Neo-adjuvant Chemoradiotherapy Using Infusional Gemcitabine Followed by Surgery for Locally Advanced Rectal Cancer

Phase II Study of Neo-adjuvant Chemoradiotherapy using infusional Gemcitabine followed by Surgery for Locally Advanced (T3 and T4 or Node positive) Rectal Adenocarcinoma.

Results of neo-adjuvant chemo-radiation for advanced rectal cancer have plateaued with pathological complete response rates of 10-20% in spite of the addition of new cytotoxic agents and/ or molecular targeted therapies. The combination of 5-fluorouracil and radiation produces effective sensitization but further improvements require assessment of other sensitizers to increase the pathological complete response rates. Gemcitabine has been used in combination with radiation for several GI cancers but few studies have examined its role in rectal cancer. This study will examine a combination of Gemcitabine and radiation as neo-adjuvant therapy in advanced rectal cancer to increase the pathological complete response (pCR) rate from the investigators traditional 6% to \> 40 %.

Eligibility Criteria:
Inclusion Criteria:

1. Adenocarcinoma of the rectum without evidence of distant metastases
2. Patient must be 18 years of age or greater
3. Potentially resectable disease based upon surgeons evaluation
4. Clinical stages T3 or T4a, and/ or positive nodes based upon endorectal ultrasound and/ or MRI.
5. Absolute neutrophil count of \> 1500 per microliter and platelet count \> 100,000 per microliter; Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) and alkaline phosphatase \< 2.5 X upper limit of normal (ULN), bilirubin \< = 1.5 ULN, calculated creatinine clearance \> 50 ml/min using Cockcroft-Gault formula:

   Male: Creatinine Clearance = (140 - age) x weight/(72 X serum creatinine) Female: Creatinine Clearance = (140 - age) x weight/(72 X serum creatinine x 0.85)
6. Eastern cooperative oncology group (ECOG) performance status 0-2
7. No history of other malignancies within 5 years, except non-melanoma skin cancer, in situ carcinoma of the cervix, or ductal carcinoma in situ of the breast. Previous invasive cancer permitted if disease free at least 5 years.
8. Signed study-specific informed consent prior to enrolment

Exclusion Criteria:

1. Any evidence of distant metastasis
2. Synchronous primary colon carcinomas, except T1 lesions (full colonoscopy not required for enrollment)
3. Extension of malignant disease to the anal canal
4. Prior radiation therapy to the pelvis
5. Prior chemotherapy for malignancies
6. Pregnancy or lactation, (exclusion due to potential adverse effects of therapy). Women of childbearing potential with either a positive or no pregnancy test (serum or urine) at baseline. Women/men of childbearing potential not using a reliable and appropriate contraceptive method. (Postmenopausal women must have been amenorrheic for at least 12 months to be considered to be of non-childbearing potential.) Patients will agree to continue contraception for 30 days from the date of the last study drug administration.
7. Serious, uncontrolled, concurrent infection(s).
8. Participation in any investigational drug study within 4 weeks preceding the start of study treatment
9. Clinically significant cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication) or myocardial infarction within the last 12 months.
10. Evidence of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance of oral drug intake
11. Other serious uncontrolled medical conditions that the investigator feels might compromise study participation.
12. Major surgery within 4 weeks of the study treatment
13. Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome
14. Known, existing uncontrolled coagulopathy
15. No concurrent cimetidine allowed