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Ifosfamide and paclitaxel salvage chemotherapy for advanced epithelial ovarian cancer
Annals of Oncology 8: 195-197,1997. O 1997 Kluwer Academic Publishers. Printed in the Netherlands.
Short report Ifosfamide and paclitaxel salvage chemotherapy for advanced epithelial ovarian cancer M. A. Dimopoulos, C. Papadimitriou, C. Gennatas, T. Akrivos, G.Vlahos, Z.Voulgaris, E. Diacomanolis, P. Athanassiades & S. Mihalas Departments of Clinical Therapeutics, Obstetrics and Gynecology, University of Athens School of Medicine, Athens, Greece
Summary Objective: To evaluate the efficacy and toxicity of the combination of ifosfamide (1.5 g/m2 i.v. on days 1, 2, 3) and paclitaxel (135 mg/m2 i.v. over 3 hours on day 3) with G-CSF (5 ug/kg/d subcutaneously, days 7-11) administered every 3 weeks on an outpatient basis in patients with advanced epithelial ovarian cancer previously treated with platinum-based chemotherapy. Patients and methods: Thirty-five consecutive patients were treated, 12 of whom had previously received two regimens. Twelve of the 35 were defined as platinum-resistant and 23 as potentially platinum-sensitive. Results: Fifteen patients (43%; 95% CI: 26%-61%) achieved objective responses, five of them complete and ten partial. Ob-
Introduction
Although epithelial ovarian cancer is a highly chemosensitive tumor, most patients eventually relapse and die of progressive disease. Thus, there is a need for new active agents and combinations that may be used as salvage therapy. Paclitaxel has induced objective responses in 20% to 40% of patients with advanced ovarian cancer who had previously received platinum-based chemotherapy [1, 2]. Ifosfamide is another chemotherapeutic agent which has shown activity in 10% to 15% of patients with platinum-refractory ovarian cancer and when it was combined with other agents a higher response rate was observed [3-6]. On the basis of these data we assessed the activity of the combination of ifosfamide and paclitaxel (IP) in patients with platinum-pretreated ovarian cancer.
jective responses occurred in 17% of the platinum-resistant patients and in 57% of those with potentially platinum-sensitive disease. The median duration of response was seven months and the median overall survival 11 months. The treatment was well tolerated and only 15% of the patients developed grade 3 or 4 neutropenia. With the exception of alopecia there were no other grade 3 or 4 toxicities. Conclusions: The combination of ifosfamide and paclitaxel was well tolerated and showed activity in patients with ovarian cancer who had previously undergone platinum-based chemotherapy. Key words: ifosfamide, ovarian cancer, paclitaxel
instances of progressive disease or unacceptable toxicity. Ifosfamide was given at a dose of 1.5 g/m2 i.v. on days 1-3 as a 3-hour infusion in 1 L of 0.9% normal saline. Mesna was given at a dose of 300 mg/m 2 i.v. 15 minutes before and after each dose of ifosfamide. The same dose of mesna was given orally at home four and eight hours after the administration of ifosfamide. Paclitaxel 135 mg/m2 was diluted in 1000 ml of 5% dextrose in water and administered as a 3-hour infusion with standard premedication after the ifosfamide on day 3. G-CSF 5 ug/kg was administered subcutaneously daily from day 7 to 11 (5 days). Baseline evaluations consisted of complete physical examination, bimanual gynecological examination, chest X-ray, computed tomography of the abdomen and pelvis and serum CA 125. Complete blood cell counts and creatinine were obtained on day 10 and at the start of each cycle, and urine specimens every day during ifosfamide administration. Tumor response was evaluated every two cycles by repeating all abnormal tests. Standard response and toxicity criteria were used. Survival and time to progressive disease were measured from the date of entry into the study.
Results Patients and methods Our study included 35 consecutive patients with recurrent ovarian cancer. Eligibility criteria were age between 18 and 75 years, ECOG performance status < 3, presence of measurable disease, adequate renal, cardiac, hepatic and bone marrow function and no prior treatment with ifosfamide or paclitaxel. Patients were divided into three groups according to their prior platinum response (Table 1), as suggested by Markman and Hoskins [7]. Courses of IP were given on an outpatient basis every 21 days for a maximum of six cycles. Chemotherapy was discontinued in
All 35 patients were assessable for response, toxicity and survival; their characteristics are shown in Table 1. The primary therapy in all patients consisted of cyclophosphamide combined with cisplatin or carboplatin. Epirubicin was included in the initial therapy of 13 patients. Twelve patients had received second-line therapy which included carboplatin or cisplatin. The median number of IP cycles was five (range 2 to 6) and 15 patients completed six courses of treatment. Fifteen patients (43%; 95% CI:
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196 Table 1. Patient characteristics. Age (years) Median Range ECOG performance status 0 1 2 3 FIGO stage at entry in the study III IV Histology Serous Mucinous Endometroid Clear cell Undifferentiated Tumor grade 1 2 3 Unknown Maximum tumor diameter >5cm Number of previous therapies 1 2 Disease status PPR SPR PPS
controlled with a short course of non-steroidal antiinflammatory drugs or low-dose steroids. 62 41-75
Discussion 12 14 7 2 28 7 26 1 1 3 4
19 3 22 13 23 12 7 5 23
Abbreviations: PPR - primary platinum-resistant, SPR - secondary platinum-resistant, PPS - potentially platinum-sensitive.
26%—61%) achieved objective responses, 5 (14%) of them complete and 10 (29%) partial. All complete responders had a pretreatment maximum tumor diameter of < 5 cm and in all of them CA 125 serum levels returned to normal after treatment. Two of 12 patients (17%) with primary or secondary platinum resistance had objective responses, as did 13 of 23 patients (57%) with potentially platinum-sensitive disease. The median time to progression of the patients as a whole was six months (range 2 to 10 months) and the median duration of response for the 15 responding patients was seven months (range 2 to 10 months). The median overall survival was 11 months (range 2 to 20+ months). The treatment was well tolerated with no treatmentrelated deaths. Only 15% of patients developed grade 3 or 4 neutropenia, which resulted in 3 episodes of neutropenic fever. Grade 3 or 4 anemia or thrombocytopenia did not occur. None of the patients developed grade 3 or 4 non-hematologic toxicity except for alopecia, which was universal but reversible. Grades 1 and 2 nausea and vomiting were observed in 41% and 23% of patients, grades 1 and 2 mucositis in 23% and 11%, and grades 1 and 2 peripheral neuropathy in 15% and 4%. None of them developed nephrotoxicity. Mild or moderate arthralgias and myalgias occurred in 42% of patients during the first week of treatment but this side effect was readily
Downloaded from https://academic.oup.com/annonc/article-abstract/8/2/195/214100 by guest on 11 April 2018
We combined ifosfamide and paclitaxel for the treatment of patients with recurrent ovarian cancer. This regimen was given to outpatients, was well tolerated, and associated with acceptable toxicity. With administration of paclitaxel at a dose of 135 mg/m 2 over 3 hours, grades 1 or 2 neurotoxicity occurred in 19% of our patients. This incidence is similar to that observed in the EuropeanCanadian trial which reported more severe neurotoxicity with a higher dosage of paclitaxel. Because both agents can induce significant neutropenia, we used a limited course of G-CSF. Despite the fact that severe neutropenia was unusual in our patients, the contribution of the growth factor is not clear and its use may not have been justified. We observed responses in 43% of our patients and the median times to progression and survival were 6 and 11 months, respectively. Since the number of our patients is relatively small, we cannot draw firm conclusions about the activity of our regimen; however, it is of interest to note that similar preliminary results have been reported by Pucci et al. and Klaasen et al. who used a similar regimen [8, 9]. Our regimen appeared more active in patients with potentially platinum-sensitive disease. However, in a recent randomized study, this subgroup of patients survived longer when retreated with a platinumcontaining regimen than when treated with paclitaxel [10]. Thus, the latter approach may be more appropriate for patients with potentially platinum-sensitive disease.
References 1. Eisenhauer EA, ten Boklcel Huinink WW, Swenerton KD et al. European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High-dose versus low-dose and long versus short infusion. J Clin Oncol 1994; 12: 2654-66. 2. Thigpen JT, Blessing JA, Ball H et al. Phase II trial of paclitaxel m patients with progressive ovarian carcinoma after platinum-based chemotherapy: A Gynecologic Oncology Group Study. J Clin Oncol 1994; 12: 1748-53. 3. Sutton GP, Blessing JA, Homesley HD et al. Phase II trial of ifosfamide and mesna in advanced ovarian carcinoma: A Gynecologic Oncology Group study. J Clin Oncol 1989; 7:1672-6. 4. Markman M, Hakes T, Reichman B et al. Ifosfamide and mesna in previously treated advanced epithelial ovarian cancer. Activity in platinum-resistant disease. J Clin Oncol 1992; 10: 243-8. 5. Sorensen P, Pfeiffer P, Bertelsen K. A phase 2 trial of ifosfamide/ mesna as salvage therapy in patients with ovarian cancer refractory to or relapsing after prior platinum-containing chemotherapy. Gynecol Oncol 1995; 56: 75-8. 6. Marzola M, Parma G, Bonazzi C et al. Salvage therapy with ifosfamide and mitoxantrone in advanced ovarian cancer. Ann Oncol 1996; 7: 419-21. 7. Markman M, Hoskins W. Responses to 'salvage' chemotherapy in ovarian cancer. A critical need for precise definitions of the treated population. J Clin Oncol 1992; 10: 513-4. 8. Pucci F, Bella M, Salvagni S et al. Pachtaxel and ifosfamide in
197 heavily pretreated patients with advanced ovarian cancer. Proc ASCO 1996; 15: 301. 9. KJaassen U, Harstrick A, Stahl M et al. Paclitaxel and ifosfamide in pretreated patients with advanced ovarian carcinoma. Proc ASCO 1996; 15: 295. 10. Colombo N, Marzola M, Parma G et al. Paclitaxel vs. CAP (cyclophosphamide, adriamycin, cisplatin) in recurrent platinum sensitive ovarian cancer: A randomized phase II stady. Proc ASCO 1996; 15: 279
Received 8 October 1996; accepted 5 December 1996.
Correspondence to. Meletios A. Dimopoulos, MD 227 Kifissias Avenue Kifissia, Athens 14561 Greece
Downloaded from https://academic.oup.com/annonc/article-abstract/8/2/195/214100 by guest on 11 April 2018
Short report Ifosfamide and paclitaxel salvage chemotherapy for advanced epithelial ovarian cancer M. A. Dimopoulos, C. Papadimitriou, C. Gennatas, T. Akrivos, G.Vlahos, Z.Voulgaris, E. Diacomanolis, P. Athanassiades & S. Mihalas Departments of Clinical Therapeutics, Obstetrics and Gynecology, University of Athens School of Medicine, Athens, Greece
Summary Objective: To evaluate the efficacy and toxicity of the combination of ifosfamide (1.5 g/m2 i.v. on days 1, 2, 3) and paclitaxel (135 mg/m2 i.v. over 3 hours on day 3) with G-CSF (5 ug/kg/d subcutaneously, days 7-11) administered every 3 weeks on an outpatient basis in patients with advanced epithelial ovarian cancer previously treated with platinum-based chemotherapy. Patients and methods: Thirty-five consecutive patients were treated, 12 of whom had previously received two regimens. Twelve of the 35 were defined as platinum-resistant and 23 as potentially platinum-sensitive. Results: Fifteen patients (43%; 95% CI: 26%-61%) achieved objective responses, five of them complete and ten partial. Ob-
Introduction
Although epithelial ovarian cancer is a highly chemosensitive tumor, most patients eventually relapse and die of progressive disease. Thus, there is a need for new active agents and combinations that may be used as salvage therapy. Paclitaxel has induced objective responses in 20% to 40% of patients with advanced ovarian cancer who had previously received platinum-based chemotherapy [1, 2]. Ifosfamide is another chemotherapeutic agent which has shown activity in 10% to 15% of patients with platinum-refractory ovarian cancer and when it was combined with other agents a higher response rate was observed [3-6]. On the basis of these data we assessed the activity of the combination of ifosfamide and paclitaxel (IP) in patients with platinum-pretreated ovarian cancer.
jective responses occurred in 17% of the platinum-resistant patients and in 57% of those with potentially platinum-sensitive disease. The median duration of response was seven months and the median overall survival 11 months. The treatment was well tolerated and only 15% of the patients developed grade 3 or 4 neutropenia. With the exception of alopecia there were no other grade 3 or 4 toxicities. Conclusions: The combination of ifosfamide and paclitaxel was well tolerated and showed activity in patients with ovarian cancer who had previously undergone platinum-based chemotherapy. Key words: ifosfamide, ovarian cancer, paclitaxel
instances of progressive disease or unacceptable toxicity. Ifosfamide was given at a dose of 1.5 g/m2 i.v. on days 1-3 as a 3-hour infusion in 1 L of 0.9% normal saline. Mesna was given at a dose of 300 mg/m 2 i.v. 15 minutes before and after each dose of ifosfamide. The same dose of mesna was given orally at home four and eight hours after the administration of ifosfamide. Paclitaxel 135 mg/m2 was diluted in 1000 ml of 5% dextrose in water and administered as a 3-hour infusion with standard premedication after the ifosfamide on day 3. G-CSF 5 ug/kg was administered subcutaneously daily from day 7 to 11 (5 days). Baseline evaluations consisted of complete physical examination, bimanual gynecological examination, chest X-ray, computed tomography of the abdomen and pelvis and serum CA 125. Complete blood cell counts and creatinine were obtained on day 10 and at the start of each cycle, and urine specimens every day during ifosfamide administration. Tumor response was evaluated every two cycles by repeating all abnormal tests. Standard response and toxicity criteria were used. Survival and time to progressive disease were measured from the date of entry into the study.
Results Patients and methods Our study included 35 consecutive patients with recurrent ovarian cancer. Eligibility criteria were age between 18 and 75 years, ECOG performance status < 3, presence of measurable disease, adequate renal, cardiac, hepatic and bone marrow function and no prior treatment with ifosfamide or paclitaxel. Patients were divided into three groups according to their prior platinum response (Table 1), as suggested by Markman and Hoskins [7]. Courses of IP were given on an outpatient basis every 21 days for a maximum of six cycles. Chemotherapy was discontinued in
All 35 patients were assessable for response, toxicity and survival; their characteristics are shown in Table 1. The primary therapy in all patients consisted of cyclophosphamide combined with cisplatin or carboplatin. Epirubicin was included in the initial therapy of 13 patients. Twelve patients had received second-line therapy which included carboplatin or cisplatin. The median number of IP cycles was five (range 2 to 6) and 15 patients completed six courses of treatment. Fifteen patients (43%; 95% CI:
Downloaded from https://academic.oup.com/annonc/article-abstract/8/2/195/214100 by guest on 11 April 2018
196 Table 1. Patient characteristics. Age (years) Median Range ECOG performance status 0 1 2 3 FIGO stage at entry in the study III IV Histology Serous Mucinous Endometroid Clear cell Undifferentiated Tumor grade 1 2 3 Unknown Maximum tumor diameter >5cm Number of previous therapies 1 2 Disease status PPR SPR PPS
controlled with a short course of non-steroidal antiinflammatory drugs or low-dose steroids. 62 41-75
Discussion 12 14 7 2 28 7 26 1 1 3 4
19 3 22 13 23 12 7 5 23
Abbreviations: PPR - primary platinum-resistant, SPR - secondary platinum-resistant, PPS - potentially platinum-sensitive.
26%—61%) achieved objective responses, 5 (14%) of them complete and 10 (29%) partial. All complete responders had a pretreatment maximum tumor diameter of < 5 cm and in all of them CA 125 serum levels returned to normal after treatment. Two of 12 patients (17%) with primary or secondary platinum resistance had objective responses, as did 13 of 23 patients (57%) with potentially platinum-sensitive disease. The median time to progression of the patients as a whole was six months (range 2 to 10 months) and the median duration of response for the 15 responding patients was seven months (range 2 to 10 months). The median overall survival was 11 months (range 2 to 20+ months). The treatment was well tolerated with no treatmentrelated deaths. Only 15% of patients developed grade 3 or 4 neutropenia, which resulted in 3 episodes of neutropenic fever. Grade 3 or 4 anemia or thrombocytopenia did not occur. None of the patients developed grade 3 or 4 non-hematologic toxicity except for alopecia, which was universal but reversible. Grades 1 and 2 nausea and vomiting were observed in 41% and 23% of patients, grades 1 and 2 mucositis in 23% and 11%, and grades 1 and 2 peripheral neuropathy in 15% and 4%. None of them developed nephrotoxicity. Mild or moderate arthralgias and myalgias occurred in 42% of patients during the first week of treatment but this side effect was readily
Downloaded from https://academic.oup.com/annonc/article-abstract/8/2/195/214100 by guest on 11 April 2018
We combined ifosfamide and paclitaxel for the treatment of patients with recurrent ovarian cancer. This regimen was given to outpatients, was well tolerated, and associated with acceptable toxicity. With administration of paclitaxel at a dose of 135 mg/m 2 over 3 hours, grades 1 or 2 neurotoxicity occurred in 19% of our patients. This incidence is similar to that observed in the EuropeanCanadian trial which reported more severe neurotoxicity with a higher dosage of paclitaxel. Because both agents can induce significant neutropenia, we used a limited course of G-CSF. Despite the fact that severe neutropenia was unusual in our patients, the contribution of the growth factor is not clear and its use may not have been justified. We observed responses in 43% of our patients and the median times to progression and survival were 6 and 11 months, respectively. Since the number of our patients is relatively small, we cannot draw firm conclusions about the activity of our regimen; however, it is of interest to note that similar preliminary results have been reported by Pucci et al. and Klaasen et al. who used a similar regimen [8, 9]. Our regimen appeared more active in patients with potentially platinum-sensitive disease. However, in a recent randomized study, this subgroup of patients survived longer when retreated with a platinumcontaining regimen than when treated with paclitaxel [10]. Thus, the latter approach may be more appropriate for patients with potentially platinum-sensitive disease.
References 1. Eisenhauer EA, ten Boklcel Huinink WW, Swenerton KD et al. European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High-dose versus low-dose and long versus short infusion. J Clin Oncol 1994; 12: 2654-66. 2. Thigpen JT, Blessing JA, Ball H et al. Phase II trial of paclitaxel m patients with progressive ovarian carcinoma after platinum-based chemotherapy: A Gynecologic Oncology Group Study. J Clin Oncol 1994; 12: 1748-53. 3. Sutton GP, Blessing JA, Homesley HD et al. Phase II trial of ifosfamide and mesna in advanced ovarian carcinoma: A Gynecologic Oncology Group study. J Clin Oncol 1989; 7:1672-6. 4. Markman M, Hakes T, Reichman B et al. Ifosfamide and mesna in previously treated advanced epithelial ovarian cancer. Activity in platinum-resistant disease. J Clin Oncol 1992; 10: 243-8. 5. Sorensen P, Pfeiffer P, Bertelsen K. A phase 2 trial of ifosfamide/ mesna as salvage therapy in patients with ovarian cancer refractory to or relapsing after prior platinum-containing chemotherapy. Gynecol Oncol 1995; 56: 75-8. 6. Marzola M, Parma G, Bonazzi C et al. Salvage therapy with ifosfamide and mitoxantrone in advanced ovarian cancer. Ann Oncol 1996; 7: 419-21. 7. Markman M, Hoskins W. Responses to 'salvage' chemotherapy in ovarian cancer. A critical need for precise definitions of the treated population. J Clin Oncol 1992; 10: 513-4. 8. Pucci F, Bella M, Salvagni S et al. Pachtaxel and ifosfamide in
197 heavily pretreated patients with advanced ovarian cancer. Proc ASCO 1996; 15: 301. 9. KJaassen U, Harstrick A, Stahl M et al. Paclitaxel and ifosfamide in pretreated patients with advanced ovarian carcinoma. Proc ASCO 1996; 15: 295. 10. Colombo N, Marzola M, Parma G et al. Paclitaxel vs. CAP (cyclophosphamide, adriamycin, cisplatin) in recurrent platinum sensitive ovarian cancer: A randomized phase II stady. Proc ASCO 1996; 15: 279
Received 8 October 1996; accepted 5 December 1996.
Correspondence to. Meletios A. Dimopoulos, MD 227 Kifissias Avenue Kifissia, Athens 14561 Greece
Downloaded from https://academic.oup.com/annonc/article-abstract/8/2/195/214100 by guest on 11 April 2018