October 2010, Vol 1, No 5 by Value-Based Cancer Care

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OCTOBER 2010 VOL 1 NO 5

www.ValueBasedCancer.com

Breast Cancer Screening Recommendations: Evidence, Fear, and Politics

Adding Comparative Effectiveness to Formulary Evidence WellPoint argues for real-world informational needs An interview with Brian Sweet, RPh, MBA

By Michael K. Gusmano, PhD, and Bradford H. Gray, PhD Dr Gusmano is Research Scholar, The Hastings Center, Garrison, NY, and Adjunct Assistant Professor, Department of Health Policy and Management, Columbia University; Dr Gray is Senior Fellow with the Urban Institute, Washington, DC.

n November 2009, the US Preventive Services Task Force (USPSTF) published new recommendations about routine breast cancer screening mammography.1 If followed, the new recommendations would substantially reduce the use of the procedure among women aged 40 to 49 years.2 The recommendations were touted by some leading health policy researchers as “rational”3 and “objective.”4 Yet, the positive evaluations were overwhelmed by an avalanche of negative reactions from professional associations, patient advocates, and elected officials from both political parties.5 Within a month, the Senate

agreed by voice vote to an amendment that effectively required the federal government to ignore the Task Force’s recommendations.6 Lessons Learned It is not unprecedented for new practice guidelines to generate powerful opposition. Professional and advocacy opposition, along with financial interests and ideological concerns about government “rationing,” may create barriers to the implementation of comparative effectiveness research (CER) and evidence-based medicine (EBM), Continued on page 12

Guiding Patients Through CostBased Treatment Choices Assistance with a topic not yet on medical school curriculum By Rosemary Frei, MSc

aving a conversation with patients about the cost benefit of their cancer treatments is difficult, and many clinicians are unprepared for this discussion. Fortunately, however, resources are becoming available to help clinicians aid patients in determining how much they are willing and able to pay for treatments that may cure them—or only buy a few extra weeks of life.

PAF Brochures for Providers and Patients At the annual meeting of the American Society of Clinical Oncology, representatives from the Yu-Ning Wong, MD, MSCE Patient Advocate Continued on page 22

n May 2010, the health benefits company WellPoint, Inc, announced a policy of using comparative effectiveness research (CER) as part of the firm’s formulary decision-making process. This is not surprising given the emphasis on CER after the dedication of $1.1 billion for these efforts in the American Recovery and Reinvestment Act of 2009, but for WellPoint Chief Pharmacy Officer Brian Sweet, RPh, MBA, this is both a natural development in the company’s evolution as well as a reflection of the times. We were curious to know how the CER formulary policy has played out so far for this early adopter, so we asked Continued on page 7

Accelerated Approval: Good Intentions, Difficult Implementation By Margot J. Fromer

US Food and Drug Administration (FDA) decision originally set for September 17, 2010, on using bevacizumab (Avastin) in breast cancer has been postponed until December 17, 2010. Although bevacizumab is the first antiangiogenic drug for treating cancer and is the bestselling cancer drug in the world, the FDA Oncologic Drugs Advisory Committee (ODAC) recommended that approval for this indication be revoked in an almost unanimous vote (12-1) at a July 20, 2010, meeting. Accelerated Approval This particular indication was granted in 2008 under the FDA’s accelerated approval (AA) program. Unlike traditional approval, AA is based on a sur-

rogate end point, an indirect or substitute marker representing a clinically meaningful outcome. Progression-free survival is often chosen as the primary end point for AA trials, because it measures a direct effect of treatment. Overall survival (OS), ordinarily the “gold standard” of clinical trials, is increasingly difficult to measure for first-line treatment, because treatments administered after a clinical trial has ended cannot be controlled. The FDA decides whether a particular surrogate end point is acceptable for a clinical trial and generally bases its decision on whether the end point is reasonably likely to predict a real clinical end point. AA is predicated on the condition that Continued on page 5

IN THIS ISSUE Recent highlights from the oncology literature............................................ 9 An interview with David Meltzer, MD, PhD, on the utility of health economics .............................................................. 11 Jason Slotnik considers premarket parallel review ................................... 17 Continuing education for pharmacists on non–small-cell lung cancer....... 24 ©2010 Engage Healthcare Communications, LLC

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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

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FDA UPDATES Glass Flakes Spur Recall of Some Epoetin Alfa The FDA and Amgen announced a recall of some lots of epoetin alfa (Epogen and Procrit) after extremely thin glass flakes (called lamellae) were found in some vials. The lamellae result from the drug interacting with the glass vials over the shelf life 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=633) (N=194) 3/2/163

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VOL. 1

NO. 5

of the product. The precautionary recall is intended to prevent potential serious adverse events including embolic, thrombotic, and other vascular events (eg, phlebitis) associated with intravenous delivery, and foreign body granuloma, local injection site reactions, and increased immunogenicity resulting from subcu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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@

taneous injection. In a â&#x20AC;&#x153;Dear Healthcare Professional Letter,â&#x20AC;? the manufacturer noted the potential for limited, short-term availability of 2000-, 3000-, 4000-, and 40,000-unit Procrit vials. Information on the affected lots can be found at www.fda.gov/Safety/ Recalls/ucm227202.htm. (September 24, 2010) Pediatric Use &/43BG /<2 34431B7D3<3AA 7< >/B73<BA 03:=E B63 /53 =4

G3/@A 6/D3 <=B 033< 3AB/0:7A632 Geriatric Use #=>C:/B7=< >6/@;/1=97<3B71A /</:GA7A 272 <=B @3D3/: /<G 27443@3<13A 7< >/:=<=A3B@=< >6/@;/1=97<3B71A 03BE33< 1/<13@ >/B73<BA â&#x2030;Ľ G3/@A =4 /53 /<2 G=C<53@ >/B73<BA B= G3/@A "4 B63

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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< (&

Pioglitazone/Bladder Cancer Link Sparks Safety Review The FDA has begun a safety review of the diabetes drug pioglitazone (Actos) after early results from an ongoing, long-term epidemiologic study indicated an increased risk of bladder cancer for patients with the longest exposure to pioglitazone and those with the highest cumulative dose of the drug. The 10-year observational study is being conducted by the manufacturer, Takeda Pharmaceuticals of North America, Inc, and these findings stem from 5-year data. The agency emphasizes that it has not concluded that the drug increases the risk of bladder cancer and that their review is ongoing. Healthcare professionals should continue to follow the prescribing recommendations in the drug label, and patients should continue to take the drug until otherwise advised by their physician. (September 17, 2010) FDA Lights into E-Cigarette Manufacturers The FDA has moved to regulate electronic cigarettes and at the same time issued warning letters to 5 electronic cigarette distributors for various violations of the Federal Food, Drug, and Cosmetic Act. In general, FDA approval is contingent on a manufacturer demonstrating that a product is safe and effective for intended use, and that manufacturing methods are adequate to preserve the strength, quality, and purity of its product. The FDA has not reviewed the evidence reporting the companiesâ&#x20AC;&#x2122; claims that their products help users quit smoking, but in a letter to the Electronic Cigarette Association, it stated that â&#x20AC;&#x153;the FDA invites electronic cigarette firms to work in cooperation with the agency toward the goal of assuring that electronic cigarettes sold in the United States are lawfully marketed.â&#x20AC;? Certain companies were also warned for including unapproved liquid forms of drugs in their inhalers. (September 9, 2010) Lymphadenopathy Added to Cervarix Adverse Reactions The FDA approved a request by GlaxoSmithKline Biologicals to supplement its Biologics License Application for human papillomavirus (HPV) bivalent (types 16 and 18) vaccine (Cervarix) to add lymphadenopathy to the Adverse Reactions, Postmarketing Experience Section of the prescribing information. Cervarix was approved in October 2009 for the prevention of cervical pre-cancers and cervical cancer associated with oncogenic HPV types 16 and 18 for use in girls and young women (aged 10-25 years). (September 2, 2010)

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TABLE OF CONTENTS Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895

October 2010 FDA Updates 3 Glass Flakes Spur Recall of Some Epoetin Alfa

Pioglitazone/Bladder Cancer Link Sparks Safety Review

Directors, Client Services John Hennessy john@greenhillhc.com 732-992-1886

FDA Lights into E-Cigarette Manufacturers

Phil Pawelko phil@greenhillhc.com 732-992-1887 Cristopher Pires cris@engage hc.com 732-992-1896 Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889

Lymphadenopathy Added to Cervarix Adverse Reactions Value Propositions 8 Stopping Hospice Care Boosts Healthcare Costs

Similar Thoughts on Cancer Costs in the United States and Canada

Managing Editor Colin Gittens colin@engagehc.com 732-992-1536

Hard Times Bring Medication Discontinuance Economic Downturn Threatens Cancer Prevention Gains

Senior Production Manager Robyn Jacobs 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.

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

Vol. 1

Cancer Quick Takes 9 Cancer Costs: What Do Patients, Physicians Think?

Higher Quality Care, But Later Diagnosis, for Uninsured Breast Cancer Patients Myelodysplastic Syndromes Common and Costly Health Economics 10 Real-World Decision Makers Decry Information Provided

11 Improving Health Economics Research

No. 5

Commentary 17 CMS-FDA Proposed Premarket Parallel Review—The Devil is in the Details

18 Who Decides on Healthcare Value? Colon Cancer 20 CRC Screening Economics: Diminishing Returns as Technology Advances?

As Economy Worsens, Financial Factors May Hinder CRC Screening VBCC Perspective 22 Resource Allocation for Colorectal Cancer Screening/Naimish Pandya, MD Continuing Education 24 Maintenance Therapy for Non–Small-Cell Lung Cancer: A Value-Based Approach to Improve Patient Care and Outcomes, Part I

In this issue...

“CER will be an addition to the information available and could leave consumers better off—in some instances, it could lead to lower prices.” —David Meltzer, MD, PhD, from “Improving Health Economics Research,” page 11

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 © 2010 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a 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: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

VBCC Editorial Board Bruce A. Cutter, MD, MMM Cancer Care Northwest Spokane, WA

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

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

Craig Deligdish, MD Florida Comprehensive Cancer Network Melbourne, FL

Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN

Jayson Slotnik, JD, MPH Foley Hoag Washington, DC

Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers Pittsburgh, PA

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

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

Arlene A. Forastiere, MD ITA Partners Philadelphia, PA

Naimish Pandya, MD University of Maryland Baltimore, MD

Tracy Gosselin, RN, MSN Duke University Medical Center Durham, NC

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

Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute New York, NY

Denise K. Pierce DK Pierce & Associates Zionsville, IN

David Hom, MBA Solucia Farmington, CT

VALUE-BASED CANCER CARE

October 2010

G. Rhys Williams, ScD, MS Amgen Thousand Oaks, CA Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS BioPharma Partners, LLC New York, NY

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Accelerated Approval... the sponsor will conduct postmarketing trials. If the sponsor fails to conduct these trials, or if they do not confirm clinical benefit, the FDA can revoke the AA and remove the drug from the market. GAO Finds Fault AA has not been without its problems and detractors, one of which is the Government Accountability Office (GAO). Last year, it took the FDA to task with a report that concentrated on surrogate end points. The report noted that the FDA granted 90 AAs (79 for cancer) based on surrogate end points from 1992 through the end of 2008 and that 69 of the 204 drugs approved via the traditional process were new molecular entities, many for cancer. Of the 175 postmarketing studies requested, half have been closed as of February 2009. The GAO report concluded that “weaknesses in FDA’s monitoring and enforcement process hamper its ability to effectively oversee postmarketing studies.” Moreover, the agency does not consider this oversight a priority. Even more troublesome, the FDA has the authority to remove a drug from the market if a sponsor does not comply with the law, but it has not specified the conditions under which it would do so. “It has never exercised its authority, even when study requirements have gone unfulfilled for nearly 13 years,” the report stated. The GAO recommended that the FDA commissioner clarify the conditions under which the agency would exercise its authority. Two Examples of AA Gone Awry Gemtuzumab (Mylotarg) was granted accelerated approval in May 2000

at a glance ➤ Accelerated approval (AA) can allow earlier availability of drugs, but the programs necessitate proactive follow-up by manufacturers and regulators. ➤ The FDA decides whether a surrogate end point in AA is acceptable for a clinical trial, based on whether the end point is reasonably likely to predict a real clinical end point. ➤ Current FDA oversight of the AA process has been deemed lacking by the Government Accountability Office, especially regarding surrogate end points.

Continued from cover

“When lives are at stake, we need to maintain a regulatory system that ensures that perfect is not the enemy of good, or analysis is not the enemy of action.”

for the treatment of acute myeloid leukemia. However, postmarketing studies cast doubt on the agent’s effectiveness and a shadow over its safety.

—Kip Piper, MA, FACHE

Continued on page 6

Help reduce the risk of infection in patients receiving moderate-risk* chemotherapy regimens

Act before febrile neutropenia strikes Potential consequences of febrile neutropenia may be serious and can impact patient care First- and every-cycle Neulasta® achieved: ■ 94% reduction in febrile neutropenia (17% placebo vs 1% Neulasta®; P < 0.001).1,2 ■ 93% reduction in febrile neutropenia– related hospitalization (14% placebo vs 1% Neulasta®; P < 0.001).1,2 ■ 80% reduction in febrile neutropenia– related IV anti-infective use (10% placebo vs 2% Neulasta®; P < 0.001).1,2 Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta® is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Important Safety Information Do not administer Neulasta® to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Splenic rupture, including fatal cases, can occur following the administration of Neulasta®. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta®. Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta®. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta® for ARDS. Discontinue Neulasta® in patients with ARDS. Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta®. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta® in patients with serious allergic reactions. Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta®. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. The granulocyte colony-stimulating factor (G-CSF) receptor, through which pegfilgrastim and filgrastim act, has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded. Bone pain and pain in extremity occurred at a higher incidence in Neulasta®-treated patients as compared with placebo-treated patients. Please see brief summary of Neulasta® Prescribing Information on the adjacent page. *Regimens associated with 17% risk of febrile neutropenia. References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen. © 2010 Amgen. All rights reserved.

MC49047-A-1

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Accelerated Approval... Initial approval was granted on the basis of surrogate end points in 3 clinical trials with a total of 142 patients. A confirmatory trial with 627 patients was begun in 2004 to determine if adding BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use INDICATIONS AND USAGE Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. CONTRAINDICATIONS Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. WARNINGS AND PRECAUTIONS Splenic Rupture Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta. Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS. Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta in patients with serious allergic reactions. Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Use in Patients With Sickle Cell Disorders Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the Brief Summary: s 3PLENIC 2UPTURE ;3EE Warnings and Precautions] s !CUTE 2ESPIRATORY $ISTRESS 3YNDROME ;3EE Warnings and Precautions] s 3ERIOUS !LLERGIC 2EACTIONS ;3EE Warnings and Precautions] s 5SE IN 0ATIENTS WITH 3ICKLE #ELL $ISORDERS ;3EE Warnings and Precautions] s 0OTENTIAL FOR 4UMOR 'ROWTH 3TIMULATORY %FFECTS ON -ALIGNANT #ELLS ;3EE Warnings and Precautions] The most common adverse reactions occurring in r 5% of patients and with a between-group difference of r 5% higher in the pegfilgrastim arm in placebo controlled clinical trials are bone pain and pain in extremity. Clinical Trials 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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Neulasta clinical trials safety data are based upon 932 patients receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma (n = 56) received Neulasta after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles. The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer

Continued from page 5

gemtuzumab to standard chemotherapy would improve survival. The trial was stopped early because in addition to not being proved more efficacious, more patients in the gemtuzumab study receiving docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and <1% Asian, Native American or other. Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients. Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3 System Organ Class Preferred Term

Placebo (N = 461)

Musculoskeletal and connective tissue disorders Bone pain

26%

31%

Pain in extremity

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post approval use of Neulasta. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal relationship to Neulasta. Gastro-intestinal disorders: 3PLENIC RUPTURE ;SEE Warnings and Precautions] Blood and lymphatic system disorder: Sickle cell crisis ;SEE Warnings and Precautions] Respiratory, thoracic, and mediastinal disorder: ARDS ;SEE Warnings and Precautions] General disorders and administration site conditions: Injection site reactions Skin and subcutaneous tissue disorders: Allergic reactions/ hypersensitivity, including anaphylaxis, skin rash, and urticaria, Sweet’s syndrome, generalized erythema and FLUSHING ;SEE Warnings and Precautions] DRUG INTERACTIONS No formal drug interaction studies between Neulasta and other drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider these findings when interpreting boneimaging results. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Pegfilgrastim was embryotoxic and increased pregnancy loss in pregnant rabbits that received cumulative doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity occurred at these doses. Neulasta should be used during

Neulasta 6 mg SC on Day 2 (N = 467)

VALUE-BASED CANCER CARE

arm died than in the control arm. Moreover, gemtuzumab was associated with an increasing incidence of venoocclusive liver disease. A second trial of 1100 patients conpregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/ developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

October 2010

“Thousands of lives have been saved... . From a population health perspective, the benefits of AA far outweigh the risks.”

Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman.

—Kip Piper, MA, FACHE

Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard DEVIATION ;3$= SYSTEMIC EXPOSURE !5#0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain.

Bevacizumab is a highly lucrative source of income for Roche: $6 billion in annual sales, $1 billion of which derives from breast cancer. Even if the FDA withdraws approval, it could still be used off label for that indication. However, Medicare and most private insurers would refuse to reimburse for it, and at a cost of upwards of $50,000 per year, few patients could afford it.

Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

Picture Not All Bleak Kip Piper, MA, FACHE, President, Health Results Group, Washington, DC, is positive about the AA process. “No regulatory process is perfect, but thousands of lives have been saved because treatments for cancer and other life-threatening conditions received expedited approval. From a population health perspective, the benefits of AA far outweigh the risks.” Unfortunately, he added, we live in a risk-aversive, fear-centric country. “Exceptions get amplified, small risks are exaggerated, scientific nuances are obliterated, clinical context is lost in the 24-hour news cycle, and costs are confused with benefits.” For life-threatening conditions, priority must be on ensuring that patients have maximum access to treatments, but premarket studies will never match the scope of postmarket clinical experience. Patients may be negatively impacted by an on-again, off-again AA process. “But when lives are at stake, we need to maintain a regulatory system that ensures that perfect is not the enemy of good, or analysis is not the enemy of action,” he said. ■

Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim. Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed. NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product. This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2010 Amgen Inc. All rights reserved. www.neulasta.com 1-800-77-AMGEN (1-800-772-6436) v 11.0

firmed the dismal results. As a result, gemtuzumab will be withdrawn as of October 15, 2010. In the case of bevacizumab, at their July 20 2010 meeting, members of ODAC reviewed 2 postmarketing studies comprising almost 2000 patients and concluded that bevacizumab does not favor benefit over risk. Specifically, there was no additional OS or time to disease progression, and the agent caused significant serious side effects.

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COMPARATIVE EFFECTIVENESS RESEARCH

Adding Comparative Effectiveness... Mr Sweet to discuss the preliminary outcomes and lessons learned. What is the genesis of the WellPoint CER formulary process? WellPoint had been working with Healthcore, Inc, a Delaware-based clinical outcomes research firm, since the late 1990s, before acquiring the company in 2003. Healthcore researchers study the real-world safety and effectiveness of drugs, medical devices, and care management interventions to support evidence-based medicine, product development decisions, coverage decisions, and overall cost-effective care. Our alliance with them has been helpful in identifying the data elements missing from traditional research efforts that would be used for coverage decisions and how they could be added to comparative effectiveness efforts. Healthcore researchers are kept separate from the WellPoint Pharmacy & Therapeutics (P&T) Committee, however, to avoid any conflict of interest. Why this change now? Data beyond that produced by randomized clinical trials (RCTs) are needed. Although RCTs have strong science and produce very good evidence, they possess significant limitations that don’t give us insights as to what could happen when the drug is released into the real world. In addition, using these types of outcomes reflects the global call for better outcomes data that has occurred over the past 15 to 20 years, as witnessed by the National Institute for Health and Clinical Excellence in the United Kingdom and like-minded health economic efforts in Australia and Toronto, Canada. How does the WellPoint outcomesbased formulary work, and how does it differ from other types of formularies? Rather than focusing on surrogate markers that a physician would use to track progress in clinical practice, such as whether a drug lowers blood pressure or hemoglobin A1C, WellPoint instead looks at end points such as did heart attack or stroke rates go down, were the number of nephropathies or retinopathies reduced, did we put people back to work, did we keep them out of the hospital, did we reduce the emergency department visit rate, or did we improve their quality of life? Clinical markers are important, but they don’t always correspond to an end point that matters to patients. The basis of the formulary

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is that we are utilizing end points that really matter to patients to make coverage decisions. In terms of the mechanics of the process, WellPoint has a formal drug information specialist team (comprised of pharmacists and doctors of pharmacy) that regularly monitors and evaluates the literature, the US Food and Drug Administration website, other

We have been very transparent in publishing what we accept as evidence in making a coverage decision. government websites, and the websites of pharmaceutical firms. They also monitor the drug pipeline using approximately 30 informational sources to keep up with new drugs, as well as new indications for existing drugs. The drug evaluation team rates both clinical and cost impact on a scale of 1 to 3, because we understand it’s about value, not just clinical end points. Employers are concerned with improving the health and productivity of their members, and these improvements have a direct impact on their costs. To further draw in the real-world perspective, Healthcore has developed the Integrated Research Network, which registers practicing physicians in both general practice and specialties (eg, rheumatology, cardiology, endocrinology, psychiatry, oncology, and gastroenterology) to serve as subject matter experts on a particular study. These physicians will advise on the types of data to be collected, record clinical information, and participate in prospective and comparative effectiveness studies. In addition, WellPoint consults with national physician communities that weigh in on the type of evidence that would be appropriate for making a healthcare decision. The process is an open one, and we have been very transparent in publishing what we accept as evidence in making a coverage decision. As part of the CER process, the Institute of Medicine established a priority-setting agenda. Did WellPoint do the same? WellPoint works with Healthcore to prioritize research efforts, including annual planning on drug categories to be reviewed and identifying where RCTs might be leaving gaps in outcomes or safety information. Although

Continued from cover

we don’t do a CER study for every drug category, we do focus on the ones with these information gaps, or if there is something that has a really highprofile impact on our population. What, if anything, are your customers saying about your use of CER? Do they even notice or care? Although most employer customers are not aware of this procedural shift, it has caught the attention of the drug industry. Our newly published formulary criteria detail what kinds of studies are appropriate, how they will be graded, and what studies will be thrown out. But at least 1 customer so far has renewed with WellPoint because of this CER effort. In this age of health reform, everyone is asking for better health and productivity and better value for their healthcare dollar, and nothing can inform us better than this type of work. How often is CER incorporated into the WellPoint decision-making process? Roughly 50% of our reviews at this point include some sort of CER/total cost of care/health outcome analysis. We do select 2 to 3 categories of drugs each quarter that would be suitable for this work, and focus on them. Whether CER is used depends on the drug category and the answers we are getting with traditional research. What have been the early lessons learned regarding using CER? As CER and observational studies become more common, it is essential to have appropriate critical appraisal and evidence review standards. Until this happens, there may be instances where poorly designed studies are used to

at a glance ➤ WellPoint has instituted a formal process of using comparative effectiveness research (CER) in their formulary decision-making. ➤ CER is helpful in identifying the data elements missing from traditional research efforts and supplementing information gathering. ➤ At this point, CER is used in roughly 50% of WellPoint’s reviews, and more CER evidence should be available in the next several years.

make decisions or well-designed CER studies are thrown out. It is for this reason that we emphasize the transparency of our guideline process, where it is clear what comprises a well-designed study and what evidence will be accepted in the process. Second, we wouldn’t ever want to see a CER study in itself be used to make a decision. Randomized trials are still the gold standard for efficacy, safety, and tolerability, and where these fall short regarding health and productivity data, CER studies can add to the body of evidence. But CER observational and claims data also have limitations, so decision makers will need to look at the entire body of evidence, and then triangulate around to ensure we’re making the best decision with the evidence today.

We make provisional decisions based on available evidence, and then review new evidence as it comes out—even if it is a month later. Third, coverage or formulary decision evaluations should never be time stamped; instead, these should draw on a continuous quality improvement model. We make provisional decisions based on available evidence, and then review new evidence as it comes out— even if it is a month later, we’ve got to do the right thing so we protect the health and safety of our members. How available so far is the CER evidence you want to use? Although CER data are available, we’d like to see more. Most (90%) of the evidence reviewed by the WellPoint committee is coming from randomized trials, but the body of CER evidence should increase in the next several years. Has using CER caused you to expend more resources (ie, finding, interpreting, and evaluating) on these studies compared with traditional studies? WellPoint has retained the same number of drug information evaluators, but did add 2 CER style analysts late last year to help analyze data and bring them to the WellPoint P&T Committee. In addition, Healthcore has been adding resources in health outcomes and comparative effectiveness research. ■

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VALUE PROPOSITIONS Stopping Hospice Care Boosts Healthcare Costs

Hard Times Bring Medication Discontinuance

Care costs for patients who disenrolled from hospice care were nearly 5 times higher than for patients who remained with hospice, a new study finds (J Clin Oncol. 2010;28:4371-4375). Medicare data from 90,826 patients with cancer served by 1384 hospices were analyzed, and nearly 11% of patients disenrolled from hospice care. Nearly 34% of disenrollees were admitted to an emergency department (vs 3.1% who remained in hospice) and nearly 40% were admitted as hospital inpatients (vs 1.6% in the hospice group). Overall costs from time of hospice enrollment until death were $6537 in the hospice group versus $30,848 among those leaving hospice.

A letter to the editor in the August 5 issue of the New England Journal of Medicine (2010;363:596-598) describes how 3 patients of a California practice who had metastatic gastrointestinal stromal tumor discontinued imatinib therapy as a result of economic hardship. High-dose imatinib can restore control to tumors refractory to other treatments, but the retail cost can exceed $4500 per month. One patient discontinued treatment because of decreased earnings; the second patient was unable to purchase an affordable insurance policy because of the preexisting condition, and the last patient stopped taking the drug after his business failed. The practice now emphasizes the importance of medication adherence, referring patients to social workers and financial counselors, and providing information about drug manufacturers’ patient-assistance programs.

Similar Thoughts on Cancer Costs in the United States and Canada A survey comparing US (n = 1355) and Canadian (n = 238) oncologists’ attitudes toward costs, cost-effectiveness, and health policies regarding expensive cancer drugs (J Clin Oncol. 2010;28:4149-4153) finds attitudes generally similar despite the differences in healthcare systems. The overall response rate was 59%; more US than Canadian oncologists favored access to effective treatments regardless of costs (67% vs 52%), and more Canadians favor access to treatments only if they are cost-effective (75% vs 58%). A majority of oncologists favor expanded use of cost-effectiveness data in coverage decisions (80% US, 69% Canadian), but fewer than half in both countries feel well-equipped to use this information. Determining the value of drugs should be the responsibility of physicians and nonprofit agencies, as indicated by oncologists in both countries.

Robots Taking Over as Cost Driver “It is unlikely that robot-assisted surgeries will completely replace conventional surgeries for the full range of procedures for which cost studies have been done. If such a substitution did occur, however, it would generate nearly $1.5 billion in additional healthcare costs annually—excluding the (amortized) cost of the robots, which would bring the total to more than $2.5 billion.” —From a perspective in the New England Journal of Medicine (2010;363:701-704) examining the reasons for growth in robotic surgery use and the associated costs. The authors suggest that comparative effectiveness research could rein in the fragmented decision-making that has led to this growth. Also see Value-Based Cancer Care, September 2010, page 19, for more on robotic surgery in prostate cancer.

New Healthcare Environment Demands New Focus on Costs “The exciting explosion in new medical treatments creates an economic challenge that cannot be ignored. The pricing of medications and other interventions is one issue to consider, but the range of patients in whom the treatments are used—beginning with patients in whom the treatments may be most beneficial and cost-effective but rapidly expanding to those for whom the benefit and cost-effectiveness may be less clear— should also be considered.” —From an editorial in the New England Journal of Medicine (2010;363: 1278-1280) discussing a study showing clinical benefit in fondaparinux (Arixtra) use for superficial-vein thrombosis in the legs. Even with positive clinical findings, the economic component of drug therapies cannot be overlooked, the authors say, and they recommend that the FDA push for “phase 3.5 trials” to document cost, quality of life, and cost-effectiveness of new therapies.

VALUE-BASED CANCER CARE

October 2010

Economic Downturn Threatens Cancer Prevention Gains A special issue of the European Journal of Cancer (September 2010;46[14]) focused on cancer prevention considers a number of ways that economic pressures fostered by the current global financial crisis could impact cancer rates. Public donations to cancer research and government and industry funding of research may decrease, and occupational exposure to carcinogens may increase as safety shortcuts are taken, thereby boosting cancer rates. On the reduction side, people may reduce unhealthy and cancer-causing habits to reduce personal expenditures, or governments may increase taxes on unhealthy goods such as tobacco.

Putting Economic Reality into Medical Classrooms A JAMA commentary (2010;304:1229-1230) urges that medical education be expanded to include economic considerations as part of the curriculum. The authors argue that a core, required course covering economic factors that shape medical research, available treatments, development of clinical guidelines, and definition of diseases, as well as the players affecting cost and consumption, and the interactions of these forces, should be created. Second, a revision of the medical school curricula that reflects the core course should be undertaken. Instead of considering economic forces as extraneous, physicians need to realize their dual role as patient advocates and allocators of resources, the authors say. Also see “Guiding Patients Through Cost-Based Treatment Choices” (cover) for more on physician–patient economic discussions.

NIH Makes Pharmacogenomics Push Targeting drug therapies through genomic information can improve patient outcomes, and the National Institutes of Health (NIH) has recently announced several grants that will foster research in the area of pharmacogenomic research. The first one, a $15-million grant over 5 years, will support the Pharmacogenomics Knowledge Base (PharmGKB), which began in 2000 as a catalog of links between human genetic variation and drug responses. PharmGKB genetic information was used by a worldwide team of researchers in 2009 to better predict optimal warfarin dosing. A second grant of $161.3 million over 5 years will expand the Pharmacogenomics Research Network, which has already discovered gene variants linked to responses for treating several cancers, heart disease, asthma, and nicotine addiction.

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CANCER QUICK TAKES Cancer Costs: What Do Patients, Physicians Think? A literature review on patient and physician attitudes regarding communication on the cost of cancer care finds that limitations—on what is known about these communications, and on techniques and tools to improve it—hamper discussions, even as costs continue to rise (J Oncol Pract. 2010;6:188-192). Costs have intruded into decisionmaking, say the authors, with oncologists reluctant to bring up intrusive topics or ones for which they have no solution. And despite ASCO issuing guidance stating that “discussion of cost is an important component of highquality care,” there is little evidence on patient perspectives on the costs of care. Tools and techniques to foster discussion include prompt lists (questionnaires that suggest topics for discussion distributed in waiting rooms), decision aids, a greater willingness on the part of physicians to broach the cost discussion, and directly providing patients with information on costs. Beyond this, physicians must be ready to discuss alternative treatment strategies if cost discussions indicate that patients cannot afford a suggested treatment. Higher Quality Care, But Later Diagnosis, for Uninsured Patients Uninsured California women with breast cancer treated under the Breast and Cervical Cancer Treatment Program (BCCTP) generally received high-quality care, but these women also presented at a later disease stage (J Clin Oncol. 2010;28: 3479-3484). The authors examined quality of care using 29 evidence-based quality measures developed for the National Initiative for Cancer Care Quality (NICCQ), studying 658 women with stage I to III breast cancer who received care under the state/federal program. Adherence to recommended care ranged from 87% for posttreatment surveillance to 97% for diagnostic evaluation; on average, patients received 93% of recommended care, a rate that bested all but one of the NICCQ domains. For 4 of 5 measures addressing the need to provide patients with information on diagnostic and treatment options, adherence was lower than 85%. Twenty-three percent of the cohort presented with stage III cancer, a point that “underscores the challenges in obtaining timely diagnosis in an uninsured population,” even when programs like BCCTP exist, say the authors. Myelodysplastic Syndromes Common and Costly Myelodysplastic syndromes (MDS) are a common and costly hematologic

malignancy of the elderly, and patients with this disease are at greater risk of comorbidities (J Clin Oncol. 2010;28: 2847-2852). Authors conducted a retrospective review of Medicare claims–identified patients newly diagnosed with MDS in 2003, and followed them for 3 years, recording comorbidities dur-

ing that period. In the 3-year follow-up period, 76.8% of patients with MDS were hospitalized, nearly 80% had at least 1 emergency department visit, and almost 40% received growth factor treatments. Medicare payments for patients with MDS were substantially higher in each of the 3 years, with payment spiking in

the first year after diagnosis ($16,181 compared with $1575 for a non-MDS Medicare beneficiary). This more than 10-fold greater expenditure alarms the authors, who write, “As the US population continues to age, MDS will become a more prominent medical problem with a significant impact on the healthcare system.” ■

UNITED WE HEAL IN THE WAR ON CANCER, THERE’S ONLY ONE SIDE.

With a unique focus on supporting the patient throughout their care continuum, Innovent Oncology offers health plans and oncology practices a comprehensive solution that enhances the quality and consistency of patient care. With evidence-based medicine as the foundation of the program, we further help patients by providing direct, personalized support and education between office visits as well as advance care planning regarding future treatment and care preferences. Through this patient-centric approach, we help health plans and oncology practices collaborate by aligning incentives to drive better patient outcomes as well as encourage the efficient use of healthcare resources. After all, isn’t cancer a disease we should manage together? To learn more about how Innovent Oncology is transforming cancer care, visit us at innoventoncology.com or call 866-214-2194.

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HEALTH ECONOMICS

Real-World Decision Makers Decry Information Provided Health economics tools often difficult to apply By Colin Gittens

tlanta, GA—A plenary session billed as a “candid discussion with medical and pharmacy directors” on the value of health economics research in real-world decision-making proved to be all that and more, with several of the managed care medical directors on the panel taking issue with the type and quality of health outcomes research supplied by researchers and the pharmaceutical industry.

for a decision maker to compare one placebo study with another, Dr Rizzoli said. There is very little comparison of new therapies to existing products, so there is no way of knowing whether the new product provides any advantage over an existing product. The research time frame is also an issue, Dr Rizzoli said. Companies may offer an argument for long-term return on investment—usually many years—

“We have a hard time quantifying quality of life and translating that into financial data.” —Albert J. Rizzoli, MD

Even as he acknowledged the health services research expertise of the audience members at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) meeting, Albert J. Rizzoli, MD, a medical director at Presbyterian Health Plan in Albuquerque, NM, also expressed skepticism regarding their work, because decision makers such as himself only see a very small part of what those researchers do. “Largely, what we see in managed care are pharmacoeconomic models that are brought to us by the pharma industry,” he said. “That’s almost entirely what we see.” Models Lack Real-World Connection There is a disconnect between models and real-world experience that often leaves the real world not meeting best-case modeling assumptions, Dr Rizzoli argued. For a model to actually work, “the best result has to happen from…linked studies,” he said. Models also often consider indirect costs and tout the importance of the employer’s perspective, said Dr Rizzoli, but these factors are difficult for managed care decision makers to digest. Studies frequently emphasize the importance of the treatment on the patient’s quality of life, he said, and seem to say, “we know this costs a lot of money, but think about the quality of life,” with the implication that if the quality of life is improved, the medical care costs will be lessened. Another difficulty is presented by the current US Food and Drug Administration approach of comparing drugs with placebo, which makes it necessary

but “in managed care, we’re looking for return on investment over a short period of time,” he said. Despite arguments about the positive impact of efficacious treatments to the broader budget, pharmacy costs are still contained in a silo. Dr Rizzoli knows “better than anybody that everything we do has an effect on the entire system,” but that’s still not the way the world looks at it. “You don’t get much credit for medical cost-savings,” he lamented. In addition, Dr Rizzoli worries that widespread off-label use distorts costcontrol efforts, as do coupons and copays offered by manufacturers, which allow patients to get around drug tiering systems.

part of the mission, “you’re going to make a conservative decision.” “Gleevec was a game-changer,” Dr Schaecher pointed out, but “the fifth ARB [angiotensin receptor blocker] in the class was not a game changer.” Nevertheless, health services research was used to support both drugs, despite only 1 truly being innovative, he said. “We are a cynical, skeptical lot in the insurance industry,” he acknowledged. John Watkins, RPh, MPH, a pharmacy manager in formulary development at Premera BlueCross, a network plan in Seattle, WA, also worries about slanted studies. “It’s a no-brainer— funding bias is something forefront in our mind,” he said, pointing out that study funders get to control the frame around that study. Nevertheless, 2way communication and some level of trust must be developed. He emphasized that when his group evaluates studies, they try not to be cynical, but will give a fair hearing to the evidence presented. At Premera, Mr Watkins shows a model’s decision-analytic tree to his clinical experts and asks if it resembles how patients are treated. If it bears no real-world resemblance, it goes no further. A final panelist, Harold “Hank” L. Gardner, MD, at HCMS group in Cheyenne, WY, argued for less complexity and the primacy of the consumer. How do outcomes get translated into verbiage that patients and business managers at employers can understand, he asked.

“What is the decision that [decision makers] need to make, what data do they need to properly inform that decision, and how do I get from there to studies that will provide that information?” —John Watkins, RPh, MPH Concern for Economic End Points From the perspective of Kenneth L. Schaecher, MD, a medical director with SelectHealth in Salt Lake City, UT, health outcomes research represents an attempt to add an economic end point to studies that are traditionally clinically focused, thereby creating economic value. But in his eyes, those end points are rarely pertinent. “If you don’t give us anything pertinent, we’re going to make the best decisions we can. We’re not trying to ration care,” he said, adding that when controlling cost is

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October 2010

Putting Meaning to Models Overall, Mr Watkins took a more charitable view of relationships between pharma, healthcare researchers, and decision makers, and offered several suggestions about what might be done to improve them. First, he suggested, manufacturers should keep several pragmatic questions in mind. “What is the decision that [decision makers] need to make, what data do they need to properly inform that decision, and how do I get from there to studies that will provide that infor-

mation?” he asked. He suggested it is essential to keep in mind who the decision maker is and who the end user is, because this may influence the model used. Mr Watkins said he would like to raise the bar in cost-effectiveness modeling studies by having clinical and economic end points included in the trial design, and making sure the studies are adequately powered for their end points. The outcomes research developers should be at the table when the trial registration process is being planned, he argued. Changing Models’ Focus Dr Schaecher had several suggestions. First, health outcomes research should include appropriate financial outcomes related to the therapy and the intended population. Conducting studies that will get a drug covered will also be increasingly important, and when those studies are conducted, they will be considered and may change his firm’s policies, Dr Schaecher said. “Evidence that shows quality will lead to an improvement in cost of care over time,” he said. In addition, it is important not to settle for surrogate end points when it is possible to measure meaningful end points. For Dr Rizzoli, the minimum requirement is that models should be transparent, understandable, and focus only on cost and utilization. “We have a hard time quantifying quality of life and translating that into financial data,” he emphasized. And although the National Institute for Health and Clinical Excellence in the United Kingdom has engendered much controversy, Dr Rizzoli said that this may be an approach worth trying. “We desperately need that kind of model in the United States. We need somebody objective,” he argued. During the question session, Milt Weinstein, PhD, of Harvard University, indicated disbelief at what he was hearing from Drs Rizzoli and Schaecher, saying it sounded like they did not care about outcomes, but only about costs. Marc Berger, MD, of Eli Lilly, pointed out that insurers have only recently started to ask for better evidence, and he echoed the importance of a skeptical, not cynical, approach to evidence by decision makers and “the need for good dialogue. If there’s cynicism on either side, we’re not going to get where we need to get to.” ■

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HEALTH ECONOMICS

Improving Health Economics Research A conversation with David Meltzer, MD, PhD Dr Meltzer is with the Department of Medicine and the Harris School of Public Policy and Department of Economics, The University of Chicago How would you respond to complaints on the utility of health economics research? It is true that some branches of academic economics sometimes value theoretical insights and technical details over pragmatic results that can be broadly applied. However, most of the core insights of economic analysis tend to be accessible and have highly pragmatic implications. An important part of the art of being a good economist is being able to crystallize complex ideas down to their essence and then explain them to others. Good teachers have to do this, and so do good researchers and others who wish to see sophisticated economic arguments translated into practice. In all these cases, the key is simplifying the idea to its essence so that the basic intuition behind an insight can be explained. After that, additional complexities can be explored if need be. Health economics studies often emphasize a long-term time frame for outcomes and return on investment, but managed care organizations [MCOs] and insurers have shorter outlooks—quarterly or yearly. Can these perspectives be reconciled? Incentive problems are real, and the solution is good public policy. Say there

is an operation that is an investment now and saves money in the future (eg, bariatric surgery). Any insurer that pays for that is going to have to charge higher premiums to cover costs, which means that people looking to save money on their premiums will look

ter, and there are important limitations in the current QOL measures, but these are better than the immediate alternative—which is to not consider them at all. QOL is a hard thing to measure, and it certainly does have an idiosyncratic

Most of the core insights of economic analysis tend to be both accessible and to have highly pragmatic implications.

elsewhere. This puts that plan at a competitive disadvantage, because people will sign up for the expensive policy when they need the expensive treatment, and then switch to the cheaper policy once they’ve got it. The solution is for the government to mandate coverage. The current market is not a complete market—if that were true, you would have to pay a penalty if you chose an insurance policy that did not cover this sort of treatment that produces long-run savings, and that’s not the case. Can quality of life [QOL] be quantified better in health economics studies? I’m sure QOL can be quantified bet-

element to it, but it is also an important area for research. It is the kind of thing that both firms and the NIH [National Institutes of Health] are interested in, and that people are interested in. Do you see comparative effectiveness research [CER] changing the current practice of comparing placebo studies against one another? Are head-to-head comparisons in our future? People who make coverage decisions and patients probably really do want these head-to-head trials, because they are the most meaningful. I don’t think they are the only sort of evidence—approvals, for example, should not be based on only

head-to-head trials. CER will be an addition to the information available and could leave consumers better off—in some instances, it could lead to lower prices and provide more information for patients. It is going to provide useful information about relative value. Can studies presenting economic end points be made more relevant? Can more meaningful end points, rather than surrogate end points, be used? There is a challenge in thinking about economic end points and overall end points. The perspectives of an individual, an MCO, or society are all valid, but no single perspective is relevant to everyone. The field needs to move to multiple perspective studies—what are the costs and benefits to different parties who might be affected by this? We need to know what must be done in terms of a regulation or a subsidy for it to have the desired effect. Take the example of bariatric surgery. You can say this is going to save healthcare costs, but it’s not going to save them for MCOs, so why would they pay for it? What you want to do is say this has societal benefits, and we need to figure out who wins and who loses so that the desired thing happens. ■

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New Tools Arriving to Measure and Manage Chemotherapy Care Business, clinical concerns now connected in value-focused approach By Daniel Denvir Baltimore, MD—A long-held business truism is that “if you can’t measure it, you can’t manage it.” The application of this belief to the oncology setting was demonstrated at a session of the Association of Community Cancer Centers’ (ACCC) 36th Annual National Meeting. Kimberly Bergstrom, PharmD, chief clinical officer for McKesson Specialty Care Solutions, told attendees of the growing importance of developing and using standardized chemotherapy treatment regimens, and of the tools that

can benchmark performance and foster compliance with treatment guidelines. Public and private payers are moving to control exploding healthcare costs, Dr Bergstrom told attendees, and because increased cost control was inevitable, it is in providers’ interest to get a seat at the table. “It is an important topic, because this is one of those things, if we don’t get a handle on it, it’s going to happen to us,” she said. “People and groups and organizations are going to start dictating how we provide cancer care, and we can’t let that happen.” Continued on page 8

Value-Based Cancer Care will be at the ASCO Annual Meeting, June 4-8, in Chicago.

NCCN Roundtable: Clinical and Economic Issues Impacting Cancer Care Delivery “Collision course” in sight By Audrey Andrews Hollywood, FL—Clinical practice guidelines issued by the National Comprehensive Cancer Network (NCCN) are followed by conscientious oncologists in their everyday practice, but they are developed based on clinical efficacy and without regard to costs. At a roundtable held during the NCCN’s 15th Annual Conference, moderator Clifford Goodman, PhD, Senior Vice President at The Lewin Group, predicted, “The appropriate use of evidence-based guidelines is on a collision course with the financial nonsustainability of the healthcare system.”

Dr Goodman alluded to a level of frustration that has never been higher in cancer care. “Too many patients are still dying young. We need innovations and a cure,” he said. But the inadequacy of current treatments for cancer is no longer the main problem. Equally challenging, he suggested, is finding a means to pay for the ever-costlier care that threatens to bankrupt the healthcare system. As society struggles to find solutions, “the ground is shaking beneath us,” Dr Goodman commented. Continued on page 19

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SEER-Medicare Database Analysis Confirms Expensive Prostate Breast Cancer Survival Improves, Cancers Gaining Supremacy Photo by © ASCO/Todd Buchanan 2009

Thanks to New Therapies By Colin Gittens Barcelona—Survival for patients with metastatic breast cancer has improved dramatically in the last 20 years, especially in the subgroup of patients with HER2-positive tumors, according to research presented at the 7th European

Breast Cancer Conference (EBCC7). This improvement, the researchers suggest, is due to increased use of anthracyclines and the rise of targeted therapies. “There is no doubt that trastuzumab (Herceptin), which targets the HER2 gene, is the most important Continued on page 27

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But cost-effectiveness of this move remains to be determined By Rosemary Frei, MSc San Francisco, CA—The popularity of minimally invasive radical prostatectomy (MIRP), intensity-modulated radiation therapy (IMRT), and of brachytherapy combined with IMRT for prostate cancer started to take off after 2002, a new database analysis has confirmed. At the American Society of Clinical Oncology’s 2010 Genitourinary Cancers Symposium, Paul L. Nguyen, MD, presented the results of his team’s analysis of data from the Surveillance, Epidemiology and End Results (SEER)-Medicare database. Dr Nguyen, director of Prostate Brachytherapy, Dana-Farber/Brigham

The 2010 Genitourinary Cancers Symposium: Progress in Multidisciplinary Management was held March 5-7 in San Francisco. All sessions emphasized a multidisciplinary approach to care; a number of them brought out the cost and value issues associated with caring for genitourinary cancers. and Women’s Hospital, Harvard Medical School, Boston, and his coinvestigators found MIRP jumped from 1.5% of radical prostatectomies (RPs) in 2002 to 28.7% in 2005. They also found that IMRT soared from 8.7% of external radiation treatments for prostate cancer to 81.7%. In addiContinued on page 24

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HEALTH POLICY

Breast Cancer Screening... particularly when existing practices are challenged. This seems more likely when health policy issues are highly salient to industry, professional, and consumer organizations. With the adoption of US healthcare reform and the future expansion of government-funded health insurance, healthcare costs will continue to be a major concern for policymakers. Both governmental and private purchasers

mendations suggest that the health services research community needs to understand better what the public believes about evidence and ways that healthcare costs might be constrained. Greater focus on likely public reactions

Highlights from the Important Safety Information ZOMETA is contraindicated in patients with 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. Patients being treated with ZOMETA should not be treated with Reclast® (zoledronic acid) as they contain the same active ingredient.

➤ Health services researchers need to understand public beliefs about evidence and ways to constrain healthcare costs. ➤ Providing opportunities for public comment may help build support. of care will continue to have to make decisions about what services to pay for. Although analysts disagree about the potential for CER to reduce healthcare spending,7-9 the idea of using evidence to improve healthcare policy decisions enjoys support from a broad range of actors.8,10-13 Nevertheless, the strong negative reaction to the 2009 mammography recommendations from the USPSTF is a powerful signal that the implementation of CER and EBM can encounter great resistance, particularly when this research suggests that broadly accepted healthcare technologies that have been promoted by the healthcare community and patient advocates may not be worth the cost. Although, to date, controversies regarding practice guidelines have been unusual, the conditions that produced the objections in the mammography case could become more important, and more common, as the use of CER and EBM is extended. The USPSTF did not base its mammography recommendations on possible cost-savings, but proponents of CER and EBM often claim that this research will reduce spending by eliminating unnecessary care.8 The reactions to the mammography recom-

In patients with impaired renal function, the risk of adverse reactions (especially renal adverse reactions) may be greater. ZOMETA treatment is not recommended in patients with bone metastases with severe renal impairment. Preexisting renal insufficiency and multiple cycles of ZOMETA and other bisphosphonates are risk factors for subsequent renal deterioration with ZOMETA. Do not use doses greater than 4 mg. ZOMETA should be administered by IV infusion over no less than 15 minutes. Monitor serum creatinine before each dose. Please see brief summary on the following page. References: 1. Lipton A, Zheng M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer. 2003;98:962969. 2. ZOMETA Prescribing Information. Novartis Pharmaceuticals Corporation. 3. Aredia Prescribing Information. Novartis Pharmaceuticals Corporation. 4. Actonel Prescribing Information. Procter & Gamble Pharmaceuticals. 5. Boniva Prescribing Information. Roche Laboratories Inc. 6. Didronel Prescribing Information. Procter & Gamble Pharmaceuticals. 7. Fosamax Prescribing Information. Merck & Co. 8. Skelid Prescribing Information. sanofiaventis US LLC. 9. Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer. 2000;88: 1082-1090.

This article was adapted from “Evidence and Fear: Navigating the Politics of Evidence-Based Medicine,” which appeared in the June 2010 issue of AcademyHealth Reports. To read the full article, please visit www.academyhealth. org/files/publications/academyhealth reports/AHReportsJune2010.pdf.

VALUE-BASED CANCER CARE

the USPSTF appear to be moving in that direction already by providing additional opportunities for public comment on forthcoming recommendations, which will be posted at www.preventiveservices.ahrq.gov.14

ZOMETA is indicated for the treatment of patients with multiple myeloma and 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.

➤ Comparative effectiveness research and evidence-based medicine that challenge existing practices are difficult to implement.

may encourage the research community and entities like the USPSTF to work with the media, anticipate possible misinterpretations, and reduce public anxiety. Leaders at the Agency for Healthcare Research and Quality and

Indication

at a glance

Continued from cover

October 2010

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HEALTH POLICY Providing such opportunities for public comment may help the health services research community build support for basing policy decisions and practice guidelines on a strong evidence base and perhaps increase understanding of and confidence in the research base for such decisions. The

new health reform legislation calls for establishment of a methodology committee to advise the Patient-Centered Outcomes Research Institute, which is charged with conducting CER. The methodology committee is required to “develop and improve the science and methods of comparative clinical effec-

tiveness research.”15 Establishing the credibility of its methods among a broad array of stakeholders will not insulate the new institute, or health services researchers more generally, from controversy. Nevertheless, establishing broader support for the value of health services research, coupled with

sustained efforts to communicate more effectively with the public, is crucial as the United States grapples with how best to improve the quality and efficiency of its health system. ■ References for this article are listed online at www.valuebasedcancer.com.

Because skeletal-related events (SREs)† can have devastating consequences, help protect your patients with ZOMETA • ZOMETA may help reduce and delay SREs in more malignancies than any other bone-targeted agent1-8

Metastatic breast cancer

Metastatic hormone-refractory prostate cancer

Multiple myeloma

Metastatic lung cancer and other solid tumors

Metastatic renal cell carcinoma

*ZOMETA should be used in prostate patients with bone metastases that have progressed after treatment with at least one hormonal therapy. † SRE=skeletal-related event, defined as pathologic fracture, spinal cord compression, hypercalcemia of malignancy, and the need for radiation or surgery to the bone.9

More than

April 2010

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YEARS of real-world experience C-ZOM-100050

www.ValueBasedCancer.com

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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%) —

VBCC_October_100810_Follow ASCO Tabloid 10/12/10 2:35 PM Page 15

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

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. 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)]. 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. Table 6. Percentage of Patients with Adverse Events ≥10% Reported in Three Bone Metastases Clinical Trials by Body System

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 Neoplasms Malignant Neoplasm Aggravated

Zometa 4 mg

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 (%)

(%)

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

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

316 143 131 106 84

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

205 (20)

(17)

284 74 73 40 52

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

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

(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.

Placebo

(%)

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%)

1Grade 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 2Grade 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%) —

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 Zometa 4 mg n/N Normal Abnormal Total Solid Tumors

569 239 216 156 143

n/N

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

Multiple Myeloma and Breast Cancer

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

Pamidronate 90 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.

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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

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CMS-FDA Proposed Premarket Parallel Review—The Devil is in the Details By Jayson Slotnik, JD, MPH Mr Slotnik is an attorney at Foley Hoag, LLP, and an editorial board member of Value-Based Cancer Care.

n June 25, 2010, the Centers for Medicare & Medicaid Services (CMS) and the Food and Drug Administration (FDA) entered into a Memorandum of Understanding (MOU) stating that the agencies will work together to “promote initiatives related to the review and use of FDAregulated drugs, biologics, medical devices, and foods, including dietary supplements.”1 Quickly following up on the MOU, the agencies jointly published a notice on September 17, requesting comments regarding the agencies’ joint proposal to establish a process for “Parallel Review of Medical Products” (hereafter “parallel review notice”) in the premarket setting.2 These coordinated actions taken by CMS and FDA will have dramatic implications for the pharmaceutical, biotechnology, and device industries. The CMS-FDA parallel review notice proposes a new premarket process for innovators to consider in lieu of the current staggered process. The new process, if finalized, would be completely voluntary. Currently, most innovators seek FDA approval and then, after that approval is secured, coverage, coding, and reimbursement decisions from CMS. The new process would combine these sequential events such that the innovator would have both market approval and national coverage at the end of the same process. Although superficially, this may seem to be a “good government” initiative, this proposal in fact raises many significant issues for innovators because of the new analysis that each sponsor must do on each asset, which potentially impacts the commercial viability for any given product.

Issues to Consider The proposal states that the product sponsor will be able to decide whether or not to engage in the process, yet it also contemplates the possibility of allowing another party other than the product sponsor to be able to initiate a request for the parallel review. Will the agencies allow a competitor, for exam-

ple, to ask for a parallel review? If so, how could such a system plausibly be called “voluntary”? This raises questions about what kinds of criteria the agencies will use in selecting the products for the new review system. Additionally, and perhaps of greater concern, is the effect this process will have on clinical development. For example, should a sponsor decide not to volunteer for this process, what guarantees will be put into place that this decision will not haunt the sponsor later on? One can envision discussions with either agency questioning the sponsor for not using the parallel review process. During FDA deliberations, the agency could state that certain problems could have been avoided had the sponsor chosen the parallel review path. The sponsor could face similar issues with CMS should the process not be used. The process envisions a positive national coverage decision (NCD) immediately or shortly after FDA approval, and the proposal states that

the sponsor be that the representatives (particularly CMS) on the other side of the table have a good understanding of the technology, the costs and burdens of clinical trial recruitment, and the sponsor’s obligations to its investors? A firm could leave this meeting with a recipe to make a unicorn. What is the sponsor to do then? Shifting Regulatory Goalposts Of further concern regarding this notice is the introduction of cost and quality data into the preapproval process. As the notice states, and stated above, the agencies believe they must address a need to “speed[] consumer access to and spur[] development of new, affordable, reliable, safer, and more effective medical products and services” (emphasis added).2 Although this may seem like something that CMS would consider in coverage and payment decisions, it is a new concept in the realm of the FDA, which has traditionally focused on “safety and effectiveness.”

Should a sponsor decide not to volunteer for this process, what guarantees will be put into place that this decision will not haunt the sponsor later on? this will expedite market uptake. It therefore seems reasonable to expect, given the tone and text of the proposal, that a sponsor ignoring parallel review should expect the year-long NCD process once the product is approved by the FDA. Ignoring the process, it seems, could easily result in significant delays caused by either regulatory agency. Conversely, should the sponsor use this process, it will necessitate joint meetings with the FDA and CMS to discuss, among other things, clinical trial design to ascertain the information needed for both FDA and CMS approval. When negotiating a clinical trial program with the government on a new technology, how confident should

The CMS-FDA parallel review notice also suggests possible future consideration of “comparative effectiveness” as the agencies state in the notice that currently “materials submitted by manufacturers to FDA may not adequately address the issues of importance to payers . . . and the incremental clinical utility of these products compared to currently available technologies.”3 In addition, the notice describes CMS’ current NCD process as including a review of the product “as compared to alternative treatments or diagnostics already covered by the program” (emphasis added).3 Will the sponsor need to demonstrate affordability and superiority in order to gain FDA and CMS approval?

at a glance ➤ A concurrent, parallel review by the FDA and CMS is intended to speed the regulatory process. ➤ This process holds serious potential implications for technical innovation. ➤ Comments regarding the “Parallel Review of Medical Products” are due no later than December 16, 2010. Underlying these concerns is the uncertainty about if—and if so, how— the agencies will share data and further protect confidential data between FDA and CMS as a product is reviewed. As discussed above, the recently published CMS-FDA notice and request for comments (which are due no later than December 16, 2010) on the proposed parallel review process raises numerous and potentially significant issues for innovator companies. Should this process or something similar be finalized, it seems to me that as part of any due diligence process or clinical evaluation, one should ask why or why not the sponsor decided to volunteer or ignore the parallel review process. ■ References 1. Memorandum of Understanding between United States Food and Drug Administration and Centers for Medicare & Medicaid Services. 75 Federal Register 48699 (August 11, 2010). 2. CMS-FDA Parallel Review of Medical Products, Notice and Request for Comments. 75 Federal Register 57045 (September 17, 2010). 3. CMS-FDA Parallel Review of Medical Products, Notice and Request for Comments. 75 Federal Register 57046 (September 17, 2010).

Acknowledgment Ross Margulies assisted in the preparation of this acticle.

Representatives from Value-Based Cancer Care will be at the American Society of Hematology Annual Meeting in Orlando, FL, December 4-7.

Please visit us at booth 150.

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CRC Screening Economics: Diminishing Returns as Technology Advances? By Colin Gittens

reating colon cancer is expensive, with a recent study estimating the cost 1 year after diagnosis at $29,196 in a cohort of Medicare colon cancer patients aged 66 years and older.1 Reducing colorectal cancer (CRC) incidence through screening could restrain

Cost-Effectiveness of Screening Emerging Because of the number of screening tests available, studies have also begun to examine the cost-effectiveness of individual screening methods. Another Canadian study modeled the costs and

“What you want with a colorectal cancer screening test is one that’s less sensitive than colonoscopy,” so that clinically unimportant findings are not acted on. —Russell Harris, MD, MPH

these expenditures, and several recent studies have pointed out screening’s benefits. A 2006 study looked at whether changes in Medicare’s reimbursement policy to provide for coverage of screening colonoscopies for patients with increased risk for colon cancer (in 1998) and then for all individuals (in 2001) led to an increase in colonoscopy use or early-stage colon cancer diagnosis.2 Colonoscopy use increased from an average of 285 of 100,000 before the policy change to 1919 of 100,000 after the change. The changes were also strongly associated with cancer being diagnosed at an early stage. Rabeneck and colleagues conducted a naturalistic, 14-year follow-up of Canadian men and women aged 50 to 90 years who underwent varying intensities of colonoscopy.3 Colonoscopy increased in all regions during 19932006, and among this cohort of 2,412,077 persons, the authors found that for each 1% increase in colonoscopy rates, there was a concomitant 3% decrease in colon cancer deaths.

at a glance ➤ Colorectal cancer (CRC) screening leads to diagnosis at earlier-stage disease and decreased number of deaths. ➤ CRC screening can be too effective, revealing nonsignificant findings that are nonetheless treated. ➤ The cost-effectiveness of various CRC screening approaches is presently being evaluated.

quality-adjusted life expectancy of not screening and screening with any of 10 tests.4 The authors found that an annual high-sensitivity fecal occult blood test (FOBT), such as a fecal immunochemical test, or colonoscopy every 10 years, offered the best value. The Centers for Medicare & Medicaid Services (CMS) has begun to commission cost-effectiveness studies of CRC screening approaches. Currently, Medicare covers the following screening tests: annual FOBT; flexible sigmoidoscopy every 5 years (both alone and in conjunction with annual FOBT), and colonoscopy every 10 years. One study evaluated the conditions under which stool DNA testing could be cost-effective compared with these currently reimbursed tests.5 Using microsimulation modeling, the authors looked at lifetime expectancy, lifetime costs, incremental cost-effectiveness ratios, and threshold costs in a population aged 65 years. At a cost of $350 per test, testing every 3 or 5 years yielded fewer lifeyears and higher costs than the current recommended screening strategies. The authors conclude that there is no way for the test to be cost-effective at this rate; the journal’s editors suggest that “stool DNA testing will not be a costeffective screening test for the foreseeable future.” Computed tomographic colonography (CTC) has emerged as another option in colon cancer screening, but the test is also relatively costly and the CMS has decided not to cover the procedure. The authors of the previous study also explored what the reimbursement rate for CTC would have to be for this procedure to be cost-effective relative to other screening methods (and for the CMS to cover it).6 The

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simulation models used in the paper found that although the number of undiscounted life-years gained from CTC screening was comparable to 5yearly sigmoidoscopy with annual FOBT, the strategy was the most costly one when it was reimbursed at a perscan rate of $488 (slightly less than the reimbursement for colonoscopy without polypectomy). The strategy could be cost-effective, however, when reimbursed at $108 to $205 per scan. Cost-Benefits and Harms An editorial accompanying this second study, by Russell Harris, MD, MPH, of the University of North Carolina School of Medicine, cautions of the dangers associated with both

an improved fecal test could well be the new “gold standard,” he writes. But in a follow-up interview with Value-Based Cancer Care, Dr Harris explained that “net effectiveness,” which considers costs and benefits minus harms, might be an additional, helpful way of considering cost-effectiveness. “What you want with a colorectal cancer screening test is one that’s less sensitive than colonoscopy,” so that clinically unimportant findings are not acted on, Dr Harris said. “Where colonoscopy is going too far, we need to back up a bit and find some test that is better suited to what we’re looking for.” ■ References

Simulation models found that although the number of undiscounted life-years gained from CTC screening was comparable to 5-yearly sigmoidoscopy with annual FOBT, the strategy was the most costly one. CTC and optical colonoscopy and wonders if there might be a third option.7 In terms of cost-effectiveness,

1. Luo Z, Bradley CJ, Dahman BA, Gardiner JC. Colon cancer treatment costs for Medicare and dually eligible beneficiaries. Health Care Financ Rev. 2010;31:35-50. 2. Gross CP, Anderson MS, Krumholz HM, et al. Relation between Medicare screening reimbursement and stage at diagnosis for older patients with colon cancer. JAMA. 2006;296:2815-2822. 3. Rabeneck L, Paszat FL, Saskin R, Stukel TA, et al. Association between colonoscopy rates and colorectal cancer mortality. Am J Gastroenterol. 2010;105:1627-1632. 4. Telford JJ, Levy AR, Sanbrook JC, et al. The costeffectiveness of screening for colorectal cancer. CMAJ. 2010;182:1307-1313. 5. Lansdorp-Vogelaar I, Kuntz KM, Knudsen AB, et al. Stool DNA to screen for colorectal cancer in the Medicare population. Ann Intern Med. 2010;153:368-377. 6. Knudsen AB, Lansdorp-Vogelaar I, Rutter CM, et al. Cost-effectiveness of computed tomographic colonography screening for colorectal cancer in the Medicare population. J Natl Cancer Inst. 2010;102:1238-1252. 7. Harris R. Speaking for the evidence: colonoscopy vs computed tomographic colonography. J Natl Cancer Inst. 2010;102:1212-1214.

As Economy Worsens, Financial Factors May Hinder CRC Screening

ven as screening rates for colorectal cancer (CRC) remain down as a result of low patient awareness of benefit or their choice to forego a potentially unpleasant procedure, that low rate may decrease further because of the worsening national economic situation. The reasons for this decrease are varied. A comprehensive review of more than 100 studies conducted between 1998 and 2009 found that high out-ofpocket costs, lack of health insurance, and low household income were some of the reasons people did not get screened.1 Lead author Debra Holden,

PhD, acknowledged that access to care is only part of the problem; the study, which was funded by the Agency for Healthcare Research and Quality, emphasized the need for policy-level interventions to improve screening. A second recent study found that despite expanded Medicare coverage for CRC screening, the procedure was still underused for a number of reasons, including lack of supplemental health insurance.2 In addition, as new technologies for CRC screening are developed, financial obstacles related to whether these new technologies are covered by insurers

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As Economy Worsens... may hamper screening. Computed tomographic colonography (CTC) can be used for CRC screening, but the Centers for Medicare & Medicaid Services has so far denied coverage, saying “the evidence is inadequate to conclude that CT colonography is an appropriate colorectal cancer screening test”.3 A study of 68 patients surveying their willingness to pay for CTC found that they were not willing to pay when not covered by insurance.4 What they were willing to pay ($244 mean, $150 median) is well below the currently charged procedural rate (between $500 and $1500). But because the CTC test is less invasive, there is thinking in some quarters that it could increase screening rates, especially for those at higher risk of disease.5

Continued from page 20

Medicare enrollees over time. Ann Fam Med. 2010; 8:299-307. 3. Centers for Medicare & Medicaid. Decision memo for screening computed tomography colonography (CTC) for colorectal cancer (CAG-00396N). May 12, 2009. www.cms.gov/mcd/viewdecisionmemo.asp? from2=viewdecisionmemo.asp&id=220&. Accessed September 13, 2010.

Legislative Remedies Legislation to cover CTC as a colon cancer screening technique was introduced by Rep Danny Davis (D-IL) on May 28, 2010 (HR 5461), and this is now

Legislation intended to make grants that provide CRC screening to individuals aged 50 years or older or who are at high risk for such cancer has been introduced.

4. Ho W, Broughton DE, Doneland K, et al. Analysis of barriers to and patients’ preferences for CT colonography for colorectal cancer screening in a nonadherent urban population. AJR Am J Roentgenol. 2010;195:393-397. 5. Finlayson E. Computed tomographic colonography for patients at high risk of colorectal cancer: trading accuracy for access and compliance. JAMA. 2009;301: 2498-2499.

We are here, where you need us most We are committed to the discovery and development of innovative immunotherapeutic approaches aimed at helping patients fight cancers, such as advanced melanoma. Together, we can make a difference.

under review by House subcommittees. Another, more general policy remedy to address cost barriers was introduced in the last session of Congress. Rep Kay Granger (R-TX) authored and introduced legislation intended to make grants that provide CRC screening to individuals aged 50 years or older or who are at high risk for such cancer. The legislation would also develop and disseminate public information and education programs for the detection and control of CRC and promote the benefits of receiving screenings through this program. Called the Colorectal Cancer Early Detection, Prevention, and Treatment Act (HR 1189), the legislation was introduced February 25, 2009, and has been referred to committee as the first step in the deliberative process.—CG ■ References 1. Holden DJ, Jonas DE, Porterfield DS, et al. Systematic review: enhancing the use and quality of colorectal cancer screening. Ann Intern Med. 2010; 152:668-676. 2. Doubeni CA, Laiyemo AO, Young AC, et al. Primary care, economic barriers to health care, and use of colorectal cancer screening tests among

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VBCC PERSPECTIVE

Resource Allocation for Colorectal Cancer Screening By Naimish Pandya, MD Dr Pandya is Assistant Professor at the University of Maryland Medical Center/Marlene & Stewart Greenebaum Cancer Center, Baltimore, MD, and a member of the editorial board of Value-Based Cancer Care.

ore than 142,000 estimated new cases of colorectal cancer will be diagnosed in the United States in 2010, and more than 51,000 will die from this disease this year.1 However, this could have been prevented among all individuals if the cancer was caught in an early stage. Unlike many other cancers, we recognize that in most cases there is a clear link from benign polyp formation through progression to eventual col-

cost-effective. Few organizations have also recommended using FOBT and sigmoidoscopy testing between these 10-year intervals. Although screening rates have increased since the 1980s, only 50% to 60% of the population is estimated to have been screened in 2006. This dismal rate is attributed to lack of awareness, barriers to access to healthcare, lower education level, low minority participation, and avoidance of undergoing a bowel preparation for colonoscopy evaluation.2 Many strategies are being developed to address these issues and improve overall screening rates. In trying to address some of these

It is appropos for third-party payers to weigh in on the appropriateness of each screening tool, and use financial incentives to direct the public toward the more medically and cost-effective test. orectal cancer. If these are successfully identified early, and eventually removed, colorectal cancer can be prevented. There are numerous screening tools currently approved for the use of identifying colon cancer among asymptomatic individuals, including fecal occult blood testing (FOBT), immunochemical FOBT, double-contrast barium enema, flexible sigmoidoscopy, and colonoscopy. Recommendations from various task forces and organizations vary, but all have mostly agreed that, among the general population, a colonoscopy performed once every 10 years after age 50 is useful to identify cancer early and is also

concerns, additional noninvasive tests have been developed and added to the repertoire of screening tools. Computed tomography (CT) colonography is a noninvasive look at the colon using a CT scan and is recommended to be performed once every 5 years. Advantages of this procedure include avoidance of sedation and an invasive procedure, and being fairly safe and quick. However, disadvantages include requirement of a full bowel prep, inability to identify small lesions, ultimate requirement of a colonoscopy (if suspicious lesions are found that require biopsy), exposure to unnecessary radiation, and finding extracolonic lesions

that increase unnecessary procedures to the patient and cost to the healthcare system. At the current cost of the procedure, the Centers for Medicare & Medicaid Services has recently determined that it is not a cost-effective screening tool and has refused reimbursement.3 Stool DNA testing avoids the unpleasantries of a bowel prep and the invasive procedure and sedation. However, it, too, is neither specific nor sensitive enough, when compared with a colonoscopy, and would still require the invasive procedure, should it be positive. Furthermore, because it performs various genetic analyses, the cost of the procedure is quite exorbitant. A recent analysis determined that this test is only cost-effective if screening adherence increased by more than 50% its current rate; otherwise, the cost of the test would have to be about 10% its current cost levels to justify its use.4 Screening Rates the Real Issue Although new screening tools perhaps add to improved detection and potentially improved patient experience while undergoing the testing, neither of these new tools would address the underlying problem of low screening rates. Supposedly, these tools would just add to the menu of options for the patients to choose from when deciding to undergo screening, likely adding to the confusion of the lay person in determining which is the better screening test. Indeed some US states have passed legal mandates that all screening tools be available to citizens based on guidelines set forth by various medical societies and task force opinions. Unfortunately, discussions on the pros and

cons of various tests and the consequences of results are never preemptively discussed by healthcare professionals (or occur infrequently) or are not processed properly by all patients. Therefore, it is appropos for third-party payers to weigh in on the appropriateness of each screening tool, and use financial incentives to direct the public toward the more medically and costeffective test. As a practicing gastrointestinal medical oncologist, it is regrettable to be treating so many patients annually, when one recognizes that many of these cases were likely preventable. Progress in medical care, both in diagnostics and in therapeutics, occurs by developing ever more molecular, more sophisticated, and more modern tools that are less unpleasant or burdensome to the patient. However, given the high colorectal cancer mortality that exists today, it would be more useful, at the population level, to spend precious capital in overcoming barriers to screening that numerous patients face. Improving this will not only drive down costs of screening tests, which could allow for newer and better screening tools, but also drive down costs of overall healthcare-related expenses for colorectal cancer by prevention. ■ References 1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277-300. 2. Holden DJ, Jonas DE, et al. Systematic review: enhancing the use and quality of colorectal cancer screening. Ann Intern Med. 2010;152: 668-676. 3. Knudsen AB, Lansdorp-Vogelaar I, Rutter CM, et al. Cost-effectiveness of computed tomographic colonography screening for colorectal cancer in the Medicare population. J Natl Cancer Inst. 2010;102:1238-1252. 4. Lansdorp-Vogelaar I, Kuntz KM, Knudsen AB, et al. Stool DNA testing to screen for colorectal cancer in the Medicare population: a cost-effectiveness analysis. Ann Intern Med. 2010;153:368-377.

PATIENT COMMUNICATIONS

Guiding Patients Through Cost... Foundation (PAF) unveiled a primer for providers on discussing healthcare treatment costs with patients (www. patientadvocate.org/pdf/pubs/gu_ provider_cost.pdf) and a companion brochure for patients. Beth Patterson, President of Mission Delivery at the PAF, said the material is being well-received, as is the foundation’s advice to clinicians dispensed over the phone on how to help patients make what can be extremely tough decisions. “Providers realize the financial implications of medical care are a

major issue for their patients, but it falls outside the scope of their healthcare training,” Ms Patterson explained. “It’s not an area that they’re confident and comfortable in talking about yet. So they’re very appreciative of having at least a starting point.” She said the 4 recommendations that providers have found most useful are: • Gain the patients’ trust and encourage them to see their relationship with you as a partnership. This will help ensure open and honest communication

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Continued from cover • Ensure that your staff creates a chart of insurance plans with which your office is contracted, and list each one’s referral requirements. Also create a list of approved facilities for such services as laboratory tests, blood work, imaging, and hospital admittance • Have your office verify what type of coverage each patient has, and arrange a meeting with the patient to discuss the treatment protocol and out-of-pocket requirements • Have a list available in your office of practical and financial resources for

patients, including the Patient Advocate Foundation, CancerCare, the American Cancer Society, and the National Coalition for Cancer Survivorship. The list should also include resources such as national copay programs, discounted drug programs offered by pharmaceutical companies and pharmacies, and pharmaceutical companies’ indigent-drug programs. Charity-care programs that are available through the physician’s local office/institution/community should also be listed. “Unless patients are in

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Guiding Patients Through Cost... a financial crisis, and unless they locate one of these charity-care programs on their own, they might not be aware that these are options,” said Ms Patterson. Guiding Points of Discussion A recent study corroborates that patients may be less willing to commit to high copayments for treatments with modest benefit (Wong YN, et al. Understanding how out-of-pocket expenses, treatment value, and patient characteristics influence treatment choices. Oncologist. 2010;15:566-576). It also showed patients who had made sacrifices to be able to afford treatment

and any insurance denials. They suggest a discussion that follows the acronym SPIKES—Setting and listening skills, Patient perception, Information, Knowledge in giving facts, Explore emotions and options, and Strategy and

summary—to ensure financial issues are covered. “If we want patients and families to make the most informed decisions, the oncologist must give an honest and realistic estimate of the benefit of a

treatment and put that in terms relative to its cost,” urge the authors. “Almost all data suggest that patients want us to give them the most complete information available, even if they choose to ignore it or misinterpret it.” ■

We focus on the human in human health care

“If a patient wants to go for broke for their treatment, that’s a personal decision, but we need to help them put it in context of their other financial responsibilities.” —Yu-Ning Wong, MD, MSCE

in the past were far less willing to accept higher copayments than were those who had not made such sacrifices. This can be critical information for clinicians, says lead author Yu-Ning Wong, MD, MSCE, Attending Physician and Assistant Professor, Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA. “If a patient wants to go for broke for their treatment, that’s a personal decision, but we need to help them put it in context of their other financial responsibilities,” she told Value-Based Cancer Care. “It was only after one of my patients died that I found out his wife had spent all their money providing for his care.… Should families spend a significant portion of their savings on noncurative treatments that may only extend life for a short period of time? Those are uncomfortable conversations, but we need to get better at having them.” The authors of a 6-step protocol for discussions about the cost of medical care proposed using the simple question, “Are you having financial worries about your treatment?” to broach the topic (McFarlane J, et al. SPIKE$: a sixstep protocol for delivering bad news about the cost of medical care. J Clin Oncology. 2008;26:4200-4204). They also recommend modifying the standard patient–physician discussion form to include financial issues such as levels of copayments, out-of-pocket payments,

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At Eisai (a•zi), caring for people is our work Satisfying unmet medical needs and increasing benefits to patients, their families, and caregivers is Eisai’s human health care (hhc) mission. This includes the development of innovative medicines– notably the discovery of the world’s most widely used treatment for Alzheimer’s disease. Eisai is recognized for our business and patient advocacy partnerships, as well as our commitment to working with healthcare professionals to achieve improved patient care worldwide. That is our quest. That is our promise. That is what makes us Eisai.

Ingenuity that Drives Innovation in Neurology, GI Disorders, and Oncology/Critical Care

www.ValueBasedCancer.com

VBCC_October_100810_Follow ASCO Tabloid 10/12/10 2:35 PM Page 24

CONTINUING EDUCATION

Maintenance Therapy for Non–Small-Cell Lung Cancer: A Value-Based Approach to Improve Patient Care and Outcomes, Part I of II PROGRAM P10065

PHARMACISTS’ DESIGNATION

Initial Release Date: October 15, 2010 • Expiration Date: October 15, 2011. Estimated time to complete activity: 1 hour.

Medical Learning Institute, Inc., is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal activity number for this activity is 0468-9999-10-059-H01-P. For questions regarding the accreditation of this activity, please contact Medical Learning Institute, Inc., at 609-333-1693 or cgusack@mlicme.org.

SPONSOR

This activity is jointly sponsored by Medical Learning Institute, Inc. (a nonprofit medical accreditation company), and Center of Excellence Media, LLC. TARGET AUDIENCE

This activity was developed for oncology pharmacists and other healthcare professionals practicing in oncology. LEARNING OBjECTIVES

• Evaluate the benefits and risks of maintenance therapy compared with re-treating upon disease progression in order to rationalize maintenance in patients with stage IIIB or IV non– small-cell lung cancer (NSCLC) who have responded to or are stable after induction therapy • Identify molecular and histologic characteristics of NSCLC tumors that impact choice of therapeutic agent for specific patient populations and formulate strategies for value-based care • Develop optimal side effect management strategies for patients receiving maintenance therapy for NSCLC in order to provide optimal care while considering the associated costs. COMMERCIAL SUPPORT ACkNOWLEDGMENT

This activity is supported by an educational grant from Eli Lilly and Company. INSTRUCTIONS FOR CREDIT

There is no fee for this activity. After reading this CE activity in its entirety, participants must complete the posttest and evaluation. The posttest and evaluation can be completed online at www.mlicme.org/P10065.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.

ung cancer is the most common type of cancer in the United States.1,2 An estimated 221,520 people (115,750 men and 105,770 women) will be diagnosed with cancer of the lung and bronchus in 2010, and only 15.8% of patients with lung cancer survive 5 years or more after diagnosis.3 Lung cancer accounts for more cancer deaths in the United States than any other type of cancer.4 Advances in surgical techniques and combined therapies have helped increase the 1-year relative survival for patients with lung cancer to 42% in 2002-2005, from 35% 2 decades earlier in 1975-1979.2 Although the 5year survival rate is greater than 50% for early-stage disease, unfortunately only 15% of lung cancers are detected when the disease is still localized.2 According to the National Cancer Institute, lung cancer costs the American public an estimated $10.3 billion a year and is the third costliest cancer after breast cancer and colorectal cancer.5 Furthermore, lung cancer tops the list in terms of lost productivity, accounting for $36.1 billion in lost lifetime earnings—lost productivity costs 3 times greater than those associated with breast cancer or colorectal

cancer.5 The financial burden of cancer may continue to expand with the aging of the US population, improved survival, and the increasing cost of cancer treatments.5 The median age at diagnosis of lung cancer is 71 years.3 As the baby boom generation (people born between 1946 and 1964) reaches age 65 and older over the next 2 decades,6 the number of Americans in this age-group is expected to increase by 36% from 2010 to 2020.7 Because lung cancer is widespread and carries a dire prognosis, urgency prevails in the search for better therapies and improved outcomes for patients. Efforts are particularly robust in non–small-cell lung cancer (NSCLC), which accounts for 85% of all cases.4 For patients with advanced NSCLC, maintenance therapy may help control the disease and extend a patient’s life.8 Administered after induction chemotherapy and generally in lower doses than initial chemotherapy, maintenance therapy often involves standard chemotherapy (an agent used in the initial treatment plan therapy or another drug), or it may include a combination of therapies, including vaccines,

VALUE-BASED CANCER CARE

October 2010

DISCLOSURES

Before the activity, all faculty will disclose the existence of any financial interest and/or relationship(s) they might have with the manufacturer(s) of any commercial product(s) to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speaker’s bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. Beth Eaby-Sandy, CRNP, is on the speaker’s bureau for Genentech, Eli Lilly and Company, and Merck. Loretta Fala participated in the development of this article. She has no financial relationships to disclose. The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CE activity for any amount during the past 12 months. DISCLAIMER

The information provided in this CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Trade names used in this supplement are for the learner’s reference only. No promotion of or bias toward any product should be inferred.

hormones, or other drugs.8 Decisions about maintenance therapy include consideration of the associated benefits, risks, and costs, as well as patientspecific factors and preferences. Two chemotherapy agents have recently received US Food and Drug Administration (FDA) approval for the maintenance therapy of patients with advanced NSCLC. Recent advances have also yielded a number of novel agents that target specific molecular pathways in tumor

For patients with advanced NSCLC, maintenance therapy may help control the disease and extend a patient’s life. cells, and research on these discoveries is ongoing. The molecular/genetic profiling of NSCLC can now be used to characterize tumors by their expression of specific markers. These molecular profiles hold promise for their potential in predicting a response, or resistance, to specific standard or novel ther-

apies and in identifying a benefit from a new or standard agent, based on clinical trial evidence.9 Maintenance Therapy Brings a New Treatment Approach for Advanced NSCLC Maintenance therapy, a relatively new paradigm in the treatment of NSCLC, constitutes a shift from the past paradigm of treating recurrent disease.10 However, maintenance therapy has been used for years in the treatment of patients with acute lymphocytic leukemia and acute myeloid leukemia to lower the risk of disease recurrence, and it is also being studied in a number of other cancers.8 Histologic information about the lung carcinoma is particularly useful for tailoring maintenance therapy toward improving outcomes for patients with NSCLC.11 Molecularly targeted agents, including those that inhibit epidermal growth factor receptor (EGFR) and vascular endothelial growth factor, also represent a crucial inroad into personalized therapy for patients with lung cancer.9 Maintenance therapy has been shown to prolong progression-free survival

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CONTINUING EDUCATION (PFS) and overall survival (OS) in the appropriate patients, based on randomized, controlled studies of 2 agents—pemetrexed and erlotinib.12-14 Pemetrexed In July 2009, pemetrexed was the first drug to be FDA-approved for maintenance therapy of advanced or metastatic lung cancer.15 Pemetrexed, a folate analog metabolic inhibitor, received this new indication specifically for patients with nonsquamous NSCLC that has not progressed after 4 cycles of platinum-based first-line chemotherapy.16 Pemetrexed is also indicated for initial treatment in combination with cisplatin, as well as after prior chemotherapy as a single agent in patients with locally advanced or metastatic nonsquamous NSCLC.16 Based on a randomized, doubleblind, phase 3 international study (N = 663), patients with stage IIIB or IV NSCLC (without progress after 4 cycles of platinum-based chemotherapy) who were treated with pemetrexed showed a significant improvement in PFS: 4.3 months (95% confidence interval [CI], 4.1-4.7) compared with 2.6 months (95% CI, 1.7-2.8) in the placebo group (hazard ratio [HR], 0.50; 95% CI, 0.420.61; P <.001).13 The pemetrexed group also showed a significantly greater OS: 13.4 months (95% CI, 11.9-15.9) versus 10.6 months (95% CI, 8.7-12.0) in the placebo group (HR, 0.79; 95% CI, 0.650.95; P = .012). No pemetrexed-associated mortalities occurred.13 Grade 3 or higher adverse events were more frequent in the pemetrexed group than in the placebo group, and included fatigue (5% vs 1%) and neutropenia (3% vs 0).13 The most common anygrade adverse reactions compared with placebo were nausea (19% vs 6%) and anorexia (19% vs 5%).16 Erlotinib In April 2010, the FDA approved an expanded indication for erlotinib, a tyrosine kinase inhibitor (TKI), as a maintenance treatment for patients with locally advanced or metastatic NSCLC whose disease has not progressed after 4 cycles of platinumbased first-line chemotherapy.17,18 Erlotinib is also indicated for the treatment of locally advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy regimen.18 Results from a randomized, doubleblind, international phase 3 study (N = 889) showed a significant median PFS of 12.3 weeks for patients in the erlotinib group versus 11.5 weeks for the placebo group (HR, 0.71; 95% CI, 0.62-0.82; P <.001).14 In patients with EGFR-positive immunohistochemistry treated with erlotinib, compared with EGFR-positive patients receiving

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placebo, PFS was also significantly longer in the erlotinib group (12.3 weeks) versus the placebo group (11.1 weeks; HR, 0.69; 95% CI, 0.58-0.82; P <.001).14 The study also showed an improvement in OS of 1 month with erlotinib versus placebo as maintenance therapy (HR, 0.81; 95% CI, 0.700.95; P = .009).18

Maintenance therapy constitutes a shift from the past paradigm of treating recurrent disease. Serious adverse events were reported in 11% of the patients in the erlotinib group compared with 8% in the placebo group; the most common serious adverse events were pneumonia (2% with erlotinib vs <1% with placebo).14 The most common grade 3 or higher adverse events included rash (9% in the erlotinib group vs 0 in the placebo group) and diarrhea (2% in the erlotinib group vs 0 in the placebo group).14 The most common any-grade adverse reactions compared with placebo were rash (49.2% vs 5.8%) and diarrhea (20.3% vs 4.5%).18 Maintenance Therapy: Benefits, Risks, and Costs Maintenance therapy is associated with several potential benefits, including preventing the recurrence of cancer, slowing disease growth, and prolonging life.8 However, these benefits must be weighed against potential risks, which include increased side effects, more frequent doctor visits, and drug resistance.8 Maintenance therapy may also be associated with higher treatment costs.8 In addition, the data on the survival benefits associated with maintenance therapy are limited,8 as are data on the quality of life associated with maintenance therapy8,19—in particular, the cumulative toxicity of prolonged chemotherapy.19 Other study limitations include the variability in measurable end points such as the definition of progression (in PFS) and frequency of response assessment; additionally, the use of multiple agents in the poststudy setting may confound the impact of maintenance treatment.19 Although patients receiving maintenance therapy may not have the opportunity of a reprieve from chemotherapy during the “wait-and-see” period, this period is often accompanied by anxiety about disease progression or recurrence.19 The rising cost of cancer care persists as a major healthcare challenge. The American Society of Clinical Oncology (ASCO) encourages members to dis-

cuss the cost of care directly with patients.10 Although maintenance chemotherapy for advanced NSCLC is associated with increased costs, it may decrease costs related to palliative radiotherapy and hospital admissions resulting from deteriorating performance status.12 Furthermore, the concept of extended survival—in terms of additional months, or even weeks of life—may represent an immeasurable benefit for patients and their loved ones. The Importance of Histology and Molecular Biomarkers Lung cancer is classified as either non–small-cell or small-cell, based on its biology, therapy, and prognosis.4 The 5-year survival rate for NSCLC is 17%, compared with a lower survival rate of 6% for small-cell lung cancer.2 NSCLC is categorized into 2 types: nonsquamous carcinoma (adenocarcinoma, large-cell carcinoma, and others) and squamous cell carcinoma.4 Squamous cell lung carcinoma accounts for 25% of lung cancers in the United States, whereas large-cell carcinoma (nonsquamous) accounts for 10% to 20% of all lung cancers.20 Identifying the histologic subtype of NSCLC is an essential step in selecting the appropriate therapy, and it may also be particularly useful when augmented by molecular testing.21 For example, the detection of the bronchoalveolar subtype of NSCLC adenocarcinoma may suggest a specific treatment strategy, particularly if it carries specific mutations in the EGFR tyrosine kinase domain, suggesting it will respond to treatment with an EGFR TKI.21 Several of the key predictive molecular biomarkers in the treatment of NSCLC include4: • Presence of the EGFR exon 19 deletion or exon 21 L858R mutation is associated with a treatment benefit from EGFR TKI therapy • High levels of ERCC1 expression are associated with a poor response to platinum-based chemotherapy • The presence of KRAS mutations is associated with a lack of benefit from platinum/vinorelbine chemotherapy or from EGFR TKI therapy • High levels of RRM1 expression are associated with a poor response to gemcitabine-based chemotherapy. Patients with EGFR mutations E19 deletion and L858R mutation have shown a significantly better response to erlotinib or gefitinib (both EGFR TKI agents), with initial retrospective studies suggesting that an estimated 90% of patients with a tumor response to these agents had mutations, whereas patients without a response did not have these mutations.4

According to the National Comprehensive Cancer Network (NCCN) practice guidelines for NSCLC, pathologic evaluation should be performed to classify the lung cancer, determine its extent of invasion, determine the status of surgical margins, and identify molecular abnormalities that may predict the benefit of, or resistance to, EGFR TKI therapy.4 Preoperative assessment may include bronchial brushings or washings, fine-needle aspiration biopsy, core needle biopsy, endobronchial biopsy, transbronchial biopsy, as well as sampling of mediastinal lymph nodes to stage the disease and help determine therapeutic options. Intraoperative (lobectomy or pneumonectomy) evaluation may include determining the surgical resection margin status, diagnosing any incidental nodules found during the surgery, or checking the status of regional lymph nodes.4 Postoperative pathology provides information neces-

Although maintenance chemotherapy for advanced NSCLC is associated with increased costs, it may decrease costs related to palliative radiotherapy and hospital admissions. sary for classifying the tumor type, stage, and prognostic factors. According to NCCN guidelines, the surgical pathology report should use the histologic classifications established by the World Health Organization for lung carcinomas.4 Adequate tissue sampling may provide the key to identifying the treatment most appropriate for a specific patient and improving the likelihood of identifying an effective treatment as early as possible.21 Refinements in histology and the evolving role of molecular testing will undoubtedly play a role in predicting responses to particular treatments for NSCLC.21 Clinical Practice Guidelines for Maintenance Therapy The NCCN practice guidelines for NSCLC, which were updated in March 2010, added a new section with recommendations on maintenance therapy (Table). Although ASCO released a clinical practice guideline update on chemotherapy for stage IV NSCLC, the guideline went to press in 2009 without the opportunity of a comprehensive data review on recent data supporting the indication/use of pemetrexed for Continued on page 26

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CONTINUING EDUCATION

Maintenance Therapy for NSCLC... maintenance therapy in patients with advanced NSCLC.22 In this 2009 update, ASCO included an announcement that an update would be forthcoming on consideration of relevant data on the use of pemetrexed in maintenance therapy. Results of 2 studies evaluating erlotinib as maintenance therapy were also anticipated by the ASCO review committee at the time of the 2009 guideline publication.22

Selecting the appropriate patient population is a guiding factor in selecting the appropriate maintenance therapy. In June 2010, the National Institute for Health and Clinical Excellence, based in London, issued guidance to the National Health Service, United Kingdom, recommending pemetrexed for the maintenance treatment of NSCLC.23 The guidance states that pemetrexed is recommended as an option for maintenance therapy in people with locally advanced or metastatic NSCLC other than predominantly squamous cell histology if the cancer has not progressed immediately after platinum-based chemotherapy in com-

bination with gemcitabine, paclitaxel, or docetaxel.23,24 It also states that people who have received pemetrexed in combination with cisplatin as first-line therapy cannot receive pemetrexed maintenance treatment.23,24 Maintenance Therapy Considerations Treatment considerations include the stage of the cancer and invasion status, the type of cancer, the patient’s performance status, patient-specific preferences, the costs of treatment, as well as other patient- and agent-specific factors. Evidence-based clinical practice guidelines can be a valuable decision-support resource for clinicians. Selecting the appropriate patient population, as characterized by histologic (nonsquamous) or molecular (EGFR mutation) profile, is a guiding factor in selecting the appropriate maintenance therapy.19 Furthermore, the use of a well-characterized tumor profile as a tool for selecting the appropriate patients for maintenance therapy may improve the therapeutic index, and thereby improve the survival benefit in these patients.19 In addition, identifying predictive biomarkers for specific agents used in maintenance therapy may help to improve the benefits and reduce risks. Pemetrexed is a maintenance therapy option for patients with

Table NCCN Guideline Recommendations (March 2010) for NSCLC Maintenance Therapy Continuation Maintenance Therapya

Switch Maintenance Therapyb

Continue with biologic agents (given initially in combination with conventional chemotherapy) until disease progression or unacceptable toxicity (per clinical trial design that led to approval): • Bevacizumab may be continued beyond 4-6 cycles of platinum-doublet chemotherapy given with bevacizumab (Category 1) • Cetuximab may be continued beyond 4-6 cycles of therapy with cisplatin, vinorelbine, and cetuximab (Category 1) • Pemetrexed may be continued after 46 cycles of therapy with cisplatin and pemetrexed for patients with nonsquamous cell carcinoma (Category 2B)

Initiation of pemetrexed or erlotinib after first-line chemotherapy (4-6 cycles) in patients without disease progression, based on 2 recent studies demonstrating a benefit in progression-free survival and overall survival: • Pemetrexed may be initiated after 4-6 cycles of first-line platinum-doublet chemotherapy in patients with nonsquamous cell carcinoma (Category 2B) • Erlotinib may be initiated after 4-6 cycles of first-line platinum-doublet chemotherapy (Category 2B) • Docetaxel may be initiated after 4-6 cycles of first-line platinum-doublet chemotherapy (Category 3)

• No randomized trial data are available to support continuing maintenance of conventional cytotoxic agents beyond 4-6 therapy cycles • Pemetrexed is not recommended for patients with squamous cell carcinoma • Close follow-up without therapy is a reasonable alternative to switch maintenance a

Continuation maintenance = use of at least 1 of the agents administered as first-line therapy. Switch maintenance = initiation of an agent that was not included as part of the first-line treatment regimen. NCCN indicates National Comprehensive Cancer Network; NSCLC, non–small-cell lung cancer. Data adapted from reference 4. Refer to that source for definitions of evidence categories. b

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October 2010

Continued from page 25

nonsquamous histology.4 Moreover, a molecular-based strategy may be important for selecting the appropriate subgroup of patients best suited for maintenance therapy with erlotinib.19 The risks and benefits of maintenance therapy must be considered and weighed, along with the safety, efficacy, and tolerability of the agents used in this setting. Similarly, the risks associated with delaying additional therapy must also be considered: a delay strategy may be associated with a faster disease progression and shorter survival time than immediate additional therapy.25,26 Extending chemotherapy, particularly with a third-generation regimen, has been shown to improve PFS substantially, and OS modestly.26 Conclusion Maintenance therapy represents a new treatment paradigm for patients with advanced NSCLC, given its potential for improved survival. Ideally, the agent selected for maintenance therapy should be well-tolerated by the patient, have minimal side effects/cumulative toxicities, and demonstrate improved patient outcomes.19 The histology of the carcinoma is an important tool in tailoring maintenance therapy for a specific patient. In addition, molecular profiling can help characterize tumors and predict response or resistance after standard or novel therapies.27 Molecular tests will continue to play an important role in redefining patients with NSCLC into specific subgroups that may respond to different optimal treatment pathways.22 The risks and benefits of maintenance therapy must be considered and addressed with the patient. Similarly, the risks and benefits of a delayed/waitand-see treatment approach must likewise be weighed carefully. The future holds promise, based on recent advances that foster targeted, personalized treatment approaches with the potential to improve response and survival for patients with advanced NSCLC. ■ References 1. National Cancer Institute, National Institutes of Health. Common cancer types. www.cancer.gov/cancer topics/typescommoncancers. Accessed September 21, 2010. 2. American Cancer Society. Cancer Facts & Figures 2010. Atlanta, GA: American Cancer Society; 2010. 3. National Cancer Institute, National Institutes of Health. Surveillance Epidemiology and End Results. SEER Stat Fact Sheets: Lung and Bronchus. http://seer.cancer.gov/statfacts/html/lungb.html. Accessed September 20, 2010. 4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, V.2.2010. March 5, 2010. www.nccn.org/ professionals/physician_gls/PDF/nscl.pdf. Accessed September 15, 2010.

5. Wang BH. The financial burden of cancer—NCI benchmarks. April 23, 2010. http://benchmarks.can cer.gov/2010/04/the-financial-burden-of-cancer/. Accessed September 20, 2010. 6. Vincent GK, Velkoff VA. The Next Four Decades, the Older Population in the United States: 2010 to 2050. Current Population Reports, P25-1138. Washington, DC: US Census Bureau: May 2010. 7. US Department of Health and Human Services, Administration on Aging. A Profile of Older Americans: 2007. www.agingcarefl.org/aging/AOA-2007 profile.pdf. Accessed August 27, 2010. 8. American Society of Clinical Oncology. Explaining maintenance therapy. Cancer.net. Updated February 22, 2010. www.cancer.net/patient/All+About+Cancer/ Cancer.Net+Feature+Articles/Treatments%2C+Tests %2C+and+Procedures/Explaining+Maintenance+ Therapy. Accessed September 20, 2010. 9. Herbst RS, Lippman SM. Molecular signatures of lung cancer—toward personalized therapy [editorial]. N Engl J Med. 2007;356:76-78. 10. Peck P. Maintenance pemetrexed extends NSCLC survival by three months. Medpage Today. May 30, 2009. www.medpagetoday.com/tbprint.cfm?tbid=14437. Accessed September 22, 2010. 11. Lilly receives fourth FDA approval for ALIMTA— first chemotherapy approved as maintenance therapy for nonsquamous non-small cell lung cancer. Medical News Today. July 8, 2009. www.medicalnewstoday. com/articles/156659.php. Accessed September 22, 2010. 12. Eaton KD. Maintenance chemotherapy in nonsmall cell lung cancer. J Natl Compr Canc Netw. 2010;8: 815-821. 13. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for nonsmall-cell lung cancer: a randomized, double-blind, phase 3 study. Lancet. 2009;374:1432-1440. Epub September 18, 2009. 14. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced nonsmall-cell lung cancer: a multicentre, randomized, placebo-controlled phase 3 study. Lancet Oncol. 2010;11:521-529. Epub May 20, 2010. 15. Riley K. FDA approves first maintenance drug therapy for advanced lung cancer [press release]. July 6, 2009. US Food and Drug Administration. www.fda. gov/NewsEvents/Newsroom/PressAnnouncements/ ucm170515.htm. Accessed September 22, 2010. 16. Alimta (pemetrexed disodium) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2010. 17. Waknine Y. FDA approves use of erlotinib as maintenance therapy for advanced non-small cell lung cancer [press release]. April 20, 2010. www.medscape.com/ viewarticle/720446. Accessed September 22, 2010. 18. Tarceva (erlotinib) [package insert]. Melville, NY: OSI Pharmaceuticals Inc; and South San Francisco, CA: Genentech; 2010. 19. Owonikoko TK, Ramalingam SS, Belani CP. Maintenance therapy for advanced non-small cell lung cancer: current status, controversies, and emerging consensus. Clin Cancer Res. 2010;16:2496-2504. 20. Cleveland Clinic. Lung cancer overview. Reviewed October 23, 2008. http://my.clevelandclinic.org/ disorders/Lung_Cancer/hic_Lung_Cancer.aspx. Accessed September 23, 2010. 21. Neal JW. Histology matters: individualizing treatment in non-small cell lung cancer [editorial]. Oncologist. 2010;15:3-5. Epub January 19, 2010. 22. Azzoli CG, Baker S Jr, Temin S, et al. American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol. 2009;27:6251-6266. 23. NICE recommends pemetrexed for the maintenance treatment of non-small-cell lung cancer [press release]. Medical News Today. June 23, 2010. www.med icalnewstoday.com/articles/192709.php. Accessed September 22, 2010. 24. National Institute for Health and Clinical Excellence (NICE). Final appraisal determination—pemetrexed for the maintenance treatment of non-small cell lung cancer. March 2010. www.nice.org.uk/nicemedia/ live/12091/48303/48303.pdf. Accessed September 22, 2010. 25. Belani CP, Liao J. Maintenance therapy for nonsmall cell lung cancer [comment]. Lancet. 2010;375: 281-282; Stinchcombe T, West H. Comment in: Lancet. 2009;374:1398-1400. 26. Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration of chemotherapy for advanced non-smallcell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol. 2009;27:32773283. Epub May 26, 2009. 27. Herbst RS, Heymach JV, Lippman SM. Molecular origins of cancer. N Engl J Med. 2008;359:1367-1380.

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A Friday Satellite Symposium preceding the 52nd ASH Annual Meeting

Challenging Cases in Multiple Myeloma A Dialogue Between Community and Academic Clinicians to Improve Patient Care and Outcomes December 3, 2010 Rosen Centre Hotel Ballrooms A & B, Orlando, Florida

PROGRAM AGENDA

This continuing medical education symposium will serve as a forum for discussion of current questions and concerns regarding the treatment and management of patients through the multiple myeloma (MM) life cycle. A panel of domestic and international myeloma experts will be joined by representatives from community cancer care facilities and private oncology practices. By thoroughly engaging participants with interactive cases and physician point-counterpoint-style discussions, this symposium will provide evidence-based treatment and management recommendations and address new treatment regimens and management strategies based on recent clinical trials and emerging data. In addition to considering differences in domestic and international care, barriers and/or limitations faced by community cancer centers and private-practice oncologists will be debated.

12:30 -

1:00 PM

Registration and Lunch Service

1:00 -

1:10 PM

Welcome and Introduction Sundar Jagannath, MD - Chair

CASE PRESENTATIONS Each case will be presented by an expert faculty member and discussed by the international and community panel. 1:10 – 1:40 PM

Case 1: Difficult diagnosis G. David Roodman, MD, PhD

1:40 – 2:10 PM

Case 2: Newly diagnosed, stem cell transplant eligible patient Sundar Jagannath, MD

2:10 – 2:40 PM

Case 3: First-line therapy in a non-SCT eligible patient Stefan Knop, MD

2:40 – 3:10 PM

Case 4: Multiple risk factors Jonathan L. Kaufman, MD

3:10 – 3:40 PM

Case 5: Treatment of MM across the life cycle Noopur Raje, MD

3:40 -

3:50 PM

Question & Answer Session

3:50 -

4:00 PM

Closing Remarks Sundar Jagannath, MD

LEARNING OBJECTIVES At the end of this activity participants will be able to: • Apply early management strategies that consider new diagnostic and staging criteria for SMM, MGUS, and MM and new imaging studies in order to improve prognosis for your patients. • Evaluate novel therapeutic regimens as induction therapy for your patients considering an SCT in order to provide the most rapid response and allow the largest amount of stem cell collection, while maintaining safety and tolerance. • Integrate novel agent-based regimens that provide optimal outcomes and a survival benefit into your management strategy for patients ineligible for SCT after appraising emerging data from clinical trials. • Identify patient- and disease-associated factors that impact choice of therapeutic agent and formulate management strategies using a risk-adapted approach to treatment of MM. • Construct optimal treatment regimens based on novel combinations and make informed treatment decisions in order to improve the long-term outlook for myeloma patients across the life cycle of the disease.

TARGET AUDIENCE This activity has been developed for hematologists and medical oncologists, as well as nurses, pharmacists, and other allied health professionals who are interested in meeting the challenges faced when treating patients with multiple myeloma in academic and community settings.

ACCREDITATION INFORMATION Physician Accreditation The University of Cincinnati designates this activity for a maximum of 3 AMA PRA Category 1 Credits ™. The University of Cincinnati 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 3.0 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 3.0 contact hours (0.3 CEUs) of continuing education credit. The universal activity number for this activity is 0468-9999-10-058-L01-P.

FACULTY CHAIR: Sundar Jagannath, MD Professor, Hematology and Medical Oncology Mount Sinai School of Medicine’s Tisch Cancer Institute Director of the Multiple Myeloma Program, The Mount Sinai Medical Center New York, NY Leon Dragon, MD, FACP Medical Director Kellogg Cancer Center Northshore University HealthSystem Highland Park, IL Charles M. Farber, MD, PhD Section Chief of Hematology and Oncology Department of Medicine Carol G. Simon Cancer Center, Morristown, NJ Shoba Kankipati, MD Associate Physician EPIC Care East Bay Partners in Cancer Care San Francisco Bay Area, CA Jonathan L. Kaufman, MD Assistant Professor Blood and Marrow Transplantation Department of Hematology and Medical Oncology Emory University School of Medicine Member, Winship Cancer Institute Emory University, Atlanta, GA

ACKNOWLEDGMENT This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.

This activity is jointly sponsored by the University of Cincinnati, Medical Learning Institute, Inc., a nonprofit medical accreditation company, and Center of Excellence Media, LLC.

Stefan Knop, MD University Hospital Würzburg Würzburg, Germany Noopur Raje, MD Associate Professor of Medicine Harvard Medical School Director, Center for Multiple Myeloma Massachusetts General Hospital Boston, MA G. David Roodman, MD, PhD Professor of Medicine Vice Chair for Research Department of Medicine Director, Myeloma Program Director, Bone Biology Center University of Pittsburgh Medical Center Pittsburgh, PA Ari Umutyan, MD Redwood Regional Medical Group Hematology and Medical Oncology Napa, CA

VBCC_October_100810_Follow ASCO Tabloid 10/12/10 2:35 PM Page 28

Image: Colored scanning electron micrograph (SEM) of a pancreatic cancer cell.

goal One goal: discovering and delivering breakthrough medicines to combat cancer. Now the innovative science of a leading American biopharmaceutical company joins the global assets of Takeda, Japanâ&#x20AC;&#x2122;s largest pharmaceutical company, for a global commitment to oncology. Millennium: The Takeda Oncology Company is developing an extensive pipeline â&#x20AC;&#x201D; among the top in oncology worldwide â&#x20AC;&#x201D; with more than 17 compounds in development for a broad range of solid and hematological cancers. Our pipeline â&#x20AC;&#x201D; rich in novel compounds â&#x20AC;&#x201D; includes multiple candidates that target seven disease pathways: protein homeostasis, anti-angiogenesis, growth-signaling inhibition, cell-cycle inhibition, apoptosis, immunomodulators and hormone regulation. We are dedicated to a strong partnership with the oncology community. Together we can make a dramatic impact on cancer therapeutics over the next decade.

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