Weekly Cisplatin and Gemcitabine with Concurrent Radiotherapy in Locally Advanced Cervical Carcinoma

Abstract & Commentary

Synopsis: The association of cisplatin and gemcitabine with concurrent radiotherapy is active and well-tolerated in untreated LACC.

Source: Zarba JJ, et al. Ann Oncol. 2003;14: 1285-1290.

Cervical cancer is the most frequent gynecologic cancer in the world and the most frequent cancer in women in many underdeveloped and developing countries, where almost half of the patients are diagnosed with locally advanced disease. Older women, particularly minorities, have the highest incidence of mortality (http://www.seer.cancer.gov/). The current standard of care is the concurrent administration of chemotherapy and radiotherapy.1 It has been shown to improve the control of pelvic disease and significantly increase overall survival rates in numerous randomized trials.2-6 The most widely used chemotherapeutic agent is cisplatin, but not a single drug or schedule is accepted as standard. In randomized trials, weekly cisplatin 40 mg/m2 with concurrent radiotherapy has an acceptable therapeutic ratio. Despite these improvements, there is a need for further optimization of care. Gemcitabine has shown some single-agent activity in metastatic or recurrent cervical cancer and has shown radiosensitizing properties in preclinical trials. Patients have been treated with concurrent radiotherapy and gemcitabine at a dose of 150-300 mg/m2 with acceptable toxicity and favorable outcome. The current study was designed to determine whether the addition of gemcitabine to cisplatin 40 mg/m2 and concurrent radiotherapy is safe and feasible.

Comment by Stuart M. Lichtman, MD, FACP

This trial involved women with untreated invasive squamous cell carcinoma of the cervix with International Federation of Gynecology and Obstetrics (FIGO) stages IIB, III or IVA (involvement of the bladder or rectal mucosa). Patients with disease outside the pelvis and para-aortic lymph node metastases were ineligible. The performance status was 0-2. Radiotherapy was administered to the whole pelvic region in 28 fractions for a total of 50.4 Gy followed 1 or 2 weeks later by intracavitary brachytherapy. The chemotherapy consisted of cisplatin that was administered weekly at 40 mg/m2. Gemcitabine was given as a 30-min infusion started at 75 mg/m2 and escalated with a 25-mg/m2 increment in successive cohorts of 3 patients.

At a dose of 125 mg/m2 grade 3 toxicity was observed, while at 150-mg/m2 grade 4 toxicity occurred (diarrhea, skin). Therefore, the 125 mg/m2 dose was considered the maximal tolerated dose (MTD). The study was expanded, and 26 patients were treated at the MTD. In this phase II study, 3 grade 3 toxicities (diarrhea, mucositis, nausea, and vomiting) occurred in 11.5% of patients. Grade 4 toxicities were less than 5%. The overall objective response rate was 97.3% (PR 8.3%). At a median follow-up of 26 months, median disease free survival (DFS) and overall survival (OS) were not reached. The 3-year DFS rate is 67%, and the OS rate is 72%.

Advanced cervical cancer is common in developing countries often due to lack of screening and early detection programs. In the United States older women have the highest incidence of mortality from this disorder. Therefore, locoregional control is important to improve survival. A major advance in therapy was the result of 5 randomized phase III trials, which have shown an OS advantage for cisplatin-based therapy given concurrently with radiation therapy. While study design varied, they all demonstrated significant survival benefit for combined modality therapy, decreasing the risk of death by 30-50%. Despite the superiority of the combined approach, the local recurrence rate was still between 19% and 24%. Gemcitabine is a known radiosensitizer and has been studied in pancreatic cancer, non-small-cell-lung cancer, cervical cancer, and head and neck cancer. Concomitant radiation and the gemcitabine/cisplatin combination has been evaluated in pancreatic and non-small cell lung cancer. These reported study results are in the same range that has been reported in the randomized trials. There is a clear need for newer therapies in this lethal disorder. This trial is a first step in this regard, particularly with its low reported toxicity. The study limitations are its small size and the median age of 48 years. While this is probably representative of many patients in less-developed countries, it is approximately 20 years less than many of the women in the United States who are treated for locally advanced disease. Trials in which cisplatin is combined with another radiation sensitizer (ie, gemcitabine, paclitaxel) need to be studied in an older and less fit population to truly determine whether it can be used to treat a large number of patients. As approximately 50% of recurrences occur outside the radiation field, better systemic therapies also need evaluation. 

Dr. Lichtman, Associate Professor of Medicine, NYU School of Medicine, Division of Oncology; Don Monti Division of Medical Oncology, North Shore University Hospital, Manhasset, NY.

References

1. National Cancer Institute. Clinical Announcement: Concurrent chemoradiation for cervical cancer. Washington, DC; 1999.

2. Keys HM, et al. N Engl J Med. 1999;340:1154-1161.

3. Rose PG, et al. N Engl J Med. 1999;340:1144-1153.

4. Morris M, et al. N Engl J Med. 1999;340:1137-1143.

5. Whitney CW, et al. J Clin Oncol. 1999;17:1339-1348.

6. Peters WA, et al. J Clin Oncol. 2000;18:1606-1613.