Outcomes and toxicity profiles of two-drug versus three-drug neoadjuvant chemotherapy for locally advanced cervical cancer in a setting without radiotherapy: Insights from Malawi.

BACKGROUND: 
Malawi has the second-highest global incidence and mortality rate for cervical cancer. For locally advanced cervical carcinoma (LACC), concurrent chemoradiotherapy is the standard treatment. However, until 2024, this was unfeasible in Malawi due to the absence of radiotherapy services. Since 2015, neoadjuvant chemotherapy (NACT) followed by surgery has therefore been adopted as an alternative. Given the lack of a consensus on the optimal NACT regimen in the literature, either a 2-drug regimen (platinum plus taxane, 2DR), or a 3-drug regimen (platinum, taxane, and 5-fluorouracil, 3DR) was used. This study evaluates the health outcomes of NACT with the 2DR vs. the 3DR in women with LACC in Blantyre, Malawi.

METHODS: 
A retrospective cohort analysis was performed on women aged 20–75 years who received NACT for confirmed LACC, FIGO 2018 stages IB3, IIA2, and IIB, between January 2020 and December 2022. The decision to start either 2DR or 3DR was based on ECOG status, drug availability, renal function and CD4-count if HIV+. Clinical characteristics, treatment regimen and tolerability, and operability outcomes after completing NACT were descriptively analyzed. Univariable regression followed by multivariable regression analysis was conducted using a backward selection approach. Overall survival was estimated using the Kaplan-Meier method, and differences between groups were assessed with the log-rank test. 

RESULTS:
A total of 382 women were included (median age 48 years; 24-75), with 55.5% living with HIV and 95% having ECOG 0-1. Vaginal discharge/bleeding were presenting symptoms in 65%; 6% of women were asymptomatic. FIGO stage at diagnosis was IB3 (14.7%), IIA2 (11.5%), and IIB (73.8%), with squamous cell carcinoma in 90%. The 2DR was given to 95 women, the 3DR to 273, and 14 receiving other regimens were excluded. Groups differed in age (median 55 vs. 46 years for 2DR vs 3DR) and stage at diagnosis (IIB in 84% vs. 70% for 2DR vs. 3DR, p<0.05). Most women (87%) received 3-6 cycles of NACT (median: 5 for 2DR vs. 4 for 3DR (p<0.05)). Toxicity was comparable, except for less neuropathy (18% vs. 30%) and more neutropenia (67% vs. 55%) with 3DR, leading to more delays (60% vs. 43%) and increased granulocyte colony-stimulating factor use (55% vs. 34%) (p<0.05). Operability rates post-NACT were 38% for 2DR vs. 51% for 3DR (p<0.05), but multivariable analysis showed only hemoglobin level pre-NACT, not regimen type, predicted surgery likelihood. Two-year overall survival did not differ by regimen but was higher in operable women compared to non-operable women (88% vs. 40%). 

CONCLUSIONS: 
NACT followed by surgery remains an essential alternative to chemoradiotherapy in settings without adequate radiotherapy services. This retrospective study found no evidence that a 3DR improves operability nor survival rates compared to a 2DR.