SUMMARY: The American Cancer Society estimates that 44,850 new cases of rectal cancer will be diagnosed in the US in 2022. Based on the information from the SEER database, the 5-year relative survival rates for rectal cancer, all SEER stages combined is 67%.
Patients with high-risk clinical T1 and T2N0 rectal tumors undergo surgical resection along with total mesorectal excision, combined with preoperative chemoradiation for patients with T3 or N1 tumors. Even though locoregional relapse rates with neoadjuvant therapy are low with excellent survival rates, total mesorectal excision can result in bowel and sexual function issues, as well as bowel incontinence. Up to 60% of patients can experience these symptoms with the addition of perioperative radiation.
Transanal excision surgery is increasingly used for treatment of select T1N0 or T2N0 rectal tumors. There is however an increased rate of local relapse with local excision compared with surgical resection, as a significant proportion of clinical T1-2N0 tumors are pathologically node-positive. Pelvic chemoradiation followed by transanal excision surgery in patients with clinical T1-3 rectal cancer is associated with an organ preservation rate of 50%-68%. However, preoperative radiation can significantly effect wound-healing and adversely affect sphincter and sexual function. Neoadjuvant chemotherapy followed by surgical excision can potentially reduce locoregional recurrence as well as distal relapse in Stage II/III rectal cancer. There are no prospective studies with regards to neoadjuvant chemotherapy and transanal excision surgery for Stage I rectal tumors.
The Canadian Cancer Trials Group (CCTG) CO.28 NEO is a Phase II trial, designed to determine the outcomes and organ preservation rate among patients with early stage rectal tumors treated with neoadjuvant chemotherapy followed by transanal excision surgery, and to further explore the prognostic value of tumor biomarkers for the outcomes. A total of 58 eligible patients were enrolled in Canada and the United States. Enrolled patients had clinical T1-T3ab, N0 (node negative) low or mid-rectal invasive, well/moderately differentiated adenocarcinoma, deemed eligible for endoscopic resection by the study surgeon. All patients were required to have a pelvic MRI and CT scan of the chest, abdomen, and pelvis. Neoadjuvant chemotherapy could be either six cycles of mFOLFOX6 or four cycles of CAPOX, at the discretion of the investigator. mFOLFOX6 consisted of Leucovorin 400 mg/m2 and Oxaliplatin 85 mg/m2 in one 2-hour IV infusion, Fluorouracil 400 mg/m2 IV bolus on day 1, and 46-hour IV infusion of Fluorouracil 2400 mg/m2, given every 14 days. CAPOX consisted of Capecitabine 1000 mg/m2 orally twice daily for 14 days, and Oxaliplatin 130 mg/m2 IV on day 1, given every 21 days. Patients with a history of external-beam pelvic radiation, prior therapy for rectal cancer, or metastatic disease were excluded. The median age was 67 years, 95% had preserved mismatch repair status and in 5% was unknown, two thirds of the patients had clinical T2 lesion by MRI, median tumor distance from the anal verge was 6 cm, and 60% of the tumors were RAS mutated.
Following neoadjuvant chemotherapy, patients underwent pelvic MRI imaging and proctoscopy, 2-3 weeks after the last dose of chemotherapy. Tumors with protocol-defined evidence of response proceeded to have transanal excision surgery and those with progression or no response to chemotherapy were recommended total mesorectal excision surgery and preoperative pelvic radiation if the MRI revealed clinical T3ab disease, Node positive or involved or threatened circumferential radial margin. Transanal excision surgery was performed between 2-6 weeks after the last cycle of chemotherapy. Tumor excision included a minimum of 1 cm gross margin. Patients with yp Stage T0/N0 or T1N0 with no poor prognostic features were recommended observation, whereas ypT1 tumors with poor prognostic features, ypT2/3, or any N+ were recommended radical total mesorectal excision surgery. Poor prognostic features included poorly differentiated histology, lymphovascular invasion, and/or positive margin less than 1 mm. Patients assigned to observation were followed for 36 months from the time of transanal excision surgery, with proctoscopy every 6 months, pelvic MRI every 6 months or pelvic CT at months 12, 24, and 36, CEA every 6 months, and annual contrast CT of the chest, abdomen, and pelvis for 3 years. The Primary end point was organ preservation rate, defined as the proportion of patients with tumor downstaging to ypT0/T1 N0/X, and who avoided radical surgery.
Neoadjuvant induction chemotherapy followed by transanal excision surgery was well tolerated and resulted in downstaging to ypT0/T1 clinical N0 tumors in 57% of the enrolled patients and the protocol-specified organ preservation rate was 79%. The median follow up was 15.4 months. The 1-year and 2-year locoregional Relapse Free Survival was 98% and 90% respectively, and there were no distant recurrences or deaths. There was no significant change noted in Quality of Life and rectal function scores, compared to baseline scores.
It was concluded that three months of neoadjuvant induction chemotherapy may successfully downstage a significant proportion of patients with early stage rectal cancer, allowing a much-desired organ-sparing surgical treatment option.
Kennecke HF, O’Callaghan CJ, Loree JM, et al. DOI: 10.1200/JCO.22.00184 Journal of Clinical Oncology. Published online August 18, 2022.
