NEOADJUVANT DOSE-DENSE CHEMOTHERAPY IN LOCALLY ADVANCED CERVICAL CANCER: FROM MOLECULAR TO CLINICAL PRACTICE

Title: Neoadjuvant dose-dense chemotherapy in locally advanced cervical cancer: from molecular to clinical practice Introduction Cervical cancer is the second most commonly diagnosed cancer and the third leading cause of cancer death among women in less developed countries. Many molecular mechanisms are implicated in the development of this tumor and scientific research is increasingly focusing on the development of new molecules and therapeutic plans not only to treat this pathology but also to reduce the impact of detrimental treatments especially in young patients. Objective The primary endpoint of the study is to evaluate the feasibility of dose-dense neoadjuvant chemotherapy (NACT) with carboplatin and paclitaxel followed by radical surgery in locally advanced cervical cancer (LACC), avoiding harmful treatments such as radiation therapy. Secondary endpoints are the analysis of predictors of response to dose-dense at imaging before surgery and of predictors of receiving radiotherapy after surgery. Tertiary endpoint is the analysis of follow-up and possible relapses. Methods Patients with LAAC undergoing dose-dense NACT at the European Institute of Oncology, Milan from July 2014 to December 2022 were identified. Patients received weekly dose-dense carboplatin AUC2 + paclitaxel 80 mg/m2 or carboplatin AUC2.7 + paclitaxel 60 mg/m2 for 6-9 cycles followed by radical surgery or exclusive chemoradiotherapy (CCRT) depending on radiological response evaluated by RECIST criteria. Final pathologic response, predictors of receiving radiotherapy after surgery and follow-up were subsequently evaluated. Results From 2014 to 2022, a total of 82 patients were triaged to NACT dose-dense followed by surgery (radical hysterectomy with pelvic lymphadenectomy) for locally advanced cervical cancer. According to FIGO 2018, the stage distribution of disease was the following: 2 (2,4%) stage IB1, 20 (24,3%) stage IB2, 37 (45,1%) stage IB3, 3 (3,6%) stage IIA1, 2 (2,4%) stage IIA2, 6 (7,3%) stage IIB, and 12 (14,6%) stage IIIC1. After NACT, 11 (13,4%) had complete response, 48 (58,5%) partial response, 19 (23%) stable disease and 4 (4,9%) progressive disease, according to RECIST criteria. After discussion by multidisciplinary team 13 (15,8%) patients were deemed inoperable and received exclusive chemoradiation (CCRT). Among the 69 patients (84,14%) undergoing surgery, due to the presence of high or intermediate risk factors, 17 (24,6%) underwent chemoradiation, 2 (2,89%) radiotherapy alone and 7 (10%) chemotherapy alone. In particular, 50 (72,5%) did not receive radiation after surgery. If we consider overall 82 patients, we can conclude that dose- dense NACT spared radiotherapy in 60.9% of patients. The median follow-up time among patients who did not experience disease recurrence was 52 months (range 6-94). During the follow-up after surgery only 12 (17,3%) patients reported a recurrence of disease and at the time of the last follow-up, 60 (86,9%) were NED (no evidence of disease), 2 (2.9%) were AWD (alive with disease) and 7 (10%) were DOD (death of disease). Progression free survival (PFS) at 36 months was 84% and at 60 months 79%. Conclusion Dose-dense NACT achieved a good response rate. Although CCRT remains the gold standard treatment of LACC, dose-dense NACT followed by surgery can be considered an alternative approach and allows to avoid radiotherapy in over 60% of the patients without affecting recurrence rate