Annals of Oncology Advance Access published online on November 27, 2007
Annals of Oncology, doi:10.1093/annonc/mdm548
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© 2007 European Society for Medical Oncology
Treatment outcome and survival in participants of phase I oncology trials carried out from 2003 to 2006 at Institut Gustave Roussy
1 Department of Medicine
2 Department of Biostatistics and Epidemiology
3 Department of Radiotherapy
4 Clinical and Translational Research Division, Institut Gustave Roussy, Villejuif
5 Department of Medical Oncology, Institut Claudius Regaud, Toulouse, France
* Correspondence to: Dr J.-C. Soria, Department of Medicine, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France. Tel: +33-1-42-11-43-39; Fax: +33-1-42-11-50-38; E-mail: soria{at}igr.fr
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionReferences |
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Background: The oncology community usually perceives phase I oncology trials as associated with poor or limited benefits and substantial risks. There is scarce data concerning outcome and survival of patients enrolled in current phase I oncology trials.
Patients and methods: We reviewed all phase I oncology trials conducted by investigators from the Adult Phase I Unit at Institut Gustave Roussy from 2003 to 2006. We report data concerning patient demographics, treatment outcome, toxicity, survival and type of care after trial exit.
Results: We analyzed 10 trials involving 180 participants. The overall response rate was 7.2%. Disease control (objective response plus stable disease) was achieved in 48.2% of patients. The rate of toxic death was 0.5%. In all, 38% of patients had at least one episode of grade 3 or 4 toxic events. The median progression-free survival and the median overall survival (OS) were 2.3 and 8.7 months, respectively. On multivariate analysis, a time between diagnosis of disease and inclusion in the phase I trial 
24 months and evidence of disease control were statistically significant predictors of improved OS.
Conclusion: Current phase I oncology trials are safe and are associated with clinical benefit in a substantial proportion of patients.
anticancer drugs, early clinical trials, oncology, phase I trials, targeted therapies
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Phase I clinical trials play a crucial role for the development of innovative anticancer drugs. Although demonstration of a therapeutic effect is not a primary objective of phase I studies, most cancer patients and medical oncologists expect benefit from trial participation [1]. On the basis of these considerations, many authors have expressed ethical concerns about phase 1 cancer research [2–6]. Indeed, several meta-analyses placed the average response rate for phase 1 oncology trials at <6% and the rate of death from toxic effects at
0.5% [7–11]. Therefore, critics argue that there is an extremely low likelihood of a benefit and substantial risks for cancer patients to participate in phase 1 studies. It could, however, be objected that most of these reports included studies published from 1970 to 1991 [7–11]. Moreover, these reviews excluded phase 1 trials which tested more than one agent and therefore did not reflect the full spectrum of phase 1 oncology trials. Furthermore, they usually did not report data on stable disease (SD), whereas molecular-targeted therapies, which are increasingly being evaluated in cancer trials, are more likely to result in SD than to produce tumor regression [12]. To date, only one meta-analysis took into account both single agent and combination agent trials [13]. In this study, the authors reviewed phase I oncology trials which were sponsored by the Cancer Therapy Evaluation Program from 1991 to 2002. Interestingly, instead of restricting themselves to conventional criteria of objective response, they also assessed the data on SD. The overall response rate and the SD rate were 10.6% and 34.1%, respectively, suggesting a higher benefit from phase I oncology trials than previously reported. One of the limitations of this study as well as of the previous reviews, however, is that data concerning survival of patients are not reported. In order to determine the treatment outcome and survival of patients included in modern phase I oncology trials, we carried out a systematic review of all the phase 1 oncology studies conducted by the Adult Phase I Unit of the Institut Gustave Roussy from 2003 to 2006. |
patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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patients
This study included all the patients who had participated in a phase I oncology trial conducted by investigators from the Adult Phase I Unit, Department of Medicine, at Institut Gustave Roussy in time period from 1 January 2003 to 30 June 2006. All the data concerning the patient characteristics, their clinical outcome and treatment toxic effects were prospectively recorded by the investigators. Their accuracy was retrospectively validated by two independent observers. Toxicity was assessed according to the National Cancer Institute (NCI)—Common Toxicity Criteria version 3.0. The best response was classified according to the Response Evaluation Criteria In Solid Tumors criteria [14].
statistical analysis
The statistical analysis for baseline demographics and clinical outcome are on the basis of all data available up to the cut-off date of 30 April 2007.
The disease control rate was defined as the objective response plus SD. Overall survival (OS) was defined as the interval from the start of therapy to the time of death or the last follow-up. Progression-free survival (PFS) was calculated from the beginning of therapy to the time of disease progression or death due to any cause. Survival rates were estimated with the use of the Kaplan–Meier method with TIGRE software developed by the Institut Gustave Roussy for survival curves. Univariate and multivariate analyses were carried out by Cox regression and included the following variables: age (<60 years old or 60 years old), sex, number of previous lines of treatment (<2 or 2), treatment with at least one anticancer agent approved by the European Agency for the Evaluation of Medicinal Products (EMEA), time between diagnosis and inclusion (<24 or 24 months) and pattern of response. Variables associated with survival with a P value <0.20 in the univariate analysis were included in the multivariate regression. All reported P values are two-sided. Analyses were carried out using SAS statistical software 9.0 (SAS Institute, Cary, NC).
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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patients characteristics
A total of 180 patients (104 males and 76 females) were included in this study. Their characteristics are described in Table 1. The median age was 52 years and 80.5% of the patients were between the ages of 40 and 70 years. Almost all (n = 178; 99%) of the enrolled patients had a good performance status at inclusion (Eastern Cooperative Oncology Group performance status 0 or 1). They had cancer for a median of 31 months and had received a mean of 2.8 prior lines of treatment (range 0–10). One hundred and seventy-one patients (95%) had documented progressive disease at enrollment. One hundred and thirty-eight patients (77%) had three or less previous lines of chemotherapy. At the time of analysis (30 April 2007), five patients (2.8%) were still treated within phase I trials. One hundred and ten patients (61%) were referred from the inside of the Institution and 70 (39%) came from outside (39 from other academic centers and 31 from private practice).
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clinical trials
A total of 10 phase I trials were actively recruiting during the study period (Table 2). These included five studies of investigational agent alone and five studies of investigational agent plus an agent already approved by the EMEA. The investigational agent was a cytotoxic drug in four studies, a signal transduction inhibitor with or without antiangiogenic properties in four studies, a vascular disrupting agent in one study and a cell cycle inhibitor in one study. Two of these trials were first in human trials. In two trials involving a signal transduction inhibitor, patients were requested to consent to sequential tumor biopsies as well as skin biopsies in order to carry out laboratory correlative studies.
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research-related biopsies
All the patients (n = 46) included in the two trials requiring research-related biopsies had two sequential skin biopsies (at baseline and day 8 of the first cycle). Twenty-nine patients (63%) accepted also to undergo two sequential tumor biopsies (at baseline and day 8 or 21 of the first cycle). All of them but one underwent both tumor biopsies. The sites of tumor biopsies included among others liver, lung, lymph nodes, skin and sinus.
response rate
Fourteen patients (8%) were not assessable for response. Two patients died from their disease few days after the inclusion, nine patients discontinued the trial because of substantial toxicity, one patient died of treatment toxicity (as per investigator evaluation) and two patients exited the trial due to a general status alteration. Thirteen patients (7.2%) had either a complete (one patient) or a partial response (12 patients). SD was reported as the best overall response in 74 patients (41%). The median duration of SD was 129 days. The disease control rate (objective response plus SD) was significantly higher in patients enrolled in trials including a combination of an investigational agent with a chemotherapeutic agent approved by the EMEA than in patients enrolled in pure investigational studies (68% versus 21%; P < 0.0001).
survival
The median follow-up was 27 months (range 10–56 months). At the time of analysis (30 April 2007), 142 patients had died and 38 were still alive. Causes of death were progressive disease in 138 patients (97.2%), toxicity related to treatment in one patient (0.7%) and intercurrent disease in three patients (2.1%). The median PFS was 2.3 months. The 1-year and the 2-year PFS rates were 14% [95% confidence interval (CI) 9.5–20] and 7% (95% CI 4–13), respectively (Figure 1). The median OS was 8.7 months. The 1-year and the 2-year survival rates were 39% (95% CI 32–46) and 20% (95% CI 15–27), respectively (Figure 1). On univariate analysis, a time between diagnosis of disease and inclusion in the phase I trial 24 months and evidence of disease control were statistically significant predictors of OS. On multivariate analysis, these parameters remained highly significant independent predictors of improved OS (Table 3; Figure 2). Moreover, as comparison between patients with evidence of disease control and patients with progressive disease may be biased, the analysis was repeated after exclusion of the patients with early deaths (landmark methods). Similar results were observed whether early death was defined as death within 2 months (19 patients excluded) or as death within 4 months (45 patients excluded) from the beginning of treatment (data not shown).
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patient care after trial exit
After trial completion, 73 patients (40.6%) were offered only best supportive care, whereas 67 patients (37.2%) and 35 patients (19.4%) received one or more further lines of chemotherapy, respectively. Treatment modalities after trial exit were not known for five patients (2.8%).
toxicity
One death (0.5%), due to renal failure considered by the investigator as related to treatment, occurred in a trial involving a signal transduction inhibitor. Sixty-eight patients (38%) had grade 3 or 4 toxic events, all reversible. Among them, 25 patients (14%) withdrew because of adverse events related to treatment. None of the patients presented with late sequelae. Among the 46 patients who had undergone research-related biopsies, no major complication (i.e. clinically significant pneumothorax, hemorrhage or traumatic organ injury) attributed to the procedure was recorded. Only, one episode of liver subcapsular hemorrhage, which did not require additional intervention, occurred on a liver biopsy.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Institut Gustave Roussy decided in September 2006 to strengthen its phase I cancer trials capacity in order to deal with the increasing number of patients referred for inclusion in such trials and to adequately address the expectations of the pharmaceutical industry. Before deciding what measures were appropriate to achieve this broad objective, investigators from the Adult Phase I Unit decided to evaluate the patient's characteristics, results, therapeutic outcome and tissue banking compliance in phase I trials conducted in their institution from January 2003 to June 2006.
The patient population included at Institut Gustave Roussy during this 3-year period is comparable to that reported in a previous pooled analysis of phase I trials [15, 16]. Patients had a long experience with cancer and cancer treatments. Patients had cancer for a median of 31 months and had received a mean of 2.8 previous lines of treatment.
The disease control rate of 48.2% observed in our review (objective response 7.2%; SD 41%) is similar to that reported in the study of Horstmann et al. [13] which includes 460 trials sponsored by the NCI and showed that 10.6% of patients experienced an objective response and 34.1% a SD. In addition to the evidence reported by Horstmann et al., our study confirms that recent phase I trials result in higher disease control rates. Several authors, however, have objected that an objective response or a stabilization of disease is not predictive of potential benefit for patients [17, 18]. There are several arguments against this allegation. First, it appears logical that cancer patients in good general status and no organ dysfunction, as those included in phase 1 studies, will not die of their disease unless it progresses. Moreover, several studies have showed that tumor response is associated with symptom's improvement and increased survival [19–23]. Furthermore, in our study, the median PFS and the median OS of 2.3 and 8.7 months, respectively, were significantly associated with tumor response on multivariate analysis. Importantly, these results were achieved in a population of pretreated metastatic patients. For example, in the trial which lead to the recent approval of erlotinib for the treatment of metastatic non-small-cell lung cancer in second- or third-line setting, the median PFS and the median OS in the erlotinib group were 2.2 and 6.7 months, respectively, whereas the disease control rate was 45% [24]. Similarly, in a recent study which aimed to determine the activity of cetuximab in heavily pretreated patients with metastatic colorectal refractory to both irinotecan and oxaliplatin, the disease control rate was 43.4%, the median PFS was 1.4 months and the median survival time was 6.6 months [25]. Such indirect comparisons, despite their limits, clearly show that the clinical benefit from current phase I oncology trials is not worse than those observed with many agents that were recently approved by the European and American sanitary administrations. As previously shown by Horstmann et al. [13], not all phase I trials, however, are alike. Indeed, in our study, the response rate among patients who were treated in trials involving an investigational agent plus an agent approved by the EMEA was higher than among patients who were treated with only investigational agents.
Interestingly, the majority of patients (56.6%) received at least one further chemotherapy regimen after the exit of phase I trial essentially with drugs used off-label. This demonstrates that oncologists who refer patients for phase I studies have integrated that participation in phase I trials belongs in fact to a treatment strategy which aims to offer their patients a real chance of benefit.
The toxicity-related death rate observed in our study (0.5%) is similar to that previously reported [13, 16]. In all, 38% of patients experienced at least one grade 3 or 4 toxic event. Discontinuation of study treatment for adverse events related to treatment occurred in 25 patients (14%). As a comparison, in the pivotal phase III trial which lead to the recent approval of bevacizumab as a component of first-line therapy for advanced colorectal cancer in combination with i.v. 5-fluorouracil-based chemotherapy, the incidence of grade 3 or 4 adverse events in the bevacizumab group was 84.9% and discontinuation of treatment occurred in 8.4% of cases [26].
In this study, we have also reported our experience with sequential research-related biopsies, in two phase I trials involving targeted therapies. Sequential tumor biopsies are crucial for the rational development of targeted therapies in order to correlate their preclinical and clinical activities to the modulation of the target in vivo. In our study, the majority of the patients accepted skin biopsies (100%) as well as tumor biopsies (63%) despite a clear written information, indicating that the biopsy specimens would be for research purposes only. This result is in agreement with a recent report which showed that most patients enrolled in clinical trials with sequential tumor biopsies tolerate easily the biopsy procedures and readily allow their specimens to be tested for research purposes [27]. As previously indicated [28], our data confirm that sequential tumor biopsies are feasible and safe during early-phase clinical trials. Indeed, no major complication (i.e. clinically significant pneumothorax, hemorrhage or traumatic organ injury) attributed to the procedure was recorded even in patients treated with an antiangiogenic agent.
Importantly, besides a hope of disease control related to the experimental agent, it has been demonstrated that patients with cancer in phase I trials also receive secondary benefit from their participation. Indeed, routines associated with participation in a phase I study such as the regular visits with the oncologist and the frequent biological and radiological investigations are integrated in a coping strategy and represent for many patients a source of comfort [29, 30].
Altogether, our study showed that it is simply misleading to still consider that phase I oncology trials have no therapeutic aim. Therefore, the frequent critics about informed consent in phase I cancer trials and their frequent lack of an explicit statement that efficacy was not to be expected are clearly irrelevant [31, 32]. Moreover, a recent study of Agrawal et al. has demonstrated that the vast majority of patients participating in phase I oncology studies are aware of alternatives to the phase I study, are not dissuaded by potential serious adverse effect of treatment and do not feel coercion to enroll [33]. Therefore, current phase I oncology trials should be considered as an excellent compromise between the objectives of science and those of care of advanced cancer patients in good general condition.
Received for publication September 25, 2007. Revision received October 29, 2007. Accepted for publication October 30, 2007.
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References |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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1. Meropol NJ, Weinfurt KP, Burnett CB, et al. Perceptions of patients and physicians regarding phase I cancer clinical trials, regarding phase I cancer clinical trials: implications for physician-patient communication. J Clin Oncol (2003) 21:2589–2596.
2. Emanuel EJ. A phase I trial on the ethics of phase I trials. J Clin Oncol (1995) 13:1049–1051.[Web of Science][Medline]
3. Lipsett MB. On the nature and ethics of phase I clinical trials of cancer chemotherapies. JAMA (1982) 248:941–942.
4. Miller M. Phase I cancer trials. A collusion of misunderstanding. Hastings Cent Rep (2000) 30:34–43.[Web of Science][Medline]
5. Kodish E, Stocking C, Ratain MJ, et al. Ethical issues in phase I oncology research: a comparison of investigators and institutional review board chairpersons. J Clin Oncol (1992) 10:1810–1816.
6. Miller M. Phase I cancer trials: a crucible of competing priorities. Int Anesthesiol Clin (2001) 39:13–33.[Medline]
7. Itoh K, Sasaki Y, Miyata Y, et al. Therapeutic response and potential pitfalls in phase I clinical trials of anticancer agents conducted in Japan. Cancer Chemother Pharmacol (1994) 34:451–454.[Web of Science][Medline]
8. Estey E, Hoth D, Simon R, et al. Therapeutic response in phase I trials of antineoplastic agents. Cancer Treat Rep (1986) 70:1105–1115.[Web of Science][Medline]
9. Decoster G, Stein G, Holdener EE. Responses and toxic deaths in phase I clinical trials. Ann Oncol (1990) 1:175–181.
10. Von Hoff DD, Turner J. Response rates, duration of response, and dose response effects in phase I studies of antineoplastics. Invest New Drugs (1991) 9:115–122.[Web of Science][Medline]
11. Smith TL, Lee JJ, Kantarjian HM, et al. Design and results of phase I cancer clinical trials: three-year experience at M.D. Anderson Cancer Center. J Clin Oncol (1996) 14:287–295.[Abstract]
12. Korn EL, Arbuck SG, Pluda JM, et al. Clinical trial designs for cytostatic agents: are new approaches needed? J Clin Oncol (2001) 19:265–272.
13. Horstmann E, McCabe MS, Grochow L, et al. Risks and benefits of phase 1 oncology trials, 1991 through 2002. N Engl J Med (2005) 352:895–904.
14. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst (2000) 92:205–216.
15. Bachelot T, Ray-Coquard I, Catimel G, et al. Multivariable analysis of prognostic factors for toxicity and survival for patients enrolled in phase I clinical trials. Ann Oncol (2000) 11:151–156.
16. Roberts TG Jr, Goulart BH, Squitieri L, et al. Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. JAMA (2004) 292:2130–2140.
17. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med (1996) 125:605–613.
18. Rothschild BB, King NM. Phase 1 clinical trials in oncology. N Engl J Med (2005) 352:2451–2453.
19. Lokich J. Tumor response and survival end points in clinical trials: a clinician's perspective. Am J Clin Oncol (2004) 27:494–496.[CrossRef][Web of Science][Medline]
20. Pazdur R. Response rates, survival, and chemotherapy trials. J Natl Cancer Inst (2000) 92:1552–1553.
21. Modi S, Panageas KS, Duck E, et al. Prospective exploratory analysis of the association between tumor response, quality of life, and expenditures among patients receiving paclitaxel monotherapy for refractory metastatic breast cancer. J Clin Oncol (2002) 20:3665–3673.
22. Geels P, Eisenhauer E, Bezjak A, et al. Palliative effect of chemotherapy: objective tumor response is associated with symptom improvement in patients with metastatic breast cancer. J Clin Oncol (2000) 18:2395–2405.
23. Le Cesne A, Van Glabbeke M, Verweij J, et al. Is a stable disease according to RECIST criteria a real stable disease in GIST patients treated with imatinib mesylate (IM) included in the intergroup EORTC/ISG/AGITG trial? J Clin Oncol (2006) 24. (Abstr 9510).
24. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non small-cell lung cancer. N Engl J Med (2005) 353:123–132.
25. Lenz HJ, Van Cutsem E, Khambata-Ford S, et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol (2006) 24:4914–4921.
26. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med (2004) 350:2335–2342.
27. Agulnik M, Oza AM, Pond GR, Siu LL. Impact and perceptions of mandatory tumor biopsies for correlative studies in clinical trials of novel anticancer agents. J Clin Oncol (2006) 24:4801–4807.
28. Dowlati A, Haaga J, Remick SC, et al. Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation. Clin Cancer Res. (2001) 7:2971–2976.
29. Moore S. A need to try everything: patient participation in phase I trials. J Adv Nurs (2001) 33:738–747.[CrossRef][Web of Science][Medline]
30. Hutchison C. Phase I trials in cancer patients: participants' perceptions. Eur J Cancer Care (Engl) (1998) 7:15–22.[CrossRef][Medline]
31. Daughtery CK. Impact of therapeutic research on informed consent and the ethics of clinical trials: a medical oncology perspective. J Clin Oncol (1999) 17:1601–1617.
32. Horng S, Emanuel EJ, Wilfond B, et al. Descriptions of benefits and risks in consent forms for phase 1 oncology trials. N Engl J Med (2002) 347:2134–2140.
33. Agrawal M, Grady C, Fairclough DL, et al. Patients' decision-making process regarding participation in phase I oncology research. J Clin Oncol (2006) 24:4479–4484.
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