Are we making progress in curing advanced cervical cancer-again?

Abstract

Major improvements in radiotherapy over the past two decades in the definitive treatment of locally advanced cervical cancer have significantly improved loco-regional control and survival, whereas little progress has been made with chemotherapy since the implementation of concomitant cisplatin 25 years ago. However, the randomized study INTERLACE (A phase III multicenter trial of weekly induction chemotherapy followed by standard chemoradiation versus standard chemoradiation alone in patients with locally advanced cervical cancer) of neoadjuvant chemotherapy presented recently, has shown significant improvement in survival with the use of six cycles of weekly carboplatin and paclitaxel. Although INTERLACE is yet to be published, neoadjuvant chemotherapy is already being advocated as the new standard, and studies are being designed with neoadjuvant chemotherapy followed by chemoradiation and brachytherapy as the standard arm. It is noteworthy that INTERLACE was initiated before the improvements in radiotherapy mentioned above were broadly implemented. The survival rate in the standard arm of INTERLACE was therefore inferior to the results obtained with the latest state-of-the-art external beam radiotherapy and image guided adaptive brachytherapy (EMBRACE, Magnetic Resonance Imaging (MRI)-Guided Brachytherapy in Locally Advanced Cervical Cancer). Moreover, patient selection impedes the comparison of INTERLACE with other studies as the patients included in INTERLACE were younger, had better performance status, and had less advanced disease than in other studies. Notably patients with involved para-aortic nodes were excluded. In this review, we discuss neoadjuvant chemotherapy in the frame of the EMBRACE studies and show how the impact of modern radiotherapy and patient selection affects the interpretation of the results of INTERLACE. This has led us to conclude that neoadjuvant chemotherapy is not needed for the majority of patients with cervical cancer treated with definitive modern radiotherapy, and may cause harm. However, it is possible that short course neoadjuvant chemotherapy may benefit a minor subgroup of patients who need to be identified. Comprehensive understanding, including cost utility analyses, are needed to draw conclusions regarding the potential benefit of neoadjuvant chemotherapy in low and middle income countries with limited access to modern radiotherapy.

Keywords: Brachytherapy; Cervical Cancer; Radiotherapy, Image-Guided; Radiotherapy, Intensity-Modulated.

Figure 1. Progression free survival and overall survival in INTERLACE (a phase III multicenter trial of weekly induction chemotherapy followed by standard chemoradiation versus standard chemoradiation alone in patients with locally advanced cervical cancer), reconstructed from the graphics presented at the 2023 ESMO congress. The reconstructed curves are not based on actual numeric data. Data points of the EMBRACE 1 (Magnetic Resonance Imaging (MRI)-Guided Brachytherapy in Locally Advanced Cervical Cancer) 'Interlike' cohort are projected over the INTERLACE curve sketches. The EMBRACE 1 'Interlike' cohort was selected to mirror the INTERLACE patients, specifically with regard to the absence of para-aortic nodal metastases. However, the 'Interlike' patients were older, and had more advanced stages and worse performance status than INTERLACE patients. Nevertheless, the EMBRACE 1 'Interlike' data points overlap with the sketched INTERLACE curve for induction chemotherapy up to the 5 year mark, before deviating downwards. Notably, the number of patients remaining for analysis after 5 years is low, and only a small proportion of events occurred after 5 years in EMBRACE 1. It can be argued that the neoadjuvant chemotherapy is merely compensating for suboptimal radiotherapy of the INTERLACE study. NACT, neoadjuvant chemotherapy; CRT, chemoradiation; pts, patients.