Risks and Benefits of Phase 1 Oncology Trials, Revisited
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《新英格兰医药杂志》
Cancer is the most common cause of death in the United States, with more than 500,000 people succumbing each year.1 Despite dramatic advances in the treatment of certain cancers, the vast majority of patients with metastases die from the cancer. These sobering facts have evoked an intensive and increasingly successful endeavor to unravel the mechanisms that drive the growth of cancer cells, an enterprise that has produced a large number of new drugs, especially agents aimed at particular molecules.
Investigations of anticancer drugs follow a characteristic path: in vitro experiments are followed by studies in animals, and then there is a preliminary clinical introduction in patients with cancer — the phase 1 trial. Built on the phase 1 foundation, phase 2 studies are performed to determine the efficacy of the drug, and if they show a reasonable benefit, phase 3 trials are conducted to compare the new drug with one or more conventional treatments. A demonstration that the new agent is efficacious and safe in a phase 3 trial often leads to its approval by the Food and Drug Administration (FDA).
Phase 1 trials are closely scrutinized, and their ethics debated, because of the many unknown factors that participants in the trials face and because of the critical role the trials have in the development of new cancer treatments. In this issue of the Journal, Horstmann et al.2 point out that phase 1 trials are often referred to as first-in-human studies, but actually these trials are considerably more heterogeneous than that term indicates. In addition to testing investigational drugs, phase 1 trials assess new combinations or dosing schedules, or both, of FDA-approved drugs. The expectations differ in regard to the risks and benefits associated with each of these types of trials. The unknown factors involved in a first-in-human trial with a new drug are much greater than are any unforeseen outcomes in a trial of an investigational drug and an FDA-approved drug or a new combination of two approved drugs. Furthermore, a drug that is used in the clinic for the first time has no track record of benefit, in contrast with FDA-approved medications.
An often-repeated misconception is that the sole function of phase 1 trials is to find the right dose and to assess toxicity — that evaluation of clinical responses is not an objective.3 It is true that the design of phase 1 trials generally precludes the statistical assessment of response rates, but we and other investigators engaged in phase 1 trials think that describing responses is important. Indeed, almost all new anticancer agents approved in recent years by the FDA brought about objective clinical responses among patients in phase 1 trials.4,5 For this reason, the hope for a benefit from phase 1 trials that patients (and their physicians) have is not discordant with the objectives of these trials. Our own experience and the literature on the topic6 support this view. Even so, the ethics associated with phase 1 trials have been questioned,3 in part because the prospect for improvement is perceived as low (overall response rate, 4 to 6 percent) and in part because of the risk of irreversible harm (death rate, 0.5 percent).4,5 These numbers do not, however, represent all phase 1 trials but derive from reviews of only single-agent studies.
In contrast with prior analyses of phase 1 trials, Horstmann et al. reviewed the full spectrum of such trials — a total of 460, involving 11,935 participants — conducted under the auspices of the National Cancer Institute, the major sponsor of phase 1 oncology trials in the United States. Instead of restricting themselves to conventional measures of outcome (i.e., complete or partial remission), the authors also assessed the data on stable disease. They made several key observations. Whereas the toxicity-related death rate, as in prior analyses, was about 0.5 percent, the overall response rate of 10.6 percent was higher than that previously reported. Furthermore, an additional 34.1 percent of patients had either stable disease or a "less-than-partial" response. From this perspective, then, 44.7 percent of participants derived a benefit, since all patients had to have progressive cancer to qualify for a phase 1 trial.
These results are not inconsequential. The importance of stable disease or minimal regression has increased substantially, as exemplified by the use of imatinib mesylate in the treatment of gastrointestinal stromal tumors. Patients with minimal regression or decreased tumor density, as seen on computed tomography (i.e., stable disease according to standard criteria), had remarkable clinical improvement, prolonged progression-free survival, and responses, as measured by positron-emission tomography, that were equivalent to the responses seen in patients with a partial remission.7
Another key observation made by Horstmann and colleagues is that not all phase 1 trials are alike. One could use this fact to argue that trials with very low response rates — that is, phase 1 trials involving one investigational chemotherapeutic agent — trade on the hopes of a vulnerable population. But patients can differ from the critics in their thinking. Studies of this question indicate that most patients enrolled in a phase 1 trial hope they will benefit from it, but they understand that this outcome is unlikely.8 Our clinical experience with such patients — who often tell us that they have sought out a phase 1 trial, even if the chances of a response are small, because their quality of life is improved by "not giving up" — confirms this point. The intense lobbying efforts of activists for earlier access to experimental therapies for AIDS and breast cancer are further evidence that patients facing inevitable death may be less risk-averse than is the regulatory community.
Horstmann and colleagues also meticulously review the issue of serious toxicity in the protocols they studied. They found a treatment-related death rate of, at most, 0.49 percent. Since virtually all participants have a deadly disease (and, often, a rapidly fatal one) and have exhausted the conventional options for treatment, a toxicity-related death rate of less than 1 percent suggests to us that safety concerns should not stop these trials. Conservative starting doses and dose-escalation schemes must be considered as factors that account for the low death rate in these trials. The downside to this conservative approach may be a compromise in efficacy due to subtherapeutic doses. More aggressive dose escalation may therefore be preferable in the treatment of a lethal disease. Indeed, in a phase 1 trial that allowed fully informed patients to choose among doses of a therapeutic agent, 28 percent chose the highest available dose.9
Horstmann et al. did not investigate the role of clinical trials in children with incurable cancer. We already know that the proportion of pediatric patients with cancer who enter trials of any phase that are sponsored by the National Cancer Institute dwarfs the enrollment of adults (about 50 percent vs. 2 percent, respectively).10 Barriers to enrollment with advancing age may include the expectations of patients and their physicians, inadequate social support, coexisting illnesses, and financial or insurance constraints. The widespread participation of children in trials is believed to account, at least in part, for the marked improvement in the survival of children with cancer.
Phase 1 trials are crucial for the development of new cancer therapies. The scope of these trials continues to undergo expansion and refinement. End points now include determination of the dose for optimal modulation of the neoplastic target rather than just the highest dose tolerated by most patients. Indications of a response in specific cancers that arise during phase 1 trials serve as a major impetus for phase 2 efficacy studies.11 Several phase 1 trials have proved so pivotal that they have changed the landscape of cancer therapy. Perhaps the most striking example is the phase 1 trial of imatinib mesylate for the treatment of chronic myelogenous leukemia.12 This relatively nontoxic drug, which targets the molecular genetic defect that causes chronic myelogenous leukemia, yielded a 93 percent response rate in the phase 1 setting.12 This study was not included in the analysis by Horstmann et al., since it was not sponsored by the National Cancer Institute. For most phase 1 studies, the proportion of patients who benefit is considerably lower than in the imatinib mesylate trial, but the benefit-versus-risk ratio is, nevertheless, favorable.
Drs. Kurzrock and Benjamin report having received grant support from the National Institutes of Health and from pharmaceutical companies for the conduct of clinical trials.
Source Information
From the Phase I Program (R.K.) and the Department of Sarcoma Medical Oncology (R.S.B.), Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston.
References
Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10-30.
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.
Miller M. Phase I cancer trials: a crucible of competing priorities. Int Anesthesiol Clin 2001;39:13-33.
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.
Sekine I, Yamamoto N, Kunitoh H, et al. Relationship between objective responses in phase I trials and potential efficacy of non-specific cytotoxic investigational new drugs. Ann Oncol 2002;13:1300-1306.
Meropol NJ, Weinfurt KP, Burnett CB, et al. Perceptions of patients and physicians regarding phase I cancer clinical trials: implications for physician-patient communication. J Clin Oncol 2003;21:2589-2596.
Choi H, Charnsangavej C, Macapinlac HA, et al. Correlation of computerized tomography (CT) and positron emission tomography (PET) in patients with metastatic GIST treated at a single institution with imatinib mesylate. Prog Proc Am Soc Clin Oncol 2003;22:819. abstract.
Agrawal M, Emanuel EJ. Ethics of phase 1 oncology studies: reexamining the arguments and data. JAMA 2003;290:1075-1082.
Daugherty CK, Ratain MJ, Minami H, et al. Study of cohort-specific consent and patient control in phase I cancer trials. J Clin Oncol 1998;16:2305-2312.
Sateren WB, Trimble EL, Abrams J, et al. How sociodemographics, presence of oncology specialists, and hospital cancer programs affect accrual to cancer treatment trials. J Clin Oncol 2002;20:2109-2117.
Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 2002;20:4420-4427.
Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-1037.(Razelle Kurzrock, M.D., a)
Investigations of anticancer drugs follow a characteristic path: in vitro experiments are followed by studies in animals, and then there is a preliminary clinical introduction in patients with cancer — the phase 1 trial. Built on the phase 1 foundation, phase 2 studies are performed to determine the efficacy of the drug, and if they show a reasonable benefit, phase 3 trials are conducted to compare the new drug with one or more conventional treatments. A demonstration that the new agent is efficacious and safe in a phase 3 trial often leads to its approval by the Food and Drug Administration (FDA).
Phase 1 trials are closely scrutinized, and their ethics debated, because of the many unknown factors that participants in the trials face and because of the critical role the trials have in the development of new cancer treatments. In this issue of the Journal, Horstmann et al.2 point out that phase 1 trials are often referred to as first-in-human studies, but actually these trials are considerably more heterogeneous than that term indicates. In addition to testing investigational drugs, phase 1 trials assess new combinations or dosing schedules, or both, of FDA-approved drugs. The expectations differ in regard to the risks and benefits associated with each of these types of trials. The unknown factors involved in a first-in-human trial with a new drug are much greater than are any unforeseen outcomes in a trial of an investigational drug and an FDA-approved drug or a new combination of two approved drugs. Furthermore, a drug that is used in the clinic for the first time has no track record of benefit, in contrast with FDA-approved medications.
An often-repeated misconception is that the sole function of phase 1 trials is to find the right dose and to assess toxicity — that evaluation of clinical responses is not an objective.3 It is true that the design of phase 1 trials generally precludes the statistical assessment of response rates, but we and other investigators engaged in phase 1 trials think that describing responses is important. Indeed, almost all new anticancer agents approved in recent years by the FDA brought about objective clinical responses among patients in phase 1 trials.4,5 For this reason, the hope for a benefit from phase 1 trials that patients (and their physicians) have is not discordant with the objectives of these trials. Our own experience and the literature on the topic6 support this view. Even so, the ethics associated with phase 1 trials have been questioned,3 in part because the prospect for improvement is perceived as low (overall response rate, 4 to 6 percent) and in part because of the risk of irreversible harm (death rate, 0.5 percent).4,5 These numbers do not, however, represent all phase 1 trials but derive from reviews of only single-agent studies.
In contrast with prior analyses of phase 1 trials, Horstmann et al. reviewed the full spectrum of such trials — a total of 460, involving 11,935 participants — conducted under the auspices of the National Cancer Institute, the major sponsor of phase 1 oncology trials in the United States. Instead of restricting themselves to conventional measures of outcome (i.e., complete or partial remission), the authors also assessed the data on stable disease. They made several key observations. Whereas the toxicity-related death rate, as in prior analyses, was about 0.5 percent, the overall response rate of 10.6 percent was higher than that previously reported. Furthermore, an additional 34.1 percent of patients had either stable disease or a "less-than-partial" response. From this perspective, then, 44.7 percent of participants derived a benefit, since all patients had to have progressive cancer to qualify for a phase 1 trial.
These results are not inconsequential. The importance of stable disease or minimal regression has increased substantially, as exemplified by the use of imatinib mesylate in the treatment of gastrointestinal stromal tumors. Patients with minimal regression or decreased tumor density, as seen on computed tomography (i.e., stable disease according to standard criteria), had remarkable clinical improvement, prolonged progression-free survival, and responses, as measured by positron-emission tomography, that were equivalent to the responses seen in patients with a partial remission.7
Another key observation made by Horstmann and colleagues is that not all phase 1 trials are alike. One could use this fact to argue that trials with very low response rates — that is, phase 1 trials involving one investigational chemotherapeutic agent — trade on the hopes of a vulnerable population. But patients can differ from the critics in their thinking. Studies of this question indicate that most patients enrolled in a phase 1 trial hope they will benefit from it, but they understand that this outcome is unlikely.8 Our clinical experience with such patients — who often tell us that they have sought out a phase 1 trial, even if the chances of a response are small, because their quality of life is improved by "not giving up" — confirms this point. The intense lobbying efforts of activists for earlier access to experimental therapies for AIDS and breast cancer are further evidence that patients facing inevitable death may be less risk-averse than is the regulatory community.
Horstmann and colleagues also meticulously review the issue of serious toxicity in the protocols they studied. They found a treatment-related death rate of, at most, 0.49 percent. Since virtually all participants have a deadly disease (and, often, a rapidly fatal one) and have exhausted the conventional options for treatment, a toxicity-related death rate of less than 1 percent suggests to us that safety concerns should not stop these trials. Conservative starting doses and dose-escalation schemes must be considered as factors that account for the low death rate in these trials. The downside to this conservative approach may be a compromise in efficacy due to subtherapeutic doses. More aggressive dose escalation may therefore be preferable in the treatment of a lethal disease. Indeed, in a phase 1 trial that allowed fully informed patients to choose among doses of a therapeutic agent, 28 percent chose the highest available dose.9
Horstmann et al. did not investigate the role of clinical trials in children with incurable cancer. We already know that the proportion of pediatric patients with cancer who enter trials of any phase that are sponsored by the National Cancer Institute dwarfs the enrollment of adults (about 50 percent vs. 2 percent, respectively).10 Barriers to enrollment with advancing age may include the expectations of patients and their physicians, inadequate social support, coexisting illnesses, and financial or insurance constraints. The widespread participation of children in trials is believed to account, at least in part, for the marked improvement in the survival of children with cancer.
Phase 1 trials are crucial for the development of new cancer therapies. The scope of these trials continues to undergo expansion and refinement. End points now include determination of the dose for optimal modulation of the neoplastic target rather than just the highest dose tolerated by most patients. Indications of a response in specific cancers that arise during phase 1 trials serve as a major impetus for phase 2 efficacy studies.11 Several phase 1 trials have proved so pivotal that they have changed the landscape of cancer therapy. Perhaps the most striking example is the phase 1 trial of imatinib mesylate for the treatment of chronic myelogenous leukemia.12 This relatively nontoxic drug, which targets the molecular genetic defect that causes chronic myelogenous leukemia, yielded a 93 percent response rate in the phase 1 setting.12 This study was not included in the analysis by Horstmann et al., since it was not sponsored by the National Cancer Institute. For most phase 1 studies, the proportion of patients who benefit is considerably lower than in the imatinib mesylate trial, but the benefit-versus-risk ratio is, nevertheless, favorable.
Drs. Kurzrock and Benjamin report having received grant support from the National Institutes of Health and from pharmaceutical companies for the conduct of clinical trials.
Source Information
From the Phase I Program (R.K.) and the Department of Sarcoma Medical Oncology (R.S.B.), Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston.
References
Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10-30.
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.
Miller M. Phase I cancer trials: a crucible of competing priorities. Int Anesthesiol Clin 2001;39:13-33.
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.
Sekine I, Yamamoto N, Kunitoh H, et al. Relationship between objective responses in phase I trials and potential efficacy of non-specific cytotoxic investigational new drugs. Ann Oncol 2002;13:1300-1306.
Meropol NJ, Weinfurt KP, Burnett CB, et al. Perceptions of patients and physicians regarding phase I cancer clinical trials: implications for physician-patient communication. J Clin Oncol 2003;21:2589-2596.
Choi H, Charnsangavej C, Macapinlac HA, et al. Correlation of computerized tomography (CT) and positron emission tomography (PET) in patients with metastatic GIST treated at a single institution with imatinib mesylate. Prog Proc Am Soc Clin Oncol 2003;22:819. abstract.
Agrawal M, Emanuel EJ. Ethics of phase 1 oncology studies: reexamining the arguments and data. JAMA 2003;290:1075-1082.
Daugherty CK, Ratain MJ, Minami H, et al. Study of cohort-specific consent and patient control in phase I cancer trials. J Clin Oncol 1998;16:2305-2312.
Sateren WB, Trimble EL, Abrams J, et al. How sociodemographics, presence of oncology specialists, and hospital cancer programs affect accrual to cancer treatment trials. J Clin Oncol 2002;20:2109-2117.
Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 2002;20:4420-4427.
Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-1037.(Razelle Kurzrock, M.D., a)