Editorial

Susana M. Campos, MD, MPH, Instructor in Medicine, Harvard Medical School, Breast/GYN Oncology Center, Dana-Farber Cancer Institute, Boston, Massachusetts

Ovarian cancer is one of the most common gynecologic malignancies and the fifth most frequent cause of cancer death in women, with half of all cases occurring in women over age 65.¹ Ovarian cancer is often asymptomatic in its early stages and most patients have widespread disease at the time of diagnosis. Despite aggressive surgical procedures and intensive chemotherapy, the 5-year survival rate is less than 50%. In 2002, it is estimated that 23,300 new cases of ovarian cancer will be diagnosed and 13,900 deaths due to ovarian cancer will occur.² Women who carry mutations in BRCA1 and BRCA2 genes have an increased lifetime risk of developing ovarian cancer ranging from 16% to 60%.^3,4

Currently, the standard of care for newly diagnosed advanced-stage ovarian cancer includes cytoreductive surgery followed by combination chemotherapy with platinum (e.g., cisplatin, carboplatin) and paclitaxel. Despite high overall clinical response rates achieved with platinum-based chemotherapy (up to 80%), most patients subsequently relapse and require additional chemotherapy.⁵ Therefore, the goals of second-line chemotherapy include disease stabilization to maintain quality of life and extend survival. The chemotherapeutic options must be efficacious while exhibiting a favorable toxicity profile. Therapeutic options for relapsed ovarian cancer include retreatment with platinum-based chemotherapy, (if treatment free interval > 6 months⁶), topotecan (Hycamtin, GlaxoSmithKline), gemcitabine (Gemzar, Eli Lilly), liposomal doxorubicin (Doxil, Alza Corp.), ifosfamide (Ifex, Bristol-Myers Squibb), melphalan (Alkeran, GlaxoSmithKline), etoposide (VePesid, Bristol-Myers Squibb), and cyclophosphamide (Cytoxan, Bristol-Myers Squibb). In particular, topotecan has demonstrated efficacy comparable to paclitaxel across all categories of platinum sensitivity⁷ and exhibited activity in patients with ovarian cancer resistant to both platinum and paclitaxel.^8-11 Dose-limiting toxicity with topotecan is hematologic but is reversible and noncumulative.^8,11 Further investigation into topotecan's dosing administration in the hopes of improving its toxicity profile was the subject of several abstracts at the 38th Annual Meeting of the American Society of Clinical Oncology (ASCO 2002) held May 18-21, 2002 in Orlando, Florida.

Topotecan: Weekly Administration

Standard topotecan administration is 1.5 mg/m² by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course.¹² However, myelosuppression is associated with this dosing schedule. According to reports from ASCO 2002, a new weekly dosing regimen of topotecan may favorably alter the toxicity profile allowing for potentially higher doses and combinations with other chemotherapeutic agents.^13-15

"If we can give topotecan more conveniently while maintaining efficacy and minimizing toxicity, we can enhance the quality of life of our relapsed ovarian patients," stated Susana M. Campos, MD, MPH, Instructor in Medicine, Harvard Medical School, Breast/GYN Oncology Center, Dana-Farber Cancer Institute, Boston, Massachusetts.

Morris et al¹³ enrolled 12 patients with stage III/IV ovarian cancer (to date) in a prospective Phase II trial. The purpose of the study was to evaluate the activity and toxicity of weekly bolus topotecan in potentially platinum-sensitive ovarian and peritoneal cancer. Patients had only one prior platinum-based chemotherapy regimen (median time from first-line platinum-based therapy was 50 weeks), a treatment-free interval greater than 6 months, bidimensional measurable disease, and Gynecologic Oncology Group (GOG)(Zubrod) Performance Status < 3.

Topotecan was administered as a weekly 30-minute bolus infusion with a starting dose of 4.0 mg/m². The total number of weekly topotecan treatments was 169, with a median of 14.1 (range, 1-27). All twelve patients were evaluated for toxicity and 10 patients were evaluable for response.

With weekly topotecan administration, partial responses were achieved in five of the ten patients (50%), and two patients (20%) were noted to have stable disease. Among the responders, the median time to response was 7.7 weeks and the median progression-free interval was 24.6 weeks (range, 17.9-32.7 weeks). The two patients with stable disease had progression-free intervals of 13 weeks and 32 weeks, reported lead author Robert T. Morris, MD, Wayne State University, Detroit, Michigan.

Myelotoxicity in the study was infrequent and included grade 3 or 4 neutropenia following two treatments (1.1%) and grade 3 anemia following three treatments (1.8%). There was no neuropathy or gastrointestinal toxicity reported. Nonhematologic toxicity included grade 3 fatigue in two patients (17%) prompting their removal from the study. Investigators proposed that fatigue might be a limiting side effect in some patients.

Similar findings were demonstrated with weekly topotecan administration in recurrent metastatic endometrial carcinoma.¹⁴ According to an ongoing Phase I/II study by Finkler et al, adverse events that are commonly observed with other endometrial carcinoma treatments, i.e., cardiomyopathy, have not been observed with topotecan. Topotecan was administered as a weekly bolus infusion in dose-escalation (2.5-4.5 mg/m²) with a median of 9 doses (range, 1-32) received (range, 1.5-3.5 mg/m²/week).

The most frequently reported serious adverse events associated with topotecan included grade 4 neutropenia (8%), grade 4 fatigue (8%), grade 3 fatigue (31%), grade 3 anemia (54%), grade 3 neutropenia (31%), and grade 3 thrombocytopenia (31%). Partial responses were seen in three patients (23%).

"Weekly bolus topotecan was convenient and safe, and exhibited preliminary activity in endometrial cancer patients. This dosing schedule appears to offer improved tolerability compared with the current FDA-approved five-day topotecan regimen," stated lead author Neil J. Finkler, MD, Walt Disney Memorial Cancer Institute, Orlando, Florida.

Dose-Finding Study

According to a dose-escalation study presented at ASCO 2002, weekly bolus topotecan in higher doses than those used in the studies by Morris and Finkler (described above) is being investigated. Efforts are still underway to establish the maximum tolerated dose of weekly bolus topotecan, and researchers reported the results of their dose-escalation study in 48 heavily pretreated patients with various advanced malignancies.¹⁵

Topotecan was administered as a 30-minute bolus intravenous infusion on days 1, 8, and 15 every 28 days at doses ranging from 1.5 mg/m² to 8.5 mg/m². At a topotecan dose of 3 mg/m², one of six patients experienced a dose-limiting toxicity (prolonged absolute neutrophil count (ANC) < 1500 for 21 days), however, no further dose-limiting toxicities were noted, even at the highest topotecan dose level. Transient grade 3 or 4 ANC was noted in one patient each at dose levels 4 mg/m², 5.5 mg/m², 6.25 mg/m², 7 mg/m² and 8.5 mg/m². Grade 3 thrombocytopenia was noted in two patients, one patient at 7 mg/m² and another at 8.5 mg/m². Nonhematologic toxicities were minimal, reported lead author Benjamin R. Tan, MD, Washington University, St. Louis, Missouri.

Minor responses were observed in two patients with sarcoma and prostate cancer, and prolonged stable disease (> 4 months) was demonstrated in three patients (colon, lung, head and neck cancer).

The investigators concluded that the maximum tolerated dose has not been reached for weekly bolus topotecan. Further, high doses of topotecan given weekly are tolerable, even in heavily pretreated cancer patients. "This may be a suitable schedule for combination with other antineoplastic agents," Dr. Tan suggested. "We are presently treating patients at a 10 mg/m² dose level and pharmacokinetic studies are being done on this dose level."

References

1. Yancik R: Ovarian Cancer: Age Contrasts in Incidence, Histology, Disease Stage at Diagnosis, and Mortality. Cancer 1993;71(2, Suppl):517-523.
2. American Cancer Society: Cancer Facts and Figures-2002. Available at: http://www.cancer.org/eprise/main/docroot /stt/stt_0. Accessed May 22, 2002.
3. Struewing JP, Hartge P, Wacholder S, et al. The Risk of Cancer Associated with Specific Mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997;336(20):1401-1408.
4. Easton DF, Ford D, Bishop DT. Breast and Ovarian Cancer Incidence in BRCA1-Mutation Carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 1995;56(1):265-271.
5. McGuire WP, Ozols RF. Chemotherapy of Advanced Ovarian Cancer. Semin Oncol 1998;25:340-348.
6. Markman M, Rothman R, Hakes T, et al. Second-Line Platinum-Therapy in Patients with Ovarian Cancer Previously Treated with Cisplatin. J Clin Oncol 1991;9:389-393.
7. 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.
8. Creemers GJ, Bolis G, Gore M et al. Topotecan, an Active Drug in the Second-Line Treatment of Epithelial Ovarian Cancer: Results of a Large European Phase II Study. J Clin Oncol 1996;14:3056-3061.
9. Kudelka AP, Tresukosol D, Edwards CL et al. Phase II Study of Intravenous Topotecan as a 5-Day Infusion for Refractory Epithelial Ovarian Carcinoma. J Clin Oncol 1996;14:1552-1557.
10. Swisher EM, Mutch DG, Rader JS et al. Topotecan in Platinum- and Paclitaxel-Resistant Ovarian Cancer. Gynecol Oncol 1997;66:480-486.
11. 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.
12. Hycamtin Professional Prescribing Information. GlaxoSmithKline. Available at: http://www.gsk.com/products /prescriptionmedicines.shtml. Accessed May 22, 2002.
13. Morris RT, Munkarah A, Field J, Baker VV, Drake R, Malone J. Phase II Trial of Weekly Topotecan in Patients with Potentially Platinum Sensitive Relapsed Ovarian and Peritoneal Cancer. 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 2512.
14. Finkler NJ, Holloway RW. A Phase I/II Trial of Weekly Topotecan in the Treatment of Advanced Recurrent Metastatic Endometrial Carcinoma. 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 2504.
15. Tan BR, Picus J, Fracasso PM, Clark R. Weekly Bolus Topotecan (T): Update on a Phase I Dose Escalation Trial. 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 2149.