BREAST CANCER - Amazon S3...The T H E O F F I C I A L J O U R N A L O F of PROSTATE CANCER...

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PROSTATE CANCERIntermittent Androgen Deprivation with the GnRH Antagonist Degarelix in Men with Biochemical Relapse of Prostate CancerE. David Crawford, MD, Neal Shore, MD, FACS, Celestia S. Higano, MD, FACP, Anders Neijber, MD, PhD, MBA, and Vladimir Yankov, MD

BREAST CANCERAurora Kinase Inhibitors in Breast Cancer TreatmentMateusz Opyrchal, MD, PhD, Kothai Divya Guruswamy Sangameswaran, MBBS, Thaer Khoury, MD, FCAP, Patrick Boland, MD, Evanthia Galanis, MD, Tufia C. Haddad, MD, and Antonino B. D’Assoro, MD, PhD

MULTIPLE MYELOMAClinical Decision Making in Multiple Myeloma for the Transplant-Eligible Patient—Upfront Transplant versus Maintenance TherapyNoa Biran, MD, and David Vesole, MD, PhD

NATIONAL INITIATIVES‘Choosing Wisely’ Campaigns from ASCO and ASH: A Review for Clinicians in Haematology and OncologyIlana Kopolovic, MD, Henry Conter, BESc, MD, MSF, MSc, FRCPC, and Lisa Hicks, MD, MSc, FRCPC

A m e r i c a n

J o u r n a l

H e m a t o l o g y /

O n c o l o g y ®

A Peer-Reviewed Resource

for Oncology Education

ajho

www.AJHO.com ISSN 1939-6163 (print) ISSN 2334-0274 (online)

Volume 11 Number 12 12.15

SOFT-TISSUE SARCOMAS CME-certified enduring materials sponsored by Physicians’ Education Resource®, LLC

Evolving Management Options for Soft-Tissue Sarcomas

Lung Cancer

F O C U S O N L E U K E M I A S , LY M P H O M A S , A N D M Y E L O M A

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Program ChairPatrick I. Borgen, MD Maimonides Hospital Brooklyn, NY

Program DirectorsJ. Michael Dixon, MD Edinburgh Breast Unit Edinburgh, UK Hyman B. Muss, MD University of North Carolina Lineberger Comprehensive Cancer Center Chapel Hill, NC Debu Tripathy, MD The University of Texas MD Anderson Cancer Center Houston, TX

Co-Chairs

March 18-20, 2016EDEN ROC MIAMIMIAMI BEACH, FL

Co-Chairs

Co-ChairsOmid Hamid, MD Chief, Translational Research and Immunotherapy Director, Melanoma Therapeutics The Angeles Clinic and Research Institute Los Angeles, CA

Jeffrey S. Weber, MD, PhDDeputy DirectorLaura and Isaac Perlmutter Cancer CenterProfessor of MedicineNYU Langone Medical CenterNew York, NY

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Planning Committee

Andre Goy, MD, MS John Theurer Cancer Center at Hackensack University Medical CenterHackensack, NJ

Sagar Lonial, MD, FACP Winship Cancer InstituteEmory UniversityAtlanta, GA

Susan O’Brien, MD Chao Family Comprehensive Cancer CenterUniversity of California, IrvineIrvine, CA

David P. Steensma, MDDana-Farber Cancer InstituteBoston, MA

Thomas J. Lynch, Jr., MDMassachusetts General Physicians Organization Boston, MA

Heather A. Wakelee, MD Stanford University Medical Center Stanford, CA

Leonard G. Gomella, MD, FACS Thomas Jefferson University Philadelphia, PA

Daniel P. Petrylak, MD Yale Cancer Center New Haven, CT

AJHO_per.indd All Pages 12/2/15 3:50 PM

Table of Contents

PROSTATE CANCER

Intermittent Androgen Deprivation with the GnRH Antagonist Degarelix in Men withBiochemical Relapse of Prostate CancerE. David Crawford, MD, Neal Shore, MD, FACS, Celestia S. Higano, MD, FACP, Anders Neijber, MD, PhD, MBA, and Vladimir Yankov, MDAndrogen deprivation therapy (ADT) is a mainstay treatment for men with metastatic prostate cancer. A recent study of men with prostate cancer requiring ADT demonstrated that intermittent androgen deprivation (IAD) with degarelix was well tolerated. This article reviews research to determine if 7 months of intermittent degarelix treatment is noninferior to IAD in surpressing prostate-specific anti-gen.

BREAST CANCER

Aurora Kinase Inhibitors in Breast Cancer TreatmentMateusz Opyrchal, MD, PhD, Kothai Divya Guruswamy Sangameswaran, MBBS, Thaer Khoury, MD, FCAP, Patrick Boland, MD, Evanthia Galanis, MD, Tufia C. Haddad, MD, and Antonino B. D’Assoro, MD, PhD Aurora-A kinase has been implicated in breast cancer tumorigenesis and progression of the disease. Pre-clinical data have been encouraging with inhibitors of Aurora-A kinase signaling. The authors review research in developing further specific Aurora-A and pan-Aurora kinase inhibitors.

MULTIPLE MYELOMA

Clinical Decision Making in Multiple Myeloma for the Transplant-Eligible Patient—Upfront Transplant versus Maintenance TherapyNoa Biran, MD, and David Vesole, MD, PhDWith the development of novel therapies for treating multiple myeloma, the role of autologous stem cell transplant (ASCT) has come into question. This article explores current progress in the treatment of transplant-eligible multiple myeloma as it pertains to ASCT, consolidation, and maintenance thera-py.

NATIONAL INITIATIVES

Choosing Wisely Campaigns from ASCO and ASH: A Review for Clinicians in Haematology and Oncology Ilana Kopolovic, MD, Henry Conter, BESc, MD, MSF, MSc, FRCPC, and Lisa Hicks, MD, MSc, FRCPCThe American Society of Hematology and American Society of Clinical Oncology have produced rec-ommendations for the Choosing Wisely campaign, a quality improvement initiative aimed to minimize medical testing and interventions. These recommendations are reviewed in this article, which high-lights the rationale and anticipated benefits of each.

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CME

CME-certified enduring materials sponsored by Physicians’ Education Resource®, LLCSOFT-TISSUE SARCOMAS

Evolving Management Options for Soft-Tissue SarcomasDespite being a relatively rare form of cancer, soft-tissue sarcomas (STS) are a topic of major research inter-est. George D. Demetri, MD, of the Dana-Farber Cancer Center Institute in Boston, shares his insights on the significance of recent discoveries and the optimal application of emerging data to the planning and imple-menting of multidisciplinary treatment for patients with STS.

30

Patrick I. Borgen, MDChairman, Department of Surgery Maimonides Medical CenterDirector, Brooklyn Breast Cancer ProgramBrooklyn, NY

Julie R. Brahmer, MDAssociate Professor, Oncology Johns Hopkins University School of

MedicineSidney Kimmel Comprehensive Cancer

CenterBaltimore, MD

J. Michael Dixon, MD, OBEProfessor of Surgery and Consultant

SurgeonClinical Director, Breakthrough Research

UnitEdinburgh Breast UnitEdinburgh, UK

David R. Gandara, MDProfessor of MedicineDirector, Thoracic Oncology ProgramSenior Advisor to the DirectorDivision of Hematology/OncologyUC Davis Comprehensive Cancer CenterSacramento, CA

Andre Goy, MD, MSChairman and DirectorChief of LymphomaDirector, Clinical and Translational Cancer ResearchJohn Theurer Cancer Center at Hackensack University Medical CenterHackensack, NJ

Omid Hamid, MDChief, Translational Research and ImmunotherapyDirector, Melanoma TherapeuticsThe Angeles Clinic and Research InstituteLos Angeles, CA

Roy S. Herbst, MD, PhDEnsign Professor of Medicine (Medical

Oncology)Professor of PharmacologyChief of Medical OncologyAssociate Director for Translational ResearchYale Cancer CenterYale School of Medicine New Haven, CT

Thomas J. Lynch, Jr, MDCEO and ChairmanMassachusetts General Physicians

OrganizationMassachusetts General HospitalBoston, MA

Maurie Markman, MDPresident, Medicine and ScienceNational Director, Medical OncologyCancer Treatment Centers of AmericaPhiladelphia, PA

John L. Marshall, MDChief, Hematology and Oncology Director, Otto J. Ruesch Center for the

Cure of Gastrointestinal CancersLombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashington, DC

Hyman B. Muss, MDProfessor of OncologyUniversity of North CarolinaDirector of Geriatric OncologyLineberger Comprehensive Cancer CenterChapel Hill, NC

Joyce A. O’Shaughnessy, MDCo-Director, Breast Cancer ResearchBaylor Charles A. Sammons Cancer

Center Texas Oncology The US Oncology NetworkDallas, TX

Daniel P. Petrylak, MDProfessor of Medicine (Medical Oncology) and of UrologyCo-Director, Signal Transduction Research

ProgramYale Cancer Center and Smilow Cancer

HospitalNew Haven, CT

Heather A. Wakelee, MDAssociate Professor, Medicine (Oncology)Stanford University Medical CenterStanford, CA

Jeffrey S. Weber, MD, PhDSenior Member and DirectorDonald A. Adam Comprehensive Melanoma Research CenterMoffitt Cancer CenterTampa, FL

PER® Executive Board/AJHO Editorial Board

4 www.ajho.com DECEMBER 2015

This month’s issue of American Journal of Hematology/Oncology (AJHO), a peer-reviewed resource for education and the official journal of Physicians’ Education Resource®, LLC, features four peer-re-viewed articles on recent advances that could be vital to the future of hematology and oncology treatment.

Our first story focuses on promising prostate cancer research indicating that degarelix may be a viable therapeutic option in the intermittent setting for maintaining PSA suppression, with the therapy found to be a suitable treatment option for men being considered for intermittent androgen ablation.

Metastatic breast cancer is the topic of our next article, which reviews inhibitors for Aurora A kinase signaling. Encouraging trials with alisertib have shown early signals of activity, especially among patients whose tumors are HR+ and HER2-positive.

Next, we look at recent progress in the treatment of transplant-eligible multiple myeloma. While chemotherapy with autologous stem cell transplant has been the mainstay of treatment since the mid-90s, a number of new therapeutic approaches, such as posttransplant consolidation therapy and maintenance therapy, have gained attention as potential treatment strategies.

The American Society of Hematology and the American Society of Clinical Oncology have developed recommendations for “Choosing Wisely,” a national initiative to optimize safety and efficiency in healthcare by encouraging evidence-based application of medical investigations and interventions. Our fourth article evaluates these recommendations, highlighting their rationale and anticipated benefits.

This month’s CME article is a discussion with George D. Demetri, MD, of the Dana-Far-ber Cancer Institute in Boston, on the evolving options currently available for managing soft tissue sarcomas.

Thank you for your support of AJHO in 2015. We look forward to serving you in the new year. Your comments and suggestions are always welcome, and we also invite you to submit original articles and commentaries.

I hope you have a happy, safe, and enjoyable holiday season!

Michael J. Hennessy, Sr

Chairman and Chief Executive Officer

Chairman’s Note

The content of this publication is for general information purposes only. The reader is encouraged to confirm the information presented with other sources. American Journal of Hema-tology/Oncology makes no representations or warranties of any kind about the completeness, accuracy, timeliness, reliability, or suitability of any of the information, including content or advertisements, contained in this publication and expressly disclaims liability for any errors and omissions that may be presented in this publication. American Journal of Hematology/Oncology reserves the right to alter or correct any error or omission in the information it provides in this publication, without any obligations. American Journal of Hematology/Oncology further disclaims any and all liability for any direct, indirect, consequential, special, exemplary, or other damages arising from the use or misuse of any material or information presented in this publication. The views expressed in this publication are those of the authors and do not necessarily reflect the opinion or policy of American Journal of Hematology/Oncology.

VOL. 11, NO. 12 THE AMERICAN JOURNAL OF HEMATOLOGY/ONCOLOGY® 5

EDITORIAL STAFF

In the December issue of AJHO, a timely review of a major branch-point decision in the treatment of multiple myeloma is presented. It is impres-sive enough that long-term remissions are being seen with autologous stem cell transplantation, now with over 20 years of experience, and some patients have achieved an apparent cure. The more surprising turn of events has been the evolution of biological therapies that have lower toxicities and longer disease control when used sequentially or in com-binations. The decision to undergo transplant with acute toxicities and risk of death (albeit much lower than in earlier decades), or to proceed with non-curative, gentler therapy, is now more difficult but still uses the same metrics of age, comorbidities, and personal preferences. However, the terrain is definitely changing with the development of newer bio-logical agents. While autologous stem cell transplant is still favored for transplant-eligible patients, the timing of this procedure – at diagnosis, or after induction with biological or other combinations – has yet to be settled. Also, the optimal agents and treatment lengths of consolidation and maintenance therapy remain unclear, even though, in general, they do improve the quality and duration of remission.

The optimal approach may pivot over time as more effective drugs for relapse/progression are approved. Just in the last month, the FDA granted accelerated approval for the anti-CD38 antibody daratumumab, the first monoclonal antibody approved for multiple myeloma, to treat patients who have received at least three prior treatments, including a proteasome inhibitor and an immunomodulatory agent. Also approved was the new proteasome inhibitor ixazomib in combination with lena-lidomide and dexamethasone as second-line therapy, even more mark-edly superior in the setting of high-risk cytogenetics compared to the control arm of lenalidomide and dexamethasone alone. In this same period, the second antibody elotuzumab, against signaling lymphocytic activation molecule F7 (SLAMF7), was approved also in combination with lenalidomide and dexamethasone for multiple myeloma after pro-gression to 1 - 3 prior therapies.

This flurry of activity in myeloma may be narrowing the gap between upfront or delayed transplant and the use of biological therapies for the whole course of the disease.

CORPORATE OFFICERS Chairman and CEOMichael J. Hennessy, Sr

Vice Chairman Jack Lepping

Senior Vice President, Operations and Clinical Affairs Jeff Prescott, PharmD, RPh

Chief Creative Officer Jeff Brown

Debu Tripathy, MD Editor-in-Chief

From the Editor Editor-in-ChiefDebu Tripathy, MD

Professor and Chair Department of Breast Medical Oncology The University of Texas MD Anderson Cancer Center Houston, TX

Associate EditorJason J. Luke, MD, FACP

Assistant Professor of MedicineUniversity of ChicagoChicago, IL

Managing EditorHoward Whitman [email protected] Art Director Marie Graboso

Editorial OfficesPhysicians’ Education Resource®, LLC666 Plainsboro Road, Ste 356Plainsboro, NJ 08536(609) 378-3701

PresidentPhil Talamo, CHCP

Medical DirectorMichael Perlmutter, PharmD, MS

· PROSTATE CANCER ·


Intermittent Androgen Deprivation with the GnRH Antagonist Degarelix in Men with Biochemical Relapse

of Prostate Cancer

E. David Crawford, MD, Neal Shore, MD, FACS, Celestia S. Higano, MD, FACP, Anders Neijber, MD, PhD, MBA, Vladimir Yankov, MD

IntroductionAndrogen deprivation therapy (ADT) is the mainstay of treat-ment for men with metastatic prostate cancer (PCa) and has been shown to improve survival in combination with radiation therapy in men with high-risk localized disease.1-3 It is also com-monly used to treat men with biochemical relapse, especially when classified as high risk. Unlike bilateral orchiectomy, med-ical castration is reversible and may be used on an intermittent basis. ADT is associated with characteristic side effects including hot flashes; decreased libido, bone mineral density, body mass, muscle mass, and strength; increased body fat, weight; insulin resistance; cardiovascular toxicity; and emotional and cognitive changes.4,5 The potential physical benefits of an intermittent regi-men with one or more off-treatment periods are considered to be due to complete or partial testosterone recovery allowing moder-ation of side effects and improvement of quality of life (QoL).6

Two phase III noninferiority trials of luteinizing hormone-re-leasing hormone (LHRH) agonists have compared intermittent androgen deprivation (IAD) with continuous androgen depriva-tion (CAD).7,8 The National Cancer Institute of Canada trial, PR-7 (NCT00003653), enrolled patients with biochemical fail-ure after primary or salvage radiotherapy for localized disease.7 IAD was noninferior to CAD for overall survival (8.8 vs 9.1 years, respectively; HR = 1.02), and scores for hot flashes, de-sire for sexual activity, and urinary symptoms were significantly improved. Also, men in the CAD arm of PR-7 who achieved nadir testosterone levels <20 ng/mL had an increased time to hormone resistance, demonstrating the importance of achieving low testosterone levels while on treatment.9

The second trial, SWOG 9346 (NCT00002651), compared IAD with CAD for patients diagnosed with metastatic disease (me-dian follow-up, 9.8 years).8 Median survival was 5.8 years and 5.1

Abstract

Objective: To determine if 7 months of intermittent degarelix

treatment is noninferior to continuous androgen depriva-

tion in maintaining suppression of prostate-specific antigen

(PSA) at 14 months.

Patients and Methods: Patients with rising PSA after prior de-

finitive therapy were randomized to intermittent (degarelix)

or continuous (degarelix or leuprolide) treatment arms. All

patients initially received 7 months of androgen deprivation.

After 7 months, men randomized to intermittent therapy

were scheduled to enter a 7-month off-treatment period; de-

garelix was restarted if PSA levels were >2 ng/mL. Predefined

criteria for noninferiority of the primary endpoint, proportion

of patients with PSA ≤4 ng/mL, was the lower limit of the

95% CI difference between the intermittent and continuous

treatment arms being greater than -12.5% at month 14. PSA,

testosterone, and quality-of-life measures were assessed in

all patients at multiple time points.

Results: A total of 409 patients were randomized to in-

termittent (degarelix, n = 177) or continuous (degarelix,

n = 50; leuprolide, n = 182) treatment. At month 14, the lower

confidence interval limit for intermittent versus continuous

treatment was -0.19%; therefore, noninferiority was estab-

lished. No patients in the intermittent arm had PSA >4 ng/mL

at month 14, although 35 patients restarted degarelix before

month 14. PSA was >4 ng/mL in 3 (1.6%) patients receiving

continuous treatment. In the intermittent arm, 116 (85%) men

had testosterone >0.5 ng/mL at a median of 112 days off ther-

apy (95% CI, 112-140). Intermittent treatment was associated

with improved sexual drive assessed by the sexual function

inventory at month 14 (P = 0.027). The most frequently report-

ed adverse event in all arms was hot flashes. Injection site

reactions were more frequent in patients receiving degarelix.

Conclusion: Intermittent degarelix administered as described

is noninferior to continuous androgen deprivation in main-

taining PSA suppression at month 14. These data indicate

that degarelix is a suitable treatment option in men being

considered for intermittent androgen ablation.

Key words: Degarelix, intermittent androgen deprivation, le-

uprolide, quality of life, testosterone

INTERMITTENT ANDROGEN DEPRIVATION WITH THE GNRH ANTAGONIST DEGARELIX


years in the CAD and IAD arms, respectively (HR = 1.10). Although survival noninferiority for IAD was inconclusive, IAD was associat-ed with better erectile function and mental health 3 months after discontinuing ADT in the IAD arm compared withthe CAD arm.

Degarelix is a gonadotropin-releasing hormone (GnRH) an-tagonist providing rapid and sustained testosterone suppression, yet, it has a short half-life of approximately 4 weeks.10,11 Unlike LHRH agonists, GnRH antagonists immediately suppress the secretion of luteinizing hormone (LH), follicle-stimulating hor-mone (FSH), and testosterone without initially overstimulating the GnRH receptor. Thus, there is no transient increase in tes-tosterone, no need for flare protection with an antiandrogen, and a more rapid castration,10 which may be favorable character-istics for IAD therapy.

A recent noncomparative study of European men with histo-logically confirmed prostate cancer requiring ADT demonstrat-

ed that IAD with degarelix was well tolerated, and increases in testosterone were associated with improved erectile function pri-or to prostate-specific antigen (PSA) reaching the predefined lev-el at which treatment was reinitiated (>4 ng/mL).12 The current trial aimed to determine if intermittent use of a GnRH antago-nist, degarelix, is non-inferior to continuous use of an LHRH agonist in maintaining a pre-specified level of PSA suppression at month 14 (≤4 ng/mL) while evaluating testosterone levels and potential impact on QoL. Non-inferiority in regards of PSA lev-els was established if the lower limit of the 95% CI difference between the intermittent and continuous treatment arms was greater than -12.5%, a predefined difference considered not clin-ically relevant. Addressing this endpoint will provide preliminary data as to whether an antagonist such as degarelix is equivalent to LHRH agonists when used as intermittent therapy and assess tolerability compared with continuous ADT.

TABLE 1. Patient Demographics and Baseline Characteristics (at enrollment)

Variable Intermittent degarelix

Continuous degarelix

Continuous leuprolide

Combined continuous arms

Total

FAS, n 175 50 178 228 403

Median age, years (range) 73 (50–91) 71 (56–88) 71 (51–89) 71 (51–89) 72 (50–91)

Median baseline BMI, kg/m2

(range)27.8

(16.3–51.2)28.1

(20.4–40.7)28.8

(17.8–49.5)28.7

(17.8–49.5)28.3

(16.3–51.2)

Median testosterone, ng/mL (range)

3.51 (0.8–9.62)

3.56 (1.2–9.21)

3.51 (0.62–7.84)

3.54 (0.62–9.21)

3.51 (0.62–9.62)

Median PSA, ng/mL (range) 5.15 (0.2–655)

6.45 (0.31–214)

4.52 (0.17–262)

4.96 (0.17–262)

5.1 (0.17–655)

Disease stage, n (%)

LocalizedLocally advancedMetastaticNot classifiablea

65 (37)7 (4)0 (0)

103 (59)

17 (34)1 (2)0 (0)

32 (64)

60 (34)13 (7)1 (<1)b

104 (58)

77 (34)14 (6)1 (<1)

136 (60)

142 (35)21 (5)1 (<1)

239 (59)

Gleason score (at diagnosis)

2–45–67–10

4 (2)56 (32)

115 (66)

1 (2)22 (44)27 (54)

3 (2)61 (35)

112 (64)

4 (2)83 (37)

139 (62)

8 (2)139 (35)254 (63)

Primary therapyc

Radical prostatectomyRadiotherapyCryotherapyOtherNot recorded

39 (22)107 (61)24 (14)

5 (3)0 (0)

10 (20)33 (66)6 (12)1 (2)0 (0)

38 (21)120 (67)17 (10)

2 (1)1 (<1)

48 (21)153 (67)23 (10)

3 (1)1 (<1)

87 (22)260 (65)47 (12)

8 (2)1 (<1)

aAs only a scan was required for study entry, “not classifiable” was chosen when an investigator could not medically conclude that a sub-ject’s prostate cancer was definitely localized, locally advanced, metastatic. bPatient data were censored at 1 month and 4 days after initiation of drug treatment, contrary to trial protocol. cPrimary (definitive) data were recorded at screening.



Patients and MethodsStudy Design: This open-label, controlled, parallel-arm, multi-center trial (NCT00928434) randomized patients 7:2:7 to inter-mittent (degarelix; n = 177) or continuous (degarelix; n = 50; leuprolide; n = 182) treatment, respectively. Randomization lists were prepared centrally (Department of Global Biometrics, Fer-ring Pharmaceuticals A/S) using a validated computer program. The trial was conducted in accordance with the Declaration of Helsinki, with applicable FDA regulations and the Internation-al Conference on Harmonization Guidelines for Good Clinical Practice. Appropriate Institutional Review Boards for each site approved the study protocol and amendments, and all patients provided written, informed consent.

Patient Selection: Men ≥18 years with histologically confirmed prostate adenocarcinoma and a negative bone scan with rising se-rum PSA levels after prior definitive therapy for whom hormone therapy was indicated were eligible. The minimum criteria were screening serum testosterone ≥1.5 ng/mL, Eastern Cooperative Oncology Group score ≤2, and a rise in PSA of ≥0.2 ng/mL following radical prostatectomy or 3 separate PSA levels higher than nadir PSA after other primary therapy. Exclusion criteria included hormone therapy within 6 months or bicalutamide within 2 months of randomization. Patients receiving neoadju-vant hormone therapy for more than 4 months or adjuvant hor-

mone therapy for more than 6 months were excluded.

Treatment Plan and Toxicity Evaluation: The initiation phase comprised 7 months of de-garelix 1-month depot formulation (starting dose 240 mg; 6 monthly 80-mg maintenance doses) or leuprolide (1-month injection [7.5 mg] and two 3-month [22.5 mg] injections). Patients with PSA ≤2 ng/mL at month 7 en-tered a second 7-month phase. Intermittent arm patients entered an off-treatment peri-od. If PSA increased to >2 ng/mL, degarelix was reintroduced (240 mg followed by 80 mg monthly) until PSA was ≤2 ng/mL or the in-vestigator determined the patient needed an-other treatment. Patients in the continuous treatment arms were maintained on monthly degarelix or leuprolide every three months. Blood samples for testosterone and PSA were obtained monthly and analyzed at a certified central laboratory. Serum testosterone levels were determined using a validated liquid chromatography system with tandem mass spectrometry assay. PSA was analyzed using a validated immunoassay.

The safety analysis set comprised all men who received at least one dose of ADT and included laboratory values (biochemistry, he-

matology, and urine analysis) and clinical variables (including patient-reported injection-site tolerability, adverse events (AEs), electrocardiograms, and physical examination). AEs were graded according to National Cancer Institute Common Terminology Criteria for AEs (Version 4.02).

Response Evaluation: The primary endpoint was the proportion of patients with serum PSA ≤4.0 ng/mL at month 14 for inter-mittent degarelix treatment vs continuous therapy (degarelix and leuprolide arms combined). Noninferiority was established if the lower limit of the 95% CI difference between the intermittent and continuous treatments was greater than -12.5%. Secondary endpoints included time to PSA >2 ng/mL in the intermittent arm during off-treatment time vs continuous therapy, time to testosterone >0.5 ng/mL and ≥1.5 ng/mL in the intermittent arm, proportion of intermittent-arm patients requiring addition-al degarelix dosing, development of castration resistance (2 con-secutive rises in PSA ≥2 weeks apart and 50% greater than nadir despite castrate levels of testosterone),13,14 and disease progression (rising PSA despite castrate testosterone levels, additional PCa therapy, or death from any cause). Efficacy endpoints were as-sessed at month 14 in all patients eligible for the second phase (with at least one primary endpoint efficacy measurement be-tween months 7 – 14).

Additional secondary endpoints relating to QoL and sexu-

FIGURE 1. Patient Flow

Patient flow (numbers in parenthesis denote percentage of randomized patients for that treatment arm). FAS, full analysis set.

Screened N = 480

Intermittent(degarelix)

n = 177 (100)

Continuous(degarelix)

n = 50 (100)

Continuous(leuprolide)

n =182 (100)

Totaln = 409 (100)

n = 403 (99)n = 178 (98)n = 50 (100)n = 175 (99)

n = 328 (80)n = 150 (82)n = 41 (82)n = 137 (77)

n = 301 (74)n = 134 (74)n = 36 (72)n = 131 (74)

n = 71

n = 12 (7) n = 5 (10) n = 8 (4) n = 25 (6)

n = 14 (8)n = 5 (3)n = 1 (<1)n = 5 (3)n = 2 (1)n = 5 (3)

n = 5 (10)n = 0 (0)n = 0 (0)n = 3 (6)n = 0 (0)n = 1 (2)

n = 18 (10)n = 8 (4)n = 3 (2)n = 2 (1)n = 3 (2)n = 2 (1)

n = 37 (9)n = 13 (3)n = 4 (1)n = 10 (2)n = 5 (1)n = 8 (2)

Screened Failures

Randomized

FAS

Months 7-14 FAS

Completed

Ineligible at month 7(PSA >2 ng/mL)

Discountinuations (months 0-14)

AEsProtocol violationLost to follow-up

Withdrew consentDiscontinued by PI

Other



al function were assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) and the sexual function inventory (SFI), respectively. FACT-P was completed at every visit during the study and assesses physical, social/family, emotional, and functional well-being, as well as prostate-related symptoms. The

SFI was completed at baseline, visit 4, and prior to stopping treat-ment. During the off-treatment phase, the SFI was completed every 2 months and at the end-of-trial visit. It is a widely used, multidimensional, self-report instrument specifically designed to evaluate sexual function and satisfaction of men on treatment or

TABLE 2. Treatment-Emergent AEs With an Overall Incidence of ≥5% by MedDRA Preferred Term (Safety Analysis Set)

Summary of AEs Intermittent degarelix n = 175, n (%)

Continuous degarelix n = 50, n (%)

Continuous leuprolide n = 178, n (%)

All AEs 159 (91) 47 (94) 158 (89)

AEs leading to discontinuation 14 (8) 5 (10) 18 (10)

Deaths* 2 (1) 0 (0) 2 (1)

AEs by grade** Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe

Hot Flashes 61 (35) 23 (13) 5 (3) 16 (32) 9 (18) 1 (2) 81 (46) 24 (13) 6 (3)

Injection site reactions

Injection site pain

Injection site erythema

Injection site swelling

Injection site edema

Injection site induration

72 (41)

37 (21)

19 (11)

5 (3)

1 (<1)

25 (14)

12 (7)

4 (2)

3 (2)

0 (0)

0 (0)

0 (0)

0 (0)

0 (0)

0 (0)

28 (56)

16 (32)

5 (10)

3 (6)

3 (6)

10 (20)

4 (8)

1 (2)

1 (2)

2 (4)

1 (2)

1 (2)

0 (0)

0 (0)

1 (2)

17 (10)

1 (<1)

0 (0)

0 (0)

0 (0)

5 (3)

0 (0)

0 (0)

0 (0)

0 (0)

0 (0)

0 (0)

0 (0)

0 (0)

0 (0)

Fatigue 24 (14) 5 (3) 3 (2) 9 (18) 0 (0) 1 (2) 21 (12) 11 (6) 0 (0)

Cough 4 (2) 3 (2) 0 (0) 5 (10) 2 (4) 0 (0) 2 (1) 1 (<1) 0 (0)

Arthralgia 5 (3) 8 (5) 0 (0) 3 (6) 2 (4) 0 (0) 12 (7) 7 (4) 0 (0)

Hypertension 6 (3) 6 (3) 0 (0) 2 (4) 2 (4) 0 (0) 5 (3) 13 (7) 0 (0)

Constipation 8 (5) 1 (<1) 0 (0) 3 (6) 1 (2) 0 (0) 4 (2) 7 (4) 1 (<1)

Urinary tract infection 1 (<1) 5 (3) 0 (0) 2 (4) 3 (6) 0 (0) 4 (2) 10 (6) 0 (0)

Nausea 5 (3) 4 (2) 1 (<1) 2 (4) 2 (4) 0 (0) 3 (2) 2 (1) 0 (0)

Hematuria 5 (3) 3 (2) 0 (0) 3 (6) 1 (2) 0 (0) 6 (3) 3 (2) 0 (0)

Back pain 3 (2) 5 (3) 0 (0) 2 (4) 1 (2) 0 (0) 5 (3) 5 (3) 0 (0)

Nasopharyngitis 2 (1) 5 (3) 0 (0) 2 (4) 1 (2) 0 (0) 4 (2) 7 (4) 0 (0)

Procedural pain 1 (<1) 5 (3) 1 (<1) 0 (0) 3 (6) 0 (0) 2 (1) 7 (4) 1 (<1)

Diarrhea 8 (5) 2 (1) 0 (0) 3 (6) 0 (0) 0 (0) 4 (2) 2 (1) 0 (0)

Sinusitis 3 (2) 6 (3) 0 (0) 1 (2) 2 (4) 0 (0) 0 (0) 3 (2) 0 (0)

Headache 7 (4) 3 (2) 0 (0) 1 (2) 0 (0) 0 (0) 5 (3) 4 (2) 0 (0)

Dizziness 6 (3) 5 (3) 0 (0) 2 (4) 0 (0) 0 (0) 5 (3) 1 (<1) 0 (0)

Upper respiratory tract infection 3 (2) 4 (2) 0 (0) 1 (2) 0 (0) 0 (0) 4 (2) 7 (4) 0 (0)

Pyrexia 2 (1) 3 (2) 0 (0) 3 (6) 0 (0) 0 (0) 1 (<1) 1 (<1) 0 (0)

Bronchitis 1 (<1) 5 (3) 0 (0) 0 (0) 3 (6) 0 (0) 0 (0) 1 (<1) 0 (0)

Dysuria 0 (0) 4 (2) 0 (0) 3 (6) 0 (0) 0 (0) 3 (2) 0 (0) 0 (0)

Dyspepsia 0 (0) 1 <1() 0 (0) 1 (2) 2 (4) 0 (0) 0 (0) 0 (0) 0 (0)

Nasal congestion 1 (<1) 0 (0) 0 (0) 1 (2) 2 (4) 0 (0) 2 (1) 0 (0) 0 (0)

Epistaxis 0 (0) 0 (0) 0 (0) 2 (4) 1 (2) 0 (0) 0 (0) 1 (<1) 0 (0)

*No deaths were considered related to study treatment (causes of death in the intermittent arm were cardio-respiratory arrest, sepsis, and/or bile duct cancer; in the continuous leuprolide arm, myocardial infarction and renal failure). **Mild, moderate and severe relate to CTCAE grades 1, 2 and 3, respectively.



with conditions that may affect sexual function.Statistical Analysis: Primary endpoint response rates between

intermittent and continuous therapy were compared using Fish-er’s exact test and the confidence interval determined using a normal approximation to the binomial distribution. Assuming a common response rate of 80% of patients with PSA <4 ng/mL at month 14 and adjusting for patients potentially discontinued after 7 months, 175 patients in both the intermittent degarelix and continuous leuprolide arms and 50 in the continuous de-garelix arm would give 80% power to detect a non-inferiority limit of -12.5%. Secondary endpoints comprising time-to-event variables were assessed by the Kaplan-Meier method and log-rank test. QoL and SFI outcomes were assessed by cross-sectional anal-yses of covariance (ANCOVA) using baseline values as a covari-ate. Exploratory sub-analyses for the intermittent arm included

time to testosterone >0.5 ng/mL according to age, baseline PSA, disease stage, and PSA at month 7. Efficacy analysis were carried out for the subjects eligible for the second phase of the study with at least one efficacy mea-surement in this phase. Results and DemographicsIn total, 409 patients were randomized to in-termittent (degarelix, n = 177) or continuous treatment (degarelix, n = 50; leuprolide, n = 182). Baseline characteristics are shown in Table 1. Of 403 patients who initiated treat-ment, 25 (6%) patients had PSA >2.0 ng/mL at month 7 and were ineligible to enter the second phase of the study (Figure 1). An ad-ditional 50 patients discontinued before the seventh month, 328 patients entered the sec-ond phase, and 301 (74%) patients completed the trial (Figure 1). Overall, 37 patients dis-continued due to AEs; the other main rea-sons for patients not completing the trial are shown in Figure 1.

Response Analysis: The response rate was sim-ilar between the intermittent arm (100%; 95% CI, 97.3–100.0) and the combined continuous arms (98.4%, 95% CI; 95.5–99.7; P = 0.268) (Figure 2a). The lower CI limit for the compar-ison of intermittent vs combined continuous arms was –0.19%; and therefore the threshold for noninferiority was met. Time to PSA >4.0 ng/mL was similar between the intermittent arm and the combined continuous arms (P = 0.4758). Time to PSA >4.0 ng/mL was not different between the intermittent arm and either continuous degarelix or leuprolide (Figure 2b). At month 14, no patients in the

intermittent arm and 3 (1.6%) in the combined continuous arms had PSA >4 ng/mL (1 [2.4%] and 2 [1.3%] patients in the con-tinuous degarelix and leuprolide arms, respectively; Figure 2a). In the intermittent arm, 35 (26%) patients restarted degarelix be-fore month 14 for PSA >2 ng/mL.

During months 7 to 14, 38 (28%) patients in the intermittent arm had PSA >2 ng/mL compared with 3 (6%) and 8 (5%) pa-tients in the continuous degarelix and leuprolide arms, respec-tively (P <0.001). Castration resistance occurred in 3 (2%) pa-tients in the intermittent arm prior to month 7, 1 (2%) patient in the continuous degarelix arm between month 7 and 14, and no patients in the continuous leuprolide arm.

Testosterone Levels: Testosterone suppression was similar across study arms after treatment initiation. Median testosterone levels at month 3 were 0.07 ng/mL (range 0.02–0.31 ng/mL), 0.06 ng/

Proportion of patients with (a) serum PSA ≤4.0 ng/mL (± 95% CI) at month 14 (last observation carried forward) and (b) time to PSA >4.0 ng/mL during months 7-14.

0

20

40

Subj

ects

with

PSA

≤4

ng/m

L at

mon

th 1

4(%

±95

% C

l)

Continuousdegarelix

ContinuousLeuprolide

Intermittentdegarelix

Combinedcontinuous arms

n=137 n=41 n=150 n=191

60

100

80

80

85

Prob

abili

ty (%

)

10 117 13

90

100

95

8 9 12 14

Intermittent degarelixContinuous degarelix


13740

150

13740

150

13538

147

134

142

37

139

133

131

137

13036

132

Month

Intermittent degarelixContinuous degarelixContinuous leuprolide

a.

b.

FIGURE 2.



mL (range 0.02–0.22 ng/mL), and 0.08 ng/mL (range 0.02–0.38 ng/mL) in the intermit-tent and continuous degarelix and leuprolide arms, respectively. Testosterone values were significantly higher in the intermittent arm during months 9 to 14 when patients were off therapy (P <0.05 at each monthly measure-ment) (Figure 3a). At month 14, median tes-tosterone was 1.65 ng/mL (range 0.015–16.2) in the intermittent arm, 0.075 ng/mL (range 0.015 – 0.94) in the continuous degarelix arm, and 0.07 ng/mL (range 0.015 – 0.25) in the continuous leuprolide arm.

Testosterone levels >0.5 ng/mL occurred in 116 (85%) intermittent-arm patients after a median of 112 days (95% CI, 112–140) from the cessation of degarelix (28 days after the last dose). The probability of testosterone >0.5 ng/mL was higher for patients aged <65 years (P = 0.0135). There were no differences in time to testosterone >0.5 ng/mL in the in-termittent arm by disease stage, baseline PSA level, and PSA level at month 7 (P = 0.077, 0.506, and 0.384, respectively). Increase in testosterone to normal levels (>1.5 ng/mL) occurred in 94 (69%) intermittent-arm pa-tients (median 168 days, 95% CI 140–168 days) and 0 (0%) and 1 (<1%) in the continu-ous degarelix and leuprolide arms, respective-ly. After 14 months, the median testosterone levels in men in the intermittent arm who had reached normal levels was 2.67 ng/mL (range 0.015 – 16.2).

Quality of Life: Sexual drive as measured in the SFI was im-proved at month 14 in patients in the intermittent arm versus those on continuous degarelix or leuprolide therapy (P = 0.027) (Figure 3b). In the intermittent arm, men with normal SFI scores at baseline were more likely to have significant increases in total SFI score (P = 0.034), sexual drive (P = 0.005), and erection (P = 0.010) while off treatment than than those on continuous degarelix and leuprolide arms with normal SFI scores at baseline.

Safety: Treatment emergent AEs were reported for 159 (91%) intermittent patients and 47 (94%) and 158 (89%) of patients in the continuous degarelix and continuous leuprolide arms, re-spectively (Table 2). The most frequently reported AE was hot flashes in 87 (50%), 26 (52%), and 110 (62%) of patients in the intermittent degarelix, continuous degarelix, and continuous le-uprolide arms, respectively. Injection site reactions were report-ed by 58% and 66% of intermittent and continuous degarelix patients, respectively, and by 12% of patients in the continuous leuprolide arm. Injection site reactions were mild to moderate (grade 1–2) except 1 patient with grade 4 injection site erythema,

induration, and pain (continuous degarelix arm).The type and frequency of AEs during the first 7 months and

months 7 to 14 of the study were similar. Grade 3 AEs were reported for 26 (15%), 6 (12%), and 18 (10%) patients in the intermittent degarelix, continuous degarelix, and continuous leuprolide arms, respectively (Table 2). There were 4 deaths (2 patients each in the intermittent degarelix and continuous le-uprolide arms), none of which were considered related to study treatment or prostate cancer. Overall, 37 patients discontinued therapy due to treatment-related AEs (grades 1–3); 14 (8%), 5 (10%), and 18 (10%) patients from the intermittent degarelix, continuous degarelix, and continuous leuprolide arms, respec-tively (Table 2). The frequency, type, and grade of AEs leading to discontinuation was similar across treatment arms.

DiscussionThese data suggest that intermittent use of degarelix as defined in this trial is non-inferior to continuous treatment with either degarelix or leuprolide with regard to maintenance of PSA ≤4

Median testosterone values (± interquartile range) for intermittent degarelix, con-tinuous degarelix and continuous leuprolide treatment arms (a) and change from baseline in sexual drive (± standard error) for intermittent degarelix patients and the combined continuous treatment patients (b) over the entire course of the study.

0

1

Med

ian

test

oste

rone

± in

terq

uart

ile r

ange

(ng/

mL)

6 80 12

2

4

3

2 4 10 14

Intermittent degarelixContinuous degarelix


17250

176

16649

168

16148

166

150 47162

13539

150

13437

140

13335

137

13136

131

Month1 3 5 7 9 11 13

17250

173

16649

167

15746

162

14846

161

13538

148

13338

139

13236

132

5Intermittent degarelixContinuous degarelixContinuous leuprolide

-1.5

Sexu

al d

rive

(cha

nge

from

bas

elin

e, m

ean

± SE

)

0

-1.0

0.0

-0.5

14

Intermittent degarelix

Combined continuous arms

175228

128167

Month3 7 9 11 13

165214

139193

131182

131172

128167

Intermittent degarelixCombined continuous arms

a.

b.

FIGURE 3.



ng/mL at month 14. In the continuous treatment arms, rising PSA during months 7 to 14 may signal early castration resistant prostate cancer (CRPC). In contrast, rising PSA in the inter-mittent arm while off treatment was associated with increasing testosterone levels. As all patients in the intermittent arm who resumed ADT had a fall in PSA, there was no indication of early CRPC in this arm. This did not occur in any patients confirming that, despite a rise in PSA, these patients were not yet castration resistant. The treatment cycle length and PSA parameters (start intermittent phase if PSA ≤4 ng/mL and restart ADT when PSA >2 ng/mL) of this study are broadly similar to those used in oth-er randomized trials of IAD versus CAD. Induction therapy is typically 6 to 8 months and the off-treatment period is initiated if PSA reaches <0.5 to <10 ng/mL (or a predefined percentage reduction from baseline).15 Reintroduction of ADT in previous trials was triggered by PSA reaching either 10 or 20 ng/mL (or exceeding baseline)7,8 or >4 ng/mL in the previous single-arm trial of degarelix in the intermittent treatment setting.12

Following discontinuation, the short half-life of degarelix11 appears to allow a rapid testosterone increase to above castrate levels. After 7 months off degarelix, testosterone levels reached normal (1.5 ng/mL or 5.21 nmol/L) in 69% of patients, with a median level of 2.67 ng/mL. The data reported here are similar to those from a recent uncontrolled, open-label European-based study of degarelix.12 In the first off-treatment period, the median time to testosterone >0.5 ng/mL was 112 days and time to PSA >4 ng/mL, 392 days.

Direct comparison with other trials is challenging due to dif-ferences in patient characteristics, treatments, and reporting pa-rameters. However, the PR-7 study reported that, after 8 months of ADT with an LHRH analog, testosterone returned to base-line (>1.45 ng/mL or 5 nmol/L) in 79% of patients within 24 months of stopping ADT.7 It could be speculated that an inter-mittent regimen with degarelix may allow a more rapid increase in testosterone that, in turn, may translate into more rapid im-provement of side effects related to testosterone suppression. A comparison trial would be necessary to confirm this possibility.

In the current study, increased mean testosterone levels with intermittent therapy were associated with statistically higher sex-ual drive at month 14 compared with patients on continuous ADT. Patients with normal sexual function before initiating ADT had greater SFI improvements once testosterone levels in-creased, and there is a possibility these patients may benefit most from the potential sexual function improvements associated with IAD therapy. No other robust improvements in QoL for patients stopping treatment were found, which may partly be due to weak-nesses of the QoL instruments for such assessments. Benefits in QoL with IAD for individual patients may depend on treatment cycle, testosterone status, and age.7,4

Administration of degarelix or leuprolide for up to 14 months was well tolerated. There was a higher rate of injection site re-

actions associated with the subcutaneous administration of degarelix compared with intramuscular injection of leuprolide. Injection site reactions were generally mild in nature and most-ly reported following the first dose, consistent with results of previous studies.8 The distinct different mechanism of LHRH agonists versus GnRH antagonists may be of relevance for the safety profile. Recently, LHRH agonist therapy has been associ-ated with an increased risk of cardiovascular events in men with a history of cardiovascular disease15 and of acute kidney injury in men with newly diagnosed nonmetastatic prostate cancer.16 Interestingly, the same mechanism has been hypothesized to explain both these effects: GnRH receptor-mediated activation of T lymphocytes and cytokine secretion promoting subsequent inflammation and atherosclerotic plaque rupture.16,17 Alternatively, GnRH antagonists or orchiectomy would not activate these inflam-matory pathways, possibly explaining differences in the AEs associat-ed with these different methods of androgen deprivation.16,18

Limitations of this study include the proportion of patients with an unclassifiable disease stage (due to limited imaging work-up at baseline) and following patients for only 14 months. As subjects in the intermittent group were treated if their PSA exceeded 2.0 ng/mL while off treatment, it is not possible to conclude whether men in the intermittent arm would have expe-rienced PSA >4.0 ng/mL during the study term if left untreated. Also, 14 months may be insufficient time to assess the develop-ment of castration resistant disease (2 PSA measurements of >4 ng/mL while receiving ADT) in the intermittent arm due to the inherent delay caused by the off-treatment period.

ConclusionsADT is associated with a number of AEs, some of which may be alleviated by intermittent treatment. In this trial, intermittent degarelix treatment was noninferior to CAD in terms of PSA control at 14 months, indicating degarelix is a viable therapeutic option in the intermittent setting. The potential clinical rele-vance of the difference in mechanism of action between a GnRH antagonist and LHRH agonists in this setting, for example, in patients at risk of cardiovascular disease, requires longer-term randomized controlled trials. Affiliations: E. David Crawford, MD, is from University of Col-orado, Denver, Aurora, CO. Neal Shore, MD, FACS, is from Carolina Urologic Research Center, Myrtle Beach, SC. Celestia S. Higano, MD, FACP, is from University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA. Anders Nei-jber, MD, PhD, MBA, is from Ferring Pharmaceuticals, Copen-hagen, Denmark. Vladimir Yankov, MD, is from Ferring Phar-maceuticals, Parsippany-Troy Hills, NJ.Acknowledgements: E. David Crawford, MD, and Neal Shore, MD, FACS, were co-principle investigators of the trial. Anders Neijber, MD, PhD, MBA, and Vladimir Yankov, MD were re-sponsible for data analysis. All authors were responsible for inter-



pretation of data, drafting the paper and critical revisions. Disclosure: The trial reported in this analysis was sponsored by Ferring Pharmaceuticals. Medical writing support (funded by Ferring) was provided by Matthew deSchoolmeester, PhD, of Bioscript Medical. Professor Crawford has received honoraria from Ferring Pharmaceuticals and other companies for partic-ipating in scientific meetings and advisory boards. Dr. Shore has received honoraria from Ferring Pharmaceuticals and other companies for participating in scientific meetings and advisory boards. Dr. Higano has received honoraria from Ferring Pharma-ceuticals for participating in an advisory board. Drs. Neijber and Yankov are Ferring employees.Address correspondence to: E. David Crawford, MD, Uro-logic Oncology, School of Medicine, University of Colora-do Denver, P.O. Box 6510, Mail Stop F710, 1665 Aurora Ct., Aurora, CO 80045. Phone: 720-848-0195; fax: 728-848-0203; email: [email protected]

REFERENCES1. Pilepich MV, Winter K, Lawton CA, et al. Androgen sup-pression adjuvant to definitive radiotherapy in prostate carcino-ma--long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys. 2005;61(5):1285-1290.2. Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med. 2011;365(2):107-118.3. Bolla M, Van Tienhoven G, Warde P, et al. External irradia-tion with or without long-term androgen suppression for pros-tate cancer with high metastatic risk: 10-year results of an EO-RTC randomised study. Lancet Oncol. 2010;11(11):1066-1073.4. Higano CS. Side effects of androgen deprivation therapy: mon-itoring and minimizing toxicity. Urology. 2003;61(2 suppl 1):32-38.5. Cary KC, Singla N, Cowan JE, Carroll PR, Cooperberg MR. Impact of androgen deprivation therapy on mental and emotion-al well-being in men with prostate cancer: analysis from the CaP-SURE registry. J Urol. 2014;191(4):964-970.6. Buchan NC, Goldenberg SL. Intermittent androgen suppres-sion for prostate cancer. Nat Rev Urol. 2010;7(10):552-560.7. Crook JM, O’Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. The N Engl J Med. 2012;367(10):895-903.8. Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013;368(14):1314-1325.9. Klotz L, O’Callaghan C, Ding K, et al. Nadir testosterone with-in first year of androgen-deprivation therapy (ADT) predicts for time to castration-resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous ADT. J Clin Oncol. 2015;33(10):1151-1156..10. Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy

and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with pros-tate cancer. BJU Int. 2008;102(11):1531-1538.11. Balchen T, Agerso H, Olesen T, Jensen J, Senderovitz T. Phar-macokinetics, pharmacodynamics, and safety of a novel fast-act-ing gonadotropin-releasing hormone receptor blocker, degarelix, in healthy men. Poster presented at 8th International Symposium on GnRH Analogues in Cancer and Human Reproduction.12. Boccon-Gibod L, Albers P, Morote J, et al. Degarelix as an intermittent androgen deprivation therapy for one or more treatment cycles in patients with prostate cancer. Eur Urol. 2014;66(4):655-663.13. D’Amico AV, Moul JW, Carroll PR, Sun L, Lubeck D, Chen MH. Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst. 2003;95(18):1376-1383.14. Patel A, Dorey F, Franklin J, deKernion JB. Recurrence pat-terns after radical retropubic prostatectomy: clinical usefulness of prostate specific antigen doubling times and log slope prostate specific antigen. J Urol. 1997;158(4):1441-1445.15. Klotz L, Toren P. Androgen deprivation therapy in advanced prostate cancer: is intermittent therapy the new standard of care? Curr Oncol. 2012;19(suppl 3);S13-S21.16. Levine GN, D’Amico AV, Berger P, et al. Androgen-depri-vation therapy in prostate cancer and cardiovascular risk: a sci-ence advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. Circulation. 2010;121(6):833-840.17. Gandaglia G, Sun M, Briganti A, Karakiewicz PI. Reply to E. David Crawford and Bo-Eric Persson’s Letter to the Editor re: Giorgio Gandaglia, Maxine Sun, Jim C. Hu, et al. Gonado-tropin-releasing Hormone Agonists and Acute Kidney Injury in Patients with Prostate Cancer. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2014.01.026. European Urology. 2014.18. Albertsen PC, Klotz L, Tombal B, Grady J, Olesen TK, Nils-son J. Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. European Urology. 2014;65(3):565-573.19. Crawford ED, Persson BE. Re: Giorgio Gandaglia, Max-ine Sun, Jim C. Hu, et al. Gonadotropin-releasing Hormone Agonists and Acute Kidney Injury in Patients with Prostate Cancer. Eur Urol. In press. http://dx.doi.org/10.1016/j.euru-ro.2014.01.026. European Urology. 2014.

· METASTATIC BREAST CANCER ·


Aurora Kinase Inhibitors in Breast Cancer Treatment

Mateusz Opyrchal, MD, PhD, Kothai Divya Guruswamy Sangameswaran, MBBS, Thaer Khoury, MD, FCAP, Patrick Boland, MD, Evanthia Galanis, MD, Tufia C. Haddad, MD, and Antonino B. D’Assoro, MD, PhD

Breast cancer, despite many medical advances, remains a major health problem in the United States and worldwide. De novo and acquired resistance to systemic therapy remains a significant issue contributing to poor clinical outcomes. It is most evident in patients with metastatic disease, as these breast cancer cells develop resistance to sequential therapies, ultimately leading to disease progression and death. Novel approaches to both prevent and overcome resistance to breast cancer therapies are in devel-opment and urgently needed.

Pre-Clinical Studies of Aurora-A Kinase in Breast CancerAurora-A kinase (AURKA) belongs to the family of serine-thre-onine kinases that play an integral part in cell cycle regulation by recruiting the cyclin B1/CDK1 complex and committing cells to mitosis.1-3 AURKA overexpression in murine fibroblasts and breast epithelial cells results in centrosome amplification and aneuploidy, suggesting it plays an important role in malignant transformation.4,5 AURKA is expressed in multiple carcinomas including breast cancer.6-9 AURKA overexpression has been as-sociated with centrosome amplification and DNA instability.10-12 It has been proposed that cancer cells may overexpress AURKA through a switch in mRNA transcription through cap to internal ribosome entry site (IRES)-dependent translation, which allows for change in transcriptional regulation and increased mRNA production.13 The non-mitotic function of AURKA has been implicated in breast cancer progression and resistance to chemo-therapy agents through epithelial to mesenchymal transition and the acquisition of stem cell-like characteristics.14,15 Breast cancer cells with stem cell-like properties have been associated with resistance to standard therapies, tumor progression and onset of distant metastasis.16-19 AURKA can activate NOTCH signal-ing, a pathway implicated in breast cancer cells acquiring stem cell-like properties.15,20 The NOTCH pathway has furthermore been shown to be important in mammary carcinomas in tumor-igenesis,21 development of resistance to endocrine treatments,22 and cross-talk with the HER2 signaling pathway.23,24 Therefore, increasing interest in targeting AURKA for the treatment of breast cancer has evolved. There are several compounds target-ing AURKA in clinical development, with the most advanced being alisertib (MLN8237), a selective AURKA inhibitor. Oth-er compounds, targeting AURKA selectively or as part of their broader activity, are under evaluation in pre-clinical and early clinical testing (Table 1).25

Translational Studies With AURKA Inhibitors in Breast CancerIncreased expression of both mRNA and protein correlates with worse clinical outcomes in patients with estrogen receptor positive (ER+), HER2-negative breast cancer; in cohorts of tri-

Abstract

Metastatic breast cancer, despite many medical advanc-

es, remains an incurable disease. Therefore, treatments

that overcome cancer cell resistance to current treat-

ments are needed to decrease relapse and onset of met-

astatic disease. Aurora-A kinase has been implicated in

breast cancer tumorigenesis and progression of the dis-

ease. It has also been shown to play a role in increasing a

more chemotherapy-resistant, mesenchymal phenotype,

and cells with stem cell-like characteristics. Pre-clinical

data have been encouraging with inhibitors of Aurora-A

kinase signaling, showing decreased proliferation and

increased sensitivity of breast cancer cells to both hor-

monal and chemotherapy treatments. In early clinical tri-

als with Alisertib, the most clinically advanced Aurora-A

inhibitor, there have been early signals of activity, espe-

cially in the HR+ and HER2-positive breast cancer patient

population. There is ongoing research in developing fur-

ther specific Aurora-A and pan-Aurora kinase inhibitors

and to identify biomarkers to show appropriate patient

population for treatment. The first breast cancer-specific

clinical trial with an Alisertib and Fulvestrant combination

has completed accrual, and we are eagerly awaiting data

to confirm that Aurora-A kinase inhibition has a role in

the treatment of breast cancer.

Key Words: Aurora-A kinase, breast cancer, novel thera-

peutics, alisertib

AURORA KINASE INHIBITORS IN BREAST CANCER TREATMENT


ple-negative breast cancer, the same analyses have yielded mixed results.26-30 AURKA has been identified as a relevant therapeutic target in ER+, endocrine resistant, breast cancer cell lines in a genetic screen by Thrane et al.31 Experimental testing has shown that AURKA activation has been associated with resistance to endocrine therapies in ER+ breast cancer models.32-34 Aurora-A and B have been identified through the kinase inhibitor screen as targets for the treatment of aromatase inhibitor-resistant breast cancer cells.34 One proposed mechanism of AURKA causing re-sistance to endocrine therapies is down-regulation of the ERα through expansion of a sub-population of ERlow/- tumor-initiat-ing cells.32 An alternative proposed mechanism is through direct phosphorylation of ERα.33 Importantly, inhibition of AURKA either resulted in growth arrest or restored sensitivity to estro-gen blockade in ER+ breast cancer cells and increased efficacy of hormonal therapies in in vitro and in vivo models of ER+ breast cancer.32-34

Inhibition of AURKA results in reversal of mesenchymal pho-notype and reduction of cancer stem cell-like cells with increased sensitivity to chemotherapy agents.14,35 The combination of AUR-KA inhibitors with chemotherapy was much more effective than either treatment when compared in various breast cancer mod-els with anthracyclines36 and taxanes.37 AURKA inhibitors may target cancer cells with increased propensity for metastasis and treatment-resistance either directly or through interference with the NOTCH signaling pathway.

Clinical Studies With Aurora Inhibitors in Breast CancerAlisertib is an orally administered, small molecule inhibitor highly selective for AURKA.38 The safety and tolerability of al-isertib has been investigated in multiple phase I clinical trials in patients with hematologic and solid malignancies. In a first-in-human trial performed by Dees et al, 87 patients with solid ma-lignancies (3 with breast cancer) were treated at escalating doses of 2 different formulations of alisertib from 5 mg to 150 mg twice daily for 7, 14, or 21 consecutive days followed by 14 days of recovery. The recommended phase II dose (RP2D) was 50 mg twice daily for 7 days with a 14-day recovery. The most common adverse events were fatigue, nausea, and neutropenia. Twenty patients achieved stable disease (SD) for a period greater than 3 months, with 1 patient achieving partial response lasting for over a year.39 Cervantes et al corroborated the RP2D results in a sep-arate, dose escalation phase I study in 59 adults with advanced solid malignancies (one with breast cancer).40 Pharmacokinetic studies revealed fast absorption, and at the RP2D the steady-state concentration exceeded that associated with saturating pharma-codynamic effects and preclinical activity. There was one partial response, and 22 (37%) patients achieved SD, 6 of whom (10%) maintained it for a period > 6 months.40 A third phase I trial of 58 patients with refractory hematologic malignancies supported the same RP2D, and it further determined enteric coated tablets

to be the preferred formulation.35 Hematological toxicities were the most frequent dose-limiting toxicities (DLTs), particularly neutropenia. There were also DLTs of stomatitis and skin tox-icities.35,39,40

A phase II trial reported by Melichar et al investigated the ef-ficacy of single-agent alisertib in patients with pre-treated breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous cell carcinoma, and gastro-esophageal ade-nocarcinoma.41 There were 53 patients with breast cancer treated and 49 were evaluable for response. Of these, 26 patients had hormone receptor positive (HR+), HER2-negative breast can-cer, 9 had HER2-positive breast cancer, and 14 had HR-nega-tive, HER2-negative breast cancer. The majority of the breast cancer patients (80%) had received 4 or more prior treatment regimens. Of all patients, 9 (18%) had an objective response. Of those with HR+ disease, 6 (23%) had an objective response, 8 (31%) achieved SD at least 6 months, and PFS was 7.9 months. In the small HER2-positive cohort, response rates were similar though the duration of response was longer at 11.2 months, an impressive finding given the absence of concurrent HER2-di-rected therapy. In this heavily pre-treated population, the overall results were very encouraging and the authors concluded that further investigation was recommended, especially in HR+ and HER2-positive patient populations.41

Grade 3-4 drug-related neutropenia was reported in 53% of patients with breast cancer; however, febrile neutropenia was only reported in 4% of this cohort. Thrombocytopenia, skin tox-icities, and infections were also reported in a small percentage of patients.

In 2014, a phase I trial of alisertib in combination with fulves-trant in endocrine-resistant breast cancer (NCT02219789) was the first dedicated breast cancer trial with an AURKA inhibitor to be open to enrollment; this trial remains active but is no lon-ger recruiting.

TABLE 1. Agents Targeting Aurora-A Kinase and the Phase of Their Clinical Development

Compound Name

Target Phase of Development

Enmd 2076 Multi kinase inhibitor, AURKA II

Danusertib/ PHA-739358

Pan-Aurora II

At-9283 Aurora A, B II

MK-5108 AURKA I

AMG 900 Pan-Aurora I

KW-2449 Aurora A, B I

TAS-119 AURKA I

AURKA indicates Aurora-A kinase.



Other active and planned trials specifically in the breast cancer patient population are listed in Table 2. Alisertib has been com-bined with taxanes in early clinical trials that form the basis for future trials in patients with breast cancer, and specifically with triple-negative breast cancer (TNBC).42,43

ConclusionThere are promising data to support the development of breast cancer therapeutics targeting the inhibition of Aurora kinase. Promising single-agent activity has been observed with the selec-tive Aurora-A kinase inhibitor alisertib, and there is particular interest to evaluate these agents in combination with endo-crine therapy in HR+ disease and with HER2-directed thera-pies in HER2+ disease, given the non-overlapping toxicities. Beyond the molecular subtypes of breast cancer, the pre-clinical data that suggest AURKA inhibition reduces the sub-popula-tion of breast cancer stem cell-like cells is indeed encouraging and suggest a role for this class of drugs to be combined with other agents that target the main tumor bulk. Triple-negative breast cancers in particular have been shown to have a higher percentage of stem cell-like population leading to worse clin-ical ooutcomes44-47 and decreasing the metastatic potential of breast cancer cells. New treatment options in this patient pop-ulation are sorely needed, and we will await any hints of activ-ity in any future clinical trials, including ongoing and planned clinical trials with alisertib; another specific AURKA inhibi-tor, TAS-119; and pan-Aurora kinase inhibitors, as correlative studies from the phase II study of alisertib in all solid tumors. Affiliations: Mateusz Opyrchal, MD, PhD, Kothai Divya Gu-ruswamy Sangameswaran, MBBS, Thaer Khoury, MD, FCAP, and Patrick Boland, MD, are from Roswell Park Cancer Insti-tute, Buffalo, NY. Evanthia Galanis, MD, Tufia C. Haddad, MD, and Antonino B. D’Assoro, MD, PhD, are from Mayo Clinic, Rochester, Minnesota

Disclosure: Dr. Opyrchal reports no disclosures.Address correspondence to: Mateusz Opyrchal, MD, PhD, As-sistant Professor of Oncology, Breast Service, Department of Medicine, Roswell Park Cancer Institute, Carlton House - A-414, Elm & Carlton Sts., Buffalo, NY, 14263, Phone: 716-845-4695, Fax: 716-845-3423, email: [email protected]

REFERENCES1. Marumoto T, Honda S, Hara T, et al. Aurora-A kinase main-tains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem. 2003; 278(51):51786-51795.2. Portier N, Audhya A, Maddox PS, Green RA, Dammermann A, Desai A, Oegema K. A microtubule-independent role for cen-trosomes and aurora a in nuclear envelope breakdown. Dev Cell. 2007;12(4):515-529.3. Hirota T, Kunitoku N, Sasayama T, et al. Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Cell. 2003;114(5):585-598.4. Zhou H, Kuang J, Zhong L, et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet. 1998; 20(2):189-193.5. Goepfert TM, Adigun YE, Zhong L, Gay J, Medina D, Brin-kley WR. Centrosome amplification and overexpression of auro-ra A are early events in rat mammary carcinogenesis. Cancer Res. 2002;62(14):4115-4122.6. Tanaka T, Kimura M, Matsunaga K, Fukada D, Mori H, Okano Y. Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast. Cancer Res. 1999;59(9):2041-2044.7. Sakakura C, Hagiwara A, Yasuoka R, et al. Tumour-amplified kinase BTAK is amplified and overexpressed in gastric cancers with possible involvement in aneuploid formation. Br J Cancer. 2001;84(6):824-831.8. Gritsko TM, Coppola D, Paciga JE, et al. Activation and over-expression of centrosome kinase BTAK/Aurora-A in human

TABLE 2. Clinical Trials of Alisertib with Special Interest in Breast Cancer

Study Treatment Primary Outcome Current Status

Phase II: NCT02187991 Alisertib + Paclitaxel Vs Paclitaxel alone in metastatic and locally advanced breast cancer

TDP Not yet recruiting

Phase I: NCT02219789 Safety of addition of Alisertib to fulvestrant in Advanced HR + Breast Cancer

Safety and tolerability by MTD

Closed to recruiting

Phase I/II: NCT01091428 Alisertib + Weekly paclitaxel in advanced breast cancer (Phase I only) and recurrent ovarian cancer

Safety and tolerability by MTD

PFS

Active, Not recruiting

Phase I: NCT01639911 Alisertib + Pazopanib (Selective VEGFR inhibitor) in solid tumors (including breast cancer)

Optimal tolerated dose Recruiting

AURKA indicates Aurora-A kinase.

AURORA KINASE INHIBITORS IN BREAST CANCER TREATMENT


ovarian cancer. Clin Cancer Res. 2003;9(4):1420-1426.9. Staff S, Isola J, Jumppanen M, Tanner M. Aurora-A gene is frequently amplified in basal-like breast cancer. Oncol Rep. 2010;23(2):307-312.10. D’Assoro AB, Lingle WL, Salisbury JL. Centrosome am-plification and the development of cancer. Oncogene. 2002; 21(40):6146-6153.11. Chou CH, Yang NK, Liu TY, et al. Chromosome instabili-ty modulated by BMI1-AURKA signaling drives progression in head and neck cancer. Cancer Res. 2013;73(2):953-966.12. Goepfert TM, Moreno-Smith M, Edwards DG, et al. Loss of chromosomal integrity drives rat mammary tumorigenesis. Int J Cancer. 2007;120(5):985-994.13. Dobson T, Chen J, Krushel LA. Dysregulating IRES-depen-dent translation contributes to overexpression of oncogenic Au-rora A Kinase. Mol Cancer Res. 2013;11(8):887-900.14. D’Assoro AB, Liu T, Quatraro C, et al. The mitotic kinase Aurora—a promotes distant metastases by inducing epitheli-al-to-mesenchymal transition in ERalpha(+) breast cancer cells. Oncogene. 2014;33(5):599-610.15. Regan JL, Sourisseau T, Soady K, et al. Aurora A kinase regulates mammary epithelial cell fate by determining mitotic spindle orientation in a Notch-dependent manner. Cell Rep. 2013;4(1):110-123.16. Creighton CJ, Li X, Landis M, Dixon JM, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA. 2009;106(33):13820-13825.17. Piva M, Domenici G, Iriondo O, et al. Sox2 promotes tamoxifen resistance in breast cancer cells. EMBO Mol Med. 2014;6(1):66-79.18. Giancotti FG. Mechanisms governing metastatic dormancy and reactivation. Cell. 2013;155(4):750-764.19. Oskarsson T, Acharyya S, Zhang XH, et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med. 2011;17(7):867-874.20. Takebe N, Harris PJ, Warren RQ, Ivy SP. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol. 2011;8(2):97-106.21. Gallahan D, Callahan R. The mouse mammary tumor associ-ated gene INT3 is a unique member of the NOTCH gene family (NOTCH4). Oncogene. 1997;14(16):1883-1890.22. Rizzo P, Miao H, D’Souza G, et al. Cross-talk between notch and the estrogen receptor in breast cancer suggests novel thera-peutic approaches. Cancer Res. 2008;68(13):5226-5235.23. Osipo C, Patel P, Rizzo P, et al. ErbB-2 inhibition activates Notch-1 and sensitizes breast cancer cells to a gamma-secretase inhibitor. Oncogene. 2008; 27(37):5019-5032.24. Baker AT, Zlobin A, Osipo C. Notch-EGFR/HER2 Bidirec-tional Crosstalk in Breast Cancer. Front. Oncol. 2014;12:4:360.25. Cheung CH, Sarvagalla S, Lee JY, Huang YC, Coumar MS.

Aurora kinase inhibitor patents and agents in clinical testing: an update (2011 - 2013). Expert Opin Ther Pat. 2014;24(9):1021-1038.26. Yamamoto S, Yamamoto-Ibusuki M, Yamamoto Y, FujiwaraS, Iwase H. A comprehensive analysis of Aurora A; transcript levels are the most reliable in association with proliferation and prognosis in breast cancer. BMC Cancer. 2013;13:217.27. Xu J, Wu X, Zhou WH, et al. Aurora-A identifies early recur-rence and poor prognosis and promises a potential therapeutic target in triple negative breast cancer. PloS One. 2013;8(2):e56919.28. Tokes AM, Szasz AM, Geszti F, et al. Expression of prolifera-tion markers Ki67, cyclin A, geminin and aurora-kinase A in pri-mary breast carcinomas and corresponding distant metastases. J Clin Pathol. 2015;68(4):274-282.29. Ali HR, Dawson SJ, Blows FM, Provenzano E, Pharoah PD,Caldas C. Aurora kinase A outperforms Ki67 as a prognostic mark-er in ER-positive breast cancer. Br J Cancer. 2012;106(11):1798-1806.30. Siggelkow W, Boehm D, Gebhard S, et al. Expression of aurora kinase A is associated with metastasis-free survival in node-negative breast cancer patients. BMC Cancer. 2012;12;562.31. Thrane S, Pedersen AM, Thomsen MB, et al. A kinase inhib-itor screen identifies Mcl-1 and Aurora kinase A as novel treat-ment targets in antiestrogen-resistant breast cancer cells. Onco-gene. 2015;34(32);4199-4210.32. Opyrchal M, Salisbury JL, Zhang S, et al. Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERalpha expression in initially ERalpha+ breast cancer cells. PloS One. 2014;9(5):e96995.33. Zheng XQ, Guo JP, Yang H, et al. Aurora-A is a determi-nant of tamoxifen sensitivity through phosphorylation of ERa in breast cancer. Oncogene. 2014;33(42):4985-4996.34. Hole S, Pedersen AM, Lykkesfeldt AE, Yde CW. Aurora kinase A and B as new treatment targets in aromatase inhibitor-resistant breast cancer cells. Breast Cancer Res Treat. 2015;149(3):715-726.35. Kelly KR, Shea TC, Goy A, et al. Phase I study of MLN8237—investigational Aurora A kinase inhibitor—in relapsed/refractory multiple myeloma, non-Hodgkin lymphoma and chronic lym-phocytic leukemia. Invest New Drugs. 2014;32(3):489-499.36. Zheng FM, Long ZJ, Hou ZJ, et al. A novel small molecule au-rora kinase inhibitor attenuates breast tumor-initiating cells and overcomes drug resistance. Mol Cancer Ther. 2014;13(8):1991-2003.37. Huck JJ, Zhang M, Mettetal J, et al. Translational exposure-ef-ficacy modeling to optimize the dose and schedule of taxanes combined with the investigational Aurora A kinase inhibitor MLN8237 (alisertib). Mol Cancer Ther. 2014;13(9):2170-2183.38. Manfredi MG, Ecsedy JA, Chakravarty A, et al. Characteri-zation of Alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacody-namic assays. Clin Cancer Res. 2011;17(24):7614-7624.39. Dees EC, Cohen RB, von Mehren M, et al. Phase I study of



aurora A kinase inhibitor MLN8237 in advanced solid tumors: safety, pharmacokinetics, pharmacodynamics, and bioavailability of two oral formulations. Clin Cancer Res. 2012;18(17):4775-4784.40. Cervantes A, Elez E, Roda D, et al. Phase I pharmacokinetic/pharmacodynamic study of MLN8237, an investigational, oral, selective aurora a kinase inhibitor, in patients with advanced sol-id tumors. Clin Cancer Res. 2012;18(17):4764-4774.41. Melichar B, Adenis A, Lockhart AC, et al. Safety and activ-ity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gas-tro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lan-cet Oncol. 2015;16(4):395-405.42. Jeffrey E, Xiaofei Z, Jay M, et al. Rational dose and schedule selection for the combination of paclitaxel and the investigation-al agent alisertib in recurrent ovarian cancer: optimization of therapeutic index based on translational hematological toxicity and exposure-efficacy modeling. AACR 104th Annual Meeting 2013; Apr 6-10, 2013.43. Falchook GS, Goff BA, Kurzrock R, et al. Phase I/II study of weekly paclitaxel with or without MLN8237 (alisertib), an investigational aurora A kinase inhibitor, in patients with re-current epithelial ovarian, fallopian tube, or primary peritoneal cancer (OC), or breast cancer (BrC): phase I results. J Clin Oncol. 2012;30. Abstract 5021.44. Idowu MO, Kmieciak M, Dumur C, et al. CD44(+)/CD24(-/low) cancer stem/progenitor cells are more abundant in tri-ple-negative invasive breast carcinoma phenotype and are associ-ated with poor outcome. Hum Pathol. 2012;43(3):364-373.45. Sheridan C, Kishimoto H, Fuchs RK, et al. CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res. 2006;8(5):R59.46. Honeth G, Bendahl PO, Ringner M, et al. The CD44+/CD24- phenotype is enriched in basal-like breast tumors. Breast Cancer Res. 2008;10(3):R53.47. Giatromanolaki A, Sivridis E, Fiska A, Koukourakis MI. The CD44+/CD24- phenotype relates to ‘triple-negative’ state and unfavorable prognosis in breast cancer patients. Med Oncol. 2011;28(3):745-752.

· MULTIPLE MYELOMA ·


Clinical Decision Making in Multiple Myeloma for the Transplant-Eligible Patient—Upfront Transplant Versus

Maintenance Therapy

Noa Biran, MD, and David Vesole, MD, PhD

IntroductionHigh dose chemotherapy with autologous stem cell transplant (ASCT) following induction therapy has been the mainstay of treatment of multiple myeloma since the mid-90s given the improvement in progression-free survival (PFS) and potentially overall survival (OS). However, with the development of novel therapies, the role and optimal timing of ASCT have come into question. The role of consolidation therapy posttransplant as well as maintenance therapy have also been investigated. Given the long-established correlation between depth of response and prolonged survival, there has been an increasing interest in striv-ing for minimal residual disease (MRD) as a surrogate end point for risk-adapted treatment, particularly in the consolidation and maintenance setting. Here, we review the current progress in the treatment of transplant-eligible multiple myeloma (MM) as it pertains to the role of ASCT, consolidation, and maintenance therapy.

The Role of High Dose Chemotherapy With Autologous Stem Cell Rescue in Multiple Myeloma in the Era of Conventional Cytotoxic Chemotherapy Before the introduction of proteasome inhibitors (PIs) and im-munomodulatory agents (IMiDs), high dose melphalan with ASCT following induction therapy was considered the standard approach for transplant-eligible patients with newly diagnosed MM. The first randomized controlled trial from the Intergroupe Francais du Myelome (IFM90), published in 1996, randomized newly diagnosed MM patients to an older chemotherapy regi-men (vincristine/carmustine, cyclophosphamide, prednisone al-ternating with carmustine, vincristine, adriamycin, prednisone; VMCP/BVAP) for 12 cycles versus 4 to 6 cycles of VMCP/BVAP followed by high dose therapy with autologous bone marrow transplant.1 Those patients randomized to the transplant arm compared with the high dose chemotherapy arm had a superior 5-year event-free survival (EFS) (28% versus 10%, respectively, P = .01) and OS (52% versus 12%, respectively P = .03). Seven years later, the United Kingdom’s Medical Research Council (MRC VII) published their trial randomizing newly diagnosed MM patients to adriamycin, carmustine, cyclophosphamide, and

melphalan for 4 to 12 cycles or to adriamycin, vincristine, cy-clophosphamide, and methylprednisolone for a minimum of 3 cycles followed by high-dose melphalan with autologous ASCT.2 The patients randomized to ASCT versus non-ASCT demon-strated an improvement in PFS (32 vs 20 months, respectively, (P <.001), and a trend toward improved OS (55 vs 42 months, respectively, P = .04). Both of these trials restricted eligibility to patients under the age of 65 years and utilized interferon main-tenance posttransplant.

Subsequent randomized trials comparing single ASCT versus conventional chemotherapy demonstrated a benefit in PFS in the ASCT versus delayed or non-ASCT arm, although no benefit in OS was demonstrated.3-5 These studies, however, with the ex-ception of the 2005 Fermand trial, did not truly compare trans-plant versus no transplant. Patients who progressed were eligible for salvage transplant. Thus, they compared early versus delayed transplant. A systematic review and meta-analysis of 9 random-ized controlled trials published between 1990-2000 evaluating upfront single ASCT versus standard-dose therapy (with conven-tional cytotoxic chemotherapy) concluded that upfront ASCT provided a PFS but not an OS benefit,6 although this analysis may be compromised due to the mixture of studies comparing early versus late transplant and transplant versus no transplant.The preponderence of evidence suggests a survival benefit of ASCT. A preplanned or unplanned introduction of delayed ASCT does not call into question the role of ASCT.

Novel Therapies Have Changed Survival Outcomes in Multiple Myeloma and the Role of ASCTTherapy for MM has markedly changed in the past decade with the introduction of PIs (bortezomib was approved in 2003) and IMiDs (lenalidomide and thalidomide were FDA approved in 2006). As such, survival has improved significantly for patients with MM over the past decade, with 5-year OS improving from 31% to 56% in patients diagnosed between 2001-2005 and 2006-2010, respectively.7

Thus, with the achievement of high response rates with PIs and IMiDs, including an overall response rate of 100% with the combination of bortezomib, lenalidomide, and dexamethasone



in newly diagnosed MM,8 the role of ASCT as part of frontline therapy has become a matter of debate.

Only 1 trial has evaluated the role of ASCT versus no trans-plant with the use of IMiDs as part of therapy. Palumbo et al randomized 273 patients under 65 years of age or younger after induction with lenalidomide and dexamethasone for 4 cycles to either consolidation of melphalan, prednisone, and lenalid-omide (MPR) for 6 cycles or to 2 cycles of high dose melphalan with ASCT.9 Patients were subsequently randomized to lenalido-mide maintenance or no maintenance. The study design was to perform ASCT in the non-transplant arm at the time of disease progression. With a median follow-up of 51.2 months, both PFS (43 months vs 22.4 months, (P <.001) and 4-year OS (81.6% vs 65.3%; P = .02) were significantly longer with high-dose mel-phalan with ASCT compared with MPR. Of note, of those randomized to MPR, only 63% received the planned ASCT at first relapse, which may have led to the significant difference in OS. However, this may be reflective of community practice. Re-garding maintenance therapy among those randomized to both the transplant and non-transplant arm, the median PFS was sig-nificantly longer with lenalidomide maintenance than with no maintenance (41.9 months vs. 21.6 months; P <.001) but 3-year OS was not significantly prolonged (88% versus 79.2%; P = .14).

Thus, newly diagnosed patients under the age of 65 years re-ceiving upfront ASCT, utilizing either older conventional regi-mens or modern IMiD-based therapies, have shown significant prolongation of PFS compared to those receiving non-ASCT chemotherapy consolidation. Transplant serves as another treat-ment modality with efficacy in MM, and as long as the disease remains incurable, there is no reason to remove this therapeutic option from the treatment armamentarium. Although most ther-apies may be administered at any time, ASCT may be tolerated earlier in the disease course when the patient has less exposure to therapeutic intervention. Although the accepted standard of care does include high-dose therapy with ASCT, there are out-standing research investigations into the timing of transplant, the incorporation of consolidation therapy, and the use of main-tenance therapy.

Timing of Autologous Transplant: Early Versus LateTwo older multicenter, international, randomized studies com-pared outcomes with early versus delayed transplant, both com-pleted prior to the incorporation of IMiD- or PI-based agents into treatment algorithms. Fermand et al showed an improve-ment in EFS and improvement in quality of life in terms of time without symptoms, treatment, or treatment toxicity (TWiSTT) in patients transplanted early, although there was no benefit in OS.3 Similarly, Barlogie et al compared high dose therapy with melphalan 140 mg/m2 and total body irradiation 12 centigray to maintenance with vincristine, carmustine, melphalan, cyclo-phosphamide and prednisone (VBMCP). Upon disease progres-

sion, the patients in the VBMCP arm were to receive autologous transplantation. There was no differences in response rate, PFS or OS between arms, possibly due to an inferior transplant pre-parative regimen.10

Although prospective, randomized clinical trials evaluating the outcomes of early versus delayed ASCT in the era of IMiD- and PI-based therapies are ongoing (IFM/DFCI 2009 study NCT01208662 and the European Intergroup Trial), no results are currently available. The IFM/DFCI 2009/CTN 1304 paral-lel phase III study is randomizing newly diagnosed MM patients treated with induction bortezomib, lenalidomide, and dexa-methasone (RVD) for 3 cycles and cyclophosphamide for stem cell mobilization to either melphalan 200 mg/m2 with ASCT followed by 2 cycles of RVD consolidation or 5 cycles of RVD consolidation. Both arms receive lenalidomide maintenance for 1 year in the IFM cohort and until progression in the US cohort. Enrollment has been completed in Europe, but is ongoing in the United States. The ongoing European Intergroup Trial random-izes newly diagnosed patients treated with 3 cycles of bortezomib, cyclophosphamide, dexamethasone (VCD) and stem cell collec-tion to either high-dose melphalan or bortezomib, melphalan, prednisone (VMP) followed by another randomization to 2 cy-cles of VRD followed by lenalidomide maintenance or lenalido-mide maintenance alone until progression.

A retrospective analysis of 290 patients with newly diagnosed MM who received IMiD-based initial therapy (thalidomide-dex or lenalidomide-dex) before ASCT revealed no significant dif-ference in time to progression (20 months vs 16 months, P value non-significant) after ASCT and 4-year OS (68% vs 64%) be-tween patients who received early versus delayed ASCT, respec-tively.11 Another retrospective study evaluating the outcome of 167 newly diagnosed patients receiving IMiD- or PI-based induc-tion showed a difference in PFS (28 months vs 23 months; P = .055) but not in OS in patients receiving early versus delayed ASCT, respectively.12

Until the results of the 2 large prospective studies become available, upfront ASCT remains the standard of care for trans-plant eligible, newly diagnosed MM patients. In fact, the Interna-tional Myeloma Working Group (IMWG) continues to support high-dose therapy with autologous transplant as consolidation following induction therapy,13 as does the UK Myeloma Forum (“HDT with ASCT should be part of primary treatment in newly diagnosed patients up to the age of 65 years with adequate per-formance status and organ function [Grade A recommendation; level IB evidence] and HDT with ASCT should be considered in patients aged older than 65 years with good performance status [Grade B recommendation; level IIA evidence14 and the European Myeloma Network [“Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit pa-tients remains the standard of care (1A).”].15 Finally, the Amer-ican Society for Blood and Marrow Transplant (ASBMT) also

CLINICAL DECISION MAKING IN MULTIPLE MYELOMA FOR THE TRANSPLANT-ELIGIBLE PATIENT


recommend autologous stem cell transplant as consolidation for induction therapy.16

It is also important to note that relapses after ASCT general-ly respond to salvage therapy with IMiD- and PI-based therapy, while there is no definitive proof that the disease responds as well to melphalan-based high-dose chemotherapy after prolonged ex-posure to combination therapy.

Consolidation TherapyPosttransplant consolidation strategies defined as the adminis-tration of 2to 4 cycles of therapy after ASCT, were developed with the goal of extending post-transplant remission and ultimately OS.

One of the initial trials incorporating post-ASCT consolida-tion was reported by Attal et al (IFM 2005-02) in which patients received 2 months of lenalidomide 25 mg daily prior to random-ization to maintenance with lenalidomide 10 mg daily or pla-cebo. They observed an improvement in the rate of a complete or very good partial response: 58% before consolidation versus 69% after consolidation (P <.001).17 However, it is unclear if the deeper response was a result of the lenalidomide consolidation or as a result of continued response from the transplant.

A number of other trials using a combination of bortezomib or IMiD-based therapy for posttransplant consolidation: the Nor-dic Myeloma Study Group conducted a randomized study com-paring bortezomib as consolidation therapy given after ASCT with no consolidation in bortezomib-naïve newly diagnosed MM patients. Although deeper responses were observed post-consol-idation, (ie, ≥ very good partial response 71% vs 57%; P <.01in the consolidation vs non-consolidation therapy groups, respec-tively), this did not translate into a significant improvement in median PFS (27 vs 20 months; P = .05).18 In a phase III study, the Italian investigators (GIMEMA MM0305) randomized 474 new-ly diagnosed patients to bortezomib-thalidomide-dexamethasone (VTD) or thalidomide-dexamethasone (TD) therapy before and after tandem ASCT.19 VTD consolidation significantly increased complete response (CR) and CR/nCR rates posttransplant but TD did not, and translated into a significantly longer 3-year PFS (68% vs 56% in the VTD vs TD groups; P = .057, respective-ly). Those with high-risk cytogenetics, especially t(4;14), had the greatest benefit from induction and consolidation with VTD. A small IFM phase II study of 31 newly diagnosed MM patients evaluated VRD as induction and posttransplant consolidation (two 21-day cycles) and showed an improvement in ≥VGPR from 70% at the completion of ASCT to 87% at the completion of consolidation.20

Taken together, most of trials examining the role of post-ASCT consolidation show improvement in the depth of re-sponse, but conclusive improvement in PFS and OS has yet to be determined, with the exception 1 trial of t4,14 patients receiving bortezomib-based consolidation. Many of the currently ongoing

transplant trials, such as the BMT CTN (Blood and Marrow Transplant Clinical Trials Network) 0702 (NCT02322320) and the IFM/DFCI 2009 are incorporating consolidation strategies, with most using PI/IMiD/corticosteroid combinations for 2 to 4 cycles followed by varying durations of lenalidomide mainte-nance therapy.

Maintenance TherapyMaintenance therapy, particularly in the post ASCT setting, con-sists of the administration of reduced-intensity treatments on a continuous, long-term basis with the dual purpose of deepening and potentially prolonging the previously achieved responses. It is clear from 3 randomized trials that lenalidomide maintenance (10 mg daily) provides a 14- to 26-month improvement in PFS compared with observation.17,21,22 However, only the CALGB (Cancer and Leukemia Group B) 100104 trial, in a retrospective subgroup analysis, demonstrated an improvement in OS.21 The median OS was not achieved in the lenalidomide arm, whereas it was 73 months in the placebo arm (P = .008), although the study design was not powered to detect early survival differences with a median follow-up of 48 months. Three subsequent analyses of the IFM trial with a median follow-up of 64 months failed to demonstrate a difference in OS with maintenance lenalidomide compared to placebo.17,23,24

The improvement with lenalidomide maintenance in PFS comes with a number of absolute or potential disadvantages: (1) at least a 2- to 3-fold increase in the risk of second primary ma-lignancies; (2) an approximate 15% discontinuation rate due to toxicities, in particular myelosuppression; (3) the propagation of lenalidomide-resistant clones by continuous, metronomic, sub-therapeutic lenalidomide administration, potentially negating the future use of lenalidomide for anti-MM therapy; (4) shorter duration of PFS2 (defined as PFS with the next line of therapy after progression on maintenance lenalidomide) in patients with prior lenalidomide exposure; and (5) the high cost—financial and otherwise—to the patient and health care system (especially in the absence of clear improvement in OS).

Data investigating the use of bortezomib in the maintenance setting is available from 2 large randomized trials. The HOV-ON/GMMG4 group conducted a randomized trial that found that bortezomib-based induction followed by ASCT with borte-zomib maintenance provided a superior PFS and OS compared with non-bortezomib induction followed by ASCT with thalido-mide maintenance (hazard ratio [HR] = 0.78, P = .002 and HR = 0.78, P = .027, respectively).25 Another study, conducted by the Spanish Myeloma Group, completed a 3-arm posttransplant maintenance trial in standard-risk patients that compared inter-feron vs thalidomide vs thalidomide/bortezomib.26 There was an improvement in PFS but not OS in the thalidomide/bortezomib cohort. Although both studies showed bortezomib maintenance therapy to be effective, the optimal use of bortezomib remains



unclear in terms of the scheme as well as the duration of thera-py. Furthermore, bortezomib-associated peripheral neuropathy, shown to affect 38% of those treated with subcutaneous bortezo-mib,27 must be weighed against the benefits.

Minimal Residual DiseaseTechniques for assessing MM disease burden have transitioned from serum and urine protein electrophoresis and immunofix-ation to highly sensitive, novel assays developed to measure cel-lular minimal residual disease (MRD) in the bone marrow and peripheral blood of MM patients. As such, MRD assessment has gained importance in the depth of response. Multiparam-eter flow cytometry can detect phenotypically aberrant clonal plasma cells in >95% of MM patients with a sensitivity of up to 10-4.28.29 The analysis of MRD by molecular techniques relies on the study of immunoglobulin gene rearrangements, and can identify a molecular marker in >90% of patients.30 The 3 main techniques available to analyze immunoglobulin gene rearrange-ments are fluorescent polymerase chain reaction (PCR) using family primers of immunoglobulin genes with a sensitivity of 10-3,31 allele-specific oligonucleotide (PCR),30,32 and high-through-put sequencing, applicable to 80% to 90% of patients and reach-ing a sensitivity of up to 10-6.33

Several studies have shown that patients achieving MRD negativity have improved PFS and OS post-ASCT,30,32-34 main-tenance,29 and non-ASCT transplant-eligible settings.35 It is important to note that MRD-negativity can provide a degree of uncertainty in prognosis in that it is unclear whether there is a true absence of clonality versus a sampling inaccuracy. MRD-pos-itivity, however, is almost always an adverse prognostic feature. It is important to note that although we have data that MRD neg-ativity is a favorable prognostic factor, there are no data that it should be a goal of therapy or guide therapeutic decisions. Some examples of unanswered questions regarding MRD include the following: (1) Do patients achieving MRD-negativity before trans-plant benefit from an early transplant or should these patients be considered for consolidation/maintenance therapy followed by high-dose chemotherapy with ASCT at first relapse. (2) Do pa-tients with MRD-positivity after transplant require consolidation and maintenance? (3) Can maintenance therapy be discontinued once MRD-negativity has been achieved? (4) Is MRD negativity a surrogate marker for prognosis in high risk myeloma? Clinical trials are being designed with these very important questions in mind. The ultimate goal is to use MRD assessments as a risk stratification tool to dictate therapy and for earlier identification of response in the setting of clinical studies.

ConclusionThe initial incorporation of high-dose melphalan followed by ASCT and subsequent introduction of PI and IMiD-based ther-apy pre- and post-ASCT has dramatically changed the treatment

landscape for MM. Although ASCT is standard of care for treat-ment of transplant-eligible MM patients, the ideal timing for its use has been challenged by the marked efficacy of novel drugs. Until prospective studies prove otherwise, ASCT as consolida-tion after first remission is still recommended. Extended treat-ment with consolidation and maintenance therapy improves the quality and duration of clinical responses; however the optimal timing, doses, and duration of therapy have not yet been de-fined. Further, the exact population of patients for whom these therapies will provide the most benefit has yet to be elucidated. Further research, including the use of MRD assessment, cytoge-netic risk stratification, and prospective clinical trials, will ulti-mately allow us to individualize treatment.

Affiliations: Noa Biran, MD, and David H. Vesole, MD, PhD, are from the John Theurer Cancer Center, Myeloma Division, Hackensack, NJ.Address Correspondence to: Noa Biran, MD, John Theurer Cancer Center, Myeloma Division, 92 2nd Street, Suite 340, Hackensack, NJ 07601. Phone: 551-996-8704; Fax 551-996-0582

REFERENCES1. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, ran-domized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335(2):91-7.2. Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348(19):1875-1883.3. Fermand JP, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005;23(36):9227-9233.4. Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood. 1998;92(9):3131-3136.5. Blade J, Rosinol L, Sureda A, Ribera JM, et al. High-dose ther-apy intensification compared with continued standard chemo-therapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005;106(12):3755-3759.6. Koreth J, Cutler CS, Djulbegovic B, et al. High-dose thera-py with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: a systematic review and

CLINICAL DECISION MAKING IN MULTIPLE MYELOMA FOR THE TRANSPLANT-ELIGIBLE PATIENT


meta-analysis of randomized controlled trials. Biol Blood Marrow Transplant. 2007;13(2):183-196.7. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improve-ment in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28(5):1122-1128.8. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bor-tezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116(5):679-686.9. Palumbo A, Cavallo F, Gay F, et al. Autologous transplanta-tion and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895-905.10. Barlogie B, Kyle RA, Anderson KC, et al. Standard chemo-therapy compared with high-dose chemoradiotherapy for mul-tiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol. 2006;24(6):929-936.11. Kumar SK, Lacy MQ, Dispenzieri A, et al. Early versus de-layed autologous transplantation after immunomodulatory agents-based induction therapy in patients with newly diagnosed multiple myeloma. Cancer. 2012;118(6):1585-1592.12. Dunavin NC, Wei L, Elder P, et al. Early versus delayed autol-ogous stem cell transplant in patients receiving novel therapies for multiple myeloma. Leukemia & Lymphoma. 2013;54(8):1658-1664.13. Moreau P, Garban F, Attal M, et al. Long-term follow-up re-sults of IFM99-03 and IFM99-04 trials comparing nonmyeloabla-tive allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood. 2008 Nov 1;112(9):3914-3915.14. Bird JM, Owen RG, D’Sa S, Snowden JA, Pratt G, Ashcroft J, et al. Guidelines for the diagnosis and management of multiple myeloma 2011. Br J Haematol. 2011 Jul;154(1):32-75.15. Engelhardt M, Terpos E, Kleber M, Gay F, Wasch R, Morgan G, et al. European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with mul-tiple myeloma. Haematologica. 2014;99(2):232-242.16. Shah N, Callander N, Ganguly S, et al. Hematopoietic Stem Cell Transplantation for Multiple Myeloma: Guidelines from the ASBMT. Biol Blood Marrow Transplant. 2015;21(7):1155-1166.17. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myelo-ma. N Engl J Med. 2012;366(19):1782-1791.18. Mellqvist UH, Gimsing P, Hjertner O, et al. Bortezomib con-solidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood. 2013;121(23):4647-4654.19. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with tha-lidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study.

Lancet. 2010;376(9758):2075-2085.20. Roussel M, Lauwers-Cances V, Robillard N, et al. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myelome. J Clin Oncol. 2014;32(25):2712-2717.21. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1770-1781.22. Gay F, Magarotto V, Crippa C, et al. Bortezomib induc-tion, reduced-intensity transplantation, and lenalidomide con-solidation-maintenance for myeloma: updated results. Blood. 2013;122(8):1376-1383.23. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide Maintenance After Stem-Cell Transplantation for Multiple My-eloma: Follow-Up Analysis of the IFM 2005-02 Trial. ASH 2013 Annual Meeting Abstracts. Blood. 2013;406.24. Attal M, Lauwers-Cances V, Marit G, et al. Maintenance Treatment with Lenalidomide After Transplantation for Myelo-ma: Final Analysis of the IFM 2005-02. ASH 2010 Annual Meet-ing Abstracts. Blood. 2010;310.25. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bor-tezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012; 30(24):2946-2955.26. Rosinol L, Oriol A, Teruel AI, et al. Superiority of borte-zomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012;120(8):1589-1596.27. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous ver-sus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferior-ity study. Lancet Oncol. 2011;12(5):431-440.28. Paiva B, Vidriales MB, Cervero J, et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood. 2008;112(10):4017-4023.29. Rawstron AC, Child JA, de Tute RM, Davies FE, Gregory WM, Bell SE, et al. Minimal residual disease assessed by multi-parameter flow cytometry in multiple myeloma: impact on out-come in the Medical Research Council Myeloma IX Study. J Clin Oncol. 2013;31(20):2540-2547.30. Sarasquete ME, Garcia-Sanz R, Gonzalez D, et al. Minimal residual disease monitoring in multiple myeloma: a comparison between allelic-specific oligonucleotide real-time quantitative polymerase chain reaction and flow cytometry. Haematologica. 2005;90(10):1365-1372.31. Martinez-Lopez J, Fernandez-Redondo E, Garcia-Sanz R, et al. Clinical applicability and prognostic significance of molecular



response assessed by fluorescent-PCR of immunoglobulin genes in multiple myeloma: results from a GEM/PETHEMA study. Br J Haematol. 2013;163(5):581-589.32. Putkonen M, Kairisto V, Juvonen V, et al. Depth of response assessed by quantitative ASO-PCR predicts the outcome after stem cell transplantation in multiple myeloma. Eur J Haematol. 2010;85(5):416-423.33. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for minimal residual disease detec-tion in multiple myeloma. Blood. 2014;123(20):3073-3079.34. Ladetto M, Bruggemann M, Monitillo L, et al. Next-gen-eration sequencing and real-time quantitative PCR for min-imal residual disease detection in B-cell disorders. Leukemia. 2014;28(6):1299-1307.35. Paiva B, Martinez-Lopez J, Vidriales MB, et al. Comparison of immunofixation, serum free light chain, and immunopheno-typing for response evaluation and prognostication in multiple myeloma. J Clin Oncol. 2011;29(12):1627-1633.

· NATIONAL INITIATIVES ·


‘Choosing Wisely’ Campaigns from ASCO and ASH: A Review for Clinicians in Haematology and Oncology

Ilana Kopolovic, MD; Henry Jacob Conter, MD, MSF, MSc, FRCPC; and Lisa Kristine Hicks MD, MSc, FRCPC

IntroductionThe Choosing Wisely campaign is an ongoing quality improve-ment initiative that aims to minimize medical testing and inter-ventions for which little evidence exists to support a benefit, and that are associated with unnecessary costs, burdens, or risks to patients and the healthcare system.1 The campaign is led by the American Board of Internal Medicine Foundation in collabora-tion with medical professional societies across the United States. Choosing Wisely has also inspired similar initiatives around the world.2

The American Society of Hematology (ASH) and the Amer-ican Society of Clinical Oncology (ASCO) have each produced ten Choosing Wisely recommendations in the fields of benign and malignant oncology.3-6 These recommendations have been proposed by practicing hematologists and oncologists, inspired by common practices with questionable value, and ultimately se-lected by a task force, after having undergone literature reviews to examine the evidence to support each recommendation.

Herein, we discuss the 20 recommendations in the realms of-clinical care to which they apply.

ScreeningScreening is an integral part of cancer care, requiring a balance of optimizing benefits to as many people as possible, while mini-mizing risks associated with procedures and incidental findings. While most cancer screening falls within the scope of primary care providers, hematologists and oncologists have critical roles in their communities in educating general practitioners and other healthcare providers and advocating for programs that use screening tests appropriately. Among their recommendations, ASCO discouraged the routine use of prostate- specific antigen (PSA) testing to detect asymptomatic prostate cancer in men ex-pected to live less than 10 years. In such cases, PSA testing is highly unlikely to yield results that will prolong life, and may result in unnecessary invasive testing or anxiety. Routine use of PSA screening in an unselected population has been shown to decrease prostate cancer-related mortality, but not overall mortal-ity,7,8 or at the expense of quality of life.9 Furthermore, given the slow growth rate of many prostate cancers, PSA screening is very unlikely to be beneficial when life expectancy is limited.

Diagnostic TestingThe ASH Choosing Wisely campaign includes two examples of recommendations focused on diagnostic testing, both in the realm of non-malignant hematology. For instance, in 2013 the ASH Choosing Wisely campaign recommended that throm-bophilia testing not be undertaken in patients with venous thromboembolism (VTE) provoked by a transient risk factor, such as postoperative VTE. Testing for thrombophilia has be-come a common practice, but it is clear that in certain settings, such testing should not influence clinical decision making. In unselected populations, hereditary thrombophilias do not ap-pear to portend a higher risk of recurrence.10 Furthermore, in the absence of routine thrombophilia testing, patients with pro-voked VTE have a very low risk of recurrent thrombosis.11 Thus, thrombophilia work-ups in this setting serve only to potentially confer clinically inconsequential genetic diagnoses, which may have both negative psychological and practical implications (eg, denial of insurance).

In its 2014 Campaign, ASH offered another recommenda-

Abstract The “Choosing Wisely” campaign is a national initiative

whose aim is to optimize the safety and efficiency of

health care by encouraging evidence-based applications

of medical investigations and interventions. In recent

years, the American Society of Clinical Oncology (ASCO)

and the American Society of Hematology (ASH) and

have contributed to the Choosing Wisely campaign, each

publishing ten recommendations for practicing hema-

tologists and oncologists. These recommendations can

be considered in the categories of screening, diagnostic

testing, disease-specific therapies, supportive care, and

cancer staging and surveillance. We review the recom-

mendations of ASH and ASCO, highlighting their ratio-

nale and anticipated benefits.

Keywords: screening, diagnostic testing, ASH, ASCO, in-

vestigations, interventions, staging, surveillance



tion on diagnostic testing, cautioning against testing for hepa-rin- induced thrombocytopenia (HIT) in patients with a low pre-test probability (PTP). In this setting, the probability of a false positive result far outweighs the probability of a true positive; thus, HIT testing is more likely to be misleading than helpful and should not be performed.12 The consequences of testing for HIT in low-risk patients include exposing patients to risk from full-dose anticoagulation with a non-heparin anticoagulant and its attendant bleeding risks, and risks from withholding heparin when indicated.13

Disease-Targeted TreatmentWith a rapidly expanding armamentarium, an emerging chal-lenge facing oncologists and hematologists is to resist the urge to offer intervention in the absence of strong supportive evidence and where the potential for harm outweighs the realistic estima-tion of benefit. The theme of avoiding overtreatment underlies several of the ASH and ASCO recommendations. A particular-ly high-impact recommendation from ASCO in this category is one that reminds clinicians not to recommend cancer-directed treatment to a patient with poor performance status who has not benefited from evidence-based anti-cancer treatment who is not eligible for clinical trials, and where there is no strong evidence supporting further anti-cancer treatment. Instead, in this scenar-io, palliation should be the focus of care.

A second ASCO recommendation in this category is to avoid using combination chemotherapy for metastatic breast cancer in the absence of compelling evidence. Instead, ASCO advises that single-agent regimens be used. Multi-agent chemotherapy is often more costly with the potential for more adverse effects than single-agent regimens; thus, in the absence of strong clinical data, single-agent regimens are preferred.

In a similar vein, ASCO recommends that targeted therapies should only be used where a biomarker predicting a response to the therapy is demonstrable in the patient’s tumor. Targeted therapies have shown exciting promise, often with impressive efficacy and sometimes less toxicity than conventional cytotox-ic chemotherapies; however, their costs and the boundaries of their efficacy must be appreciated.14 For example, the success of BRAF inhibition in BRAF mutant metastatic melanoma has not translated to similar success in BRAF mutant metastatic colon cancer,15 nor has the success of HER2/neu- targeted therapy in HER2/neu amplified breast and gastric cancer translated into similar advances in other solid tumors to date.16 Ultimately, the potential to expand the roles of targeted agents should be ex-plored in clinical trials, where safety and efficacy can be defin-itively established, prior to incorporation into clinical practice.

ASH has also made recommendations in over treatment. For example, ASH recommends that patients who experience a VTE in the setting of a major transient risk factor be anticoagulated for three months, rather than longer durations. In this setting,

the risk of recurrence declines dramatically after a three-month course of treatment, for example, to less than 1% in the case of postoperative VTE.11 Thus, ongoing therapy with an antico-agulant exposes patients to the risk of anticoagulant-associated hemorrhage without clinical benefit.17

A second recommendation by ASH in this category, also about VTE, relates to the routine use of vena cava filters (VCF); anticoagulation for acute DVT affords excellent outcomes, and the introduction of VCFs as an adjunct is associated with little or no added benefit. The only randomized controlled trial of this intervention showed no reduction in symptomatic pulmonary embolism (PE).18 Furthermore, VCFs impose substantial risks, among them, increased rates of leg DVT and the potential for filter fracture, migration, or embolization.19 Despite minimal evidence to support a benefit of VCF and growing concerns sur-rounding safety, its use is becoming increasingly common in the United States.19

The ASH Choosing Wisely task force also identified immune thrombocytopenia (ITP) as a disease whose subjects may be over-treated to their detriment. ASH recommended against treatment of ITP in the absence of bleeding or a very low platelet count. De-spite moderate or even severe thrombocytopenia, most patients with ITP have bleeding rates that are low20 in absolute terms and also when compared to those with similar degrees of throm-bocytopenia from other etiologies. All therapies for ITP confer risks; steroids, the most common treatment for ITP, are associ-ated with substantial morbidity. Several studies have found that ITP patients are more likely to die of infection than hemorrhage; since steroids, splenectomy, and other ITP-directed therapies heighten infectious risk, these data have inspired reevaluation of the treatment paradigm in this disease.

Finally, the ASH Choosing Wisely campaign advised against the use of prothrombin complex concentrates (PCCs) for vita-min K antagonist (VKA) reversal in a non-bleeding patient in whom an urgent procedure is not planned. PCCs are costly and introduce risks of uncommon but serious advere events includ-ing thromboembolism,21 so their use should be limited to urgent clinical circumstances.

With our therapeutic toolbox enriched with a growing array of novel and exciting agents and interventions, the Choosing Wise-ly campaign underscores an important message: More treatment does not always translate into better care.

Supportive TherapiesManaging complex diseases involves not only disease-directed treatments, but also supportive care to prevent complications and manage symptom burden. As with disease-directed thera-pies, the oncologist and hematologist do a great service to pa-tients and the system within which care is delivered by embracing a stewardship role in using supportive care measures.

ASCO has two important recommendations in this category.

‘CHOOSING WISELY’ CAMPAIGNS FROM ASCO AND ASH


First, ASCO recommends against the use of granulocyte colony stimulating factor (gCSF) in patients at low risk of febrile neu-tropenia (FN). In patients at moderate to high risk of FN, gCSF decreases the incidence of FN,22 decreases hospitalizations,23 and may reduce infectious mortality in both solid and lymphoid can-cers. Most major cancer societies recommend its routine use in patients with a risk of FN >20%.24-26 However, when the risk of FN is low, a benefit has not been established. Thus, using gCSF in this setting exposes patients to side effects such as bone pain and financial burdens without expectation of benefit.

ASCO’s second recommendation in this category is against the routine use of highly effective but expenscive anti-emeto-genic drugs in patients receiving low or moderately emetogenic chemotherapy. Highly effective prophylactic antiemetic regi-mens have been established, and their use endorsed for primary prevention with specific regimens. However, these drugs have side effects such as constipation, and they are expensive. Liberal use of highly effective antiemetic drugs is likely to yield marginal benefit in most patients and may not outweigh associated costs and risks.27

ASH’s two recommendations in the category of supportive care both involve transfusion, which is a common supportive practice whose application extends into the management of be-nign and malignant disease. Dramatic strides have been made to mitigate the risks of transfusion associated infection — most notably viral hepatitis and the human immunodeficiency virus — and have contributed to the perception of the safety of blood transfusion. However, transfusion is not risk free. It is associated with important complications including transfusion-associated volume overload, transfusion-associated lung injury (TRALI), ABO reactions, and allo-immunization. A large body of litera-ture suggests that patient outcomes are the same or better when restrictive transfusion strategies are employed rather than liberal strategies.28-32 Thus, ASH recommends judicious red cell transfu-sion, such that the minimum number of units required to restore a safe and asymptomatic degree of anemia are prescribed.

In patients with sickle cell disease (SCD), ASH recommends against the routine use of red cell transfusions for chronic ane-mia or uncomplicated pain episodes where no improvements in clinical outcome have been demonstrated with transfusion. Transfusion-associated cardiac overload, acute lung injury, al-lergic or febrile reactions, iron overload, and acute or delayed immune-mediated hemolytic transfusion reactions are of special concern in patients with SCD due to their high lifetime need for transfusion and to the fact that they frequently express minor red cell antigens that are less common in the donation pool.33,34 It should be appreciated that transfusion medicine is an area where practice can be uniquely impactful. As a therapeutic realm relevant to generalists and other specialists, transfusion poses an opportunity, and possibly a responsibility, to educate colleagues and lead by example.

Cancer Staging and Posttreatment SurveillanceA number of ASCO and ASH Choosing Wisely recommen-dations deal with staging tests and posttreatment surveillance with imaging. For example, ASH recommends that patients with early-stage chronic lymphocytic leukemia (CLL) without an indication for treatment should not routinely undergo staging computed tomography (CT) scans. Unlike in lymphoma, CLL can be staged and prognosticated with a clinical exam and lab work. Thus, in early-stage disease, scans do not guide or alter management, are not necessary for prognostication, and have never demonstrated the ability to improve outcomes.

Similarly, ASCO recommends that patients with early-stage prostate or breast cancers should not undergo positron emission tomography (PET), CT, or radionuclide bone scans as part of staging assessments.35 As with CLL, such additional testing does not aid with either prognostication or management of most pa-tients with early-stage breast and prostate cancer.

Imaging investigations are also often overutilized in the post-treatment setting where they can trigger many additional tests due to incidental findings and expose patients to a substantial cumulative dose of radiation. Surveillance CT and PET scans are also costly — which can burden individual patients and the healthcare system. ASH and ASCO chose to highlight the im-portance of limiting surveillance CT and/or CT/PET scans in patients who have been treated for cancer with curative intent, and specifically for aggressive lymphomas or breast cancers, where a minority of relapses will present initially with isolated radiographic findings in the absence of clinically apparent re-lapse.36 Importantly, surveillance imaging has not been associat-ed with improved survival in either setting.

Practical Considerations and Future DirectionsDespite widespread presentation and expanding awareness of the Choosing Wisely campaign, uptake of the guidance present-ed therein remains a challenge. Several reviews of institutional practices have demonstrated suboptimal adherence to Choosing Wisely recommendations, and in some instances, practices do not appear to have changed at all following their presentation.37-40 This is consistent with evidence that education alone is rarely sufficient to trigger practice change. Thus, the Choosing Wisely campaigns ought to be viewed as critical first steps in changing dialogue around overuse, but not an end in themselves. Programs that inte-grate information on current practices and patient outcomes, such as the CancerLINQ system,41 allow clinicians to actively assess and revise the quality of care they provide, while also contributing to knowledge generation. Such initiatives will continue to iterative-ly shape both guidelines and individual practices.

ConclusionASH and ASCO have made important recommendations to the Choosing Wisely campaign, which can be considered in 5



categories: screening, diagnostic testing, disease-targeted thera-py, supportive care, and cancer staging or surveillance. None of the recommendations are intended to replace clinical judgment, which by necessity should be nuanced and patient centered. All Choosing Wisely lists are intended to spur conversations and to encourage thoughtful, evidence-based practice. Next time you are in a clinical situation relevant to one of the ASH or ASCO Choosing Wisely items, we encourage you to consider the item, discuss it with your patients, students, and colleagues, and make the best recommendation you can for the patient in front of you.

Affliations: Ilana Kopolovic, MD, is from Lakeridge Health, Durham Regional Cancer Centre , Oshawa, Ontario, Canada. Henry J Conter, MD, MSF, MSc, FRCPC, is from University of Western Ontario, London, Ontario, Canada, and Division of Hematology and Oncology, William Osler Health System, Brampton, Ontario, Canada. Lisa Kristine Hicks, MD, MSc, FRCPC, is from St. Michael’s Hospital, Division of Hematolo-gy/Oncology, Toronto, Ontario, Canada, and from the Univer-sity of Toronto, Toronto, Ontario, Canada. Address correspondence to: Lisa K. Hicks, St Michael’s Hospi-tal, Room 2 084 Donnelly Wing, 30 Bond St., Toronto, ON M5B 1W8. Phone: 416-864-5632, Fax: 416-864-3055, email: [email protected]

REFERENCES1. Wolfson D, Santa J, Slass L. Engaging physicians and con-sumers in conversations about treatment overuse and waste: a short history of the choosing wisely campaign. Acad Med. 2014;89(7):990-995.2. Levinson W, Kallewaard M, Bhatia RS, Wolfson D, Shortt S, Kerr EA. ‘Choosing Wisely’: a growing international campaign. BMJ Qual Saf. 2015;24(2):167-174.3. Hicks LK, Bering H, Carson KR, et al. The ASH Choosing Wisely campaign: five hematologic tests and treatments to ques-tion. Hematology Am Soc Hematol Educ Program 2013;2013:9-14.4. Hicks LK, Bering H, Carson KR, et al. Five hematologic tests and treatments to question. Blood. 2014;124(24):3524-3528.5. ASCO.Choosing Wisely five things physicians and patients should question. http://www.choosingwisely.org/choosing-wise-ly-five-things-physicians-and-patients-should-question-press-re-lease-april-4-2012/.6. Schnipper LE, Smith TJ, Raghavan D, et al. American Society of Clinical Oncology identifies five key opportunities to improve care and reduce costs: the top five list for oncology. J Clin Oncol. 2012;30(14):1715-1724.7. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360(13):1310-1319.8. Schroder FH, Hugosson J, Roobol MJ, et al. Prostate-cancer

mortality at 11 years of follow-up. N Engl J Med. 2012;366(11):981-990.9. Heijnsdijk EA, Wever EM, Auvinen A, et al. Quality-of-life effects of prostate-specific antigen screening. N Engl J Med. 2012;367(7):595-605.10. Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA. 2005;293(19):2352-2361.11. Iorio A KC, Filippucci E, Marcucci M, et al. Risk of recurrent after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch In-tern Med. 2010;170(19):1710-1716.12. Cuker A, Cines DB. How I treat heparin-induced thrombo-cy-topenia. Blood. 2012;119(10).13. Warkentin TE. HITlights: a career perspective on heparin-in-duced thrombocytopenia. Am J Hematol. 2012;87(suppl 1):S 92-S99.14. Tsimberidou AM, Iskander NG, Hong DS, et al. Personalized medicine in a phase I clinical trials program: the MD Ander-son Cancer Center initiative. Clin Cancer Res. 2012;18(22):6373-6383.15. Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback acti-vation of EGFR. Nature. 2012;483(7387):100-103.16. Martin V, Cappuzzo F, Mazzucchelli L, Frattini M. HER2 in solid tumors: more than 10 years under the microscope; where are we now? Future Oncol. 2014;10(8):1469-1486.17. Palareti G, Leali N, Coccheri S, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet. 1996;348(9025):423-428.18. Decousus HL, A Parent, F , Page Y, Tardy B, et al. A clinical trial of vena cava filters in the prevention of pulmonary embo-lism in patients with proximal deep- vein thrombosis. N Engl J Med. 1998;338(7):409-415.19. Wang SL, Lloyd AJ. Clinical review: inferior vena cava filters in the age of patient-centered outcomes. Ann Med. 2013;45(7):474-481.20. Norgaard M, Jensen AO, Engebjerg MC, et al. Clinical outcomes of patients with primary chronic immune throm-bocytopenia: a Danish population-based cohort study. Blood. 2011;117(13):3514-3520.21. Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safe-ty of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128(11):1234-1243.22. Cooper KL, Madan J, Whyte S, Stevenson MD, Akehurst RL. Granulocyte colony-stimulating factors for febrile neutrope-nia prophylaxis following chemotherapy: systematic review and meta-analysis. BMC Cancer. 2011;11:404.23. Lyman GH, Delgado DJ. Risk and timing of hospitalization

‘CHOOSING WISELY’ CAMPAIGNS FROM ASCO AND ASH


for febrile neutropenia in patients receiving CHOP, CHOP-R, or CNOP chemotherapy for intermediate-grade non-Hodgkin lym-phoma. Cancer. 2003;98(11):2402-2409.24. Network NCC. Myeloid Growth Factors. NCCN Clinical Practice Guidelines in Oncology. 2014.25. Crawford J, Caserta C, Roila F,; ESMO Guidelines Work-ing Group. Hematopoietic growth factors: ESMO Clinical Prac-tice Guidelines for the applications. Ann Oncol. 2010;21 Suppl 5:v248-251.26. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth fac-tors: an evidence-based clinical practice guideline. J Clin Oncol. 2006;24(19):3187-3205.27. Adams JR, Angelotta C, Bennett CL. When the risk of fe-brile neutropenia is 20%, prophylactic colony-stimulating fac-tor use is clinically effective, but is it cost-effective? J Clin Oncol. 2006;24(19):2975-2977.28. Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;365(26):2453-2462.29. Cooper HA, Rao SV, Greenberg MD, et al. Conservative ver-sus liberal red cell transfusion in acute myocardial infarction (the CRIT Randomized Pilot Study). Am J Cardiol. 2011;108(8):1108-1111.30. Hajjar LA, Vincent JL, Galas FR, et al. Transfusion require-ments after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010;304(14):1559-1567.31. Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care In-vestigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340(6):409-417.32. Villanueva C, Colomo A, Bosch A, et al. Transfusion strat-egies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368(1):11-21.33. Chou ST, Liem RI, Thompson AA. Challenges of alloimmu-nization in patients with haemoglobinopathies. Br J Haematol. 2012;159(4):394-404.34. Porter J, Garbowski M. Consequences and management of iron overload in sickle cell disease. Hematology Am Soc Hematol Educ Program. 2013;2013(1):447-456.35. Makarov DV, Desai RA, Yu JB, et al. The population level prevalence and correlates of appropriate and inappropriate imag-ing to stage incident prostate cancer in the medicare population. J Urol. 2012;187(1):97-102.36. Guppy AE, Tebbutt NC, Norman A, Cunningham D. The role of surveillance CT scans in patients with diffuse large B-cell non-Hodgkin’s lymphoma. Leuk Lymphoma. 2003;44(1):123-125.37. Simos D, Hutton B, Clemons M. Are physicians choosing wisely when imaging for distant metastases in women with oper-able breast cancer? J Oncol Pract. 2015;11(1 ):62-68.

38. Butcher L. Measuring Adherence to ASCO’s ‘Choosing Wisely’ List. Oncol Times. 2014;36(22 ):24–25.39. Ramsey SD, Fedorenko C, Chauhan R, et al. Baseline esti-mates of adherence to American Society of Clinical Oncology/American Board of Internal Medicine choosing wisely initiative among patients with cancer enrolled with a large regional com-mercial health insurer. J Oncol Pract. 2015;11(4):338-343.40. Rosenberg A, Agiro A, Gottlieb M, et al. Early trends among seven recommendations from the Choosing Wisely campaign. JAMA Intern Med. 2015 Oct 12:1-9. doi: 10.1001/ jamainternmed.2015.5441. [Epub ahead of print].41. Schilsky RL, Michels DL, Kearbey AH, Yu PP, Hudis CA. Building a rapid learning health care system for oncol-ogy: the regulatory framework of CancerLinQ. J Clin Oncol. 2014;32(22):2373-2379.

CME


Dates of certification: December 21, 2015, to December 21, 2016Medium: Print with online posttest, evaluation, and request for credit

The American Journal of Hematology/Oncology® Editorial BoardDebu Tripathy, MDProfessor of Medicine and ChairDepartment of Breast Medical OncologyThe University of Texas MD Anderson Cancer CenterHouston, TX Disclosure: Grant/research support from Genentech/Roche, Pfizer, Puma Inc, and Novartis (clinical trial support contracted to the Univer-sity of Southern California and MD Anderson Cancer Center); consul-tant for Eisai, Oncoplex Diagnostics, Merck, and Novartis.

FacultyGeorge D. Demetri, MDProfessor of Medicine, Harvard Medical SchoolDirector, Ludwig Center at HarvardDirector, Center for Sarcoma and Bone OncologySenior Vice President for Experimental TherapeuticsDana-Farber Cancer InstituteBoston, MADisclosure: Consultant, consulting fees: Bayer, Novartis, Pfizer, Lilly, EMD-Serono, Sanofi Oncology, Janssen Oncology, PharmaMar, GlaxoSmithKline, Daiichi- Sankyo, Ariad, AstraZeneca, WIRB-Coper-nicus Group, ZIOPHARM Oncology, and Polaris; Research support to Dana-Farber for specific clinical trial agreements in their sarcoma unit: Bayer, Novartis, EMD-Serono, Sanofi Oncology, Janssen Oncology, and GlaxoSmithKline; Patent licensed to Novartis from Dana-Farber with royalty paid to Dana-Farber; Consultant, Scientific Advisory Board consulting fees, Equity (minor stake, nonpublic): Kolltan Pharma-ceuticals; Member, Board of Directors, Member, Scientific Advisory Board Fees and Equity (minor stake, nonpublic): Blueprint Medicines; Consultant, Scientific Advisory Board consulting fees/Equity (minor stake, nonpublic): G1 Therapeutics and Caris Life Sciences; Consultant, Scientific Advisory Board consulting fees (>$10k, <$20k) and Equity (minor stake, nonpublic): Champions Oncology; Consultant, uncom-pensated, Equity (minor stake, nonpublic): Bessor Pharma

Staff/Planner Disclosures and Conflict of Interest ResolutionThe staff of Physicians’ Education Resource®, LLC, (PER®) and the editorial staff of The American Journal of Hematology/Oncology® have no relevant financial relationships with commercial interests to disclose.

In accordance with Accreditation Council for Continuing Medical Education (ACCME) Standards for Commercial SupportSM, PER® resolved all conflicts of interest prior to the release of this CME activity using a multistep process.

OverviewThis activity is designed to inform physicians about the latest treat-ment advances in soft-tissue sarcomas (STS), including approved and investigational management strategies.

Target AudienceThis activity is directed toward medical oncologists, primary care physicians, nurses, and nurse practitioners who treat patients with STS. Surgical oncologists, radiation oncologists, pathologists, fellows, physician assistants, and other healthcare providers interested in the management of STS are also invited to participate.

Learning ObjectivesAfter participating in this CME activity, learners should be better prepared to:• Describe the shared-care model and its application to treatment of

patients with STS• Explain the significance of recent and upcoming studies in STS

management• Discuss the appropriate uses of combination therapy for STS• Describe the primary principle regarding sequencing therapy for

STS

Accreditation/Credit DesignationPER®, LLC, is accredited by the Accreditation Council for CME to provide continuing medical education for physicians.PER®, LLC, designates this enduring material for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded by Physicians’ Education Resource®.

Instructions for Participation/How to Receive AMA PRA Category 1 CreditTM

1. Read the article in its entirety.2. Use the QR Code or type http://www.ajho.com/go/Dec15CME into your Web browser to access the posttest.3. Complete and pass the posttest with a score of 70% or higher.4. Complete the evaluation and request for credit. Participants may immediately download a CME certificate upon successful completion of these steps.

Off-Label Disclosure and DisclaimerThis CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options for a specific patient’s medical condition.

DisclaimerThe opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER®.

Contact information for questions about the activity:Physicians’ Education Resource, LLC666 Plainsboro Road, Suite 356Plainsboro, NJ 08536Phone: (888) 949-0045E-mail: [email protected]

Evolving Management Options for Soft-Tissue Sarcomas

EVOLVING MANAGEMENT OPTIONS FOR SOFT-TISSUE SARCOMAS

VOL. 11, NO. 12 THE AMERICAN JOURNAL OF HEMATOLOGY/ONCOLOGY 31

Moderator: What are some of the most pressing unmet clinical needs in the management of STS?Dr. Demetri: Number 1 is to recognize that 85% if not more of can-cer patients in the United States are cared for in the community, not at specialty academic centers. Also, STS is not one disease; it’s a class of probably more than 500 or 600 different diseases. So the first thing is to be sure that patients with STS are subcategorized and man-aged appropriately. I can’t stress that enough, because the more we learn about STS, the more we realize that there are actionable differ-ences between the subtypes, important differences, and if you’re in a busy community practice, you don’t see a lot of these patients. There are just not enough of them for most community doctors to see more than 1 or 2 a year, and many doctors may not be aware of just how important it is to parse the diagnoses more finely than ever before. Going forward, it’s going to be more important that the diagnosis is right, that the right tests have been done, and that management is really bespoke, personalized, for each patient based on all the data. I think we have to get the word out that it’s not an academic exercise; it really can mean a dramatic difference in patient outcomes.

Moderator: Given that community physicians don’t see that many patients with STS, what would be the best way for them to know what to look for?Dr. Demetri: I think this is going to be a shared-care model in which community physicians who have patients with STS think, whom do I call who sees a lot of these patients? It is going to be a situation in which we in the academic centers support our colleagues in the com-munity. We’re not here to take all the patient care away, we’re here to help plan a course of action much of which can and should be delivered in the community, after certain decision points are passed. Initial diagnosis review, initial planning, and then if the disease were to come back or progress – those are decision points. I think experts are very rationally involved in those decisions with people in the community. Again, sarcomas are rare – maybe 20,000 new cases a year in the United States. There are a number of experts scattered throughout the country. Certainly the big 3 that people think of are Dana-Farber/Harvard, Memorial Sloan Kettering, and MD Ander-son. There are others, as well.

Here are 2 examples of the shared-care model: The first was GIST.

With an approximate annual estimate of 12,000 newly diagnosed soft-tissue sarcomas (STS) in the United States,1 STS is a relatively rare form of cancer. Thus, it is not seen often by community-based physicians. Despite the low incidence of STS, this group of cancers is complex and is a topic of major research interest. At the 2015 meet-ing of the American Society of Clinical Oncology (ASCO), more than 70 abstracts reporting on studies in STS were presented.2

Confounding the approach to treatment is the fact that STS com-prises a multitude of subtypes, each of which has specific biologic characteristics and may respond to different therapeutic approaches. Recently, the World Health Organization expanded its estimate of the number of STS subtypes from approximately 50 to more than 100. The characteristics of the tumor, along with patient factors such as age and comorbidities, determine the choice of treatment.3 As a result of the heterogeneity of STS subtypes and the historical paucity of large, controlled clinical trials, there is no single standard of treat-ment for patients with advanced STS,4 and the overall relative 5-year survival rate for patients with STS is only about 50%.1

Until recently, nonsurgical treatment of STS was limited to use of standard cytotoxic drugs such as doxorubicin and ifosfamide, ad-ministered as single agents, in combination, or sequentially. Cumu-lative doxorubicin treatment, however, is associated with cardiomy-opathy, and ifosfamide is associated with several potentially serious adverse events, such as neutropenia and renal toxicity. Gemcitabine, docetaxel, and dacarbazine are also used in STS, as monotherapy or in various combinations.5 Results, however, have not always been encouraging. For example, the addition of bevacizumab to the combi-nation of gemcitabine/docetaxel did not improve survival in first-line treatment of uterine leiomyosarcoma.6 Similarly, the GeDDiS trial

failed to show superiority of gemcitabine/docetaxel over doxorubicin in first-line treatment of advanced STS.7

Efforts to discover newer, more effective, less toxic agents and com-binations are ongoing. Currently, 389 clinical trials in STS are listed at ClinicalTrials.gov that are either recruiting or about to start re-cruiting.8 The efficacy of imatinib in treating gastrointestinal stromal tumors (GIST) has led to further exploration of targeted therapies for other STS subtypes.9 In addition, interest in immunotherapies in STS continues to be strong.10

Novel agents that are showing great promise include the ma-rine-derived drugs trabectedin and eribulin. In phase III, random-ized, multicenter studies, treatment with each of these drugs yielded significantly longer survival times than did treatment with dacarba-zine, with no unexpected toxicities.11,12 Also under investigation are novel formulations of existing drugs. For example, in a phase 2b open-label study, aldoxorubicin, a prodrug of doxorubicin, demon-strated superiority over doxorubicin in prolonging progression-free survival. In addition, there was no evidence of acute cardiotoxicity.13

Finally, evofosfamide (formerly known as TH-302) is a prodrug that is activated in hypoxic environments, as are seen in sarcoma tumors; thus, such an agent may have a tumor-specific therapeutic effect. The results of phase I and II trials have led to the initiation of phase III trials of evofosfamide.3

Data on current and emerging treatment options for STS were presented at the 2015 ASCO Annual Meeting. George D. Deme-tri, MD, of the Dana-Farber Cancer Institute in Boston, shares his insights on the significance of recent discoveries and the optimal application of emerging data to the planning and implementing of multidisciplinary treatment for patients with STS.

CME


GIST has a driver mutation; even the different subtypes of GIST are clinically important. This sarcoma is a totally different type. I think that community pathologists educated themselves quickly. We don’t see misdiagnoses of GIST anymore, but even with GIST, there are still subtle differences where expert input can be useful.

The other example is that melanoma is the great imitator. We see about 1000 new sarcoma referrals a year, and about 5 out of those are melanomas where our pathologists can see why the outside pa-thologist thought it was a sarcoma, but it is not a sarcoma, it is a melanoma. In this new age of immunotherapy and BRAF inhibitors and all the appropriate melanoma-targeting therapies that make such a difference for patients, it is hugely important to know whether the diagnosis is truly a sarcoma and not a melanoma.

So those are simple examples that should resonate with every physician. There are only a few places in the country that have pa-thologists with the experience to say definitively, “yes,” “no,” or “I can’t tell.” When the great pathologists say “I can’t tell,” they usually send it to some other great pathologist and ultimately get a consen-sus opinion, and that winds up being our gold standard. I’m just a medical oncologist; I can only treat what the pathologist tells me the patient has, so we are dependent on the expertise of the pathologist. And in “sarcomaland,” it’s not like breast cancer, which is far easier to diagnose. Sarcomas can be tricky. About twice a year, people come in with a sarcoma diagnosis and we are able to tell them, “Our expert pathologist says you have a benign mimic of a sarcoma. This is not something that has metastatic potential; this is a benign inflammato-ry condition. We see why your doctor thought it could be a sarcoma, but the good news is that it’s not.”

So the biggest unmet need is that education piece. We and the patient advocate groups are saying it really does make a difference to have a shared-care model where community doctors can reach out to the academic centers and we work together for the good of our patients.

Moderator: What do you think of some of the recent data coming out of clinical trials with novel agents, formulations, and combina-tions?Dr. Demetri: We know that about half the patients with sarcomas are curable with even current technology – multidisciplinary care for localized disease. That’s a wonderful number, but you can also look at that and say, that means half the people won’t be cured. That’s where we need better therapies, and that is where some of the recent data have been very exciting. We are finally getting high-quality data from our field, not limited to 1 or 2 centers but collaborative data that can be extrapolated to most practice settings.

These studies have given us a sense of objectivity, because the num-bers are bigger. We can really use the data to say to our patients, “Here’s what is likely to happen if we choose this therapy, here’s what might happen if we choose that therapy, here are the risks, here are the potential benefits.”

Ultimately, from the better knowledge comes the question of how to identify the most risky sarcomas and be able to prognosticate ac-

curately. And then from the deeper biological understanding of the disease comes the question of how we can develop better drugs that actually work, that have meaningful clinical benefit and a real impact on how patients feel, function, and survive – the classic trio that the FDA looks for.

Before 2012, except for the dramatic push of targeted therapies for the GISTs, we really hadn’t done much for our patients with STS despite years of trial, years of arguing, many years of wishful thinking about developing effective drugs. We were still very reliant on drugs from the 1970s, such as doxorubicin, dacarbazine, ifosfamide – older drugs. The 1980s and 1990s brought us the ability to mix and match these drugs in different doses and schedules, and at the end of the day there were marginal changes. The late ‘90s brought us gemcit-abine, and it took a while to recognize that that drug, which was first approved for pancreatic cancer, also works in lung cancer and breast cancer, and a decade later we found it works in sarcomas.

So, it’s been an evolution of developing newer drugs for sarcomas, and now we’ve finally got some new drugs, some promising data. There have been some new FDA approvals, and there are a number of large studies heading towards registration endpoints.

Moderator: Is there a particular class of drugs that looks most prom-ising? Dr. Demetri: I think the WHO classification of STS is a vast over-simplification; for example, there are at least 15 clinically meaning-ful different types of GIST alone. One interesting thing about this diversity of human cancers that we call sarcomas is that we’re going to be able to pull from kinase inhibitors, antibody therapy, standard cytotoxics, both natural and engineered, antibody drug conjugates. Part of our challenge as a community of investigators is to do that match.com, or eHarmony of experiments to say, what’s the good match here? What’s the right kind of sarcoma to match up with the right type of drug?

Moderator: And not to be formulaic about it?Dr. Demetri: I don’t think we can be. We’re learning new things al-most on a monthly basis about issues that we thought we understood. Right now the epigenetic space happens to be particularly exciting. Some of the ways of targeting epigenetic aberrations in different sar-comas are very scientifically promising, with some clinical data al-ready showing, for example, that an EZH2 [catalytic subunit of the polycomb repressive complex 2, a histone methyltransferase] inhibi-tor has extraordinary activity in certain molecularly defined subtypes of very rare sarcomas.

If we can identify an STS subtype whose mechanism we under-stand and then find a drug that targets that mechanism, if it hits that mechanism in a human as opposed to just in a mouse model, then we’re on the road to either proving that our knowledge of that cancer was right or to saying, why didn’t it work? Was there some other com-pensatory mechanism that blocked the intended effect? Or if we do see the effect, we can all pat the patient on the back and say, here’s a good drug for you, go live a nice life and prosper. There’s no feeling



as good as doing that for a patient. Developing drugs becomes an addiction, because you start seeing

that we can help the next generation. We are helping this patient right now, but we are also helping the next generation of patients with this kind of disease. It is an extraordinary time for our field. It comes from such a wasteland too. It comes from 15 years during which nothing was working; in the early ‘90s you could see the seeds planted by some extraordinary molecular biology advances where, for example, people were first discovering the unique chromosome translocations that defined Ewing sarcoma. There has also been a tight correlation between basic science advances, clinical pathology, and diagnostic advances, and then moving from that to a rational therapeutic approach.

A lot of things haven’t worked where we had hoped they would work; mTOR [mammalian target of rapamycin] inhibitors are a good example. I ran a big randomized trial with an mTOR inhibitor that was statistically positive. The drug had an impact, but the impact was so small that the academic community and the FDA agreed, “this is not clinically meaningful enough to use an mTOR inhibitor by itself in all STS.” Subsequently, though, investigators identified a specific kind of sarcoma, known as a PEComa [perivascular epithelial cell sarcoma], that has TSC1/TSC2 mutations. In that kind of sarcoma, the mTOR inhibitors have impressive activity.

Before, we were treating all sarcomas as if they were the same, with very specific targeted therapies. Now, there are other less-specific therapies also. There’s a whole new way of looking at STS where we can paint with either a very fine brush or a broader brush. To me sarcomas are a microcosm of what’s happening in oncology in gener-al. There are advances with standard broad-brush chemotherapy, but then also very exciting advances in the most targeted therapies you can imagine for the most precise molecular mechanisms.

Moderator: Are there differences in terms of toxicity between stan-dard chemotherapy and these new targeted and more specific drugs?Dr. Demetri: There are, and it varies to some extent by patient. For all of us who trained in the 1980s and 1990s, it’s a different world now. We are really trying to develop better, smarter drugs. Like the car ad, it’s not your grandfather’s chemotherapy. There are a lot of differences, both in the drugs themselves and in their formulations. For example, one of the first known HIV diseases was Kaposi sar-coma. In the early days it was treated with doxorubicin, a standard drug for sarcomas, and HIV patients couldn’t tolerate doxorubicin because their immune systems were already so compromised. So one of the first interesting formulation differences was to put the drug in a fat bubble called a liposome, which changed the toxicity profile, and now liposomal doxorubicin is approved for sarcoma as well as for ovarian cancer. It was that type of discovery that got me interested in formulation research as something that could make a significant difference.

There currently are some exciting studies with completely new drugs. Even though they may not have been genetically engineered

by scientists, they were genetically engineered over the millennia by sea creatures. Sea creatures have some of the best, most advanced chemistry sets on the planet, because they’re sitting in a dark, dank environment. How do they protect themselves from predators? They synthesize really impressive chemical warfare weapons.

Two new drugs have shown activity in sarcomas. One, trabectedin, is from a sea squirt; the other, eribulin, is from a sea sponge. Both of them have had positive phase III clinical trials. Trabectedin was approved by the FDA in October 2015. It was approved just about everywhere else in the world in 2007. It took a new trial to finally reach FDA registration. Both of these molecules have beautiful chem-ical complexity. They are extraordinary anticancer drugs. We have to figure out how to use them better. We have to figure out what the biomarkers of sensitivity are, because some patients, especially with trabectedin, can get a tremendous amount of benefit, even if most patients only have a few months of benefit. A few patients can stay on the drug for several years and control their metastatic disease. If we could figure out who those extraordinary responders are, we could probably target therapy even better.

Trabectedin also is a pretty good quality of life drug for many pa-tients. Even though it’s given intravenously, a lot of patients find that they’re still able to live a pretty normal quality of life. For a few days they might be tired, but it does not cause hair loss. It is a very interesting drug on multiple levels.

Eribulin has been FDA approved for breast cancer for several years, so most doctors know how to use it, and it’s got some activity. We understand the side-effect profile, and it’s pretty well-tolerated chemotherapy in general for most patients. It’s all about appropriate combinations. There’s an old adage that says drug development starts when a drug gets FDA approved for an indication, and I think that’s true for these two drugs. Putting them into combinations, figuring out how to use them is now the primary responsibility of our whole research community.

We’ve also seen a great deal of interest in older drugs such as gem-citabine. It took a long time for our field to recognize that gemcit-abine, with or without docetaxel, has activity against many types of STS, most notably leiomyosarcomas, but also other forms of STS. Then the question comes up, is that something that should dis-place other therapies? What’s the right first-line therapy? Is there a best first-line therapy? The GeDDiS trial, comparing gemcitabine/docetaxel with doxorubicin alone, showed that you can customize the choice for your patient. There’s no right or wrong answer. The side-effect profile and other logistical elements may help a doctor have a rational conversation with a patient, use that patient’s prefer-ences for risk and convenience, other comorbid clinical findings, to choose a way to start.

Moderator: What about sequencing therapy?Dr. Demetri: The nice thing is that if you choose one, if it doesn’t work, you can switch to the other one and vice versa. What’s inter-esting about sarcomas is that most people will get most drugs. If you

CME


start with drug X, or combination X, you’ll then get drug Y as num-ber two. If you start with drug Y, you’ll get drug X. Sarcoma patients and their doctors, especially at the academic centers, are very nimble about switching quickly so that they can give patients the benefit of sequential therapies, if need be. Or, they can keep somebody on a drug for a reasonably long time if that drug is working to control the disease.

Moderator: Is the switching happening primarily because you find out a drug wasn’t working optimally, or because they lose efficacy as time goes on?Dr. Demetri: The switching is either because there’s primary resis-tance; in other words, you give the drug and the tumor grows without having stopped. Or there’s secondary resistance, which means you give the drug, the tumor is controlled for a while, but it starts to grow later. Sometimes patients can be switched because of tolerance issues, but that’s usually not the reason; sarcoma patients tend to be younger and healthier than many other kinds of carcinoma patients, so peo-ple wind up switching easily for lack of effectiveness rather than for any kind of side-effect profile problem.

The other important thing is that our field has recognized that a tumor can be controlled without shrinking. For example, with ima-tinib, you can stop a GIST cold in its tracks even if the tumor does not shrink. That is true in other kinds of sarcomas treated with the newer chemotherapies. We used to see that with doxorubicin all the time, and now we’re seeing it with drugs like trabectedin and eribu-lin. That was the basis for FDA approval of the other targeted drug, the multikinase inhibitor pazopanib.

The sequence issue is a huge challenge for our field because most patients are well enough to receive multiple lines of therapy, and it’s up to the doctor not to give up too early, not to be unrealistic. For example, there have been patients who have had doxorubicin, ifos-famide, gemcitabine, docetaxel, pazopanib, and for some of them, nothing ever worked. They start trabectedin and it controls their dis-ease for a long time. Had the doctor said, “nothing else has worked, I’m not even going to try this,” those patients never may have gotten to that point. Trabectedin is a good example of a situation in which patients can go from one drug to the next, to the next and get sequen-tial benefit from each one.

We’re pretty good about predicting where a kinase inhibitor is going to work, but with chemotherapies – ifosfamide, doxorubicin, gemcitabine – we’re still not so good at predictions. Decisions wheth-er and when to switch from one drug to another are very difficult decisions based on specific patient factors, and this is where that shared-care model often comes in. Oncologists at sarcoma centers have enough experience to be able to tell patients, “I’ve seen 30 pa-tients like you and here’s what happened to 20 of them, here’s what happened to 10. Let’s make a decision about what’s best for you; then we can talk to your community physician, who can continue to care for you.”

Moderator: What is the role of combination therapy?Dr. Demetri: There are very few cancers that could be cured with a single drug. Even the easiest-to-treat solid tumors such as testicular cancer are not curable with platinum alone. You need a combina-tion. In “sarcomaland,” we expect that part of having new drugs will be the ability to build new combinations, new regimens, that might offer better benefit to patients from the start. That’s part of the value of clinical trials. If there aren’t clinical trials, it’s our job as investiga-tors to write those protocols if there are good ideas to be tested.

I find this a particularly exciting time, because we have these new drugs, and we have many others I haven’t talked about here. For example, we know that even though cancer is thought of as a genetic disease, which it generally is, there are many cancers that are driven by the epigenome, by the readers of the DNA. This is a whole other level of biology, and we’re just starting to see that we can target that as well. It’s so exciting to be able to take these pathways, turn them into drugs, and then figure out where they’re going to work, where they’re not going to work, and offer those things to patients.

Moderator: In the meantime, what would you offer to patients?Dr. Demetri: What we offer currently is a menu. We can choose one from column A, one from column B, one from Column C, go sequentially and in any order you want. We can even start with C, move to B, go to A, whatever.

Moderator: So sequencing doesn’t mean just continuing on a set path. You set the path as you go.Dr. Demetri: And you vary. It is so individual for patients, based on where they live, what is important to them in terms of quality of life, activity level, etc. Those differences help us customize a plan for a patient. And this is what community doctors do very well. They know their patients, and they match the goals set up by the patient with the evidence, with the available medicines. This is not a one-size-fits-all disease by any means. STS is a large field to deal with but it’s very rewarding right now, because we’re really making advances that are meaningful.

Moderator: What about old gold standard drugs like doxorubicin? Do they still have a place?Dr. Demetri: Absolutely. I think doxorubicin is undergoing a renais-sance right now, because it is being formulated differently and also combined with newer agents. People have yet to show that anything is superior to doxorubicin in the first-line setting. Some new data are coming out saying that the combination of doxorubicin with olara-tumab, a monoclonal antibody targeting the PDGF receptor, is effec-tive. In a small, underpowered study, there was a very dramatic overall survival difference without quite as dramatic a difference in control of disease. This is the basis of a very large international effort that’s currently under way to test the hypothesis that the addition of olara-tumab improves outcomes versus those with doxorubicin alone. If the hypothesis is supported, this would be a very big benefit to patients.



Formulating doxorubicin differently is also interesting. As an anal-ogy, if you take paclitaxel and put it in a nanoparticle, you’ve got nab-paclitaxel, which has very different clinical properties from those of the parent taxane. This idea of nanoparticle formulation is the basis of one of the newer drugs, aldoxorubicin, which has a linker molecule to doxorubicin, so that the minute it hits the bloodstream, it forms a conjoiner, a moiety, with albumin, and that makes it essen-tially a nanoparticle.

What it seems to have done is change the side-effect profile of doxorubicin so as to get rid of one of the most feared side effects of cumulative doxorubicin, which is cardiotoxicity. It’s been known for years that if you get enough doxorubicin, you damage the heart irreversibly. So far many patients have gotten really huge cumulative doses of aldoxorubicin without evidence of cardiac damage. There’s a very large phase III trial still accruing, and then it will take a while for the data to mature, but if that shows benefit, that will be a very nice addition to the armamentarium.

Finally, there is a new drug that used to be known as TH-302, now known as evofosfamide, which takes the active part of ifosfamide and puts a warhead on it so it seeks out areas of tumors that are hypoxic, and then that activates the drug. The booster rocket falls off as it were, and the active drug is there in the hypoxic environment and goes after the tumor cell targets. That phase III trial has completed accrual, and we are all waiting for the data to come out – hopefully it will be at ASCO 2016 – to see whether a properly powered and expertly executed clinical trial will show benefit for that drug. So our field has all these very nice, very clever chemically sophisticated ideas just about to be told.

Moderator: Is there anything else you think is important to mention?Dr. Demetri: I’d like to say a word about how great the FDA has been. They have given us two approvals in the last 3 years, trabectedin and pazopanib for STS. I think it’s a good example of how the FDA is fulfilling their mission, paying attention to safety and efficacy but also recognizing that we’re not going to have big 10,000-patient clin-ical trials in the world of sarcoma. They’re respecting the limitations of the rarer disease populations, and I think that’s important, and we’ve been able to make progress because of that. It’s been a great working relationship.

REFERENCES1. American Cancer Society. Sarcoma: adult soft tissue cancer. http://www.cancer.org/cancer/sarcoma-adultsofttissuecancer/de-tailedguide/sarcoma-adult-soft-tissue-cancer-what-is-cancer. Accessed November 27, 2015.2. ASCO University. Soft Tissue Sarcoma. http://meetinglibrary.asco.org/abstractbysubcategory/2015%20ASCO%20Annual%20Meeting/146. Accessed November 27, 2015.3. Hendifar AE, Van Tine B, Chawla N, Yafee P, Chawla SP. A novel approach to soft tissue sarcoma therapy: targeting tumor hypoxia.

Ann Cancer Res. 2015;2:5. http://www.vipoa.org/cancer. Accessed November 27, 2015. 4. Wagner M, Amodu LI, Duh MS, et al. A retrospective chart review of drug treatment patterns and clinical outcomes among patients with metastatic or recurrent soft tissue sarcoma refractory to one or more prior chemotherapy treatments. BMC Cancer. 2015;15:175.5. Schöffski P, Cornillie J, Wozniak A, Li H, Hompes D. Soft tissue sarcoma: an update on systemic treatment options for patients with advanced disease. Oncol Res Treat. 2014;37(6):355-362.6. Hensley ML, Miller A, O’Malley DM, et al. Randomized phase III trial of gemcitabine plus docetaxel plus bevacizumab or placebo as first-line treatment for metastatic uterine leiomyosarcoma: an NRG Oncology/Gynecologic Oncology Group study. J Clin Oncol. 2015;33(10):1180-1185.7. Seddon BM, Whelan J, Strauss SJ, et al. GeDDiS: a prospective ran-domised controlled phase III trial of gemcitabine and docetaxel com-pared with doxorubicin as first-line therapy in previously untreated advanced unresectable or metastatic soft tissue sarcomas (EudraCT 2009-014907-29). J Clin Oncol. 2015;33 (suppl; abstr 10500). 8. ClinicalTrials.gov. Soft-tissue sarcoma. https://www.clinicaltrials.gov/ct2/results?term=soft+tissue+sarcoma&recr=Open&no_unk=Y. Accessed November 27, 2015.9. George S, Demitri GD. Systemic treatment of metastat-ic soft tissue sarcoma. http://www.uptodate.com/...etastat-ic - sof t - t i ssue -sarcoma?topicKey=ONC%2F7743&elapsed-TimeMs=13&view=print&displayedView=full. Accessed November 29, 2015.10. Tseng WW, Somalah N, Engleman EG. Potential for immunother-apy in soft tissue sarcoma. Hum Vaccin Immunother. 2014;10(11):3117-3124.11. Schöffski P, Maki RG, Italiano A, et al. Randomized, open-label, multicenter, phase III study of eribulin versus dacarbazine in patients (pts) with leiomyosarcoma (LMS) and adipocytic sarcoma (ADI). J Clin Oncol. 2015;33 (suppl; abstr LBSA10502).12. Demetri GD, von Mehren M, Jones RL, et al. A randomized phase III study of trabectedin (T) or dacarbazine (D) for the treat-ment of patients (pts) with advanced liposarcoma (LPS) or leiomyo-sarcoma (LMS). J Clin Oncol. 2015;33 (suppl; abstr 10503).13. Chawla SP, Papai Z, Mukhametshina G, et al. First-line aldoxoru-bicin vs doxorubicin in metastatic or locally advanced unresectable soft-tissue sarcoma: A phase 2b randomized clinical trial. JAMA On-col. 2015.Sep 17:1-9.Doi: 10.1001/jamaoncol.2015.3101.

INSTRUCTIONS FOR AUTHORS

The rapid pace of discovery in the field of oncology presents practicing oncologists with the difficult challenge of implementing novel research findings into clinical practice. To accelerate the translation of academic advances to community-based practice, The American Journal of Hematology/Oncology® aims to provide practical interpretations of the latest advances in medical and hematologic oncology and to help practicing oncologists gain a better understanding of how these advances are changing the treatment landscape for both solid and hematologic malignancies. The editors are pleased to consider manuscripts on a wide range of topics related to the journal’s mission. Articles of interest include:• Original research• Reviews

- State-of-the Art Updates- On the Horizon- Emerging Guidelines

• Editorials and perspectives- Clinical Controversies - Looking Forward- Brief Reports- Pivotal Trials- New Technologies- Meeting Updates - Case Reports- Survivorship Issues- Team Approaches (Allied Health/Care Extenders)

- Pharmacology Updates- Oncology Practice Issues

Detailed descriptions of each category can be found in the Instructions for Authors at www.ajho.com

T h e

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FFICIAL J

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F o f

BREAST CANCERAccelerated Partial-Breast Irradiation: Outcomes and Future PerspectivesChirag Shah, MD, Vivek Verma, MD, Michael A. Weller, MD, Eric Westerbeck, BS, Kyle Reilly, BS, and Frank Vicini, MD, FACR

TREATMENT-RELATED DIARRHEAEffective Management and Prevention of Neratinib-Induced DiarrheaFederico Ustaris, MD, Cristina Saura, MD, Jack Di Palma, MD, Richard Bryce, MBChB, MRCGP, MFPM, Susan Moran, MD, Linda Neuman, MD, and Rolando Ruiz, MD

DUCTAL CARCINOMADuctal Carcinoma In Situ: Review of the Role of Radiation Therapy and Current ControversiesFrank Vicini, MD, FACR, and Chirag Shah, MD

HEAD AND NECK CANCERMoving Forward in the Management of Squamous Cell Carcinoma of the Head and Neck: Promising Immuno-Oncology ApproachesBarbara Burtness, MD

A m e r i c a n

J o u r n a l

H e m a t o l o g y /

O n c o l o g y ®

A Peer-Reviewed Resource

for Oncology Education

ajho

www.AJHO.com ISSN 1939-6163 (print) ISSN 2334-0274 (online)

Volume 11 Number 11 11.15

TRIPLE-NEGATIVE BREAST CANCER CME-certified enduring materials sponsored by Physicians’ Education Resource®, LLC

Evolving Management Strategies for Triple-Negative Breast Cancer

All manuscripts will undergo peer review, and authors of accepted articles will receive an honorarium and will be required to sign an authorship form disclosing any possible conflicts of interest. To submit an article to The American Journal of Hematology/Oncology® or if you wish to speak to an editor, please e-mail Howard Whitman at [email protected]

Call for Papers

· BREAST CANCER ·

6

www.ajho.com

NOVEMBER 2015

Accelerated Partial-Breast Irradiation:

Outcomes and Future Perspectives

Chirag Shah, MD, Vivek Verma, MD, Michael A. Weller, MD, Eric Westerbeck, BS, Kyle Reilly, BS, and Frank Vicini, MD, FACR

Introduction

Breast-conserving therapy (BCT) represents one of the most sig-

nificant advances in breast cancer treatment over the past sev-

eral decades. With more than 20 years of follow-up, BCT has

been shown to have equivalent rates of local control and overall

survival (OS) compared with mastectomy, with improvements in

patient quality of life.1-5 Randomized trials comparing BCT and

mastectomy have consistently utilized whole-breast irradiation

(WBI) with or without a tumor bed boost. Whole-breast irradia-

tion typically requires 5 to 6 1/2 weeks of adjuvant radiotherapy

(RT) for its completion. This lengthy duration of therapy is one

factor responsible for many women failing to undergo adjuvant

RT following breast-conserving surgery (BCS), despite the im-

provement in breast cancer mortality associated with RT.4,6

Over the past 2 decades, alternatives to standard WBI have

emerged, including hypofractionated WBI (15–16 fractions) and

accelerated partial-breast irradiation (APBI). Accelerated par-

tial-breast irradiation is a technique that treats only the lumpec-

tomy cavity plus a small area surrounding the surgical bed (mar-

gin of tissue), rather than the whole breast. This concept is based

upon patterns of failure data demonstrating that the majority of

ipsilateral breast failures occur in close proximity to the lumpec-

tomy cavity.7,8 The purpose of this review is to examine the data

supporting the utilization of APBI, as well as clinical guidelines

and future directions to help clinicians decide on appropriate

adjuvant RT techniques for their patients with early stage breast

cancer.

Results of Clinical Trials

Clinical Outcomes

The earliest technique utilized to deliver APBI was interstitial

brachytherapy (IB). This was initially used as either a boost fol-

lowing WBI or as the sole radiation modality; consequently, it

represents the technique with the most mature data. A random-

ized study of 258 women from Hungary compared WBI with

APBI delivered with either IB or electrons. At 10 years of fol-

low-up, no difference in clinical outcomes, including local re-

currence (5.1% vs 5.9%), was noted. Improvement in cosmetic

outcomes compared with WBI was seen for those women treated

with IB (81% vs 63%).9 These findings were consistent with a

prospective study of 45 patients from the same institution: 12-

year outcomes demonstrated a 9% rate of local recurrence, 78%

excellent/good cosmesis, and low rates of toxicity, including a

2% rate of grade 3 fibrosis.10

A large, multi-institutional phase 3, noninferiority random-

ized trial compared IB-based APBI to WBI, randomizing 1184

patients with low-risk, early stage breast cancer and was recent-

ly published. With a median follow-up of 6.6 years, there was

no difference in the 5-year rates of local recurrence (1.44% with

APB–I vs 0.92% with WBI; P = 0.42) and no difference in the

rates of regional recurrences, distant metastases, disease-free sur-

vival, breast cancer mortality, or OS was noted. With respect

to toxicity, WBI was associated with increased grade 2–3 breast

Abstract

Accelerated partial-breast irradiation (APBI) is an adjuvant

radiotherapy technique that allows for the completion of

radiation therapy (RT) in 1 week or less for women under-

going breast conservation. Traditionally delivered using

interstitial brachytherapy, APBI can also be performed

using newer techniques that include applicator-based

brachytherapy and external-beam techniques (3D-con-

formal RT, intensity-modulated RT). Long-term outcomes

with APBI encompass data from randomized trials, pro-

spective data, and single-institution series, which have

highlighted the efficacy as well as comparable recurrence

risks compared with whole-breast irradiation (WBI). Pro-

spective randomized comparisons of APBI with WBI have

demonstrated similar rates of tumor control, although

toxicity results vary based on the technique used with the

potential for improved toxicity with brachytherapy based

techniques. Moving forward, studies are under way to

evaluate shorter courses of APBI, with evidence-based

guidelines evolving to the increasing literature support-

ing the technique.

Key Words: breast cancer, radiation therapy, breast-con-

serving therapy, accelerated partial-breast irradiation,

brachytherapy

· BREAST CANCER ·

8

www.ajho.com

NOVEMBER 2015

TABLE. Key Accelerated Partial-Breast Irradiation StudiesStudy Type Patients

(n)Median Follow-Up (months)

Technique Local Recurrence

ToxicityInterstitialNational Institute of Oncology, Hungary

Randomized 258 122 HDR (n=88)/ electrons (n=40)

10-year LR (5.1% WBI vs. 5.9% PBI, NS)

Improved excellent/good cosmesis with partial breast 81% vs 63%

GEC-ESTRO Randomized 1184 78 HDR/PDR 5 year LR (0.9% WBI vs. 1.4% APBI, NS)

Reduced breast pain and trend for reduced grade 2-3 late skin toxicity with APBI

RTOG 9517 Prospective 99 73 HDR (n=66)/ LDR (n=33)

5-year LR 3%/6% (HDR/LDR)13% grade 3 skin toxicity, 37% skin dimpling, 45% fibrosis, 45% telangiectasias, 15% symptomatic fat necrosis, 66% excellent/good cosmesis

Harvard University Prospective 50 134 LDR (dose-escalation)

12-year LR 15% 67% excellent/good cosmesis, 35% fat necrosis, 34% telangiectasias, 22% grade 3/4 skin toxicity

William Beaumont HospitalMatched-Pair Analysis

199 127 HDR 12-year LR (3.8% WBI vs 5% APBI, NS), no difference in RR, DFS, CSS, OS

ApplicatorMammoSite Initial Trial Prospective 70 (43

treated)65 (n=36) Single-Lumen 5-year LR 0% 9.3% infection, 33% seroma, 12% symptomatic seroma, 4 patients with fat necrosis, 83% excellent/good cosmesis

MammoSite Registry

Prospective 1449 63 Single-Lumen 5-year LR 3.8% (3.7% invasive, 4.1% DCIS)

91% excellent/good cosmesis, 9.6% infection, symptomatic seroma 13%, 13% telangiectasias, 2.5% fat necrosis

External BeamNSABP B-39/RTOG 0413; 2011

Randomized 1367 37 3D-CRT3% Grade 3+ fibrosis

RAPIDRandomized 2135 36 3D-CRT

Increased adverse cosmesis with APBI, Grade 3 toxicity 1.4%, increased grade 1/2 toxicity with APBI

University of Florence

Randomized 520 60 IMRT 5-year IBTR 1.5%, no difference with WBI

Reduced acute and chronic toxicity with APBI, improved cosmetic outcome with APBI

RTOG 0319 Prospective 52 63 3D-CRT 4-year LR 6% 64% excellent/good cosmesis at 3 years, 5.8% grade 3 toxicity

William Beaumont HospitalRetrospective 192 56 3D-CRT 5-year LR 0% 81% excellent/good cosmesis, 7.5% grade 3 fibrosis, 7.6% telangiectasias

Tufts University Retrospective 60 15 3D-CRT8% grade 3/4 fibrosis, 82% excellent/good cosmesis

University of Michigan

Prospective 34 60 3D-CRT 5-yr LR 3% 73% excellent/good cosmesis, 0% grade 3 fibrosisAPBI=accelerated partial-breast irradiation; CRT= conformal radiotherapy; CSS=cancer-specific survival; DCIS=ductal carcinoma in situ;

DFS=disease-free survival; HDR=high dose rate; IBTR= ipsilateral breast tumor recurrence; IMRT=intensity-modulated radiotherapy;

LDR=low dose rate; LR=local recurrence; NS=nonsignificant; OS=overall survival; PBI=partial-breast irradiation; RR=regional recurrence;

3D-CRT=3-dimensional conformal radiotherapy; WBI=whole-breast irradiation.

AJHO_CallForPapers_12'15.indd 5 12/9/15 10:14 AM



Mission & ScopeThe American Journal of Hematology/Oncology is a monthly peer-reviewed publication that provides original research, reviews, and editorial/commentaries that address cutting-edge developments in genomics, targeted therapies, molecular diagnostics, and pathways related to on-cological science and clinical practice. As the official publication of Physicians’ Education Resource® (PER®), the Journal’s mission is to advance cancer care through professional education.

The Journal aims to provide practical interpretations of the latest advances in medical and hematologic oncology and to help practic-ing oncologists gain a better understanding of how these advances have changed the treatment landscape for both solid and hematologic malignancies. Articles published in the Journal will illustrate successes and failures in clinical practice and will provide practical insights into the myriad decisions that oncologists face in everyday clinical prac-tice.

ReadershipThe American Journal of Hematology/Oncology circulates to 10,000 prac-ticing oncologists across the country. Our audience includes medi-cal oncologists, hematologists, pathologists, dermatologists, radiation oncologists, and surgical oncologists.

Submitting ManuscriptsRequirements for all submissions generally conform to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals from the International Committee of Medical Journal Editors.1 Our peer-review process is blinded, so all identifying information (eg, au-thor names, affiliations) is removed from the manuscript file before submission to peer review.

Manuscripts submitted for publication in The American Journal of Hematology/Oncology must not have been published previously (either in whole or in part), nor currently be submitted elsewhere in either identical or similar form. Material posted on the Internet or dissemi-nated in any other electronic form constitutes prior publication and may not be considered. Previous publication of a small portion of the content of a manuscript does not necessarily preclude its being published in the Journal, but the editors require information regard-ing previous publication when deciding how to use space in the Jour-nal efficiently.

These restrictions on prior publication, however, do not apply to abstracts or poster presentations published in connection with scien-tific meetings, or to working papers that have been posted online to facilitate peer feedback.

Authors must indicate in the cover letter whether any portion of the manuscript has been previously published, and are required to submit copies of related publications (either published, in prepara-tion, or submitted), as well as any manuscripts cited as “in press,” to

the editors for review. Duplicate, redundant, and/or fragmented pub-lications are not permitted. Refer to Chapter 5 of the American Medical Association (AMA) Manual of Style for further information on dupli-cate publication.2 Authors of original research should also include a statement in the body of the paper that indicates whether the study was approved by an institutional review board. For all original re-search (when appropriate), a statement confirming that the informed consent of study subjects was obtained should be included with the manuscript.

Types of Manuscripts The editors are pleased to consider manuscripts on a wide range of topics related to the Journal’s mission.

Authors should write for a sophisticated general audience and rec-ognize that many of The American Journal of Hematology/Oncology read-ers are not researchers. In addition to evaluating articles for scientific merit, the editors will assess the overall relevance of the work to the Journal’s audience.

If you are uncertain of an article’s appropriateness for The American Journal of Hematology/Oncology, we encourage authors to send an abstract or outline of an article to the editorial office ([email protected]) to facilitate a pre-submission review by the editor-in-chief.

Submissions generally fall into one of the following categories: (1) original research; (2) reviews; or (3) editorials or commentaries.

Original research articles should employ a clear hypothesis-driven research question and an appropriate research design and analysis to report clinically relevant outcomes. Articles should be 2000-2500 words (excluding abstract, references, tables, etc) and contain no more than 5 graphic elements. Supplemental data (extra tables, fig-ures, or appendices) will be made available on the Journal’s website at the time of publication. Authors should indicate what material is in-tended as online-only content, and include the appropriate reference or callout to these Web-exclusive elements in the text.

• Ethical Considerations: Authors must abide by the rules of a formally constituted research ethics committee, and/or their Institutional Review Board (IRB), and the tenets of the World Medical Association’s Declaration of Helsinki. Investigators are asked to explain in detail how the ethics of their study were justified. Any relevant information must be provided in the cover letter or included as a supplemental file when submit-ting the article. This information will be made available to peer reviewers and editorial committees. Peer reviewers are asked to consider and comment on the ethics of submitted work. (The editor-in-chief—contact via [email protected]—will provide more detailed information on ethical considerations for origi-nal research that is submitted.) All trials involving an active intervention, either treatment or diagnostic, must be accompanied by a statement of approval by the local IRB or similar ethics committee and a statement guaranteeing that all patients gave written informed consent Non-intervention studies, including survey studies regard-ing patient opinion, quality of life, or attitudes toward cancer, should also be accompanied upon submission by a statement verifying that the study has been approved, or determined

INSTRUCTIONS FOR AUTHORSINSTRUCTIONS FOR AUTHORS


exempt, by an independent ethics committee, that informed consent has been obtained even if documentation of informed consent has been waived, and that the information contained is kept confidential and all identifiers have been removed prior to submission for publication.

• Animal Welfare: Manuscripts reporting on studies that involve experiments with animals must include a statement verifying that the care of animals was in accordance with institutional guidelines.

Review articles should provide concise, up-to-date reviews of the lit-erature on novel therapies and treatment strategies or other clinically relevant overviews. Authors should present real-world examples and discussion of the inherent challenges of incorporating new therapeu-tics, new treatment strategies, and new diagnostic tools into clinical practice. Articles should be 1500-2000 words, with at least 1 graphic element to illustrate a key concept. The Journal’s graphic design staff is available to develop original figures based on a sketch provided by authors. Types of review articles are as follows:

• State-of-the-Art Update: Reviews of the evidence support-ing recent key developments in the treatment of cancer, with a particular focus on information essential and applicable to clinical practice. Please illustrate key points with tables and/or figures (assistance is available from the Journal staff for the development of figures).

• On the Horizon: Reviews of translational research, therapies, and technology that are in development but that clinicians will need to be aware of within the next few years. If applicable, please illustrate key points with figures (assistance is available from the Journal staff).

• Emerging Guidelines: Highlights of the key points of the most recent clinical practice guidelines, with expert perspec-tives/opinions on the changes to the guidelines. This can be 1000 words or less, without graphic elements.

Editorials and perspectives can employ several formats that pro-vide concise and lively discussions on timely and relevant topics. These would typically involve areas of rapid change, controversy, or new areas that have the potential for major future clinical impact in oncology. These should be brief (<1500 words), with appropriate citations. Examples include:

• Clinical Controversies: Opinion pieces that discuss relevant and controversial issues in oncology (eg, maintenance ritux-imab and its role in indolent lymphoma; should DCIS be con-sidered a cancer?; when to intervene in prostate cancer; what is the quality-of-life impact of PFS vs OS improvements?)

• Looking Forward: New areas of research or clinical care that are not well known to many oncologists, but may in the future impact cancer care or research directions. The perspective would be a “thought piece” without significant amounts of data or citations.

• Brief Reports: Brief and topical perspectives and updates on new concepts, treatments, and diagnostic assays (less than 1000 words).

• Pivotal Trials: Summaries of clinical trials of interest. Should

include the background/rationale, eligibility, treatment schema, contact information, and NCT link (up to 1000 words).

• New Technologies: Discussions of topics such as imaging and tissue-based technologies, genomics, bioinformatics (up to 1000 words).

• Meeting Updates: Summaries of presentations at key CME meetings, conferences, and congresses, with expert perspec-tives on the reported findings. (Please query the editor-in-chief first to avoid duplication of coverage of meetings.)

• Case Reports: Unusual cases, situations, exceptional respond-ers, including histology and imaging.

• Survivorship: Discussions of survivorship topics and symp-tom management (1000-1500 words).

• Allied Health/Care Extenders: Topics can include discus-sions of how best to use a team approach, eg, in a case report format, such as a discussion of how an individual team met and overcame a challenge or streamlined a process to improve patient care using allied health professionals/care extenders (1000-1500 words). The Journal’s editors encourage allied health professionals on the oncology care team to author or coauthor these articles.

• Pharmacology Updates: Brief overview of new drugs—mechanisms, dosing, side effects, drug interactions (1000-1500 words). These could be contributed by a RPh or PharmD, and may have the look of a write-up typical of a Pharmacy & Therapeutics Committee formulary application.

• Oncology Practice Issues: Evolving aspects of oncology practice such as insurance coverage, electronic medical records, quality assurance, accelerated drug approvals, survivor-ship, and patient education/communication that presents new perspectives and useful information for oncologists (1000-1500 words).

• Letters to the Editor: Letters commenting on articles pub-lished in the Journal will be considered for publication.

AuthorshipOnly persons who have made a direct contribution to the content of a paper should be listed as authors.

The number of authors listed with the manuscript should not exceed 10; more than 10 requires written justification and approval from the editor-in-chief.

The American Journal of Hematology/Oncology uses the criteria pro-vided by the Uniform Requirements for Manuscripts Submitted to Biomedical Journals1 to determine authorship. Each author should have participated sufficiently in the work to take public responsibility for the content. Authorship credit should be based only on substan-tial contributions to the following conditions: (1) conception and de-sign, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final ap-proval of the version to be published. All 3 conditions must be met.1

Individuals who have contributed to a paper but who do not meet the criteria for authorship can be acknowledged.

DisclosuresIt is the Journal’s policy to require that all authors disclose relation-ships with any commercial interest that may present a real or per-ceived conflict of interest if: (a) the relationship is financial and



occurred within the past 12 months; and (b) the author discusses products or services of that commercial interest. Relevant financial relationships are those relationships in which the author (and/or the author’s spouse or partner) benefits receiving a salary, royalty, intel-lectual property rights, consulting fee, honoraria, ownership interest (eg, stocks, stock options, or other ownership interests, excluding di-versified mutual funds), or other financial benefit. Financial benefits are typically associated with such roles as employment, management position, independent contractor (including contracted research), consulting, speaking and teaching, membership on advisory commit-tees or review panels, board membership, and/or other activities for which remuneration is received or expected. In addition, authors are required to report all financial and material support for their research, which includes (but is not limited to) grant support and funding sources and any provision of equipment or supplies. To this end, all authors must read and sign the Journal’s “Author Disclosure Form.”

The name of the organization funding or initiating a research proj-ect should be made explicit on the title page (eg, “This study was funded by the XYZ Corporation.”). Relevant financial relationships (whether direct to the authors or through a third party) for research and/or writing, including funding, grants, honoraria, etc, must also be named on the title page. If the funding organization had any role in the collection of data, its analysis and interpretation, and/or in the right to approve or disapprove publication of the finished manu-script, this must be noted in the cover letter and described in the text. The editorial staff may inquire further about financial disclosure after the manuscript is submitted. If the manuscript is accepted for publication, disclosure statements will be printed with the published article.

Manuscript SpecificationsManuscript components (eg, cover letter, text, tables, figures, related papers) must be included as a part of the submission process. All manuscripts must include the following components:

Cover Letter: A cover letter must accompany each submission and include any background information about the submission (eg, how it contributes to the existing literature, whether any portion has been previously presented or published) that would aid in the editors’ ini-tial evaluation. Include a statement that the manuscript has been read and approved by all authors.

Titles. Titles should be concise (fewer than 10 words) and stimulate reader interest. Provide a brief running title on the general topic area in addition to the main article title.

The title page should include the following information:• Complete manuscript title and subtitle, if any • Full names of all authors, followed by their highest academic

degrees • Name, address, telephone, fax, and e-mail information for the

corresponding author • Institutional affiliations for each author at the time the work

was completed • Concise summary of the article for the Table of Contents (up

to 25 words)• Indication of the source of funding (including grant numbers,

grant agencies, corporations, and sponsors)

• Number of pages, references, figures, and tables • Word count (excluding references, tables, and figures) • Key words

Abstract. A paragraph (unstructured) abstract is required for all re-view manuscript submissions. The abstract should not exceed 150 words and should summarize the salient data and the principal con-clusion of the piece. A structured abstract should accompany all original research with headings such as Background, Patients, Methods, Results, and Conclusions.

Text. All text should be in Times New Roman 12-point type, includ-ing acknowledgments, references, tables, and legends. Cite references, tables, and figures in sequential order in the body of the paper. Mea-surements of length, height, weight, and volume should be report-ed in metric units. Temperature should be given in degrees Celsius. Blood pressure should be listed in millimeters of mercury. Except for units of measure, abbreviations are discouraged.

All abbreviations and acronyms must be spelled out in full when it first appears in the text, followed by its abbreviation in parentheses. State the generic name (not the trade name) for all drugs.

Permissions. Data and/or figures reproduced from another pub-lished source must be properly cited and credited. Authors are re-quired to obtain written permission from the appropriate author and/or copyright holder to reproduce previously published or copy-righted material. Authors must also obtain permission from at least 1 author when citing unpublished data, “in-press” articles, and/or personal communication. Copies of permission statements must be included with manuscript submission.

Acknowledgments. Include a list of acknowledgments, if appropri-ate. Refer to the “Authorship” section for an explanation of what constitutes authorship and for guidance in distinguishing contribu-tions that warrant an acknowledgment. The corresponding author must affirm that he/she has received permission to list the individuals in the acknowledgment section (see bottom of “Authorship Form”).

References. Begin the reference section on a new page and double-space between reference citations. Number references sequentially in the order cited in the text; do not alphabetize by author names. Pro-vide the names of all authors when there are 4 or fewer; if there are more than 4 authors, list only the first 3 authors followed by “et al.” All references must be verified by the authors and should conform to the AMA Manual of Style.2 If using EndNote, please format in JAMA style.

References cited only in tables or figure legends should be num-bered in accordance with the sequence established by the first men-tion of the particular table or figure in the text.

References to papers accepted but not yet published should be designated as “in press” and included in the reference section. Infor-mation from manuscripts submitted but not accepted should be cited in the text as “unpublished observations” with written permission from the source. (Include copies of any “in press” and “submitted” manuscripts [ie, papers under consideration at other journals] for the editors’ evaluation as a part of your submission.)

Avoid citing “personal communication” unless it provides essential

INSTRUCTIONS FOR AUTHORSINSTRUCTIONS FOR AUTHORS


information not available from a published source, in which case the name of the person, her/his degree, and the date of communica-tion should be cited in parentheses in the text. Authors should obtain written permission and confirmation of accuracy from the source of a personal communication (see “Permissions” section). Note the format and punctuation in the following sample references:

1. Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus ima-tinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial [published online September 4, 2012]. J Clin Oncol. 2012;30(28):3486-3492. 2. Wierda WG, O’Brien S. Chronic lymphoblastic leukemia. In: De-Vita VT Jr, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. 3. American Cancer Society. Cancer facts and figures 2014. http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfig-ures2014. Accessed March 18, 2015.

Graphic Elements. Use of graphic elements is strongly encouraged, and each article can contain up to 5 graphic elements. All supple-mental data (eg, appendices and lengthy tables) will be posted on the Journal’s website at the time of publication. Authors should indicate what material is intended for Web-exclusive content and include the appropriate reference or callout in the text to these Web-exclusive elements.

Tables. Place each table on a new page. Number tables sequen-tially in the order in which they are cited in the text. Include a title for each table. Special characters, abbreviations, and symbols must be explained in the table key in the following format: “OS indicates overall survival; PFS, progression-free survival.” Footnoted mate-rial in tables should be indicated with superscript, lowercase letters: “a,” “b,” “c,” and so on. Footnotes are listed at the bottom of the table, each on its own line.Figures. The Journal’s production team is available to create fig-ures from sketches provided by the authors. Avoid the use of shad-ing in bar graphs or pie charts—use color or crosshatch patterns instead. Number all figures in the order in which they are mentioned in the text. Any previously published figures must be accompanied by written permission from the publisher and/or copyright holder (see “Permissions” section). Any payment associated with repro-ducing figures is the responsibility of the author(s).

Legends. Legends should include the figure number and a brief description of the graphic. Identify all abbreviations used in the figure at the end of each legend.

Peer Review ProcessEach manuscript is sent to the editor-in-chief for an internal evalua-tion to determine its appropriateness. Manuscripts that do not meet the Journal’s criteria for overall appropriateness, relevance, originality, and scientific merit will be returned promptly (usually within 2 weeks) so that authors may pursue alternate avenues for publication.

Although reviewer selection is ultimately the decision of the edi-

tors, authors may provide the names and e-mail information of pre-ferred and nonpreferred peer reviewers. Manuscripts deemed appro-priate for The American Journal of Hematology/Oncology will be sent to external peer reviewers via a double-blinded review process. Typically, a manuscript will be sent to a minimum of 2 reviewers to provide feedback on the scientific merit of the paper.

Reviewers are requested to complete their evaluation of a manu-script within 2 weeks. They are asked to treat manuscripts as confi-dential communications and not to share their content with anyone (except colleagues whom they ask in confidence to assist in review-ing) or to use the content for their own purposes. The Journal does not send manuscripts to any reviewers who are affiliated with the same institution as any of the authors, and requires that reviewers declare any potential conflicts of interest, such as personal ties to an organization with a vested interest in the content of the manuscript.

Editorial DecisionsThe editors and peer reviewers judge manuscripts on the interest and importance of the topic, the intellectual and scientific strength, the clarity of the presentation, and relevance to readers. We also con-sider the strength of the paper compared with other papers under review, as well as the number of accepted and previously published articles in the same category. Authors of original research and review articles should clearly describe how their findings add to the existing literature.

The editorial office is committed to providing prompt processing times and to communicating timely decisions to authors. While the editorial office makes every effort to notify authors and keep them informed of any delays, most authors can expect a first decision on their manuscript in approximately 4-6 weeks. The editors will com-municate editorial decisions on acceptance or rejection to the cor-responding author only.

Accepted ManuscriptsPage proofs (PDFs) are e-mailed to the corresponding author before publication. Authors can expect to receive proofs approximately 3-4 weeks before the scheduled issue date. All proofs should be returned to the editorial office within 48 hours.

References1. International Committee of Medical Journal Editors. Uniform re-quirements for manuscripts submitted to biomedical journals: writing and editing for biomedical publication. www.icmje.org/urm_full.pdf. Accessed March 18, 2015. 2. Iverson C, ed. Ethical and legal considerations. In: American Medical Association Manual of Style. 10th ed. New York, NY: Oxford University Press; 2007:125-300.

Editorial Offices:The American Journal of Hematology/OncologyOffice Center at Princeton Meadows, Bldg 400Plainsboro, New Jersey 08536E-mail: [email protected]

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