Aebi, S.

Castiglione-Gertsch, M.

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Annals of Oncology 12: 583-584, 2001.© 2001 Kluwer Academic Publishers. Primed in the NetherlandsEditorialHigh-dose chemotherapy for ovarian cancer: Are we ready to go?"The wise man doesn't give the right answers, he poses the right questions."-Claude Levi-StraussSixty to seventy percent of patients with invasive epithe-lial ovarian cancer have chemotherapy-sensitive tumors.Nevertheless, despite excellent responses most of thetumors eventually recur and the patients die of thedisease. Numerous mechanisms have been invoked toexplain the emergence of drug resistance, one of thembeing inadequate dose intensity during the initial treat-ment resulting in the selection of resistant cell clones.An increase of the dose of chemotherapy is the logicalconsequence of this observation.Prior to the 'taxane era' several randomized trialsinvestigating platinum dose intensity failed to demon-strate benefit for moderate increases in chemotherapydosage without stem cell support [1-7]. The standardregimens in these trials usually contained cisplatin at adosage of 50 mg/m2 or carboplatin at a projected areaunder the curve (AUC) of 4-6 mg/ml • min. Only theScottish trial reported that a higher dose of cisplatin(100 mg/m2) yielded an advantage in terms of survival[8]. This study, however, has been criticized for theunexplained poor outcome of the patients in the lowerdose arm. Overall, there is still no evidence fromrandomized trials suggesting that an increase of thedose intensity of cisplatin beyond 25 mg/m2/week orof carboplatin beyond an AUC of 6 mg/ml-min everythree weeks is beneficial [9].At this time, we are not aware of any randomizedclinical trial that would provide support for using higherthan standard doses of paclitaxel.those of the recently reported North Americanregistry study [13].• Clinical data were often unavailable: the extent ofresidual cancer after surgery or before beginninghigh-dose therapy was unknown for a relevantproportion of patients. The amount of residualtumor might have an important prognostic valueas illustrated by the substantially different out-comes reported by Legros (59% DFS at five years)[14] and Stiff (less than 20% DFS at five years) [15].• Toxicity data show a considerable percentage ofprocedure-related deaths (7%). Similar resultshave been reported by Stiff (11%) [13]; in recentyears, however, mortality decreased substantiallyto 3% with improvements in supportive measures.This paper clearly demonstrates that high-dose che-motherapy is feasible and reasonably safe in patientswith ovarian cancer. The results in terms of survival arecomparable to those in chemosensitive recurrences re-ported by Rose (median progression free survival ninemonths) using a standard dose paclitaxel/carboplatinregimen [16]. Unfortunately, the current retrospectiveregistry analysis does not allow the definition of sub-groups for which high-dose therapy is more effectivethan conventional therapy.In the light of the development of high-dose chemo-therapy in breast cancer, the authors of this report onthe same type of treatment for ovarian cancer are to becommended for avoiding the error of drawing prematureThe paper by Ledermann et al. in this issue [10]-^Lconclusions but for embarking on a randomized con-reports on one of the largest series of patients treatedwith high-dose chemotherapy in ovarian cancer. Mostof these patients have received high-dose chemotherapyin phase II studies or outside of a clinical trial. Healthagencies seem to be prepared to finance expensive treat-ments outside the context of clinical research, althoughthey are still reluctant to support the same therapieswithin randomized clinical trials.The paper reveals a few weak points that are unavoid-able in this type of retrospective study:• The data come from a registry report; therefore,the selection of patients is heterogeneous, and itis very likely that only patients with a relativelyfavorable prognosis were selected, as in similarprevious studies in breast cancer [11, 12]. Never-theless, the treatment results in terms of recur-rence-free and overall survival are very similar totrolled trial comparing modern conventional chemo-therapy with high-dose treatment with autologous stemcell support. Their effort merits the full support of theoncology community.S. Aebi' & M. Castiglione-Gertsch1'2' Institute of Medical Oncology, University of Bern,2 Swiss Institute of Applied Cancer Research,Bern, SwitzerlandReferences1 Colombo N, Piltelh MR, Parma G et al. Cisplatin (P) doseintensity in advance ovarian cancer (AOC): A randomized studyof conventional dose (DC) vs dose-intense (DI) cisplatin mono-chemotherapy. Proc Am Soc Clin Oncol 1993; 12.5842 Conte PF, Bruzzone M, Carnino F et al. High-dose versus low-dose cisplatin in combination with cyclophosphamide and epi-doxorubicin in suboptimal ovarian cancer- A randomized studyof the Gruppo Oncologico Nord-Ovest. J Clin Oncol 1996; 14 (2):351-6.3. Dittrich C, Obermair A, Kurz C et al Prospective randomizedtrial of cisplatin/carboplatin vs. conventional cisplatin/cyclo-phosphamide in epithelial ovarian cancer: First results of theimpact of platinum dose intensity on patient outcome (Meetingabstract). Proc Am Soc Clin Oncol 1996; 15.4. Gore M, Mainwaring P, A'Hern R et al. Randomized trial ofdose-intensity with single-agent carboplatin in patients with epi-thelial ovarian cancer. London Gynaecological Oncology Group.J Clin Oncol 1998, 16 (7): 2426-34.5. Jakobsen A, Bertelsen K, Andersen JE et al. Dose-effect study ofcarboplatin in ovarian cancer: A Danish Ovarian Cancer Groupstudy. J C1in Oncol 1997; 15(1): 193-8.6. McGuire WP, Hoskins WJ, Brady MF et al. Assessment of dose-intensive therapy in suboptimally debulked ovarian cancer: AGynecologic Oncology Group study J Clin Oncol 1995; 13 (7):1589-99.7 Ngan HY, Choo YC, Cheung M et al. A randomized study ofhigh-dose versus low-dose cis-platinum combined with cyclo-phosphamide in the treatment of advanced ovarian cancer. HongKong Ovarian Carcinoma Study Group. Chemotherapy 1989;35 (3). 221-7.8. Kaye SB, Paul J, Cassidy J et al. Mature results of a randomizedtrial of two doses of cisplatin for the treatment of ovarian cancer.Scottish Gynecology Cancer Trials Group J Clin Oncol 1996; 14(7): 2113-9.9 Thigpen JT. Dose-intensity in ovarian carcinoma: Hold, enough?^ J Clin Oncol 1997; 15 (4): 1291-3.10 Ledermann JA, Herd R, Maraninchi D et al. High-dose chemo-therapy for ovarian carcinoma: Long-term results from the SolidTumour Registry of the European Group for Blood and MarrowTransplantation (EBMT). Ann Oncol 2001; 12 (5): 693-9 (thisissue).11 Rahman ZU, Frye DK, Buzdar AU et al. Impact of selectionprocess on response rate and long-term survival of potential high-dose chemotherapy candidates treated with standard-dose doxo-rubicin-containing chemotherapy in patients with metastaticbreast cancer. J Clin Oncol 1997; 15 (10): 3171-7.12. Garcia-Carbonero R, Hidalgo M, Paz-Ares L et al. Patientselection in high-dose chemotherapy trials: Relevance in high-risk breast cancer. J C1in Oncol 1997; 15 (10): 3178-8413 Stiff PJ, Veum-Stone J, Lazarus HM et al. High-dose chemo-therapy and autologous stem-cell transplantation for ovariancancer' An autologous blood and marrow transplant registryreport. Ann Intern Med 2000; 133 (7)' 504-15.14. Legros M, Dauplat J, Fleury J et al. High-dose chemotherapywith hematopoietic rescue in patients with stage 111—IV ovariancancer: Long-term results. J Clin Oncol 1997; 15 (4): 1302-8.15. Stiff PJ, Bayer R, Kerger C et al. High-dose chemotherapy withautologous transplantation for persistent/relapsed ovarian can-cer. A multivariate analysis of survival for 100 consecutivelytreated patients. J Clin Oncol 1997; 15 (4): 1309-17.16. Rose PG, Fusco N, Fluellen L, Rodriguez M. Second-line therapywith paclitaxel and carboplatin for recurrent disease followingfirst-line therapy with paclitaxel and platinum in ovarian orperitoneal carcinoma J Clin Oncol 1998; 16(4). 1494-7.

High-dose chemotherapy for ovarian cancer: Are we ready to go?

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