The role of the tumor primary chemosensitivity relative to the success of the medical-surgical management in patients with advanced ovarian carcinomas

Abstract

In patients with advanced ovarian carcinomas, the first-line treatment has historically relied on debulking surgery and platinum-based chemotherapy. If the major therapeutic/prognostic role of the surgery part is well understood, and integrated in disease-management algorithms, the impact of chemotherapy efficacy has been insufficiently addressed.This review describes the main indicators of the chemosensitivity reported in the literature (pathological response score & biomarkers; genomic alterations; DNA scars; imaging; and circulating tumor markers), and investigates the respective roles of the debulking surgery and tumor primary chemosensitivity relative to the success of the comprehensive medical-surgical treatment. The tumor primary chemosensitivity exhibits a major independent prognostic impact on the feasibility of complete interval debulking surgery after neoadjuvant chemotherapy, risk of subsequent platinum-resistant relapse, efficacy of subsequent maintenance therapies with bevacizumab or PARP inhibitors, progression-free survival, overall and long-term survival. While both the completeness of the surgery and the tumor primary chemosensitivity are undoubtedly major prognostic factors, the impact of the surgery may differ according to the primary chemosensitivity. This assumption raises a potential new concept: in patients with advanced ovarian carcinomas, the maximum tumor debulking should ideally be both biological (induced by systemic treatments) and physical (induced by surgery) for maximizing patient survival. Besides BRCA and HRD biomarkers, future trials and algorithms may integrate indicator(s) of the tumor primary chemosensitivity for guiding more subtly the surgical and medical management in first-line setting. Moreover, such a parameter would help in the development of novel approaches meant to reverse the resistance to chemotherapy and PARP inhibitors.

The Increasing Prognostic and Predictive Roles of the Tumor Primary Chemosensitivity Assessed by CA-125 Elimination Rate Constant K (KELIM) in Ovarian Cancer: A Narrative Review

“…While international guidelines have now widely recognized and incorporated the significant prognostic and therapeutic role of complete debulking surgery, the relevance of the tumor primary chemosensitivity has been insufficiently considered, although it may have a major impact on the success of the first-line medical–surgical treatment, on decision-making regarding the type of systemic therapy to prescribe, and on the comprehensive prognosis of patients [ 41 ].…”

“…Obtaining a complete cytoreduction without microscopic residues (CC0 surgery) is already widely recognized as the main goal of the surgery, as it was shown to be a major prognostic factor [ 37 , 38 , 39 , 40 ]. As a consequence, the success of the first-line of treatment seems to logically depend on the tumor primary sensitivity to chemotherapy and the likelihood of complete IDS [ 41 ].…”

Identification of Patients With Ovarian Cancer Experiencing the Highest Benefit From Bevacizumab in the First-Line Setting on the Basis of Their Tumor-Intrinsic Chemosensitivity (KELIM): The GOG-0218 Validation Study

“…9 Among them, the modeled cancer antigen-125 (CA-125) ELIMination rate constant K (KELIM; on the basis of the CA-125 longitudinal kinetics observed during the first 100 treatment days and calculated using mathematical modeling) was shown to be a reproducible indicator of the tumor intrinsic chemosensitivity using data from more than 12,000 patients enrolled in 12 randomized trials, the Netherlands Cancer Registry, and the Gynecologic Cancer InterGroup (GCIG) meta-analysis database. 9 The relationship between KELIM and benefit from bevacizumab in the first-line setting was assessed in a post hoc analysis of the ICON-7 trial. Patients with a highly chemosensitive tumor, defined by a favorable KELIM score ($ 1.0), had no benefit from bevacizumab, whether they had a lowrisk or high-risk disease.…”

Neoadjuvant treatment in ovarian cancer: New perspectives, new challenges

“…The tumor primary chemosensitivity affects the feasibility of R0 IDS after NACT, the efficacy of subsequent maintenance therapies with PARP inhibitors or bevacizumab, the risk of subsequent platinum-resistant relapse, and consequently PFS and OS. Provided that the completeness of the surgery may differ according to the primary chemosensitivity, we could assume that the maximum biological response (succeeded by systemic treatment) and the achievement of maximum debulking will maximize the OS ( 63 ).…”