Radiotherapy for newly diagnosed oligometastatic prostate cancer
Authors: Luca Boeri, Vidit Sharma, R Jeffrey Karnes
Journal: The Lancet (2018)

The standard of care for metastatic prostate cancer is systemic therapy in the form of androgen deprivation therapy with or without novel antiandrogens or chemotherapy.1Cornford P Bellmunt J Bolla M et al.EAU-ESTRO-SIOG guidelines on prostate cancer, part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer.Eur Urol. 2017; 71: 630-642Summary Full Text Full Text PDF PubMed Scopus (1034) Google Scholar Administering local treatment to the primary tumour in the setting of metastatic prostate cancer has long been postulated to have a survival benefit on the basis of retrospective series.2Bayne CE Williams SB Cooperberg MR et al.Treatment of the primary tumor in metastatic prostate cancer: current concepts and future perspectives.Eur Urol. 2016; 69: 775-787Summary Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 3Culp SH Schellhammer PF Williams MB Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study.Eur Urol. 2014; 65: 1058-1066Summary Full Text Full Text PDF PubMed Scopus (313) Google Scholar, 4Löppenberg B Dalela D Karabon P et al.The impact of local treatment on overall survival in patients with metastatic prostate cancer on diagnosis: a national cancer data base analysis.Eur Urol. 2017; 72: 14-19Summary Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 5Leyh-Bannurah S-R Gazdovich S Budäus L et al.Local therapy improves survival in metastatic prostate cancer.Eur Urol. 2017; 72: 118-124Summary Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 6Rusthoven CG Jones BL Flaig TW et al.Improved survival with prostate radiation in addition to androgen deprivation therapy for men with newly diagnosed metastatic prostate cancer.J Clin Oncol. 2016; 34: 2835-2842Crossref PubMed Scopus (173) Google Scholar, 7Pompe RS Tilki D Preisser F et al.Survival benefit of local versus no local treatment for metastatic prostate cancer: impact of baseline PSA and metastatic substages.Prostate. 2018; 78: 1-5Crossref Scopus (23) Google Scholar But such series can have selection bias in that patients undergoing local treatment can also have a low volume of metastatic disease (oligometastases), creating a major confounder in most analyses. To date randomised controlled trials investigating this subject have been sparse, and the value of local control in metastatic prostate cancer has been debated. In The Lancet, Christopher Parker and colleagues8Parker CC James ND Brawley CD et al.Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.Lancet. 2018; (published online Oct 21.)http://dx.doi.org/10.1016/S0140-6736(18)32486-3Summary Full Text Full Text PDF Scopus (649) Google Scholar present results of the STAMPEDE randomised controlled trial comparing standard of care (androgen deprivation therapy with or without docetaxel) with external-beam radiotherapy to the prostate. 2061 men with newly diagnosed metastatic prostate cancer who had received no previous treatment to the primary tumour were enrolled from 117 hospitals in Switzerland and the UK. Radiotherapy improved failure-free survival compared with standard of care alone (hazard ratio [HR] 0·76, 95% CI 0·68–0·84; p<0·0001), but overall survival was not improved (0·92, 0·80–1·06; p=0·266). However, in a prespecified analysis, men were stratified using the CHAARTED9Sweeney CJ Chen YH Carducci M et al.Chemohormonal therapy in metastatic hormone-sensitive prostate cancer.N Engl J Med. 2015; 373: 737-746Crossref PubMed Scopus (1754) Google Scholar definition for low or high metastatic burden. In patients with a low metastatic burden (n=819), radiotherapy improved 3-year overall survival compared with standard of care (81% vs 73%; HR 0·68, 95% CI 0·52–0·90; p=0·007), and failure free survival was also improved (0·59, 0·49–0·72; p<0·0001). Patients with a high metastatic burden did not benefit from radiotherapy in terms of failure-free survival or overall survival. Parker and colleagues concluded that radiotherapy should be an option for men with newly diagnosed metastatic prostate cancer and a low metastatic burden.8Parker CC James ND Brawley CD et al.Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.Lancet. 2018; (published online Oct 21.)http://dx.doi.org/10.1016/S0140-6736(18)32486-3Summary Full Text Full Text PDF Scopus (649) Google Scholar A relevant trial in this area of research is the HORRAD study.10Boevé LMS Hulshof MCCM Vis AN et al.Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial: data from the HORRAD trial.Eur Urol. 2018; (published online Sept 25.)DOI:10.1016/j.eururo.2018.09.008Google Scholar 432 men with metastatic prostate cancer were randomly allocated androgen deprivation therapy either alone or with radiotherapy. No difference in overall survival was noted between the two treatment groups, but in the subgroup of men with low volume of metastatic disease (n=160), radiotherapy showed some improvement in overall survival (HR 0·68, 95% CI 0·42–1·10), although the finding was not significant. The similar effect size for radiotherapy in men with low metastatic burden in the HORRAD and STAMPEDE trials, but the absence of statistical significance in HORRAD, suggests that HORRAD was underpowered from the standpoint of metastatic burden. We estimate that more than 250 men would have needed to be randomised to have an 80% probability of detecting a difference with an HR of 0·75. Taken together, both these trials build the case for local radiotherapy in selected men with newly diagnosed oligometastatic prostate cancer. As with any trial, STAMPEDE does have several limitations. First, the main finding of improved survival with radiotherapy in the cohort with a low metastatic burden is based on a subgroup analysis and should be interpreted cautiously. Next, the analysis did not test various definitions of oligometastatic prostate cancer, leaving open the possibility for patients with (for instance) five bone metastases to potentially benefit from local therapy. Defining a metastatic volume threshold above which patients are unlikely to benefit from local therapy is an important area of further study. Also, metastatic deposits in STAMPEDE were identified using conventional imaging, and such a trial might hold less weight as more sensitive PET imaging becomes commonplace. The trial also did not comment on patients with non-regional (eg, retroperitoneal or thoracic or other) lymph-node-only metastases, a relatively common scenario. Do they benefit more from cytoreductive radiotherapy than the average oligometastatic patient with bone metastases? Moreover, the incidence of symptomatic local events was similar between control and radiotherapy groups, suggesting that radiotherapy might not add much local control benefit beyond androgen deprivation therapy with the dosage used in STAMPEDE—a counterintuitive finding. Furthermore, the total dose of radiation delivered in STAMPEDE (either 36 Gy in six fractions or 55 Gy in 20 fractions) was significantly lower than the 70 Gy or greater given for high-risk localised prostate cancer.11Carroll PH Mohler JL NCCN guidelines updates: prostate cancer and prostate cancer early detection.J Natl Compr Canc Netw. 2018; 16: 620-623Crossref PubMed Scopus (184) Google Scholar Thus, dose-optimisation studies are needed to reach a balance between local and oncological control and quality of life in the metastatic setting. Based on the findings of STAMPEDE,8Parker CC James ND Brawley CD et al.Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.Lancet. 2018; (published online Oct 21.)http://dx.doi.org/10.1016/S0140-6736(18)32486-3Summary Full Text Full Text PDF Scopus (649) Google Scholar radiotherapy could be considered for patients with newly diagnosed oligometastatic prostate cancer, but further studies are needed to delineate the clinical implementation of such treatment. We declare no competing interests. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trialRadiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer. Full-Text PDF Open Access