Methodological advances with new framework adaptive meta-analysis

James Fleck & Fernando Souza: Anticancerweb 26 (04), 2019

Treatment of metastatic hormone-sensitive prostate cancer (m-HSPC) is mainly based on androgen deprivation therapy (agonists or antagonists-LHRH), which more recently has been combined with abiraterone or docetaxel. Elegant experimental models for m-HSPC have supported the associated use of radiotherapy directed to the primary tumor. In October 2018, the journal Lancetpublished the results of the multicenter British Stampede Trial - Arm H.A total of 2061 patients diagnosed with m-HSPC were randomly assigned to exclusive systemic treatment (control group) or systemic treatment + primary tumor-directed radiotherapy (PT-RT). Two radiotherapy programs were used: Weekly fractions of 6 Gy / 6 weeks, totaling 36 Gy or 20 daily fractions of 2.75 Gy / 4 weeks, totaling 55 Gy. In contrast to the alternative hypothesis, PT-RT did not improve overall survival (HR 0.92 p = 0.266). However, in an exploratory analysis, it was identified a subgroup of patients (40% of the sample) with a low metastatic burden (<4 bone metastases restricted to the axial skeleton and / or lymph node involvement) had a global survival benefit with PT-RT (HR 0.68 p = 0.007). The benefit included both used radiotherapy programs. PT-RT low acute and late toxicity allowed to suggest a new standard treatment for m-HSPC, which should be restricted to the low metastatic burden subgroup.

In order to improve the level of evidence, in February 2019, the journal European Urology publishes the results of the systematic review + meta-analysis known by the acronym STOPCAP. A new framework for adaptive meta-analysis was used, prospectively defining its revision method, which included access to the database of the selected studies. Whenever possible, criteria standardization was sought, potentially reducing the degree of heterogeneity of the meta-analysis. In addition, Cochrane Collaboration's tool for assessing risk of bias was used. Preliminarily, the review evaluated 19830 cases, distributed in seven clinical trials. However, four studies were excluded and one had not completed the accrual of patients. Only two clinical trials (STAMPEDE and HORRAD) remained, and the first one participated with a number of patients almost four times greater, which weakened the meta-analysis. However, this is an interesting evolving methodology that has been supported by the Medical Research Council and Prostate Cancer UK allowing gradual incorporation of new individual data, perhaps generating a new cooperative clinical research model. Given the temporary limitations of the method, the current STOPCAP publication did not identify benefit with the addition of PT-RT both in the overall survival (HR = 0.92, p = 0.195) or progression-free survival (HR = 0.94, p = 0.238) of m-HSPC. The benefit of adding PT-RT to the androgen deprivation treatment was restricted to two surrogate outcomes: biochemical failure (HR = 0.74) and failure-free survival (HR = 0.76). As this latter one included biochemical progression in its definition criteria, the observed overlapped results were expected. As previously anticipated at the Stampede Trial publication, the STOPCAP meta-analysis also identified an overall survival benefit only in the m-HSPC subgroup of low-metastatic burden, showing 4 or fewer sites of bone dissemination. In this specific subgroup there was an increase of 7% in survival over three year-period. The progressive inclusion of mature new data from other clinical studies will make the adaptive meta-analysis more robust and consolidating the new methodology.

References:

Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ343:5928, 2011

Christopher C Parker, Nicholas D James, Christopher D Brawley, et al: Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomized controlled phase 3 trial, Lancet, Oct 21^st, 2018

Sarah Burdett, Liselotte M. Boeve, Fiona C. Ingleby, et al: Prostate Radiotherapy for Metastatic Hormone-sensitive Prostate Cancer: A STOPCAP Systematic Review and Meta-analysis, Eur Urol, Feb 5, 2019