RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing
so they stop growing or die. Pemetrexed disodium may stop the growth of tumor cells by
blocking the enzymes necessary for tumor cell growth. It is not yet known whether
gemcitabine is more effective with or without pemetrexed disodium in treating pancreatic
PURPOSE: Randomized phase III trial to compare the effectiveness of gemcitabine combined
with pemetrexed disodium to that of gemcitabine alone in treating patients who have
unresectable stage II, stage III, or stage IV pancreatic cancer.
- Compare the overall survival of patients with stage II, III, or IV unresectable
pancreatic cancer treated with gemcitabine with or without pemetrexed disodium.
- Compare the progression-free survival of patients treated with these regimens.
- Compare the time to treatment failure and duration of response in patients treated with
- Compare tumor response rate in patients treated with these regimens.
- Compare the effects of these regimens on health-related quality of life in these
- Compare the toxic effects of these regimens in these patients.
OUTLINE: This is a randomized, open-label, parallel, multicenter study. Patients are
stratified according to baseline ECOG performance status (0-1 vs 2), disease stage (II or
III vs IV), baseline homocysteine level (at least 12 µmol/L vs less than 12 µmol/L), and
participating center. Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive gemcitabine IV over 30-60 minutes on days 1 and 8 and
pemetrexed disodium IV over 10 minutes on day 1. Treatment repeats every 3 weeks for up
to 8 courses in the absence of disease progression or unacceptable toxicity. Patients
also receive oral folic acid and cyanocobalamin intramuscularly every 9 weeks beginning
1-2 weeks before day 1 and continuing until 3 weeks after end of study therapy.
- Arm II: Patients receive gemcitabine IV over 30-60 minutes on days 1, 8, and 15.
Treatment repeats every 4 weeks for up to 6 courses in the absence of disease
progression or unacceptable toxicity.
Quality of life is assessed at baseline, at the end of each course, and then every 3 months
Patients are followed every 3 months.
PROJECTED ACCRUAL: A total of 520 patients (260 per treatment arm) will be accrued for this
- Histologically or cytologically confirmed adenocarcinoma of the pancreas
- Stage II, III, or IV disease that is not amenable to resection with curative
- At least 1 bidimensionally measurable lesion with clearly defined margins by CT scan
or MRI or by palpation with both diameters at least 2 cm
- No clinically significant third-space fluid collection (e.g., ascites or pleural
effusions) NOTE: Fluid collections may be drained
- No documented brain metastases
- 18 and over
- ECOG 0-2
- At least 12 weeks
- Absolute neutrophil count at least 1,500/mm^3
- Platelet count at least 100,000/mm^3
- Hemoglobin at least 9 g/dL
- Bilirubin no greater than 1.5 times upper limit of normal (ULN)
- AST/ALT no greater than 3 times ULN (5 times ULN if liver metastases present)
- Alkaline phosphatase no greater than 3 times ULN (5 times ULN if liver metastases
- Endoscopic or radiologic stenting allowed for biliary obstructions (bilirubin must
meet study requirements and AST/ALT and alkaline phosphatase must be no greater than
5 times ULN)
- Creatinine clearance at least 45 mL/min
- No unstable angina pectoris
- See Disease Characteristics
- No other malignancy within the past 5 years except carcinoma in situ of the cervix or
adequately treated nonmelanoma skin cancer
- No active infection
- No other serious concurrent systemic disorders that would preclude study
- No uncontrolled diabetes mellitus
- No weight loss of 10% or more within the past 6 weeks
- No inability or unwillingness to take folic acid or vitamin B12 supplementation
- Not pregnant or nursing
- Fertile patients must use effective contraception during and for 3 months after study
PRIOR CONCURRENT THERAPY:
- No prior immunotherapy
- No prior biological therapy for pancreatic cancer
- No concurrent immunotherapy
- No concurrent routine colony-stimulating factors
- No concurrent stimulators of thrombopoiesis
- No prior chemotherapy for pancreatic cancer
- No prior fluorouracil for pancreatic cancer (including as a radiosensitizer)
- No other concurrent chemotherapy
- No prior hormonal therapy for pancreatic cancer
- No concurrent hormonal therapy for cancer
- No prior radiation to whole pelvis
- Prior radiotherapy to less than 25% of bone marrow allowed
- At least 4 weeks since prior radiotherapy and recovered
- Concurrent palliative radiotherapy for small, painful metastases allowed
- No concurrent surgery for cancer
- At least 30 days since prior investigational agents or devices
- No other concurrent experimental medications (except thymidine)
- No other concurrent antitumor therapy
- No concurrent aspirin, salicylates, or other nonsteroidal anti-inflammatory drugs for
2-5 days before, during, and for 2 days after each dose of pemetrexed disodium