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Temporary drug treatment cessation might alleviate toxicity without substantially compromising efficacy in patients with cancer. We aimed to determine if a tyrosine kinase inhibitor drug-free interval strategy was non-inferior to a conventional continuation strategy for first-line treatment of advanced clear cell renal cell carcinoma. This open-label, non-inferiority, randomised, controlled, phase 2/3 trial was done at 60 hospital sites in the UK. Eligible patients (aged ≥18 years) had histologically confirmed clear cell renal cell carcinoma, inoperable loco-regional or metastatic disease, no previous systemic therapy for advanced disease, uni-dimensionally assessed Response Evaluation Criteria in Solid Tumours-defined measurable disease, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) at baseline to a conventional continuation strategy or drug-free interval strategy using a central computer-generated minimisation programme incorporating a random element. Stratification factors were Memorial Sloan Kettering Cancer Center prognostic group risk factor, sex, trial site, age, disease status, tyrosine kinase inhibitor, and previous nephrectomy. All patients received standard dosing schedules of oral sunitinib (50 mg per day) or oral pazopanib (800 mg per day) for 24 weeks before moving into their randomly allocated group. Patients allocated to the drug-free interval strategy group then had a treatment break until disease progression, when treatment was re-instated. Patients in the conventional continuation strategy group continued treatment. Patients, treating clinicians, and the study team were aware of treatment allocation. The co-primary endpoints were overall survival and quality-adjusted life-years (QALYs); non-inferiority was shown if the lower limit of the two-sided 95% CI for the overall survival hazard ratio (HR) was 0·812 or higher and if the lower limit of the two-sided 95% CI of the marginal difference in mean QALYs was -0·156 or higher. The co-primary endpoints were assessed in the intention-to-treat (ITT) population, which included all randomly assigned patients, and the per-protocol population, which excluded patients in the ITT population with major protocol violations and who did not begin their randomisation allocation as per the protocol. Non-inferiority was to be concluded if it was met for both endpoints in both analysis populations. Safety was assessed in all participants who received a tyrosine kinase inhibitor. The trial was registered with ISRCTN, 06473203, and EudraCT, 2011-001098-16. Between Jan 13, 2012, and Sept 12, 2017, 2197 patients were screened for eligibility, of whom 920 were randomly assigned to the conventional continuation strategy (n=461) or the drug-free interval strategy (n=459; 668 [73%] male and 251 [27%] female; 885 [96%] White and 23 [3%] non-White). The median follow-up time was 58 months (IQR 46-73 months) in the ITT population and 58 months (46-72) in the per-protocol population. 488 patients continued on the trial after week 24. For overall survival, non-inferiority was demonstrated in the ITT population only (adjusted HR 0·97 [95% CI 0·83 to 1·12] in the ITT population; 0·94 [0·80 to 1·09] in the per-protocol population). Non-inferiority was demonstrated for QALYs in the ITT population (n=919) and per-protocol (n=871) population (marginal effect difference 0·06 [95% CI -0·11 to 0·23] for the ITT population; 0·04 [-0·14 to 0·21] for the per-protocol population). The most common grade 3 or worse adverse events were hypertension (124 [26%] of 485 patients in the conventional continuation strategy group vs 127 [29%] of 431 patients in the drug-free interval strategy group); hepatotoxicity (55 [11%] vs 48 [11%]); and fatigue (39 [8%] vs 63 [15%]). 192 (21%) of 920 participants had a serious adverse reaction. 12 treatment-related deaths were reported (three patients in the conventional continuation strategy group; nine patients in the drug-free interval strategy group) due to vascular (n=3), cardiac (n=3), hepatobiliary (n=3), gastrointestinal (n=1), or nervous system (n=1) disorders, and from infections and infestations (n=1). Overall, non-inferiority between groups could not be concluded. However, there seemed to be no clinically meaningful reduction in life expectancy between the drug-free interval strategy and conventional continuation strategy groups and treatment breaks might be a feasible and cost-effective option with lifestyle benefits for patients during tyrosine kinase inhibitor therapy in patients with renal cell carcinoma. UK National Institute for Health and Care Research.

Metastatic spinal cord compression (MSCC) carries a poor prognosis and management is based on the likelihood of maintaining mobility and predicted survival.SCORAD is a randomised trial of 686 patients comparing a single dose of 8 Gy radiotherapy with 20 Gy in 5 fractions. Data was split into a training set (412, 60%) and a validation set (274, 40%). A multivariable Cox regression for overall survival (OS) and a logistic regression for ambulatory status at 8 weeks were performed in the training set using baseline factors and a backward selection regression to identify a parsimonious model with p ≤ 0.10. Receiver Operating Characteristic (ROC) analysis evaluated model prognostic performance in the validation set. Validation of the final survival model was performed in a separate registry dataset (n = 348).The survival Cox model identified male gender, lung, gastrointestinal, and other types of cancer, compression at C1-T12, presence of non-skeletal metastases and poor ambulatory status all significantly associated with worse OS (all p 0.05). The ROC AUC for the selected model was 75% (95%CI: 69-81) in the SCORAD validation set and 68% (95%CI: 62-74) in the external validation registry data. The logistic model for ambulatory outcome identified primary tumour breast or prostate, ambulatory status grade 1 or 2, bladder function normal and prior chemotherapy all significantly associated with increased odds of ambulation at 8 weeks (all p 0.05). The ROC AUC for the selected model was 72.3% (95% CI 62.6-82.0) in the validation set.Primary breast or prostate cancer, and good ambulatory status at presentation, are favourable prognostic factors for both survival and ambulation after treatment.

Aims Real-world evidence of radium 223 (Ra-223) for the treatment of men with metastatic castration-resistant prostate cancer is emerging. In this prospective single-centre service evaluation, we report for the first time in the UK, real-world quality of life (QoL) and survival outcomes, including the sequencing impact, in 228 treated patients. We aim to share our 5-year experience on how to optimise Ra-223 treatment. Materials and methods Patients who received Ra-223 therapy between 2014 and 2018 at the Northern Centre for Cancer Care, Newcastle upon Tyne, UK were included in this evaluation. Demographics, clinical characteristics, blood parameters, treatment sequencing and QoL data using abbreviated Functional Assessment of Cancer Therapy-Prostate questionnaires were prospectively collected and analysed. Results In total, 228 patients were included; median age 72 years (51–87). The medium overall survival was 11.1 months. Overall survival in post-chemotherapy and chemotherapy-naive patients was 8.1 and 12.3 months, respectively (P = 0.02, hazard ratio 1.52, 95% confidence interval 1.06–2.17); in pre-enzalutamide and post-enzalutamide patients was 11.3 and 10.4 months, respectively (P = 0.65, hazard ratio 0.92, 95% confidence interval 0.63–1.33); in pre-abiraterone and prednisolone and post-abiraterone and prednisolone patients was 11.8 and 10.5 months, respectively (P = 0.08, hazard ratio 0.74, 95% confidence interval 0.51–1.06); in this latter group, the fracture rate was 24% (15/63). QoL post Ra-223 (n = 101 evaluated) showed that pain scores improved in 54%, there was no change in 17% and pain scores worsened in 30% of treated patients. Overall QoL scores showed a similar trend. QoL was not significantly associated with overall survival. Conclusions Ra-223 palliates pain and improves disease-related QoL in most patients in the real-world setting. Our survival outcome is comparable with other real-world studies. Chemotherapy-naive patients seemed to have better survival than those who received prior chemotherapy. No significant survival differences were observed between pre- and post-abiraterone and prednisolone or enzalutamide patients. The fracture rate in the post-abiraterone and prednisolone group seemed to be high. Bone health evaluation and protection should be incorporated as standard of care.

Aims Concomitant chemoradiation is the standard of care in patients with inoperable non-small cell lung cancer. The purpose of this study was to analyse the survival outcome and toxicity data of using hypofractionated chemoradiation. Materials and methods One hundred patients were treated from June 2011 to November 2016. Treatment consisted of 55 Gy in 20 daily fractions concurrently with split-dose cisplatin vinorelbine chemotherapy over 4 weeks followed by two cycles of cisplatin vinorelbine only. Survival was estimated using Kaplan–Meier and Cox regression was carried out for known prognostic factors. A systematic search of literature was conducted using Medline, Embase and Cochrane databases and relevant references included. Results In total, 97% of patients completed radiotherapy and 73% of patients completed all four cycles of chemotherapy. One patient died of a cardiac event during consolidative chemotherapy. There were two cases of grade 4 toxicities (one sepsis, one renal impairment). Grade 3 toxicities included nausea/vomiting (17%), oesophagitis (15%), infection with neutropenia (12%) and pneumonitis (4%). Clinical benefit was seen in 86%. Two-year progression-free survival and overall survival rates were 49% and 58%, respectively. The median progression-free survival and overall survival were 23.4 and 43.4 months, respectively. The only significant prognostic factor was the number of chemotherapy cycles received (P = 0.02). The systematic review identified 13 relevant studies; a variety of regimens were assessed with variable reporting of outcomes and toxicity but with overall an improvement in survival over time. Conclusion Our experience compared with the original phase II trial showed improved treatment completion rates and survival with acceptable morbidity. With appropriate patient selection this regimen is an effective treatment option for locally advanced non-small cell lung cancer. This study helps to benchmark efficacy and toxicity rates while considering the addition of new agents to hypofractionated concurrent chemoradiotherapy. The agreement of a standard regimen for assessment in future trials would be beneficial.

PURPOSE SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence. PATIENTS AND METHODS We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo. RESULTS Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, −0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib. CONCLUSION Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.

Introduction For limited stage small cell lung cancer (LS-SCLC) where concurrent chemoradiotherapy is inappropriate due to tumour bulk, co-morbidities or performance status, sequential treatment using chemotherapy followed by radiotherapy is the standard of care. The outcomes are not well established; we assessed in a single institution, the survival of these patients, prognostic factors and compared to the limited existing literature. Materials and method Retrospective data was collected on all 59 patients diagnosed with LS-SCLC from 2011 to 2016 who received chemotherapy consisting of Carboplatin or Cisplatin + Etoposide followed by thoracic radiotherapy (50 Gy in 25 fractions) +/- prophylactic cranial irradiation (PCI). Results Median age at diagnosis was 66 years (range 46-90). Patients received a median of four cycles of chemotherapy (range: 1-6) and all the patients completed a full course of radiotherapy with only one patient experiencing grade >2 radiation induced toxicity. With a median follow up of 20.6 months, 45 patients had died with a median survival of 20.6 months. 2-year overall survival (OS) rates were 42%. Age using a cut-off of 65 was prognostic (median OS 25.6 months ≤65 years versus 14.1 months >65 years, p = 0.013) but gender, stage and receipt of PCI were not. Conclusions Most of the literature reporting outcome from sequential treatment in LS-SCLC is old and used a variety of radiotherapy regimens. Our data shows inferior outcomes to the gold standard concurrent chemoradiotherapy but support its usage in less fit patients with reasonable outcome observed.

Importance: Malignant spinal canal compression, a major complication of metastatic cancer, is managed with radiotherapy to maintain mobility and relieve pain, although there is no standard radiotherapy regimen.Objective: To evaluate whether single-fraction radiotherapy is noninferior to 5 fractions of radiotherapy.Design, Setting, and Participants: Multicenter noninferiority randomized clinical trial conducted in 42 UK and 5 Australian radiotherapy centers. Eligible patients (n = 686) had metastatic cancer with spinal cord or cauda equina compression, life expectancy greater than 8 weeks, and no previous radiotherapy to the same area. Patients were recruited between February 2008 and April 2016, with final follow-up in September 2017.Interventions: Patients were randomized to receive external beam single-fraction 8-Gy radiotherapy (n = 345) or 20 Gy of radiotherapy in 5 fractions over 5 consecutive days (n = 341).Main Outcomes and Measures: The primary end point was ambulatory status at week 8, based on a 4-point scale and classified as grade 1 (ambulatory without the use of aids and grade 5 of 5 muscle power) or grade 2 (ambulatory using aids or grade 4 of 5 muscle power). The noninferiority margin for the difference in ambulatory status was -11%. Secondary end points included ambulatory status at weeks 1, 4, and 12 and overall survival.Results: Among 686 randomized patients (median [interquartile range] age, 70 [64-77] years; 503 (73%) men; 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer), 342 (49.8%) were analyzed for the primary end point (255 patients died before the 8-week assessment). Ambulatory status grade 1 or 2 at week 8 was achieved by 115 of 166 (69.3%) patients in the single-fraction group vs 128 of 176 (72.7%) in the multifraction group (difference, -3.5% [1-sided 95% CI, -11.5% to ∞]; P value for noninferiority = .06). The difference in ambulatory status grade 1 or 2 in the single-fraction vs multifraction group was -0.4% (63.9% vs 64.3%; [1-sided 95% CI, -6.9 to ∞]; P value for noninferiority = .004) at week 1, -0.7% (66.8% vs 67.6%; [1-sided 95% CI, -8.1 to ∞]; P value for noninferiority = .01) at week 4, and 4.1% (71.8% vs 67.7%; [1-sided 95% CI, -4.6 to ∞]; P value for noninferiority = .002) at week 12. Overall survival rates at 12 weeks were 50% in the single-fraction group vs 55% in the multifraction group (stratified hazard ratio, 1.02 [95% CI, 0.74-1.41]). Of the 11 other secondary end points that were analyzed, the between-group differences were not statistically significant or did not meet noninferiority criterion.Conclusions and Relevance: Among patients with malignant metastatic solid tumors and spinal canal compression, a single radiotherapy dose, compared with a multifraction dose delivered over 5 days, did not meet the criterion for noninferiority for the primary outcome (ambulatory at 8 weeks). However, the extent to which the lower bound of the CI overlapped with the noninferiority margin should be considered when interpreting the clinical importance of this finding.Trial Registration: ISRCTN Identifiers: ISRCTN97555949 and ISRCTN97108008.

There is no standard of care in the UK or Ireland for second-line chemotherapy for patients with advanced transitional cell carcinoma (TCCU). Vinflunine is approved for TCCU patients who have failed a platinum-based regimen, and is standard of care in Europe but is not routinely available in the UK. Data were collected retrospectively on patients who received vinfluine as a second-line treatment. The aims were to document the toxicity and efficacy in a real life setting. Data were collected on 49 patients from 9 sites across the UK and Ireland [median age, 64 (IQR, 57-70) years, 33 males]. All patients had advanced metastatic TCCU. Thirteen patients had bone or liver metastases, 4 patients had PS 2 and 11 patients had HB < 10. Median vinflunine administration was 3.5 cycles (range 1-18). Most common grade 3-4 toxicities were constipation (4 patients) and fatigue (3 patients). Partial response rate was 29% (14 PR, 11 SD, 19 PD, 4 NE, 1 not available). Median OS was 9.1 (6.0, 12.7) months. Results are consistent with real life data from Europe. Toxicity is further reduced with prophylactic laxative and oral antibiotics. Vinflunine is an efficient and tolerable second line treatment in advanced TCCU.

Aim\ud \ud To explore the practice and attitudes of uro‐oncologists in the UK regarding monitoring testosterone levels and the use of testosterone replacement therapy (TRT) in their prostate cancer patients treated with androgen deprivation therapy (ADT).\ud \ud \ud Methods\ud \ud An expert‐devised online questionnaire was completed by the members of the British Uro‐oncology Group (BUG).\ud \ud \ud Results\ud \ud Of 160 uro‐oncologists invited, 84 completed the questionnaire. Before initiating ADT in patients with non‐metastatic prostate cancer, only 45% of respondents measured testosterone levels and 61% did not measure testosterone at all during ADT in the adjuvant or neoadjuvant setting. However, in men with metastatic prostate cancer, 71% of the uro‐oncologists measured testosterone before starting ADT and the majority continued testing during treatment. Approximately two‐thirds of respondents did not prescribe TRT for their patients who were in remission following neo(adjuvant) ADT and who had castration levels of testosterone.\ud \ud \ud Discussion\ud \ud Among UK uro‐oncologists, the measurement of testosterone levels before and during ADT was not typically part of routine practice in the management of patients with prostate cancer. However, testosterone levels were checked more frequently for patients with metastatic disease than disease at an earlier stage. Testing could be conducted in parallel with PSA measurement as testosterone levels are linked to biochemical failure. The majority of specialists participating in the survey did not prescribe TRT for their patients in remission following ADT.\ud \ud \ud Conclusion\ud \ud Uro‐oncologists in the UK do not generally measure testosterone as part of their patient management and they remain cautious about the possible benefits of TRT in men with prostate cancer.

Background: The patient pathway for muscle invasive bladder cancer (MIBC) is multidisciplinary. Trans-urethral resection of bladder tumour (TURBT) counts as the first definitive treatment and subsequent definitive therapy thereafter is often delayed, which may adversely affect outcome. We elected to scrutinise the management pathway in detail to understand these delays and improve the patient experience. Method: A retrospective mapping analysis was conducted on 17 patients with MIBC. The causes of any delays and measures to avoid these were identified. A prospective study of 17 patients with MIBC was then undertaken to see if the strategies used to re-engineer the patient care pathway had been effective. Result: The median time from GP referral to first appointment was 9 days (range: 1–37) and from TURBT to subsequent radical treatment was 75 days (range: 27–105) in keeping with published literature. The median time for a referral letter from urology to oncology following MDT was 15 days. We therefore modified the MDT proforma to use as a formal referral, and a project manager proactively managed the patient pathway. Capacity issues were addressed by protecting clinical slots for bladder patients and establishing monthly evening clinics. After implementing the strategies, the median days from first appointment to TURBT improved from 31 to 23 days and time from TURBT to subsequent treatment improved from 75 to 66 days. The time from MDT referral to being seen by an oncologist or urologist significantly reduced from 32 to 15 days. Conclusion: Retrospective analysis identified delays between initial TURBT to definitive therapy and strategies adopted to reduce these were effective. TURBT is a diagnostic process and if acknowledged as first treatment results in delays of what is the definitive treatment. We found the initial diagnostic pathway to work well but non-muscle invasive bladder cancer (NMIBC) and MIBC are then managed very differently and warrant two separate pathways.

Objective Haemorrhagic cystitis (HC) is a relatively common complication of chemotherapy and radiotherapy to the pelvic area, but can be a challenging condition to treat, particularly since there is currently a lack of UK-led guidelines available on how it should optimally be defined and managed. Materials and methods A comprehensive literature search was undertaken to evaluate the evidence for the diagnosis, prevention and management of cancer treatment-induced HC. Results Recommendations and a proposed management algorithm for the diagnosis, prevention and treatment of HC, as well as the management of intractable haematuria, have been developed based on the expert opinion of the multidisciplinary consensus panel following a comprehensive review of the available clinical data. Conclusion These guidelines are relevant and applicable to current clinical practice and will help clinicians optimally define and manage this potentially serious condition.

223 Background: Radium 223 (Ra-223) is a FDA and EMA approved alpha particle radiopharmaceutical used to treat men with metastatic castrate resistant prostate cancer (mCRPC) with symptomatic bone metastasis. In view of emerging systemic options, new EMA 2018 licence indication is for 3rd line onwards. We aim to evaluate the impact of systemic therapy sequencing on survival outcomes from a heterogeneous cohort of 228 patients treated with Ra-223 in a single UK centre. Methods: We prospectively collected data from 228 men underwent Ra-223 therapy for mCRPC between April 2014 and August 2018. Survival outcomes in relation to sequence of systemic treatment used prior to Ra-223 were analysed. Results: Medium age = 72 (51-87) years. Most patients (n = 142, 69%) received at least one systemic agent prior to Ra-223: docetaxel and/or cabaxitaxel chemotherapy (n = 60, 29%), abiraterone (n = 62, 30.1%) and enzalutamide (n = 67, 32.5%) in various sequences. No patients received concurrent Ra-223 /systemic treatment other than LHRH analogue. Key findings are summarized in table below. Conclusions: Our data demonstrated better survival trend in patients who received Ra-223 early. Patients who received prior chemotherapy have worse survival compared with those who were chemo-naïve likely due to bone marrow depletion. Ra-223 should not be offered to patients who have already had both cabaxitaxel and docetaxel as their medium survival is too poor to justify a treatment which takes 6 months to complete.[Table: see text]

This report is based on a workshop seminar held during the 8th Annual Meeting of the British Uro-oncology Group. The workshop covered a range of topics in bladder chemotherapy, from a discussion of the use of multidisciplinary teams in this area, to a review of UK practice and an international update on second-line treatment of metastatic bladder cancer. The session closed with the presentation of two bladder cancer case histories.

A single centre phase II study was conducted to determine the toxicity and activity of Caelyx in hormone refractory metastatic prostate cancer. Doxorubicin is known to be active in this setting and liposomal encapsulation may enhance its therapeutic efficacy and also reduce toxicity. Fourteen patients with hormone refractory metastatic prostate cancer were treated with CaelyxTM 50 mg/m2 once every four weeks. All patients had radiologically proven bone metastases and three also had soft tissue metastatic disease. All patients were evaluable for toxicity and response was assessable in thirteen cases. Three PSA responses were documented in patients with non-measurable disease. No patient had an objective response in measurable disease. The commonest toxicity was cutaneous and this was dose limiting in two patients. Gastrointestinal upset was frequent but generally mild. One patient died shortly after an episode of neutropaenic sepsis with associated grade 3 mucositis following his third cycle of chemotherapy. We confirmed the toxicity profile of Caelyx but its modest antitumour efficacy in this group of patients suggests little promise for future study in metastatic prostate cancer.

259 Background: Androgen deprivation therapy has been the standard of care for advanced prostate cancer for many years. However recent studies have reported a survival benefit for upfront docetaxel chemotherapy in men with hormone sensitive prostate cancer. The GenTax trial was a single institution phase II study investigating clinical outcome and gene profiling for patients with treatment naïve prostate cancer treated with either docetaxel chemotherapy plus androgen deprivation therapy (D+ADT) or androgen deprivation therapy alone (ADT). We report on updated clinical outcome data for this trial. Methods: Patients with newly diagnosed T3/T4, PSA ≥ 50ng/ml or Gleason score ≥ 8, or metastatic disease were enrolled. Patients were randomised to ADT or D+ADT (docetaxel 75mg/m2 q21 days for 6 cycles). Data were analysed for overall survival, toxicities, time to second line treatment and number of subsequent treatments. Results: 30 patients were randomly assigned to ADT (n = 15) or D+ADT (n = 15) between 10/13/2005 and 12/02/2009. 7 patients in each arm had metastatic disease. Grade 3-4 toxicities were infrequent in D+ADT arm and were not noted in the ADT arm. There were no significant differences between treatment arms for overall survival (log rank p = 0.977) or time to second line treatment (log rank p = 0.954). Median overall survival was 98 months (95% CI 72.3 - 123.7) for ADT and 87 months (95% CI 71.5 - 102.5) for D+ADT. Median time to second line treatment was 45 months (95% CI 13.4 - 76.6) for ADT and 46 months (95% CI 13.2 – 78.8) for D+ADT. Number of subsequent treatments ranged from 0-6 (mean 2.40) for ADT-only and 0-5 (mean 2.13) for D+ADT. Conclusions: The combination of docetaxel and ADT in the hormone sensitive setting is well tolerated, as previously reported. This study was not sufficiently powered to detect statistically significant differences in survival. Patients proceeded to receive a number of subsequent lines of therapy although the order in which these were given was variable. There is a need to establish optimal sequencing of treatments in the upfront docetaxel era. Clinical trial information: 2004-004874-96.

Background Cure of lung cancer is impossible without local tumour control. This can be compromised by accelerated repopulation of tumour cells during radiotherapy and chemotherapy. A strategy to minimise accelerated repopulation might improve local control. We investigated whether concurrent chemo-radiotherapy could be given safely over four weeks. Methods We conducted a randomised phase II trial in which patients with inoperable Stage III Non-Small Cell Lung Cancer (NSCLC) received a radical radiation dose over four weeks rather than conventional fractionation. Treatment was given either sequentially or concurrently with three to four cycles of cisplatinum and vinorelbine. 130 patients with inoperable stage III NSCLC and PS 0-1 were randomised to receive cisplatinum and vinorelbine with either sequential or concurrent chemo-radiation using 55 Gy in 20 fractions over four weeks. The primary end-point was treatment related mortality. Secondary end-points were toxicity and survival. Findings Treatment related mortality was: 2.9% (exact 95% confidence interval [CI] 0.36–10.2%) and 1.7% (exact 95% CI 0.043–9.1%) for the Concurrent and Sequential group respectively; relative risk (RR) 1.25; (95% CI 0.55, 2.84). Toxicity was similar between arms; grade 3 or worse oesophagitis was 8.8% versus 8.5%; RR 1.02 (95% CI 0.58, 1.79). OS HR was 0.92; 95% CI (0.60–1.39; p = 0.682). The 2 year overall survival rates were: 50% versus 46%; RR 1.06 (95% CI 0.77, 1.46) for Concurrent versus Sequential. Interpretation A strategy to minimise the effects of accelerated repopulation using accelerated hypofractionated radiotherapy with chemotherapy is feasible, and reasonably safe for patients with stage III NSCLC. The reported two year survival is promising and suggests that a four week regime of radiotherapy should be compared with conventionally fractionated radiotherapy in an adequately powered randomised controlled phase III trial.

• To review the published data on predisposing risk factors for cancer treatment-induced haemorrhagic cystitis (HC) and the evidence for the different preventive and therapeutic measures that have been used in order to help clinicians optimally define and manage this potentially serious condition. • Despite recognition that HC can be a significant complication of cancer treatment, there is currently a lack of UK-led guidelines available on how it should optimally be defined and managed. • A systematic literature review was undertaken to evaluate the evidence for preventative measures and treatment options in the management of cancer treatment-induced HC. • There is a wide range of reported incidence due to several factors including variability in study design and quality, the type of causal agent, the grading of bleeding, and discrepancies in definition criteria. • The most frequently reported causal factors are radiotherapy to the pelvic area, where HC has been reported in up to 20% of patients, and treatment with cyclophosphamide and bacillus Calmette-Guérin, where the incidence has been reported as up to 30%. • Mesna (2-mercaptoethane sodium sulphonate), hyperhydration and bladder irrigation have been the most frequently used prophylactic measures to prevent treatment-related cystitis, but are not always effective. • Cranberry juice is widely cited as a preventative measure and sodium pentosanpolysulphate as a treatment, although the evidence for both is very limited. • The best evidence exists for intravesical hyaluronic acid as an effective preventative and active treatment, and for hyperbaric oxygen as an equally effective treatment option. • The lack of robust data and variability in treatment strategies used highlights the need for further research, as well as best practice guidance and consensus on the management of HC.

Background:\ud Androgen-deprivation therapy (ADT) is standard treatment for locally advanced or metastatic prostate cancer (PCa). Many patients develop castration resistance (castration-resistant PCa [CRPC]) after approximately 2–3 yr, with a poor prognosis. The molecular mechanisms underlying CRPC progression are unclear.\ud \ud Objective:\ud To undertake quantitative tumour transcriptome profiling prior to and following ADT to identify functionally important androgen-regulated pathways or genes that may be reactivated in CRPC.\ud \ud Design, setting, and participants:\ud RNA sequencing (RNA-seq) was performed on tumour-rich, targeted prostatic biopsies from seven patients with locally advanced or metastatic PCa before and approximately 22 wk after ADT initiation. Differentially regulated genes were identified in treatment pairs and further investigated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) on cell lines and immunohistochemistry on a separate CRPC patient cohort. Functional assays were used to determine the effect of pathway modulation on cell phenotypes.\ud Outcome measurements and statistical analysis:\ud We searched for gene expression changes affecting key cell signalling pathways that may be targeted as proof of principle in a CRPC in vitro cell line model.\ud \ud Results and limitations:\ud We identified ADT-regulated signalling pathways, including the Wnt/β-catenin signalling pathway, and observed overexpression of β-catenin in a subset of CRPC by immunohistochemistry. We validated 6 of 12 (50%) pathway members by qRT-PCR on LNCaP/LNCaP-AI cell RNAs, of which 4 (67%) demonstrated expression changes consistent with RNA-seq data. We show that the tankyrase inhibitor XAV939 (which promotes β-catenin degradation) reduced androgen-independent LNCaP-AI cell line growth compared with androgen-responsive LNCaP cells via an accumulation of cell proportions in the G0/G1 phase and reduction in the S and G2/M phases. Our biopsy protocol did not account for tumour heterogeneity, and pathway inhibition was limited to pharmacologic approaches.\ud \ud Conclusions:\ud RNA-seq of paired PCa samples revealed ADT-regulated signalling pathways. Proof-of-principle inhibition of the Wnt/β-catenin signalling pathway specifically delays androgen-independent PCa cell cycle progression and proliferation and warrants further investigation as a potential target for therapy for CRPC.

Background: The use of magnetic resonance (MR) imaging as a part of preparation for radiotherapy is increasing. For delineation of the prostate several publications have shown decreased delineation variability using MR compared to computed tomography (CT). The purpose of the present work was to investigate the intra- and inter-physician delineation variability for prostate and seminal vesicles, and to investigate the influence of different MR sequence settings used clinically at the five centers participating in the study. Methods: MR series from five centers, each providing five patients, were used. Two physicians from each center delineated the prostate and the seminal vesicles on each of the 25 image sets. The variability between the delineations was analyzed with respect to overall, intra-and inter-physician variability, and dependence between variability and origin of the MR images, i.e. the MR sequence used to acquire the data. Results: The intra-physician variability in different directions was between 1.3 - 1.9 mm and 3 - 4 mm for the prostate and seminal vesicles respectively (1 std). The inter-physician variability for different directions were between 0.7 - 1.7 mm and approximately equal for the prostate and seminal vesicles. Large differences in variability were observed for individual patients, and also for individual imaging sequences used at the different centers. There was however no indication of decreased variability with higher field strength. Conclusion: The overall delineation variability is larger for the seminal vesicles compared to the prostate, due to a larger intra-physician variability. The imaging sequence appears to have a large influence on the variability, even for different variants of the T2-weighted spin-echo based sequences, which were used by all centers in the study.

403 Background: Functional imaging techniques which evaluate early treatment responses may identify non-responders who would benefit from a switch in therapy. This is a prospective feasibility study of serial diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI scanning in patients undergoing neoadjuvant chemotherapy for muscle-invasive bladder cancer. Methods: Scans were performed before and during chemotherapy (10-17 days after the first and second cycles). A repeatability DW-MRI scan was acquired on the first visit. Regions-of-interest (ROI) encompassing the entire tumour were defined. Analysis of MRI parameters was undertaken and related to findings from the routine restaging CT scan performed after 3 cycles of chemotherapy. Results: 10/16 patients were male, median age 59 years, 14/16 had T3/4 disease, and 5/16 were node positive. 10/16 have completed 3 or 4 cycles of chemotherapy to date and attended for the restaging CT scan. Radiological response was identified in all cases. In the DW-MRI analysis there was no significant difference in mean tumour ADC or tumour volume between baseline and repeatability scans (mean ADC 1.19 and 1.2 respectively, n=16). Visual assessment showed a fall in contrast agent uptake within the primary bladder tumour after treatment. Conclusions: The scanning protocols enabled visualisation of the bladder tumours and derivation of kinetic parameters. DW-MRI measurements were comparable between baseline and repeat scan, suggesting that a change in ADC was more likely to be attributable to treatment response or disease progression than measurement error or inherent variation. Statistically significant rises in mean ADC and decreases in tumour volume were observed early in the treatment pathway. No patients progressed on treatment in this study. Larger studies of DCE and DW-MRI as surrogate response imaging biomarkers in bladder cancer are recommended. Clinical trial information: Study ID 14489. [Table: see text]

A better understanding of the molecular biology of renal cell carcinoma (RCC) and the emergence of tyrosine kinase inhibitors (TKIs) have revolutionized the treatment for patients with metastatic RCC (mRCC). Multikinase inhibitors (sunitinib and sorafenib) and the inhibitors of mammalian target of rapamycin (temsirolimus and everolimus) have recently shown superiority over IFN-α or placebo; and bevacizumab + IFN-α have demonstrated improved activity when compared to IFN-α alone in patients with mRCC. Newer antivascular endothelial growth factor (VEGF) agents such as axitinib, pazopanib and cediranib are currently under investigation to expand and elucidate future treatment options. Several studies have investigated the synergistic potential of TKIs with a view to blocking multiple signalling pathways simultaneously, but this approach has resulted in a significant increase in toxicity. Sequential TKI administration has demonstrated encouraging results but the optimal sequence of TKIs is yet to be determined. Studies combining TKIs with immunotherapy have resulted in varying degrees of success; with bevacizumab + IFN-α being the only studies with positive outcomes. The purpose of this review is to summarize the current evidence supporting the role of TKIs and to discuss potential future directions in the management of mRCC. The role of TKIs as monotherapy, in combination with immunotherapy or other TKIs (combined or sequential approach) will be discussed.

Aims Recent improvements in planning systems have made use of sophisticated dose calculation algorithms such as collapsed cone, a realistic possibility for routine lung radiotherapy treatment planning. However, it is more difficult to achieve ICRU 50/62 compliant plans (i.e. a minimum of 95% of the prescribed dose to the planning target volume) with the collapsed cone algorithm, due to the more accurate modelling of dose in heterogeneous media. The aim of this study was to determine planning guidance for the implementation of the collapsed cone algorithm for conventional radiotherapy treatment planning. Materials and methods Ten pencil beam lung plans were recalculated using the collapsed cone algorithm. Then, beam weights were optimised on the recalculated collapsed cone plan, without altering field sizes. Finally, both field sizes and beam weights were optimised on the same plan in an attempt to deliver a minimum of either 90 or 95% of the prescribed dose to the planning target volume. Thus, four sets of plans were available for comparison. Results Compared with pencil beam plans recalculated with the collapsed cone algorithm, all collapsed cone plans had improved dose coverage of the planning target volume. For two of the beam weight optimised plans, less than 80% of the planning target volume received 90% of the prescribed dose. For the field size, beam weight optimised plans, nearly 100% of the planning target volume attained 90% of the prescribed dose, with the clinical target volume generally reaching 95%. Compared with the original pencil beam plans, the volume of lung receiving greater than 20Gy ( V 20 ) increased by 3.1 and 6.8%, respectively, for those plans optimised to deliver a minimum of 90 or 95% of the prescribed dose to the planning target volume. Conclusions We suggest that the collapsed cone algorithm might reasonably be implemented for conventional radiotherapy treatment planning with the aim of delivering a minimum of 90% of the prescribed dose to the planning target volume and 95% of the prescribed dose to the clinical target volume. This guidance offers consistent prescription of dose to target volumes.

Background and objective Sequential tissue biopsies taken during clinical trials of novel systemic anticancer therapies for advanced prostate cancer (PCa) may aid pharmacodynamic evaluation and biomarker discovery. We conducted a single institution phase-II open-labeled randomized study to assess the safety, tolerability, and early efficacy of docetaxel chemotherapy plus androgen deprivation therapy (ADT) vs. ADT alone for patients with advanced non–castration-resistant PCa with sequential prostatic biopsies. Patients and methods We randomized 30 patients with newly diagnosed high-grade locally advanced or metastatic (cT3–4/N0–1/M0–1) PCa to receive ADT with (n = 15) or without (n = 15) docetaxel. Transrectal ultrasound–guided prostatic biopsies were taken at randomization and ~22 weeks after treatment initiation. Primary end point: biochemical response rate. Secondary end points: time to progression and tumor profiling. Results Both treatments appear to be well tolerated, and there was no difference in mean nadir prostate-specific antigen and time to prostate-specific antigen relapse between treatment arms (P>0.05). No adverse effects of pre- and post-treatment prostatic biopsies were observed. The study was neither designed nor sufficiently powered to demonstrate statistically significant differences in oncological outcomes or safety profiles between the 2 treatment arms. Conclusions Despite the lack of statistical power, our study suggests that docetaxel and ADT in combination may be well tolerated with apparently similar short-term efficacy compared with ADT alone for high-grade locally advanced or metastatic non–castration-resistant PCa, Sequential prostatic biopsies may provide tissue for tumor profiling to yield mechanistic or prognostic insights relating to novel systemic anticancer therapies.

Background and purpose To assess the effectiveness of radiotherapy in preventing tumour seeding after chest drain or pleural biopsy in patients with malignant mesothelioma and to determine, if tract metastases appear, whether they are tender or troublesome to patients. Patients and methods Patients with a histological diagnosis of pleural mesothelioma and an invasive procedure within the preceding 21 days were stratified by age, performance status and treatment centre. Randomisation was performed between immediate drain site radiotherapy 21 Gy in three fractions (XRT arm) or best supportive care (BSC) with follow-up to 12 months. Patients were asked to complete questionnaires on treatment toxicity and on symptoms from any tract metastases detected. Results Sixty-one patients were recruited from two centres between 1998 and 2004; 56 men, 5 women, median age 70. 31 were allocated to drain site radiotherapy. Seven patients developed tract metastases associated with the drain site (four XRT arm, three BSC) and four developed metastases associated with subsequent procedures at other sites (three XRT, one BSC). Two patients each developed two tract metastases. Of the 12 metastases, nine overlay the previous drain site but three were adjacent to the site. No statistically significant difference was found in the risk of tract metastasis associated with the drain site between the arms (p = 0.748). Conclusions Prophylactic drain site radiotherapy in malignant pleural mesothelioma does not reduce the incidence of tumour seeding by the margin indicated by previous studies.

To understand current practice of the treatment of advanced bladder cancer in the United Kingdom, and in particular, the use of second-line chemotherapy.To gain insight into uro-oncologists' use of first-line chemotherapy, imaging following first-line chemotherapy, use of second-line chemotherapy, and the role of the multidisciplinary tumor board (MTB) in making decisions about second-line chemotherapy.From August 2011 to September 2011 uro-oncologists from UK cancer centers were surveyed regarding treatment of advanced bladder cancer.Delegates at the British Uro-oncology Group conference were invited to fill out an electronic survey.Uro-oncologists from 28 of 42 UK cancer centers (67%) participated, who treated, on average 45 patients per year with advanced bladder cancer.Fifteen "always" reimage after first-line chemotherapy, mostly "after 2-4 cycles." Symptomatic patients with progressive distant disease on imaging were most likely to trigger second-line chemotherapy (P = 0.004).Twenty-one respondents would interrupt first-line chemotherapy to start second-line chemotherapy for progressive disease and 10 would never do this. Of the patients given first-line chemotherapy, 19% go on to receive second-line chemotherapy.Seven different regimes were specified for second-line chemotherapy with no clear preference. National Institute for Health and Clinical Excellence approval, trial data, inclusion in hospital formulary, clinical trials, or commissioning guidelines, and easy access to imaging help to access second-line chemotherapy (P ≤ 0.001). Constraints to second-line chemotherapy were lack of evidence and patient comorbidities.MTB effectiveness did not improve access to second-line chemotherapy. Of the 33 respondents, 19 do not rediscuss patients at the MTB before starting second-line chemotherapy.The investigation and treatment of patients with advanced bladder cancer following first-line chemotherapy is variable.Optimizing the modality and frequency of imaging and increasing the usefulness of the MTB process may improve care.