There have been multiple FDA-approved systemic therapies for metastatic prostate cancer attempting to convert the disease from a fatal condition to a chronic condition. To date, the 5-year survival rate for metastatic prostate cancer is only 30%.2 Urologic surgeons and radiation oncologist are attempting to change and increase the survival rate.
The concept of oligometastatic disease was formed in 1995. It is a distinct clinical state within an advanced disease spectrum. It has a favorable phenotype ripe for intensified therapy. It manifests an intermediate biological state of attenuated pro-metastatic activity. However, even if the oligometastatic disease is detected and treated, aside from the adverse effects created by the given treatment, it appears that the survival advantage is not significant, and a lead time bias is witnessed (Figure 1).
Figure 1 – Does treatment of oligometastasis change anything?
An oligometastasis model suggested by Alongi F. at the Italian national congress in 2018 is shown in Figure 2. It is comprised of four distinct clinical scenarios.
Figure 2 -Oligometastasis model:
The rationale behind metastases directed therapy is that early treatment delays adverse outcomes and prevents symptoms, skeletal events, development of castration resistance, and initiation of systemic therapies. It is feasible and safe due to advanced surgical and radiation approaches, including stereotactic ablative radiation (SABR), which is also known as stereotactic body radiation therapy (SBRT).
SBRT is highly focused radiation concentrated on limited-volume tumors. It consists of 1-5 treatments with very high dose per fraction, and it can deliver precise radiotherapy through sophisticated techniques, with a low dose to the surrounding tissue. There have been several metastasis-directed SABR case series with overall good local control results and relatively low toxicity. There have also been some phase 2 prospective studies. These include the STOMP trial3 demonstrating median androgen deprivation therapy (ADT) free survival of 21 months vs. 13 months in surveillance only group. Another study is the ORIOLE trial4 comparing SABR vs. observation in oligometastatic patients. The results demonstrated a 67% vs. 33% progression rate at six months in favor of the SABR group. Lastly, the SAVR-COMET trial compared comprehensive therapy of oligometastasis vs. standard of care palliation, demonstrating nearly 2-fold more patients alive in the SABR arm after five years (46% vs. 24%).5
Next, Dr. Vapiwala continued to discuss the rationale for treating the primary tumor in oligometastatic disease. Radical prostatectomy and metastasectomy result in cytoreduction, while radiotherapy cause cytoreduction + abscopal effect of metastasis regression. Radiotherapy causes natural immunity induction via increased antigen presentation (Figure 3).
Figure 3 – Cancer immunoediting with radiotherapy:
There have been some retrospective studies showing the benefit of treating the primary tumor in oligometastatic disease. These include a SEER-based study of approximately 14,000 metastatic patients, with only 474 patients who received local treatment. These patients demonstrated lower cancer-specific mortality (HR 0.4, p<0.001) vs. patients with no local treatment on multivariable analysis, maintained in both surgically-treated and radiotherapy-treated patients6. In an NCDB analysis of over 3,000 metastatic patients treated with ADT, those who received prostate-directed radiotherapy (approximately 500 patients) had better overall survival compared to those who received ADT alone (HR 0.55).
There has also been prospective data analyzing the benefit of primary tumor treatment in oligometastatic disease. These include the HORRAD trial8, including 432 patients with primary bone metastatic prostate cancer, with no limit on the number of metastases. Patients were treated with radiotherapy to the primary tumor with ADT vs. ADT alone. The dose was relatively low (70 Gy/35), and the pelvic nodes were not included in the radiotherapy field. The results showed a comparable overall survival rate, and none of the subgroups showed any improvement (when stratified by Gleason score, stage, age, and a number of metastatic lesions). Another important prospective study was the UK/Swiss STAMPEDE trial9 including 2,061 newly diagnosed metastatic prostate cancer patients with no prior therapy. Patients were given radiotherapy (55 GY/20 or 36Gy/6) to the prostate with ADT and with or without docetaxel and compared to standard of care alone without radiotherapy. The radiotherapy improved the failure-free survival but not the overall survival rate. However, radiotherapy improved failure-free survival and 3-year overall survival rate in the low burden group in a prespecified analysis. In contrast, in the high burden metastatic disease, radiotherapy had no benefit.
The limitations of HORRAD include the fact that a relatively low dose of radiotherapy was given, that the pelvic nodes were not treated, and that the patients were heavy with high-volume disease. In any case, the current published prospective data do not technically support radiotherapy for treatment of the primary tumor in metastatic prostate cancer. Despite this, 69% of expert panelists have reported that radical local treatment is appropriate for newly diagnosed oligometastatic disease.10
Summarizing her talk, Dr. Vapiwala stated that there are known limitations in the existing literature regarding the treatment of oligometastatic disease with localized radical therapy. The beneficial effect is currently unclear, and we need to continue to assess its role, incorporating genomic and clinicopathologic characteristics to refine further subsets most likely to benefit.
There are a plethora of ongoing clinical trials assessing the effect of treating the primary tumor in oligometastatic disease (Figure 4), and we eagerly await these results.
Figure 4 – Current ongoing studies assessing the effect of treating the primary tumor in metastatic prostate cancer:
Presented by: Neha Vapiwala, MD, Pereman School of Medicine, University of Pennsylvania, Philadelphia, PA
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, @GoldbergHanan at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA
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- Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017 Jan;67(1):7-30. doi: 10.3322/caac.21387. Epub 2017 Jan 5.
- Ost P, Reynders D, Decaestecker K, et al. Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. DOI: 10.1200/JCO.2017.75.4853 Journal of Clinical Oncology 36, no. 5 (February 10 2018) 446-453.
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- Palma et al. ASTRO 2018: SABR-COMET: Stereotactic Ablative Radiation Therapy for Oligometastatic Tumors
- Culp SH, Schellhammer PF, Williams MB, et al. Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. Eur Urol. 2014 Jun;65(6):1058-66. doi: 10.1016/j.eururo.2013.11.012. Epub 2013 Nov 20.
- Rusthoven 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 Aug 20;34(24):2835-42. doi: 10.1200/JCO.2016.67.4788. Epub 2016 Jun 20.
- Boevé 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. 2019 Mar;75(3):410-418. doi: 10.1016/j.eururo.2018.09.008. Epub 2018 Sep 25.
- Parker C, James N, PhD, Brawley C, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial Lancet 2018; 392: 2353–66 Published Online October 21, 2018 http://dx.doi.org/10.1016/ S0140-6736(18)32486-3
- Gillessen S, Attard G, Beer TM, et al. Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017. Eur Urol. 2018 Feb;73(2):178-211. doi: 10.1016/j.eururo.2017.06.002. Epub 2017 Jun 24