Jean-Philippe Durand

Sarcopenia Predicts Early Dose-Limiting Toxicities and Pharmacokinetics of Sorafenib in Patients with Hepatocellular Carcinoma

Background Sorafenib induces frequent dose limiting toxicities (DLT) in patients with advanced hepatocellular carcinoma (HCC). Sarcopenia has been associated with poor performance status and shortened survival in cancer patients. Patients and Methods The characteristics of Child Pugh A cirrhotic patients with HCC receiving sorafenib in our institution were retrospectively analyzed. Sorafenib plasma concentrations were determined at each visit. Toxicities were recorded during the first month of treatment, and sarcopenia was determined from baseline CT-scans. Results Forty patients (30 males) were included. Eleven (27.5%) were sarcopenic. Eighteen patients (45%) experienced a DLT during the first month of treatment. Sarcopenic patients experienced significantly more DLTs than non-sarcopenic patients did (82% versus 31%, p = 0.005). Grade 3 diarrhea was significantly more frequent in sarcopenic patients than in non-sarcopenic patients (45.5% versus 6.9%, p = 0.01), but not grade 3 hand foot syndrome reaction (9% versus 17.2%, p = 1). On day 28, median sorafenib AUC (n = 17) was significantly higher in sarcopenic patients (102.4 mg/l.h versus 53.7 mg/l.h, p = 0.013). Conclusions Among cirrhotic Child Pugh A patients with advanced HCC, sarcopenia predicts sorafenib exposure and the occurrence of DLT within the first month of treatment.

Early Sorafenib-Induced Toxicity Is Associated with Drug Exposure and UGTIA9 Genetic Polymorphism in Patients with Solid Tumors: A Preliminary Study

Background Identifying predictive biomarkers of drug response is of key importance to improve therapy management and drug selection in cancer therapy. To date, the influence of drug exposure and pharmacogenetic variants on sorafenib-induced toxicity remains poorly documented. The aim of this pharmacokinetic/pharmacodynamic (PK/PD) study was to investigate the relationship between early toxicity and drug exposure or pharmacogenetic variants in unselected adult outpatients treated with single-agent sorafenib for advanced solid tumors. Methods Toxicity was recorded in 54 patients on days 15 and 30 after treatment initiation and sorafenib exposure was assessed in 51 patients. The influence of polymorphisms in CYP3A5, UGT1A9, ABCB1 and ABCG2 was examined in relation to sorafenib exposure and toxicity. Clinical characteristics, drug exposure and pharmacogenetic variants were tested univariately for association with toxicities. Candidate variables with p<0.1 were analyzed in a multivariate analysis. Results Gender was the sole parameter independently associated with sorafenib exposure (p = 0.0008). Multivariate analysis showed that increased cumulated sorafenib (AUCcum) was independently associated with any grade ≥3 toxicity (p = 0.037); UGT1A9 polymorphism (rs17868320) with grade ≥2 diarrhea (p = 0.015) and female gender with grade ≥2 hand-foot skin reaction (p = 0.018). Using ROC curve, the threshold AUCcum value of 3,161 mg/L.h was associated with the highest risk to develop any grade ≥3 toxicity (p = 0.018). Conclusion In this preliminary study, increased cumulated drug exposure and UGT1A9 polymorphism (rs17868320) identified patients at high risk for early sorafenib-induced severe toxicity. Further PK/PD studies on larger population are warranted to confirm these preliminary results.

Relationship between GSTP1 Ile105Val polymorphism and docetaxel-induced peripheral neuropathy: clinical evidence of a role of oxidative stress in taxane toxicity

BACKGROUND Glutathione-S-transferases (GST) regulate the cellular response to oxidative stress. We previously highlighted the importance of oxidative stress in taxane toxicity and therefore investigated the relationship between the GST isoforms M1, T1 and P1 gene polymorphisms and docetaxel (Taxotere)-induced peripheral neuropathy (DIPN). PATIENTS AND METHODS The GSTM1 (null), GSTT1 (null) and GSTP1 (Ile(105)Val and Ala(114)Val) polymorphisms were determined in a cohort of cancer patients treated with docetaxel and entered in a clinical trial database. The relationship between GST polymorphisms and grade > or = 2 DIPN as primary end point was studied. RESULTS Fifty-eight patients (median age 61 years) received a total of 261 cycles of docetaxel given as single agent. Patients with GSTP1 (105)Ile/(105)Ile genotype had a higher risk of developing a grade > or = 2 DIPN than did those with other GSTP1 genotypes (8 of 27 versus 2 of 31, respectively, odds ratio 6.11; 95% confidence interval 1.17-31.94; P = 0.03). In multivariate analysis, grade > or = 2 DIPN was strongly correlated with GSTP1 (105)Ile/(105)Ile genotype (P = 0.01) and the number of cycles (P = 0.03). CONCLUSION We found a significant correlation between GSTP1 (105)Ile/(105)Ile genotype and the development of grade > or = 2 DIPN. This finding strongly suggests a role of oxidative stress in the pathophysiology of DIPN.

Clinical activity of venlafaxine and topiramate against oxaliplatin-induced disabling permanent neuropathy

Venlafaxine (Effexor; Wyeth Lederle), a serotoninergic-like anti-depressant, and Topiramate (Epitomax; Jansen Cilag), a new anti-epileptic drug, share some evidence of clinical activity in the treatment of neuropathic pain. Several anti-cancer agents have neurosensory toxicity as limiting toxicity of their repeated administration. One of the most recent and the most widely used is oxaliplatin. No medication is presently known to be active against oxaliplatin permanent neurosensory toxicity. We observed that venlafaxine hydrochloride or low-dose topiramate could be active against the permanent neuropathy-related symptoms of oxaliplatin. Both agents allowed pain relief and a significant autonomy improvement. These preliminary results invite us to evaluate further venlafaxine hydrochloride and topiramate for the treatment of permanent anti-cancer chemotherapy-induced neuropathies.

An Observational Study of Bevacizumab-Induced Hypertension as a Clinical Biomarker of Antitumor Activity

BACKGROUND Hypertension is a common toxicity of bevacizumab, but the frequency of assessment of blood pressure and standardized grading remain to be defined. This study aimed to describe the incidence of bevacizumab-induced hypertension and factors associated with its development, then to retrospectively assess its relation with activity. PATIENTS AND METHODS One hundred nineteen patients with advanced or metastatic non-small cell lung cancer, colorectal cancer, or ovarian cancer receiving bevacizumab (2.5 mg/kg per week) and chemotherapy were eligible for this analysis. Blood pressure was measured at home twice daily according to international guidelines, and graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 3.0, and the European Society of Hypertension (ESH) criteria. RESULTS Home-based measurements detected significantly more cases of hypertension than in-clinic measurements did, according to the ESH criteria (54.6% versus 24.4%; p < .001) or the NCI-CTC (42.9% versus 22.7%; p = .0015). Very early hypertension (within 42 days, according to the ESH criteria) but not hypertension (occurring at any time during treatment period) was predictive of response (p = .0011 and p = .26, respectively). CONCLUSIONS Our preliminary results indicate that home-based measurement and grading according to the ESH criteria represents a reliable method to detect bevacizumab-induced hypertension. Whether hypertension is a biomarker of bevacizumab activity remains to be determined in a prospective study.

Dramatic recovery of paclitaxel-disabling neurosensory toxicity following treatment with venlafaxine.

Venlafaxine is an antidepressant which acts through the inhibition of the reuptake of norepinephrine and serotonin. Venlafaxine is active against neuropathic and chronic pain. We report the case of a 69-year-old woman who presented a paclitaxel-induced neuropathy. She presented paresthesias, pin pricks in both hands with functional impairment. Venlafaxine hydrochloride was introduced at 37.5 mg twice daily. The patient noticed a dramatic recovery of her symptoms within 2 days, with both reduction of the paresthesias and functional improvement. This is the first report of efficacious use of venlafaxine for the treatment of paclitaxel cumulative neurosensory toxicity.

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 oncologists 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.

Effect of glucuronidation on transport and tissue accumulation of tyrosine kinase inhibitors: consequences for the clinical management of sorafenib and regorafenib

Introduction: UDP-glucuronosyltransferases (UGTs) are a multigenic family of enzymes responsible for the glucuronidation reaction. Many therapeutic classes of drugs used in solid tumors are UGT substrates, including cancer therapies. Areas covered: This article describes the tyrosine kinase inhibitors (TKIs) undergoing hepatic glucuronidation; its effect on transport and tissue accumulation and the clinical consequences of this particular metabolism. A PubMed search concerning the pharmacokinetics of the TKIs was performed. All are extensively metabolized by CYP450. Two TKIs, sorafenib and regorafenib, also have a major UGT-mediated metabolism and were therefore studied. Expert opinion: The prescription of the same dose of sorafenib and regorafenib for all patients may be inappropriate since at each enzymatic step of this multistep metabolism inter-individual fluctuations exist. Having a non-exclusive CYP-mediated route of metabolism may reduce the risk of variability in drug exposure when CYP3A4 substrates are concomitantly given. Several clinical consequences derive from this pharmacokinetic particularity of sorafenib and regorafenib. Since no clear difference distinguishes TKIs in efficacy in large randomized trials, the differences for the clinical management of their toxicity is a critical aspect.

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 (

Feasibility of gemcitabine and oxaliplatin in patients with advanced biliary tract carcinoma and a performance status of 2.

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.