The views and opinions of and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense.
Men with clinical stage T3a disease are at high risk and are often encouraged to undergo radiation therapy with concomitant hormonal therapy. The long-term outcomes among men treated with radical prostatectomy for clinical stage T3a disease were examined.
Among 3397 men treated by radical prostatectomy by 1 surgeon between 1987 and 2003, 62 (1.8%) men were identified who had clinical stage T3a disease. Among the 56 men not treated with neoadjuvant or adjuvant therapies before prostate-specific antigen (PSA) recurrence, the long-term outcomes of PSA-free survival, metastasis-free survival, and prostate cancer specific survival were examined. Median and mean follow-up after surgery were 10.3 and 13 years, respectively (range, 1–17).
Ninety-one percent of men in this group had pathological T3 disease. PSA-free survival at 15 years after surgery was 49%. Metastasis-free survival and cause-specific survival at 15 years after surgery were 73% and 84%, respectively. Among men with a PSA recurrence, 46% received secondary therapy before metastasis. The only preoperative or pathological feature that predicted risk of prostate cancer death was lymph node metastasis (hazard ratio [HR]: 9.22, 95% confidence interval [CI]: 1.06–80.02, P = .044). Among the 28 men with a PSA recurrence, PSA doubling time (PSADT) data were available for 23, of which 11 (48%) has a PSADT ≥9 months. No patient with a PSADT ≥9 months died of prostate cancer. A PSADT <9 months was significantly associated with increased risk of prostate cancer death (log-rank, P = .004).
Due to the introduction of prostate-specific antigen (PSA)-based screening in the late 1980s and early 1990s, there has been a dramatic stage migration in prostate cancer.1 Despite this stage migration, a small percentage of patients continue to present with clinical stage T3 disease. Although the optimal treatment for these patients is debated, the majority of these patients when treated with curative intent will undergo some form of radiation therapy combined with hormonal therapy.2 Indeed, this approach has been shown to result in improved prostate cancer-specific survival relative to treatment with radiation alone.3 In a landmark study, Bolla et al3 found that the combination of hormonal therapy plus external beam irradiation for men with locally advanced prostate cancer (89% had T3-T4) resulted in a 5-year cause-specific survival rate of 94% compared with 79% for men treated with irradiation alone. However, recent surgical series of select men with clinical stage T3 disease have suggested similar survival rates with 5- and 10-year prostate cancer-specific survival rates around 85% to 99% and 72% to 92%, respectively.4–7 Whereas these results may not be directly comparable to those for radiation series due to differences in patient populations, they do seem to suggest that for select men with clinical stage T3 disease, surgery may be a reasonable option. We sought to examine long-term (ie, 15-year) outcomes among men with clinical stage T3a disease treated by radical prostatectomy.
MATERIALS AND METHODS
After obtaining Institutional Review Board approval and informed consent when required, 3397 consecutive patients treated with radical prostatectomy for prostate adenocarcinoma by 1 surgeon (P.C.W.) from 1987 to 2003 were identified. Of these patients, 62 (1.8%) had clinical stage T3a disease. Thus, no patient had clinical evidence of seminal vesicle invasion. We excluded 2 patients who received neoadjuvant hormonal therapy and 2 patients who received neoadjuvant chemotherapy, resulting in a total study population of 58 patients. Two patients received immediate adjuvant radiation therapy. These 2 patients are included for analyzing pathological features, but are not included in the follow-up analyses. No patient received hormonal therapy until after biochemical progression.
Biochemical recurrence was defined as a single postoperative PSA ≥0.2 ng/mL. Radionuclide bone scans were performed either at our institution or by the referring physicians at the time of biochemical recurrence and on a yearly basis thereafter unless performed earlier for symptoms suggestive of distant metastasis. A positive bone scan result or other radiographic or histologic (lymph node biopsy) evidence of distant failure was used for the diagnosis of distant metastasis. Prostate cancer death was defined as death in any patient with metastasis that showed progression after hormonal therapy or death in any patient not treated with hormonal therapy but with widespread metastases without another obvious cause of death.
Among men with a PSA recurrence, data to calculate PSA doubling time (PSADT) was available for 23 men (ie, ≥2 PSA values separated by ≥3 months within 2 years after biochemical recurrence). For these men PSADT was calculated by the natural log of 2 (0.693) divided by the slope of the linear regression line of natural log of all PSA values obtained within the first 2 years after biochemical recurrence.8 Thus, PSADT was not calculated until after PSA recurrence and all PSA values used for PSADT calculations were ≥0.2 ng/mL. PSADT was examined as a categorized variable of <3.0, 3.0–8.9, 9.0–14.9, and ≥15.0 months.9 No patients had a negative or zero PSADT (no increase in PSA). All PSA values were obtained before subsequent therapy (radiation or hormonal) and therefore subsequent therapy had no impact on PSADT calculation.
Predictors of progression (ie, biochemical, metastasis, or prostate cancer-specific death) were determined using a Cox proportional hazards model. The preoperative clinical variables considered for entry included age (continuous variable), year of surgery (continuous variable), serum PSA (continuous variable after logarithmic transformation), and biopsy Gleason sum (2–6, 3 + 4, ≥4 + 3). We repeated the analysis including pathological Gleason sum and the binary pathological features of positive surgical margins, extracapsular extension, seminal vesicle invasion, and lymph node metastasis. For multivariate analysis, a forwards-stepwise Cox proportional hazards model was used with P < .15 determining which variables should be entered into the model at each step. The variable with the highest P value was successively deleted until only variables with P < .1 remained. All statistical analyses were performed using STATA 9.0 (College Station, TX).
The clinical and pathological characteristics of the 58 patients with clinical stage T3a disease are shown in Table 1. Although a majority (54%) of patients had biopsy Gleason scores of 2–6, the vast majority (74%) had pathological Gleason scores of 3 + 4 or higher. Nearly all patients (91%) had extracapsular extension (ie, pathological stage T3 disease). Almost 1 in 3 patients had seminal vesicle invasion, with a similar percentage having lymph node metastasis.
Table 1. Preoperative Clinical and Pathological Characteristics of 58 Men With Clinical Stage T3a Disease
PSA indicates prostate-specific antigen; DT, doubling time; SD, standard deviation.
PSADT data was available only for 23 of 28 men who developed a PSA recurrence.
We excluded 2 patients who received immediate radiation therapy, resulting in a follow-up cohort of 56 men. Mean and median follow-up were 10.3 and 13 years, respectively (range, 1–17) among men without a biochemical recurrence. During this time, 28 patients (50%) developed a biochemical recurrence, 12 (21%) went on to develop metastasis, and 7 (13%) died from prostate cancer (Fig. 1). Of the 28 men who developed a biochemical progression, 7 (25%) received hormonal therapy, 5 (18%) received radiation therapy, and 1 (4%) patient received radiation therapy followed by hormonal therapy before metastasis. Thus, 13 of 28 (46%) patients who had a PSA recurrence received some form salvage therapy before metastasis. The 5-, 10-, and 15-year estimates of biochemical progression-free survival, metastasis-free survival, and prostate cancer-specific survival are demonstrated in Table 2.
Table 2. Survival Estimates at 5-, 10-, and 15-Years (95% Confidence Interval [CI]) of Biochemical Progression-Free Survival, Metastasis-Free Survival, and Prostate Cancer-Specific Survival Among Men With Clinical Stage T3a Disease
Biochemical progression-free survival
Prostate cancer-specific survival
On multivariable analysis of only preoperative clinical characteristics, only the preoperative PSA was significantly predictive of time to biochemical progression (hazard ratio [HR]: 1.59, 95% confidence interval [CI]: 1.03–2.46, P = .04), whereas no features were predictive of time to metastasis or time to prostate cancer death. When pathological features were included in the multivariable analyses, seminal vesicle invasion (HR: 3.81, 95% CI: 1.59–9.13, P = .003) and lymph node metastasis (HR: 3.42, 95% CI: 1.44–8.12, P = .005) were significantly associated with shorter time to biochemical progression. Only lymph node metastasis was significantly associated with a shorter time from surgery to metastasis (HR: 12.21, 95% CI: 2.63–56.70, P = .001) and shorter time to prostate cancer specific mortality (HR: 9.22, 95% CI: 1.06–80.02, P = .044).
PSADT data at the time of recurrence were available for 23 of the 28 men with biochemical recurrence. Median PSADT among the 23 men was 8.5 months. Although the numbers were extremely small, a PSADT ≥9 months was associated with significantly better metastasis-free survival (log-rank, P = .0001) and prostate cancer-specific survival (log-rank P = .004; Fig. 2). No patient (n = 11) with a PSADT ≥9 months died from prostate cancer, whereas among men with a PSADT <9 months (n = 12), the 5-, 10-, and 15-year prostate cancer-specific survival was 92% (95% CI: 54%–99%), 62% (95% CI: 27%–84%), and 37% (95% CI: 9%–66%).
Despite dramatic stage migration due to widespread PSA screening,1 some patients continue to present with clinical stage T3 disease. Although these patients are often counseled to undergo radiation therapy combined with hormonal therapy, several studies have suggested that outcomes after radical prostatectomy are reasonable.4–7 In the largest single surgeon series of clinical stage T3a disease reported to date, we found that approximately half of patients at 15 years after surgery had not developed a PSA recurrence. Moreover, of patients that did develop a PSA recurrence, the PSADT at the time of recurrence was ≥9 months in nearly 50% and ≥15 months in 33%. At 15 years after surgery, only 16% of patients died of prostate cancer. These findings suggest that radical prostatectomy is a reasonable option for select men with clinical stage T3a disease.
Although fortunately not common today, patients with clinical stage T3 disease represent a therapeutic challenge. Traditionally, and even today, these patients are often encouraged to undergo combined radiation and hormonal therapy. Indeed, the combination of hormonal therapy plus radiation therapy results in favorable 5- and 10-year cause-specific survival rates of 94%3 and 84%,10 respectively. Given these favorable outcomes with combination hormonal and radiation therapy, it remains an issue of debate what role if any there is for surgery for select men with clinical stage T3a disease.
Several recent studies have addressed this issue and reported outcomes among men with clinical stage T3 disease treated by radical prostatectomy. Overall, these studies have suggested that long-term outcomes are reasonable, with 5-, 10-, and 15-year prostate cancer-specific survival rates around 85% to 99%, 72% to 92%, and 76% to 79%, respectively.4–7 The current study demonstrated similar or better long-term survival, with 10- and 15-year prostate cancer-specific survival of 91% and 84%, respectively. Moreover, at 15 years after surgery nearly 50% of patients had an undetectable PSA. Thus, the current study provides further evidence that in select men with clinical stage T3a disease, radical prostatectomy can result in very good long-term cancer control.
Of note, we found that 9% of patients were overstaged in that they had pathological T2 disease. This is lower than in prior series, which found 24% to 27% of patients were overstaged.4–6 Regardless of the exact percentage, it is clear that some men with clinical stage T3a disease will harbor organ-confined disease. Although it would be assumed that men with organ-confined disease would have better outcomes, we were unable to assess this due to the small numbers of men with organ-confined disease in the current study. Likewise, the limited number of men in the current study precluded us from examining which clinical characteristics were most predictive of organ-confined disease. Future studies are needed to assess whether organ-confined disease can be reliably predicted preoperatively, as these patients would likely have excellent long-term results with radical prostatectomy alone.
In the current study, nearly 50% of patients did not experience a PSA recurrence. This is in line with prior studies.4–6 Moreover, of those that did recur, only 50% received salvage treatments before metastasis. Thus, approximately 75% of the men in the current series were treated with radical prostatectomy alone, receiving no other therapies until metastasis (ie, no secondary treatment). This is in contrast to some prior series of men with clinical stage T3 disease treated with radical prostatectomy in which 56% to 78% of all men received secondary therapy.4, 6 Although it is difficult to directly compare between series, the prostate cancer-specific survival rate in the current study was as good or better than in those series with much higher rates of secondary therapies. Moreover, other series with secondary treatment rates similar to the current study have also reported high prostate cancer survival rates for radical prostatectomy for men with clinical stage T3 disease.5 Whereas these findings would seem to suggest that secondary therapies do not impact survival, unfortunately the number of men in the current study prohibits a meaningful analysis of this important issue. However, secondary treatments for men who are at low risk of prostate cancer death are unlikely to have a benefit, although men who are at high risk of prostate cancer death likely do derive benefit. Therefore, our goal should be to rapidly identify the men at highest risk of cancer death and target them for secondary therapies.
Nearly 50% of men who recurred in the current study had a modest to slow PSADT at the time of recurrence (ie, ≥9 months). Importantly, no patient in the current study who recurred with a PSADT ≥9 months died from prostate cancer. This highlights the important role PSADT plays in risk stratification of men with PSA recurrence after radical prostatectomy. Indeed, using a much larger sample size, we have previously shown that men who recur with a PSADT <9 months are at significantly increased risk of prostate cancer death.9 Likewise, others have also found that the PSADT at the time of recurrence is a significant predictor of prostate cancer death.11–13 Given that only 50% of men had a PSA recurrence and only 50% of those had a rapid PSADT, this suggests that 75% of men with clinical stage T3a disease may be appropriately treated with surgery alone and can likely be spared from secondary therapies. Among the remaining 25% who recurred with a rapid PSADT, these are the patients that stand the most to benefit from multimodal treatment including salvage radiation and early chemohormonal therapy.
Besides PSADT, the only prognostic variable for prostate cancer death in the current study was the presence of lymph node involvement. We recently published our long-term results among men with positive lymph nodes.14 In that prior study, we found that the PSA-free survival rate at 7 years was 11%, confirming the very high-risk nature of men with lymph node metastasis. A prior small prospective randomized clinical trial found that adjuvant lifelong hormonal therapy can dramatically improve survival for men with lymph node involvement after radical prostatectomy relative to delaying hormonal therapy until the time of metastasis.15 It is unknown whether a similar survival benefit could be obtained by delaying hormonal therapy until the time of PSA progression and after identification that the patient has a rapid PSADT rather than beginning lifelong hormonal therapy immediately after surgery. Clearly, more research is needed to evaluate the impact of early secondary treatments on long-term outcomes for men with high-risk disease after primary therapy.
Limitations to the current study include the small number of men, which limited our power to identify risk factors for organ-confined as well as better-defined risk factors for prostate cancer death. Although follow-up was longer than many studies (median, 13 years), today patients are often in their 50s when diagnosed and treated. As such, for these men even longer follow-up is needed. Therefore, continued follow-up of these patients will be insightful to identify the very long-term natural history of treated prostate cancer. The positive surgical margin rate (22%) was relatively low considering the high-risk nature of the cohort (91% extracapsular extension). This implies excellent surgical technique, which may have played a role in the relatively low prostate cancer mortality rates. Whether similar results can be achieved among other surgeons is unknown. Although the number of men with PSADT data was small, our findings are consistent with prior studies that demonstrate the importance of PSADT as a prognostic variable for men with PSA recurrence after radical prostatectomy.11–13 Finally, the number of men in the current study was too small to assess whether salvage therapy impacted survival. Ultimately, prospective randomized trials are needed to determine the role of secondary therapies for prostate cancer.
In the current study of a select cohort of men with clinical stage T3a disease treated with radical prostatectomy, nearly 50% of patients were PSA-free at 15 years after surgery. Of those that recurred, nearly half recurred with modest to slow PSADT (≥9 months), and in that group no patient died from prostate cancer. The 15-year prostate cancer-specific survival was 84%. This study provides further evidence that radical prostatectomy and secondary treatments, when necessary, result in very good long-term cancer-specific survival.
Supported by the National Institute of Health/National Cancer Institute, SPORE Grant P50CA58236, the Prostate Cancer Foundation, the Department of Defense Prostate Cancer Research Program, and the American Urological Association Foundation Astellas Rising Star in Urology Award.