PRJNA841396
Randomized multicenter phase II trial of prophylactic irradiation of para-aortic lymph nodes in advanced cervical cancer according to tumor hypoxia: Korean Radiation Oncology Group (KROG 07-01) study
We conducted a prospective phase II study on whether extended-field irradiation (EFI) confers survival benefits depending on hypoxic markers in locally advanced uterine cervical cancer (LAUCC). RNA-seq was performed to identify immune and hypoxic gene signatures. A total of 288 patients were randomized to either EFI or pelvic radiotherapy (PRT). All patients completed chemoradiotherapy. Overall, significantly higher 5-yr para-aortic recurrence free survival (PARFS) rate occurred in EFI (97.6%) than in PRT group (87.2%), with marginal tendency to improve disease-free survival (DFS) (78% vs. 70%, P=0.066). Subgroup analyses were performed based on carbonic anhydrase 9 (CA9)-only positive, CA9/hypoxia-inducible factor (HIF) double positive, and CA9 negative. In the CA9-only positive, EFI successfully reduced 5-yr PARFS (100% vs. 76.4%, P=0.010), resulting in significantly improved long-term DFS (85.7% vs. 54.7%, P=0.023) compared to the PRT, while there was no such benefit of EFI in the CA9/HIFs double positive. RNA-seq analysis identified distinct immune(high) subgroup with negative correlation with hypoxia gene signatures (R=-0.37, P<0.01), which showed a higher 5-yr DFS than the immune(low) (P=0.032). Hypoxia-related genes were upregulated in the CA9/HIFs double positive compared to CA9 negative (P<0.05). Only 17.4% of patients in CA9-negative group showed immune(low) signatures, while 40.0% of patients in the double-positive group exhibited immune(low) signatures. In conclusion, EFI improved PARFS significantly in all patients, but therapeutic efficacy of EFI in terms of improved DFS was solely observed in CA9-only positive LAUCC, and not in CA9/HIFs double-positive subgroup. RNA-seq analysis suggested that hypoxia-induced immunosuppression may be related to treatment resistance in LAUCC.