title: Adaptive intrapatient dose escalation of cisplatin in combination with low-dose vp16 in patients with nonsmall cell lung cancer.
abstract: The objective of this phase II and pharmacologic study was to explore the feasibility, toxicity and activity of adaptive intrapatient dose escalation of cisplatin in a dose-intensive weekly schedule using predefined levels of exposure, with the ultimate aim to improve the antitumour activity of the therapy in patients with nonsmall cell lung cancer (NSCLC). Platinum DNA-adduct levels in peripheral white blood cells during treatment were used as the primary parameter for adaptive dosing. If DNA-adduct levels were not available, the area under the concentration-time curve (AUC) of unbound platinum in plasma was used for dose adaptation. Target levels for DNA-adducts and AUC have been defined in a previously performed pharmacologic study. The feasibility of adaptive dosing was tested in 76 patients with stage IIIB and IV NSCLC, who were planned to receive 6 weekly courses of cisplatin at a starting dose of 70 mg m(-2), together with daily low oral dose of 50 mg VP16. In total, 37 patients (49%) who were given more than one course received a dose increase varying from 10 to 55%. The majority of patients reached the defined target levels by a dose increase during course two. Relevant grade 2 neurotoxicity was observed in eight (10%) patients and reversible ototoxicity grade 2 in 14 (18%) patients. The strategy of adaptive intrapatient dose adjustment of cisplatin is practically feasible in a research setting even when results for dose adaptation have to be reported within a short time-period of 1 week. The toxicity appeared to be manageable in this cohort of patients. In some patients, exposure after the standard dose was substantially lower than the defined target level and significant dose escalations of more than 50% had to be applied. The response rate (RR) was relatively high: overall 40% (29 out of 72 patients) partial remission (PR), in patients with stage IIIB the RR was 60% (15 out of 25 patients) and with stage IV 30% (14 out of 47 patients). Randomised studies are needed to determine whether the adaptive dosing strategy results in better efficacy than standard dosing.
authors.affiliation: The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, The Netherlands. jhm@nki.nl
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: A S T
authors.initials: AS
authors.lastname: Planting
authors.forename: N
authors.initials: N
authors.lastname: van Zandwijk
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.forename: M
authors.initials: M
authors.lastname: Maliepaard
authors.forename: M E L
authors.initials: ME
authors.lastname: van der Burg
authors.forename: M
authors.initials: M
authors.lastname: de Boer-Dennert
authors.forename: E
authors.initials: E
authors.lastname: Brouwer
authors.forename: A
authors.initials: A
authors.lastname: van der Gaast
authors.forename: M J
authors.initials: MJ
authors.lastname: van den Bent
authors.forename: J
authors.initials: J
authors.lastname: Verweij
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D018736:DNA Adducts; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D018736:DNA Adducts; D005047:Etoposide; D002945:Cisplatin