Neoadjuvant vs Upfront Surgery for Resectable Pancreatic Cancer and Periampullary Cancer

Official title

Neoadjuvant Chemotherapy Followed by Surgery Versus Upfront Surgery for Clearly Resectable Pancreatic Head Cancer and Periampullary Cancer: A Randomized Controlled Trial

Overview

Adjuvant chemotherapy after surgery significantly improved the survival of pancreatic cancer (PC) patients, but there is a problem that only about 50% of patients start adjuvant chemotherapy after pancreatectomy. Neoadjuvant chemotherapy might control potential metastatic lesions which are not being detected in early disease status and improve the R0 resection rate. In addition, it prevents futile surgery by selecting patients with rapid progression of disease. Furthermore, compared to chemotherapy administered after surgery, more patients can complete the planned chemotherapy schedule in neoadjuvant setting. There are still few studies worldwide that prospectively explored the efficacy of neoadjuvant chemotherapy in resectable PC and periampullary cancer and the administration of neoadjuvant therapy in resectable PC depends on individual clinical judgment. Therefore, systematic and prospective clinical trials are essential to standardize treatment protocol in resectable PC and periampullary Cancer. This randomized controlled trial compares neoadjuvant chemotherapy followed by surgery versus upfront surgery for patients with clearly resectable pancreatic head cancer and periampullary cancer. The study aims to determine if neoadjuvant chemotherapy improves overall survival compared to immediate surgery followed by adjuvant chemotherapy.

Detailed description

Pancreatic cancer is the seventh highest cause of death from cancer worldwide, with only 20% of patients presenting with resectable disease. Despite potentially curative resections, 5-year survival remains at 20%. This study evaluates whether neoadjuvant chemotherapy can improve outcomes by eliminating occult metastatic disease and improving resection margins.

Patients with clearly resectable pancreatic head cancer or periampullary cancer will be randomized 1:1 to either neoadjuvant chemotherapy followed by open or laparoscopic pancreaticoduodenectomy (Arm A) or upfront laparoscopic pancreaticoduodenectomy followed by adjuvant chemotherapy (Arm B). The primary endpoint is overall survival, with secondary endpoints including R0 resection rate , disease-free survival and perioperative outcomes.

Interventions

• Drug Neoadjuvant chemotherapy
  Neoadjuvant chemotherapy (mFOLFIRINOX) followed by pancreaticoduodenectomy
• Procedure Upfront Surgery Group
  Pancreaticoduodenectomy followed by adjuvant chemotherapy

Primary outcome measures

• Overall survival rate [Time frame: Up to 3 years.]

Secondary outcome measures (12)

• Disease-free survival (DFS) [Time frame: Up to 3 years post-procedure.]
• Local recurrence rate [Time frame: Up to 3 years post-procedure.]
• Recurrence rate [Time frame: Up to 3 years post-procedure.]
• Time to locoregional recurrence (TLR) [Time frame: Up to 3 years post-procedure.]
• Response rate in neoadjuvant setting [Time frame: 12 to 16 weeks.]
• Time to distant metastases (TDM) [Time frame: Time between randomization and metastases prior to surgery, metastases detected during surgery, or distant recurrence after resection, assessed up to 3 years.]
• Resection rate [Time frame: At time of surgery or planned time of surgery.]
• R0 resection rate [Time frame: One to two weeks postsurgery.]
• Lymph node-negative (N0) resection rate [Time frame: One to two weeks postsurgery.]
• Pathologic complete response (pCR) rate [Time frame: One to two weeks postsurgery.]
• Biomarker Response during neoadjuvant chemotherapy . [Time frame: Baseline level is measured before start of neoadjuvant chemotherapy( within 1 week) , then after neoadjuvant therapy completion( 12 to 16 weeks).]
• Rate of unresectability [Time frame: At time of surgery or planned time of surgery.]

Eligibility criteria

Inclusion criteria

• Histologically or cytologically confirmed pancreatic head cancer or periampullary carcinoma(endoscopic ultrasound (EUS)-guided biopsy).
• Clearly resectable disease as defined by National Comprehensive Cancer Network (NCCN) criteria on cross-sectional imaging:

No involvement or abutment of the celiac artery, common hepatic artery, superior mesenteric artery, or replaced right hepatic artery .

Less than 180 degree interface between tumor and vessel wall of the portal vein or superior mesenteric vein, and patent portal vein/splenic vein confluence No evidence of metastatic disease.

• Eastern Cooperative Oncology Group (ECOG)=0-1 \& American Society of Anesthesiologists (ASA) score <4.
• Written informed consent.
• Medical history without previous pancreatic resection or pancreatic cancer.
• Adequate organ function (liver, kidney, bone marrow) (serum creatinine ≤2.0 mg/dL,reference range 0.5-1.20 mg/dL; serum albumin ≥2.5 g/dL, reference range 3.5-5.3; aspartate aminotransferase (AST) ≤95 U/L, reference range 0-38; Alanine aminotransferase (ALT) ≤102 U/L, reference range 0-41; prothrombin time ≤1.8, reference range 0-1.20; partial thromboplastin time ≤1.8, reference range 0.82-1.25; leukocyte count greater than 3.5×109/L, reference range 4.2-9.0; platelet count greater than 100×109/L, reference range 130-400; hemoglobin ≥9 g/dL, reference range 12-16).

Exclusion criteria

• Borderline resectable or locally advanced pancreatic or periampullary cancer.
• Tumor at the body or tail of the pancreas.
• Distant metastases.
• Prior chemotherapy , surgery or radiotherapy for pancreatic cancer.
• Severe comorbidities precluding surgery or chemotherapy.
• Pregnancy or lactation.
• Other neoplastic diseases (malignant)diagnosed in the past 5 years.
• Major surgery or traumatic event in the past 28 days.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Egypt · 1 center

• Liver and GIT hospital , Minia University — Minya

Publications

• Evans DB. The Complexity of Neoadjuvant Therapy for Operable Pancreatic Cancer: Lessons Learned From SWOG S1505. Ann Surg. 2020 Sep 1;272(3):487. doi: 10.1097/SLA.0000000000004131. No abstract available. PMID 32657915
• Murphy JE, Wo JY, Ryan DP, Jiang W, Yeap BY, Drapek LC, Blaszkowsky LS, Kwak EL, Allen JN, Clark JW, Faris JE, Zhu AX, Goyal L, Lillemoe KD, DeLaney TF, Fernandez-Del Castillo C, Ferrone CR, Hong TS. Total Neoadjuvant Therapy With FOLFIRINOX Followed by Individualized Chemoradiotherapy for Borderline Resectable Pancreatic Adenocarcinoma: A Phase 2 Clinical Trial. JAMA Oncol. 2018 Jul 1;4(7):963-96 PMID 29800971
• Golcher H, Brunner TB, Witzigmann H, Marti L, Bechstein WO, Bruns C, Jungnickel H, Schreiber S, Grabenbauer GG, Meyer T, Merkel S, Fietkau R, Hohenberger W. Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer: results of the first prospective randomized phase II trial. Strahlenther Onkol. 2015 Jan;191(1):7-16. doi: 10.1 PMID 25252602
• Casadei R, Di Marco M, Ricci C, Santini D, Serra C, Calculli L, D'Ambra M, Guido A, Morselli-Labate AM, Minni F. Neoadjuvant Chemoradiotherapy and Surgery Versus Surgery Alone in Resectable Pancreatic Cancer: A Single-Center Prospective, Randomized, Controlled Trial Which Failed to Achieve Accrual Targets. J Gastrointest Surg. 2015 Oct;19(10):1802-12. doi: 10.1007/s11605-015-2890-4. Epub 2015 Jul PMID 26224039
• Goetze TO, Reichart A, Bankstahl US, Pauligk C, Loose M, Kraus TW, Elshafei M, Bechstein WO, Trojan J, Behrend M, Homann N, Venerito M, Bohle W, Varvenne M, Bolling C, Behringer DM, Kratz-Albers K, Siegler GM, Hozaeel W, Al-Batran SE. Adjuvant Gemcitabine Versus Neoadjuvant/Adjuvant FOLFIRINOX in Resectable Pancreatic Cancer: The Randomized Multicenter Phase II NEPAFOX Trial. Ann Surg Oncol. 2024 PMID 38459418
• Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010 Apr 20;7(4):e1000267. doi: 10.1371/journal.pmed.1000267. PMID 20422030
• Artinyan A, Anaya DA, McKenzie S, Ellenhorn JD, Kim J. Neoadjuvant therapy is associated with improved survival in resectable pancreatic adenocarcinoma. Cancer. 2011 May 15;117(10):2044-9. doi: 10.1002/cncr.25763. Epub 2010 Nov 18. PMID 21523715
• Mokdad AA, Minter RM, Zhu H, Augustine MM, Porembka MR, Wang SC, Yopp AC, Mansour JC, Choti MA, Polanco PM. Neoadjuvant Therapy Followed by Resection Versus Upfront Resection for Resectable Pancreatic Cancer: A Propensity Score Matched Analysis. J Clin Oncol. 2017 Feb 10;35(5):515-522. doi: 10.1200/JCO.2016.68.5081. Epub 2016 Sep 30. PMID 27621388

Identifiers

NCT: NCT07081360 · 1563/06/2025

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗