Phase I trial using a time-to-event continual reassessment strategy for dose escalation of cisplatin combined with gemcitabine and radiation therapy in pancreatic cancer.
OBJECTIVE
The primary objective of this study was to determine the maximum-tolerated dose of cisplatin that could be added to full-dose gemcitabine and radiation therapy (RT) in patients with pancreatic cancer.


METHODS
Nineteen patients were treated. Gemcitabine 1,000 mg/m(2) was administered over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Cisplatin followed gemcitabine on days 1 and 15. The initial dose level of cisplatin was 30 mg/m(2), escalated to a targeted dose of 50 mg/m(2) using Time-to-Event Continual Reassessment Method. RT was initiated on cycle 1, day 1, in 2.4 Gy fractions to a total dose of 36 Gy. A second cycle of chemotherapy was planned following a 1-week rest.


RESULTS
Four of eight patients experienced acute dose limiting toxicity at the 50 mg/m(2) cisplatin dose level. Patients treated at 30 and 40 mg/m(2) cisplatin dose level tolerated therapy without dose-limiting toxicity. Median survival was 10.7 months (95% CI, 5.4 to 18.2) for all patients, and 12.9 months (95% CI, 7.4 to 21.2) for those without metastasis.


CONCLUSIONS
Cisplatin at doses up to 40 mg/m(2) may be safely added to full-dose gemcitabine and conformal RT. The Time-to-Event Continual Reassessment Method trial design allowed rapid completion of the study and confidence in the conclusion about the maximum tolerated dose, but accrued more patients to a dose level above the maximum tolerated dose than the typical phase I design. Local and systemic disease control and survival in this study cohort supports further investigation of gemcitabine-based RT and combination chemotherapy in this disease.
Muler
Jeffrey H
JH
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109-0934, USA.
McGinn
Cornelius J
CJ
Normolle
Daniel
D
Lawrence
Theodore
T
Brown
Diane
D
Hejna
Gwen
G
Zalupski
Mark M
MM
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D020266:Radiotherapy, Conformal; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D000093542:Gemcitabine
D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine