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High-Dose Chemotherapy in Ovarian Cancer: Still Waiting for the Right Study
Gynecologic Oncology 88, 1–2 (2003) doi:10.1006/gyno.2002.6934
EDITORIAL High-Dose Chemotherapy in Ovarian Cancer: Still Waiting for the Right Study Michele L. Donato, M.D. 1 Department of Blood and Marrow Transplantation, University of Texas M. D. Anderson Cancer Center, Box 423, 1515 Holcombe Avenue, Houston, Texas 77030-4095
Over the past decade numerous small phase I/II trials of high-dose chemotherapy for the treatment of ovarian cancer have been reported. The size of these studies, the wide variety of design, high toxicity, and lack of randomization have fueled the controversy on the use of such approaches. The trial reported in this issue of Gynecologic Oncology is no exception [1]. In this study, nine patients with optimally debulked stage III disease received three cycles of high-dose paclitaxel and carboplatin followed by one cycle of high-dose melphalan. The study end point was the second-look operation finding, and after only one patient (12.5%) achieved a pathological CR at second-look, the study was stopped early. The design of this study warrants a review of high-dose chemotherapy concepts and models. Dose intensification is defined as an increase in dose delivered over time. This dose rate is most often described in mg/m 2/week and an increase in dose rate is the overall goal of high-dose treatment. This is often achieved by either increasing the dose per cycle or decreasing the interval between doses (referred as dose density), or both. The end result should be that of increased dose rate and cumulative dose (total dose delivered). The first part of this study was designed to intensify the paclitaxel and carboplatin combination. But did it? Assuming that most patients would receive as part of standard treatment a minimum of 6 cycles of paclitaxel (175 mg/m 2) and carboplatin (5–7.5 mg 䡠 min/ml) administered every 21 days, the dose rate for the standard paclitaxel would be 70 mg/m 2/week with a cumulative dose of 1050 mg/m 2. The dose rate for the carboplatin would be 2–3 mg 䡠 min/ml/week, with a cumulative dose of 30 – 45 mg 䡠 min/ml. In this current study since only three cycles of paclitaxel and carboplatin were given at a 4- to 5-week interval, patients received a very similar dose intensity and cumulative dose: paclitaxel 75–95 mg/m 2/week, cumulative dose of 1050 mg/m 2, and carboplatin 4.5–5.6 mg 䡠 min/ ml/week, cumulative dose 45 mg 䡠 min/ml. With such a small increase in dose intensity and almost no increase in cumulative dose, it would be unrealistic to expect a significant advantage for the paclitaxel/carboplatin dose and schedule administered 1
in this study. It is clear however that this method of delivery leads to higher toxicity and thus six cycles of paclitaxel and carboplatin at standard doses is the preferable regimen. If similar dose intensity and cumulative dose are achieved, then why such a low rate of pathological complete remission? The expectation of a negative second-look operation in this patient population would be approximately 35%. One can only formulate hypotheses for the 12.5% achieved in the study group. Total duration of treatment and number of treatment cycles may be important factors. The authors make mention of one patient who was hospitalized prior to the start of therapy due to shortness of breath from tense ascites. This is not congruent with an optimally debulked patient and at least raises some questions about delays in treatment initiation. Also it is possible that, with a large confidence interval, the low rate could be attributed to chance and could be in the 35% range. The last part of this study consists of the administration of melphalan 140 mg/m 2 for consolidation. The concept of consolidation assumes that patients have achieved at least a complete clinical remission prior to the administration of a highdose chemotherapy agent. In all models, the optimal use of high-dose chemotherapy is for eradication of minimal residual disease. It is clear that in the current trial, melphalan was mostly used for remission induction, not consolidation. Highdose single-agent melphalan has been previously studied in ovarian cancer for the purpose of consolidation following second-look operation. In the study by Legros et al. [2] patients with macroscopic or no macroscopic disease at second-look operation had a 5-year DFS rate of 19.2 and 26.9% respectively. Bertucci et al. [3] showed a 5-year PFS of 29% for patients receiving a high-dose melphalan-based regimen for first remission consolidation. Not surprisingly, patients in a pathological complete remission had the most favorable results. Overall, it is unlikely that single-agent melphalan at 140 mg/m 2 could salvage patients with macroscopic residual disease. In retrospect, the failure to achieve adequate cytoreduction with the high-dose paclitaxel and carboplatin regimen did not allow patients to receive consolidation within melphalan’s expected scope of efficacy.
Fax: (713) 794-4902. E-mail: [email protected]. 1
0090-8258/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.
2
EDITORIAL
Fairly extensive phase II data are available for remission consolidation in ovarian cancer but, unfortunately, selection biases have made it impossible to draw strong conclusions from any of these trials. Recently, the European Blood and Marrow Transplant (EBMT) registry reported on 254 patients with ovarian cancer treated with high-dose chemotherapy. Patients with stage III disease transplanted in first complete or partial remission (pathological) had a median survival of 59 months [4]. Preliminary data are available from one small randomized study by Cure et al. [5]. One hundred ten patients with advanced ovarian cancer showing chemotherapy sensitivity at second-look operation were randomized to receive either 3 cycles of standard dose cyclophosphamide and carboplatin or 1 high-dose cycle of the same drugs. With a median follow-up of 36 months the progression-free survival is superior for the high-dose arm (22 months vs 11 months). It is clear that a large, well-designed randomized trial is needed. The transplant arm should ensure that the goal of significantly increasing the dose intensity is reached. If highdose chemotherapy with stem cell transplantation is shown to be superior in such a study, the current standard of care would need to be reassessed. It is therefore important that the design of the transplant arm allow its broad application. Treatmentrelated morbidity, mortality, quality of life, and cost should be evaluated. Unfortunately, as demonstrated in the current study, multiple cycles of chemotherapy agents which allow only a marginal increase in dose intensity can significantly impair
quality of life over many months of treatment and lead to disappointing results. Remission consolidation by a single cycle of high-dose multiagent chemotherapy may be more easily delivered and may be better supported by the available phase II data. If provided with a well-designed randomized study, support from the medical community would hopefully allow the successful completion of such a trial, and finally give us long-awaited answers. REFERENCES 1. Schilder R, Brady MF, Spriggs D, Shea T. Pilot evaluation of high-dose carboplatin and paclitaxel followed by high-dose melphalan supported by peripheral blood stem cells in previously untreated advanced ovarian cancer. Gynecol Oncol 88:3– 8, 2003. 2. Legros M, Dauplat S, Fleury J, et al. High-dose chemotherapy with hematopoietic rescue in patients with stage III to IV ovarian cancer: Long-term results. J Clin Oncol 15:1302– 8, 1997. 3. Bertucci F, Viens P, Delpero JR, et al. High-dose melphalan-based chemotherapy and autologous stem cell transplantation after second look laparotomy in patients with chemosensitive advanced ovarian carcinoma: long-term results. Bone Marrow Transplant 26:61–7, 2000. 4. Ledermann JA. High-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) in ovarian cancer. Int J Gynecol Cancer 10(Suppl 1):53– 6, 2000. 5. Cure´ H, Battista H, Guastalla JP, et al. Phase III randomized trial of high-dose chemotherapy (HDC) and peripheral blood stem cell (PBSC) support as consolidation in patients (pts) with responsive low-burden advanced ovarian cancer (AOC): preliminary results of a GINECO/FNCLCC/SPGM-TC study. Proc Am Soc Clin Oncol 815a, 2001. (abstract)
EDITORIAL High-Dose Chemotherapy in Ovarian Cancer: Still Waiting for the Right Study Michele L. Donato, M.D. 1 Department of Blood and Marrow Transplantation, University of Texas M. D. Anderson Cancer Center, Box 423, 1515 Holcombe Avenue, Houston, Texas 77030-4095
Over the past decade numerous small phase I/II trials of high-dose chemotherapy for the treatment of ovarian cancer have been reported. The size of these studies, the wide variety of design, high toxicity, and lack of randomization have fueled the controversy on the use of such approaches. The trial reported in this issue of Gynecologic Oncology is no exception [1]. In this study, nine patients with optimally debulked stage III disease received three cycles of high-dose paclitaxel and carboplatin followed by one cycle of high-dose melphalan. The study end point was the second-look operation finding, and after only one patient (12.5%) achieved a pathological CR at second-look, the study was stopped early. The design of this study warrants a review of high-dose chemotherapy concepts and models. Dose intensification is defined as an increase in dose delivered over time. This dose rate is most often described in mg/m 2/week and an increase in dose rate is the overall goal of high-dose treatment. This is often achieved by either increasing the dose per cycle or decreasing the interval between doses (referred as dose density), or both. The end result should be that of increased dose rate and cumulative dose (total dose delivered). The first part of this study was designed to intensify the paclitaxel and carboplatin combination. But did it? Assuming that most patients would receive as part of standard treatment a minimum of 6 cycles of paclitaxel (175 mg/m 2) and carboplatin (5–7.5 mg 䡠 min/ml) administered every 21 days, the dose rate for the standard paclitaxel would be 70 mg/m 2/week with a cumulative dose of 1050 mg/m 2. The dose rate for the carboplatin would be 2–3 mg 䡠 min/ml/week, with a cumulative dose of 30 – 45 mg 䡠 min/ml. In this current study since only three cycles of paclitaxel and carboplatin were given at a 4- to 5-week interval, patients received a very similar dose intensity and cumulative dose: paclitaxel 75–95 mg/m 2/week, cumulative dose of 1050 mg/m 2, and carboplatin 4.5–5.6 mg 䡠 min/ ml/week, cumulative dose 45 mg 䡠 min/ml. With such a small increase in dose intensity and almost no increase in cumulative dose, it would be unrealistic to expect a significant advantage for the paclitaxel/carboplatin dose and schedule administered 1
in this study. It is clear however that this method of delivery leads to higher toxicity and thus six cycles of paclitaxel and carboplatin at standard doses is the preferable regimen. If similar dose intensity and cumulative dose are achieved, then why such a low rate of pathological complete remission? The expectation of a negative second-look operation in this patient population would be approximately 35%. One can only formulate hypotheses for the 12.5% achieved in the study group. Total duration of treatment and number of treatment cycles may be important factors. The authors make mention of one patient who was hospitalized prior to the start of therapy due to shortness of breath from tense ascites. This is not congruent with an optimally debulked patient and at least raises some questions about delays in treatment initiation. Also it is possible that, with a large confidence interval, the low rate could be attributed to chance and could be in the 35% range. The last part of this study consists of the administration of melphalan 140 mg/m 2 for consolidation. The concept of consolidation assumes that patients have achieved at least a complete clinical remission prior to the administration of a highdose chemotherapy agent. In all models, the optimal use of high-dose chemotherapy is for eradication of minimal residual disease. It is clear that in the current trial, melphalan was mostly used for remission induction, not consolidation. Highdose single-agent melphalan has been previously studied in ovarian cancer for the purpose of consolidation following second-look operation. In the study by Legros et al. [2] patients with macroscopic or no macroscopic disease at second-look operation had a 5-year DFS rate of 19.2 and 26.9% respectively. Bertucci et al. [3] showed a 5-year PFS of 29% for patients receiving a high-dose melphalan-based regimen for first remission consolidation. Not surprisingly, patients in a pathological complete remission had the most favorable results. Overall, it is unlikely that single-agent melphalan at 140 mg/m 2 could salvage patients with macroscopic residual disease. In retrospect, the failure to achieve adequate cytoreduction with the high-dose paclitaxel and carboplatin regimen did not allow patients to receive consolidation within melphalan’s expected scope of efficacy.
Fax: (713) 794-4902. E-mail: [email protected]. 1
0090-8258/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.
2
EDITORIAL
Fairly extensive phase II data are available for remission consolidation in ovarian cancer but, unfortunately, selection biases have made it impossible to draw strong conclusions from any of these trials. Recently, the European Blood and Marrow Transplant (EBMT) registry reported on 254 patients with ovarian cancer treated with high-dose chemotherapy. Patients with stage III disease transplanted in first complete or partial remission (pathological) had a median survival of 59 months [4]. Preliminary data are available from one small randomized study by Cure et al. [5]. One hundred ten patients with advanced ovarian cancer showing chemotherapy sensitivity at second-look operation were randomized to receive either 3 cycles of standard dose cyclophosphamide and carboplatin or 1 high-dose cycle of the same drugs. With a median follow-up of 36 months the progression-free survival is superior for the high-dose arm (22 months vs 11 months). It is clear that a large, well-designed randomized trial is needed. The transplant arm should ensure that the goal of significantly increasing the dose intensity is reached. If highdose chemotherapy with stem cell transplantation is shown to be superior in such a study, the current standard of care would need to be reassessed. It is therefore important that the design of the transplant arm allow its broad application. Treatmentrelated morbidity, mortality, quality of life, and cost should be evaluated. Unfortunately, as demonstrated in the current study, multiple cycles of chemotherapy agents which allow only a marginal increase in dose intensity can significantly impair
quality of life over many months of treatment and lead to disappointing results. Remission consolidation by a single cycle of high-dose multiagent chemotherapy may be more easily delivered and may be better supported by the available phase II data. If provided with a well-designed randomized study, support from the medical community would hopefully allow the successful completion of such a trial, and finally give us long-awaited answers. REFERENCES 1. Schilder R, Brady MF, Spriggs D, Shea T. Pilot evaluation of high-dose carboplatin and paclitaxel followed by high-dose melphalan supported by peripheral blood stem cells in previously untreated advanced ovarian cancer. Gynecol Oncol 88:3– 8, 2003. 2. Legros M, Dauplat S, Fleury J, et al. High-dose chemotherapy with hematopoietic rescue in patients with stage III to IV ovarian cancer: Long-term results. J Clin Oncol 15:1302– 8, 1997. 3. Bertucci F, Viens P, Delpero JR, et al. High-dose melphalan-based chemotherapy and autologous stem cell transplantation after second look laparotomy in patients with chemosensitive advanced ovarian carcinoma: long-term results. Bone Marrow Transplant 26:61–7, 2000. 4. Ledermann JA. High-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) in ovarian cancer. Int J Gynecol Cancer 10(Suppl 1):53– 6, 2000. 5. Cure´ H, Battista H, Guastalla JP, et al. Phase III randomized trial of high-dose chemotherapy (HDC) and peripheral blood stem cell (PBSC) support as consolidation in patients (pts) with responsive low-burden advanced ovarian cancer (AOC): preliminary results of a GINECO/FNCLCC/SPGM-TC study. Proc Am Soc Clin Oncol 815a, 2001. (abstract)