were treated with radiotherapy alone, 68 with chemotherapy/immunotherapy (CIT) alone, 28 with combined radiotherapy and CIT, and 38 were simply observed. Patients undergoing FDG-PET scans were much more likely to be treated within 6 months of diagnosis, and were more likely to receive an anthracycline-based treatment regimen. A treatment trend that did not reach statistical significance was greater use of chemotherapy and less use of radiotherapy among those receiving an FDG-PET scan.

The study was limited by being set in academic centers only, and by the authors not having the imaging results that would allow them to determine the upstaging rate, said Dr AbouNassar. Nevertheless, when asked if the study indicates that America’s best cancer hospitals are overtreating patients with FL, Dr Abou-Nassar agreed that patients are receiving early therapy, and “there is no evidence that early therapy improves long-term outcomes.” The study was not set up to track patient outcomes, he said. ■

Heparin-Induced Thrombocytopenia Scoring System Could Reduce Complications Orlando, FL—The heparin-induced thrombocytopenia (HIT) 4T scoring system, developed by G.K. Lo in 2006 and established as a clinical practice guideline by the American Society of Hematology in 2009, could reduce unnecessary use of direct thrombin inhibitor therapy that may result in serious bleeding complications. The pretest scoring system looks at the degree of thrombocytopenia, timing of platelet fall, thrombosis or

a major bleed requiring blood transfusion support. “A lot of low-probability-risk patients were started on a direct thrombin inhibitor and had major bleeding complications, yet all of them tested negative,” Dr Vatanparast said. “The patients were empirically treated and, unfortunately, suffered complications as a result. If the physicians had applied the 4T system at the bedside, that might have been prevented.”

“The patients were empirically treated and, unfortunately, suffered complications as a result. If the physicians had applied the 4T system at the bedside, that might have been prevented.” other sequelae, and the possibility of other etiologies for thrombocytopenia. Patients are then divided into low, intermediate, or high probability of having HIT. Physicians typically diagnose HIT on clinical grounds—the presence of thrombocytopenia while the patient is taking heparin. A retrospective study applying the 4T system to 100 patients who received direct thrombin inhibitor therapy by Rodina Vatanparast, MD, and colleagues found that a low 4T score correlated 100% with a negative HIT antibody assay. Of the 100 patients, 73 fell into the low-probability group. Of the low-risk patients, 14 started with a direct thrombin inhibitor, and 10 developed

Dr Vatanparast has informed the medical staff about the study findings and presented them to hospital administrators, who added using the 4T scoring system to the institution’s core measures when assessing a patient with suspected HIT and then selecting only patients with intermediate-tohigh probability for further therapeutic intervention. On follow-up, Dr Vatanparast has found physicians are applying 4T more often, and they are being more judicious in starting patients on inhibitor therapy, which has led to a decrease in bleeding complications. “Education about the intervention has seemed to help,” Dr Vatanparast said.—DW ■

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SABCS CONFERENCE

Future Anti-HER2 Therapies...

Moving Beyond Trastuzumab It is clear that other agents targeting the HER2 protein are needed, beyond trastuzumab. Although trastuzumab is highly effective, in the advanced-disease setting patients generally develop resistance to the drug within 1 year. “But HER2 is still a relevant target, once this happens, since HER2 overexpression is still maintained,” Dr

Spector said in a plenary lecture. “In fact, patients who have tumor progression on HER2 targeted therapies benefit from continued HER2 blockade.”

Photo by © SABCS/Todd Buchanan 2010

therapy with pertuzumab, trastuzumab, and docetaxel (Taxotere) produced 50% more pCRs (46%) than were achieved with other doublets. In addition, the completely “chemotherapyfree” combination of pertuzumab plus trastuzumab eradicated tumors in 17%, leading investigator Luca Gianni, MD, of Milan, to suggest that a subset of patients might benefit from targeted therapy minus the more toxic chemotherapy. In the NeoALLTO trial, treatment with trastuzumab plus lapatinib (Tykerb), given with paclitaxel, produced a 51% pCR rate compared with 25% for lapatinib and 29% for trastuzumab.

Continued from cover trastuzumab, lapatinib, and pertuzumab together, because they “act differently but at the same target.” “But in doing so we would bust the

“No question, the cost of these therapies will be higher, but you have to put this in context with the therapeutic benefit...that many more patients will not require treatment for disease recurrence. This is a sea change in how we explore these therapies.”

Using the agents that were evaluated in these trials, Dr Spector acknowledged that cost would be very high with trastuzumab plus lapatinib, higher yet with trastuzumab plus pertuzumab, and essentially unimaginable should the 3 drugs be combined. He remarked that “if money were abundant” he would like to use

—Jose Baselga, MD

economy, and I can’t imagine this will go over well with payers,” he said. “If only 5 of 100 patients can afford this blockade, we will need to rethink this approach.” Jose Baselga, MD, codirector of the Massachusetts General Cancer Institute, Boston, said at a press conference, “No question, the cost of these thera-

pies will be higher, but you have to put this in context with the therapeutic benefit, with the fact that many more patients will not require treatment for disease recurrence. This is a sea change in how we explore these therapies.” More anti-HER2 combinations will be evaluated, Dr Spector said in his presentation, including trastuzumab paired with novel agents targeting PI3kinase, mTOR, insulin growth factor receptor, and heat shock protein 90. The immunoconjugate TDM-1 is also highly promising. He predicted the most affordable approach may be anti-HER2 vaccines, which essentially generate trastuzumab- and pertuzumab-like antibodies directly in patients. Laboratory experiments now under way have shown that an HER2 vaccine plus lapatinib significantly diminished tumor volume. If this pans out, complete HER2 blockade would become “more affordable and therefore more accessible” to the 30% or so of patients with breast cancer with this subtype. ■

Ambulatory Care Key Financial Driver in Metastatic Breast Cancer Costs escalate after progression to chemotherapy for older women By Charles Bankhead San Antonio, TX—Healthcare costs increase after progression to chemotherapy among postmenopausal pa tients with hormone-sensitive metastatic breast cancer, although ambulatory care drives the cost before and after progression, data from a retrospective chart review showed, as reported at the San Antonio Breast Cancer Symposium. Six-month costs increased by almost 50% after progression, and the 2- and 3-year costs were more than twice as high compared with the same length of observation before progression. An analysis of individual cost contributors showed that ambulatory care accounted for 60% to 70% of total monthly costs before and after progression to chemotherapy. No other type of healthcare expenditure, including pharmacy, accounted for as much as 10% of the total cost. “Both before and after progression to chemotherapy, ambulatory care is the principal driver of healthcare costs,” said Kim Lew, PharmD, of Amgen in Thousand Oaks, CA. “This issue had not been studied in great detail, and these findings might be helpful in evaluating the risks and benefits of therapy for this subgroup of breast cancer patients.”

Hormone Receptor Status Affects Treatment Decisions Treatment decisions in the setting of metastatic breast cancer are strongly influenced by a tumor’s hormone receptor status. For patients with receptor-positive tumors, hormonal therapy offers effective tumor control for many patients and is less toxic compared with chemotherapy. For reasons that are not completely understood, some receptor-positive tumors do not respond to hormonal therapy (de novo resistance). In other cases, hormone-sensitive tumors develop acquired resistance to endocrine therapy. Either type of patient might be a candidate for cytotoxic chemotherapy, which is associated with a variety of adverse effects, including some serious and potentially lifethreatening effects. The investigators sought to quantify the direct healthcare costs associated with managing metastatic postmenopausal receptor-positive breast cancer before and after progression to chemotherapy. They retrospectively reviewed claims for women aged 55 to 63 years with a diagnosis of metastatic breast cancer from July 2001 through December 2007. The final analysis included 1202 pa-

VALUE-BASED CANCER CARE

February 2011

tients, of whom 366 (30.4%) progressed to chemotherapy. Each patient was followed until disenrollment from the health plan, death, or December 2008. Annual costs incurred during the prechemotherapy period averaged $79,139 compared with $132,796 after initiation of chemotherapy. Medical costs accounted for $74,149 per patient-year during the prechemotherapy period and $120,942 in the postchemotherapy period. Pharmacy costs accounted for the remaining $4990 per patient-year in the prechemotherapy group and $11,843 after initiation of chemotherapy.

Further analysis showed that medical costs associated with ambulatory care averaged $44,405 annually and $87,299 annually before and after initiation of chemotherapy, respectively. Inpatient costs averaged $27,147 and $30,118 in the pre- and postchemotherapy periods. After adjustment for duration of follow-up, total healthcare costs averaged $54,725, $73,107, and $84,200 during years 1, 2, and 3 of the prechemotherapy period compared with $92,639, $148,228, and $176,163 for the same duration of follow-up after initiation of chemotherapy. ■

Trastuzumab plus Chemotherapy Improves pCR San Antonio, TX—Combining trastuzumab (Herceptin) with anthracycline-taxane–based chemotherapy resulted in a greater pathologic complete response (pCR) compared with a lapatinib-anthracycline combination in women with HER2-positive metastatic breast cancer.

This randomized trial evaluated these 2 combinations as part of presurgical therapy for previously untreated patients, said Michael Untch, MD, of the Helios Klinikum Berlin-Buch, Gynecological Clinic, Germany. Patients in both arms Continued on page 21

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FISH-Guided Therapy Balances Clinical Benefits and Cost By Charles Bankhead San Antonio, TX—Treatment of recurrent metastatic breast cancer based on reassessment of HER2 status offers the optimal combination of clinical effectiveness and cost, based on 6 different clinical strategies. The largest gain in quality-adjusted life-years (QALYs) with an acceptable incremental cost occurred with a strategy of retesting tumors by fluorescence in situ hybridization (FISH) and giving trastuzumab only to patients with positive tests. A treatment strategy based on positive results with both immunohistochemistry (IHC) staining and FISH also resulted in a balance between effectiveness and cost. “It is interesting to notice that the strategy of no retesting on recurrence—probably the most common one used in clinical practice—is dominated and thus suboptimal,” Mattias Bernow, MD, of Karolinska Institute in Stockholm, reported at the San Antonio Breast Cancer Symposium.

FISH Tops Smorgasbord of Strategies In as many as 30% of cases of recurrent metastatic breast cancer, the HER2 status of the tumor has changed. However, most physicians base their decisions about anti-HER2 therapy with trastuzumab on the HER2 status of the primary tumor, Dr Bernow and colleagues noted in a poster presentation. The clinical value and cost of reevaluating HER2 status on recurrence remain unclear. To evaluate those issues, Dr Bernow and colleagues used a Markov state transition model to simulate 6 different strategies for retesting HER2 status and use of trastuzumab: • No retesting and use of chemotherapy alone for all patients • No retesting and use of trastuzumab in patients with HER2-positive primary tumors • Retesting with IHC, giving trastuzumab to patients who test IHC 3+

• Retesting with IHC and giving trastuzumab to IHC 2+ and 3+ patients • Retesting with IHC, follow-up FISH testing for IHC 2+ or 3+ tumors, and trastuzumab for FISH+ tumors • Retesting with FISH and trastuzumab for all FISH+ patients.

The largest gain in QALYs with an acceptable incremental cost occurred with a strategy of retesting tumors by FISH and giving trastuzumab only to patients with positive tests. The strategies were evaluated in patient cohorts: one based on treatment guidelines and published data and the other derived from actual patient records in a Swedish breast cancer database.

Of the various strategies, a strategy of retesting with FISH and giving trastuzumab to FISH+ patients resulted in a gain of 1.543 QALYs, at costs of $59,500 and $55,400, respectively, and incremental cost-effectiveness ratios (ICERs) of $75,500 and $73,300, respectively, for the guideline and actualpatient cohorts. A strategy of retesting with IHC, FISH for IHC 2+ or 3+, and trastuzumab plus chemotherapy for FISH+ patients yielded a gain of 1.525 QALYs. The improvement was associated with a cost of $58,100 and ICER of $63,200 in the guideline cohort and a cost of $54,100 and ICER of $61,100 in the actual-patient cohort. “A previous Swedish study estimated willingness to pay of $88,900 per QALY gained,” Dr Bernow and colleagues noted. “Thus, retesting of HER2 status of recurring breast cancer patients is clinically relevant and costeffective.” ■

High Copays Associated with Discontinuation of Hormonal Breast Cancer Therapy By Caroline Helwick have been shown to reduce the risk of recurrence. However, at least one third of women may stop taking them, partially because of side effects. The study suggested that having to pay more for the drug may be another reason. Women with out-of-pocket expenses of ≥$90 for a 3-month period were 26% to 34% more likely to stop filling their prescriptions than those paying <$30. Dr Hershman and colleagues combed the Medco database of approximately 12 million subscribers to select 21,160 women diagnosed with

Trastuzumab plus... Continued from page 20 received adjuvant trastuzumab after surgery as part of the standard of care. A total of 620 patients were randomized to trastuzumab (n = 309) or to lapatinib (n = 311). Patient and tumor characteristics were similar between the 2 arms, and the rates of severe adverse events were similarly balanced. The overall discontinuation rate was higher in the lapatinib arm (23% vs 13%). The rate of pCR was 31.3% in the trastuzumab arm and 21.7% in

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the lapatinib arm (P <.05). Breast conservation rate was higher in the trastuzumab arm (65.6% vs 56.0%). The study confirms previous research, demonstrating a 50% pCR rate in HER2-positive patients receiving trastuzumab therapy. Lapatinib users had a lower pCR rate, but the higher rate of discontinuation in that group could have affected that number. Data on overall survival and disease-free survival are forthcoming as the trial continues. ■

early breast cancer in 2007 and 2008 who filled at least 2 mail-order prescriptions for an AI. Copayments were stratified as <$30, $30 to $89.99, and ≥$90. Photo by © SABCS/Todd Buchanan 2010

San Antonio, TX—Higher prescription copayments contribute to early discontinuation of aromatase inhibitors (AIs) for breast cancer, according to a study presented at the annual San Antonio Breast Cancer Symposium. “Noncompliance is a problem, even among patients with pharmaceutical plans,” said Dawn Hershman, MD, of Columbia University, who led the study based on a claims database from Medco Health Solutions. AIs are routinely prescribed as maintenance therapy in endocrineresponsive early breast cancer and

“Public policy efforts to control outof-pocket expenses for hormonal therapy may improve breast cancer survival.” —Dawn Hershman, MD

Median copayment for a 90-day prescription was $50 for patients aged <65 years and $40 for those aged ≥65 years. Approximately 21% of the younger women and 25% of the older women completely stopped taking their AI over the 2-year study period. Older women with copayments of $90 or more over 3 months were 34% more likely to discontinue their AI therapy than those paying >$30. Younger women were 26% more likely to stop.

In addition, the more prescriptions a patient needed, the more likely she was to discontinue AI therapy. Prescriptions provided by a primary care physician rather than an oncologist were also less likely to be filled. “Out-of-pocket costs influence both nonadherence and nonpersistence with AI treatment, and the elderly are particularly vulnerable to this,” Dr Hershman noted. “Public policy efforts to control out-of-pocket expenses for hormonal therapy may improve breast cancer survival.” In British Study, One Quarter Discontinue “Free” Drug In a study from the United Kingdom, also presented at the meeting, investigators found high rates of discontinuation there as well, although the drugs are provided at no charge in that healthcare system, suggesting the issues surrounding treatment adherence are complex. Of the patients, 75% were treated with tamoxifen, and just 8% started on AIs. Nevertheless, 23% of patients had discontinued this drug at 2 years. “We found similar levels of noncompliance when payment was not an issue,” said Alistair Thompson, PhD, from the University of Dundee in Scotland. ■

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in su 3 y pr rviv ea M evi al r o ul ou ad ve tip s v ra le ly u an ll M nt tag ye re e lo at m ed a

If You Deﬁne Value as an Overall Survival Advantage:

In Previously Untreated Multiple Myeloma IMPORTANT 3-YEAR UPDATE- SUSTAINED BENEFIT UPDATED VISTA* OVERALL SURVIVAL (OS) ANALYSIS: VcMP† vs MP (36.7-month median follow-up) 100

MEDIAN OS NOT REACHED FOR VcMP

% Patients Without Event

80 70 60 50 40 30 20 10

VELCADE+MP (n=344) MP (n=338)

HR 0.65 (95% CI, 0.51-0.84); P=0.00084

0 0

Months Kaplan-Meier estimate.

Patients treated with VELCADE + MP as initial therapy sustained an overall survival benefit over patients randomized to MP alone The overall survival benefit was sustained despite subsequent treatments Median duration of VcMP treatment was 46 weeks/54 planned1 At the initial analysis (median 16.3-month follow-up), median TTP was 20.7 months with VELADE in combination with MP vs 15 months for MP alone (P=0.000002) * VISTA was a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. Primary endpoint was TTP and secondary endpoints were CR, ORR, PFS, and OS. At a prespecified interim analysis (median follow-up 16.3 months) VcMP resulted in significantly superior results for TTP, PFS, OS, and response rates. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. † VcMP=VELCADE + melphalan/prednisone (MP).

If You Deﬁne Value as Medication Cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1398.00 per 3.5mg vial as of January 1, 2011. Health plans should consider medication cost, length of therapy, and dosing regimens when determining the value of a prescription drug regimen. This list of considerations is not meant to be all-inclusive; there are multiple other factors to consider when determining value for a given regimen.

VELCADE Warnings, Precautions, and Adverse Events VELCADE is contraindicated where hypersensitivity to bortezomib, boron, or mannitol exists. Warnings and Precautions for VELCADE include: advising women to avoid pregnancy and breastfeeding; peripheral neuropathy, sometimes severe may occur—manage with dose modifications or discontinuation and carefully consider risk/benefit in pre-existing severe neuropathy; hypotension may occur, use caution with patients on antihypertensives, history of syncope, dehydration; closely monitor patients with risk factors for or existing heart disease; acute diffuse infiltrative pulmonary disease has been reported; nausea, diarrhea, constipation, and vomiting may require symptomatic treatment; regular monitoring of blood counts throughout treatment for thrombocytopenia or neutropenia. Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and acute hepatic failure have been reported. In patients with moderate or severe hepatic impairment use a lower starting dose. In addition, patients with diabetes may require close monitoring of blood glucose and antidiabetic medication. Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported.

Please see Brief Summary for VELCADE on the next page of this advertisement. To contact a reimbursement specialist: Please call 1-866-VELCADE, option 2 (1-866-835-2233).

www.VELCADE.com 1. San Miguel, Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma. New England Journal of Medicine 2008.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer's prescribing information. Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. MA 02139Company. Cambridge, MA 02139 Millennium Pharmaceuticals, Inc., Cambridge, The Takeda Oncology 10 Millennium Pharmaceuticals, Inc. Copyright ©2009, V-10-0204 10 All rights reserved. Printed in USA V1215 12/09

SABCS CONFERENCE

Triple-Negative Breast Cancer Has Highest Hospitalizations, Mortality Rates By Charles Bankhead San Antonio, TX—Triple-negative breast cancer not only confers a worse prognosis but it drives up inpatient healthcare costs by almost 50% compared with other types of breast cancer, an analysis of a managed care database suggested. Patients with triple-negative disease had a 2-fold greater mortality risk compared with other patients with breast cancer. The number of hospitalizations, hospital days, and emergency department visits also were significantly higher in patients with triplenegative disease. “Triple-negative breast cancer patients experience significantly greater clinical burden compared with non– triple-negative breast cancer patients, especially in duration and costs of inpatient stays,” Wenhui Wei, PhD, health

outcomes researcher at sanofi-aventis in Bridgewater, NJ, reported at the San Antonio Breast Cancer Symposium.

Triple-negative breast cancer was associated with more hospitalizations, hospital days, emergency department visits per year, and cancerrelated hospitalizations. Triple-negative breast cancer—a subtype defined by absence of estrogen, progesterone, and HER2 receptors—exhibits aggressive biological and clinical behavior and has no standard therapy. The subtype accounts

for about 15% of all breast cancer, but little is known about the inpatient and economic burden associated with triple-negative disease. Investigators analyzed medical and pharmacy claims linked with mortality data from a large US managed care plan. They identified patients with new breast cancer diagnoses from 1999 to 2009 and separated the patients according to tumor receptor status. The final analysis comprised 450 patients with triple-negative breast cancer and 1807 patients with other breast cancer subtypes. Patients were followed from diagnosis to the end of health plan enrollment or death. The primary outcomes were survival and healthcare utilization and costs. The analysis showed that triple-negative breast cancer, com-

pared with other breast cancer subtypes, was associated with: • A relative risk of mortality of 2.34 for stages I to III (P <.001) and 1.60 for stage IV disease (P = .0148) • More hospitalizations (1.32 vs 0.97; P <.001), hospital days (10.98 vs 6.42; P <.001), and emergency department visits (1.30 vs 0.94; P = .029) per year • More cancer-related hospitalizations (0.65 vs 0.51; P = .002) and hospital days (4.64 vs 3.49; P = .047) • Greater risk-adjusted annualized inpatient costs ($8395 vs $4745; P <.001) and plan-paid inpatient costs ($8213 vs $4486; P <.001) • Greater cancer-related risk-adjusted annual inpatient costs ($5070 vs $2675; P <.001) and plan-paid ($4844 vs $2533; P <.001). ■

Imaging Use in Breast Cancer Grows, Despite Evidence Gap San Antonio, TX—Results of an Italian study showed that use of newer imaging studies in early breast cancer has increased substantially despite a lack of evidence for benefits. Per-patient use of computed tomography (CT), positron-emission tomography (PET), and magnetic resonance imaging (MRI) roughly doubled from 2005 to 2008. During the same period, use of routine imaging—such as mammography and chest x-ray—remained stable or increased slightly, resulting in an overall increase in imaging studies. Use of these newer imaging modalities for routine imaging of patients with early breast cancer “has been steadily growing over the past 4 years,

with important cost implications,” Grazia Arpino, MD, PhD, of Universita di Napoli Federico II in Naples, Italy, reported at the San Antonio Breast Cancer Symposium. “Further studies are needed to characterize patient subsets that deserve these more invasive staging and follow-up procedures.” Current clinical guidelines for breast cancer do not support routine use of newer imaging studies, including CT, PET with fluorodeoxyglucose (FDG), or MRI. Nonetheless, imaging studies are requested with increasing regularity, even in the absence of clear clinical indications, Dr Arpino and colleagues noted in a poster presentation.

To quantify the change in volume of newer imaging studies in breast cancer, investigators performed a retrospective cohort study, based on med-

The number of new cases of early breast cancer declined, but the use of CT imaging in early breast cancer increased. ical records provided by 457 physicians involved in the care of patients with breast cancer. They identified patients with new diagnoses of

early breast cancer from 2005 through 2008 and assessed the use of all imaging studies for those patients. The number of new cases of early breast cancer declined from 576 in 2005 to 467 in 2008, and the use of CT imaging increased from 0.55 procedures per patient to 1.02 (P <.001). The rate of FDG-PET imaging increased from 0.07 to 0.14 per patient (P = .004), and MRI use increased from 0.14 to 0.23 per patient (P = .023). In addition, small but significant changes occurred in the use of abdominal ultrasound and bone density scans. The rate of use did not change significantly for mammography chest x-ray or bone scintigraphy.—CB ■

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AVBCC PREVIEW

Conference Promises Valuable Perspectives

he Association for Value-Based Cancer Care’s First Annual Stakeholder Integration Conference will be held in Philadelphia on March 2930, 2011 (see full agenda below). To help set the stage for this meeting, ValueBased Cancer Care (VBCC) interviewed Gary Owens, MD, one of the cochairs of the meeting. Dr Owens is president of Gary Owens Associates, a medical management and pharmaceutical consulting firm in the Philadelphia area. Dr Owens is a primary care physician who has spent 20 years in health plans, and one of his major areas of focus during that time has been oncology.

area that will continue to grow, so it was essential that we cover this. In the future, I suspect that drugs will come to market with companion diagnostics attached to them. I’m not sure that health plans, providers, or

anyone else is tuned in as to how to manage these situations effectively. Other areas to be covered will include clinical treatment of cancer patients, the use of guidelines, and patient navigators and patient-assis-

tance programs. With the growing number of uninsured and underinsured patients, we can’t forget about the difficulties these individuals face in accessing treatment, so these latter sessions will be important.

March 29-30, 2011 Philadelphia, PA Loews Philadelphia Hotel

First Annual Stakeholder Integration Conference Integrating Payers, Providers, and the Entire Oncology Team

VBCC: Why this meeting now? Gary Owens, MD: A number of reasons, the first being the obvious rapid growth of spending that the players in the oncology world—including the federal government, health plans, and the public—is seeing. As Peter Bach noted several years ago in the New England Journal of Medicine (2009;360: 626-633), the cost of cancer care agents has risen dramatically over the years, and the ability to control those costs has been limited. Baby boomers are aging, and people are living longer with cancer. It is an almost-perfect storm (see Sidebar, page 27). Ultimately, the goal is to provide the best care possible for patients with malignant disorders but to spend those care resources wisely. We don’t want to withhold treatment from those who need it, but we don’t want to waste treatment in those for whom it is ineffective or unproven. This meeting will examine all these topics. VBCC: Who will be presenting at this meeting, and what topics can we expect to be covered? Dr Owens: We have some key thought leaders. On the clinical side, Al Benson, MD, the current president of the Association of Community Cancer Centers, and A. Mark Fendrick, MD, from the University of Michigan, will both present. Dr Fendrick is a driving force behind the value-based benefit movement, and it will be interesting to hear his perspective. Along the lines of targeted therapy, we have a session on the age of personalized oncology therapy that promises to be a very cogent topic. Right now, these offer more promise than reality. Although there are a few successful examples of this so far—KRAS testing and colorectal cancer, HER2/neu testing and breast cancer, and ABR-BCL mutations in chronic myelogenous leukemia—this is an

VALUE-BASED CANCER CARE

PROGRAM OVERVIEW

PRIMARY CONFERENCE LOCATION

This is the first national stakeholder integration meeting dedicated to advancing the understanding of value in cancer care. Guided by the expertise of leaders in these fields, attendees will receive a thorough understanding of the evolution of the value equation as it relates to cancer therapies and will be able to implement, improve, and sustain their companies and institutions, while improving access for patients and ultimately patient care.

WHO SHOULD ATTEND All stakeholders in a position to impact cancer patient care are invited to join this exciting forum. Specifically this conference is intended for: • Medical Oncologists • Advanced Practitioners • Hematologists/Oncologists • Managed Care Professionals • Medical Directors • Surgical Oncologists • Nurses • Practice Managers/Administrators • Pharmacists • Pharmacy Benefit Managers (PBMs)

CONTINUING EDUCATION INFORMATION Goal The Association for Value-Based Cancer Care’s First Annual Stakeholder Integration Conference will foster an open dialogue between providers, payers, and/or other members of the oncology team in order for attendees to gain a better understanding of various points of view regarding cost, quality, and access in cancer care. Objectives • Examine the impact of healthcare reform on all stakeholders involved in the management of patients with cancer • Identify issues and potential solutions to challenges with access and affordability of oncology therapeutics • Determine the value equation of cost, quality, and access when evaluating the diagnosis, treatment, and overall management of cancer patients • Define appropriate comparative effectiveness research and clinical pathways as tools to evaluate current recommendations for patient management • Analyze trends in the delivery of care in the management of cancer patients Co-Chairs

Gary Owens, MD

Burt Zweigenhaft, BS

President, Gary Owens Associates

President, CEO, OncoMed

Loews Philadelphia Hotel 1200 Market Street, Philadelphia, PA 19107-3615 Phone: 215-627-1200 http://www.loewshotels.com/en/Philadelphia-Hotel

ACCREDITATION INFORMATION PHYSICIAN ACCREDITATION Science Care designates this activity for a maximum of 6.0 AMA PRA Category 1 Credit(s)™. Science Care is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Physicians should only claim credit commensurate with the extent of their participation in the activity. REGISTERED NURSE DESIGNATION Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 6.0 contact hours. REGISTERED PHARMACY DESIGNATION Medical Learning Institute is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 7.50 contact hours (0.750 CEUs) of continuing education credit. The Universal Activity Number for General Sessions is: 0468-9999-11-072-L01-P. The Universal Activity Number for the lunch symposium is: 0468-9999-11-071-L01-P.

CONFERENCE REGISTRATION Register Online at

www.regonline.com/avbcc-2011 $250 Includes 1-year association membership $355 Includes 3-year association membership

CONTACT/SUPPORT If you have any questions please contact: Association for Value-Based Cancer Care™ 241 Forsgate Drive, Suite 205B, Monroe Township, NJ 08831 Phone: 732-992-1040 association@valuebasedcancer.com

www.regonline.com/avbcc-2011

February 2011

VOL. 2

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AVBCC PREVIEW

VBCC: Whatâ&#x20AC;&#x2122;s different about this meeting? Dr Owens: A big plus is that it brings together different viewpoints from various stakeholders, including health plans, pharmacy benefit man-

agers, providers, patients, government, manufacturers, and the National Comprehensive Cancer Network. Weâ&#x20AC;&#x2122;re attempting to bring together a group that owns different pieces of the cancer care equation, and to hear

Tuesday, March 29 1:30 â&#x20AC;&#x201C; 3:30 pm PAYER PRE-CONFERENCE (Off-site) Ritz-Carlton Philadelphia 10 Avenue of the Arts, Philadelphia, PA 19102 Payer Trends in Oncology - Panel Discussion MODERATOR Burt Zweigenhaft, BS PANEL Scott Breidbart, MD â&#x20AC;&#x201D; CMO, Empire BCBS Nick J. Calla, RPh â&#x20AC;&#x201D; VP, Trade Relations, Walgreens Specialty Pharmacy Maria Lopes, MD â&#x20AC;&#x201D; CMO, AMC Health Mona Chitre, PharmD â&#x20AC;&#x201D; Director, Clinical Strategy, Policy, and Services, Excellus GENERAL PRE-CONFERENCE SESSIONS Loews Philadelphia Hotel 1200 Market Street, Philadelphia, PA 19107-3615 Value-Based Insurance Design in Oncology CHAIR A. Mark Fendrick, MD â&#x20AC;&#x201C; Co-Director, University of Michigan Center for Value-Based Insurance Design Cancer Care from a Large Insurerâ&#x20AC;&#x2122;s Perspective Donald Liss, MD â&#x20AC;&#x201C; Senior Medical Director, Independence Blue Cross of Philadelphia The Role of Diagnostics from a PBMâ&#x20AC;&#x2122;s Standpoint Jane F. Barlow, MD, MPH, MBA â&#x20AC;&#x201C; VP, Clinical Innovation, MEDCO Health Solutions Panel Discussion

Welcome/Networking Reception

Wednesday, March 30

Corporate-Sponsored Breakfast Symposium Havalenâ&#x201E;˘ (eribulin mesylate) Injection: A New FDA-approved Treatment Funded by Eisai Inc.

Oncology Practicesâ&#x20AC;&#x201D;Issues with Managed Care Craig Deligdish, MD â&#x20AC;&#x201C; Medical Director, Florida Comprehensive Care Network Yu-Ning Wong, MD â&#x20AC;&#x201C; Fox Chase Cancer Center Winston Wong, PharmD â&#x20AC;&#x201C; Associate VP, Pharmacy Management, CareFirst BCBS PAYER TRACK Medicare and Reimbursement Issues Kip Piper, MA, FACHE â&#x20AC;&#x201C; President, Health Results Group Jayson Slotnik, JD â&#x20AC;&#x201C; Counsel, Foley Hoag Oncology Drug Reimbursement and Administration Issues John Aforismo, BSc Pharm, RPh, FASCP â&#x20AC;&#x201C; President & CEO, RJ Health Systems Peyton Howell, MBA â&#x20AC;&#x201C; AmerisourceBergen Scott Breidbart, MD â&#x20AC;&#x201C; CMO, Empire BCBS Evolutions in Oncology Pharmacy Management MODERATOR Burt Zweigenhaft, BS ROUNDTABLE Alan Lotvin, MD â&#x20AC;&#x201C; President, ICORE Kristen M. Reimers, RPh â&#x20AC;&#x201C; Clinical Pharmacy Operations Manager, Excellus Jeff Ulanet â&#x20AC;&#x201C; VP, Oncology, MEDCO LUNCH SYMPOSIUM Best Practices for Management of CINV: A Value-Based Approach Supported by an educational grant from Eisai Inc. Shawna Kraft, PharmD, BCOP â&#x20AC;&#x201C; Hematology/Oncology Clinical Pharmacist, University of Michigan Health System Beth Faiman, RN, MSN, CNP, AOCN â&#x20AC;&#x201C; Nurse Practioner, Cleveland Clinic Taussig Cancer Center

Stephen C. Malamud, MD â&#x20AC;&#x201C; Beth Israel Medical Center

Intro/Opening

NCCN Guidelines Acceptance and Compliance Al Benson, MD â&#x20AC;&#x201C; President, ACCC

The Impact of Personalized Oncology Therapies MODERATOR Gary Owens, MD PANEL Perry Dimas â&#x20AC;&#x201C; VP, Premier Source Diagnostics Richard Bender, MD â&#x20AC;&#x201C; CMO, Agendia Beth Davis â&#x20AC;&#x201C; Senior Director, Managed Care, Agendia Gene Morse, PharmD â&#x20AC;&#x201C; University of Buffalo

Morning Break in the Exhibit Hall

Strategies for Improving Oncology Pharmacy and Care Management Models MODERATOR Burt Zweigenhaft, BS PANEL Ira M. Klein, MD â&#x20AC;&#x201C; Medical Director, Aetna Oncology Strategy Dan McCrone, MD â&#x20AC;&#x201C; CMO, New Century Health Jeffery Scott, MD â&#x20AC;&#x201C; SVP/CMO, P4 Healthcare, Cardinal Health Winston Wong, PharmD

Afternoon Break in the Exhibit Hall

Clinical Fragmentation: Impact of Oral, Injected, and Infused Therapies MODERATOR Gary Owens, MD ROUNDTABLE Atheer Kaddis, RPh â&#x20AC;&#x201C; VP, Managed Markets, Diplomat Pharmacy Services Kirby Eng, RPh â&#x20AC;&#x201C; Director, Oncology Management Services, CVS Caremark Ellen Scharaga, BS â&#x20AC;&#x201C; SVP, Pharmacy Operations, OncoMed

Cocktails/Networking in the Exhibit Hall

PROVIDER TRACK Community Oncology: Trends Ted Okon â&#x20AC;&#x201C; Executive Director, Community Oncology Alliance Patient Navigation/Patient Assistance Steven Patierno, PhD â&#x20AC;&#x201C; Executive Director, George Washington University Cancer Institute Dawn Holcombe, MBA, FACMPE, ACHE â&#x20AC;&#x201C; President, DGH Consulting Monica Knoll â&#x20AC;&#x201C; Executive Director/Founder, CANCER101

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Cancer Care and the New Healthcare Legislation: What to Expect Next MODERATOR Jayson Slotnik, JD PANEL Scott Gottlieb, MD â&#x20AC;&#x201C; Resident Fellow, American Enterprise Institute Joseph Bailes, MD â&#x20AC;&#x201C; Texas Oncology

BREAKOUT SESSIONS

about the world of oncology through their eyes. We hope to identify common issues and understand how we might integrate these. The current situation with Avastin provides an excellent example of the

interconnected nature of cancer care today. The US Food and Drug Administration (FDA)â&#x20AC;&#x2122;s accelerated approval was based on the requirement of further data on patients with metastatic breast cancer. Compendia, however, continue to advocate coverage for this condition as do some patient groups. So we have a situation where the FDA is taking one action and the real world another. Some patients are benefiting but many are probably not. Conferences such as these can be helpful in shedding light on the issues behind these situations. Weâ&#x20AC;&#x2122;re trying to open up the lines of communication between these various groups. Currently, stakeholders may not have a chance to â&#x20AC;&#x153;cross-pollinate,â&#x20AC;? as weâ&#x20AC;&#x2122;re hoping to do here. I may have seen only 1 or 2 other meetings that have even tried to bring together this many stakeholders. We tend to live in our own world and often only see our own points of view, so it can be eyeopening to see those other viewpoints. We will feature multiple presenters, with interactivity not only among presenters but with members of the audience. We believe that this audience is going to have as much expertise as the people behind the podium, which should make for excellent interactions. â&#x2013;

Cancer Costs Projection: Population Booming, Costs Zooming The estimated total cost of cancer care in the United States is projected to be $158 billion by 2020 if current patterns of incidence, survival, and cost remain the same. If care costs increase 2% in the initial and last phases of treatment above the base estimates, however, total costs of care could reach $173 billion by 2020, an increase of 39% from 2010. This analysis appears in the Journal of the National Cancer Institute (Mariotto AB, et al. 2011;103:117-128). By 2020, the authors estimate there will be 18.1 million cancer survivors in the United States, whose care will cost $157.7 billion, a 27% increase from 2010â&#x20AC;&#x2122;s amount of $124.5 billion. Despite this profound possible increase, the authors are hopeful. â&#x20AC;&#x153;Expanding costs of cancer care due to increases in an aging population are inevitable,â&#x20AC;? they note, â&#x20AC;&#x153;but the costs of new treatments and diagnostic technologies could potentially be managed to ensure access to quality care for all patients.â&#x20AC;?

www.ValueBasedCancerCare.com

PATHWAYS IN ONCOLOGY

Implementing Clinical Pathways at an Oncology Practice An Interview with Barry Russo, Center for Cancer and Blood Disorders

To learn about implementing clinical pathways in an individual practice, VBCC spoke with Barry Russo, Chief Executive Officer, Center for Cancer and Blood Disorders, Fort Worth, TX. What was life like before pathways at your 18-physician practice? Prior to pathways, we didn’t give a lot of thought to assessing differences in what individual physicians were doing for, say, patients with stage II breast cancer or standardizing care processes. With pathways in place, standard treatments are now top of mind. Was there a single event that precipitated moving to pathways? No. It was more of a strategic, developmental process within our practice—we thought about the future in relation to market changes, healthcare reform, and changes in reimbursement. Over the past 5 years, oncology reimbursement has changed more than in the past 20, and the combined forces pushed us to look at pathways as one of the top strategies to address these changes. Was there a push for pathway involvement from payers? Payers have been pushing us over the past few years to look at costs and work out the costs of care for particular conditions (such as breast cancer), and this did influence our practice’s approach. In talking to payers, we realized we did not have specific standard processes, and therefore did not have the means to determine care costs. Overall, we did not have unreasonable variability, but there was enough variability to be uncomfortable in costing out a care process for different disease presentations and knowing it would be applicable in all similar cases across the practice. So the payer market was influential in the process, but they did not specify what approach we used.

How long have you been on a pathway program? What have been the financial and clinical implications? We’ve been using them for 18 months, and although the pathways have not yet generated income for us, I think that opportunities are arising with the infrastructure in place. For example, pathways have allowed us to become involved in a pilot program with UnitedHealthcare on episode-fee reimbursement, which requires standardization of care and costs in certain diseases, and we are now 10 months into that pilot. We are also currently having discussions with 2 other payers regarding oncology medical homes and case-rate reimbursement. When we have had discussions with other oncology groups about consolidating or becoming a multispecialty group, an initial point of discussion is how to determine the quality of care. Pathways and pathway compliance are some of the best quality indicators, and we would not be having these discussions if not for them.

they did not have to before. But our practice had been discussing strategic needs in terms of payer and integrated delivery system relationships, and it was easy to make the argument that this tool makes us a factor with those relationships. So physicians accepted it, and implementation went very smoothly. Via Oncology is very astute at implementing this product, and the IT support was awesome. Pathways really have become second nature for us and our physicians—it’s our new norm.

How do financial pressures and regulatory reform affect practice? We’re not facing financial trouble, but in terms of what we expect with healthcare reform (changes in reimbursement, accountable care organizations, and bundled payments), these are all rooted in the idea of large integrated delivery systems. That’s the primary reason for looking at these kinds of consolidations, and pathways can help us tremendously in this regard. Most people implement pathways because they want help with standardization, for quality reporting, or for pay for performance. But we’ve found their benefits go way beyond that in terms of relationship development.

What investments have been necessitated by the program? We did not have to build a lot of infrastructure for pathways. We did have to identify the individuals responsible for rolling out the pathways, but we did not have to upgrade computers. Via Oncology pathways is a web-based system, and our practice uses an EMR system. We wanted the pathway system to interface with our medical record, so that when the physician picked the pathway, the

How often do the pathways change? The pathway development committees convene once per quarter, which is frequent enough to consider new research developments and new drugs. All our doctors are committee members, so they have input on how the pathways operate, change, and improve over time. They want input, because, ultimately, they will have to use the product. What has been the reaction of your physician staff? Caution, certainly. It’s always difficult to implement a new process and have physicians answer questions

VALUE-BASED CANCER CARE

February 2011

What administrative burdens have been reduced by pathways? We have seen enrollment in research trials go up because these are now listed on the pathways. In addition, the interface to the electronic medical record (EMR) prevents having to write in additional orders and reduces data entry, cutting down on errors. So there’s some administrative relief, but we were really trying to establish an infrastructure for the future. We have not had to reduce or increase staffing because of pathways.

VBCC Perspective, page 31 order set associated with that pathway would go directly into the EMR. Your center recently received Quality Oncology Practice Initiative (QOPI) certification. What was that process like, and did it tie into pathway use? Everything we do clinically ties into pathway use because of the associated processes of care and documentation. The QOPI process was onerous, requiring a lot of chart reviews and data analysis, but embarking on the pathway process was helpful in this regard. If you’re going to be certified by ASCO or QOPI, the process should be onerous, and we’re thrilled that we are currently the only QOPI-certified practice in Texas. Has the Center for Cancer and Blood Disorders’ approach to supplying drugs for patients been impacted by pathways? We’ve narrowed the number of therapies—pathways define the regimens, and this has focused on our drug purchasing process. Via Oncology emphasized at the outset that we should not share what was on or not on the pathway with pharmaceutical representatives so as to avoid any outside pressure. So as new drugs come out, they are reviewed during the pathway review process. We’ve had a policy for the past 8 years preventing pharmaceutical reps from having conversations with the group’s physicians about pricing and margins—they can only discuss clinical efficacy. There was some initial grumbling, but 18 months into the process, most people are over that. ■

Radiation Oncology Pathways By Colin Gittens

edical oncology pathways have arisen in the past several years as a means to standardize care, improve patient outcomes, and structure clinical/financial arrangements so that practices can more easily work with payers. That approach is now being attempted on the radiation oncology side by D3 Radiation Oncology Solutions, an affiliate of the University of Pittsburgh Medical Center (UPMC), which has also created the Via Oncology pathways. Dwight E. Heron, MD, chief medical officer of D3 and vice-chairman of Radiation Oncology at UPMC Depart-

ment of Radiation Oncology, discussed the similarities and differences between medical and radiation oncology pathways. “In many ways, both types of pathways aim to get to the same place,” Dr Heron said. Although the National Comprehensive Cancer Network guidelines integrate radiation therapy into their pathway process, this guidance is fairly broad, Dr Heron said. And the many components of radiation care—selecting the appropriate patients, treating them with the right technology, and determining the correct number of treatments—leave Continued on page 29

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PATHWAYS IN ONCOLOGY

Radiation Oncology... loopholes for variability. As with medical oncology, radiation pathways evolved from the recognition of this wide variation in treatment patterns. Radiation pathways aim to ensure quality and minimize toxicity, and, in the scope of the overall package, to also minimize cost. For example, some of the technologies recommended in the pathways are more expensive, Dr Heron acknowledged, but in looking at the big picture, they are beneficial in terms of side effects.

“The upfront cost of treatment may be slightly more...but if you look at the significant reduction in toxicities...the additional costs may be worth it.” —Dwight E. Heron, MD

“In the prostate cancer and the GYN malignancies that we treat, the upfront cost of treatment may be slightly more (by using intensity-modulated radiation therapy vs 3D conformal therapy), but if you look at the significant reduction in toxicities (ie, reduction in diarrhea or bowel complications that require hospitalization or surgery), the additional costs may be worth it.” Looking at the big picture is important, Dr Heron emphasized. “In a patient who’s only going to live 2 months, to take an entire month to treat them palliatively is a problem, particularly when there is evidence that a shorter course of treatment is just as effective.” Two Lines in the Pathway Family Kathleen G. Lokay, president and chief executive officer of D3 and Via Oncology, suggested that there are more similarities than differences between radiation and medical oncology pathways. Both use disease-specific committees chaired by academic- and community-based physicians; both follow the same hierarchy of efficacy, toxicity, and cost; and with both, the goals are the same. Unlike pharmaceutical-based pathways, however, the radiation oncology evidence base changes less frequently.

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Continued from page 28

Another key difference with this pathway is that it “attempts to ensure that the delivery of the dose is what the physician intended,” she said. The 2 pathways—medical and radiation oncology—are linked when used

together so that referral for a patient needing care in both areas is seamless. Finally, pathways need to rely on the evidence base to retain their integrity, said Ms Lokay, and this may result in recommendations for using a technology not possessed by the organization

using the pathway. An organization may be reluctant to do this, and although a physician can opt to go off pathways in such cases, she believes that the best evidence of the pathway is what should be adhered to. ■

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HCPCS code

Description

Effective

J9302

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January 1, 2011

Contact your GSK representative for additional information or visit www.ARZERRA.com.

www.ValueBasedCancerCare.com

PATHWAYS IN ONCOLOGY

Proventys’ Decision-Support Systems Promote Personalized Medicine PDx Oncology is the first-in-class in a new category of medical devices

VBCC Perspective, page 31

By Colin Gittens

n emerging player in the clinical decision-support marketplace is Proventys, whose products fall into 2 distinct categories. The first is a broad, web-based National Comprehensive Cancer Network (NCCN) Guidelines–driven system called Proventys CDS Oncol ogy, the second, called Proventys PDx Oncology, is the first-in-class in a new category of medical devices known as software-based predictive tests. Proventys CDS Oncology has 2 distinguishing characteristics that may separate this company’s offering from some of the other clinical pathways programs. First, the decision support is based on NCCN Clinical Practice Guidelines in Oncology, which is the result of an exclusive collaboration between Proventys and NCCN. Second, the company is focused on aligning the interests of oncology providers and payers through an innovative program built on the CDS Oncology system. This program, called AlignQI, is aimed at increasing transparency and collaboration between stakeholders to improve the quality of oncology care. Proventys PDx Oncology is a predictive medicine system that employs a formal, statistically driven set of models to help plan care; the planned first component of this tool will help assess a patient’s risk of developing febrile neutropenia. Because of the newness of this modeling approach, the US Food and Drug Administration (FDA) considers this a new category of regulated medical device, and Proventys has been working with the FDA to create a control guidance document that will aid its own approval and help guide future, similar technologies. The release date for the predictive component is unknown, but Chief Medical Officer Surya Singh, MD, described the process of working with the agency as “very collaborative.” The Proventys CDS Oncology system (the broad decision-support tool powered by the NCCN) is expected to be released by April 2011. The system fosters the ability to tailor care to the individual patient, and the Proventys notion of personalized care goes beyond advanced biomarkers and genetic testing, said Dr Singh. A physician has dozens, if not hundreds, of variables to take into account

in any particular decision, Dr Singh said, and it’s inevitable that some items will be weighted more than others, depending on personal experience. That personal experience is necessarily less extensive than the experience that would inform and weight a database.

The system will also link to specific payer factors (within NCCN guidelines) that may influence a physician’s decision if all clinical factors are equal. For example, by choosing a particular chemotherapy regimen among 6 recommended by NCCN for a particular condition, a physician may not

Oncologists take into account 60 to 80 variables in each treatment decision, which “is more than the human cognitive capacity.” —Surya Singh, MD

According to an informal survey of his colleagues in Brigham and Women’s Hospital, oncologists take into account 60 to 80 variables in each treatment decision, which “is more than the human cognitive capacity,” Dr Singh noted. As with other pathways programs, the system is constructed to account for these variables. The program, Dr Singh emphasized, includes the evidentiary consensus behind the guidelines. Not all pathways provide this primary evidence, and it is important to “present all options,” he said. Incorporating NCCN Guidelines Updates Proventys is working with NCCN to plan how regular guideline updates will be incorporated into the program. A potential advantage of the system, according to Dr Singh, is that it will help roll out updated guideline information through user prompts. Incorporating NCCN updates into practice currently requires active information seeking by physicians. “I’m not saying that doesn’t happen,” said Dr Singh, but “it doesn’t happen in a comprehensive and systematic way.” With the CDS Oncology system, according to Dr Singh, for the first time guidelines will be vetted against realworld practice in real time, without relying on retrospective claims data or electronic medical record (EMR) review. “If somebody deviates from guidelines, and they’re using this tool, we’ll know it.”

VALUE-BASED CANCER CARE

February 2011

have to arrange for prior authorization, or will get paid without an appeals process. Communicating that message without restricting choice is “really important,” Dr Singh suggested. “We’re providing choice within the standard of care.” Future Directions Payer variables will not be hard coded into the programming, maintaining the flexibility to customize the program for different users. In addition, the CDS Oncology system will be

at a glance ➤ The Proventys system goes beyond an “ordinary” pathway by adding predictive care planning ➤ The first element to be addressed by decision support will be febrile neutropenia prophylaxis ➤ The system incorporates guidelines from the National Comprehensive Cancer Network and includes customizable payer-related links that may influence a decision if clinical factors are the same ➤ The CDS Oncology system will be customizable to integrate with various EMR programs

customizable to integrate with various EMR programs. Guidelines incorporated initially in the program will include breast, colon, non–small-cell lung cancer, and Hodgkin lymphoma; later in 2011, Proventys plans to add guidelines for non-Hodgkin lymphoma and smallcell lung, prostate, and rectal cancers. Based on feedback from physicians, the program has been designed with an order entry component that forestalls the use of a separate or a solely paper-based system, and supports electronic ordering for diagnostic tests and supportive medicines. The program allows automated chemotherapy dose calculations and ordering, which is then printed out and signed. Dr Singh indicated that of the 150 clinicians who have so far been involved in testing the product, only 1 had a negative reaction to it. “I expected that we would see a huge variety of responses on the predictive test side,” but that has not been the case.

“If somebody deviates from guidelines, and they’re using this tool, we’ll know it.” —Surya Singh, MD

There is a growing awareness of the utility of algorithms to support individualized patient care, and deciding to make this the initial topic for decision support was well chosen. The recent pilot program by UnitedHealthcare to bundle payments for treatment of select cancers may offer additional opportunities for clinical support systems such as this, Dr Singh suggested. With the current disconnect between the patient and physician on the one hand, and the third-party payer on the other, the idea of episodic bundled payments is “very closely related” to these systems. The economic beneficiary for these types of tools, Dr Singh said, is the payer, and organizations such as the Centers for Medicare & Medicaid Services will likely be very interested in them. Evolving reimbursement models will necessarily be driven by information technology to increase efficiency through decision support. ■

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VBCC PERSPECTIVE

What Do We Need in Decision-Support Tools to Guide Value-Based Care? By Arlene Forastiere, MD Dr Forastiere is Senior Vice President, Medical Affairs, ITA Partners, Philadelphia, PA, and an Editorial Board Member of Value-Based Cancer Care

ncology pathways and decision-support tools are being developed to address gaps in care that affect quality and to enable the realignment of payer and provider incentives. Concerns surrounding care variability, the high cost of emerging therapies (radiation technology as well as molecularly targeted therapeutics) and diagnostics, and the rapid pace of new knowledge that must be assimilated by the physician into his or her everyday practice are propelling the development of decision-support tools that aim to move beyond treatment algorithms. The fundamental dilemma we face is how to control costs without restricting the provider’s ability to prescribe evidence-based treatment that fits a specific clinical situation. In addition, how is the provider to receive appropriate reimbursement? Are pathways that narrow the physician’s prescribing options the answer or is a broader, more comprehensive solution needed? More often than not, a patient may be treated with a number of possible regimens that vary widely in cost but have a narrow differential range in efficacy. The challenge is to develop models that appropriately weight and integrate cost, efficacy, and toxicity (both acute and late) to present a coherent approach for comparing various options, thereby improving value. Models such as this will empower physicians at the point of care, allowing them to prescribe value-based oncology treatments, without being unduly limited in their treatment options. Aligning reimbursement with such a value-based system should be welcomed by payers and by providers. To accomplish this goal, web-based tools usable by the physician and the payer at the point of prescribing are

Society of Clinical Oncology, and the National Comprehensive Cancer Network. These types of electronic tools can also serve as platforms for continuous learning.

The fundamental dilemma we face is how to control costs without restricting the provider’s ability to prescribe evidence-based treatment that fits a specific clinical situation. needed. Retrospective claims review is inefficient, costly to the entire healthcare system, and cannot improve patient outcomes or quality. Because multiple modalities are utilized in the course of nearly every patient’s care, decision tools must be holistic—they must include surgery and radiation therapy in addition to systemic therapies and associated supportive care drugs—and they must comprehensively cover all cancers, not just the most common types. The basis of the content must be transparent and supported by evidence from high-quality clinical trials, along with specified endorsements by national guideline sources, such as the US Food and Drug Administration (FDA), the National Cancer Institute/Physician Data Query, American

Decision Support in Radiation Therapy: A New Frontier Radiation therapy is another highcost treatment modality that aims to improve local control and lower the risk of late complications. However, technologies such as intensity-modulated radiation therapy, daily imageguided radiation therapy, proton beam therapy, and stereotactic radiosurgery have all been rapidly adopted within the radiation oncology community, without the rigor of prospective comparative trials in the majority of clinical settings in which they are used. This may stem in part from the process used by the FDA to evaluate new devices. Under the 510(k) premarket evaluation program, technologies that demonstrate a “substantial equivalence” to a currently marketed existing technology are approved without undergoing a traditional clinical trial.

Decision-support tools offer the opportunity to reduce the overuse of high-cost technology while ensuring that the correct treatment is prescribed and reimbursed for the right clinical situation.

Web-based tools usable by the physician and the payer at the point of prescribing are needed.

Finally, to offer patients access to new, innovative therapies and reduce the use of ineffective therapies, decision tools should incorporate clinical trial options side by side with conventional, evidence-based regimens. As our healthcare system and the practice of oncology change over the next few years, we need to be prepared to comprehensively address the full continuum of care that includes initial treatment, continuing care, and survivorship. ■

When attending the AVBCC First Annual Stakeholder Integration Conference... Be sure to attend the breakfast symposium on Wednesday, March 30, 7:30-8:30 AM. Halaven™ (eribulin mesylate) Injection:

An organization you’ll want to be part of.

A meeting you’ll want to attend. The First Annual Stakeholder Integration Conference March 29-30, 2011 • Philadelphia, PA Turn to page 26 for the full agenda, and make your plans to attend this meeting.

VOL. 2

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A New FDA-Approved Treatment Presented by Stephen C. Malamud, MD, Beth Israel Medical Center Funded by Eisai, Inc. www.ValueBasedCancerCare.com

In advanced RCC:

Afinitor doubled median PFS after progression on sunitinib*1 Progression-free survival (PFS) after progression on sunitinib or sorafenib1 100

Hazard Ratio=0.33 95% CI [0.25, 0.43] Kaplan-Meier medians Afinitor: (n=277) 4.9 months (95% CI, 4.0-5.5) Placebo: (n=139) 1.9 months (95% CI, 1.8-1.9) Log rank P value=<0.0001

Probability (%)

1.9

4.9

months

Placebo 40

Afinitor 20

Time (months)

4.9 months median PFS with Afinitor + BSCâ&#x20AC; (vs 1.9 months with placebo + BSC; P<0.0001)1 HR 0.33=67% reduction in risk of progression Effective for patients with all prognostic scores1 For more information about Afinitor, call 1-888-4Afinitor (1-888-423-4648) or visit www.AFINITOR.com For reimbursement questions, call 1-888-5AfiniTRAC (1-888-523-4648). *In the RECORD-1 trial, Afinitor extended PFS after progression on sunitinib or sorafenib.1,2 â&#x20AC; BSC=best supportive care.

Important Safety Information There have been reports of non-infectious pneumonitis and infections, some with fatal outcomes. Oral ulceration has been reported. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Please see Important Safety Information on right side of page. Please see Brief Summary of full Prescribing Information on the following pages.

Afinitor is indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Important Safety Information Afinitor is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. Non-infectious pneumonitis is a class effect of rapamycin derivatives, including Afinitor. Fatal outcomes have been observed. If symptoms are moderate or severe, patients should be managed with dose interruption until symptoms improve or discontinuation, respectively. Corticosteroids may be indicated. Afinitor may be reintroduced at 5 mg daily depending on the individual clinical circumstances. Afinitor has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoan infections, including infections with opportunistic pathogens. Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, and viral infections including reactivation of hepatitis B virus have occurred. Some of these infections have been severe (e.g. leading to respiratory or hepatic failure) or fatal. Complete treatment of pre-existing invasive fungal infections prior to starting treatment. While taking Afinitor be vigilant for signs and symptoms of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Afinitor. If a diagnosis of invasive systemic fungal infection is made, discontinue Afinitor and treat with appropriate antifungal therapy. Oral ulcerations (i.e. mouth ulcers, stomatitis, and oral mucositis) have occurred in patients treated with Afinitor. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes,

neutrophils, and platelets have been reported in clinical trials. Renal function, hematological parameters, blood glucose, and lipids should be evaluated prior to treatment and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on Afinitor. Avoid concomitant use with strong CYP3A4 or PgP inhibitors. If co-administration with moderate CYP3A4 or PgP inhibitors is required, use caution and reduce dose of Afinitor to 2.5 mg daily. Increase the Afinitor dose if co-administered with a strong CYP3A4 inducer. Afinitor should not be used in patients with severe hepatic impairment. Afinitor dose should be reduced to 5 mg daily for patients with moderate hepatic impairment. The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with Afinitor. Fetal harm can occur if Afinitor is administered to a pregnant woman. The most common adverse reactions (incidence ≥30%) were stomatitis (44%), infections (37%), asthenia (33%), fatigue (31%), cough (30%), and diarrhea (30%). The most common grade 3/4 adverse reactions (incidence ≥3%) were infections (9%), dyspnea (8%), fatigue (5%), stomatitis (4%), dehydration (4%), pneumonitis (4%), abdominal pain (3%), and asthenia (3%). The most common laboratory abnormalities (incidence ≥50%) were anemia (92%), hypercholesterolemia (77%), hypertriglyceridemia (73%), hyperglycemia (57%), lymphopenia (51%), and increased creatinine (50%). The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (18%), hyperglycemia (16%), anemia (13%), hypophosphatemia (6%), and hypercholesterolemia (4%). Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the Afinitor arm.

References: 1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2010. 2. Motzer RJ, Escudier B, Oudard S, et al; for the RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449-456. 2.5mg 5 mg 10mg

Printed in U.S.A.

10/10

AFI-1002330

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009 BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. 4 CONTRAINDICATIONS Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS 5.1 Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. In the randomized study, non-infectious pneumonitis was reported in 14% of patients treated with AFINITOR. The incidence of Common Toxicity Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was 4% and 0%, respectively [see Adverse Reactions (6.1)]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at 5 mg daily. For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy and the use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with AFINITOR may be re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances. 5.2 Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoan infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)]. Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy.

while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: • Non-infectious pneumonitis [see Warnings and Precautions (5.1)]. • Infections [see Warnings and Precautions (5.2)]. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451) for patients receiving AFINITOR and 60 days (range 21-295) for those receiving placebo. The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common grade 3/4 adverse reactions (incidence ≥3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure (0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis. Table 1 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency. Table 1 Adverse Reactions Reported in at least 10% of Patients and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm AFINITOR 10 mg/day N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

Grade 3 %

Grade 4 %

Any Adverse Reaction

5.3 Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR. In the randomized study, approximately 44% of AFINITOR-treated patients developed mouth ulcers, stomatitis, or oral mucositis, which were mostly CTC grade 1 and 2 [see Adverse Reactions (6.1)]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions (7.1)].

Gastrointestinal Disorders Stomatitisa Diarrhea Nausea Vomiting

44 30 26 20

4 1 1 2

<1 0 0 0

8 7 19 12

0 0 0 0

Infections and Infestationsb

5.4 Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine, usually mild, have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter.

General Disorders and Administration Site Conditions Asthenia 33 3 Fatigue 31 5 Edema peripheral 25 <1 Pyrexia 20 <1 Mucosal inflammation 19 1

<1 0 0 0 0

23 27 8 9 1

4 3 <1 0 0

0 <1 0 0 0

Respiratory, Thoracic and Mediastinal Disorders Cough 30 <1 Dyspnea 24 6 Epistaxis 18 0 c Pneumonitis 14 4

0 1 0 0

16 15 0 0

0 3 0 0

0 0 0 0

Skin and Subcutaneous Tissue Disorders Rash 29 Pruritus 14 Dry skin 13

1 <1 <1

0 0 0

7 7 5

0 0 0

<1 0

9 2

<1 0

0 0

Musculoskeletal and Connective Tissue Disorders Pain in extremity 10 1

Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematological Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. 5.5 Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or P-glycoprotein (PgP) should be avoided. Grapefruit, grapefruit juice and other foods that are known to affect cytochrome P450 and PgP activity should also be avoided during treatment [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.1)]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 inhibitor (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) or PgP inhibitor [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.1)]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer (e.g., St. John’s Wort (Hypericum perforatum), dexamethasone, prednisone, prednisolone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.2)]. 5.6 Hepatic Impairment The safety and pharmacokinetics of AFINITOR were evaluated in a study in eight patients with moderate hepatic impairment (Child-Pugh class B) and eight subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore a dose reduction is recommended. AFINITOR has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population [see Dosage and Administration (2.2) in the full prescribing information and Use in Specific Populations (8.7)]. 5.7 Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. 5.8 Use in Pregnancy Pregnancy Category D There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception

Metabolism and Nutrition Disorders Anorexia 25 Nervous System Disorders Headache Dysgeusia

19 10

Median Duration of Treatment (d)

141

CTCAE Version 3.0 a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. b Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis (3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%). c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of <10% include: Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing (<1%) Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%) Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (<1%) Psychiatric disorders: Insomnia (9%) Nervous system disorders: Dizziness (7%), paresthesia (5%) Eye disorders: Eyelid edema (4%), conjunctivitis (2%)

Vascular disorders: Hypertension (4%)

In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft) and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities occurred at approximately 4% the exposure (AUC0-24h) in patients receiving the recommended dose of 10 mg daily. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose approximately 1.6 times the recommended human dose on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

Renal and urinary disorders: Renal failure (3%) Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%) Musculoskeletal and connective tissue disorders: Jaw pain (3%) Hematologic disorders: Hemorrhage (3%) Key treatment-emergent laboratory abnormalities are presented in Table 2. Table 2 Key Laboratory Abnormalities Reported at a Higher Rate in the AFINITOR Arm than the Placebo Arm Laboratory Parameter

AFINITOR 10 mg/day N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

92 51 23 14

12 16 1 0

1 2 0 <1

79 28 2 4

5 5 0 0

<1 0 <1 0

77 73 57 50 37

4 <1 15 1 6

0 0 <1 0 0

35 34 25 34 8

0 0 1 0 0

0 0 0 0 0

21 3

1 <1

0 <1

4 2

0 0

Hematologya Hemoglobin decreased Lymphocytes decreased Platelets decreased Neutrophils decreased Clinical Chemistry Cholesterol increased Triglycerides increased Glucose increased Creatinine increased Phosphate decreased Aspartate transaminase (AST) increased Alanine transaminase (ALT) increased Bilirubin increased

Grade 3 %

Grade 4 %

CTCAE Version 3.0 a Includes reports of anemia, leukopenia, lymphopenia, neutropenia, pancytopenia, thrombocytopenia. Information from further clinical trials In clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcomes. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At approximately 10% of the recommended human dose based on body surface area, there were no adverse effects on delivery and lactation and there were no signs of maternal toxicity. However, there was reduced body weight (up to 9% reduction from the control) and slight reduction in survival in offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Doses that resulted in embryo-fetal toxicities in rats and rabbits were ≥0.1 mg/kg (0.6 mg/m2) and 0.8 mg/kg (9.6 mg/m2), respectively. The dose in the pre- and post-natal development study in rats that caused reduction in body weights and survival of offspring was 0.1 mg/kg (0.6 mg/m2). 8.3 Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use In the randomized study, 41% of AFINITOR-treated patients were ≥65 years in age, while 7% percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment is required in elderly patients [see Clinical Pharmacology (12.3) in the full prescribing information]. 8.6 Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

7.1 Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with:

8.7 Hepatic Impairment For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mg daily [see Dosage and Administration (2.2) in the full prescribing information, Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) in the full prescribing information].

• ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively.

The impact of severe hepatic impairment (Child-Pugh class C) has not been assessed and use in this patient population is not recommended [see Warnings and Precautions (5.6)].

• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 and PgP should not be used [see Warnings and Precautions (5.5)]. Use caution when AFINITOR is used in combination with moderate CYP3A4 or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose. [See Dosage and Administration (2.2) in the full prescribing information] 7.2 Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers: In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong inducers of CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) or PgP if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2) in the full prescribing information].

10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. 16 STORAGE Store AFINITOR (everolimus) tablets at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.] Store in the original container, protect from light and moisture. Keep this and all drugs out of the reach of children. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. AFINITOR tablets should not be crushed. Do not take tablets which are crushed or broken.

7.3 Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.8)] There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment.

Revised: June 2010 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

T2010-56

VBCC PERSPECTIVE

Perspectives on Avastin from VBCC Editorial Board Members Lynn Nishida, RPh Director, Pharmacy Services RegenceRx

ven before the FDA’s determination, Regence was one of the few health plans that did not recognize coverage of Avastin for breast cancer (ie, HER2-negative breast cancer in patients who have had no prior chemotherapy). Our rationale for this decision developed during our evaluation of Avastin—simply put, we did not think the science was reliable enough to show that the benefit of the drug outweighed the risk. The lack of proven clinical benefit combined with the fact that other therapy alternatives were available for breast cancer informed our decision to not provide coverage. In light of this stance, the impact of the FDA’s change did not necessarily surprise us, and because our policy already addressed this, it will have minimal impact on how we handle requests for Avastin. However, for health plans that did cover Plans need to be Avastin, I can see where this may be careful in deciding if challenging whether FDA indications are to continue to cover really enough to patients receiving treatment. My guess determine value. is they will find a happy medium in allowing patients to continue for those “showing a response,” but not provide coverage for those newly starting on the drug. For me, the take-home message is that plans need to be careful in deciding if FDA indications are really enough to determine value and aid in making coverage decisions.

Winston Wong, PharmD Associate Vice President, Pharmacy Management CareFirst BlueCross BlueShield, Baltimore

Weighing In on the Avastin... uncertainty as to whether insurers will cover the drug. A statement released by the NCCN on January 24, 2011, addressed the questions about the evidence base used by payers to make coverage decisions for this indication. Summarizing reports from various sources, the statement emphasized the credibility of the NCCN guidelines and the transparency of the evaluation process, and quoted the chair of the NCCN Guidelines Panel for Breast Cancer, Robert W. Carlson, MD, of Stanford Comprehensive Cancer Center, as saying Avastin had been discussed 3 times in the past several months, but that the panel had seen no new evidence that would cause a shift in their recommendations. The 28-member Breast Cancer Panel

t is my understanding that the original approval of Avastin use in metastatic breast cancer was based on the results of the combination of Avastin/Taxol, which showed a 5-month progression-free survival advantage for the combination versus Taxol (paclitaxel) alone. The studies failed to show any benefit for combinations other than Taxol, namely, Taxotere and Xeloda. Interestingly, there was no benefit to overall survival in either study. At this point, there are 2 direcThe question then tions we can follow: (1) the benefit is needs to be asked, specific to the with so many agents Avastin/Taxol comrecently approved bination, and there based on progression- should be continued free survival benefits support for this combination, as has only, will those been determined in Europe; or (2) we approvals be should accept the rescinded as well? fact that there was no overall benefit to survival, hence the use of Avastin overall should be discouraged, which appears to be the path the FDA has taken. The question then needs to be asked, with so many agents recently approved based on progression-free survival benefits only, will those approvals be rescinded as well?

Coverage Decisions Private payers, including UnitedHealthcare, Aetna, Humana, and WellPoint, have indicated that they’re

February 2011

n terms of survival in the setting of metastatic disease for refractory (or at least incurable) disease, what I come back to is the lack of definition for whether a drug is working or providing benefit. It is difficult to demonstrate a survival advantage for much of what is done for metastatic solid tumors. Does that mean treatment is of no benNo amount of efit? What if someone regulatory activity is gets substantial, real going to substitute for palliation (eg, improved symptom conthose conversations. trol and quality of life with little toxicity) with little or no improvement in survival? Frankly, to me that seems of greater benefit than short-term prolongation of survival with substantial toxicity, or even short-term prolongation of survival with little toxicity but no improvement in quality of life. The cost-value relationship is difficult to boil down to a simple number. There are also 2 levels of decision-making here. One is a regulatory decision, deciding whether to approve a drug for use in a certain disease based on the published evidence. (And then, of course, there is the clinician’s decision of whether to use the drug off-label.) The other, critical level is at the provider/patient/family nexus—that is, the point of shared decision-making, where there needs to be an important discussion about values/goals/risks/benefits (and the likelihood of upsides vs downsides). No amount of regulatory activity is going to substitute for those conversations.

Continued from cover

“evaluated the data, and this is probably the most authoritative decision out there, based on the data, their experience, and their clinically informed evaluation,” emphasized Bill McGivney, PhD, Chief Executive Officer of the NCCN. Dr McGivney indicated that his group has not heard questions from physicians about the discrepancy. “Any time one of our panels evaluates an issue, we just put the decision up online,” he said, acknowledging that there “is not a real mechanism for physicians to get back to us, and we haven’t gone out and asked them.”

VALUE-BASED CANCER CARE

Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting

going to cover the breast cancer indication based on the NCCN compendium, he pointed out. Defending FDA’s Decision Allan Korn, MD, the Chief Medical Officer and Senior Vice President for Clinical Affairs for the Blue Cross and Blue Shield Association, Chicago, IL, took a contrary view. “Avastin highlights a critical issue in cancer treatment. Increasingly, agents are approved by the FDA based on progression-free survival data, assuming that improved survival will follow,” he told Value-Based Cancer Care. “This is not always the case, often due to drug toxicities or unknown tumor pathways. Nor is progressionfree survival a reliable surrogate for quality of life, certainly not when toxi-

city is worse. The FDA made a difficult but correct choice in withdrawing approval for Avastin in breast cancer. We owe patients evidence-based treatments that improve survival and quality of life. Otherwise, we offer only false hope,” Dr Korn said. A spokesperson for the American Society of Clinical Oncology said that the organization generally does not comment on FDA decisions. As of early January 2011, neither the Center for Evidence-based Policy nor the Drug Effectiveness Review Project had reviewed this issue, according to Alison Little, MD, MPH, Medical Director of the Drug Effectiveness Review Project at the Center for Evidence-Based Policy, Oregon Health and Sciences University, Portland. ■

VOL. 2

NO. 1

ASTRO ANNUAL MEETING

Presidential Address Calls for Practitioners to Look Beyond the Pocketbook, Prove their Value By Jennifer Erickstad San Diego, CA—Many radiation oncology practitioners have become obsessed with technology and face potential perils in a new cost-conscious era of medicine, according to Anthony L. Zietman, MD. “For the last decade, practicing radiation oncology has been like driving a Ferrari at 140 mph down the freeway—there has been forward progress indeed, which is very fast and very thrilling, but very risky,” Dr Zietman said during his presidential address at the American Society for Radiation Oncology (ASTRO) meeting.

“For the last decade, practicing radiation oncology has been like driving a Ferrari at 140 mph down the freeway—there has been forward progress indeed, which is very fast and very thrilling, but very risky.”

still conduct randomized controlled trials for significant technical innova-

tions to justify their use. In addition, ASTRO will cautiously advocate new

technologic codes and will develop credible practice guidelines. ■

NOW

AVAILABLE

—Anthony L. Zietman, MD Beginning by examining physicians’ sense of “professionalism,” Dr Zietman highlighted passages from both the Hippocratic Oath and the 2002 Physicians’ Charter. For the most part, we practice medicine according to this charter, and it’s our conscience that guides the way,” leading physicians to put the patient’s welfare “above all else” and to avoid “superfluous tests and procedures.” However, “life strews our paths with temptation,” he said, leading some physicians to elevate financial incentives over patient benefit. Citing the example of prostate cancer treatment, Dr Zietman noted that far too many low-risk elderly men have received radiation therapy when active surveillance would have sufficed. In addition to overtreatment, reimbursement issues have caused some radiation oncologists to abdicate clinical care in favor of providing a technological service, narrowing their scope of practice and essentially making them “image-guided deliverers of a physical therapy,” Dr Zietman said. To survive in a new era of healthcare, he said that radiation oncologists must provide “conscience-based medicine,” where evidence dictates treatment decisions. The specialty should

VOL. 2

NO. 1

www.halaven.com

www.ValueBasedCancerCare.com

ASTRO ANNUAL MEETING

A Transatlantic Look at Value Considerations in Care Delivery By Jennifer Erickstad San Diego, CA—Discussing the British government’s attempts to provide low-cost, high-quality care to its citizens, Sir Michael Rawlins, MD, the Chairman of the National Health Service (NHS)’s National Institute for Health and Clinical Excellence (NICE), discussed how the twin considerations of clinical effectiveness and cost-effectiveness guide the process and provided insights into the cost and quality evaluations conducted on drugs, devices, surgical procedures, and diagnostic methods in the United Kingdom. How NICE Works NICE functions in many different ways, Sir Rawlins explained at the American Society for Radiation Oncology (ASTRO) meeting, including promoting public health, developing quality standards, and enabling Internet-based research for practitioners. Its primary concerns, however, are conducting appraisals on the safety, efficacy, and cost of new treatments and drafting guidelines for appropriate care. When undertaking clinical evaluations, NICE looks at randomized controlled trials (RCTs), observational studies, and systematic reviews, Sir Rawlins noted. In addition, the agency conducts comparative effectiveness research (CER) to determine if a new treatment is sufficiently better than an existing one. Calling CER “quite tricky,” Sir Rawlins stated that although direct comparisons are ideal, their expense

and unavailability often cause NICE to use indirect comparisons or mixed treatment comparisons. He hopes that the focus currently placed on CER by the US government will “make strides” in improving its methodology. Although he noted that NICE’s clinical evaluations are robust, Sir

focuses on whether the intervention provides value based on the opinion of NHS and the patient. The third principle—and what Sir Rawlins called the “most critical”—includes “walking a tightrope between utilitarianism and egalitarianism in distributing our resources.” Specifically, the agency strives to

“We have the problem that if you introduce one new treatment, something else has got to give. We do not have enough money to do everything we want.” —Sir Michael Rawlins, MD Rawlins admitted “the real challenge” in the agency’s responsibilities is balancing its budget. “We have the problem that if you introduce one new treatment, something else has got to give,” he said, adding “we do not have enough money to do everything we want.” The agency, as part of the NHS, is funded by income tax and receives a finite budget each year from Parliament. According to Sir Rawlins, this has led to cost-effectiveness being required by law alongside clinical effectiveness as part of NICE’s evaluations. Economic Evaluation Three overarching principles influence the agency’s economic evaluation, Sir Rawlins explained. The economic perspective looks at the costs of the healthcare service, whereas an examination of cost-effectiveness

provide a just distribution of resources that lays somewhere in between providing the “greatest good to the greatest number” and “providing every-

at a glance ➤ Evaluations by NICE attempt to balance clinical and costeffectiveness ➤ This balancing act is required due to the United Kingdom’s fixed healthcare budget that provides a finite amount of resources ➤ The agency is responsible for conducting comparative effectiveness research to determine the merit of newer treatments relative to older ones

thing for everybody.” To examine how a new treatment compares to an existing one, the agency conducts a cost-utility analysis and determines the incremental costeffectiveness ratio. However, even after calculating this, the question still remains of what the cost-effectiveness threshold should be, Sir Rawlins noted. After examining the analyses of other governments and taking advice from the World Health Organization, NICE determined that any treatment that costs less than $30,000 per qualityadjusted life-year (QALY) would likely be regarded as cost-effective, whereas any treatment valued at above $45,000 per QALY would likely be regarded as cost-ineffective. Sir Rawlins noted, however, that in some circumstances, advisory bodies do suggest treatments above the threshold, adding that the panels are encouraged “to make a judgment,” not follow a mathematical formula. Summarizing the success that NICE has experienced while using its clinical and cost evaluations, Sir Rawlins stated that the agency “has managed to get respect from parliamentarians, health professionals, most patient organizations, and the public.” In addition, he noted that although Sarah Palin described him as the “chairman of the death panel,” NICE has garnered significant international respect, with countries such as China, Columbia, Jordan, and Turkey seeking its assistance in improving their own health systems. ■

The Benefits of Early Adjuvant Radiation after Radical Prostatectomy San Diego, CA—Performing early adjuvant radiation therapy (RT) on patients with prostate cancer plus adverse pathologic features after radical prostatectomy results in an incremental cost of $25,441 per success across 10 years, according to Timothy N. Showalter, MD, who presented an abstract at the meeting. Dr Showalter explained that although prospective, randomized trials support the use of adjuvant RT in this patient population, it is not universally delivered, largely because of concerns about toxicity, overtreatment, and cost. The research team developed a decision-analytic model to estimate the real-world cost of providing RT compared with not providing RT,

within the context of the treatment’s effectiveness. The model was populated with patient data from the Southwest Oncology Group prospective trial of adjuvant RT (SWOG 8794), including the probabilities of treatment success, salvage RT, androgen deprivation therapy (ADT), and adverse events. Treatment success was defined as the absence of prostate-specific antigen (PSA) failure (PSA <0.2 ng/mL). Cost inputs—including adjuvant RT, ADT, salvage RT, and the management of adverse events—were based on the 2010 Medicare reimbursement rates. The SWOG data showed that the use of early RT resulted in a higher

VALUE-BASED CANCER CARE

February 2011

PSA success rate than without RT, at 58 versus 28 successes per 100 treated

“We demonstrated that adjuvant radiation is a relatively cost-effective intervention.” —Timothy N. Showalter, MD

men. The decision model calculated the mean incremental cost per patient

to be $5917 with the addition of adjuvant RT, and the incremental cost per success with RT to be $2554 per patient per year. The study adds to the debate surrounding the utility of early adjuvant RT, and Dr Showalter highlighted that the model can also be used to determine potential cost reductions or increases with such treatments as hypofractionation or intensity-modulated RT, respectively. Although he acknowledged there is no published willingness-to-pay threshold available in the unit of cost per PSA success, Dr Showalter added, “I think we demonstrated that adjuvant radiation is a relatively cost-effective intervention.”—JE ■

VOL. 2

NO. 1

For your patients receiving or about to start treatment with DOXIL® for recurrent ovarian cancer or relapsed/refractory multiple myeloma…

DOXIL® C.A.R.E.S. Provides Help and Support DOXIL® C.A.R.E.S. Complements the Efforts of the Healthcare Team With: ◗ Treatment follow-up — Regularly scheduled telephone calls from oncology nurses to review lifestyle tips to help manage potential side effects of DOXIL® therapy such as hand-foot syndrome and stomatitis ◗ Patient education materials Invite your patients to enroll in DOXIL® C.A.R.E.S.: 1-877-CARES-49 (1-877-227-3749) Monday to Friday, 9:30 AM to 10:00 PM (ET). To learn more, visit www.doxil.com.

INDICATIONS

◗ DOXIL® is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy ◗ DOXIL® in combination with VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma who have not previously received VELCADE and have received at least one prior therapy

IMPORTANT SAFETY INFORMATION BOXED WARNINGS Cardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution ◗ The use of DOXIL® may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2 — Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose — Cardiac toxicity may also occur at lower cumulative doses (400 mg/m2) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy ◗ Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL®. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate — Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have occurred. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use — The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions ◗ Severe myelosuppression may occur ◗ DOXIL® dosage should be reduced in patients with impaired hepatic function ◗ Accidental substitution has resulted in severe side effects. Do not substitute for doxorubicin HCl on a mg per mg basis CONTRAINDICATIONS ◗ Patients with a history of hypersensitivity reactions to a conventional doxorubicin formulation or the components of DOXIL® ◗ Nursing mothers

ADDITIONAL SAFETY INFORMATION ◗ Cardiac function should be carefully monitored

— Congestive heart failure or cardiomyopathy may occur after discontinuation of anthracycline therapy — For patients with a history of cardiovascular disease, or if the results of cardiac monitoring indicate possible cardiac injury, the benefit of therapy must be weighed against the risk of myocardial injury — In the randomized multiple myeloma study, 25 patients (8%) in the VELCADE arm and 42 patients (13%) in the DOXIL® plus VELCADE arm experienced left ventricular ejection fraction decrease (defined as absolute decrease 15% over baseline or a 5% decrease below institutional lower limit of normal)

◗ Myelosuppression may occur; frequently monitor complete blood count (including platelet count), at least prior to each dose of DOXIL® — In patients with recurrent ovarian cancer, hematologic toxicity (based on platelet count or absolute neutrophil count) may require dose reduction or delay in administration of DOXIL® — In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL® and/or VELCADE — Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage — Sepsis occurring during neutropenia has resulted in discontinuation of treatment and in rare cases of death ◗ DOXIL® may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow ◗ Hand-foot syndrome (HFS) may occur during therapy with DOXIL® — Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL® may be required — HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier • The reaction was mild in most patients, resolving in 1 to 2 weeks • The reaction can be severe and debilitating in some patients, resulting in discontinuation of therapy ◗ DOXIL® is an irritant, not a vesicant; use precautions to avoid extravasation ◗ DOXIL® can cause fetal harm when used during pregnancy ◗ Recall reaction has occurred with DOXIL® administration after radiotherapy ◗ DOXIL® may interact with drugs known to interact with the conventional formulation of doxorubicin HCl ◗ In patients with recurrent ovarian cancer, the most common all-grade adverse reactions (ARs) 20% (DOXIL® vs topotecan, respectively) included: asthenia (40% vs 51%), fever (21% vs 31%), nausea (46% vs 63%), stomatitis (41% vs 15%), vomiting (33% vs 44%), diarrhea (21% vs 35%), anorexia (20% vs 22%), dyspnea (15% vs 23%), HFS (51% vs 1%), and rash (29% vs 12%) — In addition, 19% vs 52.3% reported alopecia (all grades) — Grade 3/4 hematologic ARs reported in 5% (DOXIL® vs topotecan, respectively) were neutropenia (12% vs 76%) and anemia (6% vs 29%) ◗ In patients with multiple myeloma, the most common all-grade ARs 20% (DOXIL® plus VELCADE vs VELCADE, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%), pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/ stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%) — In addition, 19% vs <1% reported HFS Please see brief summary of Prescribing Information, including Boxed WARNINGS, on adjacent pages. VELCADE is a registered trademark of Millennium Pharmaceuticals, Inc.

Distributed by: Centocor Ortho Biotech Products, L.P., Horsham, Pennsylvania 19044-3607 © Centocor Ortho Biotech Products, L.P. 2010 9/10 08D10019A

DOXIL®

reaction at the recommended dose of 20 mg/m2 [see Adverse Reactions]. Leukopenia is the most common adverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsis occurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably related to DOXIL. Eleven patients (1.6%) discontinued study because of bone marrow suppression or neutropenia. Table 10 presents data on myelosuppression in patients with multiple myeloma receiving DOXIL and bortezomib in combination [see Adverse Reactions].

(doxorubicin HCl liposome injection) for intravenous infusion BRIEF SUMMARY. Please see Full Prescribing Information. WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTAL SUBSTITUTION 1. The use of DOXIL (doxorubicin HCl liposome injection) may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at a starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2 or between 500550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dosage. Cardiac toxicity may also occur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy [see Warnings and Precautions]. 2. Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes lifethreatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. DOXIL should be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [see Warnings and Precautions]. 3. Severe myelosuppression may occur [see Warnings and Precautions]. 4. Dosage should be reduced in patients with impaired hepatic function [see Full Prescribing Information]. 5. Accidental substitution of DOXIL for doxorubicin HCl has resulted in severe side effects. DOXIL should not be substituted for doxorubicin HCl on a mg per mg basis [see Full Prescribing Information]. INDICATIONS AND USAGE: Ovarian Cancer: DOXIL (doxorubicin HCl liposome injection) is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy. AIDS-Related Kaposi’s Sarcoma: DOXIL is indicated for the treatment of AIDS-related Kaposi’s sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy. Multiple Myeloma: DOXIL in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy. CONTRAINDICATIONS: DOXIL (doxorubicin HCl liposome injection) is contraindicated in patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of DOXIL [see Warnings and Precautions]. DOXIL is contraindicated in nursing mothers [see Full Prescribing Information]. WARNINGS AND PRECAUTIONS: Cardiac Toxicity: Special attention must be given to the risk of myocardial damage from cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin, particularly in patients who have received a total cumulative dosage of doxorubicin exceeding the currently recommended limit of 550 mg/m2. Lower (400 mg/m2) doses appear to cause heart failure in patients who have received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide. Prior use of other anthracyclines or anthracenodiones should be included in calculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered after discontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should be administered DOXIL only when the potential benefit of treatment outweighs the risk. Cardiac function should be carefully monitored in patients treated with DOXIL. The most definitive test for anthracycline myocardial injury is endomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have been used to monitor cardiac function during anthracycline therapy. Any of these methods should be employed to monitor potential cardiac toxicity in patients treated with DOXIL. If these test results indicate possible cardiac injury associated with DOXIL therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2, or between 500–550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. In this study, cardiotoxicity was defined as a decrease of >20% from baseline if the resting left ventricular ejection fraction (LVEF) remained in the normal range, or a decrease of >10% if the resting LVEF became abnormal (less than the institutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity and congestive heart failure (CHF) are in the table below. Table 1: Number of Patients With Advanced Breast Cancer Patients who Developed Cardiotoxicity (LVEF Defined) Cardiotoxicity (With Signs & Symptoms of CHF) Cardiotoxicity (no Signs & Symptoms of CHF) Patients With Signs and Symptoms of CHF Only

DOXIL (n=250) 10 0 10 2

In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiac failure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema and pulmonary edema) was similar in the DOXIL+bortezomib group and the bortezomib monotherapy group, 3% in each group. LVEF decrease was defined as an absolute decrease of 15% over baseline or a 5% decrease below the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and 42 patients in the DOXIL+bortezomib arm (13%) experienced a reduction in LVEF. Infusion Reactions: Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL in the randomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treated with DOXIL (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDSrelated Kaposi’s sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL therapy because of infusion-related reactions. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. The majority of infusion-related events occurred during the first infusion. Similar reactions have not been reported with conventional doxorubicin and they presumably represent a reaction to the DOXIL liposomes or one of its surface components. The initial rate of infusion should be 1 mg/min to help minimize the risk of infusion reactions [see Full Prescribing Information]. Myelosuppression: Because of the potential for bone marrow suppression, careful hematologic monitoring is required during use of DOXIL, including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With the recommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reduction or delay or suspension of DOXIL therapy. Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted in discontinuation of treatment and, in rare cases, death. DOXIL may potentiate the toxicity of other anticancer therapies. In particular, hematologic toxicity may be more severe when DOXIL is administered in combination with other agents that cause bone marrow suppression. In patients with relapsed ovarian cancer, myelosuppression was generally moderate and reversible. In the three single-arm studies, anemia was the most common hematologic adverse reaction (52.6%), followed by leukopenia (WBC <4,000 mm3; 42.2%), thrombocytopenia (24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most common hematologic adverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm3; 36.8%), neutropenia (ANC <1,000; 35.1%), and thrombocytopenia (13.0%) [see Adverse Reactions]. In patients with relapsed ovarian cancer, 4.6% received G-CSF (or GM-CSF) to support their blood counts [see Full Prescribing Information]. For patients with AIDS-related Kaposi’s sarcoma who often present with baseline myelosuppression due to such factors as their HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse

Hand-Foot Syndrome (HFS): In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL at 50 mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of the patients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skin toxicity. HFS toxicity grades are described in Dosage and Administration section [see Full Prescribing Information]. Among 705 patients with AIDS-related Kaposi’s sarcoma treated with DOXIL at 20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing. In the randomized multiple myeloma study, 19% of patients treated with DOXIL at 30 mg/m2 every three weeks experienced HFS. HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manage HFS [see Full Prescribing Information]. The reaction can be severe and debilitating in some patients and may require discontinuation of treatment. Radiation Recall Reaction: Recall reaction has occurred with DOXIL administration after radiotherapy. Fetal Mortality: Pregnancy Category D: DOXIL can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If DOXIL is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs in the first few months following treatment with DOXIL, the prolonged half-life of the drug must be considered. Women of childbearing potential should be advised to avoid pregnancy during treatment with Doxil. [see Full Prescribing Information]. Toxicity Potentiation: The doxorubicin in DOXIL may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-induced toxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration of doxorubicin HCl. Monitoring: Laboratory Tests: Complete blood counts, including platelet counts, should be obtained frequently and at a minimum prior to each dose of DOXIL [see Warnings and Precautions]. ADVERSE REACTIONS: Overall Adverse Reactions Profile: The following adverse reactions are discussed in more detail in other sections of the labeling. • Cardiac Toxicity [see Warnings and Precautions] • Infusion reactions [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hand-Foot syndrome [see Warnings and Precautions] The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. The most common serious adverse reactions observed with DOXIL are described in Section Adverse Reactions in Clinical Trials. The safety data described below reflect exposure to DOXIL in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma and 318 patients with multiple myeloma. Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The following tables present adverse reactions from clinical trials of DOXIL in ovarian cancer, AIDS-Related Kaposi’s sarcoma, and multiple myeloma. Patients With Ovarian Cancer: The safety data described below are from 239 patients with ovarian cancer treated with DOXIL (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in a randomized, multicenter, open-label study. In this study, patients received DOXIL for a median number of 98.0 days (range 1-785 days). The population studied was 27-87 years of age, 91% Caucasian, 6% Black and 3% Hispanic and other. Table 2 presents the hematologic adverse reactions from the randomized study of DOXIL compared to topotecan. Table 2: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian Cancer DOXIL Topotecan Patients Patients (n = 239) (n = 235) Neutropenia 19 (7.9%) 33 (14.0%) 500 - <1000/mm3 10 (4.2%) 146 (62.1%) <500/mm3 Anemia 6.5 - <8 g/dL 13 (5.4%) 59 (25.1%) <6.5 g/dL 1 (0.4%) 10 (4.3%) Thrombocytopenia 3 3 (1.3%) 40 (17.0%) 10,000 - <50,000/mm <10,000/mm3 0 (0.0%) 40 (17.0%) Table 3 presents a comparative profile of the non-hematologic adverse reactions from the randomized study of DOXIL compared to topotecan. Table 3: Ovarian Cancer Randomized Study Non-Hematologic Adverse Reaction 10% or Greater

Body as a Whole Asthenia Fever Mucous Membrane Disorder Back Pain Infection Headache Digestive Nausea Stomatitis Vomiting Diarrhea Anorexia Dyspepsia Nervous Dizziness Respiratory Pharyngitis Dyspnea Cough increased Skin and Appendages Hand-foot syndrome Rash Alopecia

DOXIL (%) treated (n = 239) All Grades grades 3-4

Topotecan (%) treated (n =235) All Grades grades 3-4

40.2 21.3 14.2

7.1 0.8 3.8

51.5 30.6 3.4

8.1 5.5 0

11.7 11.7 10.5

1.7 2.1 0.8

10.2 6.4 14.9

0.9 0.9 0

46.0 41.4 32.6 20.9 20.1 12.1

5.4 8.3 7.9 2.5 2.5 0.8

63.0 15.3 43.8 34.9 21.7 14.0

8.1 0.4 9.8 4.2 1.3 0

4.2

10.2

15.9 15.1 9.6

0 4.1 0

17.9 23.4 11.5

0.4 4.3 0

50.6 28.5 19.2

23.8 4.2 N/A

0.9 12.3 52.3

0 0.4 N/A

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks. Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis. Patients With AIDS-Related Kaposi’s Sarcoma: The safety data below is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m 2 and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2. Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients’ median CD4 count was 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm3. Patients received a variety of potentially myelotoxic drugs in combination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim) sometime during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi’s sarcoma. Those that did so included bone marrow suppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons. Table 4: Hematology Data Reported in Patients With AIDS-Related Kaposi’s Sarcoma Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 74) Neutropenia <1000/mm3 <500/mm3 Anemia <10 g/dL <8 g/dL Thrombocytopenia <150,000/mm3 <25,000/mm3

Total Patients With AIDS-Related Kaposi’s Sarcoma (n = 720)

34 8

(45.9%) (10.8%)

352 96

(48.9%) (13.3%)

43 12

(58.1%) (16.2%)

399 131

(55.4%) (18.2%)

45 1

(60.8%) (1.4%)

439 30

(60.9%) (4.2%)

Table 5: Probably and Possibly Drug-Related Non-Hematologic Adverse Reactions Reported in With AIDS-Related Kaposi’s Sarcoma Adverse Reactions

Nausea Asthenia Fever Alopecia Alkaline Phosphatase Increase Vomiting Diarrhea Stomatitis Oral Moniliasis

Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 77) 14 5 6 7 1 6 4 4 1

(18.2%) (6.5%) (7.8%) (9.1%) (1.3%) (7.8%) (5.2%) (5.2%) (1.3%)

Infections and infestations Herpes zoster Herpes simplex Investigations Weight decreased Metabolism and Nutritional disorders Anorexia Nervous system disorders Peripheral Neuropathy* Neuralgia Paresthesia/dysesthesia Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Rash** Hand-foot syndrome

11 10

2 0

0 0

9 6

2 1

0 0

42 17 13

7 3 <1

<1 0 0

45 20 10

10 4 0

1 1 0

22 19

1 6

0 0

18 <1

1 0

0 0

*Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. **Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized. Post Marketing Experience: The following additional adverse reactions have been identified during post approval use of DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, StevensJohnson syndrome and toxic epidermal necrolysis have been reported. DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interact with drugs known to interact with the conventional formulation of doxorubicin HCl. USE IN SPECIFIC POPULATIONS: Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients have not been established.

5% of Patients

Total Patients With AIDS-Related Kaposi’s Sarcoma (n = 705) 119 70 64 63 55 55 55 48 39

Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. (continued) Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4

(16.9%) (9.9%) (9.1%) (8.9%) (7.8%) (7.8%) (7.8%) (6.8%) (5.5%)

The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi’s sarcoma. Incidence 1% to 5%: Body as a Whole: headache, back pain, infection, allergic reaction, chills. Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouth ulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia. Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1%: Body As A Whole: sepsis, moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic and Nutritional Disorders: dehydration. Respiratory: cough increase, pharyngitis. Skin and Appendages: maculopapular rash, herpes zoster. Special Senses: taste perversion, conjunctivitis. Patients With Multiple Myeloma: The safety data below are from 318 patients treated with DOXIL (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combination group were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 6 lists adverse reactions reported in 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma. Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4 Blood and lymphatic system disorders Neutropenia 36 22 10 22 11 5 Thrombocytopenia 33 11 13 28 9 8 Anemia 25 7 2 21 8 2 General disorders and administration site conditions Fatigue 36 6 1 28 3 0 Pyrexia 31 1 0 22 1 0 Asthenia 22 6 0 18 4 0 Gastrointestinal disorders Nausea 48 3 0 40 1 0 Diarrhea 46 7 0 39 5 0 Vomiting 32 4 0 22 1 0 Constipation 31 1 0 31 1 0 Mucositis/Stomatitis 20 2 0 5 <1 0 Abdominal pain 11 1 0 8 1 0

Geriatric Use: Of the patients treated with DOXIL in the randomized ovarian cancer study, 34.7% (n=83) were 65 years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. OVERDOSAGE: Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis. 0016716-5B Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Distributed by: Ortho Biotech Products, LP Raritan, NJ 08869-0670

An ALZA STEALTH® Technology Product

STEALTH® and DOXIL® are registered trademarks of ALZA Corporation.

ASTRO ANNUAL MEETING

How CMS and the FDA May Respond to the Evidence Gap By Jennifer Erickstad San Diego, CA—Citing a “significant level of concern about how clinical trials are conducted in this country,” Steve Phurrough, MD, MPA, chief operating officer and senior clinical director at the Center for Medical Technology Policy, discussed the Centers for Medicare & Medicaid Services (CMS) and the US Food and Drug Administration (FDA), speculat-

Phurrough, former director of coverage and analysis at CMS. To show conference attendees how the field of radiation oncology can better develop this sufficient evidence, Dr Phurrough discussed at the annual meeting of the American Society for Radiation Oncology (ASTRO) what the FDA and CMS will be looking for in their technology assessments.

If Medicare were to conduct NCDs around radiation therapy, “a significant number of therapies would not have sufficient evidence to meet their reasonable and necessary standard.” —Steve Phurrough, MD, MPA ing on how these agencies may change their policies to help “rectify some of the evidence gaps” in trials of new technologies. Approximately 18,000 randomized controlled trials are performed each year, with thousands of other types of studies adding to the literature, yet “new technologies are rapidly spreading without sufficient data,” said Dr

Sufficient Evidence Is Necessary Dr Phurrough explained that the FDA is currently undergoing 510(k) reform, which will bring about a higher level of evidence required for device approvals. Specifically, greater evidence will likely be needed to prove a device is the substantial equivalent of an already marketed product, with special attention paid

to demonstrating parallel outcomes. Similarly, Dr Phurrough estimated that greater weight will also be placed on outcomes in the premarket approval process, noting that the FDA is “quite interested in seeing if technologies will change outcomes, not just [asking] ‘does it do what it is supposed to do?’” CMS and CER CMS will likely focus on using the coverage process to improve quality, Dr Phurrough suggested. The agency’s current standard is to cover anything that is “reasonable and necessary,” yet these terms have never been formally defined, leaving individual national coverage determinations (NCDs) to provide clarification. As a result of this ambiguity, Dr Phurrough wagered that if Medicare were to conduct NCDs around radiation therapy, “a significant number of therapies would not have sufficient evidence to meet their reasonable and necessary standard.” To use the coverage process to influence care quality, Dr Phurrough

believes CMS will likely continue to use “coverage with evidence development”—which provides treatment coverage only to those in a trial or other kind of research program—and may, despite significant industry concern, also use “conditional coverage,” in which a device is quickly brought to market and reimbursed but can be removed if subsequent data collection does not provide confirmatory benefit. Dr Phurrough also examined the question of whether CMS will require comparative effectiveness research (CER) for its coverage decisions. He thinks that CMS is unlikely to use CER in a type of “winners and losers” fashion, where the better-performing treatment would be covered and the lesser-performing intervention would not. “Most CMS coverage decisions are based on evidence that something does or does not work, not that it works better or worse than something else,” he explained. Dr Phurrough believes CER “should certainly be used as a payment tool, and if A is better than B, then A gets some incentives or B gets some disincentives.” ■

The Role of Evidence in Technology Approval and Coverage Decisions San Diego, CA—The “real problem” leading to escalating healthcare costs is the “rapidly uncontrolled manner of the introduction of new treatments before their effectiveness, cost, and comparative value are satisfactorily evaluated,” said Michael L. Steinberg, MD, professor and chair, UCLA Department of Radiation Oncology, at the Presidential Symposium at the ASTRO annual meeting. Dr Steinberg noted that 40% to 60% of healthcare cost increases can be attributed to the introduction of new technology, and that oncology has “become a target” for cost-cutting, because the specialty’s inflationadjusted direct medical spending has exceeded inflation for care provided by other specialties by 50% year after year across the past 2 decades. Dr Steinberg detailed how evidence influences the entry of new technologies into the market and how technology assessment leads to coverage. As he explained the “convoluted

pathway of incorporating new treatments” into the US healthcare system, Dr Steinberg emphasized that although the US Food and Drug Administration (FDA) tests drugs for safety and effectiveness (which “invariably means a clinical trial”), devices—such as those used to deliver radiation therapy—can enter the market by either a premarket approval or the 510(k) process. The device must only prove it is the potential equivalent to a so-called predicate device that entered the market before the regulation was enacted in 1976, and that it delivers the treatment in a safe manner, without further proof of efficacy. Dr Steinberg said that radiation oncologists have already seen this type of escalation occur with the coding process. He explained that the Current Procedural Terminology (CPT) panel previously required 5 articles from US journals to award a code. Now, however, they have specified

VALUE-BASED CANCER CARE

February 2011

that at least 1 article must be level III evidence, and that the applicant must submit any articles with opposing views. In addition, the CPT panel also requires that the applicant provide a much more detailed summary of the evidence.

Oncology has “become a target” for cost-cutting because the specialty’s inflation-adjusted direct medical spending has exceeded inflation across the past 2 decades. —Michael L. Steinberg, MD

According to Dr Steinberg, the panel’s requirements were significantly higher than when a code was assigned for intensity-modulated radi-

ation therapy back in 2000. The panel wanted “outcome data that showed the intervention yielded a meaningful outcome, not simply a technical enhancement,” he said. Even as he advocated for evidencebased medicine (EBM) as part of the coverage process, Dr Steinberg noted that using it as the sole method of coverage determination “also has its problems.” Payers have used EBM to “control spending and protect their profits,” and at the same time been insensitive to the real barriers of clinical trials, he said. Despite these potential pitfalls, Dr Steinberg concluded that policies should be established to make sure new technology is quickly available, while still embracing the use of evidence-based assessment to ensure solvency of the system, finding a balance between what he calls the “evidencebased medicine Taliban” and the “professors of anecdotal evidence.”—JE ■

VOL. 2

NO. 1

ONE QUESTION FOR

IS RIGHT

EVERY PATIENT. IS THERE A HISTORY OF BREAST OR OVARIAN CANCER? As a health care professional, you have the power to identify women at risk for hereditary breast and ovarian cancer (HBOC) by asking every one of your patients this simple question. BRACAnalysis®—a test that identiﬁes the BRCA mutations that cause most cases of HBOC—can help you identify patients in need of special attention and take steps to reduce their cancer risk. While you are empowering your patients and their families with valuable information, you are also able to individualize medical management for better patient care.

JUST ASK IF SHE HAS A PERSONAL AND/OR FAMILY HISTORY OF:* Breast cancer before age 50 Ovarian cancer at any age Two primary breast cancers in an individual at any age Both breast and ovarian cancer in an individual at any age Male breast cancer at any age Two or more breast cancers in a family, one under age 50 Women of Ashkenazi Jewish descent with breast or ovarian cancer at any age A previously identified BRCA mutation in the family *Assessment criteria based on medical society guidelines. For these individual medical society guidelines go to www.myriadpro.com/guidelines For reference and supporting data on risk factors and medical management visit www.myriadpro.com/references

TO LEARN MORE OR TO ORDER BRACAnalysis MATERIALS FOR YOUR PRACTICE, PLEASE CONTACT YOUR MYRIAD REPRESENTATIVE AT 800-469-7423. Myriad Genetic Laboratories, Inc. 320 Wakara Way Salt Lake City, UT 84108 Myriad, the Myriad logo, BRACAnalysis, and the Just Ask logo are either trademarks or registered trademarks of Myriad Genetics, Inc. in the United States and other jurisdictions. ©2010 Myriad Genetic Laboratories, Inc.

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VBCC PERSPECTIVE

What the Essential Health Benefits Provision Means for You By Jayson Slotnik, JD, MPH, and Ross D. Margulies Mr Slotnik is an Attorney and Mr Margulies is a Health Policy Specialist, both at Foley Hoag, LLP, in Washington, DC

he Patient Protection and Affordable Care Act (ACA) not only bars discrimination in enrollment or the availability of coverage based on health status, it also establishes a minimum standard of coverage that must be satisfied by individual and small group health plans sold in exchange and nonexchange markets, as well as by any qualified health plan sold in the state exchange market, regardless of group size. This minimum standard of coverage is known as an “essential benefit” package, and its requirements take effect beginning in 2014.1 Although the terms “essential health benefits package” and “qualified health plan” are described in detail in the ACA, the term “essential health benefits” is left largely to the discretion of the Secretary of the Department of Health and Human Services (DHHS) to determine its specific meaning, within the statutory parameters, through regulation. The essential benefit statute sets forth a series of broad benefit classes that the secretary’s definition must include (eg, ambulatory patient services, maternity and newborn care, and prescription drugs) and also sets forth important rules for developing essential benefit standards.

Implementation Process The “essential health benefits” provision will be implemented by DHHS in several steps prior to 2014. One step is the employer-sponsored coverage survey that the Department of Labor (DOL) must conduct to determine the benefits typically covered by employers, including multiemployer plans. As of January 2011, the Bureau of Labor Statistics has identified the existing National Compensation Survey (NCS) to fulfill the ACA requirement that DOL conduct a survey of employer-based health plans to advise DHHS on a “typical” employer plan. NCS is voluntary and some employers may choose not to participate. DHHS requested the Institute of Medicine (IOM) to conduct a study that will help to inform the determination of “essential health benefits.” On November 8, 2010, the IOM launched a Consensus Study on Essential Health Benefits, with an accompanying public comment period.2 The comment period closed on December 6, 2010, and the committee received 300 responses from the public. The IOM Committee on Essential

Jayson Slotnik

The essential health benefit standards reflect value-based purchasing principles in their emphasis on prevention without cost-sharing, chronic disease management, and coverage. Health Benefits held its first public meeting January 13-14, 2011. (For a full list of committee members visit www. iom.edu/Activities/HealthServices/ Essential HealthBenefits.aspx.) Individuals from DHHS’ Office of Assistant Secretary for Planning and Evaluation, the DOL, the Centers for Medicare & Medicaid Services and other experts and stakeholders discussed the statutory requirements of the ACA, as well as the implementation process. Stakeholders, including the National Coalition for Cancer Survivorship, advocated for a broad interpretation of the 10 categories of essential benefits in the ACA and sought further clarification on coverage requirements. Relevance for Payers, Providers, and Other Oncology Stakeholders The essential health benefit standards reflect value-based purchasing principles in their emphasis on prevention without cost-sharing, chronic disease management, and coverage (with cost-sharing assistance for lower-income individuals and sharing) for a broad array of treatment and health promotion activities that better enable appropriate management of serious illness. Because the ACA does not name the specific services that must be covered or the amount, duration, and scope of covered services, and merely sets forth coverage categories (of most relevance for the oncology community are “chronic disease management” and “prescription drugs”), payers, providers, and other oncology stakeholders

VALUE-BASED CANCER CARE

February 2011

are closely monitoring the regulatory development process. At the recent IOM meeting, Thomas P. Sellers, MPA, of the National Coalition for Cancer Survivorship, urged the committee, for purposes of defining essential health benefits, to define cancer as a chronic disease and to include cancer care planning and care coordination services in the list of essential health benefits. In addition, Mr Sellers noted the urgent need for access to and coverage of off-label uses of cancer drugs. As the regulatory process continues, the oncology community has an important role to play while the DHHS secretary works to define the specifics of the essential health benefits package. Although the ACA enumerates certain considerations that must be taken into account, the secretary retains wide authority in making determinations on covered benefits and services. Payers, providers, and other oncolo-

Payers, providers, and other oncology stakeholders must seek out opportunities to weigh in to make sure important benefits are included in this major new development in the insurance market. gy stakeholders must seek out opportunities to weigh in to make sure important benefits are included in this major new development in the insurance market. ■ References 1. ACA § 1301(a)(1)(B). Internal Revenue Code § 36B(b)(2)(A), added by ACA § 1401(a). 2. Institute of Medicine. Determination of Essential Health Benefits. www.iom.edu/Activities/Health Services/EssentialHealthBenefits.aspx. Accessed January 31, 2011.

HEALTH POLICY

House Votes to Repeal Healthcare Reform Legislation—What Next? By Crystal Kuntz, MPA Ms Kuntz is Director, Government Policy, at Astellas Pharma US, and an Editorial Board Member of Value-Based Cancer Care

n January 19, 2011, House Republicans voted 245-189 to pass a bill that would overturn the comprehensive healthcare reform legislation. The vote was seen by many as symbolic, as Republicans face significant roadblocks in their effort to fully repeal last year’s healthcare overhaul. Democrats in the Senate have said they will not allow a similar bill to move forward in the upper chamber. And, even if such a bill were able to get through the more closely divided Senate, President Obama would certainly veto it. The Republican vote, however, does mark the beginning of a lengthy debate on healthcare that will likely continue between Republicans and Democrats throughout 2011. The next salvo in that debate was fired on January 31, 2011, when US District Judge Roger Vinson of Florida ruled that the healthcare reform law was unconstitutional because of its

mandate that Americans have health insurance beginning in 2014. However, the ruling has no immediate effect pending resolution on appeal and likely will have to be decided by the Supreme Court—a process that will take at least a year or more.

One tactic would be to try to “defund” specific provisions in the healthcare legislation. However, such a strategy is not assured of success. Absent the ability to fully repeal the legislation, Republicans will start focusing on strategies aimed at dismantling the legislation “piece by piece.” One tactic would be to try to “defund” specific provisions in the Continued on page 48

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HEALTH POLICY

Articulating a Better Way for Patients with Advanced Cancer By Colin Gittens

hen a patient has advanced, incurable cancer, physician– patient discussions should be individualized and reflect both disease-directed and supportive care options so that quality of care is improved, according to a new policy statement issued by the American Society of Clinical Oncology (ASCO) and published online on January 24, 2011, in the Journal of Clinical Oncology. Such discussions should be initiated by physicians and should be candid, presenting the full range of palliative care and treatment options. These discussions presently happen late in the course of illness or not at all, and the recommendation is that such discussions begin soon after an initial diagnosis of advanced cancer. The recommendation emerges almost 2 years after a component of the healthcare reform bill—which would have allowed Medicare reimbursement to physicians to discuss living wills and other end-of-life measures—became infamously known as “death panels,”

so there still may be some risk in raising the issue. But “patients have a right to make informed choices about their care. Oncologists must lead the way in discussing the full range of curative and palliative therapies to ensure that patients’ choices are honored,” said ASCO President George W. Sledge, Jr, MD, who is Ballve-Lantero Professor of Oncology and Professor of Pathology and Laboratory Medicine at the Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, and Chairman of the Breast Cancer Committee, Hoosier Oncology Group. Although “improving survival is the oncologist’s primary goal, helping individuals live their final days in comfort and dignity is one of the most important responsibilities of our profession,” said Dr Sledge. Key recommendations in the proposal include emphasizing quality of life and a greater advocacy for clinical trials. Physicians must help patients to fully understand their prognosis and

“Patients have a right to make informed choices about their care. Oncologists must lead the way in discussing the full range of curative and palliative therapies.” —George W. Sledge, Jr, MD

House Votes to Repeal Healthcare... healthcare legislation. However, such a strategy is not assured of success. Spending for healthcare reform is intricately linked to spending for hundreds of other programs that are contained within the large appropriations bills Congress must pass each year to fund the government, making potential cuts even more controversial. Republicans will aim to hold numerous congressional hearings on the Democrats’ healthcare legislation, with the goal of demonstrating that the Democrats’ approach is too costly and ineffective. Republicans will also push “smaller” government solutions to address the problems of the uninsured. For example, Republicans would like to bring down costs by allowing families and businesses to buy health insurance across state lines or by giving individuals, small businesses, and associations the ability to form insurance pools. Another Republican priority is legislation aimed at addressing the costs of malpractice insurance and what they believe are frivolous lawsuits. In his State of the Union address on January 25, the president signaled his willingness to work with Republicans on certain improvements to the comprehensive legislation. Somewhat of a surprise was the president’s interest in medical malpractice reform, an issue

traditionally advanced by Republicans but almost universally opposed by Democrats. He also expressed support for a less controversial fix to a provision in the law that imposed a tax paperwork burden on businesses.

Continued from page 46

It is too early to tell whether Republicans or Democrats will be more successful in making their case to the American public on healthcare reform and potential next steps. Further complicating the matter is

A recent survey from the Kaiser Family Foundation found that 26% of the public favored full repeal, 25% favored repealing some parts of the law and keeping other parts, 21% favored keeping the law as it is, and 20% favored expanding the law. —Crystal Kuntz, MPA At the same time, the president set forth a strong defense of his health overhaul and stated that efforts should focus on improving—not dismantling—the legislation from 2010. He cited examples of how the insurance market reforms are already benefiting individuals, such as requirements that prevent denials of coverage based on preexisting conditions and require coverage of children and young adults under the age of 26 as well as a new program to provide cost-sharing assistance to enrollees in Medicare Part D.

VALUE-BASED CANCER CARE

February 2011

the sharp division between the American public on the issue. A recent survey from the Kaiser Family Foundation found that 26% of the public favored full repeal, 25% favored repealing some parts of the law and keeping other parts, 21% favored keeping the law as it is, and 20% favored expanding the law (www.kff.org/ pullingittogether/repeal.cfm). It is also unclear how much of an appetite the American public will continue to have for healthcare issues as the economy continues to struggle. ■

the risks and benefits of treatment, as well as help to reduce the barriers that have kept more patients from participating in trials that may improve cancer care. Other important recommendations for individualizing care include providing insurance reimbursement for advanced care planning discussions and expanding pilot programs by private insurers that will maximize palliative care without requiring patients to abandon cancer-focused treatment. In addition to this statement, ASCO has also released a patient guide intended to help those with advanced cancer to broach difficult conversations about prognosis, treatment, and palliative care options. Later this year, ASCO will issue similar conversational guidance to physicians. The statement is a “clarion call for oncologists as individual practitioners, and for our profession in general, to take the lead in curtailing the use of ineffective therapy and ensuring a focus on palliative care and relief of symptoms throughout the course of illness,” the authors write. ASCO Pushes on Political Fronts A letter advocating a $750 million increase in funding for the National Institutes of Health (NIH) in fiscal year 2011 was signed by more than 270 medical research stakeholders known as the Ad Hoc Group for Medical Research, including ASCO, and sent to all members of Congress on January 24, 2011. The letter emphasized that support for the NIH is essential in fostering its roles in basic research, scientific progress, and general economic development. In a second effort, oncology drug shortage legislation that draws on recommendations from the November 2010 Drug Shortages Summit, which was convened by ASCO, the American Society of Anesthesiologists, the American Society of Health-System Pharmacists, and the Institute for Safe Medication Practices, was introduced on February 7, 2011. Among the provisions of the bill introduced by Sens. Amy Klobuchar (D-Minn) and Robert Casey (D-Pa) are expanding US Food and Drug Administration authority to require manufacturer notification of shortages and market withdrawals, and enhancing communication among healthcare providers and stakeholders in the pharmaceutical supply chain about the nature and duration of shortages. ■

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ASHP CLINICAL MEETING

Hospital Implements New Oral Chemotherapy Handling Process in Effort to Increase Safety By Wayne Kuznar Anaheim, CA—A new process for handling oral chemotherapy medications that delineates prescriber privileges may help to avert errors or drug–drug interactions, said Brian L’Heureux, PharmD, at the American Society of Health-System Pharmacists meeting. On August 1, 2010, at Suburban Hospital in Bethesda, MD, a new procedure for processing oncology orders was implemented, said Dr L’Heureux, an oncology pharmacy resident. Under the new system, oncologyspecific medications have to be ordered by prescribers with delineated privileges using a specific chemotherapy order form. In explaining the need for the new process, he said that most outpatient oral chemotherapy medications were continued by admitting physicians who were unfamiliar with them. “Therefore, they were prescribing medications for which they didn’t necessarily know all of the ins and outs, and this was particularly true of oral chemotherapy,” he said. More important, oral chemotherapy medications were being improperly handled by nurses on patient care units who were not chemotherapy certified.

The new process did allow for some exceptions for ordering medications that can also be used outside of oncology, such as methotrexate and hydroxyurea, for nonchemotherapy indications. L’Heureux and colleagues conducted a medical-use evaluation for the immediate 2 months following implementation of the new process for handling oral chemotherapy medications.

write chemotherapy orders, the person transcribing the order to the chemotherapy order form, any major drug– drug interactions that required intervention, and whether certified chemotherapy nurses administered the medication. “A big part was whether chemotherapy nurses were actually administering the medication. Previously, on admission, if the prescribing doctor

“Previously, on admission, if the prescribing doctor didn’t write that it’s chemotherapy, and the drug is continued, the nurses would not necessarily know that the [continued] drug is a chemotherapy medication.” —Brian L’Heureux, PharmD

Daily reports were generated through the pharmacy computer system, searching for formulary and nonformulary oral chemotherapy. Concurrent chart reviews were performed on all patients receiving oral chemotherapy. The data collected included drug name, drug class, indication, the name of the prescriber and whether the prescriber had delineated privileges to

didn’t write that it’s chemotherapy, and the drug is continued, the nurses would not necessarily know that the [continued] drug is a chemotherapy medication,” he said. “When it was entered into our computer system, it came across as patients on medication, so there weren’t a lot of flags telling the nurses.” Twenty-six oral chemotherapy or-

ders were reviewed over the 2-month period. Seventy percent of the orders were written by physicians with delineated privileges and 23 orders were written on the appropriate form, of which 17 were transcribed by the pharmacist. The prescribing physicians were hospitalists 46% of the time, hematologists/oncologists 23% of the time, and intensivists 8% of the time. “With this information, we progressed to better delineated privileges to finalize who was allowed to prescribe which drugs,” said Dr L’Heureux. Eight drug–drug interactions were identified during chart review; of these, one was intervened upon at the time of the chemotherapy order. “In the Pyxus automated dispensing machines that we use, there are alerts for an oncology nurse to come down and give the medication, but we found that many times, nurses weren’t alerted to come down and administer it,” he said. During the 2 months of the oral chemotherapy review, only 70% of chemotherapy orders were administered by chemotherapy-certified nurses. ■

For Overweight Patients, Dosing Chemotherapy Based on Total Body Weight Does Not Lead to More Toxicities Anaheim, CA—Overweight as well as obese chemotherapy recipients who are dosed according to total body weight do not experience more adverse drug events or cycle delays than normal weight recipients. The finding, which comes from a 10year retrospective analysis of patients with gastrointestinal (GI) cancers, should allay concerns about overdosing and the potential for increased toxicities when calculating the chemotherapy dose using total body weight, said lead investigator Tiffany Dea, PharmD. Dea and colleagues sought to determine how chemotherapy is dosed in practice in normal weight, overweight, and obese patients as well as that dose’s impact on adverse drug events. They assessed 42 patients with GI cancers identified through a tumor registry who were treated at the San Francisco Veterans Affairs Medical Center.

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The chemotherapy drugs used in treatment were bevacizumab, capecitabine, cetuximab, cisplatin, epirubicin, fluorouracil, irinotecan, leucovorin, mitomycin, and oxaliplatin. Of the 42 patients included, 13 were normal weight (body mass index [BMI], 18.5-24.9 kg/m2), 22 were overweight (BMI, 25-29.9 kg/m2), and 7 were obese (BMI, >30 kg/m2). “Most of our oncology fellows are dosing on total body weight for overweight patients,” said Dr Dea, an oncology pharmacist. “There is some literature out there that says that you shouldn’t cap the body surface area, but there’s no rationale for that. A lot of oncologists still prefer to dose based on adjusted or capped body surface area.” All 13 of the normal weight patients were dosed using total body weight. Of the 29 overweight or obese patients, 21 were dosed using total body weight—1 using adjusted body

weight, 5 using capped body surface area, and 2 using both total body weight and capped body surface area. “We didn’t find that overweight or obese patients had more side effects than normal-weight patients,” said Dr Dea.

“More normal-weight patients were in stage IV disease; in the overweight/ obese category, there were more in stage III disease.” —Tiffany Dea, PharmD Grade 1 or 2 toxicities were experienced by 100% of the normal-weight patients and 79.3% (16) of the overweight/obese patients. Of the overweight or obese patients experiencing toxicities, 76% were dosed according

to total body weight compared with 100% dosed using adjusted body weight and 60% dosed using capped body surface area. “In looking at the cancer stage, more normal-weight patients were in stage IV disease; in the overweight/obese category, there were more in stage III disease,” she said. “Whether or not that may have been a factor in the rate of side effects isn’t known.” Some 54% of normal-weight patients had stage IV disease, 50% of overweight patients had stage III disease, and 43% of obese patients had stage II disease. Thirty-one percent of normal-weight patients had decreases in their dosage between cycle 1 and 2 compared with 14% of overweight/obese patients. Second cycle delays were also more frequent in the normal-weight patients versus the overweight/obese patients (31% vs 28%, respectively).—WK ■

www.ValueBasedCancerCare.com

ASHP CLINICAL MEETING

Cost-Effectiveness Comparison: FOLFIRI versus FOLFOX By Wayne Kuznar Anaheim, CA—As first-line treatment of metastatic colorectal cancer, a regimen of leucovorin, 5-fluorouracil, and irinotecan (FOLFIRI) is more costeffective than a regimen of leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX), investigators at Northeastern University School of Pharmacy, Boston, have suggested. They presented their data at the clinical meeting of the American Society of Health-System Pharmacists. The slight survival advantage offered by the FOLFOX regimen is out-

weighed by a more than $500,000 increase in total costs, the researchers believe. However, in a 1-way sensitivity analysis, when the cost of the FOLFOX regimen exceeds $2621.60, FOLFIRI is the more cost-effective treatment regimen. Both FOLFOX and FOLFIRI are first-line chemotherapy regimens for metastatic colorectal cancer; “however, each regimen causes a broad array of adverse reactions that influences costs to third-party payers,” according to the investigators.

Preventing Emesis Can Save Money Differentiating the uses of 5-HT3 antagonists Anaheim, CA—Assessing palonosetron use for the prevention of emesis associated with chemotherapy has the potential to differentiate appropriate and inappropriate use and can lead to cost-savings, said John P. Jezak, PharmD, a pharmacy practice resident at Dartmouth-Hitchcock Medical Center, Lebanon, NH, at the American Society of Health-System Pharmacists.

Potential interchange of palonosetron with another 5-HT3 antagonist would be appropriate if the chemotherapy regimen carried either high or moderate risk for emesis, there was no prior failure with ondansetron, and no risk of delayed-onset emesis. Palonosetron, like the other 5-HT3 antagonists, is indicated for the prevention of emesis with high- and moderate-risk emetic regimens. It has been shown to be superior to other 5-HT3 antagonists for the prevention of delayed emesis only, probably owing to its long half-life (approximately 40 hours), notes Dr Jezak. 5-HT3 antagonists were recommended by the National Comprehensive Cancer Network (NCCN) for use in high- and moderate-emetic risk chemotherapy, but “the NCCN guidelines don’t really differentiate if there’s a preferential antiemetic drug for a

specific clinical situation,” he said. Palonosetron has a 50-fold greater average wholesale price (AWP) than ondansetron, so curbing inappropriate use could result in substantial savings, he said. Dr Jezak conducted a retrospective evaluation of 129 patients (involving 269 encounters) who received palonosetron at the Dartmouth-Hitchcock infusion center over a 2-month period in 2010. Each patient’s chemotherapy regimen was evaluated on the level of acute and delayed emesis potential. Any patient who had delayed-onset risk of emesis, based on the 4 regimens listed in the NCCN criteria, was automatically deemed appropriate for palonosetron use. “The other qualifier we used is failure of another 5-HT3, such as ondansetron. It would also be appropriate to use palonosetron in this type of patient,” Dr Jezak stated. Potential interchange of palonosetron with another 5-HT3 antagonist would be appropriate if the chemotherapy regimen carried either high or moderate risk for emesis, there was no prior failure with ondansetron, and no risk of delayed-onset emesis. Pharmacist intervention identified 47 cases of inappropriate palonosetron use and 17 cases for a potential 5-HT3 interchange. Preventing inappropriate use had the potential to result in a cost-savings of $8792 during the 2-month study period, assuming that the actual drug acquisition cost was 65.93% below AWP. The ease of the intervention—a simple phone call—argues for its use, Dr Jezak said.—WK ■

VALUE-BASED CANCER CARE

February 2011

They performed a modeled costeffectiveness analysis of the 2 chemotherapy regimens, administered every 2 weeks for 10 cycles.

The slight survival advantage offered by the FOLFOX regimen is outweighed by a more than $500,000 increase in total costs. However, when the cost of the FOLFOX regimen exceeds $2621.60, FOLFIRI is the more cost-effective treatment regimen. Average wholesale prices were used to calculate the cost of the treatment regimens and the cost associated with side effects. The costs of clinic visits and hospitalizations were derived from the Centers for Medicare & Medicaid

Services fee schedules. Randomized controlled trials and US Food and Drug Administration monographs were used to determine survival at 18 months and the probabilities of adverse drug reactions. Patients were assumed to have stage IV metastatic colorectal cancer. The cost analysis did not take into account dose reductions resulting from adverse drug reactions, the use of adjunct chemotherapy, or the costs of second-line chemotherapy regimens. The costs per 10-day cycle were $49,031 for FOLFOX compared with $36,922 for FOLFIRI. The probability of survival at 18 months was 52% with the FOLFOX regimen and 50% with the FOLFIRI regimen, yielding average cost-effectiveness ratios of $93,606 per patient surviving at 18 months with FOLFOX versus $71,502 with FOLFIRI. The incremental cost-effectiveness ratio was an additional $646,200 per patient surviving with FOLFOX treatment at 18 months versus FOLFIRI treatment. ■

Economic Analysis of ChemoInduced Nausea and Vomiting Anaheim, CA—Chemotherapy-induced nausea and vomiting (CINV) is associated with a large clinical and economic burden among patients with cancer in a hospital outpatient setting.

Preventing or controlling the onset of CINV in the index chemotherapy cycle could lead to fewer events in subsequent cycles. Preventing or controlling the onset of CINV in the index chemotherapy cycle could lead to fewer events in subsequent cycles, said Sanjeev Balu, PhD, Health Outcomes, Eisai, Woodcliff Lake, NJ, and lead investigator of a retrospective observational study. His data were presented at the clinical meeting of the American Society of Health-System Pharmacists. Data from a hospital-service database (Premier’s Perspective), which contains data from more than 600 hospitals across the United States, were analyzed to identify 11,495 patients

with cancer who were treated with chemotherapy; 8606 received antiemetic prophylaxis for the entire follow-up period (8 chemotherapy cycles or 6 months postindex date) and 2689 did not. All-cause treatment costs, which included costs for CINV treatments (inpatient, outpatient, and emergency department visits) totaled $138 million, for an average cost per day of $2881.90, said Dr Balu. Considering only CINV treatment– related pharmacy costs, the total was $89 million, with an average cost per day of $1854.70. There were 13,225 CINV events treated in the inpatient setting, with an associated total cost of $32 million (average cost per day, $2421.80). There were 15,306 CINV events treated in the emergency department setting, with an associated total cost of $30 million (average cost per day, $1987.20). There were 19,457 CINV events in the outpatient setting, with an associated total cost of $26 million (average cost per day, $1364.90). The presence of a CINV event during the index chemotherapy cycle predicted subsequent events.—WK ■

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NO. 1

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