Advances in Managing Ovarian Cancer: ASCO 2002May 18-21Orlando, FloridaNancy B. Davis M.D.
Scientific Editor: C. D. Buckner M.D.
Regardless of an initial high response rate to systemic chemotherapy, a majority of patients with ovarian cancer will relapse and may develop drug resistant disease. While recurrent disease may be palliated, cure is unlikely. Survival following relapse may be one year or more in a substantial proportion of patients due to good response to further chemotherapy regimens or possibly indolent disease. Currently there is no consensus regarding a standard second-line chemotherapy regimen. Reported here are summaries of drug combinations presented at ASCO 2002 for the management of advanced ovarian cancer.
An update of the SCOTROC 1 study of Taxotere®/Platinol® (DC) vs. paclitaxel/Platinol® (PC) for first-line chemotherapy in FIGO stages Ic-IV epithelial ovarian cancer revealed confirmation of previously released information describing statistically significantly less neurotoxicity (p<0.001), arthralgia/myalgia (p<0.001) and motor weakness (p<0.001) with DC as compared to PC. This significance for difference in neurotoxicity is present during therapy, as well as 6 and 10 months post randomization, although the difference is lessened by the latter. This updated analysis confirmed that DC offers similar efficacy with less toxicity than PC for first-line chemotherapy in epithelial ovarian cancer. In addition to DC being confirmed as appropriate first line treatment, the results of other novel chemotherapy combinations were reported.
Shami 2, et al., evaluated the efficacy and toxicity of combination Gemzar® and Platinol® for first-line therapy of FIGO stage IIIc and IV advanced ovarian cancer in 34 patients with bulky residual disease (> 2 cm) following primary cytoreductive surgery. The median age was 48 (range 26-70 years). Gemzar® (1250 mg/m 2 IV over 30 mins) was given on days 1 and 8 on a 21-day cycle with Platinol® (75 mg/m 2 ) on day 1 only. Thirty patients were evaluable for response and 34 patients were evaluable for toxicity. The overall response was 76.7%, with 8 CR (26.7%) and 15 PR (50%). An additional 6 patients had stable disease and only 1 patient progressed. Toxicities were mild with no grade III/IV toxicities. Given the high response rate, the combination of Gemzar® and Platinol® appears to be a safe and efficacious alternate first-line therapy for patients with bulky residual ovarian cancer.
Gupta 3 , et al., studied a triplet combination of Gemzar®, paclitaxel and Platinol® for first-line therapy in 46 patients with FIGO stage IIIb-IV epithelial ovarian cancer. All 3 agents have activity as single agents, and the paclitaxel/Platinol® combination provides high response rates, albeit low cure rates. The primary endpoint was response rate, which was 81%, with 1CR, 22PR, 5SD and 1PD. Secondary end points included toxicity, time to progression (TTP) and 1 and 3-year survivals. Grade 3/4 hematologic toxicities were significant, with 52 episodes of neutropenia in 46 patients, 59% with anemia, and 31% of patients developing thrombocytopenia. Of note, however, is that only 5% of those with neutropenia developed febrile neutropenia. Non-hematologic toxicities were tolerable, with 1 grade 4 each nausea/vomiting and constipation; a high rate of alopecia was seen and a modest occurrence of grade 1/2 diarrhea. Other endpoints, specifically time to progression and 1 and 3-year survival rates were not presented. Although this triplet appears to have a high response rate in chemonaive patients with ovarian cancer, the high rate of hematologic toxicity and lack of mature survival data remains problematic.
The preliminary results of the SCOTROC 2A trial 4 indicated that Paraplatin® followed by either Taxotere® as a single agent or in combination with Gemzar® is a well-tolerated and feasible option for first-line chemotherapy following diagnosis. This randomized trial evaluated primary systemic treatment of FIGO stages Ic-IV primary peritoneal, fallopian tube or ovarian cancers. Following biopsy, patients were randomized to receive Paraplatin® (AUC 7) every 3 weeks for 4 cycles followed by either Taxotere® (100 mg/m 2) q3 weeks x 4 cycles (ARM A 42 pts), Taxotere® (75 mg/m2 on day 8) + Gemzar® (1250 mg/m 2 on days 1 and 8) q3 weeks x 4 cycles (ARM B 42 pts), or Taxotere® (25 mg/m 2) + Gemzar® (800 mg/m 2 ) on days 1, 8, and 15 q3 weeks x 4 cycles (ARM C 41 pts).
The ORR following Paraplatin® in 93 evaluable patients was 76%. (See Table 1 for response following taxane therapy and Table 2 for best response by treatment arm). Median dose intensity for Paraplatin® was 90%, Taxotere® 98%, Taxotere®/Gemzar® 85% and weekly Taxotere®/Gemzar® 70%. The response rates are similar for the three taxane-containing arms, although comparison reveals that the weekly therapy was not as well tolerated, with increased grade 2/3 fatigue (71% vs. 47%, 48%), decreased median dose intensity (67% vs. 93%, 82%) and an increase in early stopping (30% vs. 16%, 18%). Treatment with Gemzar® was associated with an increase in grades 2-4 shortness of breath, including one toxic death. Although it remains too early to make conclusions regarding efficacy, both Taxotere® and Taxotere® plus Gemzar® are feasible regimens following 4 cycles of Paraplatin®.
Salimichokami and Aminian 5 (Tehran, Iran) presented the results of a phase II trial of a weekly Gemzar® and Taxotere® regimen for 18 patients with FIGO stage III/IV ovarian cancer who had relapsed within 6 months of receiving standard first-line therapy. Taxotere® (40 mg/m2) and Gemzar® (1000 mg/m2) were given on days 1, 8 and 15 of a 28-day cycle to patients with measurable disease by CA-125 levels. All patients completed 6 cycles of therapy and were evaluable for both response and toxicity. The overall response rate (ORR) was 61%, with 2CR, 9PR, 6SD and 1PD). Median TTP was 33 weeks (range 6-59), with median survival 43 weeks (range 14-110). Toxicities included 2 grade 3/4 nausea/vomiting, 1 grade 4 and 4 grade 3 neutropenia, 1 grade 3 thrombocytopenia and 4 grade 3 fatigue. There were no episodes of neutropenic sepsis or hospitalization. This novel regimen appears to offer a high response rate, with modest toxicity in platinum-resistant recurrent ovarian cancer.
D’Agostino 6 , et al., from Italy reported on the efficacy of liposomal doxorubicin (CAE), 30 mg/m2 on day 1, followed by Gemzar® (GEM), 1000 mg/m2 on days 1 and 8 of a 21-day cycle. LVEF was measured at baseline and after every 2 cycles by echocardiogram. In this phase II study of 46 evaluable patients with recurrent ovarian cancer, the ORR was 30.4% with 4 CR and 10 PR. Of 52 enrolled patients, 18 (34.6%) patients had platinum/paclitaxel refractory disease, 9 (17.3%) had resistant disease and 25 (48.1%) had platinum-sensitive disease. See Table 3 for best response based on platinum sensitivity. The median duration of response was 16 weeks (range 4-34) and the median duration of stable disease was 31 weeks (range 12-52). Toxicity was mild, with 32.7% grade 4 neutropenia and no grade 4 non-hematologic toxicities. This combination has modest activity in recurrent ovarian cancer with a comparable toxicity profile to either single agent. The overall benefit of 78.2% (CR+PR+SD) is a valid option for salvage therapy.
In summary, first-line systemic chemotherapy for epithelial ovarian cancer should remain platinum based; however, in lieu of paclitaxel, both Gemzar® and Taxotere® could be considered, as they offer similar efficacy with potentially less morbid toxicity. Paraplatin® followed by Taxotere® with or without Gemzar® is an interesting regimen with tolerable toxicity, although its efficacy needs to be determined in comparative trials. The addition of Gemzar® to the paclitaxel/Platinol® combination yields more toxicity, especially hematologic, without a definitive increase in benefit.
Salvage therapy for chemotherapy-sensitive disease should include a platinum compound; however, in regards to second-line/salvage therapy in a platinum-resistant setting, combination chemotherapy with either Taxotere®/Gemzar® or liposomal doxorubicin/Gemzar® are well tolerated, with good response rates, although appreciable survival benefits over single agent therapy has not been demonstrated. Larger studies in the future should focus on other Gemzar® or taxane-based regimens to identify those with high response rates, as well as survival benefits.
Vasey PA. Survival and longer-term toxicity results of the SCOTROC study: Taxotere®-Paraplatin® (DC) vs. Taxol®-Paraplatin® (PC) in epithelial ovarian cancer (EOC). Proceedings of the 38th Annual Meeting of the American Society of Clinical Oncology. 2002;21:Abstract 804.
Shami N, Mahmood I, Alauddin Z, et al. A phase II trial of Gemzar® and Platinol® combination chemotherapy in advanced epithelial ovarian cancer with bulky residual disease. Proceedings of the 38th Annual Meeting of the American Society of Clinical Oncology. 2002;21:Abstract 2518.
Gupta SK, Arora R, John S, et al. Gemcitabine, Paclitaxel and Cisplatin in chemotherapy-naïve advanced ovarian cancer: results of a multicenter phase II study. Proceedings of the 38th Annual Meeting of the American Society of Clinical Oncology. 2002;21:Abstract 857.
Rustin GJS. Preliminary results of SCOTROC 2A, a randomized feasibility study of Paraplatin® (C), then sequential Taxotere® (D) or two schedules of Taxotere® + Gemzar® (G) in ovarian/mullerian cancers. Proceedings of the 38th Annual Meeting of the American Society of Clinical Oncology. 2002;21:Abstract 810.
Salimichokami M, Aminian S. Weekly Gemzar® and Taxotere® (GETAX), a novel 2nd line regimen in recurrent platinum-resistant epithelial ovarian cancer, a phase 2 study. Proceedings of the 38th Annual Meeting of the American Society of Clinical Oncology. 2002;21:Abstract 2537.
D’Agostino G, Ludovisi M, Lorusso D, et al. The liposomal doxorubicin (CAE) and Gemzar® (GEM) combination is active in relapsed ovarian cancer: a phase II study. Proceedings of the 38th Annual Meeting of the American Society of Clinical Oncology. 2002;21:Abstract 875.