Trends in the Risks and Benefits to Patients With Cancer Participating in Phase 1 Clinical Trials

Roberts, Tony; Goulart, Bernardo H. L.; Squitieri, Lee; Stallings, Sarah; Halpern, Elkan F.; Chabner, Bruce A.; Gazelle, G. Scott; Finkelstein, Stan N.; Clark, Jeffrey W.

doi:10.1001/jama.292.17.2130

Cited by 279 publications

(222 citation statements)

References 38 publications

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“…Patients had a high expectation of benefit from a phase 1 trial, with 43% believing that their tumor would shrink. This is more than double the reported response rates1, 2, 3 and represents a large discrepancy between expectations and what phase 1 trials offer. Although this is high for early clinical trials, these patients had more realistic expectations than those in a previous study in which 75% of patients expected a personal clinical benefit greater than 50% 12.…”

Section: Discussionmentioning

confidence: 79%

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A study of motivations and expectations of patients seen in phase 1 oncology clinics

Dolly

Kalaitzaki

Puglisi

et al. 2016

Cancer

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BACKGROUNDTo better inform clinical practice, this study was aimed at capturing patients' motivations for enrolling in phase 1 trials and at quantifying their expectations of the benefits, risks, and commitment associated with clinical trials and the impact of the initial consultation on their expectations.METHODSThis was a single‐center, prospective, quantitative study of newly referred adult patients considering their first phase 1 oncology trial. Participants completed questionnaires before they were seen and an abbreviated follow‐up version after their consultation.RESULTSQuestionnaires were completed by 396 (99%) and 301 (76%) before and after the clinic, respectively. Participants ranked the possibility of tumor shrinkage (84%) as the most important motivation for considering a phase 1 trial; this was followed by no alternative treatments (56%), their physician's recommendation (44%), and the fact that the research might benefit others (38%). When they were asked about the potential personal benefit, 43% predicted tumor shrinkage initially. After the consultation, this increased to 47%. Fourteen percent of patients expected a cure. When asked about risks, 71% of the participants expected moderate side effects. When asked about expectations of time commitments, a majority of patients did not anticipate weekly visits, although this was understood by 93% of patients after the consultation. Overall, patients were keen to consider trials and when asked before and after the consultation 72% and 84% were willing to enroll in studies, respectively.CONCLUSIONSThis study reports that more than 80% of patients enroll in early‐phase clinical oncology trials motivated by the potential of a clinical benefit, with approximately half expecting tumor shrinkage and approximately a tenth anticipating a cure. The typical phase 1 response rate is 4% to 20%, and this discrepancy exemplifies the challenges faced by patients and healthcare professionals during their interactions for phase 1 studies. Cancer 2016;122:3501–3508. © 2016 American Cancer Society

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Section: Discussionmentioning

confidence: 79%

“…Thus, patients in phase 1 trials can receive subtherapeutic doses with little realistic chance of efficacy or an excessively high drug dose with a risk of serious toxicity. Several studies over the past 20 years have quantified typical response rates of phase 1 trials as 4% to 20% with a median overall survival of 6 months 1, 2, 3…”

Section: Introductionmentioning

confidence: 99%

A study of motivations and expectations of patients seen in phase 1 oncology clinics

Dolly

Kalaitzaki

Puglisi

et al. 2016

Cancer

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“…Previous retrospective analyses have studied the outcome for patients on phase I trials and have reported RRs between 3.8 and 17.8% with higher RR in patients who received classical cytotoxic drugs compared to patients who received biological agents (Sekine et al, 2002;Roberts et al, 2004;Horstmann et al, 2005). These studies however reviewed the outcome over a long period of time, sometimes more than 10 years, which may not reflect the current status of drug development.…”

Section: Discussionmentioning

confidence: 99%

Clinical outcome and prognostic factors for patients treated within the context of a phase I study: the Royal Marsden Hospital experience

et al. 2008

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The main aim of phase I trials is to evaluate the tolerability and pharmacology of a new compound. However, investigating the potential for clinical benefit is also a key objective. Our phase I trial portfolio incorporates a range of new drugs, including molecular targeted agents, sometimes given together with cytotoxic agents. We performed this analysis of response rate, progression-free (PFS) and overall survival (OS) to assess the extent of clinical benefit rate (CBR: partial response (PR) þ stable disease (SD)) derived from current trials. We analysed 212 consecutive patients who were treated in 29 phase I studies, from January 2005 to June 2006. All patients had progression of disease prior to study entry. The median age was 58 years (range: 18 -86) with a male/female ratio of 2 : 1. A total of 148 patients (70%) were treated in 'first in human trials' involving biological agents (132 patients) or new cytotoxic compounds (16 patients) alone, and 64 patients (30%) received chemotherapy-based regimens with or without biological agents. After a median follow-up time of 34 weeks, the median PFS and OS were 11 and 43 weeks, respectively. The CBR was 53% (9% PR and 44% SD) after the first tumour evaluation after two cycles (between weeks 6 and 8) and has been maintained at 36 and 26% at 3 and 6 months, respectively. Treatment related deaths occurred in 0.47% of our patients and treatment had to be withdrawn in 11.8% of patients due to toxicity. A multivariate analysis (MVA) of 13 factors indicated that low albumin (o35 g l À1 ), lactate dehydrogenase4upper normal limit and 42 sites of metastasis were independent negative prognostic factors for OS. A risk score based on the MVA revealed that patients with a score of 2 -3 had a significantly shorter OS compared to patients with a score of 0 -1 (24.9 weeks, 95% CI 19.5 -30.2 vs 74.1 weeks, 95% CI 53.2 -96.2). This analysis shows that a significant number of patients who develop disease progression while receiving standard therapy derived benefit from participation in phase I trials. Risk scoring based on objective clinical parameters indicated that patients with a high score had a significantly shorter OS, and this may help in the process of patient selection for phase I trial entry.

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“…For a patient whose illness has progressed on standard therapy and for whom no other established therapy is available, a less than 5% chance of therapeutic benefit could be regarded as reasonable justification for study entry. Furthermore, with increased use of targeted therapy, the risk of toxic effects experienced by participants in phase I trials is improving (Roberts et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…A recent systematic review, however, has questioned whether participation in clinical trials is of any benefit to participants (Peppercorn et al, 2004). Various studies have reported that the chance of therapeutic response for those volunteering to take part in phase I trial is less than 5% (Estey et al, 1986;Decoster et al, 1990;Von Hoff and Turner, 1991;Smith et al, 1996;Roberts et al, 2004). In phase II clinical trials, the overall objective response rate (partial and complete) is also usually low.…”

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confidence: 99%

Patient motivations surrounding participation in phase I and phase II clinical trials of cancer chemotherapy

et al. 2005

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Successful advances in the treatment of advanced malignant diseases rely on recruitment of patients into clinical trials of novel agents. However, there is a genuine concern for the welfare of individual patients. The aim of this study was to examine motives of patients entering early clinical trials of novel cancer therapies. Questionnaire survey with both open- and close-ended questions. The patients were surveyed after they had given informed consent and before or during the first cycle of treatment. In all, 38 phase I/II trial patients participated and completed the survey. Obtaining possible health benefit was listed by 89% as being a ‘very important' factor in their decision to participate, with only 17% giving reasons of helping future cancer patients and treatment. Other items cited as a ‘very important' motivating factor were ‘trust in the doctor' (66%), ‘being treated by the latest treatment available' (66%), ‘better standard of care and closer follow-up' (61%), and ‘closer monitoring of patients in trials' (58%). Only 47% patients indicated that someone had explained to them about any ‘reasonable' alternatives to the trial. In total, 71% strongly agreed that ‘surviving for as long time as possible was the most important thing (for them)'. Nearly all (97%) indicated that they knew the purpose of the trial and had enough time to consider participation in the trial (100%). In this survey, most patients entering phase I and II clinical trials felt they understood the purpose of the research and had given truly informed consent. Despite this, most patients participated in the hope of therapeutic benefit, although this is known to be a rare outcome in this patient subset. Trialists should be aware, and take account of the expectations that participants place in trial drugs.

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Trends in the Risks and Benefits to Patients With Cancer Participating in Phase 1 Clinical Trials

Cited by 279 publications

References 38 publications

A study of motivations and expectations of patients seen in phase 1 oncology clinics

A study of motivations and expectations of patients seen in phase 1 oncology clinics

Clinical outcome and prognostic factors for patients treated within the context of a phase I study: the Royal Marsden Hospital experience

Patient motivations surrounding participation in phase I and phase II clinical trials of cancer chemotherapy

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