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Ovarian Carcinoma Treated with High-Dose Chemotherapy and Autologous Stem Cell Transplantation
Abstract & Commentary
Synopsis: Patients in clinical remission are most likely to benefit from autologous transplantation, with the exception of patients with clear cell histology.
Source: Donato ML, et al. Bone Marrow Transplant. 2004 May 3. (E-pub ahead of print).
In an effort to identify important characteristics defining progression-free and overall survival in patients with advanced-stage recurrent or progressive ovarian cancer, Donato and colleagues studied 96 patients undergoing 3 high-dose chemotherapy regimens. Over the 77-month accrual period, 102 autologous peripheral stem cell transplantations were delivered. The regimens studied were paclitaxel and carboplatin (PC), topotecan-melphalan-cyclophosphamide (TMC), and cyclophosphamide-BCNU-thiotepa (CBT). A heterogeneous cohort of patients made up the study population including 43% in clinical complete response, 34% in partial response to prior chemotherapy, 18% with progressive disease, and 5% with stable disease. Repeat transplantation was administered to 6 patients. The majority of the patient cohort had serous histology although a small subset was clear cell carcinoma. All patients were required to be "physiologically" 60 years of age or younger and have adequate metabolic chemistries. Differing methodologies for blood stem cell mobilization and collection were used over the years of the trial representing refinement in technique, but importantly no transplant-related mortality was observed. Median follow-up for the entire study population was 18 months (3.5-68 months).
Overall, the 6-year survival was 38%. For patients receiving transplantation for remission consolidation, the 6-year survival was 53% and progression-free survival, 29% (median 20 months). Evaluating important predictive survival characteristics, Donato and associates identified clear cell histology and disease status other than complete remission as adverse prognostic factors. Although different populations were studied among the 3 regimens, the TMC combination appeared to be superior for survival characteristics, likely representing the benefit from chemotherapeutics that are non-cross resistant with standard front-line agents. Donato et al call for continued work in the consolidation setting given the results from this patient collection.
Comment by Robert L. Coleman, MD
It is a not uncommon occurrence and a distinctly disappointing situation when a patient’s tumor recurs after being declared "in remission." The chemosensitivity of ovarian cancer lends itself fittingly to the emotional roller coaster a patient suffers following the frequent regression-and-recurrence cycle that this difficult-to-eradicate tumor poses. Unfortunately, it is well documented that most patients who suffer a recurrence ultimately lose this war despite an occasional battle win. Many efforts to derail this pattern have been tried including modifications to surgery, chemotherapy, and even radiation. Novel strategies such as prolonged standard chemotherapy, high-dose chemotherapy, intraperitoneal chemotherapy and radiation, consolidation chemotherapy, biological therapy, and gene therapy have been investigated with few, if any, demonstrating clear survival advantage to these patients. Nonetheless the endeavor continues, as the prize is high.
The current study by Donato et al is a good example of the effort being extended. One treasured end point of solid tumor chemotherapy treatment is to find a way to overcome acquired resistance to conventional agents. Bolstered by in vitro and in vivo data of a dose-response correlation, high-dose chemotherapy would seemingly be a "high-benefit" approach, if it could be delivered safely. Previous work in dose intensification using conventional agents without hematopoietic support has not shown an advantage; and initial evaluation of high-dose strategies demonstrated excessive toxicity. However, much has been learned about this latter technique including use of peripheral blood to source hematopoietic progenitors, improved supportive care, and better patient selection. Morbidity and mortality from high-dose chemotherapy has dropped significantly and evaluation of specific myeloablative chemotherapy combinations, as seen in the current study, has been accomplished.
While the results from this and other single institution high-dose series show some promising response and survival characteristics, they are difficult to evaluate not only against one another but also against our collective experience with conventionally dosed chemotherapy.1,2 Donato et al argue that those patients in clinical remission or those found with minimal disease at second look represent the best patients to undergo this intensive treatment. This same patient population has also been targeted for conventionally dosed consolidation strategies. In a recent randomized trial comparing 3 vs 12 cycles of intravenous paclitaxel in patients with clinical remission (Gynecologic Oncology Group Trial #178), Markman and colleagues reported the 12-cycle arm produced a significantly improved median progression free survival of 29 months.3 This seemingly compares favorably with the 20-month progression-free survival reported by Donato et al in the current report. Survival data are not available in the GOG study, so it is unknown in what context the observed 53% 6-year survival would abide. However, this number is laudable and the oncology community would welcome further development of this modality if it can safely improve the lives women with ovarian cancer.
1. Omura GA, et al. J Clin Oncol. 2003;21:2843-2848.
2. Schilder RJ, et al. Gynecol Oncol. 2003;88:3-8.
3. Markman M, et al. J Clin Oncol. 2003;21(13): 2460-2465.
Robert L. Coleman, MD, Dept. of Gynecologic Oncology, University of Texas Southwestern Medical Center, Dallas, TX, is Associate Editor for OB/GYN Clinical Alert.