Long-term follow-up of a randomized prospective trial comparing a standard 81 mg dose of intravesical bacille Calmette-Guérin with a reduced dose of 27 mg in superficial bladder cancer.

OBJECTIVES: To determine the efficacy of a three-fold reduced dose (RD, 27 mg) of intravesical bacille Calmette-Guérin (BCG) against the standard dose (81 mg) in patients with superficial bladder cancer, assessing recurrence, progression and differences in toxicity. PATIENTS AND METHODS: Five hundred patients with superficial bladder cancer (Ta, T1, Tis) were enrolled and randomly assigned to be treated after transurethral resection of all visible lesions with intravesical BCG Connaught strain (weekly x six and thereafter fortnightly x six) either with the standard or RD instillation. RESULTS: All but one of the 500 patients were evaluable for efficacy and toxicity (252 in the standard arm and 247 in the RD arm). The median follow-up was 69 months (maximum 104); 71 (28%) patients in the standard arm and 76 (31%) in the RD arm developed recurrences; the median time to recurrence has not yet been attained, but at 5 years the mean (sd) percentage of recurrence-free patients was 70.5 (3.12) and 70.4 (3.1) for the standard and RD arms, respectively. In patients presenting with multifocal tumours, the standard dose was more effective against recurrences than the RD (P=0.0151). In those with G3 and high-risk tumours overall, the superiority of the standard dose was marginal (P=0.060 and P=0.082). Twenty-nine (11.5%) tumours in the standard arm and 33 (13.3%) in the RD arm progressed to invasive disease; the median time to progression has not yet been attained, but the percentage of progression-free patients at 5 years was 88.8 (2.23) and 86.9 (2.31) for the standard and RD arms, respectively. The standard dose was more effective than the RD against progression only in patients with multifocal disease (P=0.048). Twelve (4.8%) cystectomies were performed in the standard and 15 (6.1%) in the RD arm. Currently, 106 (21.2%) patients have died, but only 38 (7.6%) from bladder cancer, i.e. 20 (7.9%) in the standard and 18 (7.5%) in RD arm. Overall the disease-specific death rate was lower for those patients who completed the scheduled treatment. The cause-specific survival at 5 years did not differ between the arms (P=0.76) but there was a trend toward better cause-specific survival for patients with multifocal tumours in the standard arm. Toxicity differed between the arms, significantly more patients having no toxicity in the RD arm, and fewer having delayed instillations or withdrawing. However, severe systemic toxicity occurred even in patients treated with the RD, in a similar proportion to those receiving the standard dose. CONCLUSION: Overall, the RD gave similar results for recurrence and progression but with significantly less toxicity. However, patients with multifocal tumours fared better with the standard dose and there was a trend towards better recurrence rates in patients with high-risk tumours. We recommend continuing to use the standard dose for high-risk tumours, while we consider the reduced dose safe and effective for intermediate-risk lesions and for maintenance schedules.

[Influence of prostatic intraepithelial neoplasia on blood levels of PSA and free PSA percentage]. / Influencia de la neoplasia intraepitelial prostática en la concentración sérica de PSA y porcentaje de PSA libre.

OBJECTIVE: To analyze the influence of prostatic intra-epithelial neoplasia (PIN) on serum total PSA levels and free PSA percentage. MATERIAL AND METHODS: Total and free PSA concentrations (IRMA Tandem and Tandem free PSA, Hybritech Inc) were determined in 349 patients with normal DRE and PSA greater than 4 ng/ml, undergoing prostatic biopsy by sextant and in 81 patients with prostate cancer in clinical stage T1c N0 M0 undergoing radical prostatectomy. In the group of patients undergoing prostatic biopsy, benign hyperplasia was diagnosed in 284 (81.6%) patients, 234 (82.4%) were PIN free, 41 (14.4%) with low grade PIN and 9 (3.2%) with high grade PIN. Cancer was diagnosed in 65 patients (18.6%), 30 of whom (46.2%) had associated high grade PIN. High grade PIN was detected in 62 (76.5%) patients in the group undergoing radical prostatectomy. RESULTS: No statistically significant differences were detected among total PSA and free PSA percentage serum concentrations relative to the detection of associated PIN, regardless of its degree, in patients undergoing prostatic biopsy. Cancer detection was the single most significant contributing variable. In patients undergoing radical prostatectomy, high degree PIN did not influence significantly. The greatest contribution in this group was the pathological stage. CONCLUSIONS: PSA serum concentration and PSA percentage are not influenced by the existence of PIN. High degree PIN is strongly associated to cancer. Accordingly, repeat biopsies are warranted in any patient presenting such lesions.

[Effect of finasteride on the percentage of free PSA: implications in the early diagnosis of prostatic cancer]. / Efecto del finasteride en el porcentaje de PSA libre: implicaciones en el diagnóstico precoz del cáncer de próstata.

OBJECTIVE: To analyze the behaviour of free PSA percentage in finasteride-treated patients and to evaluate whether this ratio allows an increased PSA specificity in the early diagnosis of prostate cancer. MATERIAL AND METHODS: Evaluation of PSA serum levels and free PSA ratio in 336 patients initially diagnosed with prostate benign hyperplasia (PBH). A group of 82 patients were treated with finasteride for 14 to 58 months. A second group of 254 patients received no treatment. All patients were within the same age range and had similar PSA serum levels. In total, 141 prostate biopsies were performed: 19.5 (16/82) and 49.1 (125/254) respectively. RESULTS: Median PSA level in PBH patients was 1.6 ng/mL for the finasteride-treated group and 3.5 for the untreated group, p < 0.0001. Free PSA ratio was 18.6 and 18.8%, respectively, p > 0.05. Carcinoma detection rate was 25% (4/16) for the finasteride group and 27.2% (34/125) for the untreated group. If biopsy had been requested when PSA percentage was below 25%, 17.7 and 19.8% respectively would have been prevented and all carcinoma detected. CONCLUSION: Long-term treatment with finasteride reduces PSA serum concentration about 50% without changing the free PSA ratio. Carcinoma detection rate was similar in finasteride-treated and untreated patients. Free PSA ratio allows to increase PSA specificity and avoid unnecessary biopsied also in finasteride-treated patients.

Early results of the value of p53 in predicting survival in a homogeneous cohort of patients with invasive bladder cancer treated with a neoadjuvant carboplatin-based regimen (M-CAVI).

AIMS AND BACKGROUND: Several reports on prognostic factors for infiltrating-bladder cancer have given controversial results. We assessed the prognostic value of p53 nuclear overexpression together with known prognostic factors for survival in patients with invasive T2-4 N0 M0 bladder cancer treated with neoadjuvant chemotherapy. STUDY DESIGN: Thirty-five paraffinized tumor samples from initial transurethral resection of patients with bladder cancer were analyzed immunohistochemically to detect overexpression of p53 protein. Patients were treated with 3 to 4 cycles of neoadjuvant methotrexate, carboplatin, and vinblastine (M-CAVI) and then underwent radical cystectomy. Prechemotherapy, treatment, and postchemotherapy factors were analyzed for correlation with survival by univariate and multivariate analysis. Fifty-seven percent of tumors were positive for p53 protein, 71.5% had grade III-IV tumors, and 72% had organ-confined disease. The median follow-up was 20 months (range 5-71+). RESULTS: By univariate analysis, the significant pretreatment factors were initial tumor (T) stage (P < 0.0001) and the male sex (P = 0.03). Five postchemotherapy variables were found significant: surgery performed according to protocol (P = 0.003), overall clinical (P = 0.004), and overall pathologic (P = 0.02) response to therapy, postchemotherapy pathologic stage (P = 0.0002), and tumor status after surgery (P = 0.0006). By multivariate analysis, the initial prechemotherapy T stage was the only factor that demonstrated independent significance. CONCLUSIONS: Although the median follow-up of the study is still too short, in this group of patients treated with a neoadjuvant carboplatin-based regimen, a classical variable (prechemotherapy T stage) rather than p53 nuclear overexpression was an independent prognostic factor for survival. Further follow-up will be required to assess the value of p53 overexpression as a prognostic factor in invasive bladder cancer patients treated with neoadjuvant carboplatin-based chemotherapy.

M-CAVI, a neoadjuvant carboplatin-based regimen for the treatment of T2-4N0M0 carcinoma of the bladder.

Carboplatin, methotrexate, and vinblastine (M-CAVI) is an active and well-tolerated regimen for bladder cancer patients ineligible for cisplatin-based regimens. We treated 47 T2-4 N0 M0 bladder cancer patients with M-CAVI in a neoadjuvant phase II trial. These 47 patients are evaluable for clinical response and toxicity. Clinical overall response rate was 34%, for a 95% confidence interval (CI95%) of 21-49%. Pathological response was seen in 40% of the patients (CI95%, 26-56%) with a 26.5% rate of pathological complete response (CI95%, 15-42%). Factors associated with the achievement of a response to therapy were the initial TNM stage (pT3a or lower, greater than pT3a, p = 0.001) and a Karnofsky score greater or equal than 90%, which was marginally significant (p = 0.08). With a median follow-up of 14 months, the disease-specific actuarial survival at 2 years is 42%. No patient has relapsed beyond 21 months of follow-up in a disease-free status. Toxic effects have been moderate. In conclusion, M-CAVI is an active and well-tolerated regimen that should be compared in terms of response rate and survival with a cisplatin-based regimen for invasive bladder cancer.

[Final results of complete hormone blockade versus monotherapy in prostatic metastatic cancer. PSA implications]. / Resultados definitivos del bloqueo hormonal completo versus monoterapia en el cáncer de próstata metastásico. Implicaciones del PSA.

Of 102 patients with metastatic prostate cancer, 52 were treated with orchidectomy and 50 with CHB; 22 of these received a LHRH analog + Flutamide and 28 orchidectomy + Flutamide. No differences were seen in either arm in terms of age (69.9 vs 70.2 years) or initial PSA (493.3 vs 486.5 ng/ml) variables. After three months treatment, CHB achieved a decrease of PSA higher than monotherapy (52.9 vs 34.5 ng/ml) p<0.01 as well as minimum PSA level during follow-up (41.2 vs 17.5 ng/ml) (p<0.001). Initial clinical response rates were higher in the group treated with complete blockade (42.3% vs 52%) (p=n.s.). Overall, no significant differences were seen between the actuarial curves of biological progression, clinical progression and survival, with expected mean values of 13 vs 12, 14 vs 15 and 34 vs 28 months, respectively. However, when survival was considered as a function of bone disease dissemination, a greater survival rate was seen in patients with minimal M1 disease (p<0.05), and there were no differences between the M2 and M3 arms.

[Prostate-specific antigen as an evaluation method in the treatment of hormone-refractory cancer of the prostate]. / El antígeno prostático específico como método de evaluación en el tratamiento del cáncer de próstata hormonorrefractario.

Out of 62 patients with hormone-refractory metastatic prostate cancer, 34 received rescue treatment with estramustine phosphate and 28 received non-steroidal symptomatic treatment. All patients undergoing symptomatic treatment experienced increased PSA levels while in 16 (47%) patients treated with estramustine phosphate, PSA decreased between 13-96%. In 11 cases (32.3%) the decline in PSA was higher than 50%. In 5 (14.7%) the decline was lower than 50% and in 18 cases (53%) PSA levels were increased. SCR rate was 82%, 60% and 6% respectively while OCR were 36.4%., 0% and 0% respectively. No clinical response was seen in patients undergoing symptomatic treatment. A decline in PSA levels higher than 50% 12 weeks after treatment appears to be a "good prognosis" factor related to the best clinical response rates and survival.

[The concept of biologic progression in metastatic cancer of the prostate hormonally treated]. / El concepto de progresión biológica en el cáncer de próstata metastásico tratado hormonalmente.

A total of 110 patients with hormone-treated metastatic prostate cancer were monitored quarterly with serial PSA determinations. At the first control, 6 patients had progressed clinically, 5 of which had decreased PSA ranging between 9-77%. After a period of response, 69 patients progressed clinically, of which 1 showed no elevation of PSA levels, 14 showed progression concurrent with PSA increase, and 54 showed a period of gradual elevation of PSA over a range of 2-31 months. The probability of biological progression when the first rise occurred ranged between 72-96%, which after a second increase ranged between 92-100%, and all patients with three consecutive increases progressed clinically.

[The clinical and prognostic value of inversion of the PSA/PAP ratio in prostatic cancer]. / Valor clínico y pronóstico de la inversión del cociente PSA/PAP en el cáncer de próstata.

The inversion of PSA/PAP ratio is not common in patients with prostate cancer. Of 215 patients, 7 showed PSA levels below those of PAP (3.2%). All patients had metastatic disease at the time of diagnosis, 57% in multiple organs and tissues, with a Gleason value in all cases 4. Forty-three percent showed no early response to hormone therapy; mean survival interval recorded in these 7 patients was 21 months. Such a situation may suggest a poor prognosis for this neoplasia.

[Clinical course of hormone refractory cancer of the prostate]. / Evolución del cáncer de próstata hormonorrefractario.

Analysis of the clinical progression of 61 patients with prostate cancer undergoing hormone therapy. PSA allowed early detection in 86.9% cases. In 25 patients no rescue treatment was instituted, and 36 patients were treated with estramustine phosphate resulting in decreased PSA levels in 58% and objective response in 36%. Of these, 82% showed decreased PSA levels for over six months. Survival rate was higher in respondent, treated patients and comparable in non-respondents, treated versus non treated patients.

[Can we do without bone gammagraphy in the staging of prostatic cancer?]. / Podemos prescindir de la gammagrafía ósea en el estadiaje del cáncer de próstata?

Correlation between findings on bone gammagraphy and PSA levels in 144 patients with untreated prostate cancer are analyzed. With prevalence of metastatic disease in 57.6% cases and considering the predictive cut value of metastasis to be 20 ng/ml, there were positive and negative predictive values of 64.9% and 73.9%, with a diagnostic confidence of 66.6%. We conclude that bone gammagraphy is essential for staging prostate cancer even in patients with PSA below 20 ng/ml.

[Treatment of hormone-refractory prostate cancer with estramustine phosphate]. / Tratamiento del cáncer de próstata hormonorrefractario con fosfato de estramustina.

Twenty-one patients with hormone refractory prostate cancer were treated with oral estramustine phosphate, 600 mg/day, and the response was monitored through serial dosages of prostatic specific antigen (PSA). Patients showed biological response (67%) and clinical response (43%). The duration of the biological response was 6 months in 50% cases and over 12 months in 18%. Survival was higher for responders than non responders. It is concluded that estramustine phosphate is effective in this type of therapy and that PSA allows to measure the type of response and its duration.

[Effects of transurethral resection on the serum concentration of prostate specific antigen and prostatic acid phosphatase]. / Effectos de la resección transuretral en la concentracíon sérica de antígeno prostático específico y fosfatasa ácida prostática.

Serum concentration of PSA and PAP in 30 patients (25 prostate benign hyperplasias and 5 carcinomas) are evaluated prior to transurethral resection, right at the end, after 24 hours and 5 days later. Following TUR a significant increase in BHP is detected, this being less severe in the case of carcinomas. Subsequently, after 24 hours, PSA and PAP levels in BHPs are similar to baseline values, while there is a significant decrease in carcinomas after 5 days. Thus, determination of these markers in prostatic carcinomas should never be postponed after a TUR.

[Usefulness of bone gammagraphy versus tumor markers (PSA/PAP) in monitoring cancer of the prostate]. / Utilidad de la gammagrafía ósea versus marcadores tumorales (PSA/PAP) en la monitorización del cáncer de próstata.

In this paper, data obtained through bone gammagraphia, prostatic specific antigen and prostatic acid phosphatase in 159 measurements carried out in 76 patients with treated prostate cancer, 41 locoregional and 35 metastatic, is compared. Sensitivity to detect progression was higher for PSA (89% in LR and 92% in M) versus bone GF (22% in LR an 83% in M) and PAP (11% in LR and 79% in M). The results indicate that it is possible to use bone gammagraphia optimizing its efficacy.

Clinical utility of prostatic specific antigen and prostatic acid phosphatase serum levels in monitoring prostate cancer.

We analysed 696 prostatic specific antigen (PSA) and prostatic acid phosphatase (PAP) serum samples by double antibody radioimmunoassay (RIA)I125 in the follow-up of 122 patients with prostate cancer under treatment. PSA levels were significantly correlated to response to treatment, whereas PAP results did not differentiate patients with partial or complete remission. Progression of the disease was detected in 95.2 and 85.4% of PSA and PAP samples, and increased to 99.9% using both simultaneously. On the whole, PSA was better than PAP in monitoring prostate cancer, and the efficacy was greater using both markers together.

Bone marrow prostatic specific antigen and prostatic acid phosphatase levels: are they helpful in staging prostatic cancer?

We analyzed serum and bone marrow levels of prostatic specific antigen and prostatic acid phosphatase quantified by double antibody radioimmunoassay in 70 patients. Of the patients 36 had prostatic cancer, including 23 with metastatic disease. There was a significant correlation between the serum and bone marrow levels of prostatic specific antigen and prostatic acid phosphatase independently of the metastases (p less than 0.001). No patient with prostatic cancer and positive bone marrow prostatic specific antigen or prostatic acid phosphatase levels had normal serum levels. Quantification of bone marrow prostatic specific antigen and prostatic acid phosphatase does not provide more information than does serum determination.