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ORLANDO -- A negative study from the "Jurassic age" of medicine nonetheless could help inform decision making about contemporary investigations of adjuvant chemotherapy after radical prostatectomy, investigators reported here.

The primary finding -- that adding mitoxantrone and prednisone to androgen deprivation therapy (ADT) did not improve outcomes compared with ADT alone -- would surprise no one, if the trial were conducted today. However, when the trial began in 1999, mitoxantrone and prednisone were standard options for systemic therapy in prostate cancer, and the feasibility, safety, and efficacy of adjuvant therapy remained open for discussion, , of the University of Colorado in Denver, said at the .

"This study goes back almost to the Jurassic age, and I'm the dinosaur," Glode quipped.

The Southwest Oncology Group 9921 trial demonstrated the feasibility of conducting a trial of adjuvant systemic therapy after prostatectomy for high-risk prostate cancer. Otherwise, almost nothing went according to plan. The addition of mitoxantrone (the default chemotherapy agent at the time) and prednisone failed to improve overall survival or any other key outcomes.

The trial fell well short of the accrual goal of 1,300 patients, even after the trial was amended to allow 9.5 years for patient accrual. Mitoxantrone turned out to be associated with an increased risk of leukemia. More patients in the chemotherapy arm died of prostate cancer, and twice as many died of other types of cancer as compared with ADT alone. Patients in both arms had substantially better survival than expected.

A good rationale existed for conducting the trial. No clinical consensus had emerged with regard to optimal treatment of high-risk prostate cancer in men undergoing radical prostatectomy. Short-term preoperative ADT reduced the frequency of positive surgical margins but had no effect on disease-free (DFS) or overall survival, said Glode. Adjuvant estramustine had improved progression-free survival (PFS) in trials of patients treated with prostatectomy and radiotherapy.

Mitoxantrone received approval for advanced prostate cancer on the basis of two randomized trials that showed higher rates and duration of palliation and objective and PSA response rates when added to corticosteroids versus steroids alone.

"We hypothesized that 2 years of adjuvant ADT would improve overall survival and progression-free survival, although definitive data were unavailable," said Glode. "We also assumed that the addition of modestly active chemotherapy earlier in the course of the disease might improve overall and progression-free survival."

Eligible patients had clinically localized disease (T1-3 N0 M0), a negative bone scan (if PSA ≥20 ng/mL), and had undergone radical prostatectomy within the past 120 days. They also had to meet at least one other criterion: pathologic Gleason sum ≥8; seminal vesicle involvement (pT3b) or pT4 or N1; pathologic Gleason sum 7 and positive margins; preoperative PSA >15 ng/mL or biopsy Gleason score >7, or PSA >10 ng/mL and biopsy Gleason score >o6.

All patients were required to have a postoperative PSA level ≤0.2 ng/mL before starting any hormonal therapy.

The trial had a primary endpoint of overall survival, and the key secondary endpoint was DFS, defined as an increase in PSA level to >0.2 ng/mL on three separate occasions or a positive radiographic scan. Patient accrual began Oct. 15, 1999 and ended with 963 patients on Jan. 12, 2007, following a recommendation from the data and safety monitoring committee.

The chemotherapy added substantially to toxicity, particularly grade 3/4 neutropenia (149 versus 1 patient). Additionally, six patients in the mitoxantrone-prednisone arm developed leukemia (one case of acute promyelocytic leukemia and five cases of acute myeloid leukemia).

The 10-year overall survival was 86% with chemotherapy and 87% with ADT alone. The two groups had identical 10-year DFS of 72%.

Invited discussant , of Memorial Sloan Kettering Cancer Center in New York City, offered a forward-looking perspective of SWOG 9921. A of adjuvant chemotherapy in high-risk, postprostatectomy prostate cancer suffered a fate similar to that of the SWOG trial. TAX-3501 compared 18 months of hormonal therapy with or without docetaxel, with immediate or deferred administration.

TAX-3501 ended prematurely because of slow patient accrual (228 of a planned 1,696) and therefore lacked the statistical power to demonstrate a difference in the primary endpoints of PFS and PSA recurrence.

More recently, a Veterans Affairs cooperative study yielded some positive data regarding adjuvant chemotherapy after radical prostatectomy. Overall, the VA 553 trial showed a 10-month improvement in median PFS among patients with high-risk disease who received docetaxel. However, the difference did not achieve statistical significance (HR 0.82, 95% CI 0.59-1.14, P=0.24).

A prespecified subgroup analysis of "higher" high-risk patients did yield a significant difference. The subgroup consisting of patients with pathologic T3b disease and African Americans had a median PFS of 47.2 months versus 29.2 months for standard of care.

Some recent developments afford an opportunity to identify subgroups of patients with high-risk prostate cancer who might be more likely to benefit from adjuvant chemotherapy, said Slovin. A new provides simpler yet more more accurate grade-stratification of tumors. Use of the system can reduce overtreatment of indolent prostate cancer, she said.

A second development that can aid patient selection for adjuvant chemotherapy is genomic interrogation. A recent evaluation of the showed significant correlation between a tumor specimen's genomic score and the incidence of biochemical recurrence, distant metastasis, and prostate cancer-specific mortality.

Slovin concluded that trials of adjuvant therapy remain feasible and that recently developed tools to refine the criteria for "high risk" could improve patient selection.

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