Efficacy and Safety of High-Dose Vitamin C Combined with Total Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer (HCCSC R02 Study).

Abstract

Forpatients with locally advanced rectal cancer (LARC), the standard treatment is fluoropyrimidine (FU) -based neoadjuvant chemoradiotherapy (NCRT) combined with curative surgery. The CAO/ARO/AIO-04 trial and FORWARC trial reported that the addition of oxaliplatin to FU -based NCRT contributed to improve pathologic complete response (pCR), nevertheless, increased the acute therapeutic toxicity. Some studies showed that vitamin C (VitC) had potential benefits on anti-tumor therapy and anti-inflammatory response. Therefore, we conducted this HCCSC R02 study to explore the efficacy and safety of adding a high-dose intravenous VitC to mFOLFOX6/XELOX -based NCRT in LARC. HCCSCR02 study was designed as a prospective, single-center phase II trial, which including pts aged 18-75 years with stage II/III rectal adenocarcinoma, distance from anus ≤12cm. The enrollment criteria included: staged with MRI as cT3/cT4 or cN1/2, or mesorectal fascia involvement (MRF+), or difficult to preserve the anus. Patients with glucose-6-phosphate dehydrogenase enzyme(G6PD) deficiency were excluded. Pelvic intensity modulated radiation therapy (IMRT) was given in 45-50.4Gy/25-28 fractions. Concurrently, two cycles of chemotherapy (mFOLFOX6 or XELOX) were administered during IMRT, as well as intravenous VitC (24g) delivered daily after the end of each radiation therapy. Additional 2-3 cycles of mFOLFOX6 / XELOX were adopted between the completion of radiotherapy and surgery. The primary endpoint was pCR rate. The secondary endpoints included radiation-related toxicities, overall survival (OS) and disease-free survival (DFS). This study is still recruiting. From May 15, 2021 to Feb 8, 2023, 19 pts were recruited and finished all the scheduled NCRT, of which the proportion of cT4, cT3, cN2, cN1 were 31.6%, 63.2%, 52.6%, 36.8%, respectively. In addition, 10 pts (52.6%) were diagnosed as MRF+ initially, and 8 pts (42.1%) had a lower primary tumor(≤5cm) who were considered difficult for anal preservation before NCRT. All subjects enrolled were confirmed to be proficient mismatch repair (pMMR). As a result, 18 pts underwent a total mesorectal excision (TME) all with R0-resection, and 8 pts were evaluated as pCR (44.4%, 8/18, confidence interval: 0.246-0.663), 11 as major pathological response rate (MPR) (61.6%, 11/18), respectively. The anus preservation rate in patients with lower diseases was 87.5% (7/8). One case accepted a watch-and-wait strategy because of clinical complete response (cCR). Overall, grade 3 toxicities were observed in 4 pts, including 3 leucopenia (15.8%, 3/19), 2 neutropenia (10.5%, 2/19) and 1 diarrhea (5.3%, 1/19). No grade 4 adverse event was observed. The addition of high-dose VitC to the mFOLFOX6/XELOX-based NCRT in LARC showed a promising pCR, well tolerance, particularly low rate of diarrhea, thus warrants further investigation. NCT04801511.