Search

Funder: Victorian Cancer Agency, Funder: NIHR Manchester Biomedical Research Centre, Funder: Cancer Research UK, Funder: Cancer Council Tasmania, Funder: Instituto de Salud Carlos III, Funder: Cancer Australia, Funder: NIHR Oxford Biomedical Research Centre, Funder: Fundación Científica de la Asociación Española Contra el Cáncer, Funder: Cancer Council South Australia, Funder: Swedish Cancer Society, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Institut Català de la Salut, Funder: Cancer Council Victoria, Funder: Prostate Cancer Foundation of Australia, Funder: National Institutes of Health, BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

Purpose: Renal cell carcinoma (RCC) is the most common tumor of the kidney. Considering the TNM classification of 2009, locally advanced and metastatic diseases are included in the groups stage III and IV. The surgical treatment of these tumors could be divided into 3 categories: (1) curative (nephrectomy and/or metastasectomy), (2) cytoreductive, and (3) palliative. Targeted agents showed impressive antitumor efficacy and prolongation of progression-free survival. The integration between target therapy and surgery in patients with locally advanced or metastatic RCC has sometimes facilitated surgery. We aimed to evaluate patients’ response to tyrosine kinase inhibitor (TKI) therapy and the feasibility of surgery after that and to observe complications related to surgery. Methods: From February 2007 to September 2014 in the Istituto Tumori of Milan, IRCCS, we selected patients with locally advanced or metastatic diseases, treated with target therapy before surgery (which comprised nephrectomy or partial nephrectomy, cytoreductive surgery, and metastasectomy) and cryoablation. Results: We selected 33 patients who underwent surgery after TKI therapy. As for response to TKIs, 20 patients (60%) had stable disease, 9 patients (28%) had a partial response, and 4 patients (12%) had progressive disease. A total of 17 patients (51%) presented complications directly or indirectly related to surgery and most of those were classified as grade II Clavien-Dindo score. Conclusions: The association between TKI and surgery seems to have no contraindications. Our dataset provides an example of how surgery after TKI is possible in locally advanced metastatic tumor and does not have an excessive rate of postoperative complications.

The administration of adjuvant chemotherapy for patients with penile squamous cell carcinoma (PSCC) with high-risk features is controversial. In 21 patients who had received adjuvant taxane, cisplatin, and 5-fluorouracil, the expression of p53 in the tumor-positive lymph nodes was the only factor that showed a trend toward poorer survival endpoints. If confirmed, these findings could help in selecting the best candidates for adjuvant chemotherapy. Background: Little is known about the outcomes and prognostic factors of adjuvant chemotherapy for locally advanced penile squamous cell carcinoma after regional lymphadenectomy (LAD). Patients and Methods: We retrospectively reviewed the data from 21 patients who had received taxane, cisplatin, and 5-fluorouracil (TPF, every 3 weeks) in the adjuvant setting at our center. Univariable and multivariable Cox regression analyses were undertaken for disease-free (DFS) and overall survival (OS) of TPF. Results: The patients had received TPF from July 2004 to July 2012 after inguinal (n = 6) or inguinal plus pelvic LAD (n = 15), and the median follow-up was 52 months. Thirteen (61.9%) had pelvic and 5 (23.8%) bilateral inguinal nodal metastases. The median time from LAD to the start of TPF was 5.4 weeks (interquartile range [IQR], 4.1-7.3 weeks). Metastatic tumor tissue from 11 of 19 evaluable patients (57.9%) showed positive immunohistochemistry staining for p53. Univariably, only the expression of p53 showed a trend toward poorer DFS (hazard ratio [HR], 4.14; 95% confidence interval [CI], 0.87-19.68; P = .074) and OS (HR, 4.54; 95% CI, 0.95-21.56; P = .056). The same results were obtained multivariably for DFS (HR, 3.76; 95% CI, 0.78-17.96; P = .096) and OS (HR, 4.29; 95% CI, 0.89-20.57; P = .067). The median DFS was 8.9 months (IQR, 5.9-22.7 months) for p53-expressing patients versus not estimable for non p53-expressing patients (P = .051) and the median OS was 17.2 months (IQR, 12.8-22.7 months) and not estimable, respectively (P = .037). Conclusion: In patients who had received adjuvant TPF for node-positive penile squamous cell carcinoma, p53 IHC expression seemed to be associated with a poorer outcome, and further study is warranted in larger data sets to confirm these findings. This information might be useful to improve the prognostic allocation. (C) 2016 Elsevier Inc. All rights reserved.

Background No compelling evidence is available about surveillance and follow-up of patients with testicular germ cell tumour (TGCT). Methods In the light of the best clinical evidence, the Italian Germ cell cancer Group (IGG) and the Associazione Italiana di Oncologia Medica (AIOM) set up a multidisciplinary national consensus conference, involving 42 leading experts and 3 TGCT survivors. A minimum of 50% of votes was required in order to achieve a consensus recommendation on 29 questions. Results Recommendations have been summarized in three tables, divided by stage I seminoma, stage I nonseminoma and the advanced disease, which may be useful for clinicians to appropriately choose the clinical investigation and its timing during the surveillance and follow-up of TGCT patients based on an accurate estimation of their risk of disease relapse. Conclusions The IGG-AIOM consensus recommendations may help clinicians to choose appropriate clinical investigations for the surveillance and follow-up of TGCT patients.

Objective To harness the frontline therapy in advanced penile squamous cell carcinoma (PSCC), for which chemotherapy exerts moderate activity but poor efficacy. Dacomitinib is an irreversible, pan-epidermal growth factor receptor (HER) inhibitor. Patients and Methods In a phase 2 study (NCT01728233), patients received dacomitinib 45 mg/day, orally, continuously. Inclusion criteria were SCC histology, clinical stage N2-3 or M1 (TNM 2009), and no prior chemotherapy administration. The primary endpoint was the objective response-rate (ORR, according to RECIST v1.1). Stopping rules based on the Bayesian posterior probability (PP) to demonstrate that the ORR exceeded 20% were set. Results From June 2013 to October 2016, 28 patients were treated. Eight (28.6%) had visceral metastases, 14 (50%) had pelvic and 17 (60.7%) clinically-involved bilateral lymph nodes. One complete and eight partial responses were obtained (ORR: 32.1%, 80% credibility interval 21.0-43.0%). The median follow-up duration was 19.8 months (IQR: 6.3-25.7); 12-month progression-free survival was 26.2% (95%CI: 13.2-51.9); 12-month overall survival (OS) was 54.9% (95%CI: 36.4-82.8). The median OS of locally-advanced patients was 20 months (IQR: 11.1-not reached). The Bayesian PP of exceeding the 20% ORR target was 92.3%. Grade 3 adverse events (skin rash) were seen in 3 patients (10.7%). Tissue samples from 25 patients were analyzed. Only two patients had HR-HPV-positive tumor. EGFR amplification was found in 4 patients (equally responders and non responders) and it was confirmed in all post-dacomitinib samples. TERT mutations (60%) were found in responders only, PI3K/mTOR pathway gene mutations in 42.9% responders versus 8.3% non responders. Conclusion Dacomitinib was active and well tolerated in patients with advanced PSCC and may represent an option when combination chemotherapy cannot be administered. Mutations in downstream effectors of EGFR signaling in relation to dacomitinib activity deserve further studies. This article is protected by copyright. All rights reserved.

Background Outcomes of neoadjuvant chemotherapy in patients with muscle-invasive urothelial bladder carcinoma (MIUBC) should be improved. Sorafenib was combined with gemcitabine and cisplatin chemotherapy (SGC) in an open-label, single-arm, phase 2 trial (NCT01222676). Patients and methods After transurethral resection of the bladder, T2–T4a N0 patients received four cycles of SGC followed by cystectomy. Sorafenib 400 mg q12h daily, continuously, was added to standard GC chemotherapy. In a Simon's 2-stage design, the primary endpoint was the pathologic complete response (pT0), assuming H0: ≤0.20 and H1: ≥0.40, with a type I and type II error of 5% and 10%, respectively. Results From April 2011 to June 2016, 46 patients were enrolled. Pathologic T0 response was obtained in 20 patients (43.5%, 95% CI: 28.9–58.9); pT ≤ 1 in 25 (54.3%, 95% CI: 39.0–69.1). After a median follow-up of 35 months, the median progression-free survival was not reached (NR, interquartile range: 23.6–NR), nor was median overall survival (interquartile range: 30.3–NR). Hematologic and extrahematologic grade 3 to 4 adverse events occurred in 45.6% and 26.1% of patients, respectively. In 29 samples from responders (pT ≤ 1) and nonresponders, different distribution of missense mutations involved DNA-repair genes, RAS-RAF pathway genes, chromatin-remodeling genes, and HER-family genes. ERCC1 immunohistochemical expression was associated with pT ≤ 1 response ( P = 0.047). The absence of a comparator arm prevented us to quantify sorafenib contribution. Conclusions SGC combination was active in MIUBC, and the identified molecular features included alterations that may help personalize treatment in MIUBC with new more potent targeted agents, combined with chemotherapy.

Germ-cell tumours (GCT) of the testis and penile squamous cell carcinoma (PeSCC) are a rare and a very rare uro-genital cancers, respectively. Both tumours are well defined entities in terms of management, where specific recommendations - in the form of continuously up-to-dated guide lines- are provided. Impact of these tumour is relevant. Testicular GCT affects young, healthy men at the beginning of their adult life. PeSCC affects older men, but a proportion of these patients are young and the personal consequences of the disease may be devastating. Deviation from recommended management may be a reason of a significant prognostic worsening, as proper treatment favourably impacts on these tumours, dramatically on GCT and significantly on PeSCC. RARECAREnet data may permit to analyse how survivals may vary according to geographical areas, histology and age, leading to assume that non-homogeneous health-care resources may impact the cure and definitive outcomes. In support of this hypothesis, some epidemiologic datasets and clinical findings would indicate that survival may improve when appropriate treatments are delivered, linked to a different accessibility to the best health institutions, as a consequence of geographical, cultural and economic barriers. Finally, strong clues based on epidemiological and clinical data support the hypothesis that treatment delivered at reference centres or under the aegis of a qualified multi-institutional network is associated with a better prognosis of patients with these malignancies. The ERN EURACAN represents the best current European effort to answer this clinical need.

Context Patients with clinical stage I (CS I) seminoma testis with large primary tumours and/or rete testis invasion (RTI) might have an increased risk of relapse. In recent years, these risk factors have frequently been employed to decide on adjuvant treatment. Objective To systematically review the literature on tumour size and RTI as risk factors for relapse in CS I seminoma testis patients under surveillance. Evidence acquisition Relevant databases including Medline, Embase, and the Cochrane Library were searched up to November 2016. Randomised controlled trials (RCTs) or quasi-RCTs, prospective observational studies with controls, retrospective matched-pair studies, and comparative studies from well-defined registries/databases were included. The primary outcome was the rate of relapse and relapse-free survival (RFS). The risk of bias was assessed by the Quality in Prognosis Studies tool. Evidence synthesis After assessing 3068 abstracts and 80 full-text articles, 20 studies met the inclusion criteria. Although evidence to justify a cut-off of 4cm for size was lacking, it was the most frequently studied. The reported hazard ratio (HR) for the RFS for tumours >4cm was 1.59–2.8. Accordingly, the reported 5-yr RFS ranged from 86.6% to 95.5% and from 73.0% to 82.6% for patients having tumours ≤4 and >4cm, respectively. For tumours with RTI present, the reported HR was 1.4–1.7. The 5-yr RFS ranged from 86.0% to 92.0% and 74.9% to 79.5% for patients without versus those with RTI present, respectively. A meta-analysis was considered inappropriate due to data heterogeneity. Conclusions Primary tumour size and RTI are associated with the risk of relapse in CS I seminoma testis patients during surveillance. However, in the presence of either risk factor, the vast majority of patients are cured by orchiectomy alone and will not relapse. Furthermore, the evidence on the prognostic value of size and RTI has significant limitations, so prudency is warranted on their routine use in clinical practice. Patient summary Primary testicular tumour size and rete testis invasion are considered to be important prognostic factors for the risk of relapse in patients with clinical stage I seminoma testis. We systematically reviewed all the literature on the prognostic value of these two postulated risk factors. The outcome is that the prognostic power of these factors in the published literature is too low to advocate their routine use in clinical practice and to drive the choice on adjuvant treatment in clinical stage I seminoma testis patients.

Purpose Few studies have examined the role of radiation therapy in advanced penile squamous cell carcinoma. We sought to evaluate the association of adjuvant pelvic radiation with survival and recurrence for patients with penile cancer and positive pelvic lymph nodes (PLNs) after lymph node dissection. Materials and methods Data were collected retrospectively across 4 international centers of patients with penile squamous cell carcinoma undergoing lymph node dissections from 1980 to 2013. Further, 92 patients with available adjuvant pelvic radiation status and positive PLNs were analyzed. Disease-specific survival (DSS) and recurrence were analyzed using the Kaplan-Meier method and multivariable Cox proportional hazards model. Results 43% ( n = 40) of patients received adjuvant pelvic radiation after a positive PLN dissection. Median follow-up was 9.3 months (interquartile range: 5.2–19.8). Patients receiving adjuvant pelvic radiation had a median DSS of 14.4 months vs. 8 months in the nonradiation group, respectively ( P = 0.023). Patients without adjuvant pelvic radiation were associated with worse overall survival (hazard ratio [HR] = 1.7; 95% CI: 1.01–2.92; P = 0.04) and DSS (HR = 1.9; 95% CI: 1.09–3.36; P = 0.02) on multivariable analysis. Median time to recurrence was 7.7 months vs. 5.3 months in the radiation and nonradiation arm, respectively ( P = 0.042). Patients without adjuvant pelvic radiation was also independently associated with higher overall recurrence on multivariable analysis (HR = 1.8; 95% CI: 1.06–3.12; P = 0.03). Conclusions Adjuvant pelvic radiation is associated with improved survival and decreased recurrence in this population of patients with penile cancer with positive PLNs.

Purpose In Italy, the spread of prostate-specific antigen (PSA) testing varies in different areas. A peak of incidence was reached in 2003-2004 in some areas, while in others the incidence is still increasing. Mortality has declined since 1999 in some areas, while it remains stable in others. We compared mortality and the risk of advanced cancer over 2 periods (1996-1998; 2005-2007) and by geographic area characterized by a different spread of PSA, to understand the possible impact of PSA on the epidemiology of prostate cancer. Methods In 8 Italian Cancer Registries (CRs), 4,632 cases diagnosed over 2 periods, 1996-1998 and 2005-2007, were sampled to assess risk class. The CRs were classified into late and early phase of PSA testing depending on whether an incidence peak had been reached by 2008. Incidence by risk class was estimated based on overall incidence in each CR and on risk class distribution in the sample. We calculated standardized mortality (MRR) and risk class-specific incidence rate ratios (IRR) to compare the 2 periods. Results Incidence increased from 1996-1998 to 2005-2007 (IRR 1.5; 95% CI 1.4, 1.6). High-risk and metastatic cancer incidence decreased only in late-phase areas (IRR 0.78; 95% CI 0.69, 0.88; and 0.40; 95% CI 0.30, 0.54, respectively), while in early-phase areas, incidence remained virtually stable (IRR 1.2; 95% CI 1.0, 1.4; and 0.77; 95% CI 0.59, 1.0, respectively). Mortality decreased only in late-phase areas (MRR 0.81; 95% CI 0.85, 0.97; vs 1.1; 95% CI 0.92, 1.2) in early-phase areas. Conclusions Mortality reduction and a decrease in high-risk and metastatic cases occurred simultaneously only in areas in late phase of PSA spread.

Background: Therapeutic options for patients with chemoresistant germ cell tumors (GCTs) are limited. Pazopanib is a selective tyrosine kinase inhibitor with distinct antiangiogenic activity. We aimed to evaluate pazopanib activity in patients with refractory GCT. Patients and methods: In the open-label, single-arm, phase 2 Pazotest study (NCT01743482), patient eligibility included failure of >= 2 platinum-based regimens, and allowed prior high-dose chemotherapy administration. Patients were given pazopanib 800 mg/day until disease progression (PD) or onset of unacceptable toxicity. Measurements of serum tumor markers (STM), computed tomography and FDG-PET were carried out at baseline, after 4 weeks of pazopanib treatment, and every 8 weeks thereafter. PD was defined as increasing levels of STM, increasing size of non-teratomatous masses, or appearance of new lesions. The study primary endpoint was progression-free survival (PFS, H0: 3-month PFS = 25%, alpha = 5%, beta = 20%). Results: Forty-three patients were enrolled from May 2013 to July 2016. The number of prior chemotherapy regimens was: 2 (11.6%), 3 (51.2%), >3 (37.2%). Grade 3 adverse events were observed in six patients (13.9%). Overall, 70.3% of patients had reduced levels of STM after 4 weeks. There were 2 partial responses (4.7%), 19 cases of stable disease, and 16 cases of PD (6 not evaluable by RECIST). The median follow-up duration was 29.6 months. The 3-month PFS probability was 12.8% [95% confidence interval (CI): 5.7%-28.9%]. The 24-month OS probability was 14.2% (95% CI: 6.0%-33.7%). In patients with a > 50% decline in STM, the 24-month OS probability was 24.1% (95% CI: 8.3%-69.6%). The small sample size was the major limitation. Conclusions: Despite pazopanib showed potent but short-lived activity in refractory GCT, long-term survival was obtained in a proportion of treated patients. According to the kinetics of pazopanib activity, this drug may be investigated in less pre-treated patients as an optimal bridging therapy preceding and/or combined with salvage chemotherapy.

Patients with locally advanced penile squamous-cell carcinoma have a poor prognosis. No difference in survival was noted when using chemotherapy before or after surgery. Uncertainties persist regarding the optimal management of these patients, and new treatments are urgently required, particularly for patients at highest risk, with bilateral and/or pelvic lymph node involvement. BACKGROUND: The prognosis of patients with locally advanced penile squamous-cell carcinoma is primarily related to the extent of lymph node metastases. Surgery alone yields suboptimal results, and there is a paucity of data on these patients’ outcomes. PATIENTS AND METHODS: This retrospective study evaluated patients who received neoadjuvant or adjuvant chemotherapy from 1990 onward at 12 centers. Cox models were used to investigate prognostic factors for relapse-free survival and overall survival (OS). RESULTS: Among the 201 included patients, 39 (19.4%) had disease of T3-4 and N0 clinical stage; the remaining patients had clinical lymph node involvement (cN+). Ninety-four patients received neoadjuvant chemotherapy (group 1), 78 received adjuvant chemotherapy (group 2), and 21 received both (group 3). Eight patients for whom the timing of perioperative chemotherapy administration was unavailable were included in the Cox analyses. Forty-three patients (21.4%) received chemoradiation. Multivariate analysis for OS (n = 172) revealed bilateral disease (P = .035) as a negative prognostic factor, while pelvic cN+ tended to be nonsignificantly associated with decreased OS (P = .076). One-year relapse-free survival was 35.6%, 60.6%, and 45.1% in the 3 groups, respectively. One-year OS was 61.3%, 82.2%, and 75%, respectively. No significant differences were seen on univariable analyses for OS between the groups (P = .45). Platinum type of chemotherapy and chemoradiation were not significantly associated with any outcome analyzed. CONCLUSION: Benchmark survival estimates for patients receiving perioperative chemotherapy for locally advanced penile squamous-cell carcinoma have been provided, with no substantial differences observed between neoadjuvant and adjuvant administration. This analysis may result in improved patient information, although prospective studies are warranted.

In a large series of intermediate and poor risk nonseminomatous germ-cell tumors we were able to identify new prognostic factors and to construct an improved risk classification system. Fewer cycles of cisplatin, etoposide, and bleomycin chemotherapy might be necessary in most cases to attain a cure. Background: The International Germ Cell Cancer Collaborative Group (IGCCCG) classification has been used since 1997 to allocate metastatic germ cell tumors (GCTs), but its applicability needs an update. We aimed to revisit the outcomes of intermediate and poor risk nonseminomatous GCTs (NSGCTs). Patients and Methods: Individual patient-level data from the databases of 2 institutions were collected. Outcomes of consecutive patients who received first-line chemotherapy from 1990 to 2014 were used. The Kaplan Meier method was used to estimate relapse -free (RFS) and overall survival (OS). Cox regression analyses were used to evaluate potential prognostic factors of RFS and OS univariably. Forward stepwise selection was used to construct a multivariable model. A risk factor (RF) model was then constructed and compared with IGCCCG classification using the concordance statistics (CS). Results: A total of 647 patients were identified. Four RFs for OS in the multivariable model were identified: primary mediastinal NSGCT (P

Purpose: CD30 is expressed by untreated embryonal carcinoma, supporting the rationale for a targeted approach. However, the reported chemotherapy induced switching off of CD30 noted on immunohistochemistry may affect its therapeutic potential for disease relapse. We evaluated persistent CD30 expression and its prognostic meaning in cases of post-chemotherapy residual disease. Materials and Methods: Paraffin blocks of surgical samples that yielded nonteratomatous viable cells after 1 or more cisplatin based chemotherapy treatments were retrieved and reassessed by 2 pathologists blinded to the study purpose. Multivariable analysis was done for prespecified factors. Results: A total of 49 cases of pure embryonal carcinoma or mixed germ cell tumor from August 1991 to August 2012 had full clinical data and suitable tissue available for analysis. Of the 35 cases (71.4%, 95% CI 56.7-83.4) with preserved CD30 positivity 14 (40.0%) showed residual disease after a median of 1 regimen (IQR 1-2). Five-year overall survival in CD30 positive and negative cases was 37.0% (95% CI 22.1-61.8) and 50.1% (95% CI 27.9-90.0, p 0.078), while after first line treatment it was 23.2% (95% CI 8.6-62.5) and 47.6% (95% CI 18.8-100, p - 0.025), respectively. On multivariable analysis CD30 positivity was a significant prognostic factor for progression-free survival (HR 2.32, 95% CI 1.04-5.19) and overall survival (HR 2.77, 95% CI 1.05-7.29). Conclusions: CD30 was retained even after an intensive pretreatment load, confirming that it is a reliable treatment target. Its expression was associated with a significantly poorer prognosis in multiple relapse/ chemoresistant cases and it was an independent prognostic factor for survival.

Purpose: We assessed prognostic factors, treatments and outcomes in patients with teratoma with malignant transformation, a rare occurrence among germ cell tumors. Materials and Methods: Data on patients diagnosed with teratoma with malignant transformation between June 1981 and August 2014 were collected across 5 referral centers. Chemotherapy was dichotomized as based on germ cell tumor or teratoma with malignant transformation. Cox analyses were done to evaluate prognostic factors of overall survival, the primary end point. Each factor was evaluated in a univariable model. Forward stepwise selection was used to construct an optimal model. Results: Among 320 patients the tumor primary site was gonadal in 287 (89.7%), retroperitoneal in 17 (5.3%) and mediastinal in 16 (5%). Teratoma with malignant transformation and germ cell tumor were diagnosed concurrently in 130 patients (40.6%). A total of 49 patients (16.8%) initially presented with clinical stage I. The remaining patients were at good (123 or 42.3%), intermediate (42 or 14.4%) and poor (77 or 26.5%) risk for metastasis according to IGCCCG (International Germ Cell Cancer Collaborative Group). First line chemotherapy was given for germ cell tumor in 159 patients (49.7%), chemotherapy for teratoma with malignant transformation was performed in 14 (4.4%) and only surgery was done in 147 (45.9%). Median followup was 25.1 months (IQR 5.4-63.8). Five-year overall survival was 83.4% (95% CI 61.3 to 93.5) in patients with clinical stage I and it was also worse than expected in those with metastasis. On multivariable analyses nonprimitive neuroectodermal tumor histology (overall p = 0.004), gonadal primary tumor (p = 0.005) and fewer prior chemotherapy regimens (p < 0.001) were independent predictors of better overall survival. Chemotherapy was not independently prognostic. Conclusions: Less heavily pretreated teratoma with malignant transformation with a gonadal primary tumor and nonprimitive neuroectodermal tumor histology appears to be associated with longer overall survival. Generally, teratoma with malignant transformation had a worse prognosis than germ cell tumor. Uncertainties persist regarding optimal chemotherapy.

Background Progress in developing effective salvage therapies for UC is warranted. Alisertib is an orally available, selective inhibitor of the aurora kinase A. Methods A single-group, phase 2 trial was conducted with alisertib 50 mg orally BID for 7 days, with 14d rest until disease progression (PD) (NCT02109328). The primary endpoint (EP) was RECIST 1.1 objective response-rate (ORR, H-0 a parts per thousand currency sign 5 %, H-1 a parts per thousand yen 20 %, alpha = 10 % and beta = 20 %). Eligibility included failure of at least one platinum-based regimen. Results From 10/2014 to 04/2015, 22 patients were enrolled (20 evaluable for response), 8 (36.4 %) in second-line and 14 (63.6 %) beyond the second-line. Eight (36.4 %) had an ECOG-performance status 1-2. Two partial responses (PR, ORR: 9.1 %), 7 stable disease (SD) and 11 PD were obtained. Median follow-up was 8.3 months (IQR: 7-10.3), 6-month progression-free survival (PFS) was 13.6 % (95%CI: 4.8-39.0). Two SD are still receiving treatment after 11.5 and 6.3 months. Median overall survival (OS) was not reached (6-month OS: 59.1 %, 95%CI: 41.7-83.7). Hb < 10 g/dl was significantly associated with shorter PFS and OS multivariably (p = 0.031 and p = 0.033). Tissue of the case with 11.5 month SD harbored a missense mutation of mTOR (E1813D), the nonsense mutation Q527STOP of TSC1, HER3 and TAF1L missense mutations. Grade 3-4 adverse events (AE) were: 40.9 % mucositis, 36.4 % fatigue, 18.2 % neutropenia (13.6 % febrile neutropenia). There were 2 treatment-related deaths. Conclusions The study did not meet the primary EP, yet sustained disease control was obtained in about 14 % of patients. The incidence of AE and the issue of patient selection are two major concerns.

We addressed the use of perioperative chemotherapy in nodal metastates from penile cancer. Forty-seven N2 to 3M0 patients received perioperative taxane, cisplatin and 5-fluorouracil (T-PF) and 38.3% are disease-free at 22 months. Neoadjuvant T-PF allowed 12 (43%) clinical responsesand4 (14%) complete pathologic remissions among 28 patients, and the 2-year disease-free survival (DFS) was 7.1%. The 2-year DFS was 36.8% after adjuvant T-PF. T-PF is active and is associated with long-term survival after surgery. Chemotherapy must be offered with caution in patients with resectable nodal metastases. Background: The role of chemotherapy in nodal metastases from penile squamous cell carcinoma is not defined. We evaluated the efficacy of a combination of T-PF(a taxane, cisplatin, and 5-fluorouracil) in neoadjuvant and adjuvant settings. Patients and Methods: Since June of 2004, T-PF was administered to stage N2 to 3 patients. With time, neoadjuvant chemotherapy administration prevailed with respect to use in the adjuvant setting. Primary end points were progression-free (PFS) and overall (OS) survival. Secondary objectives were tolerability and activity in the neoadjuvant setting. Nonparametric tests, Kaplan-Meier, and regression analyses were performed. Results: As of October of 2012, 47 consecutive N2 to 3 M0 patients had undergone neoadjuvant (n = 28) or adjuvant (n = 19) T-PF: 18 patients (38.3%) remain disease-free after a median follow-up of 22 months (interquartile range, 17-42 months). The 2-year disease- free survivals were 36.8% (95% confidence interval [CI], 15.2-58.5) versus 7.1% ( 95% CI, 0-16.7) after adjuvant and neoadjuvant therapy, respectively. N3 metastases were associated with a poorer PFS, and bilateral metastases and mutated p53 were associated with a poorer OS. After neoadjuvant treatment, 43% clinical responses and 14% complete pathologic remissions were recorded, but responses were not associated with survival. Neutropenia (25.5%) was the most frequent Grade >= 2 toxicity. Conclusion: The T-PF regimen is well tolerated and compares with other regimens in terms of activity and efficacy in the neoadjuvant setting, and very long survivals have been recorded after adjuvant administration. The role of perioperative treatment in these patients remains controversial. Some caution in administering preemptive treatment in patients with resectable disease is needed. (C) 2015 Elsevier Inc. All rights reserved.

The molecular-targeted agent sorafenib is the first anticancer agent able to slow the progression of advanced/metastatic renal cell carcinoma, a tumor that was formerly refractory to conventional therapy. Experience from everyday clinical practice and investigations exploring the suitability of this agent for patients with harmful pathological conditions has extended the use of sorafenib to other settings of renal cell carcinoma and to particular risk populations. The aim of this review is to provide evidence on the most effective and safe use of sorafenib. The review pays particular attention to patients who have several comorbidities, such as impaired renal and cardiac function, and older patients whose frailty due to impaired organ function necessitates the most careful administration of targeted antineoplastic agents.

OBJECTIVE • To assess the efficacy of ketoconazole in patients with castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS • From April 2008 to November 2009, 37 patients with CRPC have been treated with ketoconazole. The primary endpoint was the prostate-specific antigen (PSA) response; the secondary endpoints were progression-free survival and safety profile. • Ketoconazole was administered by oral route at a dose of 200 mg every 8 h continuous dosing until the onset of serious adverse events or disease progression. • The study was based on a two-step design with an interim efficacy analysis carried out on the first 12 patients accrued. RESULTS • Main characteristics of population were: median age 75 years (range 60-88); baseline mean PSA 28.8 ng/mL (4.3-1000); 30 patients previously challenged with at least two lines of hormone therapy; 15 patients previously treated with chemotherapy. • Biochemical responses accounted for: two complete responses (5%), six partial responses (16%), 13 patients with stable disease (35%), and 14 with progressive disease (38%). Of 15 patients resistant to chemotherapy, overall disease control (complete plus partial responses plus stable disease) was recorded in seven of them. • Treatment was feasible without inducing grade 3-4 adverse events. The most common grade 1-2 adverse events were asthenia (27%), vomiting (8%) and abdominal pain (8%). CONCLUSION • Treatment with low-dose ketoconazole is feasible and well tolerated. The efficacy was satisfactory in patients previously treated with chemotherapy.

Study Type – Therapy (case series) Level of Evidence 4 OBJECTIVE • To investigate the optimal management and prognostic factors of patients with malignant transformation (MT) in germ-cell tumour (GCT) by re-evaluating Institutional series. PATIENTS AND METHODS • Patients with an MT within GCT have been identified from the institutional database and all slides have been reviewed by the referral pathologist. RESULTS • From June 1982 to October 2009, 48 patients and 13 somatic histologies have been identified. Twelve patients presented with stage I, 12 with stage II and 24 with stage III disease. All stage I patients are alive and disease-free after a median follow up of 88 months (interquartile range 38–103). • Of the 36 metastatic cases, 11 underwent GCT-oriented chemotherapy plus surgery and seven of them are currently disease-free. Three patients underwent MT-chemotherapy, one relapsed and is still under treatment. Overall, 17 patients relapsed (35%) and three of them have been rescued by GCT-chemotherapy. Five-year overall survival was 100% for stage I, 80% (95% CI 40–94) for stage II and 44% (95% CI 19–67) for stage III patients. Stage III disease at MT, incomplete surgical removal and primitive neuroectodermal tumours plus adenocarcinoma histologies were significant adverse prognostic factors for survival. CONCLUSIONS • New insights emerged into the impact of histology and chemotherapy on MT. The development of an adenocarcinoma component as well as the possible efficacy of a GCT-tailored chemotherapy in a multimodal strategy are addressed for the first time, while disease extent at transformation and extent of radical surgery are confirmed as significant prognosticators. • An international web database for registration of all cases of MT worldwide is presented.

What's known on the subject? and What does the study add? Scientists have found a number of genetic factors that increase prostate cancer risk, including heritable mutations in the genes BRCA1 and BRCA2. These mutations are not common but can have major impact, as a BRCA2 mutation increases risk by up to seven-fold while a BRCA1 mutation is thought to double risk in men under 65. The IMPACT study aims to determine whether targeted screening in men with a known BRCA1 or BRCA2 mutation would lead to earlier diagnosis of prostate cancers. This data from the IMPACT study adds to the increasing evidence that BRCA mutation carriers develop more aggressive disease. Although these are early results, it appears that PSA screening is more accurate at predicting potentially aggressive prostate cancer among men at higher risk of the disease due to a genetic predisposition than general population screening. This study provides support for continued screening in men with genetic mutations. OBJECTIVE To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (+/- 5 years) who were negative for the familial mutation. RESULTS In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47 center dot 6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.

90 Background: Prostate biopsy findings at diagnosis and follow-up are essential criteria in Active Surveillance (AS). In a previous work (Nicolai Eur Urol Suppl 2013) upgrading (UPG) and upsizing (UPS) at 1-yr rebiopsy resulted to be independent outcomes with different predictors. Aim of the present work is to validate these models on an independent population and to evaluate the probability of not-developing UPG, thus the chance of continuing AS Methods: Pts enrolled in 2011-2017 were considered for validation, while 318 AS pts enrolled in 2005-2011 were considered for model development. UPG model included: age (risk), PSA density (risk), prostate volume (>60 cc, protective); UPS model: age (protective), % core length containing cancer (>5%, risk), number of positive cores (>1, risk) Performance on the independent population was evaluated through AUC and calibration. Logistic model for not-developing UPG at 1 yr was fitted using all available AS pts Results: 433 pts were included in the validation set. UPG and UPS were registered in 43 and 29 pts, respectively; 38 pts had UPG+UPS. Predictors for UPG and UPS were mainly confirmed in the validation cohort (Table), with Odds Ratios (OR) very similar to the development model. Discrimination was confirmed (AUCs) and calibration was excellent (slope~1, R2>0.90). Probability of not-developing UPG (evaluated on 751 pts) was associated to age, prostate volume and PSA density (Table). Conclusions: UPG and UPS in AS pts should be considered as independent events and their management implying different strategies. Specifically, age, volume and PSA density play a key role in the chance to continue AS, i.e. in not developing UPG. A nomogram estimating the likelihood of continuing AS has been developed and will be presented. [Table: see text]

Objectives Approximately one-third of the metastatic germ cell tumors (GCT) in patients are classified as intermediate-risk metastatic GCT, and available guidelines recommend the same treatment of poor-risk cases. Yet the prognosis of these patients is heterogeneous, and consequently refining the intensity of treatment is warranted. We aimed to address the heterogeneity of this category by providing a proof of principle for reclassification attempt. Patients and methods Data on consecutive patients with intermediate-risk metastatic GCT and who received treatment at Fondazione INT Milano in the time frame between February 1980 and March 2014 were collected. Cox regression analyses were done, evaluating potential prognostic factors for overall survival (OS, primary end point) to first-line therapy. Each factor was evaluated in a multivariable model. Recursive partitioning was performed to define prognostic risk groups. Results A total of 224 patients were suitable for the present analysis. Median age was 26 years (interquartile range: 22–31), 11 patients (4.9%) had a retroperitoneal primary tumor, 6 yielded seminomatous histology, 85 (37.9%) had lung metastases, and 58 (25.9%) had bulky (i.e.,≥10 cm) retroperitoneal lymph nodes. Patients received cisplatin, bleomycin, and etoposide (PEB, n = 199) or vinblastine (PVB, n = 23); however, 2 patients received other treatments. Median follow-up was 135 months (interquartile range: 81–223). Globally, 5-year progression-free survival and OS rates were 72.8% (95% CI: 67.1–79.0) and 86.2% (81.7–91.0), respectively. In the multivariable model for OS, elevated alfa fetoprotein (AFP) level was the only significant prognostic factor (hazard ratio = 1.48, 95% CI: 1.12–1.96). The 2 separate prognostic groups with differential OS outcomes were identified based on the cutoff level of 6,200 IU/ml. The 10-year OS rate was 55.6% (95% CI: 36.6–84.3), and it was 86.7% (95% CI: 82.0–91.7) for those with AFP levels more than (n = 19, 8.5%) and less than (n = 205, 91.5%) the cutoff, respectively. Conclusions A small fraction of patients with highly elevated AFP levels have an OS approximating the poor prognostic category, whereas most of them are close to good-risk cases. This might have implications to select outlier patients for clinical trials and molecular characterization.

In this retrospective study, patients with poor-prognosis germ cell tumors (GCT) treated from a single referral center demonstrated high survival estimates that were stable through the years. Indeed, the major clinical implication is that using the available prognostic classification of metastatic GCT cannot allow the recognition of patients with a true chemoresistant disease. Moreover, the prognostic effect of treating patients with disseminated disease in referral centers should be further assessed. Background: Survival estimates with first-line treatment for patients with metastatic poor prognosis germ cell tumors (GCT) are still suboptimal in the literature. We conducted a retrospective study to evaluate the outcome of patients referred to our tertiary cancer center. Patients and Methods: A retrospective analysis was conducted on patients who received at least first-line chemotherapy at our center. Distribution of clinical characteristics was evaluated in the periods < 1997, 1997 to 2001, 2001 to 2006, and 2007 to 2013. The Kaplan-Meier method was used to estimate progression-free (PFS) and overall survival (OS). Univariable and multivariable Cox models with prespecified clinical variables were undertaken for PFS and OS. All tests and confidence intervals were 2-sided and set at a P = .05 level of significance. Results: Between 1982 and 2013, 168 patients were identified. The median age was 27 years (inter-quartile range [IQR], 22-34). The presence of liver, bone, or brain metastases trended to greater incidence from 1997 onward (27.5% < 1997 to 55.6% in 2007-2013; chi(2) P = .054). Median follow-up was 102 (IQR, 63-166) months. Global 5-year PFS was 48.5% (95% confidence interval [CI], 41.5-56.8) and OS was 63.2% (95% CI, 56.0-71.2). In multivariable analysis, treatment period was not significantly associated with either PFS (overall P = .229) or OS (overall P = .216). Conclusion: In this single-center series of consecutive poor prognosis GCT we could observe greater PFS and OS than the historical estimates. This observation was independent from the period of treatment. Based on the present results, studies focused on improving the outcome in the sole poor-risk cohort should be discouraged. Results were biased by their retrospective quality.

Background In the late 1990s, the use of high-dose chemotherapy (HDCT) and stem-cell rescue held promise for patients with advanced and poor prognosis germ-cell tumors (GCT). We started a randomized phase II trial to assess the efficacy of sequential HDCT compared with cisplatin, etoposide, and bleomycin (PEB). Patients and methods Patients were randomly assigned to receive four cycles of PEB every 3 weeks or two cycles of PEB followed by a high-dose sequence (HDS) comprising HD-cyclophosphamide (7.0 g/m2), 2 courses of cisplatin and HD-etoposide (2.4 g/m2) with stem-cell support, and a single course of HD-carboplatin [area under the curve (AUC) 27 mg/ml × min] with autologous stem-cell transplant. Postchemotherapy surgery was planned on responding residual disease in both arms. The primary end point was progression-free survival (PFS). The study was designed to detect a 30% improvement of 5-year PFS (from 40% to 70%), with 80% power and two-sided α at 5%. Results From December 1996 to March 2007, 85 patients were randomized: 43 in PEB and 42 in HDS arm. Median follow-up was 114.2 months [interquartile range (IQR): 87.7–165.8]. Complete or partial response with normal markers (PRm-) were obtained in 28 (65.1%) and 29 (69.1%) patients, respectively. Five-year PFS was 55.8% [95% confidence interval (CI) 42.8–72.8] and 54.8% (95% CI 41.6%–72.1%) in PEB and HDS arm, respectively (log-rank test P = 0.726). Five-year overall survival was 62.8% (95% CI 49.9–79.0) and 59.3% (95% CI 46.1–76.3). One toxic death (PEB arm) was recorded. Conclusions The study failed to meet the primary end point. Furthermore, survival estimates of conventional-dose chemotherapy higher than expected should be accounted for and will likely limit further improvements in the first-line setting. ClinicalTrials.gov NCT02161692.

Background We provide updated estimates of survival and survival trends of male genital tumours (prostate, testicular and penis cancers), in Europe and across European areas. Methods The complete approach was used to obtain relative survival estimates for patients diagnosed in 2000–2007, and followed up through 2008 in 29 countries. Data came from 87 cancer registries (CRs) for prostate tumours and from 86 CRs for testis and penis tumours. Relative survival time trends in 1999–2007 were estimated by the period approach. Data came from 49 CRs in 25 countries. Results We analysed 1,021,275 male genital cancer cases. Five-year relative survival was high and decreased with increasing age for all tumours considered. We found limited variation in survival between European regions with Eastern Europe countries having lower survival than the others. Survival for penile cancer patients did not improve from 1999 to 2007. Survival for testicular cancer patients remained stable at high levels since 1999. Survival for prostate cancer patients increased over time. Conclusions Treatment standardisation and centralisation for very rare diseases such as penile cancers or advanced testicular tumours should be supported. The high survival of testicular cancer makes long-term monitoring of testicular cancer survivors necessary and CRs can be an important resource. Prostate cancer patients’ survival must be interpreted considering incidence and mortality data. The follow-up of the European Randomised Study of Screening for Prostate Cancer should continue to clarify the impact of screening on prostate cancer mortality together with population based studies including information on stage and treatments.

Background: The prognosis of patients (pts) with PSCC is primarily depending on the involvement of regional lymph nodes. Owing to the limited efficacy of chemotherapy, new drugs are warranted. Dacomitinib (Daco) is a potent, irreversible TKI of human EGFR/HER1, HER2 and HER4. Methods: In a phase 2 study (NCT01728233), pts received Daco 45 mg/d, orally, continuously. Inclusion criteria were SCC histology, and clinical stage N2-3 or M1; no prior chemotherapy was allowed. Computed tomography (CT) and PET/CT scans were repeated q8 weeks. Responding (R) pts with locally-advanced (LA) PSCC were offered radical surgery. The primary endpoint was the objective response-rate (ORR=CR+PR according to RECIST v1.1). Stopping rules based on the Bayesian posterior probability (PP) were set; the target was to demonstrate that the ORR exceeded 20%. Translational analyses on pre-Daco tumor samples included: EGFR and HER2 amplification, in-situ hybridization for HPV, and next generation sequencing. Results: From 06/13 to 010/16, 28 patients were treated. 8 (28.6%) had visceral metastases. 50% had pelvic and 60.7% clinically-involved bilateral LN. 1 CR + 8 PR were obtained (ORR=32.1%, 80% credibility interval 21.0-43.0%). The median follow up was 19.8 months (IQR: 6.3-25.7); 12-m PFS was 26.2% (95%CI: 13.2-51.9); 12-m OS was 54.9% (95%CI: 36.4-82.8). The median OS of LA pts was 20 months (IQR: 11.1-NR). The current Bayesian PP of exceeding the 20% ORR target is 92.3%. Grade 3 adverse events (skin rash) were seen in 3 pts (10.7%). The median drug exposure was 2.2 months. Tissue samples from 25 pts were analyzed. Only 2 pts were HPV+ (1SD, 1PD). EGFR ampl was found in 4 pts (1 CR, 1 PR, 2 SD) and it was confirmed in all post-Daco samples. TERT mutations (60%) were found in responders only, PI3K/mTOR pathway gene mutations in 42.9% R vs 8.3% non responders, IGF2R in 40% and 20%, respectively. Mutations were largely consistent between matched pre- and post-therapy samples in 7 evaluated pts. Conclusions: Daco was active in advanced PSCC and provided the best ORR with a single agent in PSCC. The biology underlying response to Daco seems to be independent from HER-pathway alterations. The frontline therapy can provide a suitable window of opportunity to test new drugs in PSCC. Note: This abstract was not presented at the meeting. Citation Format: Andrea Necchi, Salvatore Lo Vullo, Daniele Raggi, Patrizia Giannatempo, Nicola Nicolai, Giuseppina Calareso, Elena Togliardi, Maurizio Colecchia, Federica Perrone, Annunziata Gloghini, Luigi Mariani, Roberto Salvioni. First-line therapy with dacomitinib, an orally available pan-her tyrosine kinase inhibitor, for locally-advanced or metastatic penile squamous cell carcinoma: Results of an open label, single-arm, single-center, phase 2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT139. doi:10.1158/1538-7445.AM2017-CT139

e16018 Background: S-GC neoadjuvant chemotherapy (NACT) was active in a phase 2 trial in MIBC, showing a response rate (downstaging to pT < 2) of 54.3% in 46 pts within a single-arm, phase 2 trial ( Necchi et al, GU ASCO 2017). The addition of S to GC may help investigators unravelling key molecular features underlying response in MIBC. Methods: Analyses were made on pre- and post-treatment TURB and cystectomy (Cy) specimens (10µm sections) and matched germline DNA of 29/46 pts. Analyses included measurements of ERCC1 (by immunohistochemistry, IHC) on TURB specimens, baseline circulating VEGF levels (ELISA), copy number variations (CNV, Affymetrix), and next generation sequencing (NGS, custom gene panels through the Ion AmpliSeq Library Kit2.0™ and the Ion Torrent Personal Genome Machine™ platform). Results: We analyzed TURB samples from 15 responders (R) and 4 non-R (NR). An additional 10 Cy samples were used for NR. Baseline VEGF levels were not associated with PFS or OS on univariable analyses (p = 0.943 and p = 0.669, respectively). Differences in R vs. NR pts were found according to CNVs and NGS. CN gains on regions of chromosome (chr) 18 and 20 and loss in chr 5 were found in 56-60% of R and in none of the NR. Gains on regions of chr 3 and losses in chr 1 and 20 were more frequent in the NR ( > 50%) vs. R ( < 20%). The median number of somatic mutations (mut) per sample was 3 (range, 0-19). Missense mut in DNA-repair genes ( POLK; FANCM; PRKDC; BLM; MSH2; MSH6; RAD50) were found in 63.6% R vs 16.7% NR, in RAS-RAF pathway genes ( CDKN2A; RAC1; KRAS; NF1) in 45.4% vs 7.1%, in chromatin-remodelling genes ( ARID1A; ARID2; KDM5C; SMARCA4; ATRX; KMT2C; DAXX; SETD2) in 54.5% vs 16.7%, and in HER-family genes in R only (36.4%). ERCC1 IHC expression was found in 55.6% R vs 93.3% NR (p = 0.047). Conclusions: We identified distinct molecular features of R vs NR to S-GC in MIBC. These features may be linked to a potentially-additive effect of S and CT. The identification of the targets of CNVs will further elucidate the underlying biology. These results may help developing personalized medicine in MIBC with new more potent targeted agents with CT. Clinical trial information: NCT01222676.

In a trial-level meta-analysis of randomized studies, bleomycin administration was independently significantly associated with the development of pulmonary toxicity in patients with metastatic germ cell tumors receiving first-line chemotherapy. This effect was mainly seen with respect to all-Grade pulmonary toxicity. This study provided a further argument in favor of reducing the burden of curative chemotherapy in these highly curable malignancies. Background: Limited information is available about the effect of bleomycin administration on the development of pulmonary toxicity in metastatic germ cell tumors (GCT). Patients and Methods: A literature search was conducted to identify randomized trials of first-line chemotherapy for GCT. We conducted univariate and multivariate analyses using random effects models to evaluate the predictive role of bleomycin administration in the development of all Grade and Grade 3 to 4 (G3-4) pulmonary toxicity. The results were adjusted for length of follow-up, prognostic risk group, year of treatment, presence of lung metastases, and primary mediastinal GCT. Results: Fifty-three study arms of 25 phase II and III trials encompassing 6498 patients were selected: 40 that used bleomycin (n = 5093) and 13 that did not (n = 1405). The pooled probability of all-Grade pulmonary toxicity in the bleomycin and nonbleomycin arms was 11.7% (95% confidence interval [CI], 8.4%-16.0%) and 1.7% (95% CI, 0.7%-4.2%), respectively. Univariate analysis indicated that bleomycin administration was associated with the incidence of all-Grade (odds ratio [OR], 7.57; 95% CI, 2.84-20.18; Wald test P < .001) and G3-4 pulmonary toxicity (OR, 5.19; 95% CI, 1.57-17.16; P = .007). Multivariate analysis showed a significant association of bleomycin administration with the incidence of all-Grade pulmonary toxicity (OR, 4.14; 95% CI, 1.36-12.59; P = .012) and a trend toward significance for G3-4 toxicity (OR, 2.24; 95% CI, 0.91-5.51; P = .080). Conclusion: We quantified the bleomycin-associated effect on the development of pulmonary toxicity in patients with GCT who received first-line chemotherapy. This information might be useful for planning clinical trials aimed at reducing chemotherapy as well as to inform patients in the clinic. (C) 2016 Elsevier Inc. All rights reserved.

414 Background: Therapeutic options for patients (pts) with chemoresistant GCT are limited and prognosis is poor. PZP is a potent and selective tyrosine kinase inhibitor (TKI) with distinct antiangiogenic activity. Methods: In Pazotest trial (NCT01743482), pts were given PZP 800 mg/day until disease progression (PD) or unacceptable toxicity. Eligibility included failure of ≥ 2 platinum-based CT, including high-dose (HD)-CT. Baseline serum tumor markers (STM), computed tomography and FDG-PET were repeated after 4 wks and q8 weeks thereafter. The primary endpoint was PFS (H0: 3-m PFS ≤ 10%, H1: ≥ 25%, α = 5%/β = 20%). PD was defined as rising STM, increasing size of nonteratomatous masses (RECIST v1.1), or the appearance of new lesions. Translational analyses included circulating IL8 levels and next generation sequencing of pre-PZP tissue from extreme responders. Results: 43 pts were enrolled from 05/2013 to 07/2016. 35 pts (81.4%) had nonseminoma, 6 (14%) primary mediastinal GCT. The number of failed CT regimen was: 2 (11.6%), 3 (51.2%), > 3 (37.2%). 53.5% had failed HDCT. 39 pts had elevated STM: 56.4% AFP, 43.6% HCG. Grade 3-4 adverse events were seen in 4 pts (increased AST/ALT). 26/39 pts (66.7%) had STM reduction (38.5% > 50% from baseline) after 4 wks. RECIST results: 1 partial response, 20 stable disease, 16 PD (6 not evaluable). 12 (27.9%) had a decreased FDG uptake. Median follow-up was 29.6 months. 3-m PFS was 12.8% (95%CI: 5.7-28.9), median PFS was 2.5 m (IQR: 1.0-3.0). 24-m OS was 14.2% (95%CI: 6.0-33.7). In pts with > 50% STM decline, 24-m OS was 24.1% (95%CI: 8.3-69.6). Univariably, STM was associated with OS (HCG vs AFP: HR: 2.73, 95%CI: 1.24-6.02, p = 0.042). Baseline and +4wks IL8 levels did not predict for PFS/OS. In 2 responding pts, new mutations were found ( FLT3, G846V and RAD50 E448Q classified as damaging; TSC2, R197M and TNF A16V classified as benign). Conclusions: PZP was well tolerated and showed predictable activity, with early but short-living STM decline. Long term survival was obtained in a significant proportion of pts. Based on the present results, PZP may be investigated in earlier disease stages as an optimal bridging therapy preceding salvage curative treatment. Clinical trial information: NCT01743482.

345 Background: Despite cisplatin-based chemotherapy (CT) is recommended in MIUBC, an unmet need is to identify new drugs or combinations to improve the outcomes. SGC combination was evaluated in an open-label, single-arm, phase 2 trial (NCT01222676). Methods: After TURB, pts with T2-T4a N0 MIUBC received 4 cycles of cisplatin 70 mg/m2 d1, gemcitabine 1000 mg/m2d1 and 8, q3 wks. Sorafenib 400 mg q12h was administered daily from day 1 until radical cystectomy. In a Simon’s 2-stage design, the primary endpoint was pathologic complete responses (pT0). Residual carcinoma in situ was considered pT0. ITT analysis was applied. Statistical hypothesis assumed H0: ≤0.20 and H1: ≥0.40 (α and β of 5% and 10%). ERCC1 immunohistochemistry (IHC) and next-generation sequencing (NGS) of TURB tissue, and measurement of baseline circulating VEGF levels, were planned. Results: From 04/2011-06/2016, 45 pts were enrolled. 28 pts (62.2%) had macroscopical residual disease after TURB, 17 (37.8%) presented with clinical stage T3-4. pT0 was obtained in 19 pts (42.2%, 95%CI: 27.6-57.9); pT≤1 in 24 (53.3%, 95%CI: 37.9-68.3). After median follow-up of 35 months, median PFS was not reached (IQR: 29.4-NE), like median OS (IQR: 30.3-NE). Pathological response (pT0 vs pT≤1 vs other) predicted for both PFS (p=0.015) and OS (p=0.046). Hematologic (hem) G3-4 adverse events (AE): platelet 28.9%, neutrophils 15.6%, Hb (4.4%). Extra-hem AEs were seen in 9 pts (20%). 24 (53.3%) pts needed S temporary interruption (5 cases discontinuation). Tumor samples were available from 23 pts for ERCC1-IHC, 24 for NGS: ERCC1 IHC expression was associated with non response (pT≥2, p=0.033). ERBB2/ERBB3 mutations were found only in responders (pT≤1, 20%). PIK3CA/AKTmutations (missense, and newly-identified mutations) were more frequent in pT≥2 pts (35.7% vs 20%). Baseline VEGF levels did not predict for PFS/OS. NGS of the remaining pts of the trial is ongoing. Conclusions: SGC combination was active and effective in MIUBC. Translational analyses are providing information to develop combination of CT with new more potent and selective TKIs, possibly in more selected pts. Clinical trial information: NCT01222676.

399 Background: The prognosis of patients (pts) with PSCC is primarily depending on the involvement of regional lymph nodes (LN). Owing to the limited efficacy of chemotherapy (ChT), new drugs are warranted. Daco is a potent, irreversible TKI of human EGFR/HER1, HER2 and HER4. Methods: In a phase 2 study (NCT01728233), pts received Daco 45 mg/d orally continuously. Inclusion criteria were SCC histology, and clinical stage N2-3 or M1; no prior ChT was allowed. Computed tomography (CT) and PET/CT scans were repeated q8 wks. Responding pts with LA-PSCC were offered radical surgery. The primary endpoint was the objective response-rate (ORR = CR+PR according to RECIST v1.1). The study was conducted according to a Bayesian design, based on predictive probability; the target was to demonstrate that the ORR exceeded 20%. Translational analyses on pre-Daco tumor samples included: EGFR and HER2 amplification (ampl), in-situ hybridization for HPV, and next generation sequencing. Results: From 06/13 to 09/16, 26 pts were treated. 7 (26.9%) had visceral metastases. 50% had pelvic and 57.7% clinically-involved bilateral LN. 1 CR + 7 PR were obtained (ORR = 30.4%, 95% credibility interval 14.9-48.6%). Median follow up = 16.6 months; 12-m PFS = 24.1% (95%CI: 11.1-52.3); 12-m OS = 50.7% (95%CI: 31.7-80.9). The current Bayesian posterior probability of exceeding the 20% ORR target is 89%. Tissue samples from 23 pts were analyzed. Only 2 pts were HPV+ (1SD, 1PD). EGFR ampl was found in 4 pts (1 CR, 1 PR, 2 SD) and it was confirmed in all post-Daco samples. TERT mutations (60%) were found in responders (R) only. Mutations in genes potentially associated with resistance to EGFR inhibitors ( HRAS, BRAF, PIK3CA, PTEN, STK11) were found in 47% non responders (NR) vs 25% R. HRAS and BRAF mutations segregated with NR (20%). Additional unfrequent mutations of druggable targets were found: RAC1, TSC1 and mTOR in R, FGFR2, RAD50, PDGFRB and FLT4 in NR, IGF2R in both. Conclusions: Dacomitinib was active in HPV-negative, advanced PSCC. Among multiple altered pathways, we were able to delineate the possible molecular profile of responders. An expansion cohort to confirm the translational findings is planned. Clinical trial information: NCT01728233.

BACKGROUND: Outcomes of radiotherapy (RT) compared with chemotherapy (CT) remain poorly defined for clinical stage (CS) IIA and IIB seminoma. We aimed to evaluate the current role of the two treatment modalities in this setting of testicular seminoma. PATIENTS AND METHODS: A systematic review and meta-analysis (MA) was carried out to identify all evaluable studies. Search was limited to studies published after 1990 and included the Medline, Embase databases, and abstracts from ASCO (GU), ESMO, AUA, and ASTRO meetings up to April 2014. Sensitivity analyses were applied including the following: CSIIA and CSIIB, paraortic + iliac RT only in both stages, RT dose (≥30 versus