Hydroxyurea as a radiation sensitizer in women with carcinoma of the uterine cervix. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. Treatment of metastatic and recurrent cervix cancer with chemotherapy: a randomised trial comparing hydroxyurea with cisdiamminedichloro-platinum plus methotrexate. Hydroxyurea: a radiation potentiator in carcinoma of the uterine cervix. A randomized double-blind study. Intratumoral and parametrial infusion of metronidazole in the radiotherapy of uterine cervix cancer: preliminary report.
Hydroxyurea was evaluated as a possible radiation sensitizer in 130 evaluable women with Stages IIB and IIIB (International Federation of Gynecology and Obstetrics) carcinoma of the uterine cervix. This was a prospective double-blind randomized study in which hydroxyurea or placebo was compared in conjunction with continuous or split-course radiation therapy. Of all patients with Stage IIB cancer without biopsy proof of aortic node metastasis, a significant improvement in survival (P less than 0.01) was achieved in the hydroxyura group (74.0%) as compared to the patients receiving placebo (43.5%). In women with Stage IIIB cervical cancer there was a trend toward longer survival in those receiving hydroxyurea (52.1%) as compared to those receiving placebo (33.3%). However, there was a statistically significant improvement in survival in those women with Stage IIIB cervical cancer who had staging done at operation, were found to have negative para-aortic nodes, and subsequently received continuous radiation therapy (90.9%) as compared to those receiving split-course therapy (29.4%) (P = 0.005). 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, or IVA, 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 micromol 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 per square meter on days 1 and 29, followed by 4 g of fluorouracil per square meter given as a 96-hour infusion on days 1 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).
                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 for 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.
                Regimens of radiotherapy and chemotherapy that contain cisplatin improve the rates of survival and progression-free survival among women with locally advanced cervical cancer. In a randomised trial comparing single-agent chemotherapy (hydroxyurea) to combination chemotherapy in advanced cervix cancer, response was seen in 57% (including 13% CR) of patients receiving the combination (DDP + MTX) regimen. Responding patients survived significantly longer (11 months) than either those receiving hydroxyurea or those not responding to combination chemotherapy (4 months). Two patients remain in complete remission for 14+ and 17+ months. From June, 1972, to December, 1976, 40 patients with FIGO (International Federation of Gynaecology and Obstetrics) Stage IIB carcinoma of the uterine cervix were entered into a prospective, double-blind, randomized study to evaluate the possible radiation-potentiating properties (i.e., improved survival) of the S-phase cell cycle-specific inhibitor of DNA synthesis, hydroxyurea. All patients were documented to be without aortic lymph node metastasis by pretherapy staging para-aortic lymphadenectomy. All 40 patients were followed up for longer than 5 years (5.2 to 9.2 years) or until death. The double-blind code was not broken until all patients had been followed up for a minimum of 2 to 5 years. Leukopenia (white blood cell count less than 2,500 mm3) was significantly increased in the patients given hydroxyurea as compared to those given placebo (P less than 0.0001). There was no statistically significant difference relative to anemia, thrombocytopenia, radiation-induced skin reaction, and radiation-induced intestinal reaction between the patients given placebo or those given hydroxyurea. Life-table survival for the patients given hydroxyurea was 94% as compared to 53% for the patients given placebo (P = 0.006). Only one (5%) patient given hydroxyurea died of cervical cancer. Of the other patients who died in the group given hydroxyurea, all were confirmed by postmortem examination to have been without recurrent cervical cancer. In contrast, 45% (nine) of the patients given placebo died of cervical cancer. In a recently started clinical trial, the short-term effects of radiotherapy of cervix cancer Stage IIb and III in combination with topical infusion of metronidazole solution were evaluated by determining the local clearance rate and cytologic damage in randomized and non-randomized cases. In regard to the short term effects the combined treatment was found to be superior to treatment without metronidazole.
We found no evidence to support the use of hydroxyurea in addition to radiotherapy in the routine treatment of cervix cancer.