Intraperitoneal Chemotherapy for Ovarian Cancer
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《新英格兰医药杂志》
To the Editor: Armstrong et al. (Jan. 5 issue)1 may have overestimated the benefit of intraperitoneal therapy in ovarian cancer, as compared with standard intravenous carboplatin plus paclitaxel. We undertook an exploratory cross-trial analysis (Figure 1) comparing intraperitoneal cisplatin plus paclitaxel in the patients in the study by Armstrong et al. with intravenous carboplatin plus paclitaxel in 392 patients with a similar stage of ovarian cancer in the previous study by the same cooperative group.2 In both studies, the median overall survival in the control group receiving intravenous cisplatin plus paclitaxel was similar: 49.7 months and 48.7 months, respectively. The median progression-free survival and overall survival among patients treated with carboplatin plus paclitaxel were 20.7 months and 57.4 months, respectively, as compared with 23.8 months and 65.6 months, respectively, among those treated with the intraperitoneal regimen.
Figure 1. Survival among Patients in the Study by Armstrong et al. Treated with Intraperitoneal Therapy or Intravenous Cisplatin plus Paclitaxel, as Compared with Those in the Study by Ozols et al. Treated with Intravenous Carboplatin plus Paclitaxel.
The area under the curve for carboplatin plus paclitaxel is 7.5. Data are from Armstrong et al.1 and Ozols et al.2
Instead of the 15.9-month improvement in median overall survival reported for intraperitoneal therapy,1 the difference might have been substantially less (8.2 months) if the comparison group had been treated with carboplatin and paclitaxel. There is no apparent difference in the shape of the actuarial survival curve or in survival at two and four years. Before intraperitoneal therapy was recommended for routine use by the alert from the National Cancer Institute,3 the treatment should have been prospectively compared with a safer, much less toxic regimen of intravenous carboplatin plus paclitaxel.
Robert F. Ozols, M.D., Ph.D.
Michael A. Bookman, M.D.
Robert C. Young, M.D.
Fox Chase Cancer Center
Philadelphia, PA 19111
robert.ozols@fccc.edu
References
Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34-43.
Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2003;21:3194-3200.
National Institutes of Health. NCI issues clinical announcement for preferred methods of treatment for advanced ovarian cancer. January 2006. (Accessed March 23, 2006, at http://www.nih.gov/news/pr/jan2006/nci-04.htm.)
To the Editor: Armstrong et al. report an impressive overall survival gain of 15.9 months for patients with optimally debulked stage III ovarian cancer who were treated with intraperitoneal chemotherapy. Remarkably, only 86 patients (42 percent) of 205 eligible patients assigned to intraperitoneal therapy completed six cycles of the treatment, and 98 patients (48 percent) received three or fewer cycles of the assigned chemotherapy. Since this regimen is toxic, it would be interesting to know whether overall survival, disease-free survival, or both were affected by the number of cycles of intraperitoneal chemotherapy administered.
Gilberto de Castro, Jr., M.D.
Igor M. Snitcovsky, M.D., Ph.D.
Miriam H.H. Federico, M.D., Ph.D.
Hospital das Clínicas da Faculdade de Medicina da Universidade de S?o Paulo
05403-001 S?o Paulo, Brazil
castrojrg@aol.com
The authors reply: We are aware of the exploratory retrospective analysis by Dr. Ozols and colleagues. It was a noninferiority study that found no statistically significant difference in overall or progression-free survival between the control group treated with intravenous cisplatin plus paclitaxel, which is identical to the control group in our study, and the group that received intravenous carboplatin plus paclitaxel, which they chose for comparison. Nonrandomized comparisons with historical controls, such as the study cited by Ozols et al., can be useful for exploratory analyses and for generating hypotheses, but they are not to be relied on to generate credible conclusions.1 We agree that less toxic therapies are preferable when clinical outcomes are equal; however, the 16-month improvement in survival seen with intraperitoneal therapy in our study is an important advance, not merely equivalence. For many patients with cancer, a gain in survival of six months is sufficient to justify an increase in the toxicity and inconvenience of therapy.2 The National Cancer Institute alert ensures that the data from trials of intraperitoneal therapy are available to women with ovarian cancer and their health care providers so that, together, they can determine whether intraperitoneal therapy is appropriate.
We agree with Dr. de Castro and colleagues that it would be of great interest to know whether survival was affected by the number of cycles of intraperitoneal therapy. Unfortunately, our study was not designed to answer this question. A comparison between the patients assigned to intraperitoneal therapy who received all six cycles of the assigned therapy and those who received fewer cycles would be valid only if disease status and response to treatment did not contribute to the failure to receive intraperitoneal therapy — an assumption that is potentially flawed.
Deborah K. Armstrong, M.D.
Johns Hopkins Kimmel Cancer Center
Baltimore, MD 21231
Brian Bundy, Ph.D.
Gynecologic Oncology Group Statistical and Data Center
Buffalo, NY 14263
Joan Walker, M.D.
University of Oklahoma
Oklahoma City, OK 73190
References
Theory and practice of clinical trials. In: Kufe DW, Pollock RE, Weichselbaum RR, Bast RC Jr, eds. Cancer medicine. 6th ed. Hamilton, Ont., Canada: B.C. Decker, 2003.
Duric V, Stockler M. Patients' preferences for adjuvant chemotherapy in early breast cancer: a review of what makes it worthwhile. Lancet Oncol 2001;2:691-697.
Figure 1. Survival among Patients in the Study by Armstrong et al. Treated with Intraperitoneal Therapy or Intravenous Cisplatin plus Paclitaxel, as Compared with Those in the Study by Ozols et al. Treated with Intravenous Carboplatin plus Paclitaxel.
The area under the curve for carboplatin plus paclitaxel is 7.5. Data are from Armstrong et al.1 and Ozols et al.2
Instead of the 15.9-month improvement in median overall survival reported for intraperitoneal therapy,1 the difference might have been substantially less (8.2 months) if the comparison group had been treated with carboplatin and paclitaxel. There is no apparent difference in the shape of the actuarial survival curve or in survival at two and four years. Before intraperitoneal therapy was recommended for routine use by the alert from the National Cancer Institute,3 the treatment should have been prospectively compared with a safer, much less toxic regimen of intravenous carboplatin plus paclitaxel.
Robert F. Ozols, M.D., Ph.D.
Michael A. Bookman, M.D.
Robert C. Young, M.D.
Fox Chase Cancer Center
Philadelphia, PA 19111
robert.ozols@fccc.edu
References
Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34-43.
Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2003;21:3194-3200.
National Institutes of Health. NCI issues clinical announcement for preferred methods of treatment for advanced ovarian cancer. January 2006. (Accessed March 23, 2006, at http://www.nih.gov/news/pr/jan2006/nci-04.htm.)
To the Editor: Armstrong et al. report an impressive overall survival gain of 15.9 months for patients with optimally debulked stage III ovarian cancer who were treated with intraperitoneal chemotherapy. Remarkably, only 86 patients (42 percent) of 205 eligible patients assigned to intraperitoneal therapy completed six cycles of the treatment, and 98 patients (48 percent) received three or fewer cycles of the assigned chemotherapy. Since this regimen is toxic, it would be interesting to know whether overall survival, disease-free survival, or both were affected by the number of cycles of intraperitoneal chemotherapy administered.
Gilberto de Castro, Jr., M.D.
Igor M. Snitcovsky, M.D., Ph.D.
Miriam H.H. Federico, M.D., Ph.D.
Hospital das Clínicas da Faculdade de Medicina da Universidade de S?o Paulo
05403-001 S?o Paulo, Brazil
castrojrg@aol.com
The authors reply: We are aware of the exploratory retrospective analysis by Dr. Ozols and colleagues. It was a noninferiority study that found no statistically significant difference in overall or progression-free survival between the control group treated with intravenous cisplatin plus paclitaxel, which is identical to the control group in our study, and the group that received intravenous carboplatin plus paclitaxel, which they chose for comparison. Nonrandomized comparisons with historical controls, such as the study cited by Ozols et al., can be useful for exploratory analyses and for generating hypotheses, but they are not to be relied on to generate credible conclusions.1 We agree that less toxic therapies are preferable when clinical outcomes are equal; however, the 16-month improvement in survival seen with intraperitoneal therapy in our study is an important advance, not merely equivalence. For many patients with cancer, a gain in survival of six months is sufficient to justify an increase in the toxicity and inconvenience of therapy.2 The National Cancer Institute alert ensures that the data from trials of intraperitoneal therapy are available to women with ovarian cancer and their health care providers so that, together, they can determine whether intraperitoneal therapy is appropriate.
We agree with Dr. de Castro and colleagues that it would be of great interest to know whether survival was affected by the number of cycles of intraperitoneal therapy. Unfortunately, our study was not designed to answer this question. A comparison between the patients assigned to intraperitoneal therapy who received all six cycles of the assigned therapy and those who received fewer cycles would be valid only if disease status and response to treatment did not contribute to the failure to receive intraperitoneal therapy — an assumption that is potentially flawed.
Deborah K. Armstrong, M.D.
Johns Hopkins Kimmel Cancer Center
Baltimore, MD 21231
Brian Bundy, Ph.D.
Gynecologic Oncology Group Statistical and Data Center
Buffalo, NY 14263
Joan Walker, M.D.
University of Oklahoma
Oklahoma City, OK 73190
References
Theory and practice of clinical trials. In: Kufe DW, Pollock RE, Weichselbaum RR, Bast RC Jr, eds. Cancer medicine. 6th ed. Hamilton, Ont., Canada: B.C. Decker, 2003.
Duric V, Stockler M. Patients' preferences for adjuvant chemotherapy in early breast cancer: a review of what makes it worthwhile. Lancet Oncol 2001;2:691-697.