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Upfront radical surgery with total mesorectal excision followed by adjuvant FOLFOX chemotherapy for locally advanced rectal cancer (TME-FOLFOX): an open-label, multicenter, phase II randomized controlled trial.

ABSTRACT: BACKGROUND:Preoperative chemoradiotherapy (PCRT) followed by surgery and adjuvant chemotherapy is the current standard treatment for stage II/III rectal cancer. However, radiotherapy in the pelvic area is commonly associated with complications such as anastomotic leakage, sexual dysfunction, and fecal incontinence. Recently, the MERCURY study showed that preoperative high-resolution magnetic resonance imaging (MRI) helped to selectively avoid PCRT. It remains unclear whether PCRT is necessary in patients who can achieve a negative circumferential resection margin (CRM) with surgery alone and in patients with cT1-2N1 or cT3N0 without CRM involvement and lateral lymph node metastasis. This study aims to evaluate the efficacy of upfront radical surgery with total mesorectal excision (TME) followed by adjuvant chemotherapy with folinic acid (or leucovorin), fluorouracil, and oxaliplatin (FOLFOX) versus the current standard treatment in patients with surgically resectable, locally advanced rectal cancer. METHODS:This study, named TME-FOLFOX, is a prospective, open-label, multicenter, phase II randomized trial. Patients with locally advanced rectal cancer will be randomized to receive PCRT followed by TME and adjuvant chemotherapy (arm A) or upfront radical surgery with TME followed by adjuvant FOLFOX chemotherapy (arm B). Clinical stage II/III rectal cancer without CRM involvement and lateral lymph node metastasis will be defined using preoperative MRI. The primary endpoint is 3-year disease-free survival (DFS). Secondary endpoints include 5-year DFS, local recurrence rate, systemic recurrence rate, cost-effectiveness, and overall survival. We hypothesized that our experimental group (arm B) will have a 3-year DFS of 75% and a non-inferiority margin of 15%. DISCUSSION:Identifying whether patients require PCRT is one of the critical issues in locally advanced rectal cancer. This study aims to elucidate whether PCRT may not be required for all patients with stage II/III rectal cancer, especially for the MRI-based intermediate-risk group (with cT1-2N1 or cT3N0) without CRM involvement and lateral lymph node metastasis. If the findings indicate that our proposed treatment, which omits PCRT, is non-inferior to the standard treatment, then patients may avoid unnecessary radiation-related toxicity, have a shorter treatment duration, and save on medical costs. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02167321. Registered on 19 June 2014.

SUBMITTER: Lee JB

PROVIDER: S-EPMC7140505 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Upfront radical surgery with total mesorectal excision followed by adjuvant FOLFOX chemotherapy for locally advanced rectal cancer (TME-FOLFOX): an open-label, multicenter, phase II randomized controlled trial.

Lee Jii Bum JB Kim Han Sang HS Jung Inkyung I Shin Sang Joon SJ Beom Seung Hoon SH Chang Jee Suk JS Koom Woong Sub WS Kim Tae Il TI Hur Hyuk H Min Byung Soh BS Kim Nam Kyu NK Park Sohee S Jeong Seung-Yong SY Baek Jeong-Heum JH Kim Seon Hahn SH Lim Joon Seok JS Lee Kang Young KY Ahn Joong Bae JB

Trials 20200407 1

<h4>Background</h4>Preoperative chemoradiotherapy (PCRT) followed by surgery and adjuvant chemotherapy is the current standard treatment for stage II/III rectal cancer. However, radiotherapy in the pelvic area is commonly associated with complications such as anastomotic leakage, sexual dysfunction, and fecal incontinence. Recently, the MERCURY study showed that preoperative high-resolution magnetic resonance imaging (MRI) helped to selectively avoid PCRT. It remains unclear whether PCRT is nece ...[more]

PMID: 32264919

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Project description:The outcomes of robot-assisted mesorectal excision for rectal cancer, compared with open resection, have not been fully characterized. A retrospective analysis of pathologic, short-term, and long-term outcomes in patients with rectal adenocarcinoma who underwent total or tumour-specific mesorectal excision at a high-volume cancer centre between 2008 and 2017 was conducted. Outcomes after robotic and open surgery were compared on an intention-to-treat basis. Out of 1048 resections performed, 1018 patients were reviewed, with 638 who underwent robotic surgery and 380 open surgery. Robotic surgery was converted to the open approach in 17 (2.7 per cent) patients. Patients who underwent robotic surgery were younger (median 54 (range 22-91) years versus median 58 (range 18-97) years; P < 0.001), had higher tumours (median 80 (range 0-150) mm from the anal verge versus median 70 (0-150) mm; P = 0.001), and were less likely to have received neoadjuvant therapy (64 per cent versus 73 per cent; P = 0.003). For patients who underwent a robotic total mesorectal excision, the operating time was longer (median 283.5 (range 117-712) min versus median 249 (range 70-661) min; P < 0.001). However, the rate of complications was lower (29 per cent versus 45 per cent; P < 0.001) and length of hospital stay was shorter (median 5 (range 1-32) days versus median 7 (range 0-137) days; P < 0.001). Median follow-up of survivors was 2.9 years. The proportion of patients with a positive circumferential resection margin did not differ between the groups, nor did the rate of local recurrence (robotic versus open: 3.7 per cent, 95 per cent c.i. 1.9 to 5.6 versus 2.8 per cent, 95 per cent c.i. 1.0 to 4.6; P = 0.400), systemic recurrence (robotic versus open: 11.7 per cent, 95 per cent c.i. 8.5 to 14.8 versus 13.0 per cent, 95 per cent c.i. 9.2 to 16.5; P = 0.300), or overall survival (robotic versus open: 97.8 per cent, 95 per cent c.i. 96.3 to 99.3 versus 93.5 per cent, 95 per cent c.i. 90.8 to 96.2; P = 0.050). The same results were documented in a subanalysis of 370 matched patients, including 185 who underwent robotic surgery and 185 open surgery, for the overall incidence of any postoperative complications, overall survival, disease-free survival, local recurrence, and systemic recurrence. In patients with rectal cancer who are candidates for curative resection, robotic mesorectal excision is associated with lower complication rates, shorter length of stay, and equivalent oncologic outcomes, compared with open mesorectal excision.

Project description:Current standard for most of the locally advanced rectal cancers is preoperative chemoradiotherapy, and, variably per institution, postoperative adjuvant chemotherapy. Short-course preoperative radiation with delayed surgery has been shown to induce tumour down-staging in both randomized and observational studies. The concept of neo-adjuvant chemotherapy has been proven successful in gastric cancer, hepatic metastases from colorectal cancer and is currently tested in primary colon cancer.Patients with rectal cancer with high risk features for local or systemic failure on magnetic resonance imaging are randomized to either a standard arm or an experimental arm. The standard arm consists of chemoradiation (1.8 Gy x 25 or 2 Gy x 25 with capecitabine) preoperatively, followed by selective postoperative adjuvant chemotherapy. Postoperative chemotherapy is optional and may be omitted by participating institutions. The experimental arm includes short-course radiotherapy (5 Gy x 5) followed by full-dose chemotherapy (capecitabine and oxaliplatin) in 6 cycles before surgery. In the experimental arm, no postoperative chemotherapy is prescribed. Surgery is performed according to TME principles in both study arms. The hypothesis is that short-course radiotherapy with neo-adjuvant chemotherapy increases disease-free and overall survival without compromising local control. Primary end-point is disease-free survival at 3 years. Secondary endpoints include overall survival, local control, toxicity profile, and treatment completion rate, rate of pathological complete response and microscopically radical resection, and quality of life.Following the advances in rectal cancer management, increased focus on survival rather than only on local control is now justified. In an experimental arm, short-course radiotherapy is combined with full-dose chemotherapy preoperatively, an alternative that offers advantages compared to concomitant chemoradiotherapy with or without postoperative chemotherapy. In a multi-centre setting this regimen is compared to current standard with the aim of improving survival for patients with locally advanced rectal cancer.ClinicalTrials.gov NCT01558921.

Dataset Information

Upfront radical surgery with total mesorectal excision followed by adjuvant FOLFOX chemotherapy for locally advanced rectal cancer (TME-FOLFOX): an open-label, multicenter, phase II randomized controlled trial.

Publications

Upfront radical surgery with total mesorectal excision followed by adjuvant FOLFOX chemotherapy for locally advanced rectal cancer (TME-FOLFOX): an open-label, multicenter, phase II randomized controlled trial.

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