Neoadjuvant FOLFIRINOX Versus Upfront Surgery in Resectable Pancreatic Head Cancer: A Multicenter, Randomized Phase 2 Trial

The primary objective of this study is to evaluate the **additional value of neoadjuvant chemotherapy** in conjunction with the standard treatment regimen, which includes surgery followed by adjuvant chemotherapy, for patients with resectable pancreatic head cancer. This evaluation aims to determine whether the inclusion of neoadjuvant chemotherapy can reduce early mortality and enhance overall survival rates in this patient population. The clinical relevance of this objective lies in its potential to improve treatment outcomes and survival rates for individuals diagnosed with this form of cancer, which is known for its poor prognosis and high mortality rate.

The clinical trial focuses on individuals diagnosed with **resectable pancreatic head cancer**. The study population includes both male and female participants, aged over 18 years, who are considered fit for major surgery. The trial does not involve a vulnerable population. Participants are required to have a resectable tumor of the pancreatic head, radiologically suspected to be pancreatic adenocarcinoma, classified as T1-3, Nx, M0 according to the UICC 7th version, 2010. The sponsor has not provided information regarding the total number of participants. Participants must provide written informed consent and be deemed capable of receiving the study-specific chemotherapy. No specific lifestyle considerations such as diet or physical activity are highlighted in the trial details.

The clinical trial is designed to evaluate the efficacy of **neoadjuvant chemotherapy** in addition to standard treatment for patients with resectable pancreatic head cancer. This is a multicenter, randomized, phase 2 trial with a double-blind, controlled design. The trial aims to assess the impact of neoadjuvant chemotherapy on overall survival and progression-free survival, with a primary endpoint of overall survival at 18 months post-randomization. The trial is expected to run until December 31, 2030, with recruitment having commenced on February 1, 2017.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a resectable tumor of the pancreatic head, age over 18 years, and fitness for major surgery. Following randomization, participants will receive either neoadjuvant chemotherapy or proceed directly to surgery, followed by adjuvant chemotherapy. The chemotherapy regimen includes **fluorouracil**, **gemcitabine hydrochloride**, **irinotecan hydrochloride**, **capecitabine**, **oxaliplatin**, and **calcium folinate**, administered via infusion or orally, depending on the specific drug.

Follow-up visits will be scheduled to monitor treatment response, adverse events, and overall health status. These visits will assess secondary endpoints such as progression-free survival, overall mortality, histopathological response, and quality of life. The end-of-study visit will occur after the completion of the treatment regimen and follow-up period, providing a comprehensive evaluation of the trial outcomes.

Participant involvement is expected to last up to six months for the treatment period, with additional time for follow-up assessments. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any medical condition that contraindicates continued participation. The trial's rigorous design ensures that data collected will contribute valuable insights into the potential benefits of neoadjuvant chemotherapy for resectable pancreatic head cancer.

The clinical trial involves the administration of several **antineoplastic** agents, each with specific dosing regimens and routes of administration. **Fluorouracil**, also known as 5-FU, is administered in the form of an infusion. The maximum daily dose is 5280 mg, with a total maximum dose of 63360 mg over a treatment period of up to 6 months. This chemical substance is utilized for its efficacy in inhibiting cancer cell growth.

**Gemcitabine hydrochloride** is another infusion-based treatment used in the trial. The maximum daily dose is set at 2200 mg, with a cumulative maximum dose of 39600 mg over the same 6-month period. This agent is known for its role in disrupting DNA synthesis in cancer cells.

**Irinotecan hydrochloride** is administered via infusion, with a maximum daily dose of 330 mg and a total maximum dose of 3960 mg over 6 months. This drug functions by inhibiting topoisomerase I, an enzyme critical for DNA replication.

**Capecitabine** is the only oral medication in the trial, with a maximum daily dose of 3652 mg and a total maximum dose of 460152 mg over 6 months. It is a prodrug that is metabolized into 5-FU in the body, providing targeted antineoplastic effects.

**Oxaliplatin** is administered through infusion, with a maximum daily dose of 187.5 mg and a total maximum dose of 2244 mg over the treatment period. This platinum-based drug forms cross-links in DNA, preventing cancer cell replication.

**Calcium folinate**, also known as leucovorin calcium, is used as a vitamin analog in the trial. It is administered via infusion with a maximum daily dose of 880 mg and a total maximum dose of 10560 mg over 6 months. This agent is often used to enhance the effects of fluorouracil by stabilizing the bond between fluorouracil and the enzyme thymidylate synthase.

All treatments are monitored for participant compliance, ensuring adherence to the dosing schedules and administration routes. The trial aims to evaluate the efficacy of these treatments in improving outcomes for patients with resectable pancreatic head cancer.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the overall survival at 18 months after the date of randomization. Secondary endpoints include progression-free survival assessed at 18 months and as time since randomization, overall mortality at 1 year after the commencement of allocated treatment for patients who ultimately underwent resection, and overall survival in both the intention-to-treat (ITT) and per-protocol populations. Additional secondary endpoints are overall survival following resection, histopathological response including R0 resection and [y]pN0 disease, complication rates at 90 days after surgery, feasibility of neoadjuvant and adjuvant chemotherapy as assessed by adverse events, dose reductions, and dose delays, completion rates of all parts of multimodal treatment, health economics, and quality of life.

The trial aims to evaluate the additional value of neoadjuvant chemotherapy to the standard treatment for resectable cancer of the pancreatic head. The efficacy parameters will be measured and collected at specified timepoints, including 18 months for overall survival and progression-free survival, and 1 year for overall mortality. The analysis will involve comparing these endpoints between the treatment groups to determine the impact of neoadjuvant chemotherapy on survival and other clinical outcomes. The trial will utilize validated scales and laboratory tests to ensure accurate and reliable data collection and analysis.