Systemic therapies for salivary gland carcinoma (excluding adenoid cystic carcinoma): REFCOR recommendations by the formal consensus method.

OBJECTIVE: To determine the therapeutic indications for systemic medical treatment in the management of salivary gland carcinoma (excluding adenoid cystic carcinoma) according to the clinical situation. MATERIALS AND METHODS: The French Network of Rare Head and Neck Tumors (REFCOR) formed a steering group who drafted a narrative review of the literature published on Medline and proposed recommendations. The level of adherence to the recommendations was then assessed by a rating group, according to the formal consensus method. RESULTS: Salivary gland carcinoma is rare and there is currently insufficient evidence to indicate chemotherapy at the localized stage. At the metastatic stage, initial management can be based on a phase of monitoring for indolent disease. Some histological subtypes (salivary duct carcinoma and adenocarcinoma) are more aggressive and require systemic treatment from the outset. To guide systemic treatment, it is recommended to perform immunohistochemistry and molecular biology analyses (overexpression of HER2 and androgen receptors, NTRK fusion, next-generation sequencing). CONCLUSION: Salivary gland carcinoma is a rare tumor for which there are currently few effective medical treatments. It is therefore recommended to include patients in clinical trials.

Systemic therapies for salivary gland cancer: Adenoid cystic carcinoma. REFCOR recommendations by the formal consensus method.

OBJECTIVE: To determine the therapeutic indications for systemic medical treatment in the management of adenoid cystic carcinoma (ACC) according to the clinical situation. MATERIALS AND METHODS: The French Network of Rare Head and Neck Tumors (REFCOR) formed a steering group, which drafted a narrative review of the literature published on Medline and proposed recommendations. The level of adherence to the recommendations was then assessed by a rating group, according to the formal consensus method. RESULTS: ACCs are rare tumors and there is currently insufficient evidence to indicate chemotherapy at the localized stage. At the metastatic stage, progression is often slow. In case of oligometastatic ACC, local treatment should be discussed. The most often indolent nature of polymetastatic ACC can allow management by active surveillance. Molecular screening is recommended, for abnormalities potentially accessible to targeted therapy. CONCLUSION: ACCs are rare tumors for which there are currently few effective medical treatments. It is therefore recommended to include patients in clinical trials.

Radiotherapy for salivary gland cancer: REFCOR recommendations by the formal consensus method.

OBJECTIVE: To determine the indications for radiotherapy in salivary gland cancer and to specify the modalities and target radiation volumes. MATERIAL AND METHODS: The French Network of Rare Head and Neck Tumors (REFCOR) formed a steering group which drafted a narrative review of the literature published on Medline and proposed recommendations. The level of adherence to the recommendations was then assessed by a rating group, according to the formal consensus method. RESULTS: Postoperatively, radiotherapy to the primary tumor site±to the lymph nodes is indicated if one or more of the following adverse histoprognostic factors are present (risk>10% of locoregional recurrence): T3-T4 category, lymph node invasion, extraglandular invasion, close or positive surgical margins, high tumor grade, perineural invasion, vascular emboli, and/or bone invasion. Intensity-modulated radiation therapy (IMRT) is the gold standard. For unresectable cancers or inoperable patients, carbon ion hadrontherapy may be considered. CONCLUSION: Radiotherapy in salivary gland cancer is indicated in postoperative situations in case of adverse histoprognostic factors and for inoperable tumors.

Are there variations in adherence to colorectal cancer clinical guidelines depending on treatment place and recommendation novelty? The French EvaCCoR observational study.

BACKGROUND: Studies have shown clinical practices variation between centers in colorectal cancer (CRC) management. After the implementation of national cancer plans, we tested for differences in center and patients' socioeconomic position (SEP)-related variation in CRC guidelines. METHODS: All patients aged 18 years and over, cared for a first CRC in 2010 in Southwest of France. We used mixed effect model to test for center-related heterogeneity (CRH) in recommendation, from the oldest to the more recent: (1) at least 12 lymph nodes analysed for stage II, (2) the prescription of adjuvant chemotherapy stage III and (3) the assessment of CRC molecular phenotype regarding KRAS status for stage IV. Patients' SEP was approached by an ecological social deprivation index. RESULTS: We found: higher adherence for the oldest than for the most recent recommendations; no CRH in recommendation No. 2 but lower adherence in academic centers; a CRH for recommendations No. 1 and 3; no SEP-related differences in clinical practices. CONCLUSION: Results showed that older recommendations have higher adherence but did not support increasing influence of centers characteristics and CRH as recommendations are more recent.

Hypoxia imaging with [18F]-FMISO-PET for guided dose escalation with intensity-modulated radiotherapy in head-and-neck cancers.

BACKGROUND AND PURPOSE: Positron emission tomography (PET) with [(18)F]-fluoromisonidazole ([(18)F]-FMISO) provides a non-invasive assessment of hypoxia. The aim of this study is to assess the feasibility of a dose escalation with volumetric modulated arc therapy (VMAT) guided by [(18)F]-FMISO-PET for head-and-neck cancers (HNC). PATIENTS AND METHODS: Ten patients with inoperable stages III-IV HNC underwent [(18)F]-FMISO-PET before radiotherapy. Hypoxic target volumes (HTV) were segmented automatically by using the fuzzy locally adaptive Bayesian method. Retrospectively, two VMAT plans were generated delivering 70 Gy to the gross tumour volume (GTV) defined on computed tomography simulation or 79.8 Gy to the HTV. A dosimetric comparison was performed, based on calculations of tumour control probability (TCP), normal tissue complication probability (NTCP) for the parotid glands and uncomplicated tumour control probability (UTCP). RESULTS: The mean hypoxic fraction, defined as the ratio between the HTV and the GTV, was 0.18. The mean average dose for both parotids was 22.7 Gy and 25.5 Gy without and with dose escalation respectively. FMISO-guided dose escalation led to a mean increase of TCP, NTCP for both parotids and UTCP by 18.1, 4.6 and 8% respectively. CONCLUSION: A dose escalation up to 79.8 Gy guided by [(18)F]-FMISO-PET with VMAT seems feasible with improvement of TCP and without excessive increase of NTCP for parotids.

[mTOR inhibitors: temsirolimus and everolimus in the treatment of renal cell carcinoma]. / Inhibiteurs de mTOR : temsirolimus et évérolimus dans le traitement du cancer du rein.

mTOR signaling pathway (mammalian target of rapamycin) is a major pathway in cell physiology and malignant behavior implicated in cell growth, cell proliferation, cell metabolism, protein synthesis and angiogenesis. Temsirolimus has shown in a randomized phase III trial for patients with poor risk feature of metastatic renal cell carcinoma, a significant gain in overall survival compared to this obtained with alpha interferon (7.3 à 10.9 months; HR: 0.73; P < 0.0069). Everolimus has shown in a randomized phase III trial for patients with metastatic renal cell carcinoma having failed under VEGFR tyrosine kinase inhibitor a significant gain in progression-free survival compared to this obtained with placebo VEGFR (1,8 à 4,6 months; HR: 0.33; P < 0.001). Temsirolimus and everolimus are now part of the reference treatments in renal cell carcinoma. This paper is a review of these two drugs in this setting.

[Hand-foot syndrome and sorafenib]. / Sorafénib et syndrome main-pied.

Sorafenib (Nexavar) is a targeted therapy acting as VEGFR and PDGFR tyrosine-kinase inhibitor that has been approved in France in the treatment of metastatic renal cell carcinoma and hepatocarcinoma. Hand-foot syndrome is one of the more frequent toxicity related to sorafenib. This paper up lights the main points concerning this toxicity in the view of specialists working together in the care of these patients: a pharmacologist, a dermatologist and a medical oncologist. The clinic and symptoms of hand-foot syndrome as the biological interpretation, the symptomatic treatment and the impact on the specific treatment of sorafenib are developed.

Aggressive multimodal therapy of sporadic malignant insulinoma can improve survival: a retrospective 35-year study of 12 patients.

AIM: Sporadic malignant insulinoma (SMI) is a rare disease, and the consequent paucity of data in the literature and the development of aggressive treatments for liver metastases have led us to retrospectively analyze a series of 12 cases of SMI. METHODS: Every patient presenting with SMI, according to the WHO 2004 histopathology criteria, between 1970 and June 2005 in Marseille was included in the study. Patients with multiple endocrine neoplasia type 1 (MEN-1) and tumours of uncertain malignant potential were excluded. RESULTS: The ratio of male/female was 4/8, and mean age at diagnosis was 52.5 years. A 48-h fasting test in 10 patients was conclusive in nine, after a mean duration of 12 h 45 min. SMI size ranged from 7-120 mm (mean 30.3mm). Six patients had liver metastases and one had isolated lymph-node invasion. Surgery was performed in 12 patients. Five persisting diseases (mean follow-up of 1.8 years) required other treatments (chemoembolization, radiofrequency thermoablation [RFTA], liver transplantation); one patient relapsed 8.5 years after surgery; six were still in complete remission (mean follow-up of 5.8 years), and one patient had died by the time of the 24-month follow-up. CONCLUSION: Aggressive sequential multimodal therapy can prolong the survival of patients with SMI even in the presence of liver metastases.

Recurrences following primary osteosarcoma in adolescents and adults previously treated with chemotherapy.

In this retrospective analysis, we report on the detailed management of 33 recurrent osteosarcoma patients from a population of 81 adolescents and adults previously treated (between November 1979 and November 1998) at the La Timone Adults Hospital, for an extremity-localised osteosarcoma. The site of the first recurrence was limited to the lung in 24 patients (73%), was local in 4 patients (12%), at multiple sites in 4 patients (12%), and limited to the bone for 1 patient (3%). The median interval between the diagnosis of the primary osteosarcoma and the first recurrence was 16 months (range 4-108 months). For all patients, the treatment combined aggressive chemotherapy and surgical resection of the recurrences whenever possible. 19 patients (58%) achieved a second complete remission. The median follow-up time from the first recurrence was 18 months (range 4-150 months). For all patients, the median overall survival from first recurrence was 17 months (95% confidence interval (CI), 11-22 months) and the projected 3- and 5-year survival rates were 31.6 and 23.7%, respectively. Patients with a second complete remission had a better 5-year survival than patients without (44.6% versus 0%, P=0.001). The achievement of a second complete remission has an independent significant prognostic value for an improved survival. Aggressive surgery with the removal of recurrence sites combined with multi-agent chemotherapy can either cure patients with recurrent osteosarcoma or significantly prolong their survival.

Acentromeric micronuclei are increased in peripheral blood lymphocytes of untreated cancer patients.

Increased micronucleated cell rates, dicentric chromosomes, and other chromosomal damages have been reported in lymphocytes of cancer patients prior to the initiation of chemotherapy, and/or radiotherapy. The cause of these chromosomal damages in these lymphocytes remains unclear. In the present work, we investigated whether these micronuclei mainly reflect structural or numerical chromosomal aberrations by applying the cytokinesis-blocked micronucleus (CBMN) assay in combination with fluorescent in situ hybridization (FISH) of a DNA centromeric probe on blood samples of 10 untreated cancer patients (UCPs), and 10 healthy subjects (HSs). Micronucleated binucleated lymphocyte rate was significantly increased in patients (mean+/-S.D.: 19.0 per thousand +/-14.1 versus 9.2 per thousand +/-4.6 in controls). Trinucleated cytokinesis-blocked cells were not significantly higher in patients than in controls. Acentromeric, centromeric, and multicentromeric micronucleus levels were two-fold higher in patients than in controls, but the difference was significant only with acentromeric micronuclei. The percentage of micronuclei containing one or more centromeres averaged 69.2, and 71.5% in patients, and controls, respectively. The percentage of micronuclei containing several centromeres was 44.7% in patients, and 54.6% in controls. Among centromere-positive micronuclei, the percentage of micronuclei containing several centromeres averaged 59.7% in patients, and 75.4% in controls. These results indicate that genetic instability in peripheral blood lymphocytes of UCPs occurs because of enhanced chromosome breakage. However, a substantial proportion of this genetic instability occurs because of defects in chromosome segregation.

Osteosarcomas of flat bones in adolescents and adults.

BACKGROUND: Osteosarcomas typically are long bone tumors and rarely affect the flat bones of the axial or appendicular skeleton. METHODS: The authors examined cases of high grade osteosarcoma of flat bones diagnosed at La Timone Adults University Hospital during a 16-year period. RESULTS: Sixteen patients with flat bone osteosarcomas were treated between 1980-1997. The median age of the patients was 25 years, with a male-to-female ratio of 14:2. Common presenting symptoms were swelling, pain, or both. Primary therapy included resection (n = 11 patients: alone in 8 patients and with radiation therapy in 3 patients), radiation therapy (n = 2 patients), or no local treatment (n = 3 patients). All patients received polychemotherapy, 7 preoperatively and postoperatively and 9 in the adjuvant setting. The overall 5-year survival rate was 47.7%; the overall median survival was 39 months (range, 4-211 months). The adequate local control rate was 68.7%. The local recurrence rate in patients who benefited from local treatment was 54%. Significant adverse prognostic factors on survival included the presence of synchronous metastases (three patients), metastases at any time during the course of the disease (eight patients), and inadequate local control (five patients). The overriding predictor of survival appeared to be the presence of metastases. Local recurrence appeared to have no influence on survival. No patient with metastases was alive at 3 years, whereas patients without recurrence or with local recurrence alone had a 5-year survival rate of 100%. Because the majority of patients with flat bone osteosarcomas ultimately die of metastatic disease, intensive systematic polychemotherapy should be an important component of treating these tumors. CONCLUSIONS: Based on the very encouraging results observed in the treatment of long bone osteosarcomas, the therapy for flat bone osteosarcomas should combine radical surgery with preoperative and postoperative adjuvant chemotherapy.

Micronucleated lymphocyte rates from head-and-neck cancer patients.

We investigated whether head-and-neck cancers are associated with an increased micronucleated cell rates (MN cell rates) and whether risk factors for these cancers are associated with alterations in micronucleated lymphocytes. MN cell rates were assessed in cytokinesis-blocked lymphocytes of 57 head-and-neck cancer patients (CP) before any anticancer treatment and of 198 male and female healthy subjects (HS). In the HS group, only smoking status significantly affect MN cell rates. In CP group age, sex, tobacco status, alcohol status, tumor stage, family history of cancer had no significant effect. For the non-smokers, the comparison between MN cell rates in HS and CP adjusted for age and sex showed a significant difference. The increase of MN cell rates in non-smokers patients may be attributable to cancer status. For the smokers, the comparison of MN cell rates in HS and CP matched for age and sex showed no significant difference. Pathological status could mask the smoking effect on peripheral blood lymphocytes in patients. Moreover, it probably could partly explain why MN cell rates in matched-CP smokers and HS smokers were similar. The authors do not recommend the CBMN assay in this present form to study smoking DNA-damage effects in peripheral blood lymphocytes of cancer patients, especially for patients with upper aero-digestive tract cancers or lung cancers for which tobacco is the major risk factor.

Evaluation of the genotoxic activity of paclitaxel by the in vitro micronucleus test in combination with fluorescent in situ hybridization of a DNA centromeric probe and the alkaline single cell gel electrophoresis technique (comet assay) in human T-lymphocytes.

Paclitaxel is a recent chemotherapeutic agent that inhibits tubulin depolymerization in tumoral cells. Despite its increasing use against various human cancers, the genotoxicity of paclitaxel has never been studied on normal human cells. The in vitro genotoxic effects of the drug were evaluated with two complementary mutagenesis tests on human T-lymphocytes: (1) the cytokinesis-blocked micronuclei assay (CBMN) in combination with fluorescent in situ hybridization (FISH) of nonspecific centromeric probes and (2) the comet assay performed in three ways: on stimulated lymphocytes as in the CBMN, and on freshly isolated lymphocytes at both 4 and 37 degrees C. A slight cytotoxicity of 2.5 to 10 nM paclitaxel was found in the CBMN and a significant increase in the binucleated micronucleated cell rates was observed, with a concentration-dependent manner. In the FISH analysis, more than 85% of the micronuclei (MN) were centromere positive, and a ratio of 72. 2 to 78.6% of these MN contained more than one centromere. Moreover, at 10 nM of paclitaxel, 35.6% of the cells are multimicronucleated lymphocytes. Unexpectedly, paclitaxel induced single-strand breaks on proliferating lymphocytes at 5 and 7.5 nM but not in resting cells, even at 5 to 15 microM. These in vitro results showed that (1) paclitaxel does not present any direct DNA action in resting cells, (2) DNA damage detected in stimulated lymphocytes may be linked either to a high frequency of cells in the S-phase cell cycle or to a direct DNA damaging effect on replicating cells, and (3) paclitaxel is a strong in vitro aneugenic drug on human normal cells, at clinically relevant concentrations.

[Genotoxic and clastogenic effects of doxorubicin]. / Pouvoir génotoxique et clastogène de la doxorubicine.

Doxorubicine is an anthracyclin used widely in medical oncology. The purpose of this investigation was to evaluate the genotoxic and clastogenic effects of this substance through the cytokinesis-block micronucleus assay. This short-term mutagenicity assay is of easy realization and quick interpretation. It has enabled the demonstration of a significant decrease, after exposure of cells to doxorubicin, of the rate of micronucleated cells (average = 10.8 +/- 5.7 micronucleus versus 31.9 +/- 11.5 after exposure, p < 0.0001) and chromosomic aberrations (1 aberration for the control culture versus 17 since the first dose, p < 0.001). At the end of this study, the cytokinesis-block micronucleus assay represents a reliable test to study and evaluate the genotoxic power of some substances.

[Doxorubicin and cisplatin genotoxicity: search for a real indication using the micronucleus test]. / Génotoxicité de la doxorubicine et du cisplatine: recherche d'un témoin positif pour le test des micronoyaux.

Doxorubicin and cisplatin are two major anticancer drugs, and are also known to be mutagen. Using short term mutagenesis tests, the cytokinesis-block micronucleus test and chromosome aberrations test, a study of the cytotoxicity and the mutagenicity of these two drugs has been aimed to determine a genotoxic of reference for these tests. Cisplatin and doxorubicin were genotoxic and gave positive results with the two tests. Since cisplatin was more cytotoxic than doxorubicin for a same genotoxicity, doxorubicin has been selected as a positive control for these two short-term mutagenesis tests. A study of the individual variability in the response to in vitro doxorubicin exposure was made using the cytokinesis-block micronucleus test, applied to cultured T lymphocytes form healthy subjects and cancer patients. Micronucleated cell rate before (T0) and after in vitro exposure to doxorubicin (T1) were determined in the two groups of subjects. Micronucleated cell rates T1 were significantly higher than T0 for healthy subjects and cancer patients. A calculated sensitivity index [(T1)-(T0)] is proposed to evaluate the individual sensitivity to the positive control doxorubicin.

[Importance of micronucleus tests in cultured binuclear T lymphocytes for the detection of genotoxic events in cancer patients]. / Intérêt du test des micronoyaux dans les lymphocytes T binucléés en culture pour la mise en évidence d'un événement génotoxique chez les patients cancéreux.

The cytokinesis-blocked micronucleus assay (CBMN) is a short-term mutagenesis test which offers an easier and less tedious alternative to metaphase chromosome analysis, with the advantage that exposure to both clastogens and aneugens may be detected. The CBMN assay has been used in evaluating the genotoxic consequences of exposures to environmental and occupational mutagens and carcinogens. Micronucleated cell rates (MN cell rates) were assessed in cytokinesis-blocked lymphocytes of 70 male and female cancer patients prior to any anticancer treatment. The study of interindividual variation factors showed that only age significantly affect MN cell rate, whereas sex, tobacco, alcohol, imaging techniques and tumour stage had no significant effect. The comparison of micronucleated cell rates in 198 healthy subjects and 70 cancer patients matched for age and sex showed a statistically significant difference. Spontaneous elevated MN cell rates of cancer patients refer to previous exposition of genotoxic or mutagenic environmental agents. Moreover, the MN cell rates in cancer patients most probably refers to various cellular lesions and genetic damages.