SIU Virtual Congress 2020: Debate: Management of the Metastases in Oligometastatic Prostate Cancer - The Metastases Should be Treated with Best Systemic Therapy Alone

(UroToday.com) At the Société Internationale d'Urologie (SIU) 2020 Virtual Annual Congress' debate on the management of oligometastatic prostate cancer, Dr. Noel Clarke argued that metastases should be treated with systemic therapy alone. Dr. Clarke started by noting that there are several definitions for “metastasis”. According to Wikipedia, metastasis is a pathogenic agent’s spread from an initial or primary site to a different or secondary site within the host’s body. In the Oxford English dictionary, metastasis is defined as the development of secondary malignant growths at a distance from a primary site of cancer. Furthermore, ‘oligo’ in Wikipedia is defined as a prefix meaning “few”.

At the 2017 Advanced Prostate Cancer Consensus Conference (APCCC)1, the experts were asked to define oligometastatic prostate cancer. The following question was posed “A clinically meaningful definition of oligometastatic prostate cancer that influences treatment decision (local treatment of all lesions +/- systemic therapy) includes:

1. Only patients with limited bone and/or lymph node metastases that can be treated with local therapy
2. Only patients with limited lymph node metastases that can be treated with local therapy
3. A limited number of any metastases (including visceral)
4. I do not believe that oligometastatic prostate cancer exists as a meaningful entity 
5. Abstain

The majority of the experts (61%) felt that the best definition was only patients with limited bone and/or lymph node metastases that can be treated with local therapy:

treatment with local therapy

The experts were then asked, “What is your cut-off for the number of metastases to consider a patient as oligometastatic?”

1. ≤2 metastases

2. ≤3 metastases

3. ≤5 metastases

4. Abstain

5. Unqualified to answer

The majority of experts (66%) thought that ≤3 metastatic lesions was the best definition for the number of lesions for oligometastatic disease:

lesions for oligometastatic disease

Moving forward to APCCC 2019,in Basel, Switzerland, Dr. Clarke notes that the experts were asked “For men with oligometastatic prostate cancer, do you recommend irradiating all treatable lesions?”. More than half of the experts thought that all lesions should be irradiated, despite the fact that there was no consensus as to how many lesions defined oligometastatic disease. As such, Dr. Clarke notes that this is a highly controversial disease space without consensus as to what defines oligometastatic disease and how these patients should be treated.

To assess whether high versus low volume tumor burden matters, Dr. Clarke turned to data from the STAMPEDE trial, specifically an analysis of outcomes stratified by metastatic burden for M1 patients.3 In this trial, patients were randomly allocated patients in 2:1 ratio to standard-of-care (control group, n=724) or standard-of-care plus docetaxel (n=326). Metastatic disease burden was categorized using retrospectively-collected baseline staging scans where available. Over a median follow-up of 78.2 months, there were 494 deaths on standard-of-care, and there was good evidence of the benefit of docetaxel over standard-of-care on overall survival (OS) (hazard ratio [HR] = 0.81, 95% confidence interval [CI] 0.69-0.95, p = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction p = 0.827). Thus, according to Dr. Clarke, those with low volume metastatic burden (ie. oligometastatic disease) do have a survival benefit with receipt of docetaxel chemotherapy. Furthermore, presented recently as ESMO 2020, Dr. Clarke highlighted that the STAMPEDE long-term outcomes of abiraterone acetate plus prednisolone for hormone-naïve prostate cancer showed a durable benefit among those treated with abiraterone acetate, with a hazard ratio for death of 0.55 (95% CI 0.41-0.76).

Dr. Clarke highlighted that there is very little data regarding metastasis directed therapy to date. The STOMP trial randomly assigned 62 patients to either surveillance or metastasis-directed therapy of all detected lesions (surgery or stereotactic body radiotherapy), with a primary endpoint of androgen deprivation therapy (ADT)-free survival. At a median follow-up time of 3 years (IQR 2.3-3.75 years), the median ADT-free survival was 13 months (80% CI 12 to 17 months) for the surveillance group and 21 months (80% CI 14 to 29 months) for the metastasis-directed therapy group (HR 0.60, 80% CI 0.40 to 0.90; log-rank p = 0.11). As such, in a small Phase II trial, there are far fewer patients enrolled compared to the large Phase III trials that have assessed docetaxel and abiraterone among patients with low (ie. oligometastatic) disease burden. Surgically, the TROMBONE trial is a feasibility trial testing radical prostatectomy in men with prostate cancer and oligometastatic disease and is still actively recruiting patients. As this is a feasibility trial, Dr. Clarke notes that it is not actually telling us whether there is a survival benefit among these patients receiving surgery to the primary organ. The PLATON trial is a randomized Phase III trial of local ablative therapy or not for hormone-sensitive oligometastatic prostate cancer. In this trial, patients with hormone-sensitive oligometastatic prostate cancer (less than or equal to 5 metastatic tumors with no more than 3 in any non-bone organ system) will be randomized to standard systemic therapy plus ablative therapy to untreated prostate primary for patients with low volume metastatic disease burden versus standard systemic therapy plus local ablative therapy to all sites of disease (including untreated prostate primary). The primary endpoint in this trial is failure-free survival.

Currently, the STAMPEDE group has developed Arm M, which will specifically include patients with oligometastatic disease as follows (900 patients per arm):

STAMPEDE trial 2020

Dr. Clarke summarized his presentation suggesting that oligometastatic disease should be treated with best systemic therapy alone rather than using local therapy to the oligometastatic lesions, given that the latter to date is unproven.

Presented by: Noel William Clarke, MD, Consultant Urologist, Salford Royal Hospital and The Christie Hospital, Manchester, United Kingdom

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, Twitter: @zklaassen_md at the 2020 Société Internationale d'Urologie Virtual Congress (#SIU2020), October 10th - October 11th, 2020

References:

1. Gillessen, Silke, Gerhardt Attard, Tomasz M. Beer, Himisha Beltran, Alberto Bossi, Rob Bristow, Brett Carver et al. "Management of patients with advanced prostate cancer: the report of the Advanced Prostate Cancer Consensus Conference APCCC 2017." European urology 73, no. 2 (2018): 178-211.

2. Gillessen, Silke, Gerhardt Attard, Tomasz M. Beer, Himisha Beltran, Anders Bjartell, Alberto Bossi, Alberto Briganti et al. "Management of patients with advanced prostate cancer: report of the Advanced Prostate Cancer Consensus Conference 2019." European urology (2020).

3. Clarke, Noel W., Adnan Ali, F. C. Ingleby, A. Hoyle, C. L. Amos, G. Attard, C. D. Brawley et al. "Addition of docetaxel to hormonal therapy in low-and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial." Annals of Oncology 30, no. 12 (2019): 1992-2003.

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Read the Opposing Debate: SIU Virtual Congress 2020: Debate: Management of the Metastases in Oligometastatic Prostate Cancer - The Metastases Should be Treated with Metastasis-Directed Therapy

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