Bruce A. Lowe

Bilateral orchiectomy with or without flutamide for metastatic prostate cancer

BACKGROUND Combined androgen blockade for the treatment of metastatic prostate cancer consists of an antiandrogen drug plus castration. In a previous trial, we found that adding the antiandrogen flutamide to leuprolide acetate (a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate. In the current trial, we compared flutamide plus bilateral orchiectomy with placebo plus orchiectomy. METHODS We randomly assigned patients who had never received antiandrogen therapy and who had distant metastases from adenocarcinoma of the prostate to treatment with bilateral orchiectomy and either flutamide or placebo. Patients were stratified according to the extent of disease and according to performance status. RESULTS Of the 1387 patients who were enrolled in the trial, 700 were randomly assigned to the flutamide group and 687 to the placebo group. Overall, the incidence of toxic effects was minimal; the only notable differences between the groups were the greater rates of diarrhea and anemia with flutamide. There was no significant difference between the two groups in overall survival (P=0.14). The estimated risk of death (hazard ratio) for flutamide as compared with placebo was 0.91 (90 percent confidence interval, 0.81 to 1.01). Flutamide was not associated with enhanced benefit in patients with minimal disease. CONCLUSIONS The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer.

Analysis of Risk Factors Associated with Prostate Cancer Extension to the Surgical Margin and Pelvic Node Metastasis at Radical Prostatectomy

We analyzed data from 107 consecutive patients with clinical stage B prostate cancer in an attempt to identify those at high risk for having involved margins or nodal metastasis. Each patient underwent transrectal ultrasound-guided sextant biopsies of the prostate. Patient age, surgical approach to prostatectomy, pre-biopsy prostate specific antigen (PSA) level, and number, location and maximum Gleason score of positive biopsies were statistically evaluated for all patients groups. Prostate volume and PSA density (PSAD) were calculated for all patients undergoing prostatectomy. Of the 101 patients who underwent radical prostatectomy 64 had negative margins, 37 had at least 1 positive margin and 11 of the 37 had more than 1 positive margin. Involved margins were most common at the apex (62%) and mid portion (59%) of the gland. Prostatectomy was not performed on 6 patients with nodal metastases evident on frozen section examination. Therefore, 43 patients are considered to be at high risk for having residual disease after surgery. The mean PSAD, PSA level and number of positive biopsies were significant (p < 0.05) predictors of tumor extension to the surgical margin. The mean number of positive biopsies, biopsy Gleason score and PSA level were significantly greater (p < 0.05) in patients with nodal metastases. Only 15% of the patients with a single positive biopsy had positive margins versus 47% of those with multiple positive biopsies (p < 0.05). Of the patients with tumor positive nodes on frozen section 67% had 5 or more positive biopsies, whereas only 9% of all others had that many positive biopsies (p < 0.05). The number of positive biopsy sites, PSAD and PSA level were significantly associated with tumor at the surgical margin or metastatic to the pelvic nodes.

Fatal Sepsis Following Intravesical Bacillus Calmette-Guerin Administration for Bladder Cancer

Intravesical administration of bacillus Calmette-Guerin has been shown to be highly effective treatment of superficial bladder cancer. Complications from bacillus Calmette-Guerin therapy are usually minor but serious and even fatal reactions can occur. Five recent cases illustrate the gravity of bacillus Calmette-Guerin sepsis. One man with severe debility and the organic brain syndrome died acutely with a fever of 40 C. Two men had frank sepsis that progressed to multiorgan failure and death. Sepsis progressed despite the use of isoniazid, rifampin and streptomycin. Two men who had equally progressive sepsis with intravesical bacillus Calmette-Guerin survived with the use of cycloserine for the first 72 hours of treatment. Triple antituberculous antibiotics, including cycloserine, may be lifesaving. Sepsis resulted from intravenous absorption through inflamed or disrupted urothelium. Bacillus Calmette-Guerin treatment should not be administered in the presence of severe cystitis or after grossly traumatic catheterization.

COMPARISON OF BLADDER NECK PRESERVATION TO BLADDER NECK RESECTION IN MAINTAINING POSTPROSTATECTOMY URINARY CONTINENCE

OBJECTIVES This study compares the effectiveness of a bladder neck preservation procedure with that of bladder neck resection in maintaining postprostatectomy urinary continence. METHODS Bladder neck preservation was attempted in 107 men and completed in 91; bladder neck resection was performed in 99 patients. Successful follow-up was performed in 90 and 98 patients, respectively, during a mean interval of 42 months. The two groups were compared for return of urinary continence at monthly intervals to 1 year, the incidence of positive surgical margins, and recurrence, using an unpaired t test and regression curves. RESULTS Continence at 1 month was 11.2% for patients undergoing a bladder neck resection and 23.3% for those with preservation of the bladder neck. At 3 months, the continence rates were 44.3% and 62.4%, respectively; at 6 months, they were 70.1% and 82.4%, respectively; and at 1 year, they were 86.3% and 89.4%, respectively. There was no significant difference in time to continence at 1 year between the two groups; however, there was a significantly decreased time to continence seen in patients with preservation of the bladder neck. The incidence of positive margins and organ-confined disease was not significantly different between the two groups. Detectable serum prostate-specific antigen levels were seen in 17.3% of patients undergoing bladder neck resection and in 16.7% of those with bladder neck preservation. CONCLUSIONS Preservation of the bladder neck is technically feasible; in selected patients, it is effective in eradicting disease without an increased recurrence rate. The procedure does not produce an improved rate of postprostatectomy incontinence, although it can be expected to shorten the interval of incontinence.

Phase II trial of bicalutamide in patients with advanced prostate cancer in whom conventional hormonal therapy failed : A Southwest Oncology Group study (SWOG 9235)

OBJECTIVES To determine the efficacy and tolerability of bicalutamide in patients with advanced prostate cancer with progression after conventional hormonal therapy. METHODS Fifty-two patients received bicalutamide, 150 mg once daily, as second-line therapy after progressing following treatment with orchiectomy or luteinizing hormone-releasing hormone analogue or diethylstilbestrol, alone or in combination. Patients had measurable (n = 8) or assessable (n = 44) disease, a Southwest Oncology Group performance status of 0 to 2, and no prior antiandrogen therapy or chemotherapy. The objective response to treatment was assessed every 12 weeks; symptoms and pain were assessed monthly with questionnaires for 6 months. RESULTS There was evidence of palliation with three measures of pain and, to a lesser extent, with a measure of overall symptom status after 3 months of taking bicalutamide. No complete or partial responses occurred. However, 9 (20%) of 44 subjects with adequate prostate-specific antigen data had a 50% or higher decrease in their prostate-specific antigen levels, which did not correlate with symptom improvement. The median survival time was 15 months. The most common side effects were hot flashes (23%) and nausea (21%). CONCLUSIONS These data suggest that bicalutamide decreases pain and improves symptom status in patients with prostate cancer in whom first-line hormonal therapy failed.

Randomized intergroup comparison of bacillus calmette-guerin immunotherapy and mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of the bladder a southwest oncology group study☆

To compare the toxicity and efficacy of intravesical bacillus Calmette-Guérin (BCG) immunotherapy and mitomycin C (MMC) chemotherapy in the prophylaxis of recurrent transitional cell carcinoma, 469 patients with completely resected stage Ta or TI transitional cell carcinoma were enrolled in a randomized Southwest Oncology Group Phase III study. All patients were judged to be at increased risk for tumor recurrence due to having had two occurrences of tumor within 56 weeks, stage T I tumor or three or more tumors within 16 weeks, or concurrent carcinoma in situ. Three hundred and seventy-seven evaluable patients received either 50 mg of Tice BCG in 50 cc saline or 20 mg MMC in 20 cc water weekly for 6 weeks and then monthly to one year. Local and systemic grade I and 2 toxicity was seen significantly more frequently following BCG treatment (P = 0.003), but no life threatening toxicity was seen with either treatment. Recurrence-free survival was significantly prolonged (P = 0.017, proportional hazard regression) in patients randomized to the BCG arm compared to the MMC arm, but there were no statistically significant differences at this analysis for worsening-free survival and overall survival, although the number of these events is too low for a definitive analysis of these long-term outcomes. Therefore, when compared to MMC chemotherapy, BCG immunotherapy is associated with a significantly higher frequency of grade 1 and 2 adverse reactions and a significantly lower first recurrence hazard rate.

DISEASE RECURRENCE AND PROGRESSION IN UNTREATED PATHOLOGIC STAGE T3 PROSTATE CANCER: SELECTING THE PATIENT FOR ADJUVANT THERAPY

PURPOSE Optimal management of pathologic T3 prostate cancer is poorly defined. We conducted a prospective study of untreated pT3 patients to improve understanding of the natural history of this disease and to identify clinical parameters useful in patient selection for adjuvant therapy. MATERIALS AND METHODS Of 583 consecutive patients with clinical stage T1 to 2 disease managed by total prostatectomy, 206 had pT3 disease. Excluding patients requesting immediate adjuvant treatment or neoadjuvant therapy, 156 subjects were eligible for the study, including 34 with pT3a, 80 pT3b, 22 pT3c, and 20 pT3N+ disease. Patients were followed for prostate-specific antigen (PSA) recurrence of greater than 0.2 ng./ml. and biopsy proved local or distant tumor progression demonstrated by imaging studies. RESULTS After a median of 45 months, PSA recurrence was seen in 29.4% of pT3a (10/34), 30% of pT3b (24/80), 27.3% of pT3c (6/22), and 80% of pT3N+ (16/20 cases). Local or distant progression was seen in 2.9% of pT3a (1), 6.2% of pT3b (5), 9.1% of pT3c (2), and 55% of pT3N+ (11 cases). Recurrence and progression correlated with the number of surgical margins involved by tumor, pathological Gleason score and baseline pre-prostatectomy PSA levels. PSA recurrence was seen in 20.8% (10/48) patients with 1 surgical margin involved, 40.9% (9/22) with 2 margins involved and 50% (5/10) with 3 or more margins involved. PSA recurrence was 20.3% (14/69) with Gleason scores of less than 7, 33.9% (19/56) with a score of 7 and 74.2% (23/31) with scores of greater than 7. Pre-prostatectomy PSA levels less than 10 ng./ml. were associated with a PSA recurrence of 17.3% (14/81) and 45.4% (25/55), with levels greater than 10 ng./ml. Selecting patients for high or low risk based upon the results of these parameters allowed accurate prediction of PSA recurrence; 8.5% (4/47) for low risk patients and 44.8% (30/67) for high risk. Tumor progression was seen in no low risk patient and in 9% (6) with high risk. The difference between the 2 risk groups was highly significant (p <0.0001). CONCLUSIONS The majority of patients with pT3 prostate cancer will not experience recurrent disease for many years if ever. Immediate use of adjuvant treatment should be reserved for those patients with a high risk of recurrent disease.

Weekly high-dose calcitriol and docetaxel in advanced prostate cancer☆

Novel treatment regimens for androgen-independent prostate cancer (AIPC) are needed because currently available approaches have not been shown to improve survival. Docetaxel provides a good foundation for new therapeutic combinations because of its promising single-agent activity against prostate cancer and its favorable tolerability profile, particularly when administered weekly. In both tissue culture and animal models of prostate cancer, calcitriol (the biologically active form of vitamin D) enhanced the activity of docetaxel, paclitaxel, and platinum compounds. These effects were particularly notable at supraphysiologic calcitriol concentrations. Weekly calcitriol dosing is associated with minimal toxicity and permits substantial dose escalation over the daily schedule. A weekly calcitriol dose of 0.5 microg/kg produces plasma calcitriol levels 25-fold higher than the physiologic range. In a preclinical study at the Oregon Health Sciences University, calcitriol 5 micromol/L plus docetaxel 0.15 nmol/L was at least additive in inhibiting PC-3 colony formation. A phase II study is evaluating weekly administration of 0.5 microg/kg calcitriol orally on day 1 followed by 36 mg/m(2) docetaxel intravenously on day 2 in patients with AIPC (repeated for 6 consecutive weeks of each 8-week cycle). At the time of a preliminary analysis, 11 patients had been enrolled and were actively being treated. All 5 patients who had completed 8 weeks of calcitriol/docetaxel treatment achieved prostate-specific antigen (PSA) reductions of > or =50%. Two of these patients had confirmatory assessments, both meeting the formal PSA response criteria. Treatment has been well tolerated, with 1 patient experiencing a self-limited grade 3 toxicity and no patients experiencing grade 4 or 5 toxicities.

Neoadjuvant Therapy Before Radical Prostatectomy For Clinical T3/T4 Carcinoma of the Prostate: 5-Year Followup, Phase II Southwest Oncology Group Study 9109

PURPOSE Several investigators have examined the role of hormonal therapy before definitive local therapy for locally advanced prostate cancer to improve outcome. We evaluated the resectability rate and clinical response rate to 16 weeks of total androgen blockage therapy for clinically locally prostate cancer before radical prostatectomy, and progression-free survival in this multi-institutional study. MATERIALS AND METHODS Southwest Oncology Group 9109 was a phase II feasibility study designed to treat patients with clinical stage C prostate cancer (T3, T4, N0 and M0). Cases were classified by stage T3 versus T4 and bulky (greater than 4 cm.) versus nonbulky (or less 4 cm.) disease. The neoadjuvant agents used were goserelin and flutamide before radical prostatectomy. RESULTS A total of 62 patients were accrued to the study and 1 patient was ineligible. There were 2 protocol deviations and these patients refused to undergo prostatectomy after hormonal therapy. Four patients went off protocol treatment because they were not considered surgical candidates. The racial distribution was 72% white, 20% black, 7% Hispanic and 2% Asian. Clinical stage at diagnosis was T3 in 97% and T4 in 3% of cases. Of the patients 39% were diagnosed with bulky disease. Of the 61 eligible patients 55 (90%) underwent a prostatectomy. The 5-year progression-free survival estimate was 70% (24 of 61 cases failed) and the 5-year survival estimate was 90% (11 of 61 deaths). Most of the patients in this trial would have been considered inoperable and referred to radiation oncology. CONCLUSIONS Neoadjuvant hormonal therapy followed by radical prostatectomy is reasonable and appropriate for clinical stage T3 prostate cancer. A progression-free and overall 5-year survival of 70% and 90%, respectively, compares favorably to Radiation Therapy Oncology Group neoadjuvant trial outcomes for this stage of prostate cancer.

A RATIONAL APPROACH TO MANAGING STAGE I NONSEMINOMATOUS GERM CELL CANCER

Regardless of the treatment option selected for management of low-stage germ cell cancer, ultimate survival is nearly identical. Treatment-related morbidity is very low regardless of management modality and the individual patient can expect similar physical limitations owing to therapy. The overall difference in loss of productivity between treatment programs varies by little more than 1 week. The cost of treatment is similar for all methods, although there is a definite financial advantage to surveillance, less so for selective surveillance, when compared with other forms of management. Socioeconomic factors are of importance when managing limited resources for a large population, but are of less concern to an individual, especially when the mean differences in per patient costs vary by only