A feasibility study of topotecan with standard-dose cisplatin and concurrent primary radiation therapy in locally advanced cervical cancer

Abstract

Objectives

Topotecan improves response rate (RR), progression-free survival (PFS) and overall survival (OS) when added to cisplatin in treating metastatic and recurrent cervical cancer. The objective of this study was to assess the feasibility of adding weekly topotecan to cisplatin in patients with primary, locally advanced carcinoma of the cervix receiving pelvic irradiation.

Methods

Patients with primary, previously untreated, histologically confirmed invasive squamous cell, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, stages IB2–IVA were treated with external beam pelvic radiotherapy (45 Gy), intracavitary low dose rate brachytherapy (40 Gy) and a parametrial boost (5.4–9 Gy) with overall treatment time not to exceed 8 weeks. Concurrent chemotherapy was IV cisplatin 40 mg/m²plus IV topotecan 2 mg/m² on days 1, 8, 15, 22, 29 and once during parametrial boost for 6 cycles. Patients were monitored with history, physical examination, tumor measurement and laboratory evaluation before entering the study, before each cycle of chemotherapy, at study termination and every three months thereafter.

Results

The study met its accrual goal of 12 patients. With a median follow-up of 22 months, eleven patients completed treatment and ten are in long term follow up without evidence of recurrent disease. The 12th patient developed progressive disease during therapy. All patients completed at least 4 cycles of chemotherapy, with the majority (82%) completing 5 or more. Grade 2 or higher neutropenia delayed treatment in 54% of cycles. The median treatment delay was 1.5 cycles (range: 1 to 5 cycles). Median treatment time was 59 days (range 46 to 81 days). The complete RR was 92% (95% confidence interval, 55%–100%).

Conclusions

The addition of weekly topotecan to cisplatin at this dose and schedule during pelvic irradiation for locally advanced cervical cancer appears to be feasible. Based on this primary treatment data and the activity of cisplatin–topotecan in the recurrent disease setting, phase II and III studies of this combination are warranted.

Introduction

There will be approximately 11,070 cases of invasive cervical cancer expected in the United States in 2008, with an estimated 3870 deaths [1]. In developing countries, cervical cancer is the leading cause of cancer-related mortality causing over 272,000 deaths in 2007 [2]. Between 1988 and 2001, there were 95,353 registered cases of cervical carcinoma in the Surveillance Epidemiology and End Results (SEER) database, of which approximately 55% were locally advanced disease diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage IB2-IVA [3]. A new standard for the treatment of locally advanced cervical cancer was established in 1999 [4], [5]. The addition of weekly cisplatin at 40 mg/m² for 6 weeks in combination with radiation (RT) reduces the relative risk of death from cervical cancer by approximately 50% by decreasing local failure and distant metastases [6], [7], [8], [9], [10]. This combination was favored because Gynecologic Oncology Group (GOG) Protocol 120 showed it to be less toxic and as equally efficacious when compared with other combinations using hydroxyurea and/or 5-flourouracil (5-FU) [8]. Multimodality therapy is now the standard of care for locally advanced cervical carcinoma [11].

Topotecan acts synergistically with cisplatin and potentiates its cytotoxic activity against cancer cells. The mechanism is thought to occur through DNA repair inhibition [12]. The combination of these two agents was hypothesized to cause greater antitumor activity than might be expected from the additive effects of the two drugs. Clinical trials have since proven this hypothesis in patients with advanced or recurrent cervical cancer [13], [14]. Although more hematologically toxic, the combination does not appear to significantly reduce patient quality of life (QOL) when compared with cisplatin alone [15]. GOG Protocol 179 was the first randomized phase III trial to demonstrate a survival advantage for the combination of cisplatin and topotecan over cisplatin alone in recurrent or stage IVB cervical cancer [14]. Topotecan is also a radiosensitizing agent [16] and has been studied at various daily dosing regimens in patients with advanced cervical cancer receiving external beam RT and low-dose rate (LDR) brachytherapy [17], [18].

Based on these data, the objective of the present study was to assess the activity, feasibility and toxicity of adding weekly topotecan which is less marrow toxic than the previously studied daily schedules to cisplatin in previously untreated patients with primary, locally advanced (FIGO stage IB2 through IVA) carcinoma of the cervix receiving concurrent pelvic RT.