Lionel Védrine

Whole-brain radiation therapy in breast cancer patients with brain metastases

Over the past 10 years, improving the outcome of breast cancer patients with brain metastases has become an important challenge. The suboptimal results of whole-brain radiation therapy (WBRT) in these patients have led to the development of irradiation modalities with new technical and biological approaches. By ensuring better sparing of critical organs such as the hippocampus, highly conformal irradiation therapy may partially preserve long-term neurocognitive functions. An additional radiation boost to the tumor bed improves local control. Radiosensitizing agents and radioprotectors that modify response to radiation have also been designed to improve the efficacy of treatment or prevent neurological toxicity. This Review outlines the current strategies and novel developments in WBRT, with a particular focus on new irradiation modalities and experiences of radiosensitization.

Facteurs de radiorésistance des cellules souches cancéreuses et perspectives de radiosensibilisation: l'exemple du glioblastome

Cancer stem cells are a subject of increasing interest in oncology. In particular, several data suggest that cancer stem cells are involved in the mechanisms of tumor radioresistance, and may explain the therapeutic failures after radiotherapy. Because of its poor prognosis and high recurrence rate after irradiation, glioblastoma model is often studied in the search for new radiosensitizers. There are several preclinical data suggesting that cancer stem cells could be a potential therapeutic target for improving the biological effectiveness of radiation therapy. Through the example of glioblastoma, we review the main signaling pathways involved in the mechanisms of radiation resistance of cancer stem cells and for which pharmacological targeting could potentially enhance tumor radiosensitivity.

Inhibitors of angiogenesis: new hopes for oncologists, new challenges for anesthesiologists.

ANESTHESIOLOGISTS are involved in many aspects of cancer treatment that may interfere with perioperative care. Some of these treatment considerations may have a major impact on patient outcomes. Basic research in oncology has recently led to a wealth of knowledge about novel biologic pathways for more efficient and selective tumor cell targeting. Antiangiogenic therapy has demonstrated significant activity in patients with solid tumors, such as metastatic breast cancer, renal cell carcinoma, brain tumors, non-small-cell lung cancers, and colorectal carcinoma (table 1). By targeting vascular endothelial growth factor (VEGF), these agents have demonstrated clinical efficacy in medical oncology. However, angiogenic factors are also involved in a number of physiologic processes, including tissue remodeling and wound repair. The VEGF family consists of seven related glycoproteins (VEGF-A, B, C, D, E, and placenta growth factors 1 and 2). Commonly referred to as VEGF, VEGF-A was initially identified by its ability to increase vascular permeability. The most important effects of VEGF include endothelial cell activation, tumor growth, and cell migration. The physiologic function of VEGF is to generate new blood vessels after injury to promote collateral circulation. Its production is induced in hypoxic cells through hypoxia-inducible factor (HIF) production. Circulating VEGF then binds to VEGF receptors on endothelial cells, leading to angiogenesis. Two main anti-VEGF strategies have been developed over recent years: neutralizing anti-VEGF antibody and small molecule tyrosine kinase inhibitors (TKI) targeted against VEGF receptors. While potentially improving overall survival, inhibitors of VEGF are subject to considerable uncertainty concerning their potential toxicity. An increase in wound complications and thromboembolic events has been observed in patients who undergo surgery while receiving inhibitors of angiogenesis. This paper highlights the toxicities of VEGF inhibitors, with special focus on consequences for anesthesiologists.

First case of posterior reversible encephalopathy syndrome associated with vinflunine.

The vinca alkaloids are a family of cytotoxic that was discovered in the late fifties. At the molecular level, tose agents act by targeting tubulin. By blocking microtubule polymerization and depolymerization of established microtubules, vinca alkaloids activate cell cycle blockage in G2/M and exhibit marked antitumor activity [1]. Vinflunine is a third generation vinca alkaloid which has recently demonstrated its benefit as second line therapy for patients who experienced tumor progression after Platinum-based chemotherapy in urothelial carcinoma of bladder, with a better safety profile than other agents in this family [2]. The posterior reversible encephalopathy syndrome (PRES) consists of a rare entity combining various neurological symptoms and posterior reversible leukoencephalopathy. Various etiologies have been advocated for this recently described syndrome but the underlying physiopathological mechanisms remain uncertain. Some cases of PRES have been related to the use of cytotoxic agents [3]. Early management should help optimizing the treatment of PRES in order to potentially reduce morbidity and mortality resulting from a delayed diagnosis. To our knowledge, we report the first case of posterior reversible encephalopathy syndrome after injection of vinflunine.

Analysis of feasibility and toxicity of radiotherapy in centenarians.

nicate with people with dementia (85.4%); most employers will fire a 65-year-old employee with dementia (76.4%); individuals with dementia would not understand other people’s concern or worry (68.5%); individuals with dementia are impulsive and unpredictable (62.9%). These attitudes prevent the Chinese-American general public from encouraging older adults to seek early treatment and hinder public acceptance of individuals with dementia. Discrimination and shame can have a devastating effect on Chinese-Americans with dementia. Several areas of the lives of individuals with dementia would be affected, including employment and social relationships. Because community support is necessary for dementia treatment, participation of the general public remains crucial to overcoming the stigma of dementia, but lack of understanding of dementia in the Chinese community may contribute to social exclusion and discrimination toward individuals with dementia. An antistigma campaign, especially for Chinese-American immigrants, should focus on clarifying that people with dementia are neither dangerous nor unpredictable and that people with dementia are still functional, productive, and independent citizens in the Chinese-American community and on putting a human face (e.g., recruiting speakers with dementia) to inform the Chinese-American lay public that individuals with dementia understand other people’s concerns and worries. Future studies examining the relationship between knowledge about dementia and the shame associated with it in the Chinese American general public will better illustrate how to alleviate negative stereotyping of dementia. Because the media can play an important role in reaching out to this ethnic minority group, it is important to work on media interventions to prevent shame regarding dementia in the Chinese-American general public.

Knowledge and screening of testicular cancer in the French Armed Forces: a prospective study.

We performed a prospective study in the French Armed Forces regarding testicular cancer. Our primary objective was to assess whether willingness to have a testicular examination by medical doctor could be improved by a self-administered questionnaire through invitation to self-reflection. A total of 415 soldiers were enrolled. The study used a test-posttest design in that soldiers estimated their willingness to have a testicular palpation before and after responding to a self-administered questionnaire. The willingness to have testicular palpation significantly increased after responding to the questionnaire (p < 0.000001). Acceptance of testicular palpation after responding the questionnaire did not change in 82.25%, increased in 15%, and decreased in 2.75%. Analysis of responses to the questionnaire showed that 26.75% of soldiers (n = 107) had previously received general information on testicular cancer and 85.8% (n = 343) declared that they would be delighted if they were proposed a short educational course on testicular cancer. As a conclusion, this study demonstrates that the willingness to have a testicular examination by medical doctor could be easily improved, since there is a strong demand on medical education regarding testicular cancer.

Chemotherapy Regimen in Nonagenarian Cancer Patients: A Bi-Institutional Experience

Background: The elderly population in Western countries is growing and constitutes a public health issue. Concomitantly, age-related diseases such as cancer increase. There are few data on the efficacy, tolerability and toxicity of specific anticancer therapy in the very elderly patients; therefore, their management is not standardized. Methods: In this bi-institutional study, we reviewed medical records of patients who received or continued specific anticancer therapy beyond the age of 90 years. Geriatric assessment was not reported for our patients. Twelve patients were enrolled. Their general health condition was good, and half of them were living in elderly institutions. Ten patients had a solid tumor and 2 were treated for hematological malignancies. Most were diagnosed with a locally advanced or metastatic disease, and the goal of treatment was curative for only 1 patient. Six patients received chemotherapy as first-line treatment, 4 patients received targeted therapy and 2 received concomitant chemoradiation. Four patients received a second-line treatment. Results: Despite a significant reduction in treatment posology in half of the patients, 8 acute grade 3/4 toxicities were reported and 2 patients died of treatment-related septic shock. Median duration of first-line treatment was 3.2 months, and progression-free survival ranged from 18 to 311 days. Overall survival ranged from 18 days to 11 years. Conclusion: Aging is a heterogeneous process, and management of elderly patients is a multidisciplinary approach. Geriatric assessment helps to identify older patients with a higher risk of morbidity/mortality and allows to assess the risks and benefits of specific anticancer therapy. The choice of treatment should be based primarily on the expected symptomatic benefit, and treatment should not compromise the quality of life.

Evaluation of circulating tumor cells (CTCs) enumeration and 18F-Choline positron emission tomography/computed tomography (FCH PET/CT) as early efficacy response biomarkers in metastatic castration-resistant prostate cancer (CRPC) patients (pts) treated with abiraterone acetate.

63 Background: Circulating tumor cells (CTCs) and FCH PET/CT are both promising tools for treatment monitoring in CRPC pts. In this study, we assessed prostate specific antigen (PSA), CTC and FCH PET/CT for monitoring treatment response in metastatic CRPC pts receiving recently approved abiraterone acetate therapy after chemotherapy. METHODS Twenty nine metastatic CRPC pts progressing after docetaxel chemotherapy received abiraterone acetate 1,000 mg daily with prednisone 5 mg twice daily in continuous 28-day cycles. Pts were evaluated monthly for efficacy and safety. CTCs counts (using the CellSearch assay) and FCH PET/CT were performed at baseline and at 4 weeks (PERCIST criteria and SUV Peak). RESULTS After one month of treatment, 12 pts (41%) had a PSA rise and 17 pts (59%) had a PSA decline. At baseline, 18 pts had detectable CTCs (at least 5 CTCs), and 6 of them (33%) had a decline from at least 5 to less than 5 CTCs after 4 weeks of treatment. 10 of 29 pts (34%) had a > or = 30% decline in CTCs. Amongst 22 pts who were evaluable by FCH PET/CT, response assessment was as follows: response (n=8), stable disease (n=12), progression (n=1). PSA decline and CTCs levels correlated in 16 of 29 pts (55%), and were discordant in 13 of 29 pts (45%). In all 12/29 pts (41%) with a 50% or more decline in PSA both a CTCs response and a FCH PET/CT response was observed. In patients with a PSA rise while on abiraterone acetate, 8 pts did not have a CTCs increase or a CTC conversion from unfavourable to favorable, and 7 of 8 pts had a PSA decline at 3 months or a FCH PET/CT response. No flare phenomenon on FCH PET/CT was observed. CONCLUSIONS Monitoring pts with CRPC who receive abiraterone using both CTCs and metabolic imaging indicate discrepancy in 45% with response assessment using PSA. Association between CTC drop, early FCH PET/CT response and clinical benefit is currently under study.

Combination of paclitaxel and bevacizumab in heavily pre-treated non-small-cell lung cancer (NSCLC) patients: a case series study on 15 Patients

BACKGROUND The combination of paclitaxel and bevacizumab was EMA-approved as first-line therapy in metastatic breast cancer. Moreover, in vitro studies showed a potential antiangiogenic synergistic effect of paclitaxel and bevacizumab. METHODS Between November 2008 and March 2010, this case series study included 15 patients with metastatic non squamous-cell lung carcinoma (NSCLC). Those were bevacizumab eligible and received the same regimen used in metastatic breast cancer with weekly paclitaxel (80 mg/m(2), days 1, 8 and 15) and bevacizumab (10 mg/kg at days 1 and 15) after at least one prior line of chemotherapy. Efficacy was evaluated by CT-scan and PET-FDG every two months. Circulating endothelial progenitor cells (CEP) and circulating endothelial cells (CEC) levels were explored in a subset of patients. RESULTS Median age 56 (36-75), female: 47%, never smokers: 27%, adenocarcinoma: 100%, PS 0-1: 87% and PS 3: 13%. All patients were treated with a first-line platinum-based doublet with or without bevacizumab and 70% of them with erlotinib in the second-line. No major toxicity was observed. Partial response (PR) rate was 44% (31-63%) using RECIST criteria on CT-scan, and 65% (29-88%) with PET FDG. PS improved in 33% of the cases. Median progression free survival was 4.6 months. An increase of CEC and CEP was observed in patients with NSCLC treated with paclitaxel and bevacizumab. CONCLUSION In this retrospective series, our results suggest efficacy signal in pre-treated metastatic NSCLC and warrant further assessment in a randomized clinical trial.

Ipilimumab in cancer patients: the issue of early metabolic response.

In a recent issue of the Journal of Clinical Oncology, McArthur et al. [1] examined the metabolic response rate to vemurafenib in patients with advanced BRAF-mutant melanoma. The authors reported that F-fluorodeoxyglucose (F-FDG)-PET could be used for the early assessment of a response to vemurafenib. We highlight the need to examine underlying biological mechanisms before applying this strategy to other anticancer drugs.