Nordic ORgan Preservation Pilot Approach Nonrandomised Single-Arm Trial for Non-Operative Management of Rectal Cancer

Nordic ORgan Preservation Pilot Approach - A Nonrandomised Single-Arm Trial for Non-Operative Management of Rectal Cancer (NORPPA-1)

The goal of this one-arm clinical trial is to implement and study the oncological outcomes of nonoperative management of rectal cancer having complete clinical response to neoadjuvant therapy. The main questions to answer are

• if the oncological results of nonoperative management after Nordic practice in chemoradiotherapy indications differ from experiences elsewhere
• what is the organ preservation rate
• what is the local regrowth rate

Background: Non-operative management (NOM) for rectal cancer is an accepted treatment option that has not been commonly utilized in Finland but has been widely adopted in major cancer centers worldwide. NOM can be considered if the rectal tumor disappears with neoadjuvant treatment, resulting in a complete clinical response.

Objective: The aim of the study is to establish a unified NOM protocol for national use and determine whether the outcomes of Finnish and Estonian treatment practices align with international experiences.

Design: The study is a prospective, non-randomized, single-arm, international multicenter trial examining the oncological and quality-of-life consequences of NOM.

Primary Endpoint: The primary endpoint is disease-free survival 2 years after the initiation of NOM.

Secondary Endpoints: These include overall survival, disease-specific survival, survival free from total mesorectal excision (TME) surgery, survival free from circulating tumor DNA (ctDNA) detection after complete clinical response, recurrence-free survival, incidence of local recurrence and metastases, salvage TME success rate, quality of life at 1 year post-NOM, and treatment-related morbidity up to 5 years.

Inclusion Criteria: Patients must have histopathologically confirmed primary rectal adenocarcinoma before neoadjuvant treatment, achieve clinical complete response (cCR) after neoadjuvant therapy, and express willingness to undergo rectum-preserving treatment after considering the risk of recurrence.

Exclusion Criteria: Patients with evidence of metastasis at diagnosis, aged under 18, those not receiving neoadjuvant treatment, or those unable to provide informed consent are excluded.

Diagnosis and Treatment: Pretreatment of patients follows standard practice. Upon meeting inclusion criteria with confirmed cCR, patients undergo protocolized monitoring with clinical examination, laboratory tests, and imaging.

Randomization: No randomization is performed.

Follow-up: Patients are monitored every 3 months for the first 2 years, then every 6 months for 3 years. Monitoring replaces surgical intervention unless cancer recurs. Follow-up is part of standard care, with costs covered by the healthcare system.

Safety: Incidence of local recurrence and success of resection post-recurrence are monitored closely. If over 30% local recurrence occurs post-cCR, it may necessitate study termination at the center.

Data Collection: Clinical data are entered into electronic case report forms (eCRFs) based on primary healthcare documentation and stored pseudonymized on the primary research center's server. Molecular and pseudonymized clinical data are collected securely for analysis.

Sample Size Calculation and Statistical Analysis: A sample of 200 patients is estimated to provide sufficient data for the primary and key secondary endpoints and to meet other study objectives accurately.

Data Handling: Data handling adheres to privacy legislation, with information stored pseudonymously.

Inclusion Criteria:

• Histopathological verification of primary rectal adenocarcinoma
• Complete clinical response at response assessment after neoadjuvant therapy
• Informed consent to organ preservation study

Exclusion Criteria:

• Evidence of metastatic disease (fulfilling M-class criteria of TNM)
• No neoadjuvant therapy
• Inability to understand the information related to harms and benefits