Aggressive Approach to High-Grade Prostate Cancer May Be Best

Pam Harrison

March 07, 2018

An aggressive approach to the treatment of prostate cancer in patients with Gleason scores of 9 or 10 appears to pay important clinical dividends compared to less intense regimens, according to the authors of large retrospective cohort study.

In this high-risk setting, the combination of external-beam radiotherapy with a brachytherapy boost (EBRT+BT) accompanied by androgen-deprivation therapy (ADT) led to reductions in prostate cancer–specific mortality and to better outcomes overall compared to either radical prostatectomy or the combination of EBRT plus ADT.

"The type of aggressive prostate cancer that we focused on has sometimes been regarded as so high risk that some patients even forgo local treatments like surgery or radiation because they are worried that the cancer has already spread and is incurable," said lead study author Amar Kishan, MD, assistant professor of radiation oncology and urology at the University of California, Los Angeles, in a statement.

"Our findings in fact show just the opposite — in this study, the patients with the best outcomes were those who received an aggressive therapy that included so-called extremely dose–escalated radiotherapy along with hormonal therapy," he added.

"I think the important theme is that many patients with Gleason score 9-10 disease need a multimodality strategy that includes both intense local treatment and some form of systemic treatment," Kishan added in an email to Medscape Medical News.

The study was published online March 6 in the Journal of the American Medical Association.

Only about 7% to 10% of men who present with prostate cancer have disease of Gleason score 9 or 10.

Nevertheless, investigators from 12 tertiary care centers in the United States and one in Norway analyzed 1809 patients who had received treatment for prostate cancer of Gleason score 9 or 10 between 2000 and 2013.

A total of 639 men underwent surgical removal of their prostate, 734 received EBRT, and 437 received EBRT+BT. Of the men who underwent radical prostatectomy, 43% also received some form of postoperative radiotherapy. The majority of men who received EBRT also received ADT as part of their initial treatment.

The study authors point out that those in the EBRT+BT arm received ADT for a median of 12 months, whereas those in the EBRT arm received treatment for a median of 21.9 months (P < .001).

The median follow-up for men in the radical prostatectomy group was 4.2 years; it was 5.1 years for the EBRT plus ADT group and 6.3 years for the EBRT+BT plus ADT group. The difference between the groups was significant (P < .05).

On every endpoint assessed, outcomes were superior for patients in the extremely dose–escalated radiotherapy plus ADT arm than for patients in either the surgical arm or the EBRT plus ADT arm.

In absolute numbers, at 5 years, adjusted prostate cancer–specific mortality rates were 12% in the radical prostatectomy arm, 13% for the EBRT plus ADT arm, and 3% in the EBRT + BT plus ADT arm.

Again at 5 years, incidence rates of distant metastasis were 24% for the radical prostatectomy group, 24% for the EBRT plus ADT group, and 8% for the EBRT + BT plus ADT group.

At 7.5 years' follow-up, all-cause mortality rates were 17% in the radical prostatectomy group, 18% in the EBRT plus ADT group, and 10% in the EBRT + BT group.

Analyzed with regard to hazard ratios (HRs), men in the EBRT+BT arm had a 59% lower risk for prostate cancer–specific mortality compared with those treated with EBRT plus ADT (HR, 0.41; P = .002)

Results were similar when EBRT+BT was compared to radical prostatectomy. Prostate cancer–specific mortality was 62% lower for those in the EBRT+BT group compared to the surgery-alone group (HR, 0.38; P = .001).

In contrast, prostate cancer–specific mortality was not significantly different among men treated with EBRT plus ADT and those treated with radical prostatectomy.

A similar pattern was observed with regard to risk for distant metastasis and overall survival, at least within the first 7.5 years or less of follow-up.

Distant Metastasis (Propensity Score Adjusted*) Cause-Specific HR P Value
EBRT vs surgery 0.90 .38 (NS)
EBRT+BT vs surgery 0.27 <.001
EBRT+BT vs EBRT 0.30 <.001
Overall Survival ≤7.5 years    
EBRT vs surgery 1.07 .64
EBRT+BT vs Surgery 0.66 .03
EBRT+BT vs ERBT 0.61 .002
*Propensity score includes age, initial prostate-specific antigen level, clinical tumor stage, and Gleason score.


Optimal Regimens

"Patients receiving less than 70 Gy had a significantly higher rate of prostate cancer–specific mortality than those receiving greater than or equal to 78 Gy," the investigators state. The risk was nearly threefold greater (HR, 2.70; P < .05)

On the other hand, the association between the risk of developing distant metastasis and radiation dose was not significant.

The authors also note that the small percentage of patients in the EBRT cohort who received a dose of at least 78 Gy and who received ADT for at least 24 months had a 55% lower risk for prostate cancer–specific mortality as well as a 69% lower risk for distant metastases compared with patients who underwent radical prostatectomy (P < .05 for both endpoints).

Nevertheless, "EBRT+BT was still associated with lower rates of distant metastasis outcomes than this 'optimal regimen,' " the investigators point out, although prostate cancer–specific mortality outcomes were not significantly different between men who received at least 78 Gy of radiotherapy and at least 24 months of ADT and those who underwent radical prostatectomy, the authors add.

"A limitation of our study is that we do not have toxicity data," Kishan elaborated when asked how well the extremely–dose escalated radiotherapy regimen was tolerated.

On one hand, a single randomized trial of EBRT+BT vs EBRT did show a greater risk for significant genitourinary side effects with EBRT+BT, but two other smaller randomized trials did not show an increase in toxicity, Kishan observed.

Kishan also noted that brachytherapy is very operator dependent, so the risk for adverse events may be more related to the operator than the treatment itself.

"When considering if a patient is appropriate for EBRT+BT, one must take into account prostate size, current urinary function, and other factors," Kishan stressed.

"However, one must also balance the potential for an increased risk of adverse events from brachytherapy vs an increased risk of side effects related to salvage therapies in the event of disease progression," he said.

"I do feel that the data are compelling enough that [EBRT+BT] should be at least presented as an option for patients Gleason score 9-10 disease," he added.

Kishan summarized: "I would also stress that, should patients move forward with standard radiotherapy, they consider the importance of receiving at least high-dose radiation, along with a long duration of androgen-deprivation therapy, as in this subgroup. Outcomes were better."

Dr Kishan has disclosed no relevant financial relationships. Several coauthors have financial ties to industry, as detailed in the original article.

JAMA. Published online March 6, 2018. Abstract

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