Wave on wave.

Top Line: How does local recurrence relate to distant metastasis and mortality after primary radiation for prostate cancer?

The Study: LEVIATHAN is a, wait for it, huge study from the MARCAP consortium that pooled data from >12,533 patients (50% intermediate risk, 50% high risk) treated with definitive radiation on 18 randomized clinical trials. The goal of LEVIATHAN was to explore the relationship between local disease control/recurrence, distant metastasis, and mortality. In other words, does metastatic disease from localized prostate cancer disseminate from the original tumor or from a “second wave” following local disease recurrence, and do those recurrences impact survival? With a median follow up of 11 years, the rates of local local and distant failure were 7.2% and 7.2% for those with IR disease and 13% and 21% for those with HR disease. Does local recurrence really matter when it comes to survival? Yes. Among those with HR disease, local recurrence was associated with DMFS, PCSM, and OS. Among those with IR disease, local recurrence was significantly associated with DMFS, but not PCSM or OS. So how were DM events related to local recurrence? The majority of DM events (80%) occurred after local therapy and without local recurrence. This “first wave” of DM occurred 2-4 years after primary treatment following a disease-free interval–suggesting early occult metastatic disease. The first wave was mostly seen in HR disease. The smaller “second wave” of DM (20%) that occurred after a local recurrence was typically later (6-10 years), and was seen in both IR and HR disease–suggesting a true seeding of DM from recurrent local disease. This helps us understand the roles of local and systemic therapy for localized prostate cancer. Both local and regional/systemic therapies are necessary to optimize outcomes. Improved local therapy (such as dose escalation) improves local control, which reduces late DM events. But because most DM events (the first wave) don’t necessarily seed from local recurrences (especially with increasing risk), ADT appears to have a greater impact on DMFS regardless of RT dose by treating early occult metastatic disease.

TBL: Most distant metastasis events after radiation for localized prostate cancer are not related to a local failure. However, local recurrence is associated with poor outcomes and contributes to a sizeable proportion of late metastatic events. | Ma, Eur Urol 2022