Bestimmung der Stoffwechselprodukte nach topischer und systemischer Applikation von 5-Aminolävulinsäure zur Fluoreszenzdiagnostik von Karzinomen der oberen Luft- und Speisewege

In Germany carcinomas of the head and neck region rank seventh in the annual newly diagnosed carcinoma rate. The Incidence rate is steadily increasing and long-term survival rate is more or less stable over the last decades despite the further development of diagnostic and therapeutic tools. A satisfying treatment and an improvement of the prognosis can only be achieved by early detection and determination of the carcinoma site. A new method applicable to diagnostic and therapeutic purpose is using the fluorescence inducing substance 5-aminolevulinic acid (5-ALA). It is a metabolic precursor in the biosynthetic pathway of heme and protoporphyrin IX (PPIX) is formed as an intermediate product which shows characteristic fluorescence patterns and accumulates selectively in malignant cells. In Germany 5-ALA induced fluorescence endoscopy has obtained clinical approval for the detection of carcinomas of the urinary bladder as well as for treatment of superficial carcinomas and premalignant lesions of the skin. Further diagnostic and therapeutic applications are currently evaluated by medical research. The aim of the present study was to investigate quality and quantity of the metabolic products of 5-ALA in urine and blood samples to draw conclusions about the possible accumulation of these products in the body. Special attention was turned to the pharmacologic differences between topical and systemic administration. 66 patients with a histologically proven or suspected squamous cell carcinoma of the head and neck region underwent endoscopic examination of this region from February to August 2000. 5-ALA was applied preoperatively by inhalation (200 mg), mouth wash (200 mg) or orally/systemic (20 mg/kg body weight). Urine and blood samples were collected after examination. The biochemical assay of porphyrins and porphyrin-precursors was performed by the laboratory of clinical chemistry of the university hospital Marburg. Urinary porphyrin precursors (ALA, PBG) and total porphyrins (GESAMT) after topical application returned well below baseline level 36 hours after application at the latest. After systemic administration porphyrins and porphyrin precursors exceeded normal values many times over but also return to baseline levels within 36 hours, except URO and KOPRO which were still slightly increased. Significant differences have not been ascertained between the two topical methods but between mouth wash and systemic application 24 hours after administration. Most significant differences between inhalation and systemic application were found at both times. Protoporphyrin concentration in blood already reached baseline level 12 hours after examination in every patient. Accumulation of metabolic products of 5-ALA can be excluded, undesirable side effects have not been observed. In accordance with other authors it can be concluded that topical application of 5-ALA in the amount of 200 mg to 250 mg as well as systemic administration of 20 mg/kg body weight does not lead to accumulation of porphyrins or its precursors in urine or blood. Protoporphyrins in blood do not exceed baseline levels longer than 36 hours. It is not clear how much renal and hepatic disorders interfere with the elimination of metabolic products of 5-ALA. Animal experiments have shown that side effects like vomiting after 5-ALA application are dependent on the dose. The frequency of vomiting rises proportionally to the increase of 5-ALA from a dose of 25 mg/kg body weight. Side effects seem to be related to the dose of 5-ALA, but further research is needed to verify this. Both topical methods are equal from the pharmacological point of view, but show differences in practicality. Inhalation is more advantageous than mouth wash due to its independency of pulmonary function and cooperation of the patient regarding the deepness of breath. Reducing the oral bacteria count by professional toilet of the mouth prior to the mouth wash improves the outcome. Further investigations should be performed to clarify the causal relations between the administered dose of 5-ALA and PPIX-fluorescence in non-malignant and malignant tissues for further adaptation of the 5-ALA dose for diagnostic and therapeutic purpose. Performing the photodynamic therapy the cytotoxic effect can help damage tumor cells, but on the other hand long-term side effects have to be enlightened before approval of this method. Concerning the long-term damage and induction of carcinogenesis by the method of fluorescence endoscopy more clarification is needed.