A phase II trial of S-1 monotherapy in metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens

Jeung, Hei Cheul; Rha, Sun Young; Cho, B. C.; Yoo, Nae Choon; Roh, Jae Hoon; Roh, W. J.; Chung, Hyun Cheol; Ahn, Joong Bae

doi:10.1038/sj.bjc.6603468

Cited by 32 publications

(31 citation statements)

References 19 publications

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“…We assumed that the S-1-induced anemia was related to erythropoiesis rather than bleeding or hemolysis, based on the following: (a) the anemia occurred continuously after initial treatment; (b) there existed interpersonal variability in the velocity of mean Hb reduction per cycle after S-1 treatment; (c) 6 weeks per cycle is long enough to affect erythropoiesis by S-1; (d) there was gradual macrocytosis with S-1 treatment (from 91 to 106 fl of mean corpuscular volume), reflecting deranged DNA synthesis and mitosis; and (e) the anemia comprised a unique toxicity profile of the S-1-treated Korean population in colorectal cancer [40]. Based on these findings, we tried to find genetic changes that are related to S-1-induced anemia with pharmacogenomic evaluation.…”

Section: Discussionmentioning

confidence: 99%

Multi-Institutional Phase II Study of S-1 Monotherapy in Advanced Gastric Cancer with Pharmacokinetic and Pharmacogenomic Evaluations

et al. 2007

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This study describes the first phase II study of S-1, a novel oral fluoropyrimidine, in a non-Japanese Asian population with advanced gastric cancer. S-1 was administered twice daily for 28 days every 6 weeks. A pharmacokinetic study was performed on day 28 of cycles 1 and 3. Genomic DNA from peripheral mononuclear cells was analyzed using a cDNA microarraybased comparative genomic hybridization (CGH) method. Thirty-one patients were initially given a dose of 35 mg/m 2 twice daily (bid) (group 1); then, the protocol was amended by increasing the dose to 40 mg/m 2 bid for an additional 31 patients (group 2) because of good tolerability to S-1. The overall response rate was 19.3% (95% confidence interval, 9.2%-29.5%). Over a median follow-up duration of 265 days, the median time to progression and overall survival time were 126 and 264 days, respectively. The 1-year survival rate was 34%. There was no grade 4 toxicity and the major adverse event was anemia. Pharmacokinetic parameters were similar to those of the previous Japanese reports. Microarray CGH identified 18 genes with copy number changes that were associated with hemoglobin reduction with S-1 treatment. A logistic regression analysis, integrating one clinical parameter (initial hemoglobin level) combined with three genetic copy number variations (HIST1H2BL, C10orf127, and XPNPEP2), provided a predictive model for the development of severe hemoglobin reduction. In conclusion, this study showed the feasibility of using S-1 at 35 mg/m 2 bid in gastric cancer. We suggest that the pharmacogenomic markers identified in this study may be potential candidates for predicting anemia after S-1 treatment. The Oncologist 2007;12:543-554

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Section: Discussionmentioning

confidence: 99%

Multi-Institutional Phase II Study of S-1 Monotherapy in Advanced Gastric Cancer with Pharmacokinetic and Pharmacogenomic Evaluations

et al. 2007

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“…(1) S-1-related adverse reactions commonly appear 2 -3 weeks after treatment starts (Nagashima et al, 2005); (2) a 2-week schedule showed the possibility of mitigated toxicity and prolonged the medication period (Kimura et al, 2003); (3) this schedule showed feasibility in heavily pretreated metastatic colorectal cancer (Jeung et al, 2006); and (4) recent phase I study of 2-week S-1 schedule demonstrated an antitumour activity in chemotherapy-refractory gastric cancer, with a similar pharmacokinetic profile to the conventional schedule (Zhu et al, 2007).…”

Section: S-1 Monotherapy In Poor Performance Status H-c Jeung Et Almentioning

confidence: 99%

A phase II study of S-1 monotherapy administered for 2 weeks of a 3-week cycle in advanced gastric cancer patients with poor performance status

et al. 2007

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Systemic chemotherapy for gastric cancer is often associated with treatment-related toxicity, which is particularly severe in patients with a poor performance status. In this paper, we describe the first study to evaluate S-1 monotherapy as an option for advanced gastric cancer patients who are not candidates for combination chemotherapy due to poor clinical condition. Fifty-two patients with Eastern Cooperative Oncology Group (ECOG) performance scale 2 -3, whose general condition had made use of combination chemotherapy impossible, were enrolled. S-1 was administered to 30 patients as second-or third-line therapy. The initial dose of S-1 was 35 mg m À2 , administered b.i.d for 14 days every 3 weeks. With a median follow-up period of 33 weeks, the median progressionfree survival, and overall survival were 11 weeks (95% CI, 8 -14) and 33 weeks (95% CI, 19 -47), respectively. The overall 1-year survival rate was 29% by intent-to-treat analysis. The overall response rate was 12% (95% CI, 3 -21), and the percentage of stable disease was 35%, resulting in the disease control rate of 47% (95% CI, 32 -60). Significant drug-related toxicity included grade 3 diarrhoea (14%), anorexia (14%), fatigue (10%), neutropenia (10%), and leucopenia (6%). In conclusion, this study indicated the modest activity of S-1 in gastric cancer patients with poor performance status.

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“…Anemia is a unique side effect found in Korean gastric and colorectal cancer patients after S-1 monotherapy (8,9,15). Factors contributing to the ethnic differences in toxicity are clinical status of the patient, pharmacokinetics, pharmaco- dynamics, pharamacogenetics especially in genes with drug metabolism, and pharmacogenomics.…”

Section: Discussionmentioning

confidence: 99%

Copy number changes can be a predictor for hemoglobin reduction after S-1 monotherapy in gastric cancer

Jeung

Rha²,

Park

et al. 2009

Int J Oncol

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Abstract. Anemia is a unique side effect in Korean gastric cancer patients after S-1 monotherapy. We studied gastric cancer patients from a phase II trial of S-1 monotherapy with a 2-week treatment and 1-week rest schedule. Patients from a phase II trial of S-1 monotherapy with a 4-week treatment and 2-week rest were used as a reference group. The patients were categorized into two groups based on the degree of hemoglobin reduction per cycle of S-1: the mild reduction group (MRG ΔHb/cycle ≤1.0) or severe reduction group (SRG ΔHb/cycle >1.0). ΔHb/cycle was calculated from maximum reduction of hemoglobin per one cycle of the treatment. Microarray-CGH was performed using a 17K cDNA microarray containing 15,723 unique genes. We selected genes with copy number variation defined as amplification (log 2 R/G >0.68) or deletion (log 2 R/G <-0.68), and a genetic aberration frequency difference of ≥30% between the MRG and the SRG. There were no differences in clinical factors, S-1 treatment-related factors (dose, dose intensity), toxicity, S-1 metabolism-related gene copy numbers (CYP2A6, DPD), or progression-free survival between the MRG and the SRG. Three genes were selected from microarray-CGH and logistic regression model: logit LN(Z) = (1.321) + (1.038 x PTX1) + (0.211 x MYO5A) + (0.516 x ZNF664). In the SRG, all 3 genes showed a trend of higher copy numbers than the MRG. There were no common anemia-related genes identified from different chemotherapy schedule of S-1 monotherapy. The logistics obtained from 3 genes predicted the hemoglobin reduction with an accuracy of 78%. The AUC was 0.744 for the final regression model. The combined copy number changes of the 3 genes can be developed into a biomarker in predicting S-1 treatment-related anemia.

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A phase II trial of S-1 monotherapy in metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens

Cited by 32 publications

References 19 publications

Multi-Institutional Phase II Study of S-1 Monotherapy in Advanced Gastric Cancer with Pharmacokinetic and Pharmacogenomic Evaluations

Multi-Institutional Phase II Study of S-1 Monotherapy in Advanced Gastric Cancer with Pharmacokinetic and Pharmacogenomic Evaluations

A phase II study of S-1 monotherapy administered for 2 weeks of a 3-week cycle in advanced gastric cancer patients with poor performance status

Copy number changes can be a predictor for hemoglobin reduction after S-1 monotherapy in gastric cancer

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