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Background Actual tolerability of sunitinib is still poorly documented in elderly patients with metastatic renal cell carcinoma (mRCC). Patients and methods Charts of elderly patients treated with sunitinib for mRCC were reviewed in six Italian centers to assess safety (primary objective), efficacy and correlation of toxicity with comprehensive geriatric assessment (CGA) (secondary objectives). Results Sixty-eight patients were eligible, and the median age was 74 years. CGA was carried out in 34 patients (41% fit, 41% vulnerable and 18.5% frail). The dose reduction to 37.5 mg was made upfront or soon after the first cycle in 69.1%. More frequent toxic effects were fatigue (80.9%), mucositis (61.8%) and hypertension (58.8%). Cardiac events occurred in nine patients. In 10 patients, therapy was interrupted early due to rapidly progressive disease (10.3%) or severe toxicity (4.4%: 1 cardiac failure, 1 fatigue, 1 febrile neutropenia). At a median follow-up of 27.1 months, the median OS was 18.3 months and the median PFS was 13.6 months. Correlation was not found between frailty at CGA with severe toxicity nor with response. Conclusions Treatment with sunitinib is effective in elderly patients; yet early interruptions were frequent. Starting treatment at reduced dose and escalating in the absence of severe toxicity could be suggested.

Background: Recently, we developed an apoptotic assay for expanding the monitoring capabilities of the circulating tumour cells (CTC) test during therapy. An automated platform for computing CTCs was integrated with a mAb (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 in early apoptosis; we showed that live CTCs were associated with progression, consistent with enhanced cell migration and invasion. The test was first applied here to mRCC. Methods: Live/apoptotic CTCs changes were measured in mRCC patients receiving first-line Sunitinib and compared with circulating endothelial cell (CEC) levels. Results: The presence of EpCAM-positive, live CTCs predicts progression in individual mRCC patient, being associated with distant metastasis under first-line Sunitinib. Synchronous detection of CTCs and CEC levels discloses for the first time an association between their dynamic changes and outcome: a rapid increase of the CEC number as early as the first cycle of therapy is associated with CTC decrease in non-progressed patients, whereas a delayed response of CECs is related to higher CTC values in the progressed group indicating treatment failure. Conclusion: We demonstrated that a delayed response to antiangiogenic treatment indicated by persistent detection of CECs correlates with persistent live CTCs and more aggressive disease.

Background The development of new drugs for patients with refractory urothelial cancer is still an unmet medical need. Preclinical evidence lends support to a rationale for targeting of the VEGF or platelet-derived growth-factor axis. We therefore investigated the activity and safety of pazopanib, a multitarget drug with antiangiogenic activity, in patients with urothelial cancer. Methods In an open-label, single-group, phase 2 study, patients (aged >= 18 years) with relapsed or refractory urothelial cancer were given pazopanib 800 mg per day, orally. They were treated until disease progression or prohibitive toxicity occurred. The primary endpoint was the proportion of patients who achieved a confirmed objective response, defined as complete or partial response, after independent review, and was analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01031875. Findings The trial has been completed. 21 (51%) of 41 patients enrolled were given pazopanib as third-line or further-line treatment. 26 (63%) patients had an Eastern Cooperative Oncology Group performance status of 1 or 2. Seven patients had a confirmed objective response (17.1%, 95% CI 7.2-32.1), all of which were partial responses. The most frequent treatment-related grade 3 adverse events were hypertension (three [7%]), fatigue (two [5%]), and gastrointestinal and vaginal fistulisations (two each [5%]). One patient died as a result of duodenal fistulisation that was related to tissue response of bulky tumour masses. Interpretation Pazopanib has single-agent activity in patients with heavily pretreated metastatic urothelial cancer, and warrants further study in this setting. Particular attention should be paid to patients with bulky tumour masses adjacent to viscera because fistulisation is probably related to the response to pazopanib and is the most frequent serious adverse event. Background: The development of new drugs for patients with refractory urothelial cancer is still an unmet medical need. Preclinical evidence lends support to a rationale for targeting of the VEGF or platelet-derived growth-factor axis. We therefore investigated the activity and safety of pazopanib, a multitarget drug with antiangiogenic activity, in patients with urothelial cancer. Methods: In an open-label, single-group, phase 2 study, patients (aged ≥18 years) with relapsed or refractory urothelial cancer were given pazopanib 800 mg per day, orally. They were treated until disease progression or prohibitive toxicity occurred. The primary endpoint was the proportion of patients who achieved a confirmed objective response, defined as complete or partial response, after independent review, and was analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01031875. Findings: The trial has been completed. 21 (51%) of 41 patients enrolled were given pazopanib as third-line or further-line treatment. 26 (63%) patients had an Eastern Cooperative Oncology Group performance status of 1 or 2. Seven patients had a confirmed objective response (17·1%, 95% CI 7·2-32·1), all of which were partial responses. The most frequent treatment-related grade 3 adverse events were hypertension (three [7%]), fatigue (two [5%]), and gastrointestinal and vaginal fistulisations (two each [5%]). One patient died as a result of duodenal fistulisation that was related to tissue response of bulky tumour masses. Interpretation: Pazopanib has single-agent activity in patients with heavily pretreated metastatic urothelial cancer, and warrants further study in this setting. Particular attention should be paid to patients with bulky tumour masses adjacent to viscera because fistulisation is probably related to the response to pazopanib and is the most frequent serious adverse event. Funding: Fondazione IRCCS Istituto Nazionale dei Tumori provided the grant. GlaxoSmithKline provided the study drug and provided funding for the independent radiological review.

There are few studies of the treatment of relapse in patients with esophageal squamous cell cancer (ESCC). Moreover, those trials were not randomized and without convincing data. Cumulative overall 1-year and 2-year survival rates after recurrence were around 30% and 12%, respectively, with a median survival of 6 months [1]. For this reason, the goal of the treatment is usually adequate palliation instead of cure, taking into account many factors: patient characteristics (performance status, age, co-morbidity), mode of relapse (local vs. locoregional vs. systemic), site of the primary cancer (non-local recurrences are more frequent in cervical or upper thoracic cancers) [2]; site of relapse (liver recurrence is the worst prognostic site, with a median overall survival < 6 months) [3]; kinetics of relapse (indolent or aggressive, symptomatic or asymptomatic disease); and previous treatments and their toxicities.

There is considerable debate in the literature on the appropriate preoperative treatment of esophageal squamous cell carcinoma (ESCC), with valid options being chemotherapy (CT), chemoradiotherapy (CRT), followed or not by surgery. Some authors are of the opinion that in patients with good clinical response, surgery can improve local control and minimize, in case of relapse, the need for palliative stenting; however, surgery does not seem to improve overall survival. Late surgical morbidity and mortality, even in high-volume centers, is still considerable. For this reason, definitive CRT has been proposed for patients with advanced ESCC (cT3-cT4), restricting surgery to non-responding patients (salvage surgery) [1, 2, 3, 4, 5].

Central nervous system (brain or leptomeningeal) metastases (BLm) are considered rare in castration-resistant prostate cancer (CRPC) patients. Now that docetaxel has become the reference drug for first-line treatment of CRPC, patients whose disease is not controlled by hormonal manipulations may live much longer than before and have higher risk of developing BLm. We retrospectively reviewed the records of all patients with CRPC attending our centres from 2002 to 2010, and identified all of those who were diagnosed as having BLm and received (or were considered to have been eligible to receive) docetaxel-based treatment. We identified 31 cases of BLm (22 brain metastases and 9 leptomeningeal metastases) with an incidence of 3.3%. BLm-free survival was 43.5 months, and survival after BLm discovery was 4 months. With six patients surviving for more than 1 year after developing BLm, the projected 1-year BL-S rate was 25.8%. The findings of our study may be relevant in clinical practice as they indicate that incidence of BLm in CRPC patients in the docetaxel era seems to be higher than in historical reports, meaning that special attention should be paid to the appearance of neurological symptoms in long-term CRPC survivors because they may be related to BLm.

What's known on the subject? and What does the study add? Data on quality of life during docetaxel treatment in castration resistant prostate cancer was mainly provided by SWOG and TAX327 trials. In the TAX327 trial biochemical response and pain predicted survival, whereas quality of life outcomes did not. In the present study, there were no statistically significant changes in the quality of life scales during treatment except in the case of patients receiving docetaxel and estramustine, who experienced a significant decrease in pain. Our data seem to suggest that patients with a better baseline quality of life (and consequently with fewer symptoms) are more likely to achieve a biochemical response.• To assess quality of life (QoL) outcomes and pain changes in patients affected by castration-resistant prostate cancer enrolled in a phase II randomized trial of 3-week docetaxel (DOC)-based chemotherapy. • To provide further data to clarify the conflicting published data concerning the impact of DOC on the patients' QoL.• QoL outcomes were assessed using the European Organisation for the Research and Treatment of Cancer QLQ-C30 questionnaire. • Pain changes were evaluated by means of the Brief Pain Inventory at baseline and after every two DOC courses. • The patients completing at least two questionnaires (at baseline and before the third course) were considered evaluable.• In all, 59 patients were evaluable. • Asymptomatic patients and responders had a better baseline QoL than symptomatic patients and non-responders. • There were no statistically significant changes in the QLQ-C30 scales during treatment except in the case of patients receiving DOC and estramustine, who experienced a significant decrease in pain. • There was a progressive improvement in the mean intensity and interference scores of the Brief Pain Inventory.• Our data confirm that QoL is generally maintained during chemotherapy. • There is a substantial reduction in pain. • Our results also suggest that baseline QoL may predict treatment response.

Aim: To evaluate the physiopathology of follicle-stimulating hormone (FSH) along the pituitary-testicular-prostate axis at the time of initial diagnosis of prostate cancer in relation to the available clinical variables and to the subsequent cluster selection of the patient population. Patients and Methods: The study included 98 patients who were diagnosed with prostate cancer. Age, percentages of positive cores (P+) at transrectal ultrasound scan biopsy, biopsy Gleason score (bGS), luteinizing hormone (LH), FSH, total testosterone, free testosterone (FT) and prostate-specific antigen (PSA) were the continuous clinical variables. All patients had not previously received hormonal manipulations. FSH correlation and multiple linear analyses were computed in the population. The FSH/PSA ratio was computed and then ranked for clustering the population as groups A (0.13≤FSH/PSA≤0.57), B (0.57Results: In the patient population, FSH correlated to LH (p < 0.0001), FT (p = 0.007) and age (p = 0.004). FSH was independently predicted by both LH (p < 0.0001) and PSA (p = 0.04). PSA predicted FSH/PSA A (p < 0.0001), B (p < 0.0001) and C (p = 0.04). On multiple regression analysis, FSH/PSA A was predicted by PSA (p < 0.0001), P+ (p = 0.03) and bGS (p = 0.04); FSH/PSA B by LH (p = 0.002) and PSA (p < 0.0001); FSH/PSA C by LH (p < 0.0001) and PSA (p < 0.0001). Moreover, FSH/PSA A, B and C differed for mean values of FSH (p < 0.0001), LH (p < 0.0001), PSA (p < 0.0001) and PSA/FT ratio (p < 0.0001). FSH/PSA clusters showed features of decreasing aggressive disease as the FSH/PSA ratio progressed from A to C. Conclusion:At the diagnosis of prostate cancer and along the pituitary-testis-prostate axis in a patient population FSH significantly correlated to LH, FT and age, and FSH was independently and significantly predicted by both LH and PSA. Because of the independent prediction of PSA by FSH, the prostate cancer population at diagnosis was clustered and ranked according to the FSH/PSA ratio in groups A, B and C. Also, the predictive model of PSA on FSH for the different groups proved to be effective at selecting potential prognostic clusters in which the risk of progression might be assessed as low (group C), intermediate (group B) and high (group A). The FSH/PSA model might be considered as a tool for prostate cancer study and for use in individualized, risk-adapted approaches. However, confirmatory studies are needed.

Objectives: To explore, in operated prostate cancer patients, functional relationships of total testosterone (tt) predicting free testosterone (ft) and total PSA. Patients and Methods: 128 operated prostate cancer patients were simultaneously investigated for tt, ft and PSA before surgery. Patients were not receiving 5α-reductase inihibitors, LH-releasing hormone analogues and testosterone replacement treatment. Scatter plots including ft and PSA versus tt were computed in order to assess the functional relationship of the variables. Linear regression analysis of tt predicting ft and PSA was computed. Results: tt was a significant predictor of the response variable (ft) and different subsets of the patient population were assessed according to the ft to tt ratio. PSA was related to tt according to a nonlinear law. tt was a significant predictor of PSA according to an inversely nonlinear law and different significant clusters of the patient population were assessed according to the different constant of proportionality computed from experimental data. Conclusions: In our prostate cancer population, ft was significantly predicted by tt according to a linear law, and the ft/tt ratio was a significant parameter for assessing the different clusters. Also, tt was a significant variable predicting PSA by a nonlinear law and different clusters of the patient population were assessed by the different constants of proportionality. As a theory, we explain the nonlinear relation of tt in predicting PSA as follows: (a) the number of androgen-independent prostate cancer cells increases as tumor volume and PSA serum levels rise, (b) the prevalence of androgen-independent cells producing a substance which inhibits serum LH, and (c) as a result lower levels of serum tt are detected.

Objective Although there is no standard treatment after docetaxel failure in patients with castration-resistant prostate cancer (CRPC), second-line chemotherapy is increasingly required. Its mechanism of action and toxicity profile make pemetrexed suitable for testing in this setting. Methods and materials Patients with docetaxel-resistant CRPC received pemetrexed 500 mg/m 2 every 3 weeks for 6 courses. The usual premedication with vitamin supplementation and dexamethasone prophylaxis was regularly administered. The primary objective was to quantify the biochemical response rate. Results The biochemical response rate was 10.5% (95% CI 1.3–33.1), with 2 patients showing a reduction in prostate specific antigen (PSA) of ≥50%. The null hypothesis that the PSA response rate would be less than 20% was therefore accepted, and patient accrual was stopped after the evaluation of the 19th patient. The 1-year overall survival rate was 61.5%, with a median survival of 14 months. A considerable proportion of the patients (36%) were withdrawn from the study because of hematologic and nonhematologic toxicity. Conclusions Our experience with pemetrexed in CRPC patients appears discouraging in terms of activity and toxicity. No further studies of this drug should be performed in CRPC patients.

Objectives: To explore the significance of the pretreatment total prostate-specific antigen (PSA) to free testosterone (FT) ratio (PSA/FT) as a marker for assessing the pathologic Gleason sum (pGS) and levels of tumor extension (pT) in prostatectomy specimens. Patients and Methods: 128 of 135 consecutive patients diagnosed with prostate cancer underwent radical prostatectomy. Simultaneous pretreatment serum samples were obtained to measure serum total testosterone, FT and total PSA levels. The statistical design of the study included 2 sections: the first part trying to explore the role of the PSA/FT ratio in clustering patients with different pathologic prognostic factors, and the second to investigate the PSA/FT ratio distribution in different groups of patients according to the pathologic stage and pGS of the specimen after radical prostatectomy. Results: The average age was 65.80 (range 51.21–77.26) years, mean PSA was 8.88 (range 1.22–44.27) µg/l, mean FT was 35.32 (range 13.70–69.30) pmol/l, and the mean PSA/FT ratio was 0.27 (range 0.04–1.48). The PSA/FT ratio significantly clustered both the pT and pGS groups. Analysis of variance for the distribution of the PSA/FT ratio was significant for the pT model groups. The mean PSA/FT ratio increased as the tumor extended and grew through the prostate gland (high-stage disease). Analysis of variance for the different distributions of the PSA/FT ratio was significant for all model pGS groups. In our investigation we also found (data not shown) that a PSA/FT ratio of ≧0.40 was strongly correlated with large extensive (pT3b+pT4) and high-grade cancers (pGS8+pGS9). Conclusions: Prostate cancer patients may be classified into 3 different pathologic prognostic groups according to the PSA/FT ratio: low risk (PSA/FT ≤0.20), intermediate risk (PSA/FT >0.20 and ≤0.40), and high risk (PSA/FT >0.40 and ≤1.5). The PSA/FT ratio may be considered as the marker expressing different biology groups of prostate cancer patients, and it is strongly associated with pT and pGS.

Purpose: This study aimed to detect the M30 neoepitope on circulating tumor cells (CTC) as a tool for quantifying apoptotic CTC throughout disease course and treatment. Experimental Design: An automated sample preparation and analysis platform for computing CTC (CellSearch) was integrated with a monoclonal antibody (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 (CK18) in early apoptosis. The assay was validated using cell lines and blood samples from healthy volunteers and patients with epithelial cancer. Results: M30-positive CTC could be detected in >70% of CTC-positive carcinoma patients, which were free for both chemotherapy and radiologic treatments. The fraction of M30-positive CTC varied from 50% to 80%, depending on the histotype. To investigate the potential application of the M30 CTC assay for the evaluation of response in early phase trials, CTC and M30-positive CTC were enumerated in a small case series of breast cancer patients during treatment. Results indicate that changes in the balance of M30-negative/positive CTC may be used as a dynamic parameter indicating an active disease, as documented by consistent radiologic findings. Conclusions: M30 expression on CTC is detectable by immunofluorescence. The M30-integrated test has potential for monitoring dynamic changes in the quote of apoptotic CTC (in addition to CTC count) to evaluate response in clinical trials of molecularly targeted anticancer therapeutics as well as for translational research, in which there is a pressing need for informative circulating biomarkers. Clin Cancer Res; 16(21); 5233–43. ©2010 AACR.

Objectives: Prostate cancer is an interesting tumor for endocrine investigation. The prostate-specific antigen/free testosterone (PSA/FT) ratio has been shown to be effective in clustering patients in prognostic groups as follows: low risk (PSA/FT ≤0.20), intermediate risk (PSA/FT >0.20 and ≤0.40) and high risk (PSA/FT >0.40 and ≤1.5). In the present study we explored the total PSA and FT distributions, and linear regression of FT predicting PSA in the different groups (PSA/FT, pT and pG) and subgroups (pT and pG) of patients according to the prognostic PSA/FT ratio. Patients and Methods: The study included 128 operated prostate cancer patients. Pretreatment simultaneous serum samples were obtained for measuring free testosterone (FT) and total PSA levels. Patients were grouped according to the total PSA/FT ratio prognostic clusters (≤0.20, >0.20 and ≤0.40, >0.40), pT (2, 3a and 3b+4) and pathological Gleason score (pG) (≤6, = 7 >3 + 4, ≧7 >4 + 3). The pT and pG sets were subgrouped according to the prognostic PSA/FT ratio. Linear regression analysis of FT predicting total PSA was computed according to the different PSA/FT prognostic clusters for the: (1) total sample population, (2) pT and pG groups, (3) intraprostatic (pT2) and extraprostatic disease (pT3a/3b/4), and (4) low-intermediate grade (pG ≤6) and high-grade (pG ≧7) prostate cancer. Results: Analysis of variance always showed highly significant different PSA distributions for (1) the different PSA/FT, pT and pG groups; and (2) the pT and pG prognostic subgroups. Significant FT distributions were detected for the (1) PSA/FT and pT groups; and (2) the pT2, pT3a and pG ≤6 prognostic PSA/FT subgroups. Correlation, variance and linear regression analysis of FT predicting total PSA was significant for (1) the PSA/FT prognostic clusters, (2) all the pT2 and pT3a subgroups, and (3) the pT3b/4 subgroup with PSA/FT >0.20 and ≤0.40, and (4) all the pG subsets. Linear regression analysis showed that the slopes of the predicting variable (FT) were always highly significant for patients with (1) intraprostate and extraprostate disease, and (2) low-grade and high-grade prostate cancer. Conclusions: According to the prognostic PSA/FT ratio, significantly lower levels of FT are detected in prostate cancer patients with extensive and high-grade disease. Also, significant linear correlations of FT predicting PSA are assessed in the different groups and subgroups of patients clustered according to the prognostic PSA/FT ratio. Confirmatory studies are needed.

Objective Although docetaxel (DOC) plus prednisone is currently the treatment of choice for hormone-refractory prostate cancer (HRPC), no standard therapy is available for those patients who progress during DOC treatment. The aim of this study was to evaluate whether the addition of estramustine (E) can overcome DOC resistance. Methods Patients who had not responded to DOC in a previous randomised phase II trial received a one-hour intravenous infusion of DOC 70 mg/m 2 on day 2 in combination with oral E 840 mg/day divided into three daily administrations on days 1–5. The primary endpoint was a >50% decrease in PSA; the secondary endpoints were biochemical progression-free survival, overall survival, the objective response rate, and toxicity. Results A biochemical response was observed in 52% of the 25 patients evaluable for response. The only grade 4 event was a cerebral stroke that occurred a few days after the administration of the first treatment course. Treatment discontinuation due to worsened compliance was observed in the patients who received a higher cumulative number of courses. Conclusions Our findings suggest that the addition of E may be useful in selected HRPC patients resistant to DOC alone.

To show that prostate cancer biology is related to serum levels of both free testosterone (FT) and prostate-specific antigen (PSA), that PSA level is linearly related to FT and that the PSA to FT ratio may be considered as the growth rate parameter expressing cancer phenotype biology.The study includes 135 consecutive patients diagnosed with prostate cancer. Pretreatment simultaneous serum samples for analyzing total testosterone (TT), FT and total PSA levels were obtained. The study was assessed according to a multidimensional approach of the five continuous variables including TT, FT, PSA, AGE and percentage of positive biopsies (=P+). The all sets of data were considered as one--sample with no groupings among the observations. Multivariate analysis included factor analysis (FA) and principal component analysis (PCA). Multivariate inferential statistics for comparing different groups of patients according to the PSA to free testosterone ratio (PSA/FT) included Hotteling's multivariate two-sample T²-Test for comparing two mean vectors as well as Box's M-Test with the chi-square approximation for comparing multiple covariance matrices when patients were sampled in more than two groups.Factor analysis showed the two natural grouping of variables, FT-TT and PSA-P+. PCA assessed FT and PSA as the two variables with large variances having a notable influence on the first two principal components. Multiple linear regression analysis showed that all the income variables, except age, significantly predicted the PSA/FT ratio. Patients were first sampled according to the PSA/FT ratio in group 1 (PSA/FT ≤ 0.20) and group 2 (PSA/FT0.20), and Hotteling's multivariate two sample T²-Test was significant (P0.01). Patients were then sampled according to the PSA/FT ratio in group 1 (PSA/FT ≤ 0.20), group 2 (PSA/FT0.20 and ≤ 0.40), and group 3 (PSA/FT0.40), and Box's M-Test comparing the covariance matrices of the 3 groups differed significantly (P0.001). Finally, patients were sampled according to the PSA/FT ratio in 6 groups, and Box's M-Test was again significant (P0.001).The PSA to FT ratio is the growing rate parameter expressing different biology patterns and assessing different groups of prostate cancer patients. In our opinion, the results of the present study might have wide applications in understanding, assessing and planning prostate cancer studies including basic science, screening, assessing risk of the disease, predicting disease stage as well natural history after a planned treatment involving biochemical recurrence, progression, hormone refractory prostate cancer and disease-specific survival.

Stage I seminoma is highly curable. There are different treatment options for this disease: radiotherapy, surveillance and chemotherapy. In recent years, adjuvant chemotherapy in particular has been extensively evaluated. This paper offers suggestions about the advantages and disadvantages of the different strategies, which will be discussed considering prognostic factors; future perspectives will also be evaluated. Through a review of the literature and their clinical experience, the authors outline the importance of prognostic factors in the management of patients suffering from seminomas. Although no treatment modalities have demonstrated survival advantages over others, acute and late side effects, acceptability and quality of life are the main elements of comparison between them. Our findings support the hypothesis that the final decision about the treatment of these tumors depends essentially on three different aspects: risk factors, the patient's own preferences, and single-center expertise. These aspects should play a fundamental role in the final decision-making.

549 Background: T and N stage, Fuhrman grade, necrosis and sarcomatoid features in the primary tumor are key prognostic factors for relapse of ccRCC, but they are not part of Heng's algorithm applied to predict OS in the metastatic setting, which instead is based on 6 clinical/laboratory items. Methods: Retrospective analysis on correlation between pathological parameters and OS (from start of first-line targeted therapy) and Heng's prognostic factors in a multicenter cohort of pts with advanced ccRCC, all of whom had undergone surgery on the kidney. Results: From 2006 to 2012, data of 903 eligible metastatic pts were collected from 33 Italian Oncology Institutions, median age 66 years, 72.6% males, 36.4 metastatic at diagnosis. After a median observation of 42 mo, 70,5% of pts died, estimated OS is 28.5 mo. Heng good prognosis pts were 14.45%, intermediate 69.1% and poor 16.45%. Univariate analysis showed that all pathological parameters significantly correlated with OS: T stage 3-4 vs 1-2 (HR 1.3), N1 vs N0 (1.3), Fuhrman grade 3-4 vs 1-2 (1.7) presence of necrosis (1.5) and sarcomatoid features (1,6). All pathological parameters had a strong correlation with a time to metastases < 1 year, while only weak correlations were found with the other clinical prognostic items of Heng's model. At multivariate analysis only N stage showed an independent impact on OS (table). Conclusions: T3-4 stage, N1, Fuhrman grade 3-4, presence of necrosis and sarcomatoid features negatively affect OS of metastatic ccRCC, but clinical items of Heng's model confirm to have a more robust prognostic significance at multivariate analysis. [Table: see text]

210 Background: Abiraterone acetate (AA), cabazitaxel (CABA), and enzalutamide (ENZ) are NAs which demonstrated their efficacy in mCRPC pts who have previously treated with DOC. Unfortunately all pts develop a resistance to these drugs and eventually show a progression of disease. Since the androgen receptor machinery remains the ultimate target of NAs in mCRPC post-DOC, some mechanisms of resistance could be common to all NAs. To date, NAs are sequentially administered in the hope of obtaining a cumulative survival benefit. To date it is unknown if the DC duration influence the outcomes of the subsequent treatments. The present study was aimed to retrospectively assess this issue in a large series of mCRPC pts. Methods: We recorded the clinical outcomes of all treatments received after DOC. For the study purpose, we categorized the pts according to the duration of DC (absence of progression) during NA-based second line: DC ≤ 3 mos (primary resistance – PRe); DC from 3.1 to 11.9 mos (intermediate sensitivity – IS); DC ≥ 12 mos (long term disease control – LTDC). Results: A consecutive series of 291 mCRPC pts, median age 71 yrs (46-91), with bone (88%), nodal (53%) or visceral (18%) mets, was collected. All pts received a NA-based as second line after DOC: 160 (55%) received AA, 99 (33%) CABA and 32 (11%) ENZ. PRe was observed in 56 pts (23 AA – 25 CABA – 8 ENZ), IS in 178 (101 AA – 58 CABA – 19 ENZ), LTDC in 57 (36 AA – 16 CABA – 5 ENZ). The third-line clinical outcomes are detailed in the table. Conclusions: From this data, it appears that DC duration may be a prognostic factor, as a probable result of pts/disease selection. In fact, pts progressing more than 12 mos from the start of NA-based second line appear to have more probabilities to live longer, compared to pts progressing earlier, when they receive another NA-based third line therapy. [Table: see text]

211 Background: The NLR is a marker of systemic inflammatory response: several studies investigated its prognostic relevance in mCRPC but to date no information is available concerning this issue in pts treated in third line therapy. The present study is aimed to assess the possible relationship between third line clinical outcome and NLR in a large series of mCRPC pts treated with a NA [abiraterone acetate (AA), cabazitaxel (CABA), or enzalutamide (ENZ)] after the failure of docetaxel (DOC) and another NA. Methods: We collected data of pts who received sequentially two NAs after DOC in 38 Italian hospitals. For each pt we recorded the clinical outcome of all treatments received after DOC. Cox regression analysis was used to assess the independent prognostic value of a series of pretreatment covariates, in terms of overall survival (OS), comprising NLR. Results: A consecutive series of 291 mCRPC pts with bone (88%), nodal (53%) or visceral (18%) mets, was collected. All pts received a NA-based third line: 90 received AA, 123 CABA and 78 ENZ. At the time of this analysis, data on NLR were available for 198 pts (68%): AA 68 (75%) – CABA 80 (65%) – ENZ 50 (64%): the median value was 3.1 (IQR 2.2-4.7). In the univariate analyses, the NLR as a discrete variable using the median value of 3.1 as threshold, was significantly associated with both OS and progression free survival (PFS), calculated from the third line start (p < 0.0001 and p = 0.001, respectively). No association was observed with either biochemical or objective response. These results were confirmed at the multivariate analysis. In Kaplan-Meier analysis, the median OS from the start of third-line was higher (18.2 vs 8.1 mos) in pts with NLR ≤ 3.1 compared to those with NLR > 3.1 (log-rank; P < 0.0001). Similarly, the median PFS was 6.3 and 3.5 in pts with NLR ≤ 3.1 and > 3.1, respectively. Conclusions: At the best of our knowledge, this is the first report on the NLR value in mCRPC third line treatment. From our preliminary data, it appears that NLR may be a prognostic and predictive factor in mCRPC pts, treated with NA-based third line.

332 Background: For one decade, docetaxel (DOC) represented the only therapeutic option for mCRPC pts. Recently, AA and enzalutamide demonstrated a survival gain in first line setting. Lacking direct comparison with DOC and considering some differences in selection criteria of the pivotal trials, the choice between DOC and these hormonal agents, which have a quite different toxicity profile, is often driven by pts’ characteristics and feelings and by clinicians’ attitudes and preferences as well. To date, only AA is available in Italy, from September 2014, for the first line setting and the present study explores the attitudes and preferences of clinicians in choosing between DOC and AA. Methods: We retrospectively reviewed the clinical records of all mCRPC pts who received a first-line treatment in 5 Italian hospitals after the introduction of AA in the clinical practice. All pts were treated with AA 1,000 mg po + prednisone (PDN) 10 mg po daily or with DOC at the dose of 75 mg/sqm i.v. every three wks. For each pt we have recorded the pre-first line clinical history and the baseline characteristics. Results: From September 2014 to August 2015, we collected a consecutive series of 70 mCRPC pts: 49 received AA, 21 DOC. The median age was 74 yrs (range 46-90), 6% had visceral mets; 8% had a performance status 2; 47% had pain. Pts treated with AA were significantly older (75.8 vs 69.7 yrs; p = 0.002); received more previous hormone therapies (2.19 vs 1.76; p = 0.03), had a longer interval between first hormone therapy and the start of mCRPC first line (47.6 vs 21.2 mos; p = 0.01) and finally, were less frequently symptomatic (27% vs 67%; p = 0.02%). Conclusions: The present study is the first to explore the clinicians’ attitudes and preferences, in the routine clinical practice, in choosing the first line drug for mCRPC pts. From our preliminary data, it appears that some pts characteristics are important in driving the choice of the clinicians between AA and DOC. Data collection is ongoing in other Italian hospitals.

547 Background: A systemic immune-inflammatory index (SII) based on lymphocyte (L), neutrophil (N), and platelet (P) counts has been recently developed. In this retrospective analysis, we explored its prognostic and predictive value at baseline and changes at week 6 during first-line sunitinib in patients (pts) with metastatic renal cell cancer (mRCC). Methods: We included 335 consecutive pts mRCC treated with first-line sunitinib for which P,N, and L data were available at start of therapy, and 6 weeks thereafter. The SII was defined as follows: SII = P x N/L. The X-tile 3.6.1 software (Yale University, New Haven, CT) was used for bioinformatic analysis of the baseline data to determine the cutoff value of SII. Progression-free survival (PFS), overall survival (OS) and their 95% confidence interval (95% CI) were estimated by Kaplan-Meier method and compared with logrank test. The impact of SII conversion on PFS and OS was evaluated by Cox regression analyses. Results: An optimal cutoff point for the SII of 730 x 109stratified these pts into high (≥ 730) and low SII (

Germ cell tumours are highly curable, especially when still at the localized stage, which is the case for most testicular tumours. Various options are available for organ-confined disease; depending on the histological review, patients with clinical stage I seminomas can be offered radiotherapy, surveillance or chemotherapy, whereas those with clinical stage I nonseminomas can be offered retroperitoneal lymph node dissection, surveillance or chemotherapy. As it is unlikely that any of these approaches will have a clear survival advantage, the most appropriate variables to be considered are acute and late side-effects, acceptability and quality of life. In recent years adjuvant chemotherapy has been extensively evaluated in patients with seminoma or nonseminoma. In this review we discuss the advantages and disadvantages of the different strategies for treating seminomas and nonseminomas, and their associated prognostic factors, and then consider future developments.

Background The prognosis of younger patients with prostate cancer is unclear, and the very few studies assessing those with metastatic castration-resistant prostate cancer (mCRPC) have mainly involved patients treated with older therapies. The aim of this observational study was to evaluate the clinical outcomes of a contemporary series of docetaxel-treated patients with mCRPC who were 60 years and younger. Patients and methods We retrospectively identified 134 patients who were 60 years and younger who were treated with docetaxel in 25 Italian hospitals and recorded their predocetaxel history of prostate cancer, their characteristics at the start of chemotherapy, and their postdocetaxel treatment history and outcomes. Results Most of the 134 consecutive patients with mCRPC received the standard 3-week docetaxel schedule; median progression-free survival (PFS) was 7 months, and 90 patients underwent further therapies after progression. The median overall survival (OS) from the start of docetaxel treatment was 21 months, but OS was significantly prolonged by the postprogression treatments, particularly those based on the new agents such as cabazitaxel, abiraterone acetate, or enzalutamide. OS was significantly shorter in the patients with a shorter interval between the diagnosis of prostate cancer and the start of docetaxel treatment; those who received hormonal treatment for a shorter period; those with shorter prostate-specific antigen doubling times; and those with lower hemoglobin levels, a worse performance status, and higher lactate dehydrogenase levels before starting treatment with docetaxel. Conclusions The findings of this first study of clinical outcomes in a contemporary series of younger patients with mCRPC showed that their survival is similar to that expected in unselected patients with mCRPC who were of any age.

Despite the limited efficacy of systemic chemotherapy in the treatment of metastatic melanoma, it remains the gold standard in the case of patients with a good performance status and no major comorbidities for whom radical surgery is unsuitable. Various drugs have been employed as monochemotherapy with response rates ranging from 0 to 20%. Many Phase III trials have compared the role of polychemotherapy with that of single-agent chemotherapy, or evaluated the impact of biological response modifiers alone or in combination with chemotherapeutic agents. However, the current scenario does not seem to be significantly different from the situation of 20 or 30 years ago. To date, no single drug, combination chemotherapy in addition to a hormonal or biotherapy compound, has demonstrated an overall survival benefit in a randomized clinical trial.

Hormone-refractory prostate cancer (HRPC) is a major issue in Western countries and the second leading cause of cancer death in North American men. In the prostate-specific antigen era, most HRPCs are currently diagnosed in asymptomatic patients based on biochemical failure, with increasing demand for active treatment. Until recently, chemotherapy for HRPC patients was not considered a standard of care due to the absence of clear data evidencing an overall survival benefit. In fact, few Phase III studies conducted in the 1980s and early 1990s had documented a superiority over corticosteroids alone in terms of biochemical response (declines in serum prostate-specific antigen levels) and quality of life, but not survival. Due to their impact on pain control, mitoxantrone and prednisone were long considered the best regimen for symptomatic HRPC patients. In recent years, more chemotherapeutic agents have been tested, among which the microtubule inhibitors (vinca alkaloids and taxanes) have obtained the most promising results in Phase II trials and have entered Phase III testing. Two well-designed randomized trials have changed this scenario. Both compared docetaxel (with or without estramustine) against mitoxantrone and prednisone, and demonstrated a significant advantage not only in terms of response, pain control and quality of life, but also in terms of overall survival. Which patients need to be treated, the regimen of choice and duration of chemotherapy will be the next questions to be answered in the coming years in the field of HRPC, along with the role of new signal transduction inhibitors and other targeted therapies.

To our knowledge, there are no published reports on the effectiveness of radiosurgery in the management of brain metastases from testicular nonseminomatous germ cell tumor. The authors evaluate the results of gamma knife (GK) treatment in three patients with these unusual intracranial lesions. Between April 1995 and July 2001, three patients with brain metastasis from testicular nonseminomatous germ cell tumor underwent adjuvant radiosurgery at our department. The primary tumor had been surgically removed in all cases. At diagnosis, one patient was stage IB and two were stage III poor risk. Chemotherapy and whole brain radiotherapy were administered before radiosurgery in all cases. Pre-GK radiotherapy was administered with a daily fraction dosage of 1.8-2.0 Gy. The indications for radiosurgery were tumor volume

Aim: Loss of chromosomes 9p and 14q correlates with poor prognosis in patients (pts) with clear cell renal cell carcinoma (ccRCC). Both chromosomal loci also do harbor several hot spot molecular pathways suitable for targeted therapies. We sought to investigate the presence of losses of the hot spots chromosomal loci 9p and 14q in primary ccRCC and matched metastatic cancer tissue in pts treated with angiogenic inhibitors. Methods: 7 pts with ccRCC, with available metastatic tissue were recruited. CD10 and CD13 was performed at immunophenotypical level. Molecularly, cytogenetic interphase fluorescente in situ hybridization analysis was performed on formalin-fixed and paraffin embedded primary and matched metastatic tissues by using the locus specific probes mapping the 9p and 14q loci. Cases were scored as having loss of chromosome if >40% nuclei presented single signals and gains when >15% showed three or more signals. Results: Loss of chromosome 9p was observed in 6/7 (85%) primary ccRCC and in 6/7 (85%) matched metastases; one case showed discordance between primary tumor and metastases. Loss of chromosome 14q was detected in 4/7 (57%) primary ccRCC and in 4/7 matched metastases. The concordance of the 14q chromosomal status between primary tumors and corresponding tissue metastases was not demonstrated in 3/7 cases (42%). 3/4 cases (75%) with concordance in cytogenetic status for chromosome 14q developed metastases after at least 3 years of follow-up, the remaining within 1 year. Conclusions: Heterogeneity of cytogenetic status between metastatic and primary ccRCC is observed for loss of chromosome 14q rather than chromosome 9p. Chromosome 14q cytogenetic status, harboring the HIF-1 gene, may affect the efficacy of targeted inhibitors, whereas loss of chromosome 9p, harboring the p16 gene, seems to influence the metastatic behavior per se, without cytogenetic modulation. Those pts showing an homogeneous status for chromosome 14q loss developed metastases after longer years of follow-up. Re-profiling metastatic tissue for re-targeting pts affected by metastatic renal cell carcinoma may be proposed to overcome resistance to anti-angiogenic agents. Disclosure: All authors have declared no conflicts of interest.

Aim: Characteristics, treatment and outcome of patients (pts) with brain metastases (BMet) from GCT are largely unknown due to a lack of data. We addressed these issues in a large international retrospective cohort. Methods: Data on pts diagnosed with BMet between 1990 and 2013 was retrospectively collected across 46 institutions worldwide. Data collection and analyses followed a predefined protocol and had obtained appropriate ethical approval. Univariate analysis was used to identify prognostic factors. The Kaplan Meier method was used to assess outcome. Results: Data on 523 patients were collected: 228 (44%) in pts with BMet at initial diagnosis (group A) and 295 (56%) in pts with BMet at relapse (group B), 150 (31%) pts were asymptomatic at presentation. Median age was 29 years (range 16-67 years). Median follow-up after diagnosis of BMet was 7 years. Pts from group A had a significantly better PFS (median 6.9 versus 3.6 months, HR 0.60: 95%CI; 0.49 – 0.73; P Conclusions: Conclusions: Pts with GCT and BMet can be cured. Pts with BMet at initial diagnosis and those with solitary BMet have superior outcomes compared to pts with BMet at relapse or with multiple BMet lesions. Surgery and/or radiotherapy in addition to chemotherapy as well as HDCT in pts with BMet at relapse may improve survival. Disclosure: All authors have declared no conflicts of interest.

4559 Background: Bone metastases (BM) are rare in germ cell tumor (GCT) patients (pts). Systematic data on risk factors, treatment and outcome are largely lacking. Methods: An international data ba...

208 Background: Although EP exerts a synergism with D and a meta-analysis suggested a survival advantage in combining EP to chemotherapy, D+EP combination is usually discouraged due to a marginal improvement in disease control at cost of an enhanced toxicity compared to D alone. In order to assess the role of EP added to D we have analyzed data from pts enrolled in two randomized trials with D ± EP conducted by our group (BJU Int 2008 – ASCO GU 2012). Methods: All patients received D 70 mg/m2IV q 3 wks ± E 280 mg/TID PO for 5 days starting 1 day prior to D. Ninety-five pts of the first study (started in 2002) were treated until progression; 148 pts of the second study received 8 D courses in continuous or intermittent fashion. We evaluated PSA response, PFS according to PCWG2, OS and toxicity. Results: We shared the clinical data from all 243 pts (123 D, 120 D+EP): the median baseline PSA values were 53 and 60 respectively; 49.5% and 59.1% of the D and D+EP pts presented visceral metastases, respectively. Clinical outcomes and main toxicities are summarized in the Table. Conclusions: The addition of EP to D was tolerable with a mild toxicity profile; it was able to double the biochemical responses which did not translate in any PFS or OS advantage. From our data the addition of EP addition to D should not further role in first line of CRPC, while it may help to overcome D resistance in selected cases according to our previously published data (Urol Oncol 2010). However, this statement should be critically considered at the light of new drugs availabile and active after D failure. Clinical trial information: 2006-005728-17. [Table: see text]

90 Background: Eight consecutive courses of D are usually considered a standard first line treatment for CRPC pts. The pts quality of life (QL) may be worsened and an I administration could mitigate this effect. We verified if an I therapy may reduce the impact on pts’ QL compared to continuous (C) treatment. Methods: The treatment was D 70 mg/m2IV q 3 wks ± estramustine (E) 280 mg/TID PO for 5 days. Pts were randomized to receive 8 courses D±E continuously (C) or intermittently, with a 3-month rest period after the first 4 courses. QL was evaluated by EORTC QLQ C30 at baseline and every 6 weeks. For the study aim, we considered evaluable for QL pts who received at least 5 D±E courses and filled the QL instruments. Results: 148 CRPC pts were enrolled from 11/06 to 10/10 with 94 pts evaluable for QL (53 and 41 treated with I with C therapy, respectively). No statistically differences were observed between C and I treatments for QL outcomes: the table shows the median value of single EORTC QLQ C30 scales scores at each assessment time-point. Conclusions: The present study failed to demonstrate that I treatment may produce a QL advantage compared to C treatment which remains the reference therapy for first-line of CRPC pts. Clinical trial information: 2006-005728-17. [Table: see text]

415 Background: The Retrospective analysis of Sorafenib (So) as the first- or second- target therapy (RESET) study in metastatic renal cell carcinoma (mRCC) patients assessed the use and safety of sorafenib under daily-life treatment conditions in a community-based patient population in Italian centers. Methods: RESET was a retrospective, observational, non-interventional field study in mRCC patients. Treatment decisions were determined by each physician according to local prescribing guidelines and clinical practice. Patients for whom a decision to treat with sorafenib single agent as first- or second- target therapy (TT) for mRCC has been made, were eligible for inclusion. Patients that started So treatment between January 1, 2008 and December 31, 2010 were included. Data collection started retrospectively in 2012, in order to have a period of observation of at least 1 year up to 31st Dec 2011. Endpoints included safety, overall survival (OS), progression-free survival (PFS), response rate (RR), and treatment duration. Subgroup analyses included age, Eastern Cooperative Oncology Group performance status, prior therapy, number of metastases, and line of TT with So. Results: From February to Jululy 2012, 358 pts from 37 Italian centers were enrolled. The most common ≥ grade 3 drug-related adverse events were hand-foot skin reaction (6.3%), rash (2.3%), hypertension, fatigue, and diarrhea (1.7% each). In the overall population, median OS was 17.2 months (mos) (95% CI 15.5 – 19.6 mos) and median PFS was 5.9 mos (95% CI 5.0-6.8 mos). Median duration of treatment with So was 5.09 mos. Complete response was observed in 3 (0.8%) pts, partial response in 53(15.0%) pts and stable disease in 139(39.4%) pts. In pts receiving So as first- or second- TT, median OS was 19.9 mos (95% CI 15.4-25.3 mos) and 16.6 mos (95% CI 13.1-18.4 mos) respectively, and median PFS was 6.6 mos (95% CI 4.9-9.3 mos) and 5.3 mos (95% CI 4.4-6.2 mos) respectively. Conclusions: The efficacy and safety of So under routine clinical practice conditions in the setting of community-based practice in Italy were similar to that reported in prospective clinical trials. The efficacy of So was observed in the subgroup of pts receiving So as either the first or second TT for mRCC.

e15160 Background: Pts who receive first line for CRPC are usually treated with 8-10 consecutive courses of D. The pts quality of life (QL) may be worsened and an I administration could limit this effect. E is an old drug showing a synergistic action with D. This study is aimed to compare QL of C and I D and whether E added to D improved its activity, in a 2 × 2 factorial design. Methods: CRPC pts were randomized to: C D 70 mg/m2 IV q 3 wks for 8 courses alone (arm A) or with E 280 mg/TID PO for 5 days starting 1 day prior to D (arm B), or the same treatments given with a 3-month rest period after the first 4 courses (arm C and D, respectively). The primary end points were QL (EORTC QLQ C30 and BPI) of A+B vs C+D and 1-y PFS (according to PCWG2) of A+C vs B+D. Results: 148 CRPC pts were enrolled from 11/06 to 10/10 with 128 pts evaluable at this time. The median age was 69 (range 42-81) and the median baseline PSA was 55.6 (range 0.33-4212). The major hematological toxicities were: anemia G3 (3 pts), neutropenia G3 (4 pts) – G4 (5 pts), febrile neutropenia (5 pts). Comparing C and I, QL outcomes were not statistically different in terms of general QL items. Comparing D and DE, 1-y PFS was superimposable (10% and 13.5%, respectively). The 2-y overall survival was not different between I and C arms 42.5% and 53.7% respectively) and between D and DE arms (42.8% and 53.5% respectively). Conclusions: These preliminary results suggest that I treatment did not produce a QL advantage compared to C treatment, while the addition of E to D did not improve 1-y PFS of CRPC pts.

220 Background: DOC given for 8 consecutive courses is considered a standard first line treatment for CRPC pts and I administration could reduce its impact on quality of life (QL). E is considered synergistic with DOC. Aim of this study was to evaluate in a 2 × 2 factorial design, if I DOC could improve QL compared to C DOC and whether E added to DOC could improve its activity. Methods: CRPC pts were randomized to: C DOC 70 mg/m2 i.v. q 3 wks for 8 courses, alone (arm A) or with E 280 mg/TID p.o. for 5 days starting on -1 day (arm B), or the same treatments given with a 3-month rest period after the first 4 courses (arm C and D, respectively). The primary end points were QL (EORTC QLQ C30 and BPI) of A+B vs C+D and 1-y PFS (according to PCWG2) of A+C vs B+D. Results: From 11/06 to 10/10, 148 CRPC pts were enrolled and 124 pts are presently evaluable (24 too early). The median age was 69 (range 42–81) and the median baseline PSA was 55.6 (range 0.33–4212). The major hematological toxicities were: anemia G3 (3 pts), neutropenia G3 (4 pts) – G4 (5 pts), febrile neutropenia (5 pts). QL outcomes of C and I groups, were not statistically different in terms of general QL items. 1-y PFS was also superimposable (10% and 13.5%, respectively) for DOC and DOC+E groups. The 2-y overall survival was also evaluated with no differences between I and C groups (42.5% and 53.7% respectively) and between DOC and DOC+E groups (42.8% and 53.5% respectively). Conclusions: These preliminary results seem to indicate that I treatment may not improve QL compared to C treatment. Moreover, the addition of E to DOC did not improve 1-y PFS of CRPC pts. Updated data with the complete sample analysis will be presented.

411 Background: Many medical oncologists are still reluctant to use the standard sunitinib regimen in older patients (pts) with metastatic renal cell cancer (mRCC) because of concerns about tolerance. We assessed the routine use of first-line sunitinib in mRCC pts aged ≥70 yrs. Methods: We reviewed the clinical files of 154 pts aged ≥70 yrs with mRCC treated with first-line sunitinib in sixteen Italian Oncology Units from February 2006 to April 2011. Sunitinib 50 mg/d 4 wk on/2 wk off was considered the standard regimen (SR). All alternative schedules of sunitinib administration were considered as adapted regimens (AR). After univariate analysis a multivariate analysis was carried out by Cox regression model and included the following variables: age (1,000/microL), prognostic score for VEGF-targeted agents according to Heng 2009 (good + intermediate prognosis vs poor prognosis), and treatment schedule (SR vs AR). Results: Median age was 74 yrs (range, 70-88 yrs). One hundred six pts (68.8%) received a SR and 48 (31.2%) received an AR consisting of 37.5 mg/d 4 wk on/2 wk off (32 cases, 67%), 25 mg/d 4 wk on/2 wk off (12 cases, 25%) and 37.5 mg continuous once-daily dosing in (4 cases, 8%). Pts treated with an AR were older than those treated with the SR (≥75 yrs, 56% vs 32%, respectively, p=0.008); with no differences for the other variables. Pts received a median of 4 sunitinib cycles with either SR or AR. Grade 3-4 toxicities occurred in 65% of SR and 42% of AR (p=0.008); dose reductions were required in 64% and 40%, respectively (p=0.005); discontinuations due to therapy-related adverse events occurred in 23% and 21%, respectively (p=0.967). Median progression-free survival (PFS) was 10.6 months (95% CI 8.7-15.3) and median overall survival (OS) was 20.1 months (95% CI 15.5-not reached). In multivariate analysis, only PS and the Heng score were predictors of either PFS or OS. Conclusions: Sunitinib is active and feasible in pts with mRCC aged ≥70 yrs. AR does not appear to influence PFS and OS and has a favorable impact on toxicity.

4618 Background: Discouraging results have been achieved in relapsed/refractory UC with the use of either single agents or combination therapies (Rx), including targeted Rx. Promising phase II results with PZP, a multitargeted drug with distinct anti-angiogenic activity, were recently reported (ESMO 2010, LBA23). An update of trial results is presented. Methods: Eligible patients (pts) include histologically confirmed UC unresponsive/relapsing after ≥1 CDDP-based Rx for metastatic disease (perioperative Rx excluded). PZP 800 mg once daily until disease progression or unacceptable toxicity was planned. All pts underwent CT scan and FDG-PET/CT scan at baseline and q4weeks thereafter. An optimal 2-stage Simon’s design was applied with the 1st stage recruiting 21 pts and, if ≥2 responses, a full enrollment of 41 pts. RECIST v.1.1 was used; response-rate (RR) was the primary endpoint. Results: 30 pts were enrolled from 02 to 12/2010. Median age was 64 yrs (43-79). 12 pts (29%) had UC of the upper urinary tract...

217 Background: The occurrence of BMm is usually viewed as an exceptional event in the history of prostate cancer (PC) patients (pts). In two large retrospective series the incidence of BMm in PC pts was about 0.5%. Since the introduction of DOC as first line treatment has improved survival of CRPC pts, we have retrospectively evaluated the occurrence of BMm in such setting of pts, to explore whether the incidence of BMm has changed. Methods: The clinical records of a series of 801 pts with CRPC treated from 2002 to 2010 were reviewed. All pts met the definition of CRPC according to international guidelines: all pts received or were eligible for DOC-based treatment. Results: We collected a series of 28 pts with BMm (incidence 2.9%). Sixteen pts had a median number of 1 brain metastases (range 1-8) and neurological symptoms were present in 11 cases. Teen cases presented meningeal metastases: in this case all but one pt were symptomatic. To date, no detailed information are available for the 2 remaining cases. After BMm diagnosis, local treatments were proposed in 16 pts: 5 pts underwent metastasectomy (M) + external brain irradiation (BI), 1 M alone, 9 BI alone, 1 gamma-knife. Eleven pts received chemotherapy after BMm, while the remaining received only best supportive care. The median interval from the PC diagnosis and the achievement of CRPC was 23 mos (range 7-141) while the appearance of BMm was documented after 6-173 mos (median 42) The median survival after BMm was 3 mos (range 1-29) with 6 pts surviving more than 1 year. These long-term survivors had brain metastases in 5 cases and meningeal metastases in 1 case and were managed with surgery in 3 cases, radiotherapy in 2 cases and DOC in 1 case. Conclusions: It appears from our data that in the DOC era 1) the incidence of BMm in CRPC pts is higher than in the historical reports; 2) the interval from PC diagnosis and the appearance of BMm is clearly longer (42 mos) compared to that reported in historical series (28 mos). These findings could be related to the changes in survival of CRPC, produced by DOC introduction in the clinical practice. A special attention should be reserved to the appearance of neurological symptoms in a long-term CRPC survivor due to a possible relation with BMm. No significant financial relationships to disclose.

e16013 Background: Malignant transformation (MT) is a rare phenomenon characterized by a neoplastic somatic differentiation within a GCT. Little is known concerning its clinical implications. An international registry (INTera Project) has been established to collect all past and new cases worldwide. Methods: Patients (pts) with a MT within GCT have been retrospectively identified from registries of contributing Institutions. Significant clinical and pathological data have been collected and data files gathered at the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. Results: 47 pts have been identified as well as a variety of 12 histologies. 25 pts had MT in primary tumor: 14 of them had no metastases (11 underwent primary retroperitoneal lymph-node dissection - RPLND), and 11 underwent chemotherapy (CT) ± surgery due to metastatic disease. All 14 pts with no metastases remain disease-free (DF) following a median follow-up (f-up) of 72 months (2–236+ months). 6 of 11 pts undergoing chemotherapy remain disease-free following a median f-up of 155 months (8–297+). 22 pts had MT in metastases only and 20 of them are evaluable. Following CT, 7 underwent radical surgery and 5 of them remain DF following a median f-up of 77 months (19–166+ months), while 13 could not undergo radical removal of disease, and 3 of them have been rescued by further CT and are DF at 37+, 41+ and 79+ months. So far, all 14 pts with no metastases as well as 7/9 (78%) who had radical removal of disease are alive and DF versus only 7/22 pts (32%) who could not receive a radical excision of residual masses. Median disease-free survival of pts with MT in primary only versus distant sites only was 54 (0–326+) and 2.5 (0–166+) months respectively (p=0.064 - at Log-rank test). No relevant outcome differences have been observed according to histology. Conclusions: Ongoing INTera project is a collaborative effort of MT case- collection worldwide. Stage of disease and radical surgery seem to associate with outcome. The growing number of cases and a centralized pathology review would help to increase knowledge on this rare disease. No significant financial relationships to disclose.

Background and Aims: To assess helical CT sensitivity in detecting preoperatively Multifocal Renal Cell carcinoma (MFRCC) and clinical occult multifocality in a contemporary and consecutive set of patients according to a multidisciplinary approach. Methods: The renal masses were assessed preoperatively by volumetric multislice helical CT with the objective to detect multifocality. Renal cells carcinoma (RCCs) were classified as unifocal (UF) or multifocal (MF). MFRCCs were selected in 2 groups including CT detected (CT+) and CT undetected (CT-). RCCs were classified in UF and MF. MFRCCs were selected in 2 groups including CT+ and CT-. CT and pathologic findings of MFRCCs were correlated and CT sensitivity was assessed. Statistical methods were performed in order to compare the CT sensitivity with the overall mean sensitivity calculated from the reported literature, to assess statistical inference between UF and MF – RCCs; and to detect statistical significance between CT(+) and CT(-) MFRCCs . Results: Over a period of 24 months, 116 kidney units (KU) of 111 patients were surgically treated for RCC. Multifocality was assessed in 13/116 KU of 12 patients (10.8%). Helical CT detected preoperative multifocality in 8/111 patients (7.2%) and preoperative occult multifocality was assessed in 4 (3.6%), as well. Helical CT sensitivity difference between our (66.7%) and the reported literature experience (22.9%) was significant (p