NACRE 2_Randomized phase III study evaluating two treatment strategies for locally advanced rectal cancer in patients ≥75 years old

The primary objective of this study is to evaluate the efficacy of short-course radiotherapy (SCRT) followed by 6 cycles of FOLFOX4s chemotherapy compared to SCRT without chemotherapy in terms of organ preservation rate in elderly patients with locally advanced rectal cancer (cT3-T4). This comparison is clinically relevant as it addresses the potential benefit of adding systemic chemotherapy to radiotherapy in the geriatric population with advanced rectal tumors, aiming to preserve the rectum and avoid radical surgical resection.

The secondary objectives assess multiple clinical endpoints between the two treatment arms:

• Rate of clinical complete response (cCR) at 21 weeks
• 24-month overall survival (OS)
• Rate of locoregional-free survival (LRFS) at 24 months
• 24-month disease-free survival (DFS)
• 24-month local regrowth rate
• 24-month metastasis-free survival (MFS)
• Rate of R0 resection
• Rate of postoperative complications of initial surgery at 3 months
• Rate of postoperative complications of salvage surgery after initial non-operative management (NOM) at 3 months
• Safety profile
• Bowel dysfunction at inclusion, 3 months post-radiotherapy, 12 months and 24 months post-inclusion
• Quality of life (QoL) at inclusion, 3 months post-radiotherapy, 12 months and 24 months post-inclusion
• Geriatric evaluation at inclusion, 3 months post-radiotherapy, 12 months and 24 months post-inclusion

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consists of elderly patients aged **75 years and older** diagnosed with **locally advanced rectal adenocarcinoma** (clinical stage T3/T4). Both **male** and **female** subjects are eligible for participation. Participants are required to have a **WHO performance status** of 0-1, indicating good functional capacity. The trial targets patients with **cT3a-b tumors** with a maximum diameter greater than 5 cm, **T3c-d**, or **cT4 tumors** as confirmed by pretreatment **pelvic MRI**, with the distal part of the tumor located within 10 cm from the anal margin. Participants must be considered suitable for radical **pelvic surgery** and systemic therapy with **FOLFOX chemotherapy**, as well as eligible for **radiotherapy** and **total mesorectal excision (TME) surgery**. Approval from an **oncogeriatrician** is required for enrollment. Key inclusion criteria include histologically confirmed **rectal adenocarcinoma**, adequate biological function with specific hematological and biochemical parameters (including **neutrophils** ≥1500/mm³, **platelets** ≥100,000/mm³, **hemoglobin** ≥10 g/dL, **creatinine clearance** >50 mL/min, and liver function tests within acceptable limits), and affiliation to a social security system. Male participants must agree to use adequate contraception methods during and for at least 12 months following treatment with **oxaliplatin**.

This is a randomized phase III clinical trial evaluating two treatment strategies for patients aged 75 years and older with locally advanced rectal adenocarcinoma. The trial investigates the efficacy of short-course radiotherapy (SCRT) followed by six cycles of FOLFOX4s chemotherapy compared to SCRT without chemotherapy in terms of organ preservation rate. The study population consists of elderly patients with cT3/T4 rectal adenocarcinoma who are eligible for radiotherapy, FOLFOX chemotherapy, and total mesorectal excision (TME) surgery. The trial employs a randomized design to compare the two treatment arms. The primary endpoint is the 24-month TME-free survival, defined as the proportion of patients without TME, nonsalvageable pelvic disease, and without permanent diversion stoma. The primary endpoint will be estimated using the Kaplan-Meier method and presented with its 95% confidence interval.

The investigational medicinal products administered via intravenous use include oxaliplatin at a maximum daily dose of 85 mg/m² and a maximum total dose of 510 mg/m², calcium levofolinate at a maximum daily dose of 200 mg/m² and a maximum total dose of 1200 mg/m², folinic acid at a maximum daily dose of 400 mg/m² and a maximum total dose of 2400 mg/m², and fluorouracil at a maximum daily dose of 2800 mg/m² and a maximum total dose of 16800 mg/m². The maximum treatment period for all products is 12 weeks. All active substances are of chemical origin and are administered as solutions for infusion or injection.

Key inclusion criteria require patients to have histologically confirmed adenocarcinoma of the rectum with cT3a-b tumors having a maximum diameter greater than 5 cm, T3c-d, or cT4 tumors on pretreatment pelvic MRI. Patients must be at least 75 years old with a WHO performance status of 0-1. The distal part of the tumor must be located within 10 cm from the anal margin as measured by pelvic MRI. General condition must be suitable for radical pelvic surgery and systemic therapy with FOLFOX, with approval from an oncogeriatrician. Adequate biological function is required, including neutrophils ≥1500/mm³, platelets ≥100,000/mm³, hemoglobin ≥10 g/dL, total bilirubin ≤1.5 times the upper limit of normal (ULN), alkaline phosphatases ≤1.5 times ULN, creatinine clearance greater than 50 mL/min (MDRD), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤2.5 times ULN. Patients must be affiliated to a social security system and must have signed written informed consent. Male patients must agree to use adequate contraception methods during treatment and for at least 12 months after the end of treatment with oxaliplatin.

Secondary endpoints include the rate of clinical complete response (cCR) defined as the percentage of complete response confirmed by central review after 21 weeks. Complete response is defined by specific criteria including flat white scar with telangiectasia on endoscopic evaluation, no induration on digital rectal examination, normal appearing bowel wall without fibrosis in the tumor bed on pelvic MRI-T2W, no visible signal on B800-B1000 MRI-DW, and no metastatic dissemination on chest and abdominal CT scan. Additional secondary endpoints include 24-month overall survival, locoregional failure at 24 months, 24-month disease-free survival, 24-month regrowth rate, 24-month metastasis-free survival, rate of R0 resection among patients with TME surgery, and rates of postoperative complications assessed using the Clavien-Dindo classification. Safety profile will be described using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Functional and quality of life assessments include bowel function evaluated using the LARS score at inclusion, 3 months post-radiotherapy, 12 months, and 24 months post-inclusion. Quality of life will be assessed using the QLQ-C30 and ELD-14 scores at the same time points. Geriatric assessment will be performed using multiple instruments including G8, MMS, ADL, IADL, TUG, Charlson, ACE 27, SARC F, hand grip, 5-time chair, and G Code at inclusion, with G Code repeated at 3 months post-radiotherapy, 12 months, and 24 months post-inclusion. The estimated recruitment start date is January 15, 2026, and the estimated end date of the trial is February 15, 2032. Participants who are alive at the time of analysis or lost to follow-up will be censored at the date of the latest news for survival analyses. Early termination from the study may occur based on protocol-defined criteria, although specific conditions are not detailed in the available information.

The experimental treatment regimen consists of a combination chemotherapy protocol designated as FOLFOX4s, administered following short-course radiotherapy in patients with locally advanced rectal cancer. This chemotherapy regimen comprises four medicinal products administered via intravenous route over a treatment period of up to 12 weeks.

**Oxaliplatin** is administered as a **solution for infusion** via **intravenous use**. The maximum daily dose is 85 mg/m², with a maximum total dose of 510 mg/m² over the treatment period. The dosing is expressed in milligrams per square meter of body surface area. The treatment duration extends up to 12 weeks, corresponding to 6 cycles of the FOLFOX4s chemotherapy protocol.

**Calcium levofolinate** is provided as a **solution for injection** administered via **intravenous use**. The maximum daily dose is 200 mg/m², with a maximum total dose of 1200 mg/m² throughout the treatment period. The dosing follows the same body surface area-based calculation as the other agents in the regimen. Administration occurs over a maximum treatment period of 12 weeks.

**Folinic acid** is administered as a **solution for injection/infusion** via **intravenous use**. The maximum daily dose is 400 mg/m², with a maximum total dose of 2400 mg/m² over the complete treatment course. This agent is dosed according to body surface area and is administered over a maximum period of 12 weeks as part of the combination chemotherapy protocol.

**Fluorouracil** is delivered as a **solution for infusion** via **intravenous use**. The maximum daily dose is 2800 mg/m², representing the highest individual dose among all agents in the regimen, with a maximum total dose of 16800 mg/m² over the treatment period. Dosing is calculated based on body surface area, and administration extends over a maximum of 12 weeks.

The comparator arm in this randomized phase III study consists of short-course radiotherapy without subsequent chemotherapy, allowing for evaluation of the added benefit of the FOLFOX4s chemotherapy regimen in terms of organ preservation rate in elderly patients aged 75 years or older with locally advanced rectal cancer.

The primary efficacy endpoint is the 24-month TME-free survival, which will be estimated using the Kaplan-Meier method and presented with its 95% confidence interval. Organ preservation rate at 24 months is defined as the proportion of patients without total mesorectal excision, or nonsalvageable pelvic disease, and without permanent diversion stoma. Patients alive at the time of analysis or lost from follow-up will be censored at the date of the latest news.

Secondary efficacy endpoints include the rate of clinical complete response, defined as the percentage of complete response confirmed by central review after 21 weeks. Complete response is assessed through endoscopic evaluation showing flat, white scar with telangiectasia and no ulcer or nodularity, digital rectal examination showing no induration, pelvic MRI-T2W demonstrating normal appearing bowel wall without fibrosis in the tumor bed with dark T2 signal and no mesorectal lymph node, MRI-DW showing no visible signal on B800-B1000, and chest and abdominal CT scan showing no metastatic dissemination. The 24-month overall survival is defined as the period between the date of randomization and the date of death related to cancer, and will be estimated with the Kaplan-Meier method and presented with its 95% confidence interval. Patients who did not die at the time of analysis or are lost-of-follow-up will be censored at the date of the latest news.

Locoregional failure at 24 months is defined as either an unresectable rectal primary tumor following protocol neoadjuvant treatment, an R2 resection for the rectal primary tumor, or recurrence in the primary tumor bed after an R0-R1 resection. The 24-month disease-free survival is defined as the period between the date of randomization and the date of locoregional failure, distant metastasis, a new invasive colorectal primary cancer, or death from any cause, and will be estimated with the Kaplan-Meier method and presented with its 95% confidence interval. The 24-month regrowth rate will be defined as the proportion of patients presenting tumor regrowth during their surveillance in the watch and wait strategy or after local scar excision after they achieved clinical complete response. The 24-month metastasis-free survival is defined as the period between the date of randomization and the date of detection of distant metastasis, and will be estimated with the Kaplan-Meier method and presented with its 95% confidence interval.

Additional secondary endpoints include the rate of R0 resection, defined as the percentage of R0 resection among patients with total mesorectal excision surgery. The rate of postoperative complications of initial surgery will be assessed at 3 months using the Clavien-Dindo classification. The rate of postoperative complications of salvage surgery after initial non-operative management will also be assessed at 3 months using the Clavien-Dindo classification. Safety profile in each arm will be described using the common toxicity criteria from the CTCAE v5.0. Bowel function will be assessed using the LARS score at inclusion, 3 months postradiotherapy, 12 months and 24 months post inclusion. Quality of life will be assessed by QLQ-C30 and ELD-14 score at inclusion, 3 months postradiotherapy, 12 months and 24 months post inclusion. Geriatric assessment will be evaluated using G8, MMS, ADL, IADL, TUG, Charlson, ACE 27, SARC F, Hand grip, 5-time chair, and G Code at inclusion, then G Code at 3 months post radiotherapy, 12 and 24 months post inclusion.