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Background To analyze the long-term outcomes and prognostic value of hematological parameters in anal cancer patients receiving intensity-modulated radiation therapy (IMRT). Materials Hospital records of consecutive patients with anal squamous cell carcinoma who received curative-intent IMRT according to a standardized contouring protocol between 2010 and 2020 were reviewed. Locoregional failure-free survival (LRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Coverage of locoregional recurrences by the initial IMRT volumes were assessed. The prognostic value of pretreatment blood counts for PFS and OS were determined using Cox regression analysis. Results A total of 166 patients were analyzed with a median follow-up of 3.3 years. Forty-six percent and 54% of patients had Stage I-II and IIIA-B cancers, respectively. The 5-year LRFS, DMFS, PFS and OS were 81%, 89%, 65% and 76% respectively. Grade ≥ 3 toxicity occurred in 5% of patients. Of all patients who relapsed, 70% had only locoregional recurrence as first site of failure. Ninety percent of locoregional recurrences were in-field. Hemoglobin, neutrophil and platelet counts were associated with PFS on univariable analysis, but only cancer stage and p16 status remained prognostic on multivariable analysis. Patients with more advanced cancer stages also had higher baseline neutrophil counts. Performance status and neutrophil counts were prognostic for OS on multivariable analysis. Conclusion This study affirms the long-term efficacy and safety of IMRT. Treatment resistance, rather than radiation geographic miss, is a major issue underpinning locoregional recurrences. Pretreatment blood counts were not validated to be independently prognostic for disease recurrence.

Colorectal cancer is the 3rd most commonly diagnosed cancer, with rectal cancer accounting for 30% of cases. The current standard of care curative treatment for locally advanced rectal cancer is (chemo)radiotherapy followed by surgery and adjuvant chemotherapy. Although neoadjuvant radiotherapy has reduced the risk of local recurrence to less than 10%, the risk of distant metastasis remained high at 30% affecting patient survival. In addition, there is a recognition that there is heterogeneity in tumour biology and treatment response with good responders potentially suitable for treatment de-escalation. Therefore, new treatment sequencing and regimens were investigated. Here, we reviewed the evidence for current neoadjuvant treatment options in patients with locally advanced rectal adenocarcinoma, and highlight the new challenges in this new treatment landscape.

The only curative treatment for localised gastric cancer is surgical resection. However, survival outcomes post-surgery alone remain poor, particularly in those with node-positive disease with 5-year survival of approximately 30%. Therefore, additional perioperative treatment strategies such as radiotherapy and/or chemotherapy have been explored to improve survival outcomes. Early studies established the role of postoperative radiotherapy in improving locoregional control. However, there are now several adjuvant treatment options available, with many centres favouring perioperative chemotherapy. The delivery of radiotherapy in the postoperative setting can be challenging, thereby resulting in suboptimal patient compliance. Hence, the role of preoperative radiotherapy is currently being evaluated. This review focuses on and summarises the landmark clinical trials that have established the current role of radiation therapy in patients with resectable gastric and gastroesophageal adenocarcinoma, and highlights the potential for preoperative radiotherapy.

BackgroundEvidence-based clinical practice guidelines recommend discussion by a multidisciplinary team (MDT) to review and plan the management of patients for a variety of cancers. However, not all patients diagnosed with cancer are presented at an MDT.Objectives(1) To identify the factors (barriers and enablers) influencing presentation of all patients to, and the perceived value of, MDT meetings in the management of patients with pancreatic cancer and; (2) to identify potential interventions that could overcome modifiable barriers and enhance enablers using the theoretical domains framework (TDF).MethodsSemistructured interviews were conducted with radiologists, surgeons, medical and radiation oncologists, gastroenterologists, palliative care specialists and nurse specialists based in New South Wales and Victoria, Australia. Interviews were conducted either in person or via videoconferencing. All interviews were recorded, transcribed verbatim, deidentified and data were thematically coded according to the 12 domains explored within the TDF. Common belief statements were generated to compare the variation between participant responses.ResultsIn total, 29 specialists were interviewed over a 4-month period. Twenty-two themes and 40 belief statements relevant to all the TDF domains were generated. Key enablers influencing MDT practices included a strong organisational focus (social/professional role and identity), beliefs about the benefits of an MDT discussion (beliefs about consequences), the use of technology, for example, videoconferencing (environmental context and resources), the motivation to provide good quality care (motivation and goals) and collegiality (social influences). Barriers included: absence of palliative care representation (skills), the number of MDT meetings (environmental context and resources), the cumulative cost of staff time (beliefs about consequences), the lack of capacity to discuss all patients within the allotted time (beliefs about capabilities) and reduced confidence to participate in discussions (social influences).ConclusionsThe internal and external organisational structures surrounding MDT meetings ideally need to be strengthened with the development of agreed evidence-based protocols and referral pathways, a focus on resource allocation and capabilities, and a culture that fosters widespread collaboration for all stages of pancreatic cancer.

Background The aim of this systematic review is to examine patient-reported outcome measures (PROMs), their attributes and application in patients with pancreatic cancer (PC). Method A systematic literature search was undertaken of articles published to June 2018 to identify PROMs applied in primary studies in PC. Characteristics of the included studies and PROMs were described with identified scales grouped into five domains. The psychometric properties of the identified PROMs were further assessed for reliability and validity among patients with PC. Results From 1688 studies screened, 170 were included. Almost half (48%) were conducted in patients with unresectable PC; the majority of these (68%) were evaluated in randomized controlled trials. Median questionnaire completion rates fell below 10% of the original cohort within 12 months in patients with unresectable PC compared to 75% in patients with resectable PC. Seventy PROMs were identified, 32 measuring unidimensional parameters (e.g. pain) and 35 measuring multidimensional (e.g. quality of life) constructs. Only five (7%) PROMs were disease-specific and 13 (19%) were validated in patients with PC. Fifty scales were grouped into 19 physical, 9 psychological, 6 psychiatric, 9 social and 7 other domains. Conclusion Three multidimensional PROMs, the: (i) FACT-HEP in unresectable PC; (ii) QLQ-PAN26 (in conjunction with its core QLQ-C30 PROM) in resectable PC; and (iii) MDASI-GI are recommended as instruments to capture quality of life in patients with PC. Summarised scales and psychometric evaluation provide a framework to choose PROMs for scales not captured by the recommended PROMs.

Introduction Pancreatic cancer remains a challenging malignancy due to the high proportion of patients diagnosed at advanced stages and the limited treatment options. This article discusses recent evidence in the management of both localised and advanced pancreatic cancer and offers an expert opinion on current best practice. Areas covered For patients with localised disease, the evidence for adjuvant chemotherapy is discussed as well as emerging neoadjuvant approaches for resectable, borderline resectable and locally advanced disease. Advances in metastatic disease are discussed including cytotoxic chemotherapy, targeted therapies and the role of genomic testing to identify patients with molecular alterations. Reviewed literature included; journal publications, abstracts presented at major international oncology meetings and ongoing clinical trials databases. Expert opinion Pancreatic cancer is a devastating diagnosis and despite recent advances has a very poor prognosis. Only a minority of patients, 20%, are diagnosed with potentially curable disease. The shifting paradigm towards neoadjuvant therapy may improve resectability and survival rates however robust evidence is required. Thus far, there has only been limited progress in advanced stage disease. Genomic testing may potentially identify more treatment targets although limited to small subgroups.

Total neoadjuvant therapy in rectal cancer refers to the administration of chemoradiotherapy plus chemotherapy before surgery. Recent studies have shown improved pathological complete response and disease-free survival with this approach. However, survival benefits remain unproven. Our objective is to present a metaanalysis of oncological outcomes of total neoadjuvant therapy in locally advanced rectal cancer. A comprehensive search was performed on PubMed, Medline, and Google Scholars. Studies comparing total neoadjuvant therapy with standard neoadjuvant chemoradiotherapy were included. Data extracted from the individual studies were pooled and a metaanalysis performed. The outcomes of interest are the rate of complete pathological response, nodal response, resection margin, anal preservation, anastomotic leak, local recurrence, distant recurrence, disease-free survival, and overall survival. There were 15 comparative studies with 2437 patients in the neoadjuvant chemoradiotherapy group and 2284 in the total neoadjuvant therapy group. The pooled complete pathological response was 22.3% in the total neoadjuvant therapy group, compared with 14.2% in the standard neoadjuvant chemoradiotherapy group (p

Background Pancreatic cancer (PC) remains a highly fatal disease. There is a gap in the literature on the of quality care on survival in a real-world population. Objectives This study: (1) assessed compliance with a consensus set of quality indicators (QIs); and (2) evaluated the association between compliance with these QIs and survival. Methods Data were collected on a core set of quality indicators by the Upper Gastrointestinal Cancer Registry (UGICR) for patients diagnosed with PC between 1 January 2016 and 31 December 2019. Univariable and multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs for the association between survival and patient characteristics, hospital characteristics and QIs, stratified by resectability. A multivariable analysis tested the relationship between significant patient and hospital characteristics, patient cluster effects within hospitals and survival. Results 1061 patients were eligible for this study with 52% male, 71% over the age of 65, 23% potentially resectable and 51% with metastatic disease at diagnosis. 52% received some form of cancer directed treatment. Significant association with improved survival were: (1) in the potentially resectable group having adjuvant chemotherapy administered following surgery or a reason documented (HR, 0.29; 95 CI, 0.19-0.46); (2) in the locally advanced group included having chemotherapy ± chemoradiation, or a reason documented for not undergoing treatment (HR, 0.38; 95 CI, 0.25-0.58) and (3) in the metastatic disease group included having documented ECOG at presentation and/or American society of Anaesthesiologists (ASA) performance status at a diagnostic procedure (HR, 0.65; 95 CI, 0.47-0.89), being seen by a medical oncologist and/or a radiation oncologist in the absence of treatment (HR, 0.48; 95 CI, 0.31-0.77), and having disease management discussed at an MDT meeting (HR, 0.79; 95 CI, 0.64-0.96). Conclusion Capture of a concise data set has enabled quality of care to be assessed and an analysis of factors associated with improved survival identified.

Purpose/Objective(s) The TOPGEAR (Trial of Preoperative Therapy for Gastric and Esophagogastric Junction Adenocarcinoma) international phase III trial hypothesized that adding preoperative chemoradiation (CRT) to perioperative chemotherapy will improve survival in patients (pts) with gastric cancer. Owing to the complexity of gastric irradiation, a comprehensive radiation therapy quality assurance (RTQA) program was implemented. The objective of this report is to describe the RTQA methods and outcomes. Materials/Methods RTQA was undertaken in ‘real time’ prior to treatment for the first 5 pts randomized to CRT from each center. Once acceptable quality was achieved, RTQA was completed for one third of subsequent cases. RTQA consisted of evaluating the following parameters: 1) clinical target volume (CTV) and organ-at-risk (OAR) contouring; 2) RT planning parameters (CT simulation, dose prescription/planning technique, per-protocol planning constraints). Protocol violations between high- (defined as 20+ pts enrolled) and low-volume centers were compared using Fisher's exact test. Results As of December 2020, 554 pts from 70 centers were enrolled. In total, 277 were randomized to receive RT and 196 (71%) were included for RTQA; of these, 57 (29%) and 139 (71%) were from high- and low-volume centers, respectively. The initial RTQA pass rate was 72% (n = 141). There was no significant difference in the initial pass rate between the high- and low-volume centers (79% vs 69%; P = 0.22) For the 55 cases requiring resubmission, detailed feedback was provided, and most cases had multiple protocol violations. At least one aspect of the CTV had to be adjusted in 49/55 (89%) cases with inadequate coverage of the duodenum down to the 3rd part most commonly seen (n = 28/55, 51%). Table 1 summarizes CTV contouring protocol violations. OARs were generally appropriately contoured with five (9%) cases requiring adjustment. Two cases failed RTQA due to treatment planning violations (kidney dose, lung dose) in absence of contouring (CTV, OAR) concerns. Following resubmission, 192 (98%) passed RTQA and four (2%) required a second resubmission. Conclusion In a large multicenter trial RTQA is feasible and effective in achieving high quality RT treatment plans. Ongoing education and audits should be performed to ensure consistent quality of treatment plans over the study period.

PURPOSE: We examined how radiation dose per fraction (DPF) and total dose, as represented by biological effective dose (BED), can independently and differentially affect the immunomodulatory capacity of radiation therapy (RT). METHODS AND MATERIALS: AT3-OVA mammary and MC38 colorectal tumors in C57BL/6 mice were irradiated with rationally selected dose-fractionation schedules, alone or with immune-modulating or -depleting agents. Tumor growth was monitored as a readout of therapeutic response. Flow cytometry and RNA sequencing of mouse tumors and analysis of transcriptomic data sets from irradiated human cancers were used to examine the immunomodulatory effects of the different radiation schedules. RESULTS: In AT3-OVA tumors, radiation DPF rather than BED determined the ability of RT to evoke local antitumor CD8+ T cell responses and synergize with anti-PD-1 therapy. Natural killer cell-mediated control of irradiated tumors was more sensitive to radiation BED. Radiation-induced regulatory T cell (Treg) responses, which were detected in both mouse and human tumors, were a major factor underlying the differential activation of adaptive immunity by radiation DPF and the activity of natural killer cells during the early phase of response to RT. Targeted inhibition of Treg responses within irradiated tumors rescued and enhanced local tumor control by RT and permitted the generation of abscopal and immunologic memory responses, irrespective of radiation schedule. MC38 tumors did not support the induction of an amplified Treg response to RT and were highly vulnerable to its immunoadjuvant effects. CONCLUSIONS: Local radiation-induced Treg responses are influenced by radiation schedule and tumor type and are a critical determinant of the immunoadjuvant potential of RT and its ability to synergize with T cell-targeted immunotherapy.

Background and purpose The chemotherapy exposure during chemoradiotherapy for rectal cancer is adequate for radiosensitization but suboptimal for treatment of distant micrometastasis. This study aimed to determine tolerability, dose intensity, response, and toxicity of a novel intensified neoadjuvant treatment approach. Materials and Methods Eligible patients were MRI-staged T3-4NxM0 rectal adenocarcinoma. Treatment consisted of FOLFOX chemotherapy given in weeks 1, 6, and 11 with pelvic radiotherapy (25.2 Gy in 3 weeks in 1.8 Gy/fraction with oxaliplatin and 5-FU continuous infusion) given in weeks 3–5, and weeks 8–10. Surgery was performed 4–6 weeks later. The primary endpoint was tolerability defined as the percentage of patients who were able to complete the planned treatment course. Survival rates were estimated using the Kaplan-Meier method. Results Median age of the 40 patients was 61.5 years. Rectal MRI-stage was T3 in 88%. Overall, 95% completed the regimen. All patients received 50.4 Gy. Relative dose intensity (≥75%) was 92% and 98% for oxaliplatin and 5-FU, respectively. High grade toxicities included neutropenia (25% grade 3; 7.5% grade 4) and diarrhoea (10%). Pathologic CR rate was 20%. Median follow-up was 54 months. The 5-year overall survival, freedom from relapse, locoregional control, and freedom from distant metastasis of the cohort was 82%, 72%, 97% and 72%. Conclusions Delivery of intensified neoadjuvant treatment with interdigitating chemotherapy and radiotherapy is feasible with no increase in acute perioperative complications. A larger prospective study is required to further evaluate the potential survival benefit of this design.

Optimal initial management of rectal carcinoma with synchronous metastases (RCSM) is controversial - both for patients being treated with curative and palliative intent. This study aims to evaluate the use of an upfront treatment strategy combining FOLFOX chemotherapy with split-course pelvic chemoradiation (FOLFOX + CRT) for patients with RCSM.An analysis of all patients who commenced treatment with FOLFOX + CRT at our institutions between January 2009 and June 2014 was performed. The regimen consisted of a total of 12 weeks of treatment with split-course pelvic chemoradiation (50.4Gy with concurrent oxaliplatin and 5-FU) alternating with FOLFOX chemotherapy. Restaging imaging was performed following treatment, with subsequent management as per local standard of care.78 patients (15 with resectable liver-only metastases) were identified. 77 (99%) completed at least 45Gy of radiation and 87% completed ≥75% of planned dose intensity of both oxaliplatin and 5FU. Two (2.6%) patients died within 30 days of treatment. Rates of radiological complete or partial response for local and metastatic disease were 90% and 66%, respectively. 24% patients had radiological disease progression of metastatic disease. Median overall survival for patients with unresectable metastatic disease at baseline was 23 months (95%CI: 19-28). 12 patients underwent radical surgery to both the rectum and liver and had an estimated 3-year overall survival rate of 62% (95%CI: 37-100). For those patients who did not proceed to rectal surgery, only 7% required palliative re-irradiation or surgery at a later date and all 20months from initial treatment.In patients with unresectable metastatic disease, FOLFOX + CRT provides durable pelvic control for the majority without the need for additional local treatment. For patients with an advanced primary tumor and synchronous resectable liver-only metastases, FOLFOX + CRT can be considered a feasible and tolerable upfront treatment option.

A small percentage of cancer radiotherapy patients develop abnormally severe side effects as a consequence of intrinsic radiosensitivity. We analysed the γ-H2AX response to ex-vivo irradiation of peripheral blood lymphocytes (PBL) and plucked eyebrow hair follicles from 16 patients who developed severe late radiation toxicity following radiotherapy, and 12 matched control patients. Longer retention of the γ-H2AX signal and lower colocalization efficiency of repair factors in over-responding patients confirmed that DNA repair in these individuals was compromised. Five of the radiosensitive patients harboured LoF mutations in DNA repair genes. An extensive range of quantitative parameters of the γ-H2AX response were studied with the objective to establish a predictor for radiosensitivity status. The most powerful predictor was the combination of the fraction of the unrepairable component of γ-H2AX foci and repair rate in PBL, both derived from non-linear regression analysis of foci repair kinetics. We introduce a visual representation of radiosensitivity status that allocates a position for each patient on a two-dimensional "radiosensitivity map". This analytical approach provides the basis for larger prospective studies to further refine the algorithm, ultimately to triage capability.

PurposeThe Upper Gastrointestinal Cancer Registry (UGICR) was developed to monitor and improve the quality of care provided to patients with upper gastrointestinal cancers in Australia.ParticipantsIt supports four cancer modules: pancreatic, oesophagogastric, biliary and primary liver cancer. The pancreatic cancer (PC) module was the first module to be implemented, with others being established in a staged approach. Individuals are recruited to the registry if they are aged 18 years or older, have received care for their cancer at a participating public/private hospital or private clinic in Australia and do not opt out of participation.Findings to dateThe UGICR is governed by a multidisciplinary steering committee that provides clinical governance and oversees clinical working parties. The role of the working parties is to develop quality indicators based on best practice for each registry module, develop the minimum datasets and provide guidance in analysing and reporting of results. Data are captured from existing data sources (population-based cancer incidence registries, pathology databases and hospital-coded data) and manually from clinical records. Data collectors directly enter information into a secure web-based Research Electronic Data Capture (REDCap) data collection platform. The PC module began with a pilot phase, and subsequently, we used a formal modified Delphi consensus process to establish a core set of quality indicators for PC. The second module developed was the oesophagogastric cancer (OGC) module. Results of the 1 year pilot phases for PC and OGC modules are included in this cohort profile.Future plansThe UGICR will provide regular reports of risk-adjusted, benchmarked performance on a range of quality indicators that will highlight variations in care and clinical outcomes at a health service level. The registry has also been developed with the view to collect patient-reported outcomes (PROs), which will further add to our understanding of the care of patients with these cancers.

Purpose Mitomycin C (MMC) plus standard 5-fluorouracil (FU) infusion in weeks 1 and 5 often contributes to radiotherapy interruptions and possibly less-than-ideal outcomes in anal cancer. This study was to evaluate alternative strategies for chemotherapy delivery that might be less toxic or more efficacious, and outcomes of patient-initiated treatment interruption for severe acute toxicity. Materials and methods This was a prospective, nonrandomized study for patients with T1-4N0-3M0 anal squamous carcinoma. Radiotherapy of 54 Gy in 30 fractions over 6 weeks was given with infusion FU 300 mg/m2 /day for 96 hours/week for 6 weeks plus bolus MMC at 10 mg/m2 on D1. Results Fifty patients were recruited (72% female). Median age was 60.5 years (35-84). Forty-seven patients (94%) received 54 Gy. Median duration of chemoradiation was 39 days (37-105). Grade 3 and 4 acute toxicity were observed in 66%. Thirty-one percent with severe acute toxicity developed severe late toxicity. Of those who experienced severe late skin toxicity, 29% did not have severe acute toxicity. Disease-free survival at 5 years was 74% (95% confidence interval [CI], 60-84), and at 9 years 61% (95% CI, 46-74). Overall survival at 5 years was 84% (95% CI, 71-92), and at 9 years 67% (95% CI, 50-81). Colostomy-free survival at 5 years was 70% (95% CI, 56-81), and at 9 years 57% (95% CI, 40-72). Conclusion It is feasible to deliver chemoradiation with bolus MMC and protracted infusion FU for anal cancer. Efficacy and toxicity of this regimen seem similar to conventional chemoradiation with FU/MMC. Acute skin toxicity is not a reliable predictor of severe late skin toxicity.

Background Accurate pre-operative imaging plays a vital role in patient selection for surgery and in allocating stage-appropriate therapies to patients diagnosed with pancreatic cancer (PC). This study aims to: (1) understand the current diagnosis and staging practices for PC; and (2) explore the factors (barriers and enablers) that influence the use of a pancreatic protocol computed tomography (PPCT) or magnetic resonance imaging (MRI) to confirm diagnosis and/or accurately stage PC. Methods Semi-structured interviews were conducted with radiologists, surgeons, gastroenterologists, medical and radiation oncologists from the states of New South Wales (NSW) and Victoria, Australia. Interviews were conducted either in person or via video conferencing. All interviews were recorded, transcribed verbatim, de-identified and data were thematically coded according to the 12 domains explored within the Theoretical Domains Framework (TDF). Common belief statements were generated to compare the variation between participant responses. Findings In total, 21 clinicians (5 radiologists, 10 surgeons, 2 gastroenterologists, 4 medical and radiation oncologists) were interviewed over a four-month-period. Belief statements relevant to the TDF domains were generated. Across the 11 relevant domains, 20 themes and 30 specific beliefs were identified. All TDF domains, with the exception of social influences were identified by participants as relevant to protocol-based imaging using either a PPCT or MRI, with the domains of knowledge, skills and environmental context and resources being offered by most participants as being relevant in influencing their decisions. Conclusions To maximise outcomes and personalise therapy it is imperative that diagnosis and staging investigations using the most appropriate imaging modalities are conducted in a timely, efficient and effective manner. The results provide an understanding of specialists’ opinion and behaviour in relation to a PPCT or MRI and should be used to inform the design of future interventions to improve compliance with this practice.

Purpose There is growing interest in developing individually tailored cancer radiation therapy (RT), wherein patients with high intrinsic radiosensitivity are identified before commencing treatment, to minimize severe adverse reactions. In a previous retrospective study of severely radiosensitive RT patients, we established a functional assay with a high predictive capability. The assay involves ex vivo irradiation of peripheral blood mononuclear cells and analysis of DNA repair using the γ-H2AX assay. It is unknown whether RS is a fixed phenomenon or is modulated under different conditions. We now report the impact of RT on the apparent radiosensitivity, as reflected by the assay. Methods and Materials Peripheral blood mononuclear cells of 11 patients with non-small cell lung cancer were collected before, during, and after RT. Quantitative parameters derived from the nonlinear regression analysis of γ-H2AX foci were applied to examine the cellular radiation response. Results Although the repair rate and foci yield remained constant during and after RT, the “unrepairable” component of γ-H2AX foci decreased over the course of treatment in 7 patients, signifying a generally enhanced DNA repair capacity. Interestingly, enhanced repair capacity tended to be associated with a poorer response to RT. Conclusions Although generalization of these results into normal and tumor tissues warrants further investigation, the findings of this study have important implications in future strategies for identifying radiosensitive individuals before exposure to RT. We can anticipate that the threshold values that will discriminate radiosensitive patients in a future prospective trial will differ from those established in the retrospective study.

Purpose A priori identification of the small proportion of radiation therapy patients who prove to be severely radiosensitive is a long-held goal in radiation oncology. A number of published studies indicate that analysis of the DNA damage response after ex vivo irradiation of peripheral blood lymphocytes, using the γ-H2AX assay to detect DNA damage, provides a basis for a functional assay for identification of the small proportion of severely radiosensitive cancer patients undergoing radiotherapy. Methods and Materials We introduce a new, more rigorous, integrated approach to analysis of radiation-induced γ-H2AX response, using Bayesian statistics. Results This approach shows excellent discrimination between radiosensitive and non-radiosensitive patient groups described in a previously reported data set. Conclusions Bayesian statistical analysis provides a more appropriate and reliable methodology for future prospective studies.

Purpose Fibrosis can be a disabling, severe side effect of radiotherapy that can occur in patients, and for which there is currently no effective treatment. The activins, proteins which are members of the TGFβ superfamily, have a major role in stimulating the inflammatory response and subsequent fibrosis. Follistatin is an endogenous protein that binds the activins virtually irreversibly and inhibits their actions. These studies test if follistatin can attenuate the fibrotic response using a murine model of radiation-induced fibrosis. Experimental design C57BL/6 mice were subcutaneously injected with follistatin 24 hours prior to irradiation. Mice were irradiated in a 10 x 10 mm square area of the right hind leg with 35 Gy and were given follistatin 24 hours before radiation and three times a week for six months following. Leg extension was measured, and tissue was collected for histological and molecular analysis to evaluate the progression of the radiation-induced fibrosis. Results Leg extension was improved in follistatin treated mice compared to vehicle treated mice at six months after irradiation. Also, epidermal thickness and cell nucleus area of keratinocytes were decreased by the follistatin treatment compared to the cells in irradiated skin of control mice. Finally, the gene expression of transforming growth factor β1 (Tgfb1), and smooth muscle actin (Acta2) were decreased in the irradiated skin and Acta2 and inhibin βA subunit (Inhba) were decreased in the irradiated muscle of the follistatin treated mice. Conclusions Follistatin attenuated the radiation-induced fibrotic response in irradiated mice. These studies provide the data to support further investigation of the use of follistatin to reduce radiation-induced fibrosis in patients undergoing radiotherapy for cancer.

Background Gastric cancer (GC) is a common cause of cancer mortality. There are well-documented prognostic factors for GC but these have not been rigorously examined in an Australian context. This study examines the clinical, surgical and histopathological variables associated with survival in a GC cohort from a predominantly Caucasian-based population. Methods A multi-centre cohort of patients undergoing curative resection for GC enrolled in an ongoing tissue bank study from 1999 to 2009 was retrospectively analysed. Prospectively collected demographic, surgical and pathological variables were available for this cohort. The primary endpoints investigated were cancer-specific survival and recurrence-free survival using multivariate Cox proportional hazard modelling. Results Five-year cancer-specific survival was 45.9%, 5-year relapse-free survival was 44.7% and 30-day mortality was 2.2%. Variables showing significance on multivariate analysis for cancer-specific and relapse-free survival were AJCC stage, Lauren classification and age at surgery. Conclusion This study demonstrates that the prognostic variables for a predominantly Caucasian GC population are congruent with published prognostic features. These findings emphasize the importance of the pathological review in allocating prognosis in GC.

Rachel L.G.M. Blom,1 Tatiana Bogush,2 Bjorn L.D.M. Brucher,3,4 Andrew C. Chang,5 Mikhail Davydov,2 Evgeny Dudko,2 Trevor Leong,6 Boris Polotsky,2 Paul E. Swanson,7 Peter S.N. van Rossum,8,9 Jelle P. Ruurda,8 Xavier Sagaert,10 Sergei Tjulandin,2 Marie-Celine Schraepen,11 Meindert N. Sosef,11 and Richard van Hillegersberg8 1Department of Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands. 2N.N. Blokhin Russian Cancer Research Center of the Russian Academy of Medical Sciences, Moscow, Russia. 3Surgical Oncology, Bon Secours Cancer Institute, Richmond, Virginia. 4Theodor-Billroth-Academy, Munich, Germany. 5Section of Thoracic Surgery, University of Michigan Health System, Ann Arbor, Michigan. 6Peter MacCallum Cancer Centre, Melbourne, Australia. 7University of Washington, Seattle, Washington. 8Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands. 9Department of Radiotherapy, University Medical Center Utrecht, Utrecht, the Netherlands. 10Translational Cell & Tissue Research, Department of Imaging and Pathology, University of KU Leuven, Leuven, Belgium. 11Department of Surgery, Atrium Medical Center, Heerlen, the Netherlands

Postoperative chemoradiation and perioperative chemotherapy using epirubicin/cisplatin/5-fluorouracil (ECF) represent two standards of care for resectable gastric cancer. In the TOPGEAR (Trial Of Preoperative therapy for Gastric and Esophagogastric junction AdenocaRcinoma) trial, we hypothesized that adding preoperative chemoradiation to perioperative ECF will improve survival; however, the safety and feasibility of preoperative chemoradiation have yet to be determined. TOPGEAR is an international phase III trial in which patients with adenocarcinoma of the stomach were randomized to perioperative ECF alone or with preoperative chemoradiation. The ECF-alone group received three preoperative cycles of ECF, while the chemoradiation group received two cycles of preoperative ECF followed by chemoradiation. Both groups received three postoperative cycles of ECF. A planned interim analysis of the first 120 patients was conducted, and was reviewed by the Independent Data Safety Monitoring Committee to assess treatment compliance, toxicity/safety, and response rates. The proportion of patients who received all cycles of preoperative chemotherapy was 93% (ECF group) and 98% (chemoradiation group), while 65 and 53%, respectively, received all cycles of postoperative chemotherapy. Overall, 92% of patients allocated to preoperative chemoradiation received this treatment. The proportion of patients proceeding to surgery was 90% (ECF group) and 85% (chemoradiation group). Grade 3 or higher surgical complications occurred in 22% of patients in both groups. Furthermore, grade 3 or higher gastrointestinal toxicity occurred in 32% (ECF group) and 30% (chemoradiation group) of patients, while hematologic toxicity occurred in 50 and 52% of patients. These results demonstrate that preoperative chemoradiation can be safely delivered to the vast majority of patients without a significant increase in treatment toxicity or surgical morbidity.

Introduction The purpose of this study is to assess the efficacy and toxicity using once-daily reirradiation for patients with rectal cancer having received previous pelvic radiotherapy. Method Between June 1997 and June 2008, 56 patients were identified having received previous pelvic radiotherapy and received reirradiation for rectal cancer. Reirradiation intent was palliative in 43 patients, and preoperative/postoperative in 13 patients. Eighty per cent of patients received concurrent chemotherapy (n = 45). Results The median dose-fractionation reirradiation schedule was 39.6 Gy in 22 fractions once daily (range 20–39.6 Gy), and the median cumulative radiation dose was 87.3 Gy. Seven patients experienced a grade 3 acute toxicity, with no grade 4 event. Fifty-one patients (91%) completed the treatment and five patients required a treatment break. The overall symptomatic response rate was 88% at three months post-reirradiation. There was one late effect of skin ulceration among patients reirradiated palliatively. Median overall survival was 39 months in patients undergoing radical surgery versus 15 months in patients reirradiated palliatively (P

Purpose To compare the local recurrence (LR) rate between short-course (SC) and long-course (LC) neoadjuvant radiotherapy for rectal cancer. Patients and Methods Eligible patients had ultrasound- or magnetic resonance imaging–staged T3N0-2M0 rectal adenocarcinoma within 12 cm from anal verge. SC consisted of pelvic radiotherapy 5 × 5 Gy in 1 week, early surgery, and six courses of adjuvant chemotherapy. LC was 50.4 Gy, 1.8 Gy/fraction, in 5.5 weeks, with continuous infusional fluorouracil 225 mg/m2 per day, surgery in 4 to 6 weeks, and four courses of chemotherapy. Results Three hundred twenty-six patients were randomly assigned; 163 patients to SC and 163 to LC. Median potential follow-up time was 5.9 years (range, 3.0 to 7.8 years). Three-year LR rates (cumulative incidence) were 7.5% for SC and 4.4% for LC (difference, 3.1%; 95% CI, −2.1 to 8.3; P = .24). For distal tumors (< 5 cm), six of 48 SC patients and one of 31 LC patients experienced local recurrence (P = .21). Five-year distant recurrence rates were 27% for SC and 30% for LC (log-rank P = 0.92; hazard ratio [HR] for LC:SC, 1.04; 95% CI, 0.69 to 1.56). Overall survival rates at 5 years were 74% for SC and 70% for LC (log-rank P = 0.62; HR, 1.12; 95% CI, 0.76 to 1.67). Late toxicity rates were not substantially different (Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer G3-4: SC, 5.8%; LC, 8.2%; P = .53). Conclusion Three-year LR rates between SC and LC were not statistically significantly different; the CI for the difference is consistent with either no clinically important difference or differences in favor of LC. LC may be more effective in reducing LR for distal tumors. No differences in rates of distant recurrence, relapse-free survival, overall survival, or late toxicity were detected.

What's known on the subject? and What does the study add? Condyloma acuminatum of the bladder is a rare affliction and as such its ideal management is unknown. This manuscript describes curative treatment of severe disease with external beam radiotherapy concurrent with low dose chemotherapy, an approach which has not previously been utilised. OBJECTIVES • To report the first occurrence of complete and sustained resolution of symptomatic condyloma acuminatum of the bladder with chemoradiotherapy. • To describe the relevant patient details, imaging findings and chemoradiation treatment. PATIENT AND METHOD • A 54-year-old female with extensive condyloma acuminatum of the bladder and a long history of human papilloma virus related anogenital disease was diagnosed with anal squamous cell carcinoma. • Cystectomy for the bladder disease was delayed whilst chemoradiotherapy was administered for the anal cancer. RESULTS • There was complete resolution of bladder disease at follow-up which has negated the need for cystectomy with its associated morbidity. • Condyloma acuminatum has not recurred in 4 years of follow-up. CONCLUSION • This is the first published report to our knowledge of the successful treatment of condyloma acuminatum of the bladder with chemoradiotherapy. • The individual contributions of radiotherapy vs chemotherapy cannot be discerned.

Gastric cancer represents one of the most common cancers internationally. Unfortunately the majority of patients still present at an advanced stage, and despite advances in diagnostic and treatment strategies, outcomes still remain poor with high mortality rates despite a decline in incidence. Whilst the utility of classical chemotherapy agents has been explored thoroughly (and continues to be investigated, alone or in various combinations), advances have been slow and the efficacy of these agents has reached a plateau. As such, the focus of recent study has shifted toward developing a greater understanding of the molecular biology of carcinogenesis and the cancer cell phenotype, and, in turn, the development of rationally designed drugs that target molecular aberrancies in signal transduction pathways specific to gastric cancer. These targets include circulating growth and angiogenic factors, cell surface receptors, and other molecules that comprise downstream intracellular signalling pathways, including receptor tyrosine kinases. Therapeutic advances in this area significantly lag behind other solid organ malignancies such as breast and colorectal cancer. This article reviews the role of targeted therapies in gastric cancer, including rationale and mechanism of action, current and emerging data, as single-agent therapy or in combination regimens. A recently published randomized phaseIII trial supporting the use of trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2)/neu monoclonal antibody, in a selected population of patients is discussed. Therapies that have been evaluated in phase II trials are also reviewed, as well as promising new therapies currently being investigated in preclinical or phase I studies. There is optimism that targeted therapies, whether as single-agent therapy or in combination with traditional therapies, including chemotherapy, radiotherapy and surgery, may yet have an impact on improvement of the overall prognosis of gastric cancer.

Purpose The INT0116 study has established postoperative chemoradiotherapy as the standard of care for completely resected gastric adenocarcinoma. However, the optimal chemoradiation regimen remains to be defined. We conducted a prospective, multicenter study to evaluate an alternative chemoradiation regimen that combines more current systemic treatment with modern techniques of radiotherapy delivery. Methods and Materials Patients with adenocarcinoma of the stomach who had undergone an R0 resection were eligible. Adjuvant therapy consisted of one cycle of epirubicin, cisplatin, and 5-FU (ECF), followed by radiotherapy with concurrent infusional 5-FU, and then two additional cycles of ECF. Radiotherapy was delivered using precisely defined, multiple-field, three-dimensional conformal techniques. Results A total of 54 assessable patients were enrolled from 19 institutions. The proportion of patients commencing Cycles 1, 2, and 3 of ECF chemotherapy were 100%, 81%, and 67% respectively. In all, 94% of patients who received radiotherapy completed treatment as planned. Grade 3/4 neutropenia occurred in 66% of patients with 7.4% developing febrile neutropenia. Most neutropenic episodes (83%) occurred in the post-radiotherapy period during cycles 2 and 3 of ECF. Grade 3/4 gastrointestinal toxicity occurred in 28% of patients. In all, 35% of radiotherapy treatment plans contained protocol deviations that were satisfactorily amended before commencement of treatment. At median follow-up of 36 months, the 3-year overall survival rate was estimated at 61.6%. Conclusions This adjuvant regimen using ECF before and after three-dimensional conformal chemoradiation is feasible and can be safely delivered in a cooperative group setting. A regimen similar to this is currently being compared with the INT0116 regimen in a National Cancer Institute–sponsored, randomized Phase III trial.

Aim To assess the efficacy of chemoradiotherapy in the management of primary squamous-cell carcinoma of the rectum. Method Nine patients with primary squamous-cell carcinoma of the rectum were treated with chemoradiotherapy from 1985 to 2007. All patients were female, with a mean age of 54 years (range 41–72 years). The mean distance of the tumour from the anal verge was 6 cm (range 4–10 cm). Seven patients were treated with curative intent (two postoperative, three preoperative, two chemoradiotherapy alone). Clinical stages for the curative group were T1N0M0 (1), T3N0M0 (3), T3N1M0 (1) and T4N0M0 (2). Chemoradiotherapy consisted of pelvic radiation 45–54 Gy in 1.8 Gy/fraction and concurrent 5-fluorouracil and mitomycin C. The mean follow-up duration for the curative group was 39 months (range 15–120 months). Results All seven patients treated with curative intent achieved local control. A complete pathological response was seen in all patients after preoperative chemoradiotherapy. Two patients did not have surgery and remained free of disease. One patient with gross residual disease after surgery achieved local control. 18-Fluorodeoxyglucose (FDG) avidity was detected in all patients who had FDG-PET scans. Both primary and metastatic tumours demonstrated FDG-avidity. Conclusion Primary squamous-cell carcinoma of the rectum appears to be very sensitive to chemoradiotherapy. The high complete response rate suggests that chemoradiotherapy alone with salvage surgery for local failure should be further explored. FDG-PET scan may have a role to play in the management of this disease.

Meiotic recombination plays a critical role in sexual reproduction by creating crossovers between homologous chromosomes. These crossovers, along with sister chromatid cohesion, connect homologs to enable proper segregation at Meiosis I. Recombination is initiated by programmed double strand breaks (DSBs) at particular regions of the genome. The meiotic recombination checkpoint uses meiosis-specific modifications to the DSB-induced DNA damage response to provide time to convert these breaks into interhomolog crossovers by delaying entry into Meiosis I until the DSBs have been repaired. The meiosis-specific kinase, Mek1, is a key regulator of meiotic recombination pathway choice, as well as being required for the meiotic recombination checkpoint. The major target of this checkpoint is the meiosis-specific transcription factor, Ndt80, which is essential to express genes necessary for completion of recombination and meiotic progression. The molecular mechanism by which cells monitor meiotic DSB repair to allow entry into Meiosis I with unbroken chromosomes was unknown. Using genetic and biochemical approaches, this work demonstrates that in the presence of DSBs, activated Mek1 binds to Ndt80 and phosphorylates the transcription factor, thus inhibiting DNA binding and preventing Ndt80’s function as a transcriptional activator. Repair of DSBs by recombination reduces Mek1 activity, resulting in removal of the inhibitory Mek1 phosphates. Phosphorylation of Ndt80 by the meiosis-specific kinase, Ime2, then results in fully activated Ndt80. Ndt80 upregulates transcription of its own gene, as well as target genes, resulting in prophase exit and progression through meiosis., Author summary Sexual reproduction requires that cells deliberately introduce large numbers of double strand breaks into their chromosomes. Repair of these breaks creates physical connections between homologs that promote proper segregation during meiosis. It is critical that segregation not proceed until all the breaks have been fixed. How does the cell determine when sufficient double strand break repair has occurred? Our work provides a mechanistic explanation to this question. The meiosis-specific Mek1 kinase is activated by double strand breaks. High numbers of breaks result in high Mek1 activity, resulting in phosphorylation of the meiosis-specific Ndt80 transcription factor. Negative charges conferred by phosphorylation prevent Ndt80 from binding the promoters of its target genes, including genes necessary for completing recombination and meiotic progression, thereby preventing their transcription. As breaks are repaired, Mek1 kinase activity decreases and the inhibitory phosphorylation on Ndt80 is lost, allowing Ndt80 to activate transcription of its target genes. As a result, crossover formation is completed and intact chromosomes proceed properly through the meiotic divisions.

Background: Locally advanced oesophageal cancer (LAEC) is associated with poor survival and more effective treatments are needed. The aim of this phase I trial was to assess the maximum tolerated dose (MTD) of a novel weekly docetaxel and cisplatin regimen concurrent with radical radiotherapy. Methods: Patients with unresectable, non-metastatic LAEC were eligible. Treatment comprised docetaxel 15–30 mg m−2 per week and cisplatin 15–30 mg m−2 per week in six planned dose levels (DLs) in 3–6 patient cohorts with 50 Gy radiotherapy in 25 fractions. Maximum tolerated dose was based on defined dose-limiting toxicities (DLTs) during therapy and 2 weeks post therapy. Results: A total of 24 patients were enrolled. There were two DLTs: grade 3 fever in DL1 (docetaxel 15 mg m−2, cisplatin 15 mg m−2) and grade 3 nausea in DL2 (20 mg m−2, 15 mg m−2). These DLs were each expanded to six patients without further DLTs. The most common acute toxicity was grade 3 radiation oesophagitis (37.5%). There were no grade 4 toxicities, and haematologic toxicity was minimal. Cisplatin and docetaxel dose intensity was 100% at the highest dose level (DL6). A MTD was not reached in this trial. Tumour overall response rate was 50% (33% complete, 17% partial). Conclusion: Cisplatin and docetaxel each 30 mg m−2 per week concurrent with 50 Gy radiotherapy is recommended for use in phase II clinical trials in oesophageal cancer.

Objective: To describe the management and outcomes of a population-based cohort of patients with pancreatic cancer treated with chemotherapy or radiotherapy in Victoria, Australia. Design, setting and patients: Questionnaire-based study of patients diagnosed with pancreatic cancer during 2002–2003 in Victoria who were retrospectively identified from the Victorian Cancer Registry and followed up for a minimum of 5 years. Main outcome measures: Reported treatment, referral patterns and survival rates. Results: 1044 patients with pancreatic cancer were identified, of whom 927 were eligible for the study. Completed questionnaires were obtained for 831 eligible patients (response rate, 89.6%) and data for 66 patients with tumours of the ampulla of Vater and neuroendocrine tumours were excluded. Of the remaining 765 patients, 6.5% were managed in multimodality clinics. Chemotherapy was considered for 413 patients and radiotherapy was considered for 162. One-third of the cohort (275 patients) received chemotherapy, most commonly as palliative treatment (185). Single-agent gemcitabine was the most common palliative treatment (154), and was associated with a median overall survival of 6.6 months. Radiotherapy was used in 119 patients (15.6% of the cohort) — it was used alone or with chemotherapy, as postoperative adjuvant treatment, as potentially curative radical treatment, or as palliative treatment. For 45 patients with locally advanced disease who were treated with chemoradiation as radical treatment, median overall survival was 13.1 months. Conclusions: There appears to be under-referral of patients to medical and radiation oncologists. Median survival of patients treated with radical chemoradiation or palliative chemotherapy is consistent with clinical trial data, but outcomes for patients in our cohort were generally poor. Development and implementation of treatment guidelines

Accurate inguinal and pelvic nodal staging in anal cancer is important for the prognosis and planning of radiation fields. There is evidence for the role of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in the staging and management of cancer, with early reports of an increasing role in outcome prognostication in a number of tumours. We aimed to determine the effect of FDG-PET on the nodal staging, radiotherapy planning and prognostication of patients with primary anal cancer. Sixty-one consecutive patients with anal cancer who were referred to a tertiary centre between August 1997 and November 2005 were staged with conventional imaging (CIm) (including computed tomography (CT), magnetic resonance imaging, endoscopic ultrasound and chest X-ray) and by FDG-PET. The stage determined by CIm and the proposed management plan were prospectively recorded and changes in stage and management as a result of FDG-PET assessed. Patients were treated with a uniform radiotherapy technique and dose. The accuracy of changes and prognostication of FDG-PET were validated by subsequent clinical follow-up. Kaplan-Meier survival analysis was used to estimate survival for the whole cohort and by FDG-PET and CIm stage. The tumour-stage group was changed in 23% (14 out of 61) as a result of FDG-PET (15% up-staged, 8% down-staged). Fourteen percent of T1 patients (3 out of 22), 42% of T2 patients (10 out of 24) and 40% of T3-4 patients (6 out of 15) assessed using CIm, had a change in their nodal or metastatic stage following FDG-PET. Sensitivity for nodal regional disease by FDG-PET and CIm was 89% and 62%, respectively. The staging FDG-PET scan altered management intent in 3% (2 out of 61) and radiotherapy fields in 13% (8 out of 61). The estimated 5-year overall survival (OS) and progression-free survival (PFS) for the cohort were 77.3% (95% confidence interval (CI): 55.3-90.4%) and 72.2% (95% CI: 51.5-86.4%), respectively. The estimated 5-year PFS for FDG-PET and CIm staged N2-3 disease was 70% (95% CI: 42.8-87.9%) and 55.3% (95% CI: 23.3-83.4%), respectively. FDG-PET shows increased sensitivity over CIm for staging nodal disease in anal cancer and changes treatment intent or radiotherapy prescription in a significant proportion of patients.

Cultural barriers in hospital ward staff may limit the use of a Medical Emergency Team (MET) service. In December 2000 the role of the existing Code Blue team in our hospital was expanded to incorporate review of patients fulfilling commonly employed MET criteria. Between January 2001 and June 2003, the average call rate was only 9.8 calls/1000 admissions. Anecdotal feedback and a group-administered questionnaire conducted in July 2003 demonstrated a number of obstacles to initiating calls and the system was modified in October 2004. Specifically, emergency response calls were separated into Code Blue calls (for cardiorespiratory arrests) and MET calls (with physiological and worried criteria). Further, loud overhead chimes as well as anaesthetist and cardiologist attendance were used only in the case of Code Blue calls (suspected arrests). Finally, the heart rate and respiratory rate criteria for MET service activation were modified. In the 12 months before the intervention (October 2003 to September 2004) there were 817 emergency response calls and 51,963 admissions (15.7 calls/1000 admissions). In the 12 months after the intervention there were 1349 emergency response calk (Code Blue plus MET calk) and 54,593 admissions (24.7 calls/1000 admissions [OR 1.59; 95% CI=1.45–1.73; P Our findings suggest that increasing the use of an existing service to review patients fulfilling MET criteria requires repeated education and a periodic assessment of site-specific obstacles to utilization.

Background: The study's aim was to determine the maximum tolerated dose (MTD) of celecoxib combined with chemoradiotherapy (CRT) for locally advanced oesophageal cancer (OC). Methods: CRT comprised of 5FU (1000 mg/m2/day, days 1–4, weeks 1 & 5), cisplatin (75 mg/m2, days 1 & 29) and radiotherapy (50 Gy in 25 fractions or 50.4 Gy in 28 fractions). Celecoxib was given daily during CRT at one of five doses (200 mg bd to 600 mg bd). Three to six patients were assigned per dose. Results: Thirteen patients were recruited before trial closure due to external safety concerns regarding celecoxib. Median follow up was 17 months (95% CI 9 – >39). The highest administered dose was 400 mg bd (n=4) with one dose-limiting toxicity at this level: grade 3 rash. Five (38%) and 8(62%) patients had grade 3 non-haematological and haematological toxicities respectively. No grade 4 toxicities occurred. Radiological response rate was 54% (n=7: all CR). Six patients had resection with one pathological CR. Median progression-free and overall survival were 8.8 (95% CI 5.1 – >24.8) and 19.6 months (95% CI 7.3 – >39) respectively. Conclusions: A MTD was not reached. The regimen was tolerable, indicating that celecoxib can be safely administered with CRT for locally advanced OC.

Summary The addition of positron emission tomography (PET) information to CT-based radiotherapy treatment planning has the potential to improve target volume definition through more accurate localization of the primary tumour and involved regional lymph nodes. This case report describes the first patient enrolled to a prospective study evaluating the effects of coregistered positron emission tomography/CT images on radiotherapy treatment planning for oesophageal cancer. The results show that if combined positron emission tomography/CT is used for radiotherapy treatment planning, there may be alterations to the delineation of tumour volumes when compared to CT alone. For this patient, a geographic miss of tumour would have occurred if CT data alone were used for radiotherapy planning.

Purpose of review The treatment of locally advanced gastric cancer remains a major challenge. After decades of investigation that have yielded little improvement in survival rates, several important studies have recently emerged that provide renewed optimism for future research endeavors. This article reviews the important advances over the past several years in the use of chemotherapy and radiotherapy for gastric cancer. Recent findings As a result of the Intergroup trial, adjuvant chemoradiotherapy after operation has emerged as a new standard of care for patients who have undergone resection for carcinoma of the stomach. Strategies currently being tested to build on the Intergroup results include the use of new chemotherapy combinations with radiotherapy and the development of modern conformal techniques to deliver radiation therapy. The preliminary results of a large neoadjuvant chemotherapy study have demonstrated the efficacy of this approach with tumor downstaging and increase in the curative R0 resection rate. For patients with metastatic gastric cancer, newer generation cytotoxic agents such as oxaliplatin, irinotecan, and taxanes show promising activity. In the near future, these agents will likely be evaluated for their role as adjuvant and neoadjuvant therapy. Summary Major advances in the treatment of gastric cancer have occurred during the past several years and have improved the care of patients with this form of tumor.

PURPOSE: This article reports the overall survival, failure-free survival, local failure, and late radiation toxicity of a phase II trial of preoperative radiotherapy with continuous infusion 5-fluorouracil for rectal cancer after a minimum 3.5 years of follow-up. METHODS: Eligible patients were those with newly diagnosed localized adenocarcinoma of the rectum, within 12 cm of the anal verge, staged T3-T4 and deemed suitable for curative resection. Radiotherapy (50.4 Gy in 28 fractions in five weeks and three days) was given with continuous infusion 5-fluorouracil throughout the course of radiotherapy. RESULTS: A total of 82 patients were accrued in 13 months. The median follow-up time was 4.1 (range, 2.3-4.5) years. There were 55 males (67 percent) and the median age was 59 (range, 27-87) years. Patients were staged pretreatment as T3 (89 percent) and resectable T4 (11 percent). Endorectal ultrasound was performed in 70 percent and magnetic resonance imaging in another 5 percent. The four-year overall and failure-free survival rates were 82 percent (95 percent Cl: 72-89) and 69 percent (95 percent Cl: 58-78), respectively. The cumulative incidence of local failure at four years was 3.9 percent (95 percent CI: 1.3-11). Risk of failures, local and distant, has not reached a plateau phase. CONCLUSION: This regimen can be delivered safely and without leading to a significant increase in late toxicity. It provides excellent local control and favorable overall survival. There is a need for longer follow-up than has commonly been used for the proper evaluation of failures after an effective regimen of preoperative chemoradiation.