Phase II study of preoperative chemoradiation with S‐1 plus oxaliplatin in patients with locally advanced rectal cancer

Abstract

A phase II study of preoperative chemoradiation (CRT) with S-1 plus oxaliplatin in patients with locally advanced rectal cancer was conducted. The total radiotherapy dose was 50.4 Gy. Chemotherapy consisted of oxaliplatin 50 mg/m 2 on days 1, 8, 22 and 29 and S-1 80 mg/m 2 per day on days 1-14 and 22-35. The tumor apparent diffusion coefficient (ADC) was measured using diffusion-weighted magnetic resonance imaging (DW-MRI) before and after CRT. Total mesorectal excision was performed within 6 ± 2 weeks. The primary end-point was the pathological complete response (pCR) rate. A total of 38 patients were enrolled. The pCR rate was 22.9% (8/35; 95% CI, 10.9-42.1), and 10 (28.6%) patients showed near-total tumor regression. There was no grade 4 adverse event, and grade 3 adverse events included leukopenia (5.4%), diarrhea (5.4%), anorexia (2.7%) and nausea (2.7%). The tumor ADC was calculated in 38 patients (including those who participated in the phase I study). The post-CRT ADC (P = 0.037) and the percentage change in ADC (P = 0.026) were significantly correlated with pathological response. In conclusion, preoperative CRT with S-1 plus oxaliplatin showed promising results in pathological responses and favorable toxicity profiles. (Cancer Sci 2013; 104: 111-115) T he treatment of locally advanced rectal cancer (LARC) has progressed significantly over the past several years. Radiation therapy, before or after surgery, significantly reduced local recurrence rates in stage II or III rectal cancer, and the addition of fluoropyrimidines, either 5-fluorouracil (5-FU) or capecitabine, afforded further benefits in local control.(1,2) Preoperative chemoradiation therapy (CRT) had been superior to postoperative CRT in terms of local control, sphincter preservation and toxicity.(3-5) Therefore, preoperative CRT with fluoropyrimidines has become accepted as the standard treatment modality for patients with LARC.To improve outcomes, the addition of other agents to fluoropyrimidine-based CRT has been investigated. Oxaliplatin, when combined with fluoropyrimidines, improved overall survival (OS) and disease-free survival (DFS) of patients with completely resected stage II or III colon cancer.(6,7) In addition, oxaliplatin was associated with radiation sensitization in a preclinical study, suggesting that this drug might be a good candidate for chemoradiation regimens in patients with rectal cancer. (8) Oral fluoropyrimidine is an attractive alternative to 5-FU, because it is easier to use and patients are constantly exposed to the drug. S-1, a novel fluoropyrimidine, was designed to enhance antitumor activity of 5-FU and to reduce gastrointestinal (GI) toxicity.(9) In addition, this drug showed antitumor activity when used as a radiosensitizer in human colon cancer xenografts.(10) We previously performed a phase I study to determine the recommended dose of S-1, in combination with oxaliplatin, for preoperative CRT in patients with LARC. We found that the recommended dose of S-1 was 80 mg/m 2 per day on days 1-14 and 22-35, co...

Locally advanced rectal cancer: Qualitative and quantitative evaluation of diffusion-weighted MR imaging in the response assessment after neoadjuvant chemo-radiotherapy

“…Our results are very similar to those obtained by Kim et al [22] that found the percentage of the ADC increase (cut-off value of 42%) to be an useful predictor for ypCR with a sensitivity of 100% and a specificity of 71%. Similarly, Lee et al [23] reported that the percentage change in ADC was significantly correlated with pathological response.…”

The role of diffusion-weighted MRI and 18F-FDG PET/CT in the prediction of pathologic complete response after radiochemotherapy for rectal cancer: A systematic review

“…Conversely, CurvoSemedo et al reported a lower ADC post in patients who achieved pCR, although this was not significant [29]. Four papers found that an ADC increase of 41-48% was predictive for pCR [25,27,28,31]. Pooled analysis shows a moderate performance of late quantitative DWI assessment with overall accuracies of 74% and 78% for ADC post and DADC post respectively.…”

Imaging biomarkers in oncology: Basics and application to MRI

“…These studies have shown that a common pattern is an increase in ADC mean to a varying extent with different therapies. This may occur within days of starting treatment; a higher change in ADC mean is also associated with a pathological good response …”

“…This may occur within days of starting treatment; a higher change in ADC mean is also associated with a pathological good response. [31][32][33][34][35][36][37][38][39] The variability of ADC in clinical studies has been reported to be relatively low at 15% 40 and in ice-water phantom studies as low as 3%. 41 Nevertheless, there are considerations to be made in the trial setting 42 and technical challenges to acquiring robust diffusion-weighted biomarkers and qualification as a biomarker.…”