Nivolumab immunotherapy rechallenge for progressive laryngeal squamous cell carcinoma after failure of conventional treatment: A CARE case report.

OBJECTIVE: Analysis of rechallenge with nivolumab as 5th-line therapy for locally and nodally failed laryngeal squamous cell carcinoma following conventional therapeutic modalities: radiotherapy, surgery and chemotherapy. OBSERVATION: A 70-year-old male, with local and nodal progression of laryngeal squamous cell carcinoma after treatment with chemoradiotherapy and surgery, was initially treated for recurrence with carboplatin, 5-fluorouracile (FU) and cetuximab, followed by second-line nivolumab, and then two lines of conventional chemotherapy with paclitaxel and cetuximab followed by carboplatin and cetuximab. He underwent rechallenge with nivolumab in 5th line, achieving 12months' response, ongoing at the time of writing, and 42.5months' survival since initiation of exclusive systemic management after failure of conventional treatment. CONCLUSION: This case report highlights the benefit of nivolumab rechallenge in 5th line following previous failure as stand-alone therapy in 2nd line for a patient with laryngeal squamous cell carcinoma locally and nodally uncontrolled after conventional treatment. Clinical trials evaluating the efficacy of this approach are necessary to assess its contribution, as it is currently not a standard therapeutic option.

Preexisting autoantibodies as predictor of immune related adverse events (irAEs) for advanced solid tumors treated with immune checkpoint inhibitors (ICIs).

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are now standard of care in many cancers. They can generate immune-related adverse events (irAEs), but no biomarkers are available to identify patients who are more likely to develop irAEs. We assess the association between pre-existing autoantibodies and occurrence of irAEs. PATIENTS AND METHODS: We prospectively collected data from consecutive patients receiving ICIs for advanced cancers, in a single center between May 2015 and July 2021. Autoantibodies testing was performed before ICIs initiation including AntiNeutrophil Cytoplasmic Antibodies, Antinuclear Antibodies, Rheumatoid Factor anti-Thyroid Peroxidase and anti-Thyroglobulin. We analyzed the associations of pre-existing autoantibodies with onset, severity, time to irAEs and with survival outcomes. RESULTS: Of the 221 patients included, most had renal cell carcinoma (n = 99; 45%) or lung carcinoma (n = 90; 41%). Grade ≥2 irAEs were more frequent among patients with pre-existing autoantibodies: 64 (50%) vs. 20 (22%) patients (Odds-Ratio= 3.5 [95% CI=1.8-6.8]; p < 0.001) in the positive vs negative group, respectively. irAEs occurred earlier in the positive group with a median time interval between ICI initiation and irAE of 13 weeks (IQR = 8.8-21.6) vs. 28.5 weeks (IQR=10.6-55.1) in the negative group (p = 0.01). Twelve patients (9.4%) experienced multiple (≥2) irAEs in the positive group vs. 2 (2%) in the negative group (OR = 4.5 [95% CI: 0.98-36], p = 0.04). After a median follow-up of 25 months, median PFS and OS were significantly longer among patients experiencing irAE (p = 0.00034 and p = 0.016, respectively). CONCLUSION: The presence of pre-existing autoantibodies is significantly associated with the occurrence of grade ≥2 irAEs, with earlier and multiple irAEs in patients treated with ICIs.

Photodynamic cystoscopy for bladder cancer diagnosis and for NMIBC follow-up: An overview of systematic reviews and meta-analyses.

INTRODUCTION: Currently, bladder cancer detection is based on cytology and cystoscopy. White light cystoscopy (WLC) is an invasive procedure and may under-detect flat lesions. Blue light cystoscopy (BLC) and narrow band imaging (NBI) cystoscopy are new modalities that could improve the detection of non-muscle invasive bladder cancer (NMIBC) and its recurrence or progression to muscle invasive bladder cancer. We present a systematic review on BLC and NBI cystoscopy for bladder cancer diagnosis and NMIBC follow-up. MATERIAL AND METHODS: All available systematic reviews and meta-analyses on cystoscopy published in PubMed® between May 2010 and March 2021 were identified and reviewed. The main endpoints were clinical performance for bladder cancer diagnosis and for recurrence or progression detection during NMIBC follow-up, and additional value compared with cytology and/or WLC. RESULTS: Most of the meta-analyses and systematic reviews published suggest a better sensitivity of BLC and NBI cystoscopy compared to WLC, particularly for the detection of flat lesions (CIS). NBI- and BLC-guided TURBT could decrease the recurrence rates. However, their clinical utility to reduce progression rate and increase survival is still unclear. CONCLUSIONS: BLC and NBI cystoscopy are efficient techniques for bladder cancer diagnosis and NMIBC follow-up. However, their clinical benefit remains to be confirmed.

Circulating Biomarkers in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma Treated With Everolimus in the Pre-nephrectomy Setting.

Many drugs are available in renal cell carcinoma (RCC), yet clinicians are still looking for predictive biomarkers of disease recurrence or progression supporting more personalised treatments. An assessment of circulating biomarkers over time was carried out in this French, open-label, single-arm, multicentre trial conducted in 25 patients with either locally advanced (n = 14) or metastatic RCC (n = 11) who received everolimus (10 mg daily) for 6 weeks prior to nephrectomy (NEORAD, NCT01715935). Circulating biomarkers, including circulating tumour cells, haematopoietic and endothelial cells, plasma angiogenesis and inflammatory markers were quantified at baseline, upon everolimus and post-nephrectomy. We assessed tumour burden, objective response rate upon RECIST1.1, disease-free survival (DFS) and progression-free survival (PFS). The correlation between circulating biomarkers was evaluated with multiple factor analysis and biomarker association with DFS/PFS by Cox regression. No objective response rate was obtained before nephrectomy. Upon everolimus, neutrophils, platelets and sVEGFR2 significantly decreased. We did not find any association between circulating biomarkers and DFS/PFS, but patients with the highest tumour burden at baseline had significantly higher plasma levels of interleukin-6, an inflammatory circulating biomarker, and lower levels of sVEGFR2, related to angiogenesis. Further understanding of the link between these circulating biomarkers could help to optimise drug combinations in RCC.

Relationship between kalemia and intensive care unit admission or death in hospitalized COVID-19 patients: A cohort study.

BACKGROUND: SARS-CoV-2 uses Angiotensin-Converting Enzyme 2 as a viral gateway to the cell and could interact with the renin-angiotensin-aldosterone system. Other studies have shown kalemia abnormalities in patients with severe forms of coronavirus disease 2019. Our goal was to assess the prognosis value of kalemia within ten days of symptom offset in the COVID-19 hospitalized population. METHODS: We analyzed data from a prospective cohort that included 65 patients with COVID-19, admitted between March 15, 2020, and March 21, 2020. The study aimed at determining the relationship between baseline kalemia and the admission to an intensive care unit (ICU) or death. RESULTS: The median age of the patients was 65 [54-79] years old, and 66.2% of the patients were men. Baseline kalemia under 3.8mmol/l occurred in 31 patients (48%), including 11 patients (35.5%) who were admitted to an ICU and one patient (3.2%) who died before ICU admission. In the primary end-point analysis, the adjusted hazard ratios for admission to an ICU or death were 3.52 [95% confidence interval (CI), 1.12 to 11.04] among patients with low baseline kalemia. CONCLUSION: Our study suggests that low kalemia levels within ten days of the first symptom onset might be associated with an increased risk of intensive care unit admission or death. The future perspective should be to better understand this relationship.

An analysis of health-related quality of life in the phase III PROSELICA and FIRSTANA studies assessing cabazitaxel in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Men with metastatic castration-resistant prostate cancer (mCRPC) are living longer, therefore optimizing health-related quality of life (HRQL), as well as survival outcomes, is important for optimal patient care. The aim of this study was to assess the HRQL in patients with mCRPC receiving docetaxel or cabazitaxel. PATIENTS AND METHODS: PROSELICA (NCT01308580) assessed the non-inferiority of cabazitaxel 20 mg/m2 (C20) versus 25 mg/m2 (C25) in patients with mCRPC after docetaxel. FIRSTANA (NCT01308567) assessed the superiority of C25 or C20 versus docetaxel 75 mg/m2 (D75) in patients with chemotherapy-naive mCRPC. HRQL and pain were analyzed using protocol-defined, prospectively collected, Functional Assessment of Cancer Therapy-Prostate (FACT-P) and McGill-Melzack questionnaires. Analyses included definitive improvements in HRQL, maintained or improved HRQL, and HRQL over time. RESULTS: In total, 2131 patients were evaluable for HRQL across the two studies. In PROSELICA, 38.8% and 40.5% of patients receiving C20 and C25, respectively, had definitive FACT-P total score (TS) improvements. In FIRSTANA, 43.4%, 49.7%, and 44.9% of patients receiving D75, C20, and C25, respectively, had definitive FACT-P TS improvements. In both trials, definitive improvements started after cycle 1 and were maintained for the majority of subsequent treatment cycles. More than two-thirds of patients maintained or improved their FACT-P TS. CONCLUSIONS: In PROSELICA and FIRSTANA, >40% of the 2131 evaluable patients with mCRPC had definitive FACT-P TS improvements; improvements occurred early and were maintained. More than 75% of patients maintained or improved their FACT-P TS.

Administration of neoadjuvant chemotherapy for muscle-invasive bladder cancer in real life: Are urologists still too cautious?

INTRODUCTION: Neoadjuvant chemotherapy (NAC) is now recommended to treat muscle-invasive bladder cancer (MIBC) but is not always executed in real life. This study aims to evaluate the proportion of patients with MIBC who receive an optimal NAC, and to present the predictive factors of its achievement. METHODS: This monocenter retrospective study included all the patients who underwent radical cystectomy for≥pT2NxM0 MIBC between 2013, January and 2018, December. NAC consisted in 4-6 cycles of MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) or 4 cycles of GC (gemcitabin, and carboplatin). Demographic (sex, age, ECOG-PS, glomerular filtration rate [GFR], and cN stage), surgical (urinary derivation, time of surgery, blood loss, and complications), and oncological characteristics were analyzed. Multivariate analysis are made to find predictors of administration of NAC. RESULTS: One hundred and twenty-seven patients were included. Thirty received CNA (24%). Patients who underwent CNA were younger, with better ECOG and better GFR. Multivariate analysis showed that cN+ stage and better GFR were significantly associated to administration of NAC. Eight patients (27%) couldn't receive an optimal treatment due to toxicity. Perioperative complication rates were similar, with or without NAC. Patients who underwent NAC had a worse GFR after treatment (-17 versus +5mL/min, P<0.01). CONCLUSION: Due to the risks of toxicity, NAC can only be proposed to selected population, which is not the current patients. Immunotherapy could allow to treat more patients because of better tolerance. LEVEL OF EVIDENCE: 3.

Variation in neutrophil to lymphocyte ratio (NLR) as predictor of outcomes in metastatic renal cell carcinoma (mRCC) and non-small cell lung cancer (mNSCLC) patients treated with nivolumab.

BACKGROUND: An elevated pre-treatment neutrophil to lymphocytes ratio (NLR) is associated with poor prognosis in various malignancies. Optimal cut-off is highly variable across studies and could not be determined individually for a patient to inform his prognosis. We hypothesize that NLR variations could be more useful than baseline NLR to predict progression-free survival (PFS) and overall survival (OS) in patients (pts) receiving anti-PD1 treatment. PATIENTS AND METHODS: All pts with metastatic renal cell carcinoma (mRCC) and metastatic non-small cell lung cancer (mNSCLC) who received anti-PD1 nivolumab monotherapy in second-line setting or later were included in this French multicentric retrospective study. NLR values were prospectively collected prior to each nivolumab administration. Clinical characteristics were recorded. Associations between baseline NLR, NLR variations and survival outcomes were determined using Kaplan-Meier's method and multivariable Cox regression models. RESULTS: 161 pts (86 mRCC and 75 mNSCLC) were included with a median follow-up of 18 months. On the whole cohort, any NLR increase at week 6 was significantly associated with worse outcomes compared to NLR decrease, with a median PFS of 11 months vs 3.7 months (p < 0.0001), and a median OS of 28.5 months vs. 18 months (p = 0.013), respectively. In multivariate analysis, NLR increase was significantly associated with worse PFS (HR 2.2; p = 6.10-5) and OS (HR 2.1; p = 0.005). Consistent results were observed in each cohort when analyzed separately. CONCLUSION: Any NLR increase at week 6 was associated with worse PFS and OS outcomes. NLR variation is an inexpensive and dynamic marker easily obtained to monitor anti-PD1 efficacy.

Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.

BACKGROUND: In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2). METHODS: One thousand two hundred and seven patients with nmCRPC were randomized 2 : 1 to apalutamide (240 mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O'Brien-Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed. RESULTS: Median follow-up was 41 months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59-0.96; P = 0.0197), although the P-value did not cross the pre-specified O'Brien-Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45-0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed. CONCLUSION: In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.

Updated recommendations of the International Society of Geriatric Oncology on prostate cancer management in older patients.

BACKGROUND: The median age of prostate cancer diagnosis is 66 years, and the median age of men who die of the disease is eighty years. The public health impact of prostate cancer is already substantial and, given the rapidly ageing world population, can only increase. In this context, the International Society of Geriatric Oncology (SIOG) Task Forces have, since 2010, been developing guidelines for the management of senior adults with prostate cancer. MATERIAL AND METHODS: Since prostate cancer and geriatric oncology are both rapidly evolving fields, a new multidisciplinary Task Force was formed in 2018 to update SIOG recommendations, principally on health status screening tools and treatment. The task force reviewed pertinent articles published between June 2016 and June 2018 and abstracts from European Association of Urology (EAU), European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO) and American Society of Clinical Oncology Genito-urinary (ASCO GU) meetings over the same period, using search terms relevant to prostate cancer, the elderly, geriatric evaluation, local treatments and advanced disease. Each member of the group proposed modifications to the previous guidelines. These were collated and circulated. The final manuscript reflects the expert consensus. RESULTS: The 2019 consensus is that men aged 75 years and older with prostate cancer should be managed according to their individual health status, and not according to age. Based on available rapid health screening tools, geriatric evaluation and geriatric interventions, the Task Force recommends that patients are classified according to health status into three groups: (1) 'healthy' or 'fit' patients should have the same treatment options as younger patients; (2) 'vulnerable' patients are candidates for geriatric interventions which-if successful-may make it appropriate for them to receive standard treatment and (3) 'frail' patients with major impairments who should receive adapted or palliative treatment. The 2019 SIOG Task Force recommendations also discuss prospects and unmet needs for health status evaluation in everyday practice in older patients with prostate cancer.

Immune checkpoint inhibitors in MITF family translocation renal cell carcinomas and genetic correlates of exceptional responders.

BACKGROUND: Microphthalmia Transcription Factor (MITF)family translocation renal cell carcinoma (tRCC) is a rare RCC subtype harboring TFE3/TFEB translocations. The prognosis in the metastatic (m) setting is poor. Programmed death ligand-1 expression was reported in 90% of cases, prompting us to analyze the benefit of immune checkpoint inhibitors (ICI) in this population. PATIENTS AND METHODS: This multicenter retrospective study identified patients with MITF family mtRCC who had received an ICI in any of 12 referral centers in France or the USA. Response rate according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. Genomic alterations associated with response were determined for 8 patients. RESULTS: Overall, 24 patients with metastatic disease who received an ICI as second or later line of treatment were identified. Nineteen (82.6%) of these patients had received a VEGFR inhibitor as first-line treatment, with a median PFS of 3 months (range, 1-22 months). The median PFS for patients during first ICI treatment was 2.5 months (range, 1-40 months); 4 patients experienced partial response (16,7%) and 3 (12,5%) had stable disease. Of the patients whose genomic alterations were analyzed, two patients with mutations in bromodomain-containing genes (PBRM1 and BRD8) had a clinical benefit. Resistant clones in a patient with exceptional response to ipilimumab showed loss of BRD8 mutations and increased mutational load driven by parallel evolution affecting 17 genes (median mutations per gene, 3), which were enriched mainly for O-glycan processing (29.4%, FDR = 9.7 × 10- 6). CONCLUSIONS: MITF family tRCC is an aggressive disease with similar responses to ICIs as clear-cell RCC. Mutations in bromodomain-containing genes might be associated with clinical benefit. The unexpected observation about parallel evolution of genes involved in O-glycosylation as a mechanism of resistance to ICI warrants exploration.

Q-TWiST analysis of patients with metastatic castrate naive prostate cancer treated by androgen deprivation therapy with or without docetaxel in the randomised phase III GETUG-AFU 15 trial.

BACKGROUND: Early chemotherapy has recently become a new standard of care for patients with metastatic castrate-naive prostate cancer (mCNPC). The survival benefit is evident in patients with high-volume disease, but less clear in those with low-volume disease. Here, we assessed the trade-offs between toxicity and survival using a Quality-adjusted Time Without Symptoms of disease and Toxicity of treatment (Q-TWiST) analysis. PATIENTS AND METHODS: This analysis was performed from the data of the Genito-Urinary Oncology Group (GETUG)-AFU 15 phase III trial evaluating the benefits of docetaxel (D) combined with androgen deprivation therapy (ADT) versus ADT alone in 385 mCNPC patients. Overall survival was partitioned into three periods, namely toxic phase of treatment (TOX), time before progression without toxicity (TWIST), and progression (PROG). These health states were weighted according to patients' utility to determine quality-adjusted survival times. In threshold analyses, utility for TOX and PROG were varied from 0 to 1. RESULTS: A better quality-adjusted survival was found in the ADT + D arm when the utility for PROG and TOX states were ≤0.2 and ≥ 0.8, respectively. When the utility for PROG was 0.4 or more, ADT + D and ADT alone yielded similar quality-adjusted survival. When patients were stratified into high-volume versus low-volume disease, we found a significant Q-TWiST benefit in favour of the ADT + D arm only for high-volume patients when the utility for PROG was less than 0.35, while we found no benefit in low-volume disease patients, whatever the coefficients tested. CONCLUSION: Early docetaxel may provide significant quality-adjusted survival benefits for patients with mCNPC, especially those with high-volume disease, depending on the values assigned to the times spent in the toxicity phase and after PROG. The Q-TWiST methodology is a useful tool for decision-making regarding trade-offs between survival, PROG and toxicity.

Controversies and consensus in the innovation access for cancer therapy in the European countries: on the subject of metastatic prostate cancer.

Innovative cancer therapies and advances in drug development have created new hopes for patients and health providers. The purpose of this article was to evaluate the discrepancies in the assessment of the magnitude of benefit of four new drugs (abiraterone acetate, enzalutamide, cabazitaxel, radium-223 dichloride) for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The comparison was done among three European countries (UK, Germany and France) and Canada, according to the statement of each country and to the European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale. Whereas those drugs are authorized by the European Medical Agency, one can observed that clear discrepancies in the magnitude of benefit assessment exist between selected countries, as well as between national pricing evaluation agencies and ESMO. However, price setting and reimbursement decisions remain national responsibility with differences in assessment of the medical value of new treatment across countries, leading to a heterogeneous accessibility to cancer treatments. In conclusion, several procedures have to be implemented to overcome the patchwork of administrative assessments. Among them, the assessment of medical value should be based on independent statements of learned societies, and the harmonization of access to cancer therapy in Europe has to be driven by a common European reimbursement and pricing policy.

Biological toxicities as surrogate markers of efficacy in patients treated with mTOR inhibitors for metastatic renal cell carcinoma.

BACKGROUND: Metabolic toxicities of mTOR inhibitors (mTORi) are well characterized. The purpose of the study was to investigate the relationship between these metabolic toxicities and mTORi efficacy. METHODS: From 2007 to 2011, metabolic toxicities were retrospectively collected in patients treated with an mTORi (everolimus, temsirolimus) for a metastatic renal cell carcinoma (mRCC) in a single institution. Patients were eligible if they have received an mTORi for at least 28 days. Changes in the following parameters were analyzed: lymphocytes, serum creatinine, glycemia, serum phosphate, liver transaminases, cholesterol, and triglycerides. The efficacy was assessed by progression-free survival (PFS) and tumor response. RESULTS: Data were collected from seventy-five patients (everolimus = 44 patients; temsirolimus = 31 patients). Six patients exhibited a partial response, 42 a stable disease and 15 had a progressive disease (12 missing). After a median follow-up of 12.8 months, the median PFS was 6.7 months (95% confidence interval: 4.0-9.1 months). Patients with CB had a statistically more severe absolute increase of glycemia and absolute decrease in phosphatemia (p = 0.002 and p = 0.02 respectively). The Progression Free Survival was significantly higher with the onset rate of hypophosphatemia (p = 0.03) and hyperglycemia (p = 0.001) and lower with the onset rate of lymphopenia (p = 0.004). CONCLUSIONS: Hyperglycemia, hypophosphatemia and lymphopenia, were significantly associated with tumor response and/or PFS. Those events, as well as their onset rate, should be prospectively monitored as predictors of response to mTORi.

Immune-related alopecia (areata and universalis) in cancer patients receiving immune checkpoint inhibitors.

Cytotoxic T-lymphocyte-associated protein-4, programmed cell death protein and programmed cell death protein ligand 1 monoclonal antibodies (immune checkpoint inhibitors), are used to treat various malignancies. Their mechanism of action involves the inhibition of negative regulators of immune activation, resulting in immune-related adverse events (irAEs) including endocrinopathies, pneumonitis, colitis, hepatitis and dermatological events. Dermatological irAEs include maculopapular rash, pruritus, vitiligo, blistering disorders, mucocutaneous lichenoid eruptions, rosacea and the exacerbation of psoriasis. Alopecia secondary to immune checkpoint inhibitors has been reported in 1·0-2·0% of treated patients. Our objective is to characterize for the first time the clinicopathology of patients with alopecia areata (AA) secondary to immune checkpoint inhibitors, including the first report of anti-PD-L1 therapy-induced AA, and review of the literature. Four cases of patients who developed partial or complete alopecia during treatment with immune checkpoint inhibitors for underlying cancer were identified from our clinics. Methods include the review of the history and clinicopathologic features. Three patients (75%) had AA and one had universalis. Two patients had a resolution after topical, oral or intralesional therapies and one had a resolution after immunotherapy was discontinued; all regrown hair exhibited poliosis. One of the four patients had coincident onychodystrophy. This report describes a series of four patients who developed partial or complete alopecia (i.e. areata and universalis) during treatment with immune checkpoint inhibitor therapies for cancer. The recognition and management of hair-related irAEs are important for pretherapy counselling and interventions that contribute to maintaining optimal health-related quality of life in patients.

[Cancer immunotherapy: Rational and recent breakthroughs]. / Immunothérapie des cancers : rationnel et avancées récentes.

Cancer immunotherapy has occupied a marginal therapeutic option in cancer despite strong arguments documenting the role of the immune system in controlling the proliferation of cancers. The recent success of immunotherapy results from a change in the past paradigm. From now on, the goal is not only to activate the immune system against tumor, but also to take account of the immunosuppressive tumor microenvironment Among these mechanisms, negative costimulatory molecules (CTLA-4, PD-1, etc.) expressed by T cells in the tumor could explain their lack of effectiveness in inhibiting tumor growth. Blocking these molecules allowed the reactivation of anti-tumor T cells. Clinically, the administration of anti-CTLA-4 antibody (ipilimumab: Yervoy®) was granted marketing authorization for patients with metastatic melanoma. The anti-PD-1 antibodies (nivolumab: Opdivo®, pembrolizumab: Keytruda®) have demonstrated clinical efficacy when compared to the standard therapy in metastatic melanomas, advanced lung cancers and metastatic renal cell carcinoma. In phase I and II clinical trials, other tumors (Hodgkin's disease, head and neck cancers, bladder cancer, gastric cancer, etc.) appear to be responsive to these immunomodulators. These treatments were associated with the occurrence of side effects dominated by autoimmunity predictable by unlocking the breaks exerted by immune system to maintain tolerance against self-antigen. The optimization of therapeutic combination based on these molecules and the search for biomarkers associated with these treatments constitute a challenge for the future for this new therapeutic class of drugs for oncology.

[Castration modalities in prostate cancer: Are they all equal?]. / Modalités de castration dans la prise en charge du cancer de la prostate: sont-elles toutes équivalentes ?

AIM: The aim of this literature review was to focus on the new highlights regarding oncologic and safety outcomes depending on the type of castration used. MATERIAL: Literature search using various algorithms "prostate cancer", "castration", "agonist", "antagonist", "orchiectomy", "GnRH", "FSH", "androgen deprivation therapy" has been performed in April 2015, through the PubMed and Embase databases. RESULTS: GnRH agonists and antagonists are both currently used in clinical practice. Nevertheless, differences regarding their pharmacologic properties have been highlighted in recent studies, specifically regarding the rapidity, sustainability and depth of the castration, but also the decrease in FSH level. Such differences may have oncological impact on the patient, regarding the disease biological control and the time to progression, and a tolerability impact, especially on the cardiovascular risks. The role of the depth and the sustainability of the castration in one hand, the FSH impact in the other hand, as well as a direct inhibition on extra-pituitary GnRH receptors by antagonist might explain these differences. CONCLUSIONS: Recent studies suggest differences between GnRH agonists and antagonist that could impact the patient clinical outcomes. However, further high level of evidence comparative studies remains warranted.

mTOR-inhibitor treatment of metastatic renal cell carcinoma: contribution of Choi and modified Choi criteria assessed in 2D or 3D to evaluate tumor response.

PURPOSE: To determine whether 2D or 3D Choi and modified Choi (mChoi) criteria could assess the efficacy of everolimus against metastatic renal cell carcinoma (mRCC). METHODS: RECIST-1.1, Choi, and mChoi criteria were applied retrospectively to analyse baseline and 2-month contrast-enhanced computed tomography (CECT) images in 48 patients with mRCC enrolled in the everolimus arm of the French randomized double-blind multicentre phase III trial comparing everolimus versus placebo (RECORD-1). The primary endpoint was centrally reviewed progression-free survival (PFS) calculated from the initial RECORD-1 analysis. Mean attenuation was determined for 2D target lesion regions of interest drawn on CECT sections whose largest diameters had been measured, and for the 3D whole target lesion. RESULTS: The median PFS was 5.5 months. The median PFS for everolimus responders defined using 3D mChoi criteria was significantly longer than for non-responders (7.6 versus 5.4 months, respectively), corresponding to a hazard ratio for progression of 0.45 (95 % CI: 0.22-0.92), with respective 1-year survival rates of 31 % and 9 %. No other 2D or 3D imaging criteria at 2 months identified patients who would benefit from everolimus. CONCLUSIONS: At 2 months, only 3D mChoi criteria were able to identify mRCC patients with a PFS benefit from everolimus. KEY POINTS: Choi criteria could not identify everolimus-treated patients with significantly prolonged PFS. mCHOI enabled identification of everolimus-treated mRCC patients with a PFS benefit. 3D attenuation measurement criteria appeared to perform better than single-slice measurement.

RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs.

BACKGROUND: Bone metastases (BMs) are associated with poor outcome in metastatic clear-cell renal carcinoma (m-ccRCC) treated with anti-vascular endothelial growth factor tyrosine kinase inhibitors (anti-VEGFR-TKIs). We aimed to investigate whether expression in the primary tumour of genes involved in the development of BM is associated with outcome in m-ccRCC patients treated with anti-VEGFR-TKIs. METHODS: Metastatic clear-cell renal cell carcinoma patients with available fresh-frozen tumour and treated with anti-VEGFR-TKIs. Quantitative real-time PCR (qRT-PCR) for receptor activator of NF-kB (RANK), RANK-ligand (RANKL), osteoprotegerin (OPG), the proto-oncogene SRC and DKK1 (Dickkopf WNT signalling pathway inhibitor-1). Time-to-event analysis by Kaplan-Meier estimates and Cox regression. RESULTS: We included 129 m-ccRCC patients treated between 2005 and 2013. An elevated RANK/OPG ratio was associated with shorter median time to metastasis (HR 0.50 (95% CI 0.29-0.87); P=0.014), shorter time to BM (HR 0.54 (95% CI 0.31-0.97); P=0.037), shorter median overall survival (mOS) since initial diagnosis (HR 2.27 (95% CI 1.44-3.60); P=0.0001), shorter median progression-free survival (HR 0.44 (95% CI 0.28-0.71); P=0.001) and mOS (HR 0.31 (95% CI 0.19-0.52); P<0.0001) on first-line anti-VEGFR-TKIs in the metastatic setting. Higher RANK expression was associated with shorter mOS on first-line anti-VEGFR-TKIs (HR 0.46 (95% CI 0.29-0.73); P=0.001). CONCLUSIONS: RANK/OPG ratio of expression in primary ccRCC is associated with BM and prognosis in patients treated with anti-VEGFR-TKIs. Prospective validation is warranted.