Aim:
Despite Australia’s progress towards cervical cancer elimination, some people will still present with locally advanced disease (LACC). Concurrent chemoradiation with brachytherapy (CCRT+BT) remains the standard of care, yet 30–35% experience disease progression. Immunotherapy has demonstrated benefit in metastatic disease and is currently being evaluated for LACC. We conducted a systematic review (SR) and GRADE Evidence-to-Decision assessment to inform the first Australian Cervical Cancer Management Guidelines.
Methods:
A SR was conducted following PRISMA 2020 guidelines comparing immunotherapy plus CCRT (I+CCRT) with CCRT alone in people with LACC (FIGO 2018 stage IB3/IIA2-IVA). Eligible studies included randomised controlled trials or SRs thereof. Outcomes included overall survival (OS), progression-free survival (PFS), grade 3-4 adverse events (AEs) and quality of life (QoL). Searches using MEDLINE, EMBASE, and Cochrane databases identified one relevant SR (Zhao 2024), which we updated. In consultation with the multi-disciplinary Guidelines Working Party (WP), 3+-year (preferably 5+-year) OS and QoL were identified as critical outcomes to inform the recommendation process.
Results:
Two trials met inclusion criteria: CALLA (durvalumab) and ENGOT-cx11/GOG-3047/KEYNOTE-A18 (pembrolizumab); (both included immunotherapy maintenance therapy to two years). Only KEYNOTE-A18 reported both critical outcomes. Three-year OS was significantly higher in the pembrolizumab (82.6%) versus the control arm (74.8%) (hazard ratio 0.67, 95%CI:0.50–0.90; p=0.00). QoL at 36 weeks did not differ significantly between the two arms.
Conclusion:
The WP conditionally recommended adding pembrolizumab to CCRT+BT for patients with FIGO 2018 III/IVA disease regardless of PD-L1 status, emphasising shared decision-making, including discussion of immunotherapy-related AEs and patient preferences. Subsequent announcement of Government subsidisation of pembrolizumab for LACC should ensure equitable access. Recommendation and subsidisation decisions were based on improvement in 3-year OS. Key uncertainties remain, including the magnitude of long-term survival benefit pending 5-year OS data, use of biomarkers to optimise patient selection, and whether the two-year-maintenance-immunotherapy duration can be safely shortened.