Daniel Ford

Bevacizumab with peri-operative epirubicin, cisplatin and capecitabine (ECX) in localised gastro-oesophageal adenocarcinoma: a safety report

BACKGROUND Peri-operative chemotherapy and surgery is a standard treatment of localised oesophagogastric adenocarcinoma; however, the outcomes remain poor. PATIENTS AND METHODS ST03 is a multicentre, randomised, phase II/III study comparing peri-operative ECX with or without bevacizumab (ECX-B). The primary outcome measure of phase II (n = 200) was safety, specifically gastrointestinal (GI) perforation rates and cardiotoxicity. RESULTS Two hundred patients were randomised between October 2007 and April 2010. Ninety-one/101 (90%) ECX and 86/99 (87%) ECX-B patients completed pre-operative chemotherapy; 7 ECX and 9 ECX-B patients stopped due to toxicity. Gastrointestinal perforations (3 ECX, 1 ECX-B), cardiac events (1 ECX, 4 ECX-B) and venous thromboembolic events (VTEs, 8 ECX, 7 ECX-B) were uncommon. Arterial thromboembolic events (ATEs, myocardial infarction (MI) or cerebrovascular accident) were more frequent with ECX-B (5 versus 1 with ECX). Delayed wound healing, anastomotic leaks and GI bleeding rates were similar. More asymptomatic left ventricular ejection fraction (LVEF) falls (≥15% and/or to <50%) occurred with ECX-B (21.2% versus 11.1% with ECX). Clinically significant falls (≥10% to below lower limit of normal, LLN) occurred in (15.3%) and (8.9%) respectively, with no associated cardiac failure (median 22 months follow-up). CONCLUSIONS Addition of bevacizumab to peri-operative ECX chemotherapy is feasible with acceptable toxicity and no negative impact on surgical outcomes.

Phase III Study Comparing a Reduced Dose of Cabazitaxel (20 mg/m2) and the Currently Approved Dose (25 mg/m2) in Postdocetaxel Patients With Metastatic Castration-Resistant Prostate Cancer—PROSELICA

Purpose Cabazitaxel 25 mg/m2 (C25) significantly improved overall survival (OS) versus mitoxantrone ( P < .001) in postdocetaxel patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase III TROPIC study. The phase III PROSELICA study ( ClinicalTrials.gov identifier: NCT01308580) assessed the noninferiority of cabazitaxel 20 mg/m2 (C20) versus C25 in postdocetaxel patients with mCRPC. Methods Patients were stratified by Eastern Cooperative Oncology Group performance status, measurability of disease per Response Evaluation Criteria in Solid Tumors (RECIST), and region, and randomly assigned to receive C20 or C25. To claim noninferiority of C20 (maintenance of ≥ 50% of the OS benefit of C25 v mitoxantrone in TROPIC) with 95% confidence level, the upper boundary of the CI of the hazard ratio (HR) for C20 versus C25 could not exceed 1.214 under a one-sided 98.89% CI after interim analyses. Secondary end points included progression-free survival, prostate-specific antigen (PSA), tumor and pain responses and progression, health-related quality of life, and safety. Results Overall, 1,200 patients were randomly assigned (C20, n = 598; C25, n = 602). Baseline characteristics were similar in both arms. Median OS was 13.4 months for C20 and 14.5 months for C25 (HR, 1.024). The upper boundary of the HR CI was 1.184 (less than the 1.214 noninferiority margin). Significant differences were observed in favor of C25 for PSA response (C20, 29.5%; C25, 42.9%; nominal P < .001) and time to PSA progression (median: C20, 5.7 months; C25, 6.8 months; HR for C20 v C25, 1.195; 95% CI, 1.025 to 1.393). Health-related quality of life did not differ between cohorts. Rates of grade 3 or 4 treatment-emergent adverse events were 39.7% for C20 and 54.5% for C25. Conclusion The efficacy of cabazitaxel in postdocetaxel patients with mCRPC was confirmed. The noninferiority end point was met; C20 maintained ≥ 50% of the OS benefit of C25 versus mitoxantrone in TROPIC. Secondary efficacy end points favored C25. Fewer adverse events were observed with C20.

Clinical outcomes in patients with castrate-refractory prostate cancer (CRPC) metastatic to bone randomized in the factorial TRAPEZE trial to docetaxel (D) with strontium-89 (Sr89), zoledronic acid (ZA), neither, or both (ISRCTN 12808747).

LBA5000 Background: Bony metastatic CRPC has a poor prognosis and high morbidity. TRAPEZE is a factorial RCT using three agents, D, ZA, and Sr89. All have palliative benefits and are used in bony metastatic CRPC to control bone symptoms and (for D) to prolong survival. ZA was approved on the basis of reducing skeletal related events (SRE). Sr89 was approved to control pain from metastases and to reduce the need for subsequent bone treatments. ZA is commonly combined with D in practice but evidence that the combination is effective is lacking and costs considerable. Sr89 is generally used as a palliative therapy in patients unfit for chemotherapy. Phase II analysis confirmed the safety and feasibility of combining these agents. TRAPEZE aimed to determine clinical and cost-effectiveness scheduling. METHODS Patients were randomised to receive 6 cycles of D plus prednisolone: alone; with ZA; with a single dose of Sr89 after cycle 6 or both. Primary outcomes were clinical progression-free survival (CPFS: pain progression, SRE or death) and cost-effectiveness. Secondary outcomes were SRE free interval (SREFI); total SREs, and overall survival (OS). The log rank test and Cox regression modelling were used to determine clinical effectiveness. RESULTS TRAPEZE randomised 757 patients; median age 68.7 yrs; ECOG 0: 40% 1: 52% 2: 8%; prior RT 45%; median PSA 144 (IQR 51, 354). Provisional stratified log rank analysis of CPFS did not reach statistical significance for either agent (Sr89 p=0.11, ZA p=0.45). Cox regression analysis adjusted for all stratification variables showed benefit of Sr89 on CPFS (HR=0.845; 95%CI 0.72, 0.99, p=0.036) and confirmed no effect of ZA (p=0.46). ZA did show a significant effect on SREFI (HR=0.76; 95%CI 0.63, 0.93, p=0.008). There was no effect of either agent on overall survival (Sr89 p=0.74, ZA p=0.91). CONCLUSIONS Sr89 after six cycles of docetaxel improved CPFS but not OS. ZA did not improve CPFS or OS but did significantly improve median SREFI, mostly post progression, suggesting a role as post chemotherapy maintenance therapy. Further health economic and QoL analyses are pending. CLINICAL TRIAL INFORMATION 12808747.

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

Abstract 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.

Postdocetaxel treatment for castrate-resistant prostate cancer: The sequential use of abiraterone and cabazitaxe.

234 Background: Large phase III trials have shown both abiraterone (Abi) and cabazitaxel (Cbz) to have a survival benefit in patients with metastatic castrate resistant prostate cancer (mCRPC). They are now used routinely throughout the UK in this setting. The mechanisms of resistance of these drugs remain unclear and therefore, their sequential use is less recognised. We present data from patients who have been exposed to both therapies. METHODS In this retrospective study, we searched our own pharmacy databases to identify all patients that had been exposed to both Abi and Cbz. All patients were treated between April 2009 and October 2012. A total of 21 patients were reviewed and clinical data was collected. SPSS software was used to create Kaplan Meier curves. RESULTS 17 of the 21 patients received Abi before Caz. Median progression free survival for patients on the sequential regimes was 16.9 months (95% Confidence interval: 10.5-23.3). Reviewing the drugs individually found progression free survival was 5.1 months (4.4-6.0 months) with Abi and 7.1 months (5.1-9.1) with Cbz. CONCLUSIONS In a select group of patients who are fit enough to receive both drugs, superior progression free survival is seen than can be expected on one drug alone. The data compares favourably to that seen in the TROPIC study where time to progression on Cbz was 2.8 months. Furthermore, lack of response to one drug did not preclude worthwhile response to the other agent. These findings are consistent with the drugs having separate mechanisms. At this stage the series is not mature enough to draw conclusions on survival benefit. An updated series, involving larger patient numbers, will be presented at the meeting.

Evaluation of the added value of 1H-magnetic resonance spectroscopy for the diagnosis of pediatric brain lesions in clinical practice

Abstract Background Magnetic resonance spectroscopy (MRS) aids noninvasive diagnosis of pediatric brain tumors, but use in clinical practice is not well documented. We aimed to review clinical use of MRS, establish added value in noninvasive diagnosis, and investigate potential impact on patient care. Methods Sixty-nine children with lesions imaged using MRS and reviewed by the tumor board from 2014 to 2016 met inclusion criteria. Contemporaneous MRI diagnosis, spectroscopy analysis, histopathology, and clinical information were reviewed. Final diagnosis was agreed on by the tumor board at study end. Results Five cases were excluded for lack of documented MRI diagnosis. The principal MRI diagnosis by pediatric radiologists was correct in 59%, increasing to 73% with addition of MRS. Of the 73%, 19.1% (95% CI, 9.1%-33.3%) were incorrectly diagnosed with MRI alone. MRS led to a significant improvement in correct diagnosis over all tumor types (P = .012). Of diagnoses correctly made with MRI, confidence increased by 37% when adding MRS, with no patients incorrectly re-diagnosed. Indolent lesions were diagnosed noninvasively in 85% of cases, with MRS a major contributor to 91% of these diagnoses. Of all patients, 39% were managed without histopathological diagnosis. MRS contributed to diagnosis in 68% of this group, modifying it in 12%. MRS influenced management in 33% of cases, mainly through avoiding and guiding biopsy and aiding tumor characterization. Conclusion MRS can improve accuracy and confidence in noninvasive diagnosis of pediatric brain lesions in clinical practice. There is potential to improve outcomes through avoiding biopsy of indolent lesions, aiding tumor characterization, and facilitating earlier family discussions and treatment planning.