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This file contains the patients characteristics: Supplementary table 1

This file contains the antiviral response in patients: Supplementary figure 3

This file contains the legends for the supplementary figures

The rapalogs everolimus and temsirolimus that inhibit mTOR signaling are used as antiproliferative drugs in several cancers. Here we investigated the influence of rapalogs-mediated immune modulation on their antitumor efficacy. Studies in metastatic renal cell carcinoma patients showed that everolimus promoted high expansion of FoxP3+Helios+Ki67+ regulatory CD4 T cells (Tregs). In these patients, rapalogs strongly enhanced the suppressive functions of Tregs, mainly in a contact-dependent manner. Paradoxically, a concurrent activation of spontaneous tumor-specific Th1 immunity also occurred. Furthermore, a high rate of Eomes+CD8+ T cells was detected in patients after a long-term mTOR inhibition. We found that early changes in the Tregs/antitumor Th1 balance can differentially shape the treatment efficacy. Patients presenting a shift toward decreased Tregs levels and high expansion of antitumor Th1 cells showed better clinical responses. Studies conducted in tumor-bearing mice confirmed the deleterious effect of rapalogs-induced Tregs via a mechanism involving the inhibition of antitumor T-cell immunity. Consequently, the combination of temsirolimus plus CCR4 antagonist, a receptor highly expressed on rapalogs-exposed Tregs, was more effective than monotherapy. Altogether, our results describe for the first time a dual impact of host adaptive antitumor T-cell immunity on the clinical effectiveness of rapalogs and prompt their association with immunotherapies. Cancer Res; 76(14); 4100–12. ©2016 AACR.

This file contains the supplementary material and methods

Scientific advances in the last decade have highlighted the use of immunotherapy, especially immune checkpoint inhibitors, to be an effective strategy in cancer therapy. However, these immunotherapeutic agents are expensive, and their use must take into account economic criteria. Thus, the objective of the present study was to systematically identify and review published EE related to the use of ipilimumab, nivolumab or pembrolizumab in melanoma, lung cancer, head and neck cancer or renal cell carcinoma, and to assess their quality. The systematic literature research was conducted on Medline via PubMed and the Cochrane Central Register of Controlled Trials to identify economic evaluations published before July 2018. The quality of each selected economic evaluation was assessed by two independent reviewers using the Drummond checklist. Our systematic review was based on 32 economic evaluations using different methodological approaches, different perspectives and different time horizons. Three-quarters of the economic evaluations are full (n = 24) with a Drummond score ≥ 7, synonymous of “high quality”. Among them, 66% reported a strategy that was cost-effective. The most assessed immunotherapeutic agent was nivolumab. In patients with renal cell carcinoma or head and neck cancer, it was less likely to be cost-effective than in patients with melanoma or lung cancer. Whether or not these findings will be confirmed remains to be seen when market approval to cover more indications is extended and new effective immunotherapeutic agents become available.

Resume Les cancers du penis sont rares, representes en grande majorite par le carcinome epidermoide, le virus HPV y est associe dans 30 a 40 % des cas. A un stade localement avance ou metastatique, la prise en charge de premiere ligne repose sur une polychimiotherapie a base de taxanes et de sels de platine. Le pronostic du cancer du penis avance ou metastatique reste sombre, la survie globale etant comprise entre 13,9 et 17,1 mois. Au-dela, les recommandations preconisent de facon heterogene des traitements de chimiotherapie ou des therapies ciblees anti-EGFR (epidermal growth factor receptor) dont les resultats, tout comme le niveau de preuve, sont limites. Une meilleure connaissance des voies oncogeniques impliquees dans le cancer du penis et une expression frequente de PD-L1 sont le rationnel pour l’elaboration de nouvelles strategies. Cette revue de la litterature presente les donnees, les recommandations et les etudes en cours dans le cancer du penis localement avance ou metastatique.

Penile cancers are rare, the vast majority is represented by squamous cell carcinoma, with HPV virus being found in 30 to 40% of cases. At a locally advanced or metastatic stage, first-line treatment relies on platinum and taxane based polychemotherapy. The prognosis for advanced or metastatic penile cancer remains poor, with overall survival ranging from 13.9 to 17.1 months. After the first line, guidelines recommend various chemotherapy treatments or targeted anti-EGFR therapies whose results as well as the level of evidence are limited. A better understanding of the oncogenic pathways involved in penile cancer and a frequent expression of PD-L1 are the rationale for the elaboration of new strategies. This review article presents the data, guidelines and ongoing studies in locally advanced or metastatic penile cancer.

344 Background: SUN is approved in mRCC setting at the dose of 50mg daily for 4 weeks followed by 2 weeks rest (4/2 schedule). The 4/2 schedule often requires dose modifications for toxicity. Current recommendation is to reduce the dose to 37.5mg per day. Alternative schedules (2 weeks of treatment followed by one-week rest (2/1 schedule) have shown promising results. SURF trial evaluated prospectively schedule 2/1 when toxicity occurs. Methods: SURF [NCT02689167] is a prospective, non-comparative randomized study. Patients (pts) with mRCC (clear cell) were included at SUN initiation. When a dose adjustment of SUN was required, patients were randomized between 4/2 schedule at 37.5mg daily and experimental 2/1 schedule at 50mg daily. Primary objective was to assess duration of SUN treatment among the 73 first evaluable pts. Overall 226 pts were enrolled with 133 randomized. All other analyses are shown for the 133 randomized patients. Results: Pts were 75.2% males, with a median age 63.7 years for 94% with a Karnofsky ≥ 80%. Of them, 54.9% had partial/total nephrectomy. IMDC risk score was favourable (45.1%), intermediate (46.6%) or poor (8.3%). Pts characteristics were well balanced between 2 arms. Metastatic sites were lungs (60.5%), bones (16.3%), lymph nodes (15.5%). At 6 months, 48 patients (65.8%) of the 2/1 schedule were still on treatment (above predefined threshold for positivity). Other data are listed on the table. No new safety signal was identified. Permanent SUN discontinuation due to toxicity was 22.2% in control arm vs 12.3% in experimental arm. Conclusions: SURF is the largest prospective randomised trial evaluating two different SUN schedules modifications in mRCC in case of toxicity. This positive trial confirms the role of adapting SUN to a 2/1 schedule rather than reducing SUN dose to the classical 4/2 schedule. Clinical trial information: NCT02689167. [Table: see text]

111 Background: Prostate cancer often occurs in an elderly population, at higher risk of drug-drug interactions (DDIs). There is a medical need to increase the knowledge of DDI prevalence and their severity among patients coming from routine care. This study used a prospective approach with the aim to quantify and describe DDIs in medical prescription of prostate cancer treatments. Methods: DDIs were assessed from two perspectives: 1) “real DDI” between the patient’s comedications and the actual anti-cancer agent prescribed; 2) “modelized DDI” between the patient’s comedications and drugs that have proven activity in metastatic endocrine sensitive prostate cancer (MESPC) or castrate resistant prostate cancer (CRPC) settings with positive phase 3 trial and gained EMA approval. French national thesaurus, Micromedex software and complementary manual analysis by pharmacist were used to identified DDIs. Clinical relevance of DDIs was scored using the validated scale of Hatoum. Results: A total of 91 patients were included, 15% of whom were participating in a clinical trial. Some imbalances were observed between patients from clinical trial and routine care (age, ECOG, MESPC/MCRPC). The median number of comedications used per patient was 6 [1-16]. Among real DDI, Enzalutamide was the anticancer agent with the higher risk of interaction (18-54% of patients). In modelized DDI, Enzalutamide and Apalutamide were the two most risky drugs (35-76% and 22-73% depending on Micromedex or Thesaurus analyze). Not all DDIs discovered were clinically significant according to Hatoum scale. Conclusions: DDIs are frequents, according to Micromedex and National Thesaurus tools but pharmacist and physician advices are essentials to determine their potential impacts.

Background Sunitinib is a tyrosine kinase inhibitor approved in the first-line metastatic renal cell carcinoma (MRCC) setting at the dose of 50 mg daily for 4 weeks followed by a pause of 2 weeks. Due to toxicity, this standard schedule (50 mg daily 4/2) can induce up to 50% of sunitinib dose modification (reduction and/or interruption). The current recommendation in such case is to reduce the dose to 37.5 mg per day (standard schedule 4/2). Recent data highlight an alternative schedule: 2 weeks of treatment followed by 1 week of pause (experimental schedule 2/1). The SURF trial is set up to evaluate prospectively experimental schedule 2/1 when toxicity occurs. This article displays the key elements of the study protocol. Methods/design SURF [NCT02689167] is a prospective, randomized, open-label phase IIb study. Patients are included at sunitinib initiation while receiving standard schedule 4/2 (50 mg daily) according to the marketing authorization indication. When a dose adjustment of sunitinib is required, patients are randomized between standard schedule 4/2 (37.5 mg daily) and experimental schedule 2/1 (50 mg daily). Key eligibility criteria are the following: patients with locally advanced inoperable or MRCC who are starting first-line treatment with sunitinib, with histologically or cytologically confirmed renal cancer clear cell variant or with a clear cell component, and with Karnofsky performance status ≥70%. The primary objective is to assess the median duration of sunitinib treatment (DOT) in each group. The key secondary objectives are progression-free survival, overall survival, time to randomization, objective response rate, safety, sunitinib dose intensity, health-related quality of life, and the description of main drivers triggering randomization. We hypothesized that experimental schedule 2/1 would result in an improvement in median DOT from 6 to 8.5 months. It was estimated that 112 patients would be needed in each arm during 24 months. In order to take into account the possibility of treatment discontinuation before randomization, 248 patients are necessary. Discussion The SURF trial is asking a pragmatic question adapted to the current practice on what is the best way to adapt sunitinib when treatment-related adverse events occur. The results of the SURF trial will bring high-value data to support the use of an alternative schedule in sunitinib treatment. Trial registration ClinicalTrials.gov, NCT02689167. Registered on 26 February 2016. Electronic supplementary material The online version of this article (10.1186/s13063-018-2613-8) contains supplementary material, which is available to authorized users.

Purpose To describe factors associated with overall survival (OS) among patients with metastatic clear-cell renal-cell carcinoma (mccRCC) in regard to evolution of systemic therapies. Patients and Methods Two hundred twenty-four consecutive patients with histologically confirmed mccRCC who received targeted therapy on first-line treatment between January 2007 and March 2015 were included. The primary end point was OS for metastatic first-line or second-line treatment. An analysis of prognostic factors of long survival was performed using a 2-step approach: univariate, then multivariate analysis. Results Median OS [95% confidence interval] was 19.4 months [16.1-24.9]. Three prognostic factors were identified in first-line treatment: Memorial Sloan Kettering Cancer Center (MSKCC) favorable and intermediate risks (hazard ratio [95% confidence interval] = 0.362 [0.207-0.630] and 0.561 [0.393-0.801], respectively, P = 4.10−4), metastasectomy (0.667 [0.468-0.951], P = .03), and lack of lymph node metastasis (0.715 [0.513-0.994], P = .049). In second-line treatment, median OS [95% confidence interval] was 11.0 months [8.9-14.4] for 167 patients. Three different prognostic factors predicted long survival: toxicity for first-line treatment discontinuation (HR [95% confidence interval] = 0.298 [0.180-0.493], P Conclusion These real-life data confirm the positive impact of targeted therapy in the mccRCC setting. Moreover, it emphasizes the importance of considering many factors in order to better estimate prognosis in patient pretreated with systemic therapy.

54 Background: A potential link between Health-Related Quality of life (HRQoL) and oncologic outcomes such as overall survival or progression-free survival has been underlined for endocrine therapies in patients with metastatic castrate resistant prostate cancer (mCRPC). Other surrogates such as circulating tumor cells (CTCs) or PSA can be used to evaluate disease control. This study explored the associations between HRQoL and biological biomarkers for patients with mCRPC treated by abiraterone / prednisone or prednisone within registration phase III trial COU-AA-301. Methods: Baseline differences of HRQoL evaluated with FACT-P total score (FACT-P TS) according to biological parameters (including CTCs and PSA) and links between HRQoL's change and variations of these parameters were assessed. The primary objective was to estimate the association between improvement or deterioration in FACT-P TS and the variations of CTCs and PSA. All analyses were conducted using clinically meaningful improvement and deterioration in FACT-P TS and subscales. Results: Among 1130 patients enrolled, 1111 (98.3%) had a baseline FACT-P TS available. At baseline, a favorable CTCs count was associated with higher FACT-P TS compared to unfavorable CTCs (difference in means 8 points, [95% CI, 4 to 12] p < 0.001). At 3 months, there were differences in mean change from baseline FACT-P TS favoring patients with biomarkers response, with clinically meaningful difference for CTCs (12.7 points, [95% CI, 6 to 19.5%] p < 0.001) and PSA (11.64 points, [95% CI, 9.3 to 14] p < 0.0001). Biological progression was associated with higher risk of FACT-P TS worsening for PSA (Odds Ratio (OR) 2.8 [95% CI, 1.9 to 4.2]) with more frequent FACT-P TS improvement in case of response for CTCs (OR 3.14 [95% CI, 1.3 to 7.7]) and PSA (OR 2.9 [95% CI 2.1 to 4]). Significantly longer time until definitive deterioration was observed for patients with CTCs or PSA response (p < 0.001) and shorter time in case of progression (p < 0.001). Conclusions: QUA-lify is the first study to show an association between HRQoL and biomarkers outcomes in patients with mCRPC treated with endocrine therapy in a post-taxane setting. This concept is reinforced by the consistency of the association for all analyses carried out.

Angiosarcomas are one of the rarest subtypes of sarcomas; those are malignant vascular tumors arising from vascular endothelial cells. Occurrence of intra-oral angiosarcoma is extremely rare (0.0077% of all cancers in Europe). We present here, to our knowledge, the first case of a 83-year-old man with gingival and both palatine tonsils localization of a grade-two angiosarcoma discovered after a two months history of a painful lesion followed by hematoma and spontaneous bleeding. Chemotherapy with paclitaxel and hemostatic radiotherapy were inefficient and he died seven months after the first symptoms. It is essential to use the vascular markers, such as CD34, CD31, ERG and FLI1, for a correct histological diagnosis, which remains difficult because it displays a wide range of morphological appearances and multiple patterns may be present in the same tumor. The main prognostic factors are chronic pre-existing lymphedema and tumor size greater than five centimeters. Malignancy grade and stage classification should be provided in all cases in which this is feasible because of predictive meaning. When possible, wide surgical resection with negative margins remains the cornerstone for the treatment of localized angiosarcomas, but despite the improvement of surgical techniques the prognosis is poor with more than half of patients died within the first year. Adjuvant radiotherapy is the standard treatment of high–grade (two and three), deep lesions, regardless of size, because it improved the local recurrence-free survival. For advanced disease, if possible, metastasectomy should be considered. The first-line chemotherapy with doxorubicin or paclitaxel should be discussed compared to best supportive care according to patient comorbidities and preference.

Resume Introduction La prise en charge de la douleur est un enjeu de sante publique important, particulierement en cancerologie. Dans une demarche d’evaluation des pratiques professionnelles, l’IRFC-FC a realise une enquete chez des patients presentant une tumeur solide metastatique osteophile en Franche-Comte. Les objectifs etaient d’evaluer la prevalence de la douleur, ses caracteristiques, sa prise en charge et son impact sur la qualite de vie. Methode Une enquete observationnelle, prospective et multicentrique a ete realisee via un questionnaire d’autoevaluation. Ont ete inclus les patients presentant un cancer metastatique du sein ou de la prostate pris en charge dans 5 hopitaux de jour de l’IRFC-FC sur une periode de 3 mois. Resultats Deux cent trente-trois questionnaires ont ete analyses. La prevalence de la douleur etait de 48,5 %. Trois-quarts des patients algiques avaient une douleur chronique de fond, d’intensite moderee a severe, associee ou non a des acces douloureux. Eu egard a l’intensite de leur douleur et a leur traitement antalgique, 42,0 % des patients semblaient sous-traites. Quatre-vingt-cinq pour cent des patients traites declaraient etre observants et estimaient que leur douleur etait bien prise en charge malgre un impact negatif sur la qualite de vie. Conclusion La mise en œuvre d’un chemin clinique est essentielle pour garantir une prise en charge standardisee, optimale et efficiente des patients algiques. L’evaluation de la satisfaction des soins et de la qualite de vie doit etre integree a la pratique clinique pour mieux identifier les patients algiques dont le traitement est inadapte.

Background Routine Electronic Monitoring of HRQoL (REMOQOL) in daily clinical care with real-time feedback to physicians could help to manage treatment-related toxicities, to personalize supportive care, and to assess the treatment benefit from the patients’ point of view. Physicians’ satisfaction with REMOQOL was evaluated in two French clinical trials (CT) assessing its feasibility. Methods Physicians’ satisfaction was evaluated in two CT: QOLIBRY a monocentric CT for breast, lung and colorectal cancers, and QUANARIE a multicentric CT involving 8 centres of France for renal cancer. Patients were invited to complete before each visit the EORTC QLQ-C30 questionnaire, cancer site-specific modules and selected items related to treatments, using the CHES software on tablets and/or computers at the hospital or at home. During the visit, the physicians had real-time access to visual summaries of HRQoL scores evolution. Physicians’ satisfaction was evaluated with a questionnaire specifically designed for these CT. The questionnaire addressed 43 items and aimed to evaluate if REMOQOL was a useful tool for the physician and the usability of the CHES software. Results Between September 2016 and March 2019, 45 physicians included 249 patients (QOLIBRY n = 193, QUANARIE n = 56). Twenty-six (58%) physicians completed the survey. Among them, 18 (69%) looked at the HRQoL results. HRQoL results helped to better understand the patient’s medical condition for 11 (61%) of the physicians. Discussion about HRQoL results with the patient was easy (n = 15; 83%) and REMOQOL improved communication with patients (n = 8; 44%). Physicians declared that REMOQOL helped them to adapt patient’s management (n = 10; 56%) and to support supportive care prescription (n = 8; 44%) without extending the time of consultations (n = 12; 67%). Seventy-three per cent (n = 19) would agree to integrate REMOQOL for all patients in their daily practice. Conclusions Physicians used REMOQOL as a complementary tool and were globally satisfied. However, information about the objectives, trainings and recommendations for using HRQoL results in routine are essentials and must be enhanced to involve all the physicians. Clinical trial identification QOLIBRY: NCT02844608 QUANARIE: NCT03062410. Legal entity responsible for the study University Hospital of Besancon. Funding Novartis. Disclosure G. Mouillet: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self): Amgen; Honoraria (self): BMS; Honoraria (self): Roche; Honoraria (self), Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Travel / Accommodation / Expenses: Astellas. A. Thiery-Vuillemin: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Honoraria (institution): Novartis; Honoraria (self), Honoraria (institution): Ipsen; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Honoraria (institution): Astellas Pharma. E. Curtit: Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Eisai; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer. G. Eberst: Honoraria (self): MSD; Honoraria (self): BMS; Honoraria (self): Boeringher Ingelheim; Honoraria (self): Roche; Honoraria (self): AstraZeneca. P. Barthelemy: Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Janssen; Advisory / Consultancy: Sanofi; Honoraria (self): Astellas. L. Geoffrois: Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: BMS. A. Anota: Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self): BMS; Honoraria (self): Roche. All other authors have declared no conflicts of interest.

The combination of cisplatin or carboplatin and etoposide is the standard treatment for certain poorly differen- tiated neuroendocrine cancers, such as small-cell lung cancer. The aim of this study was to assess the efficacy and tolera bility of the carboplatin-etoposide regimen in metastatic castra- tion-resistant prostate cancer (mCRPC). A total of 27 patients treated by carboplatin (area under the curve (AUC)=5) and etoposide (100 mg/m² intravenous infusion on days 1-3 or 75 mg orallyday for 10 days) for mCRPC were included for analysis. The median progression-free survival was 3.3 months (95% confidence interval (CI): 1.9-4.2) and the median overall survival (OS) was 8.1 months (95% CI: 4.06-12.36). The main grade 3-4 toxicities were haematological, namely anemia (33.3%), neutropenia (25.9%) and thrombocyto- penia (22.2%), whereas the most common non-hematological toxicity was asthenia (22.2%). The efficacy, compliance and safety profile were generally similar between the oral and intravenous etoposide groups. Pretreated patients with mCRPC may benefit from the carboplatin-etoposide regimen in terms of OS. The toxicities were acceptable, without reported treat- ment-related mortality. Therefore, the oral etoposide regimen may be an viable alternative for improving the quality of life of the patients. However, this regimen requires further prospec- tive investigation to confirm its efficacy.

Everolimus has demonstrated its efficacy in metastatic renal cell carcinoma (mRCC). Preliminary studies have shown high variability of everolimus blood concentrations (EBC). In other settings, its activity was correlated with EBC. We therefore decided to monitor EBC in patients treated with mRCC to assess its influence on oncologic outcomes. Our study analyzed first 3 months’ trough EBC levels in 42 patients treated in 4 French oncologic centers between March 2010 and August 2013. Patients presented a histologically confirmed diagnosis of mRCC and have failed prior anti-angiogenic (AA) therapies. Median follow-up was 25.9 months. A total of 113 EBC were analyzed. The median trough concentration was 14.1 μg/L (range 2.6–91.5). Fourteen patients (67 %) versus 8 (38 %) patients with median EBC above or below 14.1 μg/L were free from progression at 6 months (p = 0.06). Median progression-free survival was 13.3 versus 3.9 months (HR 0.66 95 % CI 0.33–1.31; p = 0.23), and the median overall survival was 26.2 versus 9.9 months (HR 0.62 95 % CI 0.28–1.37; p = 0.24), for patients above or below the median value of trough concentrations, respectively. Impact of drug exposure for AA tyrosine kinase inhibitors activity has been demonstrated in mRCC setting. Interpatients EBC variability was confirmed in the present study, and the results suggest a relationship between initial EBC within the first 3 months and the drug activity. It underlines the need to prospectively include EBC monitoring in future clinical trials to determine the need of its implementation in routine use.

Pain management is a major public health problem, especially in oncology. In order to assess professional practice, the IRFC-FC conducted a survey amongst patients with metastatic osteophilic solid tumor in Franche-Comté. The aims were to assess the pain prevalence, and its characteristics, its management and its impact on patients' quality of life in patients in pain.An observational, prospective and multicenter survey was conducted using a self-report questionnaire. Patients with metastatic breast or prostate cancer managed in 5 day-hospitals of the IRFC-FC over a period of three months were included.Two hundred thirty-three questionnaires were analyzed. Pain prevalence rate was 48.5%. Three quarters of patients in pain had chronic background pain, moderate to severe, with or without breakthrough pain. Considering their pain intensity and their analgesic therapy, 42.0% of patients seem to have an inadequate treatment. Eighty-five percent of treated patients reported to be compliant and felt that their pain was well managed despite a strong impact on their quality of life.The setting of a specific clinical pathway is essential to secure the standardized, optimal and efficient management of patients in pain. The assessment of patient satisfaction and quality of life must be integrated in clinical practice to identify patients in pain for which the treatment is inappropriate.

The rapalogs everolimus and temsirolimus that inhibit mTOR signaling are used as antiproliferative drugs in several cancers. Here we investigated the influence of rapalogs-mediated immune modulation on their antitumor efficacy. Studies in metastatic renal cell carcinoma patients showed that everolimus promoted high expansion of FoxP3+Helios+Ki67+ regulatory CD4 T cells (Tregs). In these patients, rapalogs strongly enhanced the suppressive functions of Tregs, mainly in a contact-dependent manner. Paradoxically, a concurrent activation of spontaneous tumor-specific Th1 immunity also occurred. Furthermore, a high rate of Eomes+CD8+ T cells was detected in patients after a long-term mTOR inhibition. We found that early changes in the Tregs/antitumor Th1 balance can differentially shape the treatment efficacy. Patients presenting a shift toward decreased Tregs levels and high expansion of antitumor Th1 cells showed better clinical responses. Studies conducted in tumor-bearing mice confirmed the deleterious effect of rapalogs-induced Tregs via a mechanism involving the inhibition of antitumor T-cell immunity. Consequently, the combination of temsirolimus plus CCR4 antagonist, a receptor highly expressed on rapalogs-exposed Tregs, was more effective than monotherapy. Altogether, our results describe for the first time a dual impact of host adaptive antitumor T-cell immunity on the clinical effectiveness of rapalogs and prompt their association with immunotherapies. Cancer Res; 76(14); 4100–12. ©2016 AACR.

Castration resistant prostate cancer occurs when patients experience disease progression despite appropriate hormonal manipulations. In these patients, chemotherapy remains standard treatment. Preclinical and clinical data have demonstrated the potential utility of an immunotherapy-based approach for the treatment of prostate cancer (PC). The phase III trial (IMPACT) has recently reported an advantage for Sipuleucel-T over placebo, with an overall survival 4.1 months superior to placebo. Sipuleucel-T is also the first FDA-approved immunotherapy for prostate cancer. These promising results need to be confirmed with other large studies and within previous step of PC. Neoplasic cells can escape immune responses by multiple mechanisms. A better knowledge of these mechanisms is of major concern for the future development of new immunotherapies approach.

Breast cancer incidence remains the highest among gynaecologic neoplasms. Once they have achieved their treatments, patients should undergo careful follow-up. It aims at detecting early local recurrence or controlateral breast cancer. Based on large cohorts, clinical and radiological follow-up procedures come from guidelines realised by scientific organisations. We evaluated our regional practices in Franche-Comte and compared them to current guidelines. Patients with early breast cancer positive for hormonal receptors filled a questionnaire concerning their follow-up. It included patients treated from 1999 to 2005. When frequency of consultation is evaluated, only half of the patients undergo what is recommended. Whereas mammography and non-validated complementary exams are more regularly realised. Patients consulting more one practician have a better compliance. Our study underlines significant disparities among patients follow-up. Better interactions between physicians and a greater implication of patients in their follow-up would increase its quality.

Prolonged fractionated oral administration of etoposide may present a theoretical advantage over intravenous administration of the bolus. This phase I trial was carried out to determine the recommended duration of oral etoposide in combination with a fixed dose of carboplatin. Nineteen patients with varied solid tumors, who were not candidates for standard chemotherapy, were administered an escalating duration (6, 9 or 12 consecutive days) of oral etoposide (a 25 mg capsule three times daily) combined with carboplatin AUC5 administered on day 1, by a 30 min intravenous infusion, to define the maximum tolerated dose on the basis of the acute toxicities that were reported. Etoposide was started on day 2; the cycles repeated every 28 days until disease progression or toxicity. Pharmacokinetics was carried out during the two first cycles. The maximum tolerated dose was determined to be the 12-day treatment level, with two cases of grade 4 neutropenia, grade 3 anemia and thrombocytopenia. As no severe toxicity occurred with the 9-day treatment level and in an attempt to explore an optimal combination, a new 10-day treatment plan was studied in three patients. As one patient presented dose-limiting toxicity at that level, five additional patients were included to establish the recommended regimen. Nonhematological toxicities among all patients were moderate, consisting of grade 2 nausea and asthenia. No treatment-related death occurred. Objective responses were observed in four patients and stabilization in three patients. Pharmacokinetics highlighted no interaction between etoposide and carboplatin. Fractionated oral etoposide (3×25 mg/day) for 10 days in combination with carboplatin AUC 5 presents acceptable toxicity and efficacy. The main toxicity remains hematological.

Purpose: We conducted a phase I multicenter trial in naïve metastatic castrate-resistant prostate cancer patients with escalating inecalcitol dosages, combined with docetaxel-based chemotherapy. Inecalcitol is a novel vitamin D receptor agonist with higher antiproliferative effects and a 100-fold lower hypercalcemic activity than calcitriol. Experimental Design: Safety and efficacy were evaluated in groups of three to six patients receiving inecalcitol during a 21-day cycle in combination with docetaxel (75 mg/m2 every 3 weeks) and oral prednisone (5 mg twice a day) up to six cycles. Primary endpoint was dose-limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Efficacy endpoint was ≥30% PSA decline within 3 months. Results: Eight dose levels (40–8,000 μg) were evaluated in 54 patients. DLT occurred in two of four patients receiving 8,000 μg/day after one and two weeks of inecalcitol. Calcemia normalized a few days after interruption of inecalcitol. Two other patients reached grade 2, and the dose level was reduced to 4,000 μg. After dose reduction, calcemia remained within normal range and grade 1 hypercalcemia. The maximum tolerated dose was 4,000 μg daily. Respectively, 85% and 76% of the patients had ≥30% PSA decline within 3 months and ≥50% PSA decline at any time during the study. Median time to PSA progression was 169 days. Conclusion: High antiproliferative daily inecalcitol dose has been safely used in combination with docetaxel and shows encouraging PSA response (≥30% PSA response: 85%; ≥50% PSA response: 76%). A randomized phase II study is planned. Clin Cancer Res; 20(17); 4471–7. ©2014 AACR.

Virginie Nerich,1,2 Marion Hugues,1 Marie Justine Paillard,3 Laëtitia Borowski,1 Thierry Nai,1 Ulrich Stein,3 Thierry Nguyen Tan Hon,3 Philippe Montcuquet,3 Tristan Maurina,3 Guillaume Mouillet,3 François Kleinclauss,2,4 Xavier Pivot,2,3 Samuel Limat,1,2 Antoine Thiery-Vuillemin2,3 1Department of Pharmacy, University Hospital, Besançon, France; 2Inserm U645 EA-2284 IFR-133, University of Franche-Comté, Besançon, France; 3Department of Medical Oncology, 4Department of Urology, University Hospital, Besançon, France Introduction: The aim of this retrospective clinical study was to assess, in the context of the recent evolution of systemic therapies, the potential effect of targeted therapies on overall survival (OS) of patients with metastatic clear-cell renal cell carcinoma (mccRCC) in daily practice. Patients and methods: All consecutive patients with histologically confirmed mccRCC who received systemic therapy between January 2000 and December 2010 in two oncology treatment centers in our Franche-Comté region in eastern France were included in the analysis. The primary end point was OS. The analysis of prognostic factors was performed using a two-step approach: univariate then multivariate analysis with a stepwise Cox proportional hazards regression model. Results: For the entire cohort of 111 patients, the median OS was 17 months (95% confidence interval [CI]; 13–22 months) and the two-year OS was 39%. Three prognostic factors were independent predictors of long survival: prior nephrectomy (hazard ratio =0.38 [0.22–0.64], P

Castration resistant prostate cancer occurs when patients experience disease progression despite appropriate hormonal manipulations. In these patients, chemotherapy remains standard treatment. Preclinical and clinical data have demonstrated the potential utility of an immunotherapy-based approach for the treatment of prostate cancer (PC). The phase III trial (IMPACT) has recently reported an advantage for Sipuleucel-T over placebo, with an overall survival 4.1 months superior to placebo. Sipuleucel-T is also the first FDA-approved immunotherapy for prostate cancer. These promising results need to be confirmed with other large studies and within previous step of PC. Neoplasic cells can escape immune responses by multiple mechanisms. A better knowledge of these mechanisms is of major concern for the future development of new immunotherapies approach.

Breast cancer incidence remains the highest among gynaecologic neoplasms. Once they have achieved their treatments, patients should undergo careful follow-up. It aims at detecting early local recurrence or controlateral breast cancer. Based on large cohorts, clinical and radiological follow-up procedures come from guidelines realised by scientific organisations. We evaluated our regional practices in Franche-Comté and compared them to current guidelines. Patients with early breast cancer positive for hormonal receptors filled a questionnaire concerning their follow-up. It included patients treated from 1999 to 2005. When frequency of consultation is evaluated, only half of the patients undergo what is recommended. Whereas mammography and non-validated complementary exams are more regularly realised. Patients consulting more one practician have a better compliance. Our study underlines significant disparities among patients follow-up. Better interactions between physicians and a greater implication of patients in their follow-up would increase its quality.

International audience; Importance of the field: The development of targeted anticancer therapies stems from advances in molecular biology. New agents range from antibodies that form complexes with antigens on the surface of the cancer cell to small molecules that have been engineered to block key enzymatic reactions. The interaction of the antibody or drug with its target inhibits key pathways involved in cell proliferation or metastasis, or activates pathways leading to cell death. Such pathways constitute ideal pharmacological targets. Clinical benefits from these novel therapeutic strategies are striking for patients with metastatic diseases. Areas covered: This review analyses the main toxicities among most common targeted therapies that have been approved by the FDA or European Medicines Agency for their clinical utilisation in solid tumours treatment. What the reader will gain: Here, the main toxicity and safety data among new anticancer targeted therapies are described. Data are organised through the pathways targeted by the drugs. Take home message: The emergence of new targeted anticancer therapies promises more efficient and less toxic therapies. Generally, they are well tolerated, toxicities are commonly mild to moderate and can be handled rapidly. However, if most of these adverse events are manageable, life threatening and fatal complications can still occur.

International audience

International audience; BACKGROUND: Natural epothilones and their analogs promote tumor cell death by binding to tubulin and stabilizing microtubules, causing cell death. Ixabepilone (BMS-247550, Ixempra) is an epothilone analog that optimizes the properties naturally observed with epothilone B. OBJECTIVE: To provide an overview of the results achieved by ixabepilone in metastatic breast cancer. METHODS: A PubMed search was performed to provide an extensive review of all published data on ixabepilone, in addition to all data reported from international congresses, from 2003 to 2007. RESULTS/CONCLUSION: There is a clear need for new agents active against resistant metastatic breast cancer and ixabepilone might be a welcome new compound in this situation.

International audience; BACKGROUND: Porphyrias are rare diseases, and for these patients every administration of drugs may induce an acute attack of porphyria. The list of safe compounds allowed in these patients is available for clinicians from specific websites cited in the text. OBJECTIVES: However, data concerning anticancer therapy in patients with such diseases remain poor. Therefore any publications can help clinicians to deal with this very specific group of patients. METHODS: In our institution, three patients received docetaxel and hematologic growth factors (erythropoietin and GCSF) without unexpected toxicities. Aromatase inhibitors (anstrozole and letrozole) were also given in one patient without any related problem. CONCLUSION: The present observation adds some useful data for the possible treatment of cancer in patients with porphyria.

e22113 Background: Everolimus has demonstrated activity in the treatment of metastastic renal cell carcinoma (mRCC) after failure of VEGF-targeted tyrosine kinase inhibitor. However, accumulating e...

Background: After curative local therapy, patients (pts) will experience rising PSA as an early indicator of recurrent prostate cancer and no standard of care exists. Previous studies demonstrated the clinical interest of cyclophosphamide metronomic chemotherapy (CMC) in several cancers. Multifactorial modes of action including immunological and anti-angiogenic effects have been well described by Kerbel et al and Ghiringhelli et al (Cancer Research 2006 and European Journal of immunology 2004, respectively). In the current study, we investigated the safety and immuno-modulatory effects of CMC in prostate cancer patients with PSA failure (biochemical relapse). Methods: We conducted a prospective phase II study to characterize the clinical and immunological interest of CMC in histologically proven prostate cancer patients previously treated by prostatectomy and with biochemical relapse (defined as PSA > 1 and < 20ng/mL and progressive PSA level on 3 different measures). CMC was administered per os, at daily dose of 50 mg during 6 months. PSA level, serum VEGF and immune parameters were monitored every month in blood samples. Results: Thirty-four consecutive pts were enrolled in this study and all received CMC. The median age was 68,3 (range, 56,9-82,1) and all pts had good performance status (ECOG-PS = 0). Gleason Score was 7 in 58%, ≤6 in 13%, and ≥ 8 in 13%. No serious adverse events (grade 3-5) were observed. The most common drug-related adverse event was grade 1 lymphopenia. Baseline PSA was 2,92 ng/mL (range, 1,1-9,35). Twenty-two pts presented stable PSA (64.7%), one patient had partial response defined by >50% decline in the serum PSA (3%), and 11 pts (32%) had PSA progression before 6 months. The immuno-monitoring performed in all pts who completed 6 months CMC. A decrease of immunosuppressive regulatory T cells (Treg) was observed in 56% (10/18). In addition, high rate of activated HLA-DR+ cytotoxic CD8 T cells was also detected in these pts. Furthermore, serum VEGF level decreased at month 1 but it returned to baseline level at the end of treatment in 9/17 pts evaluated (52%). In some patients the correlation was observed between the control of PSA level, the decrease of Treg and VEGF parameters. Conclusions: This study demonstrated the clinical benefit and the ability of CMC to promote the blockage of angiogenesis and immuno-modulatory effect in prostate cancer patients treated for a biochemical relapse. It will be of interest to combine CMC to vaccination in these patients. Citation Format: Olivier Adotevi, Fabien Calcagno, Tristan Maurina, Stefano Kim, Antoine Thiery-Vuillemin, Christophe Borg, Yann Godet, Caroline Laheurte. Antiangiogenic and immunomodulatory effects of metronomic cyclophosphamide (CPM) treatment in prostate cancer patients with PSA failure. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2588. doi:10.1158/1538-7445.AM2014-2588

Background Bevacizumab (Bev) with FOLFIRI or FOLFOX regimen is a standard of care in first-line metastatic colorectal cancers (mCRC). As second-line regimen after FOLFOX, FOLFIRI-3 has shown a significantly better PFS in comparison with other irinotecan-based regimen. We therefore evaluated the safety, efficacy and possible predictive factors for FOLFIRI-3 in combination with Bev as initial treatment for mCRC. Since fully validated biomarkers in mCRC are still lacking, we decided to assess the prognostic value of Angiopoietin-2 (Ang-2). Patients and methods We conducted a three-institution phase II trial of FOLFIRI-3 regimen (irinotecan 100mg/m2 before and after a 46-hour continuous infusion of fluorouracil (2400 mg/m2) with Bev (5mg/kg day 1) repeated every 2 weeks, as first-line treatment in mCRC. Induction treatment (FOLFIRI-3 and Bev) was administrated for 6 months, followed by a maintenance treatment including Bev (7.5 mg/kg day 1) and capecitabine (1000 mg/m2 day 1 to 14), repeated every 3 weeks. Plasma VEGF and serum Ang-2 were measured at baseline. The primary endpoint was ORR. Secondary endpoints were PFS, OS, and biologic analysis of potential predictive factors of response to treatment. Results 61 patients were enrolled for treatment. The ORR was 66.7% (95% CI, 55-79). SD in 25% of patients (DCR of 91.7%). PFS was 12 months (95% CI, 9-16) and OS was 33 months (95% CI, 19-44). A total of 41 patients entered the maintenance phase of the study. Bev/capecitabine maintenance therapy appeared as an appropriate and well-tolerated option. High pre-therapeutic serum Ang-2 level was identified as a potential biomarker correlated to worse outcomes in this cohort (median progression free survival of 14.7 months vs. 7.3 months, p Conclusions As front-line regimen in mCRC, FOLFIRI-3/Bev regimen, followed by a capecitabine-based maintenance therapy, is effective and might be considered for future development particularly in patients treated by oxaliplatin in the adjuvant setting. Serum angiopoietin 2 is a promising biomarker to predict PFS and OS in mCRC patients treated with chemotherapy and bevacizumab. External validation is in course. Disclosure All authors have declared no conflicts of interest.

4515 Background: Options for treatment of men with mCRPC after progression on docetaxel-based chemotherapy are limited. SU is a multitargeted inhibitor of VEGFR and PDGFR that showed antitumor activity in phase II trials in advanced mCRPC (Sonpavde; Michaelson; Zurita, 2009). Here, we report results of a phase III trial of SU+P in men with progressive mCRPC after docetaxel-based chemotherapy. Methods: In this multicenter, double-blind study, eligible men were stratified by ECOG performance status and progression type (PSA or radiographic) and randomized (2:1) to receive P 5 mg BID and either SU 37.5 mg or placebo (Pbo) on a continuous once-daily dosing schedule. Overall survival (OS) was the primary endpoint. Secondary endpoints included radiographic progression-free survival (PFS) and improvement in pain. Two interim analyses were planned. Results: Between Jul 2008 and Aug 2010, 873 men (median age 68 years; 49% Gleason score ≥8) were randomized to receive SU (n=584) or Pbo (n=289). The study was stopped...

4605 Background: Inecalcitol is a novel vitamin D receptor (VDR) agonist which shows high antiproliferative effects in human cancer cell lines and a 100-fold lower hypercalcemic activity than calci...

142 Background: Inecalcitol is a novel vitamin D receptor (VDR) agonist which shows high antiproliferative effects in human cancer cell lines and a 100-fold lower hypercalcemic activity than calcitriol the natural ligand of VDR. Methods: Escalating dosages of inecalcitol were combined to chemotherapy in naive metastatic CRPC patients. Safety and efficacy were evaluated in groups of 3-6 pts receiving inecalcitol every other day, daily or twice a day on a 21-day cycle in combination with docetaxel (75mg/m2 q3w) and oral prednisone (5mg bid). Pts received up to six cycles unless unacceptable toxicity or disease progression. Primary endpoint was dose limiting toxicity (DLT) defined as G3 hypercalcemia within the first cycle. Efficacy endpoint was PSA response defined as ≥30% decline within 3 months. Results: Eight dose levels from 40 to 8,000 μg have been evaluated in 54 pts; 83 % had bone metastases, 13% had visceral disease only. Median age was 71 years (range, 49-87), median Gleason score (Gs) 7 and median PSA 28.5 ng/mL (range, 0.8-962.4). DLT occurred in 2/4 patients receiving 8,000 μg/day after 1 and 2 weeks of treatment. Calcemia normalized in few days after interruption of treatment. The 2 other experienced only G2 and were stepped down to 4,000 μg. After dose reduction, calcemia remained within normal ranges and G1.The maximum tolerated dose is defined at 4,000 μg qd. Most of adverse events reported were grade 2. G3-4 were mainly hematological toxicity. Frequency of AEs related to docetaxel did not seem to be modified.82% of the patients had ≥30% PSA decline within 3 months of treatment whereas in historical data around 65% are responder with docetaxel as a single agent. PSA response was observed after 1 cycle of treatment in 43% of the patients. Time to biochemical relapse defined as an increase of 25% over nadir was 169 days. Conclusions: High antiproliferative daily dose of inecalcitol, a new VDR, agonist has been safely used in combination with docetaxel in CRPC patients. This combination treatment shows encouraging PSA response (> 30% PSA response: 82%). A multicenter randomized double blind phase III study is forecasted to confirm these results. [Table: see text]

5151 Background: Inecalcitol is a novel synthetic vitamin D3 analogue with potent antiproliferative effects in human cancer cell lines and a 100-fold lower hypercalcemic activity than calcitriol in animal models. Methods: Escalating dosages of inecalcitol were combined to chemotherapy in naive HRPC patients (pts). Safety and efficacy were evaluated in groups of 3–6 patients receiving oral inecalcitol daily or every other day on a 21-day cycle in combination with docetaxel (75mg/m2 q3w) and oral prednisone (5mg bid). Biphosphonates were prohibited during the first cycle. Patients received up to six cycles unless unacceptable toxicity or disease progression. Primary endpoint was dose limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Calcemia, creatininemia and CBC were assessed weekly; biochemistry, ECG and PSA every 3 weeks. Efficacy endpoint was PSA response defined as ≥30% decline within 3 months. Results: Five dose levels: 40, 80, 160, 300, 600 μg have been evaluated in 34 pts; 9 pts are still being treated at 600 μg; 25 pts have completed 6 cycles (13 bone metastases; 3 extrasqueletic metastasis, 8 bone and extrasqueletic metastases; 1 PSA-only disease). Median age was 72 years (range, 53–87), median Gleason score (Gs) 7 (36% Gs 10–8, 64% Gs 7–6) and median PSA 41.5 ng/mL (range, 0.9–962.4). No increased calcemia was reported. Most adverse events (AE) were G1–2, asthenia (19pts), constipation (14pts), diarrhea (13pts). G3–4 AEs were neutropenia (11pts) lymphopenia (9pts), asthenia (3pts), arrhythmia (2 pts), general health deterioration (2pts) and diarrhea (1pt). None of these AEs was considered related to inecalcitol. Of the 23 evaluable pts for PSA response, 20 (87%) had ≥30% PSA decline. Conclusions: Results from this ongoing study show the safe profile of inecalcitol when given daily in in HRPC pts. PSA responses with this combination are encouraging. As DLT was not reached, a higher dose of inecalcitol (1000 μg/day) will be further tested. [Table: see text]