Phase II study of biweekly S-1 and oxaliplatin combination chemotherapy in metastatic colorectal cancer and pharmacogenetic analysis.
OBJECTIVE
To evaluate the efficacy and safety of S-1 in combination with oxaliplatin in a biweekly schedule as first-line treatment in metastatic colorectal cancer and the association between genetic polymorphisms and treatment outcomes.


METHODS
Eligibility included age 18-75 years, at least one measurable lesion, no prior chemotherapy except adjuvant chemotherapy, and Eastern Cooperative Oncology Group Performance Status (PS) 0-2. S-1 40 mg/m(2) b.i.d. on days 1-7 with 85 mg/m(2) of oxaliplatin on day 1 was repeated every 2 weeks. Genomic DNA from whole blood was analyzed for 15 single-nucleotide polymorphisms (SNPs) among 8 genes.


RESULTS
Fifty-two patients (median age 63 years, range 37-74) were enrolled: 37 men and 15 women; 44 with a PS of 0 and 8 with a PS of 1; and 41 with initially metastatic cancer and 11 with relapsed disease. Among 51 evaluable patients, objective response rate was 47.1% [95% confidence interval (CI) 32.9-61.2]. Median follow-up duration was 17.1 months (range 3.9-28.2 months). Median progression-free survival (PFS) was 6.4 months (95% CI 4.8-8.1), and median overall survival had not been reached yet. Reported grade 3 toxicities were neutropenia (7.7%), thrombocytopenia (5.8%), sensory neuropathy (7.7%) and diarrhea (1.9%). There was no grade 4 toxicity or neutropenic fever. Patients with A/G or G/G genotype in GSTP1 Ile105Val SNP had longer PFS than patients with A/A (median 8.3 vs. 6.1 months, P = 0.04).


CONCLUSIONS
Biweekly S-1 with oxaliplatin is effective and has improved tolerability and convenience compared to other fluoropyrimidine with oxaliplatin combinations. GSTP1 Ile105Val SNP is associated with treatment outcomes.
Hong
Junshik
J
Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul, Korea.
Han
Sae-Won
SW
Ham
Hye Seon
HS
Kim
Tae-Yong
TY
Choi
In Sil
IS
Kim
Byung-Su
BS
Oh
Do-Youn
DY
Im
Seock-Ah
SA
Kang
Gyeong Hoon
GH
Bang
Yung-Jue
YJ
Kim
Tae-You
TY
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D010094:Oxonic Acid / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011725:Pyridines / Q000008:administration & dosage; D005641:Tegafur / Q000008:administration & dosage
D004338:Drug Combinations; D009944:Organoplatinum Compounds; D011725:Pyridines; C431073:oxiplatin; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid