Neoadjuvant Chemotherapy Does Not Give Survival Benefit Over Chemoradiation in Cervical Cancer

Neoadjuvant chemotherapy preceding surgery (NACT-S) did not result in a significant difference in 5-year overall survival (OS) rates compared with concomitant chemoradiotherapy (CCRT) in patients with stage IB2 to IIB cervical carcinoma, according to findings from the phase 3European Organisation for Research and Treatment of Cancer (EORTC)-55994 trial (NCT00039338) published in the Journal of Clinical Oncology.

At a median follow-up of 8.7 years(95% CI, 7.8-8.6), patients who received NACT-S (n = 314) experienced a 5-year OS rate of 72% (95% CI, 66%-77%) vs 76% (95% CI, 70%-80%) among patients treated with CCRT (n = 312), leading to a 4% difference in survival(95% CI, 4%-11%; P = .291). The median OS in both arms was not estimable (NE; HR, 0.84; 95% CI, 0.64-1.12; P = .240). There was a total of 198 deaths (32%) across the 2 arms.

In terms of progression-free survival (PFS), the 5-year PFS rates were 57% vs 66% (HR, 0.73; 95% CI, 0.57-0.93; P = .011) in the NACT-S and CCRT arms, respectively. The median PFS was 12.2 months (95% CI, 5.4-NE) in the NACT-S arm vs NE (95% CI, 15.0-NE) in the CCRT arm (HR, 0.72; 95% CI, 0.57-0.93; P = .010).

“Additional radiotherapy was used for a substantial proportion of patients with stage IB2 to IIB cervical cancer who were assigned to NACT-S on this trial. CCRT remains the standard of care in this setting,” investigators noted.

EORTC-55994 was an international, multicenter trial that enrolled patients between 18 and 75 years of age with International Federation of Gynecology and Obstetrics (FIGO) stage IB2, IIA2, or IIB squamous or adeno(squamous) cervical carcinoma. Patients also needed to have a World Health Organization performance status of 0 to 2, be without a previous or concurrent second malignancy besides basal cell skin carcinoma, and have adequate laboratory values. Previous irradiation or chemotherapy was not permitted. Patients were also asked to complete health-related quality of life (HRQOL) questionnaires at 6, 12, 18, and 24 months.

Once enrolled, patients were randomly assigned in a 1:1 manner to receive NACT-S or CCRT using a minimization technique to stratify for age (18-50 vs 51-75 years), FIGO stage (IB2 vs IIA2 vs IIB), cell type (adenomatous vs nonadenomatous), and institution. In the NACT-S arm, patients received platinum-based chemotherapy at a minimum cumulative cisplatin dose of 225 mg/m² and a cisplatin dose equivalent of at least 75 mg/m² every 3 weeks, with combination chemotherapy permitted. After completion of NACT, within 6 weeks, patients underwenta Piver-Rutledge type III to V radical hysterectomy with pelvic lymphadenectomy with or without para-aortic nodes. If patients had proven lymph node metastases, parametrial infiltration, or positive surgical margins, adjuvant (chemo)radiotherapy was recommended.

Among patients who received CCRT, cisplatin was administered once with 5 to 6 weekly doses of 40 mg/m² during radiotherapy. Additionally, external beam radiotherapy at a total dose between 45 Gy and 50 Gy was applied to the pelvis followed by brachytherapy. The mandatory minimal total dose was 75 Gy equivalent dose Gray 2 to point A, or 80 Gy to high-risk planning target volume. Investigators permitted adjuvant hysterectomy if there was histologically proven residual tumor.

The chemotherapy regimens that were given differed based on the center of treatment; 24% of patients in the NACT-S arm and 79% of those in the CCRT arm planned to receive cisplatin monotherapy. Combination chemotherapy was administered to those who didn’t receive cisplatin monotherapy, with paclitaxel and ifosfamide given as the most frequent regimen.

Initially, the primary end point of EORTC-55994 was OS; however, it was adjusted to 5-year OS after a June 2013 blinded review found that original estimates fell short of the observed survival. Secondary end points included PFS, toxicity, and HRQOL.

The baseline characteristics were generally well balanced between the 2 arms; the median age in the NACT-S arm was 46 years (range, 23-73) vs 47 years (range, 23-75) in the CCRT arm. Most patients in both arms had an ECOG performance status of 0 (88% vs 88%) and squamous cell histology (85% vs 85%); FIGO stages included IB2 (26.0% vs 28.0%), IIA2 (15.0% vs 15.0%), IIB (57.0% vs 57.0%), III (1% vs 0%), IV (0.0% vs 0.3%), or missing (0.3% vs 0.0%).

Findings for subgroup analyses demonstrated that there was no significant difference in OS by FIGO stage; however, OS favored CCRT over NACT-S in women older than 50 years (HR, 0.66; 95% CI, 0.42-1.03) and in patients with a body mass index (BMI) of 25 or less (HR, 0.59; 95% CI, 0.37-0.96). Data from the PFS subgroup analysis revealed that CCRT was favored over NACT-S in patients with FIGO stage IIB disease (HR, 0.61; 95% CI, 0.44-0.83), patients older than 50 years (HR, 0.55; 95% CI, 0.38-0.81), and patients with a BMI of 25 or less (HR, 0.55; 95% CI, 0.36-0.85).

Most patients in the NACT-S arm underwent surgery according to protocol (76%), and of these patients, 89% underwent a radical hysterectomy Piver-Rutledge type III or IV. Among patients who did not get surgery (n = 74), reasons for abstaining included chemotherapy-related toxicity (34%), progressive disease (24%), and insufficient response to NACT (16%). In the CCRT arm, 6% of patients did not receive radiotherapy. Of these 20 patients, reasons for the lack of radiotherapy included patient refusal (55%) and protocol violation (25%). The median radiotherapy dose was 46 Gy (range, 30.0-66.6 Gy), and of 292 patients, 19 patients received an extended field, 123 received an external boost, and 280 were given brachytherapy.

In terms of tolerability, patients in the NACT-S arm experienced grade 3 or 4 adverse effects (AEs) at a rate of 41% (n = 122/300) compared with 23% (66 of 291) in the CCRT arm. Grade 3 or higher AEs according to the Chassagne grading system were reported in 15% and 21% of patients, respectively. In the CCRT arm, there were 2 deaths, 1 from chronic small bowel obstruction/malabsorption and 1 from sepsis following surgery for a rectal stricture.

In the NACT-S arm, 71% of patients completed treatment. Reasons for discontinuation included disease progression (6.7%), toxicity (9.6%), patient refusal (3.2%), protocol violation (2.2%), surgical complication (0.3%), ineligibility for surgery (4.5%), physician decision (1.0%), and other reasons (1.6%).

In the CCRT arm, most patients finished the treatment protocol (82.4%). Reasons for discontinuation consisted of progression (0.3%), toxicity (7.4%), patient refusal (4.2%), protocol violation (1.9%), withdrawal of informed consent (0.6%), physician decision (1.9%), and other reasons (1.3%).

Investigators noted that HRQOL compliance was subpar in the study, with a baseline completion rate of 69% that fell to 27% at 2 years. Findings from a descriptive analysis of the EORTC core quality of life questionnaire showed no significant differences.

“The strength of [this] trial is that this is a multinational study with a very long follow-up,” study authors wrote. “However, the long duration because of low accrual, radiotherapy technique improvements over time, and the different NACT regimens are limitations of our study. Although this trial was not designed as a noninferiority trial, for regions in the world with poor radiotherapy facilities, NACT followed by radical surgery is an acceptable alternative for patients with FIGO stage IB2 [disease]. This registered clinical trial comparing NACT-S with CCRT in cervical carcinoma FIGO stage IB2 to IIB failed to demonstrate a superiority of NACT-S over CCRT but demonstrated acceptable morbidity and QOL in both arms.”

Reference

Kenter GG, Greggi S, Vergote I, et al. Randomized phase III study comparing neoadjuvant chemotherapy followed by surgery versus chemoradiation in stage IB2-IIB cervical cancer: EORTC-55994. J Clin Oncol. 2023;41(32). doi:10.1200/JCO.22.02852