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Paclitaxel Refractory Ovarian Cancer Who Have Not Previously Been Treated with an Alkylating Agent
GYNECOLOGIC ONCOLOGY ARTICLE NO.
70, 272–274 (1998)
GO985065
Phase 2 Trial of Single Agent Ifosfamide/Mesna in Patients with Platinum/Paclitaxel Refractory Ovarian Cancer Who Have Not Previously Been Treated with an Alkylating Agent Maurie Markman, Alexander Kennedy, Gregory Sutton, Jean Hurteau, Kenneth Webster, Gertrude Peterson, Barbara Kulp, and Jerome Belinson The Cleveland Clinic Cancer Center, and the Departments of Hematology/Medical Oncology and Gynecology/Obstetrics, The Cleveland Clinic Foundation, Cleveland, Ohio 44195; and the Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana Received February 6, 1998
Ifosfamide has been shown to possess modest activity in patients with platinum/cyclophosphamide refractory ovarian cancer. Current standard initial chemotherapy for ovarian cancer does not include an alkylating agent (paclitaxel substituting for cyclophosphamide). To evaluate the activity of ifosfamide in patients with refractory ovarian cancer who had not previously received an alkylating agent, 21 patients with platinum/paclitaxel refractory disease were treated with the drug as a single agent (1.8 g/m2/ day 3 3 days, with treatment repeated every 28 days). Treatment was reasonably well tolerated in most patients, although 1 individual was removed from study secondary to neurotoxicity. One patient exhibited an objective response of measurable disease, while a second individual had a major decrease in CA-125 levels (no measurable disease present) following therapy. An additional patient experienced disappearance of severe pelvic pain following treatment but failed to meet the criteria for a partial response. We conclude that ifosfamide has modest activity in platinum/paclitaxel refractory ovarian cancer. However, the level of effectiveness does not appear to be increased in individuals who are alkylatingagent naive, compared to previously reported experience in patients with prior exposure to this class of cytotoxic drugs (10 –15% response rate). © 1998 Academic Press
Despite the high objective response rate of ovarian cancer to platinum-based combination chemotherapy (60 – 80%), the majority of women with this malignancy will ultimately develop a recurrence and die of complications of progressive cancer [1]. The addition of paclitaxel to the treatment program in ovarian cancer has improved the objective response rate and overall survival in this malignancy [2]. Unfortunately, relapse and disease progression continue to be experienced by the majority of patients. Therefore, there remains an important need to find additional agents which can be employed in the salvage setting in ovarian cancer [3]. Ifosfamide has been known to be an active agent in ovarian cancer for more than two decades [4 – 8], being employed both as a single agent and in combination regimens. Several studies 0090-8258/98 $25.00 Copyright © 1998 by Academic Press All rights of reproduction in any form reserved.
have demonstrated that ifosfamide has activity in patients previously treated with either cisplatin or carboplatin. In a Gynecologic Oncology Group trial, a 20% objective response rate was observed in recurrent (not necessarily refractory) ovarian cancer [6]. A second study conducted at the Memorial Sloan-Kettering Cancer Center specifically examined patients with platinum-resistant ovarian cancer [3, 9] and demonstrated a 12% objective response rate [7]. It is important to note that essentially all patients treated in the ‘‘salvage setting’’ in these trials had also received the alkylating agent cyclophosphamide, in addition to cisplatin. Therefore, it is appropriate to consider patients evaluated in these studies to have had cyclophosphamide-resistant as well as platinum-resistant ovarian cancer. As ifosfamide and cyclophosphamide have major structural similarities, it is possible that the effectiveness of the former agent might be greater in the salvage setting in individuals initially treated with cisplatin or carboplatin plus paclitaxel, without an alkylating agent [2]. To carefully examine this interesting, and potentially important, clinical question, we initiated a phase 2 trial of single agent ifosfamide as secondline treatment of patients with platinum/paclitaxel refractory ovarian cancer who had not previously been exposed to an alkylating agent. METHODS AND MATERIALS Eligibility Criteria Patients considered for entry into this phase 2 clinical trial had to meet the following eligibility criteria: (a) histologically confirmed diagnosis of ovarian or fallopian tube cancer or primary papillary serous adenocarcinoma of the peritoneum; (b) patients must have received and failed (evidence of disease progression as defined below) an initial chemotherapy program which consisted of paclitaxel and either cisplatin or carboplatin; (c) patients may have received a maximum of two prior
272
IFOSFAMIDE AND PLATINUM/PACLITAXEL REFRACTORY OVARIAN CANCER
chemotherapy programs, with the only acceptable drugs permitted being cisplatin, carboplatin, and paclitaxel; (d) patients must have had a Karnofsky performance status of $60% and anticipated survival of $2 months; (e) acceptable laboratory parameters including WBC $3000/mm3, granulocytes $1500/ mm3, platelets $100,000/mm3, serum creatinine #1.8 mg%, serum bilirubin #1.5 mg%; (f) age $18 years old; and (g) sign an informed consent document. Patients who had previously received and responded to therapy with a platinum agent and paclitaxel were required to demonstrate resistance (disease progression or stable disease as best response) to the drugs administered in the second-line setting before being eligible for entry into this phase 2 trial [3]. In addition, patients had to have either measurable or evaluable disease. For the purpose of this trial, specific CA-125 criteria were acceptable to satisfy the requirement for the presence of evaluable disease [10]. For a patient to meet these criteria the minimum CA-125 level had to be $100 units/ml. In addition, this CA-125 level had to have at least doubled from a previous value for a patient to be considered to have documented evidence of disease progression from a prior chemotherapy regimen. Treatment Program Patients received ifosfamide at an initial dose of 1.8 g/m2/ day 3 3 days. The drug was administered as a 1-h infusion. In addition, mesna was administered either intravenously or subcutaneously to prevent ifosfamide-induced hemorrhagic cystitis. The intravenous mesna dosing program included administration of the agent at 20% of the ifosfamide dose, 30 min prior to the ifosfamide infusion and 4 and 8 h following the completion of the chemotherapy delivery (total mesna dosing, 60% of the ifosfamide dose). Alternatively, following the initial mesna intravenous infusion (20% of the ifosfamide dose), the remaining mesna (40% of the ifosfamide dose) was administered as a continuous subcutaneous infusion (through an ambulatory infusion pump) over 8 h, beginning 30 min following the completion of the ifosfamide infusion [11]. Antiemetics were administered at the discretion of the treating physician. Therapy was permitted to be delivered either in the inpatient or in the outpatient settings, as appropriate for an individual patient. Treatment was repeated on an every 28-day schedule in responding patients or in individuals with stable disease. Reasons for removal from the treatment program included evidence of disease progression, unacceptable toxicity, or patient request.
273
ance of all measurable disease (by noninvasive evaluation), signs, symptoms, and biochemical changes related to the tumor (including normalization of CA-125), without clinical evidence of progression for $4 weeks. A clinical partial response required that, compared to pretreatment measurements, there was a reduction of .50% in the sum of the perpendicular diameters of all measurable lesions, without appearance of new lesions for $4 weeks, and no existing lesions could enlarge. For those individuals whose CA-125 levels served as a measure of evaluable disease, two CA-125 response categories were employed: (a) reduction of CA-125 levels to #50% of pretreatment levels and (b) reduction of CA-125 levels to #10% of pretreatment levels. These declines in the antigen level had to persist for at least two monthly determinations to be considered as evidence of a response to treatment. RESULTS Patient Characteristics A total of 21 patients were entered into this phase 2 trial (median age, 66 years; range, 44 –76 years). While individuals with primary papillary serous adenocarcinoma of the peritoneum and fallopian tube cancer were permitted entry into this trial, all patients participating in the study had ovarian cancer. As required by the study entry criteria, all patients had previously received and failed treatment with a platinum agent (50 –100 mg/m2 cisplatin or carboplatin (AUC 4 –7.5) and paclitaxel (135 mg/m2 over 24 h or 135–175 mg/m2 over 3 h)). In addition, the most recent treatment with either class of agent had resulted in either disease progression or failure to exhibit a response. No patient had previously received an alkylating agent. Eleven patients had measurable disease, while 10 were evaluable by CA-125 criteria. The median number of courses of ifosfamide administered to patients on this trial was 3 (range 1– 8). Toxicity In general, as anticipated from prior experience with single agent ifosfamide in refractory ovarian cancer, treatment on this program was reasonably well tolerated. There were no grade 4 hematologic toxicities or episodes of nadir fever. Bone marrow colony stimulating factors were not required by any patient. One individual required removal from treatment due to the development of an episode of confusion (completely reversible), believed to be secondary to ifosfamide. There were no documented episodes of hemorrhagic cystitis, although one patient experienced treatment-related microscopic hematuria. Responses
Evaluation of Response Standard response criteria (clinical complete response, clinical partial response) for measurable disease were employed in this trial. A clinical complete response required the disappear-
A total of 20 patients were evaluable for response (1 patient removed for toxicity did not have reassessment for evidence of response to the treatment program). Two patients (10%) in this trial exhibited evidence of a
274
MARKMAN ET AL.
response to salvage ifosfamide, including a major reduction in tumor bulk and ascites, and elimination of severe pain in 1 patient (duration 9 months) and $50% reduction in CA-125 levels in a second individual (duration 11 months). A third patient experienced the disappearance of severe pelvic pain following treatment, but did not achieve a partial response of measurable disease. DISCUSSION In this trial we have confirmed the presence of modest, but definite, activity for ifosfamide in patients with platinum/paclitaxel refractory ovarian cancer (10% objective response rate). Unfortunately, this level of activity does not support our original hypothesis that, in the absence of prior exposure to an alkylating agent (e.g., cyclophosphamide), treatment with single agent ifosfamide would result in a higher objective response rate than that observed in a previously reported trial of the agent in platinum/cyclophosphamide refractory ovarian cancer (12% objective response rate) [7]. This experience suggests that, at a clinical level, the underlying mechanisms of resistance induced by treatment with paclitaxel and either cisplatin or carboplatin are similar or identical to those observed when a platinum drug is delivered with an alkylating agent. Alternatively, these cancer cells may possess de novo resistance to the agents which is are not significantly influenced by the actual treatment regimen. As administered in this program, ifosfamide was associated with an acceptable toxicity profile in most individuals. Patients could be easily managed in the outpatient setting, if they desired, and were able to return to the clinic daily for the 3-day treatment regimen. While it is possible that a higher dose ifosfamide program, or delivery of the drugs over 5 days, could have resulted in a superior objective response rate, there is little evidence that ifosfamide activity in ovarian cancer (or other malignancies) is strongly influenced by dose or a particular infusion schedule. In addition, in this patient population which had been exposed to multiple courses of a platinum agent and paclitaxel, a higher dose strategy would have been associated with a far greater
incidence of side effects than observed in the present clinical trial. In summary, this phase 2 study has confirmed both the safety and the modest efficacy of ifosfamide in platinum-refractory ovarian cancer. We have further demonstrated that such activity is maintained, but not increased, in individuals who are also refractory to paclitaxel. Absence of prior exposure to another alkylating agent does not appear to improve the activity of ifosfamide in this clinical setting. REFERENCES 1. Cannistra SA: Cancer of the ovary. N Engl J Med 329:1550 –1559, 1993 2. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1– 6, 1996 3. Markman M, Hoskins W: Responses to ‘‘salvage’’ chemotherapy in ovarian cancer: a critical need for precise definitions of the treated population. J Clin Oncol 10:513–514, 1992 4. Yazigi R, Wild R, Madrid J, et al: Ifosfamide treatment of advanced ovarian cancer. Obstet Gynecol 63:163–166, 1984 5. Willemse PHB, vd Burg MEL, vd Gaast A, et al: Ifosfamide given as a 24-h infusion with mesna in patients with recurrent ovarian cancer: preliminary results. Cancer Chemother Pharmacol 26 (Suppl 1):S51–S54, 1990 6. 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 7:1672–1676, 1989 7. 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 10:243–248, 1992 8. 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 56:75–78, 1995 9. Markman M, Rothman R, Hakes T, et al: Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 9:389 –393, 1991 10. Rustin GJS, Nelstrop AE, McClean P, et al: Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. J Clin Oncol 14:1545–1551, 1996 11. Markman M, Kennedy A, Webster K, Kulp B, Peterson G, Belinson J: Continuous subcutaneous administration of mesna to prevent ifosfamideinduced hemorrhagic cystitis. Semin Oncol 23 (Suppl 6):97–98, 1996
70, 272–274 (1998)
GO985065
Phase 2 Trial of Single Agent Ifosfamide/Mesna in Patients with Platinum/Paclitaxel Refractory Ovarian Cancer Who Have Not Previously Been Treated with an Alkylating Agent Maurie Markman, Alexander Kennedy, Gregory Sutton, Jean Hurteau, Kenneth Webster, Gertrude Peterson, Barbara Kulp, and Jerome Belinson The Cleveland Clinic Cancer Center, and the Departments of Hematology/Medical Oncology and Gynecology/Obstetrics, The Cleveland Clinic Foundation, Cleveland, Ohio 44195; and the Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana Received February 6, 1998
Ifosfamide has been shown to possess modest activity in patients with platinum/cyclophosphamide refractory ovarian cancer. Current standard initial chemotherapy for ovarian cancer does not include an alkylating agent (paclitaxel substituting for cyclophosphamide). To evaluate the activity of ifosfamide in patients with refractory ovarian cancer who had not previously received an alkylating agent, 21 patients with platinum/paclitaxel refractory disease were treated with the drug as a single agent (1.8 g/m2/ day 3 3 days, with treatment repeated every 28 days). Treatment was reasonably well tolerated in most patients, although 1 individual was removed from study secondary to neurotoxicity. One patient exhibited an objective response of measurable disease, while a second individual had a major decrease in CA-125 levels (no measurable disease present) following therapy. An additional patient experienced disappearance of severe pelvic pain following treatment but failed to meet the criteria for a partial response. We conclude that ifosfamide has modest activity in platinum/paclitaxel refractory ovarian cancer. However, the level of effectiveness does not appear to be increased in individuals who are alkylatingagent naive, compared to previously reported experience in patients with prior exposure to this class of cytotoxic drugs (10 –15% response rate). © 1998 Academic Press
Despite the high objective response rate of ovarian cancer to platinum-based combination chemotherapy (60 – 80%), the majority of women with this malignancy will ultimately develop a recurrence and die of complications of progressive cancer [1]. The addition of paclitaxel to the treatment program in ovarian cancer has improved the objective response rate and overall survival in this malignancy [2]. Unfortunately, relapse and disease progression continue to be experienced by the majority of patients. Therefore, there remains an important need to find additional agents which can be employed in the salvage setting in ovarian cancer [3]. Ifosfamide has been known to be an active agent in ovarian cancer for more than two decades [4 – 8], being employed both as a single agent and in combination regimens. Several studies 0090-8258/98 $25.00 Copyright © 1998 by Academic Press All rights of reproduction in any form reserved.
have demonstrated that ifosfamide has activity in patients previously treated with either cisplatin or carboplatin. In a Gynecologic Oncology Group trial, a 20% objective response rate was observed in recurrent (not necessarily refractory) ovarian cancer [6]. A second study conducted at the Memorial Sloan-Kettering Cancer Center specifically examined patients with platinum-resistant ovarian cancer [3, 9] and demonstrated a 12% objective response rate [7]. It is important to note that essentially all patients treated in the ‘‘salvage setting’’ in these trials had also received the alkylating agent cyclophosphamide, in addition to cisplatin. Therefore, it is appropriate to consider patients evaluated in these studies to have had cyclophosphamide-resistant as well as platinum-resistant ovarian cancer. As ifosfamide and cyclophosphamide have major structural similarities, it is possible that the effectiveness of the former agent might be greater in the salvage setting in individuals initially treated with cisplatin or carboplatin plus paclitaxel, without an alkylating agent [2]. To carefully examine this interesting, and potentially important, clinical question, we initiated a phase 2 trial of single agent ifosfamide as secondline treatment of patients with platinum/paclitaxel refractory ovarian cancer who had not previously been exposed to an alkylating agent. METHODS AND MATERIALS Eligibility Criteria Patients considered for entry into this phase 2 clinical trial had to meet the following eligibility criteria: (a) histologically confirmed diagnosis of ovarian or fallopian tube cancer or primary papillary serous adenocarcinoma of the peritoneum; (b) patients must have received and failed (evidence of disease progression as defined below) an initial chemotherapy program which consisted of paclitaxel and either cisplatin or carboplatin; (c) patients may have received a maximum of two prior
272
IFOSFAMIDE AND PLATINUM/PACLITAXEL REFRACTORY OVARIAN CANCER
chemotherapy programs, with the only acceptable drugs permitted being cisplatin, carboplatin, and paclitaxel; (d) patients must have had a Karnofsky performance status of $60% and anticipated survival of $2 months; (e) acceptable laboratory parameters including WBC $3000/mm3, granulocytes $1500/ mm3, platelets $100,000/mm3, serum creatinine #1.8 mg%, serum bilirubin #1.5 mg%; (f) age $18 years old; and (g) sign an informed consent document. Patients who had previously received and responded to therapy with a platinum agent and paclitaxel were required to demonstrate resistance (disease progression or stable disease as best response) to the drugs administered in the second-line setting before being eligible for entry into this phase 2 trial [3]. In addition, patients had to have either measurable or evaluable disease. For the purpose of this trial, specific CA-125 criteria were acceptable to satisfy the requirement for the presence of evaluable disease [10]. For a patient to meet these criteria the minimum CA-125 level had to be $100 units/ml. In addition, this CA-125 level had to have at least doubled from a previous value for a patient to be considered to have documented evidence of disease progression from a prior chemotherapy regimen. Treatment Program Patients received ifosfamide at an initial dose of 1.8 g/m2/ day 3 3 days. The drug was administered as a 1-h infusion. In addition, mesna was administered either intravenously or subcutaneously to prevent ifosfamide-induced hemorrhagic cystitis. The intravenous mesna dosing program included administration of the agent at 20% of the ifosfamide dose, 30 min prior to the ifosfamide infusion and 4 and 8 h following the completion of the chemotherapy delivery (total mesna dosing, 60% of the ifosfamide dose). Alternatively, following the initial mesna intravenous infusion (20% of the ifosfamide dose), the remaining mesna (40% of the ifosfamide dose) was administered as a continuous subcutaneous infusion (through an ambulatory infusion pump) over 8 h, beginning 30 min following the completion of the ifosfamide infusion [11]. Antiemetics were administered at the discretion of the treating physician. Therapy was permitted to be delivered either in the inpatient or in the outpatient settings, as appropriate for an individual patient. Treatment was repeated on an every 28-day schedule in responding patients or in individuals with stable disease. Reasons for removal from the treatment program included evidence of disease progression, unacceptable toxicity, or patient request.
273
ance of all measurable disease (by noninvasive evaluation), signs, symptoms, and biochemical changes related to the tumor (including normalization of CA-125), without clinical evidence of progression for $4 weeks. A clinical partial response required that, compared to pretreatment measurements, there was a reduction of .50% in the sum of the perpendicular diameters of all measurable lesions, without appearance of new lesions for $4 weeks, and no existing lesions could enlarge. For those individuals whose CA-125 levels served as a measure of evaluable disease, two CA-125 response categories were employed: (a) reduction of CA-125 levels to #50% of pretreatment levels and (b) reduction of CA-125 levels to #10% of pretreatment levels. These declines in the antigen level had to persist for at least two monthly determinations to be considered as evidence of a response to treatment. RESULTS Patient Characteristics A total of 21 patients were entered into this phase 2 trial (median age, 66 years; range, 44 –76 years). While individuals with primary papillary serous adenocarcinoma of the peritoneum and fallopian tube cancer were permitted entry into this trial, all patients participating in the study had ovarian cancer. As required by the study entry criteria, all patients had previously received and failed treatment with a platinum agent (50 –100 mg/m2 cisplatin or carboplatin (AUC 4 –7.5) and paclitaxel (135 mg/m2 over 24 h or 135–175 mg/m2 over 3 h)). In addition, the most recent treatment with either class of agent had resulted in either disease progression or failure to exhibit a response. No patient had previously received an alkylating agent. Eleven patients had measurable disease, while 10 were evaluable by CA-125 criteria. The median number of courses of ifosfamide administered to patients on this trial was 3 (range 1– 8). Toxicity In general, as anticipated from prior experience with single agent ifosfamide in refractory ovarian cancer, treatment on this program was reasonably well tolerated. There were no grade 4 hematologic toxicities or episodes of nadir fever. Bone marrow colony stimulating factors were not required by any patient. One individual required removal from treatment due to the development of an episode of confusion (completely reversible), believed to be secondary to ifosfamide. There were no documented episodes of hemorrhagic cystitis, although one patient experienced treatment-related microscopic hematuria. Responses
Evaluation of Response Standard response criteria (clinical complete response, clinical partial response) for measurable disease were employed in this trial. A clinical complete response required the disappear-
A total of 20 patients were evaluable for response (1 patient removed for toxicity did not have reassessment for evidence of response to the treatment program). Two patients (10%) in this trial exhibited evidence of a
274
MARKMAN ET AL.
response to salvage ifosfamide, including a major reduction in tumor bulk and ascites, and elimination of severe pain in 1 patient (duration 9 months) and $50% reduction in CA-125 levels in a second individual (duration 11 months). A third patient experienced the disappearance of severe pelvic pain following treatment, but did not achieve a partial response of measurable disease. DISCUSSION In this trial we have confirmed the presence of modest, but definite, activity for ifosfamide in patients with platinum/paclitaxel refractory ovarian cancer (10% objective response rate). Unfortunately, this level of activity does not support our original hypothesis that, in the absence of prior exposure to an alkylating agent (e.g., cyclophosphamide), treatment with single agent ifosfamide would result in a higher objective response rate than that observed in a previously reported trial of the agent in platinum/cyclophosphamide refractory ovarian cancer (12% objective response rate) [7]. This experience suggests that, at a clinical level, the underlying mechanisms of resistance induced by treatment with paclitaxel and either cisplatin or carboplatin are similar or identical to those observed when a platinum drug is delivered with an alkylating agent. Alternatively, these cancer cells may possess de novo resistance to the agents which is are not significantly influenced by the actual treatment regimen. As administered in this program, ifosfamide was associated with an acceptable toxicity profile in most individuals. Patients could be easily managed in the outpatient setting, if they desired, and were able to return to the clinic daily for the 3-day treatment regimen. While it is possible that a higher dose ifosfamide program, or delivery of the drugs over 5 days, could have resulted in a superior objective response rate, there is little evidence that ifosfamide activity in ovarian cancer (or other malignancies) is strongly influenced by dose or a particular infusion schedule. In addition, in this patient population which had been exposed to multiple courses of a platinum agent and paclitaxel, a higher dose strategy would have been associated with a far greater
incidence of side effects than observed in the present clinical trial. In summary, this phase 2 study has confirmed both the safety and the modest efficacy of ifosfamide in platinum-refractory ovarian cancer. We have further demonstrated that such activity is maintained, but not increased, in individuals who are also refractory to paclitaxel. Absence of prior exposure to another alkylating agent does not appear to improve the activity of ifosfamide in this clinical setting. REFERENCES 1. Cannistra SA: Cancer of the ovary. N Engl J Med 329:1550 –1559, 1993 2. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1– 6, 1996 3. Markman M, Hoskins W: Responses to ‘‘salvage’’ chemotherapy in ovarian cancer: a critical need for precise definitions of the treated population. J Clin Oncol 10:513–514, 1992 4. Yazigi R, Wild R, Madrid J, et al: Ifosfamide treatment of advanced ovarian cancer. Obstet Gynecol 63:163–166, 1984 5. Willemse PHB, vd Burg MEL, vd Gaast A, et al: Ifosfamide given as a 24-h infusion with mesna in patients with recurrent ovarian cancer: preliminary results. Cancer Chemother Pharmacol 26 (Suppl 1):S51–S54, 1990 6. 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 7:1672–1676, 1989 7. 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 10:243–248, 1992 8. 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 56:75–78, 1995 9. Markman M, Rothman R, Hakes T, et al: Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 9:389 –393, 1991 10. Rustin GJS, Nelstrop AE, McClean P, et al: Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. J Clin Oncol 14:1545–1551, 1996 11. Markman M, Kennedy A, Webster K, Kulp B, Peterson G, Belinson J: Continuous subcutaneous administration of mesna to prevent ifosfamideinduced hemorrhagic cystitis. Semin Oncol 23 (Suppl 6):97–98, 1996