Michael Chetner

BACKGROUND: It is not known whether short-term androgen-deprivation therapy (ADT) before and during radiotherapy improves cancer control and overall survival among patients with early, localized prostate adenocarcinoma. METHODS: From 1994 through 2001, we randomly assigned 1979 eligible patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a prostate-specific antigen (PSA) level of 20 ng per milliliter or less to radiotherapy alone (992 patients) or radiotherapy with 4 months of total androgen suppression starting 2 months before radiotherapy (radiotherapy plus short-term ADT, 987 patients). The primary end point was overall survival. Secondary end points included disease-specific mortality, distant metastases, biochemical failure (an increasing level of PSA), and the rate of positive findings on repeat prostate biopsy at 2 years. RESULTS: The median follow-up period was 9.1 years. The 10-year rate of overall survival was 62% among patients receiving radiotherapy plus short-term ADT (the combined-therapy group), as compared with 57% among patients receiving radiotherapy alone (hazard ratio for death with radiotherapy alone, 1.17; P=0.03). The addition of short-term ADT was associated with a decrease in the 10-year disease-specific mortality from 8% to 4% (hazard ratio for radiotherapy alone, 1.87; P=0.001). Biochemical failure, distant metastases, and the rate of positive findings on repeat prostate biopsy at 2 years were significantly improved with radiotherapy plus short-term ADT. Acute and late radiation-induced toxic effects were similar in the two groups. The incidence of grade 3 or higher hormone-related toxic effects was less than 5%. Reanalysis according to risk showed reductions in overall and disease-specific mortality primarily among intermediate-risk patients, with no significant reductions among low-risk patients. CONCLUSIONS: Among patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a PSA level of 20 ng per milliliter or less, the use of short-term ADT for 4 months before and during radiotherapy was associated with significantly decreased disease-specific mortality and increased overall survival. According to post hoc risk analysis, the benefit was mainly seen in intermediate-risk, but not low-risk, men. (Funded by the National Cancer Institute; RTOG 94-08 ClinicalTrials.gov number, NCT00002597.).

Prostate specific antigen (PSA), neutral serine protease secreted exclusively by prostatic epithelial cells, has a number of applications in the management of men with prostatic carcinoma. While it is widely recognized that elevated PSA correlates with the presence of carcinoma, little data exist regarding the use of PSA as the initial test in the early detection of prostatic cancer. We measured serum PSA levels in men older than 50 years and performed digital rectal examination and ultrasound guided prostate biopsy of those who had a PSA level of greater than 4.0 ng./ml. A total of 1,249 men entered the protocol, of whom 187 (15.0%) had PSA levels above 4.0 ng./ml. Digital rectal examination and ultrasound guided biopsy were performed at our facility in 105 patients (56.2%). A total of 32 carcinomas (30.5%) was detected, including 23 in men with PSA between 4.1 and 10.0 ng./ml. and 9 in men with a PSA of greater than 10.0 ng./ml. Of the 32 carcinomas 12 (37.5%) occurred in men with normal prostates or glands demonstrating only asymmetry on digital rectal examination, and 3 men had carcinoma despite normal digital rectal examination and no hypoechoic peripheral zone lesion detected on ultrasound. Of the 32 patients 30 had clinically localized carcinoma but 7 of the 16 undergoing radical prostatectomy had pathological upstaging. We conclude that PSA represents an important adjunct to digital rectal examination for the early detection of prostatic carcinoma. The efficacy of this or any other early detection test to decrease prostate cancer mortality necessitates the results of prospectively randomized clinical trials.

PURPOSE: A prospective phase 3 trial was initiated to determine whether 8 compared with 3-month neoadjuvant hormonal therapy reduces prostate specific antigen (PSA) recurrence rates after radical prostatectomy. Our interim analysis includes secondary end points of differences in biochemistry, pathology and adverse events between the 2 groups. MATERIALS AND METHODS: Men with clinically confined prostate cancer were randomized to receive 7.5 mg. leuprolide intramuscularly monthly and 250 mg. flutamide orally 3 times daily for 3 or 8 months before radical prostatectomy. Our study was powered to detect a 35% decrease in PSA recurrence, assuming a 30% recurrence rate in the 3-month arm after 3 years. RESULTS: A total of 547 men were randomized between August 1995 and April 1998. Men in the 8 and 3-month groups were equally stratified for T stage (29% T1c, 70% T2), Gleason grade (68% less than 4, 32% 4 or greater) and pretreatment PSA (63% less than 10, 27% 10 to 20 and 10% greater than 20 microg./l.). Mean pretreatment PSA was slightly higher in the 8-month compared with the 3-month group (11.64 versus 9.95 microg./l., respectively, p = 0.0539). A total of 44 men withdrew from study before surgery and, therefore, were nonevaluable. Preoperative PSA nadir was less than 0.1 microg./l. in 43.3% versus 75.1% (p <0.0001), and 0.3 microg./l. or greater in 21% versus 9.2% after 3 versus 8 months, respectively (p <0.0006). Mean serum PSA decreased 98% to 0.12 microg./l. after 3 months, with a further 57% to 0.052 microg./l. from 3 to 8 months. Transrectal ultrasound determined that prostatic volume decreased 37% from a mean of 40.6 to 25.4 cc after 3-month neoadjuvant hormonal therapy (p = 0.0001) and a further 13% to 22.2 cc after 8 months (p = 0.03). Mean hemoglobin decreased 15% (148.2 to 125.4 gm./dl.) after 3-month neoadjuvant hormonal therapy but stabilized thereafter. Radical prostatectomy was completed in 500 men, while surgery was aborted intraoperatively in 3. Positive margin rates were significantly lower in the 8 than 3-month group (12% versus 23%, respectively, p = 0.0106). There were no fatal adverse events and no differences between the 2 groups in the severity or causality (p = 0.287, 0.0564) of adverse events, or incidence of increased liver enzymes or diarrhea (p = 0.691, 0.288, respectively). However, men in the 8-month group noticed a higher number of newly reported adverse events (4.5 versus 2.9, p <0.0001) and higher incidence of hot flushes than the 3-month group (87% versus 72%, respectively, p <0.0001). CONCLUSIONS: Ongoing biochemical and pathological regression of prostate tumors occurs between 3 and 8 months of neoadjuvant hormonal therapy, suggesting that the optimal duration of neoadjuvant hormonal therapy is longer than 3 months. Longer followup is needed to determine whether longer therapy alters PSA recurrence rates.

PURPOSE: To assess the safety, tolerance, and efficacy of transurethral surgery plus concomitant cisplatin, 5-fluorouracil (5-FU), and radiation therapy in conjunction with selective bladder preservation in patients with muscle-invading bladder cancer. Patients and Methods. Thirty-four eligible patients with clinical stage T2-T4a, Nx M0 bladder cancer without hydronephrosis were entered into a protocol aimed at selective bladder preservation. Treatment began with as complete a transurethral resection as possible followed by induction chemoradiation. This consisted of cisplatin 15 mg/m(2) i.v. and 5-fluorouracil (5-FU) 400 mg/m(2) i.v. in the mornings on d 1, 2, 3, 15, 16, and 17. On d 1, 3, 15, and 17, radiation was given immediately following the chemotherapy using twice-a-day 3 Gy per fraction cores to the pelvis for a total radiation dose of 24 Gy. Response was evaluated by cystoscopy, cytology, and rebiopsy four weeks later. Patients with a complete response received consolidation therapy with the same drugs and doses on d 1, 2, 3, 15, 16, and 17 combined with twice-daily radiation therapy to the bladder and bladder tumor volume of 2.5 Gy per fraction for a total consolidation dose of 20 Gy and a total induction plus consolidation dose to the bladder and bladder tumor of 44 Gy. Patients who did not achieve a complete response were advised to undergo prompt cystectomy, as were those with a subsequent invasive recurrence. The median follow up is 29 months. RESULTS: Of the 34 eligible patients, 26 had a visibly complete transurethral resection. One patient did not complete induction treatment due to acute hematologic toxicity. After induction treatment, 22 (67%) of the 33 patients had no tumor detectable on urine cytology or rebiopsy. Of the 11 patients who still had detectable tumor, six underwent radical cystectomy and five underwent consolidation chemoradiation (one because of refusal to have the recommended cystectomy and four because the treating institutions erroneously assigned them to receive consolidation chemoradiation rather than cystectomy). No patient has required a cystectomy for radiation toxicity. Six patients have died of bladder cancer. The actuarial overall survival at three years is 83%. The probability of surviving with an intact bladder is 66% at three years. A total of seven patients (21%) developed grade 3 or grade 4 hematologic toxicity in conjunction with this treatment. CONCLUSION: This aggressive protocol comprising local surgery plus concurrent 5-FU, cisplatin, and high-dose hypofractionated radiation has been associated with moderately severe hematologic toxicity. Longer follow-up will be necessary to assess efficacy. Both the 67% complete response rate to induction therapy and the 66% three-year survival with an intact bladder are encouraging.

PURPOSE: We characterized relapse patterns in patients with sporadic renal cell carcinoma (RCC) following radical and partial nephrectomy, and developed surveillance guidelines. MATERIALS AND METHODS: Between 1989 and 2000, 495 patients underwent nephrectomy for RCC at 1 of 5 Canadian referral centers. Median followup was 42 months. RESULTS: The rate of relapse, time to relapse and site of relapse were associated with pathological stage. Five-year progression-free probability was 93% for pT1, 81% for pT2, 67% for pT3A and 57% for pT3B (p <0.001). Compared to patients with pT1-2 those with pT3A-B lesions had earlier relapse after nephrectomy (median 12 vs 26 months, p = 0.001) and were at higher risk for relapse at abdominal sites (14% vs 1.8%, p < 0.001). Abdominal relapse was detected in the absence of symptoms, abnormal biochemical profile or thoracic metastases detectable by chest x-ray in 7 patients (1.4%) overall, including 3 (0.9%) with pT1, 3 (4%) with pT3A and 1 (3%) with pT3B. CONCLUSIONS: The risk and the pattern of relapse of RCC after nephrectomy are associated with pathological stage. For the surveillance of recurrent disease after nephrectomy we recommend annual clinical assessment and chest x-ray in pT1-2 cases. Patients with pT3A-B should be followed every 6 months for the first 3 years with clinical assessment and chest x-ray, and annual followup thereafter. The higher risk of abdominal relapse in patients with pT3A-B indicates that they should receive surveillance abdominal imaging. We recommend abdominal computerized tomography 6, 12, 24 and 36 months postoperatively.