Consolidation Therapy for Ovarian Cancer
Abstract
Purpose. To review all the published randomized trials of consolidation therapy in ovarian cancer, including chemotherapy, radiotherapy, and potential targeted/ biologic agents.
Design. A Medline search was conducted to identify all publications on consolidation therapy in ovarian cancer. Proceedings of national and international meetings were also searched.
Results. Platinum-based consolidation therapy is difficult to tolerate and does not confer a survival benefit. Prolonged Paclitaxel therapy lengthens the recurrence-free interval, with increased neurotoxicity. Intraperitoneal (IP) consolidation therapy is limited by marginal clinical acceptance and catheter-related complications. Oral consolidation regimens have not yet been evaluated in a randomized study. IP ^sup 32^P is ineffective. Whole- abdominal radiotherapy (WAR) improves the progression-free but not overall survival in selected patients. Late radiation toxicities remain a concern with WAR. Oregovamab, an antibody to CA-125, is presently under evaluation. To date, the impact of consolidation therapy on quality-of-life remains unclear.
Conclusion. An effective, minimally toxic agent for consolidation therapy in ovarian cancer has not yet been identified.
Introduction
Epithelial ovarian carcinoma is the leading cause of death from gynecologic malignancy in the United States. In 2004, there will be an estimated 25,580 new cases diagnosed and 16,090 women will die of the disease [1]. The majority of women diagnosed with ovarian cancer undergo aggressive surgical cytoreduction followed by combination paclitaxel/platinum-based chemotherapy. Despite a clinical complete response rate of 60-80%, only 20% will have a complete pathologic response (negative second look surgery) [2]. Of patients with a complete pathologic response, approximately 50% will recur, requiring additional chemotherapy [3,4].
Recurrent disease is difficult to treat. Although responses may be achieved, which extend the diseasefree interval and improve the quality of life, cures are rare with second-line therapy [5]. The concept of consolidation therapy following a complete clinical remission is not new. In hormone-receptor positive breast cancer, adjuvant hormonal therapy significantly reduces recurrence and mortality [6,7]. Similarly, the use of consolidation therapy following a complete response to initial chemotherapy in ovarian cancer could prevent or delay recurrence and potentially impact patient outcome. This review will focus on consolidation chemotherapy (IV, IP, oral), radiotherapy (IP ^sup 32^P, WAR), and potential targeted/biologic agents.
Consolidation chemotherapy
Intravenous platinum
As platinum-based regimens have been the cornerstone of ovarian cancer chemotherapy over the past several decades, one approach to consolidation has been to administer additional cycles of the same chemotherapeutic agent used in the front-line setting. There have been three randomized phase III studies reported to date. None of these support the efficacy of prolonged platinum for consolidation (Table I).
The North Thames Ovary Group randomized 233 ovarian cancer patients to receive five versus eight cycles of single-agent cisplatin or carboplatin given at four-weekly intervals [8]. Chemotherapy was initiated within 6 wks of surgery. As anticipated, stage and residual tumor following debulking correlated with survival and progression-free survival. There was no difference in survival or progression free survival between the two arms of the study.
Table I. Summary of Platininum-based Consolidation Trials: No survival advantage identified.
Nearly half (49%) of the patients randomized to eight cycles did not complete the treatment. Twenty-one percent (24/115) discontinued treatment due to disease progression and 10% (11/115) were discontinued due to toxicity. This study was limited not only by the use of single-agent platinum but also by failure to restrict randomization to platinum-sensitive disease.
Smaller studies comparing 5 versus 10 and 6 versus 12 cycles of cyclophosphamide, adriamycin, and cisplatin (CAP) also failed to demonstrate a survival benefit or improved rate of complete pathologic response between the two arms [9,1O]. These studies were limited by small numbers and failure to randomize patients with platinum-sensitive disease only.
Results from these randomized trials indicate that prolonged cisplatin chemotherapy ( > 6 cycles) is poorly tolerated, and there was no survival advantage identified.
Intravenous paclitaxel
As experience with paclitaxel evolved, it has been found to be highly cell cycle specific with enhanced activity noted with increased duration of exposure. This biologic activity, coupled with the success of paclitaxel in the management of ovarian cancer in both the first-line and recurrent setting, provided the rationale for use of paclitaxel as consolidation.
Prolonged paclitaxel administration can be safely administered to patients, including those who are heavily pretreated. Prolonged use of paclitaxel has been evaluated in two small non-randomized studies documenting safety and tolerability as well as extended disease- free survival in ovarian cancer patients with platinum sensitive disease [11,12].
Based on these favorable findings, the Southwest Oncology Group (SWOG) and the Gynecologic Oncology Group (GOG) designed a Phase III randomized trial of 12 versus 3-month maintenance paclitaxel in women with advanced ovarian cancer and complete clinical response to platinum/paclitaxel-based therapy [13]. Patients were initially treated at a paclitaxel dose of 175 mg/m^sup 2^ over 3 h every 28 days. Because several patients elected to discontinue protocol treatment due to grade 2 or 3 neuropathy (n = 10 in the 12-cycle arm; n = 3 in the 3-cycle arm), the paclitaxel dose was reduced to 135 mg/m^sup 2^.
Pre-determined interim analysis found a statistically significant improvement in time to progression in the 12-cycle arm, but showed no survival advantage between the arms. The median progression-free survival was 28 and 21 months in the 12-cycle and 3-cycle arms, respectively. The most notable difference in toxicity between the two groups was sensory neuropathy (grade 2 or 3) reported as 24% (23/ 97) versus 14% (15/109) in the 12-cycle and 3-cycle arms, respectively.
This study found that prolonged paclitaxel administration could delay the onset of disease progression by 7 months. Because the study was discontinued prematurely due to the statistically significant improvement in time to progression, the possibility of a survival advantage could not be ascertained. In the absence of a distinct survival advantage, it is equivocal whether 9 additional months of chemotherapy justifies the 7-month increase in the progression-free interval. Given the increased toxicity associated with prolonged therapy, quality-of-life and symptom-free survival should be considered in future trials designed to address the efficacy of maintenance chemotherapy.
Intraperitoneal chemotherapy
The intraperitoneal (IP) route of administering chemotherapy has long been of interest in the management of ovarian cancer. Given the pharmacokinetic advantage of the intraperitoneal versus intravenous route, efficacy trials were initiated [14]. Three Phase III randomized trials (GOG 104, 114, 172) have demonstrated improved progression-free survival with IP therapy in patients who had been optimally cytoreduced [15-17]. Given the favorable findings in the first-line setting, intraperitoneal consolidation therapy was evaluated in a randomized Phase III study [18]. The European Organization for Research and Treatment of Cancer (EORTC) evaluated IP cisplatin for consolidation in ovarian cancer patients with a complete pathologic remission after first-line chemotherapy. One hundred and fifty three patients were enrolled between 1988 and 1997. Patients were randomized to receive 4 courses of IP cisplatin (90 mg/m2 q3 wks) versus observation. Thirty nine patients (25%) did not receive the intended treatment (16 patients were ineligible; 25 patients had protocol violations). After a median follow-up of 8 years, 52% of patients progressed and 49% of patients died. Hazard ratios for OS and PFS with 95% CI are 0.89 (0.59-1.3) and 0.82 (0.52- 1.3) in favor of the intraperitoneal consolidation group. Although these results suggest a treatment benefit, due to low numbers, statistical significance was not achieved in this intent-to-treat analysis. Despite the potential benefit of intraperitoneal chemotherapy, this route of administration has failed to gain clinical acceptance. Most likely this is due to the high number of intraperitoneal catheter-related complications [17]. Improved methods of intraperitoneal administration, which result in fewer complications and less morbidity, are necessary before the potential benefits of IP therapy can be realized.
Oral chemotherapy
For consolidation to be optimal, the treatment should be efficacious, well tolerated, and minimally toxic. Oral regimens should be considered due to ease of administration. To date, oral consolidation in ovarian cancer has been evaluated only in a small Phase II clinical trial.
SWOG evaluated the feasibility of administering altretamine (Hexalen) as consolidation therapy to patients in clinical complet\e remission following front-line chemotherapy for Stage III ovarian cancer [19]. Patients received 260 mg/mz/day of oral altretamine in four divided doses for 14 days every 28 days. Intended duration of treatment was six cycles. One hundred and twelve patients were registered and 97 patients were valuable. Fifty-eight patients (60%) completed the 6month consolidation regimen. Twenty-four patients (25%) discontinued treatment due to toxicity (nausea, vomiting, neuropathy), 3% withdrew consent, and 9% were discontinued due to progressive disease. The most common Grade 3 toxicities were fatigue (7%), nausea (6%), and vomiting (3%).
Six-year survival data on these patients was recently reported [2O]. Median PFS was 28 (95% CI: 19-43) months. Median PFS for optimal disease was 45 (95% CI: 27-48) months and for suboptimal disease was 17 (95% CI: 12-26) months. Forty three percent (26/61) of those optimally debulked and 14% (5/36) of those suboptimally debulked remain disease-free. While median survival for suboptimally debulked patients was 39 months, median survival for optimally debulked patients has not yet been reached. Based on this data, the authors found altretamine consolidation to be generally well tolerated and associated with prolonged progression-free and overall survival. Dfinitive conclusions as to altretamine’s efficacy would require a randomized trial, which has not yet been proposed.
Other oral agents of interest are tamoxifen, thalidomide, and fenretinide. Although these drugs have not been evaluated in the consolidation setting, they have shown some activity in ovarian cancer and are generally well tolerated [21-24].
Radiotherapy
The role of radiotherapy in the management of ovarian cancer remains unresolved. Both intraperitoneal radioisotope administration (^sup 32^P) and whole abdominal radiotherapy (WAR) have been explored in a number of non-randomized trials [25]. A review of the literature suggests that consolidation with radiation therapy is more successful in patients with minimal or no residual disease. Whether the apparent survival benefit is due to radiotherapy or inherent tumor biology can only be answered in randomized clinical trials.
Intra-peritoneal radioactive phosphorus (^sup 32^P)
The Gynecologic Oncology Group (GOG) and the North Central Cancer Treatment Group (NCCTG) designed a prospective randomized clinical trial to evaluate the role of intraperitoneal ^sup 32^P for consolidation [26]. Patients with Stage III epithelial ovarian cancer and a complete pathologic response following frontline chemotherapy were eligible. Patients were randomized to no further therapy (n = 98) or treatment with 15 mCi IP ^sup 32^P (n=104). With a median follow-up of 63 months, the 5-year recurrence-free survival rate was 42% in the IP ^sup 32^P group and 36% in the control group (log-rank test, P = 0.27). Gastrointestinal toxicity was significantly higher in the treatment group (15%) compared to control (5%). There was no improvement in recurrence-free or overall survival. It was concluded that intraperitoneal ^sup 32^P is ineffective as consolidation for patients with ovarian cancer.
Whole Abdominal Radiation (WAR)
The concept of WAR as consolidation therapy has been explored. Radiotherapy in ovarian cancer is of interest as its activity may circumvent the issues of innate/acquired chemoresistance known to complicate the management of this disease. Historically, excitement for WAR has been tempered by reported acute hmatologie toxicities and delayed intestinal side effects [27-29]. Because the value of WAR has not been clarified by the small nonrandomized studies available, the Swedish-Norwegian Ovarian Cancer Study Group designed a randomized consolidation trial comparing WAR versus chemotherapy versus expectant management [30].
This study included 172 patients who were treated with four cycles of chemotherapy (cisplatin 50 mg/m2 with doxorubicin 50 mg/ m^sup 2^ or epirubicin 60 mg/m^sup 2^). Following second-look surgery, patients with complete pathologic responses (n = 98) were randomized to WAR versus chemotherapy (6 cycles of cisplatin plus doxorubicin or epirubicin) versus no treatment (Table II). The 74 patients who had residual microscopic disease were randomized to WAR versus chemotherapy.
For patients with complete pathologic response following induction chemotherapy, a progression-free survival advantage was identified in the WAR group (p = 0.034). The overall 5-year survival, however, was not improved (p = 0.084). Neither radiotherapy nor chemotherapy impacted the progression-free or overall survival in patients with microscopic disease.
Toxicities in patients treated with WAR were common. Fifty four percent of patients reported diarrhea and 22% reported dysuria. Delayed radiation complications occurred in 10% (7/69) of patients, four of whom required corrective ileostomy/colostomy. Chemotherapy was generally well tolerated.
Despite the improved progression-free survival among a subset of patients noted in this study, there was no overall survival benefit, and the toxicity of WAR was significant. Given recent progress in the field of radiation oncology and the introduction of Intensity Modulated Radiation Therapy (IMRT), additional randomized clinical studies with WAR should be considered.
Table II. Randomization arms of the Swedish-Norwegian Ovarian Cancer Study Group consolidation trial, for patients with a complete pathologic response to four cycles of chemotherapy [30].
Biologic therapy
Advances in translational research afford the opportunity for novel biologic agents to be introduced into clinical practice. Interferon-alpha and matrix mtalloproteinase (MMP) inhibitors have been evaluated in the consolidation setting. Although both were well tolerated, there was no survival advantage to either therapy [31,32].
Oregovamab (OvaRex), a monoclonal antibody specific for CA125, remains under evaluation as an immunotherapeutic in ovarian cancer. Immunotherapy is reported to be most effective in patients with minimal residual disease, making the consolidation setting ideal. Results from a recently completed placebo-controlled Phase II study of Ovarex versus placebo for consolidation of ovarian cancer patients was reported [33]. This study involved 67 patients who were optimally debulked ( < 2 cm) and in complete clinical remission following frontline chemotherapy (chemosensitive). Patients were then randomized to receive Ovarex or placebo, intravenously at 4, 8, and 12 wks, and q3 months until relapse. The results showed a trend toward prolonging the time to disease relapse (24.0 months in the Ovarex group versus 10.8 months in the Placebo group; p = 0.06). Induction of a measurable immune response (HAMA or Ab2) correlated with increased disease-free survival (p < 0.01). Ovarex was well- tolerated, with an adverse event profile and quality-of-life analysis similar to placebo.
Patients from this study continue to be followed for effect on long-term survival. Additional protocols are ongoing, to assess disease-free survival and quality-of-life with immunotherapy.
Conclusion
The management of women with ovarian cancer remains complex. Despite an excellent initial response to chemotherapy, the majority of patients will ultimately relapse. There is clearly a need to identify novel methods of consolidation, which improve both the progression-free and overall survival. Although chemotherapy (IV, IP, PO), radiation therapy (IP, WAR), and biologic agents have been explored for consolidation, conclusive evidence of a clinical benefit to the majority of patients is lacking. Key factors to consider in a consolidation trial include ease of administration, efficacy, toxicity, quality-of-life, and cost. As the molecular characteristics of ovarian carcinoma continue to be elucidated, the quest for novel, targeted therapies continues. Results from ongoing studies in chemoprevention (fenritinide, tamoxifen, COX-2 inhibitors) and therapeutic trials (antiangiogenics, tyrosine kinase inhibitors, vaccines and other immunologies) may transition to consolidation clinical trials. The identification of an effective, minimally toxic agent for consolidation therapy remains elusive but important.
Based on the presently available literature, there is little evidence to suggest a clinical benefit to the use of consolidation therapy beyond the initial six cycles of chemotherapy, outside the clinical trial setting.
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Gloria S. Huang, Gary L. Goldberg, & Abbie L. Fields
Department of Obstetrics & Gynecology and Women’s Health, Division of Gynecologic Oncology, Albert Einstein College of Medicine, Montefiore Medical Center
Copyright CRC Press Mar 2005