Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

Gemcitabine and carboplatin in the treatment of transitional cell carcinoma of the urothelium: a single centre experience and review of the literature.

The objectives of this study are to evaluate patient outcomes in clinical practice using gemcitabine and carboplatin (GCarbo) as first-line treatment in metastatic transitional cell carcinoma (TCC) of the urothelium, and to review the published evidence on the use of GCarbo in this setting. From July 2003, all cases of metastatic TCC of the urothelium referred to a single consultant were treated using 3-weekly gemcitabine 1200 mg/m(2) i.v. days 1 and 8 plus carboplatin AUC 5-6 i.v. day 1 to a maximum of six cycles. Fifteen patients (median age 67 years) were treated. Grade 3 or 4 toxicity included neutropenia (47%), anaemia (27%) and thrombocytopenia (20%). No patients required admission for neutropenic pyrexia/sepsis, and there were no treatment-related deaths. The overall response rate was 67%. The median survival was 9 months (95% CI 7.4-10.6), and 1-year survival 42%. Gemcitabine and carboplatin is well tolerated, and has activity as first-line treatment in metastatic TCC of the urothelium. However, there is now evidence suggesting that gemcitabine and cisplatin may be more efficacious, and until the appropriate randomized phase 3 trials have been carried out, gemcitabine and cisplatin should probably remain the preferred first-line therapy. Gemcitabine and carboplatin is an effective alternative in those patients not deemed fit enough for cisplatin.

Escalation and intensification of radiotherapy for stage III non-small cell lung cancer: opportunities for treatment improvement.

In this overview we review and model how radiotherapy tumour control and complication rates vary with dose, fractionation, schedule duration, irradiated volume and use of chemotherapy for stage III non-small cell lung cancer (NSCLC), and use the modelling to study the effectiveness of different NSCLC dose-escalation approaches being developed in the UK. Data have been collated for pneumonitis, lung fibrosis, early and late oesophagitis, cord and cardiac complications, and local progression-free survival at 30 months. Dependences of the various end points on treatment-related factors are catalogued and analysed using the linear-quadratic incomplete repair model to account for dose and fractionation effects, making linear corrections for differences in schedule duration, and loosely characterising volume effects using parallel- and series-type concepts. Tolerance limits are calculated for the different end points and distilled into ranges of prescribed dose likely to be tolerable when delivered in 2.5 and 4 week radiation and 6 week chemoirradiation schedules using conformal techniques. Worthwhile ( approximately 20%) gains in 30 month local progression-free survival should be achievable at safely deliverable levels of dose escalation. The analysis suggests that longer schedules may be more beneficial than shorter ones, but this finding is governed by the relative rates of tumour and oesophageal accelerated proliferation, which are quite imprecisely known. Consequently escalated 2.5, 4 and 6 week schedules are being developed; each should lead to useful improvements in local control but it is not yet known which schedule will be most effective.

Radiotherapy after radical prostatectomy for adenocarcinoma of the prostate: a UK institutional experience and review of published studies.

AIMS: The role of radiotherapy to the prostate bed after radical prostatectomy is the subject of much debate. We carried out a retrospective analysis of all patients treated with either adjuvant radiotherapy (ART) or salvage radiotherapy (SRT) in a single UK cancer centre and compared outcomes with published studies. MATERIALS AND METHODS: All patients receiving radiotherapy at any time after a radical prostatectomy were identified and data collected. Patients were referred for ART because of positive surgical margins. SRT was carried out in patients with a detectable or rising prostate-specific antigen (PSA) postoperatively. Patients received either 55 Gy in 20 fractions or 60-64 Gy in 30-32 fractions. All but eight patients were treated using three-dimensional conformal radiotherapy. Both groups were combined for statistical analysis. Biochemical progression-free survival (BPFS) was calculated and displayed using Kaplan-Meier curves. Cox regression was used for univariate and multivariate analysis. RESULTS: In total, 40 patients received postoperative radiotherapy and had a 3-year overall BPFS of 64%. There was no significant difference in 3-year BPFS between ART and SRT (73% vs 61%, P=0.33). Univariate analysis showed that 3-year BPFS was significantly longer if the highest postoperative PSA was<0.5 ng/ml compared with> or =0.5 ng/ml (83% vs 47%, P=0.019), and if the Gleason grade was <7 compared with > or =7 (92% vs 49%, P=0.007). A PSA at diagnosis<10 ng/ml, positive surgical margins, absence of seminal vesicle involvement and neoadjuvant hormones were all associated with a trend towards improved BPFS. Patients with all of these factors had a 3-year BPFS of 91%. Multivariate analysis of the same parameters showed that only Gleason grade remained statistically significant (P=0.019). CONCLUSIONS: The results from this series are in line with published studies, and support the evidence that prostate bed radiotherapy may affect biochemical control in a proportion of patients at risk of relapse. It is not clear whether ART in patients at high risk of relapse or SRT on relapse is most effective.

Basaloid carcinoma of the prostate: a case report and review of the literature.

Malignant tumours arising from the basal cells of the prostate gland are extremely rare, and the majority of reports in the literature suggest a relatively indolent clinical course. We report a case of infiltrative basaloid carcinoma of the prostate in a 68-year old man that did not respond to systemic chemotherapy. It is essential that this aggressive disease is differentiated from more indolent basaloid proliferations, as metastatic spread can occur and outcome may be poor.

Continuous Hyperfractionated Accelerated Radiotherapy (CHART) for Non-small Cell Lung Cancer (NSCLC): 7 Years' Experience From Nine UK Centres.

AIM: Continuous hyperfractionated accelerated radiotherapy (CHART) remains an option to treat non-small cell lung cancer (NSCLC; NICE, 2011). We have previously published treatment outcomes from 1998-2003 across five UK centres. Here we update the UK CHART experience, reporting outcomes and toxicities for patients treated between 2003 and 2009. MATERIALS AND METHODS: UK CHART centres were invited to participate in a retrospective data analysis of NSCLC patients treated with CHART from 2003 to 2009. Nine (of 14) centres were able to submit their data into a standard database. The Kaplan-Meier method estimated survival and the Log-rank test analysed the significance. RESULTS: In total, 849 patients had CHART treatment, with a median age of 71 years (range 31-91), 534 (63%) were men, 55% had undergone positron emission tomography-computed tomography (PET-CT) and 26% had prior chemotherapy; 839 (99%) patients received all the prescribed treatment. The median overall survival was 22 months with 2 and 3 year survival of 47% and 32%, respectively. Statistically significant differences in survival were noted for stage IA versus IB (33.2 months versus 25 months; P = 0.032) and IIIA versus IIIB (20 months versus 16 months; P = 0.018). Response at 3 months and outcomes were significantly linked; complete response showing survival of 34 months against 19 months, 15 months and 8 months for partial response, stable and progressive disease, respectively (P < 0.001). Age, gender, performance status, prior chemotherapy and PET-CT did not affect the survival outcomes. Treatment was well tolerated with <5% reporting ≥grade 3 toxicity. CONCLUSION: In routine practice, CHART results for NSCLC remain encouraging and we have been able to show an improvement in survival compared with the original trial cohort. We have confirmed that CHART remains deliverable with low toxicity rates and we are taking a dose-escalated CHART regimen forward in a randomised phase II study of sequential chemoradiotherapy against other accelerated dose-escalated schedules.

Palliative radiotherapy regimens for non-small cell lung cancer.

BACKGROUND: Palliative radiotherapy to the chest is often used in patients with lung cancer, but radiotherapy regimens are more often based on tradition than research results. OBJECTIVES: To discover the most effective and least toxic regimens of palliative radiotherapy for non-small cell lung cancer, and whether higher doses increase survival. SEARCH STRATEGY: The electronic databases MEDLINE, EMBASE, Cancerlit and the Cochrane Central Register of Controlled Trials, reference lists, handsearching of journals and conference proceedings, and discussion with experts were used to identify potentially eligible trials, published and unpublished. SELECTION CRITERIA: Randomised controlled clinical trials comparing different regimens of palliative radiotherapy in patients with non-small cell lung cancer. DATA COLLECTION AND ANALYSIS: Fourteen randomised trials were reviewed. There were important differences in the doses of radiotherapy investigated, the patient characteristics and the outcome measures. Because of this heterogeneity no meta-analysis was attempted. MAIN RESULTS: There is no strong evidence that any regimen gives greater palliation. Higher dose regimens give more acute toxicity, especially oesophagitis. There is evidence for a modest increase in survival (5% at 1 year and 3% at 2 years) in patients with better performance status (PS) given higher dose radiotherapy. Some regimens are associated with an increased risk of radiation myelitis. AUTHORS' CONCLUSIONS: The majority of patients should be treated with short courses of palliative radiotherapy, of 1 or 2 fractions. Care should be taken with the dose to the spinal cord. The use of high dose palliative regimens should be considered for and discussed with selected patients with good performance status. More research is needed into reducing the acute toxicity of large fraction regimens and into the role of radical compared to high dose palliative radiotherapy. In the future, large trials comparing different RT regimens may be difficult to set up because of the increasing use of systemic chemotherapy. Trials looking at how best to integrate these two modalities, particularly in good PS patients, need to be carried out.

Bladder preservation in small cell carcinoma of the urinary bladder: an institutional experience and review of the literature.

AIMS: Primary small cell carcinoma (SCC) of the urinary bladder is rare, accounting for less than 1% of all primary bladder malignancies. Metastases are often present at the time of diagnosis, prognosis is poor and there is no established optimum treatment strategy. Small cell carcinoma of the lung (SCLC) shares many clinicopathological features with SCC of the bladder, and there is good evidence supporting the use of combination chemotherapy in SCLC. In addition, consolidation thoracic irradiation and prophylactic cranial irradiation (PCI) both increase 3-year absolute survival by 5.4% in SCLC patients with limited disease and a complete response to chemotherapy. Therefore, we adopted a similar staging and treatment strategy for SCC of the bladder. We report our clinical experience using this strategy, and review published studies. MATERIALS AND METHODS: All cases of SCC of the bladder referred to Velindre Hospital between 1998 and 2005 were identified and data collected retrospectively on demographic details, stage, performance status, treatment and response to treatment. For the review, the electronic databases MEDLINE, EMBASE and Cancerlit were searched, along with hand searching of journals, relevant books and review papers. RESULTS: Seven patients were identified. In total, six out of seven had platinum-based chemotherapy. Four patients received consolidation radiotherapy (CRT) to the bladder after a complete response to chemotherapy, and none have locally relapsed to date. The three patients with limited disease remain alive and disease free 14, 30 and 36 months after diagnosis. CONCLUSIONS: Combined modality therapy using platinum-based combination chemotherapy and consolidation radiotherapy may provide effective local control and allow a bladder-preserving approach to the management of SCC of the bladder. The role of PCI is controversial, and should be discussed with patients on an individual basis.

Small cell lung cancer treated in southeast Wales.

AIMS: In small cell lung cancer (SCLC), consolidation thoracic irradiation (CTI) increases 3-year absolute survival by 5.4% in patients with limited disease and a complete response to chemotherapy. Early concurrent thoracic radiotherapy has been shown to improve local control and prolong survival compared with CTI in some trials. The standard management of patients with SCLC in southeast Wales is CTI in individuals with limited disease and a complete response to chemotherapy. A review of patients with SCLC was carried out to establish whether survival locally is comparable with that reported in published studies, and if patients given CTI have survival comparable with that reported in studies where early concurrent thoracic radiotherapy was used. MATERIALS AND METHODS: Between January 2000 and December 2002, 303 patients were registered with SCLC in southeast Wales. One hundred and fifteen (47%) patients had limited disease and 60/115 (52%) received CTI. RESULTS: Patients with limited disease receiving CTI had a median survival of 17.7 months (95% confidence interval: 15-27.9 months). The 2- and 5-year survivals were 38 and 13%, respectively. CONCLUSIONS: These results compare favourably with previously published studies on SCLC. There are no plans to change our current treatment policy for SCLC in southeast Wales.

Protocol for PIT: a phase III trial of prophylactic irradiation of tracts in patients with malignant pleural mesothelioma following invasive chest wall intervention.

INTRODUCTION: Histological diagnosis of malignant mesothelioma requires an invasive procedure such as CT-guided needle biopsy, thoracoscopy, video-assisted thorascopic surgery (VATs) or thoracotomy. These invasive procedures encourage tumour cell seeding at the intervention site and patients can develop tumour nodules within the chest wall. In an effort to prevent nodules developing, it has been widespread practice across Europe to irradiate intervention sites postprocedure--a practice known as prophylactic irradiation of tracts (PIT). To date there has not been a suitably powered randomised trial to determine whether PIT is effective at reducing the risk of chest wall nodule development. METHODS AND ANALYSIS: In this multicentre phase III randomised controlled superiority trial, 374 patients who can receive radiotherapy within 42 days of a chest wall intervention will be randomised to receive PIT or no PIT. Patients will be randomised on a 1:1 basis. Radiotherapy in the PIT arm will be 21 Gy in three fractions. Subsequent chemotherapy is given at the clinicians' discretion. A reduction in the incidence of chest wall nodules from 15% to 5% in favour of radiotherapy 6 months after randomisation would be clinically significant. All patients will be followed up for up to 2 years with monthly telephone contact and at least four outpatient visits in the first year. ETHICS AND DISSEMINATION: PIT was approved by NRES Committee North West-Greater Manchester West (REC reference 12/NW/0249) and recruitment is currently on-going, the last patient is expected to be randomised by the end of 2015. The analysis of the primary end point, incidence of chest wall nodules 6 months after randomisation, is expected to be published in 2016 in a peer reviewed journal and results will also be presented at scientific meetings and summary results published online. A follow-up analysis is expected to be published in 2018. TRIAL REGISTRATION NUMBER: ISRCTN04240319; NCT01604005; Pre-results.

Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small cell lung cancer.

BACKGROUND: In non-small cell lung cancer (NSCLC), there is a relatively high incidence of brain metastases following radical treatment. At present, the role of prophylactic cranial irradiation (PCI) in this group of patients is not clear. OBJECTIVES: To investigate whether PCI has a role in the management of patients with NSCLC treated with radical intent. SEARCH STRATEGY: The electronic databases MEDLINE, EMBASE and Cancerlit, along with handsearching of journals, relevant books, and review articles used to identify potentially eligible trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing PCI with no PCI in NSCLC patients treated with radical intent. DATA COLLECTION AND ANALYSIS: Four RCTs were reviewed. Due to the small patient numbers, and variations in radiotherapy (RT) dose, no meta-analysis was attempted. MAIN RESULTS: PCI may reduce the incidence of brain metastases, but there is no evidence of a survival benefit. There is no evidence that any regimen is superior, and the effect of PCI on quality of life (QOL) is not known. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the use of PCI in clinical practice. Where possible, patients should be offered entry into a clinical trial.

A national audit of current cardiac device policies from radiotherapy centres across the UK.

AIMS: The number of patients with cardiac implantable electronic devices (permanent pacemakers and implantable cardioverter defibrillators) undergoing radiotherapy treatment is increasing. The aims of this audit were to establish current UK practice regarding the management of patients with implanted cardiac devices undergoing radiotherapy and to compare this practice with current 'gold standard' evidence-based guidelines. MATERIALS AND METHODS: All UK radiotherapy departments were contacted and asked to provide their current cardiac implantable electronic device policy or to indicate if there was no current policy. A proforma was created to analyse these policies and to compare with current best practice. RESULTS: In total, 47/67 (70%) radiotherapy departments responded and 45 departmental policies were submitted; 31/45 (69%) policies defined the radiotherapy tolerance dose to permanent pacemakers and 14/45 (31%) defined the monitoring procedure for patients in line with current best practice. Only 5/45 (11%) policies defined the radiotherapy tolerance dose to implantable cardioverter defibrillators and 12/45 (27%) defined the monitoring procedure in line with current best practice. CONCLUSION: Most UK cardiac device policies do not reflect current best evidence. Policies are based on research carried out in 1994 by the American Association of Physicists in Medicine. This evidence does not account for advances in cardiac implantable electronic device technology. Further research is urgently needed to establish the effect of radiotherapy on these devices.

What constitutes best supportive care in the treatment of advanced non-small cell lung cancer patients?--Results from the lung cancer economics and outcomes research (LUCEOR) study.

BACKGROUND: A significant proportion of advanced non-small cell lung cancer (NSCLC) patients receive supportive treatments to manage disease-related symptoms either separately or combined with systemic anti-cancer therapy (SACT). This supportive treatment is commonly referred to as best supportive care (BSC). Definition of BSC in clinical trials and its description in published comparative and real-life NSCLC studies is limited. The lack of a consensus BSC definition makes detailed evaluations of clinical trials and comparisons between clinical trials problematic. METHODS: Data were collected as part of the lung cancer economics and outcomes research (LUCEOR) study. Information on treatment and treatment outcomes from deceased stage IIIb/IV NSCLC patients across ten countries was retrospectively collected from medical records. BSC was defined as the best care available as judged by the attending physicians. RESULTS: A total of 1327 patients' data were analyzed. Of those, 774/1327 (58%), 316/631 (50%), 123/259 (47%), 25/56 (45%) and 15/26 (58%) were administered treatment defined as BSC with first, second, third, fourth and fifth-line SACT respectively. In total, 346/678 (51%), 149/335 (45%), 86/176 (49%), 11/28 (39%) and 13/25 (52%) of patients were administered treatment defined as BSC in the end-of-life setting after finishing first, second, third, fourth and fifth-line SACT respectively. BSC therapies could be grouped into 24 different categories. The most common elements did not vary substantially whether given with SACT (irrespective of treatment line), in the end-of-life setting, or between countries. The commonest categories of BSC were narcotic and non-narcotic analgesics, corticosteroids and gastrointestinal medication. CONCLUSION: There were no major differences in what constituted BSC. BSC included in all instances narcotic and non-narcotic analgesics, corticosteroids and gastrointestinal medication. To our knowledge this is the first study attempting to describe BSC in routine clinical practice. This study's results could help define a practical, up to date, evidence-based definition of BSC.

Small cell oesophageal carcinoma: an institutional experience and review of the literature.

Primary small cell oesophageal carcinoma (SCOC) is rare, prognosis is poor and there is no established optimum treatment strategy. It shares many clinicopathologic features with small cell carcinoma of the lung; therefore, a similar staging and treatment strategy was adopted. Sixteen cases referred to Velindre hospital between 1998 and 2005 were identified. Patients received platinum-based combination chemotherapy if appropriate. Those with limited disease (LD) received radical radiotherapy (RT) to all sites of disease on completion of chemotherapy. Median survival of all patients was 13.2 months. Median survival of patients with LD was significantly longer than those with extensive disease (24.4 vs 9.1 months, P=0.034). This is one of the largest single institution series in the world literature. Combined modality therapy using platinum-based combination chemotherapy and radical RT may allow a nonsurgical approach to management, avoiding the morbidity of oesophagectomy. Prophylactic cranial irradiation is controversial, and should be discussed on an individual basis.