PURPOSE: Alkylating agents (ALKY) are the main chemotherapies used for advanced neuroendocrine tumors (NETs). O ⁶ -Methylguanine-DNA methyltransferase (MGMT) status, as proficient (p) or deficient (d), may predict the response to ALKY. PATIENTS AND METHODS: MGMT-NET (ClinicalTrials.gov identifier: NCT03217097 ) was a phase II trial randomly assigning 1:1 for pMGMT or 2:1 for dMGMT-NETs to either ALKY or oxaliplatin (Ox). Inclusion criteria were a confirmed advanced pancreatic, thoracic, or unknown primary NETs with an indication for chemotherapy and tissue available. The primary aim was to detect a difference of 35% between the 3-month objective response rate (ORR) in pMGMT-NETs versus in dMGMT-NETs when treated with ALKY. A biomarker-stratified design was performed to compare ALKY and Ox in the dMGMT and pMGMT strata for the secondary end points. dMGMT was defined using pyrosequencing (PSQ; methylated MGMT ≥9%) and using immunochemistry ( H -score of MGMT <50) when PSQ was not interpretable. RESULTS: From October 2018 to October 2021, 105 patients (55 pancreas, 38 thorax, 12 unknown) started either ALKY (n = 62) or Ox (n = 43). The median age was 63 years (range, 30-84), and 59% were males. NETs were G1 (19%), G2 (69%), or G3 (10%). Among patients with interpretable MGMT status, 56.9% (58 of 102) had a dMGMT-NET. The primary end point was not reached; the 3-month ORR was 10 (29.4%) versus 2 (8%), and the odds ratio was 3.5 (0.58-21.16), P = .172. However, best ORR (18 [52.9%] v 3 [11.5%]) and median progression-free survival (14.6 [95% CI, 7.2 to 22.1] v 11.3 [9.4 to 13.2] months) were higher for dMGMT-NETs versus pMGMT-NETs. MGMT status does not seem to affect the Ox efficacy. CONCLUSION: Despite the fact that the primary end point was not reached, ALKY has clinical activity in patients with dMGMT-NETs.

Extra-pulmonary neuroendocrine carcinomas (EP-NECs) are lethal cancers with limited treatment options. Identification of contributing factors to the observed heterogeneity of clinical outcomes within the EP-NEC family is warranted, to enable identification of effective treatments. A multicentre retrospective study investigated potential differences in “real-world” treatment/survival outcomes between small-cell (SC) versus (vs.) non-SC EP-NECs. One-hundred and seventy patients were included: 77 (45.3%) had SC EP-NECs and 93 (54.7%) had non-SC EP-NECs. Compared to the SC subgroup, the non-SC subgroup had the following features: (1) a lower mean Ki-67 index (69.3% vs. 78.7%; p = 0.002); (2) a lower proportion of cases with a Ki-67 index of ≥55% (73.9% vs. 88.7%; p = 0.025); (3) reduced sensitivity to first-line platinum/etoposide (objective response rate: 31.6% vs. 55.1%, p = 0.015; and disease control rate; 59.7% vs. 79.6%, p = 0.027); (4) worse progression-free survival (PFS) (adjusted-HR = 1.615, p = 0.016) and overall survival (OS) (adjusted-HR = 1.640, p = 0.015) in the advanced setting. Within the advanced EP-NEC cohort, subgroups according to morphological subtype and Ki-67 index (<55% vs. ≥55%) had significantly different PFS (adjusted-p = 0.021) and OS (adjusted-p = 0.051), with the non-SC subgroup with a Ki-67 index of <55% and non-SC subgroup with a Ki-67 index of ≥55% showing the best and worst outcomes, respectively. To conclude, the morphological subtype of EP-NEC provides complementary information to the Ki-67 index and may aid identification of patients who could benefit from alternative first-line treatment strategies to platinum/etoposide.

Biliary tract cancers (BTCs) are rare, heterogeneous tumors associated with a poor prognosis, even after curative-intent surgery. Adjuvant capecitabine is currently the standard of care; however, real-world data on its efficacy and tolerance are lacking. This French, retrospective, multicentre study, nested within the ACABi-PRONOBIL observational cohort, assessed adjuvant capecitabine efficacy in patients, with resected intrahepatic, perihilar, distal cholangiocarcinoma, or gallbladder carcinoma. who had not received prior systemic therapy. Patients treated with adjuvant capecitabine after 2017 were compared with patients diagnosed before 2017 and managed with surveillance only. The primary endpoint was overall survival (OS), secondary endpoints were recurrence-free survival (RFS) and toxicity. Inverse probability of treatment weighting (IPTW) in Cox regressions was used to adjust for measured confounding, imbalanced factors between groups. A total of 320 patients were included (197 in the capecitabine group and 123 in the surveillance group). In IPTW analysis, adjuvant capecitabine was not significantly associated with improved RFS (IPTW HR, 0.81, CI 95%, 0.54-1.21; p = 0.304), or OS (IPTW HR, 0.94, CI 95%, 0.58-1.52; p = 0.798). The point estimate for RFS was consistent with the ITT analysis of the BILCAP trial. In the capecitabine group, 49% of patients required at least one dose reduction, and 35.7% discontinued treatment due to mainly grade 3/4 gastrointestinal (13.4%) and cutaneous (25.8%) toxicities. In this real-world cohort, adjuvant capecitabine was not significantly associated with improved RFS or OS in patients undergoing curative-intent resection for BTC, although a numerical trend in favor of capecitabine for RFS. These findings support the need for refined patient selection strategies and for prospective evaluation of novel adjuvant approaches. NCT04935853 IMPACT AND IMPLICATIONS: This multicentre real-world study - BILCAP real study provides important complementary evidence to randomized trials by evaluating the effectiveness and tolerability of adjuvant capecitabine for resected biliary tract cancers in routine clinical practice.Although no statistically significant survival benefit was observed, the consistency of the recurrence-free survival estimate with the intention-to-treat results of the BILCAP trial and the observed toxicity profile provide clinically relevant information for physicians, patients, and multidisciplinary teams involved in postoperative treatment decisions.These findings support shared decision-making by helping clinicians balance the potential benefit of delaying recurrence against the risk of treatment-related toxicity, while emphasizing the need for careful patient selection and toxicity management in daily practice.Given the retrospective design and the possibility of residual confounding despite propensity-score adjustment, these results should be interpreted cautiously and primarily serve to inform the design of future biomarker-driven and prospective adjuvant studies rather than to change current clinical practice.

The use of automated injectors for the administration of radiopharmaceuticals limits staff exposure and optimises the dose administered to patients, but many of these devices are only validated for a limited number of radiopharmaceuticals. The objectives of this study were to investigate the physicochemical phenomena occurring during the manipulation of fluorinated radiopharmaceuticals when in contact with injector tubings and to quantify and qualify the interactions between the radiopharmaceuticals and the tubing materials. For six of the radiopharmaceuticals tested, the measured doses reached 97.64 ± 0.24% of the programmed dose. These results indicate an absence of sorption phenomena and validate their use on the injector. In contrast, the three most lipophilic molecules caused the injector to malfunction, resulting in significant residual activity in the tubing of up to 67%. These results were confirmed by activimeter measurements and positron emission tomography images. from electronic microscopy results showed an alteration of the inner surface of the tubings that came into contact with lipophilic radiopharmaceuticals; however, this modification did not drastically alter the surface Zeta potential. Infrared spectroscopy confirmed the composition of the tubings as being plasticized polyvinyl chloride (PVCp), and plasticizer identification and quantification showed the presence of di-(2-ethylhexyl) adipate (reaching 37.5%) and di-(2-ethylhexyl) phthalate (more than 20%). A clear improvement was observed when co-extruded polyethylene / PVPp tubings were used. Unlike lipophilic radiopharmaceuticals, which exhibit sorption behaviour dependent on the presence of plasticizers, the tested hydrophilic radiopharmaceuticals demonstrated minimal interaction with PVCp tubing and can be reliably administered using the automated injector.