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Intraperitoneal chemotherapy for ovarian cancer: 2009 goals
Gynecologic Oncology 112 (2009) 439–440
Contents lists available at ScienceDirect
Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y g y n o
Editorial
Intraperitoneal chemotherapy for ovarian cancer: 2009 goals
In spite of the publication by the Gynecologic Oncology Group (GOG) in January 2006 of the landmark clinical trial, GOG 172 [1], with paclitaxel 135 mg/m2 IV over 24 h, followed day 2 with cisplatin 100 mg/m2 IP and day 8 paclitaxel 60 mg/m2 IP, showing a significant improvement in survival over an intravenous approach, IP therapy has not gained widespread acceptance in the oncology community. The remarkable overall median survival of 65.6 months was 16 months longer with the IP arm than the IV control arm. It appears the toxicity and difficulty in administering the IP regimen outweighed any survival benefit in the minds of treating physicians. The appropriate drugs, doses, schedule, and indications for intraperitoneal chemotherapy remain an area of controversy since the publication. In order for IP therapy to become accepted, we need to establish a regimen with acceptable toxicity, which preserves the survival advantage. Looking into the future of IP chemotherapy, we must understand what has transpired since the publication of the GOG IP regimen. In an attempt to optimize the IP regimen and make it acceptable to patients and oncologists by decreasing toxicity and preserving survival, the following areas were considered by the GOG: (1) the benefit vs. toxicity of day 8 IP paclitaxel; (2) the toxicity differences of delivery cisplatin on the day following the paclitaxel compared to the convenience of same-day delivery; (3) the toxicity and efficacy of reducing the cisplatin dose; and (4) the toxicity benefit vs. the potential reduced disease free interval with IP carboplatin compared to IP cisplatin. Valid concerns are raised by reducing the paclitaxel infusion to 3 h and giving the intraperitoneal cisplatin on the same day as an outpatient. Paclitaxel infusion of 175 mg/m2 over 3 h has been shown to be equivalent to 24-h paclitaxel infusion of 135 mg/m2 in platinum regimens (GOG-0158), although there is increased neurotoxicity with cisplatin, especially given on the same day. However, giving cisplatin via the intraperitoneal route on the same day may prove acceptable and tolerable since systemic absorption of cisplatin is delayed due to the pharmacokinetics of intraperitoneal administration. A possible benefit of reducing the paclitaxel regimen to 3 h is reduction of myelotoxicity. Metabolic and renal complications of cisplatin can be ameliorated by appropriate pre- and post-hydration and urinary output monitoring along with reducing the dose of intraperitoneal cisplatin to 75 mg/m2. Neurotoxicity may also be reduced by cisplatin dose reduction to 75 mg/m2. Dose response studies with cisplatin have not shown major differences in outcome in the 50–100 mg/m2 range when given intravenously. Toxicity may be reduced by replacing cisplatin with carboplatin. However, the efficacy of carboplatin given IP has not been compared to cisplatin. The GOG initiated a series of phase I/II trials to establish experimental arms for a new IP clinical trial; due to limitations of accrual, the ideal five arm trial is not feasible and three arms had to be chosen. The approved, but not yet enrolling GOG IP protocol will then progress from GOG 218 (assuming a positive result) to test the 0090-8258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2009.01.007
addition of bevacizumab to IP chemotherapy with careful attention to toxicity as well as survival. It includes an intravenous carboplatin/ paclitaxel arm as a control and two experimental arms: one substituting IP carboplatin for cisplatin and dropping day 8 paclitaxel and the other using a dose reduction of IP cisplatin with 3-h paclitaxel infusion and preserving day 8 IP paclitaxel. REGIMEN I: TJIV paclitaxel 175 mg/m2 IV over 3 h on day 1. Carboplatin AUC 6 IV on day 1 Repeated every 3 weeks for 6 cycles And bevacizumab 15 mg/kg IV during chemotherapy cycles 2–6 Followed by bevacizumab 15 mg/kg IV every 3 weeks, cycles 7–22 after completion of chemotherapy REGIMEN II: TJIP paclitaxel 175 mg/m2 IV over 3 h on day 1. Carboplatin AUC 6 IP on day 1 Repeated every 3 weeks for 6 cycles And bevacizumab 15 mg/kg IV during chemotherapy cycles 2–6 Followed by bevacizumab 15 mg/kg IV every 3 weeks, cycles 7–22 after completion of chemotherapy REGIMEN III: TCTIP paclitaxel 135 mg/m2 IV over 3 h on day 1 Cisplatin 75 mg/m/2 IP on day 2 Paclitaxel 60 mg/m2 IP on day 8 Repeated every 3 weeks for 6 cycles And bevacizumab 15 mg/kg IV during chemotherapy cycles 2–6 Followed by bevacizumab 15 mg/kg, cycles 7–22 after completion of chemotherapy The primary endpoint of this trial will be progression-free survival of optimal Stage II and III ovarian cancer patients. Considering the fact that only 42% of participants completed six cycles of the IP arm of GOG 172, it is conceivable that these modified regimens will have a superior survival result if we achieve 90% completion rates. The addition of bevacizumab is expected to be well tolerated based on a number of phase I trials without evidence of concern for excessive bowel complications. This trial will again determine whether the survival advantage of the IP route of administration of chemotherapy is important enough, in the era of targeted agents, to overcome the toxicity and challenges of IP administration. The two lead articles in this journal are examples of innovations in delivering intraperitoneal chemotherapy. Neither demonstrates an advance for women with ovarian cancer. The study by Tiersten et al. [2] tries to improve the outcomes of a poor prognosis population. They use neoadjuvant chemotherapy with IV carboplatin and paclitaxel for three cycles, followed by optimal cytoreduction, and then
440
Editorial
chemotherapy with IP carboplatin and IV paclitaxel for six cycles. Unfortunately, out of 58 eligible patients enrolled, only 26 received IP chemotherapy and only 18 completed the entire planned treatment. The median survival is 32 months for all 58 patients and only 34 months, post-interval debulking, for those 26 who received IP chemotherapy. It appears that interval debulking and IP carboplatin, at least at an AUC of 5, are not remarkably improving survival in this poor prognosis population. The report by Chin et al. [3] had modest goals; they wanted to demonstrate that the NCI Clinical Announcement, advising the use of IP cisplatin for ovarian cancer, could be put into practice as an outpatient, all on 1 day, and at low cost. Unfortunately, they were not able to adequately follow NCCN recommendations for prevention of nausea and vomiting and had to resort to home IV hydration to overcome nausea, vomiting, and dehydration with their protocol [4,5]. Flexibility was permitted at physician discretion and 27% of patients receiving 100 mg/m2 of cisplatin had a dose reduction, and 21% began at the lower dose. They did not use the day-8 paclitaxel IP but still demonstrated a 57% peripheral neuropathy rate during treatment. It decreased to 11 of 47 (23%) residual neuropathy in the follow-up. Today, for patients not on a clinical trial, it continues to be important to use the best regimen determined by the scientific process. The new NCCN guidelines for the prevention of nausea and vomiting, when administering cisplatin, help make the GOG 172 IP regimen feasible, as long as there is careful attention to saline hydration pre- and post-IP administration of cisplatin, and there is advanced nursing training. Carboplatin should not be substituted for IP cisplatin at this time off study, since we do not have adequate randomized trials. In summary, our specialty has a lot of work to do.
We must ask our patients to participate in clinical trials and get them opened and completed quickly to improve the survival and quality of life of women with ovarian cancer. Also, we must work to prevent ovarian cancer, teach physicians and the public to recognize signs and symptoms for earlier detection, and demand that patients get optimal surgical cytoreduction by a gynecologic oncologist. 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] Tiersten A, Liu PY, Smith H, et al. Phase II evaluation of neoadjuvant chemotherapy and debulking followed by intraperitoneal chemotherapy in women with stage III and IV epithelial ovarian, fallopian tube or primary peritoneal cancer: Southwest Oncology Group Study S0009. Gynecol Oncol 2009;112:442–7. [3] Chin S, Pinto V, Rosen B, et al. Evaluation of an intraperitoneal chemotherapy program implemented at the Princess Margaret Hospital for patients with epithelial ovarian carcinoma. Gynecol Oncol 2009;112:448–52. [4] Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology Guideline for Antiemetics in Oncology: Update 2006. Gynecol Oncol 2006;24(18): 2932–47 and 5341–42. [5] National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology Antiemesis. V.2.2009. bhttp://www.nccn.org/professionals/physician_gls/PDF/antiemesis. pdfN, accessed 02/11/09.
Joan L. Walker Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, P.O. Box 26901, WP 2410, Oklahoma City, OK 73190, USA E-mail address: [email protected].
19 January 2009
Contents lists available at ScienceDirect
Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y g y n o
Editorial
Intraperitoneal chemotherapy for ovarian cancer: 2009 goals
In spite of the publication by the Gynecologic Oncology Group (GOG) in January 2006 of the landmark clinical trial, GOG 172 [1], with paclitaxel 135 mg/m2 IV over 24 h, followed day 2 with cisplatin 100 mg/m2 IP and day 8 paclitaxel 60 mg/m2 IP, showing a significant improvement in survival over an intravenous approach, IP therapy has not gained widespread acceptance in the oncology community. The remarkable overall median survival of 65.6 months was 16 months longer with the IP arm than the IV control arm. It appears the toxicity and difficulty in administering the IP regimen outweighed any survival benefit in the minds of treating physicians. The appropriate drugs, doses, schedule, and indications for intraperitoneal chemotherapy remain an area of controversy since the publication. In order for IP therapy to become accepted, we need to establish a regimen with acceptable toxicity, which preserves the survival advantage. Looking into the future of IP chemotherapy, we must understand what has transpired since the publication of the GOG IP regimen. In an attempt to optimize the IP regimen and make it acceptable to patients and oncologists by decreasing toxicity and preserving survival, the following areas were considered by the GOG: (1) the benefit vs. toxicity of day 8 IP paclitaxel; (2) the toxicity differences of delivery cisplatin on the day following the paclitaxel compared to the convenience of same-day delivery; (3) the toxicity and efficacy of reducing the cisplatin dose; and (4) the toxicity benefit vs. the potential reduced disease free interval with IP carboplatin compared to IP cisplatin. Valid concerns are raised by reducing the paclitaxel infusion to 3 h and giving the intraperitoneal cisplatin on the same day as an outpatient. Paclitaxel infusion of 175 mg/m2 over 3 h has been shown to be equivalent to 24-h paclitaxel infusion of 135 mg/m2 in platinum regimens (GOG-0158), although there is increased neurotoxicity with cisplatin, especially given on the same day. However, giving cisplatin via the intraperitoneal route on the same day may prove acceptable and tolerable since systemic absorption of cisplatin is delayed due to the pharmacokinetics of intraperitoneal administration. A possible benefit of reducing the paclitaxel regimen to 3 h is reduction of myelotoxicity. Metabolic and renal complications of cisplatin can be ameliorated by appropriate pre- and post-hydration and urinary output monitoring along with reducing the dose of intraperitoneal cisplatin to 75 mg/m2. Neurotoxicity may also be reduced by cisplatin dose reduction to 75 mg/m2. Dose response studies with cisplatin have not shown major differences in outcome in the 50–100 mg/m2 range when given intravenously. Toxicity may be reduced by replacing cisplatin with carboplatin. However, the efficacy of carboplatin given IP has not been compared to cisplatin. The GOG initiated a series of phase I/II trials to establish experimental arms for a new IP clinical trial; due to limitations of accrual, the ideal five arm trial is not feasible and three arms had to be chosen. The approved, but not yet enrolling GOG IP protocol will then progress from GOG 218 (assuming a positive result) to test the 0090-8258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2009.01.007
addition of bevacizumab to IP chemotherapy with careful attention to toxicity as well as survival. It includes an intravenous carboplatin/ paclitaxel arm as a control and two experimental arms: one substituting IP carboplatin for cisplatin and dropping day 8 paclitaxel and the other using a dose reduction of IP cisplatin with 3-h paclitaxel infusion and preserving day 8 IP paclitaxel. REGIMEN I: TJIV paclitaxel 175 mg/m2 IV over 3 h on day 1. Carboplatin AUC 6 IV on day 1 Repeated every 3 weeks for 6 cycles And bevacizumab 15 mg/kg IV during chemotherapy cycles 2–6 Followed by bevacizumab 15 mg/kg IV every 3 weeks, cycles 7–22 after completion of chemotherapy REGIMEN II: TJIP paclitaxel 175 mg/m2 IV over 3 h on day 1. Carboplatin AUC 6 IP on day 1 Repeated every 3 weeks for 6 cycles And bevacizumab 15 mg/kg IV during chemotherapy cycles 2–6 Followed by bevacizumab 15 mg/kg IV every 3 weeks, cycles 7–22 after completion of chemotherapy REGIMEN III: TCTIP paclitaxel 135 mg/m2 IV over 3 h on day 1 Cisplatin 75 mg/m/2 IP on day 2 Paclitaxel 60 mg/m2 IP on day 8 Repeated every 3 weeks for 6 cycles And bevacizumab 15 mg/kg IV during chemotherapy cycles 2–6 Followed by bevacizumab 15 mg/kg, cycles 7–22 after completion of chemotherapy The primary endpoint of this trial will be progression-free survival of optimal Stage II and III ovarian cancer patients. Considering the fact that only 42% of participants completed six cycles of the IP arm of GOG 172, it is conceivable that these modified regimens will have a superior survival result if we achieve 90% completion rates. The addition of bevacizumab is expected to be well tolerated based on a number of phase I trials without evidence of concern for excessive bowel complications. This trial will again determine whether the survival advantage of the IP route of administration of chemotherapy is important enough, in the era of targeted agents, to overcome the toxicity and challenges of IP administration. The two lead articles in this journal are examples of innovations in delivering intraperitoneal chemotherapy. Neither demonstrates an advance for women with ovarian cancer. The study by Tiersten et al. [2] tries to improve the outcomes of a poor prognosis population. They use neoadjuvant chemotherapy with IV carboplatin and paclitaxel for three cycles, followed by optimal cytoreduction, and then
440
Editorial
chemotherapy with IP carboplatin and IV paclitaxel for six cycles. Unfortunately, out of 58 eligible patients enrolled, only 26 received IP chemotherapy and only 18 completed the entire planned treatment. The median survival is 32 months for all 58 patients and only 34 months, post-interval debulking, for those 26 who received IP chemotherapy. It appears that interval debulking and IP carboplatin, at least at an AUC of 5, are not remarkably improving survival in this poor prognosis population. The report by Chin et al. [3] had modest goals; they wanted to demonstrate that the NCI Clinical Announcement, advising the use of IP cisplatin for ovarian cancer, could be put into practice as an outpatient, all on 1 day, and at low cost. Unfortunately, they were not able to adequately follow NCCN recommendations for prevention of nausea and vomiting and had to resort to home IV hydration to overcome nausea, vomiting, and dehydration with their protocol [4,5]. Flexibility was permitted at physician discretion and 27% of patients receiving 100 mg/m2 of cisplatin had a dose reduction, and 21% began at the lower dose. They did not use the day-8 paclitaxel IP but still demonstrated a 57% peripheral neuropathy rate during treatment. It decreased to 11 of 47 (23%) residual neuropathy in the follow-up. Today, for patients not on a clinical trial, it continues to be important to use the best regimen determined by the scientific process. The new NCCN guidelines for the prevention of nausea and vomiting, when administering cisplatin, help make the GOG 172 IP regimen feasible, as long as there is careful attention to saline hydration pre- and post-IP administration of cisplatin, and there is advanced nursing training. Carboplatin should not be substituted for IP cisplatin at this time off study, since we do not have adequate randomized trials. In summary, our specialty has a lot of work to do.
We must ask our patients to participate in clinical trials and get them opened and completed quickly to improve the survival and quality of life of women with ovarian cancer. Also, we must work to prevent ovarian cancer, teach physicians and the public to recognize signs and symptoms for earlier detection, and demand that patients get optimal surgical cytoreduction by a gynecologic oncologist. 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] Tiersten A, Liu PY, Smith H, et al. Phase II evaluation of neoadjuvant chemotherapy and debulking followed by intraperitoneal chemotherapy in women with stage III and IV epithelial ovarian, fallopian tube or primary peritoneal cancer: Southwest Oncology Group Study S0009. Gynecol Oncol 2009;112:442–7. [3] Chin S, Pinto V, Rosen B, et al. Evaluation of an intraperitoneal chemotherapy program implemented at the Princess Margaret Hospital for patients with epithelial ovarian carcinoma. Gynecol Oncol 2009;112:448–52. [4] Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology Guideline for Antiemetics in Oncology: Update 2006. Gynecol Oncol 2006;24(18): 2932–47 and 5341–42. [5] National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology Antiemesis. V.2.2009. bhttp://www.nccn.org/professionals/physician_gls/PDF/antiemesis. pdfN, accessed 02/11/09.
Joan L. Walker Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, P.O. Box 26901, WP 2410, Oklahoma City, OK 73190, USA E-mail address: [email protected].
19 January 2009