Giario Conti

Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer patients : Results of an italian prostate cancer project study

PURPOSE To compare the efficacy of bicalutamide monotherapy to maximal androgen blockade (MAB) in the treatment of advanced prostatic cancer. PATIENTS AND METHODS Previously untreated patients with histologically proven stage C or D disease (American Urological Association Staging System) were randomly allocated to receive either bicalutamide or MAB. After disease progression, patients treated with bicalutamide were assigned to castration. The primary end point for this trial was overall survival. Secondary end points included response to treatment, disease progression, treatment safety, quality-of-life (QOL), and sexual function. RESULTS A total of 108 patients received bicalutamide and 112 received MAB. There was no difference in the percentage of patients whose prostate-specific antigen returned to normal levels. At the time of the present analysis (median follow-up time, 38 months; range, 1 to 60 months), 129 patients progressed and 89 died. There was no difference in the duration of either progression-free survival or overall survival. However, a survival trend favored bicalutamide in stage C disease but MAB in stage D disease. Overall and subgroup trends were confirmed by multivariate analysis. Serious adverse events and treatment discontinuations were more common in patients receiving MAB (P =.08 and P =.04, respectively). Fewer patients in the bicalutamide group complained of loss of libido (P =. 01) and of erectile dysfunction (P =.002). Significant trends favored bicalutamide-treated patients also with respect to their QOL, namely relative to social functioning, vitality, emotional well-being, and physical capacity. CONCLUSION Bicalutamide monotherapy yielded comparable results relative to standard treatment with MAB, induced fewer side effects, and produced a better QOL.

Evaluation of Tamoxifen and Anastrozole in the Prevention of Gynecomastia and Breast Pain Induced by Bicalutamide Monotherapy of Prostate Cancer

PURPOSE To determine whether tamoxifen or anastrozole prevents gynecomastia and breast pain caused by bicalutamide (150 mg) without compromising efficacy, safety, or sexual functioning. PATIENTS AND METHODS A double-blind, placebo-controlled trial was performed in patients with localized, locally advanced, or biochemically recurrent prostate cancer. Patients (N = 114) were randomly assigned to either bicalutamide (150 mg/d) plus placebo or in combination with tamoxifen (20 mg/d) or anastrozole (1 mg/d) for 48 weeks. Gynecomastia, breast pain, prostate-specific antigen (PSA), sexual functioning, and serum levels of hormones were assessed. RESULTS Gynecomastia developed in 73% of patients in the bicalutamide group, 10% of patients in the bicalutamide-tamoxifen group, and 51% of patients in the bicalutamide-anastrozole group (P < .001); breast pain developed in 39%, 6%, and 27% of patients, respectively (P = .006). Baseline PSA level decreased by > or = 50% in 97%, 97%, and 83% of patients in the bicalutamide, bicalutamide-tamoxifen, and bicalutamide-anastrozole groups, respectively (P = .07); and adverse events were reported in 37%, 35%, and 69% of patients, respectively (P = .004). There were no major differences among treatments in sexual functioning parameters from baseline to month 6. Elevated testosterone levels occurred in each group; however, free testosterone levels remained unchanged in the bicalutamide-tamoxifen group because of increased sex hormone-binding globulin levels. CONCLUSION Anastrozole did not significantly reduce the incidence of bicalutamide-induced gynecomastia and breast pain. In contrast, tamoxifen was effective, without increasing adverse events, at least in the short-term follow-up. These data support the need for a larger study to determine any effect on mortality.

Intravesical mitomycin C combined with hyperthermia for patients with T1G3 transitional cell carcinoma of the bladder

OBJECTIVES Non-muscle invasive bladder cancer (NMIBC) classified as T1G3 represents one of the most challenging issues in urologic oncology. Although it is still considered a lesion amenable for conservative management, the risk for recurrence and progression remains high. The aim of this study was to define both recurrence and progression rate in patients with T1G3 UCC treated by complete transurethral resection (TURT) and adjuvant thermochemotherapy approach. MATERIALS AND METHODS We retrospectively evaluated the clinical data of patients with T1G3 NMIBC who underwent TURT followed by thermochemotherapy (TCT) treatment. Data recorded included age, gender, previous resections, previous intravesical treatment, time to tumor recurrence, and progression. TCT was given once weekly for 6 consecutive weeks, followed by 6 maintenance sessions at 4 to 6 weeks intervals. During each treatment session, 40 mg of mitomycin C (MMC) was instilled into the bladder in combination with bladder wall hyperthermia of 42 ± 2 °C for 60 minutes. Follow-up cystoscopy and urinary cytology were performed every 3 months for the first 2 years and than biannually. RESULTS A total of 56 T1G3 patients were treated with adjuvant TCT treatment at 7 urologic centers. Mean age was 68 years (range 35-91), 10 were females and 46 were males. Twenty-six patients failed on at least 1 previous intravesical treatment. Five patients who dropped out due to adverse events before reaching the first outcome evaluation cystoscopy were referred to another intravesical therapy, and were therefore excluded from the current analysis. A total 51 patients were available for analysis. Median follow-up time of tumor-free patients was 18 months (average 20, range 2-49 months). Seventeen patients (33.3%) had tumor recurrence and 4 of them progressed to muscle invasive disease. The median time to recurrence was 9 months (average 11, range 2-31 months). The Kaplan-Meier estimated recurrence rate for this group is: 42.9% at 2 years, 51.0% at 4 years. CONCLUSIONS TCT can be an effective adjuvant treatment option after TURT to prevent recurrence in patients with T1G3 NMIBC. Progression rate after this treatment was low (7.9%). TCT treatment was documented to be effective also in those who failed previous intravesical BCG. Treatment was confirmed to be safe and well tolerated.

An Open, Randomised, Multicentre, Phase 3 Trial Comparing the Efficacy of Two Tamoxifen Schedules in Preventing Gynaecomastia Induced by Bicalutamide Monotherapy in Prostate Cancer Patients

BACKGROUND Bicalutamide monotherapy is a valuable option for prostate cancer (PCa) patients who wish to avoid the consequences of androgen deprivation; however, this treatment induces gynaecomastia and mastalgia in most patients. Tamoxifen is safe and effective in preventing breast events induced by bicalutamide monotherapy without affecting antitumor activity, but possible interference between bicalutamide and tamoxifen remains a matter of concern. To reduce the exposure to tamoxifen, we considered the putative advantages of weekly administration. OBJECTIVE To compare the efficacy of two different schedules of tamoxifen in preventing breast events. Toxicity, prostate-specific antigen behaviour, and sexual-functioning scores were also evaluated. DESIGN, SETTING, AND PARTICIPANTS This was a noninferiority trial. From December 2003 to February 2006, 80 patients with localised/locally advanced or biochemically recurrent PCa who were also candidates for bicalutamide single therapy were randomised to receive two different schedules of tamoxifen: daily (n=41) and weekly (n=39). Median follow-up was 24.2 mo. INTERVENTION Daily bicalutamide (150 mg) plus daily tamoxifen 20mg continuously (daily group) or the same but with tamoxifen at 20mg weekly after the first 8 wk of daily treatment (weekly group). Three patients in the weekly group and one in the daily group were discontinued for adverse events. MEASUREMENTS For gynaecomastia, we used ultrasonography. For mastalgia and sexual functioning, we used questionnaires. RESULTS AND LIMITATIONS Gynaecomastia developed in 31.7% of patients in the daily group and in 74.4% of patients in the weekly group (p<0.0001), and it was more severe in patients who switched to weekly tamoxifen (p=0.001). Mastalgia occurred in 12.2% and 46.1% of patients, respectively (p=0.001). There were no major differences among treatment schedules relative to sexual functioning scores and incidence and severity of adverse events. No differences between groups in PSA behaviour and disease progression have been detected so far. CONCLUSIONS This study demonstrated that tamoxifen 20mg/wk is inferior to tamoxifen 20mg/d in preventing the incidence and severity of bicalutamide-induced breast events. The safety and efficacy of tamoxifen at the common daily dose of 20mg for the prophylaxis of bicalutamide-induced breast events were confirmed.

Prednisone plus Gefitinib versus Prednisone plus Placebo in the Treatment of Hormone-Refractory Prostate Cancer: A Randomized Phase II Trial

Background: Abnormal epidermal growth factor receptor expression and pre-clinical data prompted us to investigate the activity of gefitinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, in hormone-refractory prostate cancer. Methods: Eighty-two patients were randomly assigned to receive prednisone plus gefitinib (pG; n = 44) or prednisone plus placebo (ppl; n = 38). On progression, patients initially assigned to placebo were offered the possibility to receive gefitinib. Best prostate-specific antigen response was the primary endpoint. Results: At a median follow-up time of 29.0 months (26.0–32.0), 77 patients progressed and 51 died. Prostate-specific antigen response was recorded in 6/38 (15.8%; 95% CI 4.2–27.4) and in 5/44 (11.4%; 95% CI 2.0–20.8) patients in pG and ppl groups, respectively. There was no difference between groups in time to progression (median pG 4.0 months, range 3.5–4.5; median ppl 4.5 months, range 3.5–5.0) and survival (median pG 26.5 months, range 16.0–37.0; median ppl 20.5 months, range 14.0–27.0). Adverse events occurred in 19 patients in each arm and were generally mild. Conclusions: pG showed a good tolerability profile but only a limited therapeutic activity in hormone-refractory prostate cancer.

Diagnostic imaging to detect and evaluate response to therapy in bone metastases from prostate cancer: current modalities and new horizons

Different therapeutic options for the management of prostate cancer (PC) have been developed, and some are successful in providing crucial improvement in both survival and quality of life, especially in patients with metastatic castration-resistant PC. In this scenario, diverse combinations of radiopharmaceuticals (for targeting bone, cancer cells and receptors) and nuclear medicine modalities (e.g. bone scan, SPECT, SPECT/CT, PET and PET/CT) are now available for imaging bone metastases. Some radiopharmaceuticals are approved, currently available and used in the routine clinical setting, while others are not registered and are still under evaluation, and should therefore be considered experimental. On the other hand, radiologists have other tools, in addition to CT, that can better visualize bone localization and medullary involvement, such as multimodal MRI. In this review, the authors provide an overview of current management of advanced PC and discuss the choice of diagnostic modality for the detection of metastatic skeletal lesions in different phases of the disease. In addition to detection of bone metastases, the evaluation of response to therapy is another critical issue, since it remains one of the most important open questions that a multidisciplinary team faces when optimizing the management of PC. The authors emphasize the role of nuclear modalities that can presently be used in clinical practice, and also look at future perspectives based on relevant clinical data with novel radiopharmaceuticals.

Management of metastatic castration-resistant prostate cancer: A focus on radium-223: Opinions and suggestions from an expert multidisciplinary panel

Radium-223, a calcium mimetic bone-seeking radionuclide that selectively targets bone metastases with alpha particles, is approved for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) and symptomatic bone metastases. In patients with mCRPC, treatment with radium-223 has been associated with survival benefit, regardless of prior docetaxel use, and also has a positive impact on symptomatic skeletal events and quality of life. Radium-223 is best suited for patients with symptomatic mCRPC and bone-predominant disease and no visceral metastases, and may lead to better outcomes when given early in the course of the disease. An expert multidisciplinary panel convened in Milan, Italy to review the current best-evidence literature on radium-223 and to convey their personal expertise with the use of radium-223 and identify possible strategies for best practice. This article summarizes the best available evidence for the use of radium-223, discusses the essential role of the multidisciplinary team in delivering effective treatment for mCRPC, clarifies pre- and post-treatment evaluation and monitoring, and outlines future scenarios for radium-223 in the treatment of men with MCRPC.

New Italian guidelines on bladder cancer, based on the World Health Organization 2004 classification

To provide evidence‐based recommendations on bladder cancer management

Influence of bicalutamide with or without tamoxifen or anastrozole on insulin-like growth factor 1 and binding proteins in prostate cancer patients.

BACKGROUND There is growing evidence that IGF-1 and binding proteins may be involved in prostate cancer promotion and progression. PATIENTS AND METHODS IGF-1 and binding proteins (IGFBP-1 and 3) serum levels were measured at baseline and after 3 and 6 months of treatment in a selected group of patients with prostate cancer who were randomly assigned to treatment with bicalutamide, bicalutamide plus anastrozole or bicalutamide plus tamoxifen in a comparative study investigating the role of pharmacological medication in the development of bicalutamide-induced gynecomastia. RESULTS Bicalutamide monotherapy does not appear to alter the IGF-1/IGFBP system. In fact, the increase in IGF-1 levels induced by this treatment was paralleled by comparable increases in binding protein (IGFBP-3). No major changes from baseline up to month 6 either in IGF-1 or in IGFBP-1 and 3 were observed in the bicalutamide plus anastrozole arm. The addition of tamoxifen to bicalutamide produced a sharp decrease in IGF-1 levels (p<0.001) coupled with an increase in both IGFBP-1 (p=0.001) and, to a lesser extent, IGFBP-3 (p=0.5). CONCLUSIONS The concurrent administration of tamoxifen and bicalutamide reduces the synthesis and bioavailability of IGF-1. Moreover, increased binding protein levels might exert antiproliferative and proapoptotic effects on prostate cancer cells, independently of the IGF-1/IGF receptor-mediated survival system. Both effects might have a synergistic inhibitory influence on prostate cancer growth.

Feasibility and Clinical Roles of Different Substaging Systems at First and Second Transurethral Resection in Patients with T1 High-Grade Bladder Cancer

BACKGROUND Decision making in T1 high-grade bladder cancer patients remains a challenging issue in urologic practice. OBJECTIVE To assess the feasibility and potential prognostic role of three different substaging systems in specimens from both primary and second transurethral resection (TUR) of the bladder in T1 high-grade bladder cancer patients. DESIGN, SETTING, AND PARTICIPANTS A total of 250 consecutive, confirmed pure transitional T1 high-grade bladder tumors submitted to second TUR entered the retrospective study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Feasibility of two already clinically tested microstaging systems (anatomy-based T1a/T1b/T1c and micrometric T1m/T1e with 0.5-mm thresholds of invasion) and that of a micrometric substage designed by the authors and based on a 1-mm threshold of invasion (Rete Oncologica Lombarda [ROL] system) was assessed by five independent uropathologists on both first and second TUR specimens. Univariable Cox proportional hazards models were attempted to identify significant independent predictors of recurrence and progression after TUR. Kaplan-Meier curves were plotted to compare different substaging methods analyzing recurrence and progression. RESULTS AND LIMITATIONS The ROL system proved to be feasible in nearly all cases at both first and second TUR. Median follow-up was 60 mo. The univariate Cox regression analysis documented the ROL substage (ROL2 vs ROL1) to be the only statistically significant predictor of progression (hazard ratio: 2.01; 95% CI, 1.03-3.79; p<0.03). For the first time to our knowledge, the substage was investigated and used to assess T1 tumors found at second TUR, registering a high rate of feasibility. CONCLUSIONS T1 microstaging using different procedures is feasible on both primary- and second-TUR specimens. A high rate of feasibility may be expected for T1m/T1e and ROL systems. The clinical role of microstaging on second TUR remains to be defined. PATIENT SUMMARY The Rete Oncologica Lombarda system showed feasible results in T1 high-grade bladder tumors. Our substratification was predictive of progression of disease.