Study Confirms Local Radiotherapy to Improve Survival in Metastatic Prostate Cancer

According to recent data from the American Cancer Society, about 1 in 9 men will be diagnosed with prostate cancer during his lifetime and about 6 in 10 are diagnosed at aged 65 or older. Between 1990 and 2015, the incident of of prostate cancer increased 3.7-fold. In 2018 the United States about 164,690 men are diagnosed with a new cases of prostate cancer and about 29,430 of them will die as a result of the disease.

In Europe around 417,000 new cases of prostate cancer were estimated to have been diagnosed in 2012, with the incidence rate in the United Kingdom (about 47,700) being the 17th highest in Europe, with around 7,000 men are diagnosed each year with prostate cancer that has already spread beyond the prostate. [1][2][3]

In all these cases, the burden of disease plays a major role in survival.

Photo 1.0: Chris Parker, MD, a consultant in clinical oncology at the The Royal Marsden NHS Foundation Trust and Honorary Senior Lecturer in Prostate Cancer Translational Research at the Institute of Cancer Research, Sutton, United Kingdom.

Results from a pre-planned analysis of a large comparison study reported at annual congress of the European Society from Medical Oncology – ESMO 2018, held in Munich, Germany,  shows that radiotherapy to the prostate improves overall survival in men newly diagnosed with metastatic prostate cancer who have a low metastatic disease burden but not in those with higher burden of disease. [4]

“Standard treatment for men newly diagnosed with metastatic prostate cancer is currently drug treatment alone,” explained the lead author Chris Parker, MD, a consultant in clinical oncology at the The Royal Marsden NHS Foundation Trust and Honorary Senior Lecturer in Prostate Cancer Translational Research at the Institute of Cancer Research, Sutton, United Kingdom.

“Although outcomes have improved, men still typically die from metastatic prostate cancer within around five years, so there is a need for more effective treatment. We wanted to know if radiotherapy to the prostate might not only improve local control but also slow progression of metastatic disease,” Parker added.

Newly diagnosed Prostate Cancer
The multi-arm, multi-stage STAMPEDE study* (NCT00268476) included a randomized phase III comparison to test whether radiotherapy to the prostate improves overall survival in men with newly diagnosed metastatic prostate cancer. This was based on the hypothesis that primary tumors, which are the original or first tumours occurring in a patient with cancer, could contribute to overall disease progression and shorter survival in men with metastatic prostate cancer.

Study design
The study included 2061 patients (median age 68 years) from the UK and Switzerland who were newly diagnosed with metastatic prostate cancer. They were randomly allocated to standard of care (SOC) treatment consisting of lifelong androgen deprivation therapy plus early docetaxel from 2016 or to SOC plus radiotherapy to the prostate. The radiotherapy schedule was 55Gy/20f daily over 4 weeks or 36Gy/6f weekly over 6 weeks.

Study Results
Results showed that prostate radiotherapy improved failure-free survival (hazard ratio [HR] 0.68, 95% confidence interval 0.68, 0.84) but not overall survival (HR 0.92, 95% CI 0.80, 1.06) in the whole group of patients.

Pre-specified subgroup analysis showed that radiotherapy to the prostate improved overall survival (OS) by just over one-third (32%) in the 819 men with a low burden of metastatic disease (HR=0.68, 95% CI 0.52, 0.90). In contrast, overall survival was not improved with radiotherapy in the 1120 men with higher metastatic burden.

Higher burden of disease in prostate cancer is defined as four or more bone metastases with at least one outside the axial skeleton and/or visceral metastases [5].

Radiotherapy to the prostate was well tolerated with 5% of patients having grade 3-4 adverse events during treatment and 4% following treatment.

“There was a small increase in risk of bladder and bowel side-effects but these were modest. The side-effects are certainly outweighed by the survival benefit,” Parker explained.

“Prostate radiotherapy improves the survival of men with metastatic prostate cancer who have a low disease burden,” reported Parker.

“Prostate radiotherapy, in addition to drug treatment, should now be a standard treatment option for men with oligometastatic disease,” he recommended:

Parker also noted that prostate radiotherapy is a simple technique that is widely available and relatively cheap, so he considered that it can be implemented easily. He added that the study results are also relevant to men with pelvic node positive but non-metastatic disease (N1M0) where addition of radiotherapy to drug treatment could be curative.

Local primary tumor
“For the first time, this study provides evidence that treating the local primary tumor is associated with improvement in overall survival in men with metastatic prostate cancer and minimal disseminated disease,” said Professor Karim Fizazi, MD, PhD, a medical oncologist, Head of the Department of Cancer Medicine at the Institut Gustave Roussy, Villejuif, France and Professor in Oncology at the University of Paris Sud, France, commenting on the results in behalf of ESMO.

Fizazi added that the finding that there was no significant increase in overall survival in men with higher burden of disease was in line with the previously reported results from the HORRAD trial, a multi-center study which recruited 432 patients with prostate-specific antigen (PSA) >20 ng/ml and primary bone mPCa on bone scan. This study was conducted between 2004 and 2014.

“For men with newly diagnosed oligometastatic** prostate cancer, it is quite likely that this data is practice changing,” Fizazi observed.

“For men with higher burden of disease more data are needed regarding whether upfront local treatment improves or prevents local symptoms, which, by itself, may justify its use in the absence of an overall survival benefit,” he concluded.

In terms of limitations, Fizazi said that although the study was a large, randomized Phase III trial only 18% of the patients had received early docetaxel and none had received early abiraterone, although these treatments are now part of standard treatment in fit men.

Clinical trials
Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) | NCT00268476

References
[1] Key Statistics for Prostate Cancer. American cancer Society. Online. Last accessed October 21, 2018
[2] Pishgar F, Ebrahimi H, Saeedi Moghaddam S, Fitzmaurice C, Amini E.Global, Regional and National Burden of Prostate Cancer, 1990 to 2015: Results from the Global Burden of Disease Study 2015.J Urol. 2018 May;199(5):1224-1232. doi: 10.1016/j.juro.2017.10.044. Epub 2017 Nov 9.
[3] Prostate cancer statistics. Prostate Cancer Incidence. Cancer Research UK. Online. Last accessed October 21, 2018.
[4] Abstract LBA5_PR ‘Radiotherapy (RT) to the primary tumour for men with newly-diagnosed metastatic prostate cancer (PCA): survival results from STAMPEDE (NCT00268476)’ will be presented by Chris Parker during Presidential Symposium 2 on Sunday 21 October, 16:30 to 18:10 (CEST) in Room 18 – Hall A2. Annals of Oncology, Volume 29 Supplement 8 October 2018
[5] Sweeney CJ, Chen Y-H, Carducci M et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. NEJM 2015; 373: 737-746.
[6] Boevé L, Hulshof M, Vis A et al. PD10-10 a prospective, randomized controlled trial evaluating overall survival in patients with primary bone metastatic prostate cancer (MPCA) receiving either androgen deprivation therapy (ADT) or ADT combined with concurrent radiation therapy to the prostate, final data from the HORRAD trial. The Journal of Urology 2018; 199: e231-e232.


*The STAMPEDE trial is a multi-center, randomized controlled trial for patients with locally advanced or metastatic prostate cancer who are commencing long-term Androgen Deprivation Therapy known as ADT. Participants can have either newly diagnosed disease, or have been previously treated with radical radiotherapy or surgery but now have signs of progression such as a rising prostate specific antigen (PSA), a is a protein produced by normal, as well as malignant, cells of the prostate gland which is often elevated in men with prostate cancer. The trial will assess the effects of adding different agents, both as single agents and in combinations, to the standard-of-care or substituting standard of care.

**Oligometastatic disease refers to a state of limited systemic metastatic tumors for which local ablative therapy could be curative. The purpose of local treatment for oligometastatic disease is cure, and the primary outcome to be analyzed should therefor be disease-free survival.

Last Editorial Review: October 22, 2018

Featured Image: Hands holding blue prostate cancer awareness ribbon. Courtesy: © 2010 – 2018 Fotolia. Used with permission. Photo 1.0: Chris Parker, MD, a consultant in clinical oncology at the The Royal Marsden NHS Foundation Trust and Honorary Senior Lecturer in Prostate Cancer Translational Research at the Institute of Cancer Research, Sutton, United Kingdom. Courtesy: © 2010 – 2018 European Society for Medical Oncology.

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