clinical oncology news digital edition - april 2012

Induction hormone therapy sparked a lot of discussion and interest at

the 2011 San Antonio Breast Cancer Symposium (SABCS). This attrac-tive idea uses dynamic effects of hor-mone therapy on tumor proliferation and estrogen receptor (ER) content during the first 2 to 12 weeks of ini-tial hormone therapy to generate improved estimates of prognosis com-pared with single pretreatment studies of the tumor. A reduction in tumor cell proliferation as measured by a drop in Ki67 immunostaining and persistent

Prognostication and Prediction for ER-Positive Breast CaA breakdown of tests available in 2012

San Francisco—The optimal radiation schedule for the curative treatment of prostate cancer today remains largely unknown. It is believed that using few-er fractions with a larger dose per frac-tion may result in an improved ther-apeutic ratio; however, there is little strong evidence to support this theory, according to W. Robert Lee, MD, pro-fessor of radiation oncology at Duke University in Durham, N.C.

During an oral presentation on hypo-fractionation for prostate cancer at the American Society of Clinical Oncolo-gy’s 2012 Genitourinary Cancers Sym-posium (ASCO-GU), Dr. Lee said that

Optimizing Radiation For Prostate CancerNewer techniques challenge standard schedules and ADT use

San Diego—Randomized controlled trials sponsored by a pharmaceutical company for cancer treatments were more likely to generate positive results than trials gen-erated by a public agency, according to a recent analysis.

Trials performed by the two different funding sources tended to have different emphases, which could explain the differ-ences between the two.

Two concepts are useful when con-sidering the differences between the results in randomized controlled trials

(RCTs). The first is the “equipoise prin-ciple” in which investigators cannot pre-dict the effects of treatments in advance. As a result, based on the fact that the new treatment will sometimes be supe-rior to the standard, sometimes inferior and sometimes comparable, the overall success of discovery of new treatments should be around 50%. The second con-cept is known as “design bias,” which postulates that trials are undertaken only if there is high likelihood of detecting

Among three common aggressive treatments for prostate cancer, EBRT produces higher costs and related toxicities

San Francisco —External beam radiation therapy (EBRT) results in higher long-term tox-icities and treatment-related costs than prostatectomy and brachytherapy, two other com-mon treatments for the disease, according to an analysis of 137,427 prostate cancer patients.

“Research to date has not given us a clear picture of how each prostate cancer ther-apy affects men over the long run,” said lead author Jay Ciezki, MD, staff physician at the Cleveland Clinic in Ohio. “Our analysis is one of the first to examine the quality-of-life and financial costs of these three very common prostate cancer treatment strategies for more than five years after treatment. We found that external beam radiotherapy had higher toxicity rates and was the most costly therapy per patient-year.”

Dr. Ciezki, who presented the study findings at the American Society of Clinical

External Beam Radiotherapy: More Toxic, More Expensive

Industry-Sponsored Studies More Likely To Generate Positive Results

Cost per patient-year of common aggressive prostate cancer treatments

$2,557.36 �Brachytherapy

$3,205.71 Prostatectomy

$6,412.29 External beam radiation therapy

Toxicity-related medical interventions required

3.7% �Brachytherapy

6.9% Prostatectomy

8.8% External beam radiation therapy

see RADIATION, page 6

see EBRT, page 4

see PROGNOSTICATION, page 12 see STUDIES, page 5

To order cancertherapeutic��

regimens�or�agents�pocket�guides,�

go�to�http://www.clinicaloncology.com/

PocketGuides.

Counseling About Cancer: Strategies for Genetic

Counseling, Third EditionKatherine Schneider

See�page�31.

McMahonMedicalBooks.com

EDUCATIONAL REVIEW

Treatment Options for Metastatic Renal Cell CarcinomaAccess atclinicaloncology.com

PRN

18 Clinical Conundrums: A quiz on recent American Society of Hematology data for the practicing hematologist/oncologist.

29 Overall, cancer deaths are down, but a few disease types are on the rise.

SOLID TUMORS

8 Fulvestrant plus anastrozole for metastatic breast cancer.

20 Predicting nonadherence with aromatase inhibitors.

10 Doxorubicin’s effect on recurrent ovarian cancer.

24 Adjuvant endocrine therapy and toxicity-related non-compliance.

EXPERT COMMENTARIESFROM JOHNS HOPKINS

DanijelaJelovac,�MD

Robert S. Miller,MD,�FACP

Independent�News�on�Advances�in�Cancer�Care

ClINICAloNColoGy.CoM • April 2012 • Vol. 7, No. 4

Oncology Edition Oncology Edition Oncology Edition

2 CliniCal OnCOlOgy�news •�april 2012CLINICAL ONCOLOGY NEWS

Solid TumorsBone Metastases

Allan�lipton,�MD�Milton S. Hershey Medical Center, Penn State University Hershey, PA

Breast Cancer

Andrew�Seidman,�MDMemorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Maura�N.�Dickler,�MDMemorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer

Edward�Chu,�MDUniversity of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Cathy�Eng,�MDUniversity of Texas, MD Anderson Cancer Center Houston, TX

leonard�Saltz,�MDMemorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer and Sarcoma

Ephraim�Casper,�MDMemorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Genitourinary Cancer

Ronald�M.�Bukowski,�MDTaussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic Cancer

Maurie�Markman,�MDCancer Treatment Centers of America Philadelphia, PA

Lung, and Head and Neck Cancers

Edward�S.�Kim,�MDUniversity of Texas MD Anderson Cancer Center Houston, TX

Lung Cancer, Emesis

Richard�J.�Gralla,�MDHofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center Lake Success, NY

Prostate Cancer

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

Hematologic MalignanciesJennifer�R.�Brown,�MD,�PhDDana-Farber Cancer Institute, Harvard Medical School Boston, MA

Harry�Erba,�MD,�PhDUniversity of Michigan Ann Arbor, MI

Shaji�Kumar,�MDMayo Clinic Rochester, MN

Richard�Stone,�MDDana-Farber Cancer Institute, Harvard Medical School Boston, MA

Community OncologyJohn�W.�Finnie,�MDMercy Medical Center St. Louis, MO

Michael�J.�Fisch,�MD,�MPHUniversity of Texas, MD Anderson Cancer Center Houston, TX

Steven�Vogl,�MDMedical Oncologist New York, NY

Symptom Control and Palliative Care

William�S.�Breitbart,�MDMemorial Sloan-Kettering Cancer Center New York, NY

Steven�D.�Passik,�PhDVanderbilt University Medical Center Nashville, TN

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

Russell�K.�Portenoy,�MDBeth Israel Medical Center New York, NY

Charles�F.�von�Gunten,�MDUniversity of California, San Diego, CA

Infection Control

Susan�K.�Seo,�MDMemorial Sloan-Kettering Cancer Center New York, NY

Oncology Nursing

Betty�Ferrell,�RN,�PhDCity of Hope National Medical Center Duarte, CA

Michele�Neskey,�MMSc,�PA-CPhysician Assistant University of Texas MD Anderson Cancer Center Houston, TX

Pharmacy

Cindy�o’Bryant,�PharmDUniversity of Colorado Cancer Center Denver, CO

Sara�S.�Kim,�PharmDThe Mount Sinai Medical Center New York, NY

Bioethics

Joseph�P.�DeMarco,�PhDCleveland State University Cleveland, OH

Paul�J.�Ford,�PhDCleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Policy and Management

Mary�lou�Bowers,�MBAThe Pritchard Group Rockville, MD

Rhonda�M.�Gold,�RN,�MSNThe Pritchard Group Rockville, MD

EDITORIAL BOARD

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.�They�then�review�the�articles�before�they�are�published.�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 News�are�sent�to�the�sources�quoted�in�each�article�to�review�and�verify�the�accuracy�of�the�article’s�content.

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

Mission Statement

The�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.

®

Letter to the EditorTo�the�editor:

i�read�the�articles�“applying�Clinical�Tri-als�to�‘real-world’�Care”�and�“less�

surgery�is�Better�for�some�Breast�Can-cer�patients”�(Clinical Oncology News, Feb�2012;�Vol�7:2)�with�great�interest.�

�The�information�contained�in�the�arti-cles�is�not�new.�The�articles�concisely�summarize�changes�being�seen�in�breast�cancer�management�and�reasons—clinical�trials—for�the�changes.�Below�is�a�synop-sis�i�developed�for�surgeons�and�oncolo-gists�at�our�institution,�dovetailing�use�of�sentinel�lymph�node�biopsy�(slnD)�and�nodal�radiation�for�breast�cancer�patients.�

The�summary�of�the�various�trials�regarding�axillary�lymph�node�dissection�(alnD)�was�helpful�regarding�the�use�of�alnD�after�slnD.�The�author�con-cluded:�“Doctors�now�have�additional�evidence�that�axillary�lymph�node�dis-section�does�not�add�benefit�to�sentinel�node�resection�and�clinically�node�nega-tive�breast�cancer�patients�with�minimal�sentinel�node�involvement.”�

nodal�information�is�needed�for�prognosis�and�decisions�regarding�systemic�therapy.�Use�of�slnD�has�significantly�reduced�the�risk�for�lymph-edema�and�sensory�neuropa-thy�of�the�arm�and�the�breast�compared�with�routine�alnD.�

The�issue�now�is�management�of�involved�axillary�lymph�nodes.�in�addi-tion�to�the�recent�trials,�there�are�older�trials,�specifically�nsaBp�BO-4,�which�has�a�30-plus-year�follow-up,�which�showed�no�survival�advantage�with�alnD�compared�with�no�alnD.�

review�of�the�radiation�therapy�litera-ture�would�suggest�the�following�blend�regarding�the�use�of�surgery�and�radia-tion�in�the�management�of�pn+�disease.

Clinically�involved�pn+�nodes�need�alnD�as�a�therapeutic�measure.�These�patients�additionally�need�radiation�therapy�to�the�axilla�and�supraclavic-ular�(sCF)�region.�Undoubtedly,�this�combined�treatment�increases�risk�for�lymphedema.�But�patients�with�clinical�palpable�axillary�nodes�are�at�high�risk�

for�locoregional�failure.�Bene-fits�of�combined�treatment�out-weigh�the�side�effects.�

patients�with�pn+�nodes�that�are�not�clinically�palpable�can�be�well�managed�with�slnD�

and�radiation�therapy�to�the�axilla�with�or�without�the�sCF�region.�The�follow-ing�trend�can�be�seen�in�the�radiation�therapy�literature:�if�the�primary�tumor�is�small�with�low-risk�features,�treating�the�breast�with�high�tangents�to�include�the�level�i�and�ii�axillary�nodes�is�ade-quate�therapy�based�on�the�Massachu-setts�general�Hospital�series.1�

if�the�breast�primary�has�high-risk�features—size,�receptor�status,�lym-pho-vascular�invasion,�grade—then�it�would�behoove�[the�physician]�to�treat�the�axilla�and�sCF�region�as�a�sepa-rate�field�to�the�breast�tangents.�This�is�based�on�the�recent�Canadian�Ma.20�trial,�which�compared�breast�radiation�alone�with�breast�plus�nodal�radiation�in�patients�with�one�to�three�pn+�nodes.2

addition of nodal radiation improvedlocoregional and systemic control, and

improves�disease-free�survival�with�a�trend�toward�improved�overall�survival.�in�the�absence�of�alnD,�radiation�to�the�regional�nodes�is�well�tolerated�with�less�than�5%�risk�for�lymphedema�in�the�upper�extremity.

patients�with�pn0�disease�generally�do�not�need�treatment�to�the�nodes.�

i�hope�this�information�is�useful�in�coordinating�the�locoregional�care�with�systemic�therapy.�

gilbert�lawrence,�MD

radiation�Oncologist

Faxton�st.�luke’s�Hospital

Utica,�ny�

References

1. Macdonald�sM,�abi-raad�rF,�alm�el-Din Ma,et�al.�Chest�wall�radiotherapy:�middle�ground�for�treatment�of�patients�with�one�to�three�positive�lymph�nodes�after�mastectomy.�Int J Radiat Oncol Biol Phys.�2009;75:1297-1303.

2.� whelan�TJ,�Olivotto�i,�ackerman,�et�al.�nCiC-CTg�Ma.20:�an�intergroup�trial�of�regional�nodal�irradiation�in�early�breast�cancer.�J Clin Oncol.�2011;29(suppl;�abstr�lBa1003).

+

New Editorial Board Member: Michele Neskey, PA-C

Clinical Oncology News is pleased to announce that oncologyphysician assistant Michele�neskey, MMsc,�pa-C, has joined themagazine’s editorial board.

Ms.�neskey received her master of medical science degreefrom�yale University in 2005 and currently practices in theDepartment of Thoracic/Head &�neck Medical Oncology at theUniversity of Texas MD�anderson Cancer Center in Houston.she previously worked at�yale-new Haven Hospital,�new

Haven, Conn., the University of Miami/Jackson Memorial Hospital and�aptiumOncology/Mount�sinai Comprehensive Cancer Center in Miami Beach, Fla.

she is a member of the�american�society of Clinical Oncology, the�americanacademy of�physician�assistants and the�association of�physician�assistantsin Oncology. Ms.�neskey has been published in Cancer Research, the Journal of Thoracic Oncology and the Journal of the American Academy of Physician Assistants.

Ms.�neskey will provide guidance to the magazine in our coverage of mid-level providers and the role of physician assistants and nurse practitioners inoncology and hematology.�we welcome her to our board.

If you missed any recent issues of Clinical Oncology News, visit www.clinicaloncology.com.

Visit ClinicalOncology.com for

Cancer News Review With William Nelson, MD

From the director of the Johns Hopkins Kimmel Cancer Center

Podcast Series

CliniCal OnCOlOgy�news •�april 2012 3

McMahon Publishing is a 40-year-old, family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications.

Clinical�Oncology�news�(ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Corp. Office, 83 Peaceable Street, Redding CT 00896 Copyright© 2012 McMahon Publishing, New York, NY. All rights reserved.

POSTMASTER: Please send address changes to Clinical�Oncology�news, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

Editorial Staff

Kevin�Horty,�Group�Publication�Editor�[email protected]

Gabriel�Miller,�Managing�Editor�[email protected]

Sarah�Tilyou,�Senior�Editor�[email protected]

James�Prudden,�Group�Editorial�Director

David�Bronstein,�Editorial�Director

Robin�B.�Weisberg,�Manager,��Editorial�Services

Elizabeth�Zhong,�Associate�Copy�Chief

SalES Staff

Julianna�Dawson,�Publication�Director�[email protected]

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Jessica�Pichardo,�Junior�Account�Manager�[email protected]

art and Production Staff

Michele�McMahon�Velle,�Creative�Director,�MAX�Graphics

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CLINICAL ONCOLOGY NEWS

Oncology 2012 Genitourinary Cancers Symposium (abstract 4), said there clear-ly are still some high-risk prostate can-cer patients who will benefit from exter-nal beam radiotherapy. However, for the approximately 80% or more of prostate cancer patients diagnosed with low- and intermediate-risk disease, brachythera-py or prostatectomy may be even more preferable options than had previously been assumed, he said.

The researchers analyzed data in the Surveillance, Epidemiology, and End Results (SEER)-Medicare data-base collected between 1991 and 2007. The median follow-up was 71 months. They compared treatment-related tox-icities and related outcomes among men who received EBRT, prostatectomy or brachytherapy.

Because the SEER-Medicare database provides information on cancer diagno-ses and outcomes, along with individu-al patient costs, it allowed the investiga-tors to obtain Medicare reimbursement data for both the initial treatment and any subsequent treatments related to the toxicities, which was used to calcu-late the total cost per patient-year for each of the three therapies over time. “We were able to get a good picture of the long-term costs of patient care and were surprised to see such dramatic differences among the three treatment strategies,” said Dr. Ciezki.

A total of 137,427 patients were exam-ined, including 59,559 (43.3%) treat-ed with prostatectomy, 60,806 (44.2%) who received EBRT and 17,062 (12.4%) who were treated by brachytherapy. Overall, 10,585 (7.3%) needed some type of treatment intervention for a therapy-related effect.

The investigators were not able to determine the stage of prostate cancer in individual patients included in the study. Additionally, the study was lim-ited to patients older than age 65 years with prostate cancer as their only can-cer diagnosis.

The investigators found that brachy-therapy had the lowest cost per patient-year: $2,557.36. Prostatectomy came in slightly more expensive at $3,205.71, fol-lowed by EBRT at $6,412.29. EBRT also resulted in the most treatment-related toxicities. Within treatment modalities, the percentages of patients requiring a toxicity-related intervention were 6.9% for radical prostatectomy, 8.8% for EBRT and 3.7% for brachytherapy.

The investigators found that 7.1% of patients who received EBRT experi-enced genitourinary toxicities such as urethral strictures and bladder bleed-ing compared with 6.7% of those treat-ed with prostatectomy and 3.4% of those treated with brachytherapy. Sim-ilarly, 1.7% of EBRT patients had gas-trointestinal effects compared with only 0.1% of prostatectomy patients and 0.3% of those in the brachythera-py group.

The researchers caution that the study findings are preliminary and they plan to more closely examine the data and the differences they observed, including differences in toxicities found between

older and newer techniques, and wheth-er certain types of patients might be pre-disposed to long-term effects from par-ticular therapies.

“This is a fascinating piece of work. It begs the question why brachyther-apy is less used. I am surprised we don’t see more use of this modali-ty,” said medical oncologist Nicholas Vogelzang, MD, head of the Genitouri-nary Cancer Program at the Univer-sity of Nevada School of Medicine in Las Vegas. He told Clinical Oncology News that these new findings are very important because the study included so many patients and had such a long follow-up. Studies like this one will help ensure that more prostate cancer patients receive the best possible ther-apies while avoiding unnecessary side effects and costs, he added.

—John Schieszer

Dr. Ciezki reported that he has no relevant relationships to disclose. Dr. Vogelzang reported an employment or leadership

position with US Oncology and has served as a consultant or advisor or has received honoraria from Amgen, Bayer, Boehringer Ingelheim, Celgene, Clinical Care Options,

Cougar Biotechnology, Dendreon, Eisai, Genentech, GlaxoSmithKline, Johnson &

Johnson/Centocor, Novartis, Pfizer, Takeda/Millennium, US Oncology and Veridex.

EBRT continued from page 1

Having trouble keeping up with all of the oncology and medical journals that cross your desk?

on�a�monthly�basis,�Clinical Oncology News�highlights�key�studies��

from�the�journals�and�provides�guest�clinician�perspectives�to�help��

you�stay�up�to�date.

We�hope�you�find�this�a�useful�tool.

Cost per patient-year of common aggressive prostate cancer treatments

$2,557.36| Brachytherapy

$3,205.71| Prostatectomy�

$6,412.29| External�beam�radiation�therapy�

Toxicity-related medical interventions required

3.7%| Brachytherapy

6.9%| Prostatectomy

8.8%| External�beam�radiation�therapy

numbersby�the

‘External beam radiotherapy had higher toxicity

rates and was the most costly therapy per

patient-year.’ —Jay Ciezki, MD

4 CliniCal OnCOlOgy�news •�april 2012SOLID TUMORS

Prostate

therapeutic success in favor of spon-sor’s treatment.

Speaking at the 2011 annual meeting of the American Society of Hematolo-gy, Benjamin Djulbegovic, MD, PhD, reported that the equipoise hypothesis appears to drive the results observed in publicly sponsored trials, whereas the design-bias hypothesis can explain the outcomes obtained in the industry-sponsored trials.

This conclusion was based on a retro-spective analysis of the results of all Phase III studies sponsored by GlaxoSmithKline (GSK) or the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) from 1980 through June 2010. Using three metrics to assess treatment success in clinical trials, Dr. Djulbegovic, of the Center for Evidence-Based Medicine and Health Outcomes Research, University of South Florida and H. Lee Moffitt Can-cer Center & Research Institute in Tampa, and colleagues found that new treatments are favored over standard treatments in industry-sponsored trials in comparison with trials funded by the public funder for each metric used.

Of the 40 trials funded by industry (19,889 patients) and the 77 trials funded by NCIC CTG (33,260 patients), 42% of the industry-sponsored studies and 25% (P=0.04) of the public sector–sponsored studies showed a statistically significant superiority of experimental treatment over the control arm for the primary end point. Investigators themselves conclud-ed that new treatments were superior to standard treatments in 80% of GSK ver-sus 44% of NCIC CTG trials (relative risk, 1.81; P<0.001).

Pooled quantitative analysis for the primary outcome indicated higher suc-cess rate in GSK trials (odds ratio [OR], 0.61; 99% confidence interval [CI], 0.47-0.78] versus OR, 0.86; CI, 0.74-1.00; P=0.003). However, testing for the effect of treatment over time indicated that treatment success has become sim-ilar in the last decade.

In addition to equipoise versus design bias as the main explanation of the results, a number of other explanations are possible. They include a possibility that the results can be explained by the larger proportion of industry-sponsored trials relying on the use of placebo as a comparator, as well as differences in mix between the proportion of explanatory and pragmatic trials in industry versus publicly sponsored trials. Pragmatic tri-als are rarely done by industry and the effect sizes are expected to be larger in explanatory trials, which can explain the differences in the results.

Overall, Dr. Djulbegovic concluded, “the differences in the results clearly point to differences in research agendas

between publicly versus industry-spon-sored trials.”

Asked to comment on these results, Smita Bhatia, MD, director of outcomes research at City of Hope in Duarte, Calif., called this a “a well-conduct-ed study” that generated “intriguing

findings,” but she considers the con-clusions to be preliminary and awaits a study with a larger scope.

“While the findings provide food for thought, they need to be confirmed in future studies that include representation by more than one pharmaceutical compa-ny, unlike the current study that relied on

data from only one,” Dr. Bhatia said. The findings may be useful when considering differences between industry- and public-funded studies. —Ted Bosworth

Dr. Djulbegovic reported receiving research funding from Millennium; Dr. Bhatia

reported no relevant disclosures.

STUDIEScontinued from page 1

‘The differences in the results clearly point to differences

in research agendas between publicly versus industry-

sponsored trials.’ —Benjamin Djulbegovic, MD, PhD

between publicly versus industry-spon

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CliniCal OnCOlOgy�news •�april 2012 5CLINICAL TRIALS

Evidence-based Medicine

in the United States, patients with pros-tate cancer are typically treated with external beam radiation therapy (EBRT) for five days per week for eight to nine weeks. The most common dose per frac-tion is 1.8 to 2 Gy; however, in the past 10 years a number of reports have sug-gested that the fractionation sensitivity of prostate cancer may favor hypofrac-tionated schedules.

“There is some preclinical evidence to suggest that using fewer, larger dos-es would be beneficial,” said Dr. Lee. “However, if you are going to give fewer treatments, then you have to give high-er doses. So the issue is how few dos-es should you give and how large a dose should you give.”

There are currently only two mature randomized trials comparing different fractionation schedules, Dr. Lee said. One study was performed in Canada and the other in Australia. Both studies compared the two fractionation sched-ules commonly used in each country. The problem with both trials is that they were designed many years ago and the doses and techniques studied are far from the standard of care in 2012.

The Canadian study was a noninferior-ity trial including 936 men (J Clin Oncol 2005;23:6132-6138, PMID: 16135479). There were two treatment arms: One included men treated with 66 Gy in 2-Gy fractions and the second with men treat-ed with 52.5 Gy in 2.625-Gy fractions. After a five-year follow-up, the men in the second arm had a higher biochemi-cal/clinical failure rate (hazard ratio, 1.18; 95% confidence interval, 0.99-1.41). The authors concluded that the hypofraction-ated arm was inferior.

The Australian study included 217 patients with a primary end point of late gastrointestinal/genitourinary toxicity (Int J Radiat Oncol Biol Phys 2011;81:1271-1278, PMID: 20934277). The trial compared 64 Gy in 2-Gy frac-tions to 55 Gy in 2.75-Gy fractions. To date, the researchers have found no differences in biochemical recurrence rates when using the American Society of Radiation Oncology (ASTRO) defini-tion. However, there was a difference favoring the 2.75-Gy fractionation arm if the Phoenix definition (nadir + 2 ng/mL) was used.

Dr. Lee said three other randomized trials have compared different fraction-ation schedules using more contempo-rary methods. In an Italian study with 168 patients comparing 80 Gy in 2-Gy fractions with 62 Gy in 3.1-Gy frac-tions, investigators found there were no observed differences in late rec-tal toxicity (Int J Radiat Oncol Biol Phys 2010;78:11-18, PMID: 20047800). However, the risk for biochemical

recurrence was lower in the hypofrac-tionated arm. Two American studies also have analyzed the issue but nei-ther reported a difference in biochem-ical recurrence.

“Considering all five studies published or reported to date, no consistent effect was observed,” said Dr. Lee. “Given the lack of consistency, the eight- or nine-week regimens are likely to remain the standard in the United States. There are three very large noninferiority trials that have completed accrual totaling more than 5,000 patients. The results of these studies will determine if shorter courses of four to five weeks should be adopted.”

He noted that the inconsistency might be the result of different eligibility crite-ria. The use of androgen deprivation ther-apy (ADT) also varied greatly across the studies. It is well established that hypo-fractionation schedules provide patients with convenience and lower costs. How-ever, Dr. Lee said it is still unknown whether conventional (1.8-2 Gy) or mod-erate (2.4-4 Gy) or extreme hypofraction-ation (6.5-10 Gy) is optimal in men with prostate cancer.

“The evidence is stronger for the mod-erate schedules. There are rigorous com-parisons but most of the comparison studies are relatively small and the study design was analyzing for superiority,” Dr. Lee said in an interview with Clinical Oncology News. “The results of large non-inferiority trials are eagerly anticipated. If we can determine that similar results are achievable with fewer fractions, external radiotherapy will be more convenient for patients at a lower cost.”

Modern Radiotherapy Techniques: Do More Accurate Doses Replace ADT?

ADT has been shown to improve sur-vival for men with intermediate-risk prostate cancer as well as for men with high-risk prostate cancer treated with radiation therapy with doses in the range of 65 to 70 Gy delivered without image guidance. Yet, no single multicenter,

Phase III study of dose-escalated radio-therapy demonstrating a benefit with the addition of ADT exists, according to Dan-iel Krauss, MD, an associate professor of radiation oncology at Oakland University William Beaumont School of Medicine in Royal Oak, Mich.

At an oral presentation at ASCO-GU on dose escalation and supplemental androgen deprivation, Dr. Krauss told oncologists that to date retrospective analyses have suggested that ADT offers little to no benefit for patients treated locally with brachytherapy (Int J Radiat Oncol Biol Phys 2006;65:669-677, PMID: 16682149). He added that the same is true for dose-escalated EBRT (Int J Radiat Oncol Biol Phys 2011;80:1064-1071, PMID: 20584576).

“[Luteinizing hormone-releasing hor-mone agonists] have proven to be very active against prostate cancer. But they have a lot of side effects and so if you don’t need to give them you want to avoid it,” said Dr. Krauss. “There are a lot of prospective randomized trials and they are large and well done, but the problem is that they were done in the 1980s and 1990s.”

It has created a conundrum for cli-nicians, he added. The radiation tech-niques used in the 1980s and 1990s are inferior to what are used today. The unanswered question is whether the hormones compensated for what was less-than-optimal radiation treatment. Dr. Krauss said the very nature of pros-tate cancer as an indolent malignan-cy with a protracted natural history is part of the problem when studying this issue. Today, new technologies have out-paced the clinical outcomes that objec-tively demonstrate their effectiveness. This appears to clearly be the case when it comes to the development of intensi-ty-modulated radiotherapy and image-guided radiation therapy (IGRT).

“We know the prostate moves around a bit and that target motion is now dealt with, but that was not the case when the studies were conducted,” Dr. Krauss said in an interview with Clinical Oncol-ogy News. “Clinical oncologists should

care about this because this diagnosis is so common and it affects so many men. Intermediate-risk patients are a large percentage of new diagnoses and we need to know what the best approach is and whether radiation therapy by itself is all that is necessary.”

Quality-of-life issues are paramount for many men with intermediate-risk and high-risk prostate cancer. The com-mon acute toxicities from ADT include hot flashes and sexual side effects. Addi-tionally, the use of ADT is associat-ed with increased risks for developing or exacerbating cardiovascular disease, osteoporosis and diabetes. Dr. Krauss said eliminating the need for ADT could mean a better quality of life for many men. “You don’t want to subject these folks to more side effects unless there is a clear clinical advantage to administer-ing the treatment.”

Multiple large, Phase III trials have shown that there is a clinical advantage, including an improvement in overall sur-vival, when using ADT with radiotherapy for prostate cancer patients with interme-diate- and high-risk disease, Dr. Krauss said. Additionally, studies have shown that more ADT is better than less in these patient populations.

However, Dr. Krauss added that dose-escalated radiotherapy has been shown in multiple prospective randomized tri-als to be superior to less—that is, to stan-dard radiotherapy doses. So, it may be possible that ADT is not as important as it once was in the management of men with intermediate-risk prostate cancer.

Clinicians know that the prostate is not a static target and they now factor in the interfraction and intrafraction position changes when delivering radiotherapy. Yet, today there is a lack of data showing significant clinical benefits when IGRT is combined with ADT. “One thought is that if ADT works in low-dose radiation then it should work even better with high-dose. However, I don’t think we know that, and it may be that the hormones, in those prior studies, were simply masking what was suboptimal radiation therapy,” said Dr. Krauss.

He said the Radiation Therapy Oncol-ogy Group (RTOG) is currently investi-gating the issue in a large randomized tri-al (RTOG 0815). It is designed to show a survival advantage with the addition of short-term, six-month ADT to dose-esca-lated radiotherapy in men with interme-diate-risk prostate cancer. A previous study (RTOG 9408) was able to demon-strate a survival advantage for men with early-stage prostate cancer with the addi-tion of a course of four-month ADT to radiotherapy (66.6 Gy).

—John Schieszer

Dr. Lee reported an employment or leadership position with Practical Radiation Oncology. Dr. Krauss reported that he has

no relevant relationships to disclose.

RADIATIONcontinued from page 1

said in an interview with Clinical Oncol-ogy News. “Clinical oncologists should


Prostate

The history of thalidomide provides a poignant example of the potential that new knowledge about disease pathogene-sis and drug pharmacology has to dramat-ically alter the medical and societal view of a pharmaceutical agent.1

Consider the issue of high-dose chemo-therapy and bone marrow/precursor cell “rescue” in the management of breast can-cer and other solid tumors. While these approaches are occasionally employed—for example, with recurrent chemothera-py-sensitive metastatic germ cell tumors—rather definitive data in breast cancer in both the adjuvant and metastatic settings has revealed the lack of a major impact on overall survival and led to the abandon-ment of this strategy by the large majority of the oncology community.2,3

But suppose, for example, that a group of clinical investigators used a retrospec-tive analysis of clinical data to propose a novel approach to “safely and effectively purge viable cancer from the population of precursor cells” to be re-infused back into the patient following a high-dose chemotherapy program.4 And suppose the approach progressed to the point at which the actual procedure was able to be con-ducted in a cost-effective manner—that is, entirely in the outpatient setting with few complications requiring hospitalization—and the treatment-related mortality using standard supportive care was anticipated to be very low, less than 0.5%.

In this scenario, what data should be required before an investigator proposes, an institutional review board approves and a third-party payer accepts respon-sibility for “standard-of-care” charg-es associated with the “performance of

another trial of high-dose chemothera-py in breast cancer”?

Or consider a long-standing issue in the realm of gynecologic oncology: Sec-ond-look surgical reassessment was long considered a standard component of the management of women with advanced ovarian cancer who had achieved a clin-ically defined complete response to pri-mary cytotoxic chemotherapy.5 However,

during the past decade this approach has been much less frequently used because there is no evidence that any unique diag-nostic information generated through a second-look translates into a specif-ic treatment plan that will improve the patient’s outcome. Simply stated, the per-formance of a second-look surgical assess-ment may be of prognostic value, but there is no documented predictive utility—that is, the selection of a superior management strategy associated with the procedure.

But what if a novel antineoplastic approach were developed in ovarian can-cer whose use was demonstrated to be dependent on detailed knowledge of the size and location of any residual cancer within the peritoneal cavity? Or what if there was a highly rational hypothesis, or even actual clinical data, to suggest the approach could be quite effective, but only in the absence of any macroscopic

intraperitoneal disease? Would it be rea-sonable to require a surgical assessment to evaluate the extent of disease, possibly with subsequent removal of residual can-cer, despite the fact that this approach is no longer “routine”?

Finally, we come to the elephant in the room, and specifically the two therapeu-tic concepts discussed above: Will any third-party payer agree to pay for a high-

dose chemotherapy regimen in metastat-ic breast cancer—even if it actually costs no more and is possibly considerably less expensive than several current manage-ment strategies—or for the performance of a surgical re-assessment in a clinically disease-free ovarian cancer patient when the “existing established experience” can be used to show the “absence of clinical utility” for these approaches?

It is certainly not unreasonable to pro-pose that a past strategy, examined under quite different circumstances and with insufficient knowledge, produced a less than optimal picture of its clinical utility. Consider, for a moment, where we would be today in our use of tyrosine kinase inhibitors in the management of lung cancer if we did not understand the rele-vance of specific mutations in the epider-mal growth factor receptor pathway.

Perhaps tomorrow we will learn

something critically relevant to the use of high-dose chemotherapy in the treatment of solid tumors, or develop a novel strat-egy for the management of small-volume residual ovarian cancer that will require a thorough assessment of the peritone-al cavity. Will we be willing as a clinical research community, and as a society, to re-examine these discarded approaches if they were brought forward?

References1. Stephens T, Brynner R. Dark Remedy: The

impact of thalidomide and its revival as a vital medicine. Cambridge, MA: Perseus Publishing; 2001.

2. Berry DA, Ueno NT, Johnson MM, et al. High-dose chemotherapy with autolo-gous hematopoietic stem-cell transplan-tation in metastatic breast cancer: over-view of six randomized trials. J Clin Oncol. 2011;29:3224-3231, PMID: 21768471.

3. Berry DA, Ueno NT, Johnson MM, et al. High-dose chemotherapy with autolo-gous stem-cell support as adjuvant thera-py in breast cancer: overview of 15 random-ized trials. J Clin Oncol. 2011;29:3214-3223, PMID: 21768471.

4. Muller AMS, Kohrt HEK, Cha S, et al. Long-term outcome of patients with metastatic breast cancer treated with high-dose chemotherapy and transplanta-tion of purified autologous hematopoiet-ic stem cells. Biol Blood Marrow Transplant. 2012;18:125-133, PMID: 21767515.

5. Greer BE, Bundy BN, Ozols RF, et al. Impli-cations of second-look laparotomy in the context of optimally resected stage III ovar-ian cancer: a non-randomized comparison using an explanatory analysis: a Gyneco-logic Oncology Group study. Gynecol Oncol. 2005;99:71-79, PMID: 16039699.

Should It Ever Happen?Re-examining a ‘Discarded’ Antineoplastic Strategy

Is it ever appropriate for the oncology community to legitimately decide to re-examine a previously discarded management strategy? And if the answer to this question is possibly yes, then what level of evidence—for example, epidemiological, preclinical or limited clinical considerations—should be required to justify such a decision?

The history of thalidomide provides a poignant example

of the potential that new knowledge about disease patho-

genesis and drug pharmacology has to dramatically alter

the medical and societal view of a pharmaceutical agent.

Not receiving Clinical Oncology News? Like to?Clinical Oncology News is distributed free of charge to selected oncology physicians. We use addresses provided by the AMA and AOA.

You don’t need to be a member of these organizations, but they need to have your address and specialty information. To be sure this information is up-to-date, please call the AMA at (800) 262-3211 or AOA at (800) 621-1773. You can tell them whether you prefer to have Clinical Oncology News mailed to you at your office or at home.

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Independent News for the Oncologist and Hematologist/Oncologist

Maurie Markman, MDsenior�Vice�president�of�Clinical�affairs�and�national�Director�for�Medical�Oncology,�Cancer�Treatment�Centers�of�america,�philadelphia

EDITORIAL BOARD COMMENTARY

CliniCal OnCOlOgy�news •�april 2012 7PRN

Patient Care

The findings, presented at the recent San Antonio Breast Cancer Symposium (SABCS, abstract S1-1), conflict with results from FACT (Fulvestrant and Anastrozole in Combination Trial) pre-sented at the 2009 SABCS. FACT con-cluded that there was no benefit to add-ing fulvestrant (Faslodex, AstraZeneca) to anastrozole (Arimidex, AstraZene-ca) therapy in patients with hormone receptor–positive breast cancer after first relapse.

“The combination of anastrozole plus fulvestrant cannot be recommended as a new standard in women with meta-static breast cancer,” said James Ingle, MD, a professor of oncology at Mayo Clinic who served as the discussant for the S0226 trial at SABCS. “The lack of any benefit seen in the FACT trial, a well-conducted study, is not consistent with the positive findings from S0226.”

The investigators who conducted the trial, however, said that the study pop-ulations of the two trials are different. “S0226 stands on its own merit,” said Rita Mehta, MD, an associate health sci-ence professor at the University of Cal-ifornia, Irvine, who led the Phase III study.

Because anastrozole lowers estro-gen levels and fulvestrant downregu-lates the estrogen receptor, research-ers thought the combination of the two could act as a one-two punch on breast cancer cells, a hypothesis supported by in vivo studies. Over the past four decades, however, a number of studies

have combined different endocrine therapies without success, including the recent FACT trial.

Southwest Oncology Group study S0226 enrolled postmenopausal wom-en with estrogen and/or progesterone receptor–positive, measurable or non-measurable MBC. Exclusion criteria included adjuvant or neoadjuvant che-motherapy or therapy with an aroma-tase inhibitor in the last 12 months. Indi-viduals were stratified by whether or not

they had received adjuvant tamoxifen.Patients were then randomized to

receive anastrozole either alone or in combination with fulvestrant; 41% of patients in the single-therapy arm crossed over to receive fulvestrant after disease progression. During the trial, after other studies showed that a 500-mg dose of fulvestrant was superior to 250 mg, patients were allowed to cross over to the higher dose. Nine of the 349 patients on the combination arm and five patients who crossed over received the 500-mg dose.

At SABCS, researchers presented the final analysis of 694 eligible patients.

The median age in both arms was 65 and roughly 40% of patients had prior tamox-ifen in both arms. Roughly one-third had prior chemotherapy and almost 40% had de novo metastatic disease.

Median PFS, the primary end point, was 15.0 months in patients receiv-ing anastrozole and fulvestrant and 13.5 months in patients receiving anas-trozole alone (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.68-0.94; P=0.007). Median OS was 47.7 months in

the combination arm and 41.3 months in the anastrozole-alone arm (HR, 0.81; 95% CI, 0.65-1.00; P=0.049).

Adverse events were similar in the two treatment groups. Thirteen percent of patients in the combination arm experi-enced grade 3 toxicities compared with 11% in the single arm. In the combina-tion arm, three patients had grade 5 tox-icities and two had grade 4 toxicities. Four patients in the single-agent arm had grade 4 toxicities.

In an unplanned analysis, patients who had not received prior adjuvant tamoxifen had a median PFS of 17.0 months compared with 12.6 (P=0.0055)

in those who had, and the median OS was 47.7 months compared with 39.7 months (P=0.0362). In patients who had received prior adjuvant tamoxifen, the differences in OS (49.6 months vs. 44.5 months; P=0.59) and PFS (14.1 vs. 13.5 months; P=0.37) were not statistically significant.

It is not clear whether prior tamoxifen is predictive of efficacy with the combi-nation. “We need to better understand other possible predictive factors, since the prior tamoxifen factor could be a false lead from an unplanned analysis,” Dr. Mehta said.

Dr. Ingle agreed. “The finding of no benefit in prior [tamoxifen] patients should be interpreted with caution,” he said, noting that a study in the Lan-cet showed that in 41% to 66% of simu-lated subgroups, simulations can false-ly indicate that there is no treatment effect in a particular subgroup when the trial shows overall benefit (Lancet 2005;365:176-186, PMID: 15639301).

Overall, Dr. Mehta concluded that “the combination of anastrozole and fulvestrant improves PFS and OS, the primary and secondary end points, in the first-line therapy of hormone recep-tor–positive breast cancer in postmeno-pausal women.”

The results disagree sharply with results from the FACT study. In that study, the PFS HR was 0.99 (P=0.91) and the OS HR was 1.0 (P=1.00).

“Eligibility criteria, regimens and measurable/evaluable proportions were similar,” said Dr. Ingle (Table). “There are some differences, but no glaring dif-ferences.” He pointed out, however, that 38.9% of patients in S0226 had de novo metastatic disease, and this seemed “a remarkably high figure.”

According to Dr. Mehta, one of many

Fulvestrant-Anastrozole Combo Improves SurvivalStudy conflicts with prior clinical trial resultsSan Antonio—Adding fulvestrant to anastrozole in first-line therapy of hormone receptor–positive metastatic breast cancer (MBC) in postmenopausal women improved progression-free survival (PFS) by 1.5 months and overall survival (OS) by 6 months, according to final results of the S0226 trial.

Table. Comparison of the S0226 and FACT Trial

S0226 (n=694) FACT (n=350)

Eligibility HR+�metastatic�breast�cancer;�postmenopausal

HR+�breast�cancer�after�first�relapse;�postmenopausal�or�premenopausal

Progression-free�survival 15.0�vs.�13.5�months�favoring�fulvestrant�arm�(HR,�0.80;�P=0.0070)

10.8�vs.�10.2�months;�no�difference��(HR,�0.99;�P=0.91)

overall�survival 47.7�vs.�41.3�months�favoring�fulvestrant�(HR,�0.81;�P=0.049)

37.8�vs.�37.2�months;�no�difference��(HR,�1.0;�P=1.00).

Prior�adjuvant�chemotherapy 33% 46%

No�prior�adjuvant�endocrine�therapy

60% 33%

Prior�tamoxifen 40%�(%�relapsed�unknown�on�tamoxifen) 65%�(27%�relapsed�on�tamoxifen)

Prior�aromatase�inhibitor 2% 1%

FACT,�Fulvestrant�and�anastrozole�in�Combination�Trial;�HR,�hazard�ratio;�HR+,�hormone�receptor–positive

‘The combination of anastrozole plus fulvestrant

cannot be recommended as a new standard in

women with metastatic breast cancer.’

—James Ingle, MD


Breast

differences is that FACT had patients with locally recurrent disease and S0226 specified only metastatic dis-ease. “S0226 had [patients with] endo-crine-sensitive disease with high sur-vival, despite not including patients with locally recurrent disease,” said Dr. Mehta. “Patients with locally recurrent disease can be cured again with a com-bination of local and systemic therapy.”

She pointed out that 32% of the 512 patients recruited for FACT were inel-igible, leaving 350 patients, a smaller-sized trial.

Andy Seidman, MD, an attending

physician in the Breast Cancer Med-icine Service at Memorial-Sloan Ket-tering Cancer Center in New York City, said the results of S0226 won’t spur him to make any broad changes in his prac-tice. “It is hard to understand how the overall survival analysis could not be confounded by post-protocol treatment, especially with such a modest improve-ment in PFS,” Dr. Seidman said. “I will consider the combination for the fortu-nately few patients who present to me with de novo, untreated metastatic dis-ease. This subset seemed to derive the largest incremental benefit.”

When asked about the difference in PFS and OS benefit, Dr. Mehta said that hazard ratios are a better gauge of bene-fit than median values and that the HRs for PFS and OS are similar. The OS bene-fit “follows exactly as expected,” said Dr. Mehta.

According to Dr. Ingle, “median out-comes may not tell the entire story, and subsequent therapies usually balance out in a large randomized trial.” Clarity will come from future randomized clinical tri-als in the neoadjuvant setting, he said.

Unfortunately, any clarity is unlikely to come from the ongoing Phase III trial

of fulvestrant (SoFEA [Study of Faslo-dex with or without concomitant Arim-idex following progression on Aroma-tase inhibitors). The trial has completed accrual of 700 patients and analysis is under way, but the trial involves women with disease progression on a nonste-roidal aromatase inhibitor, which was not the case with either S0226 or FACT.

—Kate O’Rourke

Dr. Mehta disclosed receiving grant/research support from AstraZeneca. Dr. Ingle and Dr.

Seidman had no relevant disclosures.

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Co-ChairsTessa Cigler, MD, MPHAssistant Professor of Medicine, Weill Cornell Medical CenterAttending Physician, NewYork-Presbyterian HospitalNew York, New York

Paula D. Ryan, MD, PhDAssociate Professor, Clinical Investigator, Section of Breast Oncology Medical Oncology, Fox Chase Cancer CenterPhiladelphia, Pennsylvania

Target AudienceOncologists, physicians, physician assis-tants, and other health care professionals involved in the treatment of patients with metastatic breast cancer (MBC). � ere are no prerequisites or fees.

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advanced human epidermal growth factor receptor 2 (HER2)-negative and HER2-positive breast tumors and novel strategies for circumventing treatment resistance.

3 Explain core guideline-recommended approaches to MBC management that take into consideration the heterogeneity of patient and tumor characteristics.

4 Compare the mechanisms, synergies, and evolving roles of current and emerging targeted therapies with activity in MBC, particularly in terms of novel combina-tions and sequences.

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Tailoring � erapy in Metastatic Breast CancerNovel Clinical Approaches

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Breast

These cancers have been shown to have higher sensitivity to

platinum-based chemotherapy com-pared with patients with the wild-type BRCA gene. Like platinum

drugs, anthracyclines cause direct DNA damage. Doxorubicin has been shown to cause single- and double-strand DNA damage. PL-DOX has been used as a single agent for treat-ment of platinum-resistant recurrent EOC, with a response rate around 20%. Because BRCA mutations disable dou-ble-stranded DNA repair, BRCA-associ-ated cancers would be expected to have higher sensitivity to any DNA-damag-ing agents, including PL-DOX.

In the present retrospective cohort study, Adams et al compared response rates and PFS and OS among patients with BRCA-associated and sporadic EOC (23 and 41 patients, respectively) who

were treated with PL-DOX. The majority of patients were platinum-resistant prior to starting PL-DOX (74% of BRCA-asso-ciated cases and 83% of sporadic cases).

The investigators noted a significant-ly improved response to PL-DOX in patients with BRCA mutations compared with patients with nonhereditary cancers: 56.5% versus 19.5%, respectively. This was associated with improved PFS (27 vs. 17 weeks) and OS (89 vs. 48 weeks) for patients with BRCA mutations. Response rates to PL-DOX for patients with wild-type BRCA were consistent with previ-ously reported rates. These findings are important and indicate that PL-DOX may prolong PFS and OS in patients with

BRCA-associated EOC.As noted by the authors, the study

has limitations that include small sample size and retrospective design. Recently, another retrospective study by Safra et al1 (Mol Cancer Ther2011;10:2000-2007; PMID: 21835933) showed longer median time to failure, OS and response rate for patients with EOC and BRCA mutations treated with PL-DOX compared with patients with wild-type BRCA. Results of an ongoing prospective Phase II study comparing PL-DOX with poly(ADP)ribose inhibitors will further eluci-date the role of PL-DOX in treatment of BRCA-associated EOC.

From�The Lancet

The mammalian target of rapamy-cin (mTOR) inhibitor everolimus

(Afinitor, Novartis), administered in combination with octreotide long-acting repeatable (Sandostatin, Novartis), has been found to improve progression-free survival (PFS) in patients with advanced neuroendocrine tumors associated with carcinoid syndrome.

The randomized, placebo-controlled RADIANT-2 trial, published in the December 10, 2011, issue of the jour-nal Lancet (2011;378:2005-2012; PMID: 22119496), compared a regimen of everolimus at a dose of 10 mg per day plus 30 mg intramuscular octreotide long-acting repeatable (LAR) every 28

days to placebo plus 30 mg intramuscu-lar octreotide LAR every 28 days in 429 adult patients with low- or intermediate-grade advanced neuroendocrine tumors (i.e., unresectable locally advanced or distant metastatic), and disease progres-sion established by radiological assess-ment within the past 12 months. PFS was the primary end point. This Phase III study was performed by an interna-tional team of researchers and funded by Novartis, which manufactures both the study drug and octreotide LAR.

Median follow-up was 28 months and median duration of treatment was 37 months in the everolimus group and 36.6 months in the placebo group. According to the authors, 140 patients in the evero-limus group (65%) and 74 in the placebo

group (35%) required dose reductions or temporary interruptions.

In the final analysis, median PFS was 16.4 months in the everolimus group compared with 11.3 months in the pla-cebo group (P=0.026). Reported drug-related adverse events (AEs) were most-ly grade 1 or 2; however, there were significantly more incidents of AEs such as stomatitis, rash, fatigue and diarrhea in the study drug group compared with placebo. The most common grade 3 or 4 drug-related AEs during the trial were stomatitis, fatigue, diarrhea, hypergly-cemia, thrombocytopenia and infec-tion. Additionally, 18 incidents of pneu-monitis in the everolimus group were reported; however, there were none in the placebo group. The authors note

that there were imbalances in baseline demographic and disease characteristics favoring the placebo group, such as the lung being the primary tumor site.

The authors write that their results, coupled with the findings of the recent-ly completed RADIANT-3 trial, “sup-port the efficacy of everolimus in a broad spectrum of advanced neuroen-docrine tumors.” They add that, given the clinical challenges posed by neuro-endocrine tumors and the lack of via-ble therapeutic options available, their results potentially position everolim-us as an important addition to the treat-ment armamentarium, although they acknowledge that further study of the drug’s safety and efficacy in this patient population is necessary.

Everolimus Plus Octreotide LAR Combo Ups Neuroendocrine PFS

From�Gynecologic Oncology

Cytoxic therapy with pegylated liposomal doxorubicin (PL-DOX;

Doxil, Janssen) may be more effec-tive in the treatment of women with BRCA-associated recurrent epithelial ovarian cancer (EOC) than in those with a “sporadic” form of the disease, a new study has found.

Published in the December 2011 issue of the journal Gynecologic Oncology (2011;123:486-491; PMID: 21945552), the study of 64 patients was designed to compare the response rate, progression-free survival (PFS) and overall survival (OS) among women with either sporad-ic ovarian cancer or ovarian cancer asso-ciated with mutations of the BRCA1 or BRCA2 genes. Patient data for the ret-rospective cohort study was obtained

from a pharmacy data-base at the University of Pennsylvania Hos-pitals. Most of the patients included in the study were treated with PL-DOX between 2001 and 2007 at the hos-pitals’ Division of Gynecologic Oncolo-gy. Their genetic informa-tion was cross-referenced against data from the Cancer Genetics Program at the Abramson Cancer Center. Addi-tionally, patients at two affiliated cen-ters—the Fox Chase Cancer Center and Cedars-Sinai Medical Center—who had undergone BRCA testing and been diag-nosed with ovarian cancer were includ-ed in the study.

In all, 23 women with EOC and BRCA1 or BRCA2 gene

mutations who received therapy with PL-DOX were identified and were compared with 41 patients with sporad-ic disease. Of this latter

group, 31 had no personal or family history of hered-

itary cancers and 10 had no documented BRCA gene muta-

tions following genetic testing.The researchers found that 56.5%

of the patients with BRCA gene muta-tions responded to treatment with PL-DOX, compared with only 19.5% among those with sporadic dis-ease (P=0.004). Median PFS with PL-DOX (from the date of the first cycle) among those with BRCA gene

mutations was 27.1 weeks; it was 17 weeks among women with sporad-ic disease (P=0.109). Finally, median OS (for the date of the first cycle) was 89.1 weeks among women with BRCA-associated ovarian cancer treated with PL-DOX and 48.3 weeks among those with sporadic disease who underwent the same treatment (P=0.002). Inter-estingly, the patients with BRCA-asso-ciated disease included in the anal-ysis had received more chemothera-py cycles prior to starting treatment with PL-DOX than those with sporad-ic cancer (mean number of cycles was 3.4 and 2.3, respectively).

While noting the small sample size and retrospective design, the authors conclude that their findings “support a wider role” for PL-DOX in the treat-ment of advanced ovarian cancer.

Pegylated Doxorubicin Aids Survival in Recurrent Ovarian Cancer

Danijela Jelovac, MDAssistant Professor of OncologyJohns Hopkins University School of MedicineSidney Kimmel Comprehensive Cancer Center at Johns Hopkins

EXPERT INSIGHT


Neuroendocrine

Ovarian

In patients with advanced and met-astatic kidney cancer, the tyrosine

kinase inhibitor (TKI) axitinib shows a significant improvement in median PFS in second-line therapy when compared with the older-generation TKI sorafenib (6.7 vs. 4.7 months; hazard ratio, 0.665). This is notable because this is the first trial directly comparing a new agent with another active, targeted agent, rather than using placebo.

The results also support the hypoth-esis that more potent inhibition of the VEGF pathway can result in a supe-rior clinical benefit. However, the

difference in PFS is more modest than most of us would have hoped for. Although a preplanned subgroup anal-ysis showed a significant superiority of axitinib over sorafenib in both pre-vious sunitinib and previous cytokine treatment subgroups, the difference in PFS for the population pretreated with the TKI was less than the overall differ-ence in PFS. Patients pretreated with cytokines had a PFS of 12.1 months (6.5 months on sorafenib) and patients pre-treated with sunitinib had a PFS of 4.8

months (3.4 months on sorafenib).Since the standard of care for first-

line treatment of advanced kidney carcinoma in 2012 is TKIs such as sunitinib and pazopanib, the data most pertinent to current clinical practice is indeed the additional 1.4 months in PFS for patients treated with axitinib. While this trial consti-tutes a new benchmark for the devel-opment of other agents, this gain is rather modest and should encourage further clinical investigations.

The RADIANT-2 study demon-strated that adding everolimus

to octreotide LAR improves PFS by 5.1 months, compared with octreo-tide LAR alone, in patients with pro-gressive advanced neuroendocrine tumors (NETs) and a history of car-cinoid syndrome. Everolimus is an mTOR inhibitor that already has been approved by the FDA for the treatment of advanced renal cell car-cinoma. After the RADIANT-3 study showed improved PFS with evero-limus in patients with NETs from a pancreatic origin, in May 2011, it also was approved for the treatment of

advanced pancreatic neuroendocrine tumors (pNETs).

The RADIANT-2 and RADIANT-3 studies were similarly designed. Patients in both studies had low-grade or inter-mediate-grade NETs and must have had progressive disease before study enroll-ment. PFS was the primary end point for both studies. Both studies showed everolimus improves PFS. RADIANT-3 met the primary end point, but RADI-ANT-2 (hazard ratio, 0.77; P=0.026) fell just short of the prespecified boundary of statistical significance (P=0.0246).

The patient population in RADIANT-3 was individuals with pNETs exclusive-ly, but the patient population in RADI-ANT-2 includes those primarily with non-pancreatic, gastrointestinal NETs and a history of carcinoid syndrome. The latter was historically referred to as carcinoid tumor. In the RADIANT-2 study, 5% and 7% of patients in each treatment group, respectively, had NETs from a pancreatic origin. pNETs and carcinoid tumors share similar patho-biologic features. The mTOR pathway is aberrantly activated in both types of

NETs. The RADIANT-2 study, howev-er, did not meet the primary end point. This could be explained by imbalanc-es between the two treatment groups in baseline factors, including primary tumor site, World Health Organization performance status and previous use of chemotherapy. Therefore, the study team is proposing to confirm the bene-fit of everolimus on PFS in non-pancre-atic NETs in a future study with a bet-ter design. When such a new study is designed, radiological challenges that were faced by both the RADIANT-2 and -3 studies associated with the assess-ment of advanced NETs and the clini-cal diversity of the patient population seen in RADIANT-2 may also need to be addressed.

Everolimus offers limited objective tumor response in both pNET and car-cinoid tumors, according to both RADI-ANT studies. Disease stabilization appears to contribute to the benefit of everolimus on PFS. Neither RADIANT study supported the benefit of everoli-mus on overall survival, possibly due to the crossover design. Considering the

slow progressive nature of low- or intermediate-grade NETs, one should carefully choose the timing of initi-ating the everolimus treatment. It is generally recommended to wait until there is evidence of recent disease progression before starting evero-limus or sunitinib, which was also recently approved for the treatment of advanced pNET.

Carcinoid has a much higher preva-lence than we had thought in the past. There is definitely an unmet need for effective treatments for this disease. With its associated secretory symp-toms, carcinoid is particularly a chal-lenge for management. The results of the RADIANT-2 study showing a sig-nificant reduction in circulating hor-monal products of carcinoid tumor cells in patients in the everolimus group are encouraging. The potential role of everolimus itself or in combi-nation with local therapies such as chemo- or radioembolization on the symptomatic management of carci-noid syndrome deserves our atten-tion in future studies.

From�The Lancet

The targeted agent axitinib (Inlyta, Pfizer) has demonstrated superior

efficacy to sorafenib (Nexavar, Bayer/Onyx) in the first published Phase III trial to compare two inhibitors of the vascular endothelial growth factor receptor (VEGFR) for second-line ther-apy in the treatment of advanced meta-static renal clear cell carcinoma.

Results of the international, mul-ticenter trial were published in the December 3 issue of the journal Lancet (2011;378:1931-1939; PMID: 22056247). The project was funded by Pfizer, which manufactures axitinib. Progres-sion-free survival (PFS; assessed by a masked independent radiology review

and analyzed by intention-to-treat) was the primary end point. The tri-al was designed to compare the agent against what was considered standard of care at the time research began; the mTOR inhibitor everolimus (Afini-tor, Novartis) has since received FDA approval for the treatment of renal cell carcinoma after failure with sunitinib (Sutent, Pfizer) or sorafenib.

Researchers enrolled 723 adult patients from 175 centers in 22 coun-tries. All the enrolled participants had been diagnosed with progressive met-astatic disease despite first-line thera-py consisting of sunitinib, bevacizum-ab (Avastin, Genentech) plus interfer-on-alfa, temsirolimus (Torisel, Pfizer) or cytokines. Patients were stratified

according to Eastern Cooperative Oncology Group performance sta-tus and type of previous treatment, and randomized (on a 1-to-1 ratio) to receive either axitinib 5 mg twice dai-ly or sorafenib 400 mg twice daily. Patients without hypertension or seri-ous adverse events (AEs; ≥grade 2) were allowed to receive higher doses of the study drug—first to 7 mg twice dai-ly and then to 10 mg twice daily.

Median PFS among the 361 patients given axitinib was 6.7 months compared with 4.7 months for the 362 patients who received sorafenib (P<0.0001). Among patients who received cyto-kines, these figures were considerably higher (12.1 and 6.5 months, respec-tively). In all, 4% of the patients in

the axitinib group discontinued ther-apy due to AEs, the most common of which were diarrhea, hypertension and fatigue. In the sorafenib group, 8% of the patients discontinued treatment as a result of AEs such as diarrhea, pal-mar-plantar erythrodysesthesia and alopecia. Although these differences are significant, the authors acknowl-edge that the open-label design of the study could result in bias in the assess-ment of toxic effects. The authors also note that overall survival figures will be provided separately when data mature.

Axitinib is a more potent inhibitor of VEGFR than is sorafenib and these results, according to the authors, “sup-port the hypothesis” that this “produces a more robust clinical effect.”

In Study of Clear Cell Carcinoma, Axitinib Edges Sorafenib

Hans Hammers, MD, PhDAssistant Professor of OncologyJohns Hopkins University School of MedicineSidney Kimmel Comprehensive Cancer Center at Johns Hopkins

EXPERT INSIGHT

Lei Zheng, MDAssistant Professor of Oncology and SurgeryJohns Hopkins University School of MedicineSidney Kimmel Comprehensive Cancer Center at Johns Hopkins

EXPERT INSIGHT

Neuroendocrine


Kidney

ER expression is more predictive of a favorable long-term prognosis than tumor shrinkage. This testing is sim-ple, easy to perform and relatively inex-pensive. It would not interfere with the usual course of needle biopsy for diag-nosis followed by surgical excision of the cancerous mass and sentinel node identification and excision a few weeks later. Giving two weeks of hormone therapy with tamoxifen or an aroma-tase inhibitor (AI) is both easy and safe.

In reviewing the literature behind this concept, limitations of all the stud-ies emerge. Rather than dwell only on induction hormone therapy, I offer a useful perspective on the range of pre-dictive and prognostic tests for ER–pos-itive breast cancer available in 2012. There is no optimal test to decide which women have such a good prognosis that they do not need chemotherapy, nor to discover characteristics that assure their physicians that chemotherapy would be of no value. Instead, there is a range of available tests in varying stages of devel-opment, each with somewhat limited supporting data. It pays to review the advantages and disadvantages of each test, as well as the shortcomings of the data underpinning each one.

PEPI Score—Prognostic

At SABCS, Matthew Ellis, MB, PhD, director of the Breast Cancer Program at Washington University School of Medi-cine in St. Louis, discussed an index he developed called the preoperative endo-crine prognostic index (PEPI). This test evolved from a randomized preoperative study (P024 Trial) of 16 weeks of tamox-ifen versus letrozole (Femara, Novartis Oncology) for women with stage II or III breast cancer.1 Of the 337 women in the study, only 158 could be fully profiled to develop the PEPI. Median follow-up was 62 months, a short time period for ER–positive breast cancer.

Prognosis worsens with a higher score on the PEPI. The points accrue

according to Table 1 and are added to estimate prognosis according to Table 2.

Failure to achieve a low Ki67 score and loss of ER were bad prognostic signs. In contrast, there were no relapses and only one death among 28 women with pT1N0 tumors. Clinical response and post-treat-ment tumor grade were prognostic in univariate analysis but fell out as non-significant in multivariate analysis.

The loss of ER expression dur-ing neoadjuvant therapy noted in the

PEPI analysis is a reproducible phe-nomenon—it was seen in 6.7% of wom-en in an American College of Surgeons Oncology Group (ACOSOG) trial of four months of preoperative AI therapy.2,3

In the IMPACT (Immediate Preoper-ative Anastrozole Tamoxifen or Com-bined with Tamoxifen) trial of 12 weeks of neoadjuvant tamoxifen versus anas-trozole, total loss of ER expression dur-ing anastrozole therapy was not seen, and only three of 54 tamoxifen-treated patients had even transient loss of ER staining.4 However, in IMPACT, a drop in ER level was deleterious in terms of overall recurrence rate.5

Issues that will need to be formal-ly addressed before reduction or loss in ER expression can be used reliably for prognostication and choice of therapy include the following: • How to reliably identify and quan-

tify reduction and loss of ER expres-sion (including initial false-positives, intra-tumoral heterogeneity, the use of different antibodies in different lab-oratories and perhaps in the same lab-oratory at different times).

• Knowledge of proper specimen handling.

• Analysis of cores for the initial mea-surement and larger tumor masses for the second measurement.

• Determining variable lengths of induc-tion hormone therapy.

• Setting cut points for ER positivity and degree of ER loss. Reproducibility of the Allred score

measuring in a continuous scale both the frequency and intensity of ER staining also is limited. In ACOSOG Z1031, entry was restricted to women with tumoral Allred scores of 6 to 8. On central testing, 20.3% had scores of 5 or lower and 2% were ER–negative with scores of 0 or 2.6

The PEPI model proved valid in an independent, 203-patient cohort in the IMPACT trial of neoadjuvant tamoxi-fen versus anastrozole, with no relaps-es for p-stage 0 to 1 patients with a PEPI score of 0.

Limitations of the PEPI Score

1. The PEPI score is based on a small number of patients in both development and validation sets. This led to lump-ing all node-positive patients together, rather than dividing them by numbers of involved nodes, and using tumor size as a discontinuous variable rather than a continuous one.

2. All patients in the development set had relatively advanced tumors; there-fore, the score is not readily applicable to women with node-negative tumors less than 2 cm in diameter. Although loss of ER and high levels of Ki67 may prove neg-atively prognostic in women with smaller tumors, the weight of these factors may change, and tumor size may prove more important.

3. The development set had only about 50% of the patients entered in the study, and biases that the exclusions introduce cannot be estimated.

4. Also, 63 of 205 patients in the PEPI data set with full clinical information at diagnosis had chemotherapy, which was much more common in women with larger tumors at excision. Although this had little influence on the prognosis of the better-risk tumors, the numbers are far too small to correct for whatever effect this chemotherapy had on the out-come of the poorer-risk patients; and the chemotherapy regimen used, as well as its quality—dose, density and duration—were not analyzed.

5. Preoperative hormone therapy may affect the Oncotype DX recurrence score (RS) determined at surgery. Many phy-sicians rely on the Oncotype DX per-formed prior to treatment to decide whether or not to give chemothera-py to women with negative nodes. The

expected drop in proliferation from pre-operative hormone therapy could lead either to a drop in RS reflecting true improvement in distant relapse–free survival (DRFS), or a drop in RS reflect-ing decrease in proliferation with no change in outcome years later. Mitch-ell Dowsett, PhD, head of Breast Can-cer Translational Research at the Royal Marsden Hospital and Institute of Can-cer Research in London, pointed out that AIs reduce progesterone receptor (PgR) in most but not all patients. A low PgR after AI treatment in a patient who ini-tially had a high PgR is a good sign, but remains negatively prognostic in wom-en whose tumors started with low PgR levels.7 Tamoxifen, in contrast, increas-es PgR in most patients and this increase is associated with a favorable prognosis.8

Interpretation of the 16 mRNA levels that make up the Oncotype DX after induc-tion hormone therapy thus depends on the initial level of proliferation, the ini-tial PgR mRNA level and which hormone is administered in the interval. Thus, the RS calculation is valid only on samples taken before therapy.

6. A Japanese study, presented as a poster at the 2011 American Society of Clinical Oncology meeting, reported early outcomes among 52 women giv-en neoadjuvant exemestane who had their RS determined at diagnosis and again at resection 24 weeks later.9 Clini-cal response was greater if the initial RS was low. No data on the effect of exemes-tane on the RS and its individual compo-nents (ER, PgR, proliferation and HER2) were given in the poster. It will be inter-esting to see if this study using Oncotype DX confirms the prior observations. The number of women in this trial likely will prove too small to demonstrate wheth-er changes in proliferation, ESR1 mRNA and PgR mRNA have the prognostic implications we expect.

Day 14 Ki67 Expression Prognostic in the IMPACT Trial

The IMPACT trial of neoadjuvant anastrozole versus tamoxifen versus a combination of both had 260 evaluable patients, 159 of whom had paired biopsy specimens available.10 In this trial, Ki67 expression after 14 days was much more prognostic of RFS than Ki67 at diagno-sis. Those patients in the highest third of Ki67 expression had an estimated five-year RFS of 60% compared with 75% for the middle third and 85% for the lowest tertile.

Table 1. PEPI Score Based on 158 Patients

Patients (n) Adverse Points

Pathologic�stage�(p-stage)�T3�or�T4 33 3

Positive�nodes�on�path�exam 90 3

Allred�score�0-2�at�resection 16 3

Ki67�staining�at�resection�<2.8% 0

� 2.8%-7.3% 1

� 7.4%-19.7% 2

� >19.7% 3

PEPI, preoperative endocrine prognostic index

Table 2. PEPI Score And Five-Year Prognosis

PEPI Score

Relapse, %

Breast Cancer Death Rate, %

0 10 2

1-3 23 11

>3 48 17

PEPI,�preoperative�endocrine�prognostic�index

PROGNOSTICATIONcontinued from page 1

Steven Vogl, MDMedical Oncologist,new�york City

EDITORIAL BOARD COMMENTARY


Breast

In multivariate analysis, baseline tumor size and two-week level of ER also were important in predicting RFS. Again, T1 tumors with low Ki67, pre-served ER expression and negative nodes had no relapses.

Limitations of this analysis include the following:

1. The analysis was based on a small number of patients, and again, not all patients had enough information for analysis.

2. The report had a short median fol-low-up of only 37 months with a short-er 30-month median duration of therapy, suggesting high rates of noncompliance with adjuvant endocrine therapy. This is very short follow-up for an ER-positive population.

3. The argument that low Ki67 expres-sion at two weeks is always favorable is undermined by the later observation in the same group that 16 of the 95 tumors that dropped their Ki67 by at least 50% within two weeks increased it again by 12 weeks, and this increase was asso-ciated with a poor prognosis—about 40% RFS at five years, the same as that of women whose tumors did not drop their Ki67 at two weeks.11

IHC4 as Prognostic Index

The same group used data from the ATAC (Arimidex, Tamoxifen Alone or in Combination) study to devel-op a simple and cheap prognostic test for ER-positive breast cancer called the IHC4 (four immunohistochemical markers), which proved equally prog-nostic in the hormone-treated popula-tion as the much more expensive Onco-type DX.12 The IHC4 prognostic index uses the sum of weighted semiquanti-tative estimates of ER and PgR, HER2 and Ki67, to which may be added a clin-ical score incorporating primary tumor size, number of involved nodes, grade and age of patient that further improves the prognostic power of the index. With or without the clinical information, the IHC4 seemed equal in prognostic pow-er to the Oncotype DX RS (recurrence score). The latter also proved stronger when clinical data were included.13 The IHC4 was validated in a separate cohort from Nottingham, England, which used a different measure of proliferation based on levels of staining with MIB1 monoclonal antibody that had to be converted to Ki67 equivalents.

Limitations of the studies of the IHC4 include the following:

1. The development set of 1,125 is only about 20% of the entire TransATAC population of 5,580 women. Although the general conclusions on prognosis will probably stand, one wonders if the likely preferential exclusion of patients from lower-quality centers—those with poorer patients and lower-quality sur-geons and pathology departments—might change the quantitative estimates

of prognosis to some degree.2. The inclusion of HER2-positive

tumors is probably no longer appropri-ate—all of us now consider these sepa-rately. The relevant model would then be an IHC3 using only ER, PgR and HER2 IHC. Apparently this is achieved by inputting “0” for HER2 into the IHC4.

3. The use of two weeks of neoadju-vant hormone therapy followed by ER and Ki67 measurement would allow the use of the more prognostic two-week Ki67. This clearly would require another large development set followed by inde-pendent validation. The resulting index

could be called IHC3’ and might contain some measure of the change in Ki67 as well as the second Ki67 determination. In the 158-patient analysis of impact, how-ever, the two-week level of Ki67 expres-sion was the best metric for prognosis.14

4. The calculation of the IHC4, IHC3 and RS plus age, grade and tumor size (RSPC) are beyond the abilities of all but the most mathematical oncologist—we need either a complicated nomogram to allow the rest of us to calculate each of them or a Web-based calculator. Genom-ic Health, which reports the RS, is now planning a Web-based calculator for

the RSPC. No calculator is available for IHC3 or IHC4.15

5. The Ki67 measurement is not stan-dardized and is not clearly reproduc-ible from one lab to another. Experts in the field recently addressed this issue, as well as those of specimen handling and scoring, and note the lack of agreement on cut points for favorable and unfavor-able levels.16 One could make similar arguments for the now widely used ER and PgR values. That we have accept-ed poor reproducibility and large tech-nique variations for hormone receptor

see PROGNOSTICATION, page 14

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measurements does not solve the prob-lems with Ki67, however.

Oncotype DX Recurrence Score

The Oncotype DX was developed as a unique prognostic tool for women with node-negative, ER-positive tumors treated with tamoxifen that could be determined on formalin-fixed, paraffin-embedded tumor tissue. It began with the selection of 250 candidate genes from the literature, as well as labora-tory studies that test designers thought might be important for tamoxifen-treated women with breast cancer. Lev-els of mRNA for these genes were mea-sured in 447 tumors from three studies of tamoxifen-alone adjuvant therapy—including some women from the NSABP (National Surgical Adjuvant Breast and Bowel Project) B20 trial where anoth-er group was randomized to tamoxi-fen plus chemotherapy—to determine each gene’s effect on distant relapse at 10 years from diagnosis. Based not only on the predictive power of each gene for distant relapse, but also on repro-ducibility in all three studies and also on consistency of primer and probe performance in the lab, 16 genes in five groups were selected for inclusion in the test and their expression compared with five reference genes that are not prognostic and do not figure into the final calculation except as reference points. This is really a 16-gene test and two of the genes included refer main-ly to HER2-overexpressing tumors. Thus, for most of our patients, this is a 14-gene test. The observed mRNA lev-els are combined through a very com-plicated, weighted calculation into a single RS that ranges from 0 to 100. Blocks with interpretable mRNA levels were available for 668 tamoxifen-treat-ed patients in NSABP B14 from the fol-lowing two populations: 1,450 random-ized to tamoxifen versus observation and another 1,235 assigned to tamoxifen without randomization. These patients were the basis of the first Oncotype DX paper.17 The initial argument was that the 93% DRFS of the low-risk patients

was so high that adjuvant chemothera-py was unnecessary.

Although the Oncotype DX RS was designed to be prognostic in a tamox-ifen-treated population, the outcomes measured were determined both by the intrinsic characteristics of the tumor—prognosis of untreated patients—as well as by the ability of tamoxifen to improve or not to improve the outcomes. When the Oncotype DX RS was determined in NSABP B14 among node-negative women randomized to observation compared with those randomized to tamoxifen, these two effects could be separated (Table 3).18

First Look: Tamoxifen Benefits Only Low- And Intermediate-risk Oncotype DX Patients

As is clear from Table 1, the relative benefit of tamoxifen in the low-risk group is 51%, about the same as the 46% relative benefit in the intermediate-risk group. The absolute benefit is much higher for intermediate-risk patients because their risk of distant relapse if untreated is much higher. One could argue that tamoxifen has no benefit in the high-risk group, although the num-bers are relatively small to be able to say this with great confidence.

Lack of Tamoxifen Benefit Best Predicted by Low ESR1 mRNA Levels

A careful reanalysis of this data has just been published in which levels of ESR1 mRNA—one of the four ER-relat-ed genes measured in the Oncotype DX RS—are better in terms of statis-tical power than the total RS for dis-criminating women who benefit from tamoxifen treatment from those who do not.19 The lowest tertile of tumors for ESR1 mRNA levels had a slightly high-er 10-year distant recurrence rate with tamoxifen than with no adjuvant hor-mone therapy. ESR1 mRNA was a far superior determinant of tamoxifen effi-cacy than ER protein by ligand-binding assay. ESR1 mRNA was not a very good prognostic test, however; 10-year DRFS was about 80% in all three tertiles of ESR1 mRNA level.

Based on Dr. Dowsett’s analysis of the Oncotype DX RS in the ATAC tri-al, it seems likely that the same group of women with a high RS and low ESR1 mRNA levels do not fare much better on anastrozole than on tamoxifen. There are two urgent clinical research tasks: confirming that tamoxifen and AIs do not benefit these women with detect-able ER protein but low levels of ESR1 mRNA, and searching for treatments—hormonal, chemotherapeutic or “tar-geted”—that do benefit them.

Oncotype DX Recurrence Score And Chemotherapy Benefit

In this regard, the Oncotype DX test was applied to NSABP B20, in which women were randomized to tamoxifen or tamoxifen started with six months of cyclophosphamide, methotrexate and fluorouracil (5-FU; CMF) chemothera-py. Obvious chemotherapy benefit was restricted to the high-RS patients (a 74% relative decrease in 10-year rate of dis-tant recurrence), although the number of events was too small in the interme-diate- and low-risk groups in my opin-ion to exclude a modest absolute benefit in 10-year DRFS.20 Women with a high RS are a substantially different popula-tion from those with low levels of ESR1 mRNA, who benefit little or not at all from tamoxifen, although they do over-lap to some extent.

One could argue that Oncotype DX “low-risk” women who are node-neg-ative have such a good prognosis that chemotherapy should be avoided. In an analysis of the Oncotype DX test in 872 node-negative and 306 node-posi-tive patients enrolled in the ATAC trial, the nine-year distant recurrence rates—not the same as DRFS—was only 4% for the node-negative women, leaving little room for improvement. In contrast, the nine-year distant relapse rate was 17% for the node-positive women, leaving considerable room for improvement. Some women will be satisfied with only a 4% distant relapse rate; others might want to aggressively try to improve on it. I will be more comfortable having this discussion with my patients when we have more information on a larger number of low- and intermediate-risk patients randomized to chemotherapy or none in TAILOR-Rx (Trial Assign-ing IndividuaLized Options for Treat-ment [Rx]).

The Oncotype DX is the only tech-nique that used randomized prospective trials of treatment versus no treatment to look at the predictive value for ben-efit of hormone therapy or chemother-apy added to hormone therapy, as well as prognosis. This is a major achieve-ment. Other advantages: results usually are available within one week of speci-men submission and the test is done in a single lab with very high levels of quali-ty control. Expert and articulate lab staff also are available to help with interpre-tation of the results.

Limitations of the Oncotype DX As a Predictor of Chemotherapy Benefit

There are several limitations of the Oncotype DX when used to predict the effect of chemotherapy:

1. All the data analyzed are based on a portion of the patients entered in each randomized trial. Although the charac-teristics of the tested patients were sim-ilar to those of patients across the entire

trial, one cannot be certain that the tumors with blocks available that had good mRNA were fair representatives of the entire population. These exclusions could change the extent of benefit from adding chemotherapy to tamoxifen.

2. The genes chosen for the Oncotype DX were selected from a limited pool after thoughtful consideration, rather than a formal and reproducible selec-tion process. There is no data to show that these are the best genes, although they are clearly useful.

3. The weights used to calculate RS were optimized for prognosis on tamoxi-fen and clearly are not very good for pre-dicting prognosis without hormone ther-apy (Table 3). Intelligent design would consider looking at expression of differ-ent genes to examine the likelihood of chemotherapy benefit, including chemo-therapy targets, proteins for DNA repair like PARP and ERCC1, target enzymes like thymidylate synthetase, topoisomer-ase II, dihydrofolate reductase and levels of drug efflux pumps like ATP-binding cassettes. Even if all 14 genes relevant to HER2-negative tumors in the Onco-type DX do have some value for predict-ing sensitivity to chemotherapy, it seems unlikely that their weights would be the same as the weights for predicting prog-nosis with tamoxifen without chemo-therapy. Sensitivity, or lack thereof, to chemotherapy is an important issue that deserves specially designed tools that are distinct from tools to measure prog-nosis on hormone therapy. Soonmyong Paik, MD, NSABP’s pathology director, on the other hand, points out that such reasoned approaches to predicting che-motherapy sensitivity have been tried in multiple human tumor systems and largely failed, whereas the Oncotype DX seems to work, and the Oncotype DX was developed in the hope that it would predict chemotherapy sensitivity.

4. Using the Oncotype DX to predict the benefit of chemotherapy for women with node-positive tumors is based on tiny amounts of data with very wide con-fidence limits. A study by Kathy Albain, MD, of Loyola University in Maywood, Ill., identified no truly low-risk group of women.21 Some argue that breast can-cer–specific survival was very high in the “low-risk” population and lower for those who had CAF (cyclophospha-mide, adriamycin, 5-FU) chemotherapy in addition to tamoxifen. It is not clear from the paper how much care went into defining a breast cancer death, and the number of patients with recurring disease and dying remains small, with large and overlapping confidence lim-its. There is no doubt that the Oncotype DX can offer prognostic information in node-positive patients.21,22 In 2012, it is still not clear how to use this informa-tion. Other trials suggest that a low-risk group of women does exist, because the prognosis of ER-positive women with

PROGNOSTICATIONcontinued from page 13

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Do�you�have�thoughts�on��Dr.�Vogl’s�commentary?

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Breast

one to three positive nodes within the past 15 years has been very good when treated with doxorubicin and cyclophos-phamide (AC), doxorubicin and pacli-taxel or docetaxel (AT), or docetaxel and cyclophosphamide (TC), with esti-mated five-year distant relapse rates of less than 10%.

5. The inclusion of HER2-positive patients in these studies and HER2 genes in the RS is probably not needed and perhaps misleading, although some argue that low-level HER2 expression may be prognostic even in non-ampli-fied tumor patients. This has not been tested. In 2012, most experts agree that the Oncotype DX should not be used in HER2-positive tumors. I believe we need a recurrence score for small HER2-positive tumors to decide which women need adjuvant systemic treatment and which of these treatments they need. This is an unmet need. Although this prognostic index would be important, the studies to create it will prove dif-ficult because (a) only 20% of breast cancers are HER2-positive, (b) many physicians have made up their minds, (c) many patients have made up their minds and (d) treatments are likely to keep changing with the availability of dual HER2 blockade with trastuzumab and pertuzumab.

6. Data already have been published showing that adding clinical information to mRNA levels improves the prognostic power of the RS score. Genomic Health has not yet made available this calcula-tor in print or online, although it plans to do so.

7. The Oncotype DX offers no infor-mation on which hormone therapy or which chemotherapy to use—it was not designed or tested for either purpose.

8. Because it is a patented test done in a single lab, it also is quite expensive.

PAM50 May Be Superior To Oncotype DX as a Prognosticator

Two larger tests based on tumor tis-sue mRNA levels are available commer-cially in the United States—the Mam-maPrint using 70 genes and the PAM50 using 50 genes. Each test can be done on formalin-fixed, paraffin-embedded tumor tissue. The PAM50 (PAM stands for prediction analysis of microarray, a mathematical means of fitting the result into predetermined categories such as luminal A and luminal B) is prognostic in ER-positive tumors.23

Dr. Dowsett determined both Oncotype DX RS and PAM50 risk of relapse (ROR) scores based on mRNA extracted from 1,007 women in the TransATAC popula-tion and compared both prognostic mod-els with an end point of 10-year DRFS.24 The PAM50 seemed more informative not because it identified more patients as lower risk (an equal percentage of low-risk patients was identified and did well

with either test), but because it moved some of the intermediate-risk patients from the Oncotype DX analysis into the high-risk group, where apparently they belonged. In Dr. Dowsett’s analysis, very little prognostic information was added to clinical parameters and PAM50 results by then using the Oncotype DX RS. In contrast, the PAM50 ROR added substan-tially to clinical parameters and the Onco-type DX RS measurement.

Recently published data suggest that PAM50’s determination that a cancer is of the luminal A or basal-like subtype predicts no benefit for giving adjuvant epirubicin compared with methotrex-ate.25 Whether PAM50 will be superi-or to the Oncotype DX for identifying groups more or less likely to benefit from adjuvant chemotherapy—a separate pre-dictive effect—is not yet clear.

What To Do in 2012

For women with smaller, clinically node-negative, HER2-negative tumors, in whom I think it may be reasonable to avoid chemotherapy, I start the appropri-ate hormone once the ER is shown pos-itive on needle biopsy. I measure Ki67 on the biopsy core and again at lumpec-tomy or mastectomy. If the ER staining stays positive and high, if Ki67 falls, if the final pathologic characteristics are not ominous and if HER2 is non-amplified, I comfortably recommend hormone ther-apy only without expensive tests of RNA levels. Once a calculator based on semi-quantitative IHC expression of Ki67, ER and PgR is available, I will then calculate IHC3 and IHC3' as an adjunct to the fall in Ki67 and use this as well. I would be most comfortable if data were available for the prognostic value of an IHC3' that incorpo-rates changes in Ki67 at two to four weeks, the usual interval between core biopsy and total excision of the primary.

For women who do not clearly have what the patient and I consider a very good prognosis after these IHC tests, I still would use the Oncotype DX—pref-erably on the initial biopsy until we have data on how to interpret a test done after a few weeks of hormonal intervention—to make sure I do not miss giving chemo-therapy to patients with high RS, and use the ESR1 mRNA level now reported as part of the test to decide how much reli-ance to place on adjuvant hormone ther-apy to prevent distant relapse and death.

References

1. Ellis MJ, Tao Y, Luo J, et al. Outcome pre-diction for estrogen receptor-positive breast cancer based on postneoadjuvant endo-crine therapy tumor characteristics. J Natl Cancer Inst. 2008;100:1380-1388, PMID: 18812550.

2. Ellis MJ. Personal communication.

3. Ellis MJ, Suman VJ, Hoog J, et al. Ran-domized phase II neoadjuvant compari-son between letrozole, anastrozole, and exemestane for postmenopausal wom-en with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker out-comes and predictive value of the baseline PAM50-based intrinsic subtype-ACOSOG Z1031. J Clin Oncol. 2011;29:2342-2349, PMID: 21555689.

4. Dowsett M, Ebbs SR, Dixon JM, et al. Bio-marker changes during neoadjuvant anas-trozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer--a study from the IMPACT trialists. J Clin Oncol. 2005;23:2477-2492, PMID: 15767642.

5. Dowsett M, Smith IE, Ebbs SR, et al. Prog-nostic value of Ki67 expression after short-term presurgical endocrine therapy for pri-mary breast cancer. J Natl Cancer Inst. 2007;99:167-170, PMID: 17228000.

6. Luo J. Personal communication.

7. Dowsett M, Ebbs SR, Dixon JM, et al. Bio-marker changes during neoadjuvant anas-trozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer--a study from the IMPACT trialists. J Clin Oncol. 2005;23:2477-2492, PMID: 15767642.

8. Dowsett M. Personal communication.

9. Masuda N, Toi M, UenoT, et al. A study of the recurrence score by the 21-gene signa-ture assay as a predictor of clinical response to neoadjuvant exemestane for 24 weeks in estrogen-receptor-positive breast cancer. J Clin Oncol. 2011:29(suppl; abstr 558).


11. Generali D, Symmans WF, Berruti A, Fox SB. Predictive immunohistochemical bio-markers in the context of neoadjuvant ther-apy for breast cancer. J Natl Cancer Inst Monogr. 2011;2011:99-102, PMID: 22043052.

12. Cuzick J, Dowsett M, Pineda S, et al. Prog-nostic value of a combined estrogen recep-tor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and compar-ison with the Genomic Health recurrence score in early breast cancer. J Clin Oncol. 2011;29:4273-4278, PMID: 21990413.

13. Tang G, Cuzick J, Costantino JP, et al. Risk of recurrence and chemotherapy bene-fit for patients with node-negative, estro-gen receptor-positive breast cancer: recur-rence score alone and integrated with

pathologic and clinical factors. J Clin Oncol. 2011;29:4365-4372, PMID: 22010013.


15. A’Hern R. Personal communication.

16. Dowsett M, Nielsen TO, A’Hern R, et al. Assessment of Ki67 in breast cancer: recom-mendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst. 2011;103:1656-1664, PMID: 21960707.

17. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817-2826, PMID: 15591335.

18. Paik S, Shak S, Tang G, et al. Expression of the 21 genes in the Recurrence Score assay and tamoxifen clinical benefit in the NSABP study B-14 of node negative, estrogen recep-tor positive breast cancer. J Clin Oncol. 2005;23, No. 16S, Part I of II (June 1 Supple-ment), 2005:510.

19. Kim C, Tang G, Pogue-Geile KL, Costantino JP, et al. Estrogen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estro-gen receptor-positive breast cancer. J Clin Oncol. 2011;29:4160-4167, PMID: 21947828.

20. Paik S, Tang G, Shak S, et al. Gene expres-sion and benefit of chemotherapy in wom-en with node-negative, estrogen recep-tor-positive breast cancer. J Clin Oncol. 2006;24:3726-3734, PMID: 16720680.

21. Albain KS, Barlow WE, Shak S, et al. Prog-nostic and predictive value of the 21-gene recurrence score assay in postmenopaus-al women with node-positive, oestrogen-receptor-positive breast cancer on che-motherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 2010;11:55-65, PMID: 20005174.

22. Goldstein LJ, Gray R, Badve S, et al. Prog-nostic utility of the 21-gene assay in hor-mone receptor-positive operable breast cancer compared with classical clinicopath-ologic features. J Clin Oncol. 2008;26:4063-4071, PMID: 18678838.

23. Parker JS, Mullins M, Cheang MC, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27:1160-1167, PMID: 19204204.

24. Dowsett M, Lopez-Knowles E, Sidhu K, et al. Comparison of PAM50 Risk of Recur-rence (ROR) score with OncotypeDx and IHC4 for predicting residual risk of RFS and Distant-(D)RFS after endocrine ther-apy: a TransATAC Study. Presented at the CTRC-AACR San Antonio Breast Can-cer Symposium; December 6-10, 2011; San Antonio, Texas. Abstract S4-5.

25. Cheang MC, Voduc KD, Tu D, et al. Respon-siveness of intrinsic subtypes to adjuvant anthracycline substitution in the NCIC.CTG MA.5 randomized trial. Clin Cancer Res. 2012 Feb 20. [Epub ahead of print], PMID: 22351696.

Table 3. NSABP B-14: 10-Year DRFS Results of 645 Randomized, Evaluable Patients Among 2,817 Entrants

10-Year DRFS

RS Patients (n)

Placebo, %

Tamoxifen for 5 y, %

Absolute Difference, % (P Value)

1-17 338 86 93 7�(P=0.04)

18-30 149 62 79 17�(P=0.02)

>30� 181 69 70 1

DRFS, distant�recurrence–free�survival;�RS,�recurrence�score

Dr. Vogl would welcome precisemodern data on the prognosis ofwomen with ER-positive, HER2-

negative tumors and 1-3 involvedaxillary nodes after treatment with

2-3 chemotherapy drugs and5 years of tamoxifen or an AI.

Please write to Clinical Oncology News managing editor Gabriel Miller

at [email protected] you have them.


Breast

Lapatinib and Trastuzumab Effective in HER2-Positive Breast Cancer

The management of HER2-posi-tive breast cancer has been revolu-tionized by the development of anti-HER2 therapies such as trastuzumab. A number of recent studies, including the Phase III NeoALTTO study pub-lished in the Lancet earlier this year, suggest that dual anti-HER2 therapy is

more efficacious than single anti-HER2 therapy. The primary end point of the NeoALTTO study was the rate of pCR obtained in each arm, with the trastu-zumab plus paclitaxel arm being com-pared formally with each investigational arm (trastuzumab, lapatinib plus pacli-taxel/lapatinib plus paclitaxel). The rate of pCR is a potential surrogate end point for survival that is commonly used in neoadjuvant studies. The high pCR rate obtained with paclitaxel plus dual anti-HER2 therapy of approximately 50% compares favorably with studies of combination chemotherapy and trastu-zumab alone. The overall pCR rate was higher in women with estrogen recep-tor (ER)–negative (61.3%) than ER-pos-itive (41.6%) disease, although whether pCR rate accurately predicts outcome

in women with ER-positive disease is debatable.

Although the therapy was relative-ly well tolerated, it must be noted that there was increased toxicity such as diar-rhea and liver enzyme alterations in the lapatinib arms. An amendment reducing the dose of lapatinib from 1,000 mg per day to 750 mg per day concurrent with paclitaxel in order to reduce the inci-dence of diarrhea was deemed neces-sary. In addition, the fact that only two-thirds of patients in the lapatinib arms were able to complete protocol therapy as planned is notable.

Clearly, dual anti-HER2 therapy appears to be associated with improved outcomes for breast cancer patients. Ide-ally, combinations of agents that min-imize toxicity alongside maximizing

efficacy will be most appealing in the clinic. Practitioners treating patients with lapatinib, as with any agent which targets the EGFR pathway, must be aggressive in their manage-ment of these side effects in order to minimize impact on patients’ safety and quality of life. Finally, it has been noted in recently presented neoadju-vant studies, such as the NeoSPHERE study, that a significant proportion of women treated with biologic thera-py alone (pertuzumab and trastuzum-ab in this case) can obtain a pCR; and this has caused great excitement in the breast oncology community. There is a clear need to determine who these patients are upfront as they could potentially be spared the added toxic-ity of chemotherapy.

From�Annals of Oncology

A recently completed Phase II trial has demonstrated the safety and

efficacy of sunitinib (Sutent, Pfizer) in patients with non–clear cell renal cell carcinoma (RCC). The results of the trial, which was led by a team of researchers from Seoul, South Korea, were published online in January by Annals of Oncol-ogy (2012 Jan 6. [Epub ahead of print], PMID: 22228449).

Sunitinib, a vascular endothelial growth factor (VEGF) pathway inhib-itor, has already received FDA approv-al for advanced or metastatic clear cell RCC, as well as other cancers. The Phase II prospective, multicenter trial

was designed to assess the drug’s viabil-ity for a new indication. Non–clear cell RCC is not the most common form of the disease; however, historically, it has been associated with the poorest treat-ment outcomes. Another VEGF path-way inhibitor, sorafenib (Nexavar, Bay-er/Onyx) also has demonstrated efficacy in the treatment of this challenging dis-ease during expanded-access trials.

For the trial, the preliminary results of which were initially presented at the American Society for Clinical Oncolo-gy’s 2011 Genitourinary Cancers Sym-posium, researchers enrolled 31 patients with advanced non–clear cell RCC (those with collecting duct carcino-ma and sarcomatoid carcinoma with-out identifiable RCC subtypes were

ineligible), 24 of whom had undergone nephrectomy prior to the study. The authors noted that 22 of the patients in the study population had papillary RCC and three had chromophobe RCC. All patients were treated with oral sunitinib 50 mg per day for four weeks, followed by two weeks of rest. The study’s prima-ry end point was overall response rate.

At the conclusion of the trial, 11 patients (36%) had partial response and 17 (55%) had stable disease. Only one patient had progressive disease. Median duration of response was 12.7 months. After a median follow-up peri-od of 18.7 months, 21 patients had dis-ease progression and 13 patients (42%) had died. Median overall survival (OS) was, therefore, 25.6 months and

median progression-free survival was 6.4 months. Median OS was not reached. The disease control rate was 86%.

High rates of grade 3 or higher adverse events such as hand–foot syn-drome, neutropenia and thrombocy-topenia were reported during the tri-al and resulted in higher rates of dose reduction and treatment interruption than those reported during the Phase III and expanded-access trials for sunitinib. In addition, one patient had an acute fatal congestive cardiomyop-athy during treatment, despite having no known risk factors. After this inci-dent, the researchers performed pre-treatment cardiac screening as well as blood pressure control and cardiac monitoring during treatment.

Sunitinib Promising for Non–Clear Cell Renal Cell Carcinoma

From�The Lancet

The results of an international, mul-ticenter, intention-to-treat Phase

III trial of combination therapy with lapatinib (Tykerb, GlaxoSmithKline) and trastuzumab (Herceptin, Genen-tech) in HER2-positive early breast cancer indicate that the combination is both safe and effective, and that dual inhibition of HER2 may be a valid ther-apeutic approach for the disease. The study findings were published in the February issue of Lancet (2012;379:633-640, PMID: 22257673).

With funding from GlaxoSmith-Kline, manufacturers of the brand-name form of lapatinib, researchers designed the NeALTTO (NeoAdjuvant

Lapatinib and/or Trastuzumab Treat-ment Optimization) trial to prove their hypothesis that two anti-HER2 agents administered simultaneously would be more effective than a single agent administered alone. To do so, they ran-domized more than 450 patients from 23 countries to receive either oral lapatinib (1,500 mg), IV trastuzum-ab (loading dose 4 mg/kg, subsequent doses 2 mg/kg) or lapatinib (1,000 mg) plus trastuzumab for a period of six weeks; weekly paclitaxel (80 mg/m2) was then added to the regi-men for 12 weeks prior to surgery (the lapatinib dose was reduced to 750 mg). Following surgery, patients received adjuvant chemotherapy and then 52 weeks of targeted therapy as before. All the women in the study had been

diagnosed with HER2-positive breast cancer, and had tumors larger than 2 cm in diameter. The study’s prima-ry end point was pathologic complete response (pCR).

Of the 152 patients in the combina-tion therapy group, 51.3% achieved pCR compared with 29.5% in the group (149 patients) receiving trastuzumab alone (P=0.0001). Only 24.7% of those in the lapatinib monotherapy group (154 patients) achieved pCR (P=0.34). How-ever, after the six-week initial treat-ment period, researchers observed a higher objective response rate in the lapatinib monotherapy (52.6%) and combination therapy (67.1%) groups than in the trastuzumab monotherapy (30.2%) group.

With regard to adverse events,

incidence of grade 3 diarrhea was significantly higher in the lapatinib monotherapy (23.4%) and combi-nation therapy (21.1%) groups than in the trastuzumab monotherapy group (2%). Incidence of grade 3 liver enzyme alterations was also higher in the lapatinib monotherapy (17.5%) and combination therapy (9.9%) groups than in the trastuzumab monothera-py group (7.4%). No incidents of cardi-ac dysfunction were reported over the course of the trial. Only 60.5% of the patients in the combination therapy group were able to complete treatment as planned because of adverse events (liver dysfunction, diarrhea, etc), compared with 66.2% in the lapatinib monotherapy and 91.9% in the trastu-zumab monotherapy groups.

Roisin Connolly, MBBSAssistant Professor of OncologyJohns Hopkins University School of MedicineSidney Kimmel Comprehensive Cancer Center at Johns Hopkins

EXPERT INSIGHT

16 CliniCal OnCOlOgy�news •�april 2012

Kidney

SOLID TUMORS

Breast

Abscopal Effect Maximizes Potential of Ipilimumab Plus Radiation

This report by Postow, Callahan and colleagues of the abscopal effect in a patient with melanoma is an impor-tant step in our understanding of how

to reorient the immune system toward tumor elimination. As the authors pointed out, ipilimumab monother-apy is effective in only 10% to 15% of patients with melanoma. Overcoming immune tolerance, then, may require combinatorial treatment regimens that build upon one or more of the immu-nologic components examined in this study. First, the temporal relationship between disease response and treat-ments administered suggests a ratio-nale for investigating various schedules of timed sequential therapy. Second, further investigation into host develop-ment of increased humoral responses,

including increases in antibody titers against the cancer testis antigen NY-ESO-1, may suggest antigenic targets that play a critical role in immune-mediated tumor destruction. Final-ly, conversion from immune tolerance to immune attack almost certain-ly involves a shift in immune cell sub-populations. Characterizing the effects that particular therapies have on the immune cell landscape may help inves-tigators rationally combine treatments for maximum anti-tumor impact.

The applicability of immune-based therapies like ipilimumab is expand-ing. For example, blockade of the PD-1/

PD-L1 immune checkpoint pathway has produced tumor regressions in malig-nancies not traditionally considered immunogenic, such as non–small cell lung and colorectal cancers. This report, though it is based on only one patient, not only suggests an approach to max-imizing the anti-melanoma potential of ipilimumab, it also raises the pos-sibility that combining multimodality approaches (eg, radiotherapy, chemo-therapy, signal transduction pathway blockade, surgery or cryotherapy) with immunotherapies may provide the required framework for destruction of a wider array of tumor types.

In this study, the authors report on the results of a multicenter, single-arm, Phase II study of sunitinib in Korean

patients with non–clear cell RCC. The optimal treatment for non-clear cell RCC remains poorly defined. Pivotal Phase III studies with tyrosine kinase inhibitors excluded non–clear cell his-tologies, leaving us with retrospective analyses or small Phase II studies. The evidence thus far suggests rather mod-est activity, mostly resulting in disease stabilization rather than significant tumor shrinkage.

The majority of patients treat-ed in this prospective Phase II study had RCCs of the papillary subtype.

Interestingly, the partial response rate of 36%, which also was the primary end point, was rather impressive and is comparable to response rates seen typ-ically in the clear cell population. How-ever, this came at the price of increased grade 3/4 toxicities (neutropenia, thrombocytopenia, hand–foot syn-drome) requiring higher rates of dose reduction and dose delays than were seen in the pivotal studies. This find-ing falls in line with a previous report of this group suggesting a higher inci-dence and severity of treatment-related

adverse events in Asian patients.It is tempting to hypothesize that

either pharmacogenomic differences or a smaller body habitus could have resulted in increased drug exposure of the Asian patients when compared with their Caucasian counterparts. While the findings of this study are mostly applicable to the Asian patient popu-lation, it makes us hopeful that VEGF pathway inhibition with more potent and selective agents might improve the outcome for patients with non–clear cell RCC in the future.

From�The New England Journal of Medicine

In a single-patient case study, researchers from Memorial Sloan-

Kettering’s Ludwig Center for Cancer Immunotherapy found that combina-tion therapy with ipilimumab (Yervoy, Bristol-Myers Squibb) and radiother-apy may be a promising approach in patients with advanced metastatic melanoma. The results of the study were published in the March 8 issue of The New England Journal of Medicine (2012;366:925-931, PMID: 22397654).

The authors attribute the success of the combination of ipilimumab and radiotherapy in this patient case to the abscopal effect, a rare phenome-non in localized radiotherapy that is, as the authors wrote, “associated with

the regression of metastatic cancer at a distance from the irradiated site” and may be “mediated by activation of the immune system.” The monoclo-nal antibody ipilimumab is known to inhibit cytotoxic T lymphocyte–asso-ciated antigen 4 (CTL-4), an immu-nologic checkpoint on T cells, and to enhance immunity to NY-ESO-1, an antigen expressed in 30% to 40% of patients with metastatic melanoma.

NY-ESO-1 expression was con-firmed in the case patient—a 33-year-old woman—via immunohistochemi-cal analysis and reverse transcriptase polymerase chain reaction assay. Prior to treatment with the study approach, the patient was seropositive for the whole NY-ESO-1 protein. Dur-ing treatment, however, the authors observed “a trend toward lower titers

as disease burden decreased.” Follow-ing radiotherapy, they noted that the patient “had an increase by a factor of more than 30 of antibodies against an epitope or epitopes within the central portion of the protein.”

As expected, during ipilimumab administration in the study patient, there was a marked increase in CD4-positive inducible T cell costimulator (ICOS) cells, which have been found to improve clinical benefit and over-all survival in patients with advanced metastatic melanoma. However, inter-estingly, the patient’s CD4-posi-tive ICOS count also showed a mod-est increase following radiotherapy, suggesting that the latter may play an immunomodulatory role. Indeed, tumor regression was seen only after radiotherapy, indicating that the case

patient’s tumor was resistant to T cell–mediated antitumor effects until the administration of radiotherapy. Seromic analysis detected 10 anti-genic targets with enhanced antibody responses after radiotherapy.

In all, the authors noted that the case study, which was funded in part by the National Institutes of Health (among other not-for-profit entities), revealed that treatment with ipili-mumab and radiotherapy resulted in “tumor shrinkage with antibody responses to the cancer-testis anti-gen NY-ESO-1, changes in peripher-al-blood immune cells, and increases in antibody responses to other anti-gens after radiotherapy.” Clinical tri-als designed to assess the benefit of the approach used in the case study are ongoing.

Evan Lipson, MDInstructor of OncologyJohns Hopkins University School of MedicineSidney Kimmel Comprehensive Cancer Center at Johns Hopkins

EXPERT INSIGHT

Hans Hammers, MD, PhDAssistant Professor of OncologyJohns Hopkins University School of MedicineSidney Kimmel Comprehensive Cancer Center at Johns Hopkins

EXPERT INSIGHT


Melanoma

QUESTIONS

1. True or False: Early treatment of patients defined as high risk for pro-gression to multiple myeloma (MM) from smoldering multiple myeloma (SMM) with lenalidomide (Revlimid, Celgene) and dexamethasone exhibited a trend toward improvement in overall survival (OS).

2. True or False: The combination of carfilzomib (Onyx Pharmaceuticals), lenalidomide and low-dose dexameth-sone (CRd) regimen has very high and stable response rates with fewer dose modifications due to peripheral neurop-athy in contrast to bortezomib (Velcade, Millennium Pharmaceuticals) combina-tions with similar agents.

3. True or False: In a Phase I trial with marizomib (Nereus Pharmaceuti-cals), a highly potent proteasome inhib-itor, once-a-week dosing of 0.4 to 0.5 mg/m2 appears to be the optimal dosing schedule for relapsed/refractory MM.

4. True or False: In patients with MM, the Phase II study of bortezomib in combination with panobinostat (Novar-tis) demonstrated activity in approxi-mately one-third of patients who were truly refractory to bortezomib.

5. True or False: Perifosine (Keryx Biopharmaceuticals) and bortezomib with or without dexamethasone demon-strated encouraging activity with an over-all response rate (ORR; defined as mini-mal response or better) of 41% in 73 eval-uable patients, including an ORR of 65% and 32% in bortezomib-relapsed and bort-ezomib-refractory patients, respectively.

6. True or False: Pomalidomide (Cel-gene) with or without dexamethasone is active in heavily pretreated patients with MM, including those refractory to bort-ezomib but not to lenalidomide.

7. True or False: Elotuzumab (Abbott Laboratories) in combination with lenalidomide and low-dose dexameth-asone exhibited 92% ORR in relapsed/refractory patients with MM.

8. True or False: Low-dose clofar-abine (Clolar, Genzyme) has signifi-cant activity in high-risk myelodysplas-tic syndromes (MDS) and acute myeloid leukemia post-MDS (sAML) following azacitidine (Vidaza, Celegene) failure.

9. True or False: The study by Emilio Paolo Alessandrino, MD, and colleagues at the University of Pavia in Pavia, Ita-ly, suggests that in eligible patients with low- or intermediate-risk MDS accord-ing to the World Health Organization’s Classification-Based Prognostic Scor-ing System (WPSS) there is no clear benefit in adopting a delayed transplan-tation strategy.

10. True or False: Treatment of thrombocytopenia in low- or interme-diate–1-risk MDS patients with romip-lostim (Nplate, Amgen) resulted in a decreased requirement for platelet transfusions, fewer clinically significant bleeding events but significantly higher rates of AML transformation.

11. True or False: The retrospective data on 2,283 patients with MM sug-gest that observed and expected sec-ondary primary malignancy (SPM) rates are higher with induction with both an alkylating agent and an immunomodu-latory agent.

12. True or False: The combina-tion of MLN9708 (Millennium), lenalid-omide, dexamethasone in patients with MM who were not previously treat-ed demonstrated 100% (n=15) partial or better response, including four com-plete responses and five very good par-tial responses.

13. True or False: A Phase II study of azacitidine and vorinostat (Zolinza, Merck) in patients with newly diag-nosed MDS or AML who were not eligi-ble for clinical trials because of poor per-formance status and the presence of oth-er comorbidities was closed early due to marked treatment-related toxicity.

14. True or False: Persistent min-imal residual disease by multiparame-ter flow cytometry at day 60+ predict-ed unsustained complete response (CR) after autologous stem cell transplanta-tion (ASCT) in MM.

15. True or False: Final results from the Phase II continuation study of lenalidomide combined with azacit-idine in patients with higher-risk MDS demonstrated an ORR of 71% in 35 eval-uable patients.

16. True or False: A randomized controlled Phase II/III trial demon-strated improved outcomes in younger adult patients (18-60 years) with mutat-ed NPM1 AML with the addition of all-trans retinoic acid (ATRA; Vesanoid, Roche) to standard chemotherapy.

17. True or False: In MM, prediction of complete response by gene expres-sion profiling (GEP) is likely to be an important goal for prospectively select-ing those patients who are more likely to benefit from a given therapy.

18. True or False: In front-line AML and higher-risk MDS a Phase II trial of vorinostat in combination with idaru-bicin (Idamycin, Pfizer) and cytarabine demonstrated high induction response rates with an acceptable safety profile.

19. True or False: Inotuzumab ozo-gamicin is an anti-CD22 monoclonal antibody that has activity in relapsed/refractory acute lymphocytic leukemia (ALL).

20. True or False: Quizartinib monotherapy produces responses in patients with relapsed or refractory AML with mutated NPM1.

Clinical ConundrumsHighlights of American Society of Hematology 2011 Annual Meeting—Malignant Hematology

Part 1: Multiple Myeloma, Myelodysplastic Syndrome and Acute Leukemias

for answers see CONUNDRUMS, page 22

Let Us Visit Your Practice Please consider inviting the staff of Clinical Oncology News to visit your practice. We want to meet you and your colleagues, listen to your concerns, and observe the physical site of your practice.

You can help us improve Clinical Oncology News and fulfill our mission—to provide evidence-based, clinically relevant information that you can use to benefit your patients and practice.

If you are interested, please contact Gabriel Miller, managing editor, at (212) 957-5300 ext. 265 or via e-mail at [email protected]

Prepared by

Syed A. Abutalib, MD

assistant�Director�Hematology��&�stem�Cell�

Transplantation�program

Cancer�Treatment�Centers�of�america

Zion,�illinois

Early treatment of

18 CliniCal OnCOlOgy�news •�april 2012PRN

Community Oncology

The investigators also found a 1.13-fold higher probability of the second primary being a different type from the first cancer.

An accompanying commentary not-ed that the study was methodological-ly sound, but that it is difficult to know how, if at all, the results apply to clinical practice (CMAJ 2012;184:19-20). This uncertainty exists because of the signif-icant heterogeneity in risks of different types of second primary cancers.

“Thus, [there is] the need for sepa-rate evaluation and discussion of risk by specific type of first–second cancer pair rather than overall risk,” observed Mary Winget, PhD, and Yutaka Yasui, PhD.

Stig E. Bojesen, MD, PhD, DMSc, of Copenhagen University Hospital and his two co-investigators extracted data from 1980 to 2007 from three nation-al databases in Denmark, including the Danish Civil Registration System. This resulted in a cohort of 7,493,705 peo-ple, of whom 765,255 were diagnosed with one or more cancers, for a total of 843,118 cancer diagnoses. The investiga-tors matched each of these individuals with up to five randomly selected peo-ple from the databases who did not have the examined cancer at the time of the subject’s diagnosis.

The investigators analyzed the asso-ciations between 27 types of cancer and the increased risks for any second pri-mary cancer. They found that after a person had any type of first cancer, he or she had a 1.25 aggregated hazard ratio (aHR) for developing any type of second primary cancer (95% confidence interval [CI], 1.24-1.26), although there is significant variation between can-cer types. The investigators also found that the aHR for developing a second primary cancer of the same type as the first was 2.16 (95% CI, 1.98-2.34) and the aHR for a second primary cancer

different from the first was 1.13 (95% CI, 1.12-1.15).

Prostate cancer was associated with the lowest likelihood, by far, of a subse-quent primary cancer. The HR for devel-oping any second primary cancer after a

primary prostate cancer was 0.80 (95% CI, 0.77-0.83), while the HR for develop-ing a second primary cancer of the same type as the first was 0.01 (95% CI, 0.00-0.02) and for developing a second pri-mary cancer different from the first was 0.79 (95% CI, 0.77-0.82).

In addition, primary cancers not related to tobacco use were associated with a significantly lower chance of any type of second primary cancer.

The study also showed that the

absolute five-year risk for people with a primary tumor to later develop a second cancer was quite low.

“For cancer patients who have had a primary tumor, [we found] the absolute five-year risk of getting a second cancer is on average far below 5% on average,” said Dr. Bojesen.

—Rosemary Frei, MSc

Drs. Winget, Yasui and Bojesen reported no conflicts of interest.

Second Primary Cancer Likely To Be Same Type as FirstA population-based, case–control study has found a 2.16-fold higher risk for a second primary cancer that is the same type as the first, than for not having a second primary cancer (CMAJ 2012;184:E57-E69).

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ChairPeter D. Stevens, MDDirector of EndoscopyNewYork-Presbyterian Hospital/Columbia University Medical CenterColumbia University College of Physicians and SurgeonsNew York, New York

FacultyJerome H. Siegel, MD, RPh, MACG, FASGE, AGAFCo-DirectorTherapeutic EndoscopyBeth Israel Medical CenterNew York, New YorkClinical Professor of MedicineAlbert Einstein College of MedicineBronx, New York

Medical WriterOren Traub, MD, PhD

Accreditation Statement� is activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Columbia University College of Physicians and Surgeons and Applied Clinical Education (ACE). Columbia University College of Physicians and Surgeons is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation StatementColumbia University College of Physicians and Surgeons designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of theirparticipation in the activity.

Goal� e goal of this activity is to educate oncologists, gastroenterologists, and other health care professionals in the latest evidence regarding the diagnosis and management of pancreatic exocrine insuffi ciency (PEI).

Learning ObjectivesAt the completion of this activity, participants should be better prepared to:1 Delineate the epidemiology and pathophysiology of chronic pancreatitis (CP)

and pancreatic cancer (PC), including how these conditions can lead to PEI and the signifi cance of PEI for nutritional health.

2 Use current techniques to assess and diagnose CP and PC, with attention to the presence of PEI.

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Patient Care

Adjuvant Radiation After R-CHOP-14 Increases Lymphoma Survival

There is no clear consensus on the optimal approach to treating patients with primary mediastinal large B-cell lymphoma (PMLBCL). While the addition of rituximab had clearly

contributed to increased response rates, event-free survival and OS in PMLBCL, the role of radiotherapy in the rituximab era has been controver-sial, with some small nonrandomized studies suggesting that the addition of rituximab to CHOP-like cytotoxic che-motherapy obviates the need for adju-vant radiation.

Agustin Avilés et al have published a randomized clinical trial evaluating adjuvant IFRT in patients who achieved a CR to 6 cycles of R-CHOP-14. The tri-al had to be stopped early after inter-im analysis on the enrolled 124 patients revealed a clear survival advantage in patients on the radiotherapy arm.

The actuarial PFS at 10 years showed a dramatic difference of 72% for the radi-ation therapy compared with 20% for the control arm, and OS of 72% and 31%, respectively. CR was defined by com-puted tomography along with gallium scans, which was standard for the insti-tution at that time (study stopped enroll-ment in 2004).

The authors must be commended for conducting a randomized trial in this disease, a rarity given the relatively low incidence of this distinct clinico-patho-logic entity. A clear pitfall is the dismal results in the control group, quite dif-ferent from prior published experienc-es with R-CHOP–like or more intensive

regimens. The Cancer and Leukemia Group B is conducting a trial of R-CHOP versus dose-adjusted EPOCH-R (etopo-side, adriamycin, vincristine, cyclophos-phamide, prednisone and rituximab; the etoposide, adriamycin and vincris-tine are given as a continuous infusion) in untreated patients with diffuse large B-cell lymphoma (including PMLBCL), which should definitively prove (or dis-prove) the benefit of the multiday infu-sional regimen. Until the results from CALGB 50303—with a significant popu-lation of PMLBCL patients being treat-ed with R-CHOP—are available, this study helps establish the role of adju-vant radiation.

The finding comes from a substudy of the NCIC Clinical Trials Group (NCIC CTG) MA.27 trial. The results were reported at the recent San Antonio Breast Cancer Symposium (SABCS, S6-2).

Oncologists should be aware that when a postmenopausal patient with breast cancer starts taking an AI and then reports being bothered by side effects, she is at an increased risk for quitting

early, said Lynne Wagner, PhD, an asso-ciate professor in the Department of Medical Social Sciences at Northwestern University Feinberg School of Medicine, in Chicago, who led the study. “These patients could benefit from close moni-toring of adherence, help with managing side effects and counseling on the bene-fits of AI therapy,” she said.

MA.27 was a Phase III trial that

randomized 7,576 postmenopausal, estro-gen receptor–positive patients with early breast cancer to five years of either anas-trozole or exemestane. The study showed the two treatments had nearly identi-cal efficacy and a similar safety profile. The E1Z03 substudy was the quality-of-life (QoL) correlative trial that assessed patient-reported outcomes among a sub-group of participants in the MA.27 trial

and focused on predictors of early treat-ment discontinuation. Patient-reported outcomes were measured before AI initi-ation (baseline) and then at three, six, 12 and 24 months after initiation. The study included information on 686 patients who provided feedback through the 46-item Functional Assessment of Cancer Ther-apy-Endocrine Symptoms (FACT-ES). This tool assesses physical, functional, social and emotional well-being, as well as breast cancer–specific concerns and endocrine symptoms.

The substudy did not identify any sig-nificant differences between the two treatment arms with regard to treat-ment-related QoL or symptoms. As suspected, symptoms such as weight

‘Bothered’ Feeling Predicts NonadherenceSubstudy finding in breast cancer patients could aid in symptom management

San Antonio—A trial comparing exemestane and anastrozole for early breast cancer has uncovered a finding that may be surprising to some clinicians: Nonadherence to therapy with aromatase inhibitors (AIs) is predicted by “feeling bothered by treatment side effects” that patients experience before AI therapy rather than the emergence of symptoms after treatment starts.

From�International Journal of Radiation Oncology

A small clinical trial has concluded that adjuvant involved-field radio-

therapy (IFRT) appears still to be the best option for patients with medi-astinal B-cell lymphoma who have achieved complete response (CR) with cyclophosphamide, doxorubicin, vin-cristine, prednisone and rituximab (Rituxan, Genentech), the regimen known as R-CHOP-14.

This study, published online in December by the International Jour-nal of Radiation Oncology (2011; Dec 13. [Epub ahead of print], PMID: 22172907), was performed at the National Medical Center of Mexico and

was funded by the Mexican Institute of Social Security, a government agency that oversees public health and pen-sions in Mexico.

To date, there has been no widely accepted standard treatment approach for mediastinal B-cell lymphoma, despite the existence of data support-ing the use and efficacy (as measured by CR) of R-CHOP-14; this is in large part because overall survival (OS) among patients treated with R-CHOP-14 in multiple studies has ranged from only 40% to 60%. Historically, clinicians have been hesitant to use IFRT in medi-astinal B-cell lymphoma because sev-eral small, noncontrolled studies have found that the approach fails to improve outcomes in this patient population.

There also is concern regarding the car-diac and lung toxicities that have been associated with IFRT in previous stud-ies. However, as the authors of the pres-ent trial note, a study published by Pugh et al in 2010 (Int J Radiat Oncol Biol Phys 2010;76:845-849, PMID: 19515509) revealed that cardiac mortality among patients with mediastinal B-cell lym-phoma actually may be associated with anthracycline use in this patient population.

For the Mexican trial, the researchers randomized 124 consecutive patients who achieved CR following R-CHOP-14 between January 2001 and June 2004. In all, 63 received IFRT (30 Gy) and 61 were assigned to the control group. Originally, the researchers had planned

to enroll 182 patients in each arm; how-ever, the study was “closed premature-ly” after a security analysis revealed that disease progression and early relapse were more frequent in patients who did not receive IFRT. The 124 patients ulti-mately enrolled in the trial were moni-tored until March 2009.

At the conclusion of the follow-up period, actuarial curves at 10 years dem-onstrated that progression-free surviv-al (PFS) was significantly higher (72%) in the IFRT group than in the control group (20%; P<0.001). OS also was sig-nificantly higher in the IFRT group (72%) than in the control group (31%; P<0.001). Patients in the IFRT group reported only mild toxicities, and the therapy was generally well tolerated.

SOLID TUMORS

Satish Shanbhag, MBBS, MPHAssistant Professor of Medicine and OncologyJohns Hopkins University School of MedicineSidney Kimmel Comprehensive Cancer Center at Johns Hopkins

EXPERT INSIGHT

20 CliniCal OnCOlOgy�news •�april 2012HEMATOLOGIC DISEASE

Lymphoma

Breast

Fludarabine Plus Rituximab Assessed in Relapsed/Refractory HCL

FR therapy was administered to 15 patients with relapsed/refractory HCL. Clinical responses were observed in 13 evaluable patients. In this retrospective analysis, FR showed clinical efficacy in

relapsed or refractory HCL.In this report from British Colum-

bia, 15 patients with relapsed/refrac-tory HCL received a median of four cycles of FR (range, two to four cycles). Patients had received a median of two prior systemic treatments. All patients had received a purine analog before FR. Thirteen patients (87%) had previous-ly received cladribine and two patients (13%) had previously received fluda-rabine. Five-year PFS and OS for the cohort were 89% and 83%, respectively. The authors conclude that FR has clini-cal efficacy in relapsed/refractory HCL and is safe and well tolerated.

Although cladribine and pentostatin have been shown to have a very high response rate (75%-90%) in the prima-ry treatment of HCL, long-term follow-up shows that the relapse rate can be as high has 30% to 40%. Retreatment with purine analogs such as pentostatin or cladribine can produce high response rates and durable remissions. In this study, the authors report a high complete response rate and durable response, which provide an alternate treatment option for relapsed/refractory HCL. The treatment of this condition often is asso-ciated with a significant infection rate. Although the authors stated that the

treatment was safe and well tolerated, the adverse effects from treatment were not reported in the paper.

In this disease, there are multiple choices of treatment in the relapsed/refractory setting, all of which have been shown to yield clinically mean-ingful responses. However, there is little data suggesting the choice and sequence of therapy. The discovery of the BRAF V600E mutation in 100% of HCL makes this mutation a potential target for the treatment of this condi-tion. Prospective clinical trials should be conducted to better guide the man-agement of relapsed/refractory HCL.

gain, decreased libido, feeling bloated, breast sensitivity, mood swings, irrita-bility, joint pain and nausea had a neg-ative impact on health-related QoL, and these symptoms increased after the start of AI therapy.

Of the entire sample of patients, 32% had no joint pain at baseline, and by month 3 of treatment, 55% of these patients reported new joint pain. New weight gain was reported by 40% of patients; 39% reported new hot flashes; 30% to 34% reported [new] decreased libido, breast sensitivity and night sweats; and 25% reported mood swings as new symptoms, reported Dr. Wagner, who is also a clinical psychologist at Robert H. Lurie Comprehensive Cancer Center of Northwestern University, also in Chicago.

Surprisingly, however, the emergence of new symptoms at three months was not a statistically significant factor in pre-dicting early treatment discontinuation

(hazard ratio [HR], 1.11; P=0.107). Rather, being bothered by treatment side effects before initiating an AI was a risk factor for this end point (HR, 1.29; P=0.006). Prior chemotherapy, prior radiation and the number of current daily medications all were found to be statistically signif-icant predictors of patients reporting bothersome symptoms at baseline.

“It is possible that women who strug-gled with side effects during previous cancer treatments are vulnerable to AI side effects and discontinue treatment early [or] women who feel beaten up by their prior treatments may have difficul-ty facing five more years of treatment

side effects and end treatment early,” said Dr. Wagner, offering possible expla-nations. “It may be that these women are telling us they are the type of people who are likely to be bothered by treatment side effects. Regardless of the reason, these results tell us how we can identi-fy women who are at risk for early treat-ment discontinuation.”

Patricia Ganz, MD, director of the Divi-sion of Cancer Prevention & Control Research at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles, served as the trial discussant at SABCS. She said that understanding the biology of post-treatment symptoms

in breast cancer may lead to innovations in management, and enhanced survival through improved adherence. “Effective symptom management strategies should be a priority,” she said.

Dr. Ganz has conducted studies show-ing that host factors, particularly sin-gle nucleotide polymorphisms in inter-leukin (IL)-1, IL-6 and tumor necrosis factor promoters, may make certain patients more vulnerable to ongoing and persistent inflammation after the prima-ry treatment of breast cancer. “Cancer and its treatment may in fact exacerbate the immune status of patients and lead to inflammation and the treatments that do this are not just chemotherapy, but also surgery and radiation,” Dr. Ganz said.

—Kate O’Rourke

Drs. Wagner and Ganz reported no relevant disclosures.

From�Blood

A team of researchers from Vancou-ver, British Columbia, has found

that treatment with combination ther-apy of fludarabine (Fludara, Genzyme; various) and rituximab (Rituxan, Genen-tech) produces positive outcomes—as measured by progression-free survival (PFS) and overall survival (OS)—in relapsed/refractory hairy cell leukemia (HCL). Their report, published in the March 1 issue of the journal Blood (2012;119:1988-1991; PMID: 22223825), confirms earlier findings originally pre-sented in 2010 at the 52nd annual meet-ing of the American Society of Hematology.

Despite significant advances in the

treatment of HCL, an estimated 30% to 40% of patients relapse. The authors reviewed the cases of 15 such patients, culled from the British Columbia Cancer Agency’s Lymphoid Cancer Database, who were treated with fludarabine-rituximab (FR) between 2004 and 2010. Two of the patients included in the study had undergone first-line therapy with cladribine; the remaining patients had undergone “multiple lines of therapy” (the authors did not elaborate).

At the time the Blood article was pub-lished, 14 of the 15 patients remained

progression-free—one patient devel-oped progressive leukemia and

died—after a median follow-up of 35 months. According

to the authors, five-year PFS and OS among the 15 patients with relapsed/refractory HCL who received FR therapy were 89% and

83%, respectively. FR therapy was started a

median of 12.8 years after initial diagnosis of HCL and a

median of 60 months after the dis-continuation of prior therapy. The regi-men consisted of 40 mg/m2 per day of fludarabine orally on days 1 to 5 (adjust-ed for renal function) and 375 mg/m2 of rituximab IV administered every 28

days (starting on day 1 of treatment) for four cycles. Median age of the patients receiving the combination regimen was 59 years at the start of treatment. Patients underwent a median of four cycles of treatment.

The authors report the regimen was largely well tolerated. No patients required the IV formulation of fludara-bine. Treatment was discontinued in one patient after two cycles as the result of a hypersensitivity reaction to rituximab; fludarabine was discontin-ued in one patient after three cycles fol-lowing the development of interstitial lung disease. Herpes zoster was report-ed in two patients, one during treat-ment and one six months after receiv-ing the last cycle. No patients required hospitalization during treatment.

SOLID TUMORS

Prior chemotherapy, prior radiation and the number of current daily medications all were found to be statistically significant predictors of patients reporting bothersome symptoms at baseline.

Nilanjan Ghosh, MD, PhDAssistant Professor of OncologyThe Johns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

EXPERT INSIGHT

CliniCal OnCOlOgy�news •�april 2012 21HEMATOLOGIC DISEASE

Leukemia

ANSWERS

1. True. Higher three-year (from study inclusion) and five-year (from diagnosis) OS rates compared with observation (hazard ratio [HR] for five-year OS from diagnosis: 5.01; 95% con-fidence interval [CI], 1-22; P=0.03) were observed. Similar to this Spanish tri-al, the ECOG (Eastern Cooperative Oncology Group) trial involved accru-al of patients with high-risk SMM for randomization to either single-agent lenalidomide or observation (Clinical-Trials.gov identifier: NCT01169337).

Mateos MV, López-Corral L, Hernández M, et al. Smoldering multiple myeloma (SMM) at high-risk of progression to symptomatic disease: a phase III, randomized, multicenter trial based on lenalidomide-dexamethasone (Len-Dex) as induction therapy followed by maintenance ther-apy with Len alone vs no treatment. ASH Annual Meeting Abstracts. 2011;118(21):991.

2. True. The majority of patients did not require dose modifications, either in the initial or in the maintenance phase of the treatment.

Jakubowiak AJ, Dytfeld D, Jagannath S, et al. Final results of a frontline Phase 1/2 study of carfilzomib, lenalidomide, and low-dose dexa-methasone (CRd) in multiple myeloma (MM). ASH Annual Meeting Abstracts. 2011;118(21):631.

3. False. Marizomib in combina-tion with dexamethsone demonstrated encouraging responses of 15% to 20% in heavily pretreated patients. Marizomib 0.4 to 0.5 mg/m2 twice weekly appears to be the optimal dosing schedule with-out reports of significant peripheral neuropathy.

Richardson PG, Spencer A, Cannell P, et al. Phase I clinical evaluation of twice-weekly mar-izomib (NPI-0052), a novel proteasome inhibi-tor, in patients with relapsed/refractory multiple myeloma (MM). ASH Annual Meeting Abstracts. 2011;118(21):302.

4. True. The combination of pan-obinostat and bortezomib seems to be promising for patients with bortezomib-refractory MM. A Phase III Spanish tri-al with panobinostat/placebo plus bort-ezomib plus dexamethasone in patients with relapsed MM (PANORAMA 1) will further define the potential role of pan-obinostat in the treatment of patients with MM.

Richardson PG, Alsina M, Weber DM, et al. Phase II study of the pan-deacetylase inhibi-tor panobinostat in combination with bortezo-mib and dexamethasone in relapsed and bortezo-mib refractory multiple myeloma (PANORAMA 2). ASH Annual Meeting Abstracts. 2011;118(21):814.

San-Miguel JF, de Moraes Hungria VT, Yoon SS, et al. Update on a Phase III study of panobinostat with bortezomib and dexamethasone in patients with relapsed multiple myeloma: PANORAMA 1. ASH Annual Meeting Abstracts. 2011;118(21):3976.

5. True. Perifosine, an orally bioavail-able, novel signal transduction modula-tor has multiple pathway effects includ-ing inhibition of Akt, NFkB and activa-tion of JNK. A Phase III trial is under way comparing perifosine with bort-ezomib plus dexamethasone with bort-ezomib plus dexamethasone in patients with relapsed/refractory MM previous-ly treated with bortezomib.

Richardson PG, Wolf JL, Jakubowiak AJ, et al. Perifosine plus bortezomib and dexamethasone in relapsed/refractory multiple myeloma patients previously treated with bortezomib: final results of a Phase I/II trial. ASH Annual Meeting Abstracts. 2011;118(21):815.

6. False. In a Phase II study with 221 MM patients who had previously received a median of five prior therapies including lenalidomide and bortezo-mib, pomalidomide was administered at 4 mg for 21 days of a 28-day cycle. For patients refractory to both lenalid-omide and bortezomib, median progres-sion-free survival was two months for pomalidomide alone and 3.9 months for pomalidomide and low-dose dexameth-asone. The regimen is now being inves-tigated in combination with pegylated liposomal doxorubicin (ClinicalTrials.gov identifier: NCT01541332) and bort-ezomib (NCT01497093).

Richardson PG, Siegel DS, Vij R, et al. Ran-domized, open label Phase 1/2 study of pomalid-omide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): Phase 2 results. ASH Annual Meeting Abstracts. 2011;118(21):634.

7. True. Elotuzumab is a humanized monoclonal immunoglobulin G1 anti-body directed against the cell surface gly-coprotein CS1, which is highly expressed on tumor cells in more than 95% of MM patients. Phase III clinical trials with similar combinations are ongo-ing—ELOQUENT2 trial—for relapsed/refractory MM (NCT01239797) and the ELOQUENT1 trial for front-line MM (NCT01335399).

Lonial S, Jakubowiak AJ, Jagannath S, et al. A Phase 2 study of elotuzumab in combina-tion with lenalidomide and low-dose dexameth-asone in patients with relapsed/refractory mul-tiple myeloma. ASH Annual Meeting Abstracts. 2011;118(21):303.

8. True. The interim results of the GFM Clo08 Dose-escalating Phase I/II Study are reassuring for patients who have limited therapeutic options. Nine-teen patients with a median age of 72 years have been enrolled in this trial. The extended alternate-day (day 1-10) schedule seems to be better tolerated and at least as efficient as the standard day 1 to 5 schedule, although a greater number of patients are required to con-firm these findings. Dose escalation in the trial is ongoing (NCT0106325).

Braun T, Raffoux E, Prebet T, et al. Low-dose

clofarabine has significant activity in high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia post-MDS (sAML) after azacitidine (AZA) failure: interim results of the GFM Clo08 dose escalating Phase I/II Study (NCT0106325). ASH Annual Meeting Abstracts. 2011;118(21):609.

9. True. Uncertainty exists about the optimal timing of allogeneic hematopoi-etic stem cell transplantation (HSCT) in the low- or intermediate-risk WPSS MDS groups and to address this issue Dr. Alessandrino and colleagues performed an ad hoc decision analysis. The risk for progression abolishes the expected gain in survival resulting from postponing the procedure in this group of patients. This is at variance with a previous deci-sion analysis based on the International Prognostic Scoring System (IPSS) (Blood 2004;104:579-585, PMID: 15039286), which concluded that for low- and intermediate-1 IPSS-risk MDS, delayed HSCT was associated with maximal life expectancy.

Alessandrino EP, Della Porta MG, Malcova-ti L, et al. Decision analysis of allogeneic stem cell transplantation in patients with myelodysplastic syndrome stratified according to the WHO Classi-fication-Based Prognostic Scoring System (WPSS). ASH Annual Meeting Abstracts. 2011;118(21):116.

10. False. Increases in peripheral blasts of greater than 10% occurred more frequently with romiplostim than with placebo, but generally resolved after romiplostim was discontinued. The clin-ical significance of this finding remains to be further investigated. OS and AML-free survival rates were similar in both arms. There was a trend for more clin-ically significant bleeding events with placebo (26.5%) compared with romip-lostim (18.6%).

Giagounidis A, Mufti GJ, Kantarjian HM, et al. Treatment with the thrombopoietin (TPO)-receptor agonist romiplostim in thrombocytope-nic patients (Pts) with low or intermediate-1 (Int-1) risk myelodysplastic syndrome (MDS): results of a randomized, double-blind, placebo (PBO)-controlled study. ASH Annual Meeting Abstracts. 2011;118(21):117.

11. False. The observed and expect-ed SPM rates are similar, even for treat-ment that includes induction with both an alkylating agent and an immunomod-ulatory agent. For all patients, the rate of SPM was 2.1% (n=48); it was 0.6% (n=2) with lenalidomide and dexameth-asone or cyclophosphamide, 2.4% (n=23) with lenalidomide and melphalan, 3.1% (n=17) with melphalan and thalidomide, and 1.4% (n=6) with melphalan and no immunomodulatory agent.

Palumbo A, Larocca A, Zweegman S, et al. Sec-ond primary malignancies in newly diagnosed multiple myeloma patients treated with lenalid-omide: analysis of pooled data in 2459 patients. ASH Annual Meeting Abstracts. 2011;118 (21):996.

12. True. MLN9708 is an oral, spe-cific, reversible inhibitor of the 20S pro-teasome. The combination with lenalid-omide and dexamethasone yielded

rapid responses, with 14 of 15 patients achieving at least 50% reduction in M-protein in cycle 1. Two patients dis-continued the therapy following cycle 6 to undergo transplantation (one in very good partial remission and one in com-plete remission [CR]).

Berdeja JG, Richardson PG, Lonial S, et al. Phase 1/2 study of oral MLN9708, a novel, inves-tigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). ASH Annual Meeting Abstracts. 2011;118 (21):479.

13. False. The combination of azacit-idine and vorinostat is safe and active in this poor-prognosis population result-ing in levels of activity and safety similar to those observed in populations eligible for clinical trials. These results support treatment of this poor-risk population and question current eligibility criteria for Phase I/II trials.

Garcia-Manero G, Estey EH, Jabbour E, et al. Final report of a Phase II study of 5-azacitidine and vorinostat in patients (pts) with newly diag-nosed myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) not eligible for clin-ical trials because of poor performance and pres-ence of other comorbidities. ASH Annual Meeting Abstracts. 2011;118 (21):608.

14. False. Dr. Bruno and colleagues investigated which prognostic markers can predict unsustained CR in a series of 241 patients in CR at day 100+ after high-dose therapy (HDT)/ASCT who were enrolled in the Spanish GEM2000 (n=140) and GEM2005 (<65 years old, n=101) trials. Twenty-nine (12%) of the 241 patients showed unsustained CR and a dismal outcome (median OS, 39 months). The presence of baseline high-risk cytogenetics by fluorescence in situ hybridization (HR, 17.3; P=0.002) and persistent minimal residual disease by multiparameter flow cytometry at day 100+ after HDT/ASCT (HR, 8.0; P=.005) were the only independent factors that predicted unsustained CR.

Paiva B, Gutierrez NC, Rosiñol L, et al. High-risk cytogenetics and persistent minimal residu-al disease (MRD) by multiparameter flow cytome-try (MFC) predict unsustained complete response (CR) after autologous stem cell transplantation (ASCT) in multiple myeloma (MM). ASH Annual Meeting Abstracts. 2011;118 (21):630.

15. True. The combination of lenalidomide and azacitidine is well tol-erated and highly active in treating high-er-risk MDS. The ORR seen in the Phase I study was supported by Phase II data, with good OS, even among highly refrac-tory patients. Subsequent randomized studies will compare the lenalidomide plus azacitidine combination to azacit-idine monotherapy and other azaciti-dine-based combinations.

Sekeres MA, Komrokji RS, Lancet JE, et al. Final results from the Phase 2 continuation study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syn-dromes (MDS). ASH Annual Meeting Abstracts. 2011;118 (21):607.

CONUNDRUMScontinued from page 18

22 CliniCal OnCOlOgy�news •�april 2012PRN

Community Oncology

16. True. NPM1 mutational sta-tus was prospectively confirmed as pre-dictive for response to all-trans retino-ic acid plus conventional chemotherapy.

Schlenk RF, Döhner K, Krauter J, et al. All-trans retinoic acid improves outcome in younger adult patients with nucleophosmin-1 mutated acute myeloid leukemia–results of the AMLSG 07-04 randomized treatment trial. ASH Annual Meeting Abstracts. 2011;118(21):80.

17. True. GEP analysis of a subgroup of patients who received bortezomib, thalidomide and dexamethasone (VTD) induction therapy provided a 41-gene signature that was able to predict attain-ment of CR/near complete remission (nCR) and, conversely, failure to achieve

at least nCR in 91% and 95% of cases, respectively.

Terragna C, Remondini D, Durante S, et al. A 41-gene signature predicts complete response (CR) to bortezomib-thalidomide-dexametha-sone (VTD) as induction therapy prior to autolo-gous stem-cell transplantation (ASCT) in multiple myeloma (MM). ASH Annual Meeting Abstracts. 2011;118(21):805.

18. True. Responses were signifi-cantly higher than with standard ida-rubicin and high-dose cytarabine (IA) therapy without additional toxicity. With a median follow-up of 82 weeks, the median OS and event-free surviv-al (EFS) for the whole group (n=75) was 82 and 47 weeks, respectively. Median OS and EFS for patients with Flt3/ITD mutations were 91 (range, six to 134) and

66 (six to 134) weeks. There was a trend toward better survival in the Flt3/ITD patients compared with the unmutated group (P=0.067). The authors conclud-ed that further studies comparing the experimental treatment to standard IA or “7+3” induction chemotherapy with cytarabine and an anthracycline and in patients with FLT3/ITD mutations should be considered.

Garcia-Manero G, Tambaro FP, Bekele N, et al. Final report of a Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). ASH Annual Meeting Abstracts. 2011;118(21):763.

19. True. Inotuzumab ozogamicin is highly active in relapsed/refractory

ALL. Overall, CR plus marrow CR plus CR without complete platelet recovery was 57% in 49 patients.

O’Brien S, Thomas DA, Ohanian M, et al. Ino-tuzumab ozogamycin (I0), a CD22 monoclonal antibody conjugated to calecheamicin, is active in refractory-relapse acute lymphocytic leuke-mia (R-R ALL). ASH Annual Meeting Abstracts. 2011;118(21):875.

20. False. Quizartinib monother-apy produced a clinically meaningful response in both relapsed and refracto-ry FLT3/ITD-positive AML.

Cortes JE, Perl AE, Smith CC, et al. A phase II open-label, AC220 monotherapy efficacy study in patients with refractory/relapsed FLT3-ITD positive acute myeloid leukemia: updated interim results. ASH Annual Meeting Abstracts. 2011;118(21):2576.

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CliniCal OnCOlOgy�news •�april�2012 23PRN

Community Oncology

Landmark trials conducted over the past 10 years have demonstrated the value of AIs in the adjuvant treatment of postmenopausal women with HR-positive, early stage breast cancer. One strategy endorsed by the Amer-ican Society of Clinical Oncology and National Comprehensive Cancer Net-work guidelines, and supported by clinical trial evidence, most notably the National Cancer Institute of Can-ada (NCIC) study MA.17 (J Clin Oncol 2012;30:718-721, PMID: 22042967), is extended adjuvant endocrine thera-py, or the use of an AI following com-pletion of a standard five-year course of adjuvant endocrine therapy, typi-cally tamoxifen.

Several studies have shown that patient compliance within an ini-tial five years of hormonal therapy is suboptimal, with adherence rates as low as 40% to 50% in some reports. This paper, by Fontein et al, evaluates patient compliance with extended

adjuvant letrozole in the Dutch IDEAL trial. In this prospective, Phase III, ran-domized, nonblinded study, postmeno-pausal women who had completed five years of adjuvant endocrine therapy (either tamoxifen for five years, an AI for five years, or a combined five years of the sequence of tamoxifen and an AI) were randomized to 2.5 versus five years of letrozole. This report looks at the inci-dence of and risk factors associated with noncompliance with letrozole after 2.5 years of follow-up, in a total of 1,215 ran-domized patients.

The authors found an 18.4% discon-tinuation rate, which was highest in the first six months of treatment. Patients discontinued letrozole because of tox-icity in 85.1% of cases. A number of interesting correlations were identi-fied. Patients whose prior endocrine therapy was the sequence of tamoxifen and an AI, particularly if that AI had been letrozole, were least likely to be noncompliant compared with patients who had previously been treated with monotherapy. Not surprisingly, lon-ger intervals between the completion of primary endocrine therapy and the start of extended adjuvant therapy also predicted for higher rates of noncom-pliance. Factors not predictive of early discontinuation included age, T stage, type of surgery and prior chemothera-py or radiotherapy.

This study makes a valuable contribu-tion to the literature since it looks at the important topic of treatment discontin-uation in a population of patients not

fully characterized to date, as the larg-er MA.17 trial has not yet reported on letrozole adherence rates and reasons for noncompliance. Table 2 in the Fon-tein paper lists the reason for treatment discontinuation by AE, and musculo-skeletal/soft tissue AEs were most com-mon at 18.8%; presumably AI-induced arthralgias and/or osteopenia/osteo-porosis. It would have been helpful to have more detail as to the reasons for discontinuation for each category list-ed, as it is unclear what toxicities were experienced under “dermatologic/skin” (11%) or “neurologic” (14.9%). Also, rea-sons for noncompliance due to sexual/reproductive factors seem surprising-ly low at 3.2%; perhaps there was some underreporting. It also was notable that certain patient factors such as age and tumor size seemed not to influence compliance. However, sample size may have contributed to this, as only 7.5% of patients were older than 75 years of age and nearly 90% of patients had a T1 or T2 tumor.

Most treatment guidelines appropri-ately note that the optimal duration of adjuvant hormonal therapy for early stage breast cancer has not been deter-mined. However, it is increasingly being recognized that HR-positive breast can-cer has a long natural history, and late recurrences after 10 years or more are not rare. Until the results of trials such as NSABP (National Surgical Adjuvant Breast and Bowel Project) B-42, which closed to accrual in 2010, are available, clinicians will not have evidence-based

guidelines to inform this important clinical issue of whether to continue an AI past five years of initial therapy. Some physicians and patients, partic-ularly those with higher-risk disease, will choose not to stop the AI at the five-year mark, a decision that is easier to make when the patient has not been experiencing any dose-limiting toxici-ty. However, that decision can be very challenging for the woman experienc-ing daily joint aches, hot flashes and vaginal dryness, particularly when the magnitude of the survival benefit, if any, is speculative.

However, if B-42 and other tri-als suggest that the optimal dura-tion of an adjuvant AI is protract-ed and more like the use of imatinib for chronic myelogenous leukemia or trastuzumab for HER2-positive met-astatic breast cancer (i.e., continua-tion until treatment failure or unac-ceptable toxicity), then oncologists must expect that noncompliance—a term that is inaccurate at best and paternalistic at worst—in a substan-tial majority of patients will be the norm, not the exception. In the con-clusion of their paper, Fontein et al wisely noted the importance of study-ing the reason that some patients are at a higher risk for premature treat-ment discontinuation based on indi-vidual metabolic or other factors. It seems likely that a tailored approach to extended adjuvant endocrine ther-apy with AIs will be the most success-ful strategy.

Adverse Effects Hinder Extended Aromatase Inhibitor Therapy From�European Journal of Surgical

Oncology

Drug toxicities are the primary cause of the high rates of treat-

ment noncompliance associated with long-term adjuvant endocrine ther-apy, according to results from a pro-spective, open-label Phase III clinical trial published in the February issue of the European Journal of Surgi-cal Oncology (2012;38:110-117, PMID: 22172646).

The IDEAL (Investigation on the Duration of Extended Adjuvant Letro-zole) trial was designed by a team of researchers from the Netherlands to identify the factors associated with treatment discontinuation among patients with hormone receptor (HR)–positive postmenopausal early breast

cancer undergoing therapy with aro-matase inhibitors (AIs) such as letro-zole (Femara, Novartis). The goal of the study was to assess noncompli-ance in the first 2.5 years of extended adjuvant therapy. The authors defined noncompliance as “early discontinua-tion of letrozole for all reasons, exclud-ing death or recurrence.” The research was supported by an educational grant from Novartis Oncology.

Researchers randomized 1,262 patients to receive either 2.5 or five years of adjuvant therapy with letro-zole. In all, 1,215 of the patients in the study population had at least one dose of the study drug during the follow-up period, and most (1,069 patients) started treatment within six months of the discontinuation of prior adjuvant endocrine therapy, with tamoxifen,

AIs or a sequence of both.Within the 2.5-year follow-up peri-

od, the overall noncompliance prob-ability was 18.4%. Median follow-up time was 1.88 years for compliant patients and 1.11 years for noncompli-ant patients, respectively (P=0.003). The highest discontinuation rates were reported during the first six months of therapy with letrozole (49.7%). The vast majority of patients (85.1%) discontinued treatment due to adverse events (AEs), the most com-mon of which included musculoskel-etal, neurologic and dermatologic dis-orders. Other reasons for treatment discontinuation included treatment refusal (18 patients).

Further analysis of the study pop-ulation revealed that patients pre-viously treated with tamoxifen/AI

sequential therapy had “the lowest probability” of treatment discontin-uation at 2.5 years of follow-up com-pared with those whose prior endo-crine therapy entailed tamoxifen or AIs alone (P=0.004). According to the authors, those patients with lon-ger treatment-free intervals (between initial endocrine therapy and adju-vant endocrine therapy) also were more likely to be noncompliant dur-ing adjuvant therapy with letrozole (P=0.011). Interestingly, prior sur-gery (mastectomy or breast-conserv-ing surgery)—both with and without radiotherapy and or chemotherapy—as well as patient age, tumor type and prior locoregional treatment were not factors associated with early treat-ment discontinuation among patients included in the IDEAL trial.

Robert S. Miller, MDClinical Associate, Breast Cancer ProgramOncology Medical Information OfficerJohns Hopkins University School of MedicineSidney Kimmel Comprehensive Cancer Center at Johns Hopkins

EXPERT INSIGHT


Breast

“These quality-of-life results pro-vide essential information for informed decision-making by women considering breast cancer chemoprevention and for their physicians,” said Harriet Richard-son, PhD, from the NCIC Clinical Trials Group and Department of Communi-ty Health and Epidemiology at Queen’s University, in Kingston, Ontario, Cana-da. She presented the study at the San Antonio Breast Cancer Symposium (SABCS, abstract S6-1) on behalf of the MAP.3 investigators.

The Phase III MAP.3 trial was a ran-domized, placebo-controlled study that demonstrated that in postmenopaus-al women at moderately increased risk for invasive breast cancer, exemestane reduced this risk by 65% without an increase in serious adverse side effects. These results were previously reported by Goss et al. in The New England Jour-nal of Medicine (2011;364:2381-2391, PMID: 21639806).

As part of that study, researchers col-lected data on quality of life (QOL) using the Menopause Specific QOL (MEN-QOL) survey and the Short Form-36. At SABCS, the researchers reported that they found no clinically meaningful changes in QOL as measured by these instruments, which were completed by more than 90% of women at scheduled visits while the women were on study medications. The proportion of wom-en on exemestane who discontinued the therapy early was greatest at six months. Vasomotor symptoms were more severe in patients receiving exemestane than in patients on placebo (P<0.01), and bodily pain also was slightly higher.

Patricia Ganz, MD, director of the Division of Cancer Prevention & Control Research at the Jonsson Comprehen-sive Cancer Center, University of Cali-fornia, Los Angeles, noted that although the Short Form-36 is an excellent vali-dated questionnaire, the MENQOL was

designed for healthy women. “[The MENQOL] was not designed

for women who might be taking a drug that would exacerbate symptoms of menopause, and when you look at the questionnaire for the physical summa-ry scale, there are 15 items on that scale and only three of them ask vaguely about aches and pains,” she said.

Comparing the MAP.3 and the P-1 tri-al that tested tamoxifen for chemopre-vention, Dr. Ganz noted that exemestane

and tamoxifen have similar rates of dis-continuation and that vasomotor symp-toms were increased with both drugs compared with placebo. Short Form-36 bodily pain scores increased for exemes-tane compared with placebo, while no difference between tamoxifen and pla-cebo was seen in P-1.

—Kate O’Rourke

Drs. Richardson and Ganz reported no relevant disclosures.

Quality of Life Unharmed by Exemestane in Prevention TrialSan Antonio—Using exemestane for breast cancer prevention does not decrease a woman’s quality of life, according to new results from the MAP.3 trial.

Vasomotor symptoms were more severe in patients receiving exemestane than in patients on placebo, and bodily pain was slightly higher.slightly higher.

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CliniCal OnCOlOgy�news •�april 2012 25SUPPORTIVE CARE

Breast

MUGA Cardiac Function Scans Unnecessary in Most Young Women

It has kind of been surprising that this recommendation—not to perform car-diac evaluation testing of young wom-en before receiving an anthracycline—hasn’t happened several years ago. It makes perfect sense that young women without any prior medical evidence or cardiac symptoms would not be required to have MUGA scans prior to starting adjuvant chemotherapy that includes an anthracycline, which carries a risk, however low, of causing cardiotoxicity.

In the thousands of women I have personally been involved with during their treatments, I have never seen a young woman with an abnormal cardiac functioning test result. This research study confirms nicely that healthy young women have a very low incidence of cardiac problems, so test-ing all young women prior to getting their chemotherapy under way is not a wise use of medical resources, and it also creates anxiety for some.

Anti-EGFR Agents Incur Increased Risk for Thromboembolic Events

In a recent Annals of Oncologyarticle, Petrelli et al report on the relative risk for venous and arterial thromboembolic events in patients receiving anti-EGFR therapy, both mAbs and TKIs.

This meta-analysis included 13 ran-domized studies that incorporated an anti-EGFR agent in one of the treat-ment arms, usually in conjunction with chemotherapy. Results suggest a slightly increased risk for VTE with the use of anti-EGFR agents, mostly

with the mAbs, although no difference in arterial or cardiac events.

While there are limitations to the ability of this kind of analysis to con-trol for potential confounders, espe-cially individual patient characteris-tics, and the absolute increased risk for VTE with anti-EGFR therapy is small (<2% in this meta-analysis), this article represents an interest-ing initial foray into a clinically sig-nificant arena. VTE is a major prob-lem in patients with cancer, and it is

incumbent upon practitioners to rec-ognize factors that increase that risk. Of course, any potential increased risk must be considered alongside the benefit afforded to patients by these agents, in terms of disease control and prolonged survival. For now, I do not feel that these data will signifi-cantly alter practice patterns in terms of anti-EGFR therapy prescribing in patients for whom a clinical bene-fit can be expected. Future study is warranted.

From�Clinical Breast Cancer

The results of multigated acqui-sition (MUGA) scans, typically

used to evaluate routine cardiac func-tion prior to the initiation of anthra-cycline-based adjuvant chemotherapy, rarely influence treatment decisions in breast cancer, according to a popula-tion-based cohort study recently pub-lished in the journal Clinical Breast Cancer (2012;12:4-9, PMID: 22154116).

The study, by researchers from Hali-fax, Nova Scotia, Canada, enrolled 593 patients who underwent curative-intent surgery for stage I, II or III breast can-cer between October 2005 and Septem-ber 2006. The researchers performed a retrospective chart review for all rel-evant clinical-pathologic variables, including baseline cardiac risk factors. The goals of the study were to mea-sure current MUGA scan usage patterns among this patient population and to determine what role scan results played in treatment decisions. Anthracycline-based treatments have been associated with rare, dose-dependent, cardiovas-cular-related adverse events, although

these largely have been mitigated in recent years through the use of strict patient selection criteria.

Within the study population, 238 (40%) of the patients received adjuvant chemotherapy; 94% of these patients received anthracycline-based therapy with doxorubicin, cyclophosphamide or combination therapy, among oth-er options. Among those who received adjuvant chemotherapy, 80% under-went MUGA scans prior to the initiation of therapy. The percentage was higher among patients who ultimately received anthracycline-based regimens during treatment, and among those diagnosed

with HER2-positive breast cancer.Only 5% of patients who under-

went MUGA scans received abnor-mal results, and all were smokers. Scan results influenced treatment decisions in only 2% of patients, all of whom were aged 65 years or older. None of these patients received anthracycline-based chemotherapy; in fact, one did not receive adjuvant chemotherapy at all.

The authors reported that routine MUGA scans obtained before the initi-ation of anthracycline-based adjuvant chemotherapy without trastuzumab “did not influence [treatment] deci-sions for younger patients” except in the

presence of “underlying cardiac risk fac-tors.” They suggest that prechemother-apy MUGA scans may not be required except in special populations, in partic-ular older women and those with other cardiac-related risk factors.

Noting that their findings echo those of Sabel et al (Am J Clin Oncol 2001;24:425-428, PMID: 11474280), the authors concluded, “There is no current evidence to support routine baseline multigated acquisition scan testing for younger, perhaps premenopausal, wom-en without underlying cardiac risk fac-tors who are not candidates for adjuvant trastuzumab.”

From�Annals of Oncology

A meta-analysis of randomized clin-ical trials involving anti-epidermal

growth factor receptor (EGFR) agents in the treatment of advanced cancers has confirmed that the monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs)—in particular, cetux-imab (Erbitux, Bristol-Myers Squibb/Lilly) and panitumumab (Vectibix, Amgen)—that make up the class are associated with an increased risk for venous thromboembolic events (VTEs; excluding catheter-related events) when compared with controls.

Although research has indicated that these agents may lead to the development of arterial thromboembolic events (ATEs) and VTEs in some patients, the incidence and level of risk associated with their use has remained unknown.

The study (Annals of Oncology 2012 Jan 11. [Epub ahead of print], PMID: 22241897), performed by researchers in the medical oncology unit at the Azien-da Ospedaliera Treviglio-Caravaggio in Italy, analyzed 13 studies encom-passing 7,611 patients undergoing ther-apy with anti-EGFR agents, includ-ing bevacizumab (Avastin, Genentech),

cetuximab, erlotinib (Tarceva, Genen-tech), gefitinib (Iressa, AstraZeneca), sorafenib (Nexavar, Bayer/Onyx), pani-tumumab and sunitinib (Sutent, Pfizer). In 11 studies including 7,073 patients, the relative risk for VTEs in patients treat-ed with the study drug was 1.32 com-pared with control patients (P=0.01). The incidence of VTEs across all stud-ies was 5%. In five studies that includ-ed 3,030 patients, the relative risk for ATEs in patients treated with the study drug was 1.34, compared with control patients (P=0.11). Across all studies, the incidence of ATEs was 4.5%.

Additionally, the authors found that

the relative risk for VTEs was higher among mAbs (1.34; P=0.01) than oral TKIs (1.16; P=0.65). Whereas cetux-imab and panitumumab carried the highest risk for ATEs and VTEs (1.61; P=0.006) within the anti-EGFR class in settings for which they are current-ly approved, erlotinib and gefitinib did not carry an increased risk for throm-botic events. Overall, the use of anti-EGFR agents increases the risk for VTEs by 32% in patients with advanced solid tumors.The authors note that thrombotic risk is “likely not correlat-ed to the longer duration of therapy in experimental arms.”

Lillie D. Shockney, RN, BS, MASUniversity Distinguished Associate Professor of Breast CancerAssociate Professor, Johns Hopkins University School of Medicine Johns Hopkins Avon Foundation Breast Center

EXPERT INSIGHT

David Cosgrove, MBBChAssistant Professor of OncologyThe Johns Hopkins University School of MedicineThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

EXPERT INSIGHT


Breast

Several new agents have shown prom-ise in studies with clinically meaning-ful end points. Vorinostat, a histone deacetylase (HDAC) inhibitor, signifi-cantly improved progression-free sur-vival (PFS) in a Phase III study, while pomalidomide, a derivative of thalido-mide, demonstrated substantial activi-ty in a Phase II study.

Outcomes in the treatment of MM have improved with the introduction of immunomodulating agents, such as lenalidomide, and the proteasome inhibitor bortezomib, but the progno-sis remains poor when patients become refractory. Until recently, reported medi-an survival for these patients has been less than six months.

However, recent data reflects the promise of these newer therapies: 60% of patients in both arms of a Phase III study with vorinostat were alive at two years; however, the patients in the arm with the experimental agent had a sig-nificantly longer PFS.

In this study, presented at the 2011 annual meeting of the American Soci-ety of Hematology (ASH, abstract 811), vorinostat combined with bortezomib was compared with bortezomib alone in 637 patients. The schedule for bort-ezomib in both arms was 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day schedule. Those in the experimental arm also received 400 mg of oral vorinostat on days 1 to 14.

The median age in the study was 61 years and the median number of prior treatment regimens was two. Approx-imately 80% of patients had received a prior alkylating agent, 60% had received a prior immunomodulating agent and 25% had received bortezomib. Almost half were nonresponsive to their last regimen.

After a median follow-up of 25 months, the median PFS was 7.63 months in the arm that received vorinostat plus bort-ezomib versus 6.38 months in the arm receiving bortezomib alone. This trans-lated into a 23% reduction in the haz-ard ratio (HR) of progression (HR, 0.77; 95% confidence interval [CI], 0.64-0.94; P=0.01). According to senior investiga-tor Meletios Dimopoulos, MD, a profes-sor of clinical therapeutics at the Uni-versity of Athens in Athens, Greece, the improvement in the primary end point was consistent with the greater activi-ty provided by vorinostat, which boost-ed the objective response rate from 41% to 56% (P<0.001) as well as the rate of

clinical benefit, a designation that also includes stable disease, from 54% to 71% (P<0.0001).

Although not yet mature, the data for overall survival (OS) moved in a favor-able direction (HR, 0.86; 95% CI, 0.62-1.18; P=0.32).

The PFS advantage was consistent when patients were stratified by age, type of melanoma and lines of prior ther-apy. The advantage also was consistent whether or not patients had received prior immunomodulating therapies, although the benefit appeared to be lost among patients who had been previous-ly exposed to bortezomib. The addition of vorinostat was characterized as well tolerated with both the rate of serious side effects (41% vs. 43%) and discontin-uations due to serious adverse events (7% vs. 10%), both numerically lower in the vorinostat arm.

Grade 3 or 4 side effects that occurred with notably great-er frequency in the vorinostat arm included thrombocyto-penia (45% vs. 24%), diarrhea (17% vs. 9%) and fatigue (17% vs. 7%).

Asked whether an additional five or six weeks of PFS could be con-sidered clinically significant, Dr. Dimo-poulos maintained that for a reasonably well-tolerated therapy, this advantage is meaningful to patients, and he expects that efforts to improve response rates by manipulating the dose or schedule of vorinostat, like successful efforts to improve the efficacy and safety of bort-ezomib, will likely build on the advantag-es demonstrated in this Phase III study.

At the same time, Phase II data with pomalidomide, an immunomodulating agent that is chemically related to lenalid-omide, and panobinostat, another HDAC inhibitor, also have suggested promise for patients with heavily pretreated MM.

In the study with pomalidomide (ASH, abstract 812), 84 patients were evaluated in two groups. Both received 4 mg of oral pomalidomide daily plus 40 mg dexamethasone weekly. In one group, the pomalidomide was adminis-tered only on days 1 to 21 of the 28-day

cycle. In the oth-er arm, patients r e c e i v e d p o m a l i d o -mide on all 28 days.

According to the inves-tigator who

presented the d a t a , X a v i e r

Leleu, MD, PhD, an associate profes-

sor of hematology at the Centre Hospitalier Région-

al Universitaire in Lille, France, “the data were impressive” with objec-tive responses in approximately 34% of patients in either group. The median PFS in those with an objective response was almost 12 months even though 69% were refractory to both bortezomib and lenalidomide and had progressed on their last line of therapy.

The Phase II study with panobino-stat (ASH, abstract 814), called PAN-ORAMA 2 (PANobinostat ORAl in Mul-tiple myelomA), was an extension of a Phase I study conducted in patients with a median prior exposure to four regimens. All patients had progressed within 60 days of a prior bortezomib regimen. In the Phase I and II studies, the patients were restarted on bortezo-mib along with 20 mg of oral panobi-nostat on days 1, 3, 5, 8, 10 and 12 of a 21-day cycle plus 20 mg of dexameth-asone on the day of and the day after

bortezomib. Again, the rate of objec-tive responses has been substantial with the length of PFS correlating with the degree of response, according to Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, the study’s lead author.

At the time of analysis, nine patients had achieved at least a partial response and an additional seven achieved a min-imal response, the investigators reported.

Like vorinostat and pomalidomide, the advantages of panobinostat include oral administration and an accept-able tolerability profile. Most of the grade 3 and 4 adverse events have been hematologic, which impose a small-er adverse effect on quality of life than neuropathy or gastrointestinal com-plaints, which were infrequent in high-er grades. According to Dr. Richard-son, the fact “that the patients were all required to be refractory to bortezomib at study entry makes the response rate all the more remarkable.” He believes the level of activity with panobinostat supports a Phase III trial, which is cur-rently under way.

—Ted Bosworth

Dr. Dimopoulos reported an honorary and/or a consultancy relationship with Celgene

and Ortho-Biotech. Dr. Lelu reported honoraria and/or research funding from

Amgen, Celgene, Janssen Cilag, Novartis and Roche. Dr. Richardson reported an

advisory relationship with Celgene, Johnson & Johnson, Keryx Biopharmaceuticals,

Millennium and Novartis.

New Options for Pretreated Multiple MyelomaSan Diego—Emerging data suggests that a range of new treatment options may be coming for patients with refractory multiple myeloma (MM) that has progressed after exposure to bortezomib, lenalidomide and other modern therapies for this disease.

‘That patients were all required to be refractory to

bortezomib at study entry makes the response rate

all the more remarkable.’—Paul G. Richardson, MD

CliniCal OnCOlOgy�news •�april 2012 27HEMATOLOGIC DISEASE

Multiple Myeloma

Ruxolitinib (Jakafi, Incyte), an inhib-itor of the Janus-associated kinase (JAK) pathway, is the first drug grant-ed an indication for the treatment of myelofibrosis (MF) by the FDA. Two simultaneous trials were conducted for regulatory approval, each with the goal of demonstrating a reduction in sple-nomegaly; however, one of the studies also showed a survival benefit in sec-ondary analysis.

“The reduction in the spleen volume was dramatic in many patients, but we were particularly impressed with the symptomatic response. Patients with quite debilitating symptoms achieved substantial relief of their symptoms, and this has not been seen with other therapies,” said Claire N. Harrison, MD, a hematologist at Guy’s and St. Thom-as National Health Service Foundation Trust in London. Presenting the results of COMFORT-II (COntrolled MyeloFi-brosis Study with ORal JAK Inhibitor Therapy), a European study conduct-ed independently but simultaneously with COMFORT-I, a North American study, Dr. Harrison reported that bene-fits were consistent across the subtypes of MF, including primary MF, postpoly-cythemia vera (PV) MF and postessen-tial thrombocythemia (ET) MF.

COMFORT-I (ASH, abstract 278), presented by Srdan Verstovsek, MD, PhD, an associate professor in the Leu-kemia Department at the University of Texas MD Anderson Cancer Center in Houston, and COMFORT-II had similar designs. In COMFORT-I, 309 patients with MF were randomized to an oral dose of ruxolitinib (15 mg if the plate-let count was 100 to 200 × 109/L or 20 mg if higher) or placebo. In COMFORT-II (ASH, abstract 279), which enrolled 219 patients, the randomization was to the same doses of ruxolitinib or best available therapy (BAT) at the investi-gator’s discretion. BAT consisted large-ly of off-label therapies such as steroids, hydroxyurea, erythropoiesis-stimulat-ing agents or androgens.

The primary end point for both stud-ies was a reduction in spleen volume of at least 35% as assessed with mag-netic resonance imaging (MRI) after 24 weeks of therapy and the two stud-ies produced nearly identical results. In COMFORT-I, the 35% reduction in spleen volume at 24 weeks was achieved by 42% of those taking ruxolitinib com-pared with 1% of those taking placebo (P<0.001; Table 1). In COMFORT-II,

the percentages meeting this end point were 31.9% for ruxolitinib and 0% for BAT (P<0.0001).

The proportion of patients achiev-ing a 50% reduction at 24 weeks in total symptom score (TSS), comprised of abdominal discomfort, pain under the ribs on the left side of the abdomen, ear-ly satiety, itching, night sweats and bone or muscle pain, was a secondary end point in COMFORT-I. This was met by 45.9% of those taking ruxolitinib com-pared with 5.3% of those taking place-bo (P<0.0001).

COMFORT-I also included a survival analysis as a secondary end point. After a median follow-up of approximate-ly 12 months, only 13 of those random-ized to ruxolitinib had died compared with 24 of those randomized to placebo,

producing a 50% reduction in risk (haz-ard ratio, 0.499; 95% confidence inter-val, 0.254-0.98; P=0.0395).

In COMFORT-II, the reduction in symptoms was marked although the TSS metric was not used. COMFORT-II also was not designed to evaluate survival.

In both studies, ruxolitinib was well tolerated. In COMFORT-II, for exam-ple, both diarrhea rates (23% ruxoli-tinib vs. 11% BAT) and headache (10% ruxolitinib vs. 4% BAT) were higher with ruxolitinib than BAT, but the rates of discontinuation for adverse events (8% ruxolitinib vs. 5% BAT) were only slightly elevated and discontinuations for any reason favored ruxolitinib (18% ruxolitinib vs. 33% BAT).

In the COMFORT-I study, the same

percentage of patients stopped therapy due to side effects for both ruxolitinib and placebo (11%).

However, the importance of the new therapy is perhaps best illustrated by a separate, combined post hoc analy-sis done to compare the benefit of BAT in COMFORT-II with placebo in COM-FORT-I. According to Ruben Mesa, MD, a professor of medicine and chair of hematology at Mayo Clinic in Scott-sdale, Ariz., who presented this analy-sis in a poster (ASH, abstract 1753), BAT did not appear to provide any advantage in spleen size, symptoms or quality of life (Table 2).

The benefit of a JAK inhibitor in MF is predicted by the role of JAK signal-ing in hematopoiesis. In particular, the JAK2V617F mutation, which can accelerate hematopoeisis and lead to fibrosis in the bone marrow, red blood cell overproduction and dysfunction-al platelets, is observed in up to 50% of patients with ET and MF and up to 90% of patients with PV. Howev-er, when the benefit from ruxolitinib was compared between those with or without the JAK2V617F mutation, the advantage of ruxolitinib over the com-parator was similar, indicating that this mutation need not be present for the agent to work.

In fact, patients receiving ruxolitinib “had higher response rates than pla-cebo regardless of baseline subgroup, including MF disease subtype, age [<65 vs. >65], IPSS [International Prognostic Scoring System] risk group, presence or absence of JAK2V617F mutation, hemo-globin level [<10 or >10 g/dL], palpable spleen length [<10 or >10 cm] and symp-tom severity,” Dr. Verstovsek said.

The activity of ruxolitinib, although clinically important, provides a proof of concept that JAK inhibition is effective in myeloproliferative diseases. Reflect-ing the intensified interest in this tar-get, new data were presented at ASH on several other JAK2 inhibitors at ear-ly stages of development.

For example, Phase II data from a 34-patient study was reported for pac-ritinib (S*Bio, SB1518). According to the lead author, Rami Komrokji, MD, the clinical director of the Depart-ment of Hematologic Malignancies at

Ruxolitinib Related To Survival in MyelofibrosisSan Diego—Updated data from regulatory approval studies has confirmed the efficacy of ruxolitinib for myelofibrosis as well as provided proof of concept that JAK inhibition is effective in myeloproliferative diseases, according to research presented at the 2011 annual meeting of the American Society of Hematology (ASH).

Table 1. Mean Percent Change in Spleen Volume And Symptom Score From Baseline to Week 24

Subgroup SV, Mean % Change TSS, Mean % Change

Ruxolitinib Placebo Ruxolitinib Placebo

Primary�MF –29.9�±�17.5 8.5�±�16.7 –38.5�±�54.3 41.7�±�92.0

Postpolycythemia�vera�MF

–37.3�±�20.9 5.9�±�14.5 –54.9�±�41.5 27.2�±�105

Postessential��thrombocythemia�MF

–27.0�±�17.4 11.1�±�11.2 –49.9�±�45.1 73.7�±�112

High�risk –30.9�±�19.5 7.7�±�15.8 –41.5�±�52.2 48.7�±�94.8

Intermediate-2�risk –32.8�±�18.4 9.1�±�14.5 –53.5�±�43.2 28.8�±�107

MF,�myelofibrosis;�SD,�standard�deviation;�SV,�spleen�volume;�TSS,�total�symptom�score

Table 2. Change in Quality-of-Life Scores at Week 24 In the Placebo and BAT Arms (Observed Cases)a

Placebo BAT

n Mean�Change�From�Baseline�at�Week�24�(SD)

n Mean�Change�From�Baseline�at�Week�24�(SD)

Global�health�status/Qol

104 -3.4�(21.53) 37 5.2�(23.76)

Fatigue 107 1.8�(24.71) 39 –1�(23.57)

Pain 104 8.3�(27.47) 39 3�(28.06)

BAT,�best�available�therapy;�SD,�standard�deviation;�QoL,�quality�of�life

a�For�patients�with�measurements�at�both�baseline�and�week�24.

‘Ruxolitinib is now clearly front-line therapy for

myelofibrosis patients.’—RubenMesa,MD

The data provides

proof of concept

that JAK inhibition

is effective in

myeloproliferative

diseases.

28 CliniCal OnCOlOgy�news •�april 2012HEMATOLOGIC DISEASE

Myeloproliferative Diseases

Moffitt Cancer Center in Tampa, Fla., the reduction in splenomegaly—which was more than 50% in 44% of treated patients—correlated with an improve-ment in MF symptoms, including reduc-tions in abdominal pain, bone pain and fatigue. Similarly, LY2784544 (Eli Lilly), another JAK2 inhibitor, reduced spleen length in all but four of 17 patients par-ticipating in a Phase I study, according to Dr. Verstovsek, who led this study.

The results of COMFORT-I and II have already led to regulatory approval

of the agent but Dr. Harrison, noting the absence of alternatives, suggested that the data supports an immediate change in practice.

“At this point, I would put all my patients with myelofibrosis on ruxoli-tinib, particularly if they have symp-tomatic splenomegaly,” reported Dr. Harrison. She suggested that the major symptomatic benefits are not now achievable with any other therapy.

Asked to comment on the significance of these results, Dr. Mesa told Clinical

Oncology News that “ruxolitinib is now clearly front-line therapy for myelofi-brosis patients, in particular for those deemed not to need immediate stem cell transplant or those whose primary MF morbidity is anemia.”

From another perspective, Dr. Kom-rokji provided a very similar comment. “At this point, JAK inhibitors are the best option for patients with symptom-atic splenomegaly and/or myelofibro-sis-related constitutional symptoms, especially if they were treated with

hydroxurea before,” he said. In particu-lar, Dr. Komrokji called the overall sur-vival data “very encouraging.”

—Ted Bosworth

Dr. Harrison reported that she has received honoraria and/or research funding from

Celgene, Incyte, Novartis, S*Bio and Sanofi-Aventis. Dr. Verstovsek reported receiving

research funding from Incyte. Dr. Mesa reported receiving research funding from

Incyte and S*Bio. Dr. Komrokji had nothing to disclose.

More than 1 million cancer deaths were avoided from 1990 through 2008, the report’s authors estimated. For 10 years with available data (1998-2008), death rates continued to decrease for all four major cancer sites—lung, colorectum, breast and prostate, with colorectal can-cer accounting for much of the decline in both men and women.

“Among men, 78% of the [overall] decline is due to decreases in the top three cancer sites—lung, prostate and colorectal cancers; while among wom-en, 56% of the decline is due to decreas-es in death rates for breast and colorectal cancers,” said lead author Rebecca Sie-gel, MPH, an ACS epidemiologist based in Atlanta.

“Lung cancer death rates have been declining among men since 1990, due to the reduction in tobacco use over the past 50 years,” she said, noting that the mortality decline has been smaller for women than for men because of the lag in decline in the lung cancer death rate among women. Smoking prevalence among women peaked 20 years later than among men.

“Decreases in prostate, female breast and colorectal cancer death rates largely reflect improvements in early detection and/or treatment,” Ms. Siegel added.

In an interview, Howard Sandler, MD, chair of radiation oncology and Ronald H. Bloom Family Chair in Cancer Thera-peutics at Cedars-Sinai Medical Center in Los Angeles, attributed the long decline in cancer death rates to a “combination of factors,” including a declining number of smokers, effective methods of early can-cer detection and better treatments.

Dr. Sandler did not believe that the novel, targeted cancer therapies had a great effect on cancer mortality rates, in

part because those therapies are usually administered to patients who have “not only cancer, but fatal cancer.” Such drugs are more important for increasing surviv-al time than for changing the death rate, explained Dr. Sandler, who is an executive

editor of the American Society of Clinical Oncology Web site CancerProgress.net.

Despite the decline in overall cancer mortality, incidence rates of some less common cancers have been increasing, according to a second article from the

ACS (Simard EP et al. CA Cancer J Clin2012 Jan 4. [Epub ahead of print], PMID: 22281605). Authors of that study docu-mented increases in cancers of the pan-creas, liver, thyroid and kidney, as well as increases in esophageal adenocarcinoma, melanoma and some kinds of throat can-cer associated with human papillomavi-rus (HPV) infection.

“The reason for the increasing rates is unknown, but the obesity epidemic is probably associated with increases for some of these cancers,” Ms. Siegel said. “Increases in early detection practices are a likely contributor as well.”

Dr. Sandler described several fac-tors that may account for the observed increases in cancer incidence rates: gas-troesophageal reflux associated with obe-sity for esophageal adenocarcinoma, hep-atitis C and B virus infections for liver cancer, increased sun exposure for mel-anoma of the skin and increased preva-lence of HPV infection for throat cancer associated with HPV. The increase in the incidence of melanoma was particularly sharp, he noted.

Ms. Siegel added that the increase in the incidence of thyroid cancer was the larg-est, and that the increase in kidney can-cer incidence was an unexpected finding.

“Although most of the increases were confined to whites, rates of kidney can-cer increased among both men and wom-en of every racial/ethnic group, although the increase was not statistically signif-icant among American Indian/Alaska Native men.”

Regarding mortality rates, Dr. Sandler expressed hope that the downward trend in deaths from cancer will continue.

“To survive [as oncologists], we have to be optimistic,” he said. “Yes, the trend is going to continue to go down.”

—George Ochoa

Ms. Siegel and Dr. Sandler reported no relevant conflicts of interest.

Cancer Deaths Down, But With a Few AberrationsCRC mortality continues to decline, reflecting better screening, treatments

In the past two decades, the overall death rate from cancer decreased by 22.9% in men and 15.3% in women, according to the most recent annual report on cancer incidence from the American Cancer Society (ACS; Siegel R et al. CA Cancer J Clin 2012;62:10-29, PMID: 22237781).

‘Decreases in prostate, female breast and colorectal

cancer death rates largely reflect improvements in

early detection and/or treatment.’—RebeccaSiegel,MPH

‘To survive [as oncologists], we have to be

optimistic. Yes, the trend [in cancer mortality rates]

is going to continue to go down.’—HowardSandler,MD


Patient Care

The retrospective study, presented at the recent San Antonio Breast Can-cer Symposium (SABCS), conclud-ed that APBI with brachytherapy is associated with inferior effectiveness and increased toxicity compared with whole breast irradiation (WBI) in old-er patients (abstract S2-1).

“From 2000 through 2007, old-er women in the United States treated with brachytherapy experienced higher risk for losing the breast, postoperative infection, postoperative wound compli-cations, breast pain and fat necrosis,” said Benjamin Smith, MD, an assistant professor in the Department of Radia-tion Oncology at the University of Texas MD Anderson Cancer Center in Hous-ton, who presented the study. He point-ed out that the study results do not apply to APBI delivered by external beam.

Press headlines following SABCS included “Quicker Radiation Therapy Doubles Mastectomy Risk” (Reuters) and “Mastectomy Risk High With Brachytherapy for Breast Cancer” (Medscape). These articles infuriat-ed some APBI investigators, including Robert Kuske, MD, a radiation oncol-ogist at Arizona Breast Cancer Spe-cialists-Scottsdale, who says that the treatment’s effectiveness is measured by recurrence rates and survival after treatment, not future mastectomies.

“The consequences of this informa-tion out of the MD Anderson analysis are potentially damaging. If the random-ized NSABP [National Surgical Adju-vant Breast and Bowel Project-39] clin-ical trial fails to reach its goal of 4,300 patients because of this misinformation, this would be a tragedy because real answers to all of our questions will come out of this scientifically pure study,” said Dr. Kuske, a principal investigator of this ongoing randomized Phase III trial, which is expected to provide a rigorous comparison of APBI and WBI.

In the SABCS study, researchers ana-lyzed Medicare records of 130,535 wom-en diagnosed with invasive breast can-cer between 2000 and 2007 who were treated with lumpectomy followed by either WBI (n=123,244) or APBI with brachytherapy (n=7,291). To assess safe-ty and effectiveness, Dr. Smith and his colleagues compared overall surviv-al, the risk for subsequent mastectomy, postoperative complications and post-radiation toxicities.

The investigators did not iden-tify any difference in survival, but brachytherapy was associated with

an increased risk for mastectomy (4% vs. 2.2%; P<0.001). Patients undergo-ing brachytherapy had a higher rate for infectious postoperative complica-tions (16% vs. 10%; P<0.001) and non-infectious postoperative complications (16% vs. 8%; P<0.001), such as a surgi-cal wound breakdown, postoperative bleeding or seroma formation. Compli-cations occurring within five years after the start of radiation therapy that also increased with brachytherapy included breast pain (15% vs. 12%; P<0.001) and fat necrosis (9% vs. 4%; P<0.001).

“Fat necrosis may not have much clin-ical significance, but generally is con-sidered a marker of tissue injury from either surgery and/or radiation therapy,” said Dr. Smith. Radiation pneumonitis, however, was more common in patients receiving WBI (0.1% vs. 0.8%; P<0.001).

Study Under a Scope

Critics say the study has many limita-tions. First, it is a retrospective analysis examining Medicare patients who were treated at the discretion of thousands of physicians, said Dr. Kuske. As such, it could not take into account tumor char-acteristics, margin status or a patient’s general medical condition. “We do know that women received more che-motherapy in the whole breast irradia-tion group of patients,” Dr. Kuske said. “This, by itself, could account for the small 1.8% difference in mastectomy rates between the two groups.”

He added that factors such as diabetes, obesity or smoking history were not taken into account and could have contributed to the higher complication rates. Poten-tially significant factors, he said, are con-trolled and recorded in greater detail in randomized trials such as the NSABP-39 trial. Dr. Kuske also pointed out that the rate of biopsy-proven breast cancer recur-rence in the two groups was not stated, and there are many noncancer reasons for subsequent mastectomy, such as test-ing positive for the BRCA gene or a false-positive magnetic resonance imaging.

Another limitation is that the SABCS trial analyzed procedures that used ear-ly-generation brachytherapy techniques and not the more advanced techniques used today.

In response to the study, the American Society for Radiation Oncology (ASTRO) issued a statement saying it was con-cerned about the potential misinter-pretation of the data. “There are limi-tations to the interpretation of the data, given that it was drawn from records of

patients [with] varying risk factors and stage treated between 2000 and 2007,” the statement reads. “Since that time, technology has dramatically improved, including the use of newer multichannel applicators with tighter dose constraints.” The statement also noted that although statistically signif-icant, the rate of mastectomy is very low in either treatment group. Many patients, said Dr. Kuske, would accept a 1.8% dif-ference in order to have a shorter treat-ment that exposes less normal tissue to ionizing radiation.

According to Peter Beitsch, MD, numer-ous retrospective studies and two pro-spective randomized studies have shown no difference in survival, locoregional cancer recurrence rates and complica-tions between APBI and WBI. Dr. Beitsch is co-principal investigator of the Amer-ican Society of Breast Surgeons (ASBS) MammoSite Registry, which includes information on 1,440 patients who were given APBI brachytherapy with the MammoSite balloon catheter device through 2004. Information gleaned from this registry shows a low rate of compli-cations and a five-year local recurrence rate of less than 5%, which is comparable to that of WBI. Several single-institution randomized and nonrandomized studies using another APBI technique, multiple interstitial catheters, also report rates of local recurrence comparable to WBI.

Dr. Beitsch also took issue with a study end point. “The study stated that sub-sequent mastectomy is a validated sur-rogate for local failure. However, I am unaware of any literature that states this,” he argued, adding that APBI often is used in older, sicker patients who may not be candidates for the six to seven weeks of WBI. This factor could introduce bias into the MD Anderson study results.

In response, Dr. Smith said the two-fold increased risk for subsequent mastectomy was found “even after adjusting for patient age, race, comor-bidity, treatment with chemothera-py, surgical assessment of the axilla and axillary lymph node involvement.”

Nevertheless, he added, “the abso-lute risk for subsequent mastectomy in patients treated with brachythera-py was still quite small at only 4%, and was consistent with the risks for sub-sequent mastectomy reported by the ASBS MammoSite Registry Study.”

According to Bruce Haffty, MD, a pro-fessor and chairman of radiation oncol-ogy at the University of Medicine and Dentistry, New Jersey-Robert Wood Johnson Medical School in New Bruns-wick, the SABCS study should provide an additional incentive for physicians to adhere to ASTRO’s APBI consensus statement. This 2009 statement, which he and Dr. Smith helped author, outlines criteria for selecting patients to be treat-ed with APBI outside of a clinical trial.

While awaiting results from the NSABP-39 trial and six other ongoing randomized trials comparing APBI and WBI, oncologists may find themselves inundated by questions from patients who have heard about the retrospective study. They can point patients to the statements issued by ASTRO and ASBS. According to ASBS, “The evidence in the MD Anderson study should be con-sidered in presurgical counseling, but is not strong enough to preclude the use of PBI in properly selected patients.”

—Kate O’Rourke

Dr. Beitsch has received lecture fees from companies making brachytherapy

equipment. Dr. Kuske disclosed receiving teaching and lecture fees from

companies making both external beam and brachytherapy equipment. Dr. Smith

disclosed research funding from Varian Medical Systems, which makes a variety

of radiation equipment, including WBI and APBI instruments. Dr. Haffty reported no

relevant disclosures.

Partial Breast Radiation Study Sparks DebateA new study has spurred some doctors to urge caution in selecting patients for accelerated partial breast irradiation (APBI) and angered others who say the study is flawed and could derail a Phase III clinical trial testing APBI.


Breast

As 2011 drew to a close, the McMahon Group bestowed honors on several employees within its talented workforce. Throughout the year, McMahon’s portfolio of clinical news magazines maintained readership numbers that solidifi ed their best-read status, and sales revenues increased despite a challenging economic climate. The diverse talents and collaborations among McMahon’s staff allowed the company to maintain its position as a trusted source of news and educational initiatives. McMahon’s publishing success was on display both in print and on the Web sites of its publications and custom media platforms.

Here is a look at those recognized for their unique contributions during 2011.

2011Spotlight On Our Very Best

SUPPORT/PRODUCTION/IT/FINANCE PERSON OF THE YEAR: The�second�winner�was�ROSA DIMICCO,�accounting�associate,�for�diligently�ensuring�that�freelance�writers�and�key�opinion�leaders�are�paid�in�a�timely�manner�for�their�exceptional�work.

SUPPORT/PRODUCTION/IT/FINANCE PERSON OF THE YEAR: employees�were�asked�to�select�the�two�most�outstanding�members�from�these�departments.�The�fi�rst�winner�was�JOHN CABA,�software��developer,�for�his�tireless�devotion�toward�improving�the�company’s�digital�platforms.�

GRAPHIC DESIGNER OF THE YEAR: JEANETTE MOONEY�won�the�award�in�recognition�of�her�creative�talents�as�art�director�for�Pain Medicine News,�along�with�her�superb�layout�designs�for�a�host�of�special�reports�and�custom�newsletters.

MOST IMPROVED SALESPERSON OF THE YEAR: each�member�of�the�sales�staff�seeks�to�improve�throughout�the�year;�however,�one�inevita-�bly�displays�accelerated�growth.�DAVID NATHANSON, account�manager,�managed�to�do�just�that�across�several�publications�in�2011.�

SPECIAL PROJECTS EDITOR OF THE YEAR: SETH KANDEL�was�voted�best�projects�editor�for�his�exemplary�work�on�numerous�custom�media�programs�for�medical�industry�clients�as�well�as�his�management�of�the�editorial�in�Infectious Disease Special Edition.

NEWSMAGAZINEEDITOR OF THE YEAR: DONALD PIZZI,�managing�editor�of�Pain Medicine News, was�recognized�for�the�excel-lence�of�his�news�coverage�throughout�2011.�Under�Don’s�discerning�eye,�the�magazine��offers�a�comprehensive�resource�for�clinicians�involved�in�the�management�of�pain.

SALES ACHIEVEMENT AWARD: DAVE KAPLAN,�publication��director�of�Pharmacy Practice News,�was�the�2011�winner�in�this�category.�Dave�has�proven�himself�to�be�an�innovator�among�his�peers�by�championing��exciting�new�platforms�and�marketing�opportunities�for�his�many�clients.

SALESPERSON OF THE YEAR: whereas�the�other�awards�are�decided�by�a�jury�of�one’s�peers,�this�honor�is�bestowed�on�the�one�salesperson�who�brings�in�the�most�revenue.�For�a�record-breaking�sixth�year�in�a�row,�the�winner�was�RICHARD TUORTO,�senior�group�publication�director�for�Anesthesiology News and Pain Medicine News. richard’s�dedication�to�his�clients’�marketing�needs�and�intimate�knowledge�of�their�products�enable�him�to�reach�the�zenith�of�sales�profi�ciency�year�after�year.

PARTNERS SPECIAL RECOGNITION AWARD 2011: The�partners�of�McMahon�publishing�occasionally�present�an�award�to�someone�who�has�contributed�to�the�success�of�the�company�over�many�years�of�service.�This�year’s�winner�was�URBAN S. MULVEHILL,�who�has�provided�legal�services�to�the�company�since�1983.�He�became�a�partner�at�his�law�fi�rm,�O’neill�DiManno�and�Kelly,�in�1980�after�having�served�as�a�trial�lawyer�for�several�years�at�the�U.s.�Department�of�Justice.�Urban’s�relaxed�demeanor�and�sage�advice�over�the�past�three�decades�have�been�greatly�appreciated.

PARTNERS AWARD

PERSON OF THE YEAR 2011: This�award�recognizes�the�cream�of�the�crop,�and�MARY LOU CAMPANELLA,�chief�fi�nancial�offi�cer,�was�the�2011�person�of�the�year.�Mary�lou�has�been�able�to�streamline�the�company’s�fi�nances�by�thwarting�ineffi�ciencies�and�highlighting�excess�expenditures.�Her�constant�professionalism,�hard�work�and�keen�eye�for�detail�have�proven�to�be�invaluable�commodities�that�are�greatly�appreciated�by�her�peers.�

PERSON OF THE YEAR

CO0412

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1 Atlas of Diagnostic Oncology: Expert Consult— Online and Print: Fourth Edition

Arthur T. SkarinElsevier/Mosby, December 23, 2009 This atlas provides the guidance you need to diagnose a full range of neoplastic conditions with greater accuracy for better patient outcomes. More than 2,500 images and drawings—combined with succinct, clini-cally focused text—equips you with essential information on pathology, diagnostic studies, staging and clinical manifestations.

2 Cancer Metastasis: Biologic Basis and TherapeuticsDavid Lyden; Danny R. Welch; Bethan Psaila

Cambridge University Press, April 25, 2011This groundbreaking text comprehensively covers the processes under-lying cancer metastasis and the clinical treatment of metastatic disease. The internationally renowned authors of this volume have summarized the state-of-the-art research in the metastasis field.

3 Counseling About Cancer: Strategies for Genetic Counseling, Third Edition

Katherine SchneiderJohn Wiley, December 6, 2011 This edition features five new chapters on breast cancer, colon cancer, other solid tumors, clients and families, and genetic test results and fol-low-up. This is the only reference and clinical book on the market for cancer genetics counselors who must quickly assimilate complex and ever-changing data on the hereditary risk for cancer.

4 DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology: Ninth Edition

Vincent DeVita, Ronald A. DePinho; Theodore S. Lawrence; Steven A. Rosenberg; Robert A. WeinbergLippincott Williams & Wilkins, May 16, 2011 The primary goal of this book is to present the practicing oncologist with the practical as well as cutting-edge information needed to ensure the best possible care for each individual patient.

5 Leibel and Phillips Textbook of Radiation Oncology: Expert Consult—Online and Print

Theodore L. Phillips; Richard Hoppe, MDElsevier/Saunders, September 23, 2010

This textbook offers a multidisciplinary look at the presentation of uni-form treatment philosophies for cancer patients emphasizing the “treat for cure” philosophy. You can also explore the implementation of new imaging techniques to locate and treat tumors, new molecularly tar-geted therapies and new types of treatment delivery.

6 MD Anderson Manual of Medical Oncology, Second Edition

Hagop M. Kantarjian; Robert A. Wolff; Charles A. KollerMcGraw-Hill, April 22, 2011

A hands-on desk reference for the practicing oncologist—from the leader in the field of cancer management. This text details the personal-ized multidisciplinary approach to cancer management pioneered by The University of Texas MD Anderson Cancer Center. It is intended to bring a pragmatic approach to cancer management that can serve as a guide for oncologists around the world.

7 MD Anderson Manual of Psychosocial OncologyJames D. Duffy; Alan Valentine

McGraw-Hill, November 23, 2010

Reflecting the collective expertise of more than 40 contributors, most from MD Anderson Cancer Center, this manual addresses key psycholog-ical and behavioral issues that should be considered when treating can-cer patients, including special populations such as children and the elderly.

8 Understanding Skin Cancer Anatomical ChartAnatomical Chart Company

Lippincott Williams & Wilkins, February 8, 2011

Defines skin cancer and provides detailed illustrations of how it devel-ops from sun exposure. Shows and discusses various types of ultra-violet radiation and how each kind penetrates the skin layers. Illustrates and shows photos of various types of precancer and cancer.

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