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Objective: We investigated the efficacy and safety of afatinib maintenance therapy in patients with head and neck squamous cell carcinoma (HNSCC) with macroscopically complete resection and adjuvant radiochemotherapy (RCT)., Methods: This French multicentric randomised phase III double-blind placebo-controlled study included adult patients with ECOG-PS≤2, normal haematological, hepatic and renal functions, and non-metastatic, histologically confirmed HNSCC of the oral cavity, oropharynx, larynx or hypopharynx, with macroscopically complete resection and adjuvant RCT (≥2 cycles of cisplatin 100 mg/m2 J1, J22, J43 and 66Gy (2Gy/fraction, 5 fractions/week, conventional or intensity modulated radiotherapy ≥60Gy). Randomised patients were planned to receive either afatinib (afa arm) or placebo (control arm (C)) as maintenance therapy for one year. Primary endpoint was disease free survival (DFS). A 15% improvement in DFS was expected at 2 years with afatinib (from 55 to 70%)., Results: Among the 167 patients with resected HNSCC included in 19 cancer centres and hospitals from Dec 2011, 134 patients were randomised to receive one-year maintenance afatinib or placebo (afa:67; C:67). Benefit/risk ratio was below assumptions and independent advisory committee recommended to stop the study in Feb 2017, the sponsor decided premature study discontinuation, with a 2-year follow-up for the last randomised patient. 2y-DFS was 61% (95% CI 0.48-0.72) in the afatinib group and 64% (95% CI 0.51-0.74) in the placebo group (HR 1.12, 95% CI 0.70-1.80)., Conclusion: Maintenance therapy with afatinib compared with placebo following post-operative RCT in patients with HNSCC did not significantly improve 2y-DFS and should not be recommended in this setting outside clinical trials., Clinicaltrials: gov identifier NCT01427478., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: To evaluate potential synergistic effect of pembrolizumab with radiotherapy (RT) compared with a standard-of-care (SOC) cetuximab-RT in patients with locally advanced-squamous cell carcinoma of head and neck (LA-SCCHN)., Patients and Methods: Patients with nonoperated stage III-IV SCC of oral cavity, oropharynx, hypopharynx, and larynx and unfit for receiving high-dose cisplatin were enrolled. Patients received once-daily RT up to 69.96 Gy in 33 fractions with weekly cetuximab (cetuximab-RT arm) or 200 mg Q3W pembrolizumab during RT (pembrolizumab-RT arm). The primary endpoint was locoregional control (LRC) rate 15 months after RT. To detect a difference between arms of 60%-80% in 15-month LRC, inclusion of 66 patients per arm was required to achieve a power of at least 0.85 at two-sided significance level of 0.20., Results: Between May 2016 and October 2017, 133 patients were randomized to cetuximab-RT (n = 66) and pembrolizumab-RT (n = 67). Two patients (one in each arm) were not included in the analysis (a consent withdrawal and a progression before treatment start). The median age was 65 years (interquartile range 60-70 years), 92% were smokers, 60% were oropharynx (46% of oropharynx with p16+) and 75% were stage IV. Median follow-up was 25 months in both arms. The 15-month LRC rate was 59% with cetuximab-RT and 60% with pembrolizumab-RT ]odds ratio 1.05, 95% confidence interval (CI) 0.43-2.59; P = 0.91]. There was no significant difference between arms for progression-free survival (hazard ratio 0.85, 95% CI 0.55-1.32; P = 0.47) and for overall survival (hazard ratio 0.83, 95% CI 0.49-1.40; P = 0.49). Toxicity was lower in the pembrolizumab-RT arm than in the cetuximab-RT arm: 74% versus 92% patients with at least one grade ≥3 adverse events (P = 0.006), mainly due to mucositis, radiodermatitis, and rash., Conclusion: Compared with the SOC cetuximab-RT, pembrolizumab concomitant with RT did not improve the tumor control and survival but appeared less toxic in unfit patients with LA-SCCHN., Competing Interests: Disclosure YT has an advisory/consultancy role with and has received honoraria from Merck & Co. (Kenilworth, NJ); AM reports consulting or advisory role for Merck KGaA (Darmstadt, Germany), BMS, AstraZeneca, Merck & Co. (Kenilworth, NJ); research funding from AstraZeneca. AC has an advisory/consultancy role with or has received honoraria from Sanofi Aventis, Takeda, BMS, Merck & Co. (Kenilworth, NJ), Roche, Merck KGaA, Darmstadt, Germany, AstraZeneca, Janssen, Astellas, Ipsen. XL has an advisory/consultancy role with Aquilab and Nanobiotix. AR has an advisory/consultancy role with Lilly, Merck KGaA (Darmstadt, Germany), Seagen, BMS, Astellas, Ipsen. JG has an advisory/consultancy role with Merck KGaA, Nanobiotix, Roche; is an invited speaker for Merck & Co. (Kenilworth, NJ). JBo has an advisory/consultancy role with BMS, Merck & Co. (Kenilworth, NJ), Merck KGaA (Darmstadt, Germany), AstraZeneca, Debiopharm, Roche, and Nanobiotix. All other authors have declared no conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Real-world data on cabozantinib in metastatic renal cell carcinoma (mRCC) is limited. This study (CABOREAL) reports treatment patterns and outcomes for patients treated with cabozantinib through the French Early Access Program., Patients and Methods: This multicentre (n = 26), observational, retrospective study enrolled patients with mRCC who had received ≥1 dose of cabozantinib. Overall survival (OS) was estimated using the Kaplan-Meier method; subgroups were compared using the log-rank test. A multiple Cox regression model assessed predictive factors of OS after cabozantinib initiation., Results: Four hundred and ten recruited patients started treatment between September 2016 and February 2018: the Eastern Cooperative Oncology Group Performance Status ≥2, 39.3%; poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk, 31.7%; 0-1, 2 and ≥3 previous treatment lines, 25.3%, 33.4% and 41.2%, respectively; bone metastases, 55.9%; brain metastases, 16.8%. Median (min-max) follow-up was 14.4 (0-30) months. Overall, 57.0% of patients had a dose reduction, 15.6% an alternative dose schedule. The median average daily dose was 40.0 mg. Median (quartile [Q]1-Q3) treatment duration was 7.6 (0.1-29.1) months, median OS was 14.4 months, and the 12-month OS rate was 56.5% (95% confidence interval: 51.5-61.2). Most patients (54.4%) received subsequent treatment. Predictive factors associated with longer OS were body mass index ≥25 kg/m 2 (p = 0.0021), prior nephrectomy (p = 0.0109), favourable or intermediate IMDC risk (p < 0.0001) and cabozantinib initiation at 60 mg/day (p = 0.0486)., Conclusions: In the largest real-world study to date, cabozantinib was effective in unselected, heavily pretreated patients with mRCC. Initiation at 60 mg/day was associated with improved outcomes. CLINICALTRIALS., Gov Identifier: NCT03744585., Competing Interests: Conflict of interest statement Laurence Albiges reports receiving funding from Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Exelixis, Ipsen, Merck KGaA, MSD, Novartis, Pfizer and Roche. Aude Fléchon reports receiving honoraria and travel expenses from Bristol Myers Squibb, Ipsen, MSD, Novartis, Pfizer and Roche. Christine Chevreau reports receiving honoraria from AstraZeneca, Bristol Myers Squibb, Ipsen, MSD and Pfizer. Delphine Topart reports receiving honoraria from Amgen, Astellas, Bristol Myers Squibb, Ipsen, Janssen and Pfizer. Gwenaëlle Gravis reports receiving travel expenses from Astellas, Bristol Myers Squibb, Ipsen, Janssen, Pfizer and Sanofi. Stéphane Oudard reports receiving honoraria from Bayer, Bristol Myers Squibb, Ipsen, Merck KGaA, MSD, Novartis and Pfizer. Lionnel Geoffrois reports receiving honoraria from Bristol Myers Squibb, Ipsen, Janssen, Merck KGaA and MSD. Antoine Thiery-Vuillemin's institution reports receiving funding from Pfizer. Antoine Thiery-Vuillemin reports receiving consulting fees and honoraria from Bristol Myers Squibb, Ipsen, MSD, Novartis, Pfizer and Roche. Philippe Barthélémy reports being on the advisory boards of Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer and Roche, and receiving honoraria from Astellas, EUSA Pharma and Sanofi. Sylvain Ladoire reports receiving travel, accommodation and consulting fees from Ipsen. Brigitte Laguerre reports receiving honoraria from Sanofi. Bernard Escudier reports receiving funding from Aveo, Bristol Myers Squibb, Ipsen, Novartis, Pfizer and Roche. Marine Gross-Goupil reports receiving honoraria from Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck KGaA, MSD, Novartis, Pfizer, Roche and Sanofi. Valérie Perrot and Anaïs Billard report being employees of Ipsen. Other authors declare no conflict of interest relating to the submitted work., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Fever of unknown origin is by far the most common diagnosis in low-risk febrile neutropenic patients undergoing chemotherapy. The current empirical regimen combines amoxicillin-clavulanic acid and fluoroquinolones in low-risk neutropenic patients. The aim of this study was to assess the appropriateness of antibiotherapy and the outcome of bloodstream infections (BSI) in patients with expected neutropenia of short duration., Methods: This 2-year monocentric retrospective study included all consecutive neutropenic febrile adult patients with expected duration of neutropenia ≤ 7 days. They were classified into low- and high-risk groups for complications using the MASCC index. Appropriateness of initial empirical antibiotic regimen was assessed for each BSI. Multivariate analysis was performed to identify factors associated with mortality., Results: Over the study period, 189 febrile episodes with positive blood cultures in neutropenic patients were reported, of which 44 occurred during expected duration of neutropenia ≤ 7 days. Patients were classified as high-risk (n = 27) and low-risk (n = 17). Gram-negative bacteria BSI represented 57% of cases, including only two multidrug-resistant bacteria in high-risk patients. Initial empirical antibiotherapy was appropriate in 86% of cases, and inappropriate in the event of coagulase-negative Staphylococcus BSI (14%), although the outcome was always favorable. In low-risk patients, no deaths and only 12% of severe complications were reported, contrasting with mortality and complication rates of 48% (p < 0.001) and 63% in high-risk patients (p < 0.001), respectively., Conclusions: Outcome of BSI is favorable in low-risk febrile neutropenic patients, even with inappropriate empirical initial antibiotic regimen for coagulase-negative Staphylococcus BSI. Initial in-hospital assessment and close monitoring of these patients are however mandatory.

Background: Chemotherapy increases the risk of infections, often severe, and some of them are vaccine-preventable infections. We aimed to assess vaccination coverage and associated factors in oncology and hematology patients., Methods: Consecutive adult patients followed in a French university hospital for hematological malignancy or solid cancer voluntarily completed an anonymous questionnaire in September and October 2016. It included questions on underlying disease, chemotherapy, flu, and pneumococcal vaccination uptakes, and attitudes toward vaccination. Factors associated with vaccination uptake were assessed by multivariate logistic regression., Results: The response rate was 41.9% (N=671) among 1,600 questionnaires distributed; 232 patients had underlying hematological malignancy and 439 had solid cancer. Half of the patients were aged over 65 years. Chemotherapy was ongoing or discontinued for less than one year in 74.7% of patients. In patients aged <65 years undergoing chemotherapy, flu vaccination rate was 19.9% whereas patients aged >65 years had coverage of 47%. Pneumococcal vaccine uptake was 7.3%. However, 64.7% of patients were favorable to vaccination. Vaccine uptake was associated with age >65 years (OR 4.5 [2.9-7.0]), information about vaccination delivered by the family physician (OR 12.9 [5.5-30.1]), follow-up in hematology unit (OR 2.0 [1.3-3.1]), and positive opinion about vaccination (OR 2.0 [1.3-3.1])., Conclusion: Despite specific recommendations regarding immunocompromised patients, anti-pneumococcal and flu vaccinations were rarely conducted, even in elderly patients. Targeted information campaigns to family physicians, oncologists, and patients should be implemented to improve vaccine coverage in patients with underlying malignancies., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Introduction: Management of elderly patients with cancer is challenging worldwide. Improvement of their care pathway should focus on unplanned hospitalizations. This study aimed to compare the geriatric and oncologic profiles of elderly patients with cancer, hospitalized for an acute pathology either in medical oncology or acute geriatric medicine units., Methods: Epidemiological, analytical, monocentric, transversal study performed in the geriatric and oncological short-stay units of the university hospital of Poitiers (France) from 07/01/2014 to 06/30/2015. Only patients with diagnosed cancer prior to hospitalization were included. The geriatric, oncological and hospitalization data were collected and analyzed., Results: In total, 230 patients were included (156 in geriatrics, 74 in oncology). Alteration of the general condition was the most frequent reason for admission. In multivariate age-adjusted analyses, factors associated with admission to a geriatric unit were co-morbidities (OR=0.18 [95% CI: 0.07-0.46], P<0.01) and dependence (OR=0.07 [95% CI: 0.01-0.36], P<0.01). Ongoing antineoplastic treatment (OR=2.60 [95%CI: 1.14-5.89], P=0.02) and metastatic cancer (OR=2.63 [95%CI: 1.18-5.86], P=0.02) influenced hospitalization in the oncology unit. During the hospital stay there was more frequent psychological support in oncology (OR=45.59 [95%CI: 9.79-212.23], P<0.01) and social support in Geriatrics (OR=0.13 [95% CI: 0.04-0.40], P<0.01)., Conclusion: This first comparative study showed a significant difference in profiles of elderly patients with cancer hospitalized for an acute problem, depending on the hospital unit. This finding paves the way of improvement of care pathway by formalizing links between these two departments to optimize care and referrals to the most appropriate care unit, according to patients condition, in case of unscheduled hospitalization., (Copyright © 2019 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

This study aimed to determine cancer prevalence occurring after the age of 75 in 45 French nursing homes (NH), as well as residents' characteristics and parameters associated with cancer-specific management. Descriptive retrospective study including 214 residents (mean age, 89.7 years) with cancer diagnosed after age 75. The studied parameters were sociodemographic, functional, nutritional and cognitive data; comorbidity assessment; date of tumoral diagnosis; cancer type; tumoral stage; treatment plan; multidisciplinary staff decision and oncologic follow-up. Our results showed that cancer prevalence in NH was 8.4 ± 1.1%, diagnosed before admission in 63% of cases. The most common tumoral sites were skin (26%), digestive tract and breast (18% for both); 12% had metastasis. Cognitive impairment was the most common comorbidity (42%), and 44% of the residents were highly dependent. Multivariate analysis showed that therapeutic decisions were associated with age. Older patients had less staging exploration (odd ratios [ORs], 0.90, 95% confidence interval [CI], 0.85-0.97) and underwent less cancer-specific treatment (ORs, 0.92; 95%CI, 0.86-0.99). Oncologic follow-up was more frequent in younger patients (ORs, 0.90; 95%CI, 0.81-0.99) and those with recent diagnosis (ORs, 0.37; 95%CI, 0.23-0.61). This study identified factors associated with substandard neoplastic management in elderly NH residents. It highlights needs for information, education and training in cancer detection to improve cancer consideration and care in NH., (© 2018 John Wiley & Sons Ltd.)

Purpose: Both concurrent chemoradiotherapy (CT-RT) and cetuximab radiotherapy (cetux-RT) have been established as the standard of care for the treatment of locally advanced squamous cell carcinoma of the head and neck. It was not known whether the addition of induction chemotherapy before cetux-RT could improve outcomes compared with standard of care CT-RT., Patients and Methods: The current trial was restricted to patients with nonmetastatic N2b, N2c, or N3 squamous cell carcinoma of the head and neck and fit for taxotere, cisplatin, fluorouracil (TPF). Patients were randomly assigned to receive three cycles of TPF followed by cetux-RT versus concurrent carboplatin fluorouracil and RT as recommended in National Comprehensive Cancer Network guidelines. The trial was powered to detect a hazard ratio (HR) of 0.66 in favor of TPF plus cetux-RT for progression-free survival at 2 years. The inclusion of 180 patients per arm was needed to achieve 80% power at a two-sided significance level of .05., Results: Between 2009 and 2013, 370 patients were included. All patients and tumors characteristics were well balanced between arms. There were more cases of grade 3 and 4 neutropenia in the induction arm, and the induction TPF was associated with 6.6% treatment-related deaths. With a median follow-up of 2.8 years, 2-year progression-free survival was not different between both arms (CT-RT, 0.38 v TPF + cetux-RT, 0.36; HR, 0.93 [95% CI, 0.73 to 1.20]; P = .58). HR was 0.98 (95% CI, 0.74 to 1.3; P = .90) for locoregional control and 1.12 (95% CI, 0.86 to 1.46; P = .39) for overall survival. These effects were observed regardless of p16 status. The rate of distant metastases was lower in the TPF arm (HR, 0.54 [95% CI, 0.30 to 0.99]; P = .05)., Conclusion: Induction TPF followed by cetux-RT did not improve outcomes compared with CT-RT in a population of patients with advanced cervical lymphadenopathy.

The anti-tumour and anti-metastatic properties of heparins have not been tested in patients with early stage cancer. Whether adjuvant low molecular weight heparin (LMWH) tinzaparin impacts the survival of patients with resected non-small cell lung cancer (NSCLC) was investigated.Patients with completely resected stage I, II or IIIA NSCLC were randomly allocated to receive subcutaneous tinzaparin 100 IU·kg -1 once a day for 12 weeks or no treatment in addition to standard of care. The trial was open-label with blinded central adjudication of study outcomes. The primary outcome was overall survival.In 549 patients randomised to tinzaparin (n=269) or control (n=280), mean±sd age was 61.6±8.9 years, 190 (34.6%) patients had stage II-III disease, and 220 (40.1%) patients received adjuvant chemotherapy. Median follow-up was 5.7 years. There was no significant difference in overall survival between groups (hazard ratio (HR) 1.24, 95% CI 0.92-1.68; p=0.17). There was no difference in the cumulative incidence of recurrence between groups (subdistribution HR 0.94, 95% CI 0.68-1.30; p=0.70).Adjuvant tinzaparin had no detectable impact on overall and recurrence-free survival of patients with completely resected stage I-IIIA NSCLC. These results do not support further clinical evaluation of LMWHs as anti-tumour agents., Competing Interests: Conflict of interest: G. Meyer reports grants and non-financial support from Leo Pharma, outside the submitted work. Conflict of interest: B. Besse has nothing to disclose. Conflict of interest: H. Doubre has nothing to disclose. Conflict of interest: A. Charles-Nelson has nothing to disclose. Conflict of interest: S. Aquilanti reports non-financial support from Leo Pharma, outside the submitted work. Conflict of interest: A. Izadifar has nothing to disclose. Conflict of interest: R. Azarian has nothing to disclose. Conflict of interest: I. Monnet has nothing to disclose. Conflict of interest: C. Lamour has nothing to disclose. Conflict of interest: R. Descourt has nothing to disclose. Conflict of interest: G. Oliviero has nothing to disclose. Conflict of interest: L. Taillade has nothing to disclose. Conflict of interest: C. Chouaid has nothing to disclose. Conflict of interest: F. Giraud has nothing to disclose. Conflict of interest: P-E. Falcoz has nothing to disclose. Conflict of interest: M-P. Revel has nothing to disclose. Conflict of interest: V. Westeel has nothing to disclose. Conflict of interest: A. Dixmier has nothing to disclose. Conflict of interest: J. Tredaniel has nothing to disclose. Conflict of interest: S. Dehette has nothing to disclose. Conflict of interest: C. Decroisette has nothing to disclose. Conflict of interest: A. Prevost has nothing to disclose. Conflict of interest: E. Pichon has nothing to disclose. Conflict of interest: E. Fabre has nothing to disclose. Conflict of interest: J-C. Soria has nothing to disclose. Conflict of interest: S. Friard has nothing to disclose. Conflict of interest: J-B. Stern has nothing to disclose. Conflict of interest: L. Jabot has nothing to disclose. Conflict of interest: G. Dennewald has nothing to disclose. Conflict of interest: G. Pavy has nothing to disclose. Conflict of interest: P. Petitpretz has nothing to disclose. Conflict of interest: J-M. Tourani has nothing to disclose. Conflict of interest: M. Alifano has nothing to disclose. Conflict of interest: Dr. Chatellier has nothing to disclose. Conflict of interest: P. Girard reports personal fees and non-financial support from Leo Pharma, outside the submitted work., (Copyright ©ERS 2018.)

Purpose To investigate the effect of adding concurrent chemotherapy (CT) to cetuximab plus radiotherapy (RT; CT-cetux-RT) compared with cetuximab plus RT (cetux-RT) in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Patients and Methods In this phase III randomized trial, patients with N0-2b, nonoperated, stage III or IV (nonmetastatic) LA-SCCHN were enrolled. Patients received once-daily RT up to 70 Gy with weekly cetuximab or with weekly cetuximab and concurrent carboplatin and fluorouracil (three cycles). To detect a hazard ratio (HR) of 0.64 for progression-free survival (PFS) with 85% power at a two-sided significance level of P = .05, 203 patients needed to be included in each arm. Results Four hundred six patients were randomly assigned to either CT-cetux-RT or cetux-RT. Patient and tumor characteristics were well balanced between arms, including p16 status. With a median follow-up of 4.4 years, the HR for PFS favored the CT-cetux-RT arm (HR, 0.73; 95% CI, 0.57 to 0.94; P = .015), with 3-year PFS rates of 52.3% and 40.5% and median PFS times of 37.9 and 22.4 months in the CT-cetux-RT and cetux-RT arms, respectively. The HR for locoregional control was 0.54 (95% CI, 0.38 to 0.76; P < .001) in favor of CT-cetux-RT. These benefits were observed regardless of p16 status for oropharynx carcinomas. Overall survival (HR, 0.80; P = .11) and distant metastases rates (HR, 1.19; P = .50) were not significantly different between the two arms. The CT-cetux-RT arm, compared with cetux-RT, had a higher incidence of grade 3 or 4 mucositis (73% v 61%, respectively; P = .014) and of hospitalizations for toxicity (42% v 22%, respectively; P < .001). Conclusion The addition of concurrent carboplatin and fluorouracil to cetux-RT improved PFS and locoregional control, with a nonsignificant gain in survival. To our knowledge, this is the first evidence of a clinical benefit for treatment intensification using cetux-RT as a backbone in LA-SCCHN.

Purpose: Medical doctors' (MDs), but not patients', perception of supportive care in cancer (SCC) in France has been previously assessed in a national survey. This study evaluated MDs and patients' perceptions of the SCC organization and implementation in France., Methods: The French SCC Association conducted two observational studies: study 1 (S1), containing a 30-point questionnaire sent to 2263 MDs, and study 2 (S2), containing a 40-point questionnaire sent to 2000 patients., Results: Overall, 711 MDs completed S1 and 1562 patients completed S2. In S1, 81% of MDs reported relying on a SCC organization and 76% attended SCC multidisciplinary discussions. MDs considered palliative (98%), psychological (98%), and social care (98%) as the top 3 SCC areas of importance for patients. In contrast, patients' priorities were psychology (61%), nutrition (55%) and organization of intake consultations (55%). The concept of SCC was familiar to 34% of patients; according to MDs, this concept was introduced mainly by MDs (78%) and admission nurses (41%). Outpatients identified as professional resources for SCC information general practitioners (84%), nurses (58%), and pharmacists (52%). Patients reported supportive treatment being prescribed in 63% of cases, with 64% receiving information on the negative side-effects. Among MDs, 87% reported proposing palliative and 41% adjuvant SCC treatment. Furthermore, 72% of MDs recommended SCC treatment at the metastatic stage, and 36% immediately following diagnosis., Discussion: Oncologists play a vital role in enhancing SCC efficacy. This can be increased by implementing a multidisciplinary integrated approach or by assuring the availability of patient information.

Aims: Vinflunine (VFL) ditartrate, a novel tubulin-targeted inhibitor, is registered for the treatment of patients with advanced or metastatic urothelial transitional cell carcinoma. This phase I study assessed the effect of renal impairment on the pharmacokinetics and tolerability of VFL., Methods: VFL was infused in patients with advanced/metastatic solid tumours once every 3 weeks with anticipated dose reduction on the first cycle stratified according to the creatinine clearance (CLcr ) values. Pharmacokinetic data were collected on the first two cycles in renally impaired patients (CLcr ≤ 60 ml min(-1) ) and were compared with a control cohort of patients (CLcr > 60 ml min(-1) )., Results: Thirty-three patients (46-86 years) were treated, 13 in group 1 (40 ml min(-1) ≤ CLcr ≤ 60 ml min(-1) ) and 20 in group 2 (20 ml min(-1) ≤ CLcr < 40 ml min(-1) ). The renal dysfunction induced a mean decrease in VFL clearance of 12% in group 1 and 28% in group 2, compared with the control group. The anticipated dose reduction given in renally impaired patients (i.e. 280 mg m(-2) and 250 mg m(-2) in groups 1 and 2, respectively) yielded similar drug exposure to control patients. The tolerance profile of VFL in patients with renal dysfunction was similar to that observed in patients with CLcr > 60 ml min(-1) ., Conclusion: In conclusion, the recommended doses of intravenous VFL administered once every 3 weeks in cancer patients with renal impairment are 280 mg m(-2) when CLcr is between 40 and 60 ml min(-1) and 250 mg m(-2) when CLcr is between 20 and <40 ml min(-1) ., (© 2013 The British Pharmacological Society.)

Background: Erlotinib, the epidermal growth factor receptor tyrosine kinase inhibitor, and the intra-venous vinflunine vinca alkaloid microtubule inhibitor have been shown to be effective in the setting of non-small-cell lung cancer (NSCLC) palliative patients with acceptable toxicities. This phase I study was conducted to determine the maximal tolerated dose (MTD) and the safety of an all-oral combination. A potential pharmacokinetic drug-drug interaction was also investigated., Patients and Methods: Patients with unresectable stage IIIB or stage IV NSCLC who failed one or two previous chemotherapy regimens were treated with flat doses of oral vinflunine from day 1 to day 5 and from day 8 to day 12 every 3 weeks and erlotinib daily on a continuous basis. The dose levels of vinflunine/erlotinib were 95/100, 115/100, 115/150 and 135/100 mg., Results: Thirty patients were enroled. The recommended dose was 115/150 mg and the MTD 135/100 mg. Dose-limiting toxicities included grade 3 febrile neutropenia (1 patient) and related death (1 patient). Non-haematologic grade 3/4 toxicities included fatigue, condition aggravated, hypokalaemia, tumour pain, acneiform dermatitis, diarrhoea, hyperbilirubinaemia and pulmonary haemorrhage, in one patient each. Of 25 patients evaluable for tumour response, 2 patients had partial response and 20 patients had stable disease., Conclusion: The recommended doses for oral vinflunine and erlotinib combination were, respectively, 115 mg/day from day 1 to day 5 and from day 8 to day 12 every 3 weeks and 150 mg/day. There was no mutual impact on pharmacokinetics. The combination was safe but evaluation in phase II is needed to further refine the activity and toxicity that can be expected with prolonged administration of this dose schedule.

It is now well established that metastatic colorectal cancer patients without KRAS mutation (codon 12) benefit from treatment with an epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb). Recently, EFGR and KRAS mutations have been shown to exist in patients who developed resistance to anti-EGFR mAb. We analyzed KRAS, BRAF V600E and EGFR S492R mutations in 37 post-anti-EGFR mAb tumor samples from 23 patients treated with chemotherapy plus anti-EGFR mAb. No EGFR S492R mutation was detected. A KRAS mutation was found after anti-EGFR mAb in only one tumor. Our results suggest that acquired EGFR S492R and KRAS mutations do not constitute the main mechanism of resistance to anti-EGFR mAb in combination with chemotherapy.

Background: Only patients with wild-type (WT) KRAS tumors benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (Mabs) in metastatic colorectal cancer (mCRC). Pyrosequencing is now widely used for the determination of KRAS mutation burden and a conservative cut-off point of 10% has been defined. Up until now, the impact of low-frequency KRAS mutations (<10%) on the response to anti-EGFR Mabs has yet to be evaluated., Patients and Methods: Tumors from patients receiving anti-EGFR Mabs based on a WT genotype for KRAS, as determined using direct sequencing, have been retrospectively analyzed by pyrosequencing. Patients were categorized as WT (no KRAS mutation) or low-frequency mutation when KRAS mutation was <10% (KRAS low MT)., Results: A total of 168 patients treated by anti-EGFR Mabs for mCRC were analyzed. According to pyrosequencing, 138 tumors remained KRAS WT, while 30 tumors were KRAS low MT. In the KRAS low MT and KRAS WT groups, the response rates were 6.7% and 37.0%, respectively, while stabilization amounted to 23.3% versus 32.6% and progression to 70% versus 29% (P < 0.01). Progression-free survival (PFS) was 2.7 ± 0.5 months for KRAS low MT and was 6.0 ± 0.3 months for KRAS WT (P < 0.01)., Conclusions: These results appear to validate consideration of low-frequency KRAS mutation tumors as positive, and justify a large-scale prospective study.

Purpose: This is a phase I, escalating-dose trial targeting exclusively patients with non-small cell lung cancer (NSCLC), investigating pemetrexed and fixed-dose cisplatin concurrently administered with high-dose radiotherapy (RT) after induction chemotherapy (CT). Primary objective was to determine the maximum tolerated dose and recommended phase II dose of pemetrexed., Patients and Materials: Patients with unresected stage III NSCLC, planned V20 ≤ 35%, and FEV ≥ 1.3 L, were treated every 21 days for 2 cycles (pemetrexed 500 mg/m2; cisplatin 75 mg/m2), followed by 2 cycles of concurrent CT-RT: pemetrexed starting dose was 400 mg/m2, escalated up to 800 mg/m2 per 100mg/m2 dose level (DL), cisplatin at 75 mg/m2 and RT at fixed dose of 66 Gy/33 fractions., Results: Nine of 10 enrolled patients (age range 46-68 years; 6 men; ECOG PS 0 [6 patients], PS 1 [4]; stage IIIA [1], IIIB [9]; 6 adenocarcinomas, 3 squamous cell carcinomas, 1 large cell carcinoma) were entered on 3 DLs. Dose escalation of pemetrexed was conducted up to 600 mg/m2 based on the independent safety monitoring board recommendation. One dose-limiting toxicity occurred at DL3: Grade 4 septic shock. Grade 3 related toxicities: 2 neutropenia at DL3, 2 lymphopenia per DL (3 recurrent), 2 leukopenia (1 recurrent) at DL3, 1 gastric pain (DL3), 1 nausea and 1 recurrent vomiting (DL2). No Grade 3/4 radiation-related toxicities were observed. No toxic death was observed. Disease control rate was 77.7% (1 CR, 4 PR, 2 SD). One-year survival rate was 90%., Conclusions: This phase I report of pemetrexed is dedicated to NSCLC with induction therapy and fixed high-dose RT. Pemetrexed at 500 mg/m2, concurrently given with cisplatin and RT was well tolerated and appears to be the only third-generation agent that can likely be recommended safely at full dose in future trials with concurrent RT., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: There are no validated markers that predict response in metastatic renal cell cancer (RCC) patients treated with sunitinib. We aim to study the impact of single-nucleotide polymorphisms (SNPs) that have recently been proposed as predictors of outcome to anti-VEGF-targeted therapy in metastatic RCC in an independent cohort of patients., Methods: We genotyped 16 key SNPs in 10 genes involved in sunitinib pharmacokinetics, pharmacodynamics and VEGF-independent angiogenesis in patients with metastatic clear-cell RCC treated with sunitinib as the first-line targeted therapy. Association between SNPs, progression-free survival (PFS) and overall survival (OS) were studied by multivariate Cox regression using relevant clinical factors associated with PFS and OS as covariates., Results: In a series of 88 patients, both PFS and OS were associated significantly with SNP rs1128503 in ABCB1 (P=0.027 and P=0.025), rs4073054 in NR1/3 (P=0.025 and P=0.035) and rs307821 in VEGFR3 (P=0.032 and P=0.011). Progression-free survival alone was associated with rs2981582 in FGFR2 (P=0.031) and rs2276707 in NR1/2 (P=0.047), whereas OS alone was associated with rs2307424 in NR1/3 (P=0.048) and rs307826 in VEGFR3 (P=0.013)., Conclusion: Our results confirm former communications regarding the association between SNPs in ABCB1, NR1/2, NR1/3 and VEGFR3 and sunitinib outcome in clear-cell RCC. Prospective validation of these SNPs is now required.

Purpose: To compare the efficacy and safety of induction chemotherapy (ICT) followed by chemoradiotherapy (CRT) or bioradiotherapy (BRT) for larynx preservation (LP)., Patients and Methods: Previously untreated patients with stage III to IV larynx/hypopharynx squamous cell carcinoma received three cycles of ICT-docetaxel and cisplatin 75 mg/m(2) each on day 1 and fluorouracil 750 mg/m(2) per day on days 1 through 5. Poor responders (< 50% response) underwent salvage surgery. Responders (≥ 50% response) were randomly assigned to conventional radiotherapy (RT; 70 Gy) with concurrent cisplatin 100 mg/m(2) per day on days 1, 22, and 43 of RT (arm A) or concurrent cetuximab 400 mg/m(2) loading dose and 250 mg/m(2) per week during RT (arm B). Primary end point was LP at 3 months. Secondary end points were larynx function preservation (LFP) and overall survival (OS) at 18 months., Results: Of the 153 enrolled patients, 116 were randomly assigned after ICT (60, arm A; 56, arm B). Overall toxicity of both CRT and BRT was substantial following ICT. However, treatment compliance was higher in the BRT arm. In an intent-to-treat analysis, there was no significant difference in LP at 3 months between arms A and B (95% and 93%, respectively), LFP (87% and 82%, respectively), and OS at 18 months (92% and 89%, respectively). There were fewer local treatment failures in arm A than in arm B; salvage surgery was feasible in arm B only., Conclusion: There is no evidence that one treatment was superior to the other or could improve the outcome reported with ICT followed by RT alone (French Groupe Oncologie Radiothérapie Tête et Cou [GORTEC] 2000-01 trial [Induction CT by Cisplatin, 5FU With or Without Docetaxel in Patients With T3 and T4 Larynx and Hypopharynx Carcinoma]). The protocol that can best compare with RT alone after ICT is still to be determined.

Purpose: Vinflunine ditartrate is a microtubule inhibitor belonging to the vinca alkaloid family. This phase I study was carried out to evaluate the maximal tolerated dose, the safety profile, the pharmacokinetics and the activity of oral vinflunine (VFL) given daily in patients with advanced/metastatic solid tumours and who have failed standard therapy., Methods: Patients were treated with oral VFL administered once daily for 6 weeks followed by a two-week rest. Sequential dose-escalating cohorts of patients were enrolled into 5 dose levels: 20, 40, 60, 75 and 95 mg/day., Results: In total, 27 patients received 53 cycles. Dose-limiting toxicities (DLT) were observed from 60 mg/day. The dose levels 75 and 95 mg/day were both assessed as maximal tolerated dose. The most frequent dose-limiting toxicities were of haematological origin. The recommended dose was defined as 60 mg/day, dose at which 4 patients experienced long stabilizations (≥4 months) and also received longer treatment duration in comparison with the other dose levels. Blood exposure of VFL and its active metabolite 4-O-deacetyl vinflunine (DVFL) increased proportionally to the dose levels. The concentrations of VFL and DVFL reached a steady state at, respectively, 5 and 20 days and remained stable for the rest of the cycle. Increased incidence of DLT/SAE was consistent with the increase of VFL dose and drug exposure., Conclusions: These results showed the feasibility of daily oral vinflunine administration on a 6-week treatment duration. This new schedule of administrations enabled sustained and stable blood concentrations of both VFL and DVFL. The recommended dose was defined at 60 mg/day, dose at which 4 patients experienced clinical benefit.

Background: Supportive care in cancer (SCC) was further enhanced in the Second National Cancer Act decreed in December 2009. The aim of our study was to assess current SCC efficacy., Patients and Methods: The French speaking association for supportive care in cancer (AFSOS) conducted an observational study to evaluate practices, organisations and information given to patients. A specific 32 point questionnaire was sent to 1621 French physicians (MDs) caring for cancer patients., Results: Three different organisations were evaluated: the individual MDs, the transversal team and its particular structure specialised in global patient care specifically developed at comprehensive cancer centres - CCC. During their disease, 68% of patients received SCC, which was more available during the palliative period (90%) than at the diagnosis (44%). Our results found that 71% of cancer departments had a specific interdisciplinary cross-team to provide SCC, particularly in CCC (62%; p=0.01) while 37% had specific inpatient units. A specific organisation dedicated to home care was greater in CCC than in public or private centres (69%, 45%, 20% respectively; p=0.01). Adverse event information was performed more by an oncologist than other specialists (p=0.01)., Conclusion: Our results suggest that the specific SCC organisation could be a useful management tool to improve supportive care for cancer patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Vinflunine (VFL) (Javlor(®)), a novel fluorinated semisynthetic vinca alkaloid has shown significant antitumor activity in advanced non-small cell lung cancer (NSCLC). We propose to define the recommended dose (RD) of VFL in combination with carboplatin in advanced NSCLC patients., Methods: This phase I and pharmacokinetic study was designed to determine the maximum tolerated dose and to establish the RD of VFL in combination with carboplatin. Twenty-one chemonaive patients with advanced NSCLC were treated with a first-line chemotherapy of VFL and carboplatin both given on day 1 every 3 weeks with 3 dose levels., Results: Five patients experienced a dose limiting toxicity consisting of constipation in 2 patients and febrile neutropenia in 2 patients. One patient experienced grade 3 abdominal pain concurrent with grade 4 neutropenia. The combination of VFL (320 mg/m(2)) and carboplatin AUC6 was defined as the maximum tolerated dose. The RD was established at the dose of VFL (320 mg/m(2)) combined with carboplatin AUC5. At the RD, 12 patients received a median number of 3 cycles of the combination. Neither VFL nor carboplatin seemed to be influencing the pharmacokinetics of the other. Among 19 patients evaluable for tumor response, 7 had a partial response and 7 experienced stable disease., Conclusions: The combination of VFL (320 mg/m(2)) and carboplatin AUC 5 given once every 3 weeks is established as the RD of the combination, which was shown to be active in these chemonaive NSCLC patients.

Background: The risks of chemoradiotherapy in elderly patients with rectal cancer have not yet been well-characterised., Methods: We retrospectively reviewed the charts of patients with rectal cancer over 70 years old who were treated with chemoradiotherapy in two French university hospitals., Results: A total of 125 patients were evaluated. Mean age was 75.1 ± 4.1 years and ranged from 70 to 90 years. Adverse effects ≥ grade 2 were observed in 32% of the patients and adverse effects ≥ grade 3 in 15%. Dose reduction for toxicity was performed in 18% of the patients and chemoradiotherapy discontinuation was necessary in 9%. Postoperative morbidity was 16% with two treatment-related deaths. Two-year survival rate was 84%. No variables had any influence on treatment-related adverse events., Conclusions: In selected elderly patients, chemoradiotherapy is well-tolerated, without any significant increase in adverse events, and the results are similar to those recorded in younger patients., (Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Glioblastoma (GBM) is the most malignant type of primary brain tumor with a very poor prognosis. The actual standard protocol of treatment for GBM patients consists of radiotherapy and concomitant temozolomide (TMZ). However, the therapeutic efficacy of this treatment is limited due to tumor recurrence and TMZ resistance. Recently isolated, glioma stem-like cells (GSCs) are thought to represent the population of tumorigenic cells responsible for GBM resistance and recurrence following surgery and chemotherapy. In addition, MGMT (O6-methylguanine-methyltransferase) methylation is considered as one of the principal mechanisms contributing to TMZ sensitivity of GBM. In this study we have isolated GSCs from 10 adult GBM patients and investigated the relationship between MGMT methylation status and Temozolomide (TMZ) sensitivity of these lines grown either in stem-like or differentiation promoting conditions. Sensitivity to TMZ was significantly associated with MGMT methylation status in cells committed to differentiation but not in stem-like cells. In addition, patients harboring highly methylated MGMT promoters had a longer overall survival. These results reveal the importance of the differentiation process when considering the predictive value of MGMT status in GSCs for clinical response to TMZ.

Glioblastoma (GBM), the highest-grade form of gliomas, is the most frequent and the most aggressive. Recently, a subpopulation of cells with stem cells characteristics, commonly named "tumor-initiating stem cells" (TISCs) or "cancer stem cells" (CSCs) were identified in GBM. These cells were shown to be highly resistant to chemotherapeutic drugs and to ionizing radiations. Consequently, the knowledge of the signals that regulate the functions and survival of TISCs is crucial. In our work, we describe a neurosphere-initiating cell (NS-IC) assay to quantify TISC/CSCs from patients with GBM and show that these cells are tumorigenic in vivo. We demonstrate that the intracellular signal transducer and activator of transcription STAT3 is constitutively activated by phosphorylation preferentially on serine 727 in these cells. Moreover, we demonstrate that the selective inhibition of STAT3 by the chemical compound Stattic or by siRNA STAT3 abrogates TISC/CSC proliferation and NS-IC suggesting that self-renewal of GBM "stem-like" cells depends on the presence of STAT3 for their maintenance. Finally, we show that inhibition of STAT3 by Stattic sensitizes TISC/CSCs to the inhibitory action of Temozolomide with a strong synergistic effect of both drugs. Overall, these results suggest that strategies focused on STAT3 inhibition are efficient at the level of "stem-like" cells and could be of interest for therapeutic purposes in patients with malignant GBM., (Copyright © 2010 UICC.)

Temozolomide (TMZ) is a second-generation alkylating agent that has recently shown some efficacy in stage IV melanoma. The purpose of this study was to test the efficacy and safety of combination therapy with TMZ and cisplatin (CDDP) in patients with metastatic melanoma. Chemo-naive patients with metastatic cutaneous melanoma were included in a phase II study of combined therapy with TMZ (200 mg/m/day), days 1-5, and CDDP (75 mg/m/day) on day 1. The treatment was given every 28 days, for up to six cycles. The primary endpoint was the overall response rate and the secondary endpoints were progression-free survival, probability of survival, and tolerance. Thirty patients were enrolled into this study. Median age was 59 years. A total of 126 cycles were administered. Grade 3 and 4 hematological toxicity was observed in 14 patients (46.6%) and clinical toxicity in seven patients (23.3%). No complete response was observed among the 30 included patients. Five patients (16.7%) achieved a partial response. An additional six patients (20%) showed disease stabilization and 17 patients (56.6%) revealed progressive disease. Median survival and median response duration were 8 and 7.2 months, respectively. One- and 2-year survivals were 36.7 and 13.3%. One- and 2-year progression-free survivals were 13.3 and 3.3%. Our results suggest that concurrent adjunction of CDDP to TMZ regimen increases toxicity according to this schedule and does not improve the outcome of stage IV melanoma. The objective response rate is close to response rates observed with single-agent chemotherapy.

Purpose: The aim of this study was to assess clinical, laboratory, and subjective (patient's preferences) prognostic factors in hospitalized patients with advanced solid tumors., Patients and Methods: This prospective study surveyed 177 patients from two French hospitals who had not reached the stage of active dying but had an estimated survival of less than 6 months (median survival, 58 days)., Results: Univariate analysis showed that 10 of the 13 clinical and laboratory factors reported in the literature affected survival at 2 months. Poor prognostic factors were number of metastatic sites, cerebral metastasis, low Karnofsky index, dyspnea at rest, anorexia, edema, confusion, low serum albumin, extremely high leukocyte counts, and high lactate dehydrogenase (LDH) levels. The patient's desire to continue curative treatment was also associated with survival. The multivariate analysis selected four independent criteria: Karnofsky index (in three classes: or= 70%), number of metastatic sites (>or= two or < two), low serum albumin (in three classes: or= 33 g/L), and LDH concentration (>or= 600 IU or < 600 IU). The combination of these four criteria assessed prognosis better than the Karnofsky index alone, producing three prognostic profiles: one with short survival (< 2 months: no patient survived to 4 months); one with an expectation of intermediate survival (25% were alive at 4 months), and a final group surviving for several months (80% were alive at 4 months)., Conclusion: The prognostic profiles defined by combinations of these four factors may be potentially useful but need further validation before their application in the daily practice.

Background: Onycholysis occurs in approximately 30% of patients treated with docetaxel. The efficacy and safety of an Elasto-Gel frozen sock (FS) was investigated for the prevention of docetaxel-induced nail and skin toxicity of the feet., Methods: Patients receiving docetaxel at a dose of 70 to 100 mg/m(2) every 3 weeks were eligible for this matched case-control study. Each patient wore an FS for 90 minutes on the right foot. The unprotected left foot acted as control. Nail and skin toxicities were assessed using National Cancer Institute Common Toxicity Criteria (version 3) and compared using a 2-sample Wilcoxon matched-pairs rank test adjusted for tied values., Results: Fifty consecutive patients were included between April 2005 and January 2007. Nail toxicity was significantly lower in the FS-protected foot compared with the control foot (grade 0: 100% versus 79%; and grade 1 and 2: 0% versus 21%, respectively) (P= .002). Skin toxicity was grade 0: 98% versus 94%; and grade 1 and 2: 2% versus 6% in the FS-protected and the control feet, respectively. The median times until toxicity occurrence were not found to differ significantly between the groups. One patient experienced discomfort because of cold intolerance., Conclusions: Cold therapy using FS significantly reduced the incidence of docetaxel-induced foot nail toxicity, as previously demonstrated using frozen gloves for the hands.

Two studies were carried out to evaluate heat-killed Mycobacterium vaccae SRL172 as an immunotherapeutic agent for patients with metastatic, post-nephrectomy, renal cell carcinoma. In the first study, 60 patients in France and the UK received injections of SRL172, and their survival was compared with that of historical controls who had been treated either with biological response modifiers (IL-2, IFN-alpha) or chemotherapy. In the second study, 36 patients were randomised to receive treatment with IL-2 alone or IL-2 plus SRL172. Survival and adverse events related to the treatments were assessed and compared between treatment groups. The first study showed that those treated with SRL172 alone survived equally as long as those receiving IL-2 or IFN-alpha and both treatment groups survived longer than those on chemotherapy (p<0.001), a result supported by Cox's proportional hazards regression analysis. The second study, stopped early due to drug supply issues, showed that the addition of SRL172 to IL-2 made no difference to survival compared to IL-2 alone, in the limited numbers treated. Adverse events occurring in those receiving SRL172 in the first study were mild and in the second study those receiving IL-2 alone had significantly more adverse events than those receiving SRL172 plus IL-2 (p<0.001). It is concluded that SRL172 may have activity in metastatic renal cancer and has very low toxicity, making it worthy of further study.

Objectives: To assess in a phase II open multicentre study the efficacy and tolerance of docetaxel administered every 14 days combined with celecoxib, in patients with hormone-refractory prostate cancer (HRPC), and to test the hypothesis that this therapeutic combination would improve overall survival., Patients and Methods: In all, 48 patients were included with a mean age of 70.4 years and Gleason score of 7.5, all had a satisfactory Karnofsky performance-status score of 92% and a metastatic bone site was measurable in 77%. The mean delay between initial diagnosis and docetaxel administration was 45 months, with a median PSA level increase of 54.8 ng/mL. The therapeutic schedule was: docetaxel (50 mg/m(2)) administered every 14 days (one cycle of two injections at 2 week intervals (Day 1 = Day 28) with a total of six cycles) and simultaneously a daily oral fixed dose of celecoxib (800 mg)., Results: In all, 237 cycles of docetaxel were administered with a dose reduction in 23 patients at the beginning of a cycle (day 1) and 36 in the middle of a cycle (day 14). The haematological toxicity included anaemia grade 1-2 (78%) and only 10% neutropenia grade 3-4. However, there was only a 15% improvement of pain intensity. The response rate for the total PSA level was 45.5 (30.4-61.1)%, the mean time to progression was 9.3 months and the tumour-response rate was 26.3%. In all, 75% of patients had an overall survival of >14.6 months., Conclusion: Our results confirm the usefulness of docetaxel for HRPC treatment and show a significant reduction of haematological toxicity with bi-weekly docetaxel administration combined with celecoxib.

Objectives: This phase II study was conducted to assess the efficacy of docetaxel plus gemcitabine in locally recurrent and/or metastatic squamous cell carcinoma of the head and neck., Patients and Methods: Forty patients with pharynx or larynx cancer were included and treated with an intravenous infusion of docetaxel 75 mg/m2 on day 8 and gemcitabine 1000 mg/m2 day 1 and day 8 every 3 weeks for 6 cycles., Results: Among the 40 patients included, 17 had metastatic disease and 18 had received prior chemotherapy. Thirty-two patients were assessable for response. The overall response rate was 20.0% (95% confidence interval [CI], 9.0%-35.7%), with 8 (20.0%) partial responses. Thirteen patients (32.5%) had stable disease, whereas 11 patients (27.5%) had progressive disease. The median response duration was 6.5 months (95% CI, 5.8-7.2). Grade 3 or 4 neutropenia was observed in 18 patients (45.0%). Three treatment-related deaths due to infection were reported., Conclusion: The docetaxel and gemcitabine combination is an active treatment of recurrent or metastatic head and neck cancer. However, this regimen is associated with a high hematologic toxicity. A new schedule of administration must be explored.

CDKN2A locus on chromosome 9p21 encodes two tumour suppressor proteins pl6INK4A, which is a regulator of the retinoblastoma (RB) protein, and p14ARF, which is involved in the ARF-Mdm2-p53 pathway. The aim of this study was to determine if CDKN2A gene products are implicated in differentiated thyroid carcinogenesis and progression. We used real-time quantitative RT-PCR and immunohistochemistry to assess both transcripts and proteins levels in 60 tumours specimens. Overexpression of p14ARF and pl6INK4A was observed in follicular adenomas, follicular carcinomas and papillary carcinomas, while downregulation was found in oncocytic adenomas compared to nontumoral paired thyroid tissues. These deregulations were statistically significant for pl6INK4a (P=0.006) in follicular adenomas and close to statistical significance for p14ARF in follicular adenomas (P=0.06) and in papillary carcinomas (P=0.05). In all histological types, except papillary carcinomas, we observed a statistically significant relationship between p14ARF and E2F1 (r=0.64 to 1, P<0.05). Our data are consistent with involvement of CDKN2A transcript upregulation in thyroid follicular tumorigenesis as an early event. However, these deregulations do not appear to be correlated to the clinical outcome and they could not be used as potential prognostic markers.

Objectives: We have carried out a phase II study to evaluate the efficacy and the toxicity associated with the combination of gemcitabine, ifosfamide, and cisplatin (GIP) in chemotherapy-naive patients with advanced nonsmall cell lung cancer (NSCLC)., Methods: Each cycle consisted of treatment with ifosfamide (3000 mg/m2) and gemcitabine (1500 mg/m2) on day 1, followed by cisplatin (100 mg/m2) and gemcitabine (1500 mg/m2) on day 15. Each treatment cycle was repeated every 28 days. A maximum of 6 cycles were administered., Results: Sixty NSCLC patients (23 stage III and 37 stage IV) were entered in this study. The median survival for all patients is 9 months (stage III: 12.3 months; stage IV: 7.5 months). The overall survival at 1 and 2 years is 38% and 17%, respectively (52% and 30% for stage III; 30% and 8% for stage IV). The median time to progression is 6.3 months (stage III: 8.8 months; stage IV: 3.6 months). Progression free survival at 1 and 2 years for all patients is 22% and 8%. The response rate is 56% for patients with stage III disease and 27% for patients with stage IV disease. Among the grade 3/4 toxicities, hematological toxicity was the most frequent (59% of patients) followed by gastrointestinal toxicity (nausea/vomiting) in 21% of patients., Conclusion: The GIP combination yields an efficacy, in terms of response and survival, comparable to that reported with other triplet combination treatments for local advanced or metastatic NSCLC, with an acceptable toxicity profile.

Objectives: To determine the dose limiting toxicity, the maximum tolerated dose and the recommended dose of pegylated liposomal doxorubicin (PLD) in association with a fixed dose of ifosfamide (IFO) to patients with recurrent, advanced ovarian cancer (AOC)., Methods: Patients with progressing platinum-sensitive or resistant disease were included in 5 dose levels consisting of PLD (25 mg/m2 to 45 mg/m2, day 1) combined with a fixed IFO dose administered as a continuous infusion (1700 mg/m2/d, day 1 to 3) to define the MTD on the basis of acute toxicity during the first 2 cycles, then confirm the MTD, by the evaluation of delayed toxicity (hand-foot syndrome)., Results: Forty-eight patients were treated. The MTD was determined in the first 29 patients to be dose level V (45 mg/m2), with 2 cases of febrile neutropenia. The recommended dose (level IV) combines 40 mg/m2 PLD on day 1 and 1700 mg/m2/d IFO day 1 to day 3. The principal toxicity was hematotoxicity (grade 3-4 neutropenia 61.8% of patients, grade 3/4 thrombcytopenia 7.2%, and grade 3/4 anemia 21.8%). Nonhematological toxicity essentially consisted of grade 3/4 nausea and vomiting (14%). Nineteen additional patients were included in levels III (11 patients) and IV (8 patients), to evaluate late-onset toxicity. No hand-foot syndrome was observed in the 48 treated patients, confirming the identification of dose level IV as recommended dose., Conclusion: This study regimen presents an acceptable tolerance. The preliminary assessment of efficacy merits confirmation in a phase II study.

Objectives: Pegylated liposomal doxorubicin (PLD) appears to be as active as doxorubicin in first-line metastatic breast cancer (MBC) patients, with lower cardiac toxicity. This phase I-II trial aimed to determine the dose limiting toxicity (DLT) and recommended dose (RD) of a first-line combination of PLD and weekly paclitaxel., Methods: MBC patients received PLD on day 1, administered over 60 minutes IV. (starting dose 30 mg/m2, escalation by 5 mg/m2 increments), and paclitaxel on days 1, 8, and 15. Initially (schedule A), paclitaxel was administered over 60 minutes (starting dose 80 mg/m2, 10 mg/m2 increments), then (schedule B) over 24 hours on day 1 (at a dose of 70 mg/m2, 10 mg/m2 increments), and in a 60 minute IV infusion at a fixed dose of 90 mg/m2 on days 8 and 15. Pharmacokinetics were assessed during cycle 1 in schedule B., Results: Thirty patients were treated (schedules A = 9; B = 21). Because of cutaneomucous toxicities in all patients in schedule A with discontinuation in 5 patients, schedule B was explored. Two DLTs (febrile neutropenia) occurred, with PLD 35 mg/m2 with paclitaxel 80 mg/m2 day 1 and 90 mg/m2 days 8 and 15 identified as recommended dose. Pharmacokinetic evaluation revealed an interaction, with increased levels of free doxorubicin and PLD during the paclitaxel infusion., Conclusions: This combination according to schedule and dosages results in cutaneomucous and hematological toxicity, probably because of a pharmacokinetic interaction, which is poorly compatible with a good quality of life for MBC patients.

A multicentre, single-arm, phase II trial designed to determine the efficacy of single-agent vinflunine in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with a platinum-based regimen. The objectives were to assess efficacy in terms of tumour response rate (primary end point), duration of response, progression-free survival (PFS) and overall survival (OS), and to evaluate the toxicity associated with this treatment. Patients with advanced NSCLC with progressive disease having failed prior platinum-based first-line treatment for advanced disease. Five responses out of the 63 treated patients were documented by WHO criteria and validated by an independent panel review (IRP), yielding a response rate of 7.9% (95% CI: 2.6-17.6) in the intent-to-treat analysis and 8.3% (95% CI: 2.8-18.4) in the evaluable population. Disease control was achieved in 35 out of 60 evaluable patients (58.3%). The median duration of response (complete response+partial response), according to modified WHO criteria was 7.8 months (95% CI: 4.6-NR). Median PFS was 2.6 months (95% CI: 1.4-3.8), and the median survival was 7.0 months (95% CI: 5.8-9.2). Grades 3-4 neutropenia was reported in 50% of patients; febrile neutropenia was observed in two patients (3.2%); grades 3-4 myalgia and grade 3 constipation were experienced by 10 (15.9%) and six (9.5%) of patients, respectively. Constipation was manageable, non-cumulative and could be prevented with laxative prophylaxis. The encouraging results from this phase II study with vinflunine warrant further investigations in phase III trials as second- or first-line treatment of advanced non-small-cell lung carcinoma, as a single agent or in combination with other active drugs.

Aim: This study was aimed to determine p73 status in thyroid tumours., Methods: Differential expression of the TAp73, DeltaTAp73 transcripts was measured in a panel of 60 thyroid malignancies by quantitative RT-PCR., Results: By comparison to normal thyroid tissue surrounding the tumours, we observed significant downregulation of TP73 transcripts in adenomas and in differentiated carcinomas. Correlations were found in normal tissue specimens between the expression of TAp73 and DeltaNp73 transcripts and that of p53, p14ARF p16INK4a, but these correlations were lost in carcinomas (PTC or FTC)., Conclusions: We have found significant variations of TAp73, DeltaNp73, p53, p14ARF p16INK4a, expressions and correlations between the expressions of those different genes in thyroid cancer.

Purpose: Onycholysis and skin toxicity occur in approximately 30% of patients treated with docetaxel. We investigated the efficacy and safety of an Elasto-Gel (84400 APT Cedex, Akromed, France) frozen glove (FG) for the prevention of docetaxel-induced onycholysis and skin toxicity., Patients and Methods: Patients receiving docetaxel 75 mg/m2 alone or in combination chemotherapy were eligible for this case-control study. Each patient wore an FG for a total of 90 minutes on the right hand. The left hand was not protected and acted as the control. Onycholysis and skin toxicity were assessed at each cycle by National Cancer Institute Common Toxicity Criteria and documented by photography. Wilcoxon matched-pairs rank test was used., Results: Between August 2002 and September 2003, 45 patients were evaluated. Onycholysis and skin toxicity were significantly lower in the FG-protected hand compared with the control hand (P = .0001). Onycholysis was grade (G) 0 in 89% v 49% and G1 to 2 in 11% v 51% for the FG-protected hand and the control hand, respectively. Skin toxicity was G0 in 73% v 41% and G1 to 2 in 27% v 59% for the FG-protected and the control hand, respectively. Median time to nail and skin toxicity occurrence was not significantly different between the FG-protected and the control hand, respectively (106 v 58 days for nail toxicity; 57 v 58 days for skin toxicity). Five patients (11%) experienced discomfort due to cold intolerance., Conclusion: FG significantly reduces the nail and skin toxicity associated with docetaxel and provides a new tool in supportive care management to improve a patient's quality of life.

The purpose of this phase I study was to determine the pharmacokinetics and toxicity of gemcitabine in patients with advanced, recurrent, and/or metastatic cancer and renal impairment. Patients were entered in 4 groups estimated by EDTA-Cr plasma clearance (CLp, mL/min): > or =80; > or =60 and <80; > or =30 and <60; and > or =30 and <80 plus renal insufficiency induced by previous chemotherapy, respectively. Gemcitabine 500 to 1000 mg/m was administered intravenously on days 1, 8, and 15 every 4 weeks. Plasma concentration data were pooled and analyzed using a population pharmacokinetic program (NONMEM). Eighteen white patients (14 females, 4 males) entered the study with a median age of 55 years. Linear regression analyses revealed no significant relationship between gemcitabine CLp and indices of renal impairment (EDTA-Cr CL; p = 0.797 or beta2-microglobulin; p = 0.153). Hematologic and nonhematologic toxicities were mild. Thus, there seems to be no significant impact of mild to moderate renal insufficiency on gemcitabine pharmacokinetics in patients with advanced cancer.

A retrospective analysis was conducted on data from four open-label, nonrandomised, phase II trials of recombinant interleukin-2 (rIL-2) in patients with metastatic renal cell carcinoma to compare the safety and efficacy of administration by subcutaneous (s.c.) and continuous intravenous (c.i.v.) infusion (n=103 s.c. and n=225 c.i.v.). No statistically significant differences were found between the cohorts in terms of overall response rate (s.c.: 13.6% vs c.i.v.: 12.4%, P=0.77), response duration (s.c.: 9.8 months vs c.i.v.: 10.1 months, P=0.99), and overall survival (P=0.08). Compared with c.i.v. administration, more patients in the s.c. cohort experienced stable disease (50.5 vs 29.8%) and fewer underwent disease progression (35.0 vs 43.6%). Subcutaneous administration was associated with a significantly lower incidence of grade 3 or 4 adverse events (46 vs 76%; P<0.001), and fewer s.c. patients required dose reductions because of toxicity (20 vs 82%). At the doses and within the schedules tested, this comparative analysis did not detect any difference in efficacy between s.c. and c.i.v. administration of rIL-2 in terms of overall survival, duration of response and response rate in patients with metastatic renal cell carcinoma. However, s.c. delivery of rIL-2 was associated with improved tolerability.

Gemcitabine (G) and cisplatin (P) are active reference agents in patients with non-small-cell lung cancer (NSCLC). Ifosfamide (I) has also been approved for NSCLC treatment. This phase I trial aimed to determine the dose-limiting toxicity (DLT), maximum tolerated dose [maximum tolerated dosage (MTD)], and recommended dose (RD) of a GIP combination in patients with advanced/metastatic NSCLC. In this study, one cycle of chemotherapy combined the following: ifosfamide: 3 g/m2 fixed dose (24-hour intravenous infusion) combined with mesna, day 1; gemcitabine: starting dose 1,000 mg/m2/d, escalating by 250 mg/m2 increments, days 1 and 15; cisplatin: starting dose 80 mg/m2, subsequently 100 mg/m2, day 15; in cohorts of at least 3 patients. Cycles were repeated every 28 days and no hematopoietic growth factors were administered. DLT was evaluated after the first chemotherapy cycle. Thirty-three patients (30 men, 3 women) with stage III (14 patients)/IV (19 patients) NSCLC were treated at eight dose levels, receiving 109 cycles of chemotherapy. Neutropenia was the only DLT reported. Although the MTD was not reached at the highest tested dose level, the RD chosen corresponds to the full doses of the GP3000 doublet standard (G: 3,000 mg/m2; P: 100 mg/m2 per cycle) every 28 days. Nonhematologic toxicities were mainly grade I-II. Relative dose intensities of G, I, and P at the RD were 96%, 98%, and 96%, respectively. Sixteen of 33 patients with measurable/evaluable disease had an objective response including two complete responses. In conclusion, GIP chemotherapy is safe and appears to be active in patients with NSCLC. The RD is gemcitabine: 1,500 mg/m2 days 1 and 15; ifosfamide: 3 g/m2 day 1; cisplatin: 100 mg/m2 day 15. A confirmatory phase II study is currently under way, before a phase III trial of GIP versus GP.