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

• Sponsor: University of Nebraska (Other)
• Overall Status: Completed
• CT.gov ID: NCT00089024
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 29
• Location: 1
• Arm: 1
• Duration (Months): 130
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Cancer	Drug: fluorouracil; Drug: gemcitabine hydrochloride; Drug: leucovorin calcium; Drug: oxaliplatin; Procedure: adjuvant therapy; Procedure: conventional surgery; Procedure: neoadjuvant therapy; Radiation: radiation therapy	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study Of Neo-Adjuvant Chemotherapy And Radiation In Patients With Locally Advanced Pancreatic Cancer
• Study Start Date: Feb 1, 2004
• Actual Primary Completion Date: Jan 1, 2010
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

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; 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; 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; Drug: oxaliplatin; 48 mg/m5 IV over 2 hr weeks 1, 2, 4, and 5; 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).

Outcome Measures

Primary Outcome Measures

1. Surgical Exploration [After 6 weeks of chemotherapy and then after 4 weeks of chemo-radiation.]

   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

2. Number of Participants Experiencing Grade 3-4 Toxicity While Receiving the Study Treatment [From time of first dose until 30 days following final treatment, approximately 24 weeks]

   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)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of adenocarcinoma of the pancreas

• Locally advanced disease

• Potentially resectable disease

• No early stage resectable disease

• No evidence of distant metastases to the liver or peritoneal area according to imaging studies and laparoscopic staging

PATIENT CHARACTERISTICS:

Age

• 19 and over

Performance status

• Karnofsky 60-100%

Life expectancy

• Not specified

Hematopoietic

• Absolute granulocyte count ≥ 2,000/mm^3

• Platelet count ≥ 100,000/mm^3

Hepatic

• 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

Renal

• Creatinine ≤ 1.6 mg/dL

Cardiovascular

• No symptomatic congestive heart failure

• No unstable angina pectoris

• No serious uncontrolled cardiac arrhythmia

Other

• 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

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy for pancreatic cancer

Endocrine therapy

• Not specified

Radiotherapy

• No prior abdominal radiotherapy

Surgery

• Not specified

Other

• No concurrent non-steroidal anti-inflammatory medication

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UNMC Eppley Cancer Center at the University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-6805

Sponsors and Collaborators

• University of Nebraska
• National Cancer Institute (NCI)

Investigators

• Study Chair: Jean L. Grem, MD, University of Nebraska

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jean Grem, MD, primary investigator, University of Nebraska
• ClinicalTrials.gov Identifier: NCT00089024
• Other Study ID Numbers: 035-04; P30CA036727; UNMC-03504
• First Posted: Aug 5, 2004
• Last Update Posted: Oct 21, 2019
• Last Verified: Sep 1, 2019

• Keywords provided by Jean Grem, MD, primary investigator, University of Nebraska: adenocarcinoma of the pancreas; stage II pancreatic cancer; stage III pancreatic cancer
• Additional relevant MeSH terms: Pancreatic Neoplasms; Leucovorin; Gemcitabine; Fluorouracil; Oxaliplatin; Calcium; Levoleucovorin

Study Results

Participant Flow

Arm/Group Title	Treatment
Arm/Group Description	neoadjuvant regimen involving gemcitabine, infusional 5-fluorouracil (5-FU), oxaliplatin and radiation therapy (RT) in patients with potentially resectable locally advanced pancreatic adenocarcinoma. Induction chemotherapy (CT) consisted of two 3-week cycles of weekly gemcitabine with 24-hour continuous infusion of 5 FU for 2 of 3 weeks. Chemoradiation (CRT) consisted of RT of 50.4 Gy in 28 fractions or 50 Gy in 25 fractions and weekly oxaliplatin with 24-hour continuous infusion of 5 FU throughout RT. The first 7 patients also received celecoxib 200 mg BID throughout induction CT and CRT.
Period Title: Overall Study
STARTED	29
Treated Subjects	29
COMPLETED	24
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Treatment
Arm/Group Description	neoadjuvant regimen involving gemcitabine, infusional 5-fluorouracil (5-FU), oxaliplatin and radiation therapy (RT) in patients with potentially resectable locally advanced pancreatic adenocarcinoma. Induction chemotherapy (CT) consisted of two 3-week cycles of weekly gemcitabine with 24-hour continuous infusion of 5 FU for 2 of 3 weeks. Chemoradiation (CRT) consisted of RT of 50.4 Gy in 28 fractions or 50 Gy in 25 fractions and weekly oxaliplatin with 24-hour continuous infusion of 5 FU throughout RT. The first 7 patients also received celecoxib 200 mg BID throughout induction CT and CRT.
Overall Participants	29
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60
Sex: Female, Male (Count of Participants)
Female	17 58.6%
Male	12 41.4%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	28 96.6%
Hispanic	1 3.4%

Outcome Measures

1. Primary Outcome

Title	Surgical Exploration
Description	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
Time Frame	After 6 weeks of chemotherapy and then after 4 weeks of chemo-radiation.

Outcome Measure Data

Analysis Population Description

Only 19 participants under went surgical exploration.

Arm/Group Title	Treatment
Arm/Group Description	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. Radiation therapy: Patients who required no treatment delays will commence chemoradiation on day 42. Restaging with repeat imaging studies will be performed four weeks after completion of the chemo-radiation. Resection will be performed six to eight weeks after completing chemoradiation. Patients who have undergone surgical resection, after post-operative recovery, will receive two additional cycles of gemcitabine/5-FU/leucovorin. 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
Measure Participants	19
unresectable disease	4 13.8%
intra-abdominal metastasis	6 20.7%
resection of the primary tumor	9 31%

2. Primary Outcome

Title	Number of Participants Experiencing Grade 3-4 Toxicity While Receiving the Study Treatment
Description	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)
Time Frame	From time of first dose until 30 days following final treatment, approximately 24 weeks

Outcome Measure Data

Analysis Population Description

A total of 29 patients started induction CT. Two patients dropped out because of progressive disease (PD) and 1 died from pulmonary embolus. 27 patients continued with CRT 24 (89%) received the full radiation dose. Of 24, 5 went off study prior to surgical exploration, for remaining 19 with surgical exploration.

Arm/Group Title	Treatment
Arm/Group Description	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. Radiation therapy: Patients who required no treatment delays will commence chemoradiation on day 42. Restaging with repeat imaging studies will be performed four weeks after completion of the chemo-radiation. Resection will be performed six to eight weeks after completing chemoradiation. Patients who have undergone surgical resection, after post-operative recovery, will receive two additional cycles of gemcitabine/5-FU/leucovorin. 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
Measure Participants	29
Induction CT, grade 3	4 13.8%
Induction CT, grade 4	5 17.2%
CRT, grade 3	11 37.9%
CRT, grade 4	0 0%
Within 1 mo. post CRT, grade 3	12 41.4%
Within 1 mo. post CRT, grade 4	1 3.4%
2-3 mos. post CRT, grade 3	9 31%
2-3 mos. post CRT, grade 4	0 0%

Adverse Events

Time Frame	Patients were followed for adverse events from the time of first treatment until they 30 days after last day of study treatment. (approximately 24 weeks)
Arm/Group Title	Treatment
Arm/Group Description	neoadjuvant regimen involving gemcitabine, infusional 5-fluorouracil (5-FU), oxaliplatin and radiation therapy (RT) in patients with potentially resectable locally advanced pancreatic adenocarcinoma. Induction chemotherapy (CT) consisted of two 3-week cycles of weekly gemcitabine with 24-hour continuous infusion of 5 FU for 2 of 3 weeks. Chemoradiation (CRT) consisted of RT of 50.4 Gy in 28 fractions or 50 Gy in 25 fractions and weekly oxaliplatin with 24-hour continuous infusion of 5 FU throughout RT. The first 7 patients also received celecoxib 200 mg BID throughout induction CT and CRT.
All Cause Mortality
	Treatment
	Affected / at Risk (%)	# Events
Total	7/29 (24.1%)
Serious Adverse Events
	Treatment
	Affected / at Risk (%)	# Events
Total	25/29 (86.2%)
Blood and lymphatic system disorders
Anemia	1/29 (3.4%)	1
Blood and lymphatic system disorders - Other, specify	1/29 (3.4%)	1
Cardiac disorders
Myocardial infarction	1/29 (3.4%)	1
Atrial fibrillation	1/29 (3.4%)	1
Gastrointestinal disorders
Gastrointestinal disorders - Other, specify	1/29 (3.4%)	1
Gastrointestinal disorders - Other, specify	2/29 (6.9%)	2
Abdominal pain	3/29 (10.3%)	3
Vomiting	4/29 (13.8%)	4
Diarrhea	2/29 (6.9%)	2
Ascites	1/29 (3.4%)	1
Gastrointestsinal disorders - other, specify	1/29 (3.4%)	1
Gastrointestinal disorders- Other, specify	1/29 (3.4%)	1
Gastrointestinal disorders - Other, specify	1/29 (3.4%)	1
Gastrointestinal disorders - Other, specify	1/29 (3.4%)	1
Gastric perforation	1/29 (3.4%)	1
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify	1/29 (3.4%)	1
Hepatobiliary disorders - Other, specify	1/29 (3.4%)	1
Hepatobiliary disorders - Other, specify	1/29 (3.4%)	1
Infections and infestations
Sepsis	4/29 (13.8%)	4
Infections and infestations - Other, specify	1/29 (3.4%)	1
Infections and infestations - Other, specify	1/29 (3.4%)	1
Investigations
Investigations - Other, specify	2/29 (6.9%)	2
Investigations - Other, specify	1/29 (3.4%)	1
Investigations - Other, specify	1/29 (3.4%)	1
Investigations - Other, specify	1/29 (3.4%)	1
Investigations - Other, specify	1/29 (3.4%)	1
Metabolism and nutrition disorders
Hyponatremia	1/29 (3.4%)	1
Hypokalemia	1/29 (3.4%)	1
Acidosis	1/29 (3.4%)	1
Dehydration	1/29 (3.4%)	1
Hypoalbuminemia	1/29 (3.4%)	1
Hypocalcemia	1/29 (3.4%)	1
Nervous system disorders
Nervous system disorders - Other, specify	1/29 (3.4%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	2/29 (6.9%)	2
Respiratory Failure	1/29 (3.4%)	1
Respiratory, thoracic and mediastinal disorders - Other, specify	1/29 (3.4%)	1
Vascular disorders
Vascular disorders - Other, specify	1/29 (3.4%)	1
Vascular disorders - Other, specify	1/29 (3.4%)	1
Other (Not Including Serious) Adverse Events
	Treatment
	Affected / at Risk (%)	# Events
Total	27/29 (93.1%)
Blood and lymphatic system disorders
Blood and lymphatic system disorders - Other, specify	6/29 (20.7%)	27
Blood and lymphatic system disorders - Other, specify	2/29 (6.9%)	12
Blood and lymphatic system disorders - Other, specify	2/29 (6.9%)	2
Blood and lymphatic system disorders - Other, specify	2/29 (6.9%)	4
Gastrointestinal disorders
Nausea	5/29 (17.2%)	5
Abdominal Pain	3/29 (10.3%)	6
Diarrhea	3/29 (10.3%)	3
Dysphagia	2/29 (6.9%)	2
Vomiting	3/29 (10.3%)	3
General disorders
Fatigue	7/29 (24.1%)	8
General disorders and administration site conditions - Other, specify	3/29 (10.3%)	4
Infections and infestations
Urinary tract infection	2/29 (6.9%)	2
Sepsis	3/29 (10.3%)	3
Investigations
Hemoglobin	8/29 (27.6%)	9
Investigations - Other, specify	5/29 (17.2%)	5
Investigations - Other, specify	5/29 (17.2%)	5
Investigations - Other, specify	2/29 (6.9%)	2
Investigations - Other, specify	2/29 (6.9%)	2
Investigations - Other, specify	2/29 (6.9%)	2
Investigations - Other, specify	2/29 (6.9%)	2
Weight loss	3/29 (10.3%)	4
Metabolism and nutrition disorders
Metabolism and nutrition disorders - Other, specify	4/29 (13.8%)	4
Hyponatremia	10/29 (34.5%)	15
Hypokalemia	12/29 (41.4%)	22
Dehydration	2/29 (6.9%)	3
Anorexia	4/29 (13.8%)	4
Hyperglycemia	4/29 (13.8%)	4
Hypoalbuminemia	6/29 (20.7%)	7
Renal and urinary disorders
Renal and urinary disorders - Other, specity	2/29 (6.9%)	2
Respiratory, thoracic and mediastinal disorders
Pleural effusion	2/29 (6.9%)	2
Vascular disorders
Thromboembolic event	8/29 (27.6%)	9
Vascular disorders - Other, specify	2/29 (6.9%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.