MEND-IT II: Neoadjuvant FOLFOXIRI and Chemoradiotherapy Versus Neoadjuvant CAPOX/FOLFOX and Chemoradiotherapy, Followed by Surgery or a Watch-and-Wait Approach in High Risk Locally Advanced Rectal Cancer.
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 394
- 试验地点
- 1
- 主要终点
- Complete response
研究概览
简要总结
The aim of this clinical trial is to compare triplet induction therapy (FOLFOXIRI) with doublet induction therapy (CAPOX/FOLFOX), followed by chemoradiotherapy and either surgery or a watch-and-wait approach, in patients with high-risk locally advanced rectal cancer. The primary questions it seeks to address are whether triplet induction therapy results in higher complete response rates, improved quality of life, and better long-term oncological outcomes compared to doublet induction therapy, despite the anticipated increased risk of toxicity.
详细描述
Rationale Total neoadjuvant therapy (TNT) with induction chemotherapy (ICT) is currently considered a standard of care option for locally advanced rectal cancer (LARC) in the Dutch national guideline, primarily due to improved tumour response and a reduced risk of distant metastases (1, 2). However, the supporting evidence remains inconsistent regarding its impact on long-term oncological outcomes. While several studies using doublet-based TNT have reported higher pathological complete response rates (pCR) compared to neoadjuvant chemoradiotherapy, few have convincingly demonstrated a survival benefit (2-6). In contrast, the PRODIGE-23 trial demonstrated a survival benefit for patients treated with TNT, yet this benefit was achieved with use of a triplet chemotherapy regimen (mFOLFIRINOX) (1). In the Netherlands, triplet chemotherapy is widely used in the palliative setting. It has been shown to be more effective than doublet chemotherapy, although it is associated with increased toxicity (7-9). Although triplet chemotherapy has not yet been routinely adopted in the TNT setting, its use as part of TNT for patients with high-risk LARC has increased rapidly in recent years, despite the lack of definitive evidence supporting its superior efficacy in these patients. Patients with high-risk tumour characteristics, such as mesorectal fascia (MRF) invasion, grade IV extramural venous invasion (EMVI), tumour deposits (TD), or extensive lateral lymph node metastases (LLN), represent a subgroup with a particularly poor prognosis (10-12), referred to as high-risk LARC. It has been hypothesized that triplet-based TNT could further improve complete response rates compared with doublet-based TNT, and that patients with high-risk tumour characteristics may derive greater benefit from intensified treatment with triplet chemotherapy. Higher complete response rates may translate into improved oncological outcomes and enable organ preservation. However, whether the increased toxicity of triplet chemotherapy is justified by greater efficacy compared with doublet chemotherapy remains the key question of this trial. The primary aim of this study is to investigate whether triplet-based TNT (FOLFOXIRI) provides superior complete response rates compared with doublet-based TNT (CAPOX/FOLFOX) in patients with high-risk LARC.
Objective The objective of this study is to evaluate the effect of neoadjuvant triplet chemotherapy (FOLFOXIRI), chemoradiotherapy, and surgery or a W&W approach (arm A) compared with neoadjuvant doublet chemotherapy (CAPOX/FOLFOX), chemoradiotherapy, and surgery or a W&W approach (arm B) on complete response rates and oncological outcomes in patients with high-risk LARC.
Main trial endpoints The primary endpoint of this study is pCR or sustained clinical complete response (cCR) rate (defined as cCR 1 year after the last day of chemoradiotherapy).
Secondary trial endpoints Secondary endpoints of this study are regrowth rate, local recurrence rate, distant metastases rate, 3- and 5-years regrowth free survival (RFS), 3- and 5-years local recurrence free survival (LRFS), 3- and 5-years distant metastases free survival (DMFS), 3- and 5-years disease free survival (DFS), 3- and 5-years overall survival (OS), successful organ preservation at 2 years, radiological response after ICT, radiological response after chemoradiotherapy, toxicity of ICT, toxicity of chemoradiotherapy, dose reductions during ICT, dose reductions during chemoradiotherapy, completion rate of ICT, completion rate of chemoradiotherapy, the number of patients undergoing surgery, surgical characteristics, pathological response, post-operative morbidity, quality of life, work-productivity, and cost-effectiveness and -utility.
Trial design This is a national, multicentre, open-label, randomised controlled phase III trial. Patients will be randomised to receive FOLFOXIRI followed by chemoradiotherapy (arm A) or CAPOX/FOLFOX followed by chemoradiotherapy as neoadjuvant treatment (arm B). The neoadjuvant treatment will be followed by surgery or a W&W approach.
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
- •18 years or older
- •WHO performance score 0-
- •Fit for (modified dose) triple chemotherapy (FOLFOXIRI)
- •Histopathological confirmed rectal cancer. (Lower border of the tumour located on or below the sigmoidal take-off as established on MRI of the pelvis.)
- •Confirmed high-risk locally advanced rectal cancer, at high risk of treatment failure, meeting one of the following imaging-based criteria:
- •cT4b-tumour or evident tumour invasion of the MRF: distance to MRF 0 mm AND thickening of the MRF over a length of approximately 5 mm (MRF ≤ 1 mm is not considered sufficient).
- •The presence of grade 4 extramural venous invasion (mrEMVI)
- •The presence of tumour deposits (TD)
- •The presence of bilateral extramesorectal lymph nodes with a short-axis size ≥ 7mm (LLN) or extensive LLN involving pelvic side wall structures, at high risk of an incomplete resection.
- •Resectable disease as determined on magnetic resonance imaging (MRI) or deemed resectable disease after neoadjuvant treatment. (Expected gross incomplete resection with overt tumour remaining in the patient after resection, tumour invasion in the neuroforamina, encasement of the ischiatic nerve and invasion of the cortex from S2 and upwards are considered not resectable.)
- •Written informed consent.
排除标准
- •Evidence of metastatic disease at time of inclusion or within six months prior to inclusion except for patients with enlarged iliac or inguinal lymph nodes and non-specific lung noduli.
- •Homozygous DPD deficiency.
- •Any chemotherapy within the past 6 months.
- •Any contraindication for the planned systemic therapy (e.g., severe allergy, pregnancy, kidney dysfunction and thrombocytopenia), as determined by the medical oncologist.
- •Previous radiotherapy in the pelvic area precluding chemoradiotherapy with a dose of 50 - 50.4 Gy.
- •Any contraindication for the planned chemoradiotherapy (e.g., severe allergy to the chemotherapy agent or no possibility to receive radiotherapy), as determined by the medical oncologist and/or radiation oncologist.
- •Any contraindication to undergo surgery, as determined by the surgeon and/or anaesthesiologist.
- •Concurrent malignancies that interfere with the planned study treatment or the prognosis of the resected tumour.
- •Microsatellite instability (MSI).
研究组 & 干预措施
Triplet induction chemotherapy (FOLFOXIRI)
Triplet induction chemotherapy (FOLFOXIRI) followed by chemoradiotherapy and surgery or a watch-and-wait approach.
干预措施: Watch-and-wait approach (Diagnostic Test)
Triplet induction chemotherapy (FOLFOXIRI)
Triplet induction chemotherapy (FOLFOXIRI) followed by chemoradiotherapy and surgery or a watch-and-wait approach.
干预措施: FOLFOXIRI (Drug)
Triplet induction chemotherapy (FOLFOXIRI)
Triplet induction chemotherapy (FOLFOXIRI) followed by chemoradiotherapy and surgery or a watch-and-wait approach.
干预措施: Chemoradiotherapy (Radiation)
Triplet induction chemotherapy (FOLFOXIRI)
Triplet induction chemotherapy (FOLFOXIRI) followed by chemoradiotherapy and surgery or a watch-and-wait approach.
干预措施: Total mesorectal excision (+/- IORT) (Procedure)
Doublet induction chemotherapy (CAPOX/FOLFOX)
Doublet induction chemotherapy (FOLFOXIRI) followed by chemoradiotherapy and surgery or a watch-and-wait approach.
干预措施: FOLFOX (5-fluorouracil, Leucovorin, Oxaliplatin) (Drug)
Doublet induction chemotherapy (CAPOX/FOLFOX)
Doublet induction chemotherapy (FOLFOXIRI) followed by chemoradiotherapy and surgery or a watch-and-wait approach.
干预措施: Chemoradiotherapy (Radiation)
Doublet induction chemotherapy (CAPOX/FOLFOX)
Doublet induction chemotherapy (FOLFOXIRI) followed by chemoradiotherapy and surgery or a watch-and-wait approach.
干预措施: Total mesorectal excision (+/- IORT) (Procedure)
Doublet induction chemotherapy (CAPOX/FOLFOX)
Doublet induction chemotherapy (FOLFOXIRI) followed by chemoradiotherapy and surgery or a watch-and-wait approach.
干预措施: Watch-and-wait approach (Diagnostic Test)
Doublet induction chemotherapy (CAPOX/FOLFOX)
Doublet induction chemotherapy (FOLFOXIRI) followed by chemoradiotherapy and surgery or a watch-and-wait approach.
干预措施: CAPOX (Drug)
Registration arm: chemoradiotherapy alone
A registration arm in which patients who do not want to participate in the randomised study and who will receive chemoradiation alone as neoadjuvant treatment - followed by surgery or a Watch-and-Wait approach in accordance with standard-of-care.
干预措施: Chemoradiotherapy (Radiation)
Registration arm: chemoradiotherapy alone
A registration arm in which patients who do not want to participate in the randomised study and who will receive chemoradiation alone as neoadjuvant treatment - followed by surgery or a Watch-and-Wait approach in accordance with standard-of-care.
干预措施: Total mesorectal excision (+/- IORT) (Procedure)
Registration arm: chemoradiotherapy alone
A registration arm in which patients who do not want to participate in the randomised study and who will receive chemoradiation alone as neoadjuvant treatment - followed by surgery or a Watch-and-Wait approach in accordance with standard-of-care.
干预措施: Watch-and-wait approach (Diagnostic Test)
结局指标
主要结局
Complete response
时间窗: pCR: date of surgery sustained cCR: from date of surgery or date of entering a watch-and-wait approach, up until 1 year later.
To evaluate if neoadjuvant FOLFOXIRI leads to higher pCR rates/sustained cCR rates (≥ 1 year) compared to neoadjuvant CAPOX/FOLFOX in patients with high risk LARC.
次要结局
- Regrowth free survival(3 and 5 years post-treatment.)
- Local recurrence free survival at 3 and 5 years(3 and 5 years post-treatment)
- Distant metastasis free survival(3 and 5 years post-treatment.)
- Progression free survival(3 and 5 years post-treatment.)
- Disease free survival (DFS)(3 and 5 years post-treatment)
- Overall survival(3 and 5 years post-treatment)
- Successful organ preservation(1 and 3 years post-treatment)
- Radiological response(At baseline, after induction chemotherapy (= approximately 12-14 weeks after enrollment), and after chemoradiotherapy (= approximately 20-28 weeks after enrollment).)
- Pathological response(Date of surgery.)
- Toxicity, compliance and dose reductions of ICT and CRT(From onset of ICT up until 3 months after last radiation (= approximately 8-10 months after enrollment).)
- Completion rates of ICT and CRT(From onset of ICT up until last radiation (=approximately 20-28 weeks after enrollment).)
- Number of patients undergoing surgery(At surgery date.)
- Patient-reported quality of life measured by the QLQ-CR29 questionnaire(At baseline, after induction chemotherapy (= approximately 12-14 weeks after enrollment), after chemoradiotherapy (= approximately 20-28 weeks after enrollment), and 3 - 12 - 24 months after surgery or entering a Watch-and-Wait approach.)
- Surgical characteristics and post-operative morbidity(At surgery date up until 3 months after surgery.)
- Patient-reported quality of life measured by the QLQ-C30 questionnaire(At baseline, after induction chemotherapy (= approximately 12-14 weeks after enrollment), after chemoradiotherapy (= approximately 20-28 weeks after enrollment), and 3 - 12 - 24 months after surgery or entering a Watch-and-Wait approach.)
- Patient-reported quality of life measured by the QLQ-CIPN-20 questionnaire.(At baseline, after induction chemotherapy (= approximately 12-14 weeks after enrollment), after chemoradiotherapy (= approximately 20-28 weeks after enrollment), and 3 - 12 - 24 months after surgery or entering a Watch-and-Wait approach.)
- Patient-reported quality of life, measured by the EQ-5D-5L questionnaire.(At baseline, after induction chemotherapy (= approximately 12-14 weeks after enrollment), after chemoradiotherapy (= approximately 20-28 weeks after enrollment), and 3 - 12 - 24 months after surgery or entering a Watch-and-Wait approach.)
- Patient-reported work productivity and activity impairment (measured by WPAI-GH questionnaires)(At baseline, after induction chemotherapy (= approximately 12-14 weeks after enrollment), and after chemoradiotherapy (= approximately 20-28 weeks after enrollment))
- Cost-effectiveness and -utility(From enrollment up until 1 year post-operatively or after entering a W&W approach.)
研究者
J. W. A. Burger
Prof. dr.
Catharina Ziekenhuis Eindhoven