Local failure tied to survival in intermediate-risk PCa after definitive radiotherapy

In men with intermediate- or high-risk prostate cancer (PCa), local failure after definitive radiation therapy (RT) is indicative of survival outcomes, according to a recent study.

“These data provide a framework for understanding the patterns of clinical relapse in high- and intermediate-risk PCa, and how different treatment intensification strategies might alter these relapse patterns,” the researchers said.

The present meta-analysis included 18 randomized controlled trials contributing a total of 12,533 PCa patients. Local failure was defined as local recurrence, and its prognostic impact on survival outcomes—overall (OS), PCa-specific (PSS), and distant metastasis-free (DMFS) survival—was assessed. Patients were followed for a median of 11 years.

Pooling data revealed a total of 795 and 449 local failure events for patients with high- and intermediate-risk PCa, and 1,288 and 451 distant metastases, respectively. [Eur Urol 2022;doi:10.1016/j.eururo.2022.07.011]

Cox proportional hazards analysis revealed that in the high-risk subgroup, local failure, when taken as a time-dependent variable, significantly increased the risk of death or distant metastasis as a composite outcome by nearly twofold (hazard ratio [HR], 1.94, 95 percent confidence interval [CI] 1.75–2.15; p<0.001).

Similarly, local recurrence showed significant and positive interactions with PCSS (HR, 2.02, 95 percent CI, 1.75–2.33; p<0.001) and OS (HR, 1.17, 95 percent CI, 1.106–1.30; p<0.01). These analyses had been adjusted for treatment, tumor stage, patient age, and other such confounders.

Local failure remained significantly associated with the composite between distant metastasis and death in intermediate-risk patients, increasing such risk by nearly 60 percent (HR, 1.57, 95 percent CI, 1.36–1.81; p<0.001). However, its interaction with OS was attenuated (HR, 0.93, 95 percent CI, 0.81–1.08; p=0.35), while such an analysis was impossible for PCSS.

Distant metastases in relapse-free patients

When looking closer into the patterns of distant metastases, the researchers found that 81 percent of such cases in high-risk patients developed from a clinically relapse-free (cRF) state and occurring after a median of 46 months. Meanwhile, only 19 percent of distant metastases happened after local failure.

The vast majority (92 percent) of local failure events also occurred from a cRF state at a median of 39 months after initial treatment.

Similar patterns were reported for intermediate-risk patients, in whom 81 percent and 95 percent of distant metastases and local recurrences occurred from a cRF state, respectively.

“The predominant mode of distant metastasis development is from a cRF state for both high- and intermediate-risk PCa, likely from occult metastatic disease at presentation, underscoring the importance of accurate upfront staging and systemic therapy,” the researchers said, noting that the first wave of distant metastases tends to occur within 4 years of RT.

Still, a second wave is apparent. “[P]articularly at late time points, an increasing proportion of distant metastasis events originated after the diagnosis of local failure, constituting a second wave of distant metastasis events,” they added.

Regional and systemic treatment, therefore, must be optimized to deal not just with the first wave of distant metastasis, but also with the second wave after patients have developed local recurrence.