A Multicenter Randomized Phase III Study of Short-term Radiotherapy Plus CAPOX and Short-term Radiotherapy Plus CAPOXIRI as Preoperative Treatment for Locally Advanced Rectal Cancer
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 608
- 试验地点
- 34
- 主要终点
- Organ-preservation adapted DFS
研究概览
简要总结
This trial is a multicenter randomized Phase III study to verify the superiority of short-course preoperative radiation (SCRT) and CAPOXIRI over SCRT and CAPOX as preoperative treatments for locally advanced rectal cancer.
详细描述
Total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC) has the promise, which means non-operative management (NOM) enable more patients (pts) with a complete clinical response (cCR) or near-complete clinical responses (nCR) after TNT to avoid subsequent radical surgery, with potentially maintaining anorectal function and quality of life (QoL). Recently, PRODIGE-23 trial demonstrated that triplet regimen (Irinotecan, oxaliplatin and fluoropyrimidine) before preoperative chemoradiotherapy (CRT) significantly improved outcomes compared with CRT. However, there has been no prospective study comparing consolidation triplet with doublet regimens following short course radiotherapy (SCRT). The aim of this randomized phase III trial is to test superiority of consolidation irinotecan, capecitabine and oxaliplatin (CAPOXIRI) vs. capecitabine and oxaliplatin (CAPOX) following SCRT as TNT in pts with LARC.
Pts in both groups will be re-staged after completing TNT before radical surgery according to the Memorial Sloan Kettering Regression Schema; pts with incomplete response (iCR) will undergo total mesorectal excision (TME), cCR pts will receive NOM, and nCR pts will undergo TME or NOM by a physician discretion under the recommendation of blind assessment by the designated NOM central committee. Pts will be followed by CT, MRI, colonoscopy and liquid biopsy every 4 months for 2 years, and every 6 months thereafter up to 5 years.
To detect a decrease in 3-year cumulative probability of organ preservation-adapted Disease free survival (DFS) from 75.0% to 81.7%, corresponding to a target hazard ratio of 0·70, a total of 608 pts (196 events) would achieve 70% power at a two-sided α significance level of 0.05.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The content of this research was fully explained, and written informed consent was obtained from the subject.
- •Histologically confirmed rectal adenocarcinoma.
- •Radical resection is clinically possible without any distant metastases on imaging studies.
- •Age of 18 years or older on the date of consent acquisition.
- •Eastern Cooperative Oncology Group (ECOG) PS 0-1 (PS 0 if aged 70 years or older on consent acquisition date).
- •Inferior margin of the tumor is within 12 cm of the AV.
- •No prior tumor treatment.
- •No history of radiation therapy to the pelvis, including treatment for other cancer types.
- •Cases with cT3-4N0M0*or T1-4N1-2M0 based on Union Internationale Contre le Cancer (UICC) 8th edition.
- •(*5 cm< AV ≤ 10 cm, T3a/bN0M0, extramural venous invasion (EMVI) -, mesorectal fascia (MRF) clear and 10 cm < AV ≤ 12 cm, T3a/bN0-1M0, EMVI-, MRF clear are eligible only for those who refused surgery)
- •UGT1A1 is wild-type or single heterozygous.
- •Criteria for major organ function within 28 days prior to enrollment. If there are multiple test results within this period, the most recent one will be used, and blood transfusions and hematopoietic factor preparations will not be administered within 14 days before the test date for measurements before registration.
- •Neutrophil count: ≥1,500/mm3
- •Platelet count: ≥10.0×10 4/mm3
- •Hemoglobin concentration: ≥9.0 g/dL
- •Total bilirubin: ≤2.0 mg/dL
- •Aspartate transaminase (AST): ≤100 IU/L or less
- •Alanine transaminase (ALT): ≤100 IU/L or less
- •Serum creatinine: Creatinine clearance ≥30 mL/min (by Cockcroft & Gault formula)
排除标准
- •Extensive surgery (excluding colostomy and central venous port construction) within 4 weeks before starting protocol treatment.
- •Complications or history of severe lung disease (such as interstitial pneumonia, pulmonary fibrosis, and severe emphysema).
- •Colonic stent in place.
- •Contraindications for MRI such as cardiac pacemakers.
- •Serious comorbidities (such as heart failure, renal failure, liver failure, intestinal paralysis, intestinal obstruction, uncontrolled diabetes, and active inflammatory bowel disease).
- •Patients with multiple active cancers (simultaneous multiple cancers or metachronous multiple cancers with a disease-free interval of 5 years or less). However, carcinoma in situ or lesions equivalent to intramucosal carcinoma, which can be cured by local treatment, are not treated as active multiple cancers.
- •Pregnant women, lactating women, positive pregnancy test, or unwillingness to use contraception.
- •Hepatitis B surface (HBs) antigen positive or hepatitis C virus (HCV) antibody-positive. However, HCV-RNA-negative can be registered.
- •Have human immunodeficiency virus (HIV) infection.
- •MSI-high (MSI-H) or defective mismatch repair (dMMR) is known.
- •Unwilling to donate specimens for "Research on gene profiling and clinical significance using clinical specimens from cancer patients" for whole-genome analysis based on the "Action Plan for Whole-Genome Analysis, etc." (CONDUCTOR study).
- •Any other patients the principal investigator or co-investigator deems inappropriate for study participation.
研究组 & 干预措施
Control arm SCRT+CAPOX
The standard-of-care group receives short-course radiation therapy (5 × 5 Gy) followed by six cycles of CAPOX (capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, q3wks).
干预措施: SCRT (Radiation)
Control arm SCRT+CAPOX
The standard-of-care group receives short-course radiation therapy (5 × 5 Gy) followed by six cycles of CAPOX (capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, q3wks).
干预措施: CAPOX (Drug)
Experimental arm SCRT+CAPOXIRI
The standard-of-care group receives short-course radiation therapy (5 × 5 Gy) followed by six cycles of CAPOXIRI (capecitabine 800 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, and irinotecan 150 mg/m2 intravenously on day 1*, q3wks).
干预措施: SCRT (Radiation)
Experimental arm SCRT+CAPOXIRI
The standard-of-care group receives short-course radiation therapy (5 × 5 Gy) followed by six cycles of CAPOXIRI (capecitabine 800 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, and irinotecan 150 mg/m2 intravenously on day 1*, q3wks).
干预措施: CAPOXIRI (Drug)
结局指标
主要结局
Organ-preservation adapted DFS
时间窗: Up to 3 years. It is defined as the period from the allocation date to the earliest of the following events.
The investigators use the definition of organ-preservation adopted DFS proposed in the international consensus statement for preoperative treatment (75). It is defined as the period from the date of allocation to the earliest of the following events. 1. Surgery difficult due to local progression or study subject unfit for surgery 2. R2 resection of primary tumor ( not including Circumferential resection margin (CRM) positive ) 3. Local recurrence after R0/1 resection of primary tumor 4. Local regrowth for which Salvage surgery is not possible during NOM 5. Appearance of distant metastases 6. Occurrence of second primary colorectal cancer 7. Development of second primary other cancers 8. Death (treatment-related death, death from the same cancer, death from a different type of cancer, non-cancer-related death)
次要结局
- cCR rate(1-3 weeks (Days 7-21) from the completion of preoperative chemotherapy or the date of discontinuation.)
- Clinical response (cCR+near CR [nCR]) rate(Within 1-3 weeks (Days 7-21) from the completion of preoperative chemotherapy or the date of discontinuation.)
- Proportion of NOM selection(3-6 weeks (Days 21-42) from the completion of preoperative chemotherapy or the date of discontinuation.)
- Recurrence type and recurrence rate(3 years (up to 5 years))
- Distant metastases free survival (DMFS)(3 years (up to 5 years))
- Local recurrence-free survival (LRFS)(3 years (up to 5 years))
- Overall survival (OS)(3 years (up to 5 years))
- TME-free DFS(3 years (up to 5 years))
- TME-free survival(3 years (up to 5 years))
- Relative dose intensity (RDI)(Immediately after the completion of preoperative chemotherapy or the date of discontinuation.)
- QOL assessment (LARS score, EORTC QLQ-C30, and SF-36)(3 years)
- Radical resection rate in the surgical subgroup(3 years (up to 5 years))
- Proportion of salvage surgery in local re-enlargement cases in the NOM subgroup(3 years (up to 5 years))
- Time until salvage surgery in the NOM subgroup(3 years (up to 5 years))
- Protocol treatment completion rate(Immediately after the completion of preoperative chemotherapy or the date of discontinuation.)
- Incidence of preoperative treatment-related adverse events(Immediately after the completion of preoperative chemotherapy or the date of discontinuation.)
- Pathological complete response (pCR) rate in the surgical subgroup(Immediately after the evaluation of the histopathological findings after surgery)
- Local recurrence-free survival (LRFS) in the surgical subgroup(3 years (up to 5 years))
- Surgery-related adverse event rate determined by Clavien-Dindo classification v2.0 in the surgical subgroup(For early (within 30 days) and late (31-90 days) postoperative adverse events after the end of surgical therapy)
- Local re-enlargement rate in the NOM subgroup(3 years (up to 5 years))
- Time for local regrowth in the NOM subgroup(3 years (up to 5 years))
- Surgery-related adverse event rate determined by Clavien-Dindo classification v2.0 in salvage surgery cases in the NOM subgroup(For early (within 30 days) and late (31-90 days) postoperative adverse events after the end of surgical therapy)
- Proportion of radical resection in salvage surgery cases in the NOM subgroup(3 years (up to 5 years))
研究者
Takayuki Yoshino
MD., PhD Head of Department of Gastroenterology and Gastrointestinal Oncology
National Cancer Center Hospital East