Combination Chemotherapy, and Radiation Therapy in Treating Patients With Locally Advanced Pancreatic Cancer

A Phase II Study Of Neo-Adjuvant Chemotherapy And Radiation In Patients With Locally Advanced Pancreatic Cancer

RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Giving combination chemotherapy with radiation therapy before surgery may shrink the tumor so that it can be removed.

PURPOSE: This phase II trial is studying how well giving combination chemotherapy together with radiation therapy works in treating patients who may undergo surgery for locally advanced pancreatic cancer.

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: fluorouracil; Drug: gemcitabine hydrochloride; Drug: leucovorin calcium; Drug: oxaliplatin; Procedure: adjuvant therapy; Procedure: conventional surgery; Procedure: neoadjuvant therapy; Radiation: radiation therapy

Detailed Description

OBJECTIVES:

• Determine the antitumor and clinical benefit response to neoadjuvant chemoradiotherapy comprising gemcitabine, fluorouracil, leucovorin calcium, and oxaliplatin in patients with potentially resectable locally advanced adenocarcinoma of the pancreas.
• Determine the toxic effects of this regimen in these patients.
• Determine the achieved steady-state plasma levels of gemcitabine and fluorouracil in these patients and correlate these plasma levels with clinical toxicity associated with this regimen.
• Determine the potential importance of polymorphic variations in genomic DNA of pertinent genes (whose protein products are targets of the antineoplastic drugs used in this study) on response to and toxicity of this regimen in these patients.
• Determine the gene expression profiles of primary and metastatic pancreatic tumors before and after treatment with this regimen.

OUTLINE:

• Neoadjuvant chemotherapy: Patients receive gemcitabine IV over 30 minutes and fluorouracil IV continuously over 24 hours on days 2 and 9, and leucovorin calcium orally on days 1 and 8 and IV on days 2 and 9. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity.
• Neoadjuvant chemoradiotherapy: Beginning on day 42, patients undergo chemoradiotherapy comprising oxaliplatin IV over 2 hours on days 42, 49, 56, 63, 70, and 77 and fluorouracil IV continuously on days 42-78 with external beam radiotherapy.
• Surgery: Patients undergo surgical resection 42-56 days after completion of chemoradiotherapy.
• Adjuvant chemotherapy: After post-operative recovery, patients receive 2 additional courses of gemcitabine, fluorouracil, and leucovorin calcium. If surgical resection is not possible, patients with stable or responsive disease resume gemcitabine, fluorouracil, and leucovorin calcium indefinitely in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Nebraska
    • Omaha, Nebraska, United States, 68198-6805
      • Eppley Cancer Center, University of Nebraska Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of adenocarcinoma of the pancreas

  o Locally advanced disease

• Potentially resectable disease
• 19 years of age and over
• Karnofsky 60-100%
• Absolute granulocyte count ≥ 2,000/mm^3
• Platelet count ≥ 100,000/mm^3

• Bilirubin ≤ 2.0 mg/dL (in the absence of biliary obstruction)

  • If biliary obstruction is present, patients must undergo biliary decompression
  • Bilirubin ≤ 3.0 mg/dL after biliary drainage has been established
• Creatinine ≤ 1.6 mg/dL

Exclusion Criteria:

• No early stage resectable disease
• No concurrent non-steroidal anti-inflammatory medication
• No evidence of distant metastases to the liver or peritoneal area according to imaging studies and laparoscopic staging
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No serious uncontrolled cardiac arrhythmia
• Not pregnant or nursing
• No uncontrolled illness
• No active or ongoing infection requiring IV antibiotics
• No marked intolerance to 5-fluoropyrimidines (i.e., fluorouracil, floxuridine, capecitabine, or fluorocytosine)
• No allergy to sulfonamides, aspirin, or non-steroidal anti-inflammatory drugs
• No allergy to platinum compounds or to antiemetics appropriate for administration in conjunction with study chemotherapy
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or adequately treated noninvasive carcinoma
• No prior chemotherapy for pancreatic cancer
• No prior abdominal radiotherapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: treatment; see interventions

Drug: fluorouracil; 2700 mg/m5 IV over 24 hr after gemcitabine weeks 1 & 2; Repeat one 3-week cycle starting day 22; Other Names: Tolak, Fluoroplex, Carac; Drug: gemcitabine hydrochloride; 750 (females) or 900 (males) mg/m5 IV over 30 min (day 2)weeks 1 & 2; Repeat one 3-week cycle starting day 22; Other Names: Gemzar; Drug: leucovorin calcium; 20 mg/m5 PO (day 1) and 20 mg/m5 IV (day 2) weeks 1 and 2; Repeat one 3-week cycle starting day 22; Other Names: folic acid analog; Drug: oxaliplatin; 48 mg/m5 IV over 2 hr weeks 1, 2, 4, and 5; Other Names: chemotherapy; Procedure: adjuvant therapy; Patients who have undergone surgical resection, after post-operative recovery, will receive two additional cycles of gemcitabine/5-FU/leucovorin. Patients will then be followed at 3 month intervals with a history and physical exam, CT scan of the chest/abdomen/pelvis, and tumor markers. If surgical resection is not possible, patients with stable or responsive disease will resume gemcitabine/5-FU/leucovorin and continue on it indefinitely until disease progression provided the patient tolerates it and wishes to remain on therapy.; Procedure: conventional surgery; Restaging with repeat imaging studies will be performed four weeks after completion of the chemo-radiation. If no contraindication for surgical resection is identified, resection will be performed six to eight weeks after completing chemoradiation. At the time of surgical resection, an extensive examination of the abdomen will be performed to exclude the presence of metastatic disease. All operations will be performed with curative intent with resection of all gross tumor (ie R0 [negative margins] or R1 [positive microscopic margins]). Resection of adjacent involved organs or vascular structures will be performed as clinically indicated.; Procedure: neoadjuvant therapy; Eligible patients will receive an initial two cycles of chemotherapy with gemcitabine 750 (females) or 900 (males) mg/m5 over 30 minutes followed by a 24-hour infusion of fluorouracil 2700 mg/m5 on days 2 and 9 of a 21-day cycle . Calcium leucovorin 20 mg/m5 will be given orally on days 1 and 8 and by IV push on days 2 and 9 prior to the 5-FU. A window of -2 up to +7 days will be allowed to start planned cycles of therapy provided all other criteria to restart the new cycle has been met. Patients will require a central venous catheter (Port, Hickman or Groshong catheter) for the administration of 5-FU.; Radiation: radiation therapy; A re-staging CT scan, which will be obtained as part of the radiation simulation, will be used to assess any possible response to the initial two cycles of chemotherapy. Unless the patient has developed evidence of metastatic disease, chemoradiation will proceed. Patients who required no treatment delays will commence chemoradiation on day 42. If a one-week delay is needed before cycle 2 of neo-adjuvant chemotherapy can be delivered, the patient will begin chemoradiation on day 49 provided treatment-related toxicity has resolved. If cycle 2 could not be given (2 or more week delay for resolution of treatment-related toxicity), then chemoradiation will begin once toxicity has resolved (may be earlier than day 42).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Surgical Exploration	Patients who completed chemotherapy & chemo-radiation had restaging imaging studies 4 weeks after completion of chemo-radiation. If there were no contraindications for surgical resection, surgical exploration was performed 6-8 weeks after completing chemo-radiation	After 6 weeks of chemotherapy and then after 4 weeks of chemo-radiation.
Number of Participants Experiencing Grade 3-4 Toxicity While Receiving the Study Treatment	Toxicity event collected during Induction chemotherapy (CT) - two 3-week cycles, Concurrent CT and Radiation Therapy (CRT) (approximately 5.5 weeks), post CRT (4 weeks after the end of CRT), 2-3 months post CRT (8-12 weeks after the end of CRT)	From time of first dose until 30 days following final treatment, approximately 24 weeks

Collaborators and Investigators

• Sponsor: University of Nebraska
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Jean L Grem, MD, University of Nebraska

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2004
• Primary Completion (Actual): January 22, 2010
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: August 4, 2004
• First Submitted That Met QC Criteria: August 4, 2004
• First Posted (Estimated): August 5, 2004

Study Record Updates

• Last Update Posted (Actual): September 29, 2023
• Last Update Submitted That Met QC Criteria: September 22, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: adenocarcinoma of the pancreas; stage III pancreatic cancer; stage II pancreatic cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Hematinics; Fluorouracil; Oxaliplatin; Leucovorin; Calcium; Levoleucovorin; Folic Acid; Gemcitabine
• Other Study ID Numbers: 0035-04-FB; P30CA036727 (U.S. NIH Grant/Contract)