FOLINIC ACID for Oesophageal adenocarcinoma|Gastroesophageal junction adenocarcinoma

Inclusion criteria

• {"criterion_text":"-•\tPatients 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 either EUS, CT-scan or 18F-FDG PET/CT. Clinical M0 status must be determined by 18F-FDG PET/CT.\n-•\tNo prior cytotoxic chemotherapy for oesophageal cancer.\n-•\tEastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 (44).\n-• Not more than 10% weight loss in the last month before inclusion.\n-•\tThe length of the primary tumor and the involved lymph nodes should be suitable for nCRT according to standard care, with the following considerations: If the tumor extends below the EGJ into the stomach, the bulk of the tumor must involve the oesophagus or the gastroesophageal junction, and tumor should be suitable for oesophagectomy with gastric conduit reconstruction, without the use of a colon interposition. In case of pathological lymph-nodes in the left or right lower paratracheal nodes (station 4R or 4L) (Appendix C), the patient can be included if nCRT is deemed beneficial for the patient and the radiotherapy toxicity is expected to be manageable. Patients with node involvement above this station are not eligible for inclusion.\n-•\tAdequate cardiac and respiratory function (cardiac or pulmonary function tests such only necessary in symptomatic patients).\n-•\tAdequate 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.\n-•\tAdequate 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.\n-•\tA negative serum pregnancy test in women of child-bearing potential during screening period.\n-•\tUse of adequate contraception during the study up to 3 months after the end of the study.\n-•\tWritten informed consent and ability to understand the nature of the study and the study-related procedures and to comply with them.\n-•\tAge ≥ 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 at baseline\n-•\tNo prior abdominal, thoracic or cervical radiotherapy overlapping with the CROSS irradiation fields."}

Exclusion criteria

• {"criterion_text":"-•\tPatients with tumours of squamous, adenosquamous or other non-adenocarcinoma histology.\n-•\tLanguage difficulty, dementia or altered mental status prohibiting the understanding and giving of informed consent and to complete quality of life questionnaires.\n-•\tPatients who are eligible for and want to participate in the TRAP-2 trial (NCT05188313)\n-•\tPatients 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.\n-•\tClinically 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).\n-•\tPeripheral neuropathy grade >1, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (37).\n-•\tHomozygous DPYD genotype (tested for *2A, *13, 2846A>T, and 1236G>A)\n-•\tPregnant 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.\n-•\tOther active malignancies with a prognosis interfering with that of oesophageal cancer.\n-•\tExpected lack of compliance with the protocol."}

Primary endpoints

• {"endpoint_text":"-•\tThe progression-free survival defined as the time interval from randomization to the first event of local failure, regional failure, progression to metastatic disease or death","definition_or_measurement_approach":"Progression-free survival defined as time interval from randomization to first event of local failure, regional failure, progression to metastatic disease or death."}

Secondary endpoints

• {"endpoint_text":"-•\tFeasibility is defined as the proportion of patients that complete all 4 cycles of FLOT and all 5 chemotherapy cycles of CROSS, permitting dose reductions and delays\n-•\tOverall survival (OS), calculated from the date of randomization to the date of death due to any cause or, for patients alive at trial closure, date of last follow-up\n-•\tThe number of patients with any major systemic therapy related toxicity, defined as grade ≥ 3 according to the Common Terminology Criteria for Adverse Events (CTCAE ) version 5.0), up to one month after the last administration of TNT (37)\n-•\tThe rate of any grade mucositis, up to one month after the last administration of TNT\n-•\tThe number of patients requiring dose reductions or treatment delays during CROSS and FLOT\n-•\tThe number of patients requiring G-CSF as primary or secondary prophylaxis\n-•\tThe number of serious adverse events (SAEs), up to one month after last administration of TNT\n-•\tSurgical morbidity (Clavien-Dindo ≥3) and mortality (30-day, 90-day and/or in-hospital mortality), monitored within the Dutch upper gastrointestinal cancer audit (DUCA) surgical complications registry (38)\n-•\tThe proportion of resections that are radical (R0), microscopically irradical (R1) and macroscopically irradical (R2)\n-•\tThe proportion of patients that is unable to undergo oesophagectomy due to clinical deterioration\n-•\tThe proportion of patients that choose for an active surveillance strategy instead of surgery after CRE-2\n-•\t Clinical complete response (cCR) rate is defined as the percentage of patients without residual locoregional disease or distant metastases at CRE-2\n-•\t Pathological complete response (pCR) rate in those who underwent an oesophagectomy is defined as ypT0N0\n-•\tMajor pathological response in those who underwent oesophagectomy, defined as Mandard 1-2 (39)\n-•\tThe distant dissemination rate, defined as the proportion of metastases at 12 weeks after completion of TNT FLOT-CROSS or TNT CROSS-FLOT, detected by 18F-FDG\n-•\tHealth-related quality of life (HRQoL), as measured by QoL questionnaires: EORTC QLQ-OG25 and EORTC-C30 (40, 41)\n-• The PD-L1 CPS will be measured as a continuous variable. This will be measured using the 28-8 monoclonal antibody.","definition_or_measurement_approach":"Definitions provided in protocol text for individual endpoints (e.g., feasibility defined as proportion completing specified cycles; OS from randomization to death; PD-L1 CPS measured with 28-8 monoclonal antibody; HRQoL measured by EORTC QLQ-OG25 and QLQ-C30; toxicity graded by CTCAE v5.0)."}

Netherlands

Earliest CTIS Part Ii Submission Date

18-06-2025

Latest Decision Or Authorization Date

20-02-2026

Processing Time Days

247

Number Of Sites

15

Number Of Participants

216

Primary sponsor

Full Name

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Netherlands

Third parties

• {"country":"","full_name":"KWF Kankerbestrijding","duties_or_roles":"Source of monetary support","organisation_type":""}