Frederick B. Stehman

BACKGROUND: Bulky stage IB cervical cancers have a poorer prognosis than smaller stage I cervical cancers. For the Gynecologic Oncology Group, we conducted a trial to determine whether weekly infusions of cisplatin during radiotherapy improve progression-free and overall survival among patients with bulky stage IB cervical cancer. METHODS: Women with bulky stage IB cervical cancers (tumor, > or =4 cm in diameter) were randomly assigned to receive radiotherapy alone or in combination with cisplatin (40 mg per square meter of body-surface area once a week for up to six doses; maximal weekly dose, 70 mg), followed in all patients by adjuvant hysterectomy. Women with evidence of lymphadenopathy on computed tomographic scanning or lymphangiography were ineligible unless histologic analysis showed that there was no lymph-node involvement. The cumulative dose of external pelvic and intracavitary radiation was 75 Gy to point A (cervical parametrium) and 55 Gy to point B (pelvic wall). Cisplatin was given during external radiotherapy, and adjuvant hysterectomy was performed three to six weeks later. RESULTS: The relative risks of progression of disease and death among the 183 women assigned to receive radiotherapy and chemotherapy with cisplatin, as compared with the 186 women assigned to receive radiotherapy alone, were 0.51 (95 percent confidence interval, 0.34 to 0.75) and 0.54 (95 percent confidence interval, 0.34 to 0.86), respectively. The rates of both progression-free survival (P<0.001) and overall survival (P=0.008) were significantly higher in the combined-therapy group at four years. In the combined-therapy group there were higher frequencies of transient grade 3 (moderate) and grade 4 (severe) adverse hematologic effects (21 percent, vs. 2 percent in the radiotherapy group) and adverse gastrointestinal effects (14 percent vs. 5 percent). CONCLUSIONS: Adding weekly infusions of cisplatin to pelvic radiotherapy followed by hysterectomy significantly reduced the risk of disease recurrence and death in women with bulky stage IB cervical cancers.

Between 1977 and 1985, the Gynecologic Oncology Group (GOG) conducted three clinical trials in locally advanced carcinoma of the cervix, clinical Stages I to IVA as classified by the International Federation of Gynecology and Obstetrics (FIGO). All 626 patients had primary carcinoma of the cervix and underwent operative assessment of the para-aortic (PA) lymph nodes. Patients received standardized external radiation therapy to the pelvis or to the pelvis and PA lymph nodes followed by one or two brachytherapy applications. To date, no statistically significant differences in progression-free interval (PFI) or survival time have been identified between the randomization treatment arms on any of these studies. Basic similarities among these studies led us to pool these data to identify patient characteristics and tumor characteristics associated with an increased risk of treatment failure. Multi-variate analysis showed patient age, performance status (PS), PA lymph node status, tumor size, and pelvic node status to be significantly associated with PFI. When modeling for survival, all these factors and clinical stage and bilateral extension were significant.

The Gynecologic Oncology Group has conducted a randomized prospective trial comparing cisplatin 50 mg/m2 every 21 days (regimen 1), 100 mg/m2 every 21 days (regimen 2), and cisplatin 20 mg/m2 for five consecutive days repeated every 21 days (regimen 3). Four hundred ninety-seven evaluable patients have been accrued on this study. The response rates were 20.7%, 31.4%, and 25.0%, for regimens 1, 2, and 3, respectively; the complete remission rates were 10.0%, 12.7%, and 8.6% for regimens 1, 2, and 3, respectively. The median duration of response ranged from 3.9 to 4.8 months, the median progression-free interval from 3.7 to 4.6 months, and the median survival time from 6.1 to 7.1 months. The difference in response rates for regimens 1 and 2 is statistically significant (P = .015) but less than the magnitude originally considered clinically significant. The differences in complete remission rates, response duration, progression-free interval, and survival times are not statistically significant. The following types of toxicity were observed: serum creatinine level greater than 2 mg/dL and/or BUN level greater than 40 mg/dL was 7%, 14%, and 17% on regimens 1, 2, and 3, respectively; leukocyte count less than 4,000/microL was 27%, 44%, and 41% on regimens 1, 2, and 3, respectively. Nausea and vomiting occurred in 74 patients (83%). The regimen consisting of a 100-mg/m2 single dose has produced a statistically significant higher response rate than the 50 mg/m2 regimen while producing no appreciable differences in complete remission rate, response duration, progression-free interval, or survival. In addition, the higher dose regimen was associated with greater myelosuppression and nephrotoxicity.