High-Grade Tertiary in Prostate Cancer Biopsy Signals Trouble

BOSTON, Oct. 3 -- The Gleason score of 7 for localized prostate cancer may be a moving prognostic target, according to investigators here.

By relying on the two most prevalent biopsy patterns, and adding up the scores (4 + 3 or 3+ 4), clinicians may be missing critical prognostic information from a tertiary pattern, reported Abhijit A. Patel, M.D., Ph.D., of the Dana Farber Cancer Institute here, and colleagues, in the Oct. 3 issue of Journal of the American Medical Association.

They found that among men with an initial Gleason score of 7, those with a tertiary grade 5 pattern progressed to PSA failure nearly two years earlier than those with a Gleason score of 7 but no tertiary grade 5.

So for men with a Gleason score that totaled 7, there may be a need for even more aggressive treatment if the third most prevalent pattern, the tertiary sample, takes the score higher.

In fact, the time to PSA failure among men with Gleason score 7 tertiary grade 5 disease was similar to that of men with Gleason scores of 8 to 10. Yet clinical guidelines recommend different management for men with Gleason scores of 7 versus men with the most aggressive tumors, the authors noted.

Current standards for treatment of men with a Gleason score of 7 include dose-escalated radiation therapy including prostate brachytherapy, with or without supplemental radiation therapy, radiation therapy and short course androgen suppression therapy, or radical prostatectomy, the authors noted.

But if the new findings can be replicated in other studies and in other populations, it would suggest that men with Gleason score of 7 but a tertiary grade 5 might be better off if managed the way that patients with higher Gleason scores are.

For patients with Gleason scores of 8 to 10, "these standards of care based on the results of randomized trials, include radiation therapy and short- or extended-course androgen suppression therapy, or radical prostatectomy with the expectation that further therapy may be needed postoperatively depending on the final pathology findings of the radical prostatectomy and postoperative PSA level," they wrote.

In addition, men with the Gleason 7/tertiary 5 pattern might be candidates for randomized clinical trials that are currently open only to men with Gleason scores of 8 or higher, they added.

The study appears to support the 2005 recommendations of an International Society of Urologic Pathology consensus conference, which held that men with biopsy Gleason score of 3 + 4 or 4 + 3 and a tertiary pattern 5 should have their prostate cancer classified as Gleason score 8 or 9, respectively.

In the current study, the authors looked at 2,370 men treated from 1989 to 2005. The patients had clinical tumor category 1c to 3b, node-negative, non-metastatic prostate cancer, and all underwent definitive therapy with surgery or radiation therapy, with or without hormonal therapy.

A pathologist with expertise in genitourinary cancers assigned Gleason scores to needle biopsy specimens for each patient. The authors conducted Cox regression analyses to see whether there were significant associations between the presence of tertiary grade 5 and time to PSA failure in men with Gleason scores of 7. They also compared such men with patients whose tumors were graded as Gleason scores 5 to 6 or 8 to 10 in analyses adjusting for known prognostic factors and treatment.

The main outcome was time to PSA recurrence (PSA failure). For patients who underwent radiation therapy, with or without hormonal therapy, PSA recurrence was defined as the date at which the PSA level became 2 ng/mL higher than the nadir, according to the 2006 consensus definition of the American Society for Therapeutic Radiology and Oncology.

For patients who underwent surgery, PSA recurrence was the date at which the PSA level became higher than 0.2 ng/mL, with a second confirmatory value higher than 0.2 ng/mL.

They found that the median time to PSA failure for men with Gleason score 7 and tertiary grade 5 disease had was 5.0 years, compared with 6.7 years for men with a score of 7 but no tertiary grade 5. The adjusted hazard ratio for men without tertiary 5 compared with those with it was 0.56 (95% confidence interval 0.32 to 0.9, P=0.04).

For men with Gleason scores or score of 6 or less, the median time to failure was 15.4 years (adjusted hazard ratio vs. Gleason 7/tertiary 5, 0.24, 95% CI, 0.13 to 0.43, P<0.001).

When they looked at men with Gleason scores of 8 to 10, however, the authors found that their time to PSA failure was not significantly different from that of the men with Gleason 7/tertiary 5 (median time, 5.1 years, adjusted hazard ratio 0.96, 95% CI, 0.54 to 1.71, P=0.90).

After a median follow-up of 4.2 years (intequartile range 1.8-6.7) years, there were 613 PSA recurrences. Estimates of PSA failure at five years following treatment were 21% (95% CI, 18% to 25%) for men with Gleason score 6 or less, 33% (95% CI, 29% to 37%) for men with Gleason score 7 without tertiary grade 5, 56% (95% CI, 37% to 77%) for men with Gleason score 7 with tertiary grade 5, and 50% (95% CI, 43% to 57%) for men with Gleason score 8 to 10.

The authors noted as a potential limitation of the study the median follow-up time of 4.2 years, which did not allow them to assess the time to prostate cancer-specific and all-cause mortality. In addition, the sample size was not large enough to allow detection of the effect of Gleason 7 with tertiary grade among patients treated with different therapies.