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SAN DIEGO -- Men with high-risk prostate cancer had a 10-month improvement in progression-free survival (PFS) with adjuvant chemotherapy, although the difference did not achieve statistical significance, results of a randomized trial showed.

When the trial ended, patients who received docetaxel after radical prostatectomy had a median PFS of 55.5 months as compared with 45.6 months with prostatectomy followed by observation. The difference translated to a hazard ratio for progression of 0.82 (95% CI 0.59-1.14, P=0.24).

However, prespecified subgroups at especially high risk -- pathologic stage T3b and African Americans -- derived larger and statistically significant PFS benefits, , reported here at the meeting.

The negative primary outcome does not signal an end to evaluation of adjuvant docetaxel in the setting of high-risk prostate cancer.

"There are many other trials in preparation, and these data will certainly support those other trials that will be coming along, most of which will include hormonal therapy," said Lin, of the Seattle Cancer Care Alliance and the University of Washington. "In this study, patient did not receive hormonal therapy along with docetaxel."

Prostatectomy specimens from the trial will undergo genetic analysis in an effort to identify patient or tumor characteristics that might improve patient selection for docetaxel, he added. Serum DNA analyses also will be performed to see whether signs of chemoresistance or responsiveness can be identified.

Despite missing the primary endpoint, the trial may still influence clinical practice.

"I think for the highest risk patients, it will come up in the discussion [of treatment options]," said Lin.

The trial will not support a case for an FDA-approved, but at the same time, "I would caution against a take-away of this as a negative phase III study," he continued.

Patients with high-risk prostate cancer, including African Americans, will be interested in the results, and clinicians should be aware of them when discussing treatment options, agreed , of Vanderbilt University.

"No question, that for high-risk patients, I will mention this," said Chang, who moderated a press briefing that included Lin's presentation. "Radiation is a localized treatment, and these patients don't fail locally. They fail systemically."

High-risk prostate cancer remains a challenge, despite effective curative treatment for early-stage disease. About half of all patients with high-risk disease eventually have recurrence (primarily biochemical, or PSA, recurrence), for which no universal standard of care exists.

Trials of adjuvant radiation therapy after radical prostatectomy have yielded mixed results with respect to overall survival, said Lin. Few studies have investigated cytotoxic chemotherapy alone. Trials of androgen deprivation therapy with or without cytotoxic chemotherapy or radiation therapy have provided no clear therapeutic direction for patients with high-risk disease.

In an effort to inform decision-making about adjuvant therapy for high-risk disease, the Department of Veteran Affairs sponsored cooperative trial 553 to evaluate docetaxel in the post-prostatectomy setting. Eligible patients had clinical T1-T2b disease, treated by radical prostatectomy. High risk was defined as not confined to the prostate, positive surgical margins associated with Gleason grade 8 to 10 disease, or a baseline PSA value >20 ng/mL.

All patients underwent lymphadenectomy, and patients with any nodal involvement were not eligible for randomization.

Patients who met entry criteria were randomized to six cycles of docetaxel plus prednisone or to observation. The primary endpoint was PFS.

From 2006 to 2011, investigators enrolled and randomized 297 of the planned 400 patients for the trial. Although the data and safety monitoring committee found no reason to stop the trial, the VA decided to halt patient accrual because of "resource issues."

As a result, "the study was underpowered to detect the expected treatment effect," said Lin.

The two randomized groups did not differ significantly with respect to demographic or clinical characteristics. About a third of patients had Gleason grade 8 to 10 disease, a third had ≥T3b disease, and more than half had positive margins.

The trial had a prespecified analysis of two "super-high risk" subgroups patients with ≥T3b disease and African Americans. Both analyses showed greater benefit with docetaxel than in the intention-to-treat population. Patients with ≥T3b disease had a statistically significant 18-month improvement in PFS docetaxel, 47.2 versus 29.2 months (HR 0.57, 95% CI 0.34-0.96, P=0.03).

The magnitude of benefit with docetaxel increased to almost 2 years in the African-American subgroup, who accounted for a fourth of the total study population. The median PFS was 55.5 months with docetaxel and 32.7 months without, a difference that just missed the cutoff for significance (HR 0.54, 95% CI 0.29-1.01, P=0.05).

Adverse events in the docetaxel group were consistent with the drug's known toxicity. Grade 3/4 adverse events included neutropenia (43%), hyperglycemia (20%), infection (11%), and fatigue (5%). Febrile neutropenia occurred in 2% of the docetaxel arm.

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