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© 2002 American Society for Clinical Oncology
Recurrent Ovarian Cancer: Evidence-Based TreatmentFox Chase Cancer Center, Philadelphia, PA DESPITE ADVANCES in surgery and the development of more effective chemotherapy, epithelial ovarian cancer remains the number one cause of death from a gynecologic cancer in the United States and in the rest of the Western world.1 Although overall survival has been only modestly improved, the disease has become more chronic in nature. In the 1960s, approximately one third of the patients survived 5 years, whereas now the 5-year survival rate is over 50%. These statistics emphasize the differences in the management of patients with previously untreated advanced disease compared with those patients with recurrent disease. Because long-term survival and cure are possible in patients with advanced ovarian cancer, the initial approach consists of aggressive surgery followed by combination chemotherapy. Based on a series of well-controlled prospective randomized trials, the combination of carboplatin plus paclitaxel is generally accepted as the current regimen of choice.2-5 Throughout the world, carboplatin plus a taxane (usually paclitaxel) is the control arm of most current randomized trials in which new combination chemotherapy regimens are being evaluated. Most patients with advanced disease will achieve a clinical complete remission with such combinations, although median time to progression will range from 18 to 24 months, depending on the volume of disease at the time therapy is initiated. When patients recur, the goal of therapy changes from curative to palliative. Recurrent ovarian cancer invariably is fatal, but patients can have meaningful palliation and good quality of life when judiciously treated with surgery, radiation, and chemotherapy. Because most patients recur, the treatment of recurrent disease is an important aspect in the overall management of patients with epithelial ovarian cancer. In contrast to the situation in previously untreated patients in whom prospective randomized phase III trials have established the current standard, in patients with recurrent disease there have been few, if any, randomized trials that have clearly demonstrated a survival advantage for a particular drug or regimen. In addition, a series of agents have been shown to have clinical activity in recurrent ovarian cancer, including topotecan,6 pegylated liposomal doxorubicin,7 gemcitabine,8 and oral etoposide.9 It has also been demonstrated that re-treatment with a platinum drug or taxane has been associated with significant clinical activity in patients with recurrent disease.10-13 The majority of studies demonstrated the length of the disease-free interval as an important factor in selection of second-line agents. Patients with a disease-free interval greater than 6 months have been categorized as platinum-sensitive. Outside of clinical trials, they are frequently treated with carboplatin, paclitaxel, or a combination of both drugs. Because the likelihood of response to platinum is dependent on the length of the disease-free interval, some have suggested that this interval be increased by treating platinum-sensitive patients with nonplatinum agents and reserving re-treatment with platinum for when nonplatinum agents are no longer effective, at which point the platinum-free interval will have been increased. Consequently, it is hypothesized that these patients would still have a high likelihood of responding to platinum.14 The heterogeneity in the recurrent ovarian cancer population, the availability of numerous active agents, and reports of higher response rates for drugs when used in combination15 all contribute to controversy regarding the optimum management of patients with recurrent ovarian cancer. Dizon et al16 from Memorial Sloan-Kettering attempt to address one of these controversies in a retrospective analysis of a combination of carboplatin and paclitaxel as initial second-line therapy for recurrent epithelial ovarian cancer. Based on this report, it is probable that more patients with platinum-sensitive disease will now be treated with a combination of carboplatin and paclitaxel because of the high response rate and prolonged survival reported. The authors include a word of caution with regard to interpretation of these results and make a plea for randomized trials. However, the data, and their interpretation, require more than a mere cautionary note. No conclusions can be drawn from this retrospective study. Patients and physicians should not accept this as evidence-based justification for the routine use of paclitaxel plus carboplatin in the routine treatment of ovarian cancer patients with recurrent platinum-sensitive disease. Selection bias has been a well-recognized factor that must be taken into account in evaluating the results of any cancer treatment. Anecdotal experience and nonprotocol treatments are fatally flawed by selection bias and have little, if any, general applicability, hence the need for prospective randomized trials carefully stratified for known prognostic factors. Ovarian cancer is a very heterogeneous disease and outcome can be influenced by a wide variety of clinical factors, including stage, volume of disease (before and after cytoreductive surgery), histologic type, grade, age, and performance status. This report is a retrospective review of 244 patients who were treated for recurrent ovarian cancer over a 7-year period, of whom 89 (36.5%) were selected to receive combination chemotherapy with carboplatin plus paclitaxel. To be eligible for this analysis, patients must have had a clinical complete remission that lasted for at least 6 months after front-line therapy. It is not clear how many patients in this database who were eligible based on the disease-free interval did not receive combination chemotherapy and were instead treated with single agents. The heterogeneity in this patient population is important to re-emphasize. Patients received different initial chemotherapy regimens (although they all included platinum-based therapy), some patients received secondary cytoreduction before initiation of carboplatin plus paclitaxel, and some patients were treated with the combination when their only evidence of measurable disease was an increasing CA-125 level. Treatment with carboplatin plus paclitaxel was also not based on any protocol that would have standardized therapy. It is probable that numerous factors were used by clinicians to select patients for treatment with the combination: long length of treatment-free interval (median, 22 months), low age (median, 51 years), and low volume of disease (13% with CA-125 elevations as only indicator of relapse and 25% with relaparotomy before chemotherapy). All these factors are generally associated with a more favorable outcome. It is, therefore, not possible to compare the complete response rate of 42.4% to a prospective phase II or III trial in a well-defined patient population. Similarly, although the median progression-free survival for the entire cohort was 13 months, with a 3-year survival rate of 72%, selection bias once again makes it impossible to make any conclusions regarding the benefit of combination chemotherapy. The favorable outcome may primarily be the result of favorable biologic and clinical factors. Although there are yet no results from randomized trials comparing single-agent carboplatin versus the combination of carboplatin plus paclitaxel in patients with platinum-sensitive recurrent ovarian cancer, the results of a large Gynecologic Oncology Group (GOG) prospective phase III randomized trial in previously untreated patients suggest what might be the expected outcome from such a trial. In GOG 132,17 638 previously untreated patients were randomized to receive either single-agent cisplatin, single-agent paclitaxel, or the combination of paclitaxel plus carboplatin. Paclitaxel-treated patients had a response rate of 42%, compared with 67% for cisplatin and 66% for the combination. There was no difference in overall survival for the three treatment groups, which likely reflects the fact that patients randomized to single-agent treatment with either paclitaxel or cisplatin were frequently crossed over, at times even before progression, to the other agent. Consequently, GOG 132 may represent a study of combination chemotherapy compared with sequential therapy with the same agents. The fact that a survival advantage could not be demonstrated with initial immediate combination chemotherapy in untreated patients strongly suggests that a prospective randomized trial would also fail to demonstrate an improvement in survival for the use of combination paclitaxel plus carboplatin compared with the sequential application of carboplatin until development of resistance and then treatment with single-agent paclitaxel (or other second-line agent). If carboplatin plus paclitaxel does produce a higher response rate in platinum-sensitive recurrent ovarian cancer (even though there is no evidence that survival is improved), why not use such a combination as initial treatment in this group of patients? The answer relates to what is generally recognized as the primary goal of therapy in recurrent ovarian cancer, palliation. Because cure is not a realistic possibility in these patients, toxicity becomes a major consideration in selection of second-line treatment. The lack of quality-of-life data and the incomplete toxicity assessment provided by Dizon et al16 represents another problem associated with such retrospective chart reviews. In the absence of requirements for protocol assessment of toxicity, it is possible that patients and physicians underreported toxicities. Alopecia associated with combination chemotherapy compared with single-agent carboplatin is not even mentioned in this retrospective study, and in this patient population with a long disease-free interval before initiation of chemotherapy, this is an important consideration. Even more importantly with regard to quality of life is the lack of meaningful data relating to the neurotoxicity of combination chemotherapy in these patients. Dizon et al16 report on only one patient who stopped therapy due to progressive sensory neuropathy. Even in previously untreated patients who received combination chemotherapy with paclitaxel plus carboplatin, the incidence of grade 2 or 3 neurotoxicity is almost 30%.5 Re-treatment with this combination would certainly be expected to pro-duce more neurotoxicity than treatment with single- agent carboplatin. Evidence-based treatment for recurrent ovarian cancer will require prospective randomized trials comparing efficacy, toxicity, and quality of life. At least two such trials are in progress in Europe, in which patients with recurrent ovarian cancer are randomized to receive treatment with either paclitaxel plus platinum or platinum alone (International Collaboration on Ovarian Neoplasms IV) or to treatment with single-agent carboplatin or to a combination of gemcitabine plus carboplatin (Arbeitsgemeinschaft Gynäkologische Onkologie trial). Until the completion of prospective randomized trials in well-defined patient populations, single-agent treatment with carboplatin is recommended for the majority of patients with platinum-sensitive recurrent ovarian cancer. Results of retrospective analyses of selected patients treated outside of a clinical trial do not provide for evidence-based recommendations and unfortunately may lead to increased use of a more toxic, but not more efficacious, treatment. REFERENCES
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Piccart MJ, Bertelsen K, James K, et al: Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: Three-year results. J Natl Cancer Inst 92: 699-708, 2000 4. duBois A, Luenck HJ, Meier W, et al: Cisplatin/paclitaxel vs carboplatin/paclitaxel in ovarian cancer: Update of an Arbeitsgemeinshaft Gynaekologische Onkologie (AGO) Study Group trial. Proc Am Soc Clin Oncol 18: 356a, 1999 (abstr 1374) 5. Ozols RF, Bundy BN, Fowler J, et al: Randomized phase III study of cisplatin (CIS)/paclitaxel (PAC) versus carboplatin (CARBO)/PAC in optimal stage III epithelial ovarian cancer (OC): A Gynecologic Oncology Group Trial (GOG 158). Proc Am Soc Clin Oncol 18: 356a, 1999 (abstr 1373) 6. Bookman MA, Malmstrom H, Bolis G, et al: Topotecan for the treatment of advanced epithelial ovarian cancer: An open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. J Clin Oncol 16: 3345-3352, 1998[Abstract]
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McGuire WP, Blessing JA, Bookman MA, et al: Topotecan has substantial antitumor activity as first-line salvage therapy in platinum-sensitive epithelial ovarian carcinoma: A Gynecologic Oncology Group study. J Clin Oncol 18: 1062-1067, 2000
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Muggia FM, Braly PS, Brady MF, et al: Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 18: 106-115, 2000 This article has been cited by other articles:
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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