Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
Yong Sang Hong , Seong Joon Park , Jeong Eun Kim , Kyu-Pyo Kim , Jae-Lyun Lee , Jin-hong Park , Jong Hoon Kim , Chang Sik Yu , Jin Cheon Kim , Tae Won Kim
Background: Preoperative chemoradiation (CRT) with capecitabine is one of the standard treatment strategies in patients with locally advanced rectal cancer (LARC). Temozolomide improved survival of patients with glioblastoma when administered with radiotherapy (RT), especially in those with hypermethylated MGMT (O6-methylguanine DNA methyltransferase). MGMT hypermethylation has been suggested as one of the colorectal carcinogenesis pathways. Methods: RT was delivered with 45 Gy/25 daily fractions with coned-down boost of 5.4 Gy/3 fractions. Concurrent chemotherapy consisted of fixed dose of capecitabine (825 mg/m2 twice daily) and escalated dose of temozolomide (45 [level 1], 60 [level 2], and 75 mg/m2/day [level 3]). MGMT hypermethylation was examined by methyl-specific PCR in the pre-treatment tumor samples. Results: Between May 2013 and Apr 2014, a total of 22 patients with LARC of cT3-4N0 or cTanyN1-2 were accrued. Dose-limiting toxicity did not occur among 10 patients up to dose level 3, and the dose level 3 was chosen as the recommended dose (RD). Additional 12 patients were accrued in the RD. There was no grade 4 adverse event (AE), and grade 3 AEs included leucopenia (9.1%), nausea (4.5%), and vomiting (4.5%). Pathologic complete responses (pCR) were observed in 7 patients (7/22, 31.8%). MGMT hypermethylation was found in 16 patients (16/22, 72.7%). The pCR rate was 37.5% (6/16) in the hypermethylated MGMT group and 16.7% (1/6) in the unmethylated MGMT group (p= 0.62). Conclusions: The RD of temozolomide was determined to 75 mg/m2/day when added in the preoperative CRT with capecitabine. Preoperative CRT with temozolomide plus capecitabine was tolerable. There was a tendency of higher pCR rates in those with hypermethylated MGMT, therefore, further randomized study will be warranted. Clinical trial information: NCT01781403
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