The effect of local failure after RT in "evidence-based medicine" on the prognosis of prostate cancer patients

Occult distant metastases may be a potential driver of disease progression in PCa, so assessing the temporal relationship between local failure and distant metastases after radiotherapy, and how different treatment strategies (i.
e.
, dose escalation and androgen deprivation therapy) affect the development of distant metastases and other clinical outcomes, is of certain research value and significance
for predicting the prognosis of patients with intermediate- and high-risk PCa.
The US research team conducted this evidence-based study to assess the impact of local failure on prognosis and the dynamics
of distant metastases after RT.

The investigators pooled and meta-analyzed
data from 12,533 patients with PCa in 18 randomized clinical trials conducted between 1985 and 2015.
The multivariate Cox proportional hazards (PH) model was used to assess the relationship between
overall survival (OS), PCa-specific survival (PCSS), survival without distant metastases (DMFS), and local failure (as a time-dependent covariate).
The Markov PH model was used to assess the relationship between
specific transitional states (clinically relapse-free state, local failure state, distant metastatic state, and death state).

Among the 12533 patients with PCa, 6288 were high-risk and 6245 were intermediate-risk, with a median follow-up of 11 years
.
Local failure and 1288 (21%) distant metastases occurred in 795 (13%) patients at high risk and 449 (7.
2%) local failures and 451 (7.
2%) distant metastases
occurred in intermediate-risk patients.
Distant metastases in 81% of patients with intermediate- and high-risk PCa develop
from a clinically relapse-free state (cRF state).

In high-risk patients, local failure was significantly associated with worse OS (HR = 1.
17, 95% CI 1.
06 to 1.
30), PCSS (HR = 2.
02, 95% CI 1.
75 to 2.
33), and DMFS (HR = 1.
94, 95% CI 1.
75 to 2.
15) (all p-values < 0.
01).
<b10> In intermediate-risk patients, local failure was also significantly associated with worse DMFS (HR = 1.
57, 95% CI 1.
36 to 1.
81), but not
with OS.
Patients without local failure had a lower probability of PCa-specific death than those who developed local failure after radiotherapy (HR = 0.
32, 95% CI 0.
21 to 0.
50, p<0.
001).
<b12> Over time, patients with local failure in the intermediate- and high-risk group were more likely to develop distant metastases
.

Fig.
1 Forest plot of Cox proportional risk model, local failure is time-dependent covariate

Approximately 10% of patients with intermediate- and high-risk PCa after radical RT experienced local recurrence and had a significantly increased
risk of disease progression.
Local failure is an independent predictor of OS, PCSS, and DMFS in patients with high-risk PCa
, as well as DMFS in patients with intermediate-risk PCa.

Approximately 80% of patients with distant metastases have no prior local recurrence
.
Distant metastases in patients develop primarily from cRF status, further underscoring the importance of
addressing occult microlesions.
Because the "second wave" of distant metastases occurs after local failure, clinicians can reduce the risk of
distant metastases in patients by optimizing local treatment strategies.

References:

Ma TM, Chu FI, Sandler H, et al.
Local Failure Events in Prostate Cancer Treated with Radiotherapy: A Pooled Analysis of 18 Randomized Trials from the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium (LEVIATHAN).
Eur Urol.
2022 Nov; 82(5):487-498.
doi: 10.
1016/j.
eururo.
2022.
07.
011.
Epub 2022 Aug 5.
PMID: 35934601.