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The aim of this abstract is to describe the multidisciplinary, multiprofessional management of prostate cancer (PC) patients activated by the Prostate Cancer Programme at Istituto Nazionale dei Tumori, Milan. PC patients should be better managed in a multidisciplinary (MD) setting since they have multiple therapeutic and observational options, depending on the risk class. The PC Programme was established in 2004 as a translational project. A MD team with urologists, radiation oncologists, medical oncologists, psychologists, palliative care experts, uropathologists and radiologists was built, diagnostic and therapeutic guidelines were shared and adopted, a MD clinic was started in March 2005 organized in: Friday clinic: urologist, radiation oncologist and psychologist (medical oncologist on demand) examine PC patients synchronously Monday case discussion (CC) to share the cases, check quality and application of guidelines, discuss problematic cases on observation and complex cases seen monodisciplinarily The MD team became multiprofessional by including a project manager, a secretary, a data manager and a nurse. Results 2760 MD clinics from March 2005 to March 2012. The organizational model was modified to better the service. Considering the % of low risk PC patients referring to the MD clinic (61% in 2009) and on active surveillance protocols (342 patients in Feb 2012), we increased resources to better manage this sub-population. The % of advanced and metastatic PC patients (5% in 2011) induced to organize the lists according to the risk class (medical oncologist on demand). Efficacy of the MD clinic is demonstrated in the drug therapies prescribed outside our Institution and terminated by the MD team (11%). Efficacy of the CC is demonstrated in the % of indications formulated in the MD clinics, changed in the following CC (6%) resulting from quality checks of our own performance. Conclusions The MD approach is proving successful. Strategies are agreed on, cases managed multidisciplinarily, critical issues shared. Psychologists help evaluate education-related and cultural factors in patients' decisions. The CC discussion is fundamental to learn the MD working, create a shared know how and approach the patient as a subject of care rather than disease to cure. Thanks to Pro ADAMO and Fond. Monzino for the support Disclosure All authors have declared no conflicts of interest.

A 20-year single-institution experience of clinical stage I nonseminomatous germ cell tumors of the testis (NSGCTT) in childhood and adolescents was reviewed in relation to clinical characteristics, treatment modalities, and survival. Thirty-one patients with clinical stage I NSGCTT were seen between 1980 and 2000: 14 children and 17 adolescents. Yolk sac tumors and/or teratomas occurred in the children, whereas mixed histologies, including embryonal carcinoma, were predominant in the adolescents. After orchiectomy, the children were assigned to surveillance and the adolescents to active treatment: 16 underwent retroperitoneal lymph node dissection (RPLND) and 1 had adjuvant cisplatin-based chemotherapy because of a high-risk histology. Three of the 14 children (21.4%) relapsed 3, 7, and 8 months after orchiectomy: all 3 had yolk sac tumors and presented with increased alpha-fetoprotein levels. No patients had retroperitoneal relapse; two recurred locally and one in the lung. All three children were treated with cisplatin-based chemotherapy with or without surgery. Among the 16 adolescents undergoing RPLND, 4 (25%) had nodal metastases. Three of the 12 patients (25%) who had negative nodes at RPLND relapsed in the lung 3, 7, and 8 months after RPLND. All were treated with cisplatin-based chemotherapy with or without surgery. Five-year relapse-free and overall survival rates for the whole series were 80.6% and 100%, respectively. This series enabled the authors to pinpoint several important aspects of stage I NSGCTT in children and adolescents. In particular, almost all the childhood cases had the same yolk sac tumor histology, the children tended to have localized disease, and an increased alpha-fetoprotein level had a very high predictive value, suggesting that follow-up should include AFP measurements. A conservative approach is the best option in children, while adolescent NSGCTT behaves like the adult disease and management must include similar treatment strategies.

Background Complete responses with third-line or later salvage chemotherapy (CT) for GCT range from 5% to 10%, and nearly all patients (pts) progressing after high-dose CT will ultimately die. CD30 is expressed by embryonal carcinoma (ECA) thus lending support to a rationale for a targeted approach. SGN-35 is an antibody-drug conjugate consisting of the chimeric anti-CD30 antibody SGN-30 chemically conjugated to an antitubulin synthetic analog. The primary objective of the study will be the activity of SGN35 in refractory GCT. Trial design 24 pts with biopsy-proven CD30+ GCT will receive intravenous SGN35 at the dose of 1.8 mg/Kg every 3 weeks until disease progression or onset of unacceptable toxicity. Further eligibility requirements will include failure of 2 or 3 platinum-based CT (including HDCT). All pts will undergo measurement of serum tumor markers, a computed tomography and a PET scan q6 weeks. An optimal Simon's 2-stage design will be applied. The primary endpoint is the objective response-rate (ORR). An ORR of 5% is not promising, while a 25% rate will be promising. In stage 1, 9 evaluable patients will be accrued. If ≥1 patient will be responding, enrollment will be extended to the 2nd stage for further 15. If, over the total of 24 stage 1 plus stage 2 pts, 3 at least will be responding, treatment will be declared worthy for further investigations. The type I and II error are set both at 0.1 (power = 90%). We will test the hypothesis that brentuximab can promote anti-tumor immunity, which might contribute to the clinical efficacy. We will use multiparametric flow cytometry to assess whether SGN-35 can: a) impact on frequency and absolute counts of all main cellular subsets; b) shift the TH1/TH2 balance, in favor of a TH1-type of response; c) reduce the frequency of circulating CD30+ regulatory T cells and CD30+ TH2 memory T cells; d) promote an increase in circulating CD161+TH17 T cells; d) reverse the condition of immune dysfunction, by assessing the expression of negative co-signaling molecules (PD-1, CTLA-4, CD160, CD244, CD57, TIM-3, LAG-3) and of activation/proliferation markers (Ki67, GranzymeB, CD69) on main T cell subsets. As of July 2014, 6 pts have been enrolled (NCT01851200). Disclosure All authors have declared no conflicts of interest.

Aim: A risk-adapted strategy for metastatic seminoma may further refine the necessary burden of chemotherapy while sparing futile treatment for early recognized good responders. The objective of this proof-of-principle study was to evaluate the association of an early metabolic response to PEB and the dimensional response at the end of treatment. Methods: Patients (pts) with newly-diagnosed seminoma and who were candidate to PEB were staged at baseline by computed tomography (CT), PET and serum tumor markers (STM). Then, restaging with PET after 2 cycles of PEB (PET2), and with CT after treatment (3-4 cycles [CT3-4]) were provided. One (greatest) target lesion was chosen to evaluate metabolic/dimensional changes in each case. The primary endpoint was the association between PET2 (EORTC criteria) and CT3-4 response. Secondary endpoints were progression-free survival (PFS) and ability to detect visceral metastases. An analysis after the initial 35 pts was planned. Results: In the time-frame 06/2010-11/2013, 35 pts have been enrolled in this single-site study. Two pts had CSIIA, 12 CSIIB, 13 CSIIC, and 8 CSIII. 3 had an intermediate prognosis because of liver (1) and bone (2) disease. These two were recognized by PET while having a bone-negative CT scan. 4 had a retroperitoneal and 1 a mediastinal primary. All pts had a PET-positive target disease (retroperitoneal in 33 and mediastinal in 2). After 2 cycles of PEB, 25 pts (71.4%) had a metabolic complete response (CR), 10 a partial response (PR). 10 pts had a CR at CT3-4. PET2-negative pts had a significantly smaller residual disease at CT3-4 scan (median 1.2 cm [IQR: 2.8-6] vs 4 cm [IQR: 1-1.9], p Conclusions: PET2 early identified pts having the greatest response to chemotherapy and who finally reached the cut off for observation only ( Disclosure: All authors have declared no conflicts of interest.

Aim: Outcomes of first-line treatment (Tx) for patients (pts) with metastatic poor prognosis GCT are still suboptimal in literature. However, the low incidence of disease and the increasing effectiveness of salvage therapy are issues against further clinical research in the field. We conducted a retrospective study to evaluate the impact of Tx period on prognosis of pts referred to our tertiary cancer center. Methods: A retrospective analysis was conducted on pts receiving at least first-line chemotherapy (CT) at our center. Distribution of frequencies of clinical characteristics were evaluated in the periods 1000 IU/ml, HCG > 1000 IU/l. All tests and confidence intervals were two-sided and set at p = 0.05 level of significance. Results: Between the years 1982 and 2013, 168 pts have been identified. Median age was 27 yrs (IQR: 22-34). No clinical factor had significantly different distribution over time, only LBB metastases trended to higher frequency from 1997 onwards (27.5% Conclusions: In this single-center series of poor prognosis GCT we could not demonstrate an effect on Tx period on survival. The slight differences in PFS on UVA are likely due to modest discrepancies in distribution of clinical variables (LBB). The global picture is that of a stable and very high cure-rate. Based on these results, attempts to improve the outcome exclusively in this field should be discouraged. Results are biased by their retrospective quality. Disclosure: All authors have declared no conflicts of interest.

Background: Transitional cell carcinoma (TCC) is the most common histology accounting for 90% of cases, and the remaining 10% are represented by pure divergent histologies (non-TCCs) such as small cell and squamous cell carcinoma, adenocarcinoma, and micropapillary variant. All non-TCCs are associated with features of aggressiveness such as advanced tumor stage, high risk of recurrence and cancer specific mortality compare to TCC. No standard of care for non-TCCs has been established. The primary objective will be to determine the activity of the combination of paclitaxel, ifosfamide, and cisplatin (TIP) (or carboplatin) in patients with non-TCCs. Secondary objectives will include safety and survival. Trial design: 66 pts with locally advanced (i.e. T3b-4 ± N+) or metastatic non-TCCs will receive paclitaxel 175 mg/m2 on day 1, and ifosfamide 1200 mg/ m2 + cisplatin 25 mg/ m2 on days 1-3 (or carboplatin AUC 4.5 on day 1) every 21 days for 6 cycles. Further eligibility requirements will include ECOG-PS ≤ 1 and no prior systemic therapy, except for relapse after >6 months of perioperative treatment. Carboplatin will be administered instead of cisplatin for patients who will be judged as cisplatin-ineligible (Galsky MD, Lancet Oncol 2011). Patients will be staged and evaluated every 2 cycles with computed tomography (CT) and positron emission tomography (PET)/CT scans. The primary endpoint is progression-free survival (PFS). Simon's Optimal 2-stage design is applied. The null hypothesis that the PFS rate at 6 months is ≤ 40% will be tested against a one-sided alternative that the 6-month PFS rate is ≥ 57%. Based on a nominal power of 80% and alpha (one-sided) of 5%, in the first stage 19 patients will be accrued. If there will be ≤ 8 progression-free patients at 6 months, the study will be stopped. Otherwise 47 additional patients will be accrued for a total of 66. The null hypothesis will be rejected if ≥ 33 patients will be progression free at 6 months. This design yields a type I error rate of 4.9% and power of 80.3% when the PFS rate at 6 months is 57%. At present, one patient has been enrolled and is under treatment. The trial is sponsored by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano Italy (EudraCT registry number 2014-000043-32). Disclosure: All authors have declared no conflicts of interest.

4547 Background: Knowledge of the expression of molecular drivers and potentially druggable targets may enhance prognostic classification of metastatic UC. We aimed at assessing the expression of m...

e15529 Background: Patients (pts) with GCT who fail to be cured following multiple chemotherapy (CT) courses (± high-dose CT) have an extremely poor prognosis and long-term remissions are anecdotal. Pazopanib (PZP) is a potent and selective, orally available, TKI of VEGFR1, 2, and 3, PDGFRα, PDGFRβ, and cKit. We updated the initial results of the ongoing open-label, single-group, phase 2 study which is sponsored by INT Milano. Methods: Patients failing at least 2 platinum-based CT (including high-dose CT) received PZP 800 mg/day orally until disease progression (PD) or evidence of unacceptable toxicity/side effects. All pts underwent measurement of serum tumor markers (STM), a computed tomography and a FDG-PET after 1 month and q2 months thereafter. In a Simon’s 2-stage design, the primary endpoint is 3-month progression-free survival (PFS). In stage 1, 18 evaluable patients will be accrued. If ≥ 3 pts will be progression-free at 3 months, enrolment will be extended to the 2ndstage. Results: From 06 to 12...

4544 Background: CTCs from patients (pts) at different clinical stages were analyzed by a never explored experimental approach based on a combination of two techniques. Provision of this informatio...

4561 Background: Patients (pts) with GCT who fail to be cured following multiple chemotherapy (CT) courses (including high-dose CT) have an extremely poor prognosis. EMA/CO regimen has shown efficacy in high-risk gestational trophoblastic tumors. Since 1992 we introduced this regimen for human chorionic gonadotropin (HCG)-producing refractory GCT. Methods: We retrieved data of adult male pts who received methotrexate (MTX) 100 mg/m2 followed by MTX 200 mg/m2 over 12h d1, etoposide 100 mg/m2 and dactinomycin 0.5 mg mg/m2 d1-2, folinic acid 15 mg orally every 6h d2-3, followed by cyclophosphamide 600 mg/m2 plus vincristine 1 mg/m2 d8, every 21 days. Treatment was continued until marker normalization. Pts had a HCG+ GCT and had failed at least 2 CT regimens. Multivariable analysis (MVA) was undertaken to analyze candidate prognostic factors. ITT analysis was applied. Results: From 02/92 to 05/13, 41 pts were treated in 3rd (20, 49%) or >3rd line (21, 51%). 36 (88%) had a mixed GCT, 2 a pure seminoma and 3 a ...

341 Background: A risk-adapted treatment for TCC may guide new trial designs for early-recognized unresponsive patients (pts). We aimed to prospectively identify early fluorodeoxyglucose (FDG)-PET/CT as a predictor of response and outcome. Methods: Pts with newly-diagnosed advanced/metastatic TCC receiving first-line chemotherapy underwent CT and FDG-PET/CT at baseline, a restaging with PET/CT after 2 cycles only (PET2), and a CT (± FDG-PET/CT) at the end of treatment and during follow up. The endpoints were PET2 metabolic response, RECIST response, progression-free (PFS) and overall survival (OS). Univariable (UVA) and multivariable (MVA) Cox models were fitted. Prespecified variables were presence of visceral metastases, nodal or soft tissue disease, and PET2 response. Results: In the time-frame 05/2010-10/2012, 31 pts with ECOG-PS 0 received a modified MVAC regimen according to Institutional protocol, every 3 weeks. After 2 cycles of MVAC, 6 patients (19.3%) had a complete (CR) and 17 (54.8%) a partial metabolic response (PR) (74% total responders; 95% CI, 55.4-88.1%), 4 had stable disease (SD), 4 progressed. Metabolic response (CR + PR) was associated with final CT response (p=0.007 at Fisher exact test). Metabolic CR was followed by a RECIST CR in all but one cases and metabolic progression at PET2 corresponded to a RECIST PD in all four patients and they all switched to second line chemotherapy. Median follow up was 18 months (IQR: 10-47). Those with metabolic response had a median (95% CI) PFS of 8 (7-11) months compared to 3 (2-5) months of patients without response (p=0.024). PET2 responders had a significant benefit in 8-month PFS (p

305 Background: The small, yet significant, survival advantage with neoadjuvant chemotherapy in MIBC needs to be improved. A rationale exists for inhibiting the RAF/MEK/ERK pathway and investigating S-CG combination in an ongoing open-label, single-group, phase II trial. Methods: Patients (pts) with T2-4N0 MIBC received 4 cycles of cisplatin 70 mg/m2 on day 1 and gemcitabine 1000 mg/m2 on day 1 and 8, every 3 weeks. Sorafenib 400 mg q12h was administered daily from day 1 to cystectomy. An optimal 2-stage Simon’s design is applied. 6 pathologic complete responses (pT0, primary endpoint) should be observed in the first stage before moving to full enrollment of 45 cases. Residual carcinoma in situ with no evidence of invasive tumor was considered as pT0. Intention-to-treat analysis was applied. Biomarker and circulating tumor cell (CTC) analysis is ongoing. Results: 23 pts were enrolled from 04/11 to 07/13. Thus far, 21 completed the treatment and are evaluable. Median age was 61yrs (IQR: 54-66). 11 had T2, 9 T3, and one a T4 disease. 6 pts had hydronephrosis at presentation. 19 pts underwent radical cystectomy. Eight pts (38.1%, 95% CI: 18.1-61.6%) had a pT0 and 2 pts a pT

376 Background: Patients (pts) with germ cell tumors (GCT) who fail to be cured following multiple chemotherapy (CT) courses (± high-dose CT) have an extremely poor prognosis and long-term remissions are anecdotal. Pazopanib (PZP) is a potent and selective, orally available, TKI of VEGFR1, 2, and 3, PDGFRα, PDGFRβ, and cKit. Here we report the initial results of the ongoing open-label, single-group, phase II study which is sponsored by INT Milano (ClinicalTrials.gov NCT01743482). Methods: Pts with refractory GCT received pazopanib 800 mg/day orally until disease progression or evidence of unacceptable toxicity/side effects. Eligibility requirements included failure of at least two platinum-based CT, including high-dose CT. All pts underwent measurement of serum tumor markers (STM), a computed tomography and a FDG-PET after one month of treatment and q2 months thereafter. Results: From May 2013 to July 2013, five pts were enrolled, three in fourth, and two in fifth-line. Median age was 39 (IQR: 33 to 48). Three out of five had failed high-dose chemotherapy (HDCT), two had an extragonadal primary, all pts had at least one elevated STM at baseline, the sole parameter in one patient, two had liver metastases, four pts had a retroperitoneal relapse. Four had elevation of alfafetoprotein (AFP), one of human choriogonadotropin (HCG). Four were nonseminomas, one a pure seminoma. After the first month of treatment, four out of five pts had a decrease in marker levels, one patient had disease progression (PD). Two of the responding pts had a necrotic evolution of disease at computed tomography corresponding to a RECIST and metabolic (PET/CT) progression, two had a stable disease. Two-month follow up is available for three out of four responders: one interrupted PZP for toxicity and had a marker PD, another an increase to baseline levels and the last one a further reduction (pure seminoma, one out of five confirmed response at two months). There were two cases of hepatic toxicities (one G2 and one G3-4 with dose interruption). Conclusions: PZP is endowed with preliminary activity in extensively pretreated patients with GCT. The unique availability of STM in interpreting densitometric and metabolic response might provide insights into response assessment of solid tumors under antiangiogenic therapy. Clinical trial information: NCT01743482.

517 Background: Nx has been established as a prognostic factor in mRCC and included in current prognostic classifications. Despite this, the prognostic value of time from Nx has not well established in patients (pts) treated with TTs. We aim to investigate if the time from Nx to diagnosis of metastatic disease is a prognostic factor in mRCC pts treated with TTs. Methods: Database of pts treated at Istituto Nazionale Tumori of Milan, was reviewed. Only pts who received an Nx were included in the final analysis. For each pt time from Nx to diagnosis of metastatic disease was collected and pts were divided in three groups based on time ≥ 1 year (A), < 1 year (B) or Nx performed at diagnosis of metastatic disease (C, cytoreductive). Age, sex, ECOG performance status and MSKCC prognostic group were also collected. Overall survival was calculated from the start of therapy to death or last follow-up. Median OSs were estimated with Kaplan-Meier method and compared with log-rank test; association of factors with survival was evaluated with Cox-analysis. Results: A total of 285 pts meet the inclusion criteria: median age was 60.8 y (IQR: 52.5 – 68), 73% were males; ECOG-PS was 0 in 61%, 1 in 34% and 2 in 5%. Prognosis based on MSKCC classification was good in 36%, intermediate in 49% and poor in 15%, and its prognostic value was confirmed (HR: 2.7; 95%CI, 2.1 – 3.4, p

319 Background: CTCs from patients (pts) at different clinical stages were analyzed by a never explored experimental approach based on a combination of two techniques. Provision of this information may contribute to optimize tailored therapies. Methods: 3 cohorts were analyzed: pts with muscle-invasive bladder cancer receiving neoadjuvant (NA) sorafenib + chemotherapy (CT) (NCT01222676), and metastatic (M1) pts receiving 1st-line MVAC, and 2nd-line (M2) anti-TGFβ receptor ALK1 PF-03446962 (NCT01620970). 5 ml of whole blood were filtered by ScreenCell Cyto devices and CTC status was assessed with centralized scoring by referral pathologists. Additional 5 ml of whole blood were processed by immunomagnetic beads (AdnaTestSelect kit) and the expression level of a panel of markers (including EPCAM and MUC1) was studied using RT-multiplex PCR. The objective was the association with clinical response/relapse. Results: From 07/2012 to 08/2013, 48 pts (17 NA, 17 M1, and 14 M2) were enrolled. Rates of baseline CTC+ were: 91, 77, 75% (ScreenCell), and 36, 41, 69% with AdnaTest, respectively. NA setting: from baseline to post-CT, all pts had a stepwise reduction of CTC count/5 ml blood by ScreenCell (median baseline of 15 [0-40] to 0 [0-3]). Increase in circulating EPCAM±MUC1 levels by CTC was seen in accordance with the 3 disease progressions (PD). M1 setting: Pts who relapsed had a median of 25 CTC/5 ml (IQR: 12-47) at the end of CT, while all the others had levels 6 month follow-up displayed an increase in EPCAM levels and CTC number which anticipated a relapse. M2 setting: increase in CTC signals from baseline to +2 months was observed in 8/9 evaluable cases by AdnaTest and 4/5 evaluable cases by ScreenCell, in accordance with PD. Conclusions: This combined technique showed a promising ability to anticipate the detection of clinical relapse, although it still needs a larger sample size. Refining molecular characterization will help designing informed clinical trials.

328 Background: Second-line chemotherapy (CT) of advanced GCT is vividly debated and no standard of care has been established. Since 1985 we introduced the modified PEI combination with the aim to reduce toxicity while maintaining efficacy over the original regimen. Methods: We retrieved data of pts who received ifosfamide at 2.5 gr/m2 (with mesna) on days 1-2, etoposide and cisplatin at 100 mg/m2 and 33 mg/m2, respectively, on days 3-5 every 21 days for a maximum of 4 cycles, followed by surgery of residuals. Multivariable analysis (MVA) was undertaken for pre-specified variables and IGCCCG-2 score was analysed as a continuous covariate. ITT analysis was applied. Results: From 02/85 to 01/12, 189 pts failing cisplatin, bleomycin, and vinblastine (PVB, N=25) or etoposide (PEB, N=164) were treated. 87% had a gonadal primary, 50.3% were MSKCC poor risk, 74.7% were IGCCCG-2 intermediate-to-very high risk, 21.8% had liver, bone or brain (LBB) mets, 16.7% were late relapses. 35 pts (18.5%) had a complete response (CR), 68 (35.9%) a marker normalization (PRm-) (major response-rate: 54.4%). 41/68 PRm- were rendered disease-free (total NED-rate: 40.2%). After a median follow-up of 122.1 mos (IQR 71.4-232), median (95%CI) PFS was 7.2 mos (6.2-9.5) and median OS was 21.7 mos (16.7-69.5). 2yr PFS was 34.3% (28.1-41.9) and 5yr OS was 42.1% (35.3-50.2). Mediastinal primary (HR 3.06, 95%CI, 1.68-5.58), LBB mets (HR 2.02, 95%CI, 1.30-3.16), and AFP>1000 ng/mL (HR 2.78, 95%CI, 1.51-5.14) were negative prognostic factors for OS at MVA while no effect was seen according to IGCCCG-2 category. 70.3% of grade 3-4 neutropenia (25% febrile neutropenia), 48.1% thrombocytopenia, 21.1% anemia, 3% neurotoxicity, and no severe renal toxicity were recored. 81 pts (78% before 2000) had a dose reduction of ≥1 drug for ≥1 cycle. No discontinuations for toxicity occurred. Conclusions: Dose-modified Italian PEI showed activity comparable with the best ones achievable by conventional-dose CT (CDCT) in an unselected patient population, and a favorable toxicity profile. Results are among the most robust available for a CDCT, and should be considered as an appropriate benchmark to be compared with high-dose CT.

284 Background: MVAC and cisplatin-gemcitabine (CG) are the established standard of care for untreated patients (pts) with locally advanced-metastatic UC. CG is the preferred choice in most cases due to the better toxicity profile. Modifying MVAC by reducing side-effects may have the potential to improve efficacy. Methods: Data relative to unresectable T/N+/M+ pts entering sequential single-institution trials were collected. Chronologically, these changes to classic MVAC were provided: deletion of day 22 and administration of 25 mg/m2CDDP d2-5 (modified MVAC [mMVAC]); deletion of day 22 only, and deletion of days 15 and 22 in a 3-week schedule (simplified [s]MVAC1 and 2). 4-6 cycles were provided. Multivariable analysis was undertaken for recognized clinical variables. ITT analysis was applied. Results: From 09/86 to 04/12, 157 pts were treated (25 mMVAC, 72 sMVAC1, 60 sMVAC2). 84% had a bladder primary, 70% had distant metastases, 53% and 36% had nodal and visceral mets, respectively. 43.9% had a Bajorin score 1-2. 65.8% attained a complete (19.1%) or partial response (46.7%), 24.3% a stable disease, with no difference among regimens. After a median follow up of 87 mos (IQR 37-161), median (95% CI) PFS was 10.2 mos (8.4-10.8) and median OS was 19.5 mos (16.3-24.1). 2yr (95% CI) PFS and 5yr OS were 30.9% (23.8-40.1) and 25.3% (18.8-34.1). Responses were mainly seen in nodal mets (OR: 2.48, 95%CI, 1.12-5.54). Presence of visceral (HR: 2.42, 95%CI, 1.37-4.30), nodal mets (HR: 1.70, 95%CI, 1.07-2.69) and mMVAC regimen (HR: 1.73, 95%CI, 1.02-2.92) were negative prognostic factors for OS. G3-4 toxicities were similar among regimens and were 36% neutropenia, 14% thrombocytopenia, 12% anemia, 10% mucositis, and 4% renal toxicity. 2 pts died for toxicity. Conclusions: Simplifying MVAC schedule may result in improved activity and efficacy while reducing toxicity. Though retrospective, the combined results of MVAC modification would claim a benefit over either classic/dose-dense MVAC or CG in terms of efficacy and safety. A reappraisal of the upfront management of advanced/metastatic UC is warranted.

329 Background: CD30 is invariably expressed by untreated EC thus lending support to a rationale for a targeted approach. However, preliminary reports claimed an effect of chemotherapy (CT)-induced downmodulation of CD30 that might affect the potential use in relapsing disease. We aimed at evaluating the persistence of CD30-positivity in post-CT residuals. Methods: We retrieved paraffin-embedded post-CT samples yielding non-teratoma viable cells after ≥ 1 CDDP-based CT from the institutional surgical series. EC component was required and assessed by morphology and Oct-3/4 staining. The entire set was re-stained for CD30 and assessed by 2 pathologists blinded to study purpose. CD30-positivity was defined as a >80% membranous staining with a diffuse moderate-to-strong intensity. Clinical data included site of tumor primary, histology, CT regimen, and type of surgery. Results: From 12/1990 to 09/2012, a total of 246 cases with pure EC or mixed GCT residuals were treated. 49 (EC: 16; mixed GCT: 33) had both complete data and suitable tissue for study purposes. 40 pts had retroperitoneal or mediastinal nodes, 12 pts had lung metastases, 4 had either liver, bone or brain mets. 35/49 cases (70%) preserved CD30 positivity. 20/35 (57%) pts had residual disease after 1stline CT, 15/35 (43%) after multiple CTs (median 3.5, range 2-5). 2 pts (6%) had undergone high-dose CT and 4/35 (11%) were late relapses. 32/35 pts (91%) had gonadal primary, 1 had a retroperitoneal and another a mediastinal primary. The median survival of 35 CD30-positive patients was 16 mos (IQR 3.3-22.9) while it was 48.5 mos (IQR 21.7-72.6) for the 14 CD30-negative patients (p=0.0297 at Gehan-Breslow-Wilcoxon test). 5-year overall survival of CD30-positive and negative patients was 35.7% (95% CI: 18.2-53.6) and 49.7% (95% CI: 19.7-74.0), respectively. Conclusions: Our results on selected relapsing pts suggest that EC retained CD30 even in the far salvage setting, thus confirming to be a reliable target for treatment. A trend towards a poorer prognosis and shorter survival characterized CD30+ cases. A phase 2 study with the antibody-drug conjugate Brentuximab vedotin is currently in plan for GCT.

Department of Preventive and Predictive Medicine, Fondazione IRCSS, Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy Department of Cancer Epidemiology, Istituto Superiore di Sanita , Viale Regina Elena 299, Rome, Italy Department of Medicine, Urology Unit, Fondazione IRCSS, Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy Department of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands Comprehensive Cancer Center Netherlands, Plesmanlaan 125, PO Box 9236, 1006 AE Amsterdam, The Netherlands Department of Medical Oncology, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands Croatian National Cancer Registry, Croatian National Institute of Public Health, Rockefellerova 7, 10000 Zagreb, Croatia Stampar School of Public Health, University of Zagreb Medical School, Rockefellerova 4, 10000 Zagreb, Croatia Consortium for Biomedical Research in Epidemiology and Public Health (CIBER Epidemiologia y Salud Publica-CIBERESP), Spain Navarra Cancer Registry, Navarra Public Health Institute, C) Leyre 15, Pamplona 31003, Spain

78 Background: Final results of INT70/09 trial of PZP in 41 multi-relapsed patients (pts) with UC reported one of the highest response-rates as 7 pts (17%) had a confirmed PR, 14 a confirmed SD (51% clinical benefit) after independent review (AACR and ASCO 2012). Final achievements on circulating biomarkers are presented. Methods: From 02/2010 to 07/2011, pts received PZP 800 mg once daily until PD or unacceptable toxicity. 50 mL of EDTA blood samples were collected at baseline (T0) and after 4wks (T1) together with disease restaging in all pts to analyze plasma levels of VEGF, sVEGFR-1,-2 and -3, c-Kit, HGF, TGF-β, IL-6, 8 and 12 by multiplex ELISA plates. Changes in marker levels were analysed with the Wilcoxon signed-rank test and matched with RECIST response with the covariance analysis. A logistic regression and Cox regression model evaluated the association with response probability, PFS and OS. Biomarker level was modelled as a continuous time varying covariate. Results: Significant increase from T0 to T1 was observed for VEGF (pT1 level associated with lower response probability at covariance analysis (p=0.0104). Both TGF-βT0 (p=0.0019) and TGF-βT1 (p=0.0017) levels associated with PFS while elevated IL8T0 (p=0.0170), IL8T1 (p=0.0107) as well as TGF-βT0 (p=0.0472) and TGF-βT1 (p=0.0013) levels associated with OS. Elevated VEGFT1 also associated with shorter OS (p=0.0084) but significance was lost when jointly modelling biomarkers. Pts having IL8T1 levels < 80 pg/ml had greater response (80%) and 6-month OS (60%) probability than those with a level ≥ 80, for whom a dramatic fall was observed. Conclusions: Both IL8 and TGF-β had a prognostic value while IL8 modulation was also associated with response probability. These markers may serve to select pts most likely to get a benefit from PZP. There is a rationale for a sequence/combination with PZP and a phase II study of an anti-TGF-β receptor ALK1 moAb (PF-03446962) for refractory UC is currently recruiting (NCT01620970).

Introduction Discouraging results have been achieved with salvage therapy for refractory UC. Final results of INT70/09 trial of PZP in 41 multi-relapsed or refractory patients (pts) were promising and the primary endpoint of objective responses was met as 7 pts (17%) had a confirmed PR, 24 had a SD (76% clinical benefit) after independent review (AACR & ASCO 2012). Final achievements on the role of IL8 are presented. Material and methods From 02/2010 to 07/2011, 41 pts received PZP 800 mg once daily until PD or unacceptable toxicity. 50 mL of EDTA blood samples were collected at baseline and q4wks together with disease restaging in all pts to analyze plasma levels of VEGF, sVEGFR-1,-2 and -3, c-Kit, HGF, IL-6, 8 and 12 by multiplex ELISA plates. Marker levels were analysed with the Kruskal-Wallis test for pre-post changes, with the covariance analysis and a flexible logistic regression model and with a multivariate Cox regression model to evaluate the relation with response probability and overall survival (OS), respectively. Results Significant increase from T0 (baseline) to T1 (+4wks) level was observed for VEGF (p Conclusions The role of IL8 in relation to the development of resistance and shorter survival was demonstrated in the clinic and 2 distinct populations were early recognized. If confirmed on larger series, levels of IL8 ≥80 pg/ml after 4 wks would be used to early decide to switch/interrupt antiangiogenic drugs, with relevant cost-saving advantages. A sequence with an anti-IL8 is characterising our current research. Disclosure All authors have declared no conflicts of interest.

4507 Background: Discouraging results have been achieved with standard and novel compounds in refractory UC. The final results with biomarker analysis of INT70/09 trial with pazopanib are presented. Methods: Pts failing ≥ 1 chemotherapy regimen for metastatic disease underwent PZP 800 mg once daily until PD or unacceptable toxicity. CT scan and PET scan were planned at baseline and q4weeks thereafter. Independent review of all CT scans was made and ≥ 5 RECIST CR+PR were required to conclude for activity according to Simon’s 2-stage design. 50 mL of EDTA blood samples were collected at baseline and q4wks in all pts to analyze plasma VEGF, sVEGFR-1,-2 and -3, c-Kit, IL-6, 8 and 12 by multiplex ELISA plates. Results: 41 pts were enrolled from 02/2010 to 07/2011. 15 pts (37%) had UC of the upper urinary tract. 20/41 pts were treated in 3rd line or beyond. 19 pts (46%) were CDDP-refractory and 22 (54%) had hepatic metastases. 27 (66%) had ECOG PS 1-2. 7 pts (17%) had a confirmed PR, 24 had a SD (76% clinical benefit). 20 pts (49%) had a confirmed necrotic evolution of metastases and/or a decreased SUV at PET consistent with PR. Median PFS and OS (95% CL) were 2.6 (1.7-3.7) and 4.7 mos (4.2-7.3), respectively but 7 pts (17%) had long-term cure for >10mos (4/7 beyond 2nd line). G3 hypertension occurred in 2 pts, diarrhoea in 5, anemia and hand-foot syndrome in 3 pts each. Significant increase from T0 (baseline) to T1 (+4wks) level was observed for VEGF (pT1 levels significantly associated with RECIST progression at covariance analysis (p=0.0104). Elevated IL8T1 levels (IQ range, HR=2.11), liver mets (HR=2.33), PS (HR=3.73) and upper tract UC (HR=0.33) were significant variables for OS at multivariate Cox analysis. Conclusions: This is the 1st trial ever presented to meet the primary endpoint with a targeted drug in UC. A role for antiangiogenesis in UC has been set. Increasing levels of IL8 were associated with PD and worse outcome and may be included in a new prognostic model. Future investigation should aim at targeting IL8 to improve efficacy results by prolonging responses.

4629 Background: Targeted Therapies (TTs) have definitely improved survival in patients with mRCC. However the optimal therapeutic strategy is not shared. This study was performed to assess the overall survival (OS) in a consecutive series of mRCC patients receiving TTs. Methods: Characteristics and outcomes of 336 patients affected by mRCC receiving TTs were collected from the database of Istituto Nazionale Tumori of Milan. The main characteristics of patients were: ECOG PS 0/1/2 186 (55%)/131 (39%)/19 (6 %); clear-cell histology 291 (87%); previous nephrectomy 293 (87%). According to Motzer criteria 32% of patients showed low risk, 48% intermediate risk and 20% poor. Overall, 167 (50%) patients received one TTs, while 116 (34%), 42 (13%) and 11 (3.3%) received 2, 3 and 4 TTs, respectively. 245 (73%) patients received sorafenib (So), 212 (63%) sunitinib (Su), 33 (10%) a bevacizumab regimen and 73 (22%) other TTs, including everolimus, temsirolimus and axitinib. The Kaplan Meier curves were used to describe the survival.The uni- and multi-variate analyses for OS were carried out by means of Cox proportional hazard regression analysis. Results: Ata median follow-up of 43 months, 199 patients (57 %) had died. The median OS was 24 months (95%CI: 20.0-27.0) and the 5-year OS was 24.6 % (95 %CI: 18.7-30.8). In univariate analyses, there were no significant differences in the hazard ratios (HR) for So followed by Su compared to Su followed by So (HRSU-SO / SO-SU = 1.16; 95%CI: 0.57-2.33) or compared with other therapies (HROther sequential th. / SO-SU = 1.21; 95%CI: 0.78-1.88; p=0.674).In the multivariate analysis, in terms of OS any statistical difference was reported as regards the sequence used (Su/So vs So/Su; p>0.05) or bevacizumab regimen as compared to Su and/or So used sequentially (p>0.05). In the uni and multivariate analysis ECOG PS, nephrectomy, Fuhrman grade and number of sites of disease are independent predictive factors of outcome (p< 0.01). Conclusions: These data suggest that TTs improve OS in mRCC without any statistical difference when using different sequences of TTs. No cross-resistance between several sequences of TTs was documented.

Introduction: Discouraging results have been achieved with standard and novel compounds in refractory UC. Promising interim results with PZP, a multitargeted drug with distinct anti-angiogenic activity, were recently reported (ESMO 2010, ASCO 2011). The final results corroborated by biomarker analysis is presented. Material and Methods: Eligible pts relapsing or progressing after at least 1 chemotherapy regimen for metastatic disease underwent PZP 800 mg once daily until disease progression or unacceptable toxicity. Whole-body contrast-enhanced CT scan with densitometric analysis of target lesions and PET scan were planned at baseline and q4weeks thereafter. Independent review of all CT scans was made. ≥5 RECIST complete + partial responses (CR+PR) were required overall to declare drug activity according to Simon's Optimal 2-stage design. 50 mL of EDTA blood samples were collected at baseline and q4wks (concurrently with CT-PET scans) in all pts to analyze drug-induced changes in the amount of plasma VEGF, sVEGFR-1,-2 and -3, c-Kit, IL-6, 8 and 12 by multiplex ELISA plates. Results: 41 pts were enrolled from 02/2010 to 07/2011. Median age was 67 yrs (40-84). 15 pts (37%) had UC of the upper urinary tract. 20/41 pts were treated in 3rd line or beyond. 19 pts (46%) were CDDP-refractory and 22 (54%) had hepatic metastases. 27 (66%) had ECOG PS 1-2. 7 pts (17%) had a confirmed RECIST-defined PR, 24 had a stable disease (76% clinical benefit). 20 pts (49%) had a clear necrotic evolution of multiple metastases and/or a decreased SUV at PET consistent with PR. Median progression-free (PFS) and overall survival (OS) were 2 (1-14) and 4 mos (2-19), respectively but 7 pts (17%) had long-term cure for >10mos (4/7 beyond 2nd line). 4 cases of cavitation-fistulization of large tumor masses were observed. G3 hypertension occurred in 2 pts, G1-2 asthenia in 11, diarrhoea in 5, anemia and hand-foot syndrome in 3 pts each. No discontinuations/dose reductions were needed. Significant increase from T0 (baseline) to T1 (+4wks) level was observed for VEGF (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-433. doi:1538-7445.AM2012-LB-433

168 Background: Abiraterone acetate (AA) is an inhibitor of extragonadal androgen biosynthesis that prolongs overall survival in CRPC patients who have received a chemotherapy including docetaxel. The most common adverse events related to AA therapy were fluid retention, hypertension, hypokaliemia and cardiac disorders. No safety data are available in patients with concomitant cardiac disease. Methods: Metastatic CRPC patients were enrolled in this prospective study if they were also suffering from a concomitant controlled cardiovascular disease. AA 1000 mg per day and prednisone 5 mg bid were administered orally until grade 3-4 adverse events (AE) or disease progression. The primary endpoint was the safety profile while the secondary endpoints were progression-free survival and PSA response. Results: From April to September 2011, 33 CRPC patients with concomitant cardiovascular disorders have been treated with AA. Main patients characteristics were: median age 71 years (range 57–81); baseline mean PSA value 40 ng/ml (6.32-995); the most common sites of disease were bone (27 pts, 81%), lung (11 pts, 33%) and liver (5 pts, 15%). All patients were previously challenged with at least 2 lines of hormone therapy and 1 chemotherapy regimen including docetaxel. The most common pre-existing cardiac disorders were hypertension 22 (66%), arrhythmias 4 (12%), cardiac ischemia 3 (9%) and conduction irregularity 2 (4%). Additionally 9 patients (27%) had metabolic disorders including dislipidemy and hyperglicemia. AA was feasible without inducing grade 3-4 AE nor treatment modification. The most common grade 1-2 AE were asthenia (27%), hypertension (18%) and fluid retention (28%). After a median time of treatment of 4 months (range 2–7 months) no dose modifications due to toxicity were required. No efficacy data are still available. Conclusions: Treatment with AA was feasible and well tolerated also in patients suffering from cardiac comorbidities and risk factors for cardiovascular disease.

341 Background: Rescue of patients (pts) who fail to be cured following 2–3 chemotherapy (CT) combinations ± high dose CT (HDCT) or who are cisplatin-refractory is still an unmet need. The identification of novel active agents/combinations is a priority. Methods: We reviewed the characteristics of consecutive pts who received TPG combination at our Institution for relapse/progression after 2 or 3 previous platinum-based CT lines. Treatment consisted of the administration of paclitaxel 80 mg/m2 IV, cisplatin 50 mg/m2 IV and gemcitabine 800 mg/m2 IV on days 1 and 8 q3w. Program provided up to 8 administrations of TPG followed by surgery of all resectable masses. Paraffin slides of all cases with residual viable cancer after TPG were retrieved: CD30 staining and somatic mutation analysis by Sequenom OncoCarta Panel v.1.0 were planned. Results: From 04/1999 to 07/2011, 74 pts have been treated with TPG, 64 in 3rd and 10 pts in 4th line. Median age was 32 (20–55), median number of prior CDDP cycles was 7 (4–10), 10 pts (13%) had already received HDCT, 4 pts had primary mediastinal GCT, 42 (57%) were CDDP-refractory/abs refractory, 25 pts (34%) had either liver, bone or brain metastases before TPG. 40% developed G3-4 hematologic and 2 pts G3 renal toxicity, none of them being dose-limiting. No treatment delays have been observed. Median number of administrations was 7 (1–10). 8 complete responses (CR), 28 partial responses with normal markers (PRm-) and 13 incomplete response/stable disease have been recorded, for a major response rate (CR+PRm-) of 49%. 34 pts (46%) underwent post-CT surgery which was radical in 15 cases (44%) and led to 7 pathologic CR. 3-, 6- and 12-month PFS was 68% (95% CI 55–76%), 31% (21–42) and 20% (12–30), respectively. 1-yr PFS after HDCT only was 24% (4–53). 12- and 24-month OS was 46% (34–57) and 26% (16–37), respectively. Median PFS and OS were 5 (1–104) and 12 mos (1–116). Conclusions: TPG combination rates first among salvage therapies for refractory GCT, even after failure of HDCT. Benchmark survival endpoints for trials on new agents/combinations have been set. Results of the biomarker analysis will be available in Feb 2012 and may help to corroborate a window of opportunity for targeted agents in GCT.

132 Background: Active Surveillance (AS) is offered to prostate cancer (PCa) patients (pts) with very low risk disease, with well defined diagnostic biopsy details. For this reason, in order to standardize diagnostic inclusion criteria, we requested pathologic review before AS enrollment. We here report on second opinion of PCa needle biopsies to determine how often the expert opinion of a uro-pathologist resulted in a different diagnosis, in the group of pts who were proposed for AS. Methods: AS institutional protocol (SAINT) started in Mar 05. Entry criteria: initial PSA≤10ng/ml, Tstage≤T2a, GPS≤3+3, positive biopsy cores≤20%, max core length containing cancer≤50%. In Nov 07 PRIAS started. PRIAS vs SAINT differs on: max 2 positive cores and PSA density Results: 40/248 (16.1%) cases had minor differences (18 SAINT and 22 PRIAS). In SAINT pts, 12/18 (66.7%) biopsies were increased in the max core length containing cancer (but still≤50%) and 6/18 (33.3%) had a change in the number of positive cores (but still≤20% of total cores). In PRIAS pts 10/22 (45.5%) changes were related to upsizing (from 1 to 2 positive cores) and 5/12 to downsizing (from 2 to 1 positive core). 7/22 changes were related to differences in core length containing cancer (from below to above 50%). Significant differences were observed in 30/248 (12.1%). 20/30 were related to upgrading, 10/30 pts had an upsizing: 1 SAINT pt exceeded 20% of positive cores, 5 SAINT pts exceeded 50% of max tumor length of positive cores, while 4 PRIAS pts increased from 2 to 3 or 4 positive cores. Conclusions: Central pathology review reduces population heterogeneity in the specific setting of AS programs, significant reclassification of risk category involved 12% of pts. Current clinical consequences of central review cannot be determined.