Total Neoadjuvant Therapy for Lymph Node-positive Adenocarcinoma of the OESophagus and Oesophagogastric Junction: a Phase II Study
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 216
- 试验地点
- 10
- 主要终点
- Progression-free survival
研究概览
简要总结
Both neoadjuvant chemoradiotherapy (CROSS) and neoadjuvant chemotherapy (FLOT) have demonstrated overall survival benefit over surgery alone in esophageal and esophagogastric junction (EGJ) cancer. Despite these survival gains, the prognosis remains poor, especially in patients with nodal-positive adenocarcinoma (cN+ AC) (5-year survival 36%, compared to 55% for cN0). This highlights the need for more effective treatment options, and justifies treatment intensification in these patients.
The aim of this study is to determine the efficacy and feasibility of TNT FLOT-CROSS and TNT CROSS-FLOT in patients with resectable, cN+ AC of the esophagus or EGJ.
详细描述
This study hypothesizes that the benefits of the locoregional control of CROSS combined with the systemic effect of FLOT leads to better disease control and survival in cN+ AC patients. This Total Neoadjuvant Treatment (TNT) strategy was found to be feasible in the previous TNT-OES-1 trial. The optimal sequence of CROSS and FLOT is yet unknown. Therefore, the hypothesis of this study is that the progression-free survival (PFS) of patients treated with TNT FLOT-CROSS and TNT CROSS-FLOT will be ≥10% compared to the PFS after CROSS in an appropriate historical cohort.
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
- •Patients with cT2-4aN+M0 resectable adenocarcinoma of the oesophagus or EGJ (Siewert type I-II) according to the 8th edition of the Union for International Cancer Control (UICC) TNM classification for Esophageal Cancer who are planned to undergo nCRT or FLOT (43). In case of stage cT4a, curative resectability has to be explicitly verified by the multidisciplinary tumor board.
- •Clinical N+ status should be determined by EUS or 18F-FDG PET/CT. Clinical M0 status must be determined by 18F-FDG PET/CT.
- •Maximum of 4 cm ingrowth in the cardia, measured by upper endoscopy.
- •In case of tumor and/or lymph node involvement below the diaphragm, the most proximal involved lymph node station cannot be higher than N7 (Appendix C).
- •In case of no tumor or lymph node involvement below the diaphragm, the most proximal involved lymph node station cannot be higher than N4 (Appendix C).
- •Age ≥ 18 years. For patients aged 70 years or older, a geriatric screening tool (G8) should be used to assess functioning across the domains. If a patient has a score of 14 or lower on the G8, a comprehensive geriatric assessment (CGA) should be done prior to inclusion (Appendix D).
- •No prior abdominal, thoracic or cervical radiotherapy overlapping with the CROSS irradiation fields.
- •No prior cytotoxic chemotherapy for oesophageal cancer.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 (44).
- •Weight loss <10%.
- •Adequate cardiac and respiratory function (cardiac or pulmonary function tests such only necessary in symptomatic patients).
- •Adequate bone marrow function (White Blood Cells >3x109/L; Haemoglobin >5.5 mmol/L; platelets >100x109/L). In the event of transfusions, the last red blood cell transfusion should be more than 2 weeks before inclusion.
- •Adequate renal function (Glomerular Filtration Rate >50 ml/min) or serum creatinine ≤1.5 x upper limit of normal (ULN) and adequate liver function (total bilirubin <1.5x Upper Level of Normal (ULN); Aspartate transaminase (AST) <2.5x ULN and Alanine transaminase (ALT) <3x ULN.
- •A negative serum pregnancy test in women of child-bearing potential during screening period.
- •Use of adequate contraception during the study up to 3 months after the end of the study.
- •Written informed consent and ability to understand the nature of the study and the study-related procedures and to comply with them.
排除标准
- •Patients with tumours of squamous, adenosquamous or other non-adenocarcinoma histology.
- •Patients who are eligible for and want to participate in the TRAP-2 trial (NCT05188313)
- •Patients with overt hematogenous (organ) metastasis, distant lymphatic metastases (cervical/retroperitoneal), peritoneal or pleural dissemination, as detected on 18F-FDG PET/CT or regular CT-scan. In patients in whom a diagnostic laparoscopy is indicated (to assess resectability or to exclude peritoneal disease), tumor-positive cytology peritoneal fluid is also an exclusion criteria.
- •Clinically significant (active) cardiac disease (e.g. symptomatic coronary artery disease of myocardial infarction within the last 12 months) or lung disease (forced expiratory volume in one second (FEV1) <1.5L).
- •Peripheral neuropathy grade >1, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (37).
- •Homozygous DPYD genotype (tested for *2A, *13, 2846A>T, and 1236G>A)
- •Pregnant and lactating women, or patients of reproductive potential who are not using effective contraception. If barrier contraceptives are used, they must be continued by both sexes throughout the study.
- •Other active malignancies with a prognosis interfering with that of oesophageal cancer.
- •Expected lack of compliance with the protocol.
- •Limitations such as language barriers, dementia, or altered mental status that make it impossible for the participant to understand the study, provide informed consent, and complete quality of life questionnaires. Participants who do not speak the primary study language may still be included if the study information is adequately translated or explained (e.g., read aloud in their native language) and they demonstrably understand the study procedures.
研究组 & 干预措施
TNT FLOT-CROSS
Patients allocated to the TNT FLOT-CROSS arm will be treated with 4 cycles of FLOT chemotherapy followed by a response evaluation consisting of a CT-scan and upper endoscopy with bite-on-bite biopsies of the primary tumor site and of any other suspected lesions in the esophagus. Patients with distant metastases will go off-study. All other patients will proceed to CROSS chemoradiotherapy.
干预措施: FLOT-CROSS or CROSS-FLOT (Drug)
TNT CROSS-FLOT
Patients allocated to the TNT CROSS-FLOT arm will be treated with CROSS chemoradiotherapy followed by a response evaluation consisting of a CT-scan and upper endoscopy with bite-on-bite biopsies of the primary tumor site and of any other suspected lesions in the esophagus. Patients with distant metastases will go off-study. All other patients will proceed to FLOT chemotherapy.
干预措施: FLOT-CROSS or CROSS-FLOT (Drug)
结局指标
主要结局
Progression-free survival
时间窗: 24 months
To determine the progression-free survival (PFS) after TNT (both FLOT-CROSS and CROSS-FLOT), the PFS is defined as the time interval from randomization to the first event of locoregional failure after surgery, or locoregional progression leading to irresectability prior to surgery , progression to metastatic disease or death
次要结局
- Feasibility, completion of treatment(30 months)
- Overall survival(24 months)
- Therapy-related toxicity(30 months)
- Dose reductions of TNT(30 months)
- Need of G-CSF(60 months)
- Postoperative morbidity and mortality(42 months)
- Surgical-related outcomes(42 months)
- Non-surgical related outcomes(30 months)
- Clinical response rate(42 months)
- Pathological response rate(42 months)
- Distant metastases(30 months)
- Quality of life assessed by EORTC-C30(42 months)
- Quality of life assessed by EORTC QLQ-OG25(42 months)
- The PD-L1 combined positive score (CPS)(42 months)
- Predictive biomarkers(63 months)
- Future ctDNA analysis(63 months)
研究者
Dr. B. (Bianca) Mostert
Principal Investigator
Erasmus Medical Center