Introduction The modern management of locally advanced rectal cancer (LARC) involves sequential radiotherapy and chemotherapy, termed Total Neoadjuvant Therapy (TNT). Although TNT significantly improves tumour regression and achieves complete response rates of approximately 30 %, treatment efficacy remains limited in part by tumour-intrinsic resistance to apoptosis. We therefore sought to investigate the effects of radiotherapy on TNFα-associated apoptotic signalling in rectal cancer and evaluate whether inhibition of Inhibitor of Apoptosis Proteins (IAPs) could enhance treatment response. Methods Transcriptomic profiling was performed on rectal tumour biopsies obtained before and after two weeks of neoadjuvant radiotherapy (n = 42). Gene Set Enrichment Analysis was used to identify pathways altered following radiotherapy. The clinically relevant IAP antagonist, tolinapant, was evaluated in rectal cancer models to assess effects on cIAP1/2 degradation, radiation- and chemotherapy-induced apoptosis, and formation of 5-fluorouracil (5FU)-induced drug-tolerant persister (DTP) cells. Mechanistic studies were performed in the presence of TNFα, and in vivo efficacy was assessed in SW837 xenograft models. Results Radiotherapy induced robust upregulation of TNFα/TNFR1 signalling and apoptosis-associated gene sets. Gene Set Enrichment Analysis confirmed enrichment of both “TNFα signalling via NFκB” and “Apoptosis” pathways. Upregulation of TNF, TNFRSF1A, RIPK1, TRADD, and CFLAR (FLIP) was observed alongside downregulation of DIABLO, suggesting that radiotherapy primes tumours for TNFα-mediated apoptosis but that elevated antiapoptotic signalling may suppress this response. Tolinapant degraded cIAP1/2 and significantly enhanced radiation-induced apoptosis in rectal cancer models. Co-treatment with TNFα further amplified apoptosis through a caspase-8-dependent mechanism. The combination of tolinapant and radiation was well-tolerated in vivo and reduced SW837 xenograft tumour volume compared to radiation alone; however, this difference did not meet statistical significance. Tolinapant also potentiated chemotherapy-induced apoptosis and prevented the emergence of 5FU-induced DTP rectal cancer cells. Conclusion These findings identify TNFα-associated apoptotic signalling as a potential radiation-induced vulnerability in rectal cancer and provide a mechanistic rationale for combining radiotherapy with IAP antagonists. Tolinapant also enhanced apoptosis induced by chemotherapy whilst suppressing drug-tolerant persisters, supporting further investigation of IAP antagonism as a strategy to improve TNT efficacy in the neoadjuvant management of rectal cancer.
Purpose Quality assurance (QA) of auto-segmentations is necessary for safe clinical deployment. Deep learning models are optimised for data similar to their training set, but reliability drops with out-of-distribution (OOD) inputs. This study evaluates whether uncertainty quantification (UQ) can detect OOD inputs arising from distribution shift in head and neck organ of interest (OOI) auto-segmentation. Materials and methods Monte Carlo dropout-based uncertainty scores and geometric accuracy of nnU-Net models were evaluated in two experiments. First, as a proof-of-concept, we assessed whether uncertainty scores detect metal artefact (N = 10) from non-artefact cases (N = 10) on a baseline model (mixed training data, N = 620) and a no-metal model (artefact-free training data, N = 620). Second, in a clinically realistic experiment, we split a fine-tuning dataset by uncertainty score to obtain a narrow model (low-uncertainty cases, N = 21) and a broad model (high-uncertainty cases, N = 21). A held-out test set (N = 76) evaluated whether segmentation accuracy differed between uncertainty categories. Results Both experiments showed that uncertainty scores reflect the learned training distribution. In the supervised experiment, the no-metal model demonstrated greater uncertainty score separation between artefact and non-artefact cases (1.1 × 105 vs 0.6 × 105) than the baseline model (1.1 × 105 vs 0.8 × 105). In the unsupervised experiment, the narrow model performed significantly better on certain than uncertain cases (p = 0.04), while no difference was seen for the broad model (p = 0.34), which did include these cases in training. Conclusions Uncertainty quantification can detect distribution shifts in radiotherapy auto-segmentation. This could support automated QA workflows by identifying in-distribution cases and enabling the application of specialised models.
Purpose To evaluate the efficacy and safety of carbon ion radiotherapy (CIRT) in patients with non-metastatic, inoperable pancreatic cancer in a prospective phase 2 setting. Methods In this single-center investigator-initiated phase 2 trial, 25 patients with locally advanced or locally recurrent pancreatic cancer were included. CIRT was performed using an intensity-controlled rasterscanning system for beam application [total dose: 48 Gy (RBE), 12 fractions]. Concurrent chemotherapy with Gemcitabine 300 mg/m2 was administered weekly. The primary endpoint was the 1-year OS rate, defined as time from study inclusion. 1y- and 2y-OS and −PFS were calculated using the Kaplan-Meier method, 95 % confidence intervals are shown. Toxicity was evaluated using CTCAEv5.0. Results Twenty-three patients were included in the final analysis. After the completed 12-month follow-up of the last patient, the 1- and 2-year OS rates were 78 % [CI 63 %; 97 %] and 59 % [CI 41 %; 84 %]. The median OS was 26.5 months. The 1- and 2-year PFS rates were 26 % [CI 13 %; 52 %] and 10 % [CI 3 %; 37 %] with a median PFS of 8.1 months. Study treatment was well tolerated with three treatment-related CTCAE grade 3 toxicities, including one case of abdominal pain, one upper gastrointestinal hemorrhage and one ureteric stricture. No treatment-related CTCAE grade 4–5 toxicities were observed. Conclusion Chemoradiation with carbon ions demonstrated encouraging overall survival and acceptable toxicity in non-metastatic pancreatic cancer patients. A subsequent randomized Phase 3 trial should investigate OS superiority of CIRT compared to conventional chemoradiotherapy or chemotherapy.
