Primary Gleason pattern does not impact survival after permanent interstitial brachytherapy for Gleason score 7 prostate cancer
Gregory S. Merric. Cancer 2007;110:289

Gleason score is 1 of the most important prognosticators for predicting biochemical progression and cause-specific survival after the definitive treatment of prostate cancer. Gleason score 7 is especially important, because it is 1 of the most common criteria for assigning patients a higher risk of treatment failure. Among patients with Gleason score 7, controversy exists regarding the importance of the primary pattern. Greater rates of extracapsular extension without significant differences in seminal vesicle or pelvic lymph node involvement have been demonstrated when clinical stage and pretreatment prostate-specific antigen (PSA) are controlled for in patients Gleason 4+3 versus 3+4. Within the uro-oncology community the perception exists that biochemical outcome for Gleason 4+3 is inferior to Gleason 3+4. However, conflicting conclusions have accumulated after radical prostatectomy  and brachytherapy, whereas external beam radiation therapy (XRT) series have consistently reported inferior biochemical outcomes for Gleason 4+3 histology.

In a large recently published radical prostatectomy series from the Mayo Clinic, higher rates of biochemical failure, systemic recurrences, and cause-specific death were reported for Gleason 4+3 versus 3+4 patients. To date, the impact of Gleason 4+3 versus 3+4 on cause-specific and overall survival after brachytherapy has not been reported. Accordingly, we chose to evaluate the impact of primary Gleason pattern in Gleason score 7 patients on cause-specific (CSS), biochemical progression-free (bPFS), and overall survival (OS) after permanent interstitial brachytherapy with or without supplemental therapies.

The impact of primary Gleason pattern was determined on cause-specific (CSS), biochemical progression-free (bPFS), and overall survival (OS) after brachytherapy for Gleason score 7 prostate cancer. From April 1995 to October 2003, 530 patients underwent brachytherapy for Gleason score 3+4 (n = 300) or Gleason 4+3 (n = 230) prostate cancer. All patients underwent brachytherapy more than 3 years before analysis. The median follow-up was 5.7 years. Of the 530 patients, 412 (77.7%) received supplemental external beam radiation therapy (XRT) and 177 (33.4%) received androgen deprivation therapy. bPFS was defined by a prostate-specific antigen (PSA) 0.40 ng/mL after nadir. Multiple parameters were evaluated as predictors of CSS, bPFS, and OS.

At 10 years, Gleason 3+4 versus 4+3 did not predict for CSS (96.7% vs 93.3%, P = .506), bPFS (97.0% vs 92.9%, P = .085), or OS (77.0% vs 78.0%, P = .933). Cox linear regression analysis demonstrated that clinical stage and radiation dose (D90) predicted for CSS, whereas pretreatment PSA, clinical stage, and prostate size predicted for bPFS. Patient age, diabetes, and tobacco were the strongest predictors for OS. To date, 57 patients have died, with 80.7% due to cardiovascular/pulmonary events or secondary malignancies. Five patients have died of prostate cancer. The primary Gleason pattern did not impact CSS, bPFS, or OS in Gleason score 7 prostate cancer. Deaths from cardiovascular/pulmonary disease and second malignancies were 9.6 times more common than death from prostate cancer.

The histologic assessment of Gleason score represents an important prognostic factor of biologic aggressiveness, with higher Gleason scores negatively influencing outcome.  Although the perception exists that Gleason score 7 can be stratified into prognostic categories by the dominant histologic grade, conflicting results have been published in the radical prostatectomy and brachytherapy literature. A Mayo Clinic Gleason score 7 radical prostatectomy series reported increased bPFS (48% vs 38%, P < .001), fewer distant metastases (8% vs 15%, P < .001), and a higher CSS (97% vs 93%, P = .013) at 10 years for Gleason score 7 patients with primary pattern-3 histology. The CSS was virtually identical in the Mayo Clinic RP series and in our current report, with absolute differences in 10-year CSS of 4% at the Mayo Clinic and 3.4% at our institution. In contrast to radical prostatectomy, the dominant histologic pattern did not predict for any of the survival variance after brachytherapy. The cause for the discrepancy could reflect differences in patient selection, pathologic evaluation, or treatment effect.

Despite an identical definition of PSA success (<0.40 ng/mL), bPFS after brachytherapy was substantially higher than radical prostectomy. Brachytherapy is possibly more resilient to extracapsular extension than radical prostatectomy and less dependent on tumor bulk than XRT because of generous periprostatic treatment margins (approximately 6 mm) and intraprostatic dose escalation. It is possible that the ability to eradicate extracapsular extension could mute the difference in cancer eradication rates for patients with Gleason 3+4 versus 4+3 cancers. Patients at significant risk for extracapsular extension but at a low risk for pelvic lymph node involvement/distant metastases should benefit from an aggressive locoregional approach. A review of the Partin tables illustrates that the vast majority of our patients possessed a substantial risk of extracapsular extension but a low risk of seminal vesicle and/or pelvic lymph node involvement.

Consistent with our bPFS findings, Herman  failed to identify the primary histologic grade in Gleason score 7 as a significant predictor of disease progression (P = .76). Groll  reported that stratification of biopsy Gleason score 7 by primary pattern 3 or 4 resulted in no significant differences in the incidence of extracapsular extension, positive surgical margins, or seminal vesicle involvement. Recently, Vira  reported that biochemical outcome in Gleason 4+3 patients was comparable to Gleason 3+4 as long as the percent positive biopsies were <50%. In our series, the mean percent positive biopsies were statistically greater but clinically comparable between the 3+4 and 4+3 cohorts (43.4% vs 50.2%).

For Gleason score 7 prostate cancer, significant controversy exists regarding patterns of failure when stratified by the dominant histologic grade. Chan  reported 10-year radical prostatectomy bPFS rates of 56% and 37% for Gleason 3+4 versus 4+3, respectively (P < .0001), with the conclusion that Gleason 4+3 resulted in greater biochemical progression independent of stage and margin status, suggesting that failure was the result of subclinical distant metastatic disease. Although only 1.5% of patients in the Mayo Clinic series had positive pelvic lymph nodes, a greater risk of distant metastatic disease was noted in patients with Gleason 4+3. These findings regarding patterns of failure in Gleason score 7 patients are inconsistent with our results and those of others. Aggressive locoregional approaches have resulted in improvements in bPFS, decreased distant metastases, and improved CSS and OS. In our current study, 10-year CSS was highly dependent on the delivered radiation dose (D90;. Consistent with a prior report, larger prostate size predicted for a more favorable biochemical outcome.

Shortcomings of our study include the retrospective, single-institutional nature of the evaluation, the administration of supplemental XRT and ADT for multiple reasons, and reliance on biopsy findings rather than whole section prostate specimens. The nonexpirative nature of brachytherapy has been used to criticize Gleason score results because of the inability to evaluate the entirety of the prostate gland and assign a pathologic Gleason score. However, the Shared Equal Access Regional Cancer Hospital (SEARCH) database reported that biopsy Gleason score was strongly correlated with disease progression even when the pathologic Gleason score was available. Although supplemental XRT doses of 20 Gy and 45 Gy were used in the current study, in a prospective randomized trial our group demonstrated that supplemental XRT dose does not impact bPFS. In addition, we previously reported that the use of ADT does not impact brachytherapy-related CSS or OS.This is in contrast to a prior brachytherapy series that reported an inverse relation between ADT use and OS. Potentially, the conflicting conclusions are due to the fact that patients in our series were substantially younger and probably healthier as witnessed by substantial differences in 10-year OS. Consistent with our previous findings, neither supplemental XRT or androgen deprivation therapy statistically impacted CSS, bPFS, or OS.

Part of the lack of primary Gleason pattern effect in our patient sample is likely due to the relatively small number of prostate cancer-related deaths. In our series cardiovascular/pulmonary disease and second malignancies accounted for 46 of the 57 deaths (80.7%), with only 5 of the deaths (8.8%) attributable to prostate cancer (0.9% of all patients). Nonprostate cancer deaths were nearly 10 times more likely than prostate cancer deaths. Changes in lifestyle to improve cardiovascular health and cessation of tobacco should improve OS in patients with clinically localized prostate cancer. In our clinic, after completion of treatment, all patients are encouraged to begin physical rehabilitation to maximize cardiovascular heath to include daily aerobic exercise, resistance training 3 times per week for the prevention of osteoporosis and maintenance of muscle strength, a high fiber/low fat diet, maintenance of ideal body weight, cessation of all tobacco products, alcohol in moderation, routine colonoscopy, and screening for hypertension, diabetes, and hypercholesterolemia.