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Despite therapeutic advancements, disease-free survival and overall survival of patients with locally advanced rectal cancer have not improved in most trials as a result of distant metastases. For treatment decision-making, both long-term oncologic outcomes and impact on quality-of-life indices should be considered (for example, bowel function). Total neoadjuvant therapy (TNT), comprised of chemotherapy and radiotherapy or chemoradiotherapy, is now a standard treatment approach in patients with features of high-risk disease to prevent local recurrence and distant metastases. In selected patients who have a clinical complete response, subsequent surgery might be avoided through non-operative management, but patients who do not respond to TNT have a poor prognosis. Refined molecular characterization might help to predict which patients would benefit from TNT and non-operative management. Specifically, integrated analysis of spatiotemporal multi-omics using artificial intelligence and machine learning is promising. Three prospective trials of TNT and non-operative management in Japan, the USA and Germany are collaborating to better understand drivers of response to TNT. Here, we address the future direction for TNT. In this article, the authors discuss the use of total neoadjuvant therapy for locally advanced rectal cancer. They highlight ongoing trials and discuss future treatment options, including the potential use of multi-omics and artificial intelligence to facilitate treatment selection and prediction of response.

Tumour hypoxia renders cancer cells resistant to cancer therapy, resulting in markedly worse clinical outcomes. To find clinical candidate compounds that reduce hypoxia in tumours, we conduct a high-throughput screen for oxygen consumption rate (OCR) reduction and identify a number of drugs with this property. For this study we focus on the anti-malarial, atovaquone. Atovaquone rapidly decreases the OCR by more than 80% in a wide range of cancer cell lines at pharmacological concentrations. In addition, atovaquone eradicates hypoxia in FaDu, HCT116 and H1299 spheroids. Similarly, it reduces hypoxia in FaDu and HCT116 xenografts in nude mice, and causes a significant tumour growth delay when combined with radiation. Atovaquone is a ubiquinone analogue, and decreases the OCR by inhibiting mitochondrial complex III. We are now undertaking clinical studies to assess whether atovaquone reduces tumour hypoxia in patients, thereby increasing the efficacy of radiotherapy. Tumour hypoxia reduces the efficacy of radiotherapy. Starting from a drug screen, here the authors demonstrate that the anti-malarial, atovaquone, reduces the oxygen consumption rate of cancer cells by inhibition of mitochondrial complex III and sensitises to radiotherapy by reducing tumour hypoxia.

There is a large variability regarding the definition and choice of primary endpoints in phase 2 and phase 3 multimodal rectal cancer trials, resulting in inconsistency and difficulty of data interpretation. Also, surrogate properties of early and intermediate endpoints have not been systematically assessed. We provide a comprehensive review of clinical and surrogate endpoints used in trials for non-metastatic rectal cancer. The applicability, advantages, and disadvantages of these endpoints are summarised, with recommendations on clinical endpoints for the different phase trials, including limited surgery or non-operative management for organ preservation. We discuss how early and intermediate endpoints, including patient-reported outcomes and involvement of patients in decision making, can be used to guide trial design and facilitate consistency in reporting trial results in rectal cancer.

Despite recent advances in the treatment of colorectal cancer (CRC), patient’s individual response and clinical follow-up vary considerably with tumor intrinsic factors to contribute to an enhanced malignancy and therapy resistance. Among these markers, upregulation of members of the inhibitor of apoptosis protein (IAP) family effects on tumorigenesis and radiation- and chemo-resistance by multiple pathways, covering a hampered induction of apoptosis/autophagy, regulation of cell cycle progression and DNA damage response. These mechanisms are tightly controlled by the tumor suppressor p53 and thus transcriptional and post-translational regulation of IAPs by p53 is expected to occur in malignant cells. By this, cellular IAP1/2, X-linked IAP, Survivin, BRUCE and LIVIN expression/activity, as well as their intracellular localization is controlled by p53 in a direct or indirect manner via modulating a multitude of mechanisms. These cover, among others, transcriptional repression and the signal transducer and activator of transcription (STAT)3 pathway. In addition, p53 mutations contribute to deregulated IAP expression and resistance to therapy. This review aims at highlighting the mechanistic and clinical importance of IAP regulation by p53 in CRC and describing potential therapeutic strategies based on this interrelationship.

Background: MicroRNAs (miRs) are involved in the regulation of many processes that contribute to malignancy, including cell proliferation, radiation resistance, invasion and metastasis. The role of miR-330-3p, an miR upregulated in breast cancer, remains unclear. Methods: We examine the association of miR-330-3p with distant relapse-free survival in the Oxford cohort of breast cancer patients. We also study miR-330-3p function using in vitro invasion and ex ovo metastasis assays. Using in vitro luciferase assays, we validate a novel target gene for miR-330-3p, Collagen And Calcium Binding EGF Domains 1 (CCBE1). We assess functional consequences of CCBE1 loss by using siRNA-mediated knockdown followed by in vitro invasion assays. Lastly, we examine the expression profile of CCBE1 in breast carcinomas in the Curtis and TCGA Breast Cancer data sets using Oncomine Platform as well as distant relapse-free and overall survival of patients in the Helsinki University breast cancer data set according to CCBE1 expression status. Results: miR-330-3p is enriched in breast cancer, and higher levels of miR-330-3p expression are associated with lower distant relapse-free survival in a cohort of breast cancer patients. Consistent with these observations, overexpression of miR-330-3p in breast cancer cell lines results in greater invasiveness in vitro , and miR-330-3p-overexpressing cells also metastasise more aggressively ex ovo . We identify CCBE1 as a direct target of miR-330-3p, and show that knockdown of CCBE1 results in a greater invasive capacity. Accordingly, in breast cancer patients CCBE1 is frequently downregulated, and its loss is associated with reduced distant relapse-free and overall survival. Conclusions: We show for the first time that miR-330-3p targets CCBE1 to promote invasion and metastasis. miR-330-3p and CCBE1 may represent promising biomarkers in breast cancer.

In locally advanced rectal cancer (LARC) neoadjuvant chemoradiotherapy is regarded as standard treatment. We assessed acute toxicities in patients receiving conventional 3D-conformal radiotherapy (3D-RT) and correlated them with dosimetric parameters after re-planning with volumetric modulated arc therapy (VMAT). Patients were randomized within the multicenter CAO/ARO/AIO-12 trial and received 50.4 Gy in 28 fractions and simultaneous chemotherapy with fluorouracil and oxaliplatin. Organs at risk (OAR) were contoured in a standardized approach. Acute toxicities and dose volume histogram parameters of 3D-RT plans were compared to retrospectively calculated VMAT plans. From 08/2015 to 01/2018, 35 patients with LARC were treated at one study center. Thirty-four patients were analyzed of whom 1 (3%) was UICC stage II and 33 (97%) patients were UICC stage III. Grade 3 acute toxicities occurred in 5 patients (15%). Patients with acute grade 1 cystitis (n = 9) had significantly higher D mean values for bladder (29.4 Gy vs. 25.2 Gy, p < 0.01) compared to patients without bladder toxicities. Acute diarrhea was associated with small bowel volume (grade 2: 870.1 ccm vs. grade 0–1: 647.3 ccm; p < 0.01) and with the irradiated volumes V5 to V50. Using VMAT planning, we could reduce mean doses and irradiated volumes for all OAR: D mean bladder (21.9 Gy vs. 26.3 Gy, p < 0.01), small bowel volumes V5–V45 (p < 0.01), D mean anal sphincter (34.6 Gy vs. 35.6 Gy, p < 0.01) and D mean femoral heads (right 11.4 Gy vs. 25.9 Gy, left 12.5 Gy vs. 26.6 Gy, p < 0.01). Acute small bowel and bladder toxicities were dose and volume dependent. Dose and volume sparing for all OAR could be achieved through VMAT planning and might result in less acute toxicities.

PurposeAs the population ages, the incidence of rectal cancer among elderly patients is rising. Due to the risk of perioperative morbidity and mortality, alternative nonoperative treatment options have been explored in elderly and frail patients who are clinically inoperable or refuse surgery.MethodsHere we present technical considerations and first clinical experience after treating a cohort of six rectal cancer patients (T1‑3, N0‑1, M0; UICC stage I-IIIB) with definitive external-beam radiation therapy (EBRT) followed by image-guided, endorectal high-dose-rate brachytherapy (HDR-BT). Patients were treated with 10–13 × 3 Gy EBRT followed by HDR-BT delivering 12–18 Gy in two or three fractions. Tumor response was evaluated using endoscopy and magnetic resonance imaging of the pelvis.ResultsMedian age was 84 years. All patients completed EBRT and HDR-BT without any high-grade toxicity (> grade 2). One patient experienced rectal bleeding (grade 2) after 10 weeks. Four patients (67%) demonstrated clinical complete response (cCR) or near cCR, there was one partial response, and one residual tumor and hepatic metastasis 8 weeks after HDR-BT. The median follow-up time for all six patients is 42 weeks (range 8–60 weeks). Sustained cCR without evidence of local regrowth has been achieved in all four patients with initial (n)cCR to date.ConclusionPrimary EBRT combined with HDR-BT is feasible and well tolerated with promising response rates in elderly and frail rectal cancer patients. The concept could be an integral part of a highly individualized and selective nonoperative treatment offered to patients who are not suitable for or refuse surgery.

Peripheral blood leukocytosis has been implicated in promoting tumor progression leading to worse survival, but the mechanisms behind this phenomenon remain unexplored. Here, we examined the prognostic role of pretreatment white blood cell (WBC) count and clinicopathologic parameters in the context of CD8+ tumor-infiltrating lymphocytes (TIL) and myeloperoxidase+ tumor-associated neutrophils (TANs) in patients with anal squamous cell carcinoma (ASCC) treated with definitive chemoradiotherapy (CRT). After a median follow-up of 26 months, leukocytosis correlated with advanced T-stage (  < 0.001) and N-stage (  < 0.001), and predicted for worse distant-metastasis-free survival (  = 0.006), disease-free-survival (DFS,  = 0.029), and overall survival (  = 0.013). Importantly, leukocytosis was associated with a lower intraepithelial CD8+ TIL density (  = 0.014), whereas low CD8+ TIL expression in the intraepithelial compartment was associated with worse DFS (  = 0.028). Additionally, high TAN expression in the peritumoral compartment was associated with a significantly lower density of CD8+ TIL (  = 0.039), albeit, TAN expression lacked prognostic value. In conclusion, leukocytosis constitutes an important prognostic marker in ASCC patients treated with CRT. In conjunction with intratumoral TIL and TAN, these data provide for the first time important insight on the correlation of peripheral blood leukocytosis with the intratumoral immune contexture and could be relevant for future patient stratification using immunotherapies in ASCC.

Introduction Locoregional recurrence (LR) is common in locally advanced head and neck cancer (HNSCC), posing challenges for treatment. We analysed outcome parameters and toxicities for patients being treated with radiotherapy (RT) for LR-HNSCC and investigated patient and disease related prognostic factors in this prognostically unfavourable group. Methods This analysis includes 101 LR-HNSCC patients treated with RT, radio-chemotherapy (RCT) or radio-immunotherapy (RIT) between 2010 and 2018 at a high-volume tertiary centre. Patient characteristics, tumour and treatment details were retrospectively collected. Overall survival (OS), progression-free survival (PFS) and toxicities according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0 were assessed. Results 62% of patients were radiotherapy-naïve (initial RT group) while 38% were re-irradiated at site of LR (re-RT group). Median OS for initial RT was 24 months, for re-RT 12 months ( p <  0.01). In the RCT subgroup, patients with initial RT had significantly longer OS with 35 months compared to re-RT 12 months ( p <  0.05). Patients with UICC grade IV tumours and percutaneous endoscopic gastrostomy (PEG) tube had significantly shorter OS in multivariate analysis: initial RT 13 vs. re-RT 32 months and initial RT 12 vs. re-RT 32 months respectively. Salvage surgery before RT at recurrence was a positive prognostic factor for OS (initial RT 35 vs. re-RT 12 months). Other significant factors for longer OS in univariate analysis included low inflammatory status (Glasgow Prognostic Score 0) and radiation doses ≥ 50 Gy. We detected 37 (15%) ≥ CTCAE Grade 3 events for initial RT and 19 (15%) for re-RT patients. Conclusion In this analysis, we identified key prognostic factors including PEG tube and inflammation status that could guide treatment decision. Our findings suggest salvage surgery as preferred treatment option with postoperative RT at LR. Adverse events due to re-RT were acceptable. A radiation dose of ≥ 50 Gy should be administered to achieve better outcomes.

Despite the implementation of consolidative immune checkpoint inhibition after definitive chemoradiotherapy (CRT), the prognosis for locally advanced non-small-cell lung cancer (NSCLC) remains poor. We assessed the impact of the C-reactive protein (CRP) to albumin ratio (CAR) as an inflammation-based prognostic score in patients with locally advanced NSCLC treated with CRT. We retrospectively identified and analyzed 52 patients with primary unresectable NSCLC (UICC Stage III) treated with definitive/neoadjuvant CRT between 2014 and 2019. CAR was calculated by dividing baseline CRP by baseline albumin levels and correlated with clinicopathologic parameters to evaluate prognostic impact. After dichotomizing patients by the median, univariate and multivariate Cox regression analyses were performed. An increased CAR was associated with advanced T-stage (p = 0.018) and poor performance status (p = 0.004). Patients with pre-therapeutic elevated CAR had significantly lower hemoglobin and higher leukocyte levels (hemoglobin p = 0.001, leukocytes p = 0.018). High baseline CAR was shown to be associated with worse local control (LPFS, p = 0.006), shorter progression-free survival (PFS, p = 0.038) and overall survival (OS, p = 0.022), but not distant metastasis-free survival (DMFS). Multivariate analysis confirmed an impaired outcome in patients with high CAR (LPFS: HR 3.562, 95% CI 1.294–9.802, p = 0.011). CAR is an easily available and independent prognostic marker after CRT in locally advanced NSCLC. CAR may be a useful biomarker for patient stratification to individualize treatment concepts.