A. Bono

Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III eortc trial (30853)

Maximal androgen blockade (MAB), the eradication of the effects of adrenal androgens on prostate cancer cells after castration, has been used with differing success in the treatment of prostatic carcinoma. The aim of this randomized phase III study was to compare the efficacy and side effects of bilateral orchiectomy versus a combination of a luteinizing hormone-releasing hormone agonist (LHRH-A) depot formulation, goserelin acetate (3.6 mg s.c. once every four weeks), and flutamide (250 mg three times daily), in patients with metastatic cancer. Treatment usually continued until disease progression (or for a minimum of three months). Efficacy was assessed by response, time to disease progression, and duration of survival. Clinical evaluations, standard laboratory tests, and imaging examinations were carried out regularly. A total of 327 patients were entered in this study. There was a difference in response only for prostatic acid phosphatase (PAP) with a more frequent decrease of the serum values to normal in the serum in patients assigned to MAB treatment. The MAB treatment, however, proved significantly better for time to subjective progression, time to objective progression, time to first (subjective and objective) progression, and duration of survival. The most frequent side effects for both treatments included hot flushes and gynecomastia. In conclusion, significant time to progression and survival benefits are achieved by adding flutamide to an LHRH-A regimen, probably improving the quality of life of patients with metastatic cancer.

Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group.

BACKGROUND Few randomised studies have compared intermittent hormonal therapy (IHT) with continuous therapy for the treatment of advanced prostate cancer (PCa). OBJECTIVE To determine whether intermittent therapy is associated with a shorter time to progression. DESIGN, SETTING, AND PARTICIPANTS 766 patients with locally advanced or metastatic PCa received a 3-mo induction treatment. The 626 patients whose prostate-specific antigen (PSA) level decreased to <4 ng/ml or to 80% below the initial value were randomised. INTERVENTION Patients received cyproterone acetate (CPA) 200mg for 2 wk and then monthly depot injections of a luteinising hormone-releasing hormone (LHRH) analogue plus 200mg of CPA daily during induction. Patients randomised to the intermittent arm ceased treatment, while those randomised to the continuous arm received 200mg of CPA daily plus an LHRH analogue. MEASUREMENTS Primary outcome measurement was time to subjective or objective progression. Secondary outcomes were survival and quality of life (QoL). Time off therapy in the intermittent arm was also recorded. RESULTS AND LIMITATIONS 127 patients from the intermittent arm and 107 patients from the continuous arm progressed, with a hazard ratio (HR) of 0.81 (95% confidence interval [CI]: 0.63-1.05, p=0.11). There was no difference in survival, with an HR of 0.99 (95% CI: 0.80-1.23) and 170 deaths in the intermittent arm and 169 deaths in the continuous arm. The greater number of cancer deaths in the intermittent treatment arm (106 vs 84) was balanced by a greater number of cardiovascular deaths in the continuous arm (52 vs 41). Side-effects were more pronounced in the continuous arm. Men treated with intermittent therapy reported better sexual function. Median time off therapy for the intermittent patients was 52 wk (95% CI: 39.4-65.7). CONCLUSIONS IHT should be considered for use in routine practice because it is associated with no reduction in survival, no clinically meaningful impairment in QoL, better sexual activity, and considerable economic benefit to the individual and the community.

Maintenance Bacillus Calmette-Guerin for Ta T1 Bladder Tumors Is Not Associated with Increased Toxicity: Results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial

OBJECTIVES After transurethral resection, the local and systemic side effects of Bacillus Calmette-Guerin (BCG) instillations were assessed during a 6-week induction course followed by 3 weekly maintenance instillations at 3, 6, 12, 18, 24, 30 and 36 months to determine if BCG toxicity increases over time. METHODS 487 patients who received BCG in a multicenter phase III trial were included. Side effects were divided into 5 different treatment periods: the first 6 weeks induction, months 3 and 6, month 12, the second year, and the third year. RESULTS 99 (20.3%) patients stopped BCG due to side effects. 72 (14.8%) stopped due to local side effects, including 59 for BCG induced cystitis, 33 during the first 6 months. 46 (9.4%) stopped due to systemic side effects: 23 due to fever, 19 within 6 months, and 15 due to general malaise, 12 within 6 months. 68% who stopped due to side effects did so during the first 6 months. The percent stopping after 6 months due to local side effects does not increase and actually decreases for systemic side effects. CONCLUSIONS The majority of local and systemic side effects are seen already during the induction and the first half-year of maintenance. During further maintenance BCG toxicity does not increase and instillations are generally well tolerated.

Final Results of an EORTC-GU Cancers Group Randomized Study of Maintenance Bacillus Calmette-Guérin in Intermediate- and High-risk Ta, T1 Papillary Carcinoma of the Urinary Bladder: One-third Dose Versus Full Dose and 1 Year Versus 3 Years of Maintenance

BACKGROUND The optimal dose and duration of intravesical bacillus Calmette-Guérin (BCG) in the treatment of non-muscle-invasive bladder cancer (NMIBC) are controversial. OBJECTIVE To determine if a one-third dose (1/3D) is not inferior to the full dose (FD), if 1 yr of maintenance is not inferior to 3 yr of maintenance, and if 1/3D and 1 yr of maintenance are associated with less toxicity. DESIGN, SETTING, AND PARTICIPANTS After transurethral resection, intermediate- and high-risk NMIBC patients were randomized to one of four BCG groups: 1/3D-1 yr, 1/3D-3 yr, FD-1 yr, and FD-3 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The trial was designed as a noninferiority study with the null hypothesis of a 10% decrease in the disease-free rate at 5 yr. Times to events were estimated using cumulative incidence functions and compared using the Cox proportional hazards regression model. RESULTS AND LIMITATIONS In an intention-to-treat analysis of 1355 patients with a median follow-up of 7.1 yr, there were no significant differences in toxicity between 1/3D and FD. The null hypotheses of inferiority of the disease-free interval for both 1/3D and 1 yr could not be rejected. We found that 1/3D-1 yr is suboptimal compared with FD-3 yr (hazard ratio [HR]: 0.75; 95% confidence interval [CI], 0.59-0.94; p=0.01). Intermediate-risk patients treated with FD do not benefit from an additional 2 yr of BCG. In high-risk patients, 3 yr is associated with a reduction in recurrence (HR: 1.61; 95% CI, 1.13-2.30; p=0.009) but only when given at FD. There were no differences in progression or survival. CONCLUSIONS There were no differences in toxicity between 1/3D and FD. Intermediate-risk patients should be treated with FD-1 yr. In high-risk patients, FD-3 yr reduces recurrences as compared with FD-1 yr but not progressions or deaths. The benefit of the two additional years of maintenance should be weighed against its added costs and inconvenience. TRIAL REGISTRATION This study was registered at ClinicalTrials.gov, number NCT00002990; http://clinicaltrials.gov/ct2/show/record/NCT00002990.

Handling and Pathology Reporting of Radical Prostatectomy Specimens

Proper examination of radical prostatectomy (RP) specimens by the pathologists is critical in accurately determining the prediction of patient outcome. The pathology report should include relevant clinical information as well as provide prognostically useful data derived from the evaluation of the RP specimen.

Intravesical BCG in patients with carcinoma in situ of the urinary bladder: long-term results of EORTC GU Group phase II protocol 30861.

Objectives: This phase II study was designed to assess the response rate, side effects and long–term efficacy of BCG in the treatment of carcinoma in situ (Cis) of the urinary bladder. Methods: 103 eligible patients with Cis were treated with 6 consecutive weekly intravesical instillations of 120 mg BCG–Connaught. In case of no response, a second 6–week course was given. Results: A complete response (CR) was observed in 77 of the 103 eligible patients (75%) and 93 evaluable patients (83%). In 6 of 10 patients the CR was induced by a second cycle of 6 weekly instillations. After a median follow–up of 7.6 years, 39 of the 77 CR patients (50%) are still alive and have retained their bladder, 31 (40%) without tumor recurrence. Another 7 patients underwent cystectomy and are still alive while 16 (20%) have died due to bladder cancer. Ten patients stopped treatment due to toxicity. In 2 patients, cystectomy was done because of severe cystitis and reduced bladder capacity. Drug cystitis, bacterial cystitis and fever occurred in 45, 15 and 15% of the patients, respectively. Severe drug cystitis was noted in 3 out of 10 patients receiving more than 6 instillations, necessitating cystectomy in 1 case. Conclusion: Intravesical short–term BCG is an effective treatment modality in Cis, yielding a high CR rate. This therapy may however be suboptimal in some patients as the 5–year disease–free rate in complete responders drops to 60%. Still, this is an acceptable result for patients in whom cystectomy would otherwise be performed in virtually all cases.

Some limitations of the radioisotope bone scan in patients with metastatic prostatic cancer : a subanalysis of EORTC trial 30853

This article reviews the serial bone scans of 149 of 327 patients entered into a randomized prospective trial comparing orchidectomy versus zoladex and flutamide in patients with metastatic prostatic cancer. Attention is drawn to the difficulty of evaluating the response rate and of the importance of tumor load in determining survival. The use of sequential bone scans once the diagnosis of metastatic disease has been confirmed is of questionable value as the scans are expensive and contribute little to the further management of the patient in the absence of symptoms requiring relief.

The side effects of Bacillus Calmette-Guerin in the treatment of Ta T1 bladder cancer do not predict its efficacy: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial.

OBJECTIVES Previous publications have suggested that patients developing local and/or systemic side effects to Bacillus Calmette-Guerin (BCG) have a better clinical result, however it is necessary to determine if toxicity is responsible for improved efficacy. METHODS After transurethral resection, intravesical instillations of BCG were given during a 6-week induction course followed by 3-weekly maintenance courses at 3, 6, 12, 18, 24, 30 and 36 months. The prognostic importance of delaying or stopping BCG due to local and/or systemic side effects was assessed in 487 patients. RESULTS Patients with local BCG side effects had a significantly longer time to first recurrence, suggesting that side effects are related to efficacy. However patients with a better outcome remain on study for a longer period of time and receive more BCG, thus increasing their risk to develop side effects. To prove whether toxicity is responsible for improved efficacy, the prognostic importance of toxicity occurring prior to the 6 month instillations was assessed using the landmark method. Neither local nor systemic BCG toxicity prior to 6 months was related to subsequent recurrence. CONCLUSIONS While a correlation between BCG toxicity and efficacy exists, this study does not confirm that BCG toxicity is actually responsible for an improved outcome.

Chemoresection in Ta-T1 bladder cancer. Members of the EORTC Genito-Urinary Group.

OBJECTIVES The authors present the results of two parallel phase II trials, instituted by the EORTC Genito-Urinary Group in 1986, whose aims were to assess the tolerability and ablative capacity of mitomycin C (study 30864) and epirubicin (study 30869) in patients with multiple primary or recurrent Ta-T1 bladder cancer. METHODS A well-defined tumour (marker lesion) was left in the bladder after transurethral resection (TUR). All patients received 8 weekly instillations, after which cystoscopy with bladder biopsies +/- TUR was performed. Responses were rated as follows: (1) complete-no visible or microscopic bladder cancer; (2) no change-persistence of the marker lesion; (3) progression-increased marker lesion size, new tumour(s) or presence of muscle-invasive disease at any site. RESULTS Ninety-six evaluable patients were treated with mitomycin and 36 with epirubicin. The overall bladder response in the former group was complete in 50%, no change in 30% and progression in 20% of patients, while the marker lesion response was complete in 57%, no change in 39% and progression in 4%. In the epirubicin group, 56% of the patients achieved a complete overall response, while there was no change in 22% and progression in 22%. The marker lesion response in this group was complete in 67%, no change in 31% and progression in 3%. Only 2 cases of progression were due to the presence of muscle-invasive disease. Both of these were in the mitomycin group; 1 was at the marker lesion site, and 1 was at a remote site. CONCLUSIONS The present studies confirm the feasibility and safety of the marker lesion model for the objective evaluation of the antitumoural activity of intravesically administered drugs.

Sequential Intravesical Chemoimmunotherapy with Mitomycin C and Bacillus Calmette-Guérin and with Bacillus Calmette-Guérin Alone in Patients with Carcinoma in Situ of the Urinary Bladder: Results of an EORTC Genito-Urinary Group Randomized Phase 2 Trial (30993)

BACKGROUND Bacillus Calmette-Guérin (BCG) is the intravesical treatment of choice for carcinoma in situ (CIS). OBJECTIVE Our aim was to assess if sequential mitomycin C (MMC) plus BCG after transurethral resection (TUR) is worthy of further study in non-muscle-invasive bladder cancer patients with CIS. DESIGN, SETTING, AND PARTICIPANTS In a noncomparative phase 2 study, 96 patients with primary/secondary/concurrent CIS of the urinary bladder were randomized to sequential MMC plus BCG or to BCG alone after TUR. INTERVENTION Patients received six weekly instillations of MMC followed by six weekly instillations of BCG or six weekly instillations of BCG, 3 wk rest, and three further weekly instillations of BCG. Complete responders received three weekly maintenance instillations at 6, 12, 18, 24, 30, and 36 mo in accordance with the initial randomization. MEASUREMENTS End points were complete response (CR) rate at the first control cystoscopy 16-18 wk after start of treatment, disease-free interval, overall survival, and side effects. RESULTS AND LIMITATIONS Ninety-six patients were randomized, 48 to each treatment group. Ten patients were ineligible, and three did not start treatment. In all randomized patients, CR rates on MMC plus BCG and BCG alone were 70.8% and 66.7%, respectively. In 83 eligible patients who started treatment, CR rates were 75.6% and 73.8%, respectively. Based on a median follow-up of 4.7 yr, 25 patients (52.1%) on MMC plus BCG and 22 patients (45.8%) on BCG alone were disease free. Twelve patients stopped treatment due to toxicity: three during induction (two MMC plus BCG, one BCG) and nine during maintenance (three MMC plus BCG, six BCG). CONCLUSIONS In the treatment of patients with CIS, sequential chemoimmunotherapy with MMC plus BCG had acceptable toxicity. CR and disease-free rates were similar to those on BCG alone and to previous publications on sequential chemoimmunotherapy. TRIAL REGISTRATION This study was registered with the US National Cancer Institute clinical trials database (protocol ID: EORTC-30993). http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=68869&version=HealthProfessional&protocolsearchid=7920643.