Annals of oncology : official journal of the European Society for Medical Oncology
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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.