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AIMS:There is a need for predictive and surrogate response biomarkers to support treatment with antiangiogenic vascular endothelial growth factor (VEGF) inhibitors. We aimed to identify a minimally-invasive biomarker predicting benefit from cediranib pretreatment or early during treatment in patients with recurrent or metastatic cervical cancer.METHODS:Blood samples were collected before treatment, during treatment and upon disease progression where appropriate from patients enrolled in CIRCCa, a randomised phase II trial of carboplatin and paclitaxel with or without cediranib. Plasma concentrations of VEGF-A, VEGF-receptor 2, Ang1 and Tie2 were measured using multiplex enzyme-linked immunosorbent assay. Pretreatment and temporal changes of the biomarkers were investigated using proportional hazard regression and unsupervised clustering analysis.RESULTS:Samples (n = 556) from 52 patients were analysed. VEGF-receptor 2 (P = .0006) and Tie2 (P = .04) were downregulated following cediranib, while VEGF-A (P = .0025) was upregulated. High Eastern Cooperative Oncology Group performance status (P = .02, hazard ratio [HR] = 2.15, 95% confidence interval [CI] 1.13-4.09) and low pretreatment Tie2 concentrations (P = .003, HR = 0.57, 95%CI 0.39-0.83) were independent prognostic factors associated with reduced progression-free survival. Two patterns of changes in VEGF-A following cediranib were identified. Patients with elevated VEGF-A in the first 3 treatment cycles, regardless of magnitude, had reduced progression-free survival in the placebo arm but improved survival with the addition of cediranib (P = .019, HR = 0.13, 95% CI 0.02-0.71).CONCLUSION:Patterns of early elevation in plasma VEGF-A should be studied further as a potential biomarker to predict treatment benefit from cediranib.

This review aimed to determine the clinician and patient reported outcome (PRO) instruments currently usedin randomized controlled trials (RCTs) of radical radiation therapy for nonmetastatic prostate cancer to report acute and late adverse events (AEs), review the quality of methodology and PRO reporting, and report the prevalence of acute and late AEs.The MEDLINE, EMBASE, and Cochrane databases were searched between April and August 2014 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Identified reports were reviewed according to the PRO Consolidated Standards of Reporting Trials (CONSORT) guidelines and the Cochrane Risk of Bias tool. In all, 1149 records were screened, and 21 articles were included in the final review.We determined the acute and late AEs for 9040 patients enrolled in 15 different RCTs. Only clinician reported instruments were used to report acute AEs3 months (eg, Radiation Therapy Oncology Group [RTOG] and Common Terminology Criteria for Adverse Events [CTCAE]). For late clinician reporting, the Late Effects on Normal Tissues-Subjective, Objective, Management and Analytic scale and RTOG were used and were often augmented with additional items to provide comprehensive coverage of sexual functioning and anorectal symptoms. Some late AEs were reported (48% articles) using PROs (eg, ULCA-PCI [University of California, Los Angeles Prostate Cancer Index], FACT-G and P [Functional Assessment of Cancer Therapy GeneralProstate Module], EORTC QLQC-30 + PR25 [European Organisation for Research and Treatment of Cancer Quality of Life QuestionnaireProstate Module]); however, a definitive "preferred" instrument was not evident.Our findings are at odds with recent movements toward including patient voices in reporting of AEs and patient engagement in clinical research. We recommend including PRO to evaluate radical radiation therapy before, during, and after the treatment to fully capture patient experiences, and we support the development of predictive models for late effects based on the severity of early toxicity.Patient reporting of acute and late AEs is underrepresented in radiation therapy trials. We recommend working toward a consistent approach to PRO assessment of radiation therapy-related AEs.

Aims Radiotherapy is an important treatment for many types of cancer, but a minority of patients suffer long-term side-effects of treatment. Multiple lines of evidence suggest a role for circadian rhythm in the development of radiotherapy late side-effects. Materials and methods We carried out a study to examine the effect of radiotherapy timing in two breast cancer patient cohorts. The retrospective LeND cohort comprised 535 patients scored for late effects using the Late Effects of Normal Tissue-Subjective Objective Management Analytical (LENT-SOMA) scale. Acute effects were assessed prospectively in 343 patients from the REQUITE study using the CTCAE v4 scales. Genotyping was carried out for candidate circadian rhythm variants. Results In the LeND cohort, patients who had radiotherapy in the morning had a significantly increased incidence of late toxicity in univariate (P = 0.03) and multivariate analysis (P = 0.01). Acute effects in the REQUITE group were also significantly increased in univariate analysis after morning treatment (P = 0.03) but not on multivariate analysis. Increased late effects in the LeND group receiving morning radiotherapy were associated with carriage of the PER3 variable number tandem repeat 4/4 genotype (P = 6 × 10−3) and the NOCT rs131116075 AA genotype (P = 5 × 10−3). Conclusion Our results suggest that it may be possible to reduce toxicity associated with breast cancer radiotherapy by identifying gene variants that affect circadian rhythm and scheduling for appropriate morning or afternoon radiotherapy.

Background An estimated 17,000 patients are treated annually in the UK with radical radiotherapy (RT) for pelvic cancer. New treatment approaches in RT have increased survivorship and changed the subjective toxicity profile for patients who experience acute and long-term pelvic-related adverse events (AE). Multi-disciplinary follow-up creates difficulty for monitoring and responding to these events during treatment and beyond. Originally developed for use in systemic oncology therapy eRAPID (electronic patient self-Reporting of Adverse-events: Patient Information and aDvice) is an online system for patients to report AEs from home. eRAPID enables patient data to be integrated into the electronic patient records for use in clinical practice, provides patient management advice for mild and moderate AE and advice to contact the hospital for severe AE. The system has now been developed for pelvic RT patients, and we aim to test the intervention in a pilot study with staff and patients to inform a future randomised controlled trial (RCT). Methods Eligible patients are those attending St James’s University hospital cancer centre and The Christie Hospital Manchester undergoing pelvic radiotherapy+/−chemotherapy/hormonotherapy for prostate, lower gastrointestinal and gynaecological cancers. A prospective 1:1 randomised (intervention or usual care) parallel group design with repeated measures and mixed methods will be employed. We aim to recruit 168 patients following recommendations for sample size estimates for pilot studies. Participants using eRAPID will report AE (at least weekly) from home weekly for 6 weeks and 6 weeks post-treatment (12-week total) then at 18 and 24 weeks. Hospital staff will review eRAPID reports and use information during consultations. Notifications will be sent to the relevant clinical team when severe symptoms are reported. We will measure patient-reported outcomes using validated questionnaires (Functional Assessment in Cancer Therapy Scale-General (FACT-G), European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire (EORTC-QLQ-C30), process of care impact (hospital records of patient contacts and admissions) and economic variables (EQ5D-5L, patient use of resources)). Staff and patient experiences will be explored via semi-structured interviews. Discussion The objectives are to establish feasibility, recruitment, integrity of the system and attrition rates, determine effect sizes and aid selection of the primary outcome measure for a future RCT. We will also refine the intervention by exploring staff and patient views. The overall goal of this complex intervention is to improve the safe delivery of cancer treatments, enhance patient care and standardise documentation of AE within the clinical datasets. Trial registration ClinicalTrials.gov NCT02747264. Electronic supplementary material The online version of this article (10.1186/s40814-018-0304-6) contains supplementary material, which is available to authorized users.

Background Pelvic radiotherapy is a treatment delivered to an estimated 150,000 to 300,000 people annually across high-income countries. Fractures due to normal stresses on weakened bone due to radiotherapy are termed insufficiency fractures. Pelvic radiotherapy-related interruption of the blood supply to the hip is termed avascular necrosis and is another recognised complication. The reported incidences of insufficiency fractures are 2.7% to 89% and risk of developing avascular necrosis is 0.5%. These complications lead to significant morbidity in terms of pain, immobility and consequently risk of infections, pressure sores and mortality. Objectives To assess the effects of pharmacological interventions for preventing insufficiency fractures and avascular necrosis in adults over 18 years of age undergoing pelvic radiotherapy. Search methods We performed electronic literature searches in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and DARE to 19 April 2017. We also searched trial registries. Further relevant studies were identified through handsearching of citation lists of included studies. Selection criteria Randomised controlled trials (RCTs) or non RCTs with concurrent comparison groups including quasi-RCTs, cluster RCTs, prospective cohort studies and case series of 30 or more participants were screened. We included studies assessing the effect of pharmacological interventions in adults over 18 years of age undergoing radical pelvic radiotherapy as part of anticancer treatment for a primary pelvic malignancy. We excluded studies involving radiotherapy for bone metastases. We assessed use of pharmacological interventions at any stage before or during pelvic radiotherapy. Interventions included calcium or vitamin D (or both) supplementation, bisphosphonates, selective oestrogen receptor modulators, hormone replacement therapy (oestrogen or testosterone), denosumab and calcitonin. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We contacted study authors to obtain missing data. Data were to be pooled using the random-effects model if study comparisons were similar, otherwise results were to be reported narratively. Main results We included two RCTs (1167 participants). The first RCT compared zoledronic acid with placebo in 96 men undergoing pelvic radiotherapy for non-metastatic prostate cancer.The second RCT had four treatment arms, two of which evaluated zoledronic acid plus adjuvant androgen suppression compared with androgen suppression only in 1071 men undergoing pelvic radiotherapy for non-metastatic prostate cancer.Both studies were at a moderate to high risk of bias and all evidence was judged to be of very low certainty.The studies provided no evidence on the primary outcomes of the review and provided limited data in relation to secondary outcomes, such that meta-analyses were not possible. Both studies focused on interventions to improve bone health in relation to androgen deprivation rather than radiation-related insufficiency fractures and avascular necrosis. Few fractures were described in each study and those described were not specific to insufficiency fractures secondary to radiotherapy. Both studies reported that zoledronic acid in addition to androgen deprivation and pelvic radiotherapy led to improvements in BMD; however, the changes in BMD were measured and reported differently. There was no available evidence regarding adverse effects. Authors' conclusions The evidence relating to interventions to prevent insufficiency fractures and avascular necrosis associated with pelvic radiotherapy in adults is of very low certainty. This review highlights the need for prospective clinical trials using interventions prior to and during radiotherapy to prevent radiation-related bone morbidity, insufficiency fractures and avascular necrosis. Future trials could involve prospective assessment of bone health including BMD and bone turnover markers prior to pelvic radiotherapy. The interventions for investigation could begin as radiotherapy commences and remain ongoing for 12 to 24 months. Bone turnover markers and BMD could be used as surrogate markers for bone health in addition to radiographic imaging to report on presence of insufficiency fractures and development of avascular necrosis. Clinical assessments and patient reported outcomes would help to identify any associated adverse effects of treatment and quality of life outcomes.

The use of multimodal treatments for rectal cancer has improved cancer-related outcomes but makes monitoring toxicity challenging. Optimizing future radiation therapy regimens requires collection and publication of detailed toxicity data. This review evaluated the quality of toxicity information provided in randomized controlled trials (RCTs) of radiation therapy in rectal cancer and focused on the difference between clinician-reported and patient-reported toxicity. Medline, EMBASE, and the Cochrane Library were searched (January 1995-July 2013) for RCTs reporting late toxicity in patients treated with regimens including preoperative (chemo)radiation therapy. Data on toxicity measures and information on toxicity reported were extracted using Quantitative Analyses of Normal Tissue Effects in the Clinic recommendations. International Society for Quality of Life Research standards on patient-reported outcomes (PROs) were used to evaluate the quality of patient-reported toxicity. Twenty-one RCT publications met inclusion criteria out of 4144 articles screened. All PRO studies reported higher rates of toxicity symptoms than clinician-reported studies and reported on a wider range and milder symptoms. No clinician-reported study published data on sexual dysfunction. Of the clinician-reported studies, 55% grouped toxicity data related to an organ system together (eg “Bowel”), and 45% presented data only on more-severe (grade ≥3) toxicity. In comparison, all toxicity grades were reported in 79% of PRO publications, and all studies (100%) presented individual symptom toxicity data (eg bowel urgency). However, PRO reporting quality was variable. Only 43% of PRO studies presented baseline data, 28% did not use any psychometrically validated instruments, and only 29% of studies described statistical methods for managing missing data. Analysis of these trials highlights the lack of reporting standards for adverse events and reveals the differences between clinician and patient reporting of toxicity. Recommendations for improving the quality of adverse event data collection are provided, with the aim of improving critical appraisal of outcomes for future studies.

BackgroundAn increasing number of people survive cancer but a significant proportion have gastrointestinal side effects as a result of radiotherapy (RT), which impairs their quality of life (QoL).ObjectivesTo determine which prophylactic interventions reduce the incidence, severity or both of adverse gastrointestinal effects among adults receiving radiotherapy to treat primary pelvic cancers.Search methodsWe conducted searches of CENTRAL, MEDLINE, and Embase in September 2016 and updated them on 2 November 2017. We also searched clinical trial registries.Selection criteriaWe included randomised controlled trials (RCTs) of interventions to prevent adverse gastrointestinal effects of pelvic radiotherapy among adults receiving radiotherapy to treat primary pelvic cancers, including radiotherapy techniques, other aspects of radiotherapy delivery, pharmacological interventions and non-pharmacological interventions. Studies needed a sample size of 20 or more participants and needed to evaluate gastrointestinal toxicity outcomes. We excluded studies that evaluated dosimetric parameters only. We also excluded trials of interventions to treat acute gastrointestinal symptoms, trials of altered fractionation and dose escalation schedules, and trials of pre- versus postoperative radiotherapy regimens, to restrict the vast scope of the review.Data collection and analysisWe used standard Cochrane methodology. We used the random-effects statistical model for all meta-analyses, and the GRADE system to rate the certainty of the evidence.Main resultsWe included 92 RCTs involving more than 10,000 men and women undergoing pelvic radiotherapy. Trials involved 44 different interventions, including radiotherapy techniques (11 trials, 4 interventions/comparisons), other aspects of radiotherapy delivery (14 trials, 10 interventions), pharmacological interventions (38 trials, 16 interventions), and non-pharmacological interventions (29 trials, 13 interventions). Most studies (79/92) had design limitations. Thirteen studies had a low risk of bias, 50 studies had an unclear risk of bias and 29 studies had a high risk of bias. Main findings include the following:Radiotherapy techniques: Intensity-modulated radiotherapy (IMRT) versus 3D conformal RT (3DCRT) may reduce acute (risk ratio (RR) 0.48, 95% confidence interval (CI) 0.26 to 0.88; participants = 444; studies = 4; I2 = 77%; low-certainty evidence) and late gastrointestinal (GI) toxicity grade 2+ (RR 0.37, 95% CI 0.21 to 0.65; participants = 332; studies = 2; I2 = 0%; low-certainty evidence). Conformal RT (3DCRT or IMRT) versus conventional RT reduces acute GI toxicity grade 2+ (RR 0.57, 95% CI 0.40 to 0.82; participants = 307; studies = 2; I2 = 0%; high-certainty evidence) and probably leads to less late GI toxicity grade 2+ (RR 0.49, 95% CI 0.22 to 1.09; participants = 517; studies = 3; I2 = 44%; moderate-certainty evidence). When brachytherapy (BT) is used instead of external beam radiotherapy (EBRT) in early endometrial cancer, evidence indicates that it reduces acute GI toxicity (grade 2+) (RR 0.02, 95% CI 0.00 to 0.18; participants = 423; studies = 1; high-certainty evidence).Other aspects of radiotherapy delivery: There is probably little or no difference in acute GI toxicity grade 2+ with reduced radiation dose volume (RR 1.21, 95% CI 0.81 to 1.81; participants = 211; studies = 1; moderate-certainty evidence) and maybe no difference in late GI toxicity grade 2+ (RR 1.02, 95% CI 0.15 to 6.97; participants = 107; studies = 1; low-certainty evidence). Evening delivery of RT may reduce acute GI toxicity (diarrhoea) grade 2+ during RT compared with morning delivery of RT (RR 0.51, 95% CI 0.34 to 0.76; participants = 294; studies = 2; I2 = 0%; low-certainty evidence). There may be no difference in acute (RR 2.22, 95% CI 0.62 to 7.93, participants = 110; studies = 1) and late GI toxicity grade 2+ (RR 0.44, 95% CI 0.12 to 1.65; participants = 81; studies = 1) between a bladder volume preparation of 1080 mls and that of 540 mls (low-certainty evidence). Low-certainty evidence on balloon and hydrogel spacers suggests that these interventions for prostate cancer RT may make little or no difference to GI outcomes.Pharmacological interventions: Evidence for any beneficial effects of aminosalicylates, sucralfate, amifostine, corticosteroid enemas, bile acid sequestrants, famotidine and selenium is of a low or very low certainty. However, evidence on certain aminosalicylates (mesalazine, olsalazine), misoprostol suppositories, oral magnesium oxide and octreotide injections suggests that these agents may worsen GI symptoms, such as diarrhoea or rectal bleeding.Non-pharmacological interventions: Low-certainty evidence suggests that protein supplements (RR 0.23, 95% CI 0.07 to 0.74; participants = 74; studies = 1), dietary counselling (RR 0.04, 95% CI 0.00 to 0.60; participants = 74; studies = 1) and probiotics (RR 0.43, 95% CI 0.22 to 0.82; participants = 923; studies = 5; I2 = 91%) may reduce acute RT-related diarrhoea (grade 2+). Dietary counselling may also reduce diarrhoeal symptoms in the long term (at five years, RR 0.05, 95% CI 0.00 to 0.78; participants = 61; studies = 1). Low-certainty evidence from one study (108 participants) suggests that a high-fibre diet may have a beneficial effect on GI symptoms (mean difference (MD) 6.10, 95% CI 1.71 to 10.49) and quality of life (MD 20.50, 95% CI 9.97 to 31.03) at one year. High-certainty evidence indicates that glutamine supplements do not prevent RT-induced diarrhoea. Evidence on various other non-pharmacological interventions, such as green tea tablets, is lacking.Quality of life was rarely and inconsistently reported across included studies, and the available data were seldom adequate for meta-analysis.Authors' conclusionsConformal radiotherapy techniques are an improvement on older radiotherapy techniques. IMRT may be better than 3DCRT in terms of GI toxicity, but the evidence to support this is uncertain. There is no high-quality evidence to support the use of any other prophylactic intervention evaluated. However, evidence on some potential interventions shows that they probably have no role to play in reducing RT-related GI toxicity. More RCTs are needed for interventions with limited evidence suggesting potential benefits.

Growing numbers of patients with cancer are surviving after treatment with pelvic radiotherapy. We evaluated the technique of volumetric modulated arc therapy (VMAT), which delivers a decreased dose to the organs at risk. We aimed to determine outcomes of this technique in terms of patient-reported acute toxicity and late effects and correlate the frequency of gastrointestinal symptoms with the volume of bowel receiving radiation dose.Patients who were to receive VMAT for gynaecological malignancy completed patient-reported outcomes at baseline, the end of treatment, 8 weeks and 1 year. The rates of patient-reported toxicity were correlated with the volume of bowel irradiated.The frequencies of patient-reported gastrointestinal symptoms increased in the acute toxicity phase and tended to improve at 1 year, with the exception of faecal incontinence and rectal bleeding (P 0.05). There was not a strong association between the volume of small bowel that was irradiated (P 0.05 at all dose levels) and reported toxicity, suggesting that other factors are involved in the development of toxicity.Although VMAT decreases the dose delivered to the small bowel, this does not translate into a reduction in patient-reported toxicity.

Introduction Following pelvic radiotherapy up to 50% of patients have a permanent change in bowel habit which will affect their quality-of-life. Malnourishment is common prior to treatment and bile acid malabsorption (BAM), lactose intolerance and small bowel bacterial overgrowth (SBBO) can occur during treatment. It was hypothesised that patients who receive a gastrointestinal (GI) care bundle during chemoradiotherapy for pelvic malignancy will have improved GI symptoms and Health-Related Quality-of-Life (HRQL). Method This pilot feasibility randomised controlled trial (RCT) included patients with cervical and bladder carcinoma who were undergoing radical chemoradiotherapy. Questionnaire and anthropometric data were collected. The intervention patients received individualised dietary counselling and when they developed lower GI symptoms hydrogen methane breath testing was arranged to detect lactose intolerance and SBBO and a SeHCAT to detect BAM. Treatment was given. Results Fifty patients were recruited between December 2012 and January 2015, 24 were randomised to the intervention group and 26 to the control group. All trial patients completed 20 fractions of external beam pelvic radiotherapy. Figure 1 demonstrates the mean bowel scores reported by patients at baseline, 6 weeks, 12 weeks and 52 weeks. As in Table 1 the median bowel score of each group increased at 6 weeks and decreased thereafter. The control group score was higher than the intervention group score at 6 weeks however this study was not powered for hypothesis testing. Abstract PWE-140 Table 1 The median bowel score of each group at each time point. The mean HRQL in the control group fell by 0.14 (0.91 at baseline to 0.77 at 52 weeks) compared to 0.06 in the intervention group (0.89 at baseline to 0.83 at 52 weeks) (see figure 2). This relative difference was in part driven by the increased mortality observed in the control arm. All patients developed GI symptoms. It was possible to perform 57/72 (79%) intervention tests. Conclusion It was feasible to recruit to and deliver an RCT of GI intervention in patients undergoing pelvic chemoradiotherapy. There was a trend for a lower median bowel score in the intervention group at 6 weeks. This needs testing in a larger RCT. Disclosure of Interest None Declared

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To determine which prophylactic interventions reduce the incidence, severity, or both of adverse gastrointestinal effects among adults receiving radiotherapy to treat primary pelvic cancers.

Despite publication of numerous radiogenomics studies to date, positive single nucleotide polymorphism (SNP) associations have rarely been reproduced in independent validation studies. A major reason for these inconsistencies is a high number of false positive findings because no adjustments were made for multiple comparisons. It is also possible that some validation studies were false negatives due to methodological shortcomings or a failure to reproduce relevant details of the original study. Transparent reporting is needed to ensure these flaws do not hamper progress in radiogenomics. In response to the need for improving the quality of research in the area, the Radiogenomics Consortium produced an 18-item checklist for reporting radiogenomics studies. It is recognised that not all studies will have recorded all of the information included in the checklist. However, authors should report on all checklist items and acknowledge any missing information. Use of STROGAR guidelines will advance the field of radiogenomics by increasing the transparency and completeness of reporting.

Bowel toxicity is a major complication of cancer treatment, and its accurate reporting is important for assessing outcomes. The NCI's Common Terminology Criteria for Adverse Events (CTCAE) is the preferred method for capturing adverse events after all cancer treatments, particularly within clinical trials. However, the CTCAE version 4 does not include urgency of defecation as an item, despite this being one of the most common and persistent adverse consequences of treatment of pelvic cancers. The importance of bowel urgency to patients is well documented, and this treatment effect has a negative impact on social function and quality of life. Bowel urgency is also important clinically because it may represent significant underlying problems. This article presents the case for including patient reported assessment of bowel urgency as an independent item in cancer treatment adverse event reporting.

Aims This paper details the considerations and calculations made by this centre for the implementation of the biologically equivalent dose in 2 Gy fractions (EQD 2 ) radiobiology calculations recommended by the Gynaecological Groupe Europeen de Curietherapie – European Society for Therapeutic Radiology and Oncology, in converting our cervix, body of uterus and vaginal vault low dose rate (LDR) treatment prescription schedules for caesium-137 to equivalent pulsed dose rate (PDR) protocols using iridium-192. Materials and methods The assumptions made in order to calculate the EQD 2 for both the LDR and the corresponding PDR schedules are detailed. The source geometries and prescription points are discussed for all standard treatment schedules. The prescription point for vaginal vault treatments has been altered to a 5 mm depth rather than the applicator surface, and the prescribed dose for all applicator sizes has been normalised at this depth. Results The calculated PDR schedules are presented, with corresponding target and organ at risk values given for LDR and PDR versions of standard treatment schedules. A standard 32.5 Gy point A cervix prescription used in Manchester with LDR has been converted to 2 × 19 Gy for PDR. Conclusions PDR schedules have been calculated to correspond with our established LDR treatments in terms of EQD 2 dose to the target. There is a theoretical improvement in the therapeutic ratio due to a reduction in the calculated EQD 2 to organs at risk.

Fifty percent of patients develop chronic gastrointestinal (GI) symptoms following pelvic radiotherapy that adversely affect quality of life. Fewer than 20 % are referred to a gastroenterologist. We aimed to determine if structured gastroenterological evaluation is of benefit to this patient group.Sixty patients with GI symptoms at ≥ 6 months after radical pelvic radiotherapy were identified prospectively from oncology clinics in this service evaluation. Those requiring urgent investigation were excluded. Patients were assessed at baseline using patient-reported questionnaires: inflammatory bowel disease questionnaire (IBDQ), Vaizey incontinence questionnaire, and the Common Terminology Criteria for Adverse Events (CTCAE) pelvis questionnaire. Participants were referred for gastroenterological evaluation using an algorithmic approach. Further assessments were made at 3 and 6 months.Twenty men and 36 women with primary gynecological (31), urological (17), or lower GI (8) tumors were included (mean age, 58.5 years). Median time from radiotherapy to baseline assessment was 3.0 years. Multiple GI symptoms were reported (median, 8; range, 4-16) including frequency, urgency, loose stool, fecal incontinence, flatulence, bloating/distension, and rectal bleeding. Common diagnoses included radiation proctopathy, bile acid malabsorption, diverticulosis, and colonic polyps. Statistically significant improvements in all questionnaire scores between baseline and 6 months were found: IBDQ (p = 0.014), Vaizey (p0.0005), and CTCAE rectum-bowel subset (p = 0.001).Gastroenterological evaluation identifies significant, potentially treatable diagnoses in patients who develop chronic GI symptoms following pelvic radiotherapy. Some findings are incidental and unrelated to previous cancer treatment. Radiation-induced GI symptoms have historically been considered "untreatable." We report the first data to show that structured gastroenterological assessment has the potential to improve outcome by identifying diagnoses and facilitating focused treatment.

Background: The microvascular contrast agent transfer constant Ktrans has shown prognostic value in cervical cancer patients treated with chemoradiotherapy. This study aims to determine whether this is explained by the contribution to Ktrans of plasma flow (Fp), vessel permeability surface-area product (PS), or a combination of both.Methods: Pre-treatment dynamic contrast-enhanced MRI (DCE-MRI) data from 36 patients were analysed using the two-compartment exchange model. Estimates of Fp, PS, Ktrans, and fractional plasma and interstitial volumes (vp and ve) were made and used in univariate and multivariate survival analyses adjusting for clinicopathologic variables tumour stage, nodal status, histological subtype, patient age, tumour volume, and treatment type (chemoradiotherapy vs radiotherapy alone). Results: In univariate analyses, Fp (HR=0.25, P=0.0095) and Ktrans (HR=0.20, P=0.032) were significantly associated with disease-free survival while PS, vp and ve were not. In multivariate analyses adjusting for clinicopathologic variables, Fp and Ktrans significantly increased the accuracy of survival predictions (P=0.0089).Conclusions: The prognostic value of Ktrans in cervical cancer patients treated with chemoradiotherapy is explained by microvascular plasma flow (Fp) rather than vessel permeability surface-area product (PS).

Background: Response to radiotherapy varies between individuals both in terms of efficacy and adverse reactions. Finding genetic determinants of radiation response would allow the tailoring of the treatment, either by altering the radiation dose or by surgery. Despite a growing number of studies in radiogenomics, there are no well-replicated genetic association results. Methods: We carried out a candidate gene association study and replicated the result using three additional large cohorts, a total of 2036 women scored for adverse reactions to radiotherapy for breast cancer. Results: Genetic variation near the tumour necrosis factor alpha gene is shown to affect several clinical endpoints including breast induration, telangiectasia and overall toxicity. In the combined analysis homozygosity for the rare allele increases overall toxicity (P=0.001) and chance of being in the upper quartile of risk with odds ratio of 2.46 (95% confidence interval 1.52–3.98). Conclusion: We have identified that alleles of the class III major histocompatibility complex region associate with overall radiotherapy toxicity in breast cancer patients by using internal replication through a staged design. This is the first well-replicated report of a genetic predictor for radiotherapy reactions.

Background and purpose: As late radiotherapy toxicity impacts negatively on the quality-of-life of cancer survivors and is often under reported, a study was set up to prospectively collect patient-reported data in an unselected series of patients with gynaecological malignancy. Aim 1 – To provide 3 year results for the longitudinal study. Aim 2 – To improve the questionnaire used to collect data by identifying redundant items and modifying for use to collect Common Terminology Criteria for Adverse Events (CTCAE) data. Material and methods: Aim 1 – Patient reported outcome data were collected prospectively by 226 patients before and up to 3 years following radiotherapy for gynaecological cancer using a questionnaire developed to collect LENT subjective data. Aim 2 – A factor analysis was performed to identify which questions gave the most and least information. Results: Aim 1 – Faecal urgency and incontinence (all grades) peaked at 79% and 24%, respectively at 1 year then settled to 69% and 18% at 3 years, respectively. Urinary urgency (all grades) increased with time and was described in 75% at 3 years. Other symptoms reported at 3 years include diarrhoea in 12%, urinary incontinence in 27% and vaginal dryness in 29%. A third of patients did not feel their sex life had changed following treatment, while a quarter felt that it had. Aim 2 – some questions overlapped and others were non-specific. The questionnaire has subsequently been altered. Conclusions: The extent of late toxicity is substantial. This detailed information is important for both patients and clinicians in terms of treatment decisions and follow-up care. The LENT questionnaire provides a feasible tool for capture of this information in the clinic.

Introduction 17,000 patients receive treatment with radical pelvic radiotherapy annually in the UK. Up to 50% of patients will develop bowel symptoms which affect quality of life. Services for this patient group are underdeveloped. Barriers to good clinical care include poor patient reporting, poor clinician recognition and a lack of established routes of referral. The National Cancer Survivorship Initiative (2007) has identified access to specialist medical care for those with complications that occur after cancer as one of the four key needs of cancer survivors. It is in this context that we aimed to determine the current practice of clinical oncologists in the UK. Methods A questionnaire was developed and sent to the 314 clinical oncologists in the UK who treat pelvic malignancies up to a maximum of three times by post. Results 190 (61%) responses were received. 76% of oncologists screen for GI dysfunction after pelvic radiotherapy. 85% screen for symptoms through history taking with only 11% using formal screening questionnaires. Clinical oncologists view toxicity as a significant problem, with 64% estimating that up to 24% patients have bowel symptoms at 1 year. 71% oncologists refer Conclusion Whilst British oncologists recognise bowel dysfunction after pelvic radiotherapy as a significant problem, they refer only a minority of patients for specialist evaluation. This may reflect the lack of clear routes of referral and access to GI expertise. The estimated proportion of patients affected was lower than that reported in the literature, which may reflect the lack of robust systems in routine practice to detect significant symptoms. The views expressed clearly highlight the need for a dedicated gastroenterology-lead multidisciplinary service to address the imbalance between this established unmet need and current service provision.

Objectives: In 1997, a study was launched to investigate the treatment of early prostate cancer. Using a patient preference design, health-related quality-of-life (HRQOL) and disease specific HRQOL was assessed prospectively to compare men undergoing radical prostatectomy (RP), hypo-fractionated conformal radiotherapy (CRT) or brachytherapy (BT). Methods: Patients with localised prostate cancer were counselled by a urological surgeon, clinical oncologist and specialist uro-oncology nurse. Patients received treatment according to individual preference. 430 men chose and received RP (n = 217), CRT (n = 161) and BT (n = 52). 354 (82%) completed pre-treatment RAND 36-Item Short-Form Health survey version-2 (SF36v2) and University of California, Los Angeles Prostate cancer index (UCLA-PCI) questionnaires. HRQOL score changes from baseline to 24 months were compared using Kruskall-Wallis test. Results: Pre-treatment, the CRT cohort scored lower for physical function (p = 0.0029) and general health perception (p = 0.0021). The BT cohort reported better baseline scores for urinary function (p = 0.0291), urinary bother (p = 0.0030), sexual function (p = 0.0009) and bowel bother (p = 0.0063). At 24 months, bowel function was similar for CRT and BT but both modalities were worse than RP (p = 0.0010). Urinary continence deteriorated most following RP (p < 0.0001) but BT had worse urinary bother (p = 0.0153). Sexual function deteriorated most following RP and BT (p < 0.0005). Percentages of patients achieving erections adequate for sexual activity (from baseline to 24 months) were 66% to 29% for RP, 62% to 49% for CRT and 88% to 65% for BT. Conclusion: This data demonstrates significant differences in disease specific quality-of-life between RP, CRT and BT and should be available for men with early prostate cancer making treatment decisions.

Study Type – Preference (prospective cohort) Level of Evidence 1b What’s known on the subject? and What does the study add? In general the literature suggests that there is a need for improvement in aiding men diagnosed with early prostate cancer in their decision making about treatment options and that our understanding of this process is inadequate. There is limited data analyzing the reasons why these men decide between potentially curative or observational treatments and data evaluating patients’ views before and after definitive therapy are scarce. This study begins the process of understanding the reasons underlying a patient’s final treatment decision. Being a prospective study, it looks at the thought processes of these men before treatment during the time the decision is made. It also documents how satisfied patients are with their choice after their treatment and whether they would choose the same treatment again. OBJECTIVE • To identify the reasons for patients with localised prostate cancer choosing between treatments and the relationship of procedure type to patient satisfaction post-treatment. PATIENTS AND METHODS • 768 men with prostate cancer (stage T1/2, Gleason ≤7, PSA

Purpose The patient’s role in toxicity reporting is increasingly acknowledged but requires the adaptation and validation of toxicity reporting instruments for patient use as most toxicity scales are designed for physician use. Recording of radiotherapy related late toxicity is important and needs to be improved. A patient-scored symptom questionnaire of late treatment effects using LENT–SOMA was compared with a recognised quality of life tool (EORTC QLQ-C30/H&N35). Materials/methods LENT–SOMA and EORTC QLQ-C30 patient questionnaires were prospectively completed by 220 head and neck cancer patients over 3 years and 72 completed EORTC QLQ-H&N35 questionnaires at 2 years post-radiotherapy. Results Endpoints common to both questionnaires (pain, swallowing, dental pain, dry mouth, opening mouth, analgesics) were matched. Spearman rank correlation coefficients with ρ > 0.6 (P < 0.001) were obtained for all “matched” scales except for analgesics scale, ρ = 0.267 (P < 0.05). There was good agreement between LENT–SOMA and EORTC QLQ-H&N35 except for analgesic endpoints. Global quality of life scores correlated negatively with average LENT–SOMA scores (P < 0.001). Significant differences in average LENT–SOMA scores between treatment modalities were found. The LENT–SOMA questionnaire has demonstrated a high Cronbach’s α value (0.786) indicating good reliability. Conclusions LENT–SOMA patient questionnaire results agreed well with those from the EORTC QLQ-H&N35 questionnaire for toxicity items where they could be compared explicitly, particularly for subjective endpoints. Patient-reported late toxicity had a negative impact on quality of life. The LENT-SOMA patient questionnaire is both reliable and sensitive to differences between patients treated with different modalities. A patient-based questionnaire is an important contributor to capturing late radiotherapy effects.

Purpose: To improve a questionnaire used to collect patient-reported outcomes from patients with early stage prostate cancer treated with brachytherapy. A secondary aim was to adapt the Late Effects of Normal Tissue (LENT) subjective toxicity questionnaire for use to collect Common Terminology Criteria for Adverse Events (CTCAE) data, the current preferred platform for assessing radiation toxicity. Materials and methods: Three hundred and seventy-seven patients were treated with permanent iodine-125 seed implant brachytherapy for early prostate cancer. Toxicity data were collected before and at nine time points post-treatment (0–36 months). Compliance rates for patients completing individual items and item-subsection correlation coefficients were calculated. A factor analysis was carried out to analyse responses to the questionnaire and identify less informative questions, which could be removed. Cronbach’s α coefficient was used to measure reliability. Results: Two thousand one hundred and eighty-eight questionnaires were analysed. There was poor compliance for questions specifically relating to operations and bowel medication. We found that the division of the questionnaire into subsections based on anatomical site was reasonable and that certain items could be safely removed. The high mean value for Cronbach’s α across all questionnaires (0.752; 95% CI: 0.726–0.779) indicated that the questionnaire was reliable. Fifteen of the 44 questions were removed from the original questionnaires. Questions on urinary incontinence severity, management of urinary and bowel incontinence, effects of reduced flow of urine and the effects of symptoms on activity of daily living and change in sexual function were required to adapt the LENT subjective questionnaire for use to collect CTCAE data. Conclusions: A questionnaire, validated over 6 years to collect LENT subjective data were adapted and is a reliable approach for collecting CTCAE data after prostate brachytherapy.

Aims To compare survival and late complications between patients treated with chemoradiotherapy and radiotherapy for locally advanced cervix cancer. Materials and methods A Royal College of Radiologists’ audit of patients treated with radiotherapy in UK cancer centres in 2001–2002. Survival, recurrence and late complications were assessed for patients grouped according to radical treatment received (radiotherapy, chemoradiotherapy, postoperative radiotherapy or chemoradiotherapy) and non-radical treatment. Late complication rates were assessed using the Franco-Italian glossary. Results Data were analysed for 1243 patients from 42 UK centres. Overall 5-year survival was 56% (any radical treatment); 44% (radical radiotherapy); 55% (chemoradiotherapy) and 71% (surgery with postoperative radiotherapy). Overall survival at 5 years was 59% (stage IB), 44% (stage IIB) and 24% (stage IIIB) for women treated with radiotherapy, and 65% (stage IB), 61% (stage IIB) and 44% (stage IIIB) for those receiving chemoradiotherapy. Cox regression showed that survival was significantly better for patients receiving chemoradiotherapy (hazard ratio = 0.77, 95% confidence interval 0.60–0.98; P = 0.037) compared with those receiving radiotherapy taking age, stage, pelvic node involvement and treatment delay into account. The grade 3/4 late complication rate was 8% (radiotherapy) and 10% (chemoradiotherapy). Although complications continued to develop up to 7 years after treatment for those receiving chemoradiotherapy, there was no apparent increase in overall late complications compared with radiotherapy alone when other factors were taken into account (hazard ratio = 0.94, 95% confidence interval 0.71–1.245; P = 0.667). Discussion The addition of chemotherapy to radiotherapy seems to have improved survival compared with radiotherapy alone for women treated in 2001–2002, without an apparent rise in late treatment complications.

BackgroundAlthough patient-reported outcomes (PROs) to assess health-related quality-of-life (QoL) are increasingly incorporated in radiotherapy trials, QoL in the acute period following treatment remains under-reported. This study assessed the relationship between QoL in the acute treatment phase, toxicity, patient and treatment variables in breast cancer patients.MethodsBreast cancer patients (n = 2,072) were recruited following breast-conserving surgery across eight centres in Europe and North America into a multicentre prospective cohort study (www.requite.eu). Treatment data, toxicity scored according to CTCAE v4.0, and PROs from EORTC-QLQ-C30 and –B23 were available for 1,750 patients at baseline and on completion of radiotherapy. Association of acute toxicity endpoints (dichotomised) and worsening QoL (≥ 10 point change from baseline) was investigated using multivariate logistic regression, adjusted for age, BMI, total radiotherapy dose, seroma, chemotherapy, tamoxifen, analgesic use, smoking and alcohol intake.ResultsBy the end of radiotherapy, 24.2 % of patient experienced ≥ grade 2 erythema, 31.6 % ≥ grade 1 oedema, and 9.5 % were affected by acute desquamation (skin loss). Global health status, fatigue, pain, and breast symptoms worsened significantly compared to baseline. Acute erythema and acute desquamation were significantly associated with worsening breast symptoms (OR 1.71, 95 % CI 1.41-2.06; and OR 1.77, 1.18-2.67), while acute erythema was also associated with worsening pain (1.24, 1.03-1.50). There was no significant association of any acute toxicity endpoint with worsening global health status.ConclusionsManagement of early toxicities that affect breast-specific symptoms and pain may improve QoL during radiotherapy. Overall QoL (global health status) during breast radiotherapy is likely to be influenced by a range of non-treatment factors.

We investigated the efficacy of data capture of patient-reported toxicity following radiotherapy by comparing electronic and paper formats. Patient-reported toxicity questionnaires based on items from the NCI Common Terminology Criteria for Adverse Events (CTCAE) were created for patients receiving radiotherapy. Electronic and paper questionnaires had identical questions. Thirty seven gynaecological cancer and 40 prostate cancer patients completed questionnaires. Both questionnaire formats (electronic and paper) were completed by each patient at time points before and after radiotherapy. The average questionnaire and subsection scores for each format were compared directly and by using intra-class correlation (ICC) coefficients. The internal consistency/reliability was assessed by determining Cronbach's alpha coefficient. Patient preference for questionnaire format including clarity and ease-of-use was recorded. 324 questionnaires were collected as part of this study. A similar pattern of average subsection scores was found for the electronic and paper questionnaires. ICC coefficients for the mean overall questionnaire scores and subsection scores were high (0.8). Cronbach's alpha was generally greater than 0.6, indicating that the reliability was high. Of the patients that responded, 27.3% preferred the electronic format, 25.7% preferred the paper format and 47% had no preference. The average time taken to complete a questionnaire was about 9 minutes for each format. The different questionnaire formats measured toxicity effects consistently and were reliable for both gynaecological cancer and prostate cancer patients. The survey indicated that patients found the questionnaires clear, easy to understand and straightforward to complete. Electronic data capture of patient-reported toxicity for CTCAE is feasible and acceptable.

Purpose: Patient-based reporting of symptoms is increasingly important in providing treatment toxicity information. However, observer-based scoring systems such as the CTCAEs which incorporate the LENT-SOMA scales are not adapted for patient-based reporting. We aim to (1) report the late toxicity in patients following head and neck radiotherapy using a LENT-SOMA patient-based questionnaire, (2) describe how the responses help to improve the questionnaire and (3) adapt the questionnaire for patient reporting using CTCAEs. Methods: A 31-item LENT-SOMA patient questionnaire was administered prospectively to 220 patients pre-treatment and at eight time periods post-radical head and neck radiotherapy over 3 years. Exploratory factor analysis was carried out and questionnaire reliability was evaluated using Cronbach’s α coefficient. Results: At 3-years follow-up, grade 3/4 toxicity was recorded for xerostomia (44%), hoarseness (14.3%), altered taste (6.1%) and oropharyngeal pain (1.9%). Factor analysis indicated that questionnaire division according to anatomical sub-site was reasonable. Cronbach’s α was 0.851 (95% CI: 0.820–0.883) indicating high reliability. Good compliance was obtained with all questions except for the ‘weight loss’ item. A satisfaction survey showed that the questionnaire was clear and concise. Teeth and mandible sections have been removed. Dietary change due to xerostomia has been incorporated in line with CTCAEs. LENT-SOMA scoring of analgesic needs and dysphagia not described in CTCAEs were found useful and have been retained. Conclusions: The questionnaire has enabled reporting of late toxicity and the responses have enabled refinement of the questionnaire. It is reliable, feasible and has been validated for patient-based collection of CTCAEs late toxicity data.

The aims of this study were to assess changes in quality of life (QoL) scores in relation to radical radiotherapy for gynaecological cancer (before and after treatment up to 3 years), and to identify the effect that late treatment effects have on QoL. This was a prospective study involving 225 gynaecological cancer patients. A QoL instrument (European Organisation for the Research and Treatment of Cancer QLQ-C30) and late treatment effect questionnaire (Late Effects Normal Tissues – Subjective Objective Management Analysis) were completed before and after treatment (immediately after radiotherapy, 6 weeks, 12, 24 and 36 months after treatment). Most patients had acute physical symptoms and impaired functioning immediately after treatment. Levels of fatigue and diarrhoea only returned to those at pre-treatment assessment after 6 weeks. Patients with high treatment toxicity scores had lower global QoL scores. In conclusion, treatment with radiotherapy for gynaecological cancer has a negative effect on QoL, most apparent immediately after treatment. Certain late treatment effects have a negative effect on QoL for at least 2 years after radiotherapy. These treatment effects are centred on symptoms relating to the rectum and bowel, for example, diarrhoea, tenesmus and urgency. Future research will identify specific symptoms resulting from late treatment toxicity that have the greatest effect on QoL; therefore allowing effective management plans to be developed to reduce these symptoms and improve QoL in gynaecological cancer patients.

Aims Two recent meta-analyses have shown a survival advantage for the addition of concurrent chemotherapy to radiotherapy in the treatment of cervical cancer. However, there is insufficient information available on late toxicity and few data from UK practice. The aims of this study were to examine treatment outcomes (survival and toxicity) in patients with cervical cancer treated with chemoradiation and to compare these with outcomes in patients treated with radiation alone. Materials and methods Between July 2000 and December 2003, 75 patients with cervical cancer were treated with chemoradiation. Case notes were reviewed retrospectively. Acute and late toxicity were recorded, with late toxicity graded using the Franco-Italian glossary. The median age was 47 years. All patients were staged with examination under anaesthesia and magnetic resonance imaging scans. Forty-two patients were treated with concurrent chemoradiation alone and 33 patients were treated with a combination of neoadjuvant and concurrent chemoradiation. This was due to waiting list problems. The chemotherapy used was cisplatin 40mg/m 2 weekly with radiotherapy, (the neoadjuvant dose was 60mg/m 2 3 weekly). External beam radiotherapy was given to the pelvis (40–45Gy/20 fractions/4 weeks) followed by low dose rate brachytherapy (22.5–32.5Gy to point A). Patients who were unable to have brachytherapy were given an external beam boost (15–20Gy/8–10 fractions). Results The 3-year overall survival rate was 70%, with an estimated 5-year overall survival rate of 60%. The 3-year disease-free survival was 63.6%, with an estimated 5-year disease-free survival rate of 55%. Compared with the cohort of 183 patients from the Christie Hospital in a 1993 audit, there was a trend towards improved overall survival from 49 to 60% ( P =0.06), which may become significant with longer follow-up. There were seven patients (9.3%) with grade 3 toxicity and no cases of grade 4 toxicity. In comparison with patients treated in the 1993 audit, the late toxicity rate has increased from 3.4 to 9.3%, but this was not statistically significant ( P =0.14). Conclusion There was a trend towards improved survival with concurrent chemoradiation in this cohort of patients that may become significant with longer follow-up.

Aims To compare the accuracy of renal assessment in patients with cancer using radioisotope glomerular filtration rate (GFR), urine collection for creatinine clearance, Cockroft–Gault, Modification of Diet in Renal Disease (MDRD) and Wright formulae. Materials and methods Measurements of isotope GFR from 367 patients were compared with estimates from the described methods (Cockroft–Gault, MDRD, Wright). An analysis including a further 252 patients with an isotope GFR≤50ml/min was also carried out. Results The Wright formula was the most accurate form of estimating renal function for the first study group. The formulae were similar in accuracy in the second study group. Conclusions The Wright formula is the most accurate form of estimation of renal function in comparison with the isotope GFR for cancer patients. When there is a large proportion of patients with a low isotope GFR (≤50ml/min), the formulae have similar accuracy.

Aims To determine the outcome and morbidity after radiotherapy for locally recurrent cervical cancer. Materials and methods Women who presented with locally recurrent cervical cancer after surgery alone during 1985 and 1997 were identified from the hospital database. Data were collected and analysed to include the stage at first diagnosis, staging investigations before surgery, the surgical procedure, the indication for radiotherapy, the type of radiotherapy, morbidity and survival. Results In total, 130 women had radical external beam radiotherapy and/or intracavitary brachytherapy for locoregional recurrence during the defined study period. The 5-year disease-specific survival for the study population was 40.2%. Women who were treated for vault recurrence had a significantly better 5-year disease-free survival compared with women who developed nodal recurrence alone (55.4% vs 12.5%). This group of women also had a significantly slower rate of disease progression after radiotherapy than women with nodal recurrence (48.7% vs 87.5%, P =0.0001). Conclusion Radical radiotherapy alone is able to salvage 55% of vaginal vault recurrences after surgery for cervical cancer with minimal late toxicity. Salvage rates in women with pelvic nodal recurrences are considerably lower. Chemoradiotherapy using intensity-modulated radiotherapy to deliver an escalated radiotherapy dose needs to be pursued to improve locoregional control.

Background In the USA, more than 7200 new cases of anal cancer were diagnosed in 2014 with incidence rising. Concurrent chemoradiotherapy improves cancer-related outcomes but has led to an increase in acute and late adverse events. Patient-reported outcomes (PRO) are increasingly included in trials as a surrogate measure for reporting of late adverse events. This study aimed to select the most effective PRO to use in clinical research and practice for anal cancer since no questionnaire specific for anal cancer has been developed. Methods A mixed methods approached was used. A systematic review estimated the frequency of use of PROs and clinician reporting instruments used in anal cancer trials including radiation treatment. Health professional semi-structured interviews explored preferred questionnaires and revealed missing items; analysis was done using the framework approach. Two symptom-based, validated questionnaires were selected and assessed by means of inductive content analysis to highlight discrepancies relevant to anal cancer. Findings 34 relevant studies reported on radiotherapy adverse events. For PROs, EORTC QLQ-C30 (n=5) and EORTC QLQ-CR38 (n=3) were used most frequently. RTOG/EORTC (n=17) and CTCAE (n=15) criteria were most commonly used for clinician reporting. EORTC QLQ-C30 and EORTC QLQ-CR38, and National Cancer Institute's (NCI) PRO-CTCAE were selected for further analysis. No consensus for questionnaire content or design was found through health professional interviews (n=8). Domains and codes relevant to anal cancer treatment were selected from interviews to inform questionnaire analysis. 27 domains and 60 codes were found in EORTC questionnaires, and 21 domains and 44 codes in NCI PRO-CTCAE. Four domains and 16 codes were not covered by EORTC systems including radiation skin reaction. Six domains and 45 codes were not covered by NCI PRO-CTCAE including vaginal stenosis and bowel urgency. Interpretation This study shows that there are gaps in the questionnaires commonly used to record adverse events using PROs for anal cancer. Expert opinion is valuable in highlighting relevant missing items but provides no consensus on design and wording preferences. For use in longitudinal follow-up of patients with anal cancer treated with (chemo)radiation, the EORTC-QLQ system has the fewest missing symptom items for use as a validated PRO in clinical research and practice. Funding This abstract presents independent research funded by the National Institute for Health Research (NIHR).

There is increasing interest in the use of patient-reported outcomes (PROs) in routine practice in cancer care to measure symptoms and health related quality of life (HRQOL). PROs are designed to capture the patient's perspective of their care and treatment, and complement the traditional clinical outcomes of survival and toxicity assessment. Integrating routine collection and feedback of PROs has been found to improve care for patients on both an individual level, through improved communication and management of symptoms, and at an organizational level, by enabling aggregation of data to compare performance. This article reviews the benefits and challenges of introducing patient-reported assessments into routine clinical practice. Methods for choosing a questionnaire; collection and presentation of results; timing and frequency of administration as well as clinician training methods to aid the ability of clinicians to integrate the use of PROs into their own practice are described. Electronic PRO capture and integration with electronic health records seems to provide the most effective method for seamless integration into existing patient care pathways. Case studies from our own practice illustrate the issues raised. Electronic methods enabling immediate collection, scoring and interpretation of the data, as well as real-time data capture, email alert systems and individualized, online self-management advice may enable severe symptoms to be managed in a more timely manner. Evaluation methods are described to establish the effectiveness of the PRO intervention. Engaging stakeholders throughout the process of initial consultation and development, during delivery and evaluation is key to success. Future work needs to focus on the effectiveness of PROs in longer-term follow-up of patients in routine care and the relationship between the PRO severity grading and clinician severity grading using the Common Terminology Criteria of Adverse Events (CTCAE).

The objective of this study was to assess treatment outcomes in a large case series of cervical cancer patients undergoing postoperative radiotherapy in a single center. Case notes of women referred to the Christie Hospital during 1985-1997 for postoperative adjuvant radiotherapy for cervical cancer were reviewed. Of 478 women eligible for analysis, 282 (58.9%) underwent radical hysterectomy and 196 (41.1%) had nonradical hysterectomy. The disease-specific 5-year survival for the study population is 70.1%, with a 5-year risk of developing any recurrence of 30.5% and a 5-year grade 3 morbidity rate of 3.9%. Survival was significantly higher, ie, 80.9% vs 62.7% (P = 0.0001) and recurrence was significantly lower, ie, 18.6% vs 38.8% (P < 0.00005) in the group of women who had adjuvant radiotherapy following a nonradical hysterectomy compared with radical surgery. Thirty percent of women having "radical" surgery had positive resection margins and required postoperative adjuvant pelvic radiotherapy. Women with node-positive disease, who received adjuvant radiotherapy, had a high rate of distant metastases. These women would receive chemoradiotherapy now as primary treatment because of the risk of developing distant metastases. If, despite staging investigations, surgery reveals node-positive disease, then these women should receive adjuvant chemoradiotherapy. Survival was better in women who had nonradical surgery due to smaller volume disease when cancers were unsuspected and hence will have been cured by surgery alone. Multidisciplinary team working, as recommended by national guidelines from 1999, should allow better patient selection for treatment.

The Bcl-2 family of apoptotic regulators is thought to play an essential role in cancer development and influence the sensitivity of tumour cells to radiotherapy. Bid is an abundantly expressed Bcl-2 family protein playing a central role in various pathways of apoptosis by integrating and converging signals at the mitochondria. The relevance of apoptotic modulation by Bcl-2 and related proteins in tumour development and radiation response for human tumours remains undefined. Therefore, a study was made regarding the expression of Bid in patients with locally advanced cervix carcinoma who received radiotherapy. Bid expression was assessed using immunohistochemistry in pretreatment archival biopsies from 98 patients. The data were correlated with clinicopathologic characteristics and treatment outcome. Pretreatment tumour radiosensitivity data were available for 60 patients. Strong Bid expression was associated with a patient age less than the median of 52 years (P=0.034) and poor metastasis-free survival. In multivariate analysis, after allowing for stage, Bid expression was a significant prognostic factor for both disease-specific and metastasis-free survival (P=0.026). It is concluded that strong tumour Bid expression is associated with poor outcome following radiotherapy regardless of intrinsic tumour cell radiosensitivity, and is adverse prognostic for disease-specific and metastasis-free survival in younger patients.

Improved patient outcomes have been correlated with high caseload hospitals for a multitude of conditions, including cancer. Using avariety of end points this is true for the treatment of brain tumours, breast cancer and particularly colorectal cancer. The most definitive evidence comes from a Cochrane meta-analysis of the treatment of colorectal cancer between high-volume/specialist hospitals and surgeons and low-volume/specialist hospitals and surgeons. Overall 5 year survival was significantly improved for patients with colorectal cancer treated in high-volume hospitals (hazard ratio ¼ 0.90, 95% confidence interval 0.5e0.96). The volume outcome relationship was somewhat stronger for the individual surgeon than the hospital as the hazard ratio for high-volume versus low-volume surgeons was hazard ratio ¼ 0.88, 95% confidence interval 0.83e0.93 [1]. Data previously published in the west of Scotland had shown that survival was significantly better in both colorectal cancer [2] and breast cancer [3] when patients were treated by high caseload surgeons. Surgeons with a high throughput may have better individual skills and as a consequence carry out a more thorough and technically demanding operation. A study from Finland has shown that surgeons with a high caseload dissect more lymph nodes from the axilla than surgeons with a low caseload (mean number of lymph nodes 11.2 versus 9.4; P ¼� 0.001) [4]. High caseload surgeons were also more likely to carry out breast conservation rather than mastectomy (P � 0.001) and higher caseloads were related to better survival (P ¼ 0.031) [5]. A high caseload may be a surrogate for more subtle factors other than just individual surgical skill. A study that examined the 7 year survival of patients with breast cancer in Quebec [6] showed a survival advantage for women treated in centres seeing more than 100 new cases of breast cancer per year. Survival was better among those treated in high case volume hospitals, but the significance of caseload disappeared when other factors that were associated with improved survival, such as teaching status, research activity and onsite radiotherapy, were taken into account. There is far less in the literature about caseload volume and outcome after radiotherapy. External beam radiotherapy treatment for nasopharynx cancer is a technically demanding exercise. Therefore it is unsurprising that a group in Taiwan found that patients had a better 10 year survival when treated by physicians who treated more than 35 cases a year compared with those who treated less than 35 cases (75% versus 61%; P � 0.01) [7]. We could find no publications correlating caseload and outcome from

Purpose: Hypoxia-inducible factor (HIF)-1α expression was studied retrospectively in locally advanced carcinoma of the cervix in relation to other methods for measuring/assessing tumor hypoxia and outcome after radiotherapy. Experimental Design: HIF-1α expression was examined in formalin-fixed tumor biopsies using a semiquantitative scoring system and correlated with measurements of hypoxia obtained using oxygen electrodes, pimonidazole staining, and carbonic anhydrase 9. Results: High HIF-1α expression showed a weak correlation with low pO2 (r = −0.26; P = 0.030; n = 72). Weak significant correlations were found between HIF-1α and pimonidazole staining (r = 0.34; P = 0.040; n = 36) and carbonic anhydrase IX (r = 0.27; P = 0.001; n = 160). There was no relationship with surviving fraction at 2 Gy. The relationship between HIF-1α expression and radiotherapy outcome was examined in 99 patients. HIF-1α expression did not correlate with disease stage, grade, tumor size, and patient age. HIF-1α alone was not a significant prognostic factor for disease-free survival, metastasis-free survival, or local recurrence-free survival. High HIF-1α expression tended to be associated with poor outcome in small tumors but good outcome in large tumors, with statistically significant interactions between HIF-1α and tumor size for survival (P = 0.046) and local control (P = 0.009). Conclusions: In this study, HIF-1α had no prognostic significance in locally advanced carcinoma of the cervix. The possible switch in large tumors for an association between high HIF-1α expression and good outcome might relate to tumor size-related changes in the balance of genes up-regulated by HIF-1α. Whereas angiogenesis-promoting genes might be preferentially up-regulated in small tumors, proapoptotic genes might be induced in large tumors. This hypothesis needs testing in future work.

Background and purpose: The European Society for Therapeutic Radiology and Oncology was funded by the EU for a project on recording providing education, and ameliorating the consequences of treatment (REACT). An European audit was carried out as part of which to assess the usefulness of current follow-up practices. Patients and methods: Over a 4-month period in 15 cancer centres in 10 countries, patients attending for routine follow-up completed a questionnaire covering their expectations of and satisfaction with the visit. This was matched with a questionnaire completed by the physician about the content and usefulness of the consultation. The feasibility of a short toxicity scale developed by Dische and Saunders was also investigated. Results: In total, 2303 matched questionnaires were analysed. Forty percent of the patients had symptoms or medical problems related to their disease. In 18% there was a positive finding on clinical examination. In 28% investigations were undertaken part of departmental routine practice. Ten percent of the investigations showed an abnormal result. Ninety nine percent of physicians and 85% of the patients expressed satisfaction. Using the short toxicity scale rates of recording toxicity could be increased from 28 to 93%. Conclusions: There is wide variation in follow-up practices among European centres. There was a low incidence of positive findings clinically or with routine investigations. A simple scale for recording morbidity has proved easy to use by departments, which have not routinely used one of the standard measures. Further work will attempt to produce an European guideline for effective routine follow-up after radiotherapy. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

To assess the correlation between the LENT (late effects on normal tissue) SOMA (subjective objective management analytic) system and the Franco-Italian glossary scores of late morbidity in cervical cancer patients treated with radiation, and to compare the ability of the scoring systems to detect differences between radiation treatment groups.The study was retrospective. Patients, invited to take part in the study, had radiotherapy for cervical cancer and had a minimum of 3 years follow-up with no evidence of recurrence. One hundred patients agreed to take part. LENT subjective data were obtained using a patient questionnaire approach in order to complete the scales as published. The LENT objective, management and Franco-Italian glossary scores were obtained by a physician. Correlations between scores and differences between treatment groups were examined using non-parametric tests.The average LENT SOMA scores had a greater resolution than the maximum scores, and using the maximum score alone underestimated treatment morbidity. The Franco-Italian glossary scores correlated strongly with the LENT objective scores (rho=0.61, P0.0005), and less strongly with the LENT subjective scores (rho=0.45, P0.0005). Significant differences in morbidity between the radiation treatment groups were measured using both the LENT SOMA system and the Franco-Italian glossary.The maximum and average LENT scores should be reported for each subsite. The LENT objective scores correlated well with the scores obtained using the established Franco-Italian glossary, but the LENT system provided additional information on subjective treatment effects. Both systems were able to measure significant differences in morbidity between radiation treatment groups. In conclusion, the LENT SOMA system is a valid and comprehensive approach for scoring the late normal tissue effects of radiotherapy.

Background and purpose : As there are few studies examining the impact of radiotherapy on sexuality, we assessed the effect of radiotherapy for carcinoma of the cervix on sexual health and the ability of the LENT system to assess sexual function. Materials and methods : Using the vagina and sexual dysfunction scales of the LENT SOMA scales, subjective scores were measured prospectively before initiation of radiotherapy for 89 women, and at the following times after the start of treatment: 21, 70, 200, 400, 600 and 800 days. Results : There was considerable variation in pre-radiotherapy scores that was not related to disease stage ( P =0.054), but was related to patient age ( P =0.037, for the average vagina scores and P =0.039 for the maximum vagina scores) The scores were influenced by prior surgery ( P P =0.042 average and 0.017 maximum sexual dysfunction scores). For 48 patients for whom data were available at the first three time points, the vagina scores decreased significantly by 70 days compared to pre-radiotherapy scores, but not for sexual dysfunction. There was heterogeneity in the pattern of changes of scores over time: for some women there was no change in vagina subsection score, some increased, and some decreased. Conclusions : The work has shown variation both in pre-treatment sexual function and in the pattern of changes seen following radiotherapy. Our questionnaire proved useful to score subjective sexual and vaginal problems as given in the LENT subjective scales. Further study is needed to assess the effectiveness of the scales in assessing late effects.

To assess the prognostic significance of imaging findings used in magnetic resonance imaging (MRI) staging of cervical carcinoma by correlation with survival after radiotherapy.MRI examinations of 99 cervical carcinoma patients were reviewed. Tumour involvement of pelvic structures was assessed. Lymph node sites, short axis diameters and signal characteristics were recorded. MRI staging was compared with clinical [International Federation of Gynaecology and Obstetrics (FIGO)] staging. Univariate analysis was performed for MRI stage, clinical stage, nodal status and pelvic structure involvement against disease-specific (DSS) and disease-free survival (DFS).MRI staging correlated with DSS (p=0.006) and DFS (p=0.007) but clinical staging did not. Pelvic nodesor = 10 mm and juxtaregional or distant nodesor = 8 mm short axis were most strongly associated with survival (p=0.014, p=0.011 and p=0.001, respectively, for association with DSS). Tumour involvement of pelvic bowel loops, pelvic sidewall and bladder mucosa were significantly associated with poor DSS and DFS (p0.05). Tumour dimensions and bladder muscle involvement alone were not associated with poor survival.MRI staging is a better predictor of survival than clinical staging in patients receiving radiotherapy for cervical carcinoma. MRI assessment of lymph node enlargement and tumour involvement of pelvic structures gives valuable prognostic information.

Purpose To examine the Late Effects Normal Tissue Task Force (LENT)-Subjective, Objective, Management, Analytic (SOMA) scales prospectively in carcinoma of the cervix treated curatively with radiotherapy (RT) using interviews and postal questionnaires and to test the sensitivity of the scales in assessing the radiation effects. Methods and materials A consecutive series of 100 patients completed questionnaires to score the subjective part of the published LENT-SOMA scales. Assessments were made before RT and at approximately 21, 70, 200, 400, 600, and 800 days after the start of treatment. The acceptability and feasibility of using the scales was examined using compliance in completion of the questionnaires. The scales were validated by evaluating the concordance of data obtained by two independent scorers and by examining the ability of the scales to measure radiation-related symptoms. Results Questionnaires were completed for 89 patients before RT. The level of noncompliance was 11%. The concordance between scores when two people completed the questionnaires independently was excellent. Subjective subsite scores were highest 21 days after treatment but generally fell by 70 days. The average baseline overall LENT-SOMA subjective scores increased with advancing stage ( p = 0.008) and were higher for patients treated with RT alone ( p = 0.044). Conclusion In cervical carcinoma, the LENT-SOMA scales were acceptable and feasible to administer in the clinic and appropriate in the measurement of early subjective morbidity from RT.

The presence of hypoxia in tumours results in the overexpression of certain genes, which are controlled via the transcription factor HIF-1. Hypoxic cells are known to be radioresistant and chemoresistant, thus, a reliable surrogate marker of hypoxia is desirable to ensure that treatment may be rationally applied. Recently, the HIF-1-regulated proteins Glut-1 and CAIX were validated as intrinsic markers of hypoxia by comparison with pO(2) measured using oxygen electrodes. We compare the expression of Glut-1 and CAIX with the binding of the bioreductive drug hypoxia marker pimonidazole. Pimonidazole was administered to 42 patients with advanced carcinoma of the cervix, 16 hr before biopsy. Sections of single or multiple biopsies were then immunostained for Glut-1 and CAIX, and the area of staining scored by eye, using a "field-by-field" semi-quantitative averaging system. Using 1 biopsy only, Glut-1 (r = 0.54, p =

Purpose: To investigate whether analysis of MRI enhancement data using a pharmacokinetic model improved a previously found correlation between contrast enhancement and tumor oxygenation measured using Po 2 histograph. To evaluate the prognostic value of gadolinium enhancement data for radiotherapy outcome, and to study the efficacy of combined enhancement and MRI volume data. Methods and materials: Fifty patients underwent dynamic gadolinium-enhanced MRI as part of their initial staging investigations before treatment. Gadolinium enhancement was analyzed using the Brix pharmacokinetic model to obtain the parameters amplitude and rate of contrast enhancement. Pretreatment tumor oxygen measurements (Eppendorf Po 2 histograph) were available for 35 patients. Results: Both standard and pharmacokinetic-derived enhancement data correlated with tumor oxygenation measurements, and poorly enhancing tumors had low tumor oxygen levels. However, only the pharmacokinetic-analyzed data correlated with patient outcome and patients with poorly (amplitude less than median) vs. well-enhancing tumors had significantly worse disease-specific survival ( p = 0.024). For the 50 patients studied, no relationship was found between enhancement and volume data. Combining MRI volume and enhancement information highlighted large differences in outcome ( p = 0.0054). At the time of analysis, only 55% of patients with large, poorly enhanced tumors were alive compared with 92% of patients with small, well-enhanced tumors. Conclusion: These preliminary results suggest that pharmacokinetic modeling of dynamic contrast-enhanced MRI provides data that reflect tumor oxygenation and yields useful prognostic information in patients with locally advanced carcinoma of the cervix. Combining MRI-derived enhancement and volume data delineates large differences in radiotherapy outcome.

Requite is using standardised forms and questionnaires, which are available for data collection in other studies. The centralised resource will be accessible to investigate relationships between different toxicity end points and quality of life and ways to identify better dosimetric predictors of toxicity. Deasy et al. [27] highlighted that the way to accelerate progress in improving radiotherapy toxicity predictive models is: ‘to begin storing high-quality datasets in repositories’ so that ‘data could then be pooled, greatly enhancing the capability to construct predictive models that are more widely applicable and better powered to accurately identify key predictive factors’. The requite project addresses the need for data pooling. Of course, the long-term goal of predictive model/assay research is to individualise cancer treatment, which will need decision aids for both radiation oncologists and their patients [28], including information on an individual's likely tumour response and their risk of side-effects. Widespread implementation will require a high level of evidence for benefit (e.g. From randomised trials), including cost-effectiveness and medico-legal issues will need to be addressed (e.g. Ce marking, food and drug administration approval). High-quality datasets from multicentre studies of routine cancer patients are essential to underpin progress in predictive model research.