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It remains unclear which patients with metastatic germ cell tumours (mGCTs) need prophylactic anticoagulation to prevent venous thromboembolic events (VTEs).To assess the risk and onset of VTEs stratified by risk factors.This multi-institutional retrospective dataset included mGCT patients treated with first-line platinum-based chemotherapy.Patients with prophylactic anticoagulation were excluded.A regression analysis was performed to select risk factors for VTEs. The simulated number needed to treat (NNT) and the number needed to harm (NNH) with prophylactic anticoagulation were calculated based on the cumulative incidences retrieved from this study and hazard rates of recently published trials describing the efficacy of prophylactic anticoagulation to prevent VTEs and the risk of bleeding events.From 1120 patients, 121 (11%) had a VTE, which occurred prior to chemotherapy in 49 (4%) and on or after chemotherapy in 72 (6%). Six patients (1%) had a bleeding event without anticoagulation. After backward regression, the one risk factor for a VTE during or after chemotherapy was the use of a venous access device. The simulated cumulative VTE incidence from prophylactic anticoagulation for patients on or after chemotherapy would translate into an NNT of 45 (95% confidence interval [CI] 36-56) and an NNH of 186 (95% CI 87-506). Limitations are mainly related to the retrospective nature of the study.The mGCTs associated VTEs are most common before and during, but not after, chemotherapy. Avoiding venous access device and/or prophylactic anticoagulation with an acceptable risk-benefit profile may decrease VTE occurring on chemotherapy.We found that venous thromboembolic events (VTEs) occur rarely after chemotherapy. Based on experience of prophylactic anticoagulation in other cancers, we conclude that the risk of VTE in men undergoing chemotherapy for metastatic germ cell tumours can be decreased by thromboprophylaxis with a reasonable risk-benefit profile and by avoidance of venous access devices.

Background Metastatic germ cell tumor (mGCT) patients receiving chemotherapy have increased risk of life‐threatening venous thromboembolism (VTE). Identifying VTE risk factors may guide thromboprophylaxis in this highly curable population. Methods Data were collected from mGCT patients receiving first‐line platinum‐based chemotherapy at 22 centers. Predefined variables included International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification, long‐axis diameter of largest retroperitoneal lymph node (RPLN), Khorana score, and use of indwelling vascular access device (VAD). VTE occurring at baseline, during chemotherapy and within 90 days, was analyzed. Results Data from 1135 patients were collected. Median age was 31 years (range 10‐74). IGCCCG risk was 64% good, 20% intermediate, and 16% poor. VTE occurred in 150 (13%) patients. RPLN >3.5 cm demonstrated highest discriminatory accuracy for VTE (AUC 0.632, P, Venous thromboembolism can cause morbidity in germ cell tumor patients receiving chemotherapy; large retroperitoneal lymphadenopathy (RPLN) and indwelling vascular access devices (VAD) are significant VTE risk factors. VAD insertion should be avoided and thromboprophylaxis can be considered for large RPLN.

PURPOSE The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium. MATERIALS AND METHODS Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients. RESULTS Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH. CONCLUSION PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.

Biochemical recurrence is an evolving space in prostate cancer, with increasing multidisciplinary involvement. Androgen deprivation therapy has shown proof of its value in complementing salvage radiotherapy in high-risk biochemical relapsing patients; ongoing trials aim to further refine this treatment combination. As systemic treatments, and notably next-generation androgen receptor targeted agents, have moved towards early hormone-sensitive and non-metastatic stages, the prostate specific antigen (PSA)-relapse disease stage will be undoubtedly challenged by future evidence from such ongoing clinical trials. With the use of modern imaging and newer molecular technologies, including integration of tumoral genomic profiling and liquid biopsies in risk stratification, a path towards a precision oncology-focused approach will become a reality to guide in the future decisions for patients with a diagnosis of biochemical recurrence.

As research focus in oncology has recently shifted to immunomodulation, the era of introduction of immunotherapeutic agents in the management of prostate cancer has just begun. With the success of checkpoint blockade drugs in certain advanced tumours, ongoing efforts are aimed at identification and validation of new actionable immune targets to consolidate and expand the initial success in other tumour types. In this paper, we review the immunotherapy research in the management of prostate cancer to date, as well as the various emerging immunotherapeutic agents and their possible use. Although monotherapy has thus far had disappointing results in prostate cancer, promising combination strategies are under evaluation.

Health-related quality of life (HRQoL) is not universally assessed in metastatic colorectal cancer (mCRC) patients. We tried to identify patient subgroups for whom HRQoL assessment should be strongly encouraged.Consecutive mCRC patients who had been deemed candidates for first-line chemotherapy were enrolled in a prospective study (NCT03873064) and asked to complete the HRQoL questionnaire EORTC QLQ-C30. Primary endpoint was the Global Health Status (GHS) of EORTC QLQ-C30. A nomogram was built for prediction of low GHS (i.e.,67%).Among recruited patients (n=173), a univariable logistic regression analysis (LRA) found that body mass index (BMI23), age (65 years) and sex (female) were significantly associated with low GHS. The multivariable LRA confirmed they were independently associated with the outcome (P values of 0.04-0.004). BMI, age and sex were included in a final predictive model (C-statistics, 67%; P=0.001) and used to build a nomogram. A total nomogram score ≥72 was associated with a risk of 28% or higher of having a low GHS. The 28% risk cut-off had a sensitivity of 90% and a specificity of 34% for identifying low GHS. A decision curve analysis revealed that a risk threshold of 28% of the model was associated to an added net benefit of ≥4% when using the nomogram. Low GHS was recorded in 58% vs. 23% of patients with28% vs.28% risk according to the nomogram, respectively (odds ratio 3.54, P=0.0004).High BMI together with young age and male sex were protective against HRQoL deterioration. In centers where HRQoL is not routinely assessed, such an assessment should be at least made for mCRC patients at risk according to the proposed nomogram (i.e., over 65-year-old females with BMI23).

Immune checkpoint inhibitors (ICIs) demonstrated improved overall survival (OS) in heavily pretreated unselected patients with metastatic gastro-esophageal junction (mGOJ)/gastric cancer (GC). Attempts to select patients based on programmed death-ligand 1 (PD-L1) expression appear to be suboptimal. A strong rationale suggests a prognostic role for inflammatory biomarkers for ICI-treated patients with mGOJ/GC. Our objective was to assess whether inflammatory markers are associated with survival in ICI-treated patients with mGOJ/GC. Ten inflammatory markers were retrospectively analyzed at baseline in 57 patients with mGOJ/GC with unknown PD-L1 status treated with second-line ICIs and correlated with OS. Selected variables were then analyzed in a multivariate Cox-regression model and used to build a GIPI nomogram. Neutrophil/lymphocyte ratio (NLR) and C-reactive protein (CRP) as continuous variables and albumin categorized as less than versus greater than 30 g/dL were the most significant predictors of OS and were used to build the GIPI nomogram. Nomogram-based lowest, mid-low, mid-high, and highest risk quartiles were associated with median OS (mOS) of 14.9, 7.1, 5.6, and 2.1 months, respectively (hazard ratio [HR] of highest vs. lowest risk 4.94; p = 0.0002). By optimally dichotomizing CRP and NLR, patients with one or more of the risk factors NLR > 6, CRP > 15 mg/L, and albumin

Background Nivolumab showed improvement in overall survival (OS) in ATTRACTION-2, the first phase 3 study in patients with gastric/gastroesophageal junction (G/GEJ) cancer treated with ≥ 2 chemotherapy regimens. The 2-year follow-up results of ATTRACTION-2 are presented herein. Methods ATTRACTION-2 was a randomized, double-blind, placebo-controlled, phase 3 trial (49 sites; Japan, South Korea, and Taiwan). The median (min–max) follow-up period was 27.3 (24.1–36.3) months. The primary endpoint was OS. A subanalysis of OS was performed based on best overall response and tumor-programmed death ligand-1 (PD-L1) expression status. Results Overall, 493 of 601 screened patients were randomized (2:1) to receive nivolumab (330) or placebo (163). OS (median [95% confidence interval; CI]) was significantly longer in the nivolumab group (5.26 [4.60–6.37] vs 4.14 [3.42–4.86] months in placebo group) at the 2-year follow-up (hazard ratio [95% CI], 0.62 [0.51–0.76]; P

The BRF14 trial is a prominent study that investigated the effect of prolonged imatinib treatment in advanced gastrointestinal stromal tumor patients. The key messages deduced from this study are as follows: imatinib drastically improved progression-free and overall survival in advanced gastrointestinal stromal tumor patients. Treatment ought to be maintained indefinitely in nonprogressing patients, as interruption entails a high risk of progression, even in patients in complete response. Imatinib rechallenge is effective, achieving new disease control in patients progressing after imatinib interruption. Rechallenge response profiles reflect the initial responses, albeit of poorer quality. Imatinib interruption does not affect the incidence of secondary resistance; however, the imatinib-free interval influences the time to secondary resistance. Specific clinical, biological and molecular characteristics seem to identify the patients who are long responders to imatinib. Surgery of residual disease after maximal imatinib response improves progression-free and overall survival.

There is controversy regarding prognosis and treatment of young patients with oral cavity cancer compared to their older counterparts. We conducted a retrospective case-matched analysis of all adult patients younger than 40 years and treated at our institution for a squamous cell carcinoma of the oral cavity. Only non-metastatic adult patients (age >18) with oral tongue cancer were eventually included and matched 1:1 with patients over 40 years of age, at least 20 years older than the cases, with same T and N category and treatment period. Sixty-three patients younger than 40 had an oral cavity squamous cell cancer out of which 57 had an oral tongue primary during the period 1999–2012, and 50 could be matched with an older control. No difference could be seen between younger and older patients with regard to overall, cancer-specific, or progression-free survival. The patterns of failure were similar, although in young patients, almost all failures occurred during the first 2 years following treatment. Although overall survival shows a trend toward lower survival in older patients, cancer-specific survival and analysis of pattern failure suggest that disease prognosis is similar between young and older adults with oral tongue cancer. Further work is needed to identify the younger patients with poorer prognosis who overwhelmingly fail during the first year after treatment and could benefit from treatment intensification. Until then, young adults ought to be treated using standard guidelines.

immune checkpoint inhibitors(ICIs) have shown contradictory results in patients with advanced gastro-oesophageal junction/gastric cancer(GOJ/GC).to identify specific patient subgroups that would derive survival benefit from ICIs.a subgroup meta-analysis of randomised clinical trials(RCTs) was carried out.four phase-III-RCTs were identified with data on the following variables: primary location(Gastric vs GOJ); age(≤ 65 vs65); gender(male vs female); ECOG PS(0 vs 1); ethnicity (Asian vs non-Asian), histology(intestinal vs diffuse), PD-L1 expression(≥ 1% vs1%). PD-L1 positivity was significantly associated with survival benefit from ICIs (HR: 0.82, p 0.047), with a significant interaction between PD-L1 expression and ICI efficacy (interaction HR: 1.41, p 0.02). Numerically, the second most relevant interaction was ICI efficacy and gender, with ICI being more effective in males.The PD-L1 positive patient subgroup derives significant survival benefit from ICI in GOJ/GC, however other predictors are eagerly needed to further refine patient selection.

4530 Background: ICIs demonstrated improved overall survival (OS) in heavily pre-treated mGOJ/GC pts. Pts selection exclusively based on PD-L1 tissue expression appears to be suboptimal, despite data from subgroup analyses of KEYNOTE trials. Strong rationale suggests a potential predictive role of inflammatory biomarkers in ICIs treated mGOJ/GC pts. Methods: Ten systemic inflammatory markers [platelets, monocytes, neutrophil/lymphocyte ratio (NLR), platelets-lymphocyte ratio, lymphocytes, sum of mononuclear cells, albumin, lactate dehydrogenase, c-reactive protein (CRP) and serum globulin] were retrospectively analyzed at baseline in 57 mGOJ/GC pts with unknown PD-L1 status treated in second-line with ICIs, and correlated with OS. Least Absolute Shrinkage and Selection Operator (LASSO) method was used to select variables (preliminarily subject to optimal coding using HR smoothed curves for OS) with the highest prognostic value. Selected variables were then analyzed in a multivariate Cox Regression Model and used to build a GIPI nomogram. Results: NLR and CRP taken as continuous variables and albumin categorized as < vs > 30 g/dL were found as the most meaningful independent predictors of OS and used to build the GIPI nomogram. Nomogram-based lowest (l), mid-low, mid-high and highest (h) risk quartiles were associated with median(m)OS of 14.9, 7.1, 5.6 and 2.1 months (mos), respectively [HR of l vs h 4.94, p 0.0002]. By optimally dichotomizing CRP and NLR, pts with one or more of the following risk factors: NLR >6, CRP >15 mg/L, albumin

Background Brain metastases (BM) from adult soft tissue or bone sarcomas are rare, and sparse data exist on their prognostic factors and management. Subjects, Materials and Methods A retrospective study was conducted in 15 centers of the French Sarcoma Group, plus one Canadian and one Swiss center, to report on clinical, histological, and treatment characteristics and to identify predictive factors of outcome. Results Between 1992 and 2012, 246 patients with a median age of 50 years (range: 16–86) were managed for BM. BM included 221 cerebral and cerebellar metastases and 40 cases of meningeal sarcomatosis. The most frequent histopathological subtype was leiomyosarcoma (18.7%). Histological grade was high in 118 (48%) cases. Surgery of BM was carried out for 38 (15.5%) patients. Radiotherapy and chemotherapy were administered in 168 (68.3%) and 91 (37.0%) patients, respectively. Irrespective of treatment modality, BM were controlled in 113 patients (45.9%), including 31 partial responses (12.6%) and 18 complete responses (7.3%). The median overall survival from diagnosis of brain metastasis was 2.7 months (range: 0–133). In the multivariate analysis, the following parameters influenced overall survival: chemotherapy (hazard ratio [HR] = 0.38; 95% confidence interval [CI]: 0.26–0.48), surgery (HR = 0.40; 95% CI: 0.22–0.72), stereotactic radiotherapy (HR = 0.41; 95% CI: 0.19–0.90), whole-brain radiotherapy (HR = 0.51; 95% CI: 0.35–0.76), and grade (HR = 0.65; 95% CI: 0.43–0.98). Conclusion BM of sarcomas are rare and associated with a dismal outcome. Multidisciplinary management with chemotherapy, radiation therapy, and surgery is associated with a better survival. Implications for Practice The incidence of brain and meningeal metastasis in bone and soft tissue sarcomas is estimated between 1% and 8%. Published data are derived from small retrospective case series, often in the pediatric population. A prognostic index is important to guide both clinical decision-making and outcomes research, but one such is lacking for adult sarcoma patients with brain metastases. The current study describes brain metastasis in a large cohort of sarcoma patients. This study, conducted within the French Sarcoma Group, describes the natural history of sarcoma brain metastasis and enables the proposal of strategic recommendations for subsequent clinical trials and for the management of such patients.

Background We previously demonstrated that interruption of imatinib mesylate (IM) in responding patients (pts) with advanced gastrointestinal stromal tumours (GISTs) results in rapid reprogression. The impact of interruption on residual tumour, quality of response and secondary resistance has not been fully investigated. Patients and methods Within the BRF14 study, 71 non-progressing patients were randomly assigned in the interruption arms after 1, 3 or 5 years. IM was resumed in the case of progressive disease (PD). Tumour status at randomisation, relapse and after IM rechallenge, progression-free survival (PFS) and time to secondary resistance were analysed. Results At data cut-off, 51 of 71 patients had restarted IM following documented PD. Eighteen patients (35%) progressed on known lesions only, while 33 patients (65%) had new lesions, with concomitant progression of known lesions in 17 patients. Only 8 (42%) of complete remission (CR) patients and 12 (52%) of partial response (PR) patients at randomisation achieved a new CR and PR. Patients progressing rapidly after interruption had a poorer prognosis. Tumour status at randomisation influenced time to progression after rechallenge. Conclusion In advanced GIST patients interrupting IM, quality of response upon reintroduction did not reach the tumour status observed at randomisation. Rapid progression after imatinib interruption is associated with poor PFS after reintroduction.

International audience; BACKGROUND: The added value of tumoural genomic profiles to conventional clinico-biological factors to predict progression-free survival (PFS) and overall survival (OS) was prospectively investigated in patients with advanced gastrointestinal stromal tumours (GIST) treated in the BFR14 study. METHODS: Of the 434 included patients, mutational analysis was performed in 322 patients. Survival analysis was performed in patients with validated mutational status. RESULTS: Mutational status was validated in 228 patients. We identified 196 patients with tumours harbouring 200 KIT alterations (exon 11: 173 patients, exon 9: 22 patients, exon 17: 3 patients, exon 13: 2 patients; 4 patients had double KIT mutations), 6 patients with PDGFRA mutations and 26 patients with wild-type (WT) GIST genotype. On a median follow-up of 73 months, median PFS/OS were 12.3/54.9 months for WT GIST, 12.6/55 months for KIT exon 9, and 39.4 months/not reached (69.1% at 5 years) for KIT exon 11. Tumour size, female gender, KIT exon 11 mutations and CD34 positivity were independent prognostic factors for a higher PFS. A higher OS was predicted by performance status (PS) \textless2, low neutrophil and normal lymphocyte counts, KIT exon 11 mutations, non-advanced tumour and female gender. KIT exon 11 mutations at codons 557-558 showed better tumour response (p=0.028) but shorter PFS (p=0.0176). CONCLUSIONS: In GIST patients, presence of a KIT exon 11 mutation is an independent prognostic factor for PFS and OS, along with gender, PS, tumour size, lymphocyte and neutrophil counts. Subsets of exon 11 mutations are associated with significantly different response patterns and PFS

BACKGROUND: Data regarding the role of systemic therapy in patients with advanced well-differentiated/dedifferentiated liposarcomas (WDLPS/DDLPS) are limited. METHODS: From 2000 to 2010, 208 patients with advanced WDLPS/DDLPS received chemotherapy in 11 participating institutions. Clinical and pathological data were collected by reviewing medical records. RESULTS: Median age was 63 years (range 32-84). Combination chemotherapy was delivered in 85 cases (41%) and single agent in 123 cases (59%), respectively. One hundred and seventy-one patients (82%) received an anthracycline-containing regimen. Using RECIST, objective response was observed in 21 patients (12%), all treated with anthracyclines. Median progression-free survival (PFS) was 4.6 months [95% confidence interval (CI) 3.3-5.9]. On multivariate analysis, age and performance status (PS) were the sole factors significantly associated with poor PFS. Median overall survival (OS) was 15.2 months (95% CI 11.8 -18.7). On multivariate analysis, grade and PS were the sole factors significantly associated with OS. CONCLUSIONS: Chemotherapy was associated with clinical benefit in 46% of patients with advanced WDLPS/DDLPS. OS remains poor, even though visceral metastatic disease is less frequent than in other sarcomas.

Interleukin (IL)-8 promotes cellular proliferation and angiogenesis in patients with non-small-cell lung cancer (NSCLC) and may be related to cachexia. Our aim was to investigate the relationship of IL-8 levels with nutritional status, and clinical outcome of patients with NSCLC. Patients with metastatic NSCLC referred for first-line therapy were eligible. Baseline IL-8 levels were measured in plasma. The Mini Nutritional Assessment (MNA) was used for the evaluation of the nutritional status, and patients were classified into 3 groups: A (score 24-30) "well nourished," B (score 17-23.5) "risk of malnutrition," and C (0-16.5) "malnourishment." Response to first-line chemotherapy, time-to-tumor progression (TTP), and overall survival (OS) were also recorded. In total, 114 patients (101 males, 88.5%; mean age = 67.5 yr) were evaluated. Performance status was 0-1 in 62% of the patients. According to the MNA, the majority of patients (71%) was either at nutritional risk or malnourished. IL-8 levels were significantly different between MNA groups (P = 0.023) and correlated with TTP (P = 0.013) and OS (P = 0.001) in univariate analysis. Baseline IL-8 levels correlate with the nutritional status of patients with metastatic NSCLC, suggesting that this cytokine may be related with cachexia.

We present a metastatic tumour from the breast to the gingiva, with the rare finding of tooth invasion. Metastatic tumours to the oral region are uncommon. The breast is the most common primary site for metastatic tumours to the jawbones in women, with the mandible being most often affected. We report the case of a 52-year-old Caucasian woman who presented with a swelling of the buccal mucosa in the molar region of the left mandible. Biopsy revealed a metastatic lesion, with involvement of the two adjacent molars. Immunohistochemical analysis ruled out other malignancies and confirmed the diagnosis of a ductal breast carcinoma origin. Management in such cases should be in the context of the treatment of a metastatic disease that could prolong survival and improve quality of life, but is not curative. Tooth invasion has been described since 1910 for different primary malignancies with distant metastases to the oral cavity. This report seems to describe the second case in the literature of a metastatic breast carcinoma to the mandible with tooth invasion. Management in such cases should be in the context of the treatment of a metastatic disease that could prolong survival and improve quality of life, but is not curative.

Prostate cancer (PCa) is a potentially curable disease when diagnosed in early stages and subsequently treated with radical prostatectomy (RP). However, a significant proportion of patients tend to relapse early, with the emergence of biochemical failure (BF) as an established precursor of progression to metastatic disease. Several candidate molecular markers have been studied in an effort to enhance the accuracy of existing predictive tools regarding the risk of BF after RP. We studied the immunohistochemical expression of p53, cyclooxygenase-2 (COX-2) and cyclin D1 in a cohort of 70 patients that underwent RP for early stage, hormone naïve PCa, with the aim of prospectively identifying any possible interrelations as well as correlations with known prognostic parameters such as Gleason score, pathological stage and time to prostate-specific antigen (PSA) relapse. We observed a significant (p = 0.003) prognostic role of p53, with high protein expression correlating with shorter time to BF (TTBF) in univariate analysis. Both p53 and COX-2 expression were directly associated with cyclin D1 expression (p = 0.055 and p = 0.050 respectively). High p53 expression was also found to be an independent prognostic factor (p = 0.023). Based on previous data and results provided by this study, p53 expression exerts an independent negative prognostic role in localized prostate cancer and could therefore be evaluated as a useful new molecular marker to be added in the set of known prognostic indicators of the disease. With respect to COX-2 and cyclin D1, further studies are required to elucidate their role in early prediction of PCa relapse after RP.

Surgery remains the cornerstone of treatment and the only curative loco-regional approach of localized resectable soft tissue sarcoma (STS) in 2011: the usual first-line treatment is wide margin surgery plus radiotherapy, especially in the case of primary tumors arising in the limbs. An optimal initial R0 resection is one of the most reproducible and reliable prognostic factors for survival in resectable STS. Nevertheless, despite improved local control rates, more than half of the patients still develop and die from unresectable, locally advanced, and/or metastatic disease. Unfortunately, very few cytotoxic drugs have shown activity in this clinical setting with the exception of doxorubicin, ifosfamide, and to a lesser extent, dacarbazine. A conventional-dose, single-agent chemotherapy is still considered to be the standard treatment for metastatic disease. The impact of adjuvant chemotherapy after resection of a high-grade STS remains controversial due to the lack of reproducible impact on survival. Because STS is a rare disease, most trials have involved a relatively small number of patients, with heterogeneous groups of histological/molecular subtypes of sarcomas, initial sites of the disease, and patient's characteristics. In a few trials, a lower risk for local recurrence was observed among patients receiving adjuvant chemotherapy but without any significant gain in overall survival. A meta-analysis based on individual data of these randomized studies has confirmed a significant impact of adjuvant chemotherapy on relapse, either local or metastatic, but without any significant benefit on survival. It should be of importance to include the last recent large trials in a new meta-analysis of source data in order to more carefully analyze a possible benefit of systemic adjuvant chemotherapy in localized sarcoma. Until this study is performed, it is an obvious conclusion that adjuvant chemotherapy has not reproducibly demonstrated its capacity to improve overall survival and relapse-free survival in an unselected population of patients. In 2011, there is therefore an urgent need to determine whether or not there are small subpopulations of patients truly benefiting from adjuvant chemotherapy (with conventional agents), and to identify prospectively these populations. With the exception of male, older than 40 years, with a non-optimal resection of their primary (R1 resection) or in the subgroup of grade 3 STS, no other relevant clinical prognostic/predictive factors have been highlighted. The take home messages in 2011 could be as follows: (1) adjuvant chemotherapy is not recommended routinely in high-grade STS; (2) adjuvant chemotherapy is recommended in patients underwent a R1 resection and with a grade 3 STS; (3) adjuvant chemotherapy cannot rescue an inadequate initial surgery; (4) if selected, chemotherapy has to be contain anthracycline and fractionated adequate dose of ifosfamide (around 9 g/m(2) per cycle); (5) the era of adjuvant chemotherapy trials with the same chemotherapy regimen in all histological subtype of sarcoma is ended; and (6) prognosis of patients with a localized STS starts at diagnosis. The dramatic activity of imatinib in GIST, the heterogeneous outcome of each histological subtype of sarcomas akin to being different diseases, and the high sensitivity of some histological subtypes of sarcoma to specific agents clearly open a new era in the management and the evaluation of new agents in the field of STS. The design of the future adjuvant trials has to incorporate these new findings and new prognostic/predictive biomarkers in order to improve the as yet dismal prognosis of patients developing high-grade localized STS.

TPS5086Background: The current first-line treatment for patients with CRPC and disease progression is either treatment with abiraterone acetate/prednisone, ENZ, or treatment with docetaxel in more ...

Background There is an urgent need for qualified predictive biomarkers of sensitivity for the treatments used in patients with castration-resistant prostate cancer (CRPC). We attempted to identify ready-to-use clinical predictors of improved outcome in metastatic CRPC (mCRPC) patients treated with next generation androgen receptor (AR) axis targeted drugs. Patients and methods We reviewed a cohort of patients who received AR axis targeted drugs for CRPC at two major French cancer centres. The predictive role of several clinical, biological and radiological parameters on progression-free survival (PFS) was studied. Results The study cohort consisted of 173 patients. Median duration of response to initial androgen deprivation therapy (ADT) (time to castration resistance, TTCRPC) was 17.8 months. The 50% prostate-specific antigen (PSA) response rate to AR axis targeted drugs was 16% (95% confidence interval (CI): 6–27) and 41% (95% CI: 30–47) in patients with TTCRPC of under and over 12 months respectively (p = 0.005). Median PFS was 2.8 months (95% CI: 2.1–3.9) and 5.8 (95% CI: 4.6–7.8; HR: 0.58, p = 0.002). In patients treated with post-docetaxel enzalutamide (n = 57), median PFS was 2.8 months and 8.6 months, (Hazard ratio (HR) = 3.1; 95% CI: 1.6–5.8, p = 0.0016) according to TTCRPC, whereas no difference was observed in placebo-treated patients (n = 27). The 50% PSA response rate to enzalutamide was 8% (95% CI: 0–38) and 58% (95% CI: 42–73) in patients with a TTCRPC of under and over 12 months respectively (p Conclusion The previous duration of response to ADT is a predictor of sensitivity to next generation AR axis targeted drugs in patients with mCRPC.

Background The paradigm change observed over the last few years in several solid tumors emphasizes the value of locoregional treatment in the presence of metastatic disease, currently ignored in de novo prostate cancer (CaP). We investigated the effect of the primary tumor that is left untreated on prostate cancer–specific morbidity and mortality, time to castration resistance, and overall survival (OS). Methods We performed a bicentric cohort study. The overall population included de novo metastatic CaP managed at the Genito-Urinary Oncology Unit of the Gustave Roussy Institute and the Urology Clinic of the University Hospital of Pointe-a-Pitre, France. Descriptive statistical and outcome analyses were performed in the overall cohort and also separately in the N+M0 and M+subgroups. Results The overall cohort included 263 patients. Approximately two-thirds of patients (64%) presented with locoregional symptoms at diagnosis, and 78% throughout the disease. Of the symptomatic patients, 59% required a locoregional procedure. Median OS of patients with locoregional symptoms at diagnosis was shorter than in those who were asymptomatic (47 vs. 86 mo, P = 0.0007); this difference was maintained in the N+M0 and M+subgroups. Median OS and time to castration resistance showed a nonsignificant trend in favor of patients undergoing a locoregional treatment at diagnosis. Conclusion The presence of symptoms due to locoregional disease in de novo metastatic CaP entails significant morbidity and even mortality and requires active management. Randomized prospective trials are needed to evaluate the role of initial definite locoregional treatment in these patients.

During the last 30 years, there has been a major shift in initial staging in prostate cancer (CaP) in Western countries, with the incidence of metastases at diagnosis decreasing from over 50% in the 1970s to currently less than 10%. Yet, CaP is still the second cause of cancer death in men. We used two monthly curated databases of patients with castration-resistant prostate cancer (CRPC) to describe the natural history of patients dying of CaP in the modern era.The outcome of 190 men with metastatic CRPC treated from 2008 to 2011 was studied. The characteristics of the patients who died from CaP (n = 113 patients, 61%) were analyzed.All 113 patients who died of CaP were assessable for the presence of metastases at diagnosis. Sixty-three patients (56%) had detectable metastases at diagnosis: 67%, 11% and 43% had bone, visceral and lymph node metastases, respectively. The median time to CRPC was 16 months and median overall survival (OS) was 5.2 years.Among the patients with localized CaP at diagnosis (n = 50, 44%), 46% had T stage ⩾ 3 and 38% had a Gleason score ⩾ 8. Overall, 64% of patients were classified as having a high-risk CaP. Only 26% who died from CaP had a Gleason score ⩽ 6. Median OS was 8.8 years.In the modern era, approximately half of the patients who die from CaP have metastases at diagnosis. The paradigm of progression from localized disease to metastasis and eventually death is only represented in the other half, although possible initial screening and staging errors ought to be taken into consideration. More efforts are needed to conduct trials in patients with newly diagnosed metastatic CaP.

Background Sorafenib is the only systemic treatment that has shown a significant benefit in overall survival (OS) and in progression-free survival (PFS) in advanced hepatocellular carcinoma (HCC) patients. No standard of care currently exists for second-line treatment. The association of Gemcitabine-Oxaliplatine (GEMOX) has shown efficacy in the first-line setting. The aim of this study was to evaluate the efficacy of GEMOX after failure of at least one line of anti-angiogenic (AA) therapy. Patient and methods We performed a multicenter retrospective analysis of advanced HCC patients that received GEMOX chemotherapy after progression on at least one line of AA therapy. Results We analyzed a total of 40 patients that received a median of 7 cycles of GEMOX over a 6-year period. Grade 3/4 toxicity was observed in 25 % of patients, mainly neurotoxicity, thrombocytopenia and neutropenia in 12.5 %, 5 % and 5 % of patients respectively. Grade

International audience; OBJECTIVES: Indications for radiotherapy and chemotherapy in stage II seminoma are currently debated. MATERIALS AND METHODS: Since 1980, the policy at Institut Gustave Roussy was to treat patients with stage IIA-B disease with external radiotherapy and patients with stage IIB-C with cisplatin-based chemotherapy. In stage IIB disease, 3 cm was the usual tumor size threshold above which individual patients were considered for chemotherapy. RESULTS: During the period 1980-2001, 67 patients with stage II seminoma were treated: stage IIA (n = 5), stage IIB (n = 31), and stage IIC (n = 31). The median age was 40 years (range: 23-64). Among 37 patients who received radiotherapy, 5, 28, and 4 had a stage IIA, IIB, and IIC, respectively. Among 30 patients who received chemotherapy, 27 had a stage IIC. With a median follow-up of 9.4 years, 19 relapses (28%) occurred, including 11 and 8 cases treated with radiotherapy (30%) and chemotherapy (27%), respectively. The 5-year relapse-free survival was 71% (95% CI: 59-80). All but three relapses were salvaged with chemotherapy followed in selected cases by surgical resection of residual masses. Only 3 patients died of seminoma. The 5-year overall survival rate is 97% (95% CI: 89-99). Five patients subsequently developed a non-germ-cell second cancer, which occurred within the radiation field in 3 cases. CONCLUSION: With an overall survival rate of 97%, the overall outcome of patients with stage II seminoma managed according to this risk-adapted strategy is good. The possibility of extending the indications for chemotherapy to selected stage IIB seminoma patients needs to be further evaluated as potentially beneficial in terms of relapse risk.

Background: Androgen receptor (AR) signalling remains critically important in metastatic castration-resistant prostate cancer (mCRPC) as confirmed by recent phase III trials, showing a survival advantage for abiraterone acetate and enzalutamide (MDV3100). The antitumour activity of abiraterone and prednisolone in patients pre-treated with enzalutamide is as yet unknown. Patients and methods: We investigated the antitumour activity of abiraterone and prednisolone in patients with mCRPC who had progressed following treatment with docetaxel (Taxotere) and enzalutamide. Clinical data were retrospectively analysed for prostate-specific antigen (PSA) and RECIST responses, clinical benefit and survival. Results: Thirty-eight patients were included in the analysis. The median age was 71 years (range 52-84); metastatic sites included bone disease in 37 patients (97%), lymph nodes in 15 patients (39%) and visceral disease in 10 patients (26%). Abiraterone was well tolerated. Three patients (8%) attained a PSA response, defined as >= 50% decline in PSA confirmed after >= 4 weeks, while seven patients (18%) had a >= 30% PSA decline. The median progression-free survival (PFS) was 2.7 months (95% Cl 2.3-4.1). Of the 12 patients assessable radiologically, only 1 (8%) attained a confirmed partial response. Conclusion: Abiraterone and prednisolone have modest antitumour activities in patients with mCRPC pretreated with docetaxel and enzalutamide.

Objective. To study the impact of the neutral endopeptidase (NEP)/neuropeptides (NPs) axis and nuclear factor kappa B (NFκB) as predictors of prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP).Patients and Methods. 70 patients with early-stage PC were treated with RP and their tumor samples were evaluated for expression of NEP, endothelin-1 (ET-1) and NFκB (p65). Time to PSA recurrence was correlated with the examined parameters and combined with preoperative PSA level, Gleason score, pathological TNM (pT) stage, and surgical margin (SM) assessment.Results and Limitations. Membranous expression of NEP (P<0.001), cytoplasmic ET-1 (P=0.002), and cytoplasmic NFκB (P<0.001) were correlated with time to PSA relapse. NEP was associated with ET-1 (P<0.001) and NFκB (P<0.001). ET-1 was also correlated with NFκB (P<0.001). NEP expression (P=0.017), pT stage (P=0.013), and SMs (P=0.036) were independent predictors of time to PSA recurrence.Conclusions. There seems to be a clinical model of NEP/NPs and NFκB pathways interconnection, with their constituents following inverse patterns of expression in accordance with their biological roles and molecular interrelations.

Bortezomib represents the first proteasome inhibitor (PI) with demonstrated antitumor activity in the clinical setting, particularly for treatment of hematological malignancies. At the preclinical level, its action is shown to be mediated by induction of growth arrest and apoptosis in many tumor types, including androgen-dependent (AD) and androgen-independent (AI) prostate cancer (PCa) cells. Hypoxia-inducible factor-1α (HIF-1α), which is directly involved in tumor growth, is one of the most studied and promising molecular targets for anti-cancer therapy and is often overexpressed in PCa. Bortezomib has been reported to impair tumor growth by also inhibiting HIF-1α. In this study, we investigated the effect of bortezomib on the expression, activity and localization of HIF-1α in LNCaP (AD) and PC3 (AI) PCa cells. First, we show that hypoxic upregulation of HIF-1α protein levels and activity involves both the PI3K/Akt/mTOR and p44/42 MAPK pathways. Second, bortezomib inhibits expression of HIF-1α protein under both normoxic and hypoxic conditions, represses HIF-1 transcriptional activity and attenuates the release of vascular endothelial growth factor. These effects correlate with the ability of bortezomib to cause dephosphorylation of phospho-Akt, phospho-p70S6K, and phospho-S6RP, thus inactivating a pathway known to be required for HIF-1α protein expression at the translational level. Furthermore, bortezomib also abrogates p44/42 MAPK phosphorylation, which results to reduced nuclear translocation of HIF-1α. Taken together, these results suggest that bortezomib inhibits HIF-1α protein synthesis and its nuclear targeting through suppression of PI3K/Akt/mTOR and MAPK pathways, respectively, in both AD and AI PCa cells.

Background Head and neck cutaneous squamous cell carcinoma (HNCSCC) although rarely fatal has significant adverse public health effects due to high medical costs, compromised quality of life, functional impairment and other serious consequences. The present longitudinal cohort study of HNCSCC was designed to determine whether certain clinical–pathologic features of HNCSCC are associated with reduced overall and recurrence-free survival, as suggested by previous data. Patients The cohort sample consisted of 315 consecutive patients presenting with primary HNCSCC of the head and neck. Life-table analysis and Kaplan–Meier survival analysis were performed. Multivariate Cox’s proportional hazards regression models were used to assess the effects of covariates on the length of the interval. Results There were 145 male and 170 female Caucasian patients. At the time of analysis, 222 patients were alive. The mean follow-up time of a patient after enrolment has been 46.7 months (range, 12–124 months). Broder’s differentiation grade, perineural involvement, the presence of inflammation and T-stage were independent adjusted predictors for overall survival. pT and N-stage, inflammation and perineural involvement were significant predictors for recurrence-free survival while adjuvant irradiation was associated with a 92% reduced risk for recurrence. Life-table analysis showed that 87% and 69% study patients were free from recurrence at years 3 and 5, respectively. Conclusions Certain clinico-pathological predictors can be used to discriminate subsets of high-risk patients that could benefit from long-term follow-up. After excision in negative margins, patients with HNCSCC should be referred to specialised multidisciplinary oncology clinics for counselling on adjuvant radiotherapy and follow-up.

Purpose Osteonecrosis of the jaws (ONJ) was initially described in 2001 in patients receiving intravenous bisphosphonate (BP) treatment. The objective of the present study was to determine whether routine dental procedures can be considered as possible risk factors for the development of ONJ in breast cancer patients receiving BP. Patients and Methods Twenty breast cancer patients who developed ONJ receiving BP treatment were included in group A, whereas group B consisted of 40 matched controls (breast cancer patients who did not progress to ONJ receiving BP treatment). Routine dental care, smoking habits, history of tooth extraction, use of dentures, and root canal therapy were recorded. Results Our results indicate that history of tooth extraction during zoledronic acid treatment (adjusted odds ratio [OR] = 16.4; 95% CI, 3.4 to 79.6) and the use of dentures (adjusted OR = 4.9; 95% CI, 1.2 to 20.1) increase the risk of developing ONJ. Conclusion The outcome of the present study suggests early referral by oncologists for dental evaluation for every patient to be treated with BP. These results raise the current American Society of Clinical Oncology Level of Evidence linking certain dental procedures with ONJ from V to III. Further studies are needed to assess other possible risk factors and also to highlight the etiopathogenesis mechanism of ONJ.

227 Background: Cross-resistance between taxanes and androgen receptor axis targeted agents is a matter of debate in metastatic castration-resistant prostate cancer (mCRPC). Preclinical data about response to taxanes after prior enzalutamide suggest some level of cross-resistance (van Soest et al, Eur J Cancer 2013) though this was not confirmed in other models (Al Nakouzi N, Eur Urol 2014). The first objective of this study was to assess the impact of previous enzalutamide therapy on the efficacy of subsequent taxane-based chemotherapy. The second objective was to investigate the prognosis of patients when chemotherapy was initiated in enzalutamide-pretreated patients. Methods: Data from 96 enzalutamide- and placebo-treated patients enrolled in the Prevail phase III trial were retrospectively collected from 14 centers in France. Changes in prostate specific antigen (PSA) levels, progression free survival (PFS) and RECIST criteria v 1.1 were used to determine the activity of docetaxel (n=89) or cabazitaxel (n=7) treatment. The Halabi model was used to predict survival probabilities for the enzalutamide- or placebo-pretreated patients when chemotherapy was initiated (Halabi et al, J Clin Oncol 2014). Results: Overall, 96 patients were included in this analysis (58 in the placebo arm vs. 38 in enzalutamide arm). PSA response to taxanes (defined as a decline of ≥50% from baseline) was marginally lower in enzalutamide-vs. placebo-pretreated patients (34% vs. 53%, p=0.10). PSA response in enzalutamide-pretreated patients was not different from that observed with docetaxel given every 3 weeks in TAX 327 trial (Tannock et al, NEJM 2004) (45%, p=0.20, binomial test). Median PFS and objective response rates were similar between the two groups (4.8m vs 6.7 m;p=0.14 and 45% vs 43%;p=0.83 respectively). Halabi score was well-balanced between the two groups (p=0.30). Conclusions: Taxanes retain efficacy in enzalutamide-pretreated mCRPC. At the time of first-line taxane-based chemotherapy initiation, the prognosis of enzalutamide-treated patients according to the Halabi score was not different from that of enzalutamide-naïve patients.

211 Background: In the last 30 years, a major shift in initial staging has occurred for men with prostate cancer (CaP) in many Western countries, with the incidence of detectable metastases at diagnosis decreasing from more than half the cases in the 1970s to currently less than 10%. Still, prostate cancer is the second killing neoplasm in men. We used two prospective databases of patients with castration-resistant prostate cancer (CRPC) to describe the natural history of metastatic CRPC in the modern era. Methods: The outcome of 190 men with CaP treated for metastatic disease from 2007-2011 was studied. Characteristics of patients who died from CaP were analyzed. Results: After a median follow-up of 6.8 years, 112 patients had died from CaP and 109 were assessable for presence of metastasis at initial diagnosis. Of these 109 pts, 53 (49%) had detectable metastasis at diagnosis: 43 pts (81%), 6 pts (11%) and 17 pts (32%) had bone, visceral; and lymph nodes metastases, respectively. Overall, 10 pts (19%) had more than one metastatic site. Median time to CRPC was 16 months (range: 3-122 months) and median overall survival was 5 years (CI 95%: 4.6 – 6.6 years) for these pts with detectable metastasis at diagnosis. Among patients with localized CaP at diagnosis (n=56; 51%), 23 pts (41%) had T stage ≥ 3, 23 pts (41%) had a Gleason score ≥ 8. Their median PSA was 15 ng/ml (4-400). Overall, 39 pts (70%) were classified as having a high-risk CaP. 13 patients (23%) dying from CaP had an initial Gleason score ≤ 6. The median overall survival was 7 years (CI 95%: 6.1 – 9.1 years). Conclusions: In the modern era, approximately half of the patients eventually dying from CaP had detectable metastases at diagnosis. The paradigm of patients progressing from localized disease to metastatic disease and eventually death is represented only in the other half. Further efforts should be made to conduct clinical trials in patients with newly diagnosed metastatic prostate cancer.

10071 Background: Data regarding the role of systemic therapy in patients (pts) with advanced well-differentiated/dedifferentiated liposarcomas (WLPS/DDLPS) are limited. Methods: From 2000 to 2010, 166 pts with a confirmed diagnosis of WDLPS/DDLPS were referred to one of the 8 participating institutions, and their medical records reviewed. Results: Median age was 63 years (range 34-84). Thirty pts had WDLPS and 136 pts had DDLPS. Primary tumor sites were: retroperitoneum n=120 (73%), limb n=19 (11%), other n=27 (16%). 111 pts (67%) had metastatic disease (peritoneal sarcomatosis n=75; lung n=30, liver n=19, bone n=5) and 55 pts (33%) had locoregional unresectable disease. 27 pts (16%) had ≥ 2 metastatic sites. 103 pts (62%) received 1st line single agent chemotherapy. 131 pts (79%) received a 1st line anthracycline-containing regimen (doxorubicin n=64, doxorubicin + ifosfamide and/or dacarbazine: n=45, other: n=22). Non-anthracycline regimens were: metronomic cyclophosphamide or etoposide: n=17; trabected...

14562 Background: The ubiquitin-Proteasome system (UPS) has emerged as an important proteolytic system for the regulation of a wide range of cellular functions. Key determinants of carcinogenesis, are regulated in multiple levels by UPS. Proteasome inhibition by the boronic containing molecule bortezomib is already in use for the treatment of multiple myeloma and is in various phases of investigation for other malignancies. Cox inhibitors such as NSAIDs have been shown to inhibit the growth of colorectal cancer cells in vitro and polyp formation in vivo. Methods: HT-29 and HCT116 colorectal cancer cell lines were treated with aspirin (ASA), bortezomib and their combination. MTT assay was used to evaluate the effect of treatment on cell proliferation compared to controls. Cox activity and proteasome activity were measured with colorimetric methods. The effect of drug treatments on specific proteins expression was assayed by western blotting. Results: Both cell lines are inhibited by ASA and bortezomib and their proliferation is further inhibited by the combination of the two drugs. In HT-29 cells both ASA and bortezomib inhibit proteasome and their combination has additive effect in this inhibition. In contrast in HCT116 cells ASA-mediated inhibition is accompanied by increased proteasome activity while bortezomib-mediated growth inhibition is accompanied as expected by proteasome inhibition. ASA-mediated inhibition is not Cox-mediated since no Cox activity was detected in either cell line. Cell cycle inhibitor p27 expression is induced in HCT116 cells by bortezomib while ASA fails to do so. In HT29 cells p27 is expressed at baseline and does not change significantly by treatments. Conclusion: The combination of ASA and bortezomib inhibited the proliferation of both cell lines more than either drug alone in a Cox-independent way. ASA had opposite effects on proteasome activity in the two lines. p27 induction may mediate at least partially the anti-proliferative effect of bortezomib in HCT116 cells. Further studies are in progress to determine other molecular components of the cellular processes taking place during treatment by the combination of these drugs in order to better understand their mechanism of action and thus explore their potential therapeutic use. No significant financial relationships to disclose.