Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. Long-term follow-up of potentiation of radiotherapy by cis-platinum in advanced cervical cancer. A randomized trial of concurrent chemoradiotherapy versus radiotherapy in advanced carcinoma of the uterine cervix. [Comparative parameters of myelotoxicity in patients treated with simultaneous chemotherapy and radiotherapy or only radiotherapy]. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. Role of chemoradiation in advanced cervical cancer. Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: an update of radiation therapy oncology group trial (RTOG) 90-01. Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. 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. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. Concurrent mitomycin C, 5-fluorouracil, and radiotherapy in the treatment of locally advanced carcinoma of the cervix: a randomized trial.
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. Between January 1982 and January 1983 all patients with advanced cervical cancer were randomized into three groups: radiotherapy only (group I), radiotherapy plus weekly cis-platinum (group II), and radiation plus twice-weekly cis-platinum (group III). Better initial central control was observed in group III patients. Long-term survival was similar in the three groups. Potentiation of radiotherapy with cis-platinum failed to show any significant improvement in long-term survival. The purpose of our study was to determine whether the chemoradiation is better than radiotherapy alone with respect to survival and treatment toxicity in patients with advanced carcinoma of the cervix. From October 1990 to April 1995, a total of 122 patients with advanced cervical carcinoma were included in this study and randomly assigned to either radiotherapy or concurrent chemotherapy and radiotherapy. The patients in the concurrent group received cisplatin, vincristine, and bleomycin every 3 weeks for a total of four courses, in combination with radiotherapy concurrently. Sixty patients were randomized to the concurrent chemoradiotherapy, and 62 were randomized to the radiotherapy alone. A tumor response was observed in 88.3% of the patients in concurrent group and in 74.2% of the patients in radiotherapy group (P = 0.04). After a median follow-up of 46.8 months, the overall disease-free survival and actuarial survival rate at 3 years were 51.7 and 61.7% in the concurrent group, and 53.2 and 64.5% in the radiotherapy group, respectively. Treatment-related toxicity appears to be higher with the combination of radiotherapy and chemotherapy compared with radiotherapy alone (36.7% versus 17.7%, P = 0.02). However, analysis by Kaplan-Meier method showed that the actuarial survival was not statistically different between the chemoradiotherapy and radiotherapy groups (mean survival time: 38.1 months versus 41.5 months, P = 0.27). In conclusion, this study showed that concurrent multiagent chemoradiotherapy did not prove to be a superior definitive therapy over radiotherapy alone for patients with advanced cervical carcinoma. The Modern oncological treatment usually consists of the different kind of the therapies. Improvement of survival and local control of disease could be possible with combined treatments: surgery, radiotherapy, chemotherapy, etc. However if these treatments are given concomitantly one can expect higher toxicity.
                Comparation of parameters of miclotoxicity: red blood cell count, white blood cell count, platelets and hemoglobin in patients with advanced cervical carcinoma treated with concomitant chemo-radiotherapy versus radiotherapy alone.
                From 1997-1999, we performed prospective, by randomised, study, and 80 patients were divided in two groups: Group A--40 patients treated with concomitant chemo-radiotherapy versus, Group B--40 patients treated with radiotherapy alone. Red blood cell count, white blood cell count, platelets and hemoglobin were evaluated before enrollement, during the theraphy, after 3 and 6 months, according to CTC toxicity criteria.
                We perform statistical analysis using H2 test, and we found no significant difference in mild nad severe toxicity in red blood cell count, white blood cell count, platelets and hemoglobin among groups. 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.
                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.
                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).
                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. A prospective randomized study was conducted in our department of Radiotherapy, Regional Institute of Medical Sciences, Imphal to evaluating the role of chemoradiation in the management of advanced inoperable cervical cancer (stage IIB-IIIB) taking only radiation treatment as control spanning the period 1996-1999. Of the fifty patients accumulated in the study group, three patients did not complete treatment, one expired due to other causes and three were lost to follow up. Likewise, of the forty-six patients in the control group, one patient did not complete treatment and 4 were lost to follow up. Thus only 43 and 41 patients were available for the result analysis for the study and control groups respectively. The early treatment response as assessed after two months of treatment conclusion were 79.1%, 13.9%, 93.0% and 58.5%, 31.7%, 90.2% as complete response (CR), partial response (PR), and total response (TR) respectively for the study and control groups. Our patients included in this study had a median follow up of 35 months and 33 months for study and control groups respectively. For this follow up, the disease-free survival, survival with disease and overall survival were 67.4%, 7.0%, 74.4% and 43.9%, 12.2%, 56.1% for study and control groups respectively. There was an increase in early side-effects in the chemoradiation group but the difference was not significant. Because of the early side effects, treatment delays ensued in 7 patients (16.3%) and in 3 patients (7.3%) in the study and control groups respectively. There was no significant increase in the late treatment toxicities in both the groups. To report mature results of a randomized trial that compared extended-field radiotherapy (EFRT) versus pelvic radiotherapy with concomitant fluorouracil and cisplatin (CTRT) in women with locoregionally advanced carcinomas of the uterine cervix.
                Four hundred three women with cervical cancer were randomly assigned to receive either EFRT or CTRT. Patients were eligible if they had stage IIB to IVA disease, stage IB to IIA disease with a tumor diameter > or = 5 cm, or positive pelvic lymph nodes. Patients were stratified by stage and by method of lymph node evaluation.
                The median follow-up time for 228 surviving patients was 6.6 years. The overall survival rate for patients treated with CTRT was significantly greater than that for patients treated with EFRT (67% v 41% at 8 years; P <.0001). There was an overall reduction in the risk of disease recurrence of 51% (95% CI, 36% to 66%) for patients who received CTRT. Patients with stage IB to IIB disease who received CTRT had better overall and disease-free survival than those treated with EFRT (P <.0001); 116 patients with stage III to IVA disease had better disease-free survival (P =.05) and a trend toward better overall survival (P =.07) if they were randomly assigned to CTRT. The rate of serious late complications of treatment was similar for the two treatment arms.
                Mature analysis confirms that the addition of fluorouracil and cisplatin to radiotherapy significantly improved the survival rate of women with locally advanced cervical cancer without increasing the rate of late treatment-related side effects. To test the hypothesis that cisplatin (CDDP) administered concurrently with standard radiotherapy (RT) would improve pelvic control and survival in patients with advanced squamous cell cancer of the cervix.
                A total of 259 patients with International Federation of Gynecology and Obstetrics stage IB to IVA squamous cell cervical cancer with central disease greater-than-or-equal 5 cm or histologically confirmed pelvic lymph node involvement were randomized to receive RT (external-beam RT plus brachytherapy) plus weekly CDDP chemotherapy (40 mg/m(2)) (arm 1) or the same RT without chemotherapy (arm 2).
                A total of 253 patients were available for analysis. Median follow-up was 82 months. No significant difference was found in progression-free survival (P =.33). No significant difference in 3- and 5-year survival rates was found (69% v 66% and 62% v 58%, respectively; P =.42). The hazard ratio for survival (arm 2 to arm 1) was 1.10 (95% confidence interval, 0.75 to 1.62).
                This study did not show a benefit to either pelvic control or survival by adding concurrent weekly CDDP chemotherapy in a dose of 40 mg/m(2) to radical RT as given in this trial. Careful attention to RT details is important for achieving optimum outcome for patients with this disease. 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. To determine whether the addition of cisplatin-based chemotherapy (CT) to pelvic radiation therapy (RT) will improve the survival of early-stage, high-risk patients with cervical carcinoma.
                Patients with clinical stage IA(2), IB, and IIA carcinoma of the cervix, initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic lymph nodes and/or positive margins and/or microscopic involvement of the parametrium were eligible for this study. Patients were randomized to receive RT or RT + CT. Patients in each group received 49.3 GY RT in 29 fractions to a standard pelvic field. Chemotherapy consisted of bolus cisplatin 70 mg/m(2) and a 96-hour infusion of fluorouracil 1,000 mg/m(2)/d every 3 weeks for four cycles, with the first and second cycles given concurrent to RT.
                Between 1991 and 1996, 268 patients were entered onto the study. Two hundred forty-three patients were assessable (127 RT + CT patients and 116 RT patients). Progression-free and overall survival are significantly improved in the patients receiving CT. The hazard ratios for progression-free survival and overall survival in the RT only arm versus the RT + CT arm are 2.01 (P =.003) and 1.96 (P =. 007), respectively. The projected progression-free survivals at 4 years is 63% with RT and 80% with RT + CT. The projected overall survival rate at 4 years is 71% with RT and 81% with RT + CT. Grades 3 and 4 hematologic and gastrointestinal toxicity were more frequent in the RT + CT group.
                The addition of concurrent cisplatin-based CT to RT significantly improves progression-free and overall survival for high-risk, early-stage patients who undergo radical hysterectomy and pelvic lymphadenectomy for carcinoma of the cervix. This is a prospective, Phase III multicenter randomized trial to assess the effectiveness of concurrent intravenous mitomycin C, oral 5-fluorouracil (5-FU), and radiotherapy (RT) in locally advanced carcinoma of the cervix.
                Between January 1988 and November 1994, 926 patients with locally advanced carcinoma of the cervix, FIGO Stage IIB-IVA, were entered into this study. The patients were randomized into four arms, as follows: Arm 1: conventional RT; Arm 2: conventional RT and adjuvant chemotherapy; Arm 3: conventional RT plus concurrent chemotherapy; Arm 4: conventional RT plus concurrent chemotherapy and adjuvant chemotherapy. Concurrent chemotherapy consisting of intravenous mitomycin C at 10 mg/m(2) was given on Days 1 and 29, and oral 5-FU at 300 mg/day was administered on Days 1-14 and 29-42 during RT. Adjuvant chemotherapy of 5-FU orally at 200 mg/day was given for three courses of 4 weeks, with a 2-week rest every 6 weeks. Six centers participated in the trial.
                The median follow-up time was 89 months. Acute side effects were generally higher in concurrent arms, but most of the patients tolerated the treatment well. Bone marrow toxicity was also higher in concurrent arms. The 5-year actuarial disease-free survival (DFS) was 48.2%, 54.1%, 64.5%, and 59.7% for arms 1, 2, 3, and 4, respectively. The pattern of failure revealed a significant increase in locoregional recurrence in the nonconcurrent chemoradiotherapy arm. The local recurrence was 25.5%, 20.6%, 14.3%, and 17.6% for arms 1, 2, 3, and 4, respectively. The metastatic rates were not significantly different in all four arms. At the time of analysis, there were no increases in late side effects, especially in gastrointestinal and genitourinary systems.
                Concurrent chemotherapy, mitomycin C, and 5-FU together with conventional RT showed an improved DFS rate when compared with conventional RT alone in patients with locally advanced carcinoma of the cervix.
Concomitant chemoradiation appears to improve overall survival and progression-free survival in locally advanced cervical cancer. It also appears to reduce local and distant recurrence suggesting concomitant chemotherapy may afford radiosensitisation and systemic cytotoxic effects. Some acute toxicity is increased, but the long-term side effects are still not clear.