Anjali Zarkar

Abiraterone for prostate cancer not previously treated with hormone therapy

Background Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long‐term androgen‐deprivation therapy (ADT), using a multigroup, multistage trial design. Methods We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node‐negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate‐specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure‐free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). Results A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node‐positive or node‐indeterminate nonmetastatic disease, and 28% had node‐negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow‐up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT‐alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment‐failure events in the combination group as compared with 535 in the ADT‐alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT‐alone group (with three grade 5 events). Conclusions Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure‐free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476, and Current Controlled Trials number, ISRCTN78818544.)

Long-term results of a phase II study of synchronous chemoradiotherapy in advanced muscle invasive bladder cancer

We conducted a phase I/II study investigating synchronous chemoradiotherapy with mitomycin C and infusional 5-fluorouracil (5-FU) in muscle invasive bladder cancer. Early dose escalation results were previously published. We report the long-term toxicity and efficacy results with the optimised regimen. Patients with muscle invasive bladder cancer with glomerular filtration rate >25 ml min−1 were eligible. Mitomycin (12 mg m−2 on day 1 only) and infusional 5-FU (500 mg m−2 day−1) for 5 days were administered during weeks 1 and 4 of radiotherapy of 55 Gy in 20 fractions. A total of 41 patients were enrolled, median age was 68 years, 33 were male and eight female patients. Out of the 41 patients, 20 (49%) had hydronephrosis at presentation and 25 (62%) had T3b or T4 disease. Four patients experienced Grade III thrombocytopenia and three patients had Grade III neutropenia. There were no episodes of febrile neutropenia. Four patients experienced Grade III diarrhoea and 1 Grade III urgency and dysuria. Six patients did not undergo cystoscopic evaluation due to early metastatic spread although there was no clinical suggestion of bladder failure. In all, out of 35 evaluable patients, 25 (71%) had macroscopic complete response at 3-month cystoscopy, and biopsy confirmed in 24 out of 25. A total of 16 (39%) patients remain alive with a median follow-up of 50.7 (range 23.5–68.8) months, 14 with a functioning bladder with no reported long-term treatment-related bladder or bowel toxicity. Five out of 41 patients have undergone salvage cystectomy: two for persistent CIS, two T1 and one muscle invasive recurrence. Four patients have received intravesical chemotherapy, of whom two remain alive with a functioning bladder. Overall 12-, 24- and 60-month (m) survival rates were 68, 49 and 36%. Local and distant progression free rates were 82 and 86% at 12-m and 79 and 75% at 24-m. Organ preservation using multimodality therapy is feasible and safe, even in patients with poor renal reserve, and does not compromise salvage therapies. A national phase III trial BC2001 (www.bc2001.org.uk) exploring the effects of synchronous chemoradiotherapy with this regimen is currently recruiting.

Consensus Guidelines and Contouring Atlas for Pelvic Node Delineation in Prostate and Pelvic Node Intensity Modulated Radiation Therapy.

PURPOSE The purpose of this study was to establish reproducible guidelines for delineating the clinical target volume (CTV) of the pelvic lymph nodes (LN) by combining the freehand Royal Marsden Hospital (RMH) and Radiation Therapy Oncology Group (RTOG) vascular expansion techniques. METHODS AND MATERIALS Seven patients with prostate cancer underwent standard planning computed tomography scanning. Four different CTVs (RMH, RTOG, modified RTOG, and Prostate and pelvIs Versus prOsTate Alone treatment for Locally advanced prostate cancer [PIVOTAL] trial) were created for each patient, and 6 different bowel expansion margins (BEM) were created to assess bowel avoidance by the CTV. The resulting CTVs were compared visually and by using Jaccard conformity indices. The volume of overlap between bowel and planning target volume (PTV) was measured to aid selection of an appropriate BEM to enable maximal LN yet minimal normal tissue coverage. RESULTS In total, 84 nodal contours were evaluated. LN coverage was similar in all groups, with all of the vascular-expansion techniques (RTOG, modified RTOG, and PIVOTAL), resulting in larger CTVs than that of the RMH technique (mean volumes: 287.3 cm(3), 326.7 cm(3), 310.3 cm(3), and 256.7 cm(3), respectively). Mean volumes of bowel within the modified RTOG PTV were 19.5 cm(3) (with 0 mm BEM), 17.4 cm(3) (1-mm BEM), 10.8 cm(3) (2-mm BEM), 6.9 cm(3) (3-mm BEM), 5.0 cm(3) (4-mm BEM), and 1.4 cm(3) (5-mm BEM) in comparison with an overlap of 9.2 cm(3) seen using the RMH technique. Evaluation of conformity between LN-CTVs from each technique revealed similar volumes and coverage. CONCLUSIONS Vascular expansion techniques result in larger LN-CTVs than the freehand RMH technique. Because the RMH technique is supported by phase 1 and 2 trial safety data, we proposed modifications to the RTOG technique, including the addition of a 3-mm BEM, which resulted in LN-CTV coverage similar to that of the RMH technique, with reduction in bowel and planning target volume overlap. On the basis of these findings, recommended guidelines including a detailed pelvic LN contouring atlas have been produced and implemented in the PIVOTAL trial.