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`Vol. 18, N0. 12, December 2013
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`Oncologist.
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`Barriers to Study Enrollment in Patients
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`Clinieal Trials Unit
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`CME.TheOncologist.com fora totalof3 new
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`education credit in this issue.
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`Volume 13, Number 12, December 2013
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`'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
`
`.
`.
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`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
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`GLOBAL HEALTH AND CANCER
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`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
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`Proma Paul, Jennifer L. Winkler, Rosario M. Bartolini, Mary E. Penny, Trinh Thu Huong, Le Thi Nga,
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`1285 Advancing Cervical Cancer Prevention in India: Implementation Science Priorities
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`1298 Breast Cancer in Young Women in Latin America: An Unmet, Growing Burden
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`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
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`Rossana Di Paola, Claudio Costantini, Cristina Tecchio, Gian Luca Salvagno, Rachele Montemezzi,
`Alessio Perandini, Giovanni Pizzolo, Stefano Zaffagnini, Massimo Franchi
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`OUTCOMES RESEARCH
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`1315 Barriers to Study Enrollment in Patients With Advanced Cancer Referred to a Phase I Clinical
`Trials Unit
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`Siding F Lt, Lacey McQuinn, Aung Naing, Jennifer J. Wheler, Filip Janku, Gerald S. Faichook,
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`SYMPTOM Mnnnor MLNT AND SUPPORTIVE CARE
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`1321 Venous Thromboembolism Risk in Patients With Cancer Receiving Chemotherapy: A Real-world
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`LETTERS to THE Eoiroe
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`1 330 Comprehensive Geriatric Assessment and Adjustment of Cancer Treatment
`Monique S. Slee-Valentijn, Andrea 8. Maier
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`1331 In Reply
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`Nadine J. McCleary, Arti Hurria, Jeffrey Meyerhardt
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`IN MEMORIAM
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`1332 In Memoriam: Michael J. Haut
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`1334 Volume 18 Acknowledgments
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`1336 Volume 18 Author Index
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`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