Cancer Stem Cell Biomarkers Predictive of Radiotherapy Response in Rectal Cancer: A Systematic Review

Background: Rectal cancer (RC) is one of the most commonly diagnosed and particularly challenging tumours to treat due to its location in the pelvis and close proximity to critical genitourinary organs. Radiotherapy (RT) is recognised as a key component of therapeutic strategy to treat RC, promoting the downsizing and downstaging of large RCs in neoadjuvant settings, although its therapeutic effect is limited due to radioresistance. Evidence from experimental and clinical studies indicates that the likelihood of achieving local tumour control by RT depends on the complete eradication of cancer stem cells (CSC), a minority subset of tumour cells with stemness properties. Methods: A systematic literature review was conducted by querying two scientific databases (Pubmed and Scopus). The search was restricted to papers published from 2009 to 2021. Results: After assessing the quality and the risk of bias, a total of 11 studies were selected as they mainly focused on biomarkers predictive of RT-response in CSCs isolated from patients affected by RC. Specifically these studies showed that elevated levels of CD133, CD44, ALDH1, Lgr5 and G9a are associated with RT-resistance and poor prognosis. Conclusions: This review aimed to provide an overview of the current scenario of in vitro and in vivo studies evaluating the biomarkers predictive of RT-response in CSCs derived from RC patients.

High Rates of Treatment Stage Migration For Early Hepatocellular Carcinoma and Its Association With Adverse Impact On Outcomes: A Multicenter Study

Background & Aims:The rate of contraindications to percutaneous ablation (PA) for inoperable early HCC, and subsequent outcomes is not well described. We investigated the prevalence and outcomes of inoperable early HCC patients with contraindications to PA, resulting in treatment stage migration (TSM). Methods:BCLC 0/A patients diagnosed between September 2013 and September 2019 across five hospitals were identified. Primary endpoint was proportion of BCLC 0/A HCCs with contraindications to PA. Secondary endpoints included overall survival (OS), local tumour control (LTC) and recurrence-free survival (RFS). The causal effects of PA versus TSM were assessed using a potential outcome means (POM) framework in which the average treatment effects (ATE) of PA were estimated after accounting for potential selection bias and confounding.Results:245 patients with inoperable BCLC 0/A HCC were identified. 140 (57%) had contraindications to PA and received TSM therapy, 105 (43%) received PA. The main contraindication to PA was difficult tumour location (47%). Patients who received TSM therapy had lower median OS (2.1 versus 5.3years), LTC (1.0 versus 4.8years), and RFS (0.8 versus 2.7years); p<0.001 respectively, compared to PA. The ATE for PA versus TSM yielded an additional 1.02years (p=0.048), 2.87years (p<0.001) and 1.77years (p<0.001) for OS, LTC and RFS respectively. 3-year LTC after PA was suboptimal (63%).Conclusions:Our study highlights high rates of contraindication to PA in early HCCs, resulting in TSM and poorer outcomes. The local recurrence rate after PA was also high. Both findings support exploration of alternative ablative options for early HCCs.

Role of Hyperbaric Oxygenation Plus Hypofractionated Stereotactic Radiotherapy in Recurrent High-Grade Glioma

BackgroundThe presence of hypoxic cells in high-grade glioma (HGG) is one of major reasons for failure of local tumour control with radiotherapy (RT). The use of hyperbaric oxygen therapy (HBO) could help to overcome the problem of oxygen deficiency in poorly oxygenated regions of the tumour. We propose an innovative approach to improve the efficacy of hypofractionated stereotactic radiotherapy (HSRT) after HBO (HBO-RT) for the treatment of recurrent HGG (rHGG) and herein report the results of an ad interim analysis.MethodsWe enrolled a preliminary cohort of 9 adult patients (aged &gt;18 years) with a diagnosis of rHGG. HSRT was administered in daily 5-Gy fractions for 3-5 consecutive days a week. Each fraction was delivered up to maximum of 60 minutes after HBO.ResultsMedian follow-up from re-irradiation was 11.6 months (range: 3.2-11.6 months). The disease control rate (DCR) 3 months after HBO-RT was 55.5% (5 patients). Median progression-free survival (mPFS) for all patients was 5.2 months (95%CI: 1.34-NE), while 3-month and 6-month PFS was 55.5% (95%CI: 20.4-80.4) and 27.7% (95%CI: 4.4-59.1), respectively. Median overall survival (mOS) of HBO-RT was 10.7 months (95% CI: 7.7-NE). No acute or late neurologic toxicity &gt;grade (G)2 was observed in 88.88% of patients. One patient developed G3 radionecrosis.ConclusionsHSRT delivered after HBO appears to be effective for the treatment of rHGG, it could represent an alternative, with low toxicity, to systemic therapies for patients who cannot or refuse to undergo such treatments.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT 03411408.

Brachytherapy for Oesophageal Carcinoma: A Comprehensive Review of Literature and Techniques

Introduction: Oesophageal carcinoma is one of the fatal cancers mainly because of its rapid spread and poor prognosis. Treatment modalities involves a multimodality approach, including surgery, radiation therapy and chemotherapy. Radiation therapy includes brachytherapy in the form of intraluminal radiation therapy. Brachytherapy permits delivery of high tumouricidal doses to superficial cancerous growth of the oesophagus while delivering much lower doses to the surrounding tissue. It is mostly given in combination with external beam radiation in patients with poor performance scores not likely to tolerate an aggressive chemoradiation regimen or as a boost to concurrent chemoradiotherapy. It is very effective in terms of local tumour control as well as in relieving symptoms in advanced/recurrent disease. Intraoperative brachytherapy and seed brachytherapy have also been tried to address the nodal disease. Methods: We undertook a review of the available literature and techniques developed in the past three decades to emphasise the role of brachytherapy in curative or palliative settings in the treatment of oesophageal carcinoma. Conclusion: Oesophageal brachytherapy will remain a tangible treatment of oesophageal cancer, although it is less commonly used due to high expertise requirement, lack of established evidence, risk of life-threatening complications and lack of interest in brachytherapy. It offers quick and useful palliation for a prolonged period, along with good quality of life and superior dosimetry. Use of novel applicators may allow dose escalation and lower toxicity. Seed brachytherapy is also emerging as a promising option in nodal recurrences.

Complete Remission of Mouse Melanoma after Temporally Fractionated Microbeam Radiotherapy

Background: Synchrotron Microbeam Radiotherapy (MRT) significantly improves local tumour control with minimal normal tissue toxicity. MRT delivers orthovoltage X-rays at an ultra-high “FLASH” dose rate in spatially fractionated beams, typically only few tens of micrometres wide. One of the biggest challenges in translating MRT to the clinic is its use of high peak doses, of around 300–600 Gy, which can currently only be delivered by synchrotron facilities. Therefore, in an effort to improve the translation of MRT to the clinic, this work studied whether the temporal fractionation of traditional MRT into several sessions with lower, more clinically feasible, peak doses could still maintain local tumour control. Methods: Two groups of twelve C57Bl/6J female mice harbouring B16-F10 melanomas in their ears were treated with microbeams of 50 µm in width spaced by 200 µm from their centres. The treatment modality was either (i) a single MRT session of 401.23 Gy peak dose (7.40 Gy valley dose, i.e., dose between beams), or (ii) three MRT sessions of 133.41 Gy peak dose (2.46 Gy valley dose) delivered over 3 days in different anatomical planes, which intersected at 45 degrees. The mean dose rate was 12,750 Gy/s, with exposure times between 34.2 and 11.4 ms, respectively. Results: Temporally fractionated MRT ablated 50% of B16-F10 mouse melanomas, preventing organ metastases and local tumour recurrence for 18 months. In the rest of the animals, the median survival increased by 2.5-fold in comparison to the single MRT session and by 4.1-fold with respect to untreated mice. Conclusions: Temporally fractionating MRT with lower peak doses not only maintained tumour control, but also increased the efficacy of this technique. These results demonstrate that the solution to making MRT more clinically feasible is to irradiate with several fractions of intersecting arrays with lower peak doses. This provides alternatives to synchrotron sources where future microbeam radiotherapy could be delivered with less intense radiation sources.

A review of radiation induced abscopal effect: combining radiotherapy and immunotherapy to treat the untreated distant metastatic tumours

Background: Radiotherapy is an effective and significant mode of definitive cancer treatment with well-established local tumour control success, especially in the treatment of localised tumours. Although, for metastatic disease, the role of radiotherapy has generally been limited to palliation of symptoms. In the treatment of metastatic diseases settings, the radiation therapy technique has always been confronted with the challenge of the simultaneous treatment of all of the various distant metastatic tumour sites, however, some recent evidence suggests that radiotherapy can potentially induce anticancer immune responses whose effectors potentially migrate to distant metastatic tumours to provoke their regression in cancer patients. Thus, unirradiated distant metastatic tumour sites can exhibit a delayed therapeutic response termed the abscopal effect. Materials and methods: This paper reports on a review of the abscopal effect, including its biological mechanism, the effect of radiation dose and fractionation regime and the timing of immunotherapy administration on radiotherapy-induced abscopal effect, the enhancement of radiotherapy-induced abscopal effects with immunotherapy, the effect of the location of the irradiated tumour and the radiotherapy of multiple tumour sites on the likelihood and effectiveness of inducing abscopal responses in the preclinical and clinical settings and also reports on some evidence of clinical observations in patients. Conclusions: Although abscopal effects of radiotherapy are still relatively rare in patients, it has gained a lot of interest due to recent development and use of immunotherapy strategies incorporating combinations of targeted immunomodulators and immune checkpoint blockade with radiation therapy. The enhancement of cancer immunotherapy could potentially enable the translation of the concept of abscopal effect into the clinics as a new strategy to induce therapeutically effective anti-tumour immune responses in cancer patients. The combination of radiotherapy and immunotherapy has the potential to expand the role of radiotherapy from a purely local tumour control treatment to play a significant role in advanced and metastatic tumour control and this could likely lead to a paradigm shift in the treatment of patients with metastatic cancer.