Phase I Study of Preoperative Chemoradiation with Temozolomide and Capecitabine in Patients with Locally Advanced Rectal Cancer
Mené en Corée du Sud sur 22 patients atteints d'un cancer rectal de stade cT3-4N0 ou cTanyN1-2, cet essai de phase I évalue la dose limitante toxique du témolozomide en combinaison avec une chimioradiothérapie pré-opératoire à base de capécitabine
Purpose : Preoperative chemoradiation (CRT) with capecitabine is a standard treatment strategy in patients with locally advanced rectal cancer (LARC). Temozolomide improves survival of patients with glioblastoma with hypermethylated O6-methylguanine DNA methyltransferase (MGMT). MGMT hypermethylation is one of the colorectal carcinogenesis pathways. We aimed to determine dose-limiting toxicity (DLT) and recommended dose (RD) of temolozomide in combination with capecitabine-based preoperative CRT for LARC. Methods and Materials : Radiotherapy was delivered with 45 Gy/25 daily fractions with coned-down boost of 5.4 Gy/3 fractions. Concurrent chemotherapy comprised fixed and escalated doses of capecitabine and temozolomide, respectively. MGMT hypermethylation was evaluated in pretreatment tumor samples. This trial is registered with ClinicalTrials.gov with the number NCT01781403. Results : Twenty-two patients with LARC of cT3-4N0 or cTanyN1-2 were accrued. Dose Level 3 was chosen as RD because DLT was noticeably absent in 10 patients treated up to Dose Level 3. An additional 12 patients were recruited in this group. Grade III adverse events were noted, and pathologic complete response (pCR) was observed in seven patients (31.8%); MGMT hypermethylation was detected in 16. The pCR rate was 37.5% and 16.7% in hypermethylated and unmethylated MGMT groups, respectively (p = 0.616). Conclusions : There was a tendency toward higher pCR rates in patients with hypermethylated MGMT. Future randomised studies are therefore warranted.