Gynecologic Cancer
Gynecologic Cancer
Lorusso V, Leone B, Di Vagno G, et al
Gynecol Oncol 68(2):172-177, 1998
This phase I-II study was conducted to determine the maximum tolerated dose (MTD) of cisplatin (on day 8 of a 28-day cycle) in combination with carboplatin (300mg/m on day 1) and ifosfamide (4000mg/m/24h by continuous infusion on day 1) in patients with ovarian cancer. From January 1991 to December 1993, 34 patients previously untreated with chemo- or radiotherapy were enrolled. The initial dose of cisplatin, 40mg/m, was continuously increased by 10mg/m up to the MTD, defined as 1 dose level below that inducing dose-limiting toxicity (DLT) in at least two thirds of treated patients. The DLT was reached at 70mg/m, so the dose recommended for the phase II study was 60mg/m. Complete plus partial response was observed in 88% of patients, with a 21% pathological complete response. With a minimum follow-up of 32 months, median progression-free survival and overall survival were 21 and 39 months, respectively. Grade 3-4 leukopenia was observed in 54% of patients and thrombocytopenia in 49%. The authors concluded that cisplatin-carboplatin-ifosfamide is an effective combination regimen for ovarian cancer and has an acceptable toxicity profile.
Piver MS, Eltabbakh GH, Hempling RE, et al
Eur J Gynaecol Oncol 19(1):5-10, 1998
This study was conducted to assess paclitaxel (PAC) plus cisplatin (CP) given over 6 months as first-line therapy in women with stage III and IV epithelial ovarian cancer with residual disease <1cm. This regimen was compared with the previous standard of CP, doxorubicin, and cyclophosphamide, given over 10 months. In 2 sequential trials totaling 100 patients, the authors compared induction CP weekly (1mg/kg × 4) followed by monthly CP (50mg/m), doxorubicin (50mg/m), and cyclophosphamide (750mg/m) × 10 (n = 56) versus induction CP followed by CP and PAC monthly over 6 months (n = 44). The mean dose of CP in the PAC patients was 617.1mg/m and in the CP + PAC patients was 567.1mg/m ( P <0.0001). Surgical response was assessed in 83.9% of PAC and 86.4% of CP + PAC patients. The incidence of nausea/vomiting, myelotoxicity, and renal toxicity was similar in the 2 groups. Peripheral neuropathy was more frequent following CP + PAC (57% vs 16%; P =0.001). Cardiac toxicity (grade 1) was more frequent in PAC patients (39% vs 4.5% of CP + PAC patients; P <0.001). Compared with PAC, the authors concluded, CP + PAC did not improve overall and surgical response rates, 2-year survival, 2-year disease-free survival, or median time of recurrence in patients with optimal (<1cm) stage III and IV ovarian cancer. Also, CP + PAC resulted in higher peripheral neuropathy rates.
Rose PG, Blessing JA, Mayer AR, et al
J Clin Oncol 16(2):405-410, 1998
This phase II trial sought to determine activity of prolonged oral etoposide in platinum-resistant and platinum-sensitive ovarian carcinoma. (Platinum-resistance was defined as progression on platinum-based chemotherapy or recurrence within 6 months post therapy.) The starting dose was 50mg/m/d (30mg/m/d if prior radiotherapy) for 21 days, every 28 days, with dose escalation up to 60mg/m/d for subsequent courses in patients who experienced no grade 3 or 4 toxicity and less than grade 2 hematologic toxicity. Of 99 patients entered, 97 were assessable for toxicity and 82 were assessable for response. Among 41 platinum-resistant patients, there was a 26.8% response rate (7.3% complete response [CR]). Median response duration was 4.3 months, median progression-free interval (PFI) was 5.7 months, and median survival time was 10.8 months. Of 25 platinum-resistant patients who had also previously received paclitaxel, 8 (32%) responded. Among 41 platinum-sensitive patients, there was a 34.1% response rate (14.6% CR). Median response duration was 7.5 months, median PFI was 6.3+ months, and median survival time was 16.5+ months. Grade 3-4 leukopenia occurred in 41.2% of patients and neutropenia in 45.4%. Three treatment-related deaths occurred: 2 from neutropenic sepsis and 1 from thrombocytopenic bleeding after an overdose. One patient developed leukemia. The authors concluded that this regimen is active in platinum-resistant and platinum-sensitive ovarian carcinoma, as well as paclitaxel-resistant ovarian carcinoma.
Platinum Compound Combinations and Platinum Resistance
Editorial Comment by William Hoskins, MD
Currently, the standard therapy for advanced epithelial ovarian cancer is a combination of paclitaxel and one of the platinum compounds. Yet there is considerable interest in testing new combinations of therapy that use either old drugs in new combinations or new drugs in combination with more standard drugs.
Lorusso and colleagues have chosen to combine 2 platinum compounds, cisplatin and carboplatin, with ifosfamide. They reason that the 2 compounds do not have overlapping toxicities and that ifosfamide, one of the more active single agents in ovarian cancer, has an acceptable toxicity profile when given by a continuous 24-hour infusion. In the phase I part of the trial, they found that they could give carboplatin 300mg/m (day 1), ifosfamide 400mg/m/24 hours (day 1), and cisplatin 60mg/m (day 8). Grade 3 or 4 hematological toxicity was seen in about half of the patients. The population of patients included 18% stage IV patients and 29% grade 3 patients; 66% of the patients had bulky (suboptimal) disease. An overall response rate of 88% and a pathologically negative second-look rate of 21% are comparable with results reported for cisplatin and paclitaxel. The medial survival of 33 months is also similar to results obtained with cisplatin and paclitaxel.
Although this regimen appears to have little advantage over standard therapy in terms of response or survival and is more difficult to administer, it is nevertheless valuable in determining an optimal method of combining cisplatin and carboplatin with ifosfamide and is a necessary step in the evaluation of new regimens. Perhaps more interesting, however, would be doublets or triplets of new drugs such as topotecan and gemcitibine with platinum and paclitaxel.
Piver and associates have compared a regimen of induction with weekly cisplatin for 4 courses at an average dose of 40mg/m per week followed by 6 courses of cisplatin 75mg/m and paclitaxel 135mg/m over 24 hours on a 28-day cycle against historical controls of a series of patients in which they used the same 4 weekly doses of cisplatin as induction followed by 10 courses of a combination of cisplatin 50mg/m, cyclophosphamide 75mg/m, and doxorubicin 50mg/m given on a 28-day cycle. The patient populations were generally comparable, but the cisplatin/paclitaxel group had a larger population of stage IV patients (22.7% versus 8.9%) and a larger population of grade 3 patients (68.2% versus 60.7%).
Because there was essentially no difference in 2-year progression-free survival and overall survival, the investigators concluded that paclitaxel combined with cisplatin for 6 months is not superior to a regimen of cisplatin, cyclophosphamide, and doxorubicin for 8 months. They did note a higher response rate with the cisplatin and paclitaxel regimen; however, it was not statistically significant.
While the regimens are interesting and the uniformity of data from a single institution are good, the study is fatally flawed by not being randomized and by the 13-year time interval required for the 2 studies. While there is a definite role for single-institution phase I and phase II trials, it is virtually impossible for single institutions to conduct phase III randomized trials. Comparisons of 2 different populations such as this cannot substitute for randomized trials.
Rose and coworkers have conducted a classic phase II study of a chemotherapy regimen in recurrent ovarian cancer. Patients were divided into platinum-resistant and platinum-sensitive groups. Only one previous chemotherapy regimen was permitted, and patients were required to have measurable disease.
The investigators found oral etoposide to be active in both patient populations, although the platinum-sensitive patients had a higher complete response rate (14.6% versus 7.3%) and a greater median response duration (7.5 months versus 4.3 months) compared with the platinum-resistant group. These investigators also found a 32% response rate in patients who had previously received paclitaxel.
However, the toxicity of the regimen was considerable, with a 41.2% to 45.4% grade 3 or 4 hematologic toxicity and 3 treatment-related deaths, including 1 case of leukemia. In addition to providing important information about a potentially beneficial salvage regimen for recurrent or persistent ovarian cancer, the investigators have conducted a well-designed trial with reliable data.
Lorusso V, Leone B, Di Vagno G, et al
Gynecol Oncol 68(2):172-177, 1998
This phase I-II study was conducted to determine the maximum tolerated dose (MTD) of cisplatin (on day 8 of a 28-day cycle) in combination with carboplatin (300mg/m on day 1) and ifosfamide (4000mg/m/24h by continuous infusion on day 1) in patients with ovarian cancer. From January 1991 to December 1993, 34 patients previously untreated with chemo- or radiotherapy were enrolled. The initial dose of cisplatin, 40mg/m, was continuously increased by 10mg/m up to the MTD, defined as 1 dose level below that inducing dose-limiting toxicity (DLT) in at least two thirds of treated patients. The DLT was reached at 70mg/m, so the dose recommended for the phase II study was 60mg/m. Complete plus partial response was observed in 88% of patients, with a 21% pathological complete response. With a minimum follow-up of 32 months, median progression-free survival and overall survival were 21 and 39 months, respectively. Grade 3-4 leukopenia was observed in 54% of patients and thrombocytopenia in 49%. The authors concluded that cisplatin-carboplatin-ifosfamide is an effective combination regimen for ovarian cancer and has an acceptable toxicity profile.
Piver MS, Eltabbakh GH, Hempling RE, et al
Eur J Gynaecol Oncol 19(1):5-10, 1998
This study was conducted to assess paclitaxel (PAC) plus cisplatin (CP) given over 6 months as first-line therapy in women with stage III and IV epithelial ovarian cancer with residual disease <1cm. This regimen was compared with the previous standard of CP, doxorubicin, and cyclophosphamide, given over 10 months. In 2 sequential trials totaling 100 patients, the authors compared induction CP weekly (1mg/kg × 4) followed by monthly CP (50mg/m), doxorubicin (50mg/m), and cyclophosphamide (750mg/m) × 10 (n = 56) versus induction CP followed by CP and PAC monthly over 6 months (n = 44). The mean dose of CP in the PAC patients was 617.1mg/m and in the CP + PAC patients was 567.1mg/m ( P <0.0001). Surgical response was assessed in 83.9% of PAC and 86.4% of CP + PAC patients. The incidence of nausea/vomiting, myelotoxicity, and renal toxicity was similar in the 2 groups. Peripheral neuropathy was more frequent following CP + PAC (57% vs 16%; P =0.001). Cardiac toxicity (grade 1) was more frequent in PAC patients (39% vs 4.5% of CP + PAC patients; P <0.001). Compared with PAC, the authors concluded, CP + PAC did not improve overall and surgical response rates, 2-year survival, 2-year disease-free survival, or median time of recurrence in patients with optimal (<1cm) stage III and IV ovarian cancer. Also, CP + PAC resulted in higher peripheral neuropathy rates.
Rose PG, Blessing JA, Mayer AR, et al
J Clin Oncol 16(2):405-410, 1998
This phase II trial sought to determine activity of prolonged oral etoposide in platinum-resistant and platinum-sensitive ovarian carcinoma. (Platinum-resistance was defined as progression on platinum-based chemotherapy or recurrence within 6 months post therapy.) The starting dose was 50mg/m/d (30mg/m/d if prior radiotherapy) for 21 days, every 28 days, with dose escalation up to 60mg/m/d for subsequent courses in patients who experienced no grade 3 or 4 toxicity and less than grade 2 hematologic toxicity. Of 99 patients entered, 97 were assessable for toxicity and 82 were assessable for response. Among 41 platinum-resistant patients, there was a 26.8% response rate (7.3% complete response [CR]). Median response duration was 4.3 months, median progression-free interval (PFI) was 5.7 months, and median survival time was 10.8 months. Of 25 platinum-resistant patients who had also previously received paclitaxel, 8 (32%) responded. Among 41 platinum-sensitive patients, there was a 34.1% response rate (14.6% CR). Median response duration was 7.5 months, median PFI was 6.3+ months, and median survival time was 16.5+ months. Grade 3-4 leukopenia occurred in 41.2% of patients and neutropenia in 45.4%. Three treatment-related deaths occurred: 2 from neutropenic sepsis and 1 from thrombocytopenic bleeding after an overdose. One patient developed leukemia. The authors concluded that this regimen is active in platinum-resistant and platinum-sensitive ovarian carcinoma, as well as paclitaxel-resistant ovarian carcinoma.
Platinum Compound Combinations and Platinum Resistance
Editorial Comment by William Hoskins, MD
Currently, the standard therapy for advanced epithelial ovarian cancer is a combination of paclitaxel and one of the platinum compounds. Yet there is considerable interest in testing new combinations of therapy that use either old drugs in new combinations or new drugs in combination with more standard drugs.
Lorusso and colleagues have chosen to combine 2 platinum compounds, cisplatin and carboplatin, with ifosfamide. They reason that the 2 compounds do not have overlapping toxicities and that ifosfamide, one of the more active single agents in ovarian cancer, has an acceptable toxicity profile when given by a continuous 24-hour infusion. In the phase I part of the trial, they found that they could give carboplatin 300mg/m (day 1), ifosfamide 400mg/m/24 hours (day 1), and cisplatin 60mg/m (day 8). Grade 3 or 4 hematological toxicity was seen in about half of the patients. The population of patients included 18% stage IV patients and 29% grade 3 patients; 66% of the patients had bulky (suboptimal) disease. An overall response rate of 88% and a pathologically negative second-look rate of 21% are comparable with results reported for cisplatin and paclitaxel. The medial survival of 33 months is also similar to results obtained with cisplatin and paclitaxel.
Although this regimen appears to have little advantage over standard therapy in terms of response or survival and is more difficult to administer, it is nevertheless valuable in determining an optimal method of combining cisplatin and carboplatin with ifosfamide and is a necessary step in the evaluation of new regimens. Perhaps more interesting, however, would be doublets or triplets of new drugs such as topotecan and gemcitibine with platinum and paclitaxel.
Piver and associates have compared a regimen of induction with weekly cisplatin for 4 courses at an average dose of 40mg/m per week followed by 6 courses of cisplatin 75mg/m and paclitaxel 135mg/m over 24 hours on a 28-day cycle against historical controls of a series of patients in which they used the same 4 weekly doses of cisplatin as induction followed by 10 courses of a combination of cisplatin 50mg/m, cyclophosphamide 75mg/m, and doxorubicin 50mg/m given on a 28-day cycle. The patient populations were generally comparable, but the cisplatin/paclitaxel group had a larger population of stage IV patients (22.7% versus 8.9%) and a larger population of grade 3 patients (68.2% versus 60.7%).
Because there was essentially no difference in 2-year progression-free survival and overall survival, the investigators concluded that paclitaxel combined with cisplatin for 6 months is not superior to a regimen of cisplatin, cyclophosphamide, and doxorubicin for 8 months. They did note a higher response rate with the cisplatin and paclitaxel regimen; however, it was not statistically significant.
While the regimens are interesting and the uniformity of data from a single institution are good, the study is fatally flawed by not being randomized and by the 13-year time interval required for the 2 studies. While there is a definite role for single-institution phase I and phase II trials, it is virtually impossible for single institutions to conduct phase III randomized trials. Comparisons of 2 different populations such as this cannot substitute for randomized trials.
Rose and coworkers have conducted a classic phase II study of a chemotherapy regimen in recurrent ovarian cancer. Patients were divided into platinum-resistant and platinum-sensitive groups. Only one previous chemotherapy regimen was permitted, and patients were required to have measurable disease.
The investigators found oral etoposide to be active in both patient populations, although the platinum-sensitive patients had a higher complete response rate (14.6% versus 7.3%) and a greater median response duration (7.5 months versus 4.3 months) compared with the platinum-resistant group. These investigators also found a 32% response rate in patients who had previously received paclitaxel.
However, the toxicity of the regimen was considerable, with a 41.2% to 45.4% grade 3 or 4 hematologic toxicity and 3 treatment-related deaths, including 1 case of leukemia. In addition to providing important information about a potentially beneficial salvage regimen for recurrent or persistent ovarian cancer, the investigators have conducted a well-designed trial with reliable data.
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