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Intraperitoneal chemotherapy and the NCI clinical announcement
Gynecologic Oncology 103 (2006) S18 – S19 www.elsevier.com/locate/ygyno
Intraperitoneal chemotherapy and the NCI clinical announcement Edward L. Trimble a,⁎, Ronald D. Alvarez b a
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 02138, USA b Department of Obstetrics and Gynecology, University of Alabama, Birmingham 35249, USA Received 22 August 2006
This session was chaired by Gillian Thomas, Deborah Armstrong, and Edward L. Trimble with presentations by Ronald D. Alvarez and Jerry Collins Topics: Integrating IP/IV regimens into Phase III clinical trials for women with stage III disease, novel approaches, new agents and combinations
The survival results from GOG 172, a phase III trial comparing intravenous (IV) cisplatin and paclitaxel to IV paclitaxel and intraperitoneal (IP) cisplatin and paclitaxel in women with optimally debulked advanced stage ovarian cancer, were made available to GOG investigators at the semi-annual GOG meeting in January 2005 [1]. Based on these results, as well as those of six other phase III trials comparing IV chemotherapy to a combination of IV and IP chemotherapy, the NCI began deliberations concerning a possible Clinical Announcement regarding the benefit of IP chemotherapy in patients with optimally debulked advanced stage ovarian cancer later that month [2]. By September 2005, the publication of such a Clinical Announcement had been approved. Participants in the NCI-GOG Ovarian Cancer SOTS meeting, held in September of 2005, were thus aware of the primary outcome of GOG 172 as well as the impending NCI Clinical Announcement (distributed in January of 2006) [3]. The Ovarian Cancer SOTS discussion on intraperitoneal chemotherapy focused on unanswered questions related to IP chemotherapy in ovarian cancer; novel approaches to IP therapy; and optimal strategies to educate physicians, nurses, patients, and their families about IP chemotherapy. The varying experimental arms used in the phase III trials evaluating IP chemotherapy have not permitted the identification of one single regimen to recommend for standard clinical use. Another critical issue at present is how best to improve the therapeutic index of IV/IP chemotherapy. In most of the phase III ⁎ Corresponding author. Cancer Therapy Evaluation Program, National Cancer Institute, 6130 Executive Blvd., Ste. 741, MSC 7436, Bethesda, MD 20892, USA. Fax: +1 301 402 0557. E-mail address: [email protected] (E.L. Trimble). 0090-8258/$ - see front matter. Published by Elsevier Inc. doi:10.1016/j.ygyno.2006.08.020
trials cited in the Clinical Announcement, women on the experimental IV/IP arms experienced greater toxicities than the women on the control IV arms. As the Clinical Announcement noted, we know neither the optimal nor the minimal number of courses of IP chemotherapy to recommend. Data from GOG 172 suggested that even patients who only received one course of the recommended six courses of IP chemotherapy received clinical benefit. We do not know whether IP carboplatin might convey the same benefit as IP cisplatin with fewer side effects. In addition, GOG 172 was the only of the seven trials to use both IP platinum and taxanes, precluding the ability to definitively state that the derived clinical benefit occurred directly as a result of route of drug administration. At present, the GOG has proposed a randomized phase II trial, to evaluate the feasibility and toxicity associated with several different IV/IP platinum/taxane regimens, in preparation for a randomized phase III trial. Certain other drugs with known activity in ovarian cancer, such as gemcitabine and topotecan also have demonstrated an impressive peritoneal/plasma ratio when given IP [4]. We do not know, however, whether these drugs can be safely given via an IP route together with IP platinum and/or taxane, or whether the IP addition of these agents would improve survival. The recent presentation of the survival results from GOG 182, which found no survival benefit associated with the addition of IV gemcitabine, topotecan, or liposomal doxorubicin to an IV platinum/ taxane regimen, make the IP evaluation of these agents less compelling [5]. Other agents with potentially greater interest include novel taxanes, including the epothilones, as well as novel platinum analogues. Catheter technology and the management of IP catheters, also remain of critical importance [6]. The ideal IP catheter would have a decreased risk of adhesions and infection compared to
E.L. Trimble, R.D. Alvarez / Gynecologic Oncology 103 (2006) S18–S19
those available today. Nonetheless, the recent report by Makhija et al. suggests that, with ongoing institutional experience, the incidence of complications with IP catheters can be drastically reduced [7]. An IP approach has also been used to deliver experimental monoclonal antibodies and gene therapeutics to women with ovarian cancer. The potential benefits of an IP approach for these novel therapies include the opportunity to deliver these interventions directly to tumor implants within the abdominal cavity, as well as to assess the biologic effect of these agents by analyzing ascitic fluid or abdominal washings sampled before and after the intervention. Agents which have been investigated include tumor antigen targeting monoclonal antibodies (both unconjugated and conjugated), gene therapies delivering tumor suppressor genes, suicide based gene therapies, and virotherapy [8,9]. To date, none of these agents has yet demonstrated adequate efficacy to warrant utilization in routine clinical practice. In addition, we do not have safety data on the combination of various monoclonal antibody based immunotherapy or gene therapy approaches with standard IV and IP chemotherapy. The continued development of humanized monoclonal antibodies that target the molecular processes associated with malignant transformation of cells will certainly result in the realization of the full potential of IV and IP monoclonal antibody based immunotherapies in this disease context. In addition, the development of improved vector systems that result in enhanced target tumor transfection and selective therapeutic gene delivery or viral replication will provide for the IP application of gene therapeutics in patients affected by this disease. Another research question is the impact of IP chemotherapy upon the immunologic milieu of the peritoneal cavity. It is possible that the benefits of IP chemotherapy may arise from both the increased concentrations of drug in the abdominal cavity as well as a heightened immunologic response in the peritoneum. The chronic irritation of a foreign body, namely the IP catheter, as well as the acute irritation associated with the administration of IP chemotherapy may well affect IP cytokine expression and elicit humoral and cellular antitumor immune responses. Evaluation of the systemic and the compartmental immunologic responses to IP chemotherapy would seem appropriate. Several centers have also sought to combine IP chemotherapy with intraoperative IP hyperthermia. Preliminary studies suggest that IP chemotherapy can be combined safely with IP hyperthermia at the time of primary or secondary surgical cytoreduction [10,11]. To date, no phase III trials evaluating this approach have been undertaken, perhaps due to the small number of centers with necessary expertise and equipment. The process underlying the NCI's Clinical Announcement regarding the potential benefit of IP chemotherapy among women with optimally debulked ovarian cancer has been outlined elsewhere. (2) As noted above, the physicians and patient advocates participating in the Ovarian Cancer SOTS emphasized the importance of professional and lay education
S19
about IP chemotherapy. This should include the critical role of primary surgical staging and optimal cytoreduction, placement of IP catheters, selection of patients for IP chemotherapy, administration of IP chemotherapy, and management of toxicities associated with IP chemotherapy. We should note that since the publication of the NCI Clinical Announcement extensive information regarding IP chemotherapy has been posted on the NCI and GOG websites with the generous assistance of many GOG physicians and nurses. The participants in the SOTS also stressed the importance of working with professional societies and ovarian cancer advocacy groups to promote the Clinical Announcement. The January 5, 2006, Clinical Announcement was, in fact, jointly issued by the GOG, NCI, Gynecologic Cancer Foundation, Oncology Nursing Society, Society of Gynecologic Oncologists, and the Society of Gynecologic Nurse Oncologists. Finally, evaluation of the Clinical Announcement's impact upon clinical practice will require thoughtful review of large databases capturing the appropriate details of cancer care. Potential sources include the National Comprehensive Cancer Network (NCCN), which links 20 of the NCI-designated clinical and comprehensive cancer centers, the Cancer Research Network, a research consortium of several large HMOs, the American College of Surgeons Commission on Cancer National Cancer Database, and the SEER/Medicare linkage. The NCCN, for example, may be able to document the use of IP chemotherapy among “early adopters” while the CRN, NCDB, and SEER/Medicare may be able to demonstrate adoption, or lack thereof, in community settings. Dissemination and diffusion of research findings into standard oncology practice remain a critical part of the National Cancer Program of the United States. References [1] Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34–43. [2] Trimble E, Christian M. Intraperitoneal chemotherapy for women with advanced epithelial ovarian carcinoma. Gynecol Oncol 2006;100:3–4. [3] www.cancer.gov. [4] Muggia F, Kosloff R. Investigational agents for epithelial ovarian cancer. Expert Rev Anticancer Ther 2005;5:855–68. [5] Bookman M. et al. [6] Walker JL, Armstrong D, Huang HQ, et al. Intraperitoneal catheter outcomes in a phase III trial of intravenous versus intraperitoneal chemotherapy in optimal stage III ovarian and primary peritoneal cancer: a Gynecologic Oncology Group study. Gynecol Oncol 2006;100:27–32. [7] Makhija S, Leitao M, Sabbatini P, et al. Complications associated with intraperitoneal chemotherapy catheters. Gynecol Oncol 2001;81:77–81. [8] Bhoola SM, Alvarez RD. Novel therapies for recurrent ovarian cancer management. Expert Rev Anticancer Ther 2004;4:437–48. [9] Wolf JK, Jenkins AD. Gene therapy for ovarian cancer (review). Int J Oncol 2002;21:461–8. [10] Yoshida Y, Sasaki H, Kurokawa T, et al. Efficacy of intraperitoneal continuous hyperthermic chemotherapy as consolidation therapy in patients with advanced epithelial ovarian cancer: a long-term follow-up. Oncol Rep 2005;13:121–5. [11] Gori J, Castano R, Toziano M, et al. Intraperitoneal hyperthermic chemotherapy in ovarian cancer. Int J Gynecol Cancer 2005;15:233–9.
Intraperitoneal chemotherapy and the NCI clinical announcement Edward L. Trimble a,⁎, Ronald D. Alvarez b a
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 02138, USA b Department of Obstetrics and Gynecology, University of Alabama, Birmingham 35249, USA Received 22 August 2006
This session was chaired by Gillian Thomas, Deborah Armstrong, and Edward L. Trimble with presentations by Ronald D. Alvarez and Jerry Collins Topics: Integrating IP/IV regimens into Phase III clinical trials for women with stage III disease, novel approaches, new agents and combinations
The survival results from GOG 172, a phase III trial comparing intravenous (IV) cisplatin and paclitaxel to IV paclitaxel and intraperitoneal (IP) cisplatin and paclitaxel in women with optimally debulked advanced stage ovarian cancer, were made available to GOG investigators at the semi-annual GOG meeting in January 2005 [1]. Based on these results, as well as those of six other phase III trials comparing IV chemotherapy to a combination of IV and IP chemotherapy, the NCI began deliberations concerning a possible Clinical Announcement regarding the benefit of IP chemotherapy in patients with optimally debulked advanced stage ovarian cancer later that month [2]. By September 2005, the publication of such a Clinical Announcement had been approved. Participants in the NCI-GOG Ovarian Cancer SOTS meeting, held in September of 2005, were thus aware of the primary outcome of GOG 172 as well as the impending NCI Clinical Announcement (distributed in January of 2006) [3]. The Ovarian Cancer SOTS discussion on intraperitoneal chemotherapy focused on unanswered questions related to IP chemotherapy in ovarian cancer; novel approaches to IP therapy; and optimal strategies to educate physicians, nurses, patients, and their families about IP chemotherapy. The varying experimental arms used in the phase III trials evaluating IP chemotherapy have not permitted the identification of one single regimen to recommend for standard clinical use. Another critical issue at present is how best to improve the therapeutic index of IV/IP chemotherapy. In most of the phase III ⁎ Corresponding author. Cancer Therapy Evaluation Program, National Cancer Institute, 6130 Executive Blvd., Ste. 741, MSC 7436, Bethesda, MD 20892, USA. Fax: +1 301 402 0557. E-mail address: [email protected] (E.L. Trimble). 0090-8258/$ - see front matter. Published by Elsevier Inc. doi:10.1016/j.ygyno.2006.08.020
trials cited in the Clinical Announcement, women on the experimental IV/IP arms experienced greater toxicities than the women on the control IV arms. As the Clinical Announcement noted, we know neither the optimal nor the minimal number of courses of IP chemotherapy to recommend. Data from GOG 172 suggested that even patients who only received one course of the recommended six courses of IP chemotherapy received clinical benefit. We do not know whether IP carboplatin might convey the same benefit as IP cisplatin with fewer side effects. In addition, GOG 172 was the only of the seven trials to use both IP platinum and taxanes, precluding the ability to definitively state that the derived clinical benefit occurred directly as a result of route of drug administration. At present, the GOG has proposed a randomized phase II trial, to evaluate the feasibility and toxicity associated with several different IV/IP platinum/taxane regimens, in preparation for a randomized phase III trial. Certain other drugs with known activity in ovarian cancer, such as gemcitabine and topotecan also have demonstrated an impressive peritoneal/plasma ratio when given IP [4]. We do not know, however, whether these drugs can be safely given via an IP route together with IP platinum and/or taxane, or whether the IP addition of these agents would improve survival. The recent presentation of the survival results from GOG 182, which found no survival benefit associated with the addition of IV gemcitabine, topotecan, or liposomal doxorubicin to an IV platinum/ taxane regimen, make the IP evaluation of these agents less compelling [5]. Other agents with potentially greater interest include novel taxanes, including the epothilones, as well as novel platinum analogues. Catheter technology and the management of IP catheters, also remain of critical importance [6]. The ideal IP catheter would have a decreased risk of adhesions and infection compared to
E.L. Trimble, R.D. Alvarez / Gynecologic Oncology 103 (2006) S18–S19
those available today. Nonetheless, the recent report by Makhija et al. suggests that, with ongoing institutional experience, the incidence of complications with IP catheters can be drastically reduced [7]. An IP approach has also been used to deliver experimental monoclonal antibodies and gene therapeutics to women with ovarian cancer. The potential benefits of an IP approach for these novel therapies include the opportunity to deliver these interventions directly to tumor implants within the abdominal cavity, as well as to assess the biologic effect of these agents by analyzing ascitic fluid or abdominal washings sampled before and after the intervention. Agents which have been investigated include tumor antigen targeting monoclonal antibodies (both unconjugated and conjugated), gene therapies delivering tumor suppressor genes, suicide based gene therapies, and virotherapy [8,9]. To date, none of these agents has yet demonstrated adequate efficacy to warrant utilization in routine clinical practice. In addition, we do not have safety data on the combination of various monoclonal antibody based immunotherapy or gene therapy approaches with standard IV and IP chemotherapy. The continued development of humanized monoclonal antibodies that target the molecular processes associated with malignant transformation of cells will certainly result in the realization of the full potential of IV and IP monoclonal antibody based immunotherapies in this disease context. In addition, the development of improved vector systems that result in enhanced target tumor transfection and selective therapeutic gene delivery or viral replication will provide for the IP application of gene therapeutics in patients affected by this disease. Another research question is the impact of IP chemotherapy upon the immunologic milieu of the peritoneal cavity. It is possible that the benefits of IP chemotherapy may arise from both the increased concentrations of drug in the abdominal cavity as well as a heightened immunologic response in the peritoneum. The chronic irritation of a foreign body, namely the IP catheter, as well as the acute irritation associated with the administration of IP chemotherapy may well affect IP cytokine expression and elicit humoral and cellular antitumor immune responses. Evaluation of the systemic and the compartmental immunologic responses to IP chemotherapy would seem appropriate. Several centers have also sought to combine IP chemotherapy with intraoperative IP hyperthermia. Preliminary studies suggest that IP chemotherapy can be combined safely with IP hyperthermia at the time of primary or secondary surgical cytoreduction [10,11]. To date, no phase III trials evaluating this approach have been undertaken, perhaps due to the small number of centers with necessary expertise and equipment. The process underlying the NCI's Clinical Announcement regarding the potential benefit of IP chemotherapy among women with optimally debulked ovarian cancer has been outlined elsewhere. (2) As noted above, the physicians and patient advocates participating in the Ovarian Cancer SOTS emphasized the importance of professional and lay education
S19
about IP chemotherapy. This should include the critical role of primary surgical staging and optimal cytoreduction, placement of IP catheters, selection of patients for IP chemotherapy, administration of IP chemotherapy, and management of toxicities associated with IP chemotherapy. We should note that since the publication of the NCI Clinical Announcement extensive information regarding IP chemotherapy has been posted on the NCI and GOG websites with the generous assistance of many GOG physicians and nurses. The participants in the SOTS also stressed the importance of working with professional societies and ovarian cancer advocacy groups to promote the Clinical Announcement. The January 5, 2006, Clinical Announcement was, in fact, jointly issued by the GOG, NCI, Gynecologic Cancer Foundation, Oncology Nursing Society, Society of Gynecologic Oncologists, and the Society of Gynecologic Nurse Oncologists. Finally, evaluation of the Clinical Announcement's impact upon clinical practice will require thoughtful review of large databases capturing the appropriate details of cancer care. Potential sources include the National Comprehensive Cancer Network (NCCN), which links 20 of the NCI-designated clinical and comprehensive cancer centers, the Cancer Research Network, a research consortium of several large HMOs, the American College of Surgeons Commission on Cancer National Cancer Database, and the SEER/Medicare linkage. The NCCN, for example, may be able to document the use of IP chemotherapy among “early adopters” while the CRN, NCDB, and SEER/Medicare may be able to demonstrate adoption, or lack thereof, in community settings. Dissemination and diffusion of research findings into standard oncology practice remain a critical part of the National Cancer Program of the United States. References [1] Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34–43. [2] Trimble E, Christian M. Intraperitoneal chemotherapy for women with advanced epithelial ovarian carcinoma. Gynecol Oncol 2006;100:3–4. [3] www.cancer.gov. [4] Muggia F, Kosloff R. Investigational agents for epithelial ovarian cancer. Expert Rev Anticancer Ther 2005;5:855–68. [5] Bookman M. et al. [6] Walker JL, Armstrong D, Huang HQ, et al. Intraperitoneal catheter outcomes in a phase III trial of intravenous versus intraperitoneal chemotherapy in optimal stage III ovarian and primary peritoneal cancer: a Gynecologic Oncology Group study. Gynecol Oncol 2006;100:27–32. [7] Makhija S, Leitao M, Sabbatini P, et al. Complications associated with intraperitoneal chemotherapy catheters. Gynecol Oncol 2001;81:77–81. [8] Bhoola SM, Alvarez RD. Novel therapies for recurrent ovarian cancer management. Expert Rev Anticancer Ther 2004;4:437–48. [9] Wolf JK, Jenkins AD. Gene therapy for ovarian cancer (review). Int J Oncol 2002;21:461–8. [10] Yoshida Y, Sasaki H, Kurokawa T, et al. Efficacy of intraperitoneal continuous hyperthermic chemotherapy as consolidation therapy in patients with advanced epithelial ovarian cancer: a long-term follow-up. Oncol Rep 2005;13:121–5. [11] Gori J, Castano R, Toziano M, et al. Intraperitoneal hyperthermic chemotherapy in ovarian cancer. Int J Gynecol Cancer 2005;15:233–9.