Phase I clinical trials evaluate the dosing and toxicities of novel agents or combinations of agents in humans after appropriate preclinical testing of safety, toxicology and pharmacology. Oncology patients who have been referred to the phase I trials clinic represent the unique subset of patients who have exhausted standard treatment options, yet continue to be functionally well. Because the risks associated with an investigational drug are unknown, and the likelihood of therapeutic response is relatively small [1], multiple studies have examined the motivations of these patients for participating in phase I oncology trials. While patients understand that it is not the purpose of phase I studies, the potential for receiving personal therapeutic benefit remains the most important motivator for trial participation [2–5]. However, in a recent review of over 10,000 participants in phase I trials sponsored by the National Cancer Institute between 1991 and 2002, the average response rate for all agents was 10.6%, and agents given in first-in-human trials produced a response rate of only 4.8% [6].

Although clinical trials are a crucial step in the development of new cancer treatments, their progress can be limited by low accrual rates. Barriers to the enrollment of newly diagnosed cancer patients into phase I to III oncology trials have been identified primarily as patient ineligibility, lack of trials, and patient refusal [7, 8]. However, due to the distinctive nature of phase I clinical trials and its patient population, the obstacles facing recruitment into phase I studies are likely to be different than those observed in oncology trials as a whole. Unfortunately, little data exist to address this issue, even though clarification of these obstacles could aid in improving and streamlining the referral and evaluation process in phase I oncology trials. Therefore, to address this question, we retrospectively reviewed the course of patients from the point of referral to trial entry or non-entry at the Princess Margaret Hospital (PMH) phase I trials clinic over the past 5 years.

This paper represents the first study to examine the referral and enrollment process in the phase I trial setting. A previous study by Corrie et al. reviewed the factors limiting the recruitment of 1,411 patients into phase I to III oncology trials at the West Anglia cancer research network in the United Kingdom [7]. Although their overall recruitment rate was 19%, no trials were available for 40% of patients, 32% of patients were ineligible, and 19% of eligible patients declined entry into a study. Another study by Lara et al. at the University of California Davis Cancer Center in the United States prospectively assessed patient accrual into phase I to III oncology trials and reported an accrual rate of 14% out of 276 patients [8]. Thirty-seven patients, or 49% of those they considered eligible for available protocols, refused to participate for reasons including a desire for other treatment, distance from the cancer center, and insurance denial. While Lara et al. described financial barriers to trial participation, these obstacles were not faced by our patients due to the universal healthcare access provided by the Canadian medical system. However, recent legislation in certain states such as California, Georgia, and Massachusetts, ensures insurance coverage for phase I clinical trials, making them more accessible to patients in those states [10]. Thus, our results should be generalizable to large academic centers with phase I programs outside of Canada.

In our review of 667 new referrals to the phase I clinic at PMH from 2000 to 2005, the overall accrual rate was 29.5%. While not directly comparable to those studies examining recruitment to all three phases of clinical trials, our accrual rate is substantially higher. The higher accrual rate seen in our study likely reflects the fact that patients were referred to our dedicated phase I clinic with the expressed intent of participating in a phase I trial. However, 24.7% of patients were still ineligible, 14% declined to enter a trial, 12.6% were recommended another treatment prior to a clinical trial, and 8.4% were unable to participate due to a lack of available trials or open cohorts. These results suggest that patient recruitment could be further improved by reducing the impact of several of these factors.

Often characterized as desperate and willing to undergo any treatment for a small chance of benefit, it seems surprising that 14% of newly referred patients, or 19% of eligible patients, declined participation in a phase I trial. However, this is similar to the rate reported by Corrie et al. [7], and lower than that reported by Lara et al [8]. Patients had multiple reasons in deciding not to participate, the most common of which was the desire to pursue other treatments, similar to the finding of Lara et al [8]. However, other important reasons included quality of life purposes, the uncertainty of benefit and toxicity, trial burden, and the desire to have no more active treatments. This finding suggests that many phase I patients do comprehend the requirements and objectives of study participation. Although phase I trial physicians are the best qualified to help patients make this decision, educating patients about the basics of phase I trials prior to their referral may help some patients determine then that it is something they do not wish to pursue. This would, in turn, make more spots available for eligible and interested patients, as well as shorten the waitlist to be seen in phase I clinic.

Although it is usually thought that patients are referred for phase I trials only after exhausting all other treatment options, a remarkable 12.6% of newly referred patients, or 16.7% of eligible patients, were recommended another treatment prior to a phase I study. Clinical experience shows that trial physicians may make such a suggestion if they feel that another treatment is better at providing symptomatic control, or can provide more benefit than the 5 to 10% response rate obtained from an experimental agent. Most of these patients are informed that they can be reevaluated for a phase I trial after they complete the recommended treatment, but unfortunately, the vast majority of them are unable to do so. Because the clinical course of these end-stage patients is unpredictable, the window of opportunity for starting a phase I trial may be limited. The delay involved in waiting for an appointment, being assessed in phase I clinic and then undergoing another therapy may be sufficient time for a patient's clinical status to deteriorate, thus rendering the patient ineligible for trial entry. Therefore, in order to expedite patient accrual into trials, it is important to ensure that all treatments have been exhausted and all symptoms are well managed prior to referral to the phase I clinic. Interestingly, 47% of chemonaïve patients in our study entered into phase I trials (data not shown), and were less likely to be recommended another treatment first (15%). These figures indicate that these were indeed the patients with malignancies for which no effective standard treatments exist, or alternatively these patients were accrued into phase I trials containing at least one active approved anticancer agent.

Lack of trial availability or open cohorts prevented 8.4% of newly referred, eligible and interested patients in our study from participating in a trial. Additionally, it was the most common reason for a delay in patients who eventually entered a trial. Given that trials were not available for 40 to 50% of patients in other studies [7, 8], our result is intriguing, although the phase I trial setting is different in that trials are neither site nor stage specific, allowing patients to enter into any open trials. Also, in contrast to the other studies which reviewed experiences in general cancer clinics, patients in our study were seen in a dedicated phase I clinic in which enrollment into a phase I trial is the main reason for the referral, and the physician and nursing staff are well aware of trial availability. Nonetheless, if more trials and spots were made available, all eligible and interested patients could be accommodated and the amount of delay in starting a trial reduced.

While nearly one quarter of newly referred patients were deemed ineligible to enter a phase I trial for various reasons, the subgroup analysis also identified specific patient factors that were more likely to preclude trial entry. Elderly patients 70 years of age or over appeared less likely to be eligible for and enter phase I trials when compared to patients less than 70 years old. The finding that elderly patients are underrepresented in oncology trials, including phase I studies, has been previously documented [11, 12]. Tumor site also affected clinical outcome, as breast cancer patients in particular were more likely to be ineligible. A further review of the data indicates that 72% (13/18) of the ineligible breast patients were excluded from trial entry because they had received too much prior treatment. The number of sarcoma patients in this study was too small to draw any conclusions about their reasons for ineligibility. Certainly, those with multiple primary cancers were always excluded from phase I trials and therefore should not be referred to the clinic for assessment. Additionally, patients with poor performance status (ECOG >2) were very unlikely to enter a trial, which is further supported by our finding that this was the most common reason for ineligibility. Heavily pre-treated patients were also unlikely to enter a trial, and accounted for 13% of patients who were excluded by trial entry criteria. Although there exist trials without restrictions on the number of prior lines of chemotherapy, this obstacle could be overcome by increasing the number of these trials. Especially in the current era of targeted agents where bone marrow toxicity is less common, the amount of prior treatment is less of a concern. Furthermore, trials with unrestricted prior therapy are generally easier to complete. Although a relaxation of some trial eligibility criteria could increase accrual rates, trial investigators would need to balance this with clinical or scientific concerns, such as avoiding undue toxicity or maintaining a more homogenous patient group.

Finally, being referred by an external physician appeared to decrease a patient's chances of entering a trial as more of these patients were ineligible or were recommended another treatment first. When compared to patients referred by PMH physicians, those referred by external physicians were more likely to have an ECOG status of 3 (4.6% vs. 10.7%) and thus be excluded from trial entry due to poor performance status (40% vs. 51.7%). PMH physicians may have the benefit of being better aware of available trials at the time of referral, thus allowing more of their patients to be enrolled. However, regardless of the referral source, educating referring physicians about the factors and characteristics that make patients ineligible may reduce the number of inappropriate referrals. Additionally, having a triage system to pre-screen referral records, such as prior therapy, laboratory results, concomitant medications, etc. may also help to ensure that more potentially eligible patients are seen in the phase I clinic.

As a retrospective study, our study has certain limitations. Although physicians' clinic notes are a useful and easily accessible source of information, they are hardly a complete record of all the complexities surrounding a patient's assessment or decision to undergo or decline a clinical trial. Certainly, in the case of 7 patients, it was unclear as to why they did not enter a trial, as well as in 10 patients in which no reason for declining trial entry was given. Additionally, 29 patients were lost to follow-up.

In examining the patterns of referral and enrollment in the phase I clinic over the past five years, our study provides future patients and physicians with better insight into the clinical realities underlying a referral to the phase I clinic. Our results identify factors and characteristics that hinder patient accrual, the knowledge of which may be helpful in defining referral guidelines and developing strategies to maximize patient recruitment.

This study reviews the referral experience from the phase I clinic at the Princess Margaret Hospital, with focus on the barriers that influence eventual trial enrollment. Better selection of patients, appropriate education of referring physicians, and opening phase I trials with fewer restrictions on some criteria such as prior therapy may enhance their recruitment rates.