Anna Wilkins

Equivalence of cisplatin and carboplatin-based chemoradiation for locally advanced squamous cell carcinoma of the head and neck: A matched-pair analysis

BACKGROUND Carboplatin can be substituted for cisplatin in concomitant chemoradiation (CRT) for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) when the latter is contraindicated. This matched-pair study aimed to compare the efficacy and acute toxicity of carboplatin and cisplatin. METHODS Patients treated with 2 cycles of concomitant carboplatin-based CRT were matched to patients treated with 2 cycles of cisplatin. Matching criteria included age, tumour site, stage, smoking status and use of induction chemotherapy. Radiation was delivered using conformal techniques. Data on weekly acute toxicity throughout CRT was compared using the chi-squared test for proportions. Kaplan Meier statistics described time to local relapse, distant relapse and overall survival, the log-rank test was used to compare 3-year survival outcomes. RESULTS Sixty-five patients who received carboplatin were matched to 65 who received cisplatin. Significant differences in toxicity included increased emesis with cisplatin and more anaemia and thrombocytopenia with carboplatin. There was no significant difference in 3-year locoregional control (87% vs. 79%, p=0.54), freedom from distant metastases (88% vs. 85%, p=0.79) and overall survival (59% vs. 68%, p=0.24) between the carboplatin and cisplatin cohorts, respectively. CONCLUSIONS When cisplatin is contraindicated, carboplatin-based CRT yields equivalent treatment outcomes in patients with LASCCHN.

Diethylstilbestrol in castration‐resistant prostate cancer

Study Type – Therapy (case series)

Treating prostate cancer with radiotherapy

This Review focuses on the adverse effects of radical radiotherapy for localized prostate cancer. The adverse effects are described in the context of alternative treatment modalities. First, we consider the methodological issues that make comparison between the different treatment modalities problematic. Such issues include differences in baseline levels of urinary, bowel and sexual dysfunction, the importance of using patient-reported outcomes and the distinction between actuarial and prevalence rates of treatment-related toxic effects. Second, we describe the pattern of adverse effects that occur over time after radiotherapy. Here, we focus on evidence for a beneficial effect of radiotherapy on some urinary symptoms, and the controversy regarding the risk of secondary malignancy. Third, predictors of radiation toxicity are discussed. Accurate prediction of radiotherapy toxicity would be an invaluable tool for treatment individualization. It is noteworthy that the data on the adverse effects of prostate radiotherapy necessarily relate to treatment as it was delivered in the past. It is likely that recent technical advances, such as intensity modulation and image guidance, will further improve the toxicity profile of prostate radiotherapy.

The melanoma-specific graded prognostic assessment does not adequately discriminate prognosis in a modern population with brain metastases from malignant melanoma

Background:The melanoma-specific graded prognostic assessment (msGPA) assigns patients with brain metastases from malignant melanoma to 1 of 4 prognostic groups. It was largely derived using clinical data from patients treated in the era that preceded the development of newer therapies such as BRAF, MEK and immune checkpoint inhibitors. Therefore, its current relevance to patients diagnosed with brain metastases from malignant melanoma is unclear. This study is an external validation of the msGPA in two temporally distinct British populations.Methods:Performance of the msGPA was assessed in Cohort I (1997–2008, n=231) and Cohort II (2008–2013, n=162) using Kaplan–Meier methods and Harrell’s c-index of concordance. Cox regression was used to explore additional factors that may have prognostic relevance.Results:The msGPA does not perform well as a prognostic score outside of the derivation cohort, with suboptimal statistical calibration and discrimination, particularly in those patients with an intermediate prognosis. Extra-cerebral metastases, leptomeningeal disease, age and potential use of novel targeted agents after brain metastases are diagnosed, should be incorporated into future prognostic models.Conclusions:An improved prognostic score is required to underpin high-quality randomised controlled trials in an area with a wide disparity in clinical care.

Genomic and Histopathological Tissue Biomarkers That Predict Radiotherapy Response in Localised Prostate Cancer

Localised prostate cancer, in particular, intermediate risk disease, has varied survival outcomes that cannot be predicted accurately using current clinical risk factors. External beam radiotherapy (EBRT) is one of the standard curative treatment options for localised disease and its efficacy is related to wide ranging aspects of tumour biology. Histopathological techniques including immunohistochemistry and a variety of genomic assays have been used to identify biomarkers of tumour proliferation, cell cycle checkpoints, hypoxia, DNA repair, apoptosis, and androgen synthesis, which predict response to radiotherapy. Global measures of genomic instability also show exciting capacity to predict survival outcomes following EBRT. There is also an urgent clinical need for biomarkers to predict the radiotherapy fraction sensitivity of different prostate tumours and preclinical studies point to possible candidates. Finally, the increased resolution of next generation sequencing (NGS) is likely to enable yet more precise molecular predictions of radiotherapy response and fraction sensitivity.

Ki67 Is an Independent Predictor of Recurrence in the Largest Randomized Trial of 3 Radiation Fractionation Schedules in Localized Prostate Cancer

Purpose To assess whether the cellular proliferation marker Ki67 provides prognostic information and predicts response to radiation therapy fractionation in patients with localized prostate tumors participating in a randomized trial of 3 radiation therapy fractionation schedules (74 Gy/37 fractions vs 60 Gy/20 fractions vs 57 Gy/19 fractions). Methods and Materials A matched case–control study design was used; patients with biochemical/clinical failure >2 years after radiation therapy (BCR) were matched 1:1 to patients without recurrence using established prognostic factors (Gleason score, prostate-specific antigen, tumor stage) and fractionation schedule. Immunohistochemistry was used to stain diagnostic biopsy specimens for Ki67, which were scored using the unweighted global method. Conditional logistic regression models estimated the prognostic value of mean and maximum Ki67 scores on BCR risk. Biomarker–fractionation interaction terms determined whether Ki67 was predictive of BCR by fractionation. Results Using 173 matched pairs, the median for mean and maximum Ki67 scores were 6.6% (interquartile range, 3.9%-9.8%) and 11.0% (interquartile range, 7.0%-15.0%) respectively. Both scores were significant predictors of BCR in models adjusted for established prognostic factors. Conditioning on matching variables and age, the odds of BCR were estimated to increase by 9% per 1% increase in mean Ki67 score (odds ratio 1.09; 95% confidence interval 1.04-1.15, P = .001). Interaction terms between Ki67 and fractionation schedules were not statistically significant. Conclusions Diagnostic Ki67 did not predict BCR according to fractionation schedule in CHHiP; however, it was a strong independent prognostic factor for BCR.

Methodology for tissue sample collection within a translational sub-study of the CHHiP trial (CRUK/06/016), a large randomised phase III trial in localised prostate cancer

Highlights • This article presents the methodology for tissue sample collection in the CHHiP trial.• 2047 patients provided tissue from 107 pathology departments between August 2012 and April 2014.• Central pathological review was important to minimise subjectivity in Gleason grade grouping and the impact of grade shift.• A key lesson learned was the need for prospective consent for tissue collection at trial recruitment.• Material Transfer Agreement (MTA) integration into the initial trial site agreement is important.