Irene Chong

Radiotherapy remains a cornerstone of cancer treatment, yet treatment response continues to be limited by tumour radioresistance and considerable biological heterogeneity. Although advances in radiation delivery have substantially improved dose conformity and reduced toxicity, increasing evidence suggests that optimising therapeutic outcomes will require greater integration of tumour biology into treatment strategies. This review examines emerging molecular approaches that seek to enhance anti-tumour responses to radiotherapy beyond direct tumour cell killing. We discuss the DNA damage response as a therapeutic target for radiosensitisation, highlighting the evolving role of DNA damage response inhibitors in promoting both tumour cytotoxicity and immune activation. We further examine the mechanisms linking radiation-induced DNA damage to anti-tumour immunity, including immunogenic cell death, cGAS–STING signalling, and remodelling of the tumour microenvironment, together with the opportunities and challenges of combining radiotherapy with immune checkpoint inhibition. Finally, we review emerging concepts in precision radiation oncology, including spatially tailored irradiation strategies, genomically informed radiation prescription, radiogenomics, and the influence of the gut microbiome on treatment response. Collectively, these advances support a shift from anatomically guided radiotherapy towards biologically personalised treatment, integrating molecular, immunological and genomic information with normal-tissue susceptibility to improve the therapeutic ratio and enable more precise, patient-centred cancer care.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related mortality. Radiological distinctions between borderline resectable (BR) and locally advanced disease (LA) are increasingly recognised as imperfect when considered without dynamic assessment. Neoadjuvant therapy (NAT) improves outcomes through tumour downstaging and early treatment of occult metastatic disease, but the optimal NAT strategy, particularly in BR disease, remains uncertain. Published data evaluating combined systemic anti-cancer therapies (SACT) with or without chemoradiation (CRT) are limited and heterogeneous. Methods: This is a single-centre retrospective analysis of 44 patients with BR PDAC and a comparator cohort of 121 patients with LA PDAC treated with a total neoadjuvant approach of SACT with or without CRT and surgical resection between June 2017 and September 2022. Results: Median overall survival (OS) did not differ significantly between BR and LA disease (18 vs. 16 months, p = 0.14). Following NAT, 47.7% of BR and 18.1% of LA patients were anatomically suitable for surgical resection. Among unresected BR and LA patients, those treated with CRT in addition to SACT had a median OS of 18 and 21 months respectively. In the resected subgroup, resection margin status was the primary factor associated with survival; with R0 resection conferring a substantial OS advantage over R1, irrespective of initial BR/LA classification as diagnosis (47 vs. 22 months, p < 0.001). Conclusions: Despite anatomical differences at diagnosis, BR and LA PDAC demonstrated comparable survival outcomes when treated with total neoadjuvant strategies in this cohort. These findings challenge traditional radiological staging-based treatment paradigms and confirm that a margin-negative surgical resection offered the greatest opportunity for long-term survival for BR/LA PDAC patients.

Colorectal cancer (CRC) develops through evolutionary processes involving genomic alterations, epigenetic regulation, and microenvironmental interactions. While traditionally explained by the stepwise accumulation of driver mutations, contemporary evidence supports a ‘Big Bang’ model in which many early-arising clones expand simultaneously to establish extensive heterogeneity. We reviewed recent studies employing spatially resolved multi-omic sequencing of tumour glands combined with computational modelling. These approaches enable high-resolution reconstruction of clonal architecture, transcriptional states, and chromatin accessibility. Findings show that although early clonal mutations shape tumour expansion, gene expression variability can be independent of genetic ancestry and instead reflects phenotypic plasticity driven by microenvironmental cues. Epigenomic analyses identified recurrent somatic chromatin accessibility alterations in promotors and enhancers of oncogenic pathways, frequently in the absence of DNA mutations, suggesting alternative mechanisms of gene regulation. Immune-focused studies demonstrated that early silencing of antigen-presenting genes and loss of neoantigens facilitate immune escape despite active surveillance. CRC is shaped by an interplay of genome, epigenome, and immune evolution, with non-genetic mechanisms and tumour plasticity emerging as important drivers of progression and therapeutic resistance.

Background/Objectives: Women carry two-thirds of the global anal cancer burden. Persistent genital (vulval, vaginal and cervical) high-risk Human Papillomavirus (hrHPV) infection and the resultant genital high-grade squamous intraepithelial lesions (HSILs) and genital cancers are now acknowledged as independent risk factor for anal dysplasia in women. Patients with both genital and anal hrHPV-related diseases, however, are poorly researched. Methods: National Cancer Registration and Analysis Service (NCRAS) data was requested via the NHS Digital data access request service (DARS). Women in England over the age of 25 years diagnosed with anal HSIL/cancer between 2001 and 2020 who also had a vulval and/or vaginal and/or cervical cancer HSIL/cancer diagnosis within the 20-year period before or 1-year period after their anal cancer/HSIL were studied. The burden of genital disease in women with anal cancer, their sociodemographic risk factors and timelines between acquisition of genital and anal pathology were assessed. Results: A total of 8% (n = 1297/16,301) of all women with anal HSIL/cancer also had metachronous or synchronous genital HSIL/cancer diagnoses. Women who were first diagnosed with cervical HSIL had a lower burden of recurrent anogenital lesions over time (p = 0.04) but a significantly higher risk of presenting with late-stage anal cancer than women first presenting with vulval pathology (p = 0.02). Women who had disease in more than one anatomical site developed disease features 10–20 years earlier compared to other published datasets on women with single site disease. Conclusions: These findings support the current IANS screening recommendation guidelines and suggest that the current anal cancer risk for women with cervical dysplasia may be underestimated.

Colorectal cancer (CRC) is a major cause of cancer mortality worldwide, with metastatic disease remaining the main driver of poor prognosis. In recent years, the concept of oligometastatic disease, where patients present with a limited number of metastases, has created an opportunity to use local therapies with curative intent. Stereotactic ablative radiotherapy (SABR) has become increasingly important in this setting, as it allows the delivery of high, ablative doses with excellent local control and generally low toxicity. Notably, randomised data such as SABR-COMET, alongside large prospective series including SABR-5, have demonstrated improvements in survival outcomes in the context of oligometastatic disease across mixed primary tumour types, with CRC patients making up a relatively small proportion in these trials. This has presented SABR as a practical treatment option for patients with oligometastatic CRC, although more CRC-specific phase III trials are needed. Other challenges include the radioresistance of CRC metastases, and treatment outcomes that vary depending on the anatomical site, tumour biology, and prior therapies. Technical issues such as motion management and organ-at-risk constraints also continue to limit dose escalation. Emerging strategies—including MR-guided radiotherapy, proton-based SABR, integration with systemic agents such as immunotherapy, and the use of biomarkers and artificial intelligence to refine patient selection—are beginning to address these limitations. This review summarises the current evidence and emerging advancements to highlight how SABR may evolve as part of an integrated approach to oligometastatic CRC.

Our study evaluated whether an MRI reporting system highlighting areas of contiguous and discontinuous extramural venous invasion (EMVI) can improve the accuracy of gross tumour volume (GTV) delineation. Initially, 27 consecutive patients with locally advanced rectal cancer treated between 2012 and 2014 were evaluated. We used an MRI reporting proforma that documented the position of the primary tumour, lymph nodes and EMVI. The new GTVs delineated were compared with historical radiotherapy treatment volumes to identify the frequency of GTV geographical miss. We observed that the delineation of involved nodes and areas of EMVI was more likely to represent sources of uncertainty wherein nodal GTV geographical miss was evident in 5 out of 27 patients (19%). Complete EMVI GTV geographical miss occurred in two patients (7%). We re-evaluated our radiotherapy practice in a further 27 patients after the implementation of a modified MRI reporting system. An improvement was seen; nodal miss was observed in two patients (7%) and partial EMVI miss in one patient (4%), although these areas were encompassed in the planning target volume (PTV). Our study shows that extramural venous invasion and involved nodes need to be highlighted on MRI to improve the accuracy of rectal cancer GTV delineation.