Preoperative Sequential Short-course Radiation Therapy and FOLFOX for Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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The treatment protocol proposed in this study is to perform short-term radiation therapy and 4 cycles of FOLFOX chemotherapy for neoadjuvant treatment of locally advanced rectal cancer. Compared to conventional chemoradiation therapy, the preoperative radiotherapy period is shortened, and the cure rate of rectal cancer patients can be improved by early treatment of micrometastasis using systemic chemotherapy. The patients who are assigned to the study group will received the short-course radiotherapy and 4 cycles of FOLFOX and patients in the control will received conventional chemoradiotherapy for preoperative treatment. All patients are recommended to receive total mesorectal excision (TME) after neoadjuvant treatment and adjuvant chemotherapy will be given according to the pathological stage.

Official Title
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A Multicenter, Randomized Controlled Trial of Preoperative Sequential Short-course Radiation Therapy and Oxaliplatin-based Consolidation Chemotherapy for Locally Advanced Rectal Cancer

Conditions
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Rectal Cancer

Intervention / Treatment
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* Radiation: short-course radiotherapy
* Drug: mFOLFOX6
* Radiation: Chemoradiotherapy
* Procedure: TME surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Asian ECOG (Eastern Cooperative Oncology Group) performance status 0-2 Pathologically confirmed rectal cancer (rectal cancer located 10 cm or low from the anal verge in pelvis MRI) Histologic type: adenocarcinoma, mucinous carcinoma, and signet ring cell carcinoma Locally advanced rectal cancer with one or more of the following factors based on pelvis MRI: cTanyN1-2, cT3-4N0, or presence of extramural vascular invasion MRI findings such as pelvic lymph node metastasis, anal sphincter invasion, and T4b are not included in the exclusion criteria, which cases will be enrolled by the researcher's discretion Patients with appropriate organ (bone marrow, kidney, liver) function A person who understands the study and willing to provide informed consent Exclusion Criteria: (one of the following criteria) Colon cancer or rectal cancer located more than 10 cm from the anal verge Stage I rectal cancer (clinical stage cT1-2N0) Clinically or pathologically diagnosed distant metastasis (cTanyNanyM1) Familial adenomatous polyposis Hereditary nonpolyposis colorectal cancer History of chemotherapy or radiotherapy within 6 months History of colorectal cancer or other type of malignancy within 5 years (except for cured nonmelanoma skin or in situ cervical cancer) Comorbidities that make it difficult to undergo chemotherapy or radiotherapy Bone marrow suppression with neutrophil count <2 ×109/L or platelet count <100 ×109/L prior to the first chemotherapy Peripheral sensory neuropathy with functional impairment (grade 2 or higher) Severe renal dysfunction (GFR ≤30ml/min by Wright or Cockroft formula) Severe hepatic dysfunction Genetic problems such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption Taking tegafur, gimeracil, and oteracil potassium complex and those within 7 days of discontinuation Taking sorivudine or brivudine Significant heart disease or myocardial infarction within the last 6 months Hereditary diseases or history of coagulopathy Central nervous system disorders with disability or mental disorders Pregnant or lactating women Currently participating in other clinical trials or receiving research medication Unhealed wounds, fractures, peptic ulcer, abscesses in the abdominal cavity Active gastrointestinal bleeding Active infections requiring antibiotics for injection Emergency Surgery History of hypersensitivity to the drugs in study protocol Patients with non-malignant tumor diseases Dihydropyrimidine dehydrogenase deficiency Not willing to participate

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study group<br>Short-course radiotherapy and 4 cycles of mFOLFOX6 followed by TME. Adjuvant chemotherapy will be given according to the pathological stage (CR pStageI: 6 cycles of capecitabine or 4 cycles of 5-FU with leucovorin, pStageII-III: 8 cycles of mFOLFOX6) | Radiation: short-course radiotherapy<br>* 25 Gy in 5 fractions for 5 days<br>Drug: mFOLFOX6<br>* Oxaliplatin 85 mg/m2, Levoleucovorin 200mg (or Leucovroin, Leucosodium 400mg)/m2, 5- FU 400 mg/m2, and continuous 5- FU 2,400 mg/m2 for 46 hours<br>Procedure: TME surgery<br>* TME surgery<br>|
| Active Comparator: Control group<br>Conventional chemoradiotherapy followed by TME. Adjuvant chemotherapy will be given according to the pathological stage (CR pStageI: 6 cycles of capecitabine or 4 cycles of 5-FU with leucovorin, pStageII-III: 8 cycles of mFOLFOX6) | Radiation: Chemoradiotherapy<br>* 45 50.4 Gy/25fr with concurrent use of either capecitabine or 5-FU+leucovorin(or levoleucovorin or leucosodium)<br>Procedure: TME surgery<br>* TME surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year disease-free survival | To compare the 3-year disease-free survival between the experimental arm and the control arm | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pCR rate | CR (complete regression), no tumor cells and only fibrotic mass or acellular mucin pools | within 30 days after TME | 
| Toxicity of neoadjuvant radiotherapy and chemotherapy | Neoadjuvant treatment associated toxicity (Common Terminology Criteria for Adverse Events version v5.0) | 6 months | 
| R0 resection | Rate of R0 resection of TME | within 30 days after TME | 
| TRG | Pathological tumor regression grade (TRG) (Dworak/Mandard/AJCC TRG classification) | within 30 days after TME | 
| Surgical complications | Surgical complications classified according to the Clavien-Dindo classification | within 60 days after TME | 
| Incidence of peripheral neuropathy | Incidence of oxaliplatin-induced peripheral neuopathy | 3 years | 
| European Organization for Research and Treatment of Cancer Quality of Life C30 | The EORTC Core Questionnaire (QLQ-C30) includes six clearly distinguishable functioning scales that have been thoroughly tested and validated on an international level and that are available in 110 different language versions | 2 year after surgery | 
| European Organization for Research and Treatment of Cancer Quality of Life CR29 | The QLQ-CR29 has five functional and 18 symptom scales. It contains four subscales (urinary frequency (UF), blood and mucus in stool (BMS), stool frequency (SF), and body image (BI)) and 19 single items (urinary incontinence, dysuria, abdominal pain, buttock pain, bloating, dry mouth, hair loss, taste, anxiety, weight, flatulence, fecal incontinence, sore skin, embarrassment, stoma care problems, sexual interest (men), impotence, sexual interest (women), and dyspareunia) [11]. Patients are asked to indicate their symptoms during the past week(s). Scores can be linearly transformed to provide a score from 0 to 100. Higher scores represent better functioning on the functional scales and a higher level of symptoms on the symptom scales. | 2 year after surgery | 
| Low Anterior Resection Syndrome score | Low anterior resection syndrome (LARS) score ; 0 to 20 (no LARS), 21 to 29 (minor LARS ) and 30 to 42 (Major LARS ) | 2 year after surgery | 
| The International Index of Erectile Function-5 score, retrograde ejaculation | Quality of life IIEF-5, retrograde ejaculation | 2 year after surgery | 
| 5-year disease-free survival | To compare the 5-year disease-free survival between the experimental arm and the control arm | 5 years | 
| 3-year overall survival | To compare the 3-year overall survival between the experimental arm and the control arm | 3 years | 
| 5-year overall survival | To compare the 5-year overall survival between the experimental arm and the control arm | 5 years | 
| Loco-regional recurrence | To compare the 3 year and 5-year loco-regional recurrence between the experimental arm and the control arm | 5 years | 
| Distant metastasis | To compare the 3 year and 5-year distant metastasis between the experimental arm and the control arm | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rectal cancer, Neoadjuvant treatment, short-course radiotherapy, Consolidation chemotherapy