A phase I study of concurrent individualized, isotoxic accelerated radiotherapy and cisplatin-vinorelbine-cetuximab in patients with stage III non-small-cell lung cancer.
BACKGROUND
In this open-label phase I study, the maximum-tolerated dose of cetuximab with concurrent chemoradiotherapy (C-CRT) in stage III non-small-cell lung cancer together with individualized, isotoxic accelerated radiotherapy (RT) was investigated.


METHODS
Patients with stage III non-small-cell lung cancer, World Health Organization performance status 0-1, forced expiratory volume in 1 second more than 50%, carbon monoxide diffusing capacity more than 50%, weight loss less than 10%, and no severe comorbidity were enrolled. Patients without progression after one to two cycles of gemcitabine-carboplatin were included and treated with cetuximab 400 mg/kg d7 and 250 mg/kg weekly together with RT and cisplatin (50 mg/m d1, 8; 40 mg/m d22)-vinorelbine for 5 weeks. Vinorelbine was escalated in three steps; (1) 10 mg/m d1, 8 and 8 mg/m d22, 29; (2) 20 mg/m d1, 8 and 8 mg/m d22, 29; (3) 20 mg/m d1, 8; 15 mg/m d22, 29. An individualized prescribed RT dose based on normal tissue dose constraints was applied (e.g., mean lung dose 19 Gy). The primary endpoint was the maximum-tolerated dose 3 months after the end of C-CRT; secondary endpoints were toxicity and metabolic response as assessed by positron emission tomography.


RESULTS
Between September 2007 and October 2010, 25 patients (12 men, 13 women, mean age 59 years) were included. The mean RT dose was 62 ± 6.6 Gy. The vinorelbine dose could be escalated to dose level 3. Twelve of 25 patients experienced greater than or equal to grade 3 toxicity (esophagitis 3, rash 1, diarrhea 1, cough 1, dyspnea 1, vomiting 1, and pulmonary embolism 1). No dose-limiting toxicities were observed. One patient with a complete pathological response in dose level 3 developed a fatal hemoptysis 4 months after RT. Metabolic remissions were observed in 19 of 22 patients.


CONCLUSIONS
C-CRT with cetuximab and cisplatin-vinorelbine is safe to deliver at full dose. The recommended phase II dose is therefore cetuximab 400 mg/m d7 and 250 mg/m weekly, cisplatin 50 mg/m d1, 8; 40 mg/m d22 and vinorelbine 20 mg/m d1, 8; 15 mg/m d22, 29 for 5 weeks together with RT.
*Department of Pulmonology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands; †Department of Pulmonology, Atrium Medical Centre, Heerlen, The Netherlands; ‡Department of Radiation Oncology (MAASTRO Clinic), GROW School for Oncology and Developmental Biology; §Department of Nuclear Medicine, and ‖Department of Radiology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands; and ¶Department of Radiation Oncology, University Hospitals Leuven/KU Leuven, Leuven, Belgium.
Anne-Marie C
AM
Dingemans
Gerben
G
Bootsma
Angela
A
van Baardwijk
Bart
B
Reymen
Rinus
R
Wanders
Boudewijn
B
Brans
Marco
M
Das
Monique
M
Hochstenbag
Arne
A
van Belle
Ruud
R
Houben
Philippe
P
Lambin
Dirk
D
de Ruysscher
D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D000068818:Cetuximab; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D057285:Precision Medicine; D011879:Radiotherapy Dosage; D012074:Remission Induction; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000077235:Vinorelbine; D000093542:Gemcitabine
D061067:Antibodies, Monoclonal, Humanized; D003841:Deoxycytidine; D014747:Vinblastine; D016190:Carboplatin; D000068818:Cetuximab; D002945:Cisplatin; D000077235:Vinorelbine; D000093542:Gemcitabine