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Journal of Clinical Oncology, Vol 24, No 4 (February 1), 2006: pp. 537-539 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.5138
Consolidation for Ovarian Cancer in RemissionMemorial Sloan-Kettering Cancer Center, New York, NY The treatment course for advanced ovarian cancer is marked both by chemotherapy sensitivity at the outset and by eventual death from resistant disease in patients who relapse. Aggressive surgical debulking and platinum plus taxane therapy have improved median survival from 1 year in 1975 to approximately 5 years in 2005, but the long-term cure rate continues to languish in the 20% to 30% range.1 Approximately 50% of patients will enter a pathologic first complete clinical remission, yet 90% of suboptimally debulked patients and 70% of optimally debulked patients relapse in 18 to 24 months. Subsequent and repeated chemotherapy responses are often seen with ever shortening intervals until broad chemotherapy resistance develops.2 Opportunities to improve the outcome for patients exist by making primary therapy more effective, or by applying consolidation or maintenance approaches to patients in a complete primary or subsequent remission. Well-designed randomized studies such as the SMART study by Verheijen et al3 in complete clinical remission patients represent a new opportunity for progress. The SMART study, evaluating intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody (90Y-muHMFG1), described in this issue of the Journal of Clinical Oncology, was logically based and appropriately designed. Ovarian cancer patients usually have disease localized to the peritoneal cavity at the time of progression, thus providing a rationale for intraperitoneal (IP) therapy. The small volume of disease during remission is appropriate to consider an immune mechanism. The MUC 1 antigen that 90Y-muHMFG1 is directed towards is well established as an attractive immunotherapy target since it is overexpressed on 90% of adenocarcinomas, including ovarian cancer. The phase II data supporting the use of 90Y-muHMFG1 administered intraperitoneally in patients in first remission was promising, with a Cox model estimate of 10-year survival at 70% compared to 32% of case matched controls (P = .003).4 Patients were stratified using a second surgical assessment where disease status at second look remains a powerful predictor of ultimate progression free and overall survival.5 Finally, the study was adequately powered to answer the question as to whether a single intraperitoneal administration of 90Y-muHMFG1 for patients in remission impacted outcome. While the negative therapeutic results are disappointing and one can speculate whether changing frequency or dose could affect efficacy, the trial serves as the largest prospective randomized study of patients in a surgically defined remission population with overall survival as the outcome. The outcome of this trial reminds us all that randomized trials are the only reasonable way to move cancer therapy forward. The value of treatment in clinical complete remission was first established in acute leukemia and additional consolidation or maintenance chemotherapy dramatically improved the outcome for some of these patients. These concepts have not found a place in solid tumor therapy.6 Even the nomenclature is confusing. Strictly speaking, consolidation should be best applied to those strategies that are of limited duration such as high-dose chemotherapy or whole abdominal radiotherapy, and maintenance is best used to describe interventions that continue for years (or until progression). As treatment options move beyond classic cytotoxic chemotherapy to hormones, immune interventions, and targeted therapy, the consolidation strategy is regaining interest in solid tumors. A recent study, for example, showed the benefit of consolidation trastuzumab for one year in patients with breast cancer.7 In ovarian cancer, no randomized consolidation study has provided a statistically significant improvement in overall survival, although many attempts have been made. Negative randomized consolidation approaches include both subcutaneous and IP interferon-alfa,8,9 high-dose chemotherapy,6 continued intravenous carboplatin versus whole abdominal radiotherapy (WART),10 chemotherapy versus observation versus WART,11 IP radioactive phosphorus (32P),12 noncross resistant chemotherapy in the form of cisplatin and fluorouracil for three cycles13or topotecan for four cycles,14 and the monoclonal antibody orgovomab which targets CA-125.15 With regards to IP cytotoxic chemotherapy as consolidation, no adequately powered randomized study versus observation has been completed. The only randomized study to show evidence of clinical benefit was the Southwest Oncology Group/Gynecologic Oncology Group study of ovarian cancer patients receiving three versus 12 additional cycles of intravenous paclitaxel following a complete response to platinum and paclitaxel therapy. This study showed a progression free survival advantage of 28 months versus 21 months in favor of the 12 cycle arm (hazard ratio [HR], 2.31; 99% CI, 1.08 to 4.94). Survival data is not available due to its early termination by the data safety monitoring committee.16 With the important exception of the paclitaxel consolidation study, the extended chemotherapy trials and radiotherapy treatments have been disappointing. A variety of clinical observations have supported the role of the immune system in determining the outcome of patients with ovarian cancer. In a study by Zhang et al with 74 patients in complete clinical remission (ie, the consolidation population), 5-year overall survival was 73.9% in those whose tumors were found to have infiltrating T lymphocytes present versus 11.9% in those that did not (P < .001).17 The characterization of surface antigens and the identification of MUC 16 as the CA-125 antigen have increased the potential number of targets for immune directed therapies.18 Orgovomab, a monoclonal antibody targeting CA-125, illustrates the passive immune approach; while the randomized study was negative, an increase in progression-free survival was seen in a subset of patients with favorable characteristics, which are now being studied prospectively.19 Numerous other antibodies are in clinical development, either alone or conjugated to specific toxins. Other investigators are developing methods to consider adoptive T-cell therapy based on preliminary data in other tumor types.20 Strategies to elicit active immunity are demonstrated by the anti-id antibody ACA125, which has shown improved outcomes in patients who develop antibody in nonrandomized trials supporting the need for further study.20 A variety of other vaccine approaches targeting telomerase, blood group antigens, and tumor related mucins are also under development. Finally, attempts to overcome immune tolerance, which is one of the most significant impediments to immune based therapy, is underway with studies of the human anti-CTLA-4 monoclonal antibody.21 These examples provide an impetus to continue to investigate passive, active, and immune-facilitated approaches. The negative results of the SMART trial should not end exploration of consolidation strategies. The large prospective population studied by Veheijen can help us learn about nontraditional prognostic factors, such as nadir CA-125, LPAAT-ß, or vascular endothelial growth factor, that can help stratify remission patients into homogeneous groups beyond those such as stage and grade.22-24 These strata may also lend themselves to preselecting patients to consider appropriate investigational interventions. In the end, patient participation in a clinical trial of consolidation is the only rational alternative to a difficult watch and wait strategy. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. Author Contributions
Acknowledgment Supported in part by Grant No. PO1 CA52477 from the National Cancer Institute. NOTES "Judge of a man by his questions rather than by his answers." Voltaire (1694–1778) REFERENCES
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Zhang L, Conejo-Garcia JR, Katsaros D, et al: Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:203-213, 2003 18. Berek JS, Taylor PT, Gordon A, et al: Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer. J Clin Oncol 22:3507-3516, 2004 19. Dudley ME, Wunderlich JR, Robbins PF, et al: Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850-854, 2002 20. Reinartz S, Kohler S, Schlebusch H, et al: Vaccination of patients with advanced ovarian carcinoma with the anti-idiotype ACA125: immunological response and survival (phase Ib/II). Clin Cancer Res 10:1580-1587, 2004 21. Ribas A, Camacho LH, Lopez-Berestein G, et al: Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. 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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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