August 2015 by McMahon Group

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Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • August 2015 • Vol. 10, No. 8

HEMATOLOGIC DISEASE Report From ASCO Meeting: Carfilzomib Bests Bortezomib in ENDEAVOR Relapsed MM Trial ...................................... 6 RAPID Study Prompting Change in Approach to Early-Stage HL .......................

Srdan Verstovsek, MD: How I Manage Primary Myelofibrosis ...........................

SOLID TUMORS Massimo Cristofanilli, MD: How I Manage Luminal A and Luminal B Breast Cancers .................................. 10 Report From ASCO Meeting: Ablation of Unresectable CRC Liver Metastases Yields Big OS Benefit ........ 13

CURRENT PRACTICE Cytotoxic vs targeted therapy: looking for cancer cures ...........................

by the

numbers

Predicted 10-y Incidence of CRC on Follow-Up Colonoscopy Men

Women

791

378

per 100,000 person-years

Story on page 14

Report From ASCO Meeting

Should WBRT Be Added to SRS for Brain Metastases? N0574 results add no support, but update of previous Japanese trial showed increased OS Chicago—In cancer patients with one to three brain metastases, adding whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) does not improve overall survival and has negative effects on cognitive function and quality of life (QoL) compared with SRS alone, according to results from the Phase III N0574 trial presented at the plenary session at the see BRAIN METASTASES, page 24

Micrograph of oral cancer, including cancer of the lips and tongue; elective neck dissection should be the standard of care for early-stage, clinically node-negative oral cancers. Story on page 18.



ASCO Roundup: Several Key MM Trials Offer Promise

Value in Cancer Care:

It’s Time for Change

espite advances in understanding disease biology, multiple myeloma (MM) largely remains an incurable yet controllable disease. Survival outcomes have improved since the integration of protea- Saad Usmani, MD some inhibitors and immunomodulatory drugs into MM therapy throughout the early to late 2000s, and now several new drug classes and immunotherapy approaches in various stages of clinical development are showing promise. Several key clinical trials in MM were presented at the 2015 annual meeting of the see MM TRIALS, page 5

or years, health care experts have been sounding the alarm that rising health care costs are unsustainable and more emphasis needs to be placed on value, particularly in cancer care. In late June, the American Society of Clinical Oncology (ASCO) released a conceptual framework for assessing the value of cancer treatment options. The document proposes a methodology to compare the relative clinical benefits, side effects and costs of treatment regimens that have been tested head-to-head in randomized clinical trials. “Our goal is to drive discussion and debate on this critical issue, and we are soliciting feedback from stakeholders. That feedback will inform the evolution of the framework, which I’m sure will change over time and, ultimately, [will result in] … a user-friendly tool for physicians and patients in the clinic,” said Julie Vose, MD, the ASCO president and the chief of oncology/hematology at University of Nebraska Medical Center, in Omaha.

Proposed Framework To Empower Patients The framework—developed by the 22-member ASCO Value in Cancer Care Task Force, in collaboration with patient advocates, physicians, payors and pharmaceutical manufacturers—was published in the Journal of Clinical Oncology (2015 Jun 22. [Epub ahead of



see VALUE, page 22

RE VIE WS & COMMENTAR IES

Expert Insights From NYP/Weill Cornell Medical Center Ibrutinib effective as rescue for Waldenstrom’s macroglobulinemia ....................................... 20

Irinotecan found equal to irinotecan + cisplatin in small gastric cancer study ............................. 19 Manish Shah, MD

Peter Martin, MD



The New Standard for Bone Marrow Biopsies Starts Here Larger specimens with a better patient experience.1, 2 For blood-borne cancer patients and their treating oncologists, a manually performed bone marrow biopsy is a critical, but often painful, procedure for diagnosis and treatment monitoring. The procedure is often physically taxing on clinical staff who must obtain a sample of adequate size and quality. Ultimately, the accuracy of the diagnosis determined by pathology is directly related to the integrity of this specimen. The ARROW® OnControl® Powered Bone Marrow Biopsy System is used for obtaining bone marrow samples in major cancer centers throughout the country. With the ARROW OnControl System, you can be conﬁdent in developing treatment plans based on the diagnosis you receive: • Larger specimens provide more usable area for diagnosis • Reduced insertion pain,1 less overall pain,3 and helps promote patient compliance3, 4 • Shorter procedure time improves efﬁciency4 Relative size comparison of manual sample to a sample obtained using the ARROW® OnControl® System

Procedure times decrease dramatically1 Comparison of mean time to sample on ﬁrst attempts Manual procedure Powered procedure

Manual Needle Core Sample

55% % Faster Fast ter

ARROW OnControl System’s Core Sample Both sample s sizes from same healthy subject, same provider. Sample sizes are most representative of sample means in a published healthy subject study.

The ARROW OnControl Bone Marrow Aspiration and Biopsy Systems should only be used by clinicians familiar with the complications, limitations, indications, and contraindications of bone marrow aspiration and bone marrow biopsy. 1. Swords RT, Anguita J, Higgins RA, et al. A prospective randomized study of a rotary powered device (OnControl) for bone marrow aspiration and biopsy. J Clin Pathol 2011; 64(9): 809-13. doi:10.1136/jclinpath-2011-200047. * 2. Reed LJ, Raghupathy R, Strakhan M et al. The OnControl bone marrow biopsy technique is superior to the standard manual technique for hematologists-in-training: a prospective, randomized comparison. Hematology Reports 2011; 3(e21). doi:10.4081/hr.2011.e21. * 3. Miller LJ, Philbeck TE, Montez DF, et al. Powered bone marrow biopsy procedures produce larger core specimens, with less pain, in less time than with standard manual devices. Hematology Reports 2011; 3:e8. * 4. Berenson JR, Yellin O, Blumenstein B, et al. Using a powered bone marrow biopsy system results in shorter procedures, causes less residual pain to adult patients, and yields larger specimens. Diagnostic Pathology 2011; 6:23.* * Research sponsored by Teleflex Incorporated or its affiliates, including Vidacare LLC Teleflex, Arrow, Never Settle and OnControl are trademarks or registered trademarks of Teleflex Incorporated or its affiliates. © 2015 Teleflex Incorporated. All rights reserved. MC-001096 Rev 1

TELEFLEX 3015 Carrington Mill Boulevard, Morrisville, NC 27560 Toll Free: 866.246.6990 Phone: +1.919.544.8000 TELEFLEX.COM

CLINICAL ONCOLOGY NEWS

CliniCal OnCOlOgy news • august 2015 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center Penn State University Hershey, PA

Breast Cancer Andrew Seidman, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Hematologic Malignancies

Betty Ferrell, RN, PhD

Joseph P. DeMarco, PhD

Cancer Treatment Centers of America Zion, IL

City of Hope National Medical Center Duarte, CA

Cleveland State University Cleveland, OH

Jennifer R. Brown, MD, PhD

Michele Neskey, MMSc, PA-C

Paul J. Ford, PhD

Dana-Farber Cancer Institute Harvard Medical School Boston, MA

University of Texas, MD Anderson Cancer Center Houston, TX

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Harry Erba, MD, PhD University of Alabama Birmingham, AL

Shaji Kumar, MD Mayo Clinic Rochester, MN

University of Pittsburgh Cancer Institute Pittsburgh, PA

Cathy Eng, MD University of Texas, MD Anderson Cancer Center Houston, TX

Leonard Saltz, MD Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

Levine Cancer Institute Carolinas HealthCare Charlotte, NC

Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO

Michael J. Fisch, MD, MPH University of Texas, MD Anderson Cancer Center Houston, TX

Gynecologic Cancer

Steven Vogl, MD Medical Oncologist New York, NY

Symptom Control and Palliative Care

Cancer Treatment Centers of America Philadelphia, PA

Memorial Sloan-Kettering Cancer Center New York, NY

Steven D. Passik, PhD

Edward S. Kim, MD

Millennium Health San Diego, CA

Levine Cancer Institute Carolinas HealthCare Charlotte, NC

Joseph V. Pergolizzi Jr., MD Johns Hopkins University School of Medicine Baltimore, MD

Richard J. Gralla, MD Albert Einstein College of Medicine New York, NY

Prostate Cancer Michael A. Carducci, MD Johns Hopkins Kimmel Cancer Center Baltimore, MD

Sara S. Kim, PharmD

Infection Control Susan K. Seo, MD Memorial Sloan-Kettering Cancer Center New York, NY

Russell K. Portenoy, MD MJHS Hospice and Palliative Care Albert Einstein College of Medicine New York, NY

Charles F. von Gunten, MD, PhD University of California San Diego, CA

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HEMATOLOGIC DISEASE

CliniCal OnCOlOgy news • august 2015 • CLINICALONCOLOGY.COM

MM TRIALS continued from page 1

American Society of Clinical Oncology. Zimmerman et al presented a Phase II trial in transplant-eligible patients with newly diagnosed MM, in which induction, post-transplant consolidation, and post-transplant maintenance with the combination of carfilzomib (Kyprolis, Onyx), lenalidomide (Revlimid, Celgene), and dexamethasone (KRd) was shown to have unprecedented stringent complete response rates of 87% (abstract 8510). Although the results are preliminary, they support further evaluation of KRd in the front-line setting. The CALGB (Cancer and Leukemia Group B) 100104 data also were updated, showing continued survival benefit in favor of post-transplant maintenance with lenalidomide versus placebo (median time to progression, 53 vs 27 months; hazard ratio [HR], 0.54; P<0.001; median overall survival [OS] not reached vs 76 months [HR, 0.60; P=0.001]) (abstract 8523). Data from 3 Phase III trials in relapsed and relapsed/refractory MM in patients

with 1 to 3 prior lines of therapy were presented. The ENDEAVOR trial compared carfilzomib-dexamethasone with bortezomib (Velcade, Millennium)-dexamethasone and demonstrated a superior overall response rate (ORR) (76.9% vs 62.6%; P<0.0001), along with near doubling of median progression-free survival (PFS) (18.7 vs 9.4 months; HR, 0.53; P<0.0001) with the carfilzomib combination (abstract 8509; see related story, page 8). The ELOQUENT-2 trial compared lenalidomide-dexamethasone either with or without elotuzumab, showed statistically significant ORR (79% vs. 66%; P=0.0002) and median PFS benefit (19.4 vs 14.9 months; HR, 0.70; P=0.0004) (abstract 8508; see related story, http:// bit.ly/1DM9Yqh). The ASPIRE updated trial data were presented, continuing to show better ORR and median PFS in favor of carfilzomib-lenalidomide-dexamethasone compared with lenalidomidedexamethasone (29.2 vs. 17.6 months; P=0.0083) in patients in first relapse (abstract 8525). Based on these results, on July 24, the FDA approved carfilzomib in combination with lenalidomide and dexamethasone in patients with relapsed MM.

It is important to appreciate that the patient populations in the 3 studies were different (prior therapies received, cytogenetics/risk categories). The ELOQUENT-2 and ASPIRE trials primarily included bortezomib-exposed or refractory patients; lenalidomide-refractory patients were excluded. The ENDEAVOR trial included patients with prior lenalidomide exposure/refractoriness but excluded bortezomib-refractory patients. The ELOQUENT-2 trial appeared to have a higher proportion of high-risk cytogenetics compared with the other 2 trials. As these drugs/drug combinations gain FDA approval for this indication, it will be important to appreciate these nuances to help choose the best strategy for a given patient. Within the studies of relapsed/refractory MM patients, there were 2 additional abstracts of note. A Phase II trial of the anti-CD38 monoclonal antibody daratumumab (Johnson & Johnson) in patients with at least 3 lines of prior therapy or double-refractory MM (median of 5 prior lines of treatment) demonstrated a 29.2% ORR, with a median PFS of 3.7 months (abstract LBA8512). The most common

EDITORIAL BOARD COMMENTARY Saad Usmani, MD Director of the Plasma Cell Disorders Program Levine Cancer Institute/ Carolinas HealthCare System Charlotte, North Carolina

adverse event (AE) was grade 1 to 2 infusion-related reactions, which occurred in 42.5% of patients, mostly during the first infusion. Based on these data, several Phase III studies are underway to combine daratumumab with existing drug classes in earlier lines of MM therapy. In a Phase I/II trial, the combination of carfilzomib-panobinostat (Farydak, Novartis)dexamethasone appeared to be safe and efficacious in patients with a median of 3 prior lines of therapy (abstract 8513). The most common AEs that were at least grade 3 included thrombocytopenia (31%), fatigue (4%), and diarrhea (4%). This study has revived hope for panobinostat as a new platform drug ■ in MM.

Look for the following hematologic chapters coming soon: Chronic Lymphocytic Leukemia

Polycythemia Vera

Myelofibrosis

by John Arnason, MD, Beth israel Deaconess Medical Center, and Jennifer R. Brown, MD, PhD, Dana-Farber Cancer institute

by Constantine Tam, MD, Peter MacCallum Cancer Center and Srdan Verstovsek, MD, university of texas MD anderson Cancer Center

by Fabios Santos, MD, and Srdan Verstovsek, MD, university of texas MD anderson Cancer Center

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HEMATOLOGIC DISEASE

CliniCal OnCOlOgy news • august 2015 • CLINICALONCOLOGY.COM

RAPID Study Prompts Changing Approach to Early HL I

n the latest of ongoing efforts to determine the least amount of treatment necessary to cure patients with Hodgkin lymphoma (HL), a recent study shows that most early-stage patients who are positron emission tomography (PET)-negative after chemotherapy do well whether or not they receive radiotherapy. There was a slight advantage in the radiation group in terms of progression-free survival (PFS), according to the results published in The New England Journal of Medicine (2015;372[17]:1598-1607, PMID: 25901426), but an accompanying editorial questioned whether it was enough to justify exposing all patients to radiotherapy (N Engl J Med 2015;372[17]:1667-1669, PMID: 25901431). “This study starts to change the way we think about treatment for early-stage HL, from [an approach] that depends on pretreatment stratification to one that looks at responsiveness to therapy as the indicator of how much treatment we should give,” said investigator John Radford, MD, a professor of medical oncology and the director of research at The University of Manchester, in England. “It’s not the whole answer, but I think it’s pointing us in the right direction, and future studies will help clarify the outstanding questions.” To investigate the need for radiotherapy after chemotherapy, Dr. Radford and his colleagues performed PET scans on 571 patients with early-stage HL after three rounds of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). In those with negative findings, 209 were randomly assigned to radiotherapy and 211 to no radiotherapy, whereas those with positive findings were assigned to a fourth round of ABVD and radiotherapy. The trial, known as the RAPID trial, was designed to show noninferiority of no further treatment in terms of PFS of

‘This study is not the whole answer, but I think it’s pointing us in the right direction.’ —John Radford, MD

seven percentage points or more. At three years, PFS was 94.6% in the group that received radiotherapy, compared with 90.8% in the group that did not. Dr. Radford and his coinvestigators concluded that although the study did not show noninferiority of the more minimal strategy (the 95% CI for the nonradiotherapy arm would have needed to be within 88% to 95% to have met the criteria for noninferiority; it was 86.9%-94.8%), patients with negative PET findings after three rounds of ABVD had a very good prognosis with or without radiotherapy. The accompanying editorial and other experts raised a number of questions about the trial, one of which was that the noninferiority margin initially was set at 10 percentage points but was later lowered based on peer opinion. Dr. Radford explained that “the point of a noninferiority margin is to balance things, in this instance, maximizing disease eradication and minimizing treatment and late toxicity. In this case, there was a small advantage for those receiving radiotherapy but at the expense of all PET-negative patients being irradiated, many of whom don’t need it.” Another point raised in the editorial is that a baseline PET scan was not performed, a weakness that Dr. Radford

acknowledged and said was unavoidable. “We simply could not get funding for that at the time, but it is now routine practice in the U.K. and the rest of Europe.” One expert questioned why the researchers did not use more specific criteria for defining early-stage HL, such as those described by the German Hodgkin Study Group (GHSG) or European Organisation for Research and Treatment of Cancer. Rather, they identified patients as early stage if they had stage IA or IIA with no bulky disease. “A lot of work has gone into defining early stage over the years using pretreatment characteristics, but we may be moving to a simpler way of defining what early stage means, using PET as a way to discriminate those people who need more treatment from those who need less,” Dr. Radford said. Another notable difference between the RAPID trial and other studies is that the researchers considered patients PETnegative with a Deauville score of 1 or 2, but not 3. “We established a conservative definition of negative because we were de-escalating treatment and wanted to be sure we were not de-escalating inappropriately,” Dr. Radford explained. Yasuhiro Oki, MD, an assistant professor at the University of Texas MD

Anderson Cancer Center, in Houston, said he would keep that in mind when advising patients. “In patients who are PET-negative with a Deauville score of 3, which in many situations is considered negative, I would tell them that in the RAPID study, they would be assigned to the PET-positive group and strongly advised to have radiation,” Dr. Oki said. In general, Dr. Oki would still advise patients with early-stage favorable disease as defined by the GHSG (two sites or less, low erythrocyte sedimentation rate, nonbulky and with no extranodal involvement) to undergo radiation after two rounds of ABVD, an approach shown to be minimally toxic and as effective as more treatment in patients with early-stage, favorable disease in the HD10 study (N Engl J Med 2010;363[7]:640-652, PMID: 20818855). “If there is no pressing reason to drop the radiation therapy, I would give two rounds of ABVD and 20 Gy for early-stage favorable disease because then they do not have to go through [a potential] four rounds. Two extra rounds of chemotherapy is not nothing,” Dr. Oki said. Dr. Radford said that at this point, the results of the RAPID trial allow for greater individualization of therapy. Whereas it may be advisable to offer radiotherapy to an older patient, where the main risk is recurrence and the need for salvage therapy, in a younger patient it may be better to avoid radiation when possible to reduce the risk for secondary cancers. “If they get a negative PET scan,” he said, “we know it’s a good option for them to have just chemotherapy because there is a very good chance [that] they will be cured by the chemotherapy alone.” —Monica J. Smith Drs. Radford and Oki reported no relevant financial conflicts of interest.

Report From ASCO Annual Meeting:

Carfilzomib Bests Bortezomib in Trial of Relapsed MM Chicago—Carfilzomib doubled progression-free survival (PFS) relative to bortezomib in patients with relapsed multiple myeloma (MM) during the large multicenter, Phase III ENDEAVOR trial, the first head-tohead study of proteasome inhibitors in this setting. Relative to bortezomib (Velcade, Millennium) and dexamethasone (Vd), which has been a standard regimen in relapsed MM, carfilzomib (Kyprolis, Onyx) and dexamethasone (Kd) resulted in a PFS advantage that was

characterized as a “remarkable improvement” by principal investigator Meletios A. Dimopoulos, MD, the chairman of the Department of Clinical Therapeutics at the University of Athens, in Greece. Presenting the results at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO; abstract 8509),

Dr. Dimopoulos reported that 929 patients with relapsed MM who had received at least one but no more than three prior lines of therapy were randomly assigned to Kd or Vd. The dose of carfilzomib, administered twice per week, was 56 mg/m2, which is two times greater than the dose currently recommended for

this agent when it is used as a single agent. Patients randomly assigned to bortezomib received 1.3 mg/m2. Both proteasome inhibitors were combined with 20 mg of dexamethasone. The mean age of the population was 65 years, with about 15% of patients being older than 75 years. After a median follow-up of 12 months, the median PFS was 18.7 months in the Kd arm versus 9.4 months in the Vd arm, producing a hazard ratio (HR) of 0.53 (P<0.0001). The advantage of Kd over Vd was consistent for every subgroup see CARFILZOMIB, page 9 

HEMATOLOGIC DISEASE

CliniCal OnCOlOgy news • august 2015 • CLINICALONCOLOGY.COM

How I Manage ...

Primary Myelofibrosis P

Srdan Verstovsek, MD, PhD Professor, Department of Leukemia The University of Texas MD Anderson Cancer Center Houston, Texas

rimary myelofibrosis (PMF) is a clonal hematopoietic progenitor cell disorder characterized by proliferation of myeloid cells and atypical megakaryocytes, bone marrow (BM) fibrosis, and variable degrees of extramedullary hematopoiesis. Patients typically present with splenomegaly, anemia, and a leukoerythroblastic blood picture. Fatigue and other constitutional symptoms, such as night sweats, pruritus, bone pain, fevers, and unintentional weight loss also are very common, especially as the disease progresses. Disease progression can involve transformation to acute myeloid leukemia, BM failure, and life-threatening complications, including infections, thrombosis, or hemorrhage.

What is the best approach to diagnose PMF? PMF should be diagnosed according to the 2008 World Health Organization (WHO) criteria (Table 1). The standard workup should include a physical examination for signs of palpable spleen and/or liver. A complete blood count and chemistry panel should be performed, as well as review of peripheral blood smear. Patients often present with blood cytopenias, but some patients, especially those in the early stages of disease, may exhibit thrombocytosis. A peripheral blood smear showing leukoerythroblastosis, teardrop-shaped red blood cells, large platelets, and few myeloblasts is indicative of PMF. A BM biopsy with reticulin and collagen staining is mandatory. Testing for mutations in JAK2, CALR, and MPL help in the diagnostic process. Testing for BCR-ABL is mandatory to exclude a diagnosis of chronic myeloid leukemia (CML). BM histology showing hypocellularity and dysplastic megakaryocytes is a crucial diagnostic criterion. Of note, BM fibrosis by itself is not enough for a diagnosis of PMF because various degrees of fibrosis are observed in other myeloproliferative neoplasms, some other hematologic malignancies (eg, myelodysplastic syndrome with fibrosis must be excluded), and inflammatory/infectious conditions.

Which prognostic model should be used and why? I use the International Prognostic Scoring System (IPSS) at initial diagnosis and the Dynamic IPSS (DIPSS) during the course of a patient’s disease because these are the most well-validated prognostic models (Table 2). Although the prognostic scoring systems can be useful for deciding when to offer an allogeneic hematopoietic cell transplant (alloHCT), a patient’s abnormal blood cell

Table 1. WHO Diagnostic Criteria for PMF Major criteria

• Megakaryocyte proliferation and atypia accompanied by either reticulin and/or collagen fibrosis; or in absence of reticulin fibrosis, megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation, and often decreased erythropoiesis (ie, prefibrotic PMF) • Not meeting WHO criteria for CML, PV, MDS, or other myeloid neoplasm • Demonstration of JAK2 V617F or other clonal marker; in absence of clonal markers, no evidence of secondary BM fibrosis

Minor criteria

• Leukoerythroblastosis • Increased serum lactate dehydrogenase • Anemia • Palpable splenomegaly

BM, bone marrow; CML, chronic myeloid leukemia; MDS, myelodysplastic syndromes; PMF, primary myelofibrosis; PV, polycythemia vera; WHO, world Health Organization a

three major and 2 minor criteria are required for a diagnosis of PMF.

Table 2. Prognostic Scoring Systems for PMF Factors

IPSS

DIPSS

DIPSS Plus

Age >65 years

Constitutional symptoms

Hemoglobin <10 g/dL

Leukocytes >25 × 10 /L Blood blasts ≥1% 9

Platelet count <100 × 10 /L

Transfusion dependence

Unfavorable karyotype

Risk stratification

Points

Low

Intermediate-1

1-2

Intermediate-2

3-4

2-3

High

≥3

5-6

≥4

DIPSS, Dynamic international Prognostic scoring system; IPSS, international Prognostic scoring system; PMF, primary myelofibrosis

count (eg, anemia), symptomatic splenomegaly, or MF-related systemic symptoms are most important to making the final decision on the initiation of medical therapy in consultation with the patient.

Which patients can be monitored without therapy? Patients with disease that does not affect them in a significant way (those without significant anemia, significant symptomatic splenomegaly, and significantly impaired quality of life [QoL]) may be observed. Most of the time, that group of patients is designated low-risk or intermediate-risk according to the IPSS/DIPSS (ie, younger than age 65 without constitutional symptoms, anemia, or leukocytosis and no peripheral blood blasts). A treatment algorithm is presented in the Figure.

When do you start targeted therapy and why? I generally initiate treatment with targeted therapy (JAK inhibitor) in patients with symptomatic splenomegaly and/or constitutional symptoms that have significantly reduced the patient’s QoL. For those with platelet counts above 50 × 109/L, ruxolitinib (Jakafi, Incyte) is a good first choice. It is effective in patients with PMF, regardless of their mutation status (ie, it is not specific for JAK2 mutation). Despite its myelosuppressive effects, in my experience, nearly all patients can be treated effectively with ruxolitinib, with close monitoring and by titrating the dose based on platelet counts over the first 3 to 6 months. The starting dose for patients with platelets above 200 × 109/L is 20 mg twice a day; for those with platelets between 100 and 200 × 109/L, it is 15 mg twice a day; and for those with platelets between 50 and 100 × 109/L, see MYELOFIBROSIS, page 8 

HEMATOLOGIC DISEASE

MYELOFIBROSIS

CliniCal OnCOlOgy news • august 2015 • CLINICALONCOLOGY.COM

Table 3. Selected Clinical Trials in PMF Currently Enrolling Patients

continued from page 7

it is 5 mg twice a day. Ruxolitinib is not recommended for patients with platelets below 50 × 109/L. The presence of anemia or red blood cell–transfusion dependence is not a contraindication for ruxolitinib use. However, for patients suffering primarily from anemia without other significant signs or symptoms (eg, symptomatic organomegaly), androgens, immunomodulatory agents (thalidomide [Thalomid, Celgene], lenalidomide [Revlimid, Celgene]), prednisone, or erythropoietin [Epogen, Amgen; Procrit, Janssen] may be used.

When do you refer patients for allo-HCT? I refer patients with intermediate-2 or high-risk disease who are younger than 75 years, have good performance status, and have few comorbidities.

Is there a role for splenectomy? Splenectomy can be useful in cases of worsening splenomegaly and associated anemia or thrombocytopenia that are refractory to all available therapies. However, significant morbidity and mortality are associated with this procedure in this particular disease. Mortality rates are 5% to 10%, and up to 50% of patients experience complications, such as progressive “rebound” hepatomegaly, which can result in

ClinicalTrials. gov Identifier

Trial Safety and tolerability study of NS-018 in patients with PMF, PPV MF, or PET MF

NCT01423851

Oral pacritinib vs best available therapy to treat MF with thrombocytopenia

NCT02055781

Phase II study of PRM-151 in subjects with MF

NCT01981850

Ruxolitinib prior to allo-HCT in patients with MF

NCT01790295

Pegylated interferon α-2b in early PMF

NCT01758588

Efficacy of momelotinib vs best available therapy in anemic or thrombocytopenic subjects with PMF, PPV MF, PET MF

NCT02101268

A study to find the maximum tolerated dose of the experimental combination of the drugs ruxolitinib and BKM120 in patients with primary or secondary MF

NCT01730248

A Phase Ib/II dose-finding study to assess the safety and efficacy of LDE225 + ruxolitinib in patients with MF

NCT01787552

Phase II LCL-161 in patients with PMF, PPV MF, and PET MF

NCT02098161

PF-04449913 single agent in patients with MF previously treated with a JAK inhibitor

NCT02226172

Panobinostat and ruxolitinib in MF

NCT01693601

Study of sotatercept (ACE-011) in subjects with MPN-associated MF and anemia

NCT01712308

allo-HCT, allogeneic hematopoietic cell transplant; MF, myelofibrosis; MPN, myeloproliferative neoplasm; PET, post-essential thrombocythemia; PMF, primary MF; PPV, post-polycythemia vera

renal failure and death. Generally, I only consider splenectomy in patients with symptomatic portal hypertension, severe splenomegaly associated with

pain or severe cachexia that is refractory to all available therapies, or severe cytopenias not responding to nonsurgical therapy.

AT A GLANCE • PMF should be diagnosed according to the 2008 WHO criteria (Table 1). • Testing for BCR-ABL is mandatory to exclude a diagnosis of CML. • A BM biopsy with reticulin and collagen staining is mandatory for diagnosis. • Use of IPSS at initial diagnosis or DIPSS during the course of a patient’s disease is reasonable. • Ruxolitinib is effective in patients with PMF, regardless of their mutation status (ie, it is not specific for JAK2 mutation). • Mortality rates in patients with splenectomy are 5% to 10%, and up to 50% of patients have complications, such as progressive “rebound” hepatomegaly, which can result in renal failure and death. • Patients with intermediate-2 or high-risk disease who are younger than 75 years should be considered for allo-HCT. • Enrollment in a clinical trial is always a preferred intervention (Table 3).

Conclusion

IPSS or DIPSS risk score

The clinical presentation of PMF is heterogeneous, with some patients only displaying mild constitutional symptoms and others with massive hepatosplenomegaly, overwhelming fatigue, and other constitutional symptoms that severely limit their QoL. Some suffer primarily from low blood cell count. Thus, there is no “one size fits all” approach to the management of PMF. ■

Series Editor Syed Abutalib, MD Assistant Director, Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

Coming Soon Relapsed Chronic Lymphocytic Leukemia Farrukh Awan, MD, MS

Figure. Treatment scoring algorithm using IPSS and DIPSS risk scores. ASCT, autologous stem cell transplantation; DIPSS, Dynamic international Prognostic scoring system; IPSS, international Prognostic scoring system; PS, performance score

The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Columbus, Ohio

HEMATOLOGIC DISEASE

Clinical Oncology News • August 2015 • CLINICALONCOLOGY.COM

CARFILZOMIB

‘It is becoming clear that carfilzomib is superior to bortezomib, especially at twice the dose.’

continued from page 6

evaluated, according to Dr. Dimopoulos, including those with high-risk cytogenetics, which represented about 25% of the population. The relative advantage of Kd over Vd was even greater in patients older than 75 years of age. The PFS advantage was consistent with response rates. In addition to a higher overall response rate (77% vs. 63%; P<0.0001), the complete response rate (13% vs. 6%; P<0.0001) and very good partial response rate (54% vs. 29%; P<0.0001) were approximately twice as great with Kd than with Vd. Survival data are not yet mature, but the HR of 0.79 suggested a favorable trend (P=0.066). Dose reductions due to adverse events (AEs) were less common with Kd than Vd (23% vs. 48%), although patients remained on Kd, on average, for a longer period (40 vs. 27 weeks). Grade 2 or higher peripheral neuropathy was observed in 32% of those in the Vd arm versus 6% of those in the Kd arm. Grade 3 or higher AEs that were more common with Kd included dyspnea (5% vs. 2.2%), pyrexia (2.4% vs. 0.7%) and hypertension (9% vs. 3%). The rates of grade 3 or higher hematologic AEs were similar in the two arms. For the treatment of MM, “it is becoming clear that carfilzomib is superior to bortezomib, especially at twice the dose,” according to the ASCO-invited discussant, Jeffrey L. Wolf, MD, the director of the Myeloma Program at the University of California, San Francisco’s Helen Diller Family Comprehensive Cancer Center.

—Jeffrey L. Wolf, MD However, Dr. Wolf noted that there is a new landscape of options for relapsed MM, and that Kd may or may not be the best option, depending on cost, high-risk cytogenetics and tolerability. In a relapsed MM trial published earlier this year called ASPIRE (N Engl J Med 2015;372[2]:142-152, PMID 25482145), the median PFS was even greater for

carfilzomib, lenalidomide and dexamethasone relative to that observed with Kd in ENDEAVOR (26.3 vs. 18 months) (see related story on MM trials, page 1). However, cautioning about the inherent limitations of cross-trial comparisons, Dr. Wolf also noted that fewer patients in ASPIRE had high-risk cytogenetics (12.6% vs. 22.6%). He emphasized that this is a factor

to consider when interpreting these and other trials in patients with relapsed MM, such as ELOQUENT 2, which evaluated elotuzumab (Bristol-Myers Squibb). Moreover, Dr. Wolf also emphasized that costs range considerably for these agents and may be part of the equation to determine the most appropriate therapy. —Ted Bosworth Dr. Dimopoulos reported financial relationships with Celgene and Onyx. Dr. Wolf reported financial relationships with Amgen, Celgene, Janssen, Millennium and Onyx.

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How I Manage ...

Luminal A and Luminal B Breast Cancers w

Massimo Cristofanilli, MD Director, Breast Care Center Sidney Kimmel Cancer Center Thomas Jefferson University Philadelphia, Pennsylvania

omen with relatively lowrisk breast cancer have more options today than in the past decade, due in large part to novel genomic and genetic tests. these tests have demonstrated the ability to predict cancers that are more aggressive and more likely to recur. although genetic tests for heritable mutations to genes including BRCA1 and 2 have become more commonplace, genomic tests for identifying which cancer-related genes are over- or underproduced are still relatively rare in clinical practice.

These diagnostics add valuable information and reflect the activity of a broader range of cancer-related genes than is possible with standard immunohistochemistry and pathology tests. They have become an integral part of our practice at the Jefferson Breast Care Center, in Philadelphia. Sometimes called genomic, mole-

AT A GLANCE • For luminal A disease that is ER-positive and HER2negative, you need to decide whether and when to add chemotherapy. Genomic analyses can be useful in helping determine the cancers that have a higher risk for relapse versus the ones that can be successfully managed with hormone therapy. • With high-grade tumors—a luminal B subtype that is HR-positive and possibly HER2-positive—you will most likely need endocrine therapy, chemotherapy, and possibly trastuzumab. • There is a role for bisphosphonates, not only for protecting against loss of bone density, but also for helping prevent bone metastasis in high-risk patients. • Dose-dense chemotherapy should be avoided in women with hormone-responsive tumors.

cular, or gene-expression analysis, these tests are most useful in stratifying patients with breast cancer into disease subtypes. This is particularly useful in cases of hormone receptor (HR)-positive or luminal-type disease, which can be further stratified into the cancer subtypes luminal A and luminal B. These 2 subtypes frequently are grouped because the cancers often can be treated successfully for many years with hormone-blocking therapies. Luminal A cancers generally are characterized as those that express high levels of the estrogen receptor (ER) and the progesterone receptor (PR), as well as low levels of the human epidermal growth factor receptor 2 (HER2), which is involved in signaling cell proliferation (Figure). Luminal B cancers generally are more aggressive and more likely to recur than luminal A cancers. Luminal B cancers also are hormone-positive, but they are highly proliferative and may have high levels of HER2, making them candidates for trastuzumab (Herceptin, Genentech/Roche).

Is chemotherapy necessary for every patient? Definitely not. Physicians are beginning to realize that some breast cancers have a very low likelihood of becoming life-threatening. Women today can make an educated decision about the right treatment course, considering how taxing chemotherapy can be and its short and long-term adverse events (AEs).

When do you order genomic analyses? We order genomic tests in conjunction with early laboratory results to confirm pathology reports and help guide our treatment decisions, especially for

low-grade disease, to help determine whether chemotherapy is likely to offer a survival advantage. In these patients, it is difficult to use standard methods to determine when we should take a more aggressive treatment approach. The tests also can help clinicians explain and educate patients about their treatment options and indicate the likelihood that their cancer will recur or metastasize. Some patients come in with the attitude that they would like to throw everything medically available at the tumor in the hope that it will not return. However, for many women, adding chemotherapy or other more aggressive therapies is unlikely to increase their already excellent chances of survival by more than a few percent, whereas the treatments carry significant short- and longterm AEs. The tests also help confirm when patients are at a high risk for recurrence or distant metastasis, in which case the best option may be to treat the cancer aggressively early on. Genomic analyses, which are now available from companies including Agendia (MammaPrint), Genomic Health (Oncotype DX), and NanoString (Prosigna), provide oncologists and patients with additional information and increase their confidence that they are choosing appropriate therapy.

What are the hormone therapy options for low-risk cancers? Hormone therapy is the standard of care for women with HR-positive disease—both luminal A and most luminal B subtypes—after lumpectomy or mastectomy. However, there are a number of options. If the woman is very young (around her 30s), tamoxifen is the best option because endocrine function is maintained for a long time. In general, premenopausal women are most effectively treated with tamoxifen, a drug that blocks the ER in the breast but not in other tissues, such as the endometrium or bone. Because it acts as a partial agonist in the endometrium, slightly increasing estrogen production, tamoxifen also has been linked to increased rates of endometrial cancers. In general, especially in premenopausal women, this risk is considered small and generally should not preclude a woman from being treated for breast cancer.1 However, because of this risk, clinicians have debated the number of years that tamoxifen can safely be given. The ATLAS study, published in March 2013, essentially settled the debate.2 Researchers determined that tamoxifen

halved the rate of recurrence in patients with breast cancer who took the drug for 10 years instead of 5, and increased overall survival. In absolute numbers, of the 3,428 women who were treated with tamoxifen for 10 years, 617 had a recurrence, whereas 711 out of 3,418 women treated for 5 years had a recurrence. Women who are near menopause usually are started on tamoxifen and then switched to an aromatase inhibitor (AI), which is generally considered more effective than tamoxifen.3 AIs block the conversion of androgens to estrogen but cannot block estrogen produced by the ovaries, making the drug ineffective in premenopausal women whose ovaries still produce estrogen. A woman who is perimenopausal during treatment will be switched to an AI at menopause. With the ATLAS results in mind, the American Society of Clinical Oncology published guidelines recommending that women be offered 10 years of hormone therapy—either with tamoxifen alone if they remain premenopausal or a combination of tamoxifen followed by an AI.4 There’s a third option, although clinicians have not yet reached consensus about how and when this therapy is most useful.5 Luteinizing hormone– releasing hormone agonists are a class of drugs used to prevent the production of female and male sex hormones. They historically have been used to block testosterone production for men with prostate cancer. Their use in premenopausal women completely blocks estrogen production, essentially chemically forcing menopause. Their most appropriate use may be in women for whom the AEs of tamoxifen, such as hot flashes or depression, are intolerable.

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How do you treat cancers that test positive for BRCA1/2? Premenopausal women who test positive for hereditary mutations such as BRCA1/2 and have a higher risk for aggressive disease may want to consider an oophorectomy, which would remove their exposure to estrogen and put them in the postmenopausal category. For women who test postitive for BRCA1/2 and who have a family history but do not have cancer, we recommend more frequent and in-depth screening. In addition, some research suggests that women with the BRCA2 (but not BRCA1) mutation can benefit from prophylactic tamoxifen treatment.6 Tamoxifen was shown to halve the risk for recurrence in both BRCA1 and 2 patients with cancer.7 Many of these cancers, however, are also triple-negative and do not respond to estrogen or HER2 therapies. Many others develop resistance to hormone treatment and chemotherapy. Because BRCA1/2 proteins are involved in DNA repair, the loss of these proteins makes cells more susceptible to cancer-causing mutations and makes them more susceptible to additional DNA-damaging agents that can put the cancer cell over the edge and instigate cell death. The PARP (poly [ADP-ribose] polymerase) inhibitors are being evaluated for their usefulness in BRCA1/2 cancers.

What if the genomic tests suggest a high risk for recurrence? Luminal B cancers have a higher risk for recurrence. They often are HER2/ neu-positive, which allows the opportunity for treatment with trastuzumab. However, these cancers generally grow faster and are more aggressive than luminal A cancers and are, therefore, treated with endocrine therapy, chemotherapy, and trastuzumab, if possible. Unfortunately, these treatments are not always effective for very long. Luminal B cancers are less responsive to both hormone inhibitors and chemotherapies and are relatively more likely to metastasize to the bone and brain. Researchers are working to define the molecular pathways that drive this subtype and are looking at treatments targeting mutations in the PI3K-AKTmTOR pathway and inhibitors for the insulin-like growth factor and fibroblast growth factor receptors.8 In addition, when the risk for recurrence is high, there often is a role for bisphosphonates in managing patient disease. Bisphosphonates sometimes

Figure. Differential expression of ER, PR, and HER2 among different subtypes of breast cancer. ER, estrogen receptor; HER2, human epidermal growth receptor 2; PR, progesterone receptor Adapted from Sandhu R, et al. LabMedicine. 2010;41:364-372.

are given to women taking AIs to protect against the bone loss that occurs with estrogen depletion.9 More recent research has shown that the drug also can protect against bone metastasis and be useful when the risk for recurrence is high and/or when the cancer is not well controlled by hormone therapy.10

What about dose-dense chemotherapy for luminal A or luminal B disease? When chemotherapy is added to the regimen, there is the option of dosedense chemotherapy, in which the therapy is administered every 2 weeks rather than every 3 weeks. Prescribing dosedense chemotherapy has become much more popular, partly because early trials had shown this regimen to be more effective. More recent studies revealed that the regimen showed little benefit for women with early-stage breast cancer, and unnecessarily exposed them to greater toxicity.11 Women with highergrade cancers, however, had extended overall and disease-free survival when they were treated with dose-dense chemotherapy.12 In general, dose-dense chemotherapy

should not be used for women whose cancers are still responding to estrogen therapy.

References 1. Committee Opinion No. 601: tamoxifen and uterine cancer. Obstet Gynecol. 2014;123(6):1394-1397, PMID: 24848920. 2. Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381(9869):805-816, PMID: 23219286. 3. Cuzick J, Sestak I, Baum M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010;11(12):1135-1141, PMID: 21087898. 4. Burstein HJ, Temin S, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline focused update. J Clin Oncol. 2014;32(21):2255-2269, PMID: 24868023. 5. Francis PA, Regan MM, Fleming GF, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372(5):436-446, PMID: 25495490. 6. King MC, Wieand S, Hale K, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant

Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001;286(18):2251-2256, PMID: 11710890. 7. Phillips KA, Milne RL, Rookus MA, et al. Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2013;31(25):3091-3099, PMID: 23918944. 8. Tran B, Bedard PL. Luminal-B breast cancer and novel therapeutic targets. Breast Cancer Res. 2011;13(6):221, PMID: 22217398. 9. Ramaswamy B, Shapiro CL. Bisphosphonates in the prevention and treatment of bone metastases. Oncology (Williston Park). 2003;17(9):1261-1270, PMID: 14569853. 10. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009;360(7):679-691, PMID: 19213681. 11. Cameron D, Barrett-Lee P, Canney P, et al. The UK TACT2 trial: comparison of standard vs accelerated epirubicin in patients requiring chemotherapy for early breast cancer. Presented at: San Antonio Breast Cancer Symposium; December 6, 2012; Abstract S3-3. 12. Moebus V, Schneeweiss A, du Bois A, et al. Ten year follow-up analysis of intense dosedense adjuvant ETC (epirubicin, paclitaxel and cyclophosphamide) confirms superior DFS and OS benefit in comparison to conventional dosed chemotherapy in highrisk breast cancer patients with ≥ 4 positive lymph nodes. Presented at: San Antonio Breast Cancer Symposium; December 6, 2012; Abstract S3-4.

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CliniCal OnCOlOgy news • august 2015 • CLINICALONCOLOGY.COM

Less Aggressive Option Posed for Some Melanoma Pts Study questions role of complete lymphadenectomy for melanoma micrometastases Chicago—Surgically removing the lymph nodes surrounding a melanoma is not necessary when micrometastases are found via lymph node biopsy, according to results from a Phase III trial. The trial showed that a complete lymphadenectomy in this patient population does not improve distant metastasis–free survival, recurrence-free survival or melanoma-specific survival. “Based on our findings, complete lymphadenectomy cannot be recommended in melanoma patients with micro-metastases,” said Ulrike Leiter, MD, a medical oncologist at the University of Tübingen, in Germany. She presented the study at the annual meeting of the American Society of Clinical Oncology (ASCO; abstract LBA9002). The status of the sentinel lymph node is an important predictor of prognosis and recurrence in patients with melanoma. The standard of care is to perform a complete lymph node dissection (CLND) if positive sentinel lymph nodes are found through a biopsy. In recent years, however, clinicians have debated whether this is necessary when only micrometastases

are identified. In patients with early breast cancer, studies have shown that axillary lymph node dissection can be avoided in patients with limited sentinel node involvement, with no adverse effect on survival (Lancet Oncol 2 0 1 3 ; 14 [ 4 ] : 2 9 7- 3 0 5, PMID: 23491275). The German Dermatologic Oncology Group trial presented at the ASCO meeting enrolled 483 patients with stage III melanoma and a positive lymph node biopsy. After undergoing surgery to remove the primary tumor, patients were randomized to observation or a CLND. All patients underwent a lymph node ultrasound examination every three months and computed tomography/MRI or positron emission tomography scans every six months. In an intent-to-treat analysis of 473 patients, with a median follow-up of 35 months, regional lymph node recurrence

was more common in the observation arm (14.6% vs. 8.3%; P=0.029). However, this did not translate to a statistically significant difference in threeor five-year recurrence-free survival, distant metastases– free survival or melanoma-specific survival. Tumor load did not influence these outcomes. According to the researchers, it is unlikely that the findings will change with longer follow-up, because the majority of melanoma recurrences occur in the first three years after diagnosis. According to Lynn Schuchter, MD, a melanoma specialist and the chief of hematology-oncology in the Department of Medicine at University of Pennsylvania Health System, in Philadelphia, the study is small but important. She said the standard of care is to provide CLND to melanoma patients with a positive sentinel lymph node

biopsy, but “more and more there have been questions about whether somebody needs it, especially if there is only microscopic involvement.” She added that CLND comes with a risk for lymphedema, which can have a big impact on function and quality of life. Lymphedema occurs in more than 20% of patients who undergo a CLND. “This study gives us important information to feel comfortable about a watch-and-wait approach,” said Dr. Schuchter. “I would say the study is important but not everybody is going to abandon complete lymph node dissection.” She said results from a larger, ongoing trial are needed before definitive changes are made to the management of patients with melanoma. The Multicenter Selective Lymphadenectomy Trial II is evaluating the benefits of CLND in patients with melanoma and is expected to report results in 2022. —Kate O’Rourke Drs. Leiter and Schuchter reported no relevant financial relationships.

Report From ASCO Annual Meeting:

Prognostic Index Helps Assess Breast Cancer Recurrence Risk Chicago—Use of an index to assess recurrence risk and the likelihood of benefit from endocrine therapy in women with estrogen receptor–positive (ER+) breast cancer resulted in treatment changes in 27% of cases, most commonly because the test results helped both physicians and patients determine that benefit from extended adjuvant therapy was unlikely, according to a prospective study. In ER+ breast cancer patients with characteristics that suggest a low risk for recurrence, “many physicians have difficulty advising patients regarding extended hormone therapy—meaning continuing therapy for 10 years versus stopping at five years,” reported Tara Sanft, MD, the medical director of adult survivorship at Yale Cancer Center Survivorship Clinic, in New Haven, Conn. The advantage of the validated Breast Cancer Index, according to the results of this study, is that it provides objective data that can render patients and their physicians more comfortable with forgoing extended adjuvant treatment. In this study, which was presented at the 2015 annual meeting of the American Society of Clinical Oncology

A prognostic index may be useful for guiding ‘decisions for low-risk women who have been intolerant to endocrine therapy, but these data are not helpful to me for women who have few side effects from these agents.’ —Maura N. Dickler, MD

Patients , %

40 30 20

10 0

Breast Cancer Index estimate

Physician estimate

Patient estimate

Figure. Variation in percentage of patients at low risk for recurrence.

(abstract 538), Dr. Sanft and her colleagues enrolled 100 women with stage I to III breast cancer who had completed at least 3.5 years of endocrine therapy. At study entry, patients and their physicians estimated risk for recurrence and whether they planned to extend adjuvant endocrine therapy to 10 years. Patients also completed the State-Trait Anxiety Inventory (STAI) and Decisional Conflict Scale (DCS) at study entry. Patients were then evaluated with the commercially available Breast Cancer Index (bioTheranostics). This index, which assesses molecular signaling pathways, yields both a composite score expressing risk for late recurrence as a percentage and a prediction of high-versus-low likelihood of obtaining benefit from extended endocrine therapy. It has been validated in several studies, including a study using tissue samples from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial (Lancet Oncol 2013;14[11]:1067-1076, PMID: 24035531). According to the Index, 59% of the patients in this study were at low risk for late recurrence, and 58% had a low likelihood of benefiting from extended therapy. The proportion of patients

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Report From ASCO Annual Meeting:

Big OS Benefit From Ablation of Unresectable CRC Liver Mets Chicago—In patients with unresectable colorectal liver metastases, radiofrequency ablation (RFA) substantially increases long-term overall survival (OS) compared with chemotherapy alone, according to the most recent analysis of a trial that now has a median follow-up of 9.7 years. More than three times more patients are still alive in the arm receiving RFA plus systemic therapy. The data provide major encouragement for specifically targeting liver metastases with ablation in patients with colorectal cancer (CRC), even if they are otherwise unresectable, according to the principal investigator of this study, Theo J. Ruers, MD, PhD, the head of the Division of Surgical Oncology at the Netherlands Cancer Institute, in Amsterdam. New data from this European Organisation for Research and Treatment of Cancer trial, called CLOCC (Chemotherapy + Local ablation versus Chemotherapy), were presented at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO; abstract 3501). When these data were initially presented at the ASCO meeting in 2010, the study had already met its primary end point, but the long-term survival advantage has continued to improve. In 2010, the OS at 30 months was 61.7% among patients randomly assigned to undergo RFA plus systemic therapy versus 57.6% for those receiving systemic therapy alone. The median progression-free survival (PFS) was 16.8 months for the RFA arm and 9.9 months for the chemotherapy-only arm, producing a hazard ratio (HR) of 0.63 (P=0.025).

After eight years, the OS was 35.9% and 8.9% for the two arms, respectively (HR, 0.58; P=0.01), and the PFS was 22.3% and 2%, respectively (HR, 0.57; P=0.005) (Table). CLOCC is the first randomized, prospective study to evaluate the value of RFA in unresectable liver metastases. Originally planned as a Phase III trial, it was changed to a Phase II trial due to slow accrual. The study investigators have randomly assigned 119 patients with CRC and unresectable liver metastases to RFA plus FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) or FOLFOX alone (plus bevacizumab [Avastin, Genentech/Roche] among those enrolled after October 2005). Patients were excluded if they had extrahepatic disease. In instances in which treatment

converted metastases from unresectable to resectable in the systemic treatment– alone study arm, surgery was allowed. This occurred in 12% of the patients. In the RFA arm, additional resection of resectable lesions was allowed, which occurred in 47% of the patients. At the most recent follow-up, which included outcomes in more than 95% of those enrolled, almost all deaths in both arms were due to progressive disease. However, the patterns of progression were different. Progression occurred primarily in the liver in 69.3% of those receiving chemotherapy alone versus 32.6% of those randomly assigned to RFA. Conversely, extrahepatic progression was observed in 34.9% of those who received RFA versus 14.3% of those treated with chemotherapy alone, underlining the ability of

at low risk exceeded both the physician estimate (49%) and the patient estimate, expressed in the questionnaire as “not at all likely” (24%; Figure). Reflecting uncertainty, the majority of patients (71%) characterized their risk as intermediate, which was expressed in the questionnaire as “somewhat likely.” After receiving the results, 27% of physicians changed their recommendation for adjuvant therapy, and 52% of patients changed their treatment decision. There

also was a significant increase in the number of physicians reporting strong confidence in their treatment decisions. In addition, after receiving the risk score, patients had significantly less anxiety based on the STAI (P=0.03). DCS scores also were significantly reduced (P<0.001). Providing an alternative viewpoint, Maura N. Dickler, MD, the section head of the Endocrine Therapy Clinical Research Program at Memorial SloanKettering Cancer Center, in New York

City, suggested that this test would have a relatively limited application in her own practice. “Given the benefit of endocrine therapy in high-risk women for prevention of breast cancer” as well as data associating endocrine therapy with protection against contralateral events in women with ductal carcinoma in situ or invasive breast cancer, “my threshold to avoid these agents is high,” Dr. Dickler explained. She said a prognostic index may be useful for guiding “decisions for

Table. OS in CLOCC Trial Over Time OS, % Follow-up Period

RFA plus systemic therapy

Systemic therapy alone

30 mo

61.7

57.6

35.9

8.9

CLOCC, Chemotherapy + Local ablation versus Chemotherapy; OS, overall survival; PFS, progression-free survival; RFA, radiofrequency ablation

‘At our tumor boards, we should be thinking of a multidisciplinary approach in these patients.’ —Ricky A. Sharma, MD, MB, BChir, PhD

RFA to control disease in the liver. This study provides evidence that patients with unresectable liver metastases achieve a major benefit from complete eradication, and this should be the objective of a multidisciplinary team, according to Dr. Ruers. The ASCO-invited discussant, Ricky A. Sharma, MA, MB, BChir, PhD, a professor in the Department of Oncology at Oxford University, in England, suggested that this trial would be better characterized as a trial of “RFA plus systemic therapy plus surgery versus chemotherapy with the possibility of surgery.” However, he called the data “very impressive” and the OS HR “very convincing.” He agreed that the study outlines an appropriate approach to routine care for the types of patients enrolled in this study. “At our tumor boards, we should be thinking of a multidisciplinary approach in these patients,” Dr. Sharma said, specifying that the data would support the CLOCC protocol in patients with CRC with up to nine liver metastasis deposits up to 4 cm in diameter in the absence of extrahepatic disease. Based on the data from this study, the subset of patients without progression of the primary disease “have a good chance of long-term survival” if liver metastases can be completely eradicated. —Ted Bosworth Drs. Ruers reported no relevant financial relationships. Dr. Sharma reported financial relationships with Biocompatibles, Cancer Research Technology, Roche, Sirtex and Vertex.

low-risk women who have been intolerant to endocrine therapy, but these data are not helpful to me for women who have few side effects from these agents.” —Ted Bosworth Dr. Sanft reported a financial relationship with bioTheranostics. Dr. Dickler reported financial relationships with AstraZeneca, Bristol-Myers Squibb, Eisai, Genentech/Roche, Lilly, Merrimack, Novartis, Pfizer and Syndax.

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Study Quantifies CRC Incidence at Various Risk Levels A

n analysis of a populationbased cohort supports the risk stratification used in American recommendations for screening intervals for colorectal cancer (CRC), but it does not support equivalent regimens for men and women. It is the first study to provide incidence data for the various levels of risk, according to the research team. The investigators predicted incidence of CRC over time in a cohort of people and compared the results with a previously published CRC risk benchmark in people aged 50 to 69 years. They found that people with one or more risk factors for CRC had a much higher incidence of the disease than those with no risk factors. However, the incidence among women with or without risk factors remained much lower than among men. “Surveillance intervals for men based on incidence of CRC are in line with [those] recommended by the current guidelines for colonoscopy, but do not support [the] recommendations for women,” Jinma Ren, PhD, and his coauthors concluded in their presentation of the results at the 2015 annual meeting of the International Society for Pharmacoeconomics and Outcomes Research (abstract PMD12). In a paper they have submitted for publication, they suggested that “an additional extension of three to five years may be appropriate for women. Further, the presence of coexisting risk factors impacts the recommended surveillance interval for CRC detection and is an area for future work.”

Table. Interval Incidence of CRC on Follow-Up Colonoscopy Number of Cancers

PersonYears

Predicted 10-y Incidence Per 100,000 Unadjusted Incidence Per Person-Years in Model b (95% CI) 100,000 Person-Years (95% CI) Men Women

3,144

191 (86-425)

791 (438-1,232)

378 (177-676)

High

7,824

166 (96-286)

1023 (601-1,518)

489 (243-833)

Medium

14,068

57 (28-114)

298 (132-557)

143 (53-306)

Low

47,943

40 (25-62)

164 (63-343)

79 (26-188)

Stratified Group Personal history of CRC a

Risk level for CRC

the patients without a history of CRC were categorized as high, medium or low risk for CRC according to the baseline colonoscopy. High risk indicated three or more adenomas, or a large (≥1 cm) adenoma or any advanced adenomas (villous, severe dysplasia, serrated and/or incomplete polyp removal) on the baseline colonoscopy. low risk meant no polyp was found on the baseline colonoscopy. Medium risk represented those between high and low risk.

Multivariable weibull regression model was adjusted by age, sex, family history of CRC and asa (american society of anesthesiologists) classification score.

CRC, colorectal cancer

Sidney Winawer, MD, the Paul Sherlock Chair in Medicine at Memorial SloanKettering Cancer Center, in New York City, said the study “presented strong CRC incidence data that should encourage better compliance with the current risk-stratification guidelines, but because of limitations of the study, I have reservations about their suggestion that the current recommendations are not appropriate.” Dr. Winawer, who was not involved in the research, added, “The study data strongly advocate for better compliance. This is a major issue.” Dr. Ren, research assistant professor in the Center for Outcomes Research at the University of Illinois College of Medicine, in Peoria, and his colleagues analyzed data from 27,325 colonoscopies performed in adults between January 2010

and March 2014 in central Illinois. Most of the patients were aged 50 to 69 years. The researchers compared the incidence rates of CRC and villous adenoma in the cohort with benchmark rates from an earlier analysis of data from the Surveillance, Epidemiology, and End Results program (J Womens Health 2012;21:393-400). They calculated the CRC incidence rates at 10 years after baseline colonoscopy in people at low risk to be 164 cases per 100,000 personyears in men and 79 cases per 100,000 person-years in women (Table). Predictions of CRC incidence rates among patients with three or more adenomas on baseline colonoscopy, a large (≥1 cm) adenoma or any advanced adenoma were significantly higher than among patients at low risk for the

CRC Deaths Spike In Regional Hot Spots

wo new studies underscore regional variations in colorectal cancer rates. investigators at the american Cancer society (aCs) identified three regions of the united states where the odds of dying from colorectal cancer (CRC) are significantly greater than in the rest of the country (Figure). in portions of the lower Mississippi Delta—including arkansas, illinois, Kentucky, louisiana, Mississippi, Missouri and tennessee—the death rate from the disease was 40% higher than normal between 2009 and 2011 (Cancer Epidemiol Biomarkers Prev 2015 July 8 [Published online]). that marked a sharp change from 1970 and 1972, when the mortality rate from CRC was 18% below normal in those areas. Hot spots in western Central appalachia and eastern Virginia/north Carolina had death rates that were 18% and 9%, respectively, above normal during the study period, the researchers found. in another study, investigators used a microsimulation model to estimate what the CRC incidence would be if louisiana had the same CRC risk profile as new Jersey (Cancer 2015 July 6 [Published online]). when the investigators applied new Jersey’s risk profile—smoking, obesity, screening and survival rates—to louisiana, the southern state was estimated to have lower CRC incidence (116.4 vs. 130) and mortality (44.7 vs. 55.8) rates per 100,000 people than the observed rates in new Jersey. screening had the biggest effect on incidence, with the potential to lower CRC incidence by more than 15%. Map reprinted with permission from the American Cancer Society.

disease. The predicted rates were also higher among people with a family history of CRC. All of the incidence rates were higher in men than in women. The highest rate was in men with incomplete polyp removal plus at least three adenomas on baseline colonoscopy: 7,319 cases per 100,000 person-years at 10 years after baseline colonoscopy. The second-highest rate was in men with incomplete polyp removal on previous colonoscopy plus a personal history of CRC: 3,886 cases per 100,000 person-years at 10 years after baseline colonoscopy. —Rosemary Frei, MSc Drs. Ren and Winawer reported no relevant financial conflicts of interest.

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Study Suggests New Standard of Care for Oral Cancer Chicago—Elective neck dissection reduced the risk for death by 36% in patients with early-stage, node-negative oral cancers, according to a randomized Phase III trial presented during the plenary session of the 2015 annual meeting of the American Society of Clinical Oncology (ASCO; abstract LBA3). “Based on the results of our trial, elective neck dissection should be the standard of care for early-stage, clinically node-negative oral cancers,” said Anil D’Cruz, MBBS, MS, a head and neck surgeon and the director of Tata Memorial Hospital, in Mumbai, India, who presented the study. “One death is prevented for every eight patients treated with elective neck dissection, and one recurrence is prevented for every four patients treated with elective neck dissection.” For more than five decades, clinicians have been debating whether patients with early oral cancers should undergo an elective neck dissection or a watch-andwait strategy after excision of the primary tumor. Several prospective and retrospective studies have examined this question, with varied results. Some clinicians argue that elective neck dissection provides better control and survival and allows for a single-stage procedure. Others argue for watching and waiting, saying there is no conclusive evidence that elective neck dissection improves survival. “[They argue] that up-front neck dissection is an unnecessary surgical procedure in up to

100 80

Patients, %

60 40 20 0

neck dissection arm

watch-andwait arm

neck dissection arm

watch-andwait arm

67.5

69.5

45.9

DFS

Figure. Outcomes of oral cancer with and without neck dissection. DFS, disease-free survival; OS, overall survival

70% of patients. Moreover, neck dissection is associated with increased costs and surgical morbidities, most importantly long-term shoulder dysfunction,” said Dr. D’Cruz. In the new study, investigators at Tata Memorial Hospital randomized 596 treatment-naive patients with early-stage (T1/T2), node-negative squamous cell oral cancers to elective neck dissection or watch and wait. Patients also underwent a second randomization to undergo surveillance with a physical examination with or without ultrasonography. Both arms were equally balanced for all factors, including mode of postoperative surveillance.

In an interim analysis of 500 patients, neck dissection significantly improved the rate of overall survival (80% vs. 67.5%; P=0.014), disease-free survival (69.5% vs. 45.9%; P<0.001) and nodal recurrence (10.28% vs. 42.68%; P<0.001) at three years (Figure). The benefit was seen across all subgroups of patients. “Of note, 20 of the 114 patients in the watch-and-wait arm who relapsed were unresectable,” said Dr. D’Cruz. Data from the surveillance randomization had not yet been analyzed. Hisham Mehanna, PhD, MD, the director of the Institute of Head and Neck Studies and Education at the University of Birmingham, in the United Kingdom,

who was not involved with the study, called the survival benefit astounding. “If you look more closely, elective neck dissection had no effect on those patients with no nodal metastases, as you would expect, but it also had no detriment,” said Dr. Mehanna. He pointed out that in patients who had nodal metastases at some point in their disease process, survival was improved by almost 20%. According to Dr. Mehanna, the biggest study limitation was that the two study arms had similar rates of adjuvant treatment with radiation. “You would expect the surveillance group to have more adjuvant treatment than the elective neck dissection group, but in this trial, it doesn’t seem to be the case,” said Dr. Mehanna. “I also think that absence of the data on the outcomes of the type of follow-up, ultrasound guidance versus clinical in the surveillance arm, limits our ability to make full recommendations. Ultrasound surveillance might detect recurrence at an earlier stage than clinical examination.” Nevertheless, he concluded, “Until [those] data [are] available, elective neck dissection should be considered the standard of care.” —Kate O’Rourke Dr. D’Cruz reported financial relationships with GlaxoSmithKline and Merck Serono. Dr. Mehanna reported financial relationships with AstraZeneca, GlaxoSmithKline, Merck, Sanofi and Silence Therapeutics.

Benefit of Metformin in Pancreatic Cancer Challenged Philadelphia—Although several previous retrospective studies had linked metformin to improved survival in various cancers, a new analysis presented at the 2015 annual meeting of the American Association for Cancer Research (AACR) challenges this association, at least in patients with pancreatic ductal adenocarcinoma (PDAC). In the analysis, any evidence for a survival advantage disappeared after investigators eliminated patients who initiated metformin after their PDAC diagnosis. These data should increase caution regarding the prospects of metformin, which has been entered into numerous clinical trials in cancer, including 11 trials in pancreatic cancer, according to Roongruedee Chaiteerakij, MD, PhD, from the Division of Gastroenterology and Hepatology at Mayo Clinic Cancer Center in Rochester, Minn. Dr. Chaiteerakij and her colleagues retrospectively analyzed data from a cohort of 1,360 patients with PDAC (abstract 8687). The patients were

stratified by the time of metformin initiation relative to PDAC diagnosis. The investigators included 908 patients who had never used metformin as a reference group, and then divided metformin users into those who started metformin more than a year before their diagnosis (84 patients), within one year of their diagnosis (212 patients), within 30 days after their diagnosis (104 patients) and more than 30 days after their diagnosis (34 patients). Consistent with previously reported studies, such as a retrospective study linking metformin to a 22% (P=0.03) improvement in overall survival (OS) on the basis of a multivariate analysis (Ann Oncol 2014; [suppl 4]):abstract 699P), data from the most recent trial also suggested a trend for a survival benefit before adjustment for the timing of metformin. In the subgroup of 413 resectable patients, for example, survival was 782 days for metformin users versus 612 days for those who had never used the drug, a difference that approached significance (P=0.07).

However, when the investigators analyzed median survival data adjusted for timing of metformin initiation, the benefits were not evident. With the exception of patients who initiated metformin 30 days after their cancer diagnosis, which was associated with a 51% improvement in survival by hazard ratio (HR) of 0.49 when compared to never use of metformin, those starting metformin 30 days or more before their diagnosis gained no advantage. For example, those starting metformin at least one year prior to their diagnosis had an 8% reduction in survival (HR, 1.08), according to Dr. Chaiteerakij. She explained that patients who initiated metformin after their diagnosis already had a period of survival behind them relative to those who started metformin before their diagnosis, yielding them an automatic survival advantage because they lived long enough to start the treatment. Although a lack of a survival advantage with metformin in PDAC may not necessarily be extrapolated to other

cancers, particularly because the short survival of PDAC makes it more prone to the survival bias observed in this study, Dr. Chaiteerakij suggested that caution is needed when using retrospective epidemiological data to develop hypotheses about cause-and-effect associations. In remarks following the presentation of these data, William Nelson, MD, PhD, the director of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, in Baltimore, complimented the Mayo Clinic researchers on a careful analysis. Dr. Nelson also found the data compelling, stating, “This study should qualify the enthusiasm about metformin for its potential value in pancreatic cancer.” He did not comment on metformin’s role in other cancers, for which it is being evaluated. —Ted Bosworth Drs. Chaiteerakij and Nelson reported no relevant financial relationships.

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Ablation System May Double Survival in Pancreatic Ca Excitement tempered with caution; for selected patients with stage 3 disease

rreversible electroporation, an emerging ablative technique in cancer treatment, may prolong survival in patients with locally advanced pancreatic adenocarcinoma, with the latest survival rates nearly double those of historical controls, according to a new study. In a study presented at the 2015 annual meeting of the American Surgical Association, surgeons reported that patients treated with irreversible electroporation (IRE), in addition to conventional chemotherapy and radiation therapy, survived for a median of 23 to 28 months after treatment. The survival rates are more than double those typically expected for patients with stage 3 pancreatic cancer. Most previous studies put median survival at approximately 11 to 13 months if patients undergo treatment with conventional therapies, the investigators said. Five-year survival is less than 6%. “These results should emphasize to the greater medical and oncology community that stage 3 pancreatic cancer is a treatable disease and not an immediate death sentence. Clearly, durable overall survival can be obtained with collaborative multidisciplinary care through the use of chemotherapy, IRE and chemoradiation therapy,” said lead author Robert C. G. Martin II, MD, PhD, the director of surgical oncology and a professor of surgery at the University of Louisville, in Kentucky. Experts caution that the results come from a small number of institutions, and the study was not conducted in a randomized design with a valid comparison arm. Even so, there is great excitement in the oncology community about the prospect of an ablative technology that can be used with good results on locally advanced pancreatic cancer. Of the 40,000 people in the United States diagnosed with pancreatic cancer annually, only a minority are candidates for surgery. A suitable ablative technique could help control local disease in patients who are ineligible for surgical resection. The thermal ablative techniques used for other cancers, notably liver cancer, are not suitable for pancreatic disease because of widespread damage

Irreversible electroporation is an emerging technique that may prolong survival in selected pancreatic cancer patients.

‘These results should emphasize to the greater medical and oncology community that stage 3 pancreatic cancer is a treatable disease and not an immediate death sentence.’ —Robert C. G. Martin II, MD, PhD to tissues beyond the cancer cells. “What this technique does is offer you an alternative for local control without the morbidity or mortality of complex resection in the select group of patients who are responsive to chemotherapy and have not metastasized, and who have disease that’s amenable to ablation,” said Keith D. Lillemoe, MD, the surgeon-in-chief at Massachusetts General Hospital and the W. Gerald Austen Professor of Surgery at Harvard Medical School, both in Boston. “It is a very select group of patients.” Dr. Lillemoe was not involved with the study and does not personally perform IRE. He does refer patients for the procedure within his institution. He called the results “encouraging,” but stressed the need for multicenter, randomized trials with long-term follow-up. “It would be great to be able to say definitively that [IRE] will add to survival,” Dr. Lillemoe said. “I don’t think we can do that yet, but I do think the door is open to the trials that can make that determination.” Approved by the FDA under a 510(k)

clearance for ablation of soft tissue, IRE (NanoKnike Angiodynamics) is an energy delivery system that ablates tumors by inducing irreversible cell membrane destruction. Clinicians administer highvoltage, nanosecond electrical pulses directly to pathologic tissues by placing minimally invasive electrodes within the targeted region. The pulses damage the porosity of cell membranes, leading to permanent cell death by apoptosis over six to eight weeks, without causing further damage to surrounding vessels, nerves and neighboring normal tissue. The system was first reported for use in patients who had locally advanced pancreatic adenocarcinoma in 2009. In this study, the largest series to date of patients treated with this technology, 200 patients with locally advanced pancreatic adenocarcinoma underwent IRE between March 2010 and October 2014. At diagnosis, the cancer was defined as greater than 180-degree encasement of the superior mesenteric artery and/or celiac artery, unreconstructable venous involvement and no evidence of lesions suspicious for metastatic disease.

All patients underwent chemotherapy or chemoradiation or both, according to each institution’s protocol. Approximately four to six weeks after completion of therapy, each patient underwent restaging with a repeat triple-phase computed tomography scan and serum tumor markers. Patients who were free of metastatic disease and did not have significant primary tumor progression were candidates for IRE. Fifty patients underwent pancreatic resection plus IRE for margin enhancement and 150 patients underwent IRE alone. All patients started with induction chemotherapy, and 52% received chemoradiation therapy for a median of six months (range, five to 13 months) before IRE. At a median follow-up of 29 months, six patients (3%) experienced a local recurrence. The progression-free interval to local recurrence was a median 10.7 months. One-fourth of patients experienced distant progression, mainly to the liver (17%). Median overall survival in the study was 24.9 months, and ranged from 4.9 to 85 months. Complications occurred in 37% of the patients and were a median grade of 2. Eleven patients had vascular complications, including deep venous thrombosis, pseudoaneurysm, hepatic arterial thrombosis and nonocclusive super mesenteric vein/portal vein thrombosis. Three patients died within the first 90 days; they had undergone IRE without resection. This procedure is only indicated in patients who can undergo general endotracheal anesthesia, the investigators noted. Dr. Martin recommended that surgeons offering IRE or referring patients for the treatment should work with the Americas Hepato-Pancreato-Biliary Association’s collaborative patient safety registry. —Christina Frangou Dr. Martin reported a financial relationship with Angiodynamics. Partial support for the Soft Tissue Ablation Registry came from an unrestricted educational grant from Angiodynamics.

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reviews & commentaries From NewYork-Presbyterian/Weill Cornell Medical Center Clinical Oncology News summarizes findings from several recently published, important studies and then asks clinicians from top cancer centers to offer their perspectives. Cancer centers are chosen based on reputation, availability and regional diversity, and we seek to have a mix of academic institutions and regionally important hospitals with expertise in cancer care.

This month we introduce NewYork-Presbyterian/Weill Cornell Medical Center. We hope you find this Reviews & Commentaries section, both here and with additional commentaries on our website (ClinicalOncology.com), to be a valuable tool.

Leaders in Cancer Research and Clinical Care t

he sandra and edward Meyer Cancer Center at weill Cornell Medical College and the Ronald P. stanton Clinical Cancer Program at newyork-Presbyterian/weill Cornell Medical Center, in new york City, work to ensure that patients have immediate access to emerging therapies in a supportive and caring environment, while training future researchers and recruiting leaders in cancer research and clinical care.

From Bench … state-of-the-art research space as well as critical technologies at the new $650-million Belfer Research Building and across campus are empowering nearly 250 doctors and scientists to conduct groundbreaking research that is then brought into the clinic to benefit patients. since joining weill Cornell in 2012, Meyer Cancer Center Director lewis Cantley, PhD, has advocated using a “team science” approach to identify new drug targets, with the goal of rapidly translating these discoveries into clinical trials. He has organized the Meyer Cancer Center into five disease-based research programs (Breast Cancer, lung Cancer, Brain Cancer, Prostate Cancer and Hematologic Malignancies); four science-based research programs that cross multiple diseases (tumor Microenvironment, Cell Biology and signaling, Cancer Metabolism, Cancer genetics and epigenetics); and one population science research

program (Cancer and Obesity). “to figure out how to use these new drugs, you need basic scientists, clinicians and molecular pathologists all working together as a team to identify the targets, and, importantly, to then develop biomarkerdriven clinical trials,” said Dr. Cantley, who also is the Margaret and Herman sokol Professor in Oncology Research and a professor of cancer biology in medicine at weill Cornell.

… to Bedside David nanus, MD, the chief of the Division of Hematology and Medical Oncology, leads the center’s clinical program, which delivers comprehensive care to each patient based on his or her unique circumstances. Patients receive the best available evaluation and treatment, whether that is through standard care or participation in an innovative clinical trial. From rehabilitation medicine and fertility preservation to pain management

Participants to Date

and nutrition counseling, newyork-Presbyterian/weill Cornell Medical Center offers patients a diverse range of resources to complement their cancer care. Rather than offering traditional one-size-fits-all medicine, oncologists at weill Cornell Medical College and newyork-Presbyterian Hospital use genomic sequencing tools to search a patient’s entire genome and locate the specific genetic alterations that have given rise to and are driving his or her tumor. armed with this information and the patient’s medical history, they can identify specific drugs, vaccines and other therapies that are precisely targeted and are, therefore, most effective and have the fewest side effects. “utilizing precision medicine, we are at the tipping point for breakthroughs in targeted therapy in which you develop treatments that hit the very gene, or gene product, that is driving the cancer,” said Dr. nanus, who also is the Mark w. Pasmantier Professor of Hematology and Oncology in Medicine and a professor of medicine and of urology at weill Cornell. By bridging the work of scientists and clinicians, the Meyer Cancer Center and stanton Clinical Cancer Program are converting conceptual breakthroughs into advanced patient therapies.

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REVIEW

Irinotecan Equal to Irinotecan + Cisplatin in Small Gastric Cancer Study From the European Journal of Cancer

n a study of outcomes in patients with advanced gastric cancer (AGC) treated with a second-line regimen of irinotecan plus cisplatin versus those treated with irinotecan alone, no significant differences were found. Gastric cancer has an unfavorable long-term prognosis; nearly half of patients treated with gastrectomy relapse. Standard treatment varies: In Europe, patients are offered EOX (epirubicin, oxaliplatin and capecitabine), and in the United States, standard therapy is DCF (docetaxel, cisplatin, 5-fluorouracil). In Japan, physicians offer their patients S-1, a novel oral fluoropyrimidine. Two previous trials have shown overall survival (OS) with S-1 monotherapy of 11.4 and 11 months. Physicians at several Japanese institutions sought to examine the outcome of irinotecan as a second-line therapy

for patients refractory to S-1 monotherapy or whose disease had progressed shortly after treatment. Additionally, researchers tested an alternative therapy: a lower dose of irinotecan in combination with cisplatin. The results of this randomized, Phase III, open-label trial were published in European Journal of Cancer (2015;51[7]:808-816, PMID: 25797356). Eligible patients were those whose disease progressed or recurred within six months after completion of S-1 adjuvant therapy. Patients needed to have Eastern Cooperative Oncology Group (or ECOG) performance status of 0 or 1, and no additional malignancies or significant comorbidities. The median number of metastatic sites was one. Patients were randomized to one of two arms. In one arm, they received IV irinotecan (150 mg/m2) on day 1 and every two weeks until disease or symptom progression or any adverse event that caused

treatment discontinuation. Patients in the other arm received irinotecan (60 mg/m2) and cisplatin (30 mg/m2) on day 1 and every two weeks thereafter. Sixty-eight patients with advanced disease and 95 with recurrent AGC were enrolled. The primary end point was OS; secondary outcomes were progression-free survival (PFS) and time to treatment failure (TTF). The study design had estimated that OS would be five months in the irinotecan arm and eight months in the irinotecan plus cisplatin arm. At the end of the study, 69 patients (82%) in the irinotecan plus cisplatin arm and 70 (83%) in the irinotecan arm had died. Median OS was 13.9 months (95% CI, 10.8-17.6 months) in the irinotecan plus cisplatin arm and 12.7 months (95% CI, 10.3-17.2 months) in the irinotecan arm. The combination therapy did not significantly decrease the risk for death (hazard ratio [HR], 0.834; 95% CI, 0.596-1.167; P=0.288).

The combination treatment arm had significantly more grade 3/4 toxicities, including anemia (16% vs. 4%) and elevated lactate dehydrogenase levels (5% vs. 0%). Leukopenia, thrombocytopenia and increased serum creatinine were more frequently observed in the combination therapy arm. Kazuhiro Nishikawa of Osaka National Hospital and co-authors noted the possibility of type II errors, based on an insufficient number of patients to power the higher observed OS and the better-than-expected prognostic characteristics of the study group (ECOG PS=1). The authors did observe that the irinotecan plus cisplatin combination therapy was significantly more effective than irinotecan alone for intestinal-type gastric cancer compared with diffuse-type gastric cancer (median OS, 15.8 vs. 14.0 months; HR, 0.569; 95% CI, 0.352-0.918; P=0.019). This confirms results seen in other ■ studies.

COMMENTARY Manish Shah, MD Director, Gastrointestinal Oncology NewYork-Presbyterian/ Weill Cornell Medical Center Assistant Professor of Medicine Division of Hematology/Oncology Weill Cornell Medical College New York, New York

dvanced gastric cancer is a global disease, with significant variation in disease subtypes and treatment paradigms around the world. In most places, AGC is treated with combination chemotherapy in the first-line setting, typically with a platinum and fluoropyrimidine backbone, such as cisplatin/ capecitabine, as was used in numerous registration studies,1,2 or FOLFOX (folinic acid, fluorouracil and oxaliplatin) chemotherapy, which is perhaps better tolerated and considered equally efficacious.

Second-line chemotherapy for AGC also now is a standard care option, with multiple clinical trials now demonstrating a benefit of single-agent chemotherapy over best supportive care. The present study, by Nishikawa and colleagues, examines the role of combination chemotherapy in the secondline setting versus monotherapy. The study was unique in that patients received only S-1, an oral fluoropyrimidine, in the first-line setting. As such, proceeding with a second-line doublet would be anticipated to improve survival. Surprisingly, in this relatively small study of 168 patients, single-agent irinotecan was equivalent to the irinotecan/cisplatin doublet. This suggests that single-agent therapy is truly a standard second-line strategy, and that combination therapy is unlikely to be useful, even in the West. This affords an opportunity for targeted therapies, as we have seen with the use of ramicirumab (Cyramza, Lilly) in the second-line setting.3

References 1. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-697, PMID: 20728210. 2. Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29(30):3968-3976, PMID: 21844504. 3. Wilke H, Muro K, Van Cutsem E, et al. Ramicirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-esophageal junction adenocarcinoma (RAINBOW): a double-blind randomised phase 3 trial. Lancet Oncol. 2014;15(11):12241235, PMID: 25240821.

Dr. Shah reported no relevant financial relationships.

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REVIEW

Ibrutinib Effective Rescue for Waldenstrom’s Macroglobulinemia From The New England Journal of Medicine

n a clinical trial of patients with Waldenstrom’s macroglobulinemia, an oral dose of ibrutinib was found to be effective and safe as a rescue therapy, especially among those with specific mutations in genes MYD88 and CXCR4. In this study, published in The New England Journal of Medicine (2015:372[15]:1430-1440, PMID: 25853747), investigators analyzed the results from 63 symptomatic patients at three U.S. institutions. The patients were aged 44 to 86 years (median, 63) and median time from initial diagnosis to enrollment was 76 months (range, 6-340). All the patients had undergone at least one previous regimen, with a median of two and a range of one to nine. They all had a platelet count of 50,000 mm3 or greater, a hemoglobin level of 8 g/dL or greater, and an

Eastern Cooperative Oncology Group performance status of 2 or lower. MYD88 mutational status was determined in all 63 patients and CXCR4 mutational status was determined in 62 patients. MYD88 triggers tumor cell growth through Bruton’s tyrosine kinase (BTK), a target of ibrutinib (Imbruvica, Pharmacyclics). CXCR4 mutations (of which there are many) confer in vitro resistance to ibrutinib. Confirming earlier studies, the investigators found three mutation variations: MYD88L265P, CXCR4WHIM (any of at least 30 different somatic mutations causing WHIM syndrome), MYD88L265P CXCR4WT (wild type), and MYD88WT CXCR4WT. The study protocol consisted of a 420-mg oral dose of ibrutinib given daily for up to 26 four-week cycles, until disease progression or unacceptable toxicity occurred. The authors, led by Steven Treon, MD, PhD, at Dana-Farber Cancer

Institute, in Boston, reported that median serum immunoglobulin M (IgM) levels decreased from 3,520 to 880 mg/ dL at the time of the best response in the 63 patients (P<0.001). The median bone marrow involvement decreased from 60% to 25% (P<0.001), and the median hemoglobin level increased from 10.5 to 13.8 g/dL at the time of the best response (P<0.001). Discordance between IgM levels and bone marrow involvement was observed at six months (r=0.03; P=0.83), 12 months (r=0.51; P<0.001) and 24 months (r=0.56; P<0.008). Although 40% of patients had disease refractory to prior treatment, very good partial response was seen in 10 of them, partial response in 36 patients and minor response in 11 patients. Overall response (OR) rate was 90.5% (95% CI, 80.4%-96.4%) and major response (MR) rate was 73% (95% CI, 60.3%83.4%). The rates of response were similar across most baseline subgroups and

at the three institutions. With analysis by genomic subgroup, the authors found that OR and MR rates were highest among patients with the MYD88L265P CXCR4WT mutation (100% and 91.2%, respectively), followed by MYD88L265P CXCR4WHIM (85.7% and 61.9%) and MYD88WT CXCR4WT (71.4% and 28.6%). Adverse events were highest among patients who had undergone multiple previous treatments, and included neutropenia and thrombocytopenia, both of which were reversible when doses were reduced or discontinued. At 24 months, estimated progression-free survival was 69.1% (95% CI, 53.2%-80.5%) and estimated overall survival was 95.2% (95% CI, 86%98.4%). This study found that ibrutinib can be a valuable second-line treatment option for patients with Waldenstrom’s macroglobulinemia, especially when MYD88 and CXCR4 mutational ■ status is known.

COMMENTARY Peter Martin, MD Director, Clinical Research Program in Lymphoma NewYork-Presbyterian/ Weill Cornell Medical Center Assistant Professor of Medicine, Division of Hematology/Oncology Weill Cornell Medical College New York, New York

tandard therapies for Waldenstrom’s macroglobulinemia have always seemed a little unsatisfying. Cytotoxic chemotherapy is effective, but often is overly aggressive for an indolent lymphoma. Moreover, in a population with a good prognosis, the risk for secondary malignancies and an increased rate of aggressive transformation justify consideration. Anti-CD20 antibodies can be effective, but responses are slow and of modest duration,

and they are often accompanied by transient flares in serum IgM concentration. Proteasome inhibitors have fewer long-term side effects than DNAdamaging drugs, but peripheral neuropathy can be problematic in a group of patients for whom disease-related neuropathy is already an issue. In January 2015, two years after the oral BTK inhibitor ibrutinib received a breakthrough therapy designation from the FDA, patients and clinicians were elated to learn that the agency had expanded the label to include Waldenstrom’s macroglobulinemia, already approved for mantle cell lymphoma and chronic lymphocytic leukemia. The Phase II trial on which approval was based (N Engl J Med 2015;372[15]:1430-1440, PMID: 25853747) illustrates why the news was so eagerly anticipated. In addition to inducing a high response rate that appeared to be durable, ibrutinib was well tolerated. Few patients came off study due to adverse

events; IgM flare did not occur; patients with neuropathy experienced subjective improvement; and rates of transformation and secondary neoplasms were low, although follow-up was relatively short. After the approval of any therapy, new questions arise. Should genetic testing become standard in this disease, and where will patients get those tests done? When should lifelong continuous ibrutinib replace a less expensive and much shorter course of rituximab (Rituxan, Genentech) or the even less expensive alternative, observation? Are there new therapies or combinations that might be better or cheaper? In a disease with an annual incidence of approximately 1,500 new diagnoses, answers are likely to be slow in coming. It will be up to the community of researchers to collaborate more closely than ever to come up with solutions. Dr. Martin reported no relevant financial relationships.

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Clinical Oncology News • August 2015 • CLINICALONCOLOGY.COM

Cytotoxic Versus Targeted Rx: Looking for Cancer Cures Philadelphia—In the realm of cancer treatment innovations, the intense focus on targeted pathway inhibitors and immune response modulators has, to a large degree, pushed conventional chemotherapy off the stage. However, the pendulum may swing back. Although very little new clinical research was devoted to cytotoxic agents at the 2015 annual meeting of the American Association for Cancer Research, participants in one symposium suggested that this needs to change. “Nothing we do has come close to what cytotoxic chemotherapy has done in terms of curing patients of cancer,” said Anthony G. Letai, MD, PhD, an associate professor in the Divisions of Hematologic Neoplasia and Hematologic Malignancies at Dana-Farber Cancer Institute, in Boston.

enhance the chemosensitivity of tumor cells, further priming the mitochondrial signals for apoptosis. One focus has been on the BCL2–interacting mediator of cell death (BIM). Dr. Letai described work with the BIM BH3 peptide, a potent mimic of apoptosis signaling derived from a domain of BIM. The sensitivity of tumor cell mitochondria to the BIM BH3 peptide predicts cancer cell susceptibility to treatment with

conventional chemotherapeutic agents, such as cytarabine and daunorubicin in acute myeloid leukemia and cisplatin in ovarian cancer. By measuring the druginduced accentuation of the response of tumor cell mitochondria to the BIM BH3 peptide, it is becoming easier to single out the most promising targeted agents. According to Dr. Letai, this technique, known as dynamic BH3 profiling, can be performed on primary cells, rather than in cancer cell lines.

Finding more and better inhibitors to potentiate apoptotic priming for improved cytotoxic effect of chemotherapy is now a focus, and this work is poised to accelerate. “We can study hundreds of exposures that could be individual drugs, different combinations of drugs or different concentrations of drugs,” Dr. Letai explained. “Now, we are no longer faced with the normal limitations of long-term ex vivo cultures. Dynamic BH3 profiling see CYTOTOXIC, page 25 

Cases in Hyponatremia

Minimizing Risks, Optimizing Outcomes To participate in this FREE CME activity, log on to

www.CMEZone.com/hyponatremia Release Date: November 11, 2014

One of several experts who is actively deconstructing why chemotherapy has been so effective, Dr. Letai is among those who believe that chemotherapy remains one of the best options for curing cancer. Moreover, he said, targeted therapy and immune modulation may further improve its prospects. Chemotherapy generally is regarded as a blunt instrument. The empirical therapeutic index of cytotoxic drugs has been developed largely on the basis of the maximum tolerable dose. Until recently, there has been only limited understanding of the mechanisms by which cytotoxic therapies kill malignant cells. However, this is changing, according to Dr. Letai and other speakers at the symposium. For Dr. Letai, the focus has been on the ability of cytotoxic drugs to prime malignant cells for apoptosis. Work in his laboratory demonstrates that this is cytotoxic drugs’ main mechanism of activity, rather than direct cytotoxic effects. Furthermore, he said, targeted therapies will help facilitate this mechanism, according to experimental models. These observations provide a rationale to build on the curative properties of conventional chemotherapy. The goal is to find targeted therapies that

Expiration Date: November 11, 2015

Faculty

Goal

Michael L. Moritz, MD

The goal of this educational activity is to provide clinicians with clinically relevant information and practice strategies concerning the assessment and management of hyponatremia.

Professor, Pediatrics Clinical Director, Pediatric Nephrology Medical Director, Pediatric Dialysis Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania

Denise H. Rhoney, PharmD

Ron and Nancy McFarlane Distinguished Professor and Chair Division of Practice Advancement and Clinical Education UNC Eshelman School of Pharmacy Chapel Hill, North Carolina

Learning Objectives At the completion of this activity, participants will be better prepared to: 1 Distinguish the various subtypes of hyponatremia. 2 Describe the comorbidities and causes commonly associated with hyponatremia and their signiﬁcance in treatment. 3 Summarize current evidence and best practices in the management of hyponatremia. 4 Explain how to mitigate adverse events secondary to treatment of hyponatremia. 5 Apply strategies to improve the management of hospitalized patients with hyponatremia.

Intended Audience The intended audience for this educational activity includes physicians (cardiologists, critical care specialists, endocrinologists, hepatologists, hospitalists, intensivists, and nephrologists), nurses, pharmacists, and other clinicians who care for individuals with hyponatremia.

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies

This activity is jointly provided by Global Education Group and Applied Clinical Education.

of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group and Applied Clinical Education. Global Education Group is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Global Education Group designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Pharmacist Continuing Education Accreditation Statement Global Education Group is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Credit Designation Global Education Group designates this continuing education activity for 1.0 contact hour(s) (0.10 CEUs) of the Accreditation Council for Pharmacy Education. (Universal Activity Number - 0530-9999-14-061-H01-P) This is a knowledge-based activity

Accreditor Contact Information For information about the accreditation of this program, please contact Global Education Group at (303) 395-1782 or inquire@globaleducationgroup.com.

Supported by an educational grant from Otsuka America Pharmaceutical Inc.

Distributed via CMEZone

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CliniCal OnCOlOgy news • august 2015 • CLINICALONCOLOGY.COM

VALUE continued from page 1

print], PMID: 26101248). The task force envisions that patients will be presented with the expected out-of-pocket and overall drug acquisition costs for the regimens being compared, along with a net health benefit score (NHB). This score represents the added clinical benefit that patients can expect to receive from the new therapy, compared with the current standard of care. For both adjuvant and advanced disease treatments, the NHB is calculated based on improvement in overall or progression-free survival, and on the number and severity of toxicities (Figure). For metastatic cancer treatments, a higher NHB is awarded for regimens that also offer relief from cancer-related symptoms or allow patients a treatment-free period. The National Academy of Medicine (formerly the Institute of Medicine) has identified six elements of quality health care delivery: safety, effectiveness, efficiency, patient centeredness, timeliness and equity. The new methodology focuses only on three of these six (safety, effectiveness and efficiency [cost]), because the other elements are not as easily measured or consistently reported in clinical trials. The task force emphasized that the proposed framework is intended to empower patients with information, not limit patient choice. “[The methodology] is not a way of ranking drugs. This is simply a way of understanding the outcome of a clinical trial,” said task force chair Lowell Schnipper, MD, the chief of hematology/oncology at Beth Israel Deaconess Medical Center, in Boston. “It is by no means a substitute for

the physician’s judgment or patient preference.” Once the framework has been finalized and adapted into a practical tool for clinical use, doctors will have the ability to adjust the parameters of the tool according to a patient’s health preferences and financial situation. “The definition of value will be highly personalized for each

patient,” said Dr. Schnipper. The task force acknowledges that the methodology has several limitations, including that it does not permit intertrial comparisons, and the scoring categories and weights to create the score are “somewhat arbitrary” although “based largely on expert, clinical opinions.” Another drawback is that the

study populations are defined by the clinical trial eligibility requirements and are unlikely to represent the general cancer population. According to Leah Ralph, the manager of provider economics and public policy at the Association of Community Cancer Centers, in Rockville, Md., ASCO’s value framework is an important step in

ACCC Panelists Share Tips To Help Enhance Value ARLINGTON, VA.—Recognizing that value is playing an increasingly important part of the equation in cancer care, a panel of experts at the association of Community Cancer Centers’ 2015 annual meeting shared practical ideas to improve value within cancer centers. shared decision-making is central to value, said Randall Oyer, MD, the medical director of the oncology program at lancaster general Hospital, in lancaster, Pa. “it’s not just obtaining consent or asking patients what they want; it’s a very formal process” that ensures that patients have choices and provides the information and support they need to make those choices. Many controlled trials have shown that shared decision-making results in patients who have better knowledge of their disease, make more conservative treatment choices and are more satisfied with those choices, he said. Dr. Oyer described three value initiatives implemented at lancaster general Health that could be readily adopted by other hospitals. in one initiative, his hospital tracked the type of cancer patients who were going to the emergency department (eD), what their complaints were and what they needed, and used these data to create a nursing triage system that anticipates patient needs and intervenes early to reduce eD visits and hospitalizations. the medical center also developed

a profile of patients who could benefit from early consultation with a palliative care professional and developed a process to facilitate early consultations. in addition,

oncology program professionals evaluated drug regimen costs and developed a process to share cost estimates with patients when possible.

CICARE Patient-Centered Care Program 1. Connect with the patient/family member using Mr./Ms. or their preferred name. 2. Introduce yourself and your role. 3. Communicate what you are going to do, how long it will take and how it affects the patient. 4. Ask for and anticipate patient needs/ concerns/questions. 5. Respond to patient/family questions and requests with immediacy. 6. Exit courteously, explaining what will come next, when you will return, and ask if the patient or family needs anything before exit.

CURRENT PRACTICE

Clinical Oncology News • August 2015 • CLINICALONCOLOGY.COM

the broader conversation about measuring value in cancer care (see sidebar). “As a conceptual framework, it has done its job—jump-starting the conversation in a thoughtful way,” said Ms. Ralph. “But, as ASCO points out, it is critical to consider this tool in context. The methodology contains significant, and noted, limitations in data, practicality and scope, and is far from being ready to be used in a clinical setting. While it’s an important starting point, and ASCO has played an important role here, policymakers and payors must be cautioned that this framework is not meant to serve as a basis for reimbursement or coverage determinations.”

Oncologists Are Taking Responsibility During the plenary session at the 2015 ASCO annual meeting, Leonard Saltz, MD, the chief of gastrointestinal oncology at Memorial Sloan-Kettering Cancer Center, in New York City, gave a presentation on value in cancer care. He said that value and cost considerations are oncologists’ responsibility and that the cancer care leadership has begun to “lead the way in taking on that responsibility,” referring to the work of the ASCO Value in Cancer Care Task Force and other organizations. The National Comprehensive Cancer Network is in the process of adding “evidence blocks” to guidelines that will rate the affordability of cancer regimens. The European Society for Medical Oncology also is focusing on value and has just released its own Magnitude of Clinical Benefit Scale. This scale uses a structured approach to derive a relative ranking of the magnitude of clinically meaningful benefit that can be expected from a new anticancer treatment. According to Dr. Saltz, new cancer

Leading Oncologists Offer Strategies To Help Make Cancer Drugs More Affordable

group of 118 of the nation’s leading cancer experts have drafted recommendations for reducing the high cost of cancer drugs in a commentary published July 23, 2015, online in the Mayo Clinic Proceedings (http://bit. ly/1ejNiHo). Citing a 2015 study by Howard et al that found that cancer drug prices have risen by an average of $8,500 per year over the past 15 years (J Econ Perspect 2015;29[1]:139-162), the group wrote that “it’s time for patients and their physicians to call for change.” They proposed following specific actions to address this problem: • Create a post-FDA drug approval review mechanism to propose a fair price for new treatments that is based on the value to patients and health care. • Allow Medicare to negotiate drug prices. • Allow the Patient-Centered Outcomes Research Institute, created through the Affordable Care Act, to evaluate the benefits of new treatments and similar organizations to include drug prices in their assessments of the treatment value. • Allow importation of cancer drugs across borders for personal use. • Pass legislation to prevent drug companies from delaying access to generic drugs. • Reform the patent system to make it more difficult to prolong product exclusivity unnecessarily (patent “evergreening”). • Encourage organizations that represent cancer specialists and patients (e.g., the American Society of Clinical Oncology, American Society of Hematology, American Association for Cancer Research, American Cancer Society, National Comprehensive Cancer Network) to consider the overall value of drugs and treatments in formulating treatment guidelines. —Based on a press release from the Mayo Clinic

‘We start by acknowledging that there must be some upper limit to how much we can, as a society, afford to pay to treat each individual patient with cancer. We (all of us) need to be willing to discuss what that limit might be.’

—Leonard Saltz, MD

drugs “cost too much,” and physicians have a duty to discuss side effects as well as financial toxicity with patients. Historically, patients with health insurance were shielded from the high cost of medical care, but, today, patients find

Frederick Regional Health System, in Maryland, is implementing similar initiatives, increasing the use of palliative care services for patients with stage IV solid tumors and expanding strategies to reduce ED utilization. In addition, oncologists in the health system have agreed to treat all patients by evidence-based pathways, said Mark Soberman, MD, MBA, the medical director of the system’s oncology service line. “It’s a little harder than it sounds sometimes, but we have a cohesive group, and we use these pathways to improve value and decrease costs.” The health system also took advantage of Maryland’s unique all-payor system, which provides different reimbursement rates for hospitalbased facilities and freestanding structures. In planning and designing the hospital’s new cancer center, “we made a very considered decision to move from an on-campus to an off-campus location,” Dr. Soberman said, in part because the rates for on-campus services are 40% higher “and we felt it was appropriate to forgo that extra revenue and to provide that service to our community at a lower charge.” UCLA Health, in Los Angeles, also has instituted programs to enhance value. In 2006, the system ranked in the 30th percentile on patient

themselves increasingly responsible for a greater proportion of their health care costs—in the form of higher premiums, deductibles and copays. “We have to discuss concerns regarding costs and finances. We have to understand and

satisfaction. New leadership wanted to improve those scores, and one outcome was a six-step patient-centered care program described by the acronym CICARE (pronounced see-I-care), a mnemonic that staff use in their interactions with patients and their family members, said Michael Steinberg, MD, a professor and the chair of radiation oncology at UCLA’s David Geffen School of Medicine. Application of CICARE increased satisfaction scores to the 90th to 95th percentile, Dr. Steinberg said. More recently, he said, UCLA radiation oncology embraced “Choosing Wisely,” a national campaign sponsored by the American Board of Internal Medicine Foundation intended to reduce unnecessary medical tests and procedures. They created decision support tools for physicians to increase the use of single-fraction treatment for bone metastasis and hypofractionated treatment for breast cancer patients. In addition, patient care teams have embraced a program called “Patient Voice,” using ethnography to better understand patient perceptions of their experience while going through medical treatment. Primary breast cancer patients receiving radiation therapy, for example, are routinely believed to tolerate treatment with minimal side effects, Dr. Steinberg said, yet the application of sophisticated ethnographic interview techniques revealed that patients often experience significant fatigue and anxiety

discuss the limitations of insurance. We need to understand their deductibles and copays,” said Dr. Saltz. “We need to be revealing this [financial] toxicity in our academic journals, just as we report on neutropenia, alopecia and nausea.” On average, a new cancer drug costs roughly $10,000 per month for a single drug, with some costing more than $30,000. A 20% copay for a drug that costs $10,000 per month is an insurmountable hurdle for most individuals. Echoing the sentiment of many clinicians, Dr. Saltz said that current drug pricing models are not rational; they simply reflect what the market will bear. A recent analysis revealed there is little difference between the median wholesale price of a novel and a next-in-class drug, and there is no significant relationship between cost and percentage improvement in overall or progressionfree survival end points (J Econ Perspect 2015;29[1]:139-162; JAMA Oncol 2015;1[4]:539-540, PMID: 26181265). Clinicians need to factor in price when considering treatment options, said Dr. Saltz. In a study presented at the ASCO annual meeting, researchers showed that in the treatment of first-line colorectal cancer in patients with KRAS mutations, outcomes are identical whether bevacizumab (Avastin, Genentech) or cetuximab (Erbitux, Eli Lilly) is added to a chemotherapy backbone, but the cost of using bevacizumab is less than half the cost of using cetuximab (abstract 6504). “That doesn’t leave us with two equivalent regimens with dealer’s choice,” said Dr. Saltz. “That leaves us with one regimen that is the clear, better choice.” The rising costs of cancer care are unsustainable, and change is clearly see VALUE, page 24 

that were generally underreported. “We’re starting to learn from these patient-reported outcome (PRO) tools the true patient point of view,” Dr. Steinberg said. “It’s opening our eyes to the importance of the patient voice in determining value in health care delivery.” Jonas de Souza, MD, a head and neck cancer specialist and assistant professor of hematology/oncology at the University of Chicago Medical Center, and his colleagues created a financial toxicity PRO tool to help patients better understand drug side effects and costs (Cancer 2014;120[20]:3245-3253, PMID: 24954526). Using an 11-item survey, they are measuring patients’ risk for, and ability to tolerate, financial stress. The questionnaire, called COST (COmprehensive Score for financial Toxicity), includes statements such as, “My out-ofpocket medical expenses are more than I thought they would be,” and ranks how much patients agree or disagree with the statements. Dr. de Souza said the answers can help physicians determine which patients are in early need of financial assistance and may need lower-cost or reduced-dose medications. —Karen Blum

The panelists reported no relevant financial relationships.

CURRENT PRACTICE

BRAIN METASTASES continued from page 1

2015 annual meeting of the American Society of Clinical Oncology (ASCO; abstract LBA4). “For patients with newly diagnosed brain metastases that are amenable to SRS, we recommend initial treatment with SRS alone and close monitoring to better preserve cognitive function and quality of life,” said lead study author Paul Brown, MD, a professor of radiation oncology at the University of Texas MD Anderson Cancer Center, in Houston. According to Dr. Brown, decisions to use adjuvant WBRT should hinge on whether radiation or tumor recurrence has a more detrimental impact on cognitive health. Trials have provided mixed results on this question. The N0574 trial randomly assigned 208 patients with one to three brain metastases less than 3 cm to receive SRS alone or with WBRT. Approximately 70% of patients had a primary lung cancer, and 50% of patients had a single brain metastasis. The investigators stratified patients by age (18-59 vs. ≥60 years), length of extracranial disease control (≤3 vs. >3 months), number of brain metastases (one vs. two vs. three) and institution. They excluded patients who received chemotherapy during radiation or had an Eastern Cooperative Oncology Group performance status score of 2 or higher. At baseline, six weeks, and three, six, nine and 12 months, patients underwent MRI to monitor disease status, the Functional Assessment of Cancer Therapy-Brain to assess QoL and several cognitive tests. The primary end point was cognitive deterioration at three months, defined as a drop in one standard deviation in one of several cognitive tests that evaluated memory, processing speed, executive function, verbal fluency and motor speed/dexterity (Table 1).

VALUE continued from page 23

needed. Cancer care costs are estimated to increase to $158 billion by 2020, up from $125 billion in 2010 (J Natl Cancer Inst 2011;103[2]:117-128, PMID: 21228314). Currently, a premium for a family insurance plan plus out-of-pocket health care costs equals approximately half of the average U.S. household income, and is expected to equal the median household income by the year 2033 (Ann Fam Med 2012;10[2]:156-162, PMID: 22412008).

The Tipping Point Dr. Saltz suggested that society needs to start the discussion about change by recognizing that there is a tipping point.

Clinical Oncology News • August 2015 • CLINICALONCOLOGY.COM

Table 1. Cognitive Deterioration at Three Months

Patients who received WBRT were more likely to have a decline in cognitive function at three months (91.7% vs. 63.5%; P=0.0007) and six months (97.9% vs. 77.8%; P=0.0007). This detriment was still seen at 12 months. “Decline in cognitive function is more frequent with the addition of wholebrain radiation therapy, specifically immediate recall, memory and verbal fluency,” said Dr. Brown. Time to intracranial progression was improved in patients who received WBRT, but there was no improvement in survival. Patients receiving WBRT experienced more alopecia and dermatitis, and had a worse QoL (Table 2). Dr. Brown concluded there was no support for adding WBRT to SRS in patients with brain metastases. Andrew Lassman, MD, the John Harris Associate Professor and the chief of the Neuro-Oncology Division at Columbia University Medical Center’s Herbert Irving Comprehensive Cancer Center, in New York City, said the trial findings could be interpreted differently if put in the context of other trial results. “N0574 concluded that WBRT is worse than recurrent metastases after 12 months [for cognitive impairment], but other studies suggest the opposite is the case,” said Dr. Lassman. He pointed out that the rate of recurrent brain metastases after SRS alone in N0574 was low relative to historical standards (50% vs. 73%78%), suggesting a highly selected population of patients. “The 213 patients enrolled on this trial represent fewer than one-tenth of 1% of patients with brain metastases diagnosed in the United States each year,” said Dr. Lassman. “Therefore,” he added, “generalizing the conclusions should be [done] with great caution.” Dr. Lassman also pointed out that new evidence shows that WBRT increases survival in the appropriate context. An update of a Japanese trial

published two weeks before the ASCO meeting showed that adding WBRT to SRS improved median overall survival by six months (16.7 vs. 10.6 months; P=0.04) in lung cancer patients with brain metastases who had favorable prognostic factors (JAMA Oncol 2015. doi: 10.1001/jamaoncol.2015.1145 [Epub ahead of print]). Specifically, survival was improved in patients with diagnosis-specific Graded Prognostic Assessment (GPA) of 2.5 to 4.

“The data from N0574 has not been analyzed according to GPA score, and we eagerly await that further analysis,” said Dr. Lassman. “Whole-brain radiotherapy should be used in selected cases when the brain metastases are a life-limiting site of disease.”

“We start by acknowledging that there must be some upper limit to how much we can, as a society, afford to pay to treat each individual patient with cancer,” said Dr. Saltz. “We (all of us) need to be willing to discuss what that limit might be. It’s a very unpleasant discussion. It is very uncomfortable. We need to encourage, rather than suppress, discussions of value of cost and cancer care.” Dr. Saltz also suggested that the United States needs to rethink the payment system for drugs. “We need to find models for paying for the performance of drugs, perhaps a price [that is] based on predetermined targets,” said Dr. Saltz. Other possible solutions include tiered coverage, in which there would be little or no copay for drugs with high value

and high copays for drugs with low value. The United States, he said, also could consider mimicking the United Kingdom’s approach to health care. That country has a process that integrates clinical and econometric analyses to determine whether the value of a new agent is great enough that it should be available to patients through the National Institute for Health and Care Excellence. In the United States, the FDA is the gatekeeper of drug approvals, and it is forbidden, by law, from considering price. The Centers for Medicare & Medicaid Services (CMS) is obligated to buy what the FDA approves, and it is forbidden from negotiating price. “We need to find ways legislatively to give the FDA and CMS the ability to consider value,

and to give CMS the ability to negotiate price,” said Dr. Saltz. Quoting Dr. Seuss, he added: “Unless someone like you Cares a whole awful lot, Nothing is going to get better. It’s not.” —Kate O’Rourke

Cognitive Test

SRS, %

SRS + WBRT, %

P Value

HVLT-R Total Recall

8.2

30.4

0.0043

HVLT-R Delayed Recall

19.7

51.1

0.0009

HVLT-R Recognition Discrimination Index

22.6

40.4

0.0585

TMT Part A

16.7

30.4

0.1063

TMT Part B

19.0

37.2

0.0677

Controlled Oral Word Association Test

1.9

18.6

0.0098

Grooved Pegboard Test (dominant hand)

29.3

47.7

0.0656

HVLT-R, Hopkins Verbal Learning Test-Revised; SRS, stereotactic radiosurgery; TMT, Trail Making Test; WBRT, whole-brain radiation therapy

Table 2. Patient-Reported Outcomes On FACT-Brain QoL Test/Subtest Physical well-being

SRS

SRS + WBRT

P Value

–4

–18

0.053

Social family well-being

–3

0.369

Emotional well-being

0.129

Functional well-being

–22

0.006

FACT-General

–12

0.001

FACT-Brain specific

–1

–9

0.029

FACT-Brain total

–1

–11

0.002

FACT, Functional Assessment of Cancer Therapy; QoL, quality of life; SRS, stereotactic radiosurgery; WBRT, whole-brain radiation therapy

Patient Factors Are Important Interpreting the results of the N0574 trial, Steve Chmura, MD, PhD, an associate professor of radiation and cellular

Dr. Vose reported financial relationships with Acerta, Bio Connections, BristolMyers Squibb, Celgene, Genentech, GlaxoSmithKline, Incyte, Janssen Biotech, Kite Pharma, Pharmacyclics, Sanofi and Spectrum Pharmaceuticals. Dr. Schnipper reported financial relationships with Eviti and Merck. Dr. Saltz reported financial relationships with Abbott Biotherapeutics, Bayer, Boehringer Ingelheim, Lilly, Pfizer, Roche/Genentech, Sun Pharma and Taiho. Ms. Ralph reported no relevant financial relationships.

CURRENT PRACTICE

Clinical Oncology News • August 2015 • CLINICALONCOLOGY.COM

oncology at The University of Chicago Medical Center, said there are a number of nuances to consider. “We all know that if people with brain metastases live long enough, they suffer substantial neurologic decline from having tumors grow in their brain—far worse than that caused by any radiation or chemotherapy,” he said. Patients in the N0574 trial, however, had a median overall survival of only 10.7 and 7.5 months in those who received SRS alone or SRS plus WBRT,

respectively, “a very short time compared with how people with few brain metastases do today,” Dr. Chmura said. “If life expectancy is short, a patient will experience the side effects of WBRT without living long enough to benefit from not developing further brain tumors. In the Japanese trial, the patients lived a long time and showed that there was a benefit to WBRT,” he said. “So it’s important to consider who the patients were, what side effects they were having and at what time.”

Dr. Chmura pointed out that the type of WBRT used in the N0574 trial is outdated, and that patients now receive memantine, “which two large randomized trials have shown improves cognitive function.” Hippocampal-sparing WBRT is another option under investigation; a Phase III trial opened up July 20 in the United States after an earlier trial showed promising results in patients ineligible for SRS. “The Phase II study showed that hippocampal WBRT actually results

in better cognitive functioning than SRS alone has ever shown in a trial,” Dr. Chmura said. Furthermore, “when you do SRS alone, there is a 50-50 chance the patient will need another SRS,” he said. Patients who undergo hippocampal-sparing WBRT run no such risk.

CYTOTOXIC

the same way” that we use the molecular pathway inhibitors that are now proliferating. “I think that we can start treating tumors with chemotherapy in a very mechanistic way with the known functions of these agents,” he said. He provided several examples of research that documents mechanisms of conventional chemotherapy beyond nonspecific cytotoxicity. One example was based on a series of studies associating cyclophosphamide and alemtuzumab (Lemtrada, Genzyme) with synergy in experimental models of B-cell malignancies. To determine the basis of the synergy, it was found that

cyclophosphamide induced cytokine release from tumor cells, which recruited macrophages into the bone marrow to kill tumor cells. Because this effect was not based on cytotoxicity, very low doses of cyclophosphamide were sufficient. “In this context, cyclophosphamide is really having a strong immunomodulatory effect,” Dr. Hemann explained. The same or similar mechanism might be relevant to the enhanced efficacy of rituximab (Rituxan, Genentech) when it is added to the CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) regimen, according to Dr. Hemann. However, the key message is that

progress is being made to understand the mechanisms by which chemotherapies provide clinical benefit. This is critical to build on the cures that are already being achieved with these agents in some patients, Dr. Hemann said. “Understanding mechanisms allows you to understand how you might define effective combination therapies or guide targeted use in specific cancer patients,” he added. “This is the appeal of targeted drugs.”

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provides a functional means to cancer precision medicine.” The identification of this and other specific mechanisms of action may allow cytotoxic chemotherapies to get more well-deserved attention, agreed Michael T. Hemann, PhD, an associate professor at Massachusetts Institute of Technology’s David H. Koch Institute for Integrative Cancer Research, in Boston. Dr. Hemann also is involved in studies suggesting that “we can use conventional chemotherapy as targeted therapy in

—Kate O’Rourke with additional reporting by Monica J. Smith Drs. Brown and Lassman reported no relevant financial relationships.

—Ted Bosworth Dr. Letai reported a financial relationship with AbbVie. Dr. Hemann reported no relevant financial relationships.

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