Pretreatment PSA Best Predictor of Radiotherapy Failure

ABSTRACT: The single most significant predictor of the inability of radiotherapy to prevent biochemical failure is the pretreatment PSA level. Palpable stage and Gleason score are also important pretreatment prognostic factors and have been combined with PSA to construct a model to predict treatment outcome. More recently, pretreatment prostate ultrasound has been used in combination with serum PSA to roughly approximate the prostate cancer volume. Originally proposed by D’Amico and Propert, this calculation has been confirmed to predict relapse (defined as a rising PSA) independently of other factors for patients with a pretreatment PSA of 4 to 20 ng/mL. Other factors that may contribute to pretreatment prognosis are ultrasound staging, DNA ploidy, Ki-67 staining and tumor angiogenesis. [Oncol News Int 6(Suppl 3):3-4, 1997]

Introduction

The pretreatment prostate-specific antigen (PSA) level was found to be the single most significant predictor of biochemical failure (that is, ‘‘a rising PSA’’ profile) in a group of 938 men with T1 to T4 prostate cancer. The men were treated with external beam radiation between 1987 and 1995 at The University of Texas M.D. Anderson Cancer Center in Houston. The pretreatment mean PSA was 12.6, with a median of 9.

“It’s well-established that pretreatment PSA is a very important prognostic factor, both in patients treated with external beam radiation and those treated with surgery, and that’s reflected in our data, using relapse (or a rising PSA) as an end point,” stated Alan Pollack, MD, PhD. Dr. Pollack, who presented his data at the First Sonoma Conference on Prostate Cancer, is with the Department of Radiation Oncology at M. D. Anderson.

None Had Androgen Ablation

The patients were all treated with external beam radiation, but without androgen ablation. “The patients who underwent lymphadenectomy and were found to have positive lymph nodes were excluded, because those patients received androgen ablation,” Dr. Pollack explained. “So primarily, these were clinically staged patients.” The mean age was 68 years.

PSA failure was defined as two consecutive rises on follow-up, with no nadir cutoff. In regard to the association of PSA level and an inability of radiotherapy to prevent biochemical failure, Dr. Pollack presented his data going out to 6 years. These data included:

• PSA level of less than 4 ng/mL was associated with a failure rate of 16%;
• PSA greater than 4 but less than or equal to 10 ng/mL was associated with a failure rate of 34%;
• PSA greater than 10 but less than or equal to 20 ng/mL was associated with a failure rate of 51%; and
• PSA greater than 20 ng/mL was associated with a failure rate of 89%.

Just What Does PSA Represent?

“What does PSA represent?” Dr. Pollack asked rhetorically. “This is a very arguable point. But we feel pretty strongly that PSA is reflecting local disease rather than distant disease. And this is, in our opinion, true for patients who have a rising PSA.”

“We’ve seen a shift in the failure pattern over the years. If you look at patients in the pre-PSA era, the failures were clinical and radiographic, and these were primarily metastatic failures versus today, in the PSA era, where it’s now mostly local.”

“If we biopsy our patients with a rising PSA, we find local disease, primarily residual disease in the prostate, suggesting that we haven’t done a good enough job in eradicating this disease from the prostate.

“These data indicate that in most cases the rising PSA profile represents an inability to eradicate the tumor from the prostate and that more effective local treatment is needed.”

Several Factors Combined Into Model

Using Cox Proportional Hazards multivariate analysis and looking at the hazard indices, PSA levels were combined with palpable T stage and Gleason score. “We’ve constructed our model about predicting outcome, using the three most important pretreatment prognostic factors: PSA, grade, and stage,” Dr. Pollack said. “Unfavorable patients were those that had PSAs greater than 20 (any Gleason score or stage), or had PSAs greater than 10 and £ 20, with a Gleason score of 8 to 10 (any stage).”

• Group I consisted of T1 and T2 patients with a PSA less than or equal to 4 and a Gleason score between 2 and 6.
• Group II consisted of T1 and T2 patients with a PSA greater than 4 but less than or equal to 10 and a Gleason score betwen 2 and 7; and a PSA £ 4 and a Gleason score ³ 7.
• Group III also included T1 and T2 patients, but these patients had a PSA > 10 and £ 20 and a Gleason score £ 7; and a PSA between 4 and 10, and a Gleason score ³ 7.
• Group IV was comprised of T3 patients with a PSA less than or equal to 10 with any Gleason score.
• Group V included patients with a PSA greater than 10 but less than or equal to 20 with a Gleason score between 2 and 7.

The accompanying graphs illustrate failure by prognostic group (Figure1 and Figure 2). For patients with T1/T2 disease, the incidence of rising PSA at 6 years ranged from less than 10% in Group I to 30% to 40% in Groups II and III. For Groups IV and V, the incidence was 45% to 55%. In the unfavorable group, which is independent of stage, incidence of rising PSA at 6 years topped 80%.

Calculated Prostate Cancer Volume

More recently, Dr. Pollack and his colleagues looked at calculated prostate cancer volume, a clinical staging system proposed by D’Amico and Propert. In patients with pretreatment PSA levels between 4 and 20 ng/mL, this staging system , was found to be “more significant than PSA level in predicting rising PSA.”

In a multivariate analysis, Dr. Pollack said, “PSA cancer volume was a significant covariant with PSA level, when all patients were considered,” but when only the patients with a pretreatment PSA level of 4 to 20 ng/mL were considered, “PSA cancer volume was the only significant predictor of outcome...I think this is an important pretreatment parameter that’s of value both for pathologic estimates of extent of disease, as well as outcome from radiotherapy.”

Other Pretreatment Correlates

Dr. Pollack briefly reviewed other pretreatment correlates of biochemical control.

• Ultrasound staging did not provide independent prognostic information for T1 and T2, but did help downstage some tumors with a clinical palpable stage of T3. “When the ultrasound did not show evidence of extracapsular extension, the prognosis was the same as T1 and T2,” Dr. Pollack said.
• DNA ploidy “is consistently a significant prognostic factor,” Dr. Pollack said, “however, the problem using flow cytometry is that too much tissue is required. Image analysis, in my opinion, is less precise.’’
• Ki-67 staining “does appear to be significant,” Dr. Pollack reported. Preliminary data suggest that Ki-67 is a strong correlate of patient outcome that might supplant DNA ploidy measurements.
• Tumor angiogenesis was found to be “very promising” in a small group of patients.

PSA Single Best Pretreatment Prognostic Factor

Dr. Pollack acknowledged that Gleason score and palpable stage also were independent correlates of patient outcome, but he concluded that pretreatment PSA is the single most significant predictor of the inability of radiotherapy to prevent biochemical failure.