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Originally published as JCO Early Release 10.1200/JCO.2007.12.1723 on August 13 2007 © 2007 American Society of Clinical Oncology.
Ovarian Cancer: Is Dose Intensity Dead?
Fox Chase Cancer Center, Philadelphia, PA Twenty years ago, Levin and Hryniuk1 published an article in the Journal of Clinical Oncology entitled "Dose Intensity Analysis of Chemotherapy Regimens in Ovarian Cancer." This retrospective analysis of the relationship between outcome and dose intensity in advanced ovarian cancer suggested that dose intensity was a major determinant of survival. While this was not the first article to suggest that high-dose therapy was important in ovarian cancer, the careful and detailed analysis of Levin and Hryniuk provided a persuasive rationale for prospective trials of dose intensity in ovarian cancer. Two decades later, we can conclude that increasing the dose intensity of currently available cytotoxic agents in ovarian cancer is a strategy that has failed to improve survival compared with conventional intravenous chemotherapy with carboplatin plus paclitaxel. The randomized trial comparing high-dose sequential chemotherapy with standard intravenous chemotherapy by Möbus et al in this issue of the Journal of Clinical Oncology2 is the last nail in the coffin of this once important concept. After the report by Levin and Hryniuk,1 investigators explored the role of dose intensity in two distinct strategies. The first was to perform randomized trials comparing regimens in which the dose intensities were essentially doubled. While the higher dose regimens were associated with increased toxicity, they could be administered with standard supportive care. Other investigators explored the role of high-dose chemotherapy, which required autologous support, initially in the form of bone marrow transplantations and, more recently, with peripheral blood stem cell (PBSC) transfusions. Eight randomized trials were conducted comparing dose-intensity regimens of platinum compounds without autologous support, and Thigpen3 summarized the results of those trials. Some of these trials increased the dose of cisplatin, others doubled the dose of carboplatin, and some trials combined cisplatin and carboplatin in the same regimen. Furthermore, some trials increased dose intensity as well as total doses of platinum compounds in the experimental arm. The Gynecologic Oncology Group (GOG) trial was perhaps the most definitive test of doubling dose intensity over a clinically relevant range.4 Patients with large-volume advanced disease were randomly assigned to either eight cycles of cisplatin (50 mg/m2) plus cyclophosphamide (500 mg/m2) or to four cycles of twice as much of each drug every 3 weeks. There were no differences in response, complete response, progression-free survival, or overall survival. Thigpen concluded that the weight of evidence from these eight trials suggested that increasing the dose intensity of carboplatin beyond an area under the curve (AUC) of 4 or a cisplatin dose greater than 25 mg/m2 per week was not likely to result in increased efficacy.3 The second strategy with intensive hematologic support permitted substantially greater increases in dose intensity than possible with standard supportive care. High-dose chemotherapy with PBSC was studied as part of initial chemotherapy,2 as a consolidation strategy in patients who entered a complete remission,5 and in patients with recurrent disease.6 More than 1,000 patients were entered on transplant registries in Europe and in the United States.7,8 While some phase II trials reported encouraging results,6 other carefully performed trials started to raise questions as to whether this strategy should be evaluated in large randomized trials. There were two studies performed in the United States in which a second-look surgical procedure was used to assess the benefit of high-dose chemotherapy. Aghajanian et al9 reported on a pilot study of 56 patients treated with a high-dose chemotherapy regimen utilizing PBSC support. While several different treatment approaches were used in this regimen, they all utilized three cycles of high-dose carboplatin and one cycle of high-dose melphalan. The pathologic complete response rate in optimal disease patients was 12 of 22 (55%) while only three of 22 (13%) suboptimal stage III and IV patients achieved a pathologic complete response.9 Subsequently, Schilder et al10 reported on an evaluation of high-dose carboplatin and paclitaxel with PBSC in a GOG pilot study in optimally debulked stage III patients. Patients received three cycles of carboplatin (AUC, 15) with paclitaxel (250 mg/m2) followed by one cycle of high-dose melphalan (140 mg/m2). Nine patients entered this trial, eight patients consented to surgical reassessment, and only one had a pathologically complete response (12.5%). In contrast, GOG studies in patients with optimal stage III disease have reported a negative second-look rate of approximately 50% in patients treated with conventional intravenous carboplatin plus paclitaxel.11 These discouraging results in pilot studies of high-dose therapy led to lack of accrual on an attempted GOG phase III randomized trial comparing six cycles of conventional-dose carboplatin plus paclitaxel to a single dose of high-dose carboplatin, mitoxantrone, and cyclophosphamide as consolidation treatment after 4 to 6 cycles of standard platinum/taxane induction chemotherapy. However, prospective randomized trials of high-dose chemotherapy with bone marrow support were conducted in Europe. Curé et al5 initially reported encouraging results from a high-dose carboplatin plus cyclophosphamide regimen as part of consolidation therapy compared with standard doses of these agents. Further follow-up showed no significant improvement in either progression-free or overall survival. The study by Möbus et al2 is the first randomized study of multicycle high-dose chemotherapy compared with standard chemotherapy as part of initial treatment in patients with advanced ovarian cancer. There was no significant difference in progression-free survival or overall survival. These randomized trials from Europe provide no evidence that this treatment has any role in advanced ovarian cancer, either as part of initial therapy or as a consolidation strategy. It is notable that it has taken two decades to arrive at a final answer regarding dose intensity in ovarian cancer since the initial publication by Levin and Hryniuk.1 What took so long? The answer is probably due to an overinterpretation of initial phase II trials that reported substantial benefit for high-dose chemotherapy. Ovarian cancer is a heterogeneous disease with numerous prognostic factors that can affect survival. Consequently, the results of phase II trials must be interpreted with caution because outcomes will be dependent on patient selection criteria, such as the length of the disease-free interval and the volume of disease at relapse. Subsequent phase II trials by Aghajanian et al9 and Schilder et al10 were in more well-defined populations, and those studies suggested that high-dose chemotherapy would not be beneficial since surgical assessment did not produce response rates superior to that which could be achieved with standard intravenous carboplatin-based regimens. The prospective randomized trials have, in fact, borne out the conclusion. While high-dose chemotherapy with PBSC support is a failed strategy, it does not mean that the dose of platinum compounds is unimportant. There clearly is a dose response to carboplatin as a single agent with a plateau at an AUC of 4 to 5.12 However, carboplatin in combination with paclitaxel may have drug-drug interactions (eg, platelet-sparing effect), such that an AUC of 6.0 to 7.5 may be beneficial when carboplatin is used in combination with paclitaxel.13 In addition, the results of GOG protocol 172 with intraperitoneal (IP) cisplatin (100 mg/m2) have led to a resurgence of interest in this modality of treatment.14 While debate continues regarding the role of IP therapy in the treatment of ovarian cancer,15,16 the lack of benefit from increasing dose intensity after intravenous administration of platinum drugs suggests that the actual dose delivered to the tumor by the IP route may not be the critical factor in this therapeutic modality. The two-decade saga of high-dose therapy in ovarian cancer emphasizes the need for earlier initiation of randomized trials in testing new treatments and concepts. While a negative phase II trial9,10 appears to be predictive of a lack of ultimate benefit, the results of a positive phase II trial often are not confirmed in phase III studies. Based on phase II trials demonstrating that three-drug combinations (eg, paclitaxel plus carboplatin plus gemcitabine) produced a very high response rate, the Gynecologic Cancer InterGroup performed a five-arm phase III trial17 of triplets and doublets compared with standard paclitaxel and carboplatin. This large trial failed to show any advantage for the experimental arms and remains a model of how new regimens can be tested in a timely manner with international cooperation. Two decades to answer a clinically important question is not acceptable, particularly in light of the expanding number of novel biologic and targeted therapies that need to be evaluated in ovarian cancer. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on August 13, 2007. REFERENCES
1. Levin L, Hryniuk WM: Dose intensity analysis of chemotherapy regimens in ovarian carcinoma. J Clin Oncol 5:756-767, 1987 2. Möbus V, Wandt H, Frickhofen N, et al: High-dose sequential chemotherapy with peripheral blood steam cell support compared with standard dose chemotherapy for first line treatment of advanced ovarian cancer: Results of a phase III Intergroup trial of the AGO-Ovar/AIO and EBMT. J Clin Oncol 25:4187-4193, 2007 3. Thigpen JT: Dose-intensity in ovarian carcinoma: Hold, enough? J Clin Oncol 15:1291-1293, 1997 4. McGuire WP, Hoskins WJ, Brady MF, et al: Assessment of dose-intensive therapy in suboptimally debulked ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 13:1589-1599, 1995 5. Curé H, Battista C, Guastalla JP, et al: Phase III randomized trial of high-dose chemotherapy (HDC) and peripheral blood stem cell (PBSC) support as consolidation in patients (pts) with advanced ovarian cancer (AOC): 5-year follow-up of a GINECO/FNCLCC/SFGM-TC study. J Clin Oncol 22:450s, 2004 (abstr 5006) 6. Stiff PJ, Bayer R, Kerger C, et al: High-dose chemotherapy with autologous transplantation for persistent/relapsed ovarian cancer: A multivariate analysis of survival for 100 consecutively treated patients. J Clin Oncol 15:1309-1317, 1997 7. Stiff PJ, Veum-Stone J, Lazarus HM, et al: High-dose chemotherapy and autologous stem-cell transplantation for ovarian cancer: An autologous blood and marrow transplant registry report. Ann Intern Med 133:504-514, 2000 8. Ledermann JA, Herd R, Maraninchi D, et al: High-dose chemotherapy for ovarian carcinoma: Long-term results from the solid tumor registry of the European Group for Blood and Marrow Transplantation (EBMT). Ann Oncol 12:693-699, 2001 9. Aghajanian C, Fennelly D, Shapiro F, et al: Phase II study of "dose-dense" high-dose chemotherapy treatment with peripheral-blood progenitor-cell support as primary treatment for patients with advanced ovarian cancer. J Clin Oncol 16:1852-1860, 1998[Abstract] 10. Schilder RJ, Brady MF, Spriggs D, et al: Pilot evaluation of high-dose carboplatin and paclitaxel followed by high-dose melphalan supported by peripheral blood stem cells in previously untreated advanced ovarian cancer: A Gynecologic Oncology Group study. Gynecol Oncol 88:3-8, 2003[CrossRef][Medline] 11. 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 21:3194-3200, 2003 12. Jodrell DI, Egorin MJ, Canetta RM, et al: Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer. J Clin Oncol 10:520-528, 1992 13. Bookman MA, McGuire WP, Kilpatrick D, et al: Carboplatin and paclitaxel in ovarian carcinoma: A phase I study of the Gynecologic Oncology Group. J Clin Oncol 14:1895-1902, 1996 14. Armstrong DK, Bundy B, Wenzel L, et al: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354:34-43, 2006 15. Ozols RF, Bookman MA, Young RC: Intraperitoneal cisplatin therapy in ovarian cancer: Comparison with standard intravenous carboplatin and paclitaxel. Gynecol Oncol 103:1-6, 2006[Medline] 16. Gore M, du Bois A, Vergote I: Intraperitoneal chemotherapy in ovarian cancer remains experimental. J Clin Oncol 24:4528-4530, 2006 17. Bookman MA for the Gynecologic Cancer InterGroup (GCIG) through the Gynecologic Oncology Group (GOG): GOGO 182-ICON5: 5-arm phase III randomized trial of paclitaxel (P) and carboplatin (C) vs combinations with gemcitabine (G), PEG-liposomal doxorubicin (D), or topotecan (T) in patients (pts) with advanced-stage epithelial ovarian (EOC) or primary peritoneal (PPC) carcinoma. J Clin Oncol 24:456s, 2006 (suppl; abstr 5002)
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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