Annals of oncology : official journal of the European Society for Medical Oncology
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The primary goal of phase I studies is to efficiently and accurately determine the recommended dose of a new agent for further investigation. Issues of concern ranging from the ethics of these trials to selection of starting dose and rapidity of dose escalation, have led to suggested modifications of the traditional phase I design. We wanted to assess the frequency with which these new approaches are being applied to recent phase I trials and, if possible, their impact. ⋯ Despite proposed new methodologies (particularly dose escalation) for phase I trials, very few are being employed in practice. A concerted effort should be made to prospectively evaluate these to determine which provides the best combination of safety and efficacy. In addition, the lack of standardization in the definition of limiting toxicity is surprising. Those involved in drug development should strive for agreement on the acceptable degree of toxicity for phase II dose selection.
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For more than 20 years now treatment strategies geared to the specific problems in children with Hodgkin's disease (HD) have been tested by different pediatric oncologic groups. In these approaches high priority was given to the reduction of late effects caused by radio- and chemotherapy, next to the goal of achieving high survival rates. Combined modality treatment as a standard option has enabled reduced dosages and fields of radiotherapy and lowered cumulative total doses of critical cytotoxic agents. ⋯ The ratio between cure rates and late effects has been favourably balanced with OPPA, respectively, OPPA/COPP plus low-dose IFI, especially in female patients. In boys the risk of testicular dysfunction can be further reduced by substituting OEPA for OPPA. Age up to 18 years does not appear to be of any significance for the treatment results with our therapy concept.
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The conventional phase I clinical trial stands as a bridge between the laboratory and the clinic in the development of novel anticancer agents. The purpose of the phase I study is primarily to determine toxicity and to define the maximum tolerated dose of the drug in man. It is assumed for this purpose that dose-response curves for toxicity and efficacy are parallel or, simply expressed, the more pain, the more gain. Novel antineoplastic drugs are being developed that are mechanistically remote from conventional cytotoxic drugs, which have DNA as their predominant target; some of these new agents have, at least in vitro, bell-shaped dose-response curves. ⋯ It is essential that flexible clinical trial methodologies are developed to accommodate new drugs and that attempts are made, when possible, to incorporate pharmacodynamic endpoints in addition to toxicological endpoints.
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Up to now, the majority of adjuvant chemotherapy trials in gastric cancer have failed to show a clear survival benefit as compared to surgical controls, and this is especially true for trials conducted in western countries. But this does not necessarily mean, that adjuvant chemotherapy of gastric cancer is in general ineffective. There are several common threads that appear repeatedly in adjuvant therapy trials which might help to explain the current situation. ⋯ There are sufficient data, that in comparison to 'limited' surgery, extended surgery with systematic lymphadenectomy of the N2 compartment markedly improves the prognosis of patients with stage II and IIIa tumors. The kind of chemotherapy, its timing and scheduling, and route of administration might also have been inappropriate to demonstrate a possible benefit of adjuvant therapy. All these things have to be considered seriously in future well designed trials, if an assumed therapeutic gain is to be demonstrated by adjuvant treatment of gastric cancer.