Renal toxicity of ifosfamide in children with cancer: an exploratory study integrating aldehyde dehydrogenase enzymatic activity data and a wide-array urinary metabolomics approach.

BACKGROUND: Ifosfamide is a major anti-cancer drug in children with well-known renal toxicity. Understanding the mechanisms underlying this toxicity could help identify children at increased risk of toxicity. METHODS: The IFOS01 study included children undergoing ifosfamide-based chemotherapy for Ewing sarcoma or rhabdomyosarcoma. A fully evaluation of renal function was performed during and after chemotherapy. Proton nuclear magnetic resonance (NMR) and conventional biochemistry were used to detect early signs of ifosfamide-induced tubulopathy. The enzymatic activity of aldehyde dehydrogenase (ALDH) was measured in the peripheral blood lymphocytes as a marker of ifosfamide-derived chloroacetaldehyde detoxification capacity. Plasma and urine concentrations of ifosfamide and dechloroethylated metabolites were quantified. RESULTS: The 15 participants received a median total ifosfamide dose of 59 g/m2 (range: 24-102), given over a median of 7 cycles (range: 4-14). All children had acute proximal tubular toxicity during chemotherapy that was reversible post-cycle, seen with both conventional assays and NMR. After a median follow-up of 31 months, 8/13 children presented overall chronic toxicity among which 7 had decreased glomerular filtration rate. ALDH enzymatic activity showed high inter- and intra-individual variations across cycles, though overall activity looked lower in children who subsequently developed chronic nephrotoxicity. Concentrations of ifosfamide and metabolites were similar in all children. CONCLUSIONS: Acute renal toxicity was frequent during chemotherapy and did not allow identification of children at risk for long-term toxicity. A role of ALDH in late renal dysfunction is possible so further exploration of its enzymatic activity and polymorphism should be encouraged to improve the understanding of ifosfamide-induced nephrotoxicity.

Comprehensive analyses of immune tumor microenvironment in papillary renal cell carcinoma.

BACKGROUND: Papillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC, and associated with poor outcomes in the metastatic setting. In this study, we aimed to comprehensively evaluate the immune tumor microenvironment (TME), largely unknown, of patients with metastatic pRCC and identify potential therapeutic targets. METHODS: We performed quantitative gene expression analysis of TME using Microenvironment Cell Populations-counter (MCP-counter) methodology, on two independent cohorts of localized pRCC (n=271 and n=98). We then characterized the TME, using immunohistochemistry (n=38) and RNA-sequencing (RNA-seq) (n=30) on metastatic pRCC from the prospective AXIPAP trial cohort. RESULTS: Unsupervised clustering identified two "TME subtypes", in each of the cohorts: the "immune-enriched" and the "immune-low". Within AXIPAP trial cohort, the "immune-enriched" cluster was significantly associated with a worse prognosis according to the median overall survival to 8 months (95% CI, 6 to 29) versus 37 months (95% CI, 20 to NA, p=0.001). The two immune signatures, Teff and JAVELIN Renal 101 Immuno signature, predictive of response to immune checkpoint inhibitors (CPI) in clear cell RCC, were significantly higher in the "immune-enriched" group (adjusted p<0.05). Finally, five differentially overexpressed genes were identified, corresponding mainly to B lymphocyte populations. CONCLUSION: For the first time, using RNA-seq and immunohistochemistry, we have highlighted a specific immune TME subtype of metastatic pRCC, significantly more infiltrated with T and B immune population. This "immune-enriched" group appears to have a worse prognosis and could have a potential predictive value for response to immunotherapy, justifying the confirmation of these results in a cohort of metastatic pRCC treated with CPI and in combination with targeted therapies. TRIAL REGISTRATION NUMBER: NCT02489695.

Extracranial germ cell tumours in children and adolescents: Results from the French TGM13 protocol.

BACKGROUND: Chemotherapy for non-seminomatous germ cell tumours (NSGCT) exposes to dose-dependent toxicities. The TGM13-NS protocol (EudraCT 2013-004039-60) aimed to decrease the chemotherapy burden compared to the previous TGM95 protocol while maintaining the 5-year event-free survival (EFS) at 80% or more. PROCEDURE: Patients less than 19 years of age with disseminated NSGCT were enrolled (May 2014 to May 2019) and stratified into four groups: two intermediate-risk (IR: localised tumour with low tumour markers [TM]) groups treated with VBP (vinblastine-bleomycin-cisplatin): three courses for IR1 (ovarian tumour any age/testis tumour less than or equal to 10 years) and four courses for IR2 (extragonadal tumour 10 years or less) groups, and two high-risk (HR: metastatic and/or high TM) groups treated with etoposide-cisplatin and either ifosfamide (VIP) or bleomycin (BEP): three courses for HR1 (ovarian tumour any age/testis tumour less than or equal to 10 years and low TM/testis tumour more than 10 years and very low TM) groups and four courses for HR2 (remainder) groups. RESULTS: One hundred fifteen patients were included: median age of 12.8 years (0.4-18.9); tumour sites: 44 ovaries, 37 testes and 34 extragonadal. The 5-year EFS and overall survival (OS) were 87% (95% CI: 80-92) and 95% (89-98), respectively (median follow-up: 3.5 years, range: 0.2-5.9), similar to those of the TGM95 protocol (5-year EFS 89% (84-93), 5-year OS 93% (89-95), p = .561). The 5-year EFS were 93% (95% CI: 80-98), 88% (71-95) and 79% (62-90) for ovarian, testicular and extragonadal tumours, respectively. The 5-year EFS varied (p = .02) according to the risk groups: 90% (66-97), 64% (30-85), 95% (72-99) and 87% (74-94) for IR1, IR2, HR1 and HR2, respectively. TM decline adjusted to tumour site, and alpha-fetoprotein (AFP) level revealed a prognostic impact of time to normalisation on EFS: HR = 1.03 (1.003-1.007). CONCLUSION: Risk-adapted and globally decreased chemotherapy burden maintains excellent outcomes, exclusive of the IR2 group, which warrants more intensive chemotherapy.

A Promising Biomarker and Therapeutic Target in Patients with Advanced PDAC: The Stromal Protein ßig-h3.

With an overall survival rate of 2-9% at 5 years, pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related deaths in the industrialized world and is predicted to become the second by 2030. Owing to often late diagnosis and rare actionable molecular alterations, PDAC has not yet benefited from the recent therapeutic advances that immune checkpoint inhibitors (ICI) have provided in other cancer types, except in specific subgroups of patients presenting with tumors with high mutational burden (TMB) or microsatellite instability (MSI). The tumor microenvironment (TME) plays a substantial role in therapeutic resistance by facilitating immune evasion. An extracellular stromal protein, ßig-h3/TGFßi, is involved in the pathogenesis of PDAC by hampering T cell activation and promoting stiffness of the TME. The study BIGHPANC included 41 patients with metastatic PDAC, and analyzed ßig-h3 levels in serum and tumor samples to assess the ßig-h3 prognostic value. ßig-h3 serum levels are significantly associated with overall survival (HR 2.05, 95%CI 1.07-3.93; p = 0.0301). Our results suggest that ßig-h3 serum levels may be considered a prognostic biomarker in patients with metastatic PDAC.

Sunitinib with concomitant radiation therapy in inoperable sarcomas: Final results from the dose escalation and expansion parts of a multicenter phase I study.

INTRODUCTION: Local control in sarcoma is rarely achieved with exclusive radiotherapy (RT). We aim to assess the feasibility and safety of sunitinib continuously administrated with concomitant RT in inoperable non-GIST sarcomas patients. METHODS: This multicentric French 3 + 3 dose escalation study included patients with inoperable locally advanced or recurrent sarcoma, ECOG-PS <2, ≤2 metastatic sites and no brain metastases, adequate organ functions and absence of uncontrolled hypertension, who had never received sunitinib or radiotherapy. The escalation phase planned to use sunitinib dose levels (DL1: 25; DL2: 37.5; DL3: 50 mg/day) with standard RT (60 Gy, 30 fractions, 5 fractions/week/6 weeks). The primary endpoint was to determine the incidence of dose-limiting toxicities (DLT) in the first 14 weeks and the maximal tolerated dose (MTD). Secondary endpoints included safety (acute and late toxicities), local control at 6 months including local progression free rate (L-PFR) progression free survival (PFS), overall survival (OS), proportion of patients eligible for surgery after treatment. RESULTS: From May 2011 to April 2016, the dose-escalation phase enrolled 10 patients (DL1 N = 4; DL2 N = 6). No DLT was observed in at DL1. One DLT (grade 4 thrombopenia) occurred at DL2. The 19 patients treated at DL2 (including the 13 patients from the expansion phase) received sunitinib for a median duration of 42.7 (2.8-79.1) days, and radiotherapy for 6.4 (1-8) weeks; all but 3 patients received 60 Gy (40 Gy, early progression (N = 1); 8 Gy, early death (N = 1), prescribed dose, 50 Gy (N = 1)). With a median follow-up of 19.5 (14-36.5) months, the median PFS was 6.5 (1.9-31.1) months. Median OS was not reached. At 6 months, L-PFR was 73.3% (95%CI 44.9%-92.2%). One patient was amendable to surgery after treatment. Sunitinib-related grade ≥ 3 adverse events occurred in 58% of the patients treated at DL2 (Escalation N = 4; Expansion N = 7). Seven (36.8%) deaths related to disease progression were reported. CONCLUSION: This is the first trial assessing the combination of continuous administration of sunitinib 37.5 mg with exclusive RT in non-GIST sarcoma. Whereas this combination was found feasible, efficient, further investigations of combinations of more recent multikinase inhibitors with RT need to be explored.

Hypofractionated stereotactic body radiation therapy (SBRT) in pediatric patients: preliminary toxicity results of a national prospective multicenter study.

OBJECTIVES: While hypofractionated stereotactic body radiotherapy (SBRT) has been largely adopted in the adult setting, its use remains limited in pediatric patients. This is due, among other factors, to fear of potential toxicities of hypofractionated regimens at a young age. In this context, we report the preliminary acute (<3 months from SBRT) and middle-term (3-24 months) toxicity results of a national prospective study investigating SBRT in pediatric patients. METHODS: Between 2013 and 2019, 61 patients were included. The first 40 patients (median age: 12 y, range: 3-20) who completed a 2-year-follow-up were included in the present analysis. SBRT was used for treating lung, brain or (para)spinal lesions, either as first irradiation (35%) or in the reirradiation setting (65%). RESULTS: Acute and middle-term grade ≥2 toxicities occurred in 12.5 and 7.5% of the patients, respectively. No grade ≥4 toxicities occurred. Almost all toxicities occurred in the reirradiation setting. CONCLUSION: SBRT showed a favorable safety profile in young patients treated for lung, brain, and (para)spinal lesions. ADVANCES IN KNOWLEDGE: SBRT appeared to be safe in pediatric patients treated for multiple oncology indications. These results support further evaluation of SBRT, which may have a role to play in this patient population in the future.

Analysis of the StoRM cohort reveals physical activity to be associated with survival in metastatic breast cancer.

Benefits of physical activity are widely demonstrated for early stage cancers but few studies have focused on metastatic disease. The purpose of this study was to determine the impact of physical activity on survival in patients with metastatic breast cancer. We conducted a secondary analysis of the national, multicentric, non-randomized, prospective cohort SNPs to Risk of Metastasis (StoRM) study. The level of physical activity was self-reported at inclusion and divided into three categories of physical activity: light level, moderate level, and vigorous level. Overall, 833 patients (56.2%) completed the physical activity questionnaire at baseline on average physical activity during the previous year: 11.6% had a light level of physical activity, 69.0% achieved moderate levels of physical activity and 19.3% reported vigorous levels of physical activity. After adjustment for confounding, physical activity was not statistically significantly associated with overall survival in the whole population. Subgroup analysis identified that both vigorous and moderate physical activity were associated with statistically significantly improved overall survival compared to light physical activity level only in the HER2 positive subgroup (HR 0.23; 95% CI 0.07-0.70, p = 0.01 and HR 0.38; 95% CI 0.15-0.96, p = 0.04). Physical activity done during the previous year was associated with survival in HER2 positive metastatic breast cancer patients. These results suggest that overall survival in metastatic breast cancer patients could be improved through physical activity which should be considered as a complementary intervention for these individuals. The study showed that moderate/vigorous levels of physical activity were associated with better overall survival, and that these associations remained statistically significant in multivariate analysis in the HER2 positive subgroup. These results have clinical relevance and justify the recommendations for physical activity interventions in metastatic breast cancer.

Axitinib in first-line for patients with metastatic papillary renal cell carcinoma: Results of the multicentre, open-label, single-arm, phase II AXIPAP trial.

INTRODUCTION: Papillary renal cell carcinoma (PRCC) represents 10%-15% of renal carcinomas. No standard treatments exist for metastatic PRCC (mPRCC) patients. Axitinib is indicated as second-line treatment in metastatic clear cell renal carcinoma, and we aim to assess the efficacy of this vascular endothelial growth factor receptor inhibitor in front line for mPRCC. METHODS: This French multicentre phase II study AXIPAP enrolled untreated mPRCC patients, with measurable disease, Eastern Cooperative Oncology Group performance status ≤ 1 and adequate organ functions. PRCC had to be confirmed by histology expert central review. Axitinib was administered orally 5 mg twice daily. Primary end-point was progression-free rate at 24 weeks (24w-PFR) by central review. RESULTS: Fifty-six patients were screened, and 44 included (13 type 1, 30 type 2 and 1 non-specified). The median follow-up was 32.0 (13.1-39.9) months. The 24w-PFR was 45.2% (95% confidence interval [CI], 32.6% to +∞), the objective response rate was 28.6% (95% CI, 15.7%-44.6%) (type 1: 7.7%; type 2: 35.7%). The overall median progression free survival was 6.6 months (95% CI, 5.5-9.2), 6.7 months (95% CI, 5.5-9.2) and 6.2 months (95% CI, 5.4-9.2) for type 1 and 2, respectively. Median overall survival was 18.9 months (95% CI, 12.8-not reached). Adverse events were as expected; grade 3-4 treatment-related adverse events were rare except hypertension (27%). CONCLUSIONS: Axitinib demonstrated encouraging efficacy in mPRCC patients, especially in type 2 PRCC. Toxicity was manageable. Axitinib appears as an interesting option for first-line treatment and to be worth further investigation in combination with immunotherapy in these patients. Expert pathology review should be recommended in this setting. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02489695.

[Osteopathy for chronic pain after breast cancer surgery: A monocentric randomised study]. / Étude randomisée monocentrique évaluant l'efficacité de l'ostéopathie dans la prise en charge des douleurs chroniques après chirurgie mammaire en oncologie.

Twenty-five to 65% of patients suffer from chronic pain after breast cancer. The treatment combines analgesic drugs and psychophysical techniques. HYPOTHESIS: Osteopathy improves the control of pain and the quality of life of patients. METHODS: This randomized prospective single center study allocated patients to the initiation of a standard analgesic treatment exclusively (arm A) or associated to osteopathy (arm B) between from 1 to 12months after surgery. MAIN OBJECTIVE: Intensity of pain (VAS at three months [j90]). SECONDARY OBJECTIVES: Pain (VAS) at 6 and 12 months, analgesic consumption, anxiety/depression (HADS), and Quality of life (QLQ-C30). Eighty patients were planned to observe a 2-point difference in VAS (5% bilateral alpha, 90% power). RESULTS: Twenty-eight patients (A: 14; B: 14, median age 50 years) were included from April 2011 to February 2014; the study was stopped due to a too slow recruitment. No difference in the VAS pain score between arms was observed at j90 (P=0.258), nor at 6 and 12 months. At j90, the HADS depression score was reduced in arm B (P=0.049). Improvement in the overall score of quality of life (P=0.015), and reduced pain sub-score (P=0.021) were observed at j90 in arm B. DISCUSSION: Patients are strongly seeking complementary therapies. Few studies exist. Our study has encountered major recruitment difficulties therefore limiting the interpretation of the results. Despite the absence of difference in the main objective, some other scores (QOL, depression) are noteworthy in favor of osteopathy. Further multicentric studies are needed.

A 96-hour continuous wound infiltration with ropivacaine reduces analgesic consumption after liver resection: A randomized, double-blind, controlled trial.

BACKGROUND: Continuous wound infiltration (CWI) with local anesthetics to reduce morphine consumption in postoperative pain management after open liver resection in patients with cancer. METHODS: This single-center randomized double-blind study allocated patients requiring resection of liver metastases to receive a 3.75 mg/mL ropivacaine (ROP) infiltration, followed by a 2 mg/mL ROP CWI, or placebo (P) for 96 hours. Postoperative analgesia included acetaminophen and patient-controlled analgesia morphine pump. The primary endpoint was to investigate the reduction of total morphine consumption (mg/kg) over the first 96 postoperative hours. RESULTS: Eighty-five patients were recruited, and randomized (ROP: 42, P: 43) between 2009 and 2014. The median morphine consumption significantly decreased in the ROP arm in the first 96 postoperative hours (ROP: 1.0, P: 1.5 mg/kg; P = 0.026). Twenty-three (27%) patients had grade 3 adverse events (ROP: 14, P: 9) and four experienced grade 3 treatment-related adverse events (ROP: mental confusion [n = 1], hallucinations [n = 2], P: hematoma [n = 1]). Two (5%) patients showed a wound inflammation (ROP: 1, P: 1). Nine (11%) patients experienced at least one serious adverse event (ROP: 6, P: 3); none related to treatment. CONCLUSION: Preperitoneal CWI of 2 mg/mL ROP significantly reduces intravenous morphine consumption during the 96 postoperative hours resulting in an absolute reduction of 0.5 mg/kg.

Does a homeopathic medicine reduce hot flushes induced by adjuvant endocrine therapy in localized breast cancer patients? A multicenter randomized placebo-controlled phase III trial.

PURPOSE: Endocrine therapy (ET) used to reduce the risk of recurrence in hormone receptor-expressing disease (75% of breast cancers) is associated with worsening of climacteric symptoms with a negative impact on quality of life (QoL). Homeopathy might allow a better management of hot flushes (HF). METHODS: In this multicenter randomized double-blind placebo-controlled phase III study ( ClinicalTrials.gov NCT01246427), we enrolled ≥ 18 years old women with histologically proven non metastatic localized breast cancer, with Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) ≤ 1, treated for at least 1 month with adjuvant ET, and complaining about moderate to severe HF. Patients should not be scheduled for chemotherapy or radiotherapy, and had no associated pathology known to induce HF. After a 2- to 4-week placebo administration, we randomly assigned (1:1) patients with HFS ≥ 10 using an interactive web-based centralized platform to BRN-01 homeopathic medicine complex (Actheane®) in arm A or Placebo (Arm P). Randomization was stratified by adjuvant ET (taxoxifen/aromatase inhibitor) and recruiting site. HF scores (HFS) were calculated as the mean of HF frequencies before randomization, at 4, and at 8 weeks post-randomization (pre-, 4w,- and 8w-) weighted by a 4-level intensity scale. Primary endpoint was assessed at 4-week post-randomization, as the variation between pre- and 4w-HFS. Secondary endpoints included HFS variation between pre- and 8w-HFS, compliance and tolerance assessed 8 weeks after randomization, and QoL and satisfaction assessed at 4- and 8-week post-randomization. RESULTS: Two hundred ninety-nine patients were included, and 138 (46.2%) randomized (A, 65; P, 73). Median 4w-HFS absolute variation (A, - 2.9; P, - 2.5 points, p = 0.756) and relative decrease (A, - 17%; P, - 15%, p = 0.629) were not statistically different. However, 4w-HFS decreased for 46 (75%) in A vs 48 (68%) patients in P arm. 4w-QoL was stable or improved for respectively 43 (72%) vs 51 (74%) patients (p = 0.470). CONCLUSIONS: The efficacy endpoint was not reached, and BRN-01 administration was not demonstrated as an efficient treatment to alleviate HF symptoms due to adjuvant ET in breast cancer patients. However, the study drug administration led to decreased HFS with a positive impact on QoL. Without any recommended treatment to treat or alleviate the HF-related disabling symptoms, Actheane® could be a promising option, providing an interesting support for better adherence to ET, thereby reducing the risk of recurrence with a good tolerance profile.

The tyrosine-kinase inhibitor sunitinib targets vascular endothelial (VE)-cadherin: a marker of response to antitumoural treatment in metastatic renal cell carcinoma.

BACKGROUND: Vascular endothelial (VE)-cadherin is an endothelial cell-specific protein responsible for endothelium integrity. Its adhesive properties are regulated by post-translational processing, such as tyrosine phosphorylation at site Y685 in its cytoplasmic domain, and cleavage of its extracellular domain (sVE). In hormone-refractory metastatic breast cancer, we recently demonstrated that sVE levels correlate to poor survival. In the present study, we determine whether kidney cancer therapies had an effect on VE-cadherin structural modifications and their clinical interest to monitor patient outcome. METHODS: The effects of kidney cancer biotherapies were tested on an endothelial monolayer model mimicking the endothelium lining blood vessels and on a homotypic and heterotypic 3D cell model mimicking tumour growth. sVE was quantified by ELISA in renal cell carcinoma patients initiating sunitinib (48 patients) or bevacizumab (83 patients) in the first-line metastatic setting (SUVEGIL and TORAVA trials). RESULTS: Human VE-cadherin is a direct target for sunitinib which inhibits its VEGF-induced phosphorylation and cleavage on endothelial monolayer and endothelial cell migration in the 3D model. The tumour cell environment modulates VE-cadherin functions through MMPs and VEGF. We demonstrate the presence of soluble VE-cadherin in the sera of mRCC patients (n = 131) which level at baseline, is higher than in a healthy donor group (n = 96). Analysis of sVE level after 4 weeks of treatment showed that a decrease in sVE level discriminates the responders vs. non-responders to sunitinib, but not bevacizumab. CONCLUSIONS: These data highlight the interest for the sVE bioassay in future follow-up of cancer patients treated with targeted therapies such as tyrosine-kinase inhibitors.

HEPATOFLUO: A prospective monocentric study assessing the benefits of indocyanine green (ICG) fluorescence for hepatic surgery.

BACKGROUND AND OBJECTIVES: Fluorescence imaging using indocyanine green (ICG) is undergoing extensive development. This study aimed to assess the merits of ICG in regard to hepatic surgery. METHODS: Patients with liver lesions that required a resection were eligible. They received an injection of ICG the day before the surgery. Step 1 allowed assessment of use of the medical device under surgical conditions. Steps 2 and 3 assessed the capacity of the MD to detect known tumorous lesions and to spot a predefined area of the liver following injection of ICG into the portal vein (ICGp). RESULTS: The 1st step allowed for validation of the MD use with three patients. Between 04-2013 and 04-2015, 45 pts were included (40 eligible) in steps 2 and 3. All of the tumorous lesions (95/119) exhibited fluorescence. Four new metastasis were detected in 3 pts, and two missing metastases in 1 pt. False positive were 22%. The maximal depth for detection by fluorescence was 13 mm. Injection of ICGp allowed the corresponding anatomical area to be identified in 16/20 patients. CONCLUSION: This study confirmed that intraoperative fluorescence is a helpful and relevant tool for the liver surgeon (NCT 01738217).

Bibliometric analysis of a century of research on oral erythroplakia and leukoplakia.

BACKGROUND: Oral squamous cell carcinoma is a major cause of cancer-associated morbidity and mortality and may develop from oral erythroplakia and leukoplakia (OEL), the most common oral potentially malignant lesions. Our objective was to provide a descriptive overview of the global research activity on OEL over the past decades. METHODS: We performed a systematic bibliometric analysis of articles and reviews on OEL up to December 31st 2016 using the SCOPUS database. Contribution of each country was analyzed by density-equalizing mapping (DEMP). The overall scientific productivity was analyzed for each journal and country. RESULTS: A total of 5098 published items (articles or reviews) were identified. They are expected to double by 2040, with an expected number of 400 items per year. Only 4% of all research on oral oncology is focused on OEL. Together with the increasing number of publications since 1980s, an increasing number of international collaborative studies were observed. Journal of Oral Pathology and Medicine and Oral Oncology are the leading journals in terms of number of published items. The US, India, and the UK were the most prolific countries in terms of publications overtime. CONCLUSIONS: We identified the leading journals as well as the leading authors and countries contributing to the research on OEL. International collaborative studies in the field are to be encouraged to refine strategies of oral cancer prevention.

Phase I dose-escalation study of pazopanib combined with bevacizumab in patients with metastatic renal cell carcinoma or other advanced tumors.

BACKGROUND: Vascular endothelial growth factor (VEGF) directed therapies are being used in a large number of advanced tumors. Metastatic renal cell carcinoma (mRCC) is highly dependent on the VEGF pathway; VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKI) and humanized VEGF monoclonal antibody have been registered for clinical use in advanced renal cell carcinoma. The VEGFR TKI, pazopanib, with a rather manageable toxicity profile, was preferred to sunitinib by mRCC patients. We investigate the combination of pazopanib and bevacizumab to determine the maximum tolerated dose (MTD) in mRCC and other advanced solid tumors. METHODS: In this bicentric phase I trial with a 3 + 3 + 3 dose-escalation design, patients received oral pazopanib once daily plus intravenous infusion of bevacizumab every 2 weeks from D15, at one of the four dose levels (DL) planned according to the occurrence of dose limiting toxicities (DLT). 400 and 600 mg pazopanib were respectively combined with 7.5 mg/kg bevacizumab in DL1 and DL2, and 600 and 800 mg pazopanib with 10 mg/kg bevacizumab in DL3 and DL4. Tumor response was evaluated every 8 weeks. Blood samples were assayed to investigate pazopanib pharmacokinetics. RESULTS: Twenty five patients including seven mRCC were enrolled. Nine patients received the DL1, ten received the DL2. No DLT were observed at DL1, five DLT at DL2, and 3 DLT in the six additional patients who received the DL1. A grade 3 microangiopathic hemolytic anemia syndrome was observed in four (16%) patients. Five (22%) patients achieved a partial response. The mean (range) plasmatic concentrations of 400 and 600 pazopanib were respectively 283 (139-427) and 494 (227-761) µg.h/mL at Day 1, and 738 (487-989) and 1071 (678-1464) µg.h/mL at Day 15 i.e. higher than those previously reported with pazopanib, and were not directly influenced by bevacizumab infusion. CONCLUSIONS: The combination of pazopanib and bevacizumab induces angiogenic toxicity in patients without any pre-existing renal or vascular damage. Even if a marginal efficacy was reported with five (22%) patients in partial response in different tumor types, the toxicity profile compromises the development of this combination. TRIAL REGISTRATION: The study was retrospectively registered on ClinicalTrials.gov (number NCT01202032 ) on 2010, Sept 14th.

Efficacy of high-intensity focused ultrasound-assisted hepatic resection (HIFU-AR) on blood loss reduction in patients with liver metastases requiring hepatectomy: study protocol for a randomized controlled trial.

BACKGROUND: Liver resection is the only potentially curative treatment for colorectal liver metastases (LM). It is considered a safe procedure, but is often associated with blood loss during liver transection. Blood transfusions are frequently needed, but they are associated with increased morbidity and risk of recurrence. Many surgical devices have been developed to decrease blood loss. However, none of them has proven superior to the standard crushing technique. We developed a new, powerful intra-operative high-intensity focused ultrasound (HIFU) transducer which destroys tissue by coagulative necrosis. We aim to evaluate whether HIFU-assisted liver resection (HIFU-AR) results in reduced blood loss. METHODS: This is a prospective, single-centre, randomized (1:1 ratio), comparative, open-label phase II study. Patients with LM requiring a hepatectomy for ≥ 2 segments will be included. Patients with cirrhosis or sinusoidal obstruction syndrome with portal hypertension will be excluded. The primary endpoint is normalized blood loss in millilitres per square centimetre of liver section plane. Secondary endpoints are: total blood loss, transection time, transection time per square centimetre of liver area, haemostasis time, clip density on the liver section area, rate and duration of the Pringle manœuvre, rate of patients needing a blood transfusion, length of hospital stay, morbidity, patients with positive resection margin, and local recurrence. Assuming a blood loss of 7.6 ± 3.7 mL/cm2 among controls, the study will have 85% power to detect a twofold decrease of blood loss in the experimental arm, using a Wilcoxon (Mann-Whitney) rank-sum test with a 0.05 two-sided significance level. Twenty-one randomized patients per arm are required. Considering the risk of contraindications at surgery, up to eight patients may be enrolled in addition to the 42 planned, with an enrolment period of 24 months. Randomization will be stratified by surgeon. DISCUSSION: We previously demonstrated the safety and efficacy of intra-operative HIFU in patients operated on for LM. We also demonstrated the efficacy of HIFU-AR in a preclinical study. Participants in the HIFU-AR group of this randomized trial can expect to benefit from reduced blood loss and decreased ischemia of liver parenchyma. TRIAL REGISTRATION: Clinicaltrial.gov, NCT02728167 . Registered on 22 March 2016.

A serum metabolomic fingerprint of bevacizumab and temsirolimus combination as first-line treatment of metastatic renal cell carcinoma.

BACKGROUND: Renal cell carcinoma is one of the most chemoresistant cancers, and its metastatic form requires administration of targeted therapies based on angiogenesis or mTOR inhibitors. Understanding how these treatments impact the human metabolism is essential to predict the host response and adjust personalised therapies. We present a metabolomic investigation of serum samples from patients with metastatic RCC (mRCC) to identify metabolic signatures associated with targeted therapies. METHODS: Pre-treatment and serial on-treatment sera were available for 121 patients participating in the French clinical trial TORAVA, in which 171 randomised patients with mRCC received a bevacizumab and temsirolimus combination (experimental arm A) or a standard treatment: either sunitinib (B) or interferon-α+bevacizumab (C). Metabolic profiles were obtained using nuclear magnetic resonance spectroscopy and compared on-treatment or between treatments. RESULTS: Multivariate statistical modelling discriminates serum profiles before and after several weeks of treatment for arms A and C. The combination A causes faster changes in patient metabolism than treatment C, detectable after only 2 weeks of treatment. Metabolites related to the discrimination include lipids and carbohydrates, consistently with the known RCC metabolism and side effects of the drugs involved. Comparison of the metabolic profiles for the three arms shows that temsirolimus, an mTOR inhibitor, is responsible for the faster host metabolism modification observed in the experimental arm. CONCLUSIONS: In mRCC, metabolomics shows a faster host metabolism modification induced by a mTOR inhibitor as compared with standard treatments. These results should be confirmed in larger cohorts and other cancer types.

Pharmacokinetics of pazopanib administered in combination with bevacizumab.

A combination of monoclonal antibody that binds and inhibits effects induced by vascular endothelial growth factor and tyrosine kinase inhibitor of vascular endothelial growth factor receptor represents a promising concept to block pathological angiogenesis completely. A phase I study combining daily oral pazopanib and bevacizumab (given iv every 2 weeks) was performed in order to determine the maximum tolerated dose of the two drugs in combination. Pazopanib pharmacokinetics were evaluated to compare pharmacokinetic parameters given alone and those observed on the day of the bevacizumab administration. Plasma pazopanib concentrations were obtained in 25 patients treated at two dose levels (400 or 600 mg) at Day 1 (given alone) and Day 15 (the day of the 7.5 mg/kg bevacizumab infusion), and analyzed using the NONMEM program. The apparent oral clearance (CL/F, mean value of 0.60 L/h) presented an inter-individual variability of 40 %, and an inter-occasion of 27 %. A modest but statistically significant decrease in CL/F was observed from Day 1 to Day 15 (-16.4, 95 % confidence interval of -8.5 to -27.2 %). However, trough pazopanib concentrations observed at Day 16 (24 h after the bevacizumab iv infusion) were not significantly higher than those observed just before the beginning of the bevacizumab iv infusion, suggesting that the pharmacokinetic change between Day 1 and Day 15 was not due to an interaction of bevacizumab. Overall, the mean observed concentrations at the maximum tolerated pazopanib dose (600 mg) at both Day 1 and Day 15 were higher than those observed at 800 mg once daily level (corresponding to the recommended dose when given alone) during the first-in-man phase 1 study of pazopanib in monochemotherapy. This first population pharmacokinetic analysis of pazopanib shows that inter-individual and inter-study pharmacokinetic variability emphasize the need for further evaluation of therapeutic drug monitoring for pazopanib as suggested for other tyrosine kinase inhibitors.

A phase II trial of sunitinib in patients with renal cell cancer and untreated brain metastases.

BACKGROUND: The expanded access program and anecdotal cases suggested sunitinib is safe in RCC patients with BM and might have worthwhile activity. PATIENTS AND METHODS: In a phase II trial, patients with untreated BM received the standard regimen of sunitinib. The primary end point was objective response (OR) rate in BM after 2 cycles. An OR rate of 35% was prospectively defined as the minimum needed to warrant further investigation. According to Simon's optimal 2-stage design, at least 3 of the initial 15 patients had to have an OR for accrual to continue. RESULTS: Among 16 evaluable patients, 1 had a complete response outside the central nervous system (CNS). CNS disease was stabilized in 5 (31%). However, no BM showed an OR. Therefore, no further accrual took place. Median time to progression was 2.3 months and overall survival was 6.3 months. There was 1 toxic death, from peritonitis with gastric perforation. Three patients experienced at least 1 treatment-related grade 3 or greater toxicity but no neurological adverse events were attributable to sunitinib. CONCLUSION: Although tolerability was acceptable in RCC patients with previously untreated BM, sunitinib has limited efficacy in this setting.

Prognostic value of serum CA9 in patients with metastatic clear cell renal cell carcinoma under targeted therapy.

AIM: Carbonic anhydrase 9 (CA9) has been found to be one of most powerful biomarkers for clear-cell renal cell carcinoma (RCC). The serum CA9 is detectable. The aim of this study was to evaluate the potential prognostic role of serum CA9 in patients with metastatic clear-cell RCC patients under targeted therapy. PATIENTS AND METHODS: Serum samples came from the randomized phase 2 TORAVA trial. All patients received a targeted therapy (arm A designed as experimental group: temsirolimus and bevacizumab combination; arm B: sunitinib; arm C: interferon-alfa and bevacizumab). Seventy cases of metastatic clear-cell RCC were analyzed. There were 49 males and 21 females. The age ranged from 33.5 to 79.1 years with a median of 61.2 years. Serum samples were collected before treatment. Serum CA9 was quantified by enzyme-linked immunosorbent assay (ELISA). The correlation of the serum CA9 levels with the clinical parameters, treatment response and overall survival was analyzed. Overall survival estimates were calculated using the Kaplan-Meier method and compared by the log-rank test. RESULTS: Serum concentrations of CA9 ranged between 0 and 897.3 pg/ml, with an average of 94.4±176.6 pg/ml. There was no association between serum CA9 and clinical parameters such as Eastern Cooperative Oncology Group (ECOG) Performance Status (p=0.367) or Motzer classification (p=0.431). The serum CA9 levels were lower in the response group (64.7±104.7 pg/ml) than the no-response group (108.2±203.8 pg/ml), but the difference was not statisticlly significant (p=0.366). For the patient group overall, the Kaplan-Meier survival curve showed that high serum CA9 levels were significantly associated with shorter overall survival (hazard ratio=2.65, 95% confidence interval=1.19-5.92, log-rank test p=0.0136). For the major group of patients treated with temsirolimus and bevacizumab, the Kaplan-Meier survival curve showed that high serum CA9 levels were significantly associated with shorter overall survival (p=0.0006). CONCLUSION: Serum CA9 levels may be of clinical interest to predict the outcome for patients under targeted therapy for metastatic clear-cell RCC. CA9 may be used to select patients with metastatic clear cell RCC for clinical trials.