JCOG2207: A phase III randomized controlled trial comparing total mesorectal excision and lateral lymph node dissection plus adjuvant chemotherapy with total neoadjuvant therapy followed by total mesorectal excision and selective lateral lymph node dissection for the patients with locoregionally advanced low rectal cancer

JRCT ID: jRCTs031230415

Registered date:20/10/2023

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Rectal cancer
• Date of first enrollment: 27/10/2023
• Target sample size: 420
• Study type: Interventional

Intervention(s)

Arm A: Surgery (TME + lateral lymphadenectomy) + adjuvant chemotherapy
(1) Surgical therapy: total mesorectal excision (TME) and bilateral lateral lymph node dissection (LLND).
(2) Postoperative adjuvant chemotherapy: 8 courses of CAPOX therapy for pStage III
Capecitabine 2,000 mg/m2/day twice daily for 14 days, oxaliplatin 130 mg/m2 day1, repeated every three weeks.

Arm B: TNT (preoperative radiotherapy + consolidation chemotherapy) + surgery (TME +/- lateral lymph node dissection)
(1) Preoperative radiotherapy: radiotherapy (pelvic cavity 25 Gy/5 fractions).
(2) Consolidation chemotherapy: 6 courses of CAPOX therapy
Capecitabine 2,000 mg/m2/day twice daily for 14 days, oxaliplatin 130 mg/m2 day1, repeated every three weeks.
(3) Surgical therapy: TME + selective LLND
In case of positive clinical diagnosis of lateral lymph node metastasis (if metastasis is suspected in pre-registration images or intraoperative findings), TME + selective LLND. In case of negative clinical diagnosis of lateral lymph node metastasis, only TME.

Outcome(s)

• Primary Outcome: Overall survival
• Secondary Outcome: Disease-free survival, progression-free survival, local progression-free survival, proportion of patients with R0 resection, response rate of total neoadjuvant therapy (arm B only), proportion of patients with pathological complete response (arm B only), proportion of patients without combined resection of other organ, anal preservation rate, anal preservation rate without stoma, protocol treatment completion rate, TNT completion rate (arm B only), adjuvant chemotherapy completion rate (arm A only), adverse event rate, severe adverse event rate, surgical complication rate, anorectal defecation function score (Wexner score, LARS score), urinary drainage score (I-PSS), sexual function score (IIEF-5)

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: <= 75age old
• Gender: Both

Include criteria

(1) Endoscopic biopsy from a primary rectal lesion has been histologically diagnosed as adenocarcinoma, (papillary adenocarcinoma, tubular adenocarcinoma, poorly differentiated adenocarcinoma, mucinous carcinoma, signet ring cell carcinoma, medullary carcinoma) or adenosqamous cell carcinoma. Or endoscopic biopsy from a primary lesion in the anal canal has been histologically diagnosed as adenocarcinoma (rectal type) or adenosquamous cell carcinoma.
(2) The tumor is predominantly located in the upper rectum (Ra), lower rectum (Rb), or anal canal (P).
(3) The lower margin of the tumor is located between the perineal reflection and the anal verge (Rb-P).
(4) Comprehensive diagnosis of cT2-cT4b by abdominal and pelvic contrast CT and pelvic contrast MRI. Among cT4b, cases with suspected organ infiltration of one or more of the following are excluded.
(a) Trigone of bladder, (b) urethra, (c) sacrum.
(5) Lymph node satisfying either (i) or (ii) below is present on comprehensive diagnosis by contrast CT of the chest, abdomen, and pelvic region with a slice thickness of 1.25 mm or less and contrast MRI of the pelvic region with a slice thickness of 5mm or less.
(i) 10 mm or more in short diameter
(ii) 7 mm or more in short diameter and one or mor e of the following (a)-(c).
(a) Irregular margins
(b) MRI shows internal inhomogeneous low-signal areas
(c) Circular (long to short diameter ratio < 1.5)
(6) No distant metastasis on chest CT and contrast abdominal/pelvic CT (cM0).
(7) Comprehensive diagnosis using colonoscopy and imaging studies (barium enema, abdominal/pelvic contrast CT, or CT colonography) does not reveal multiple carcinomas. However, cTis and cT1a (cancer is expected to remain in the submucosal layer and invade less than 1,000 micrometre) lesions that are expected to be curatively resectable by endoscopic resection are not considered multiple carcinomas.
(8) Patients must be between 18 and 75 years of age on the date of enrollment.
(9) Performance status (PS) is 0 or 1 according to ECOG criteria
(10) The patient is able to take oral intake.
(11) The patient has not undergone rectal resection (except for endoscopic resection), radiation therapy to the pelvic region, or any previous treatment , including treatment for other types of cancer.
(12) The most recent laboratory values within 14 days prior to enrollment (the same day of the week two weeks prior to the date of enrollment is accept able) meet all of the following
1. Neutrophil count >= 1,500/mm3
3. Platelet count >= 100,000/mm3
4. Total bilirubin <= 2.0 mg/dL
5. AST <= 100 U/L
6. ALT <= 100 U/L
7. Serum creatinine <= 1.5 mg/dL
8. Creatinine clearance >= 30 mL/min
(13) Written consent to participate in the study has been obtained from the patient.

Exclude criteria

(1) Active multiple cancers (simultaneous multiple cancers and multiple cancers with a disease-free interval of 5 years or less. However, multiple cancers do not include stage I prostate cancer, stage 0 or stage I laryngeal cancer that has had a complete response to radiotherapy, or cancer that has been completely resected with a 5-year relative survival rate equivalent to 95% or greater).
(2) Infectious diseases requiring systemic treatment.
(3) Have a fever of 38.0 degrees Celsius or higher at the time of registration.
(4) Pregnant, possibly pregnant, within 28 days po stpartum, or lactating. Males whose partners wish to become pregnant. Female who wish to become pregnant in the future. Female who cannot tolerate early menopause with radiation therapy.
(5) Patients with psychiatric disorders or psychiatric symptoms that interfere with daily life and make it difficult for them to participate in the study.
(6) Receiving continuous systemic administration (oral or intravenous) of steroids or other immunosuppressive drugs.
(7) Complicated with poorly controlled diabetes mellitus.
(8) Patient has uncontrolled hypertension.
(9) Complicated with unstable angina (angina with onset or worsening within the last 3 weeks) or a history of myocardial infarction within the last 6 months.
(10) Poorly controlled valvular heart disease, dilated cardiomyopathy, or hypertrophic cardiomyopathy.
(11) HBs antigen positive.
(12) HIV antibody positive.
(13) Has one or more of the following complications diagnosed by chest CT: interstitial pneumonia, pulmonary fibrosis, or severe emphysema.

Related Information

• Primary Sponsor: OHUE Masayuki
• Source(s) of Monetary Support: National Cancer Center Japan