In recent years, there have been multiple FDA approved systemic therapies for metastatic prostate cancer, turning this disease from a fatal one to chronic disease. However, the five-year survival is still only approximately 30%1. Nowadays, urologists and radiation oncologists are trying to help move the needle. The hypothesis of oligometastases has been reexplored and is being investigated.
It is still unclear whether directed treatment of metastases actually helps improve overall survival. Although it is clear that not all metastases are created equal, both CHAARTED and LATITUDE have shown the prognostic value of disease burden (Figure 1).
Figure 1- CHAARTED and LATITUDE metastases volume:
Metastasis directed therapy (MDT) has the potential of lowering disease burden and toxicity and therefore is more desirable by the patient. The rationale comes from the idea that early ablation will result in a delay of adverse outcomes. These include disease progression, castrate resistance, compromised quality of life in the form of symptoms or skeletal events, and systemic therapy-related side effects.
Adding androgen deprivation therapy is undoubtfully effective but has significant adverse effects that we should consider. These include sexual dysfunction, hot flashes, and breast and nipple symptoms. Adding additional treatments down the line causes more side effects that have a detrimental effect on the patient (Figure 2).
Figure 2 – Adverse effects of systemic therapy:
Due to significant advancements in technology, there are currently available surgical and radiation approaches that are safe and feasible for the treatment of metastases. These include stereotactic ablative radiation (SABR) and stereotactic body radiotherapy. It also includes robotic-assisted salvage node dissection, associated with reduced blood loss and less postoperative complications with a shorter hospital stay compared to an open procedure.
However, the fact that we can use metastasis directed therapy does not mean that we should use it. It is still not clear what evidence exists for a substantiated benefit gained by MDT. There have been some case series showing the use of SABR in metastatic prostate cancer. There have MDT. However, they have been relatively small in sample size. The patients involved in these studies were in the oligo-recurrent setting with most up to 3 metastasis in most patients. Most of them were ADT-naive. There have been some different endpoints assessed in these studies, including progression-free survival and systemic therapy free survival.
One example is the ORIOLE study (Tran et al. GU ASCO 2020) comparing observation versus SABR for oligo-metastatic prostate cancer. A total of 54 patients were assessed all with hormone-sensitive recurrent prostate cancer with 1-3 metastases. In this study, SABR was shown to improve progression-free survival (Figure 3). Additionally, treatment of all legions detectable by PET/CT DCFPyl showed improvement of metastasis-free survival (Figure 4).
Figure 3 – ORIOLE study progression-free survival:
Figure 4- ORIOLE study – Metastases free survival:
Another important study is the STOMP trial which compared surveillance to metastasis directed therapy for oligometastatic prostate cancer. The trial enrolled 62 men with asymptomatic recurrent prostate cancer following primary therapy with no evidence of CRPC. Patients were randomized to either surveillance or MDT. The primary endpoint was ADT free survival with a median follow up of 36 months2. Again, this trial showed a benefit for MDT with a median of 21 months versus 13 months (Figure 5).
Figure 5 – STOMP trial:
There are additional important trials assessing and showing a benefit for MDT. These include the POPSTAR trial3, assessing stereotactic ablative radiotherapy, and the TRANSFORM trial4, examining high dose radiotherapy to eradicate early metastatic prostate cancer as an alternative to hormone or chemotherapy. Other trials include the trial by Universitaria Pisana5 and the Royal North Shore hospital trial6.
When summarizing the data up until this point, there have been a total of 350 patients with recurrent prostate cancer enrolled in 5 prospective studies. There have been promising gains in both progression-free survival and metastatic free survival. There have been only one grade 3 toxicity and ten grade 2 toxicities reported so far. Importantly, there are a plethora of additional ongoing trials assessing MDT (Table 1).
The value of MDT is in the eye of the beholder (patient, provider, insurer, society). So far, the evidence has shown that it is safe, feasible and affected by a variety of important measures, but it is not clear which outcomes sufficiently justify this kind of intervention. There are no limitations in the existing literature that are being addressed. We should continue assessing genomic and clinicopathological characteristics that will help refine which patients are most likely to benefit from this unique treatment setting. Regardless of our opinions and beliefs, there is no doubt that MDT is continuing to grow and here to stay.
Table 1 – Additional open ongoing MDT trials:
Presented by: Neha Vapiwala, MD, Associate Professor of Radiation Oncology at the Hospital of the University of Pennsylvania, Department: Radiation Oncology, Perelman School of Medicine, The University of Pennsylvania
Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA @GoldbergHanan, at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California
References:
- Siegel, Rebecca L., Kimberly D. Miller, and Ahmedin Jemal. 2017. "Cancer Statistics, 2017". CA: A Cancer Journal For Clinicians 67 (1): 7-30. doi:10.3322/caac.21387.
- 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. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2018; 36(5): 446-53.
- Siva S, Bressel M, Murphy DG, et al. Stereotactic Ablative Body Radiotherapy (SABR) for Oligometastatic Prostate Cancer: A Prospective Clinical Trial. European Urology 2018; 74(4): 455-62.
- Bowden P, See AW, Frydenberg M, et al. Fractionated stereotactic body radiotherapy for up to five prostate cancer oligometastases: Interim outcomes of a prospective clinical trial. International Journal of Cancer 2020; 146(1): 161-8.
- Pasqualetti F, Panichi M, Sainato A, et al. Image-guided Stereotactic Body Radiotherapy in Metastatic Prostate Cancer. Anticancer research 2018; 38(5): 3119-22.
- Kneebone A, Hruby G, Ainsworth H, et al. Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Detected via Prostate-specific Membrane Antigen Positron Emission Tomography. European Urology Oncology 2018; 1(6): 531-7.