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Aim This is the first randomised study to evaluate toxicity and survival outcomes of two neoadjuvant chemoradiotherapy (CRT) regimens for patients with localised oesophageal adenocarcinoma (OAC) or gastro-oesophageal junction (GOJ) adenocarcinoma. The initial results showed comparable toxicity between regimens and pathological complete response (pCR) rate favouring CarPacRT. Herein, we report survival, progression patterns, and long-term toxicity after a median follow-up of 40.7 months. Methods NeoSCOPE was an open-label, UK multicentre, randomised, phase II trial. Eighty-five patients with resectable OAC or GOJ adenocarcinoma, ≥cT3 and/or ≥cN1 (TNM v7), suitable for neoadjuvant CRT, were recruited between October 2013 and February 2015. Patients were randomised to OxCapRT (oxaliplatin 85 mg/m2 on Days 1, 15, and 29; capecitabine 625 mg/m2 orally twice daily on days of radiotherapy [RT]) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m2 on Days 1, 8, 15, 22, and 29). RT dose was 45 Gy/25 fractions/5 weeks. Both arms received induction chemotherapy (two cycles oxaliplatin 130 mg/m2 on Day 1, capecitabine 625 mg/m2 orally twice daily on Days 1–21) before CRT. Surgery was performed 6–8 weeks after CRT. The primary end-point was pCR. Secondary end-points were toxicity, progression-free survival (PFS), overall survival (OS), and patterns of progression. Results Eighty-five patients were recruited from 17 UK centres. The median OS was 41.7 months (95% confidence interval [CI] 19.6 to not reached) in the OxCapRT arm and was not reached in the CarPacRT arm (multivariable hazard ratio [HR] = 0.48, 95% CIs: 0.24–0.95, P = 0.035). The median PFS was 32.6 months (95% CIs: 17.1 to not reached) in the OxCapRT arm and was not reached in the CarPacRT arm (multivariable HR = 0.54, 95% CIs: 0.29–1.01, P = 0.053). In both arms, the distant progression was twice as common as locoregional progression. Conclusions OS and PFS favoured neoadjuvant CarPacRT over OxCapRT. Distant was more common than locoregional progression; therefore, priority should be given to optimising the systemic treatment component. Clinical trial information EudraCT Number: 2012-000640-10; ClinicalTrials.gov: NCT01843829., Highlights • Randomised study of neoadjuvant chemoradiotherapy for oesophageal adenocarcinoma. • The median overall survival was significantly better with CarPacRT. • Across both arms, the distant was more common than locoregional progression.

Objective: To determine the feasibility of using radiopaque (RO) beads as direct tumour surrogates for image-guided radiotherapy (IGRT) in patients with liver tumours after transarterial chemoembolisation (TACE). Methods: A novel vandetanib-eluting RO bead was delivered via TACE as part of a first-in-human clinical trial in patients with either hepatocellular carcinoma or liver metastases from colorectal cancer. Following TACE, patients underwent simulated radiotherapy imaging with four-dimensional computed tomography (4D-CT) and cone-beam CT (CBCT) imaging. RO beads were contoured using automated thresholding, and feasibility of matching between the simulated radiotherapy planning dataset (AVE-IP image from 4D data) and CBCT scans assessed. Additional kV, MV, helical CT and CBCT images of RO beads were obtained using an in-house phantom. Stability of RO bead position was assessed by comparing 4D-CT imaging to CT scans taken 6–20 days following TACE. Results: Eight patients were treated and 4D-CT and CBCT images acquired. RO beads were visible on 4D-CT and CBCT images in all cases and matching successfully performed. Differences in centre of mass of RO beads between CBCT and simulated radiotherapy planning scans (AVE-IP dataset) were 2.0 mm mediolaterally, 1.7 mm anteroposteriorally and 3.5 mm craniocaudally. RO beads in the phantom were visible on all imaging modalities assessed. RO bead position remained stable up to 29 days post TACE. Conclusion: RO beads are visible on IGRT imaging modalities, showing minimal artefact. They can be used for on-set matching with CBCT and remain stable over time. Advances in knowledge: The role of RO beads as fiducial markers for stereotactic liver radiotherapy is feasible and warrants further exploration as a combination therapy approach.

To assess the safety and tolerability of a vandetanib-eluting radiopaque embolic (BTG-002814) for transarterial chemoembolization (TACE) in patients with resectable liver malignancies.The VEROnA clinical trial was a first-in-human, phase 0, single-arm, window-of-opportunity study. Eligible patients were aged ≥18 years and had resectable hepatocellular carcinoma (HCC) (Child-Pugh A) or metastatic colorectal cancer (mCRC). Patients received 1 mL of BTG-002814 transarterially (containing 100 mg of vandetanib) 7-21 days prior to surgery. The primary objectives were to establish the safety and tolerability of BTG-002814 and determine the concentrations of vandetanib and the N-desmethyl vandetanib metabolite in the plasma and resected liver after treatment. Biomarker studies included circulating proangiogenic factors, perfusion computed tomography, and dynamic contrast-enhanced magnetic resonance imaging.Eight patients were enrolled: 2 with HCC and 6 with mCRC. There was 1 grade 3 adverse event (AE) before surgery and 18 after surgery; 6 AEs were deemed to be related to BTG-002814. Surgical resection was not delayed. Vandetanib was present in the plasma of all patients 12 days after treatment, with a mean maximum concentration of 24.3 ng/mL (standard deviation ± 13.94 ng/mL), and in resected liver tissue up to 32 days after treatment (441-404,000 ng/g). The median percentage of tumor necrosis was 92.5% (range, 5%-100%). There were no significant changes in perfusion imaging parameters after TACE.BTG-002814 has an acceptable safety profile in patients before surgery. The presence of vandetanib in the tumor specimens up to 32 days after treatment suggests sustained anticancer activity, while the low vandetanib levels in the plasma suggest minimal release into the systemic circulation. Further evaluation of this TACE combination is warranted in dose-finding and efficacy studies.

Colorectal cancer liver metastases (CRLMs) are common. Treating CRLMs with thermal ablation can prolong survival, but compared to lesions smaller than 3 cm, local control rates and overall survival are relatively worse with larger, intermediate (3-5 cm) lesions. Local recurrence rates range between 1.7%-20.2% and 6.7%-68.9% for CRLMs less than 3 cm and greater than 3 cm, respectively. Worse outcomes are also present when ablating intermediate size hepatocellular carcinoma (HCC) and there are some pathological similarities with CRLMs, namely the presence of micrometastatic disease. Combining ablation with transarterial chemoembolization is more effective in treating intermediate-size HCC than ablation alone. A meta-analysis of robust randomized controlled trials demonstrated long-term improved survival with combination therapy compared to ablation alone (odds ratio at 1, 3 and 5 years of 2.74, 2.77 and 5.23, respectively). There is, however, minimal evidence for combination therapy in CRLMs, limited to a handful of studies that are predominantly retrospective and have heterogeneous inclusion criteria. Given the difficulty in successfully treating intermediate CRLMs, the strong evidence for combination therapy in intermediate HCC and potential pathological similarities, formal evaluation of combination treatment in CRLM is merited. This review highlights existing evidence for treatment of intermediate-size liver lesions and highlights where trials in CRLMs should focus.

FLASH radiotherapy (FLASH-RT) delivers radiation treatment at an ultra-high dose rate that is several orders of magnitude higher than current clinical practice. In multiple preclinical studies, FLASH-RT has shown consistent normal tissue sparing effects while preserving equivalent antitumour activity in comparison with conventional dose rate radiation treatment. This is known as the 'FLASH effect'. Given the recent research interest in combining hypofractionated radiotherapy with immunotherapy to try to improve clinical outcomes, there is an intriguing clinical question as to whether FLASH irradiation may be a rational partner to combine with immune modulating drugs? To better predict the synergistic effect of both modalities, here we review the biological mechanisms of how FLASH differentially impacts the immune landscape, including circulating immune cells, tumour microenvironment and the inflammatory response. In order to make recommendations for future research, we summarise all published studies that investigated the immune modulatory effects of FLASH-RT and further explore the scientific reasons for combining FLASH with immunotherapy for potential clinical applications.

Vandetanib-eluting radiopaque beads (VERB) have been developed for use in transarterial chemoembolization of liver tumours, with the goal of combining embolization with local delivery of antiangiogenic therapy. The objective of this study was to investigate how embolization-induced hypoxia may affect antitumoural activity of vandetanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), in the context of hepatocellular carcinoma (HCC) treatment. We studied the effect of vandetanib on proliferation, cell cycle and apoptosis of HCC cells, in hypoxic conditions, as well as the direct effects of the beads on 3D HCC spheroids. Vandetanib suppressed proliferation and induced apoptosis of HCC cells in vitro and was equipotent in hypoxic and normoxic conditions. High degrees of apoptosis were observed among cell lines in which vandetanib suppressed ERK1/2 phosphorylation and upregulated the proapoptotic protein Bim, but this did not appear essential for vandetanib-induced cell death in all cell lines. Vandetanib also suppressed the hypoxia-induced secretion of VEGF from HCC cells and inhibited proliferation of endothelial cells. Incubation of tumour spheroids with VERB led to sustained growth inhibition equivalent to the effect of free drug. We conclude that vandetanib has both antiangiogenic and direct anticancer activity against HCC cells even in hypoxic conditions, warranting the further evaluation of VERB as novel anticancer agents.

Purpose To evaluate the safety and efficacy of yttrium-90 transarterial radioembolization (TARE) for the treatment of unresectable, chemotherapy-refractory intrahepatic cholangiocarcinoma (ICC). Methods A prospective, observational study was carried out in 10 centers between 2013 and 2017. TARE plus standard care was delivered to patients with unresectable, chemotherapy-refractory or chemotherapy-intolerant ICC. Primary outcome was overall survival. Secondary outcomes included safety, progression-free survival (PFS), and liver-specific progression-free survival (LPFS). Results Sixty-one patients were treated with TARE. Patients were 53% male; median age was 64 years; 91% had performance status 0/1; 92% had received prior chemotherapy; and 59% had no extrahepatic disease. Median follow-up was 13.9 months (95% confidence interval [CI], 9.6–18.1). Overall survival was 8.7 months (95% CI, 5.3–12.1), and 37% of patients survived to 12 months. PFS was 2.8 months (95% CI, 2.6–3.1), and LPFS was 3.1 months (95% CI, 1.3–4.8). One severe complication (abdominal pain) occurred at the time of the TARE procedure. Thirty patients experienced a total of 49 adverse events, of which 8% were grade ≥3; most common were grade 1–2 fatigue and abdominal pain. A total of 77 abnormal laboratory value events were recorded, of which 4% were grade ≥3. Conclusions Patients with advanced ICC have limited therapeutic options and a poor prognosis. This prospective study examined the survival of patients with unresectable, chemotherapy-refractory primary ICC treated with TARE in real-world practice. The results demonstrate that this treatment merits further investigation in this patient cohort in a larger study, including collection of patient-reported outcomes.

Advances in technical radiotherapy have resulted in significant sparing of organs at risk (OARs), reducing radiation-related toxicities for patients with cancer of the head and neck (HNC). Accurate delineation of target volumes (TVs) and OARs is critical for maximising tumour control and minimising radiation toxicities. When performed manually, variability in TV and OAR delineation has been shown to have significant dosimetric impacts for patients on treatment. Auto-segmentation (AS) techniques have shown promise in reducing both inter-practitioner variability and the time taken in TV and OAR delineation in HNC. Ultimately, this may reduce treatment planning and clinical waiting times for patients. Adaptation of radiation treatment for biological or anatomical changes during therapy will also require rapid re-planning; indeed, the time taken for manual delineation currently prevents adaptive radiotherapy from being implemented optimally. We are therefore standing on the threshold of a transformation of routine radiotherapy planning via the use of artificial intelligence. In this article, we outline the current state-of-the-art for AS for HNC radiotherapy in order to predict how this will rapidly change with the introduction of artificial intelligence. We specifically focus on delineation accuracy and time saving. We argue that, if such technologies are implemented correctly, AS should result in better standardisation of treatment for patients and significantly reduce the time taken to plan radiotherapy.

Imaging has an essential role in the planning and delivery of radiotherapy. Recent advances in imaging have led to the development of advanced radiotherapy techniques—including image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic body radiotherapy and proton beam therapy. The optimal use of imaging might enable higher doses of radiation to be delivered to the tumour, while sparing normal surrounding tissues. In this article, we review how the integration of existing and novel forms of computed tomography, magnetic resonance imaging and positron emission tomography have transformed tumour delineation in the radiotherapy planning process, and how these advances have the potential to allow a more individualised approach to the cancer therapy. Recent data suggest that imaging biomarkers that assess underlying tumour heterogeneity can identify areas within a tumour that are at higher risk of radio-resistance, and therefore potentially allow for biologically focussed dose escalation. The rapidly evolving concept of adaptive radiotherapy, including artificial intelligence, requires imaging during treatment to be used to modify radiotherapy on a daily basis. These advances have the potential to improve clinical outcomes and reduce radiation-related long-term toxicities. We outline how recent technological advances in both imaging and radiotherapy delivery can be combined to shape the future of precision radiation oncology.

Radiotherapy is a fundamental component of treatment for the majority of patients with cancer. In recent decades, technological advances have enabled patients to receive more targeted doses of radiation to the tumor, with sparing of adjacent normal tissues. There had been hope that the era of precision medicine would enhance the combination of radiotherapy with targeted anticancer drugs; however, this ambition remains to be realized. In view of this lack of progress, the FDA–AACR–ASTRO Clinical Development of Drug–Radiotherapy Combinations Workshop was held in February 2018 to bring together stakeholders and opinion leaders from academia, clinical radiation oncology, industry, patient advocacy groups, and the FDA to discuss challenges to introducing new drug–radiotherapy combinations to the clinic. This Perspectives in Regulatory Science and Policy article summarizes the themes and action points that were discussed. Intelligent trial design is required to increase the number of studies that efficiently meet their primary outcomes; endpoints to be considered include local control, organ preservation, and patient-reported outcomes. Novel approaches including immune-oncology or DNA-repair inhibitor agents combined with radiotherapy should be prioritized. In this article, we focus on how the regulatory challenges associated with defining a new drug–radiotherapy combination can be overcome to improve clinical outcomes for patients with cancer.

Aims Patients with chemotherapy-refractory colorectal cancer liver metastases have limited therapeutic options. Selective internal radiation therapy (SIRT) delivers yttrium 90 microspheres as a minimally invasive procedure. This prospective, single-arm, observational, service-evaluation study was part of National Health Service England Commissioning through Evaluation. Methods Patients eligible for treatment had histologically confirmed carcinoma with liver-only/liver-dominant metastases with clinical progression during or following oxaliplatin-based and irinotecan-based chemotherapy. All patients received SIRT plus standard of care. The primary outcome was overall survival; secondary outcomes included safety, progression-free survival (PFS) and liver-specific PFS (LPFS). Results Between December 2013 and March 2017, 399 patients were treated in 10 centres with a median follow-up of 14.3 months (95% confidence interval 9.2–19.4). The median overall survival was 7.6 months (95% confidence interval 6.9–8.3). The median PFS and LPFS were 3.0 months (95% confidence interval 2.8–3.1) and 3.7 months (95% confidence interval 3.2–4.3), respectively. During the follow-up period, 143 patients experienced an adverse event and 8% of the events were grade 3. Conclusion Survival estimates from this pragmatic study show clinical outcomes attainable in the National Health Service comparable with previously published data. This study shows the value of a registry-based commissioning model to aid national commissioning decisions for highly specialist cancer treatments.

Selective internal radiotherapy (SIRT) is a liver-directed treatment involving the injection of yttrium-90 microspheres into the blood supply of liver tumours. There are very few studies assessing health-related quality of life (HRQOL) in patients treated with SIRT. Patients with liver metastases from colorectal cancer (CRC) were randomised in the FOXFIRE (FFr; ISRCTN83867919), SIRFLOX (SF; NCT00724503) and FOXFIRE-Global (FFrG; NCT01721954) trials of first-line oxaliplatin-fluorouracil (FOLFOX) chemotherapy combined with SIRT versus FOLFOX alone. HRQOL was assessed using the three-level EQ-5D, European Organisation for Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) and EORTC Colorectal Liver Metastases cancer module (EORTC QLQ-LMC21) at baseline, ≤3 months, 6 months, 12 months and annually thereafter from randomisation, and at disease progression. Analyses were conducted on an intention-to-treat basis. In total, 554 patients were randomised to SIRT + FOLFOX and 549 patients to FOLFOX alone. HRQOL was statistically significant lower in SIRT + FOLFOX patients ≤3 months after SIRT administration in all three instruments, particularly global health, physical and role functioning and symptoms of fatigue, nausea/vomiting and appetite loss. By accepted thresholds, these differences were deemed not clinically important. Differences between SIRT + FOLFOX and FOLFOX alone over the 2-year follow up and at disease progression were also not clinically important. Although there is some decrease in HRQOL for up to 3 months following SIRT, the addition of SIRT to FOLFOX chemotherapy does not change HRQOL to a clinically important degree in metastatic CRC patients.

Purpose To use a novel segmentation methodology based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to define tumour subregions of liver metastases from colorectal cancer (CRC), to compare these with histology, and to use these to compare extracted pharmacokinetic (PK) parameters between tumour subregions. Materials and Methods This ethically-approved prospective study recruited patients with CRC and ≥1 hepatic metastases scheduled for hepatic resection. Patients underwent DCE-MRI pre-metastasectomy. Histological sections of resection specimens were spatially matched to DCE-MRI acquisitions and used to define histological subregions of viable and non-viable tumour. A semi-automated voxel-wise image segmentation algorithm based on the DCE-MRI contrast-uptake curves was used to define imaging subregions of viable and non-viable tumour. Overlap of histologically-defined and imaging subregions was compared using the Dice similarity coefficient (DSC). DCE-MRI PK parameters were compared for the whole tumour and histology-defined and imaging-derived subregions. Results Fourteen patients were included in the analysis. Direct histological comparison with imaging was possible in nine patients. Mean DSC for viable tumour subregions defined by imaging and histology was 0.738 (range 0.540-0.930). There were significant differences between K trans and k ep for viable and non-viable subregions (p < 0.001) and between whole lesions and viable subregions (p < 0.001). Conclusion We demonstrate good concordance of viable tumour segmentation based on pre-operative DCE-MRI with a post-operative histological gold-standard. This can be used to extract viable tumour-specific values from quantitative image analysis, and could improve treatment response assessment in clinical practice.

In the United States of America, almost 150,000 people are estimated to be diagnosed with colorectal cancer in 2020 and up to 35% of those are expected to present with oligometastatic disease. The term 'oligometastasis' was first used in 1995, however surgical literature describing liver resection for colorectal cancer dates back to the 1940s. Five-year survival rates of up to 42% with surgery alone for solitary lesions are reported. Modern trials have demonstrated median overall survival rates of over 80 months for patients with colorectal liver metastases treated with perioperative chemotherapy. Colorectal liver metastases have accordingly been described as 'proof of concept' for the oligometastatic theory.

In patients with liver-limited oligometastatic disease, the goal of treatment can be curative intent. Historically, this was accomplished in patients presenting with upfront resectable disease. The availability of increasingly efficacious chemotherapy and biologic combinations with encouraging response rates led to the potential to convert unresectable disease to resectability. Beyond the backbone of surgery, we now have a portfolio of locoregional strategies to consider.From an interventional radiology perspective, the use of portal vein embolization can facilitate hypertrophy of the liver in anticipation of resection, thus converting unresectable disease to one amenable to a surgical approach with curative intent. Technological advances in liver-directed ablative therapies have afforded the possibility of eliminate radiographically evident disease with the hope for long-term disease control. Advanced radiotherapy techniques are further increasing the therapeutic options for patients with metastatic colorectal cancer. Improvements in external-beam radiotherapy over the past 2 decades include image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic body radiotherapy, and proton-beam therapy. Finally, selective internal radiation therapy (SIRT) with microspheres labeled with the β-emitter 90Y enable targeted delivery of radiation to hepatic tumors. A coordinated multidisciplinary approach is required to integrate these nonsurgical adjuncts in an evidence-based manner to optimize outcomes for patients with potentially resectable metastatic disease. In this article, we summarize recent developments in systemic therapy, radiotherapy, and interventional liver-directed therapies that have changed the treatment landscape for patients with oligometastatic colorectal cancer.

The purpose of this study was to establish the dose-response relationship of selective internal radiation therapy (SIRT) in patients with metastatic colorectal cancer (mCRC), when informed by radiobiological sensitivity parameters derived from mCRC cell lines exposed to

Neoadjuvant chemoradiotherapy with fluoropyrimidines is an established treatment in the management of locally advanced rectal cancer. There has been a great deal of research into improving patient outcomes by modifying this regimen by the addition of further radiosensitising agents. One of the difficulties in advancing new combination therapies has been lack of consensus on which surrogate measures best reflect clinically important outcomes. Here we review combinations of the cytotoxic, biological and other agents currently under scrutiny to improve clinical outcomes for patients with colorectal cancer. We also discuss advances in biomarkers that may ultimately result in an ability to tailor neoadjuvant chemoradiotherapy regimens to the somatic gene profile of individual patients.

International audience; A multi-disciplinary cooperative for nanoparticle-enhanced radiotherapy (NERT) has been formed to review the current status of the field and identify key stages towards translation. Supported by the Colorectal Cancer Healthcare Technologies Cooperative, the cooperative comprises a diverse cohort of key contributors along the translation pathway including academics of physics, cancer and radio-biology, chemistry, nanotechnology and clinical trials, clinicians, manufacturers, industry, standards laboratories, policy makers and patients. Our aim was to leverage our combined expertise to devise solutions towards a roadmap for translation and commercialisation of NERT, in order to focus research in the direction of clinical implementation, and streamline the critical pathway from basic science to the clinic. A recent meeting of the group identified barriers to and strategies for accelerated clinical translation. This commentary reports the cooperative’s recommendations. Particular emphasis was given to more standardised and cohesive research methods, models and outputs, and reprioritised research drivers including patient quality of life following treatment. Nanoparticle design criteria were outlined to incorporate scalability of manufacture, understanding and optimisation of biological mechanisms of enhancement and in vivo fate of nanoparticles, as well as existing design criteria for physical and chemical enhancement. In addition, the group aims to establish a long-term and widespread international community to disseminate key findings and create a much-needed cohesive body of evidence necessary for commercial and clinical translation.

Purpose: Tumor vessels influence the growth and response of tumors to therapy. Imaging vascular changes in vivo using dynamic contrast-enhanced MRI (DCE-MRI) has shown potential to guide clinical decision making for treatment. However, quantitative MR imaging biomarkers of vascular function have not been widely adopted, partly because their relationship to structural changes in vessels remains unclear. We aimed to elucidate the relationships between vessel function and morphology in vivo. Experimental Design: Untreated preclinical tumors with different levels of vascularization were imaged sequentially using DCE-MRI and CT. Relationships between functional parameters from MR (iAUC, Ktrans, and BATfrac) and structural parameters from CT (vessel volume, radius, and tortuosity) were assessed using linear models. Tumors treated with anti-VEGFR2 antibody were then imaged to determine whether antiangiogenic therapy altered these relationships. Finally, functional–structural relationships were measured in 10 patients with liver metastases from colorectal cancer. Results: Functional parameters iAUC and Ktrans primarily reflected vessel volume in untreated preclinical tumors. The relationships varied spatially and with tumor vascularity, and were altered by antiangiogenic treatment. In human liver metastases, all three structural parameters were linearly correlated with iAUC and Ktrans. For iAUC, structural parameters also modified each other's effect. Conclusions: Our findings suggest that MR imaging biomarkers of vascular function are linked to structural changes in tumor vessels and that antiangiogenic therapy can affect this link. Our work also demonstrates the feasibility of three-dimensional functional–structural validation of MR biomarkers in vivo to improve their biological interpretation and clinical utility. Clin Cancer Res; 24(19); 4694–704. ©2018 AACR.

ObjectivesLiver metastasis from a neuroendocrine tumour (NET) represents a significant clinical entity. A multidisciplinary group of experts was convened to develop state-of-the-art recommendations for its management.MethodsPeer-reviewed published reports on intra-arterial therapies for NET hepatic metastases were reviewed and the findings presented to a jury of peers. The therapies reviewed included transarterial embolization (TAE), transarterial chemoembolization (TACE) and radioembolization (RE). Two systems were used to evaluate the level of evidence in each publication: (i) the US National Cancer Institute (NCI) system, and (ii) the GRADE system.ResultsEighteen publications were reviewed. These comprised 11 reports on TAE or TACE and seven on RE. Four questions posed to the panel were answered and recommendations offered.ConclusionsStudies of moderate quality support the use of TAE, TACE and RE in hepatic metastases of NETs. The quality and strength of the reports available do not allow any modality to be determined as superior in terms of imaging response, symptomatic response or impact on survival. Radioembolization may have advantages over TAE and TACE because it causes fewer side-effects and requires fewer treatments. Based on current European Neuroendocrine Tumor Society (ENETS) Consensus Guidelines, RE can be substituted for TAE or TACE in patients with either liver-only disease or those with limited extrahepatic metastases.

Harmonious interactions between radiation, medical, interventional and surgical oncologists, as well as other members of multidisciplinary teams, are essential for the optimization of patient care in oncology. This multidisciplinary approach is particularly important in the current landscape, in which standard-of-care approaches to cancer treatment are evolving towards highly targeted treatments, precise image guidance and personalized cancer therapy. Herein, we highlight the importance of multidisciplinarity and interdisciplinarity at all levels of clinical oncology training. Potential deficits in the current career development pathways and suggested strategies to broaden clinical training and research are presented, with specific emphasis on the merits of trainee involvement in functional multidisciplinary teams. Finally, the importance of training in multidisciplinary research is discussed, with the expectation that this awareness will yield the most fertile ground for future discoveries. Our key message is for cancer professionals to fulfil their duty in ensuring that trainees appreciate the importance of multidisciplinary research and practice.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.

The SCOPE 1 trial closed to recruitment in early 2012 and has demonstrably improved the quality of UK radiotherapy. It has also shown that there is an enthusiastic upper gastrointestinal clinical oncology community that can successfully complete trials and deliver high-quality radiotherapy. Following on from SCOPE 1, this paper, authored by a consensus of leading UK upper gastrointestinal radiotherapy specialists, attempts to define current best practice and the questions to be answered by future clinical studies.The two main roles for chemoradiotherapy (CRT) in the management of potentially curable oesophageal cancer are definitive (dCRT) and neoadjuvant (naCRT). The rates of local failure after dCRT are consistently high, showing the need to evaluate more effective treatments, both in terms of optimal local and systemic therapeutic components. This will be the primary objective of the next planned UK dCRT trial and here we discuss the role of dose escalation and systemic therapeutic options that will form the basis of that trial. The publication of the Dutch 'CROSS' trial of naCRT has shown that this pre-operative approach can both be given safely and offer a significant survival benefit over surgery alone. This has led to the development of the UK NeoSCOPE trial, due to open in 2013. There will be a translational substudy to this trial and currently available data on the role of biomarkers in predicting response to therapy are discussed. Postoperative reporting of the pathology specimen is discussed, with recommendations for the NeoSCOPE trial. Both of these CRT approaches may benefit from recent developments, such as positron emission tomography/computed tomography and four-dimensional computed tomography for target volume delineation, planning techniques such as intensity-modulated radiotherapy and 'type b' algorithms and new treatment verification methods, such as cone-beam computed tomography. These are discussed here and recommendations made for their use. © 2013 The Royal College of Radiologists.

Selective internal radiation therapy (or radioembolization) by intra-arterial injection of radioactive yttrium-90-loaded microspheres is increasingly used for the treatment of patients with liver metastases or primary liver cancer. The high-dose beta-radiation penetrates an average of only 2.5 mm from the source, thus limiting its effects to the site of delivery. However, the off-target diversion of yttrium-90 microspheres to tissues other than the tumor may lead to complications. The most prominent of these complications include radiation gastritis and gastrointestinal ulcers, cholecystitis, radiation pneumonitis, and radioembolization-induced liver disease, which may occur despite careful pretreatment planning. Thus, selective internal radiation therapy demands an expert multidisciplinary team approach in order to provide comprehensive care for patients. This review provides recommendations to multidisciplinary teams on the optimal medical processes in order to ensure the safe delivery of selective internal radiation therapy. Based on the best available published evidence and expert opinion, we recommend the most appropriate strategies for the prevention, early diagnosis, and management of potential radiation injury to the liver and to other organs. (Hepatology 2017;66:969-982).

The term oligometastases is in common clinical use, but remains poorly defined. As\ud novel treatment strategies widen the therapeutic window for patients defined as\ud having oligometastatic cancer, improved biomarkers to reliably define patients who\ud benefit from these treatments are needed.\ud Multimodal imaging should be optimized to comprehensively assess the metastatic\ud sites, disease burden and response to neoadjuvant treatment in each disease setting.\ud These features will likely remain important prognostic biomarkers, and are critical in\ud planning multidisciplinary treatment. There are opportunities to extract additional\ud phenotypic information from conventional imaging, while novel imaging techniques\ud can also image specific aspects of tumour biology. Imaging can both characterise and\ud localise the phenotypic heterogeneity of multiple tumour sites. Novel approaches to\ud existing imaging datasets, and correlation with tumour biology, will be important in\ud realizing the potential of imaging to guide treatment in the oligometastatic setting.\ud This article discusses the current status and future directions of imaging in patients\ud with extracranial oligometastases.

Some of the greatest advances in the treatment of solid malignancies have resulted from the combination of chemotherapy and radiotherapy treatments. This article comprehensively reviews the current clinical evidence for oxaliplatin-based chemo-radiotherapy that may improve local control and survival. In order to understand how clinical studies should be designed, the pre-clinical evidence for the use of oxaliplatin chemotherapy as a radiosensitising agent is appraised. Particular focus is placed on oxaliplatin's biological mechanisms of action, including cell cycle effects, the formation of DNA adducts and interstrand cross-links and the role of DNA repair proteins. At a clinical level, there is currently no evidence to suggest that oxaliplatin provides an additional benefit to concurrent chemo-radiation regimes that utilise fluoropyrimidines; we evaluate the reasons for this observation, the limitations of clinical trial design and the opportunities that currently exist to design clinical trials which are underpinned by an understanding of the basic biology. © 2012 Elsevier Ireland Ltd.

PURPOSE: Although oral fluoropyrimidine prodrugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. METHOD: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m2) OGT 719. RESULTS: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. CONCLUSION: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

Background The involvement of consumers and the general public in improving cancer services is an important component of health services. However, consumer involvement in cancer research is relatively unexplored. The objective of this study was to explore different ways of involving consumers in cancer research in one regional network. Methods Thames Valley Cancer Network Consumer Research Partnership (CRP) group was formed in 2009. The group consists of consumers and professionals to help in promoting consumer involvement in Cancer Research in the Thames Valley. This study evaluated the project of consumer involvement in cancer research in the Thames Valley from March 2010 to March 2011. We used different indices to judge the level of consumer involvement: number of projects involving consumers through the group, types of projects, level of involvement (ranged from consultation on research documents to collaborating in preparing grant applications) and the methods of involving consumers in cancer research. Results Fifteen projects were submitted to the CRP group during the 12-month period studied. Of these, eight projects were clinical trials, three were qualitative research projects, two were patients' surveys and two were non-randomized interventional studies. Seven projects requested consumer involvement on patient information sheets for clinical trials. Of these seven applications, three also requested consumers' help in designing research questionnaires and another three requested that consumers should be involved in their project management group. In addition, four projects involved consumers in the proposal development phase and another four projects asked for advice on how to increase trial recruitment, conduct patient interviews or help with grant applications. Conclusions The creation of the CRP and this audit of its activity have documented consumer involvement in cancer research in the Thames Valley. We have clearly shown that consumers can be involved in designing and managing cancer research projects.

The majority of patients with advanced colorectal cancer die from hepatic metastases caused by disease progression; therefore, several novel technologies are in clinical development to potentially improve local control of liver disease. Radioembolization is a technique for administering radiotherapy internally to unresectable primary or secondary hepatic malignancies in a single procedure. This technique involves the injection of resin or glass microspheres that contain (90)Y into the arterial supply of the liver. Clinical trials of radioembolization used with concomitant radiosensitizing chemotherapy have shown promising results in patients with metastatic colorectal cancer. Several reports suggest that radioembolization is associated with significant downsizing of liver metastases to permit subsequent surgical resection. In this article, the rationale for combining radioembolization with the cytotoxic and molecularly targeted agents licensed for the systemic treatment of colorectal cancer is outlined. Clinical data from trials of radioembolization with concomitant systemic treatment are reviewed, with an emphasis on the appropriateness of primary end points in large-scale trials and the practical aspects of surgical resection in patients whose tumors are successfully downsized by this chemoradiation approach.

Purpose Liver metastases represent the principal cause of death in patients with advanced colorectal cancer (CRC). Injection of resin microspheres (SIR Spheres)—containing the β-emitter, yttrium-90—into the arterial supply of the liver can cause radioembolization of metastases. This treatment has not been tested with the radiosensitizing chemotherapy, oxaliplatin, which appears synergistic in the treatment of CRC when combined with fluorouracil and leucovorin (FOLFOX). Patients and Methods A phase I study of SIR-Spheres therapy with modified FOLFOX4 systemic chemotherapy was conducted in patients with inoperable liver metastases from CRC who had not previously received chemotherapy for metastatic disease. Oxaliplatin (30 to 85 mg/m2) was administered for the first three cycles with full FOLFOX4 doses from cycle 4 until cycle 12. The primary end point was toxicity. Results Twenty patients were enrolled onto the study. Five patients experienced National Cancer Institute (NCI; Bethesda, MD) grade 3 abdominal pain, two of whom had microsphere-induced gastric ulcers. The dose-limiting toxicity was grade 3 or 4 neutropenia, which was recorded in 12 patients. One episode of transient grade 3 hepatotoxicity was recorded. Mean splenic volume increased by 92% following 6 months of protocol therapy. Partial responses were demonstrated in 18 patients and stable disease in two patients. Two patients underwent partial hepatic resection following protocol therapy. Median progression-free survival was 9.3 months, and median time to progression in the liver was 12.3 months. Conclusion The maximum-tolerated dose was 60 mg/m2 of oxaliplatin for the first three cycles, with full FOLFOX4 doses thereafter. This chemoradiation regime merits evaluation in phase II-III trials.

How chemotherapy affects carcinoma genomes is largely unknown. Here we report whole-exome and deep sequencing of 30 paired oesophageal adenocarcinomas sampled before and after neo-adjuvant chemotherapy. Most, but not all, good responders pass through genetic bottlenecks, a feature associated with higher mutation burden pre-treatment. Some poor responders pass through bottlenecks, but re-grow by the time of surgical resection, suggesting a missed therapeutic opportunity. Cancers often show major changes in driver mutation presence or frequency after treatment, owing to outgrowth persistence or loss of sub-clones, copy number changes, polyclonality and/or spatial genetic heterogeneity. Post-therapy mutation spectrum shifts are also common, particularly C>A and TT>CT changes in good responders or bottleneckers. Post-treatment samples may also acquire mutations in known cancer driver genes (for example, SF3B1, TAF1 and CCND2) that are absent from the paired pre-treatment sample. Neo-adjuvant chemotherapy can rapidly and profoundly affect the oesophageal adenocarcinoma genome. Monitoring molecular changes during treatment may be clinically useful., Oesophageal adenocarcinoma is often treated with chemotherapy before surgery. Here, the authors sequence cancer samples before and after chemotherapy and examine how the genome changes, focusing on changes in driver gene mutations and differential clonal evolution between good and poor responders.

Multidisciplinary team meetings have become routine in many developed countries to establish the standard of cancer care for individual patients. These meetings can improve communication between team members and enhance coordination and continuity of care. 1 For example, evidence shows that multidisciplinary teams can increase resection rates, 2 reduce treatment variance, 3 and improve health outcomes after discharge.

Some of the largest improvements in clinical outcomes for patients with solid cancers observed over the past 3 decades have been from concurrent treatment with chemotherapy and radiotherapy (RT). The lethal effects of RT on cancer cells arise primarily from damage to DNA. Ruthenium (Ru) is a transition metal of the platinum group, with potentially less toxicity than platinum drugs. We postulated that ruthenium-arene complexes are radiosensitisers when used in combination with RT. We screened 14 ruthenium-arene complexes and identified AH54 and AH63 as supra-additive radiosensitisers by clonogenic survival assays and isobologram analyses. Both complexes displayed facial chirality. At clinically relevant doses of RT, radiosensitisation of cancer cells by AH54 and AH63 was p53-dependent. Radiation enhancement ratios for 5–10 micromolar drug concentrations ranged from 1.19 to 1.82. In p53-wildtype cells, both drugs induced significant G2 cell cycle arrest and apoptosis. Colorectal cancer cells deficient in DNA damage repair proteins, EME1 and MUS81, were significantly more sensitive to both agents. Both drugs were active in cancer cell lines displaying acquired resistance to oxaliplatin or cisplatin. Our findings broaden the potential scope for these drugs for use in cancer therapy, including combination with radiotherapy to treat colorectal cancer.

Although the liver possesses a dual blood supply, arterial vessels deliver only a small proportion of blood to normal parenchyma, but they deliver the vast majority of blood to primary and secondary cancers of the liver. This anatomical discrepancy is the basis for intra-arterial brachytherapy of liver cancers using radioactive microspheres, termed radio-embolization (RE). Radioactive microspheres implant preferentially in the terminal arterioles of tumors. Although biological models of the flow dynamics and distribution of microspheres are currently in development, there is a need to improve the imaging biomarkers of flow dynamics used to plan RE. Since a direct consequence of RE is vascular disruption and necrosis, we suggest that imaging protocols sensitive to changes in vasculature are highly likely to represent useful early biomarkers for treatment efficacy. We propose dynamic contrast-enhanced CT as the most appropriate imaging modality for studying vascular parameters in clinical trials of RE treatment.

Intracellular reactive oxygen species (ROS) may cause oxidative DNA damage, resulting in the formation of adducts such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and the cyclic pyrimidopurinone N-1, N(2) malondialdehyde-2'-deoxyguanosine (M(1)dG). These adducts have been associated with carcinogenesis, genomic instability and clonal evolution. We tested two hypotheses in human prostate cancer cells grown in vitro and in a xenograft model: (1) treatment of androgen-sensitive cells with DHT increases levels of oxidative DNA adduct levels; (2) flutamide, a competitive androgen receptor antagonist, prevents DHT-induced changes. Levels of M(1)dG and 8-oxo-dG adducts were determined by immunoslot blot and liquid chromatography-tandem mass spectrometry. M(1)dG and 8-oxo-dG levels were significantly higher than control levels in LNCaP cells exposed to supra-physiological concentrations (25-100 nM) of DHT (both P

BACKGROUND: Both oxaliplatin/capecitabine-based chemoradiation (OXCAP-RT) and carboplatin-paclitaxel based radiation (CarPac-RT) are active regimens in oesophageal adenocarcinoma, but no randomised study has compared their efficacy and toxicity. This randomised phase II "pick a winner" trial will identify the optimum regimen to take forward to a future phase III trial against neo-adjuvant chemotherapy, the current standard in the UK. METHODS/DESIGN: Patients with resectable adenocarcinoma of the oesophagus or Siewert Type 1-2 gastro-oesophageal junction (GOJ), ≥T3 and/or ≥ N1 are eligible for the study. Following two cycles of induction OXCAP chemotherapy (oxaliplatin 130 mg/m2 D1, Cape 625 mg/m(2) D1-21, q 3 wk), patients are randomised 1:1 to OXCAP-RT (oxaliplatin 85 mg/m(2) Day 1,15,29; capecitabine 625 mg/m(2) twice daily on days of RT; RT-45 Gy/25 fractions/5 weeks) or CarPac-RT (Carboplatin AUC2 and paclitaxel 50 mg/m2 Day 1,8,15,22,29; RT-45 Gy/25 fractions/5 weeks). Restaging CT/PET-CT is performed 4-6 weeks after CRT, and a two-phase oesophagectomy with two-field lymphadenectomy is performed six to eight weeks after CRT. The primary end-point is pathological complete response rate (pCR) at resection and will include central review. Secondary endpoints include: recruitment rate, toxicity, 30-day surgical morbidity/mortality, resection margin positivity rate and overall survival (median, 3- and 5-yr OS. 76 patients (38/arm) gives 90% power and one-sided type 1 error of 10% if patients on one novel treatment have a response rate of 35% while the second treatment has a response rate of 15%. A detailed RT Quality Assurance (RTQA) programme includes a detailed RT protocol and guidance document, pre-accrual RT workshop, outlining exercise, and central evaluation of contouring and planning. This trial has been funded by Cancer Research UK (C44694/A14614), sponsored by Velindre NHS Trust and conducted through the Wales Cancer Trials Unit at Cardiff University on behalf of the NCRI Upper GI CSG. DISCUSSION: Following encouraging results from previous trials, there is an interest in neo-adjuvant chemotherapy and CRT containing regimens for treatment of oesophageal adenocarcinoma. NEOSCOPE will first establish the efficacy, safety and feasibility of two different neo-adjuvant CRT regimens prior to a potential phase III trial. TRIAL REGISTRATION: Eudract No: 2012-000640-10. ClinicalTrials.gov: NCT01843829 .

Thalidomide is an anti-angiogenic agent currently used to treat patients with malignant cachexia or multiple myeloma. Lenalidomide (CC-5013) is an immunomodulatory thalidomide analogue licensed in the United States of America (USA) for the treatment of a subtype of myelodysplastic syndrome. This two-centre, open-label phase I study evaluated dose-limiting toxicities in 55 patients with malignant solid tumours refractory to standard chemotherapies. Lenalidomide capsules were consumed once daily for 12 weeks according to one of the following three schedules: (I) 25 mg daily for the first 7 d, the daily dose increased by 25 mg each week up to a maximum daily dose of 150 mg; (II) 25mg daily for 21 d followed by a 7-d rest period, the 4-week cycle repeated for 3 cycles; (III) 10 mg daily continuously. Twenty-six patients completed the study period. Two patients experienced a grade 3 hypersensitivity rash. Four patients in cohort I and 4 patients in cohort II suffered grade 3 or 4 neutropaenia. In 2 patients with predisposing medical factors, grade 3 cardiac dysrhythmia was recorded. Grade 1 neurotoxicity was detected in 6 patients. One complete and two partial radiological responses were measured by computed tomography scanning; 8 patients had stable disease after 12 weeks of treatment. Fifteen patients remained on treatment as named patients; 1 with metastatic melanoma remains in clinical remission 3.5 years from trial entry. This study indicates the tolerability and potential clinical efficacy of lenalidomide in patients with advanced solid tumours who have previously received multi-modality treatment. Depending on the extent of myelosuppressive pre-treatment, dose schedules (II) or (III) are advocated for large-scale trials of long-term administration.

Interventional oncology is a rapidly growing sub-speciality that aims to develop new disease-modifying treatment options beyond conventional surgical and oncological therapies in several disease settings. The evidence for interventional oncology success is dominated by single-arm studies reporting technical success or clinical efficacy. These studies have successfully resulted in the development of new techniques, but are not sufficient to change clinical practice uniformly across health-care systems. This Review discusses why clinical investigators must incorporate measures of cost-effectiveness and patient-reported outcomes into large-scale studies currently being designed to provide robust evidence for changing clinical practice. In particular, interventional oncology trials could be designed to show that certain treatments may be as effective as the current standard of care, but with significantly less morbidity and with better outcomes for patients with cancer. Innovative trial design and awareness of the challenges from interventional studies in other fields of medicine and surgery are also discussed to demonstrate how this new speciality can make progress. Registry-based models are emerging as an alternative means of deriving cohort data and can be used in parallel with local or national commissioning of new services.

When compared to a reference population, several large epidemiological studies with long-term follow-up have reported a three- to five-fold increased risk of neoplasia amongst patients who have received organ transplants, with an incidence curve that rises in a linear fashion with time. The relationship between the immune system and cancer is complex. The ability to discriminate “self” from “non-self” is one of the central roles of the immune system. Since tumors arise from transformation of host cells, it is not surprising that some aspects of tumor immunity resemble autoimmunity. The immune response to tumors shares aspects of both self- and non-self-immune recognition. What accounts for the apparent failure of immunity? In this review article, we address the role of the self/non-self-survey in the immune response to tumors, we describe mechanisms of immune surveillance against tumor cells, and we discuss models of ignorance, tolerance and tumor evasion of the immune response. The overall aim of the article is to demonstrate the scope for prevention of cancer in individuals at increased risk of developing malignancy due to immune compromise. Interventional strategies may involve the use of pro-differentiation agents such as retinoids, modifiers of polyamine biosynthesis or inhibitors of cyclooxygenase isozymes.

As the options for systemic treatment of malignant melanoma (MM) increase, the need to develop biomarkers to identify patients who might benefit from cytotoxic chemotherapy becomes more apparent. In preclinical models, oxaliplatin has activity in cisplatin-resistant cells. In this study, we have shown that oxaliplatin forms interstrand crosslinks (ICLs) in cellular DNA and that loss of the heterodimeric structure-specific endonuclease XPF-ERCC1 causes hypersensitivity to oxaliplatin in mammalian cells. XPF deficiency resulted in late S-phase arrest and persistence of double-strand breaks following oxaliplatin treatment. In a panel of 12 MM cell lines, oxaliplatin sensitivity correlated with XPF and ERCC1 protein levels. The knockdown of ERCC1 and XPF protein levels by RNA interference increased sensitivity of cancer cells to oxaliplatin; overexpression of exogenous ERCC1 significantly decreased drug sensitivity. Following immunohistochemical optimization, XPF protein levels were quantified in MM tissue samples from 183 patients, showing variation in expression and no correlation with prognosis. In 57 patients with MM treated with cisplatin or carboplatin, XPF protein levels did not predict the likelihood of clinical response. We propose that oxaliplatin should not be discarded as a potential treatment for MM on the basis of the limited activity of cisplatin in unselected patients. Moreover, we show that XPF-ERCC1 protein levels are a key determinant of the sensitivity of melanoma cells to oxaliplatin in vitro. Immunohistochemical detection of XPF appears suitable for development as a tissue biomarker for potentially selecting patients for oxaliplatin treatment in a prospective clinical trial. What's new? With options for systemic treatment of malignant melanoma (MM) on the rise, there is an increasing need to develop biomarkers for patient selection. To that end, this study explored the possibility of a biomarker to improve objective response rates to the drug oxaliplatin. The study reveals a mechanism by which mammalian cells are rendered hypersensitive to oxaliplatin that centers around the loss of endonuclease XPF-ERCC1. Sensitivity to oxaliplatin was directly related to XPF and ERCC1 protein levels. The findings indicate that XPF may be a suitable biomarker for MM patient selection for oxaliplatin therapy. © 2013 UICC.

The most common cause of death from advanced colorectal cancer is disease progression of hepatic metastases. Selective internal radiation therapy (SIRT) is a technique for administering resin or glass microspheres that contain yttrium-90 to unresectable primary or secondary hepatic malignancies via the liver’s arterial supply in a single procedure. Chemoradiation studies suggest that the greatest clinical benefit from yttrium-90 microsphere SIRT is gained by rational combination with radiosensitizing systemic chemotherapy (Figure 1) [1,2] in order to achieve both temporal modulation and biological cooperation between these treatment modalities. There is an established evidence base for rational combinations of SIRT with fluoropyrimidine-, oxaliplatinand irinotecan-based regimes, based on radiobiological principles [3–5]. In particular, patients who cannot tolerate infusional 5-fluorouracil (5-FU) or capecitabine who have liver-only or liver-dominant metastatic disease should be considered for SIRT [6,7]. Detailed histological analysis of the liver tissue in patients resected 4–9 months after chemotherapy and SIRT shows that a complete pathological response can be achieved. Furthermore, fibrosis, ectatic vessels and vascular changes were predominantly observed (i.e., histological evidence of a direct local radiotherapy effect), rather than a cellular inflammatory response (which would be suggestive of histopathological changes induced by embolization or by chemotherapy; Figure 2) [6].

Despite positive results in large scale chemoprevention trials, many physicians are unaware of the potential cancer preventive properties of drugs in common usage. The antioestrogen tamoxifen and the selective cyclo-oxygenase-2 inhibitor celecoxib have been licensed in the USA for the chemoprevention of breast and colorectal cancers respectively in selected high risk individuals. Similarly, folate and retinol have been shown to decrease the incidence of colorectal cancer and squamous cell carcinoma of the skin respectively in large scale intervention trials. Other retinoids have proved efficacious in the tertiary chemoprevention of cancers of the breast and head/neck. Epidemiological evidence also exists in favour of aspirin, non-steroidal anti-inflammatory drugs, and angiotensin converting enzyme inhibitors preventing certain cancers. Phytochemicals may represent less toxic alternatives to these agents. Although some of these drugs are available without prescription and most are not yet licensed for use in cancer chemoprevention, physicians and students of medicine should be aware of this accumulating evidence base. Practitioners should be amenable to patient referral to discuss complex issues such as risk estimation or potential benefit from intervention. Keywords: cancer chemoprevention; tamoxifen; folate; retinoids; cyclo-oxygenase

Apart from surgical approaches, the treatment of cancer remains largely underpinned by radiotherapy and pharmacological agents that cause damage to cellular DNA, which ultimately causes cancer cell death. DNA polymerases, which are involved in the repair of cellular DNA damage, are therefore potential targets for inhibitors for improving the efficacy of cancer therapy. They can be divided, according to their main function, into two groups, namely replicative and nonreplicative enzymes. At least 15 different DNA polymerases, including their homologs, have been discovered to date, which vary considerably in processivity and fidelity. Many of the nonreplicative (specialized) DNA polymerases replicate DNA in an error-prone fashion, and they have been shown to participate in multiple DNA damage repair and tolerance pathways, which are often aberrant in cancer cells. Alterations in DNA repair pathways involving DNA polymerases have been linked with cancer survival and with treatment response to radiotherapy or to classes of cytotoxic drugs routinely used for cancer treatment, particularly cisplatin, oxaliplatin, etoposide, and bleomycin. Indeed, there are extensive preclinical data to suggest that DNA polymerase inhibition may prove to be a useful approach for increasing the effectiveness of therapies in patients with cancer. Furthermore, specialized DNA polymerases warrant examination of their potential use as clinical biomarkers to select for particular cancer therapies, to individualize treatment for patients. Antioxid. Redox Signal. 00, 000–000.

DNA polymerase eta (pol η) is the only DNA polymerase causally linked to carcinogenesis in humans. Inherited deficiency of pol η in the variant form of xeroderma pigmentosum (XPV) predisposes to UV-light-induced skin cancer. Pol η-deficient cells demonstrate increased sensitivity to cisplatin and oxaliplatin chemotherapy. We have found that XP30R0 fibroblasts derived from a patient with XPV are more resistant to cell kill by ionising radiation (IR) than the same cells complemented with wild-type pol η. This phenomenon has been confirmed in Burkitt's lymphoma cells, which either expressed wild-type pol η or harboured a pol η deletion. Pol η deficiency was associated with accumulation of cells in S-phase, which persisted after IR. Cells deficient in pol η demonstrated increased homologous recombination (HR)-directed repair of double strand breaks created by IR. Depletion of the HR protein, X-ray repair cross-complementing protein 3 (XRCC3), abrogated the radioresistance observed in pol η-deficient cells as compared with pol η-complemented cells. These findings suggest that HR mediates S-phase-dependent radioresistance associated with pol η deficiency. We propose that pol η protein levels in tumours may potentially be used to identify patients who require treatment with chemo-radiotherapy rather than radiotherapy alone for adequate tumour control.

Neoadjuvant chemoradiotherapy for locally advanced rectal cancer has been shown to decrease rates of local recurrence and more than double the rate of sphincter-preserving surgery. There is now compelling evidence that pathological complete response is an independent predictor of likelihood of local recurrence, distal metastases, disease-free and overall survival in locally advanced rectal cancer following neoadjuvant chemoradiotherapy. Pathological regression grading can therefore guide clinical decisions about salvage surgical strategies, adjuvant therapy and long-term surveillance. No universally recognised regression grading system currently exists for pathologists presented with resected tumour specimens following neoadjuvant chemoradiotherapy. The purpose of this review is to highlight the relevance of accurate tumour regression grading in achieving optimal clinical care for patients with rectal cancer.

Familial breast and ovarian cancers are often defective in homologous recombination (HR) due to mutations in the BRCA1 or BRCA2 genes. Cisplatin chemotherapy or poly(ADP-ribose) polymerase (PARP) inhibitors were tested for these tumors in clinical trials. In a screen for novel drugs that selectively kill BRCA2-defective cells, we identified 6-thioguanine (6TG), which induces DNA double-strand breaks (DSB) that are repaired by HR. Furthermore, we show that 6TG is as efficient as a PARP inhibitor in selectively killing BRCA2-defective tumors in a xenograft model. Spontaneous BRCA1-defective mammary tumors gain resistance to PARP inhibitors through increased P-glycoprotein expression. Here, we show that 6TG efficiently kills such BRCA1-defective PARP inhibitor–resistant tumors. We also show that 6TG could kill cells and tumors that have gained resistance to PARP inhibitors or cisplatin through genetic reversion of the BRCA2 gene. Although HR is reactivated in PARP inhibitor–resistant BRCA2-defective cells, it is not fully restored for the repair of 6TG-induced lesions. This is likely to be due to several recombinogenic lesions being formed after 6TG. We show that BRCA2 is also required for survival from mismatch repair–independent lesions formed by 6TG, which do not include DSBs. This suggests that HR is involved in the repair of 6TG-induced DSBs as well as mismatch repair–independent 6TG-induced DNA lesion. Altogether, our data show that 6TG efficiently kills BRCA2-defective tumors and suggest that 6TG may be effective in the treatment of advanced tumors that have developed resistance to PARP inhibitors or platinum-based chemotherapy. Cancer Res; 70(15); 6268–76. ©2010 AACR.