Fabrizio Verweij

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.

In vitro synergistic cytotoxicity of gemcitabine and pemetrexed and pharmacogenetic evaluation of response to gemcitabine in bladder cancer patients

The present study was performed to investigate the capability of gemcitabine and pemetrexed to synergistically interact with respect to cytotoxicity and apoptosis in T24 and J82 bladder cancer cells, and to establish a correlation between drug activity and gene expression of selected genes in tumour samples. The interaction between gemcitabine and pemetrexed was synergistic; indeed, pemetrexed favoured gemcitabine cytotoxicity by increasing cellular population in S-phase, reducing Akt phosphorylation as well as by inducing the expression of a major gemcitabine uptake system, the human equilibrative nucleoside transporter-1 (hENT1), and the key activating enzyme deoxycytidine kinase (dCK) in both cell lines. Bladder tumour specimens showed an heterogeneous gene expression pattern and patients with higher levels of dCK and hENT1 had better response. Moreover, human nucleoside concentrative transporter-1 was detectable only in 3/12 patients, two of whom presented a complete response to gemcitabine. These data provide evidence that the chemotherapeutic activity of the combination of gemcitabine and pemetrexed is synergistic against bladder cancer cells in vitro and that the assessment of the expression of genes involved in gemcitabine uptake and activation might be a possible determinant of bladder cancer response and may represent a new tool for treatment optimization.

Results of a Randomised Controlled Trial Comparing Intravesical Chemohyperthermia with Mitomycin C Versus Bacillus Calmette-Guérin for Adjuvant Treatment of Patients with Intermediate- and High-risk Non–Muscle-invasive Bladder Cancer

BACKGROUND Despite adjuvant intravesical therapy, recurrences in non-muscle-invasive bladder cancer (NMIBC) are still high; therefore, new treatment options are needed. The use of chemohyperthermia (CHT) as an alternative treatment is expanding in Europe. To date, however, there has been a lack of prospective randomised data. OBJECTIVE To compare CHT using mitomycin C (MMC) with bacillus Calmette-Guérin (BCG) as adjuvant treatment for intermediate- and high-risk NMIBC. DESIGN, SETTING, AND PARTICIPANTS Between 2002 and 2012, 190 NMIBC patients were randomised in this controlled, open-label, multicentre trial for 1-yr CHT (six weekly treatments and six maintenance treatments) and 1-yr BCG immunotherapy (six weekly treatments and three weekly maintenance treatments at months 3, 6, and 12). Patients and physicians giving the interventions were aware of assignment. This study is registered with ClinicalTrials.gov (NCT00384891). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was 24-mo recurrence-free survival (RFS) in the intention-to-treat (ITT) and per-protocol (PP) analyses in all papillary NMIBC patients (n=147). Analyses were done with the log-rank test and Fisher exact test. All tests were two-sided. RESULTS AND LIMITATIONS The 24-mo ITT RFS was 78.1% in the CHT group compared with 64.8% in the BCG group (p=0.08). The 24-mo RFS in the PP analysis was 81.8% in the CHT group compared with 64.8% in the BCG group (p=0.02). Progression rates were <2% in both groups. Regarding the side-effects, no new safety concerns were identified. A concern is that this study closed prematurely and thus is underpowered. Furthermore, blinding of treatment for patients and physicians was impossible; this may have resulted in unavoidable bias. CONCLUSIONS CHT is a safe and effective treatment option in patients with intermediate- and high-risk papillary NMIBC. A significantly higher 24-mo RFS in the CHT group was seen in the PP analysis. Based on the results above, CHT is an option for BCG therapy as adjuvant treatment for intermediate- and high-risk papillary NMIBC. PATIENT SUMMARY Recurrences in non-muscle-invasive bladder cancer are common, despite adjuvant therapies. We compared 24-mo recurrence-free survival (RFS) with chemohyperthermia (CHT) versus bacillus Calmette-Guérin (BCG) therapy. According to these data, CHT therapy appears to be safe and has higher 24-mo RFS than BCG therapy.

Circulating Levels of VCAM and MMP-2 May Help Identify Patients with More Aggressive Prostate Cancer

BACKGROUND Prostate adenocarcinoma is generally characterized by slow progression although some phenotypes have a more aggressive behavior with tendency to local invasion and distant metastases, mainly to bones. Better specific care could be provided to the aggressive phenotype-group of patients if pre-surgical identification were available. MATERIAL AND METHODS Correlations between pre-surgical levels of 6 blood molecules and pathological tumour staging, post-surgical Gleason score and disease-free survival have been observed. Plasma and sera from 162 men affected by prostate adenocarcinoma were analysed with ELISA to assess levels of neovascularization-related molecule (VEGF), endothelial cell adhesion molecule (VCAM), extracellular matrix destruction-related molecules (MMP-2, MMP-9), and tissue inhibitors of metalloproteinase (TIMP-1 and TIMP-2). RESULTS The median values of serum determinations were for VEGF 279 pg/ml, VCAM 633 ng/ml, MMP-2 206 ng/ml and MMP-9 614 ng/ml. Plasma medians (ng/ml) were 94 for TIMP-1 and 90 for TIMP-2. Patients with VCAM values > 633 ng/ml had a worse disease-free survival than patients with values <633 ng/ml with an adjusted Hazard Ratio of 2.1, significant (95% confidence interval 0.8-5.6). Patients with levels of MMP-2 < 206 ng/ml showed an increased risk of progression (adjusted HR 1.7; 95% C.I. 0.6-4.8). CONCLUSIONS Levels of VCAM and MMP-2 should be checked in patients with prostate adenocarcinoma, because distant spread is more likely to occur in patients with high levels of VCAM and low levels of MMP-2. The scientific community should further investigate impact on prognosis of VCAM and MMP-2.

Intraoperative radiotherapy during radical prostatectomy for intermediate‐risk to locally advanced prostate cancer: treatment technique and evaluation of perioperative and functional outcome vs standard radical prostatectomy, in a matched‐pair analysis

To evaluate a novel approach with intraoperative radiotherapy (IORT) administered in the surgical field, after pelvic lymphadenectomy (PL) and before radical retropubic prostatectomy (RRP), evaluating acute and late toxicity, complications and biochemical progression‐free survival (bPFS), as the adequate treatment of locally advanced prostate cancer is still a controversial issue.

Localization of Avidin in Superficial Bladder Cancer: A Potentially New Approach for Radionuclide Therapy

OBJECTIVE To verify whether native avidin, made radioactive through the binding with technetium-99m labeled biotin (99mTc-biotin), selectively accumulated in superficial tumor tissues following intravesical administration. METHODOLOGY A total of fifteen patients with transitional cell bladder cancer were instilled intravesically with radiolabeled avidin. Cold biopsies were obtained from macroscopically normal and tumor tissues before transurethral resection (TUR) and the radioactivity in the samples was measured. RESULTS Increased accumulation of radiolabeled avidin was observed in tumor tissue compared to normal bladder tissue and in some cases, remarkably high quotients of uptake (q) in tumor versus normal tissues were determined (86 and 44). The three patients instilled with a deglycosylated avidin at neutral pI, who served as a control, showed no significant uptake in either tumor or normal urothelium and no difference in relative uptake (q=1.0). CONCLUSION This pilot study indicated that intravesical administration of radiolabeled avidin resulted in a preferential accumulation in tumor tissue compared to normal urothelium. The instillation of radiolabeled avidin warrant further investigations in order to explore the possibility to treat superficial bladder neoplasms locally by replacing 99mTc with high energy beta emitting radionuclides associated with biotin.

Phase II trial of estramustine phosphate and oral etoposide in patients with hormone-refractory prostate cancer

BACKGROUND There is a need for active agents with a better safety profile than docetaxel, yet good activity, for patients with hormone-refractory prostate cancer (HRPC). We carried out a phase II trial to determine the activity and safety of estramustine plus oral etoposide in HRPC. PATIENTS AND METHODS Patients were given estramustine (280 mg twice daily) and etoposide (100 mg/day, days 1-21) in 28-day cycles until disease progression or unacceptable toxicity. Primary end points were overall response rate and safety, as determined by prostate-specific antigen (PSA) levels and lesion assessment. RESULTS From November 2001 to February 2007, 75 patients were enrolled. All patients were assessable for safety; 17 (22.6%) had grade 3/4 toxicity. PSA response was assessable in 69, 14 of whom had a >50% reduction in PSA. Of 10 patients with one or more measurable lesions, two (20%) had partial response and two (20%) disease stabilization. Overall, median time to progression was 4.4 months (range 1 week-43 months); median survival was 23 months (range 3 weeks-64+ months). CONCLUSIONS Estramustine plus etoposide is active and has a manageable safety profile in patients with HRPC. In asymptomatic patients with nonaggressive disease this combination could be useful to delay the start of more demanding treatments.

Gefitinib combined with endocrine manipulation in patients with hormone-refractory prostate cancer: quality of life and surrogate markers of activity.

We investigated efficacy of gefitinib in hormone-refractory prostate cancer. Between March 2003 and December 2004, 23 patients with hormone-refractory prostate cancer were assigned to receive 250 mg oral gefitinib daily in addition to antiandrogen and luteinizing hormone-releasing hormone analogue for at least 2 months or until disease progression. Patients with progression stopped antiandrogen therapy, and received gefitinib and the luteinizing hormone-releasing hormone analogue. Serum HER2 and epidermal growth factor receptor extracellular domain were evaluated every 2 months. Gefitinib treatment did not result in any objective measurable response or responses in prostate-specific antigen. Median time to progression was 70 days (33–336). Median overall survival was 293 days (25–75 percentile: 235–349). HER2 extracellular domain mean value was 9.6 ng/ml (range 6.9–13.3) at basal time and was 10.1 (range 6.0–14.1) after 2 months. Epidermal growth factor receptor mean basal value was 51.0 ng/ml (range 41.4–75.3). After 2 months of treatment the mean value was 51.1 ng/ml (range 41.5–61.4). One patient had reduction in the pain score from baseline without an increase in the analgesic score. Four patients (17%) out of 23 had pain progression with an increase from baseline of at least 25% in the analgesic score. The study was discontinued before target accrual was reached owing to lack of efficacy of the drug. Our results do not support the efficacy of gefitinib in combination with endocrine treatment for hormone-refractory prostate cancer.

Metachronous bladder metastases from renal cell carcinoma: a case report and review of the literature

Introduction: adrenal gland, parotid gland, pharynx, eye and bladder are rare localizations of metastases of renal cell carcinoma (RCC). We report a case of metachronous RCC metastases to the bladder in a patient with a medical history of transitional cell carcinoma (TCC) of the bladder. Materials and methods: a case study and review of the relevant literature are presented. Results: during a follow-up cystoscopy examination following treatment of TCC, a single 5-mm lesion was detected and endoscopically resected. The histology of the resected sample was confirmed to be RCC, comparable to a primary kidney cancer and not recurrent TCC. Conclusion: the patient had a probability of metastases three years after nephrectomy of 62.9%. Survival rates following single metastasectomy are 60% and 38% at three and five years, respectively; metachronous diagnosis has a better prognosis than synchronous. During RCC follow-up, each lesion should be considered as a possible metastasis of RCC.

INTRAOPERATIVE RADIOTHERAPY FOR LOCALLY ADVANCED PROSTATE CANCER: THE EXPERIENCE OF THE EUROPEAN INSTITUTE OF ONCOLOGY

521 INTRAOPERATIVE RADIOTHERAPY FOR LOCALLY ADVANCED PROSTATE CANCER: THE EXPERIENCE OF THE EUROPEAN INSTITUTE OF ONCOLOGY Andrea Vavassori*, Mario Ciocca, Barbara Jereczek, Dario Zerini, Giovanni Ivaldi, Cristiana Fodor, Roberta Lazzari, Federica Cattani, Elena Rondi, Cristina Garibaldi, Raffaella Cambria, Victor Matei, Epifanio Scardino, Fabrizio Verweij, Gennaro Musi, Bernardo Rocco, Ottavio De Cobelli, Roberto Orecchia. Milan, Italy. INTRODUCTION AND OBJECTIVE: To present the technique adopted for intraoperative radiotherapy (IORT) for locally advanced prostate cancer. METHODS: Between June 2005 and February 2007, 24 patients (pts) with non-metastatic prostate cancer were treated with IORT before prostatectomy as part of their surgical procedure. Median