Expert Commentary

David R. Spriggs, MD, Head, Division of Solid Tumor Oncology; Winthrop Rockefeller Chair of Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York

According to the results of 3 studies presented at the 40^th Annual Meeting of the American Society of Clinical Oncology (ASCO), treatment of relapsed or recurrent ovarian cancer with weekly topotecan results in improved safety compared with the standard topotecan administration of 1.5 mg/m² daily for 5 consecutive days every 3 weeks.^1-3 Weekly topotecan was well tolerated with a low incidence of hematologic toxicity. Data was also presented on the promising combination of irinotecan (topoisomerase I inhibitor) and nedaplatin, a new platinum analog, in the treatment of advanced cervical cancer.^4,5

Epithelial ovarian cancer is an aggressive malignancy affecting more than 25,000 women and resulting in more than 16,000 deaths in the United States each year.⁶ Despite surgery and optimal chemotherapy, more than 70% of patients will relapse.⁷ If relapse occurs, patients are often given additional trials of chemotherapy, which often result in reduced duration of response with each successive line of chemotherapy.^8,9 As such, heavily pretreated patients are more susceptible to the toxicities of chemotherapeutic agents compared with those who have received only 1 prior chemotherapy regimen.^9,10

Topotecan is a topoisomerase I inhibitor approved by the FDA for the treatment of relapsed ovarian cancer and has shown beneficial results in the multiple-relapse setting.^8,11,12 Previous studies have demonstrated overall response rates ranging from 14% to 33% when using topotecan in the treatment of recurrent ovarian cancer.^13-17 However, the standard topotecan administration of 1.5 mg/m² daily for 5 consecutive days every 3 weeks has been associated with dose-limiting hematologic toxicity,¹⁸ although it is reversible and noncumulative. Emerging evidence suggests that weekly administration of topotecan in the treatment of advanced ovarian cancer will greatly diminish toxicity while maintaining response rates with those achieved using the standard dosing regimen.

This Oncology Express Report^TM reviews the latest advancements in the use of topoisomerase I inhibitors for the treatment of gynecological malignancies.

Antitumor Activity of Weekly Topotecan in Advanced or Recurrent Ovarian Cancer

According to a retrospective analysis of heavily pretreated patients with epithelial ovarian carcinoma, weekly topotecan was active and well tolerated compared to the standard 5-day administration of topotecan. Moreover, topotecan can be given at higher doses in those patients receiving a weekly topotecan dosing schedule with improved tolerability, according to David O'Malley, MD, of Yale University School of Medicine, New Haven, Connecticut.¹ The objective of the analysis was to evaluate the tolerability and antitumor activity of weekly topotecan in patients with recurrent ovarian cancer who had failed previous therapy with one or more platinum-based chemotherapy regimens.

A total of 35 patients with relapsed ovarian cancer (median prior treatments, 2; median age, 56 years) received a mean of 5 cycles of topotecan. Thirty-two patients had definable platinum sensitivity (16 sensitive, 8 resistant, 8 refractory). Weekly topotecan was administered on Days 1, 8, and 15 of a 28-day cycle at ≤3 mg/m² (n = 11), 2.5 mg/m² (n = 21), and ≤2 mg/m² (n = 3). Patients were treated until progression, with antitumor responses assessed after 2 cycles (8 weeks) by serum cancer antigen (CA) 125 levels. Dose adjustments or treatment delays were implemented for grade 2/3 myelosuppression.

The overall response rate with weekly topotecan was 18% in 34 evaluable patients, which included 1 complete response (defined as normalization of CA 125 levels with no clinical or radiologic evidence of disease), and 5 partial responses (defined as a 50% reduction in CA 125 levels) (Table 1). Stable disease was observed in 38% of patients as a best response. Median duration for those who achieved partial response was 28 weeks (range, 16-44 weeks). Median duration of stable disease was 20 weeks (range, 12-52 weeks).

Similar to the results of previous weekly-regimen studies, Dr. O'Malley reported that the weekly regimen of topotecan was well tolerated. No grade 4 myelosuppression was observed and the most common hematologic toxicity was grade 1/2 anemia (Table 2). Further, no severe nonhematologic toxicity was observed with weekly topotecan. The most common nonhematologic toxicity was fatigue.

Dr. O'Malley indicated that the majority of weekly topotecan doses were delivered with no delay and at planned dose level with 54% of patients completing a median of 4 courses of treatment.

The analysis concluded that weekly topotecan administration was active and well tolerated in previously treated advanced ovarian cancer patients. Dr. O'Malley noted that the potential for integrating weekly topotecan into novel combination regimens requires further investigation.

Tolerability and Benefit of Weekly Topotecan in Patients with Epithelial Ovarian Cancer

According to the results of another retrospective analysis, weekly topotecan administration was safe and well tolerated in heavily pretreated patients with epithelial ovarian cancer with a lower incidence of severe hematologic toxicity compared with standard 5-day topotecan administration.² Furthermore, these findings suggest that weekly topotecan has promising activity in prolonging the time-to-disease progression, reported Snehal M. Bhoola, MD, University of Alabama at Birmingham, Birmingham, Alabama.

A total of 30 heavily pretreated patients (median age, 60.5 years) with epithelial ovarian cancer were treated with weekly topotecan at 4 mg/m² in 4-week cycles until either evidence of disease progression or unacceptable toxicity. This dose was somewhat higher than the dose used by O'Malley. All patients had received paclitaxel/carboplatin as first- or second-line chemotherapy; 22 patients were platinum-sensitive. Most patients had excellent or good performance status, but >25% had poor performance status. Growth factor support was given at the discretion of the treating physician. All patients were considered evaluable for safety and patients who received 1 or more 4-week cycles were considered evaluable for efficacy, noted Dr. Bhoola.

Twenty-eight patients received a median of 2.3 cycles of therapy and were considered evaluable for response. Of those 28 patients, 3 patients (11%) achieved a partial response (median duration, 3.1 months) and 11 patients (39%) had stable disease (median duration, 6.6 months) while 14 patients (50%) demonstrated disease progression. Treatment with weekly topotecan resulted in CA 125 decreases (median decline, 41%) in 18 patients (64%).

Weekly topotecan was well tolerated with no evidence of grade 4 hematologic toxicity (Table 3). No patient experienced febrile neutropenia. Erythropoietin was administered to 23 patients (82%) while no patient received granulocyte colony-stimulating factor.

According to Dr. Bhoola, nonhematologic toxicities were mild to moderate in severity and included neuropathy observed in 3 patients and grade 1 nausea, fatigue, and alopecia observed in 1 patient each. Dr. Bhoola also noted there were 13 dose delays and 5 dose adjustments, primarily to manage hematologic toxicity.

Dr. Bhoola suggested that the results of the analysis were promising due to the long duration of both the partial responses and stable disease observed in these heavily pretreated patients with recurrent ovarian cancer. Further, Dr. Bhoola indicated that prospective clinical trials of weekly topotecan are currently being conducted to provide further insight into the safety and efficacy of weekly topotecan administration.

Weekly Topotecan in Platinum-sensitive Recurrent Ovarian and Peritoneal Cancer

Preliminary results of a prospective, multicenter phase II trial demonstrated that weekly topotecan was an active agent in patients with platinum-sensitive recurrent ovarian and peritoneal cancer and was associated with reduced hematologic toxicity compared to standard topotecan administration.³ The results of the phase II trial were presented by Michael Rodriguez, MD, FACOG, of Michiana Hematology-Oncology, South Bend, Indiana.

To date, 22 patients (median age, 64 years) have enrolled in the trial (18 with ovarian and 4 with peritoneal cancer). All patients were required to have recurrent platinum-sensitive disease and no more than 2 prior treatment regimens-a better prognosis group than the 2 studies described above. Weekly topotecan was administered on Days 1, 8, and 15 of a 28-day cycle at 4 mg/m²; escalated to 5 mg/m² if well tolerated. Patients received a median of 2 courses of topotecan.

The overall response rate to weekly topotecan was 14%; 3 partial responses in 21 evaluable patients. Stable disease was observed in 9 patients (43%); progressive disease in 9 patients (43%). The median time to progression was 10.9 weeks (range, 6.1-30.7 weeks). Among the 12 patients who achieved a partial response or stable disease, the median time from best response to progression was 17.8 weeks (range, 7.2-30.7 weeks).

Weekly topotecan was well tolerated. Grade 3/4 neutropenia occurred in 9 patients (43%); grade 3/4 leukopenia in 3 patients (14%); grade 3 anemia in 3 patients (14%); and grade 3 thrombocytopenia in 1 patient (5%) (Table 4). The incidence of grade 3/4 nonhematologic toxicity was low. The most common grade 3 nonhematologic toxicities were nausea and vomiting (3 patients each). The most common grade 4 nonhematologic toxicities were infection and fatigue (2 patients each).

"The improved safety profile observed with weekly topotecan suggests its use as an alternative schedule in heavily pretreated ovarian cancer patients," concluded Dr. Rodriguez.

Taken together, these studies confirm work reported at last year's ASCO meeting.^19,20 A weekly schedule of topotecan administration at 3 to 4 mg/m²/week is well tolerated and results in a significant objective response rate. The rate of objective response is similar to that seen with a more traditional 5 day schedule although no randomized comparison of the 2 schedules is available. The lack of severe neutropenia is particularly notable for the weekly schedule.

Irinotecan and Nedaplatin - Combination for Recurrent Cervical Cancer

Results of a phase I/II study in 27 patients with advanced or recurrent stage IV cervical cancer suggest that irinotecan plus nedaplatin, a platinum analog, represent a promising chemo-therapeutic combination that warrants further investigation in this setting, according to Hiroshi Tsuda, MD, PhD, Department of Obstetrics and Gynecology and Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan.⁴

"These patients [those with stage IV and recurrent cervical cancer] have a dismal prognosis. We decided to study these two agents in combination because each demonstrates a high response rate in cervical cancer and preclinical studies suggest that the combination is synergistic," explained Dr. Tsuda.

In the phase I portion of the study, patients (n = 18) with stage IV or recurrent cervical cancer (median age, 54 years) received a combination of 3 escalating dose levels of irinotecan (50 mg/m², 50 mg/m², and 60 mg/m²) and nedaplatin (70 mg/m², 80 mg/m², and 80 mg/m²). Before irinotecan administration, patients received a 5-HT3 serotonin receptor antagonist. Patients also received recombinant granulocyte colony-stimulating factor (50 mcg). Treatment was repeated every 4 weeks for 2 to 6 courses. Primary endpoints were toxicity and response rate.

The results of the phase II portion of the study (n = 22) demonstrated that the combination of irinotecan and nedaplatin resulted in an overall response rate of 68% (95% Confidence Interval [CI], 49%-84%) with 2 complete responses (9%) and 13 partial responses (59%). Among 12 responders who had recurrent disease, the median time to progression was 161 days (range, 61-711 days).

For both phases of the study, grade 3/4 hematologic toxicities included neutropenia (91%), leukopenia (52%), anemia (37% - grade 3 only), and thrombocytopenia (19%). All 9 patients with grade 4 neutropenia recovered after short-term recombinant granulocyte colony-stimulating factor; none developed febrile neutropenia. No grade 4 nonhema-tologic toxicities were reported. The most common nonhematologic toxicities observed were nausea (88%) and diarrhea (33%).

Similar response and toxicity results for the combination of irinotecan and nedaplatin in primary advanced or recurrent cervical cancer were presented in a separate phase II study.5 In that study, investigators stressed the importance of avoiding the combination of cisplatin and bleomycin in treating recurrent cervical cancer. Bleomycin is associated with severe pulmonary toxicity.²¹ No pulmonary toxicity was observed in the study.

This topoisomerase/platinum combination is promising for the treatment of cervical cancer. The results are consistent with a large randomized study presented at the February meeting of the Society of Gynecologic Cancer.²² In that study, cisplatin and topotecan were compared to cisplatin alone in the treat-ment of advanced/metastatic cervical cancer. The survival advantage, although modest, was the first demonstration of the superiority of combination chemotherapy in the management of metastatic cervical cancer.

Conclusion

Treatment of relapsed or recurrent ovarian cancer with weekly topotecan results in objective responses with an improved safety profile compared with the standard topotecan adminis-tration of 1.5 mg/m² daily for 5 consecutive days every 3 weeks. Combinations of topoisomerase I inhibitors and platinum complexes appear to be particularly active in metastatic cervical cancer and may point toward potential synergy in other diseases.

References

1. O'Malley DM, Makkenchery A, Tangir J, et al. Retrospective analysis of topotecan administered weekly in heavily pretreated epithelial ovarian carcinoma patients. Proc Am Soc Clin Oncol. 2004;23:467. Abstract 5079.
2. Bhoola SM, Estes JM, Leath CA, et al. Weekly topotecan is well tolerated in the third-line or later treatment of patients with epithelial ovarian carcinoma (EOC) and may prolong time to disease progression. Proc Am Soc Clin Oncol. 2004;23:464. Abstract 5067.
3. Rodriguez M, Method MW, Lewandowski G, Vaccarello L, Ansari RH. A preliminary report of a phase II study of weekly topotecan in platinum-sensitive recurrent ovarian and peritoneal carcinoma. Proc Am Soc Clin Oncol. 2004;23:463. Abstract 5063.
4. Tsuda H, Hashiguchi Y, Nishimura S, et al. Phase I-II study of irinotecan (CPT-11) plus nedaplatin (254-S) with recombinant human granulocyte colony-stimulating factor support in patients with advanced or recurrent cervical cancer. Proc Am Soc Clin Oncol. 2004;23:463. Abstract 5065.
5. Ohwada M, Machida S, Fujiwara H, et al. Phase II study of combination chemotherapy using irinotecan and nedaplatin for patients with primary advanced or recurrent cervical cancer. Proc Am Soc Clin Oncol. 2004;23:469. Abstract 5088.
6. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin. 2004;54:8-29.
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8. Herzog TJ. Update on the role of topotecan in the treatment of recurrent ovarian cancer. Oncologist. 2002;7(suppl 5):3-10.
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10. Dunton CJ. Management of treatment-related toxicity in advanced ovarian cancer. Oncologist. 2002;7(suppl 5):11-19.
11. ten Bokkel Huinink W, Gore M, Carmichael J, et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol. 1997;15:2183-2193.
12. Gordon AN, Fleagle JT, Guthrie D, et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001;19:3312-3322.
13. Bookman MA, Malmstrom H, Bolis G, et al. Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. J Clin Oncol. 1998;16:3345-3352.
14. McGuire WP, Blessing JA, Bookman MA, et al. Topotecan has substantial anti-tumor activity as first-line salvage therapy in platinum-sensitive ovarian carcinoma: a GOG study. J Clin Oncol. 2000;18:1062-1067.
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16. Kudelka AP, Tresukosol D, Edwards CL, et al. Phase II study of IV topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol. 1996;14:1552-1557.
17. Swisher EM, Mutch DG, Rader JS, et al. Topotecan in platinum- and paclitaxel-resistant ovarian cancer. Gynecol Oncol. 1997; 66:480-486.
18. Morris R, Munkarah A. Alternate dosing schedules for topotecan in the treatment of recurrent ovarian cancer. Oncologist. 2002;7(suppl 5):29-35.
19. Bhoola S, Estes J, Morris R, Bryant C, Coleman R, Alvarez RD. Retrospective analysis of weekly topotecan as salvage therapy in relapsed ovarian cancer (OC). Proc Am Soc Clin Oncol. 2003;22:474. Abstract 1905.
20. Morris R, Alvarez RD, Andrews S, Malone J, Bryant C, Munkarah A. Topotecan weekly bolus chemotherapy for potentially chemosensitive relapsed ovarian and peritoneal cancer-An update. Proc Am Soc Clin Oncol. 2003; 22:459. Abstract 1846.
21. Chambers SK, Flynn SD, Del Prete SA, Chambers JT, Schwartz PE. Bleomycin, vincristine, mitomycin C, and cis-platinum in gynecologic squamous cell carcinomas: a high incidence of pulmonary toxicity. Gynecol Oncol. 1989;32:303-309.
22. Long HJ III, Bundy BN, Grendys EC Jr, et al. Randomized phase III trial of cisplatin (P) vs cisplatin plus topotecan(T) vs MVAC in stage IVB, recurrent or persistent carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. The 2004 Annual Meeting on Women's Cancer, February 7-11, 2004.

Disclosure

David R. Spriggs, MD: No significant relationships to disclose.

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