C. Malhaire

Long-term clinical outcomes of preoperative brachytherapy in early-stage cervical cancer

The treatment of early-stage cervical cancer (CC) is primarily based on surgery. Adjuvant (chemo)radiotherapy can be necessary in presence of risk factors for relapse (tumor size, deep stromal invasion, lymphovascular space invasion (LVSI), positive margins, parametrial or lymph node involvement), increasing the risk of treatment toxicity. Preoperative brachytherapy can reduce tumor extension before surgery, potentially limiting the need for adjuvant radiotherapy. This study reports long-term clinical outcomes on efficacy and toxicity of preoperative pulse-dose-rate (PDR) brachytherapy in early-stage CC. All patients treated at Institut Curie between 2007 and 2022 for early-stage CC by preoperative brachytherapy were included. A PDR technique was used. Patients underwent hysterectomy associated with nodal staging following brachytherapy. 73 patients were included. The median time from brachytherapy to surgery was 45 days [range: 25-78 days]. With a median follow-up of 51 months [range: 4-185], we reported 3 local (4 %), 1 locoregional (1 %) and 8 metastatic (11 %) relapses. At 10 years, OS was 84.1 % [95 % CI: 70.0-100], DFS 84.3 % [95 % CI:74.6-95.3] and LRFS 92.8 % [95 % CI:84.8-100]. Persistence of a tumor residue, observed in 32 patients (44 %), was a significant risk factor for metastatic relapse (p = 0.02) and was associated with the largest tumor size before brachytherapy (p = 0.04). Five patients (7 %) experienced grade 3 toxicity. One patient (1 %) developed grade 4 toxicity. Ten patients (14 %) received adjuvant radiotherapy, increasing the risk of lymphedema (HR 1.31, 95 % CI [1.11-1.54]; p = 0.002). PDR preoperative brachytherapy for early-stage cervical cancer provides high long-term tumor control rates with low toxicity.

Nivolumab plus chemoradiotherapy in locally-advanced cervical cancer: the NICOL phase 1 trial

AbstractConcurrent chemoradiotherapy (CRT) with blockade of the PD-1 pathway may enhance immune-mediated tumor control through increased phagocytosis, cell death, and antigen presentation. The NiCOL phase 1 trial (NCT03298893) is designed to determine the safety/tolerance profile and the recommended phase-II dose of nivolumab with and following concurrent CRT in 16 women with locally advanced cervical cancer. Secondary endpoints include objective response rate (ORR), progression free survival (PFS), disease free survival, and immune correlates of response. Three patients experience grade 3 dose-limiting toxicities. The pre-specified endpoints are met, and overall response rate is 93.8% [95%CI: 69.8–99.8%] with a 2-year PFS of 75% [95% CI: 56.5–99.5%]. Compared to patients with progressive disease (PD), progression-free (PF) subjects show a brisker stromal immune infiltrate, higher proximity of tumor-infiltrating CD3+ T cells to PD-L1+ tumor cells and of FOXP3+ T cells to proliferating CD11c+ myeloid cells. PF show higher baseline levels of PD-1 and ICOS-L on tumor-infiltrating EMRA CD4+ T cells and tumor-associated macrophages, respectively; PD instead, display enhanced PD-L1 expression on TAMs, higher peripheral frequencies of proliferating Tregs at baseline and higher PD-1 levels at week 6 post-treatment initiation on CD4 and CD8 T cell subsets. Concomitant nivolumab plus definitive CRT is safe and associated with encouraging PFS rates. Further validation in the subset of locally advanced cervical cancer displaying pre-existing, adaptive immune activation is warranted.

Nivolumab in Association With Radiotherapy and Cisplatin in Locally Advanced Cervical Cancers Followed by Adjuvant Nivolumab for up to 6 Months (NiCOL)

To date, the majority of clinical trials on checkpoint inhibitors have tested these agents as monotherapy, and the next logical step is to evaluate rational therapeutic associations. The aim of the NiCOL study is to assess the safety of nivolumab in association with chemoradiation therapy and to gain initial insight into its efficacy in association with the current standard of care, including chemoradiation.