Muzaffar, Mahvish

Importance Neoadjuvant therapy (NT) is an increasingly used treatment strategy for patients with localized pancreatic ductal adenocarcinoma (PDAC). Little research has been conducted on cancer care delivery during NT, and the standards for optimal delivery of NT have not been defined. Objective To develop consensus best practices for delivering NT to patients with localized PDAC. Design, Setting, and Participants This study used a modified Delphi approach consisting of 2 rounds of voting, and a series of virtual conferences (from October to December 2023) to reach expert consensus on candidate best practice statements generated from a systematic review of the literature and expert opinion. An interdisciplinary panel was formed including 47 North American experts from surgical, medical, and radiation oncology, radiology, pathology, gastroenterology, integrative oncology, anesthesia, pharmacy, nursing, cancer care delivery research, and nutrition as well as patient and caregiver stakeholders. Main Outcome and Measures Statements that reached 75% agreement or greater were included in final consensus statements. Results Of the 47 participating panel members, 27 (57.64%) were male, and the mean (SD) age was 47.6 (8.2) years. Physicians reported completing training a mean (SD) 14.6 (8.6) years prior and seeing a mean (SD) 110.6 (38.4) patients with PDAC annually; 35 (77.7%) were in academic practice. Final consensus was reached on 82 best practices for delivering NT. Of these, 38 statements focused on pre-NT practices, including diagnosis and staging (n = 15), evaluation and optimization (n = 20), and decision-making (n = 3); 29 statements defined best practices during NT, including initiation (n = 3), delivery of therapy (n = 8), restaging practices (n = 12), and management of complications during NT (n = 6); and 15 best practices were identified to guide treatment post-NT, focusing on surgery (n = 7), pathology (n = 4), and follow-up (n = 3). Conclusions Using a modified Delphi consensus technique, best practice guidelines were developed focusing on the optimal standards for delivering NT to patients with localized PDAC. Given the prognostic importance of completing multimodality therapy, efforts to standardize and optimize the delivery of NT represent an immediate opportunity to decrease care variation and improve outcomes for patients with PDAC. Future research should focus on validating and implementing best practice standards into clinical practice.

PURPOSE In patients with high-grade ovarian cancer, predictors of bevacizumab efficacy in first-line setting are needed. In the ICON-7 trial, a poor tumor intrinsic chemosensitivity (defined by unfavorable modeled cancer antigen-125 [CA-125] ELIMination rate constant K [KELIM] score) was a predictive biomarker. Only the patients with high-risk disease (suboptimally resected stage III, or stage IV) exhibiting unfavorable KELIM score < 1.0 had overall survival (OS) benefit from bevacizumab (median: 29.7 v 20.6 months; hazard ratio [HR], 0.78). An external validation study in the GOG-0218 trial was performed. METHODS In GOG-0218, 1,873 patients were treated with carboplatin-paclitaxel ± concurrent-maintenance bevacizumab/placebo. Patient KELIM values were calculated with CA-125 kinetics during the first 100 chemotherapy days by the Lyon University team. The association between KELIM score (favorable ≥ 1.0, or unfavorable < 1.0) and bevacizumab benefit for progression-free survival (PFS)/OS was independently assessed by NGR-GOG using univariate/multivariate analyses. RESULTS KELIM was assessable in 1,662 patients with ≥ 3 CA-125 available values. An unfavorable KELIM score was associated with bevacizumab benefit compared with placebo (PFS: HR, 0.70; 95% CI, 0.59 to 0.82; OS: HR, 0.87; 95% CI, 0.73 to 1.03), whereas a favorable KELIM was not (PFS: HR, 0.96; 95% CI, 0.79 to 1.17; OS: HR, 1.11; 95% CI, 0.89 to 1.39). The highest benefit was observed in patients with a high-risk disease exhibiting unfavorable KELIM, for PFS (median: 9.1 v 5.6 months; HR, 0.64; 95% CI, 0.53 to 0.78), and for OS (median: 35.1 v 29.1 months; HR, 0.79; 95% CI, 0.65 to 0.97). CONCLUSION This GOG-0218 trial investigation validates ICON-7 findings about the association between poor tumor chemosensitivity and benefit from concurrent-maintenance bevacizumab, suggesting that bevacizumab may mainly be effective in patients with poorly chemosensitive disease. Bevacizumab may be prioritized in patients with a high-risk and poorly chemosensitive disease to improve their PFS/OS (patient KELIM score calculator available on the Biomarker Kinetics website).

5553 Background: In patients with high-grade ovarian cancer in first-line setting, predictive factors of bevacizumab efficacy are needed, for selecting patients. In ICON-7 trial, a poor tumor intrisic chemosensitivity (defined by unfavorable modeled CA-125 kinetic ELIMination rate constant KELIM) was a predictive biomarker. Among patients with high-risk diseases, only those with unfavorable KELIM had survival benefit from bevacizumab (mOS: 29.7 vs 20.6 months, HR = 0.78)(Colomban. JNCI CS 2020). The objective was to perform an external validation in GOG-0218 trial (NCT00262847). Methods: In GOG-0218, 1,873 patients were treated with carboplatin-paclitaxel +/- concurrent bevacizumab/placebo followed by a 15 month maintenance. Patient KELIM values were estimated with longitudinal CA-125 kinetics during the first 100 chemotherapy days. The association between KELIM score (categorized as favorable ≥ 1, or unfavorable < 1) and efficacy of bevacizumab (bevacizumab-concurrent + maintenance, vs placebo) for PFS and OS was assessed using univariate/multivariate analyses, in a Training set with 2/3 patients managed the investigators, and then a Validation set with all patients, managed by NGR-GOG. Results: KELIM was assessable in 1,662 patients with ≥ 3 CA-125 available values. In both sets, the patients with unfavorable KELIM derived benefit from bevacizumab compared to placebo (Training: PFS, HR = 0.65 [0.54-0.80]; OS, HR = 0.80 [0.65-0.99]; Validation: PFS, HR = 0.69 [0.59-0.82]; OS, HR = 0.87 [0.73-1.03]), whilst those with favorable KELIM had no benefit from bevacizumab (Training: PFS, HR = 0.96 [0.75-1.23]; OS, HR = 1.05 [0.80-1.37]; Validation, PFS, HR = 0.96 [0.79-1.17]; OS HR = 1.11 [0.89-1.84]). The highest benefit was observed in patients with high-risk diseases (stage IV or sub-optimally resected stage III) characterized by unfavorable KELIM, for PFS (Learning (n = 276): mPFS: 9.0 vs 5.2 months, HR = 0.61 [0.48-0.78]; Validation (n = 433): mPFS: 9.1 vs 5.6 months, HR = 0.64 [0.53-0.78]), and for OS (Learning (n = 278): mOS: 38.9 vs 27.9 months, HR = 0.72 [0.56-0.93], Validation set (n = 438): mOS: 35.1 vs 29.1 months, HR = 0.79 [0.65-0.97]). Conclusions: This validation analysis of GOG-0218 trial confirms the outcomes of ICON-7 trial about the association between poor tumor chemosensitivity and benefit from concurrent + maintenance bevacizumab, suggesting that bevacizumab is mainly effective in patients with poorly chemosensitive diseases. No benefit was found in patients with favorable KELIM. The patients who derived the highest benefit from bevacizumab in PFS and OS (OS absolute benefit ̃ 6 to 9 months) were those with high-risk diseases (stage IV, or incompletely resected stage III) associated with an unfavorable KELIM score (calculator on https://www.biomarker-kinetics.org/CA-125).