A Phase I study of weekly intravenous oxaliplatin in combination with oral daily capecitabine and radiation therapy in the neoadjuvant treatment of rectal adenocarcinoma.
OBJECTIVE
We conducted a Phase I study to determine the maximum tolerated dose (MTD) of neoadjuvant capecitabine, oxaliplatin, and radiation therapy (RT) in Stage II to III rectal adenocarcinoma.


METHODS
Capecitabine was given orally twice daily Monday through Friday concurrently with RT. Oxaliplatin was given i.v. once weekly x 5 (for 5 weeks) starting the first day of RT. RT was given daily except on weekends and holidays at 1.8 Gy per fraction x 28. Escalation for capecitabine or oxaliplatin was to occur in cohorts of three patients until the maximum tolerated dose (MTD) was defined. Endorectal tumor biopsy samples were obtained before and on Day 3 of treatment to explore the effects of treatment on thymidine phosphorylase, thymidylate synthase, dihydropyrimidine dehydrogenase, DNA repair, and apoptosis.


RESULTS
Twelve patients were enrolled on this study. Two of 6 patients at dose level (DL) 1 (capecitabine 825 mg/m2 orally (p.o.) given twice daily (b.i.d.); oxaliplatin 50 mg/m2/week) had a dose-limiting diarrhea. One of 6 patients at DL (-)1 (capecitabine 725 mg/m2 p.o., b.i.d.; oxaliplatin 50 mg/m2/week) experienced-dose-limiting diarrhea. Three of 11 patients who underwent resection had a complete pathologic response. No remarkable variations in rectal tumor biologic endpoints were noted on Day 3 of treatment in comparison to baseline. However, a higher apotosis index was observed at baseline and on Day 3 in complete pathologic responders (no statistical analysis performed).


CONCLUSIONS
Capecitabine 725 mg/m2 p.o., twice daily in combination with oxaliplatin 50 mg/m2/week and RT 50.4 Gy in 28 fractions is the recommended dose for future studies.
Fakih
Marwan G
MG
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. marwan.fakih@roswellpark.org
Rajput
Ashwani
A
Yang
Gary Y
GY
Pendyala
Lakshmi
L
Toth
Karoly
K
Smith
Judy L
JL
Lawrence
David D
DD
Rustum
Youcef M
YM
D000284:Administration, Oral; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D017209:Apoptosis; D000069287:Capecitabine; D017024:Chemotherapy, Adjuvant; D004260:DNA Repair; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D000077150:Oxaliplatin; D018714:Radiotherapy, Adjuvant; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000532:radiotherapy*; D013939:Thymidine Phosphorylase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil