ASCO GU 2020: Biologic and Clinical Rationale for Treatment of the Primary in Low-Volume Metastatic Disease

San Francisco, California (UroToday.com) Dr. Phuoc Tran discussed the topic of the biological and clinical rationale for the treatment of primary tumors in low volume metastatic prostate cancer. The oligometastatic hypothesis has initially coined by S. Hellman and R.R. Weichselbaum in 1995. In 2018 it was defined as the intermediate state of cancer spread between localized disease and wide spread metastasis that can be impacted by local therapies (Figure 1). 

oligometastatic state


Figure 1. The oligometastatic disease

According to Dr. Tran, there are several big questions we need to answer with regards to this topic. These include from where do metastasis originate? Does the oligometastatic clinical state exist? Can we find who benefits from local therapies? And can we leverage the underlying biology?

Dr. Tran began discussing the first question-where do metastasis originate. He suggested two possible theories, which include the clonal process (figure 2 )and the self-seeding hypothesis (figure 3).
Most likely, both hypotheses are probably realistic and occur synchronously. Metastatic cells can cycle back to the primary tumor or self-seed. Both the primary tumor and existing metastases can seed new metastases. Therefore, to change the natural history of oligometastatic disease, one may need to ablate both the primary tumor and the metastases.
clonal process


Figure 2. Clonal process of metastases

self seeding hypothesis

Figure 3. Self-seeding hypothesis of metastases

Next, Dr. Tran discussed the rationale for the definitive treatment of the primary tumor in metastatic prostate cancer. Firstly, there's plenty of retrospective data suggesting an improvement in overall survival when treating the primary tumor. These data suggest that local symptomatic progression is reduced following treatment of the primary tumor in a metastatic setting. It is also well known that molecularly“lethal prostate cancer” persists in primary tumors despite the administration of systemic therapy. There is also evidence suggesting that treating the primary tumor will change systemic tumor biology. For these reasons, there are ongoing randomised trials assessing the safety and feasibility of treating the primary tumor in the setting of metastatic disease.

Prospective randomized systemic therapy trials have already been published, showing that radiation to the primary tumors in M1 disease improves survival (figure 4). The best example is the Stampede trial arm H, showing that for low burden disease the hazard ratio was 0.68 with a p-value of 0.007, with an 8% overall survival benefit after 3 years when treating the primary tumor compared to no treatment (Figure 5). This same benefit was not shown in the high burden disease.

Prospective randomized systemic therapy radiation therapy in M1 disease

Figure 4. Prospective randomized systemic therapy +/- radiation therapy in M1 disease

overall survival

Figure 5. STAMPEDE trial arm H

There are additional ongoing prospective randomized controlled trials assessing androgen-deprivation therapy with and without surgery directed at the primary tumor in the setting of M1 disease (Figure 6). If oligo-progression is a pathway to widely metastatic disease, then consolidative local therapies can and should alter this disease natural history.

Dr. Tran concluded his talk with some important points. The biology of metastatic disease suggests complex primary tumor-metastatic cellular interaction that is important for metastatic competency. The oligo-metastatic state is defined by local therapies impacting the natural history of metastatic disease. Local therapy to the primary tumor has resulted in improved overall survival in men with low-volume prostate cancer. Biomarker research is desperately needed in oligo-metastatic disease to define who benefits most from local therapy to the primary tumors. Lastly, a better understanding of oligometastatic biology will have implications for polymetastatic disease as well.

Presented By: Phuoc T. Tran, MD, PhD, Associate Professor of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine

Written By: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New York, Twitter: @GoldbergHananat the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California


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