Randomized trial of epirubicin and cisplatin chemotherapy followed by pelvic radiation in locally advanced cervical cancer. Cervical Cancer Study Group of the Asian Oceanian Clinical Oncology Association. Randomized study comparing chemotherapy plus radiotherapy versus radiotherapy alone in FIGO stage IIB-III cervical carcinoma. GONO (North-West Oncologic Cooperative Group). A randomized trial of chemotherapy followed by pelvic radiation therapy in stage IIIB carcinoma of the cervix. Randomized trial of neoadjuvant cisplatin, vincristine, bleomycin, and radical hysterectomy versus radiation therapy for bulky stage IB and IIA cervical cancer. The role of neoadjuvant intraarterial infusion chemotherapy with cisplatin and bleomycin for locally advanced cervical cancer. Neoadjuvant chemotherapy in locally advanced cervical cancer: two randomised studies. Induction chemotherapy and radiotherapy of advanced cancer of the cervix: a pilot study and phase III randomized trial. A randomised, prospective, phase III clinical trial of primary bleomycin, ifosfamide and cisplatin (BIP) chemotherapy followed by radiotherapy versus radiotherapy alone in inoperable cancer of the cervix. [Neoadjuvant chemotherapy of stage IIb or III cancers of the uterine cervix. Long-term results of a multicenter randomized trial of 151 patients]. The Scottish and Manchester randomised trial of neo-adjuvant chemotherapy for advanced cervical cancer. Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian multicenter randomized study. Long-term follow-up of the first randomized trial using neoadjuvant chemotherapy in stage Ib squamous carcinoma of the cervix: the final results. Radiotherapy and neoadjuvant chemotherapy for cervical carcinoma. A randomized multicenter study of sequential cisplatin and 5-fluorouracil and radiotherapy in advanced cervical carcinoma stage 3B and 4A. A randomized trial comparing platinum-based chemotherapy followed by radiotherapy vs. radiotherapy alone in patients with locally advanced cervical cancer.
Pelvic radiation is standard treatment for women with stage IIb to IVa cervical cancer, but treatment results are disappointing, particularly for women with bulky tumors. We investigated the role of primary chemotherapy followed by pelvic radiotherapy in a randomized trial.
                Two hundred sixty patients with stage IIb and IVa cervical cancer received either standard pelvic radiotherapy or primary chemotherapy with cisplatin 60 mg/m2 and epirubicin 110 mg/m2 administered at 3-week intervals for three cycles, followed by pelvic radiotherapy.
                Ninety-nine patients have relapsed with a median follow-up duration of 1.3 years; in 62 patients, the first site of progressive disease was the pelvis. Patients who received primary chemotherapy had a significantly higher pelvic failure rate than those who received radiotherapy alone (P < .003). Seventy-six patients have died, and those who received primary chemotherapy had significantly inferior survival compared with those who received radiotherapy alone (P = .02). Tumor response following chemotherapy was observed in 63%. After radiotherapy, tumor response occurred in 72% of those who received combined modality treatment, compared with 92% of those who received radiotherapy alone.
                Primary chemotherapy with epirubicin and cisplatin, although resulting in tumor response in a significant proportion of patients, is accompanied by an inferior local control rate and survival compared with standard pelvic radiotherapy alone. Between January 1989 and December 1991, 64 patients with advanced cervical carcinoma FIGO stage IIb-III were randomized to receive radiotherapy (RT) alone or the sequential combination of chemotherapy (CT) and RT. RT consisted of external RT (40 Gy fractionated over 4 weeks)+brachy-therapy (40 Gy to point A)+an additional boost to the parameters (15-20 Gy) in arm RT; CT consisted of cisplatin 60 mg/m2 i.v. day 1 q 15 days administered for 2 cycles before the start of RT and for 4 cycles after the end of radiation treatment in CT+RT arm. Among the 58 evaluable patients objective response rate was as follows: in RT arm, CR in 40.7% of patients, PR in 40.7%, and SD in 18.6%; in CT+RT arm, CR in 42% of patients, PR in 35.5%, and SD in 22.5%. The median duration of response was 12 months (range: 3-38 + months). At a median follow-up of 36 months survival (S) and progression-free survival (PFS) were 83% and 72.4% in RT arm, 72% and 59.3% in CT+RT arm, respectively. No significant difference was observed between the 2 treatment arms, neither in terms of objective response nor in terms of S and PFS. Both treatments were generally well tolerated. In our experience the addition of chemotherapy to standard radiotherapy does not enhance morbidity and does not interfere with the correct delivery of the planned treatment. However, results of this combined modality regimen remain unsatisfactory, since no improvement in pelvic control and survival of patients with advanced cervical carcinoma was observed. Because of the poor results in stage III B carcinoma of the cervix with standard treatment using radiotherapy alone, we designed a randomized trial to determine whether administration of chemotherapy before pelvic irradiation would improve survival. Between May 1984 and August 1986, 107 patients with previously untreated squamous cell carcinoma were randomly assigned, after stratification by age (less than 50 v greater than 50 years), extent of parametrial involvement (unilateral v bilateral), and lymphangiographic findings (negative v positive) to pelvic radiotherapy (RT; arm A) or three cycles of chemotherapy (CT; bleomycin, vincristine, mitomycin, and cisplatin [BOMP]), followed by the same radiotherapy regimen (CT + RT; arm B). The groups were balanced by age, performance status, extent of parametrial involvement, bulkiness of cervical disease, nodal involvement, and presence of hydronephrosis. Minimal follow-up is 34 months. A complete local response was observed in 32.5% of the patients in arm A and in 47% of the patients in arm B (P = .19). Overall 5-year survival rates were 39% for the RT arm and 23% for the CT + RT approach (P = .02). Toxicity was severe in arm B and included fatal pulmonary toxicity in four patients. Locoregional and distant failures were similar in both groups. We conclude that, despite a satisfactory response rate, neoadjuvant BOMP chemotherapy adversely affects survival in stage III B cervical cancer and is associated with unacceptable toxicity. To compare the efficacy of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy with that of radiotherapy (R/T) for bulky early-stage cervical cancer.
                Women with previously untreated bulky (primary tumor >/= 4 cm) stage IB or IIA non-small-cell carcinoma of the uterine cervix were randomly assigned to receive either cisplatin 50 mg/m(2) and vincristine 1 mg/m(2) for 1 day and bleomycin 25 mg/m(2) for 3 days for three cycles followed by radical hysterectomy (NAC arm) or receive primary pelvic radiotherapy only (R/T arm). The ratio of patient allocation was 6:4 for the NAC and R/T arms. Women with enlarged para-aortic lymph nodes on image study were ineligible unless results of cytologic or histologic studies were negative.
                Of the 124 eligible patients, 68 in the NAC arm and 52 in the R/T arm could be evaluated. The median duration of follow-up was 39 months. Thirty-one percent of patients in the NAC arm and 27% in the R/T arm had relapse or persistent diseases after treatment, and 21% in each group died of disease. Estimated cumulative survival rates at 2 years were 81% for the NAC arm and 84% for the R/T arm; the 5-year rates were 70% and 61%, respectively. There were no significant differences in disease-free survival and overall survival.
                NAC followed by radical hysterectomy and primary R/T showed similar efficacy for bulky stage IB or IIA cervical cancer. Further study to identify patient subgroups better suited for either treatment modality and to evaluate the concurrent use of cisplatin and radiation without routine hysterectomy is necessary. To clarify the effect of neoadjuvant intraarterial infusion chemotherapy on the cure rate in advanced cervical cancer with bulky tumor, a total of 50 patients were examined prospectively. The clinical stage according to the International Federation of Gynecology and Obstetrics (FIGO) classification included 23 IIb, 6 IIIa, and 21 IIIb. These patients were randomly divided into the neoadjuvant intraarterial infusion chemotherapy group and the control group. There were no significant differences in mean age, FIGO clinical stage, and tumor histology between groups. Twenty-five patients in the former group were given 25 mg/m2 of cisplatin and 15 mg/m2 of bleomycin via each internal iliac artery. If the results of the evaluation indicated that surgery was feasible, radical surgery was performed. The patients whose tumors were inoperable received radiation therapy consisting of external irradiation and intracavitary irradiation. Twenty-five patients in the control group also underwent the same radiation therapy. The overall response rate was 80.0%. Eighteen of 20 responders underwent surgery. The 3-year survival rate was 85.7% for operated patients, 42.9% for patients receiving neoadjuvant intraarterial infusion chemotherapy followed by irradiation, and 49.5% for the control group. In the present study, neoadjuvant intraarterial infusion chemotherapy did not improve the prognosis of patients with advanced cervical cancer compared to radiation therapy alone, and only responders who underwent surgery obtained an advantage in survival. Between August 1990 and January 1992, 184 patients with squamous cell carcinoma of the cervix, FIGO stage II B IV A were randomised (study 1) to receive either two cycles of bleomycin, ifosfamide-mesna and cisplatin (BIP) chemotherapy (CT) followed by radiotherapy (RT) 'CT-RT Group' n = 94 or RT alone, RT Group n = 90. In the 'CT-RT Group', of evaluable 89 patients, 64 responded: complete response (CR) four (4.5%) and partial response (PR) 60 (67.5%). Of the remaining 25 patients 23 had stable disease and two progressed. Eighty of 89 patients completed RT as planned. Following RT 56 (70%) achieved CR, 19 (23.7%) had residual disease and five (6.3%) had progressed. Patients aged > 45 and those with Hb > 10 gm/dL had significantly better response to CT. Further, CT responders had a better response to RT; 83% (49/59) vs 33.3% (seven/21), p < 0.01. In the 'RT Group' 88 patients were evaluable; 61 (69.3%) patients achieved CR, 25 had residual disease and two progressed. The estimated overall survival at 48 months in the 'CT-RT Group' and the 'RT Group' is 38% +2.01 (SE) and 36% +1.85 (SE), p = 0.59 respectively. In a subsequent randomised study (study 2) 36 patients with stage III B cervical cancer received three cycles of BIP (as above) followed by RT vs 36 patients who received RT alone. In the 'CT-RT Group' 29 patients responded; CR-8 (22.2%), PR-21 (58.3%). Six patients had no response to CT and one patient died of CT toxicity. Following RT-24 of 35 (68-6%) patients achieved CR, eight had residual disease and three patients progressed while on RT. In the 'RT Group'-21 of 36 (58.4%) achieved CR, 12 had residual disease and three progressed. Estimated survival was 71% in the 'CT-RT Group' and 69% in the 'RT Group', p = ns. Nausea/vomiting, alopecia, grade I-II myelosuppression, diarrhoea and mucositis were the major side effects of CT. Three patients died of CT toxicity-two in study 1 and one in study 2. Cystitis, proctitis and local skin reaction after RT occurred equally in the two groups in both the studies. BIP CT prior to RT in patients with locally advanced cervical cancer results in a high response rate. Response to CT predicts response to RT. There is no increase in the toxicity to subsequent RT. Our studies have failed to demonstrate any significant difference in overall and disease-free survival when neoadjuvant CT is added prior to the standard RT regimen. This study assessed the effectiveness and toxicity of induction chemotherapy (CT) and radiation therapy (RT) in the treatment of locally advanced carcinoma of the cervix with data provided by a pilot study and a randomized trial.
                Eighty-six patients with International Federation of Gynecology and Obstetrics (FIGO) Stage IB-IVA (Stage IB >4-cm tumor diameter) (Group A) were entered in a pilot study and treated with cisplatin (50 mg/m2), vincristine (1 mg/m2 on days 1, 11, and 21), bleomycin (25 mg/m2 infusion on days 1-3, 11-13, and 21-23), and standard RT. Ninety-six patients were randomized to either this same CT regimen and RT, or RT alone (Group B: CT plus RT or RT).
                In Group A, 58% responded to induction CT. With a mean follow-up of 78 months, 73% achieved pelvic control (LRC), and 55% were disease-free survivors. Response to CT was not a marker for ultimate LRC or increased disease-free survival (DFS). In Group B, 62% responded to CT. With a mean follow-up of 43 months, LRC was 68% and 65% for all randomized patients in the CT plus RT and RT arms, respectively (p = NS). In patients who completed treatment, 78% and 70%, respectively, achieved LRC (p = NS). Disease-free survival rates were 38% and 49% for randomized patients in the CT plus RT and RT arms (p = NS), respectively, and 44% and 52% in those patients completing treatment (p = NS), respectively. Complications were acceptable.
                Data from this study did not prove the efficacy of induction CT before definitive RT in locally advanced cancer of the cervix. Induction CT with the currently used combinations and modes of administration should not be considered standard therapy. Phase II studies have shown primary (neo-adjuvant) chemotherapy with bleomycin, ifosfamide and cisplatin (BIP) is active against inoperable cervical cancer. We present here results of a randomised phase III multicentre trial comparing radical radiotherapy with neo-adjuvant BIP chemotherapy followed by radical radiotherapy in patients with inoperable cervical cancer, designed to discover whether this combination might improve survival.
                Patients with inoperable cervical carcinoma were randomised to pelvic radiotherapy alone [RT] or two to three cycles of bleomycin 30 units/24-hour infusion, ifosfamide 5 g/m2/24 hours, and cisplatin 50 mg/m2) chemotherapy followed by pelvic radiotherapy (BIP + RT). Randomisation was stratified by stage and radiotherapy centre.
                One hundred seventy-two eligible women were randomised into this trial; eighty-six to RT and eighty-six to BIP + RT. A total of 190 cycles of chemotherapy were given. Median follow-up for the 47 patients still alive is 9 years with a minimum follow-up of 3 years. Complete or partial response occurred in 51 of 86 (59%) of those randomised to RT and 60 of 86 (69%) of those randomised to BIP + RT. The difference between response rates does not reach statistical significance (chi2 = 2.06, P = 0.15). Median survival is two years with an actuarial survival at five years of 32% (95% confidence interval (95% CI): 25%-39%). There is no significant difference between the treatment groups (chi2log-rank = 0.11, P = 0.74).
                This study does not show any survival benefit from the use of neo-adjuvant BIP chemotherapy in advanced cervical cancer. Present chemotherapy, with cisplatin combinations, currently offers the possibility of seeking adjuvant therapy in locally advanced and bulky carcinomas of the cervix, which have an unfavorable prognosis (nodal involvement). This initial adjuvant chemotherapy may improve the results of classical pelvic irradiation. From 1982 to 1987, a randomized phase III trial was performed in order to determine the long term effect of induction chemotherapy before irradiation in stage IIb-N1, III, M0 squamous cell carcinomas of the cervix. Radiotherapy (R) for all patients consisted in 50 Gy in the pelvis with a boost by external irradiation of the brachytherapy (cumulative dose of 68 Gy). The chemotherapy regimen (C + R group) was an association of methotrexate, chlorambucil, vincristine and cisplatin, given every 3 weeks, at least two courses were to be given before assessing efficacy and two more courses were given to patients who responded. After a follow up of 5-10 years, 76 patients were fully evaluable in the R arm and 75 in the C + R arm. The response rate (> 50%) to chemotherapy was 42.5% and after completion of treatment, remission rate was 93% in the R arm and 96% in the C + R arm. The disease-free survival was 40% in the C + R group and 35% in the R group, and the median survival was 42 and 45 months respectively (NS). The survival of patients with a complete response at the end of radiotherapy was significantly better in the C + R group when they are responding to chemotherapy, than in R group (P < 0.05). Radiotherapy was not modified whether patients had an initial chemotherapy or not; tolerance was not significantly different between the two groups. Efficacy of induction chemotherapy is an available test for long term results. This approach has the potential for improving the outlook in patients with high-risk primary cancer: earlier use and higher dose intensity of chemotherapy may be associated with a better cytoreduction, and probably a better survival. Further controlled investigations are warranted to confirm the value of adjuvant chemotherapy in cervical cancer. 204 eligible patients were entered into a multicentre randomised trial of neo-adjuvant chemotherapy prior to radical radiotherapy. The aim of this study was to assess whether there was any survival advantage in patients undergoing chemotherapy and radiotherapy compared with those given radiotherapy alone. Patients were aged up to 70 years, performance status 0-1/2, with bulky stage IIb, stage III or stage IVa squamous or adenosquamous carcinoma. Three cycles of methotrexate 100 mg/m2 and cisplatin 50 mg/m2 were given at 2-weekly intervals before radical radiotherapy. 104 eligible patients received the combination treatment and 100 radiotherapy only. The two arms of the study were well balanced for tumour and patient characteristics. The response rate to chemotherapy was 49%, 33% of patients in the radiotherapy (XRT) alone arm and 45% of the combination arm were clinically free of tumour at the end of treatment. The median follow-up for surviving patients is 5.4 years (range: 11 months-8 years) and 84% have been followed-up for more than 4 years. 134 patients have died (68 XRT only, 66 combined arm). The median survival RT alone was 111 weeks (95% confidence interval (CI) 72-151 weeks), combination arm 125 weeks (95% CI 79-170 weeks). The estimated death ratio is 0.79 (P = 0.19, 95% CI 0.56-1.12). The estimated 3-year survival is 40% (95% CI 30-50%) RT only compared with 47% (95% CI 37-57%) in the combination arm. Acute and late toxicity of radiotherapy was not increased by the addition of chemotherapy. Neoadjuvant chemotherapy (NACT) and radical surgery (RS) have emerged as a possible alternative to conventional radiation therapy (RT) in locally advanced cervical carcinoma. In 1990, a phase III trial was undertaken to verify such a hypothesis in terms of survival and treatment-related morbidity.
                Patients with squamous cell, International Federation of Gynecology and Obstetrics stage IB2 to III cervical cancer were eligible for the study. They received cisplatin-based NACT followed by RS (type III to V radical hysterectomy plus systematic pelvic lymphadenectomy) (arm A) or external-beam RT (45 to 50 Gy) followed by brachyradiotherapy (20 to 30 Gy) (arm B).
                Of 441 patients randomly assigned to NACT+RS or RT, eligibility was confirmed in 210 and 199 patients, respectively. Treatment was administered according to protocol in 76% of arm A patients and 72% of arm B patients. Adjuvant treatment was delivered in 48 operated patients (29%). There was no evidence for any significant excess of severe morbidity in one of the two arms. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 58.9% and 55.4% for arm A and 44.5% and 41.3% for arm B (P =.007 and P =.02), respectively. Subgroup survival analysis shows OS and PFS rates of 64.7% and 59.7% (stage IB2-IIB, NACT+RS), 46.4% and 46.7% (stage IB2-IIB, RT) (P =.005 andP =.02), 41.6% and 41.9% (stage III, NCAT+RS), 36.7% and 36.4% (stage III, RT) (P =.36 and P =.29), respectively. Treatment had a significant impact on OS and PFS.
                Although significant only for the stage IB2 to IIB group, a survival benefit seems to be associated with the NACT+RS compared with conventional RT. To determine if three courses consisting of 50 mg/m2 cis-platinum, 1 mg/m2 vincristine, and 25 mg/m2 bleomycin (day 1-3) at 10-day intervals can improve survival before Wertheim-Meigs + radiotherapy.
                Two hundred five unselected stage Ib patients (having tumors > 2 cm in diameter) were divided into two groups at random: (1) The group control consisted of 103 patients (56 bulky, > 4 cm diameter) treated with Wertheim-Meigs (if the tumor was resectable with free surgical margins) + adjuvant radiotherapy to whole pelvis (extended field radiation was used only in patients with paraaortic lymph node metastases). When the tumor was unresectable, a surgical staging was performed and radiotherapy was the chosen treatment. (2) Neoadjuvant (102 patients, 61 bulky) had neoadjuvant chemotherapy and then the same treatment as the control patients.
                After 67 (31-102) months of follow-up, no difference was seen in tumors > 2 and < 4 cm in both groups (C = 77% vs N = 82%), but statistically significant differences were seen in survival and disease-free survival, in bulky tumors, and between patients with neoadjuvant chemotherapy + Wertheim-Meigs + radiotherapy (80%) and the control (61%). This was due to an increased operability that was substantially improved in bulky tumors in the neoadjuvant chemotherapy group (61/61, 100%) vs control (48/56, 85%; P < 0.01). After 7 years of follow-up, the outcome of the unresectable bulky control group of patients is significantly worse (14%) than that of the resectable group (69%; P < 0.001). With regard to recurrences, a significant decrease in pelvic failures in the neoadjuvant chemotherapy group was observed (P < 0.001). Survival was improved in bulky resectable cases (N = 81% vs C = 69%, P < 0.05). Pathological findings for the surgical specimens revealed differences between both groups because all the risk factors such as parametrial and lymph node metastases, tumor bulk, and vascular embolism had been decreased (P < 0.001).
                Neoadjuvant chemotherapy can improve survival because of increased operability with free survival margins and a decrease in pathologic risk factors in unselected, bulky (> 4 cm diameter) stage Ib patients. The locoregional failure rate remains high in advanced cervical carcinoma. Chemotherapy (CT) was added to radiotherapy (RT) in order to increase disease control and to improve 5-year survival.
                CT + RT included cisplatin administered 100mg/m2, d.1 plus 5-fluorouracil 1000 mg/m2 D.1 to 5, ci (120 hrs), q every 3rd week for 3 cycles, followed by RT. RT included external beam irradiation 64.8 Gy in 1.8 Gy fractions, five days a week, by 4-field box technique. The median follow-up was 46 months. Ninety-four patients were evaluable for survival, 47 in the CT + RT group and 47 in the RT group. Ninety-two patients were evaluable for response. Known prognostic factors were equally distributed between the two groups.
                Of the 43 patients evaluable before RT, 31 (72%) achieved a partial or complete response after CT alone. After RT, 52 patients attained a complete response, 25 in the CT + RT group and 27 in the RT-group. Sixty-three patients developed distant metastases or local relapse, 30 in the CT + RT group and 33 in the RT group. In the CT + RT group 6 of the 9 patients with metastases also had local progression at relapse, in the RT group, 7 of 17 patients. The survival rates for the two groups are not statistically different. Thirty-seven patients are alive, 29 have no evidence of disease. Fifty-seven have died, 29 in the CT + RT group and 28 in the RT group. Fifty-four deaths were related to cancer, and 3 to therapy.
                Sequential CT and RT did not improve the survival, local control, or metastasis rate compared with RT alone. Seventy-one patients with stage IIb-IVa cervical cancer were entered on a randomized trial comparing standard pelvic radiotherapy vs. 3 cycles of combination chemotherapy with cisplatin, vinblastine and bleomycin followed by pelvic radiotherapy. Four out of 34 patients randomized to PVB followed by radiotherapy received no PVB and a further 3 patients had only one or 2 cycles of chemotherapy prior to radiotherapy due to drug-related toxicity or progressive disease. After a median follow-up of 3.1 years, no significant difference in survival has emerged between the two randomized groups. However, a difference in the pattern of relapse is emerging with a relatively reduced frequency of systemic relapse in patients receiving chemotherapy prior to local radiotherapy compared to radiotherapy alone. Tumor response was seen following PVB treatment and prior to radiotherapy in 47% of patients. Overall the tumor response rate following completion of radiotherapy was 89% in those treated by radiotherapy and 94% after PVB+radiotherapy. Thirty-three percent of patients randomized to radiotherapy alone relapsed first at a distant (extra pelvic site), and only 18% of patients randomized to initial PVB followed by radiotherapy relapsed systemically initially. When results are presented according to treatment actually given, these trends in patterns of treatment failure are magnified. No treatment-related deaths were reported, and there was no excess of complications with pelvic radiotherapy in the group who had received prior PVB chemotherapy.
The timing and dose intensity of cisplatin-based neoadjuvant chemotherapy appears to have an important impact on whether or not it benefits women with locally advanced cervical cancer and warrants further exploration. Obtaining additional IPD may improve the strength of these conclusions.