Hydroxyurea as a radiation sensitizer in women with carcinoma of the uterine cervix. Hydroxyurea or placebo combined with radiation to treat stages IIIB and IV cervical cancer confined to the pelvis. Treatment of metastatic and recurrent cervix cancer with chemotherapy: a randomised trial comparing hydroxyurea with cisdiamminedichloro-platinum plus methotrexate. Hydroxyurea plus pelvic irradiation versus placebo plus pelvic irradiation in nonsurgically staged stage IIIB cervical cancer. Hydroxyurea: a radiation potentiator in carcinoma of the uterine cervix. A randomized double-blind study. Hydroxyurea plus pelvic radiation versus placebo plus pelvic radiation in surgically staged stage IIIB cervical cancer. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. Prolonged intermittent adjuvant chemotherapy with CCNU and hydroxyurea after resection of carcinoma of the lung. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer.
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). nan 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. Twenty-five patients with FIGO stage IIIB carcinoma of the cervix were entered into a prospective, double-blinded 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 (H). In contrast to our previous randomized trial of patients with FIGO stage IIIB carcinoma of the uterine cervix who were documented to be without paraaortic lymph node metastasis by pretherapy staging paraaortic lymphadenectomy [Piver et al.: J Surg Oncol 35: 129-134, 1987], these patients either refused surgical staging or, because of medical conditions, could not undergo pretherapy paraaortic lymphadenectomy. Patients were to receive 6,000 cGy/6 weeks to the pelvis by megavoltage radiation therapy followed by 2,500 cGy to point A by intracavitary and vaginal radium/cesium. The median pelvic cGy for the Hu patients was 5,967 cGy and for the placebo patients 6,013 cGy. Leukopenia (WBC less than 2,500/mm3) significantly increased in patients given hydroxyurea as compared with those given placebo (P less than 0.0001). There was no statistically significant difference relative to anemia, thrombocytopenia, radiation skin reactions, diarrhea, or radiation induced complications requiring surgical correction. The estimated 5 year disease-free interval was 54% for the hydroxyurea patients (median not reached) and 18% for the placebo patients with a median of 11 months. Because of these results, those of our previous reports, and those of the Gynecologic Oncology Group, we believe that hydroxyruea plus pelvic radiation should be the standard against which new potential radiation sensitizers are tested. 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. Forty-five evaluable patients with stage IIIB carcinoma of the uterine cervix were entered into a prospective, double-blind, randomized study to evaluate the possible radiation-potentiating properties of hydroxyurea. All patients were documented to be without para-aortic lymph node metastasis by pretherapy staging para-aortic lymphadenectomy. The original plan of therapy was for continuous therapy (200 rads/day) of 6,000 rads of pelvic radiation for 6 weeks plus intrauterine radium. However, 16 patients received 6,000 rads in 8 weeks by split-course therapy (2-week rest after 3,000 rads) plus radium. Twenty-nine patients received the planned continuous therapy. The median dose of pelvic radiation for patients who received continuous therapy or split-course radiation was 6,000 rads. Leukopenia (WBC less than 2,500/mm3) was significantly increased in the patients given hydroxyurea as compared to those given placebo (P less than .001). There was no statistically significant difference relative to anemia, thrombocytopenia, radiation skin reaction, diarrhea, or radiation-induced complications requiring surgical correction. The estimated 5-year progression-free survival rate for the combined, continuous, and split-course radiation therapy hydroxyurea patients was 60%, and its was 52% for the corresponding placebo patients (P = .49). However, the estimated 5-year progression free survival rate for the correctly treated patients (continuous therapy) was 91% for the hydroxyurea group and 60% for the placebo group (P less than .06). In 1986, a protocol comparing primary radiation therapy (RT) plus hydroxyurea (HU) to irradiation plus fluorouracil (5-FU) and cisplatin (CF) was activated by the Gynecologic Oncology Group (GOG) for the treatment of patients with locally advanced cervical carcinoma. The goals were to determine the superior chemoradiation regimen and to quantitate the relative toxicities.
                All patients had biopsy-proven invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix. Patients underwent standard clinical staging studies and their tumors were found to be International Federation of Gynaecology and Obstetrics stages IIB, III, or IVA. Negative cytologic washings and para-aortic lymph nodes were required for entry. Patients were randomized to receive either standard whole pelvic RT with concurrent 5-FU infusion and bolus CF or the same RT plus oral HU.
                Of 388 randomized patients, 368 were eligible; 177 were randomized to CF and 191 to HU. Adverse effects were predominantly hematologic or gastrointestinal in both regimens. Severe or life-threatening leukopenia was more common in the HU group (24%) than in the CF group (4%). The difference in progression-free survival (PFS) was statistically significant in favor of the CF group (P = .033). The sites of progression in the two treatment groups were not substantially different. Survival was significantly better for the patients randomized to CF (P = .018).
                This study demonstrates that for patients with locally advanced carcinoma of the cervix, the combination of 5-FU and CF with RT offers patients better PFS and overall survival than HU, and with manageable toxicity. Eight hundred sixty-five patients with a microscopically curative resection for carcinoma of the lung were accepted for study, none of whom were excluded from analysis. Adjuvant therapy was randomly assigned about the tenth to 14th postoperative day; 432 patients (treated) were to receive CCNU and hydroxyurea for one year, while 433 patients (controls) were to receive no adjuvant therapy. Toxic reactions to therapy were reported, but only 1% were severe enough to require stopping therapy. No evidence of improved survival or delayed recurrence of disease was seen in treated patients as a whole or when examined by cell type and by postsurgical TNM category. On the contrary, survival beyond the second year of follow-up may have been impaired by the drugs when administered to patients without evidence of tumor spread to the lymph nodes. 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.
We found no evidence to support the use of hydroxyurea in addition to radiotherapy in the routine treatment of cervix cancer.