The source of pretreatment serum prostate-specific antigen in clinically localized prostate cancer--T, N, or M?

PURPOSE: Prostate-specific antigen (PSA) is an important marker for prostate cancer and has been shown to be secreted from the primary tumor and from metastases. However, the relative contribution of the primary and micrometastatic disease to the serum level of PSA in patients with clinically localized disease has not been delineated. This study addresses the source of pretreatment serum PSA in patients with clinically localized disease. METHODS AND MATERIALS: The fall in serum PSA level following radical prostatectomy (280 patients; 105 T1, 165 T2, 10 T3) or definitive radiotherapy (427 patients; 122 T1, 147 T2, 158 T3/T4) was analyzed with the assumption that any fall in PSA following local treatment reflects the fraction of PSA produced in the prostate and its primary tumor. RESULTS: Serum PSA level became undetectable in 277 of the 280 (99%) patients within 6 months of radical prostatectomy. The three patients who did not achieve undetectable levels had postsurgical values < or = 0.9 ng/ml. Following definitive radiotherapy, nadir serum PSA values were between < or = 0.3 and 20.3 ng/ml, with mean and median values of 1.9 and 1.2 ng/ml, respectively. Nadir PSA was undetectable in 52 patients (12%). Four patients' PSA did not fall, but rose from the start, and each developed metastatic disease within 9 months, and in each metastases appeared to contribute to pretreatment serum PSA. In the remaining patients, the maximal factor by which PSA fell to its nadir was higher the higher the pretreatment PSA level. We present arguments that this is most consistent with the hypothesis that virtually all detectable pretreatment serum PSA derives from the primary tumor. Confirmatory evidence that little of the pretreatment serum PSA came from metastases was obtained by extrapolating the rising PSA profile in 97 patients back to pretreatment time. Back-extrapolated PSA contributed a mean of 7% and a median of 5% to the pretreatment serum value. Because such back-extrapolated values estimate the potentially maximal micrometastatic contribution, metastatic disease at diagnosis contributes little to pretreatment serum PSA. CONCLUSION: In patients with clinically localized prostate cancer, putative micrometastatic disease contributes negligibly to the pretreatment serum PSA level even when the latter is high. Most likely such patients, when they have metastases, have a very low metastatic burden.

Influence of radiotherapy on node-positive prostate cancer treated with androgen ablation.

PURPOSE: Patients with node-positive prostate cancer that is regionally localized (T1-4, N1-3, M0) have a relatively poor prognosis when a single-treatment modality such as radical surgery, definitive radiotherapy, or androgen ablation is used. While promising results using radical surgery and androgen ablation have been reported, there are no data to support an analogous approach using local radiotherapy and androgen ablation. In this retrospective review, the outcome after local radiotherapy and early androgen ablation (XRT/HORM) was compared to early androgen ablation alone (HORM). METHODS AND MATERIALS: Between 1984 and 1992 there were 181 patients treated with HORM and 27 patients treated with XRT/HORM at the University of Texas M. D. Anderson Cancer Center. The nodal status of all patients was established pathologically by lymph node dissection, which was terminated after frozen section confirmation of involvement. In the majority of cases androgen ablation was by orchiectomy. The median dose to the prostate in XRT/HORM group was 66 Gy. The median follow-up was 45 months; 49 months for the HORM group and 25 months for the XRT/HORM group. RESULTS: The distribution of prognostic factors between the HORM and XRT/HORM groups was similar, with the exception of tumor grade. There was a significantly larger proportion of high grade tumors in the HORM group. In terms of actuarial disease outcome, at 4 years the results of patients in the HORM group were significantly worse, including a rising prostate specific antigen (PSA) of 53%, any disease progression of 32%, a rising PSA or disease progression of 55%, and local progression of 22%. None of the patients in the XRT/HORM group failed biochemically or clinically. To determine the impact of grade on these findings, the analyses were repeated, using only those with grade 2 tumors. A similar pattern was evidenced with significantly worse actuarial outcome at 4 years for the HORM group using the endpoints of a rising PSA (46%), any disease progression (24%), and a rising PSA or disease progression (47%). CONCLUSION: Node-positive prostate cancer patients with regionally localized disease fared significantly better when combined local radiotherapy and early androgen ablation were used, as compared to early androgen ablation alone. Although the number of patients in the XRT/HORM group was small and follow-up was short, the combined treatment had a dramatic effect on disease outcome and, therefore, a larger prospective randomized trial is warranted.

Serum prostate-specific antigen, clinical stage, pathologic grade, and the incidence of nodal metastases in prostate cancer.

OBJECTIVES: To evaluate the potential gains in using serum prostate-specific antigen (PSA) levels for predicting the incidence of pelvic nodal metastases in patients with otherwise localized prostate cancer. METHODS: We reviewed 569 patients undergoing staging lymphadenectomy, and evaluated the correlation between clinical stage, tumor grade, presurgical PSA level, and the incidence of nodal metastatic disease using univariate and multivariate regression. RESULTS: In univariate analysis stage, grade, and PSA level were highly significant covariates with nodal metastasis. Nodal metastatic rates increased as stage increased: Stage T1 (A2), 6 of 127 (5%); Stage T2 (B), 41 of 243 (17%); Stage T3 (C), 95 of 199 (48%), (p < 0.0001). Likewise metastatic rates increased as grade increased: Gleason grades 2 to 4, 6 of 124 (5%); Gleason grades 5 and 6, 52 of 238 (22%); Gleason grade 7, 41 of 122 (34%); Gleason grades 8 to 10, 43 of 84 (51%) (p < 0.0001). The relationship between PSA level and nodal metastases was not linear and we selected the following groupings that correlated with nodal disease: 4 or less ng/mL, 4 of 104 (4%); more than 4 to 20 or less ng/mL, 73 of 335 (22%); more than 20 to 40 or less ng/mL, 35 of 85 (41%); more than 40 ng/mL, 30 of 45 (67%) (p < 0.0001). Using multivariate logistic regression, stage, grade, and PSA were independently predictive of nodal status. CONCLUSIONS: The gains in predictive accuracy from PSA beyond that obtained from stage and grade were small and in practice would benefit fewer than 15% of our patients. Staging pelvic lymphadenectomy remains the only satisfactory method for elucidating nodal status in the majority of patients with prostate cancer.

Early androgen ablation for stage D1 (N1 to N3, M0) prostate cancer: prognostic variables and outcome.

To elucidate the outcome for patients with stage D1 (N1 to N3, M0) prostate cancer we reviewed 179 patients with lymphadenectomy proved pelvic nodal metastases who underwent immediate androgen ablation as the only initial treatment. With a median followup of 43 months, the 5 and 8-year actuarial rates of freedom from disease progression were 55% and 25%, respectively, and the median interval to disease progression was 67 months. The 5 and 8-year survival rates were 85% and 57%, respectively. Median survival after disease progression was 36 months. Local and distant disease progression was equally important. At 5 and 8 years the incidence of local progression was 32% and 51%, respectively, while metastatic rates at the same intervals wer 22% and 44%, respectively. Multivariate regression revealed that tumor grade and transurethral resection in preoperative stage C disease correlated with disease progression. Pretreatment prostate specific antigen (PSA) levels were not predictive of outcome. The fact that transurethral resection predicted for local as well as distant failure suggests that the procedure selects for rather than aggravates adverse disease. Posttreatment PSA levels were a sensitive index of response to treatment and of subsequent outcome. All patients who failed to achieve undetectable PSA levels had relapse by 8 years, whereas those whose levels became undetectable experienced only a 5% incidence of disease progression. These data show that androgen ablation alone is not curative for node positive disease but is associated with significant disease control and good short-term (5-year) survival. The primary tumor is an important source of androgen insensitive cells and comprehensive treatment strategies for this stage of disease require attention to the primary tumor as well as microscopic metastases.

Mental retardation in association with a balanced X-autosome translocation and random inactivation of the X chromosomes.

A women whose karyotype shows an apparently balanced reciprocal translocation, 46,X,t(Xq +; 10q-) is described. She is profoundly mentally retarded and shows minor physical abnormalities with normal sexual development. There is a random pattern of late replication of the normal X and X involved in the translocation, whereas in most balanced X-autosome translocations there is preferential inactivation of the normal X.