Neoadjuvant chemotherapy followed by surgery for stage IB2-IIB cervical cancer is not superior to chemoradiation

Cervical cancer remains the fourth most common cause of cancer-related death in women worldwide, with substantially high incidence and mortality rates in low-income and middle-income countries (1). The existing discrepancies in resources available for treatment of cervical cancers, specifically in low-income and middle-income countries pose barriers to improve survival outcomes. The lack of uniform access to radiotherapy begs the consideration for alternative treatment options for stage IB2-IIB cervical cancer. While neoadjuvant chemotherapy (NACT) and surgery conceptually holds value as a treatment paradigm for advanced disease, it does not show superiority to chemoradiation.

In the article that accompanies this editorial, Kenter et al. report the primary results of the EORTC-55994 trial, an international multicenter randomized control trial designed to assess superiority of NACT followed by surgery (NACT-S) over concomitant chemoradiotherapy (CCRT) in stage IB2-IIB cervical cancer. In this trial, 626 patients with early-stage (adeno)squamous or adenocarcinoma of the cervix (FIGO stage IB2, IIA2, or IIB) were randomly assigned to NACT-S (n=314) or standard CCRT (n=312). The primary end point was 5-year overall survival (OS). The expected median OS in the CCRT arm was initially underestimated, updated to 6 years, and the primary end point for NACT-S increased to a 77% 5-year OS rate. NACT-S patients mainly received single-agent cisplatin (45.7%) followed by cisplatin + paclitaxel (20.3%) and cisplatin + paclitaxel + ifosfamide (19%). The CCRT arm observed a higher OS for women with a body mass index (BMI) of ≤25 kg/m² compared to NACT-S (81% vs. 71% OS at 5 years). Patients with FIGO stage IIB cervical carcinoma in the CCRT arm also fared better in terms of progression-free survival (PFS) compared to NACT-S (66% vs. 50% PFS at 5 years). OS at 5 years was 71% for NACT-S and 75% for CCRT. Notably, nearly half (48% of 223) of patients in the NACT-S arm received adjuvant chemoradiotherapy for high-risk surgical factors (positive nodes, parametrial involvement, positive margins). Grade 3/4 adverse events were more common during NACT-S treatment (41% vs. 23% in CCRT) (2).

In 1999, five randomized trials each demonstrated a substantial survival advantage of chemo-radiation over radiation alone in advanced cervical cancer, leading to cisplatin-based chemoradiotherapy as standard of care. A systematic review of 19 randomized trials of chemoradiation versus radiation alone for advanced cervical cancer showed a 29% reduction in the risk of death (3). Still, the question of whether NACT followed by radical surgery (NACT-S) as a reasonable alternative to CCRT is important to ask, especially for providers and patients in regions with high mortality rates from cervical cancer and limited access to radiation therapy.

The feasibility of NACT followed by radical surgery has been shown in several studies. Evidence from randomized studies showed that NACT followed by radical surgery resulted in an improvement in OS compared to radiation alone. As an example, Benedetti et al. showed a survival benefit for NACT-S over standard RT in stage IB2-IIB (5-year OS 64.7% vs. 46.4%; P=0.003) (4). Sardi et al. observed a similar survival benefit of NACT followed by surgery (7-year OS 65% vs. 48% in conventional RT; P<0.005) (5). A subsequent systematic review and meta-analysis of five randomized trials showed a significant reduction in the risk of death with NACT followed by surgery (3). However, none of these trials used chemotherapy with radiation as the comparative arm as now applied to standard practice after the sentinel work of Peters et al. (6). More recently, three randomized trials evaluated the efficacy of NACT followed by surgery compared to concurrent chemotherapy with radiation. The premise of the question asked by EORTC-55994, therefore, is justified given the clear benefits of radiation-sensitizing cisplatin.

Scientific validity lies in replicability. The results of EORTC-55994 and Gupta et al.’s phase III trial, with the same comparator arms, are remarkably similar. Gupta et al. also finds no superiority of NACT-S over CCRT in stage IB2-IIB, with 5-year OS rates of 75.4% and 74.7% (P=0.87), respectively. In fact, they even observed a disease-free survival decrement in the NACT-S arm compared to CCRT (69.3% vs. 76.7%; P=0.038) (7). Together, these studies align to support chemoradiotherapy as the preferred treatment modality for stage IB2-IIB cervical cancer. A recent meta-analysis published by Marchetti et.al. further supports the superiority of CCRT over NACT-S in treating patients with cervical cancer. The analysis consisted of 1,259 patients from two randomized controlled trials (RCTs) and applied the PRISMA statement along with random-effects models for data analysis. Individuals in the CCRT arm exhibited a notably reduced risk of developing severe renal, hematologic, and hemorrhage-related toxicities compared to those in the NACT-S arm. Additionally, the analysis found that patients undergoing NACT-S were 32% more susceptible to relapse in comparison to those in the CCRT treatment arm. NACT-S also had an adverse effect on disease-free survival, defined as the time interval between the date of assignment and the rate of relapse or death, whichever occurs first (8).

In the quest to improve cervical cancer outcomes, we must prioritize treatment effectiveness while minimizing toxicity. One of the most striking findings from EORTC-55994 is that almost half of patients in the NACT-S arm ultimately required adjuvant chemoradiation. Trimodal treatment should certainly be avoided when it does not confer additional oncologic benefit. Adjuvant radiation after radical surgery in cervical cancer patients is associated with significant morbidity, including fistula formation, urologic complications, and pain (9). Even though findings from EORTC-55994 revealed no differences in quality of life, health-related quality of life (HRQOL) compliance was poor throughout the trial limiting its overall assessment. Furthermore, treatment associated morbidity with NACT-S does not support trimodal treatment benefit.

The advancement of intensity-modulated radiation therapy and volumetric dosing has introduced greater precision, less morbidity, and improved outcomes in patients with cervical cancer. EORTC-55994 provides valuable evidence for exceptional circumstances and limited radiotherapy services, when NACT followed by radical surgery is the only option for treatment. Standard CT-imaging may be used in these circumstances to identify the most suitable patients (for example, without any suspicious lymph nodes) in effort to minimize the need for post-operative radiotherapy. Given the lack of a superior treatment option, chemoradiotherapy should continue to be the standard of care for stage IB2-IIB cervical cancer.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gynecology and Pelvic Medicine. The article has undergone external peer review.

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-23-45/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-23-45/coif). The authors have no conflicts of interest to declare.

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