Schedule-dependent activity of 5-fluorouracil and irinotecan combination in the treatment of human colorectal cancer: in vitro evidence and a phase I dose-escalating clinical trial

Several schedules of 5-fluorouracil (FU) and irinotecan (IRI) have been shown to improve overall survival in advanced colorectal cancer (CRC). Preclinical evidence suggests that the sequential administration of IRI and FU produces synergistic activity, although their clinical use has not been fully optimised. We investigated the interaction between short-term exposure to SN-38, the active metabolite of IRI, and prolonged exposure to FU in human CRC HT-29 cells and observed that the synergism of action between the two agents can be increased by extending the time of cell exposure to FU and reducing the interval between administration of the two agents. Based on these findings, we performed a phase I trial in 25 advanced CRC patients using a modified IRI/FU regimen as first-line therapy and evaluated three dose levels of IRI (150–300 mg/m2) and two of continuous infusion of FU (800–1000 mg/m2) in a 3-weekly schedule. The most severe grade III–IV toxicities were neutropoenia in four cycles and diarrhoea in three. One patient achieved complete response (4%), 12 a partial response (48%), the overall response rate was 52% (±20, 95% CI); seven of 25 patients had stable disease (28%), the overall disease control was 80% (±16, 95% CI). This modified IRI/FU schedule is feasible and exhibits potentially interesting clinical activity

Avis du groupe de travail missionné par l'Autorité de sûreté nucléaire concernant la radiothérapie stéréotaxique

National audiencePurpose: 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. © 2012.Objectif de l’étude :À la demande de l’Autorité de sûreté nucléaire (ASN), un groupe de travail composé d’experts pluridisciplinaires a travaillé pour élaborer un rapport sur les conditions d’exercice de la radiothérapie stéréotaxique et de la radiophysique médicale associée.Matériel et méthodes : Le groupe de travail a auditionné plusieurs experts en radiothérapie stéréotaxique, notamment les neurochirurgiens et neuroradiologues, mais aussi les oncologues radiothérapeutes, les physiciens médicaux et les manipulateurs en radiothérapie. Le groupe de travail a réalisé une enquête internationale pour connaître les réglementations et recommandations existantes en matière de radiothérapie stéréotaxique. Un état des lieux de la pratique de radiothérapie stéréotaxique en France a été réalisé auprès de 29 centres pratiquant cette technique. Le rapport du groupe de travail a été soumis à l’avis du groupe d’experts médicaux de l’ASN.Résultats : Parmi les 13 pays interrogés, les textes réglementaires sont rares et mentionnent pour certains l’obligation de réaliser la radiothérapie stéréotaxique au sein d’un service de radiothérapie et de réserver sa pratique à des professionnels disposant d’une formation spécifique. Des recommandations ont été publiées aux États-Unis décrivant le rôle de chaque intervenant au cours de l’acte de radiothérapie stéréotaxique. En France, il existe des appareils dédiés à cette technique qui est aussi réalisée avec des accélérateurs classiques adaptés. En 2009, dans les 29 centres interrogés, 4247 patients ont bénéficié d’une radiothérapie stéréotaxique (soit environ 4 % des radiothérapies externes), dont 3383 pour des lésions intracrâniennes et 864 extracrâniennes. Dans son rapport, le groupe de travail a émis sept recommandations, dont notamment la nécessité de considérer tout acte de radiothérapie stéréotaxique comme un acte de radiothérapie. Le rapport du groupe d’experts médicaux de l’ASN recommande de modifier le décret du 19 mars 2007 concernant « la radiochirurgie ».Conclusion : La radiothérapie stéréotaxique, dont le service médical rendu est reconnu, verra sa pratique se développer dans les années prochaines. Ce travail à travers ses recommandations pratiques et ses propositions réglementaires, souhaite participer à une croissance maîtrisée de cette technique de radiothérapie

Irinotecan and oxaliplatin: an overview of the novel chemotherapeutic options for the treatment of advanced colorectal cancer

Colorectal cancer is one of the most frequent malignancies in humans and an important cause of cancer death. Metastatic colorectal cancer remains incurable with available systemic therapeutic options. The most active cytotoxic drug against this malignancy, the antimetabolite 5-fluorouracil, was developed more than forty years ago, and as a single agent produces responses in only 10 to 15% of patients which in general last less than one year. Efforts to ameliorate these poor results resulted in the 5-fluorouracil/leucovorin combination, which enhances response rates about two-fold, without, however, significantly improving survival rates. The recent emergence of a handful of new 5-fluorouracil analogues and folate antagonists, as well as the topoisomerase I inhibitor irinotecan, and the third-generation platinum compound oxaliplatin, is likely to alter this gloomy scenario. These agents are at least as effective as 5-fluorouracil in patients with advanced colorectal carcinoma, both untreated and previously treated with 5-fluorouracil-based regimens. This has led to the approval of irinotecan as second-line treatment for 5-fluorouracil-refractory disease, while the use of oxaliplatin has been suggested for patients having a defective 5-fluorouracil catabolism. Recently, FDA approved the combination of irinotecan with 5-fluorouracil and leucovorin for first-line treatment of advanced colon cancer. Based on the synergistic preclinical antitumor effects of some of these agents, their meaningful single-agent activity, distinct mechanisms of cytotoxicity and resistance, and only partially overlapping toxicity profiles, effective combination regimens are now being developed, which are likely to lead to a new, more hopeful era for patients suffering from advanced colorectal carcinoma