GOG 120: Concurrent Cisplatin-Based Radiotherapy and Chemotherapy for Locally Advanced Cervical Cancer

Peter G. Rose, et al

Background and Methods. On behalf of the Gynecologic Oncology Group, we performed a randomized trial of radiotherapy in combination with three concurrent chemotherapy regimens -- cisplatin alone; cisplatin, fluorouracil, and hydroxyurea; and hydroxyurea alone -- in patients with locally advanced cervical cancer. Women with primary untreated invasive squamous-cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix of stage IIB, III, orIVA, without involvement of the para-aortic lymph nodes, were enrolled. The patients had to have a leukocyte count of at least 3000 per cubic millimeter, a platelet count of at least 100,000 per cubic millimeter, a serum creatinine level no higher than 2 mg per deciliter (177 µmol per liter), and adequate hepatic function. All patients received external-beam radiotherapy according to a strict protocol. Patients were randomly assigned to receive one of three chemotherapy regimens: 40 mg of cisplatin per square meter of body-surface area per week for six weeks (group 1); 50 mg of cisplatin rer square meter on days 1 and 29, rollowed by 4 g of fluorouracil per square meter given as a 96-hour infusion on days r and 29, and 2 g of oral hydroxyurea per square meter twice weekly for six weeks (group 2); or 3 g of oral hydroxyurea per square meter twice weekly for six weeks (group 3).

Results. The analysis included 526 women. The median duration of follow-up was 35 months. Both groups that received cisplatin had a higher rate of progression-free survival than the group that received hydroxyurea alone (P<0.001 ror both comparisons). The relative risks of progression of disease or death were 0.57 (95 percent confidence interval, 0.42 to 0.78) in group 1 and 0.55 (95 percent confidence interval, 0.40 to 0.75) in group 2, as compared with group 3.The overall survival rate was significantly higher in groups 1 and 2 than in group 3, with relative risks of death of 0.61 (95 percent confidence interval, 0.44 to 0.85) and 0.58 (95 percent confidence interval, 0.41 to 0.81), respectively.

Conclusions. Regimens of radiotherapy and chemotherapy that contain cisplatin improve the rates of survival and progression-free survival among women with locally advanced cervical cancer.

GOG 123: Cisplatin, Radiation, and Adjuvant Hysterectomy Compared with Radiation and Adjuvant Hysterectomy for Bulky Stage Ib Cervical Carcinoma

Henry M. Keys, et al

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, greater than or equal to 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.

GOG 85 / SWOG 8695. Eligible patients were women with locally advanced carcinoma of the cervix (FIGO stages IIB, III, and IVA), who had undergone extraperitoneal lymph node sampling of the para-aortic lymph nodes, as well as intraperitoneal exploration and intraperitoneal washings. Women found to have intraperitoneal or para-aortic nodal disease were excluded from the trial.

1986-1990 386 patients / Regimen I: external beam (pelvis) and intracavitary radiation therapy with 5-FU infusion and cisplatin (177 pts) Regimen II: external beam (pelvis) and intracavitary radiation therapy with hydroxyurea (191 pts) Patients on regimen I received intravenous cisplatin 50 mg/m2 on days 1 and 29, and intravenous 5-FU 1000mg/m2/day on days 2,3,4,5,30,31,32, and 33 during external beam radiotherapy. Patientso n regimen II received oral hydroxyurea 80 mg/kg twice a week during external beam radiotherapy. Radiotherapy, identical for both arms, was delivered with either AP or PA parallel ports or a four-field box technique. Patients with stage IIB tumors received 4080 cGy external beam therapy, followed by 4000 cGy to point "A" via 1-2 intracavitary implants. If necessary, a parametrial boost was given to bring the point "B" dose to 5500 cGy. Patients with stage III or IVA disease were treated with 5100 cGy external beam radiotherapy, followed by 3000 cGy to point "A" via 1-2 intracavitary implant and 6000 cGy to point "B" from both sources, with or without a parametrial boost. Further details on chemotherapy and radiotherapy are available in the reference  manuscript.

GOG Protocol 85 Results The median follow-up for survivors is 8.4 years. The three-year survival rate for women on the cisplatin-5FU arm is 67%, compared to 57% for women on the hydroxyurea arm. This difference is statistically significant. GOG Protocol 85 Conclusions These results demonstrate that concurrent radiation therapy and chemotherapy with cisplatin and 5FU result in improved survival compared to concurrent radiation therapy with hydroxyurea for women with stages IIB, III, and IVA cervical cancer.

SWOG 8797 /GOG 109, RTOG 9112 Eligible patients were women with FIGO stages IA2, IB, and IIA carcinoma of the cervix, found to have metastatic disease in the pelvic lymph nodes, positive parametrial involvement, or positive surgical margins at time of primary radical hysterectomy with total pelvic lymphadenectomy. Patients must have had confirmed negative para-aortic lymph nodes. If the para-aortic lymph nodes were not sampled, then the patients must have had confirmed negative common-iliac lymph nodes.1992-1996 243 patients Regimen I: external beam (pelvis) radiation therapy with cisplatin and 5-FU infusion (127 pts) Regimen II: external beam (pelvis) radiation therapy (116 pts) Patients on regimen I received intravenous cisplatin 70 mg/m2 followed by a 96-hour continuous intravenous infusion of 5-FU (400 mg/m2) every three weeks for 4 courses. Radiotherapy, identical for both arms, delivered 4930 cGy to the pelvis via a four-field box technique. Patients with metastatic disease in the high common-iliac nodes also received 4500 cGy to a para-aortic field.

SWOG Protocol 8797 Results The median follow-up for survivors is 43 months. The three-year survival rate for women on the adjuvant cisplatin/5-FU plus radiation arm is 87%, compared to 77% for women onv the adjuvant radiation alone arm. This difference is statistically significant. Conclusions These results demonstrate that concurrent radiation therapy and chemotherapy with cisplatin and 5-FU compared to radiation alone results in improved survival for women with FIGO stages IA2, IB, and IIA disease found to have metastatic disease in the pelvic lymph nodes, positive parametrial extension, or positive surgical margins.