November 2013 by McMahon Group

Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • November 2013 • Vol. 8, No. 11

INSIDE CURRENT PRACTICE Introducing Massachusetts General Hospital Cancer Center: Expert commentaries on recent studies ..................... 11 Clinical Conundrums ....... 15

by the

numbers

End-of-life care A study of Medicare cancer patients by the Dartmouth Atlas Project has shown that while hospice care is generally being better utilized by physicians, patients are still being overtreated at the end of life.

20032007

2010

Admitted to an ICU during the last month of life

23.7%

28.8%

Hospice initiated during the last three days of life

8.3%

Sees 10 or more 46.2% physicians within the last six months of life

10.9%

58.5%

Source: Dartmouth Atlas Project. T Trends in Cancer Care Near the End of Life. http://www.dartmouthatlas.org/downloads/reports/Cancer_brief_090413.pdf. Published Septemberr 4, 2013.

IMAGES in ONCOLOGY

ASCO 2013

Patients Care About Cost, Even When Not Paying Chicago—Two studies, although posing slightly different questions, indicate that a substantial proportion of patients with cancer want their physicians to include the costs of care in their discussion of treatment options. In one study, the figure was about 50%; in the other, it was about 70%. Both studies, presented at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO), indicate that only a minority of clinicians include any information about costs now. One study was designed to evaluate see PATIENT COST, T page 10

“Untitled (Tiny Bubbles),” a dreamscape of poikilocytes. For more information see page 2.

How I Manage...

Vogl, NY...

Follicular Lymphoma—Part I

Tamoxifen or Prophylactic Mastectomy for BRCA1/2 2 Carriers?

ollicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) in the United States, accounting for almost one-fourth of cases, and Bruce Cheson, MD the most frequently diagnosed indolent NHL. Its etiology is unknown, with no known risk factors. The median age at diagnosis is 60 years. FL is divided into three histologic grades based on the number of large cells (centroblasts) per high power field. Grades 1 to 3a, as defined by the 2008 World Health Organization (WHO) classification, have relatively comparable outcomes and generally are see FOLLICULAR LYMPHOMA, page 14

Larger cohort study confirms tamoxifen activity

elly-Ann Phillips, MBBS, of the Peter MacCallum Cancer Centre in Melbourne, Australia, and 35 co-authors published a paper in the September 1, 2013, issue of the Journal of Clinical Oncology (JCO ( ) demonstrating for the third time that tamoxifen use is associated with a reduced incidence of contralateral breast cancers in BRCA1 and BRCA2 mutation carriers.1 The paper reports on contralateral breast cancers in mutation carriers who already had one breast cancer both before and Steven Vogl, MD after they entered one of three international observational cohorts. Although these women were the subjects of the analysis, the point of the paper is that tamoxifen prevents new breast cancers in these women, and that tamoxifen should be considered as an option for breast cancer prevention in mutation carriers see CHEMOPREVENTION, N page 3

RE VIE WS & COMMENTAR IES

Expert Insights From Massachusetts General Hospital Cancer Center Low-Dose Aspirin Reduces Extent of Colorectal, Lung Tumors ....................... 12 Andrew T. Chan, MD

No Advantage To Screen Asymptomatic Women for Ovarian Cancer ..................... 13 Marcela del Carmen, MD, MPH

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2013 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

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

Breast Cancer

Prostate Cancer

Charles F. von Gunten, MD

Michael A. Carducci, MD AEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD

Joseph P. DeMarco, PhD Cleveland State University Cleveland, OH

Oncology Nursing

Hematologic Malignancies

Betty Ferrell, RN, PhD

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

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

Andrew Seidman, MD

Jennifer R. Brown, MD, PhD

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

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Michele Neskey, MMSc, PA-C

Maura N. Dickler, MD

Harry Erba, MD, PhD

University of Texas, MD Anderson Cancer Center Houston, TX

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

University of Alabama Birmingham, AL

Gastrointestinal Cancer

Mayo Clinic Rochester, MN

University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Richard Stone, MD

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

Gastrointestinal Cancer and Sarcoma

Mary Lou Bowers, MBA The Pritchard Group Rockville, MD

Cindy O’Bryant, PharmD

Matt Brow

University of Colorado Cancer Center Denver, CO

VP, Public Policy & Reimbursement Strategy McKesson Specialty Health The US Oncology Network Washington, DC

Sara S. Kim, PharmD The Mount Sinai Medical Center New York, NY

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

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

On the Cover

Syed A. Abutalib, MD Cancer Treatment Centers of America Zion, Illinois

ur cover features the artwork of Marie Sicari, MD, a pathologist, visual artist and performer whose digital art photography project focuses on imagery of human disease. Dr. Sicari specializes in the fields of anatomic pathology and dermatopathology. Dr. Sicari’s digital abstract art explores the fantastic imagery of microscopic pathology as a potential tool to access and explore the mind-body-spirit connection. Her work reflects the paradigm shift occurring in medicine toward the inclusion of holistic approaches and the role of creative arts in the healing process. If you are interested in purchasing this piece or other work from her collection, Dr. Sicari may be reached at www.behance.net/MarieSicari

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

Ephraim Casper, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Policy and Management

Pharmacy

Shaji Kumar, MD

Edward Chu, MD

Bioethics

University of California, San Diego, CA

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

Genitourinary y Cancer Ronald M. Bukowski, MD Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic y g Cancer Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Steven Vogl, MD Medical Oncologist New York, NY

Symptom Control and Palliative Care

Levine Cancer Institute, Carolinas HealthCare Charlotte, NC

Lung g Cancer,, Emesis Richard J. Gralla, MD Hofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center Lake Success, NY

William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

Lung g and Head and Neck Cancers Edward S. Kim, MD

Mission Statement he mission of Clinical Oncology News is to be an independent source of unbiased, accurate and reliable news combined with in-depth expert analysis about the issues that oncologists and hematologists care about most. We strive to be a valuable source for oncologists and hematologists in providing the best possible care for their patients.

Steven D. Passik, PhD Vanderbilt University Medical Center Nashville, TN

Editorial Philosophy The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print. Additionally, all news articles that appear in Clinical Oncology Newss are sent to the sources quoted in each article to review and verify the accuracy of the article’s content.

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

Russell K. Portenoy, MD Beth Israel Medical Center New York, NY

Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

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What do we know?

CHEMOPREVENTION continued from page 1

EDITORIAL BOARD COMMENTARY Steven Vogl, MD Medical Oncologist, New York City

who have never had breast cancer. The argument is that “a breast at risk” is exactly that, whether or not there has been a contralateral breast cancer. It makes sense to consider the presence of a contralateral breast cancer, and the treatments given to treat that cancer, as just another set of factors that modify risk in the unaffected breast, as do age, oophorectomy, age of affected family members, and as yet unidentified genetic and epigenetic characteristics. The paper is well written; the data well analyzed; the background and analysis well referenced; and the discussion and conclusions well thought out and well argued. Why then, a reader might ask, have I picked up my pen to write this editorial? For these reasons: to call the reader’s attention to the activity of tamoxifen in breast cancer prevention among mutation carriers; to point out limitations of the study design and the analysis that are important as we counsel at-risk patients; and to call for the prospective collection of detailed data to guide clinicians in the future as to when to start tamoxifen chemoprevention, when to stop it, whether to give it continuously or intermittently (i.e., five years on and five years off, then another five years on, etc.), whether to give it before or after oophorectomy, and to develop better data on how well it works, especially if given for long periods.

Summary of the JCO paper The three groups identified 2,464 carriers who met the criteria: 1,583 women with BRCA1-associated cancers

and 881 with BRCA2-associated cancers, who developed 520 contralateral breast cancers. Prospective information on the development of new breast cancers (after the mutation was identified) is available for 657 BRCA1 carriers and 426 BRCA2 carriers who developed 100 contralateral breast cancers. The latter is of interest because the availability for retrospective inclusion in a study such as this depends on the patient surviving long enough for the mutation assay to be developed and deployed—only survivors get to be tested. Both the direction and extent of this survivor bias are difficult to determine, so the prospective data should carry more weight. Tamoxifen use and the incidence of contralateral cancer were coded mostly by asking the patient, with no effort to quantify tamoxifen dose or years of exposure. Estrogen receptor (ER) data was available for the first breast cancer for only 44% of the cohort. Median followup was 6.6 years from breast cancer diagnosis and 3.2 years from cohort entry. Tamoxifen produced large reductions in the incidence of contralateral breast cancer for these women: 62% for BRCA1 carriers and 67% for BRCA2. If only the prospective period of followup that was not subject to survivor bias is considered, the benefit was 42% for BRCA1 and 52% for BRCA2—smaller, but still considerable. These benefits appeared independent of the ER status of the prior primary breast cancer. Although ER was not centrally repeated or verified, omitted far too often, and although some of the countries included in the study had notoriously unreliable ER data in the 1970s and 1980s, the hormone-receptor data reported confirms the general observation that about 75% of cancers associated with BRCA1 are ER-negative, and about 75% of those associated with BRCA2 are ER-positive. The activity of tamoxifen in preventing contralateral cancers for BRCA1 carriers—where most cancers are ER-negative—and when the index cancer was ERnegative is surprising, because primary

• Tamoxifen reduces risk for contralateral breast cancer in mutation carriers regardless of which mutation (BRCA11 or BRCA2), although most BRCA11 cancers are ER-negative. • Oophorectomy reduces risk for breast cancer in mutation carriers by about 50%. • Mastectomy nearly eliminates risk for breast cancer in mutation carriers (93%-100% reduction).

What we do not know! • When to start tamoxifen • Whether to give it continuously or intermittently • When to stop tamoxifen • The extent of tamoxifen benefit • How concurrent medications, especially antidepressants, interact with tamoxifen benefit • How the cytochrome P450 2D6 genotype interacts with tamoxifen benefit • How the extent of tamoxifen benefit is affected by age, years since menarche, number of pregnancies, number of live births, oophorectomy and years since natural or chemotherapy-induced menopause • How much tamoxifen a woman needs to take over time to get a benefit, and whether the benefit increases with increasing tamoxifen exposure • Whether continuous tamoxifen is necessary, or whether drug holidays of several years may still allow major benefits as a result of the tamoxifen “carry-over” effect • What proportion of BRCA11 and BRCA2 2 mutation carriers will opt to keep their breasts and take tamoxifen based on a given level of benefit according to their situation

prevention in the general population in the P1 study suggests that tamoxifen prevents only ER-positive cancers.2 Tamoxifen appeared less effective in premenopausal women who also had oophorectomy: reductions of 30% for both BRCA1 and BRCA2 carriers in the entire series, and 39% for BRCA1 and 26% for BRCA2 for the periods of prospective follow-up. Splitting the patients by oophorectomy makes tamoxifen seem even more effective in those with intact ovaries. For these women, it yielded reductions in contralateral cancers of 74% for BRCA1

and 79% for BRCA2 in the combined retrospective and prospective analyses. Oophorectomy largely prevents ovarian cancer (which cannot be detected reliably when localized except by serial section of resected ovaries) in mutation carriers and approximately halves the risk for breast cancer, with more benefit in BRCA2 mutation carriers.3 Oophorectomy should be recommended to all mutation carriers as soon as they have completed their families. They should therefore be encouraged to complete their families as early as possible.

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CHEMOPREVENTION continued from page 3

Tamoxifen for prevention of breast cancer is a procedure to be offered in addition to risk-reducing oophorectomy. One can conceive of circumstances in which it might be offered first. For instance, if a mutation is discovered in a 25-year-old woman who is not ready to start a family, she could take tamoxifen for two to three years, stop to have a family, then have oophorectomy when the annual risk for ovarian cancer becomes high

enough to justify suffering symptoms of menopause (the mid- to late 30s). The benefits and consequences of various sequences of these therapies have yet to be adequately defined.

Consistent Results From Two Prior Contralateral Breast Cancer Reports In a smaller cohort analysis published in the JCO from six North American

Oncologists, geneticists, surgeons and gynecologists who care for patients and families with BRCA1 and BRCA2 mutations should begin discussing tamoxifen as an alternative to riskreducing ‘prophylactic’ mastectomy now. centers, 491 women with known BRCA1 or BRCA2 mutations in their families, aged 65 years or older, with stage I or II breast cancer, were followed for contralateral breast cancer.4 Personal genetic testing was positive in 84% of the cohort

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and 16% had positive tests only among family members. The investigators estimated that 4% of all the cases—25% of cases with mutations in the family only— probably did not have associated BRCA1 or BRCA2 mutations. Tamoxifen and oophorectomy (yes or no) were abstracted from medical records. Of 491 women with breast cancer, 30% had tamoxifen, 43% had oophorectomy and 61% had chemotherapy. Tamoxifen reduced the incidence of contralateral breast cancer by 41% in this series and by 91% if coupled with oophorectomy among premenopausal women. Oophorectomy alone was associated with a 56% reduction in contralateral breast cancer, increasing to 76% if done in women younger than age 50 years at diagnosis. Some of the same investigators who conducted this smaller cohort analysis reported a case–control study twice. The larger of these compared 285 mutation carriers with bilateral metachronous breast cancer with 751 controls with unilateral breast cancer.5 Women were asked about the use of adjuvant tamoxifen (yes or no). Only 12.5% of women with contralateral breast cancer had received tamoxifen compared with 25.6% of controls. Tamoxifen use, therefore, was associated with a 50% reduction in contralateral breast cancer for BRCA1 carriers and 58% for BRCA2. Tamoxifen plus oophorectomy reduced contralateral cancer by only 13%; however, only 26 cases had undergone oophorectomy, so the confidence intervals are very broad. Adjuvant tamoxifen appeared to produce no reduction in contralateral breast cancer 10 years or more after diagnosis of the first cancer, but the benefit did persist into years 6 to 10.

BRCA11 Chemoprevention Results Are Contradicted by a Very Small Series From The P1 Trial The only prospective data on the use of tamoxifen for primary prevention of breast cancer among BRCA1 and BRCA2 mutation carriers concerns 288 genetically tested women culled from the 13,388 healthy women randomized to tamoxifen for five years or placebo in the National Surgical Adjuvant Breast and Bowel Project (NSABP) P1 trial who had positive genetic testing.6 Among 11 BRCA2 carriers, tamoxifen produced a 62% reduction in breast cancer incidence. Among eight BRCA1 carriers, tamoxifen was associated with a 67% increase in new breast cancer. I agree with Dr. Phillips and her colleagues, as

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Main Points • Tamoxifen prevents breast cancer in mutation carriers regardless of which mutation and probably significantly in women with prior ER-negative breast cancers. • In order to counsel patients on prophylactic mastectomy versus tamoxifen, we need data on breast cancer risk reduction not only according to risk factors, but also according to compliance with therapy and duration of tamoxifen therapy. • Physicians and surgeons caring for mutation carriers should begin offering tamoxifen risk reduction to women with breasts at risk for new cancers now.

they commented in their JCO report, that these results do not deserve our attention because the numbers are far too small and the confidence intervals far too wide.

What Weakens the Conclusions Of Dr. Phillips’ JCO Report? The assignment to tamoxifen was not random. Physicians and patients chose whether or not to take tamoxifen for reasons we can only now guess. Even multivariable analyses cannot correct for all of the factors that went into the decision to take tamoxifen. Furthermore, because women with higher-risk first breast cancers probably got more therapy—tamoxifen, chemotherapy and surgery—and because contralateral breast cancers were probably not reported (and, appropriately, not looked for with mammograms and magnetic resonance imaging [MRI]) after the development of distant metastases but before death, tamoxifen may seem to have reduced contralateral breast cancer incidence only because of an ascertainment bias. There is also a time bias in the study that was unappreciated by the authors. Tamoxifen did not become available in the United States until 1976, and the first paper indicating a benefit with adjuvant tamoxifen (in addition to melphalan and fluorouracil) was not published until 1981.7 The U.S. National Cancer Institute consensus in 1985 recommended only adjuvant chemotherapy for premenopausal women and tamoxifen only for postmenopausal women with positive ERs in their cancers. It was only in 1999 that the NSABP reported the benefits of adjuvant tamoxifen in pre- and postmenopausal women with ER-positive tumors and negative nodes.8 Dr. Phillips’ analysis accrued about 28% of its participants before 1990, when adjuvant tamoxifen was not “standard of care” for large subgroups of breast cancer patients in the United States or elsewhere. This biases the “no tamoxifen” group toward patients diagnosed in earlier decades (something that could easily be analyzed in the data see CHEMOPREVENTION, N page 6

• Women who opt for tamoxifen risk reduction instead of prophylactic mastectomy should be followed very carefully for compliance with therapy and duration of therapy, and all should be entered into an international registry with the end point of cancer development in a previously unaffected breast. • Because many women in historical series probably were prescribed tamoxifen for one to two years, and because many probably complied poorly, or took drugs that prevented its activation, the benefits of tamoxifen for risk reduction may be seriously underestimated in the published literature.

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CHEMOPREVENTION continued from page 5

set), when breast cancers were larger and patients generally did worse. Dr. Phillips and her statistician, Dr. Roger Milne, tell me that tamoxifen use was indeed lower before 1990, and especially before 1980—9% among BRCA2 carriers and 5% among BRCA1 carriers for the earliest period, compared with 27% and 57% after 1990 (Phillips, personal communication). In an extension of the sensitivity analysis reported in table 5

of the JCO paper, limiting the analysis to after 1990 did not change the results or the conclusions, so my concerns were misplaced (Phillips, personal communication). Finally, effective tamoxifen dose and duration are probably important and not addressed at all in Dr. Phillips’ analysis. It is not clear how much tamoxifen the women were told to take, how long they took it and how compliant

they were. Up until 2000, many protocols gave tamoxifen for only one to two years; in the 2000 Oxford overview of adjuvant tamoxifen, two-thirds of women who received tamoxifen had received it for only one to two years.9 Additionally, the accuracy of participants’ recall of tamoxifen usage is uncertain. Further, it is unknown how many of the women were taking selective serotonin reuptake inhibitors like fluoxetine and paroxetine while they were taking tamoxifen. These drugs, and others, probably inhibit the activation of tamoxifen to its most active

form, endoxifen, and could substantially reduce its benefit.10 To my knowledge, no one has looked at cytochrome P450 2D6 polymorphisms and the effects of interfering drugs on the efficacy of tamoxifen chemoprophylaxis in any population. Because their risks are so high, BRCA1/2 mutation carriers are an excellent population in which to search for such effects. Given these considerations, it is surprising that tamoxifen seemed to work at all. Because it seems to have worked quite well at preventing contralateral breast cancer, we should worry that

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its benefits far exceed what Dr. Phillips and her colleagues have reported. If this is the case, then many women will prefer a few years of tamoxifen to prophylactic mastectomy on one or both breasts. We need modern, precise data on all the factors discussed here, to define the benefit of tamoxifen for breast cancer prevention in BRCA1 and BRCA2 mutation carriers.

Proposal for an International Cohort Study To Begin Immediately I believe that Dr. Phillips is correct in

writing that a randomized trial of whether or not to use tamoxifen for breast cancer prevention in mutation carriers will be slow to mount, slow to accrue and very slow to give us useful data. I suggest instead that we give tamoxifen to women who decide to keep their breasts in place of immediate prophylactic mastectomy, and collect the data in an organized way for comparison with historical data sets like that of Susan Domchek, MD, a breast cancer specialist at the University of Pennsylvania in Philadelphia.3 Steven Narod, MD, from the University of Toronto, Canada, is already

following 14,000 mutation carriers in 33 centers in six countries. Of 2,558 who never had breast or ovarian cancer and who have two intact breasts, only 73 (3%) chose to take tamoxifen, and many of those stopped tamoxifen or later chose prophylactic mastectomy. Dr. Narod currently is not collecting the detailed information on compliance with tamoxifen and the use of interfering medications that I believe will be key to defining the benefits of tamoxifen. Clearly oncologists and surgeons, given Dr. Phillips’ data, need to do a better job describing the

efficacy of tamoxifen in breast cancer prevention for mutation carriers, and the attractiveness of avoiding bilateral mastectomy. Oncologists, geneticists, surgeons and gynecologists who care for patients and families with BRCA1 and BRCA2 mutations should begin discussing tamoxifen as an alternative to risk-reducing “prophylactic” mastectomy NOW. As Dr. Phillips and her colleagues pointed out, tamoxifen is quite safe for young women, with endometrial cancer being very rare, and venous thrombosis rates comparable see CHEMOPREVENTION, N page 8

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CHEMOPREVENTION continued from page 7

to those of oral contraceptives already widely used in the community. Importantly for women in their 30s with a newly discovered BRCA1 or BRCA2 mutation, tamoxifen will impair fertility and possibly produce birth defects, and may be a poor option for those in their late 30s who still wish to bear children, especially without expensive in vitro fertilization techniques. I propose that women who opt to take

tamoxifen and leave one or both breasts in place and thus remain at risk for a new breast cancer, be entered into a prospective cohort. A woman who just had a first breast cancer would be considered to have one breast at risk. These women should be carefully characterized initially clinically (by our usual evaluation) and also by whole-genome analysis (to find single-nucleotide polymorphisms and mutations that modify

breast cancer risk in BRCA1 and BRCA2 mutation carriers both off and on tamoxifen). Genetic modifiers of breast and ovarian cancer risk in BRCA1 carriers recently have been described.11 Compliance with tamoxifen, use of interfering medications, interim pregnancies and live births, ongoing ovarian function and oophorectomy (whenever performed) should be recorded. Annual mammograms and MRIs should be mandated because these are now “standard of care.” As usual, the cost implications for patients and for society in general are

complicated. Five or 10 years of tamoxifen is much cheaper than bilateral prophylactic mastectomy with bilateral reconstruction, especially if the latter uses autologous tissue requiring more extensive surgery. It is not clear whether society eventually will save money with prophylactic tamoxifen when the costs of annual MRI and mammogram are included, plus the costs of subsequent localizations, biopsies and therapies for the lesions that do occur. Regardless, bilateral mastectomy is a mutilating procedure and avoiding it will be attractive for large numbers

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of women, provided the risk for breast cancer can be substantially reduced by safe pharmacologic and surgical means—tamoxifen and oophorectomy. Those with good memories who regularly read Clinical Oncology News may recall that I took a position in 2011 against tamoxifen breast cancer chemoprevention because the benefit to the patient was uncertain. This proved controversial, with Victor Vogel, MD, the director of the Geisinger Cancer Institute, challenging my position in a critical letter to the editor. Among these very high-risk women, for whom the

alternative for many is immediate bilateral prophylactic mastectomy, the benefit of chemoprevention is immediate, provided it sufficiently reduces breast cancer risk until age 70 from the current 49% to 57% without any intervention to an acceptable level.12 There are probably tens of thousands of women in North America and Europe with BRCA1 and BRCA2 mutations and breasts at risk for developing cancer that come to medical attention each year. If we draft a study now to collect information on their characteristics, compliance with tamoxifen,

and outcomes, we could have answers in three to four years on how significantly tamoxifen reduces breast cancer incidence. If we recruit 2,000 women and follow them for four years, we will have 8,000 patient-years of followup on the immediate benefits of tamoxifen chemoprophylaxis for mutation carriers. If the benefit is sufficiently great, we could then offer the cohort participation in randomized trials asking very important questions about tamoxifen duration and schedule, and the alternative use of aromatase inhibitors for cancer prevention in those who have lost

ovarian function naturally, surgically or from chemotherapy.

References 1. 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;31:3091-3099, PMID: 23918944. 2. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005;97:1652-62, PMID: 16288118. 3. Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010;304:967-975, PMID: 20810374. 4. Metcalfe K, Lynch HT, Ghadirian P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2004;22:2328-2335, PMID: 15197194. 5. Gronwald J, Tung N, Foulkes WD, et al. Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update. Int J Cancer. 2006;118:2281-2284, PMID: 16331614.

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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;286:2251-2256, PMID: 11710890. 7.

Fisher B, Redmond C, Brown A, et al. Treatment of primary breast cancer with chemotherapy and tamoxifen. N Engl J Med. 1981;305:1-6, PMID: 7015139.

8. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with nodenegative breast cancer who have estrogenreceptor-positive tumors. N Engl J Med. 1989;320:479-84, PMID: 2644532. 9. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687-717, PMID: 15894097. 10. Province MA, Goetz MP, Brauch H, et al. CYP2D6 genotype and adjuvant tamoxifen: Meta-analysis of heterogeneous study populations. Clin Pharmacol Ther. 2013 Sep 23. [Epub ahead of print], PMID: 24060820.

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11. Couch FJ, Wang X, McGuffog L, et al. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. PLoS Genet. 2013;9:e1003212, PMID: 23544013. 12. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007;25:1329-1333, PMID: 17416853.

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PATIENT COST continued from page 1

the issue of cost in the context of financial distress. All of the 300 patients surveyed had health insurance, but the median out-of-pocket expenses were $592 per month. This expense led, on average, to “moderate” distress when evaluated with a standardized instrument for assessing financial well-being. The median annual income for the study population was $60,000. For 17% of individuals with cancer, the financial distress was considered

CLINICAL ONCOLOGY NEWS • NOVEMBER 2013 • CLINICALONCOLOGY.COM

“high” or “overwhelming.” Key findings of this survey included the following: • Although 52% expressed a desire to discuss costs of cancer care, only 19% reported actually discussing costs with their oncologist. • The desire to discuss costs rose to 62% of those with the highest financial distress. • Of those who discussed costs with their physicians, 57% reported that this led to lower costs. Perhaps the most important message of the study is that financial distress “is

51% of surveyed patients want physicians to account for costs in therapeutic decisions. prevalent even among insured cancer patients,” for whom “cost does matter,” S. Yousuf Zafar, MD, of Duke Cancer Institute in Durham, N.C., the study’s lead author, said. He noted that 51% of those surveyed want physicians to account for costs in therapeutic decisions.

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However, the second study suggested that patients are mindful of costs even when they do not directly affect their pocketbook. In this survey, which had a different intent and design, 169 patients with prostate cancer were questioned. “We conducted the survey because this issue has come up repeatedly. Anecdotally, it seemed that even patients with full health coverage were interested in cost,” said Jeremy Cetnar, MD, a medical oncologist at the University of Wisconsin Carbone Cancer Center in Madison. Dr. Cetnar was an author of a study that was led by Saurabh Rajguru, MD. The survey confirmed this impression. According to Dr. Cetnar, many oncologists are unsure of whether a discussion of costs is appropriate. This study, like the other, suggests that a substantial proportion of patients, perhaps the majority, want cost discussed and that this discussion may influence therapeutic decisions, even when patients are not responsible for payment. Key findings of the survey included the following: • Seventy-nine percent agreed that a discussion of costs is appropriate, although only 69% reported that they wanted to have that discussion. • Eighty-two percent agreed that prognosis provides an important context for discussing costs. • Sixty-six percent could not identify their own cancer stage. • The median willing-to-pay figure for a $100,000 drug that would improve survival on average by four months with minimal side effects was $20,000. • When stratified by demographics, 17% would refuse a $100,000 drug with a four-month survival benefit. • Those who would refuse a hypothetical $100,000 drug tended to be older and have a higher household income than those who would not. • Only 37% agreed that national health care costs should be taken into consideration by oncologists or patients selecting a therapy. “The survey suggests that prostate cancer patients want to know costs and would include this in their own decisions. We need more data to understand the motivations in discussing costs, but we hypothesize that patients do want to consider value even if they will not directly bear the cost,” Dr. Cetnar said. —Ted Bosworth Drs. Zafar and Cetnar reported no relevant financial disclosures.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • NOVEMBER 2013 • CLINICALONCOLOGY.COM

Expert Insights From Massachusetts General Hospital Cancer Center Each month, Clinical Oncology News summarizes findings from several recently published, important studies and then asks clinicians from a top cancer center to offer their perspectives. The cancer center providing the expert commentaries changes every three months. Cancer centers are chosen based on reputation, availability and regional diversity, and we seek to have a mix of academic institutions together with regionally important hospitals with expertise in cancer care. This month we introduce Massachusetts General Hospital Cancer Center. We hope you find this Reviews & Commentaries section to be a valuable tool.

Massachusetts General Hospital Cancer Center:

Left: Mehmet Toner, PhD, holding a CTC-chip, a breakthrough in cancer detection; center, the Yawkey Outpatient Care building; right, Jeff Engelman, MD, PhD, consults with colleagues.

n integral part of one of the world’s most distinguished academic medical centers, the Massachusetts General Hospital Cancer Center is among the leading cancer care providers in the United States, with approximately 7,000 newly diagnosed patients a year, including those with rare tumors. The Cancer Center, which U.S. News & World Reportt consistently ranks among the top 10 cancer centers in the country, comprises 24 fully integrated, multidisciplinary clinical programs within a network of affiliations that extends throughout New England and the southeastern United States. The Massachusetts General Hospital Cancer Center is at the forefront of delivering personalized medicine. As one example, Massachusetts General investigators were the first to identify a genetic mutation in epidermal growth factor receptors of certain patients with lung cancer—most of whom were nonsmokers.1 This discovery ignited research that eventually led to a new class of personalized medicine. Through a powerful synergy between laboratory scientists and bedside physicians, the

Massachusetts General Hospital Cancer Center fosters innovation in all phases of cancer research. Physician-investigators conduct nearly 400 clinical trials annually. To complement their robust genetic testing program, Massachusetts General Hospital Cancer Center opened the Termeer Center for Targeted Therapies in October 2012, and the cancer center is also home to the Francis H. Burr Proton Therapy Center, the second oldest facility in the country and the only proton beam therapy facility in New England. A second such facility will be breaking ground in 2014. The Massachusetts General Hospital Cancer Center is proud to be a founding member of a Harvard Medical School consortium designated by the National Cancer Institute as a comprehensive cancer center. This prestigious seven-member center forms the largest cancer research collaboration in the country. Examples of promising research abound. For instance, a landmark study published in The New England Journal of Medicine provided the first evidence that the integration of palliative and oncology care early in treatment

might improve the quality of life and survival of cancer patients.2 In 2008, investigators at the Massachusetts General Hospital Cancer Center developed a method to detect rare circulating tumor cells (CTCs), called the CTC-chip, which is a breakthrough innovation in cancer cell detection.3 The CTC-chip uses nanotechnology to capture microscopic cancer cells in a small blood sample. From the captured cells, researchers may be able to determine if a cancer has metastasized and may be able to gather genetic information regarding the nature of the cancer without an invasive biopsy. Promising new treatments developed at Massachusetts General Hospital Cancer Center are helping to revolutionize cancer medicine.

References 1.

Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:229-2139, PMID: 15118073.

Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:733-742, PMID: 20818875.

Maheswaran S, Sequist LV, Nagrath S, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008;359:366-377, PMID: 18596266.

Text and images provided by Massachusetts General Hospital Cancer Center

A Comprehensive Cancer Center

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • NOVEMBER 2013 • CLINICALONCOLOGY.COM

Low-Dose Aspirin Reduces Extent of Colorectal, Lung Tumors From the British Journal of Cancer

ong-term, low-dose aspirin use was associated with lower tumor extent in a population-based study of patients with colorectal and lung cancers. The study did not find a similar benefit for patients with prostate or breast cancers. Researchers from the Karolinska Institutet in Stockholm abstracted disease information from the Swedish Cancer Registry for more than 76,000 newly diagnosed patients with cancer of the breast, prostate, colon or rectum, and lung, between 2006 and 2009. Primary cancer information gathered included tumor extent (T1-T4), node status (N0N2) and distant metastases (M0-M1). Additionally, patients’ age, sex, educational status and residence (rural vs. nonrural) were noted because it was felt these factors might confound results. The Swedish Prescribed Drug

Registry contains information on drugs sold by pharmacies. The researchers, whose principal author was Fredrik Jonsson, PhD, estimated the registry captures 95% of daily doses dispensed. They found more than 17 million records of low-dose aspirin prescribed between 2005 and 2009 and identified patients who took a low-dose aspirin regimen for at least one year before their cancer diagnosis. Patients who averaged at least one tablet (75 mg) per day were compared with patients who did not have a history of aspirin use. The results, published in the British Journal of Cancer (2013 July 25. [Epub ahead of print], PMID: 23887604), showed that about 26% of patients diagnosed with colorectal, lung or prostate cancer used regular low-dose aspirin; among patients with breast cancer, that figure was about 14%. The authors found a significant association between aspirin use and tumor

EXPERT INSIGHT Andrew T. Chan, MD Program Director, Gastroenterology Training Program Massachusetts General Hospital Boston, Massachusetts

emarkably consistent experimental and epidemiologic evidence demonstrates that aspirin is associated with a lower risk for developing colorectal cancer.1 As compelling proof of causality, four randomized controlled trials have shown that aspirin reduces the risk for recurrent adenoma, the precursor for the vast majority of colorectal cancer.2 Recently, secondary analyses of randomized trials conducted for the prevention of vascular disease also have demonstrated that aspirin reduces risk for not only colorectal cancer, but also many other cancers.3-5 Based on this data relating aspirin to cancer incidence, identifying a potential role for aspirin for treatment of cancer among patients with established cancer has been an area of intensive investigation. The results of Jonsson et al add to a growing body of evidence supporting a role for aspirin in improving survival among patients with cancer, particularly of the colorectum.6-8 The strengths of this analysis include the large number of patients derived from a real-world population rather than a referral center. Additionally, the study was able to estimate aspirin exposure by tallying

prescriptions through a national prescription registry within a country in which low-dose aspirin is rarely purchased over the counter. Limitations include a lack of information on actual consumption of aspirin, inability to assess aspirin use after as well as before cancer diagnosis, lack of data on survival outcomes and the relatively short follow-up (three years). Moreover, similar to prior studies that addressed this hypothesis, the analysis by Jonsson et al was observational, precluding any firm conclusions about whether aspirin should be generally recommended for cancer treatment. Nonetheless, based on the consistency of these results with prior studies as well as compelling experimental and mechanistic data supporting an effect of aspirin in abrogating the progression and spreading of tumors, the study by Jonsson et al should provide an even stronger rationale for further study of aspirin as a treatment for cancer.9,10 Currently, there are two ongoing trials of aspirin among patients with established colorectal and non-small cell lung cancer, as well as a planned trial for patients with colorectal,

Villous adenoma Vill d off the h colorectum. l

extent in colorectal and lung cancers ( <0.0001), but not in cancers of the (P prostate or breast ((P>0.05). For patients with colorectal cancer, aspirin use was associated with about a 30% reduction in the odds of getting a T4 tumor. The

authors noted that these results might suggest some early and late protective effects of aspirin in patients with certain cancers. There was no association with aspirin and nodal involvement for any cancer.

The results … add to a growing body of evidence supporting a role for aspirin in improving survival among patients with cancer, particularly of the colorectum. prostate, gastroesophageal and breast cancers.9,11,12 However, because many patients with cancer and their physicians cannot afford to wait for the results of such studies, it is not unreasonable to discuss the known risks and potential benefits of aspirin use for cancer treatment within the context of the current state of the evidence.

References 1. Chan AT, Arber N, Burn J, et al. Aspirin in the chemoprevention of colorectal neoplasia: an overview. Cancer Prev Res (Phila). 2012;5:164-178, PMID: 22084361. 2. Cole BF, Logan RF, Halabi S, et al. Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the randomized trials. J Natl Cancer Inst. 2009;101:256266, PMID: 19211452. 3. Rothwell PM, Fowkes FG, Belch JF, et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011;377:31-41, PMID: 21144578. 4. Rothwell PM, Price JF, Fowkes FG, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet. 2012;379:1602-1612, PMID: 22440946. 5. Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year

follow-up of five randomised trials. Lancet. 2010;376:1741-1750, PMID: 20970847. 6. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA. 2009;302:649-658, PMID: 19671906. 7.

Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012;367:1596-1606, PMID: 23094721.

8. Rothwell PM, Wilson M, Price JF, et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet. 2012;379:1591-1601, PMID: 22440947. 9. Thun MJ, Jacobs EJ, Patrono C. The role of aspirin in cancer prevention. Nat Rev Clin Oncol. 2012;9:259-267, PMID: 22473097. 10. Langley RE, Burdett S, Tierney JF, et al. Aspirin and cancer: has aspirin been overlooked as an adjuvant therapy? Br J Cancer. 2011;105:1107-1113, PMID: 21847126. 11. Ali R, Toh HC, Chia WK, et al. The utility of Aspirin in Dukes C and High Risk Dukes B Colorectal cancer—the ASCOLT study: study protocol for a randomized controlled trial. Trials. 2011;12:261, PMID: 22168568. 12. Fontaine E, McShane J, Page R, et al. Aspirin and non-small cell lung cancer resections: effect on long-term survival. Eur J Cardiothorac Surg. g 2010;38:21-26, PMID: 20359903. Dr. Chan reported no relevant financial disclosures.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • NOVEMBER 2013 • CLINICALONCOLOGY.COM

No Advantage With Asymptomatic Screening for Ovarian Cancer From Gynecologic Oncology

creening of asymptomatic women for ovarian cancer may cause more harm than good. A recent study determined that screening results in unnecessary surgery and that no advantage to early diagnosis was found. Substantial patient anxiety is associated with false-positive screening results, the authors noted. Clinical practice guidelines recommend against screening women at average risk for ovarian cancer, yet surveys of primary care physicians

indicate up to 24% routinely offer testing to asymptomatic women. Indeed, a U.S. survey found that 97% of women want to be screened for ovarian cancer. Clare Reade, MD, and her colleagues in Canada identified 10 large-scale international randomized clinical trials of ovarian cancer with control and treatment arms. Although the data collected and presented varied among the studies, the authors found that screening did not reduce all-cause mortality (relative risk [RR], 1.0; 95% confidence interval [CI], 0.96-1.06), ovarian cancer–specific mortality (RR, 1.08; 95%

EXPERT INSIGHT Marcela del Carmen, MD, MPH

n this systematic review and metaanalysis of 10 randomized trials conducted by Reade et al, screening of asymptomatic women for ovarian cancer was not shown to reduce allcause mortality. Epithelial cancer of the ovary remains the leading cause of death from gynecologic malignancy in the United States, with approximately 22,240 cases expected to be diagnosed in the United States in 2013, and 14,030 attributable deaths.1 It is estimated that a woman’s lifetime risk for developing epithelial ovarian cancer is 2%.2 Given the associated mortality, significant efforts have been directed to screening strategies that could result in detection of early-stage ovarian cancer.3 Several screening methods have been evaluated, including transvaginal ultrasound and serum CA-125. Despite formal recommendations by clinical practice guidelines against screening, clinicians continue to offer screening to asymptomatic women in the general population. In a cross-sectional survey of physicians in the United States, one

CI, 15.7-178.1), whereas screening with the biomarker CA-125 led to four surgeries per ovarian cancer detected (95% CI, 2.7-4.5). Unnecessary surgeries increase morbidity in the form of surgical complications, pain and recovery time, and increased worry and anxiety on the part of the patient. The results, published in Gynecologic Oncology (2013;130:674-681, PMID: 23822892), demonstrated no benefit to screening asymptomatic women for ovarian cancer, and detrimental outcomes associated with testing low-risk populations.

Until data from future studies are available to support screening, asymptomatic women in the general population should be discouraged from any screening strategy outside of a clinical trial.

Gynecologic Oncology Gillette Center for Gynecologic Oncology, and The Department of Obstetrics & Gynecology, Massachusetts General Hospital Cancer Center Boston, Massachusetts

CI, 0.84-1.38) or risk for diagnosis of advanced (i.e., FIGO [International Federation of Gynecology and Obstetrics] stages III-IV) disease (RR, 0.86; 95% CI, 0.68-1.11). The researchers also found that in eight trials, false-positive results in 10.6% of the control groups led to additional testing, including surgery. Screening results demonstrated that nine surgeries (95% CI, 5.5-17.0) were performed to diagnose one case of ovarian cancer. Transvaginal ultrasound resulted in a mean of 38 surgeries per ovarian cancer detected (95%

in three providers opined that screening for ovarian cancer was effective and commonly offered testing.4 The present study represents a systematic review of the literature and has several strengths: inclusion of all languages; missing information obtained from one trialist; two investigators conducted the reviews independently; inclusion of only randomized trials; and when possible, conservative analyses of the data were conducted. The study also has some limitations. It did not include sensitivity and specificity of screening tests. Several studies did not report outcomes for controls. Lack of data with respect to controls did not permit comparative analysis. For example, it was not possible to quantify the detriment of screening surgery for the control arm and was only possible for the screening arm of the studies. The study does, however, reiterate the previous recommendation that screening for ovarian cancer in asymptomatic women does not improve health outcomes and can cause harm. With the

recent evidence that high-grade serous carcinoma may originate in the fallopian tube, and that a possible precursor exists, at least in some cases (serous tubal intraepithelial carcinoma), future screening trials should focus on detection and possible prevention of these precursor lesions.5-8 Studies should continue to investigate the potential role of serial measurements of CA-125, panels of other tumor markers or proteomic markers. Until data from future studies are available to support screening, asymptomatic women in the general population should be discouraged from any screening strategy outside of a clinical trial, given the associated morbidity from unnecessary surgery and anxiety and the lack of benefit in reducing mortality.

References 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11-30, PMID: 23335087. 2. http://www.cancer.gov/cancertopics/pdq/ genetics/breast-and-ovarian/healthprofessional. Accessed July 15, 2011. 3. Barton M, Lin K. Screening for ovarian cancer: evidence update from the U.S.

Preventive Services Task Force reaffirmation recommendation statement. AHRQ Publication No. 12-05165-EF-3. April 2012. 4. Baldwin LM, Trivers KF, Matthews B, et al. Vignette-based study of ovarian cancer screening: do U.S. physicians report adhering to evidence-based recommendations? Ann Intern Med. 2012;156:182-194, PMID: 22312138. 5. Carlson JW, Miron A, Jarboe EA, et al. Serous tubal intraepithelial carcinoma: its potential role in primary peritoneal serous carcinoma and serous cancer prevention. J Clin Oncol. 2008;26:4160-4165, PMID: 18757330. 6. Lee Y, Miron A, Drapkin R, et al. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol. 2007;211:26-35, PMID: 17117391. 7.

Medeiros F, Muto MG, Lee Y, et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol. 2006;30:230-236, PMID: 16434898.

8. Tang S, Onuma K, Deb P, et al. Frequency of serous tubal intraepithelial carcinoma in various gynecologic malignancies: a study of 300 consecutive cases. Int J Gynecol Pathol. 2012;31:103-110, PMID: 22317864.

Dr. del Carmen reported no relevant financial disclosures.

More REVIEWS and COMMENTARIES from Massachusetts General Hospital Cancer Center Online Find additional, Web-exclusive expert commentaries on important published studies at

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How I Manage ... FOLLICULAR LYMPHOMA continued from page 1

Bruce D. Cheson, MD Professor of Medicine Head of Hematology Deputy Chief, Division of Hematology/Oncology Georgetown University Hospital Lombardi Comprehensive Cancer Center Washington, DC

treated similarly; in contrast, grade 3b, which is relatively uncommon, behaves more like an aggressive diffuse large B-cell lymphoma (DLBCL), and is treated accordingly.

What are the differences between FLIPI and FLIPI-2, and do these prognostic indices influence my decisions about choice of therapy in FL? Given the clinical heterogeneity of FL, attempts have been made to identify clinical and laboratory factors that predict patient outcome. The Follicular Lymphoma International Prognostic Index (FLIPI) was based on a retrospective analysis of heterogeneously treated FL patients in the prerituximab era, and identified five adverse prognostic factors—age >60 years, Ann Arbor stage III or IV, hemoglobin level <12.0 g/dL, number of involved nodal areas >4 and elevated lactate dehydrogenase (LDH)—that separated patients into

AT A GLANCE Radiation may cure a group of patients with limitedstage FL. The Groupe d’Étude des Lymphomes Folliculaires (GELF) criteria are most often used for initiating treatment in FL. A “watch and wait” approach remains a viable option, especially for patients with asymptomatic advanced disease. In patients managed with a “watch and wait” approach, try to minimize the number of scans.

low-, intermediate- and high-risk groups with estimated 5-year overall survival (OS) rates of 91%, 78% and 52%, respectively, and 10-year OS rates of 71%, 51% and 36%, respectively.1 In a subsequent analysis using prospectively collected data in the rituximab era, the FLIPI-2 index defined risk based on age >60 years, hemoglobin level <12.0 g/dL, bone marrow involvement, greatest diameter of the largest involved node more than 6 cm, and elevated serum β2 microglobulin level to identify low-, intermediate- and high-risk patients with a 3-year progression-free survival (PFS) of 91%, 69% and 51%, respectively, and 3-year overall survival (OS) of 99%, 96% and 84%, respectively.2 Currently, neither the FLIPI nor the FLIPI-2 provide guidance on timing of therapy or choice of regimen or agents.

What are the most commonly used criteria for initiation of therapy in FL? The Groupe d’Étude des Lymphomes Folliculaires (GELF) criteria3 are most often used for initiating treatment in FL, and they include: • Any nodal or extranodal tumor mass with a diameter of 7 cm • Involvement of 3 nodal sites, each with a diameter of 3 cm • B symptoms • Symptomatic splenomegaly • Cytopenias (leukocytes <1.0 x 109/L and/or platelets <100 x 109/L) • Pleural effusions or peritoneal ascites • Leukemia (>5.0 x 109/L malignant cells)

Should “watch and wait” be retained as a management approach in FL? One of the more challenging conversations to have with FL patients is explaining that the disease is indolent and treatable, but incurable, yet the recommendation is to be followed every few months without therapy. Some patients feel relief at not needing treatment, allowing, perhaps, a bit of denial. But others require a psychological

adjustment. The explanation is that all treatments have expense and adverse effects, which might be worth taking if cure was a realistic goal. However, FL is currently considered incurable in the majority of patients, and its progress is often slow, albeit inexorable. The practice of “watch and wait” is supported by several retrospective and prospective studies comparing it with early intervention ranging from regimens of only mild to moderate intensity, to highly aggressive cytotoxic therapy with total lymphoid irradiation.3,11-13 In every instance, early intervention failed to demonstrate a survival benefit compared with the anticipatory approach, and with no suggestion that the likelihood of aggressive transformation is forestalled by therapy. Nevertheless, the argument has been made that these studies were conducted in the pre-rituximab era. More recently Kirit Ardeshna, MD, of University College Hospital in London, reported a preliminary analysis of a trial including 450 patients with asymptomatic, advanced stage, non-bulky FL, who were randomized to “watch and wait” or to four weekly doses of rituximab followed by either observation or two years of maintenance rituximab.14 The time to initiation of chemotherapy or radiotherapy was significantly prolonged in the early intervention arms. However, instead of comparing the time to initial treatment for the “watch and wait” patients with the time to second-line therapy for the treated patients, the more appropriate comparison would have been the time to second lymphoma therapy for each of the cohorts, and their OS. Moreover, there was no survival benefit for the initially treated patients. Additional support for “watch and wait” comes from the National LymphoCare Study, which suggests that the PFS of patients who are managed with a “watch and wait” approach and only treated at progression with rituximab is at least comparable to that of others treated with rituximab at diagnosis.15 Among the 1,093 patients registered in the FLIPI-2 study, there were 120 patients who were managed with a “watch and wait” approach, 80% of whom had advanced-stage disease, and all with a low tumor burden.2 At a median follow-up of 64 months, half required therapy at a median of 14 months into the observation period, whereas the median time to observation without treatment was 55 months. Once treated, the response rate was 82%, including 60% complete remissions. The only predictor of a short time to lymphoma treatment was involvement of more than four nodal areas; however, whether early treatment in that population had an effect on outcome cannot be determined. The time

to treatment failure was comparable to 242 patients from the data set with good prognostic features, but who were started on initial rituximab therapy. However, the patients treated with a “watch and wait” approach were less likely to have an increased LDH, bulky disease or anemia, and had a lower FLIPI score (although the difference in FLIPI-2 scores was only of borderline significance). The five-year OS was 87%. Thus, my standard approach to a newly diagnosed, asymptomatic FL patient with low tumor burden is to reassess every three to four months to evaluate the pace of the disease with physical examination and routine laboratory studies. I try to minimize the number of scans, especially in patients with peripheral nodes to measure.

Is stage I or II FL curable disease? One-fourth of newly diagnosed patients with FL present with stage I disease. Whether patients with FL can be cured, even in early stages, remains controversial. Involved field radiation therapy has long been considered a standard approach to patients with stage I or nonbulky stage II (<5 cm) disease. Much of the data supporting this approach arises from uncontrolled, retrospective studies prior to the introduction of rituximab.4-6 Nevertheless, only one-third of such patients in the United States are treated with radiation therapy.7 Moreover, several studies suggest that observation alone may be a suitable approach, especially if involved sites are those in which radiation might be associated with adverse effects. Ranjana Advani, MD, of Stanford University, found a 10-year survival rate of 86% with observation alone, which was comparable to historical data from other centers using radiation.8 Perhaps the most relevant data comes from the prospective, observational, National LymphoCare Study.9 Of 2,728 patients, 471 had stage I disease, 206 of whom underwent “rigorous staging” as defined by both bone marrow aspirate and biopsy, and a computed tomography (CT) or positron emission tomography (PET)CT scan, or both. Those patients considered rigorously staged had superior PFS compared with the others. Rigorously staged patients were treated with rituximab-chemotherapy (R-chemo; 28%), radiation (27%), observation (17%), systemic therapy plus radiation (13%), rituximab monotherapy (12%) or other therapy (3%). With a median follow-up of 57 months, 21% of these patients had progressed. For these patients, PFS was significantly improved with either R-chemo or

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CLINICAL ONCOLOGY NEWS • NOVEMBER 2013 • CLINICALONCOLOGY.COM

Clinical Conundrums

Prepared by

Syed A. Abutalib, MD

Clinical Hematology Review: Highlights From NEJM, Blood and d JCO QUESTIONS

1. True or False. In a

study published in Blood, decreased expression of cellular and plasma microRNA-155 (miR-155) correlated with poor overall survival (OS) in patients with chronic lymphocytic leukemia (CLL).

nilotinib (Tasigna, Novartis) and proton pump inhibitors (PPIs) may be used together if there is adequate separation of dosing.

graft-versus-host disease (aGvHD) were more likely to respond to treatment independent of type of conditioning and grade of aGvHD.

4. True or False. A

in NEJM M suggested that eculizumab (Soliris, Alexion Pharmaceuticals) could be useful in transfusion- and plasma exchange–refractory patients with atypical hemolytic-uremic syndrome (HUS).

study published in The New England Journal of Medicine (NEJM) recommended routine use of IV ganciclovir for the True or False. CD4+ CD25+ Foxp3+ regulatory prevention of cytomegT lymphocytes (Tregs) com- Primum non nocere. alovirus (CMV) infecprise approximately 5% to (First, do no harm.) tion in recipients of 10% of circulating CD4+ T allogeneic hematopoicells, and migrate to inflammatory sites etic cell transplantation (allo-HCT). to control innate and adaptive immune responses. True or False. In a study published in NEJM, patients with low True or False. In patients with levels of ST2 (suppression of tumorchronic myeloid leukemia (CML), igenicity 2) who developed acute

systemic therapy plus radiation therapy compared with patients receiving radiation alone. However, PFS curves failed to provide convincing evidence of a plateau in any of the treatment groups, and there were no differences in OS. Among stage I patients treated at academic centers, 25 were observed (29.1%), six were treated with rituximab alone (7.0%), and 25 received radiation (29.1%). Among stage I patients treated at community centers, 111 were observed (28.6%), 55 were treated with rituximab alone (14.2%), and 86 received radiation (22.2%). Radiation therapy was used in 20.9% of patients younger than 45 years at diagnosis, 25.9% of those aged 45 to 59 years, 24.3% of patients aged 60 to 74 years, and 20.0% of those aged 75 years or older at diagnosis. In 50 of 242 patients (20.7%), radiation was delivered within 90 days of completing the initial treatment, suggesting a planned combined modality approach. Thus, whereas radiation may cure a group of patients with limited-stage disease, it is not clear that it improves survival compared with other approaches, including observation alone. Up to half of treated patients relapse during longterm follow-up, and the leading cause of death in these patients remains lymphoma.5 Thus, for these patients, I generally observe them carefully and treat when there is evidence of recurrent or progressive disease that warrants therapy. The current use of chemoimmunotherapy with regimens such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and

prednisone) and R-bendamustine clearly prolongs patient survival compared with standard chemotherapy alone. Some studies suggest that there may be a plateau on the PFS curve after about eight years. 10 Whether those patients are possibly cured requires additional years of follow-up. However, whether cure is necessary is up for question; if you are free of disease for decades and then a relapse is successfully salvaged, that outcome would be considered satisfactory to many physicians and their patients.

References 1. Solal-Céligny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 2004;104:1258-1265, PMID: 15126323. 2. Federico M, Bellei M, Marcheselli L, et al. Follicular Lymphoma International Prognostic Index 2: A new prognostic index for follicular lymphoma developed by the International Follicular Lymphoma Prognostic Factor Project. J Clin Oncol. 2009;27:4555-4562, PMID: 19652063. 3. Brice P, Bastion Y, Lepage E, et al. Comparison of low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Group D’Etude des Lymphomes Folliculares. J Clin Oncol. 1997;15:1110-1117, PMID: 9060552.

6. True or False. A study published

True or False. Atypical HUS is a disease with underlying complement dysregulation that may be acquired or inherited.

8. True or False. In a study published

in Blood, investigators presented data on the identification, humanization and in vitro pharmacology of an antidote for dabigatran (aDabi-Fab).

lymphoma treated with radiation therapy. Int J Radiat Oncol Biol Phys. 2006;64:928934, PMID: 16243446. 6. Pugh TJ, Ballanoff A, Newman F, et al. Improved survival in patients with early stage low-grade follicular lymphoma treated with radiation: a Surveillance, Epidemiology, and End Results data base analysis. Cancer. 2010;116:3843-3851, PMID: 20564102. 7. Friedberg JW, Taylor M, Cerhan JR, et al. Follicular lymphoma in the United States: First report of the National LymphoCare study. J Clin Oncol. 2009;27:1202-1208, PMID: 19204203. 8. Advani R, Rosenberg SA, Horning SJ. Stage I and II follicular non-Hodgkin’s lymphoma: long-term follow-up of no initial therapy. J Clin Oncol. 2004;22:1454-1459, PMID: 15024027. 9. Friedberg JW, Byrtek M, Link BK, et al. Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare study. J Clin Oncol. 2012;30:3368-3375, PMID: 22915662. 10. Czuczman MS, Grillo-López AJ, White CA, et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999;17:268-276, PMID: 10458242. 11. Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-Hodgkin’s lymphoma. N Engl J Med. 1984;311:1471-1475, PMID: 6548796.

4. Mac Manus M, Hoppe RT. Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a longterm follow-up study of patients treated at Stanford University. J Clin Oncol. 1996;14:1282-1290, PMID: 8648385.

12. Ardeshna KM, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced stage nonHodgkin lymphoma: a randomised controlled trial. Lancet. 2003;362:516-522, PMID: 12932382.

5. Guadagnolo BA, Li S, Neuberg D, et al. Long-term outcome and mortality trends in early-stage, Grade 1-2 follicular

13. Young RC, Longo DL, Glatstein E, et al. The treatment of indolent lymphomas: watchful waiting v aggressive combined

Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

9. True or False. Currently, there is

no standardized approach to the treatment of patients with newly diagnosed primary central nervous system lymphoma (PCNSL).

10.

True or False. The CALGB 50202 study reported in the Journal of Clinical Oncology demonstrated reassuring results in terms of toxicity with the replacement of whole-brain radiation therapy (WBRT) with high-dose chemotherapy consolidation in newly diagnosed PCNSL. for answers see CONUNDRUMS, S page 16

modality treatment. Semin Hematol. 1988;25:11-16, PMID: 2456618. 14. Ardeshna KM, Qian W, Smith P, et al. An intergroup randomised trial of rituximab versus a watch and wait strategy in patients with stage II, III, IV asymptomatic, non-bulky follicular lymphoma (grades 1, 2 and 3a). A preliminary analysis. Blood. 2010;116:5. Abstract 6. 15. Sinha R, Byrtek M, DeJoubner NJ, et al. Examining the outcomes of watchful waiting (WW) among US patients with advanced stage follicular lymphoma (FL). Blood. 2011;118:351. Abstract 775.

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

Coming next month This is the first in a two-part series on how Bruce D. Cheson, MD, manages follicular lymphoma. Questions being tackled by Dr. Cheson in Part 2 of this article in next month’s issue include: • Is there a standard front-line therapy regimen for FL? • Why does FLIPI score not influence my treatment decisions? • What is the role of maintenance therapy in FL?

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • NOVEMBER 2013 • CLINICALONCOLOGY.COM

CONUNDRUMS continued from page 15

ANSWERS

1. False. This study by Alessandra

Ferrajoli, MD, from the University of Texas MD Anderson Cancer Center in Houston, and colleagues showed that increased expression of cellular and plasma miR-155, immediately before therapy initiation (n=228), correlated with poor therapeutic response and OS in patients with CLL. A large multicenter, prospective trial is needed to confirm these findings in the context of established biologic and clinical factors. Ferrajoli A, Shanafelt TD, Ivan C, et al. Prognostic value of miR-155 in individuals with monoclonal B-cell lymphocytosis and patients with B chronic lymphocytic leukemia. Blood. 2013;122:1891-1899, PMID: 23821659.

2. True. T

regs play a critical role in the prevention of autoimmunity, and several studies have suggested that Tregs also play a central role in the establishment and maintenance of immune tolerance after allo-HCT.

Koreth J, Ritz J. Tregs, HSCT, and acute GVHD: Up close and personal. Blood. 2013;122:1690-1691, PMID: 24009174. Ohkura N, Kitagawa Y, Sakaguchi S, et al. Development and maintenance of regulatory T cells. Immunity. 2013;38:414-423, PMID: 23521883.

3. False. Concomitant use of nilotinib

and PPIs is not recommended in CML. H2 receptor antagonists and antacids may be used with nilotinib if there is adequate separation of dosing. When the concurrent use of an H2 blocker is necessary, it may be administered approximately 10 hours before or approximately two hours after the dose of nilotinib. Administration of an antacid (aluminum hydroxide/magnesium hydroxide/ simethicone) to healthy subjects two hours before or two hours after a single 400 mg dose of nilotinib did not alter nilotinib’s pharmacokinetics. Tasigna (nilotinib) capsules. FDA website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm182234.htm. Accessed October 7, 2013.

4. False. The use of available antivi-

ral agents for the prevention of CMV disease in allo-HCT recipients is limited by

frequent toxic effects and the emergence of resistance. Interestingly, the study published in NEJM M showed that a new oral drug, CMX001, at a dose of 100 mg twice weekly, significantly reduced the incidence of CMV events in recipients of HCT. Myelosuppression and nephrotoxicity were not observed. Diarrhea was dose-limiting in this population at a dose of 200 mg twice weekly (ClinicalTrials.gov: NCT00942305). The drug is not yet approved by the FDA. Marty FM, Winston DJ, Rowley SD, et al. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N Engl J Med. 2013;369:1227-1236, PMID: 24066743.

True. Early identification of patients who will not respond to GvHD therapy is important because these patients are more likely to die from GvHD than those who do respond. In a study of more than 650 recipients of alloHCT, ST2 levels measured as early as 14 days after allo-HCT (before the development of aGvHD) were able to predict the development of therapy-resistant aGvHD. Compared with patients with low ST2 values at therapy initiation for aGVHD, patients with high ST2 values were 2.3 times as likely to have treatment-resistant GvHD (95% confidence interval [CI], 1.5 to 3.6) and 3.7 times as likely to die within six months of therapy (95% CI, 2.3 to 5.9). Patients with low ST2 values had lower mortality without relapse than patients with high ST2 values, regardless of the GvHD grade (11% vs. 31% among patients with grade I or II GvHD and 14% vs. 67% among patients with grade III or IV GvHD; P<0.001 for both). Prospective studies are needed to validate this and other biomarkers (e.g., REG3α), α to determine whether prophylaxis or treatment should be altered. Vander Lugt MT, Braun TM, Hanash S, et al. ST2 as a marker for risk of therapy-resistant graftversus-host disease and death. N Engl J Med. 2013;369:529-539, PMID: 23924003.

True. A total of 37 patients (17 in trial 1 and 20 in trial 2, both prospective Phase II trials) with atypical HUS received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count. In trial 1, the mean increase in platelets from baseline to week 26 was 73×109/L ((P<0.001); in trial 2, 80% of the patients had thrombotic microangiopathy event–free status. Eculizumab was

associated with significant improvements in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in four of five patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab also was associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. The duration of therapy is not known. Noteworthy are the inclusion/exclusion criteria of this study, which must be reviewed prior to administration of this medication. Importantly, both studies enrolled patients with evidence of hemolysis (i.e., lactate dehydrogenase level at or above the upper limit of normal, haptoglobin level below the lower limit of normal, or presence of schistocytes) and impaired renal function (creatinine level at or above the upper limit of normal) without ADAMTS13 deficiency (≤5%) or evidence of Shiga toxin– producing Escherichia coli infection (or diarrheal syndrome), who did not benefit from an extended period of plasma exchange. Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169-2181, PMID: 23738544.

7. True. Atypical HUS is a genetic,

chronic and progressive inflammatory disease that affects patients of all ages. The complement defects are inherited, acquired or both, with chronic, uncontrolled activation of the complement system leading to platelet, leukocyte and endothelial-cell activation and systemic thrombotic microangiopathy. Plasma exchange or infusion has been used to manage atypical HUS and may transiently maintain a normal platelet count and lactate dehydrogenase level in some patients, but the underlying complement dysregulation and thrombotic microangiopathic processes are likely to persist. End-stage renal disease (ESRD) or death occurs in approximately 33% to 40% of patients during the first clinical manifestation of atypical HUS. Within one year after diagnosis of this syndrome, up to 65% of patients treated with plasma exchange or infusion sustain permanent

renal damage with progression to ESRD, or die. Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169-2181, PMID: 23738544.

8. True. This is the first report of

a specific antidote for a next-generation anticoagulant, which may become a valuable tool in patients who require emergency procedures. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121:3554-3562, PMID: 23476049.

9. True. Although there is consen-

sus that high-dose methotrexate (HDMTX) is the cornerstone of treatment for PCNSL, the outcomes remain dismal, with a median progression-free survival (PFS) of 12 to 13 months. Addition of WBRT to the HD-MTX backbone markedly extends median PFS to 24 months; however, concerns regarding the irreversible neurocognitive effects to the brain, even at reduced doses (especially in older adults), have prompted the development of alternative chemoimmunotherapy-based consolidation strategies. Batchelor T, Loeffler JS. Primary CNS lymphoma. J Clin Oncol. 2006;24:1281-1288, PMID: 16525183. Rubenstein JL, Hsi ED, Johnson JL, et al. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol. 2013;31:3061-3068, PMID: 23569323.

10. True. Given the encouraging

results of CALGB 50202 in terms of response, survival and toxicity achieved in the multicenter setting for PCNSL, the HD-MTX, temozolomide and rituximab (Rituxan, Biogen Idec/Genentech; MT-R) regimen is being evaluated in a successor intergroup, randomized Phase II trial (CALGB 51101), that compares dose-intensive etoposide plus cytarabine (EA) chemotherapy with myeloablative chemotherapy using carmustine plus thioTEPA followed by autologous HCT. Rubenstein JL, Hsi ED, Johnson JL, et al. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol. 2013;31:3061-3068, PMID: 23569323.

Dr. Asia Maqbool assisted in preparing the manuscript.

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Harnessing the Immune System in NSCLC Implications of Emerging Data and Immunotherapeutic Strategies for Personalized Medicine To participate in this FREE CME activity, log on to

www.CMEZone.com Release date: October 1, 2013

Expiration date: September 30, 2014

Editor

TARGET AUDIENCE

Suresh S. Ramalingam, MD

The target audience for this activity is medical oncologists, hematology/oncology fellows, oncology specialty pharmacists, and other health care professionals involved in the management of individuals with nonsmall cell lung cancer (NSCLC).

Professor of Hematology and Medical Oncology Director, Division of Medical Oncology Emory University School of Medicine Winship Cancer Institute Atlanta, Georgia

EDUCATIONAL OBJECTIVES At the conclusion of this activity, participants should be able to:

Faculty Julie R. Brahmer, MD

1 Review fundamental concepts of antitumor immune responses in NSCLC.

Associate Professor Johns Hopkins University School of Medicine Baltimore, Maryland

2 Evaluate key eﬃcacy and safety data from ongoing clinical trials evaluating immunotherapeutic strategies for NSCLC, including tecemotide (formerly known as L-BLP25), belagenpumatucel-L, melanoma-associated antigenA3 (MAGE-A3) vaccine, immune checkpoint inhibitors, toll-like receptor agonists, and mycobacterial adjuvant-based agents.

John Nemunaitis, MD Executive Medical Director Mary Crowley Cancer Research Centers Dallas, Texas

Roman Perez-Soler, MD Professor of Medicine Chair, Department of Oncology Montefiore Einstein Center for Cancer Care Chief, Division of Medical Oncology Department of Medicine Deputy Director Albert Einstein Cancer Center Bronx, New York

3 Identify eﬀective immunotherapeutic strategies for early- and advanced-stage NSCLC based on patient and disease characteristics. 4 Recall the ongoing clinical trials evaluating immunotherapeutic approaches for NSCLC to aid appropriate patients for study participation.

MEDIA Monograph

ESTIMATED TIME TO COMPLETE ACTIVITY 1.0 hour