External validity of a prediction rule for residual mass histology in testicular cancer: An evaluation for good prognosis patients

We assessed the external validity of a prediction rule for nonseminomatous testicular cancer patients. The rule was developed to predict the probability of retroperitoneal metastases being benign (only necrosis/fibrosis) after chemotherapy treatment. Patients with a high probability of benign residual masses might be offered surveillance as opp

Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2–3 trial

Background: Peri-operative chemotherapy and surgery is a standard of care for patients with resectable oesophagogastric adenocarcinoma. Bevacizumab, a monoclonal antibody against VEGF, improves the proportion of patients responding to treatment in advanced gastric cancer. We aimed to assess the safety and efficacy of adding bevacizumab to peri-operative chemotherapy in patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Methods: In this multicentre, randomised, open-label phase 2–3 trial, we recruited patients aged 18 years and older with histologically proven, resectable oesophagogastric adenocarcinoma from 87 UK hospitals and cancer centres. We randomly assigned patients 1:1 to receive peri-operative epirubicin, cisplatin, and capecitabine chemotherapy or chemotherapy plus bevacizumab, in addition to surgery. Patients in the control group (chemotherapy alone) received three pre-operative and three post-operative cycles of epirubicin, cisplatin, and capecitabine chemotherapy: 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 and 1250 mg/m2 oral capecitabine on days 1–21. Patients in the investigational group received the same treatment as the control group plus 7·5 mg/kg intravenous bevacizumab on day 1 of every cycle of chemotherapy and for six further doses once every 21 days following chemotherapy, as maintenance treatment. Randomisation was done by means of a telephone call to the Medical Research Council Clinical Trials Unit, where staff used a computer programme that implemented a minimisation algorithm with a random element to establish the allocation for the patient at the point of randomisation. Patients were stratified by chemotherapy centre, site of tumour, and tumour stage. The primary outcome for the phase 3 stage of the trial was overall survival (defined as the time from randomisation until death from any cause), analysed in the intention-to-treat population. Here, we report the primary analysis results of the trial; all patients have completed treatment and the required number of primary outcome events has been reached. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 46020948, and with ClinicalTrials.gov, number NCT00450203. Findings: Between Oct 31, 2007, and March 25, 2014, 1063 patients were enrolled and randomly assigned to receive chemotherapy alone (n=533) or chemotherapy plus bevacizumab (n=530). At the time of analysis, 508 deaths were recorded (248 in the chemotherapy alone group and 260 in the chemotherapy plus bevacizumab group). 3-year overall survival was 50·3% (95% CI 45·5–54·9) in the chemotherapy alone group and 48·1% (43·2–52·7) in the chemotherapy plus bevacizumab group (hazard ratio [HR] 1·08, 95% CI 0·91–1·29; p=0·36). Apart from neutropenia no other toxic effects were reported at grade 3 or worse severity in more than 10% of patients in either group. Wound healing complications were more prevalent in the bevacizumab group, occurring in 53 (12%) patients in this group compared with 33 (7%) patients in the chemotherapy alone group. In patients who underwent oesophagogastrectomy, post-operative anastomotic leak rates were higher in the chemotherapy plus bevacizumab group (23 [10%] of 233 in the chemotherapy alone group vs 52 [24%] of 220 in the chemotherapy plus bevacizumab group); therefore, recruitment of patients with lower oesophageal or junctional tumours planned for an oesophagogastric resection was stopped towards the end of the trial. Serious adverse events for all patients included anastomotic leaks (30 events in chemotherapy alone group vs 69 in the chemotherapy plus bevacizumab group), and infections with normal neutrophil count (42 events vs 53). Interpretation: The results of this trial do not provide any evidence for the use of bevacizumab in combination with peri-operative epiribicin, cisplatin, and capecitabine chemotherapy for patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Bevacizumab might also be associated with impaired wound healing. Funding: Cancer Research UK, MRC Clinical Trials Unit at University College London, and F Hoffmann-La Roche Limited

Mathematical modelling of survival of glioblastoma patients suggests a role for radiotherapy dose escalation and predicts poorer outcome after delay to start treatment

Aims: The outcome of patients with glioblastoma (GBM) remains extremely poor. We have developed a mathematical model, using pathological and radiation biology concepts, to assess the detrimental effect of delay to start radiotherapy, the possible benefit from dose escalation, and to extract biological data from clinical data.Materials and methods: Survival data were available for 154 adult patients with GBM treated in our centre with curative intent to a dose of 60 Gy in 30 fractions between 1996 and 2002. Survival data for 129 patients from the 60 Gy arm of the MRC BR02 randomised trial of radiotherapy dose were obtained for comparison. The model generates the equivalent of individual patients with a brain tumour, and produces an explicit outcome, either death or survival. The tumour assumed to be growing exponentially, causes normal cell damage in the brain, and death occurs when the number of normal brain cells falls below a critical level. The outcome for an individual patient is determined by values of the variables assigned by the model. Parameters for the single patient include tumour doubling time, surviving fraction of tumour cells after each fraction of radiotherapy, and a waiting time from presentation to the start of radiotherapy. A surrogate for performance status is implemented, using a rule that rejects patients whose tumours are too advanced at presentation to be suitable for radical radiotherapy. Values for the parameters that determine individual patient outcome are randomly assigned from a set of probability distributions, using Monte Carlo simulation. The simulation constructs survival results for a population, typically 2000 individuals. The descriptors of the probability distributions that are used to determine the parameters that define the patient characteristics are adjusted to optimise the fit of the modelled population to real clinical data, using a combination of folding polygon and simulated annealing techniques.Results: The model fits the clinical data well. The results suggest that the surviving fraction of tumour cells after a radiation dose of 2 Gy (SF2) does influence patient outcome. The mean in vivo SF2 for the Addenbrooke's data is 0.80, implying that hypoxia is a serious problem in radiotherapy for GBM. The Addenbrooke's data suggest a mean tumour doubling time of 24 days, so that a delay to start radiotherapy would be expected to have an adverse effect. Considering patients by treatment intent, median survival plummets as delay increases, and almost no patients survive long term after a 70-day delay. Radiotherapy dose escalation has an important predicted effect on survival. Assuming that the treatment could be delivered safely, a dose of 74 Gy, given at 2 Gy/fraction, would extend the survival of all patients. The proportion of long-term survivors would increase, from 2.4% with 60 Gy. to 6.4% with 74 Gy. The model can be used to derive gamma(50), which has a value of 0.42, lower than the typical value of 1-2.Conclusion: Using the model, we have extracted biological information from clinical data. The model could be used to assess the potential benefit, or lack of benefit, from a proposed radiotherapy trial, and to estimate the necessary size. It shows that a single modality is unlikely to achieve a major improvement in long-term survival, although radiotherapy dose escalation should have a role, provided it can be given safely. The model could be extended to include chemotherapy, bio-reductive drugs, or gene therapy

Consolidation radiotherapy in patients with advanced Hodgkin lymphoma: survival data from the UKLG LY09 randomised controlled trial (ISRCTN97144519)

Purpose: this study analyzed the outcomes of nonrandomized consolidation radiotherapy (RT) given after chemotherapy in the initial treatment of advanced Hodgkin's lymphoma (HL). The results were collected prospectively within a randomized controlled trial of induction chemotherapy.Patients and methods: patients were randomly assigned between doxorubicin, bleomycin, vinblastine, and dacarbazine and one of two prespecified multidrug regimens. At least six cycles of chemotherapy were planned, with up to eight for patients showing slower response. Involved-field RT was recommended for incomplete response to chemotherapy or bulk disease at presentation. The primary outcome measure was progression-free survival (PFS), landmarked from the end of chemotherapy.Results: among 807 patients randomly assigned, 702 achieved objective response. Postchemotherapy RT for consolidation was reported in 300 (43%). With median follow-up of 6.9 years, 161 PFS events and 83 deaths were reported. Baseline characteristics showed more patients with bulk disease having RT (190 [63%] v 111 [28%]) and only partial response after chemotherapy (150 [50%] v 36 [9%]). Other baseline characteristics were similar. PFS was superior for patients having RT (hazard ratio [HR], 0.43; 95% CI, 0.30 to 0.60) with 5-year PFS 71% without RT, 86% with RT. A similar advantage was seen for overall survival (HR, 0.47; 95% CI, 0.29 to 0.77). There was no evidence of heterogeneity of treatment effect across subgroups.Conclusion: patients who received consolidation RT apparently had better outcomes, consistently across all prognostic groups which persisted in multivariate analysis. This suggests that RT contributes significantly to the cure rate for advanced HL, although patient selection for combined modality treatment requires better definition in prospective trials

Medical Research Council trial of 2 versus 5 CT scans in the surveillance of patients with stage I non-seminomatous germ cell tumours of the testis

Background: Surveillance is a standard management approach for stage 1 non seminomatous germ cell tumours (NSGCT), yet there is no agreement on the number of CT scans that are required to detect relapses. A randomised trial of 2 versus 5 CT scans was performed to determine whether the number of scans influenced the prognostic group (J Clin Oncol 15:594-603, 1997) at relapse. Methods: Patients with clinical stage 1 NSGCT opting for surveillance were randomised to chest and abdominal CT scans at either 3 and 12 or 3, 6, 9, 12, and 24 months, with all other investigations (clinical exams, markers, chest X-rays) carried out at equal frequency in the two arms. 3/5 patients were allocated to the 2 scan schedule. 400 patients were required to exclude a 3% increase in the proportion of patients relapsing with IGCCCG intermediate or poor prognosis disease with 90% power at the 5% significance level (1-sided). Results: 247 patients were allocated to 2 CT scans and 167 to 5 CT scans. With a median follow up of 40 months 37 (15%) relapses have occurred in the 2 scan arm and 33 (20%) in the 5 scan arm. No patients were poor prognosis at relapse but 2 (0.8%) of those relapsing in the 2 scan arm were intermediate prognosis compared to 1 (0.6%) in the 5 scan arm a difference of 0.2% (90% CI -1.2%, +1.6%). The mean diameter of abdominal mass at relapse was 2.1 cm in the two scan arm and 2.2 cm in the five scan arm. After chemotherapy a residual mass was present in 35% in the 2 scan and 36% in the 5 scan arm. No deaths have been reported. Conclusions: This study can exclude with 95% probability an increase in the proportion of patients relapsing with intermediate or poor prognosis disease of more than 1.6% if they have 2 rather than 5 CT scans as part of their surveillance protocol. CT scans at 3 and 12 months after orchidectomy should be considered as the new standard and will be associated with a reduction in radiation exposure