Lurbinectedin in patients with pretreated neuroendocrine tumours: Results from a phase II basket study.

BACKGROUND: Patients with neuroendocrine tumours (NETs) need alternative therapies after failure of first-line therapy. PATIENTS AND METHODS: This phase II trial evaluated lurbinectedin, a selective inhibitor of oncogenic transcription, at 3.2 mg/m2 as a 1-h intravenous infusion every 3 weeks in 32 NETs patients treated in the second- or third-line setting. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1 assessed by the investigators. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Two of 31 evaluable patients had confirmed partial responses (ORR = 6.5%; 95%CI, 0.8-21.4%). Median DoR was 4.7 months (95% CI, 4.0-5.4 months), median PFS was 1.4 months (95% CI, 1.2-3.0 months) and median OS was 7.4 months (95% CI, 3.4-16.2 months). Lurbinectedin showed an acceptable, predictable and manageable safety profile. The most common grade 3/4 toxicity was neutropenia (40.6%; grade 4, 12.4%; febrile neutropenia, 3.1%). CONCLUSIONS: Considering the exploratory aim of this trial that evaluated a heterogeneous population of NETs patients, and the signs of antitumour activity observed (two confirmed partial responses and seven long disease stabilisations), further development of lurbinectedin is warranted in a more selected NETs population. TRIAL REGISTRATION NUMBER: Sponsor Study Code: PM1183-B-005-14. EudraCT number: 2014-003773-42. CLINICALTRIALS: gov reference: NCT02454972.

Prevalence of drug-drug interactions in sarcoma patients: key role of the pharmacist integration for toxicity risk management.

BACKGROUND: The risk of drug-drug interactions (DDI) has become a major issue in cancer patients. However, data in sarcoma patients are scarce. We aimed to evaluate the frequency and the factors associated with DDI with antitumor treatments, and to evaluate the impact of a pharmacist evaluation before anticancer treatment. PATIENTS AND METHODS: We performed a retrospective review of consecutive sarcoma patients starting chemotherapy (CT) or Tyrosine kinase inhibitor (TKI). A pharmacist performed medication reconciliation and established an early toxicity risk assessment. Potential DDI with antitumor drugs were identified using Micromedex electronic software. RESULTS: One hundred and twenty-two soft-tissue and 80 bone sarcoma patients (103 males, median age 50 years,) were included before CT (86%) or TKI (14%). The median number of medications was 3; 34 patients (22% of patients with medication reconciliation) reported complementary medicine use. 37 potential DDI classified as major, were identified (12% of the 243 pre-therapeutic assessments). In multivariate analysis, TKI (p < 0.0001), proton pump inhibitor (p = 0.026) and antidepressant (p < 0.001) were identified as risk factors of DDI (p < 0.02). Only marital status (p = 0.003) was associated with complementary medicine use. A pharmacist performed 157 medication reconciliations and made 71 interventions among 59 patients (37%). In multivariate analysis, factors associated with pharmacist intervention were: complementary medicines (p = 0.004), drugs number (p = 0.005) and treatment with TKI (p = 0.0002) CONCLUSIONS: Clinical interventions on DDI are more frequently required among sarcoma patients treated with TKI than CT. Multidisciplinary risk assessment including a medication reconciliation by a pharmacist could be crucial to prevent DDI with TKI.

First referral to an integrated onco-palliative care program: a retrospective analysis of its timing.

BACKGROUND: Palliative care (PC) referral is recommended early in the course of advanced cancer. This study aims to describe, in an integrated onco-palliative care program (IOPC), patient's profile when first referred to this program, timing of this referral and its impact on the trajectory of care at end-of-life. METHODS: The IOPC combined the weekly onco-palliative meeting (OPM) dedicated to patients with incurable cancer, and/or the clinical evaluation by the PC team. Oncologists can refer to the multidisciplinary board of the OPM the patients for whom goals and organization of care need to be discussed. We analyzed all patients first referred at OPM in 2011-2013. We defined the index of precocity (IP), as the ratio of the time from first referral to death by the time from diagnosis of incurability to death, ranging from 0 (late referral) to 1 (early referral). RESULTS: Of the 416 patients included, 57% presented with lung, urothelial cancers, or sarcoma. At first referral to IOPC, 76% were receiving antitumoral treatment, 63% were outpatients, 56% had a performance status ≤2 and 46% had a serum albumin level > 35 g/l. The median [1st-3rd quartile] IP was 0.39 [0.16-0.72], ranging between 0.53 [0.20-0.79] (earliest referral, i.e. close to diagnosis of incurability, for lung cancer) to 0.16 [0.07-0.56] (latest referral, i.e. close to death relatively to length of metastatic disease, for prostate cancer). Among 367 decedents, 42 (13%) received antitumoral treatment within 14 days before death, and 157 (43%) died in PC units. CONCLUSIONS: The IOPC is an effective organization to enable early integration of PC and decrease aggressiveness of care near the end-of life. The IP is a useful tool to model the timing of referral to IOPC, while taking into account each cancer types and therapeutic advances.

[Tyrosine kinase inhibiting the VEGF pathway and elderly people: Tolerance, pre-treatment assessment and side effects management]. / Inhibiteurs de tyrosine kinase ciblant l'angiogenèse et sujets âgés : tolérance, évaluation pré-thérapeutique et gestion des effets indésirables.

Angiogenesis inhibition is a major antitumor strategy that has emerged during the last decade. Oral tyrosine kinase inhibitors (TKI) targeting the VEGF receptor, including sunitinib, sorafenib, axitinib, regorafenib, pazopanib, and vandetanib reduce tumor growth and metastasis. These agents are approved for the treatment of metastatic diseases in first or second-line. They display a narrow therapeutic index. However, data in the elderly and/or in patients with multiple illnesses remain scarce. This population is classically excluded from clinical trials. The aim of this review is to provide an overview of existing literature regarding antiangiogenic TKI tolerance in the elderly (>70 years old). We also highlight key points of the pre-therapeutic evaluation and summarize the management of common toxicities.

Drug safety evaluation of sorafenib for treatment of solid tumors: consequences for the risk assessment and management of cancer patients.

INTRODUCTION: Sorafenib is a multi-tyrosine kinase inhibitor (TKI). Considerable clinical experience has been accumulated since its first Phase III clinical trial in metastatic renal cancer patients in 2007. The management of its early acute toxicity in fit patients is well known. The management of prolonged treatment becomes the new challenge. AREAS COVERED: Using sorafenib as a key word for PubMed search, we review preclinical and clinical data and discuss the pharmacokinetics and pharmacodynamics of sorafenib, its acute and cumulative toxicities and their consequences for patient management. EXPERT OPINION: The systematic multi-disciplinary risk assessment of cancer patients prior to TKI initiation reduces the risks of acute and late toxicity, especially drug-drug interactions and arterial risks. Sarcopenia is now identified as a major risk of severe toxicity. The very diverse clinical pictures of cumulative toxicity must be known. The monitoring of sorafenib systemic exposure is helpful especially in elderly patients. Moreover, at disease progression, it allows distinguishing between underexposure to sorafenib and truly acquired resistance to the drug. The optimal use of sorafenib should allow improving the reported results of flat-dose. Finally, most of this knowledge could be used for the development and optimal use of the other TKIs.

Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir.

BACKGROUND: The majority of patients receiving the platinum-based chemotherapy drug oxaliplatin develop peripheral neurotoxicity. Because this neurotoxicity involves ROS production, we investigated the efficacy of mangafodipir, a molecule that has antioxidant properties and is approved for use as an MRI contrast enhancer. METHODS: The effects of mangafodipir were examined in mice following treatment with oxaliplatin. Neurotoxicity, axon myelination, and advanced oxidized protein products (AOPPs) were monitored. In addition, we enrolled 23 cancer patients with grade ≥ 2 oxaliplatin-induced neuropathy in a phase II study, with 22 patients receiving i.v. mangafodipir following oxaliplatin. Neuropathic effects were monitored for up to 8 cycles of oxaliplatin and mangafodipir. RESULTS: Mangafodipir prevented motor and sensory dysfunction and demyelinating lesion formation. In mice, serum AOPPs decreased after 4 weeks of mangafodipir treatment. In 77% of patients treated with oxaliplatin and mangafodipir, neuropathy improved or stabilized after 4 cycles. After 8 cycles, neurotoxicity was downgraded to grade ≥ 2 in 6 of 7 patients. Prior to enrollment, patients received an average of 880 ± 239 mg/m2 oxaliplatin. Patients treated with mangafodipir tolerated an additional dose of 458 ± 207 mg/m2 oxaliplatin despite preexisting neuropathy. Mangafodipir responders managed a cumulative dose of 1,426 ± 204 mg/m2 oxaliplatin. Serum AOPPs were lower in responders compared with those in nonresponders. CONCLUSION: Our study suggests that mangafodipir can prevent and/or relieve oxaliplatin-induced neuropathy in cancer patients. Trial registration. Clinicaltrials.gov NCT00727922. Funding. Université Paris Descartes, Ministère de la Recherche et de l'Enseignement Supérieur, and Assistance Publique-Hôpitaux de Paris.

Cost effectiveness of integrated medicine in patients with cancer receiving anticancer chemotherapy.

PURPOSE: Ambulatory chemotherapy is patient friendly but may result in toxicity-induced unscheduled hospitalizations (TIUHs). This emerging issue may increase health care costs. We studied the cost effectiveness of a hospital-home monitoring program based on systematic iterative telephone calls after chemotherapy. PATIENTS AND METHODS: We retrospectively evaluated the rates of chemotherapy-induced unscheduled hospitalizations in patients who were treated in August 2008. Patients were contacted by telephone 1 day before chemotherapy and on the second and eighth days after undergoing chemotherapy. Costs associated with TIUHs were calculated and compared with those of a cohort concomitantly treated using the standard follow-up procedure. RESULTS: A total of 259 patients entered the hospital-home monitoring program. They were compared with 86 patients who had similar characteristics but underwent the standard treatment and follow-up procedure. Inclusion in the hospital-home monitoring program resulted in patients experiencing TIUHs approximately half as frequently as patients in the other group (2.4% v 4.9%; P < .01). Patients in the program experienced TIUHs for a median length of stay of 4 days, representing a nonsignificant reduction in duration of hospitalization (P not significant). Consequently, through a two-fold reduction in TIUH annual incidence, this program represents a reduction in unscheduled hospitalizations per year of 383 days, decreasing hospital costs by €201.468 ($292,468) per year. CONCLUSION: The hospital-home monitoring program is a cost-effective strategy for offering ambulatory chemotherapy treatment to patients with cancer. This program has become our standard procedure for ambulatory chemotherapy in patients with cancer.

Sorafenib-induced hepatocellular carcinoma cell death depends on reactive oxygen species production in vitro and in vivo.

Sorafenib is presently the only effective therapy in advanced hepatocellular carcinoma (HCC). Because most anticancer drugs act, at least in part, through the generation of reactive oxygen species, we investigated whether sorafenib can induce an oxidative stress. The effects of sorafenib on intracellular ROS production and cell death were assessed in vitro in human (HepG2) and murine (Hepa 1.6) HCC cell lines and human endothelial cells (HUVEC) as controls. In addition, 26 sera from HCC patients treated by sorafenib were analyzed for serum levels of advanced oxidation protein products (AOPP). Sorafenib significantly and dose-dependently enhanced in vitro ROS production by HCC cells. The SOD mimic MnTBAP decreased sorafenib-induced lysis of HepG2 cells by 20% and of Hepa 1.6 cells by 75% compared with HCC cells treated with 5 mg/L sorafenib alone. MnTBAP significantly enhanced by 25% tumor growth in mice treated by sorafenib. On the other hand, serum levels of AOPP were higher in HCC patients treated by sorafenib than in sera collected before treatment (P < 0.001). An increase in serum AOPP concentration ≥0.2 µmol/L chloramine T equivalent after 15 days of treatment is a predictive factor for sorafenib response with higher progression free survival (P < 0.05) and overall survival rates (P < 0.05). As a conclusion, sorafenib dose-dependently induces the generation of ROS in tumor cells in vitro and in vivo. The sera of Sorafenib-treated HCC patients contain increased AOPP levels that are correlated with the clinical effectiveness of sorafenib and can be used as a marker of effectiveness of the drug. .

Effect of integrated palliative care on the quality of end-of-life care: retrospective analysis of 521 cancer patients.

OBJECTIVE: To examine the impact of oncologist awareness of palliative care (PC), the intervention of the PC team (PCT) and multidisciplinary decision-making on three quality indicators of end-of-life (EOL) care. SETTING: Cochin Academic Hospital, Paris, 2007-2008. DESIGN AND PARTICIPANTS: A 521 decedent case series study nested in a cohort of 735 metastatic cancer patients previously treated with chemotherapy. Indicators were location of death, number of emergency room (ER) visits in last month of life and chemotherapy administration in last 14 days of life. Multivariable logistic regression models were used to estimate associations between indicators and oncologist's awareness of PC, PCT intervention and case discussions at weekly onco-palliative meetings (OPMs). RESULTS: 58 (11%) patients died at home, 45 (9%) in an intensive care unit or ER, and 253 (49%) in an acute care hospital; 185 (36%) patients visited the ER in last month of life and 75 (14%) received chemotherapy in last 14 days of life. Only the OPM (n=179, 34%) independently decreases the odds of receiving chemotherapy in last 14 days of life (OR 0.5, 95% CI 0.2 to 0.9) and of dying in an acute care setting (0.3, 0.1 to 0.5). PCT intervention (n=300, 58%) did not independently improve any indicators. Among patients seen by the PCT, early PCT intervention had no impact on indicators, whereas the OPM reduced the odds of persistent chemotherapy in the last 14 days of life. CONCLUSION: Multidisciplinary decision-making with oncologists and the PCT is the most critical parameter for improving EOL care.

[Use of antioxidant and other complementary medicine by patients treated by antitumor chemotherapy: a prospective study]. / Prise d'antioxydants et d'autres thérapies complémentaires par les patients sous chimiothérapie antitumorale : étude prospective.

Use of complementary and alternative medicine (CAM) has been reported to be more and more frequent among cancer patients in USA. The aim of this study was to analyze among French cancer patients the prevalence of CAM use, focusing on antioxidants (AO) that could interfere with antitumor agents. Seventy-nine patients, treated by antitumor chemotherapy in oncology day care unit, participated to an interview (medium age  =  60 years old). CAM use was reported by 42% of patients: mostly AO (24%) (selenium, green tea and vitamins ACE, more specifically), but also relaxation, acupuncture, hypnosis (19%) and homeopathy (15%). Among patients using CAM, 66% of them indicated that their physicians were not aware of this use and 47% of them thought that CAM use was safe. Nevertheless, for seven patients who have taken AO, previous in vitro and preclinical studies suggested interactions with antitumor chemotherapy. Therefore, CAM use and, more specifically, AO use is common among cancer patients treated by antitumor chemotherapy in France. Nevertheless, AO could generate interactions with conventional treatment. Clinical studies are warranted to evaluate these interactions, and adequate communication with patients is needed.

[Role of antioxidant complements and supplements in oncology in addition to an equilibrate regimen: a systematic review]. / Place en oncologie des compléments et suppléments en antioxydants en sus d'un régime équilibre; revue générale de la littérature.

Eating fruits and vegetables reduces risk of cancer by about 30%, however the active anticarcinogenic components of food remain to be determined. The well known oncogenic potential of oxidative stress have led to the use of antioxidants, contain in high proportions in fruits and vegetables, as cancer prevention. Numerous observational and interventional studies allowed to observe conflicting results. For example, in two major trials (CARET and ABTC) the risk of lung cancer was increased rather than reduced by beta-carotene supplements in smokers. Meta-analyses analyzing studies about supplementation in primary or tertiary prevention showed no benefit on overall survival regardless of tumor type studied or anti-oxidant evaluated. Those assessing the effect of non medical antioxidants taken during the anticancer treatments (chemotherapy or radiotherapy) indicate that if the objective of reducing side effects can sometimes be achieved, the risk of tumor progression and increasing mortality must not be disregarded. Because of the absence of formal effectiveness proof and potential risk of mortality, prophylactic supplementation with antioxidants can not be recommended. Varied and balanced diet of fruits and vegetables remains the best nutritional attitude to prevent the risk of cancer and should be promoted at all levels.

Improvement of the therapeutic index of anticancer drugs by the superoxide dismutase mimic mangafodipir.

BACKGROUND: Anticancer drugs act by increasing intracellular hydrogen peroxide levels. Mangafodipir, a superoxide dismutase (SOD) mimic with catalase and glutathione reductase activities, protects normal cells from apoptosis induced by H2O2. We investigated its and other oxidative stress modulators' effects on anticancer drug activity in vitro and in vivo. METHODS: Cell lysis and intracellular reactive oxygen species levels were assessed in vitro in human leukocytes from healthy subjects and in murine CT26 colon cancer cells. Cells were exposed to the chemotherapeutic agents paclitaxel, oxaliplatin, or 5-fluorouracil, either in the presence or absence of mangafodipir and other oxidative stress modulators. Cell viability was evaluated by the methylthiazoletetrazolium assay. The effects of mangafodipir and other oxidative stress modulators on peripheral blood counts and on tumor growth were studied in BALB/c mice that were implanted with CT26 tumors and treated with 20 mg/kg paclitaxel. Survival of BALB/c mice infected with Staphylococcus aureus was also examined by treatment group. Statistical tests were two-sided. RESULTS: In vitro lysis of leukocytes exposed to paclitaxel, oxaliplatin, or 5-fluorouracil in combination with mangafodipir was decreased by 46% (95% confidence interval [CI] = 44% to 48%), 30.5% (95% CI = 29% to 32%), and 15% (95% CI = 10% to 20%), compared with lysis of cells treated with anticancer agent alone. Mangafodipir also statistically significantly enhanced in vitro anticancer drug cytotoxicity toward CT26 cancer cells. In vivo, mangafodipir protected mice against paclitaxel-induced leukopenia. Moreover, the survival rate of mice infected with S. aureus and treated with paclitaxel was higher when mangafodipir was also administered (survival: 3 of 17 versus 14 of 17, P < .001). In addition, mangafodipir amplified the inhibitory effect of paclitaxel on CT26 tumor growth in mice. CONCLUSIONS: Mangafodipir decreased hematotoxicity and enhanced cytotoxicity of anticancer agents.

Characterization and multiparameter analysis of visual adverse events in irofulven single-agent phase I and II trials.

PURPOSE: Irofulven (6-hydroxymethylacylfulvene) is a novel agent, derived from illudin S, with potent apoptotic effects in preclinical models. In the Phase I trial evaluating intermittent weekly schedules, visual symptoms were dose limiting. The aim of this analysis was to better characterize the visual adverse events of irofulven and provide treatment guidelines. EXPERIMENTAL DESIGN: Clinical data from 277 patients entered in single-agent Phase I to II clinical trials who received irofulven on days 1 and 15 every 4 weeks; days 1, 8, and 15 every 4 weeks; or days 1 and 8 every 3 weeks were included in this multiparameter analysis. RESULTS: Overall, 74 patients (27%) experienced visual symptoms. The most frequently reported symptoms were flashing lights (12% of patients), blurred vision (9%), and photosensitivity (8%). Grade 3 toxicity was observed in 12 patients (4%). The incidence and severity of visual events were dose dependent, with no grade 3 visual events occurring at doses < or =0.50 mg/kg and grade 1 to 2 events in only 12% and 8% of patients, at doses of < or =0.50 mg/kg and < or =20 mg/m2, respectively. Grade 1 to 2 toxicity was reversible in most patients. Abnormal electroretinogram and abnormal visual fields were noted after irofulven treatment in 24 of 39 patients (62%) and 15 of 26 patients (58%), respectively. All but 1 patient who had electroretinogram assessment received doses >0.50 mg/kg. Clinical examination and visual field assessment were found to be better correlated with symptoms and appear to be more appropriate for surveillance of irofulven retinal symptoms than electroretinograms. CONCLUSIONS: On the basis of retained antitumor activity and reversibility of grade 1 and 2 visual symptoms at lower doses, it appears that an irofulven dose of < or =0.50 mg/kg or < or =20 mg/m2, not to exceed 50 mg in a single dose, given as a 30-minute infusion on days 1 and 8 every 3 weeks or days 1 and 15 every 4 weeks minimizes the frequency and severity of visual symptoms.