Christine Chevreau

Sorafenib-induced eruptive melanocytic lesions.

We report 2 cases of eruptive melanocytic lesions associated with sorafenib, a multikinase inhibitor FDA-approved for the treatment of advanced renal cell carcinoma. Understanding the development of this previously unknown side effect may provide further insight into sorafenib’s mechanistic effects on tumors and normal tissues and into the development of pigmented lesions.

Population pharmacokinetics of total and unbound etoposide.

Abstract A population pharmacokinetics study using the NONMEM program was undertaken to determine the effects of different covariates on the pharmacokinetic parameters of etoposide. A total of 1,044 plasma etoposide concentrations were determined by high-performance liquid chromatography (HPLC) in 100 patients (pts; 75 men and 25 women aged 25–85 years) treated for various tumor types with i.v. (57 pts) or oral (43 pts) etoposide. For 67 pts, etoposide plasma protein binding was determined by equilibrium dialysis; the unbound fraction ranged from 4% to 24%. A linear two-compartment model with first-order absorption (for oral dosing) accurately described the concentration versus time data. The central and peripheral volumes of distribution were significantly correlated with the body surface area [Vc (L) = 5.5 × BSA (m2) and Vp = 4.1 × BSA], but even after BSA had been taken into account, the interindividual variability of the two volumes remained high (34% and 57%, respectively). The clearance (CL) was not correlated with the following covariates: age, BSA, sex, height, and levels of serum bilirubin and liver enzymes. The final regression model for CL was CL (ml/min) = 49.8 × (1 − 0.009 × PRO) × WT/Scr + 33.8 × (1 − 0.29 × META) × (1− (1 − 0.012 × ALB), where ALB, PRO, WT,and Scr, respectively, were albuminemia, proteinemia (g/l), weight (kg), and serum creatinine (μM ) and META = 1 if the patient had liver metastases (otherwise, META = 0). The interindividual variability in CL (mean value 30 ml/min) decreased only from 32% to 26% when these covariates were taken into account. The mean oral bioavailability was 66%, showing an interindividual variability of 37%. The plasma clearance of the unbound fraction was strongly and negatively correlated with Scr but was not dependent on either PRO or ALB. These data show that modifications in PRO levels do not directly affect plasma exposure to unbound etoposide. This analysis makes possible the rational consideration of modifications of covariates such as Scr in etoposide dosing. This population data base will constitute the prerequisite for adaptative control with feedback dosing for continuous oral administration of etoposide.

Intraoperative interstitial iridium brachytherapy in the management of soft tissue sarcomas: preliminary results of a feasibility Phase II study

Between May 1986 and June 1992, 48 patients with soft tissue sarcomas underwent 50 intraoperative interstitial implants in conjunction with conservative tumoral resections. Brachytherapy was part of the initial treatment in 27 cases and was done in 21 other previously treated patients. For the last ones brachytherapy was, in most of the cases, the only treatment in addition to surgery. The implant dose was 40-65 Gy. When combined with external irradiation the mean prescribed dose was 20 Gy (12-25 Gy). With a median follow-up of 33 months, the 3-year actuarial survival rate was 81% and the local disease-free survival 91.7%. Five local failures were observed only in patients with recurrent sarcomas: two were inside the treated volume and three outside (local failure 5/48 = 10.4%). Acute side-effects occurred in 11 patients (11/48 = 23%), with skin breakdown (two cases) infection and hematoma (one case), infection, lymphocele, secondary skin breakdown and vascular rupture (one case), infection and limited skin breakdown (two cases) and delayed healing (five cases). As a consequence, six patients required reoperation but no amputation was necessary. The functional results were good. Only three patients had a moderate limitation of movement. Late complications occurred in five patients: bone fracture (one case), leg oedemas not interfering with normal activity (three cases), peripheral neuropathy fibrosis related requiring surgery (one case). Therefore, this preliminary report shows that adjuvant intraoperative brachytherapy is feasible and is safe in treating soft tissue sarcomas, even in previously irradiated patients. However, further evaluation is needed to determine the real place of intraoperative implant in the management of soft tissue sarcomas.

Second non-germ cell malignancies in patients treated for stage I-II testicular seminoma.

PURPOSE To measure the incidence of second non-germ cell malignancies (SNGCM) in patients treated for a stage I-II testicular seminoma. MATERIALS AND METHODS From 1970 to 1992, 131 evaluable patients received in the Institut Claudius Regaud a post-orchiectomy treatment for a stage I-II testicular seminoma. The therapeutic modalities, including salvage treatment for six recurrences, were as follows: infradiaphragmatic radiotherapy (IDRT) (n = 55); infra- and supradiaphragmatic radiotherapy (IDRT + SDRT) (n = 64); IDRT + SDRT with chemotherapy (n = 12). The mean follow-up was 11 years. The cumulative incidence of SNGCM was compared to the overall cancer incidence in the general male population on the basis of the Tarn Cancer Registry; the relative risk was expressed as a standardized incidence ratio (SIR). RESULTS Overall, the cumulative incidence of SNGCM was 10.7% (14/131 cases). The SIR was equal to 2.81 (95% confidence interval (CI) 1.54-4.72; P < 0.001) and increased with follow-up duration. The SIR was significantly increased in 64 patients treated with IDRT + SDRT (SIR = 3.08; 95% CI 1.47-5.66; P = 0.002) but not in 55 patients treated with IDRT alone (SIR = 0.62; 95% CI 0.01-3.43; P = 0.8). The 12 patients who received chemotherapy had an SIR of 26.2 (95% CI 5.48-77.69; P < 0.001), while the SIR was 2.26 in the 119 patients who did not receive any chemotherapy (95% CI 1.13-4.04; P = 0.01 ). Of four hematologic malignancies, three appeared in the 12 patients who received chemotherapy. CONCLUSIONS An increased risk of SNGCM after SDRT + IDRT has been demonstrated. After IDRT alone, the risk of second cancer is not incremented after a median follow-up of 6 years, but further observation of the patients is necessary to achieve final conclusions. Our results suggest that the risk of second cancer and especially of hematologic malignancy is increased by the association of chemotherapy and radiation.

Radiosensibilisation induite par le vémurafénib

The recent use of vemurafenib, a specific inhibitor of BRAF, has led to a significant improvement in disease-free survival and overall survival of patients treated for a BRAF-mutated metastatic melanoma. This new class of drugs is not devoid of side effects, including skin effects. In particular, its association with concomitant radiotherapy should be taken into consideration, vemurafenib appearing to be radiosensitizer. The radiation oncologist must be aware of this potential toxicity, which is not uncommon in clinical practice.

mTOR inhibitors in advanced renal cell carcinomas: From biology to clinical practice

To date, oral everolimus is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with vascular endothelial growth factor-targeted therapy, and intravenous temsirolimus for the first-line treatment of patients with poor prognosis metastatic renal cell carcinoma. However, some factors could guide the treatment choice aiming to individualize a treatment plan. Besides the crucial issue of treatment efficacy, other factors are to be considered such as disease status, histological subtype, extent of the disease, patient-specific factors, and agent-specific factors. All of these considerations have to stay in the frame of guideline recommendations which represent evidence-based medicine. The purpose of this article is to summarize the main pharmacological and pharmacokinetic characteristics of mTOR inhibitors, and to define targeted populations according to prognostic indexes.

Effets indésirables dermatologiques des thérapies ciblées antiangiogéniques

While new anticancer angiogenesis inhibitors present a well-tolerated safety profile, they are not without adverse events. The signaling pathways and/or receptors inhibited by these new drugs are often physiologically expressed in the skin and/or hair follicle and cutaneous toxicity is on the forefront. This article reviews the main dermatologic adverse events induced by these targeted anticancer therapies with a partial or exclusive antiangiogenic activity: sorafenib, sunitinib, pazopanib, vandetanib, everolimus, temsirolimus or bevacizumab.

Les mélanomes du tronc ont-ils un pronostic individualisable? À propos d'une série de 77 cas

AIMS Truncal melanoma is characterized by lymphatic drainage to single or multiple basins, affecting different anatomic regions. Since the introduction of sentinel lymph node biopsy (SLN) several questions have aroused in regard to this particular drainage. However, published data available on SLN anatomic distribution and on the prognostic value of multiple-nodal drainage is controversial. The aim of the present study was to provide further evidence based on our own experience. METHODS From January 2003 through December 2006, a total of 77 melanoma of the trunk were diagnosed and treated at our institution. Systematic lymphoscintigraphy was obtained for all patients, followed by removal of SLN and in-transit lesions. When SLN metastasis was detected a complete lymphadenectomy was performed and adjuvant immunotherapy with interferon was administered. Statistical analysis was performed using Chi2 and Fishers exact tests for categoric variables and Kaplan-Meier curves for survival. RESULTS Lymphoscintigraphy visualized 70.1% of single and 28.6% of multiple-nodal drainage (uninterpretable data). The rate of SLN macrometastasis ranged from 7.8 to 14.3%. Micrometastasis were found in 6.5% of patients. Positive SLN were discovered in 12.9% (17/54) of single-nodal and 18.6% (2/22) of multiple-nodal drainage. Melanomas topography significantly influenced lymphatic drainage distribution, with 28.6% of single-nodal and 71.4% of multiple-nodal drainage for central tumors, and with 79.4% of single-nodal and 19.1% of multiple-nodal drainage for lateral tumors. The group with multiple-nodal drainage was associated non-significantly with primary tumor ulceration, 39 vs 24%. The Breslow thickness did not associate to multiple-nodal drainage. There were no differences in the rate of lymph node metastasis between both groups, 18 vs 12.9%. After a median follow-up of 47 months, prognosis was similar regardless of SLN status, with 80.3% overall survival for negative SLN and 81.3% for positive SLN. Single or multiple drainage did not affect survival rates significantly, with 84% survival for single-nodal drainage and 95% for multiple-nodal drainage. CONCLUSIONS Primary tumor location (medial location) was the principal risk factor for multi-nodal drainage: lymphoscintigraphy was the best technique for lymphatic drainage assessment. Primary tumor location with single or multi-nodal drainage did not influence the rate of positive SLN and had similar disease-free and overall survival. For us, truncal melanoma has not a different prognosis than melanoma of extremities.

Cancer du testicule: BEP et spermatogenèse

ResumeLes caractéristiques spermatiques de 44 hommes traités avec 2 cycles ou plus de chimiothérapie de type BEP pour des tumeurs testiculaires non séminomateuses ont été étudiées avant et 25.2 (± 19.4) mois après la fin de la chimiothérapie. La récupération des valeurs initiales de numération survenait plus fréquemment un an après la fin du traitement. Cette récupération était liée à la fonction testiculaire avant traitement et au temps écoulé depuis la fin de la chimiothérapie; dans la première année suivant la fin du traitement, cette récupération était fonction du nombre de cycles de BEP.Notre étude est rassurante dans le long terme sur la toxicité du BEP sur la spermatogenèse. Toutefois, des études génétiques sont nécessaires concernant les effets possibles des traitements sur le matériel génétique spermatique durant cette phase de récupération.AbstractThe sperm characteristics of 44 men treated with two or more courses of BEP chemotherapy for non seminomatous germ cell testicular tumours were investigated before and 25.2 ± 19.4 months after chemotherapy. Before treatment, 54.5% of patients were oligozoospermic. The mean sperm characteristics did not differ before and after chemotherapy. However, following chemotherapy, the recovery of initial sperm count was more frequent after one year than before. During the first year, recovery was more frequent in patients treated with two than in those treated with more than two BEP cycles. In patients with good pre-treatment sperm count, sperm production was reduced by half after chemotherapy. In a subgroup of men who provided two sperm samples after chemotherapy, sperm production was better in the second sample than in the first. Our data suggest that sperm recovery is related to testicular function prior to therapy, to the time elapsed after chemotherapy and in the first year to the number of chemotherapy cycles. In conclusion, our study is reassuring concerning the long-term male reproductive toxicity of BEP. However, further studies are required to analyse the possible effects on sperm genetic material during the recovery period.

Les mélanomes du tronc ont-ils un pronostic individualisable? À propos d'une série de 77 casAn individualized prognosis for truncal melanoma? A series of 77 cases

AIMS Truncal melanoma is characterized by lymphatic drainage to single or multiple basins, affecting different anatomic regions. Since the introduction of sentinel lymph node biopsy (SLN) several questions have aroused in regard to this particular drainage. However, published data available on SLN anatomic distribution and on the prognostic value of multiple-nodal drainage is controversial. The aim of the present study was to provide further evidence based on our own experience. METHODS From January 2003 through December 2006, a total of 77 melanoma of the trunk were diagnosed and treated at our institution. Systematic lymphoscintigraphy was obtained for all patients, followed by removal of SLN and in-transit lesions. When SLN metastasis was detected a complete lymphadenectomy was performed and adjuvant immunotherapy with interferon was administered. Statistical analysis was performed using Chi2 and Fishers exact tests for categoric variables and Kaplan-Meier curves for survival. RESULTS Lymphoscintigraphy visualized 70.1% of single and 28.6% of multiple-nodal drainage (uninterpretable data). The rate of SLN macrometastasis ranged from 7.8 to 14.3%. Micrometastasis were found in 6.5% of patients. Positive SLN were discovered in 12.9% (17/54) of single-nodal and 18.6% (2/22) of multiple-nodal drainage. Melanomas topography significantly influenced lymphatic drainage distribution, with 28.6% of single-nodal and 71.4% of multiple-nodal drainage for central tumors, and with 79.4% of single-nodal and 19.1% of multiple-nodal drainage for lateral tumors. The group with multiple-nodal drainage was associated non-significantly with primary tumor ulceration, 39 vs 24%. The Breslow thickness did not associate to multiple-nodal drainage. There were no differences in the rate of lymph node metastasis between both groups, 18 vs 12.9%. After a median follow-up of 47 months, prognosis was similar regardless of SLN status, with 80.3% overall survival for negative SLN and 81.3% for positive SLN. Single or multiple drainage did not affect survival rates significantly, with 84% survival for single-nodal drainage and 95% for multiple-nodal drainage. CONCLUSIONS Primary tumor location (medial location) was the principal risk factor for multi-nodal drainage: lymphoscintigraphy was the best technique for lymphatic drainage assessment. Primary tumor location with single or multi-nodal drainage did not influence the rate of positive SLN and had similar disease-free and overall survival. For us, truncal melanoma has not a different prognosis than melanoma of extremities.