Treatment of ("bulky") stage IB cervical cancer with or without neoadjuvant vincristine and cisplatin prior to radical hysterectomy and pelvic/para-aortic lymphadenectomy: a phase III trial of the gynecologic oncology group. Clinical efficacy of modified preoperative neoadjuvant chemotherapy in the treatment of locally advanced (stage IB2 to IIB) cervical cancer: randomized study. The role of neoadjuvant chemotherapy for squamous cell cervical cancer (Ib-IIIb): a long-term randomized trial. Long-term follow-up of the first randomized trial using neoadjuvant chemotherapy in stage Ib squamous carcinoma of the cervix: the final results. Randomized study of preoperative chemotherapy versus primary surgery for stage IB cervical cancer.
A randomized phase III trial was conducted to determine if neoadjuvant chemotherapy (NACT) prior to radical hysterectomy and pelvic/para-aortic lymphadenectomy (RHPPL) could improve progression-free survival (PFS) and overall survival (OS), as well as operability, with acceptable levels of toxicity. Adjuvant radiation therapy was prescribed for specific surgical/pathological risk factors for both regimens.
                Eligible patients were required to have bulky FIGO Stage IB cervical cancer, tumor diameter > or =4 cm, adequate bone marrow, renal and hepatic function, and performance status < or =2. Prospective random allocation was to either NACT (vincristine-cisplatin chemotherapy every 10 days for 3 cycles) before exploratory laparotomy and planned RHPPL (NACT+RHPPL), or RHPPL only.
                The study was closed prematurely, because of slow accrual, after 291 patients were enrolled, three were ineligible; thus 288 were eligible and randomly allocated to RHPPL (N=143) or NACT+RHPPL (N=145). There were no notable differences between regimens with regard to patient age, race, performance status, or tumor size. The median follow-up time is 62 months among living patients. The NACT+RHPPL group had very similar recurrence rates (relative risk: 0.998) and death rates (relative risk: 1.008) when compared to the RHPPL group. There were 79% that had surgery in the RHPPL group compared to 78% in the NACT RHPPL group. There were 52% who received post op RT in the RHPPL group compared to 45% in the NACT+RHPPL group (not statistically significant).
                There is no evidence from this trial that NACT offered any additional objective benefit to patients undergoing RHPPL for suboptimal Stage IB cervical cancer. The use of preoperative neoadjuvant chemotherapy (NAC) in locally advanced cervical cancer (LACC) was hindered by the disadvantages of a delay of curative treatment for nonresponders and the development of radioresistant cells. However, these disadvantages may be overcome by a 'quick' high-dose scheme administered in a short period before surgery. Our purpose is to assess the efficacy of NAC with short cycle-length, high-dose agents for LACC.
                From 1999 to 2004, 142 of patients with LACC (stage IB2IIB, tumor diameter >or=4 cm) were assigned to randomly receive either NAC followed by surgery or primary surgery directly. A modified NAC scheme with short cycle-length, high-dose agents was used.
                The overall clinical response rate was 69.4%. The chemotherapeutic response was more favorable in the squamous carcinoma and the tumors smaller than 8 cmP=0.005, P=0.029). Pathologic findings showed that the pelvic metastasis and parametrial infiltration rates were significantly lower in NAC group than in the primary surgery group (P=0.025; P=0.038). Among patients who received NAC, the lymph node metastasis rate was still as high as 45.5% in non-NAC responders, and it decreased to 16.0% in NAC responders (P=0.008). The same thing also occurred with parametrial infiltration: 45.5% in non-NAC responders compared with 16.0% in NAC responders (P=0.008). Survival analysis revealed that although test showed a longer survival in NAC group than in the primary surgery group (P=0.041), Cox hazard analysis did not indicate the therapy modality as a prognostic predictor (P=0.074). However, after further subdivision, we found that NAC responders had longer survival and lower recurrence rate than non-NAC responders (P=0.000; P=0.013). NAC response was also an independent prognostic predictor (P=0.005).
                The modified preoperative NAC is well tolerated and beneficial in reducing tumor size, eliminating pathological risk factors, and improving prognosis for responders. It also avoids the delay of effective treatment for non-NAC responders. to verify whether a regimen of preventive chemotherapy in the treatment of cervical carcinoma allows surgical treatment in a larger number of patients and whether cases treated with this combined neoadjuvant polychemotherapy/surgery regimen improves overall and disease-free survival rates. Design: prospective randomized clinical study. Setting: Department of Gynaecology and Obstetrics, University of Rome "La Sapienza".
                192 patients suffering from squamous cell carcinoma of the uterine cervix in Stages Ib-IIb were randomized to one of the following treatments: three courses of neoadjuvant chemotherapy with cisplatin, vincristine, bleomycin (NACT arm; n = 106); conventional surgery or radiotherapy alone (CO arm; n = 86). One hundred and fifty-six patients in Stage Ib-IIb (n = 86, NACT arm and n = 70, CO arm) and 16 patients in Stage III (NACT arm) who proved to be sensitive to the neoadjuvant chemotherapy, underwent radical hysterectomy. Four Stage III patients not sensitive to chemotherapy and 16 patients, Stage III, of the CO arm underwent radiotherapy.
                the 5-year overall survival rates for the NACT and CO arm, respectively, were 78.6% and 73.2% in Stages Ib-IIa (p = NS), 68.7% and 64.3% in Stage IIb (p = NS). A 5-year disease-free survival rate for the NACT arm and CO arm, respectively, of 77.1% and 64.3% in Stages Ib-IIa (p < .05), 56.2% and 57.1% in Stage IIb (p = NS) was found.
                the responsiveness of cervical cancer to neoadjuvant chemotherapy allows surgical treatment in a larger number of patients and results in longer overall and disease-free survival. 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. To determine the most effective treatment and long-term outcome of patients with stage IB carcinoma of the cervix.
                From January 1999 to December 2001, 106 women with cervical cancer stage IB received neoadjuvant chemotherapy (n = 52) or primary surgery (n = 54). These were randomly assigned. Clinical effects and pathological changes were simultaneously recorded.
                The overall clinical response rate was 84.6% and included a complete response (CR) in four patients (7.7%), partial response (PR) in 40 patients (76.9%), and stable disease (SD) in the remaining eight patients (15.4%). Surgery revealed positive nodes in 9.6% neoadjuvant chemotherapy group patients and in 29.6% primary surgery group patients (P = 0.014). Similar results occurred with vascular space involvement: 27.8% in the primary surgery group compared to 9.6% in the neoadjuvant chemotherapy group (P = 0.024). However, parametrial infiltration was found in 7.4% of the patients in the primary surgery group, while only 3.8% showed it in the neoadjuvant chemotherapy group (P = 0.679). The overall 5-year survival rate was significantly higher for all patients who received neoadjuvant chemotherapy (84.6%) than for the control group (75.9%) (P = 0.0112). The median survival time in patients with complete response and partial response to chemotherapy (83.3 months) was significantly higher than that of patients with stable disease to chemotherapy (55.2 months) (P = 0.0049). 27.3% of patients developed recurrent disease within 5 years of the primary treatment. The women with recurrence included partial response in six patients (60.0%), and stable disease in four patients (40.0%). For the other patients there was partial response and complete response in 38 patients (90.5%), and stable disease in the remaining four patients (9.5%) (P = 0.035).
                Neoadjuvant chemotherapy can effectively eliminate the pathological risk factors and improve long-term survival in patients with locally advanced cervical cancer.
Both OS and PFS were improved with neoadjuvant chemotherapy. Although the effects were less clear on all other pre-specified outcomes, they all tended to be in favour of neoadjuvant chemotherapy. Whilst these results appear to indicate that neoadjuvant chemotherapy may offer a benefit over surgery alone for women with early-stage or locally-advanced cervical cancer, the evidence is based on only a small number of trials, and further research may be warranted.