Survival and toxicity of weekly cisplatin chemoradiotherapy versus three-weekly cisplatin chemoradiotherapy for head and neck cancer: A systematic review and meta-analysis endorsed by the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

PURPOSE: To evaluate efficacy and toxicity of weekly cisplatin chemoradiotherapy versus three-weekly cisplatin chemoradiotherapy and identify differences in clinical outcomes and severe toxicity rate. METHODS: PICOS/PRISMA methods were used to identify studies on PubMed, EMBASE and Cochrane Library, 2005-2019. RESULTS: Six randomized clinical trials (554 patients) were identified. Weekly cisplatin was not associated with significant overall survival (HR 1.13, 95 % CI 0.84-1.51) and progression-free survival (HR 1.23, 95 %CI 0.91-1.65) improvement compared with three-weekly regimen. Severe acute toxicity (RR 0.95), treatment compliance to chemotherapy (RR 1.67) and radiotherapy (RR 0.61) were similar between regimens. CONCLUSION: Weekly cisplatin is not associated with better clinical outcomes compared to three-weekly cisplatin. Three-weekly cisplatin chemoradiotherapy should be considered the standard approach in the management of locally advanced head and neck cancer. Methodologically robust RCTs designs are needed to improve the quality of evidence. Differences on long-term toxicity and cost-effectiveness remain to be tested.

Sequential chemo-hypofractionated RT versus concurrent standard CRT for locally advanced NSCLC: GRADE recommendation by the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

INTRODUCTION: Almost 30% of non-small cell lung cancer (NSCLC) patients have locally advanced-stage disease. In this setting, definitive radiotherapy concurrent to chemotherapy plus adjuvant immunotherapy (cCRT + IO) is the standard of care, although only 40% of these patients are eligible for this approach. AIMS: A comparison between cCRT and hypofractionated radiotherapy regimens (hypo-fx RT) with the addition of sequential chemotherapy (sCHT) could be useful for future combinations with immunotherapy. We developed a recommendation about the clinical question of whether CHT and moderately hypo-fx RT are comparable to cCRT for locally advanced NSCLC MATERIALS AND METHODS: The panel used GRADE methodology and the Evidence to Decision (EtD) framework. After a systematic literature search, five studies were eligible. We identified the following outcomes: progression-free survival (PFS), overall survival (OS), freedom from locoregional recurrence (FFLR), deterioration of quality of life (QoL), treatment-related deaths, severe G3-G4 toxicity, late pulmonary toxicity G3-G4, and acute esophageal toxicity G3-G4. RESULTS: The probability of OS and G3-G4 late lung toxicity seems to be worse in patients submitted to sCHT and hypo-fx RT. The panel judged unfavorable the balance benefits/harms. CONCLUSIONS: The final recommendation was that sCHT followed by moderately hypo-fx RT should not be considered as an alternative to cCRT in unresectable stage III NSCLC patients.

Treatment of muscle-invasive bladder cancer in patients without comorbidities and fit for surgery: Trimodality therapy vs radical cystectomy. Development of GRADE (Grades of Recommendation, Assessment, Development and Evaluation) recommendation by the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

AIM: To compare trimodality therapy (TMT) versus radical cystectomy (RC) and develop GRADE (Grades of Recommendation, Assessment, Development and Evaluation) Recommendation by the Italian Association of Radiotherapy and Clinical Oncology (AIRO) for treatment of muscle-invasive bladder cancer (MIBC). MATERIAL AND METHODS: Prospective and retrospective studies comparing TMT and RC for MIBC patients were included. Qualitative and quantitative evaluation of evidence was made. RESULTS: Ten studies were included in the analysis. Pooled analysis showed salvage cystectomy and pathological complete response rates after TMT of 12 % and 72-77.5 %, respectively. Pooled rates of G3-G4 GU toxicity and serious toxicity rate were 18 vs 3% and 45 vs 29 % for patients undergoing TMT vs RC, respectively. The panel assessed a substantial equivalence in terms of OS and CSS at 5 years between TMT and RC. CONCLUSIONS: TMT could be suggested as an alternative treatment to RC in non-metastatic MIBC patients, deemed fit for surgery.

Loco-regional adjuvant radiation therapy in breast cancer patients with positive axillary lymph-nodes at diagnosis (CN2) undergoing preoperative chemotherapy and with complete pathological lymph-nodes response. Development of GRADE (Grades of recommendation, assessment, Development and Evaluation) recommendation by the Italian Association of radiation therapy and Clinical Oncology (AIRO).

OBJECTIVE: To perform a meta-analysis to determine the effect of loco-regional radiation therapy (RT) compared to no loco-regional RT for operated patients in clinical stage cN2 breast cancer at diagnosis and ypN0 after preoperative chemotherapy (PST). MATERIAL AND METHODS: Eligible studies were identified through a systematic search of the medical literature performed independently by two researchers using a validated search strategy. An electronic search of Medline via PubMed and Embase (Breast cancer AND preoperative chemotherapy AND radiation therapy) was conducted with no language or publication status restrictions. The effect of loco-regional RT on overall (OS), disease free (DFS), loco-regional recurrence-free (LRRFS) survival and local recurrence was evaluated. An electronic search of Medline via PubMed and Embase (Toxicity AND radiation therapy breast cancer AND preoperative therapy; toxicity AND breast surgery AND preoperative chemotherapy) was conducted for outcomes of harm: major acute and late skin toxicity, lymphedema and cardiac events. RESULTS: Of 333 studies identified, 4 retrospective studies reporting on a total of 1107 patients were included in the meta-analysis. Six and 3 reported data of acute and late skin toxicity, while 2 studies provided information on cardiac events. Pooled results showed no difference in terms of hazard ratio for loco-regional RT versus no loco-regional RT [hazard ratio (HR) = 0.82, 95% confidence interval (CI) 0.63-1.68]. Loco-regional RT was associated with an OS benefit in the subgroup analysis: IIIB-C (loco-regional RT 79.3% vs no loco-regional RT 71.2%, p = 0.027) and T3-T4 (loco-regional RT 82.6% vs no loco-regional RT 76.6%, p = 0.025). No difference was shown in terms of 5-year DFS (loco-regional RT 91.2% vs no loco-regional RT 83%, p = 0.441) and LRRFS (loco-regional RT 98.1% vs no loco-regional RT 92.3%, p = 0.148). There was no significant difference between the groups in terms of acute and late skin toxicities, lymphedema and cardiac events. CONCLUSIONS: Because of the limitations due to the small number of studies and heterogeneity in the analysis, the present study does not allow to draw any definitive conclusion, highlighting the need for well-controlled trials to determine the effect of loco-regional RT in patients with cN2 having a pathological complete response in the axillary nodes after preoperative chemotherapy.

Post-operative management of brain metastases: GRADE-based clinical practice recommendations on behalf of the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

PURPOSE: To perform a systematic review of the current level of evidence on post-operative management following brain metastasectomy (namely: adjuvant stereotactic radiosurgery, whole brain radiotherapy or observation), and to propose a GRADE-based dedicated recommendation to inform Radiation Oncologists' clinical practice. METHODS: A panel of expert Radiation Oncologists from the Italian Association of Radiotherapy and Clinical Oncology had defined the search question per the PICO methodology. Electronic databases were independently screened; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses was adopted. The individual and pooled hazard ratios with 95% confidence intervals (CI), as well as the pooled risk ratio (RR) were calculated using a fixed- or random-effects model. RESULTS: Eight full-texts were retrieved: six retrospective studies and two randomized clinical trials. Outcomes of benefit and damage were analyzed for SRS + observation (PICO A) and SRS + WBRT. SRS allowed for increased rates of local control when compared to both observation and WBRT, while evidence was less conclusive for distant brain control, leptomeningeal disease control and overall survival. In the SRS, the incidence of severe radionecrosis was higher as compared to WBRT, despite neurocognitive deterioration rates were lower. Overall, SRS seems to favorably compare with observation and whole brain RT, despite the level of evidence for the recommendation was low and very low, respectively. CONCLUSION: Despite low level of evidence, the panel concluded that the risk/benefit ratio probably favors adjuvant SRS as compared to the observation and whole brain RT as adjuvant treatments following brain metastasectomy (5 votes/5 participants, 100% attendance).

Consensus statements on ablative radiotherapy for oligometastatic prostate cancer: A position paper of Italian Association of Radiotherapy and Clinical Oncology (AIRO).

Oligometastatic prostate cancer comprises a wide spectrum of conditions, ranging from de novo oligometastatic cancer at diagnosis to oligometastatic castration-resistant disease, which are distinct entities in terms of biology and prognosis. In order to clarify and standardize the clinical role of ablative radiotherapy in oligometastatic prostate cancer, the Italian Association of Radiotherapy and Clinical Oncology (AIRO) formed an expert panel to review the current literature and develop a formal consensus. Oligometastatic prostate cancer was defined as the presence of up to three metastatic lesions involving bones or nodes outside pelvis. Thereafter, four clinical scenarios were explored: metastatic castration-sensitive disease at diagnosis and after primary treatment, and metastatic castration-resistant disease at diagnosis and during treatment, where the role of ablative radiotherapy was defined either in conjunction with systemic therapy or as the only treatment in selected cases. This paper summarizes the current literature about these issues and the proposed recommendations.

Treating advanced breast cancer with metronomic chemotherapy: what is known, what is new and what is the future?

The prognosis for patients with locally advanced or metastatic breast cancer (mBC) remains poor, with a median survival of 2-4 years. About 10% of newly diagnosed breast cancer patients present with metastatic disease, and 30%-50% of those diagnosed at earlier stages will subsequently progress to mBC. In terms of ongoing management for advanced/metastatic breast cancer after failure of hormonal therapy, there is a high medical need for new treatment options that prolong the interval to the start of intensive cytotoxic therapy, which is often associated with potentially serious side effects and reduced quality of life. Oral chemotherapeutic agents such as capecitabine and vinorelbine have demonstrated efficacy in patients with mBC, with prolonged disease control and good tolerability. Use of oral chemotherapy reduces the time and cost associated with treatment and is often more acceptable to patients than intravenous drug delivery. Metronomic administration of oral chemotherapy is therefore a promising treatment strategy for some patients with mBC and inhibits tumor progression via multiple mechanisms of action. Ongoing clinical trials are investigating metronomic chemotherapy regimens as a strategy to prolong disease control with favorable tolerability. This article provides an overview of metronomic chemotherapy treatment options in mBC, with perspectives on this therapy from a panel of experts.

A randomized, open-label, multicenter study of the efficacy and safety of intravesical hyaluronic acid and chondroitin sulfate versus dimethyl sulfoxide in women with bladder pain syndrome/interstitial cystitis.

AIMS: Intravesical instillation of hyaluronic acid (HA) plus chondroitin sulfate (CS) in women with bladder pain syndrome/interstitial cystitis (BPS/IC) has shown promising results. This study compared the efficacy, safety, and costs of intravesical HA/CS (Ialuril® , IBSA) to dimethyl sulfoxide (DMSO). METHODS: Randomized, open-label, multicenter study involving 110 women with BPS/IC. The allocation ratio (HA/CS:DMSO) was 2:1. Thirteen weekly instillations of HA (1.6%)/CS (2.0%) or 50% DMSO were given. Patients were evaluated at 3 (end-of-treatment) and 6 months. Primary endpoint was reduction in pain intensity at 6 months by visual analogue scale (VAS) versus baseline. Secondary efficacy measurements were quality of life and economic analyses. RESULTS: A significant reduction in pain intensity was observed at 6 months in both treatment groups versus baseline (P < 0.0001) in the intention-to-treat population. Treatment with HA/CS resulted in a greater reduction in pain intensity at 6 months compared with DMSO for the per-protocol population (mean VAS reduction 44.77 ± 25.07 vs. 28.89 ± 31.14, respectively; P = 0.0186). There were no significant differences between treatment groups in secondary outcomes. At least one adverse event was reported in 14.86% and 30.56% of patients in the HA/CS and DMSO groups, respectively. There were significantly fewer treatment-related adverse events for HA/CS versus DMSO (1.35% vs. 22.22%; P = 0.001). Considering direct healthcare costs, the incremental cost-effectiveness ratio of HA/CS versus DMSO fell between 3735€/quality-adjusted life years (QALY) and 8003€/QALY. CONCLUSIONS: Treatment with HA/CS appears to be as effective as DMSO with a potentially more favorable safety profile. Both treatments increased health-related quality of life, while HA/CS showed a more acceptable cost-effectiveness profile.

Concurrent gemcitabine and radiotherapy for the treatment of muscle-invasive bladder cancer: A pooled individual data analysis of eight phase I-II trials.

PURPOSE: Although radical cystectomy is still considered the standard of care for most localized muscle-invasive bladder cancer (MIBC) patients, bladder-sparing strategies with chemoradiotherapy have demonstrated comparable local control and survival rates when adjusting for tumor stage. We present a pooled analysis of individual patient data out of published trials with gemcitabine-based chemoradiotherapy for MIBC. METHODS AND MATERIALS: Individual patient data were collected from Institutions that enrolled patients into trials that evaluated gemcitabine-based chemoradiotherapy for MIBC. RESULTS: We identified eight studies published on gemcitabine-based radiochemotherapy and 190 patients were included in this analysis. A complete response (CR) was observed in 166 patients (93%). After a median follow up of 44.5months, 36 patients (18.9%) presented a bladder recurrence and 14 subsequently underwent cystectomy. The 5-year overall survival (OS), disease-specific survival (DSS), and cystectomy-free survival (CFS) rates were 59%, 80.9%, and 93.3%, respectively. The achievement of CR after chemoradiotherapy was the main prognostic variable which was associated with improved OS, DSS, and CFS. The treatment was well tolerated. CONCLUSION: This pooled analysis strengthens the evidence that chemoradiotherapy regimens with concurrent gemcitabine are feasible and well tolerated. Prospective randomized controlled trials are on-going to definitively assess the efficacy of gemcitabine-based chemoradiotherapy for MIBC.

Intermittent docetaxel chemotherapy as first-line treatment for metastatic castration-resistant prostate cancer patients.

AIMS: The intermittent administration of chemotherapy is a means of preserving patients' quality of life (QL). The aim of this study was to verify whether the intermittent administration of docetaxel (DOC) improves the patients' QL. PATIENTS & METHODS: All patients received DOC 70 mg/m(2) every 3 weeks for eight cycles. The patients were randomized to receive DOC continuously or with a fixed 3-month interval after the first four DOC courses. RESULTS: The study involved 148 patients. There was no difference in QL between the groups receiving intermittent or continuous treatment. Intermittence had no detrimental effects on disease control. CONCLUSION: Although feasible and not detrimental, our results showed that true intermittent chemotherapy in metastatic castration-resistant prostate cancer patients failed to improve the patients' QL.

Optimal use of recombinant granulocyte colony-stimulating factor with chemotherapy for solid tumors.

Neutropenia is a frequent complication of anticancer chemotherapy (CT) often associated with life-threatening infections, hospitalization, dose reduction and/or delay in the administration of CT. Administration of recombinant granulocyte colony-stimulating factor (rG-CSF) reduces the duration and the degree of CT-neutropenia. rG-CSF that stimulates both neutropoiesis and neutrophil function, has become an integral part of supportive care during cytotoxic CT, to prevent febrile neutropenia (FN), particularly in patients with a risk of FN ≥ 20%. International guidelines have standardized conditions for rG-CSF administration, however, some 'gray zones' still exist around optimal timing and tailoring of this therapy. We report here the results of a research project aimed to extend the consensus on the optimal use of rG-CSF in association with CT in patient with solid tumours. We also propose a recently developed pharmacodynamic model, based on the biological effects of CT and rG -CSF on bone marrow compartments that clearly indicates within the prophylactic rather than therapeutic setting the better way of rG-CSF administration.

Effects of exercise training on endothelial progenitor cells in patients with chronic heart failure.

BACKGROUND: The enhancement of circulating endothelial progenitor cells (EPCs) obtained by exercise training can be beneficial to patients with cardiac disease. Changes in the levels and differentiation of CD34(pos)/KDR(pos) EPCs, as well as the plasma concentration of vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1 EPC-mobilizing cytokines, were evaluated in patients with chronic heart failure after 8 weeks of supervised aerobic training (SAT) and 8 weeks of subsequent discontinued SAT (DSAT). METHODS AND RESULTS: The levels of circulating EPC and EPC differentiation potential of 22 patients who underwent SAT were studied by fluorescence-activated cell sorter analysis and colony forming-unit assay, respectively. The plasma levels of VEGF and SDF-1 were measured by enzyme-linked immunosorbent assay. In response to SAT, the levels of both EPC and VEGF/SDF-1 markedly increased (P < .001 vs baseline) but returned to the baseline levels after DSAT. A similar change was observed with the EPC clonogenic potential, but on DSAT the baseline level was incompletely attained. CONCLUSIONS: In response to SAT, patients with chronic heart failure show enhanced EPC levels and clonogenic potential that is mirrored by increased plasma VEGF and SDF-1 levels. DSAT can interfere with the maintenance of training-acquired VEGF/SDF-1-related EPC levels and clonogenic potential.

Quality of life evaluation by the EORTC QLQ-C30 questionnaire in patients treated with hormonal treatment in Italy. A QuABIOS group study.

OBJECTIVES: An observational study was planned by the QuABIOS group, to survey the hormonal treatment administered to prostate cancer patients in Italy within a time window of 12 months. We report here a prospective quality of life (QOL) evaluation over time and by hormonal treatment modalities. METHODS: Patients with diagnosis of prostate cancer and treated with hormonal therapy were eligible for this study. The EORTC QLQ-C30 v.3 questionnaire was administered at enrolment, after 6 months and after 12 months from enrolment. RESULTS: 587 patients were enrolled by 33 urological centers. When 1518 visits were considered together independently of time, antiandrogen monotherapy was associated with a significantly better QOL than LHRH-analogue containing treatment modalities in almost all functional scales; cyproterone acetate demonstrated a better physical function and general health status than bicalutamide. When QOL was analyzed in a prospective 12-month window, a worsening of physical function and general health status was observed, notwithstanding, antiandrogens remained significantly associated to a better QOL than LHRH-analogue therapies also over time: a favourable physical function and general health status appeared again to be related to cyproterone acetate than bicalutamide. CONCLUSIONS: Androgen deprivation therapy is associated with decline in QOL, particularly in the domains of physical function, energy, and general health status. This survey demonstrated that antiandrogens had a better QOL profile than LHRH-analogue containing therapies;furthermore, a more favourable tolerability for cyproterone acetate as compared to bicalutamide is suggested.

Economic evaluation of different hormonal therapies for prostate cancer. Final results from the Quality of Life Antiandrogen Blockade Italian Observational Study (QuABIOS).

OBJECTIVE: The paper compares costs and Quality-Adjusted Life Years (QALYs) of different hormonal therapies (HTs) administered to 275 out of 471 patients with prostate cancer (PC) enrolled in the Quality of Life Antiandrogen Blockade Italian Observational Study (QuABIOS), who did not change HT during the study period. METHODS: QALYs and costs related to monoHT witk cyproterone acetate (CYP) (42 patients); bicalutamide (BIC) (41 patients); LHRH-a (96 patients) and complete androgenic blockade (CAB) with: CYP (CYP CAB) (50 patients); BIC (BIC CAB) (46 patients) were compared via a cost-utility analysis (CUA) adopting the Italian National Healthcare Service (INHS) viewpoint. RESULTS: As no statistical significant difference among the mean QALYs gained with the different HTs was detected (p = 0.116), CUA was replaced by a cost minimization analysis (CMA). However, the lowest and the highest mean QALYs gained per patient were registered for BIC CAB (0.59; 95% CI: 0.50; 0.68) and for for CYP (0.75; 95% CI: 0.68; 0.82), respectively. CYP was the least costly HT, reaching the lowest and the highest savings when compared to LHRH-a (-Euros 974.99; 95% CI: -Euros 1066.86; -Euros 883.12; p<0.0001) and to monoHT with BIC (-Euros 5887.81; 95% CI: -Euros 6143.99; -Euros 5631.64; p<0.0001). A nonparametric bootstrap sensitivity analysis confirmed the robustness of the base case CMA. CONCLUSION: CYP is an interesting option for curbing the INHS drug expenditure for PC patients, with a trend towards increasing the mean number of QALYs gained.

Correlation between genetic and biological aspects in primary non-metastatic breast cancers and corresponding synchronous axillary lymph node metastasis.

This study investigated the changes, if any, in the level of expression of a well defined panel of cell proliferation, differentiation and apoptosis markers between the primary breast tumor and the corresponding synchronous lymph node metastasis from a population of patients with a comparable disease status, in terms of clinical features, and natural history.Ninety pure invasive ductal carcinomas with 10 or more axillary lymph nodes involved and without evidence of distant metastasis were included in this study. Primary tumor and corresponding metastatic lymph node tissue specimens were evaluated for the expression of Cyclin B1, MMP1 metalloproteinase, ICAM-1, RARbeta, Ki67, ER, PgR, p53, bcl-2 and c-erbB2 by immunohistochemistry using standard methods. The bivariate Pearson correlation analysis demonstrated a close relationship between primary and matching corresponding metastatic node. A high grade of correlation has been maintained even when staining results where categorized as positive/negative according to each one marker cut-off level of staining expression. We report the most extensive immunohistochemical analysis of biological determinants in a well defined population of patients with invasive ductal carcinomas and involvement of 10 or more axillary nodes and no distant metastasis. We found a close correlation between the primary tumor and corresponding metastatic node in terms of the expression of all 10 of the markers investigated in this study. The not complete concordance observed could be explained by the gene expression modulation by extrinsic factors and by the microenvironment in which the cancer cells reside.

Hormonal treatment for prostate cancer in Italy. Preliminary data from a survey of the QUABIOS Group.

OBJECTIVE: An observational study was planned by the QUABIOS group, to survey the hormonal modalities administered to prostate cancer patients in Italy within a time window of 12 months. We report here a summary of treatment schedules and related adverse effects, as recorded at the first visit. MATERIAL AND METHODS: Patients with diagnosis of prostate cancer and under hormonal therapy (LHRH-a and/or antiandrogen, previous orchidectomy) were eligible for this study. Adverse events were reported (graduated according to NCI-CTC v2.0, when pertaining) only in patients having received at least three months of hormonal treatment. RESULTS: 560 patients were enrolled from February to December, 2004 by 33 urological centers in Italy. A moderate to severe impairment of sexual function subsequent to the hormonal treatment was observed in 18.3% of patients treated with antiandrogen monotherapy, in 48.1% of patients treated with LHRH-a, and in 59.9% of patients treated with the combined approach. 24.7% patients referred a gastrointestinal toxicity (nausea/vomiting and diarrhea), without clear differences between treatment modalities. An asthenia subsequent to the hormonal treatment was moderate to severe in 3.5% of patients treated with antiandrogen monotherapy, as compared to 14.5% for LHRH-a and 12.9% for the combined approach, respectively. A gynecomastia / breast pain was present in 27.8% of antiandrogen monotherapy patients, as compared to 13.9% for LHRH-a and 13.8% for the combined approach, respectively. As compared to cyproterone acetate, bicalutamide had more sexual function impairment, more gastrointestinal toxicity, (slightly) more asthenia and more gynecomastia / breast pain. CONCLUSIONS: In our series antiandrogens were obviously associated with less sexual function impairment and less asthenia than LHRH-a containing schedules; on the other hand gynecomastia mainly affected patients receiving antiandrogen monotherapy. Within antiandrogens, cyproterone acetate generally appeared to be better tolerated than bicalutamide, with less severe impairment of sexual function, less gastrointestinal toxicity and negligible gynecomastia.

The simultaneous use of telomerase, cytokeratin 20 and CD4 for bladder cancer detection in urine.

OBJECTIVE: Because of the low sensitivity of urinary cytological diagnosis of urinary bladder carcinoma, new molecular diagnostic methods have been proposed. We decided to verify the expression of telomerase mRNA coding for the catalytic component (hTRT), cytokeratin 20 (CK20) and CD4 antigen mRNAs in urine as possible diagnostic tool. METHODS: Evaluation of hTRT, CK20, CD4 mRNAs was performed in 50 ml of naturally voided urine of 205 patients of which 153 with bladder cancer (Tis, n = 11; TaGx, n = 4; TaG1, n = 25; TaG2, n = 26; TaG3, n = 8; T1G1, n = 16; T1G2, n = 17; T1G3, n = 20; T2G2, n = 6; T2G3, n = 13; T3G3, n = 7) and 52 controls. A quantitative expression of hTRT at mRNA level versus TRAP (telomeric repeat amplification protocol) assay was performed in 20 patients and 14 controls. The expression of RT-PCR for hTRT, CK20, CD4 versus urinary cytology was analysed in 44 patients with bladder cancer. Evaluating the three molecular markers together, the result was considered correct when at least two of the markers were positive, suspected when only one marker was positive and negative for diagnosis of tumour when all markers were negative. The performance of the diagnostic model resulted from the logistic analysis evaluated with receiver operating characteristics (ROC) curve analysis. RESULTS: The sensitivity detected for each tumour marker was as follows: for hTRT 90.8%, for CK20 84.3% and for CD4 was 64.7%, while the specificity was 94.2% for CD4 and 78.8% for both hTRT and CK20. When a simultaneous evaluation of the three tumour markers was considered, 88.2% of the diagnoses were correct, 11.8% were suspected for tumour and none were mistaken. When compared with cytology, the simultaneous use of the three markers allowed reaching a correct diagnosis in 88% of the cases in comparison to 25% by urinary cytology. The sensitivity in the detection of bladder cancer was higher for hTRT at mRNA level in comparison with the enzymatic activity detection with TRAP (90% vs. 35%) while the specificity for both markers resulted very high (100%). CONCLUSIONS: These data show that in the future the diagnostic improvement of urine based molecular markers for the detection of bladder cancer in the urine could improve the sensitivity of urinary cytology reducing the need of a cystoscopy.