`
`Vol. 18, N0. 12, December 2013
`
`Oncologist.
`v. 18, no. 12 (Dec. 2013)
`Seneral Collection
`N1 ON 1 05AM
`2014-02—03 10:06:01
`
`re
`tjfibo
`
`t t w Int: ‘mational I’eer—Rew’m-w Id journal tor the l’rar‘ti't 'ng ( )naJlrJgist/Hematobgist
`
`gfin*
`
`REVIEW Ak'rtt‘uc
`
` t
`
`\ «r
`
`tI-T I’Io \I \Iilix
`
` |
`
`CME
`Metformin Is Associated With Survival
`Benefit in Cancer Palients Wilh Concurrent Type 2
`Diabetes: A Systematic Review and Mela-Analysis
`Mine, Yin, Ilt‘ Kilo“, | th'dl'tl l. (iorak ('t .1l.
`Commentary: ( 'arlu l
`.1 VP! ( lltd. ('ristina HoseIli
`
`'H . Advancing Cervical Cancer Prevention in India:
`Implementation Science Prlurlties
`Sum-eta Krishnan, lzmily Matisen.
`Dl‘lltll'dil l’ortt‘rlieltl el al.
`
`'
`'
`1 "1:: Breast Cancer in Young Women In Latin Amer
`t'\-nll1i.| Villarreal-t'rar/a,('hr'islmn.-\Ie_ti|l.1,
`Mariat .Magallant‘s-l lotus l‘l ttl.
`
`it"!
`.
`
`—
`[.\'\Itiiirn.|: (hillliiln
`llil'
`Anti-Miillerian Hormone and Antral Follicle Counl
`Reveal a Late Impairment of Ovarian _Reservt‘ In ‘ ior
`Patients Undergoing low-Gonadoloxu‘ Reglmcm
`Hematologieal Malignancies
`_
`RINKJILI Iii l'aola, t'lautlint'ustanlinl.
`trixtina lm t illll t‘l .il.
`
`|
`
`l
`
`I
`
`l
`
`I
`
`l|=.|\|
`
`It: \I :
`
`|~.
`
`Melronomit' Capetitahine in Advanced
`Hepatot'ellular Carcinoma Patients: A Phase II Study
`him-anni limnrli. lmrn m: o (It' Rum,
`Volenlina Agnslini l'l (II.
`v.1: l
`\\l x
`
`Atljuvant Therapy for Adenocart'inoma of the Lung
`
`I
`
`‘
`
`I
`
`II ".I
`
`I
`
`t
`
`.i
`Keller 1
`.IHH lfl'xlil nh‘.
`
`|
`
`|r-i~.l.t’ liistnplwr { '._ Axxlali
`
`('linit'al Efficacy of Targeted Biologir
`Agents as Second-Line Therapy of Advam'ed
`Thyroid Canter
`|.m|:-{-l\ K.(}\1.-'r)ni|\nl\u, lx‘aiaslt‘l‘|’.t'|1o\\{lr'\_.
`/ln*rl;;lid ('lli'n l’l ill.
`ll
`.l|'\\l t \u 11:
`
`ll’fil
`
`]
`
`l.l||l'.\.i
`
`lmpart of Molecular Alterations and Targeted
`lherapy in Appendiceal Adenm'arcinomas
`Kamml l’.‘w. Raghav. Aclilm \". .‘wlwth.
`Ht rwl .Nl..-\. lid/mi {'1 .1l.
`III 1|
`III
`\‘xnl
`|§|IIC
`St-rt-en-and-Treat Approach to Cervical Cancer
`Prevention Using Visual Inspection With Acetic Acid
`and Cryotherapy
`. \\-’inL|w.
`I'mma Paul, Iennilwr |
`lx’rimnri .\l
`|i.1l'll:li|1iv1al.
`
`
`
`
`
`CME
`
`[ll
`
`Il ”\tlx Rlxl
`
`\Rt ll
`
`_
`
`__
`
`.
`
`_
`
`— —---
`
`Barriers to Study Enrollment in Patients
`With Advant'ed (‘ancer Referred to a Phase I
`Clinieal Trials Unit
`Billing I u. Int m Mt (Quinn, Aunt; Nailn: t'l .II.
`
`M \II'IU\I \l\\ \t.I-\ll \l \\!I_H|. I‘l'tlltlnl- l_
`\I_\l
`_._...._.
`-.
`)_
`-ith
`i
`:.‘ i Venous Throtnhoemhohsm Risk In I atlenlcvwl {
`'
`'
`-
`-
`—
`irt
`Cancer Receiving Chemotherapy. A Rt Al
`t
`J
`-'
`'
`Analysis
`,
`(iar'x'
`l
`|.
`l vman. lament It Lt‘t'l. \.1|l\!l'l\\.l|llt1t
`
`-
`
`1
`
`_
`
`‘
`
`1|
`
`Ix \II\IUItI\\I
`
`I
`
`:
`
`-;
`
`.'
`
`In Memoriam: Michael I. Haut
`
`fiqiiigmfi
` E '54
`
`fmm LIBRARY OF
`
`
`
`MEDICINE
`
`W mun-moor Hun:
`
`lllt' Illli: idl journal ol' the
`
`-.|
`
`I:
`
`l\_ -.I
`
`Oiibologist' App
`
`Genome & Co. v. Univ. of Chicago
`PGR2019-00002
`
`UNIV. CHICAGO EX. 2059
`
`
`
`7-7 iffii f __-____.....-.-_.— _.—— pun—-m
`
`0
`The
`I ICO ogls
`
`CME.TheOncologist.com fora totalof3 new
`
`Access TheOncologistCMEOniineat
`articlesavailableforcontinuingmedical
`
`education credit in this issue.
`
`Volume 13, Number 12, December 2013
`
`'qv'
`
`indicates online-oniy article
`
`COMMENTARY
`
`1245 Metformin: Are Potential Benefits on Cancer Risk Extended to Cancer Survival?
`
`Carlo La Vecchia, Cristina Bosetti {see article on page 1248]
`
`CANCER PREVENTION
`
`Section Editor: Powel H. Brown
`
`1243 Metformin Is Associated With Survival Benefit in Cancer Patients With Concurrent Type 2
`
`Diabetes: A Systematic Review and Meta-Analysis
`Ming Yin, Jie Zhou, Edward J. Gorak, Fahd Quddus {see commentary on page 1245]
`
`CLINICAL TRIAL RESULTS
`
`.
`.
`.
`Section Editors: Susan E. Bates, Antonio Tito Foio
`
`1256 Metronomic Capecitabine in Advanced Hepatocellular Carcinoma Patients: A Phase II Study
`Giovanni Brandi, Francesco cie Rosa, Valentina Agostini, Stefania di Girolamo, Pietro Andreone, Luigi Bolondi,
`Carla Serra, Claudia Sama, Rita Golfieri, Annagiulia Gramenzi, Alessandro Cucchettl, Antonio Daniele Pinna,
`Franco Trevisani, Guido Biasco, for the ITALlAN LiVER CANCER “TAU-CA} GROUP
`
`CHALLENGING CASES
`
`.
`.
`.
`Section Editor: Davrd P. Ryan
`
`1258 Adjuvant Therapy for a 3.9-cm Adenocarcinoma of the Lung
`Rebecca Heist, Chistopher G. Azzoli
`
`ENDo RINOLOGY
`C
`
`_
`Section Editors: Herbert Chen, Stan B. Sldhu
`
`1262 Clinical Efficacy of Targeted Biologic Agents as Second-Line Therapy 9f Advanced Thyroid Cancer
`Taofeek K. Owonikoko, Rajasree P. Chowdry, Zhengjia Chen, Sungiin Kim, Nabil F‘ Saba, Dong M' Shin,
`Fadlo R. Khuri
`
`GAsrRoersriNAL CANCER
`
`.
`.
`Section Editorf-I Richard M. Goldberg, Patrick G. Johnston, Peter 1. 0 Dwynr
`
`1270 impact of Molecular Alterations and Targeted Therapy in Appendiceal Adenocarcinomas
`Kanwal P.S. Raghav, Aditya V. Shettv, Syed MA. Kazmi, Nianxiang Zhang, Jeffriy Morgs, Melissa Taggart,
`Keith Fournier, Richard Royal, Paul Mansfield, Cathy Eng, RobertA. Wolff, Mlc ae . verman
`
`The Oncoiogist {plSSN 1083—7159} and The Oncologist Oniine [eISSN 1549—490X} are publi
`Blackwell Street, Suite 260, Durham, NC 27701—2884 USA.
`
`shed 12 times per year by AlphaMed Press, 318
`
`POSTMASTER: Send address changes to The Oncoi‘ogist, P.O. Box 412, Congers, NY10920—9914 USA.
`
`d resident/intern/feiiow/student (with proofofstatus]: $98. institutions:
`,
`2014 Subscription rates effective September 1, 2013: Individual: $245 an
`_
`.
`Tier 1; $485; Tier 2: $515; Tier 3: $720; Tier 4: $1 102; Tier 5: contact AlphaMed Press for a GUOte- See WWW‘theonm'flgiSIIOTnXSUbSUlPthHS for
`tier descriptions. Subscribers in Canada and Mexico add $75 per year, all other subscribers outside the US. add $130 per year.
`
`I
`
`-
`
`.
`
`.
`
`;
`
`
`
`.i
`
`'2' 4-:memu
`
`GLOBAL HEALTH AND CANCER
`
`Section Editors: Felicia M. Knaul, Rita! Atun, Eduardo Camp
`
`1278 Screen-and-Treat Approach to Cervical Cancer Prevention Using Visual Inspection With Acetic
`Acid and Cryotherapy: Experiences, Perceptions, and Beliefs From Demonstration Projects in
`Peru, Uganda, and Vietnam
`Proma Paul, Jennifer L. Winkler, Rosario M. Bartolini, Mary E. Penny, Trinh Thu Huong, Le Thi Nga,
`Edward Kumakech, Emmanuel Mugisha, Jose Jeronimo
`
`1285 Advancing Cervical Cancer Prevention in India: Implementation Science Priorities
`Suneeta Krishnan, Emily Madsen, Deborah Porterfield, Beena Varghese
`
`1298 Breast Cancer in Young Women in Latin America: An Unmet, Growing Burden
`
`Cynthia Villarreal-Garza, Christian Aguila, Maria C. Magallanes—Hoyos, Alejandro Mohar, Enrique Bargallo,
`Abelardo Meneses, Eduardo Cazap, Henry Gomez, lebeth Lopez—Carrillo, Yanin Chévarri-Guerra,
`Raul Murillo, Carlos Barrios
`
`GYNECOLOGIC ONCOLOGY
`
`Section Editors: Dennis 5. Chi, Peter 6. Harper
`
`1307 Anti-Miillerian Hormone and Antral Follicle Count Reveal a Late Impairment of Ova rian
`Reserve in Patients Undergoing Low-Gonadotoxic Regimens for Hematological
`Malignancies
`
`Rossana Di Paola, Claudio Costantini, Cristina Tecchio, Gian Luca Salvagno, Rachele Montemezzi,
`Alessio Perandini, Giovanni Pizzolo, Stefano Zaffagnini, Massimo Franchi
`
`OUTCOMES RESEARCH
`
`1315 Barriers to Study Enrollment in Patients With Advanced Cancer Referred to a Phase I Clinical
`Trials Unit
`
`Siding F Lt, Lacey McQuinn, Aung Naing, Jennifer J. Wheler, Filip Janku, Gerald S. Faichook,
`Sarina A. Pll‘lil-PE-llll, Dennis Tu, Adrienne Howard, Apostolia Tsimberidou, Ralph Zinner, David S. Hong,
`Rozelle Kurzrock
`
`Section Editors: Scott Ramsey, Bong-Min Yang
`
`SYMPTOM Mnnnor MLNT AND SUPPORTIVE CARE
`
`1321 Venous Thromboembolism Risk in Patients With Cancer Receiving Chemotherapy: A Real-world
`Analysis
`Gary H. Lyma n, Laurent Eclcert, Yanxin Wang, Hongwei Wang, Alexander Cohen
`
`Section Editors: Eduardo Bruera, Russell R. Portenoy
`
`LETTERS to THE Eoiroe
`
`1 330 Comprehensive Geriatric Assessment and Adjustment of Cancer Treatment
`Monique S. Slee-Valentijn, Andrea 8. Maier
`
`1331 In Reply
`
`Nadine J. McCleary, Arti Hurria, Jeffrey Meyerhardt
`
`
`
`IN MEMORIAM
`
`1332 In Memoriam: Michael J. Haut
`
`1334 Volume 18 Acknowledgments
`
`1336 Volume 18 Author Index
`
`EUROPEAN PERSPECTIVES
`
`(:3
`
`e29 Addressing Cancer Disparities in Europe: A Multifaceted Problem That Requires Interdisciplinary
`Solutions
`
`Sean Duffy, Mike Richards, Peter Selby, Mark Lawler
`
`Clinical Trial Results
`
`Now accepting Phase I and Phase ll trials for publication
`
`CIinicaITriaiResults.The0ncologist.com
`
`
`
`
`El
`
`
`CORRESPONDENCE
`
`Editorial correspondence, including submissions for publication, letters to the Editor, and book reviews should be submitted to
`the Editors at www,ManuscriptSubmissions.TheOncologist.com.
`
`Reflections: The editors encourage the submission of photography, artwork, poetry, and prose dealing “lit“ the thoughts, feel-
`ings, and deep concerns of caregivers, their cancer patients, and their loved ones. These should be submitted to the Editors.
`
`information for Authors and associated submission materials may be found at www,TheOncolongt-Com-
`
`Cover Art: Oriental Poppy” by Bernique Langley. Laudanum, or tincture of opium, was for many decades the onlyr "treatment" for cancer in the Old
`West; the Oriental Peppy has, therefore, been chosen as the Journal's icon.
`
`
`
`The Oncologist {pISSN 1083-?1591 and The Oncologistonline lelSSN
`1549-490X} are published 12 times per year by AlphaMed Press, 318
`Blackwell Street, Suite 260, Durham, NC 2??01-2884.
`Postmaster
`Send all address changes to Theoncologi‘st, PO. Box 412, Congers, NY
`10920-9914 USA.
`
`Editorial Conespondence
`AlphaMed Press
`318 Blackwell St,Ste 260
`Durham, NC 27701
`Tel: [9191680—0011
`Fax: {919] 680-4411
`E-mail: Editoria|0ffice@TheOncologist.com
`
`lnformationfor Authors
`Please see the complete Information for Authors, available online at
`www.TheOncologist.AlphaMedPress.com or by contacting the Edito~
`rial Office at Auth0rs.TheOncologist.com
`
`Supplements
`Proposals for journal supplements covering clinical investigations and
`research developments, seminars, workshops, and conferences are
`invited for publication consideration.
`Contact Editors@The0ncologist.com
`
`Reprints and Permissions
`Alpha Med Press — The Oncologist
`318 BlackwellSt, Ste 260
`Durham, NC 2T701
`Tel: (919)680-0011
`Fax: (919)680—4411
`E—mail: Reprints@AlphaMedPress.com
`
`Copyright
`©2013 AlphaMed Press. The OncologistwlplSSN 1083-7159} and The
`Oncologist” Online lelSSN 1549—490X] and all contributions included
`therein are protected by copyright. All rights are reserved under
`United States and international copyright laws and other applicable
`laws and conventions. No copyright is claimed in any original work cre~
`ated by agencies or employees of the United States government. No
`part of this publication may be reproduced or transmitted in any form
`without the prior written consent of AlphaMed Press or Copyright
`Clearance Center, www.copyrightcom, e-mail: info@copyright.com.
`Certain provisions of the Copyright Act of 19?6, as amended, respect-
`ing fair use and reproduction by libraries and archives,17 U.S.C. §§
`107 and 108, may be applicable. All other permission requests should
`be directed to the Publisher. Please submit your request in writing to
`AlphaMed Press at Permissions@AlphaMedPresscom.
`Disclaimer
`While the publisher and Editorial Boa rd make every effort to see that
`no inaccurate or misleading data, opinion, or statement appear in this
`journal, they wish to state that the data and opinions in the articles
`and advertisements herein are the reSponsibility of the contribu-
`tor or advertiser concerned. Accordingly, the publisher, the Editorial
`Board, and their respective employees, officers, and agents accept
`no liability whatsoever for the consequences of any such inaccurate
`or misleading data, opinion, or statement. While every effort is made
`to ensure drug doses and other quantities are presented accurately,
`readers are advised that new methods and techniques involving drug
`usage described within this journal should only be followed in con—
`junction with the drug manufacturer’s own published literature. it is
`the responsibility of the treating physician or other health care pro-
`fessional, relying on independent experience and knowledge of the
`patient, to determine drug dosages and the best treatment for the
`patient. This is particularly serious if the agent to be administered is a
`new one or one that is infrequently used. Because ofthe uniqueness of
`each patient and the need to take into account a numberofconcurrent
`considerations, this information should be used by physicians only as a
`general guide to determining the best treatment for each patient.
`
`
`
`The
`.
`ncolog1st“
`
`The official journal of the Society for Translational Oncology
`
`The Oncologist“ Journal is regularly indexed by Index Medicus/
`MEDLINE, EMBASEfExcerpta Medica, Compendex, Geobase, Chemi—
`cal Abstracts, Biology Digest, Cumulative lndex to Nursing and Allied
`Health Literature print index and database, Science Citation index-
`Expanded, ISI AlertingServices, CurrentContents/Clinical Medicine.
`
`The Dncoiogr‘st" is printed in the United States of America on paper
`that meets ANSi/NISO 23948-1992 requirements and adheres to
`libraryrarchivai stability.
`
`Business-to—Business Opportunities
`Marty]. Murphy, 3rd
`VP, Publishing Technology& Business Development
`AlphaMed Press
`318 Blackwell St, Ste 260
`Durham,NC2T701
`Tel:l919}200-3?27
`Fax: [9191-2812ng
`Email: Marty3rd@AiphaMedPress.com
`
`Advertising Information
`Tim Wolfinger
`Pharmaceutical Media, Inc.
`30 E 33rd St, 4th floor
`New York, NY 10016
`Tel:(2121904-03T9
`Fax: (212)685-6126
`E-mail: twolfinger@pminy.com
`
`SubscriptionsrAccess IssuesiCustomer Service
`The Oncologist
`PO Box 412
`Congers, NY 10920—9914
`Tel: {800} 206-9850! [845} 267-3079
`Fale8451267-3478
`E—mail: TlteOncologist@cambeywest.com
`Claims
`When claims for undelivered or damaged issues are made within th ree
`months of publication of an issue, a complimentary replacement will
`be provided.
`
`2014 Subscription Rates
`Subscription rates are 5245’ for individuals or $98 for residentiintern}
`fellowistudent [with proof ofstatusl.
`
`Institutional Rates
`
`El Tier 1 {Institutional Print Only} - 5485*
`
`Print 8. Online"
`Online Only
`El TieFZ-SSIS“
`El Tier2—S432.50
`El Tier3-$?20*
`El Tier3-S631
`El Tier4-51102"
`CI Herzl-$937.50
`El TierS,multi-sites,andlicenses El TierS,multi—sites,andlicenses
`— contactpublisher for pricing
`—contact publisherfor pricing‘
`
`‘ Subscribers in Canada or Mexico add STS per year, all other subscrib-
`ers outside the U5. add $130 per year.
`
`Backlssue Orders
`Subject to their availability, price for single or back issues is $40 {11.5.}
`or $45 [outside the U.S.] and must be prepaid.
`
`
`
`this material mivbe named by(avvnght law [Title 17 u s cm)
`
`
`
`
`The
`ncologist""
`Barriers to Study Enrollment in Patients With Advanced Cancer
`
`Referred to a Phase I Clinical Trials Unit
`
`SIQING Fu,“ LACEY McQurNN,” AUNo NinuNo,‘1 JENNIFER]. WHELER," FILIPJANKU,“ GERALD S. FithHoor,a
`SARINA A. PlHA-PAUL," DENNIS Tu,“ ADRIENNE Howano,“ APOSTOLIA TsnvusEmoou,a RALPH ZINNER," DAVID S. HoNo,“
`RAZELLE Kuaznocit"
`
`"Department of lnvestigational Cancer Therapeutics [Phase I Clinical Trials Program], The University of Texas MD Anderson Cancer Center,
`Houston, Texas, USA; hUniversity of California San Diego Moores Cancer Center, La lolla, California, USA
`Disclosures ofootentiol conflicts of interest may be ,iound' of the end of this article.
`
`Key Words. Phaseltrial ' Enrollment
`
`' Consults - New patients - Patient referral
`
`- Barrier
`
`Learning Objectives
`
`Assess barriers for advanced cancer patients to participate in phase l trials.
`
`DiScuss strategies to improve the rate of enrollment of cancer patients in phase I trials.
`
`i'
`
`Ans‘rlinrrr
`
`
`
`
`Background. We conducted this retrospective study to iden—
`tify reasons that patients referred to a phase 1 clinical trial
`failed to enroll or delayed enrollment onto the trial.
`Materials ondMethods. Outcome analyses were cond ucted
`independently on data collected from electronic medical
`records of two sets of consecutive patients referred to a
`phase I clinical trial facility at MD Anderson Cancer Center.
`Data from the first set of 300 patients were used to deter
`mine relevant variables affecting enrollment; data from the
`second set of 957 patients were then analyzed for these
`variables.
`
`Results. Resultsfrom the two sets ofpatients were similar. Ap—
`proximately 55% of patients were enrolled in a phase i trial.
`Patients referred from within MD Anderson were more likely
`
`to be enrolled than patients seen originally outside the insti-
`
`.006]; black patients were more likely than
`tution {p
`white patientsto enroll (59% vs,43%: ,o = .04]. The median
`interval from the initial visit to initiation of treatments was
`19 days. Major reasons for failure to enroll included failure
`to return to the clinic (35%], opting for treatment in an-
`other clinic (17%], hospice referral (11%], early death
`[10%], and lack of financial clearance {5%}. Treatment was
`delayed for three weeks or more in 250 patients; in 85 pa—
`tients (34%], the delay was caused by financial and insur—
`ance issues.
`
`Conclusion. Failure to return to the clinic, pursuit of other
`therapy, and rapid deterioration were the major reasons for
`failure to enroll; lengthy financial clearance was the most
`common reason for delayed enrollment onto a phase I trial.
`'l'heOocologistZOl3;18:1315—132CI
`
`Implications for Practice: Early drug development is essential as a first step in guiding the development of cancer therapies.
`Therefore, sufficient enrollment of patients into phase I clinical trials in a timely fashion is key to facilitating cancer drug investi-
`gation. We present the results of a study designed to investigate barriers to study enrollment in patients with advanced cancers
`referred to a phase I clinical trials unit. Careful coordination between referral and phase | services may result in the referral of
`appropriate patients, thus increasing the rate of study enrollment. In addition, overcoming potential financial hurdles may signif-
`icantly helpfacilitate rapid enrollment.
`
`lN'I'lltililit'l‘ltJN
`
`_
`
`_
`
`_
`
`_
`
`— .
`
`Patie nts with advanced refractory cancer are eligible to partic—
`
`ipate in phase I trials [1]. Recently, we demonstrated that pa-
`tients who were referred to the phase l clinical trials program
`at MD Anderson Cancer Center had a median overall survival
`
`of approximately 10 months after referral [2]. Sick patients
`may do considerably worse {median survival of 3.2 weeks af-
`ter initial intensive care unit admission and one day after re—
`
`ceivihg cardiopulmonary resuscitation]
`
`[3]. Options for
`
`patients whose disease has failed to respond to conventional
`treatments may include seeking complementary approaches
`
`[4], hospice care, or participating in a clinical trial [5—7].
`A meta—analysis spanning eleven years of patients with
`cancer enrolled in a phase I trial reported an overall combined
`
`complete and partial response rate of 11%. An additional 34%
`of patients demonstrated less than a partial response or stable
`disease {1, 6]. Despite the potential benefit of participating in
`
`Correspondence: Siqing Fu, M.D., Department of Investigational Cancer Therapeutics, Unit 0455. The University of Texas MD Anderson Cancer
`Center, 1515 Holcombe Boulevard, Houston, TX 30030. Telephone: 713J92—4318; Fax: 713—745-3855; E—Mail: siqingfu@mdanderson.org Re-
`ceived June 6, 2013; accepted for publication September 24, 2013,- first published online in The Oncologist Express on October 23, 2013.
`©Alphal’v’led PreSS 1083-?159l2013l$20.00l0 http:l,z‘dx.doi.orgl]0.1534ltheoncologisi20130202
`
`The Oncologist 2013 ;18:13 15—1320 www.TheOncoIogist.com
`
`©A|phaMed Press 2013
`
`
`
`1316
`
`Bar'iiorstri l-nrrillrni'ni in lesc-I Iri..'il-'.
`
`a phase 1 trial, patients who are seen in a facility conducting
`phase I clinical trials may have enrollment delayed or may not
`be ableto participate in a trial or may choose not to participate
`[8, 9], Enrollment delay may result in ineligibility of patients
`for a specific phase I trial because of continuous tumor pro~
`gression—related systemic effect. To investigate timelines and
`factors affecting enrollment into phase I clinical trials after re—
`ferral, we undertook the present study.
`
`MA'I‘ERMLS AN I} M [-I'I'IIUIJS
`
`Patient Selection
`
`Two sets of consecutive candidate patients with cancer who
`were referred to or came as new patients to the Department
`of Investigational Cancer Therapeutics (phase I clinical trials
`program] at The University ofTexas MD Anderson CancerCen-
`ter (MDACC} were included in this retrospective chart-review
`study. Data from the first set of 300 patients were reviewed
`from December 31, 2010, backward, fOIIOWed by the other set
`of957 patients who were referred tothe phase I clinicaltrials pro—
`gram from August 1, 2011, to February 29, 2012. Two separate
`reviewers reviewed the charts independently for each set of pa-
`tients.Approximately5%ofthe patientswere randomly selected
`forcross review toconfirm accuracy. Anydisagreement between
`the reviewers or any uncertainty was brought to a joint chart re—
`view with the corresponding author to reach an agreement. Data
`from the first set ofpatients were used asa training dataset to de-
`termine variables that might affect enrollment. Data from the
`second set of patients were validated using the same variables.
`This study was conducted in accordance with the MD Anderson
`institutional review board guidelines
`
`Data Collection
`Clinical information was extracted from the electronic medi—
`
`cal records at MDACC. All patients were followed until July 31,
`2012,ordeath.Variables collected included age, gender, race,
`residence, time of the initial phase l clinic visit, time of the
`therapy under the first phase I clinical trial, reasons for lack of
`participation, and time of death. Reasons for lack of participa-
`tion in a trial were categorized as follows: [1] death before
`starting protocol treatment or before enrollment; [2] need for
`referral to hospice care; [3] patient declined participation for
`any reason; (4] ineligibility for a phase I study because of poor
`performance status, comorbidity, andfor abnormal labora-
`tory tests; {5] financial reasons for lack of participation leg,
`insurance would not cover or lack of adequate insurance]; [6}
`perceived preferable treatment options, including standard
`therapyor phase II or III trials; [7] off-protocol treatment in the
`phase I clinic; [8] patients did not return, preferred to be
`treated outside MDACC, or unknown. if more than one cate-
`gory applied, the patient was assigned to the single best cate—
`gory using the following rule: If the patient had reasons 2, 4,
`and 5, the patient was assigned to category 2 {the smallest
`number}. The data were entered into a Microsoft Excel data
`sheet for further statistical analyses.
`
`Statistical Analyses
`Categoric data were described using contingency tables. Con-
`tinuously scaled measures were summarized with descriptive
`statistical measures li.e., median with range], whereas overall
`survival rates were estimated using the Kaplan-Meier method
`and compared using the log-rank test. Patients still alive at the
`
`time of data analysis were censored at that time {July 31,
`2012] if they had not been enrolled into a phase I trial. All pa-
`tients referred tothe phaselclinicaltrialsfacility duringthe al—
`lotted time were included in the analysis, regardless of
`whether they received treatment. The chi—square test or
`Fisher exact test were used to examine the association be—
`tween two categoric variables. Statistical inferences were
`based on two—sided tests at a significance level ofp
`.05. Sta—
`tistical analyses were carried out using GraphPad Prism 5 soft—
`ware lGraphPad Software, Inc., San Diego, CA, httpflwww.
`graphpadcom].
`
`Ricsnirrs
`
`Study Patient Population
`Between August 1, 2011, and February 29, 2012, a total of 957
`patients with advanced cancer were seen at the phase I clinic
`at MDACC (Table 1]. Of these, 803 (84%] were referred from
`inside MD Anderson, and 154 [16%] were new patients re-
`ferred from outside the institution. All patients were evalu-
`ated and then given information about a potential phase I trial
`ifthey were eligible. Their median age was 58 years old-12.5%
`of patients were 70 years or older in = 120], and 0.5% were
`children 18 years or younger {n = 6]. There were more women
`in — 527; 55%] than men. In this cohort of patients, 76% ware
`white in r 728], 10% were Hispanic ln = 99], 9% were black
`{n = 89}, and 5% were other in —- 41]. The majority of patients
`had gastrointestinal cancer in = 281; 29%], gynecologic malig.
`nancies [n = 160; 17%], breast cancerin r 94; 10%), sarcoma
`in r 87; 9%], head and neck cancer in — 82; 9%], lung cancer
`in = 82; 9%}, or melanoma in = 50; 5%]. Significantly more pa—
`tients with gastrointestinal cancer and melanoma were re—
`ferred to the phase I clinical trials facility as new patients than
`those with other malignancies, who were mainly referred
`from the inside MD Anderson {,9 s“ .0001].
`
`Enrollment of the Referred Patients Into Phase I Trials
`Initially, we reviewed data from 300 patient charts from De-
`cember 3 1, 2010, backward as a pilot study to identify various
`factors that contribute to delay in or lack of participation in
`phase I trials and to determine the time lag from initial office
`visit (time of initial phase I clinic visit] to the first dose on a
`phase I trial [time of therapy], Among these 300 patients, 151
`(50.3%] received therapy in a phase I trial. Median time from
`referral to first dose was 21 days. Patients who received ther-
`apy under a phase I clinical trial after referral had a median sur-
`vival of 282 days, compared with 161 days for those who had
`
`.01]. This wastrue (289 days
`not enrolled in a phase I trial {,0
`vs. 196 days; p '
`.007] even when patients who died within 30
`days of the initial visit to the phase I trials facility were re-
`moved from the analyses.
`
`After exploratory analysis of data from the above 300 pa-
`tients, we conducted an independent chart review of data
`
`from 957 patients seen at the phase I clinical trials facility be-
`tween August 1, 201 1, and February 29, 2012. Of 957 referred
`patients, 527 patients [55%] were enrolled into phase I trials,
`The median time from the first visit to the first treatment in a
`
`phase I trial was 19 days {interquartile range of 14 “30 days}.
`Further analyses showed no significant differences in age,
`gender, pathologic diagnosis, and geographic residence be-
`tween patients who enrolled in a phase I trial and those who
`
`@AIphaMed Press 2013
`
`O’iicologisl'
`
`
`
` Hi, Mttluirm, N-'t|lil‘, F-‘l -il.
`
`
`Table 1. Patient characteristics in - 957}
`_ Not enrol-led
`
`Enrolled
`
`
` Characteristic n : 527 {55%} n = 430l45%) pvalue"
`Age (years)
`58
`57
`fl
`Modian lrangrfl
`[17—84]
`{17-491
`Gender
`
`Men
`
`Women
`Race distribution
`
`White
`Black
`
`Hispanic
`Others
`
`Cancer diagnoses by
`subspecialty
`Gastrointestinal
`
`Gynecologic
`Breast
`
`Sarcoma
`
`Thoracic
`Head and neck
`
`Melanoma
`
`Genitourinary
`Endocrine
`
`Neurologic
`
`Dual primary
`Unknown primary
`
`.74
`
`.05
`
`234 (54%]
`
`293 {56%}
`
`196 [46%]
`
`234 [44%]
`
`387 {53%}
`61l69%]
`
`55 {57%}
`23 [56%)
`
`341 {47%)
`28 {31%}
`
`43 [43%]
`18 {44%}
`
`154 {55%}
`
`127 [45%]
`
`.45
`
`90 {56%}
`51 [54%)
`
`55 (63%}
`
`48 {59%}
`47 [57%)
`
`22 (44%}
`
`23 {59%}
`14 {50%}
`
`11 {44%}
`
`7 [58%)
`3 (30%)
`
`70 [44%)
`43 (46%]
`
`32 (37%}
`
`34 [41%)
`35 [43%]
`
`28 {56%}
`
`16 [41%]
`14 [50961
`
`14 [56%]
`
`5 (42%]
`7 {70%}
`
`2 {29%}
`
`5 {71%)
`
`Hematologic
`Status of patients
`Referred from inside 458 (57%1
`MD Anderson
`85 {55%)
`69 {45%}
`New patients"
`" p values are for enrolled versus nonenrolled patients.
`“New patients are those referred from outside MD Anderson.
`
`345 {43%}
`
`.006
`
`did not. Significantly more patients referred from inside MD
`Anderson {458303; 57%} participated in phase ltrials than
`those referred from outside [69f154; 45%; p r .005). White
`patients were less likely to be enrolled in phase 1 trials than
`nonwhites (p = .04], and black patients were more likelyto be
`enrolled l61f89; 69%} in phase I trials than nonblacks 11456,:l
`868; 54%; p '— .007). Eight ofthe nine patients who were 2:80
`years old were referred from inside MD Anderson; all nine pa-
`tients were enrolled in phase I trials.
`
`Reasons for Lack of Participation in a Phase I Trial
`The initial chart review of data from 300 patients revealed the
`following reasons for failure to enroll in a phase l trial: [1) pa-
`tient did not return to the phase I trial clinic {23%}; (2]: patient
`wastreated in another department at MD Anderson (21%}; [3]
`patient was not eligible fora phase I clinical trial (20%]; [4) pa—
`tient received planned hospice care (1 1%}; (5] financial issues
`[10%]; [5} patient was not interested in participating in a phase
`I trial (7%); (7] patient was treated off protocol in the phase I
`trial clinic (7%]; or [8} patient died before starting a phase I trial
`(2%}. A total of 957 consecutive patients were referred to a
`
`www.The0ncologist.com
`
`1317
`
`Reasons that Cancer Patients Did Not Participate
`in Phase I Trials in = 430}
`
`Did Not Return
`Treatmenl al
`36%
`
`__
`other MD
`'
`_Anderson c1inics
`
`17%
`
`-
`- _Financial
`Reasons
`5%
`
`
`
`Off—Protocol
`Treatment in the
`Phase I Clinic
`10%
`
`
`
`'
`
`Not Interested
`6%
`
`_ Inelifilbility
`
`6%
`
`Hospice 11%_. -
`
`-
`
`Figure 1. Pie chart shows percentages of patients with cancer
`who were first seen in the phase I clinical trials facility at MD An-
`derson Cancer Center from August 1, 2011, to February 29, 2012.
`accordingto reason forfaiiureto enroll onto a phase I clinical trial,
`A total of 430 of 957 patients failed to enroll.
`
`phase I clinical trial; 430 of these did not participate in a phase
`I trial. The following were the most frequent reasons for fail-
`ure to enroll: [1} patient did not return to phase I trials clinic
`{36%}, (2] patient opted for treatment in another MD Ander—
`son clinic(17%], [3} patientaccepted hospice referrall11%], or
`(4] patient died (10%} (Fig. 1]. Only 5% of the patients who
`were not enrolled in a phase I trial failed to enroll because of
`financial issues, and only 6% were not enrolled because they
`were ineligible.
`Reasons for Delayed Enrollment and Treatment in a
`Phase I Trial
`Further analyses of data from our cohort of957 patients iden—
`tified 250 patients in whom treatment was not initiated
`for three weeks or longer. The median interval from the first
`visit to the phase ltrial clinic to the first dosing in a phase I clin—
`ical trial in this cohort of patients was 30 days. Compared with
`those who received their first dose in a phase I trial within
`three weeks after their initial phase I clinic visit, the cohort of
`patients who received their first dosing three weeks from the
`first office visit or beyond showed no significant differences
`with regard to age, gender, race, or pathologic diagnoses. We
`found thatt‘ne major reason for enrollment delay was thatthe
`business office needed extra time forfinancial clearance in =
`85: 34%] (Fig. 2}. Additionally, enrollment was delayed if the
`patient required extra time if initial tests were abnormal in —'-
`25; 10%], ifthe patient was admitted for acute medical illness
`in = 24; 10%], or ifthe patient was receiving concurrent ther—
`apy that did not allow the initiation of the phase I trial {n — 21;
`8%]. Finally, the need for additional time to arrange traveling
`andfor relocation delayed enrollment for 19 patients {8%}.
`
`Discussitium
`The objective of phase I trials is to define dose levels and tox-
`icity of new agents or combinations, describe responses, and
`evaluate pharmacokinetics and pharmacodynamics of new
`agents. Phase I trials are associated with a toxicity—related
`mortality of only 0.49%, and objective response rates gener—
`ally rangefrom 4%to 10% [1, 6, 101; however, higher response
`
`©A|phaMed Press 2013
`
`
`
`1318
`
`f’JJII'IIt'I‘} to l llrflfllilf'lil III I‘linsel |rr.i|-.
`
`Reasons that Cancer Patients Delayed
`the Fire! Dosing 23 Weeks in - 250]
`Radiation Therapy ‘ 9930"“ ”Gilda?
`, _ Unknown
`'.
`2%
`
`10%
`'I
`"
`'
`
`3%
`Seeklng Other_
`0 tiona
`”3%
`Pending Spot-“
`3%
`
`_
`
`
`Blarney—___ __
`
`3%
`
`_Flnancial
`34%
`
`ronto, which reported an enrollment rate of 29% ['3], and 51%
`of patients referred from inside Daniel den Hoed Cancer Cen-
`ter in Rotterdam, which reported an enrollment rate of 44%
`[26]. Patients referred from inside the institution were more
`likely to be enrolled into a phase I trial, perhaps because of
`physicians’ familiarity with the requirements of these phase
`Itrials. Other possible reasons include that the clinic was
`
`highly specialized, with physicians engaged exclusively in
`phase I ciinical trials, and the presence of dedicated ancil—
`lary assistance, including nurses, study coordinators, and
`
`business office personnel, who focused exclusively on sup—
`porting patients on these trials. Furthermore, patients
`were prescreened by a nurse, who helped them understand
`
`the demands of these trials and tried to ensure that pa-
`tients who were too iii to p