Introduction:

For men with locally advanced disease, local therapy offers the opportunity for cure. Yet approximately 30,000 are diagnosed annually with recurrence after radical prostatectomy (RP), primarily as PSA failure without other evidence of disease. If left untreated, most with elevated PSA after RP will develop bone metastases within 10 years thus driving the need to identify factors impacting oncologic outcomes after secondary treatment (advuvant or salvage therapy). We examine our institution’s outcomes after secondary treatment to identify whether margin status or pathologic stage/grade are associated with increased worse outcomes after secondary treatment.    

Methods:

Men with localized prostate cancer managed with primary RP were identified in our institutional database. Those with clinical evidence of metastatic disease or nodal disease on surgical pathology were excluded. Secondary treatment was defined as adjuvant or salvage RT after RP. Androgen deprivation therapy (ADT) was reported but not required for inclusion. Descriptive statistics were used to summarize the cohort. Surgical pathology findings (stage, Gleason grade, and margin status) were abstracted from the medical record. Patients were grouped by presence of low or high risk features on surgical pathology and surgical margin status. Low-risk features were defined as pathologic stage T2 or T3a and Gleason grade 4+3 or less. High risk features were defined as pathologic stage T3b, T4, or Gleason grade 4+4 or greater. Surgical margins (SM) were reported as positive or negative. Thus, groups of patients were classified as LOWNEG, LOWPOS, HIGHNEG, and HIGHPOS based on stage/grade risk and SM status. Kaplan-Meier survival analyses stratified by these 4 groups were used to examine differences in survival outcomes. Cox proportional hazards regression models were utilized to identify factors associated with biochemical recurrence-free survival (RFS), metastasis-free survival (MFS), and prostate cancer specific survival (CSS) after secondary treatment. Men with LOWPOS features were the referent group. Models were adjusted for age, PSA at diagnosis, and salvage (vs adjuvant) RT.

Results:

Of 3919 patients with pN0 disease at RP, 467 (11.9%) underwent secondary treatment with or without ADT. Mean age at diagnosis was 61 years (SD 6.8) with a median PSA at diagnosis of 7.5 (IQR 5.4-11.1). One-third were LOWNEG, 30% LOWPOS, 25% HIGHNEG, and 12% HIGHPOS. SM+ status was more common amongst those receiving adjuvant compared to those receiving salvage RT (62% vs 34%).

RFS, MFS, and CSS at 7 years after secondary treatment were 56%, 78%, and 96%, respectively. Compared to men with LOWPOS disease, all groups were associated with increased risk of recurrence after secondary treatment: LOWNEG, HR 2.1, 95% CI 1.3-3.3; HIGHNEG, HR 2.7, 95% CI 1.7-4.3; HIGHPOS, HR 2.4, 95% CI 1.4-4.3, p<0.01 for all. The stage/grade/margins groupings were not associated with risk of metastasis or cancer-specific mortality. For LOWPOS patients who did not receive adjuvant treatment RFS, MFS, and CSS were 64%, 98%, and 99%, respectively. Men with adjuvant RT had better outcomes at 7 years after secondary treatment compared to salvage RT (RFS, 87% vs 66%, log-rank p=0.01; MFS, 91% vs 85%, log-rank non-significant p=0.06; CSS, 100% vs 98%, log-rank p=0.05). Salvage RT was associated with increased risk of recurrence (HR 3.0, 95% CI 1.2-7.8, p=0.02) compared to adjuvant RT after adjusting for age and PSA at diagnosis. Type of secondary treatment was not associated with increased risk of metastasis. There were too few events to assess associations with cancer-specific mortality.       

Conclusion:

In a cohort of men undergoing secondary treatment after RP, SM+ was more common amongst those receiving adjuvant therapy and was associated with greater recurrence free survival at 7 years after secondary treatment compared to those with SM- and similar favorable pathologic features. Amongst LOWPOS patients, adjuvant RT was associated with better oncologic outcomes compared to salvage RT while salvage RT was associated with higher risk of metastasis. Further investigation into the impact of margin status and timing of secondary treatment may improve outcomes in men considering secondary treatment for recurrence after prostatectomy.       

Funding: N/A