- Email: [email protected]
Maintenance Therapy in Epithelial Ovarian Cancer: Rationale and Results
Comprehensive Review Maintenance Therapy in Epithelial Ovarian Cancer: Rationale and Results Maurie Markman Abstract Although ovarian cancer is highly sensitive to chemotherapy, the majority of patients experience recurrence. As a result, it is rational to consider a maintenance strategy to improve overall survival (even if it does not increase the rate of “cure”) and delay the time to symptomatic disease progression. Although a phase III trial of single-agent paclitaxel delivered on a monthly schedule for 12 cycles after the attainment of a clinically defined complete response to primary chemotherapy revealed a substantial improvement in progression-free survival, the effect of this strategy on overall survival remains unresolved. Hopefully, the role of maintenance therapy in patients with ovarian cancer will be defined by ongoing and future trials. Keywords: Cancer Antigen 125, Cisplatin, Consolidation therapy, Paclitaxel, Platinum agents, Taxanes Clinical Ovarian Cancer, Vol. 1, No. 1, 40-43, 2008; DOI: 10.3816/COC.2008.n.003 Introduction Ovarian cancer is one of the more biologically sensitive malignancies to cytotoxic chemotherapy, with > 70%-80% of patients achieving subjective and objective evidence of benefit after the initiation of a primary antineoplastic drug regimen.1,2 Unfortunately, despite this fact, the majority of patients will experience relapse after an initial response to treatment and die from complications associated with progressive disease. Thus, as one strategy to improve survival, it was perhaps natural that ovarian cancer investigators would attempt to “maintain” response achieved by a variety of approaches. This review will discuss the clinical experience with maintenance therapy of ovarian cancer and highlight ongoing and possible future research efforts. Maintenance Therapy Versus Consolidation Therapy Before discussing maintenance therapy of ovarian cancer, it is important to define what is meant by this term, particularly distinguishing this therapeutic approach from another common strategy, that of consolidation therapy. The aim of a consolidation strategy is to intensely treat an individual patient whose cancer
Department of Gynecologic Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston Submitted: Mar 5, 2008; Revised: Apr 7, 2008; Accepted: Apr 10, 2008 Address for correspondence: Maurie Markman, MD, Department of Gynecologic Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Mail Box 243, Houston, TX 77030 Fax: 713-563-9586; e-mail: [email protected]
has demonstrated a major biologic response to the immediately preceding therapy. The fundamental goal of this approach is to cure the patient with the added treatment. Thus, for example, patients with acute leukemia or aggressive lymphomas who have attained an objectively measured major response might undergo a consolidation regimen, which might entail the delivery of a highdose chemotherapy program (with bone marrow or peripheral stem cell support) designed to increase the opportunity to eliminate the malignancy. In contrast, although one goal of maintenance therapy will almost certainly be improvement in overall survival (OS), use of this approach does not imply the therapy is delivered with curative intent. With this definition, a successful maintenance approach in the management of a particular cancer type would absolutely require an improvement in a clinically meaningful objectively measured outcome (eg, time to development of cancer-related symptoms, improvement in ovarian survival) but would not mandate that patients treated with this approach achieve a higher rate of “cure.” An obvious and critically relevant extension of the distinction between consolidation and maintenance therapy is the issue of the potential toxicity associated with the treatment program. For example, the use of allogeneic stem cell transplantation as a consolidation strategy in acute leukemia is well recognized to have a finite risk of treatment-related mortality that can be justified in specific settings by the documented increased opportunity for cure. With any maintenance approach designed to extend the time that a patient experiences a favorable clinical status (disease-free, symptom-free, or even OS) but not cure the malignancy, the balance between efficacy and the negative effect of the strategy on objectively measured or individually perceived quality of life must be considered.
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1941-4390, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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Clinical Ovarian Cancer • June 2008
Early Experience with Maintenance Therapy for Ovarian Cancer The demonstration of major biologic and clinical activity of alkylating agents (eg, melphalan, cyclophosphamide) in ovarian cancer resulted in the earliest opportunity for clinicians to observe the potential effect of a maintenance approach in this malignancy.3,4 Patients who achieved objective (shrinkage of tumor masses, reduction in ascites formation) and subjective (decreased abdominal discomfort, increased appetite, improved performance status) benefit after treatment with this class of agents were often (and quite rationally in that era) continued on treatment for extended periods (> 1 year).5,6 Unfortunately, it is now appreciated that exposure to prolonged high cumulative doses of these drugs substantially increases the risk for the development of secondary acute leukemia.7-9 Thus, an unknown percentage of women whose malignancy might have remained clinically stable if chemotherapy had been discontinued at an earlier time ultimately died, not as a result of progressive ovarian cancer, but rather because of the development of a devastating complication of treatment. The well-recognized cumulative effects of other established antineoplastic agents, including the risk of doxorubicin-induced congestive heart failure and cisplatin-induced neuropathy, add to the concern of the prolonged use of any anticancer agent as a maintenance strategy in ovarian cancer and other malignancies. Experience with Maintenance Therapy for Non-Ovarian Solid Tumors Before discussing clinical trial experience related to maintenance therapy of ovarian cancer, it is important to acknowledge the experience with such approaches in non-ovarian solid tumors. In several settings, the specific issue of the number of cycles of treatment has been directly addressed in phase III clinical trials (eg, germ cell tumors, colon cancer, breast cancer).10-12 These experiences have generally been reported to be negative. Further, even where there has been a suggested improvement in time to disease progression, investigators have concluded that the favorable impact on this objectively measured outcome is insufficient to justify the toxicity experienced by individuals continuing treatment.13 Clinical Trials Examining Continuation of Primary Cisplatin-Based Chemotherapy Shortly after the demonstration of the major biologic activity of cisplatin against ovarian cancer, this drug became the cornerstone of the chemotherapeutic management of the malignancy. Since that time, several phase III trials have been conducted that explored the question of the optimal number of cycles of cisplatin-based combination chemotherapy that should be used in the setting of primary therapy of ovarian cancer.14-16 The studies, which directly compared the delivery of 5 versus 10 or 6 versus 12 cycles of a cisplatin-containing regimen failed to demonstrate that the more extended treatment programs improved any clinically relevant outcome (eg, objective response rate, progression-free survival [PFS], or OS). Further, as would have been anticipated based on knowledge of the side effects of cisplatin, the longer treatment regimens were associated with worse toxicity profiles. This experience provides no support for the general concept of
maintenance therapy of ovarian cancer, but it is also important to appreciate the limitations of these older trials. First, even though these studies were randomized, the total sample size in each trial was < 250 patients. Second, because of the known toxicity profile of cisplatin, it is understandable that many would realize the difficulty of ever considering routinely delivering 10 or 12 cycles of the drug. Third, because the cytotoxicity of platinum agents has not been shown to be highly cycle dependent in preclinical evaluation or clinical studies, even the theoretical relevance of extending the duration of treatment (from 5-6 cycles to 10-12 cycles) is questionable. Finally, the basic study design for the several cisplatin-based maintenance trials could also have contributed to the inability of the extended treatment strategy to demonstrate evidence of improved outcome. Because it is well-recognized that 20%-40% of patients with ovarian cancer have tumors that are inherently resistant to platinum agents,17 it would be reasonable to state that, for these individuals, extending treatment beyond 5 or 6 cycles has no realistic chance of improving any objective measure of outcome (eg, higher response rate, longer time to disease progression, or OS). Considering this relevant issue, a more appropriate trial design would have been to randomize the responding patient population after the completion of 5 or 6 cycles of primary therapy to receive (1) an additional 5-6 cycles of cisplatin-based chemotherapy or (2) have treatment discontinued. Several reported institutional experiences have suggested the potential utility of continuing platinum-based chemotherapy in the setting of platinum-responsive disease (compared with historical experiences), but unfortunately, there remain no randomized phase III trial data to support this general approach.18,19 Rationale for Paclitaxel as Maintenance Chemotherapy in Ovarian Cancer In contrast with cisplatin, there is a stronger preclinical and clinical rationale for the delivery of paclitaxel as a maintenance strategy in patients with ovarian cancer. In addition to the clearly documented activity of the agent in this malignancy,20,21 the biologic effects of paclitaxel have been demonstrated to be highly schedule dependent,22 leading to the rational (and testable) hypothesis that extending the duration of therapy would permit additional killing of any continually cycling and persistently viable tumor cells. Further, of particular interest to a maintenance approach, while paclitaxel is known to have important acute (eg, hypersensitivity reactions, neutropenia) and semi-acute (eg, alopecia, peripheral neuropathy) toxicities, there have been no “new” cumulative side effects (eg, leukemia, renal or heart failure) described that are associated with extended administration of the agent.23 Finally, there is more recent evidence in preclinical systems that paclitaxel has an antiangiogenic effect that might be quite relevant for an agent considered to be delivered as maintenance strategy.24 Nonrandomized Experience with Maintenance Paclitaxel in Ovarian Cancer Several reports have noted the safety of administering multiple cycles of paclitaxel given over an extended period, with provocative suggestions of patient benefit associated with these particular
Clinical Ovarian Cancer • June 2008
41
Maintenance Therapy for Epithelial Ovarian Cancer
Table 1 Southwest Oncology Group and Gynecologic Oncology Group Phase III Trial of Three Versus Twelve Cycles of Maintenance Paclitaxel in Advanced Ovarian Cancer Study (Group)
Markman et (SWOG/GOG)
al28
Treatment Regimen
Number Median of PFS Patients (Months)
3 Cycles of singleagent Paclitaxel 175 mg/m2 over 3 hours every 28 days
123
12 Cycles of singleagent Paclitaxel 175 mg/m2 over 3 hours every 28 days
134
P Value (Hazard Ratio)
21 P = .0023; HR, 2.31 28
strategies.25-27 Perhaps the most interesting study in this regard is a retrospective analysis of a large group of patients (n = 100) with heavily pretreated platinum-resistant ovarian cancer who received single-agent paclitaxel until they demonstrated disease progression. Although not a randomized trial, it was noteworthy that the 2- and 3-year survival rates for this patient population were 18% and 11%, respectively.25 Randomized Phase III Trials of Taxane Maintenance Chemotherapy in Advanced Ovarian Cancer Based on the clinical and preclinical experience noted earlier, the Southwest Oncology Group (SWOG) and the Gynecologic Oncology Group (GOG) initiated a phase III randomized trial that compared a regimen of single-agent paclitaxel (175 mg/m2 delivered over 3 hours on an every-28-day schedule) for 3 cycles or 12 cycles administered to women with advanced ovarian cancer who had attained a clinically defined complete response to platinum/paclitaxel–based primary chemotherapy.28 In this study a complete response to the primary chemotherapy program was defined as requiring a normal physical examination, normal serum cancer antigen 125 (CA-125) level, normal computed tomography scan of the abdomen and pelvis, and no symptoms suggestive of persistent ovarian cancer. This phase III study was discontinued by its Data Safety and Monitoring Committee when, at the time of a planned interim analysis (approximately 50% accrual onto the trial), there was found to be a highly statistically significant difference in PFS in favor of 12-cycle maintenance paclitaxel chemotherapy program (median, 28 months vs. 21 months; P = .0023; hazard ratio, 2.31; Table 1).28 Women treated with the 12-cycle maintenance regimen experienced a higher risk of grade 2/3 neuropathy (n = 23 vs. n = 15). Unfortunately, because of the mandated closure of the study with only one half of its initial planned accrual and crossover of approximately 10% of individuals from the 3-cycle arm to the extended treatment regimen after information being provided to patients regarding the study results, it was not possible to draw any conclusions regarding the effect of this strategy on OS.29
42
Of considerable importance, the GOG is currently conducting a phase III trial that again examines the utility of 12 cycles of maintenance paclitaxel in this exact clinical setting but, in this case, compared with a no-further-treatment control arm. A third arm in this trial includes an experimental taxane. A similar, but not identical, paclitaxel maintenance study has recently been reported from Italy, which compared an observation control arm with 6 cycles of single-agent paclitaxel (administered on an every-3-week schedule) in women with advanced ovarian cancer who have attained a clinically or surgically defined complete response to platinum/paclitaxel chemotherapy.30 In contrast with the SWOG/GOG study, the Italian investigators noted no statistically significant difference in PFS or OS between the 2 study arms. Although these results do not support the conclusion of the previously discussed SWOG/GOG trial, there are important differences between the 2 studies. First, in the SWOG/GOG study, active treatment was delivered for a much longer period (12 cycles on an every-28-day schedule versus only 6 cycles on an every-21-day schedule).28,30 Second, even though discontinued early by its Data Safety and Monitoring Committee, the SWOG/GOG study had included a larger patient population, all with a clinically defined complete response. In contrast, the Italian study included patients who were in a clinically defined and surgically defined complete response. In addition, in the preliminary report of the Italian trial, it was stated that a number of patients in the observation arm actually received the paclitaxel maintenance regimen.30 Although it was certainly correct to include these particular individuals in the control arm in an intent-to-treat analysis of survival (PFS and OS), it is uncertain how this specific patient group would have influenced the observed outcome of this study. Other Maintenance Strategies in the Management of Advanced Ovarian Cancer Despite strong theoretical justification to explore the clinical utility of a maintenance approach in the management of advanced ovarian cancer, there remain few evidence-based studies that have explored this important question. Several recently reported trials that extended therapy through the addition of topotecan after the completion of a carboplatin/paclitaxel regimen failed to reveal any clinical benefit associated with use of this strategy.31,32 A large, single-arm, phase II trial examining altretamine as a maintenance approach in women with advanced ovarian cancer who had achieved a clinically defined complete response produced interesting 2-year survival results (75%), but unfortunately, the study was not randomized.33 Therefore, it is not possible to know whether this outcome was superior to an approach of observation until documented relapse of the disease process. Although provocative preliminary results had been reported for the delivery of oregovomab (a monoclonal antibody that binds to circulating CA-125) in patients with ovarian cancer who were in remission,34 the final outcome of a large, phase III, randomized study examining the utility of this approach has recently been reported to be negative. A randomized trial evaluating interferon-α as a maintenance strategy in advanced ovarian cancer also failed to demonstrate any benefit.35
Clinical Ovarian Cancer • June 2008
Maurie Markman
The delivery of additional treatment by the intraperitoneal route after a major response to first-line therapy in advanced ovarian cancer has also been explored, but there are currently no evidence-based data demonstrating the favorable impact of this strategy on PFS or OS.36 A phase III study of primary chemotherapy (carboplatin plus paclitaxel) being conducted by the GOG is specifically exploring the clinical utility of extending treatment (beyond the completion of the chemotherapy program) with the antiangiogenic agent bevacizumab.37 Finally, an ongoing, international, randomized trial is examining a possible therapeutic role for inhibition of the epidermal growth factor receptor in improving survival in ovarian cancer when delivered to women in clinical remission after primary chemotherapy. Conclusion The concept of maintenance therapy has considerable appeal in the management of ovarian cancer. There is a high probability that patients will achieve a major objective response to primary chemotherapy, but unfortunately, these individuals also have an equally strong likelihood that the disease will ultimately progress. Agents that can successfully prevent or substantially delay the progression of ovarian cancer while limiting interference with a patient’s quality of life have the legitimate potential to serve a truly meaningful role in the management of this difficult disease. References 1. Cannistra SA. Cancer of the ovary. N Engl J Med 2004; 351:2519-29. 2. Covens A, Carey M, Bryson P, et al. Systematic review of first-line chemotherapy for newly diagnosed postoperative patients with stage II, III, or IV epithelial ovarian cancer. Gynecol Oncol 2002; 85:71-80. 3. Bateman JC. Chemotherapeutic management of advanced ovarian carcinoma. Med Ann Dist Columbia 1959; 28:537-44. 4. Kottmeier HL. Treatment of ovarian cancer with thiotepa. Clin Obstet Gynecol 1968; 11:428-38. 5. Katz ME, Schwartz PE, Kapp DS, et al. Epithelial carcinoma of the ovary: current strategies. Ann Intern Med 1981; 95:98-111. 6. Young RC, Chabner BA, Hubbard SP, et al. Advanced ovarian adenocarcinoma. A prospective clinical trial of melphalan (L-PAM) versus combination chemotherapy. N Engl J Med 1978; 299:1261-6. 7. Greene MH, Boice JD Jr, Greer BE, et al. Acute nonlymphocytic leukemia after therapy with alkylating agents for ovarian cancer: a study of five randomized clinical trials. N Engl J Med 1982; 307:1416-21. 8. Travis LB, Curtis RE, Boice JD Jr, et al. Second malignant neoplasms among long-term survivors of ovarian cancer. Cancer Res 1996; 56:1564-70. 9. Travis LB, Holowaty EJ, Bergfeldt K, et al. Risk of leukemia after platinumbased chemotherapy for ovarian cancer. N Engl J Med 1999; 340:351-7. 10. Einhorn LH, Williams SD, Loehrer PJ, et al. Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol. J Clin Oncol 1989; 7:387-91. 11. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: An overview of the randomized trials. Lancet 1998; 352:930-42. 12. Maughan TS, James RD, Kerr DJ, et al. Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial. Lancet 2003; 361:457-64. 13. Muss HB, Case LD, Richards F, et al. Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. The Piedmont Oncology Association. N Engl J Med 1991; 325:1342-8. 14. Lambert HE, Rustin GJ, Gregory WM, et al. A randomized trial of five versus eight courses of cisplatin or carboplatin in advanced epithelial ovarian carcinoma. A North Thames Ovary Group Study. Ann Oncol 1997; 8:327-33. 15. Bertelsen K, Jakobsen A, Stroyer J, et al. A prospective randomized comparison of 6 and 12 cycles of cyclophosphamide, adriamycin, and cisplatin in advanced epithelial ovarian cancer: a Danish Ovarian Study Group trial
(DACOVA). Gynecol Oncol 1993; 49:30-6. 16. Hakes TB, Chalas E, Hoskins WJ, et al. Randomized prospective trial of 5 versus 10 cycles of cyclophosphamide, doxorubicin, and cisplatin in advanced ovarian carcinoma. Gynecol Oncol 1992; 45:284-9. 17. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996; 334:1-6. 18. Gershenson DM, Mitchell MF, Atkinson N, et al. The effect of prolonged cisplatin-based chemotherapy on progression-free survival in patients with optimal epithelial ovarian cancer: “maintenance” therapy reconsidered. Gynecol Oncol 1992; 47:7-13. 19. Eltabbakh GH, Piver MS, Hempling RE, et al. Prolonged disease-free survival by maintenance chemotherapy among patients with recurrent platinum-sensitive ovarian cancer. Gynecol Oncol 1998; 71:190-5. 20. McGuire WP, Rowinsky EK, Rosenshein NB, et al. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 1989; 111:273-9. 21. Thigpen JT, Blessing JA, Ball H, et al. Phase II trial of paclitaxel in patients with progressive ovarian carcinoma after platinum-based chemotherapy: a Gynecologic Oncology Group study. J Clin Oncol 1994; 12:1748-53. 22. Eisenhauer EA, Bokkel Huinink WW, Swenerton KD, et al. European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion. J Clin Oncol 1994; 12:2654-66. 23. Rowinsky EK, Donehower RC. Paclitaxel (Taxol). N Engl J Med 1995; 332:1004-14. 24. Miller KD, Sweeney CJ, Sledge GW Jr. Redefining the target: chemotherapeutics as antiangiogenics. J Clin Oncol 2001; 19:1195-206. 25. Markman M, Hakes T, Barakat R, et al. Follow-up of Memorial Sloan-Kettering Cancer Center patients treated on National Cancer Institute Treatment Referral Center protocol 9103: paclitaxel in refractory ovarian cancer. J Clin Oncol 1996; 14:796-9. 26. Rohl J, Kushner D, Markman M. Chronic administration of single-agent paclitaxel in gynecologic malignancies. Gynecol Oncol 2001; 81:201-5. 27. VonGruenigen V, Karlen JR, Waggoner SE. A case of chronic paclitaxel administration in ovarian cancer. Gynecol Oncol 2003; 89:532-5. 28. Markman M, Liu PY, Wilczynski S, et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 2003; 21:2460-5. 29. Markman M, Liu P, Wilcyznski S, et al. Survival of ovarian cancer patients treated on SWOG 9701/GOG178: 12 versus 3 cycles of monthly single-agent paclitaxel following attainment of a clinically-defined complete response to platinum/paclitaxel. J Clin Oncol 2006; 24(18 suppl):257s (Abstract 5005). 30. Conte PF, Favalli G, Gadducci A, et al. Final results of After-6 protocol 1: a phase III trial of observation versus 6 courses of paclitaxel in advanced ovarian cancer patients in complete response after platinum-paclitaxel chemotherapy. J Clin Oncol 2007; 25(18 suppl):275s (Abstract 5505), 31. De Placido S, Scambia G, Di VG, et al. Topotecan compared with no therapy after response to surgery and carboplatin/paclitaxel in patients with ovarian cancer: Multicenter Italian Trials in Ovarian Cancer (MITO-1) randomized study. J Clin Oncol 2004; 22:2635-42. 32. Pfisterer J, Weber B, Reuss A, et al. Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a gynecologic cancer intergroup trial of the AGO-OVAR and GINECO. J Natl Cancer Inst 2006; 98:1036-45. 33. Rothenberg ML, Liu PY, Wilczynski S, et al. Phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer: a Southwest Oncology Group trial (SWOG9326). Gynecol Oncol 2001; 82:317-22. 34. Sabbatini P, Odunsi K. Immunologic approaches to ovarian cancer treatment. J Clin Oncol 2007; 25:2884-93. 35. Hall GD, Brown JM, Coleman RE, et al. Maintenance treatment with interferon for advanced ovarian cancer: results of the Northern and Yorkshire gynaecology group randomized phase III study. Br J Cancer 2004; 91:621-6. 36. Alberts DS, Hannigan EV, Liu PY, et al. Randomized trial of adjuvant intraperitoneal alpha-interferon in stage III ovarian cancer patients who have no evidence of disease after primary surgery and chemotherapy: an Intergroup study. Gynecol Oncol 2006; 100:133-8. 37. Kaye SB. Bevacizumab for the treatment of epithelial ovarian cancer: will this be its finest hour? J Clin Oncol 2007; 25:5150-2.
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Department of Gynecologic Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston Submitted: Mar 5, 2008; Revised: Apr 7, 2008; Accepted: Apr 10, 2008 Address for correspondence: Maurie Markman, MD, Department of Gynecologic Medical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Mail Box 243, Houston, TX 77030 Fax: 713-563-9586; e-mail: [email protected]
has demonstrated a major biologic response to the immediately preceding therapy. The fundamental goal of this approach is to cure the patient with the added treatment. Thus, for example, patients with acute leukemia or aggressive lymphomas who have attained an objectively measured major response might undergo a consolidation regimen, which might entail the delivery of a highdose chemotherapy program (with bone marrow or peripheral stem cell support) designed to increase the opportunity to eliminate the malignancy. In contrast, although one goal of maintenance therapy will almost certainly be improvement in overall survival (OS), use of this approach does not imply the therapy is delivered with curative intent. With this definition, a successful maintenance approach in the management of a particular cancer type would absolutely require an improvement in a clinically meaningful objectively measured outcome (eg, time to development of cancer-related symptoms, improvement in ovarian survival) but would not mandate that patients treated with this approach achieve a higher rate of “cure.” An obvious and critically relevant extension of the distinction between consolidation and maintenance therapy is the issue of the potential toxicity associated with the treatment program. For example, the use of allogeneic stem cell transplantation as a consolidation strategy in acute leukemia is well recognized to have a finite risk of treatment-related mortality that can be justified in specific settings by the documented increased opportunity for cure. With any maintenance approach designed to extend the time that a patient experiences a favorable clinical status (disease-free, symptom-free, or even OS) but not cure the malignancy, the balance between efficacy and the negative effect of the strategy on objectively measured or individually perceived quality of life must be considered.
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1941-4390, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
40
Clinical Ovarian Cancer • June 2008
Early Experience with Maintenance Therapy for Ovarian Cancer The demonstration of major biologic and clinical activity of alkylating agents (eg, melphalan, cyclophosphamide) in ovarian cancer resulted in the earliest opportunity for clinicians to observe the potential effect of a maintenance approach in this malignancy.3,4 Patients who achieved objective (shrinkage of tumor masses, reduction in ascites formation) and subjective (decreased abdominal discomfort, increased appetite, improved performance status) benefit after treatment with this class of agents were often (and quite rationally in that era) continued on treatment for extended periods (> 1 year).5,6 Unfortunately, it is now appreciated that exposure to prolonged high cumulative doses of these drugs substantially increases the risk for the development of secondary acute leukemia.7-9 Thus, an unknown percentage of women whose malignancy might have remained clinically stable if chemotherapy had been discontinued at an earlier time ultimately died, not as a result of progressive ovarian cancer, but rather because of the development of a devastating complication of treatment. The well-recognized cumulative effects of other established antineoplastic agents, including the risk of doxorubicin-induced congestive heart failure and cisplatin-induced neuropathy, add to the concern of the prolonged use of any anticancer agent as a maintenance strategy in ovarian cancer and other malignancies. Experience with Maintenance Therapy for Non-Ovarian Solid Tumors Before discussing clinical trial experience related to maintenance therapy of ovarian cancer, it is important to acknowledge the experience with such approaches in non-ovarian solid tumors. In several settings, the specific issue of the number of cycles of treatment has been directly addressed in phase III clinical trials (eg, germ cell tumors, colon cancer, breast cancer).10-12 These experiences have generally been reported to be negative. Further, even where there has been a suggested improvement in time to disease progression, investigators have concluded that the favorable impact on this objectively measured outcome is insufficient to justify the toxicity experienced by individuals continuing treatment.13 Clinical Trials Examining Continuation of Primary Cisplatin-Based Chemotherapy Shortly after the demonstration of the major biologic activity of cisplatin against ovarian cancer, this drug became the cornerstone of the chemotherapeutic management of the malignancy. Since that time, several phase III trials have been conducted that explored the question of the optimal number of cycles of cisplatin-based combination chemotherapy that should be used in the setting of primary therapy of ovarian cancer.14-16 The studies, which directly compared the delivery of 5 versus 10 or 6 versus 12 cycles of a cisplatin-containing regimen failed to demonstrate that the more extended treatment programs improved any clinically relevant outcome (eg, objective response rate, progression-free survival [PFS], or OS). Further, as would have been anticipated based on knowledge of the side effects of cisplatin, the longer treatment regimens were associated with worse toxicity profiles. This experience provides no support for the general concept of
maintenance therapy of ovarian cancer, but it is also important to appreciate the limitations of these older trials. First, even though these studies were randomized, the total sample size in each trial was < 250 patients. Second, because of the known toxicity profile of cisplatin, it is understandable that many would realize the difficulty of ever considering routinely delivering 10 or 12 cycles of the drug. Third, because the cytotoxicity of platinum agents has not been shown to be highly cycle dependent in preclinical evaluation or clinical studies, even the theoretical relevance of extending the duration of treatment (from 5-6 cycles to 10-12 cycles) is questionable. Finally, the basic study design for the several cisplatin-based maintenance trials could also have contributed to the inability of the extended treatment strategy to demonstrate evidence of improved outcome. Because it is well-recognized that 20%-40% of patients with ovarian cancer have tumors that are inherently resistant to platinum agents,17 it would be reasonable to state that, for these individuals, extending treatment beyond 5 or 6 cycles has no realistic chance of improving any objective measure of outcome (eg, higher response rate, longer time to disease progression, or OS). Considering this relevant issue, a more appropriate trial design would have been to randomize the responding patient population after the completion of 5 or 6 cycles of primary therapy to receive (1) an additional 5-6 cycles of cisplatin-based chemotherapy or (2) have treatment discontinued. Several reported institutional experiences have suggested the potential utility of continuing platinum-based chemotherapy in the setting of platinum-responsive disease (compared with historical experiences), but unfortunately, there remain no randomized phase III trial data to support this general approach.18,19 Rationale for Paclitaxel as Maintenance Chemotherapy in Ovarian Cancer In contrast with cisplatin, there is a stronger preclinical and clinical rationale for the delivery of paclitaxel as a maintenance strategy in patients with ovarian cancer. In addition to the clearly documented activity of the agent in this malignancy,20,21 the biologic effects of paclitaxel have been demonstrated to be highly schedule dependent,22 leading to the rational (and testable) hypothesis that extending the duration of therapy would permit additional killing of any continually cycling and persistently viable tumor cells. Further, of particular interest to a maintenance approach, while paclitaxel is known to have important acute (eg, hypersensitivity reactions, neutropenia) and semi-acute (eg, alopecia, peripheral neuropathy) toxicities, there have been no “new” cumulative side effects (eg, leukemia, renal or heart failure) described that are associated with extended administration of the agent.23 Finally, there is more recent evidence in preclinical systems that paclitaxel has an antiangiogenic effect that might be quite relevant for an agent considered to be delivered as maintenance strategy.24 Nonrandomized Experience with Maintenance Paclitaxel in Ovarian Cancer Several reports have noted the safety of administering multiple cycles of paclitaxel given over an extended period, with provocative suggestions of patient benefit associated with these particular
Clinical Ovarian Cancer • June 2008
41
Maintenance Therapy for Epithelial Ovarian Cancer
Table 1 Southwest Oncology Group and Gynecologic Oncology Group Phase III Trial of Three Versus Twelve Cycles of Maintenance Paclitaxel in Advanced Ovarian Cancer Study (Group)
Markman et (SWOG/GOG)
al28
Treatment Regimen
Number Median of PFS Patients (Months)
3 Cycles of singleagent Paclitaxel 175 mg/m2 over 3 hours every 28 days
123
12 Cycles of singleagent Paclitaxel 175 mg/m2 over 3 hours every 28 days
134
P Value (Hazard Ratio)
21 P = .0023; HR, 2.31 28
strategies.25-27 Perhaps the most interesting study in this regard is a retrospective analysis of a large group of patients (n = 100) with heavily pretreated platinum-resistant ovarian cancer who received single-agent paclitaxel until they demonstrated disease progression. Although not a randomized trial, it was noteworthy that the 2- and 3-year survival rates for this patient population were 18% and 11%, respectively.25 Randomized Phase III Trials of Taxane Maintenance Chemotherapy in Advanced Ovarian Cancer Based on the clinical and preclinical experience noted earlier, the Southwest Oncology Group (SWOG) and the Gynecologic Oncology Group (GOG) initiated a phase III randomized trial that compared a regimen of single-agent paclitaxel (175 mg/m2 delivered over 3 hours on an every-28-day schedule) for 3 cycles or 12 cycles administered to women with advanced ovarian cancer who had attained a clinically defined complete response to platinum/paclitaxel–based primary chemotherapy.28 In this study a complete response to the primary chemotherapy program was defined as requiring a normal physical examination, normal serum cancer antigen 125 (CA-125) level, normal computed tomography scan of the abdomen and pelvis, and no symptoms suggestive of persistent ovarian cancer. This phase III study was discontinued by its Data Safety and Monitoring Committee when, at the time of a planned interim analysis (approximately 50% accrual onto the trial), there was found to be a highly statistically significant difference in PFS in favor of 12-cycle maintenance paclitaxel chemotherapy program (median, 28 months vs. 21 months; P = .0023; hazard ratio, 2.31; Table 1).28 Women treated with the 12-cycle maintenance regimen experienced a higher risk of grade 2/3 neuropathy (n = 23 vs. n = 15). Unfortunately, because of the mandated closure of the study with only one half of its initial planned accrual and crossover of approximately 10% of individuals from the 3-cycle arm to the extended treatment regimen after information being provided to patients regarding the study results, it was not possible to draw any conclusions regarding the effect of this strategy on OS.29
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Of considerable importance, the GOG is currently conducting a phase III trial that again examines the utility of 12 cycles of maintenance paclitaxel in this exact clinical setting but, in this case, compared with a no-further-treatment control arm. A third arm in this trial includes an experimental taxane. A similar, but not identical, paclitaxel maintenance study has recently been reported from Italy, which compared an observation control arm with 6 cycles of single-agent paclitaxel (administered on an every-3-week schedule) in women with advanced ovarian cancer who have attained a clinically or surgically defined complete response to platinum/paclitaxel chemotherapy.30 In contrast with the SWOG/GOG study, the Italian investigators noted no statistically significant difference in PFS or OS between the 2 study arms. Although these results do not support the conclusion of the previously discussed SWOG/GOG trial, there are important differences between the 2 studies. First, in the SWOG/GOG study, active treatment was delivered for a much longer period (12 cycles on an every-28-day schedule versus only 6 cycles on an every-21-day schedule).28,30 Second, even though discontinued early by its Data Safety and Monitoring Committee, the SWOG/GOG study had included a larger patient population, all with a clinically defined complete response. In contrast, the Italian study included patients who were in a clinically defined and surgically defined complete response. In addition, in the preliminary report of the Italian trial, it was stated that a number of patients in the observation arm actually received the paclitaxel maintenance regimen.30 Although it was certainly correct to include these particular individuals in the control arm in an intent-to-treat analysis of survival (PFS and OS), it is uncertain how this specific patient group would have influenced the observed outcome of this study. Other Maintenance Strategies in the Management of Advanced Ovarian Cancer Despite strong theoretical justification to explore the clinical utility of a maintenance approach in the management of advanced ovarian cancer, there remain few evidence-based studies that have explored this important question. Several recently reported trials that extended therapy through the addition of topotecan after the completion of a carboplatin/paclitaxel regimen failed to reveal any clinical benefit associated with use of this strategy.31,32 A large, single-arm, phase II trial examining altretamine as a maintenance approach in women with advanced ovarian cancer who had achieved a clinically defined complete response produced interesting 2-year survival results (75%), but unfortunately, the study was not randomized.33 Therefore, it is not possible to know whether this outcome was superior to an approach of observation until documented relapse of the disease process. Although provocative preliminary results had been reported for the delivery of oregovomab (a monoclonal antibody that binds to circulating CA-125) in patients with ovarian cancer who were in remission,34 the final outcome of a large, phase III, randomized study examining the utility of this approach has recently been reported to be negative. A randomized trial evaluating interferon-α as a maintenance strategy in advanced ovarian cancer also failed to demonstrate any benefit.35
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The delivery of additional treatment by the intraperitoneal route after a major response to first-line therapy in advanced ovarian cancer has also been explored, but there are currently no evidence-based data demonstrating the favorable impact of this strategy on PFS or OS.36 A phase III study of primary chemotherapy (carboplatin plus paclitaxel) being conducted by the GOG is specifically exploring the clinical utility of extending treatment (beyond the completion of the chemotherapy program) with the antiangiogenic agent bevacizumab.37 Finally, an ongoing, international, randomized trial is examining a possible therapeutic role for inhibition of the epidermal growth factor receptor in improving survival in ovarian cancer when delivered to women in clinical remission after primary chemotherapy. Conclusion The concept of maintenance therapy has considerable appeal in the management of ovarian cancer. There is a high probability that patients will achieve a major objective response to primary chemotherapy, but unfortunately, these individuals also have an equally strong likelihood that the disease will ultimately progress. Agents that can successfully prevent or substantially delay the progression of ovarian cancer while limiting interference with a patient’s quality of life have the legitimate potential to serve a truly meaningful role in the management of this difficult disease. References 1. Cannistra SA. Cancer of the ovary. N Engl J Med 2004; 351:2519-29. 2. Covens A, Carey M, Bryson P, et al. Systematic review of first-line chemotherapy for newly diagnosed postoperative patients with stage II, III, or IV epithelial ovarian cancer. Gynecol Oncol 2002; 85:71-80. 3. Bateman JC. Chemotherapeutic management of advanced ovarian carcinoma. Med Ann Dist Columbia 1959; 28:537-44. 4. Kottmeier HL. Treatment of ovarian cancer with thiotepa. Clin Obstet Gynecol 1968; 11:428-38. 5. Katz ME, Schwartz PE, Kapp DS, et al. Epithelial carcinoma of the ovary: current strategies. Ann Intern Med 1981; 95:98-111. 6. Young RC, Chabner BA, Hubbard SP, et al. Advanced ovarian adenocarcinoma. A prospective clinical trial of melphalan (L-PAM) versus combination chemotherapy. N Engl J Med 1978; 299:1261-6. 7. Greene MH, Boice JD Jr, Greer BE, et al. Acute nonlymphocytic leukemia after therapy with alkylating agents for ovarian cancer: a study of five randomized clinical trials. N Engl J Med 1982; 307:1416-21. 8. Travis LB, Curtis RE, Boice JD Jr, et al. Second malignant neoplasms among long-term survivors of ovarian cancer. Cancer Res 1996; 56:1564-70. 9. Travis LB, Holowaty EJ, Bergfeldt K, et al. Risk of leukemia after platinumbased chemotherapy for ovarian cancer. N Engl J Med 1999; 340:351-7. 10. Einhorn LH, Williams SD, Loehrer PJ, et al. Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol. J Clin Oncol 1989; 7:387-91. 11. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: An overview of the randomized trials. Lancet 1998; 352:930-42. 12. Maughan TS, James RD, Kerr DJ, et al. Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial. Lancet 2003; 361:457-64. 13. Muss HB, Case LD, Richards F, et al. Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. The Piedmont Oncology Association. N Engl J Med 1991; 325:1342-8. 14. Lambert HE, Rustin GJ, Gregory WM, et al. A randomized trial of five versus eight courses of cisplatin or carboplatin in advanced epithelial ovarian carcinoma. A North Thames Ovary Group Study. Ann Oncol 1997; 8:327-33. 15. Bertelsen K, Jakobsen A, Stroyer J, et al. A prospective randomized comparison of 6 and 12 cycles of cyclophosphamide, adriamycin, and cisplatin in advanced epithelial ovarian cancer: a Danish Ovarian Study Group trial
(DACOVA). Gynecol Oncol 1993; 49:30-6. 16. Hakes TB, Chalas E, Hoskins WJ, et al. Randomized prospective trial of 5 versus 10 cycles of cyclophosphamide, doxorubicin, and cisplatin in advanced ovarian carcinoma. Gynecol Oncol 1992; 45:284-9. 17. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996; 334:1-6. 18. Gershenson DM, Mitchell MF, Atkinson N, et al. The effect of prolonged cisplatin-based chemotherapy on progression-free survival in patients with optimal epithelial ovarian cancer: “maintenance” therapy reconsidered. Gynecol Oncol 1992; 47:7-13. 19. Eltabbakh GH, Piver MS, Hempling RE, et al. Prolonged disease-free survival by maintenance chemotherapy among patients with recurrent platinum-sensitive ovarian cancer. Gynecol Oncol 1998; 71:190-5. 20. McGuire WP, Rowinsky EK, Rosenshein NB, et al. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 1989; 111:273-9. 21. Thigpen JT, Blessing JA, Ball H, et al. Phase II trial of paclitaxel in patients with progressive ovarian carcinoma after platinum-based chemotherapy: a Gynecologic Oncology Group study. J Clin Oncol 1994; 12:1748-53. 22. Eisenhauer EA, Bokkel Huinink WW, Swenerton KD, et al. European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion. J Clin Oncol 1994; 12:2654-66. 23. Rowinsky EK, Donehower RC. Paclitaxel (Taxol). N Engl J Med 1995; 332:1004-14. 24. Miller KD, Sweeney CJ, Sledge GW Jr. Redefining the target: chemotherapeutics as antiangiogenics. J Clin Oncol 2001; 19:1195-206. 25. Markman M, Hakes T, Barakat R, et al. Follow-up of Memorial Sloan-Kettering Cancer Center patients treated on National Cancer Institute Treatment Referral Center protocol 9103: paclitaxel in refractory ovarian cancer. J Clin Oncol 1996; 14:796-9. 26. Rohl J, Kushner D, Markman M. Chronic administration of single-agent paclitaxel in gynecologic malignancies. Gynecol Oncol 2001; 81:201-5. 27. VonGruenigen V, Karlen JR, Waggoner SE. A case of chronic paclitaxel administration in ovarian cancer. Gynecol Oncol 2003; 89:532-5. 28. Markman M, Liu PY, Wilczynski S, et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 2003; 21:2460-5. 29. Markman M, Liu P, Wilcyznski S, et al. Survival of ovarian cancer patients treated on SWOG 9701/GOG178: 12 versus 3 cycles of monthly single-agent paclitaxel following attainment of a clinically-defined complete response to platinum/paclitaxel. J Clin Oncol 2006; 24(18 suppl):257s (Abstract 5005). 30. Conte PF, Favalli G, Gadducci A, et al. Final results of After-6 protocol 1: a phase III trial of observation versus 6 courses of paclitaxel in advanced ovarian cancer patients in complete response after platinum-paclitaxel chemotherapy. J Clin Oncol 2007; 25(18 suppl):275s (Abstract 5505), 31. De Placido S, Scambia G, Di VG, et al. Topotecan compared with no therapy after response to surgery and carboplatin/paclitaxel in patients with ovarian cancer: Multicenter Italian Trials in Ovarian Cancer (MITO-1) randomized study. J Clin Oncol 2004; 22:2635-42. 32. Pfisterer J, Weber B, Reuss A, et al. Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a gynecologic cancer intergroup trial of the AGO-OVAR and GINECO. J Natl Cancer Inst 2006; 98:1036-45. 33. Rothenberg ML, Liu PY, Wilczynski S, et al. Phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer: a Southwest Oncology Group trial (SWOG9326). Gynecol Oncol 2001; 82:317-22. 34. Sabbatini P, Odunsi K. Immunologic approaches to ovarian cancer treatment. J Clin Oncol 2007; 25:2884-93. 35. Hall GD, Brown JM, Coleman RE, et al. Maintenance treatment with interferon for advanced ovarian cancer: results of the Northern and Yorkshire gynaecology group randomized phase III study. Br J Cancer 2004; 91:621-6. 36. Alberts DS, Hannigan EV, Liu PY, et al. Randomized trial of adjuvant intraperitoneal alpha-interferon in stage III ovarian cancer patients who have no evidence of disease after primary surgery and chemotherapy: an Intergroup study. Gynecol Oncol 2006; 100:133-8. 37. Kaye SB. Bevacizumab for the treatment of epithelial ovarian cancer: will this be its finest hour? J Clin Oncol 2007; 25:5150-2.
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