[Recommendation of the working group commissioned by the French Nuclear Safety Authority on stereotactic radiation therapy]. / Avis du groupe de travail missionné par l'Autorité de sûreté nucléaire concernant la radiothérapie stéréotaxique.

PURPOSE: At the request of the French nuclear safety authority (Autorité de Sûreté Nucléaire, ASN) a working party of multidisciplinary experts was initiated to elaborate a report regarding propositions for the clinical practice of stereotactic radiation therapy and the related medical physics. MATERIAL AND METHODS: Several stereotactic radiation therapy experts were audited by the working party, especially neurosurgeons and neuroradiologists, as well as radiation oncologists, medical physicists and radiation technologists. An international survey was conducted looking at legal requirements and guidelines concerning stereotactic radiation therapy. A national survey was conducted in France among 29 departments performing stereotactic radiation therapy. The working party report was submitted for advice to the permanent group of medical experts of ASN. RESULTS: Among the 13 countries who responded, very few have legal documents. Some of them are stating that stereotactic radiation therapy must be performed in a radiotherapy department and only by well-trained professionals. Guidelines describing the role of each participant have been published in the USA. In France, stereotactic radiation therapy is performed with dedicated machines or adapted linear accelerators. In 2009, within the 29 departments, 4247 patients were treated with stereotactic radiation therapy representing 4% of the patients treated with external beam radiation therapy. Intracranial lesions were: 3383 and extracranial: 864. The working party of multidisciplinary experts made 7 recommendations. The first one saying that stereotactic radiation therapy must be considered as a radiotherapy. The permanent group of medical experts is asking to modify the "décret du 19 mars 2007" regarding "radiosurgery". CONCLUSION: The medical benefit of stereotactic radiation therapy is well admitted and it is an increasingly used technique. This work through practical guidelines and legal propositions intends to promote a well-controlled development of this radiotherapy technique.

Cellular pharmacology of the combination of the DNA topoisomerase I inhibitor SN-38 and the diaminocyclohexane platinum derivative oxaliplatin.

CPT-11, a DNA topoisomerase I inhibitor, and oxaliplatin, a diaminocyclohexane platinum derivative, are cytotoxic agents that have demonstrated clinical antitumor activity in colorectal cancer. Given the therapeutic potential of their combination, we studied the cellular pharmacology of SN-38, the active metabolite of CPT-11, and oxaliplatin in the human colon cancer HT29 cell line. Growth inhibition was studied after a 1- or 24-h exposure to SN-38 or oxaliplatin, given alone or in combination. The cytotoxicity analysis by the isobolograms method elicited synergy. SN-38 delayed the reversion of oxaliplatin-induced DNA interstrand cross-links (ISCs), measured in cells by alkaline elution. The amount of detectable ISCs 15 h after a 1-h exposure to 10 microm oxaliplatin was 27% of the ISC peak levels and increased to 68% in the presence of 0.1 microM SN-38. The presence of oxaliplatin DNA adducts led to a 3.3-fold increase in the SN-38-induced DNA elongation inhibition, as measured by pulse-labeling alkaline elution. Inhibition of DNA and RNA synthesis was longer after exposure to the combination of oxaliplatin and SN-38 than after exposure to each agent alone. Consistently, flow cytometry analyses revealed that preexposure to oxaliplatin enhanced SN-38-induced S-phase arrest. Filter binding assays indicated that the cells arrested in S-phase at 48 h were undergoing apoptosis. Hence, supra-additive cytotoxicity appears related to major modifications in the cellular response to DNA damage rather than to changes in DNA damage formation. The combination of CPT-11 and oxaliplatin induced a 2-fold higher tumor growth reduction in vivo than did oxaliplatin alone at feasible nonlethal doses. This study provides a rationale for the optimal use of CPT-11 and oxaliplatin in combination.

Cellular pharmacology of the combination of oxaliplatin with topotecan in the IGROV-1 human ovarian cancer cell line.

The clinical development of combinations of cisplatin or carboplatin with DNA topoisomerase I (Topo I) inhibitors is based on their overlapping spectrum of antitumor activity and their in vitro synergy, but is limited by significant hematotoxicity. We studied the cellular interactions between oxaliplatin and topotecan in the IGROV-1 human ovarian cancer cell line prior to evaluating the combination in the clinic. Growth inhibition was studied after a 96 h exposure to oxaliplatin and topotecan. The analysis of the cytotoxicity by the isobolograms method revealed supra-additivity with maximal cytotoxicity obtained by giving oxaliplatin prior to topotecan. In the presence of topotecan, the formation of oxaliplatin-induced DNA interstrand crosslinks was not modified in cells, but their reversion was slower, as measured by alkaline elution. Successive topotecan exposures did not affect the level of Topo I-mediated DNA single-strand breaks (SSBs). Pre-exposure to oxaliplatin transiently increased Topo I-mediated SSBs, suggesting that DNA platination might stimulate Topo I DNA cleavage activity. Hence, the cellular pharmacology of oxaliplatin combined with topotecan appeared highly dependent on the schedule. Therefore, this study suggests that the combination of topotecan with oxaliplatin might exhibit sequence-dependent pharmacodynamic interactions in the clinic.