Low accrual

A combination of chemotherapy and radiation is often used to treat rectal cancer patients before surgery in an effort to shrink the tumor and make it easier to remove as well as to help increase the chances of sphincter-sparing surgery. Many previous clinical studies have suggested that rectal cancer patients may survive longer if the surgery results in a pathological complete response - that is, the absence of any tumor cells in the surgical specimen. However, there is still controversy over this. This study attempts to start to answer this question by treating rectal cancer patients with a combination of chemotherapy drugs (oxaliplatin and capecitabine), a cyclooxygenase-2 (COX-2) enzyme inhibitor and radiation before surgery. The rates of pathologic complete response, sphincter-sparing surgery, and disease-free survival are some of the therapeutic endpoints that will be studied.

Improved regional control as demonstrated by a lower incidence of local recurrence after concurrent chemoradiation delivered either pre-operatively or post-operatively for resectable rectal cancer is supported by clinical trial data but the impact on overall survival with either approach remains controversial. An ideal regimen for preoperative chemoradiation in locally advanced rectal cancer would include agents that are both potent radio-sensitizers and effective in treating micro-metastatic disease without excessive toxicity. The cyclooxygenase-2 (COX-2) enzyme is over expressed in colorectal cancer, but the exact role of this over expression in tumorigenesis remains an active area of research. The area with the most potential in using cyclooxygenase-2 inhibitors in cancer treatment may be to use them as an adjunct to other modalities of treatment.

Taking into consideration all the above, a previous pilot trial of neoadjuvant therapy with combined oxaliplatin, capecitabine, celecoxib (a COX-2 inhibitor), and radiation was conducted in four patients with operable rectal cancer. Promising results, including pain relief and downstaging of cancer, were observed.

Therefore, this single-arm phase II trial of preoperative concurrent chemoradiation for patients with T3-4N0-2M0 rectal cancer was initiated to assess patient outcomes and explore the relationship between COX-2 expression in surgical specimens and therapeutic endpoints.

Inclusion Criteria:

• All patients 18 years of age or older, with biopsy proven T3-4N0-2M0 rectal cancer are eligible.
• Life expectancy of at least 2 years.
• Zubrod performance status of 0-2.
• Patients must be able to sign an informed consent.
• Adequate bone marrow function: peripheral granulocyte count of > 1,500 cells/mm3 and platelet count >100,000/mm3, hemoglobin > 10 gm/dl and absence of a regular red blood cell transfusion requirement.
• Adequate hepatic function with a total serum bilirubin < 1.5 x ULN; alkaline phosphatase, alanine aminotransferase (ALAT), and aspartate aminotransferase (ASAT) < 2.5 x the upper limit of normal (ULN); and adequate renal function as defined by a calculated creatinine clearance > 50 ml/min [Cockroft-Gault].
• Other initial cancer diagnosis more than five years ago without evidence of residual or recurrent disease
• Prior diagnosis of squamous or basal cell carcinoma of skin,no active disease at the time of enrollment.

Exclusion Criteria:

• Known metastases

• Pregnant or lactating women. Women/men of childbearing potential not using a reliable and appropriate contraceptive method.

• May receive no other concurrent chemotherapy or radiation therapy during this trial.

• Severe medical problems such as uncontrolled diabetes mellitus or cardiovascular disease or active infections

• Prior pelvic radiation

• Known active inflammatory bowel disease, Crohn's disease or ulcerative colitis.

• Medical conditions that would preclude the patient from definitive surgery at the end of concurrent chemoradiation

• Serious, uncontrolled, concurrent infection(s).

• Prior severe reaction to fluoropyrimidine therapy, or known hyper-sensitivity to 5-fluorouracil or known dihydropyrimidine dehydrogenase (DPD) deficiency.

• Treatment for other carcinomas within the last five years, except cured non-melanoma skin and treated in-situ cervical cancer.

• Participation in any investigational drug study within 4 weeks preceding the start of study treatment.

• Clinically significant cardiac disease or myocardial infarction within the last 12 months.

• History 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.

• Other serious uncontrolled medical conditions that the investigator feels might compromise study participation.

• Major surgery <4 weeks of the start of study treatment, without complete recovery.

• Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome.

• Known, existing uncontrolled coagulopathy

• Any of the following laboratory values:

  • Abnormal hematologic values (neutrophils < 1.5 x 10^9/L, platelet count < 100 x 10^9/L, hemoglobin < 10 gm/dl)
  • Impaired renal function (estimated creatinine clearance <50 ml/min as calculated with Cockroft-Gault equation.
  • Serum total bilirubin > 1.5 x upper normal limit.
  • ALAT, ASAT > 2.5 x upper normal limit (or > 5 x upper normal limit in the case of liver metastases).
  • Alkaline phosphatase > 2.5 x upper normal limit (or > 5 x upper normal limit in the case of liver metastases or > 10 x upper normal limit in the case of bone disease).

• Unwillingness to give written informed consent.

• Unwillingness to participate or inability to comply with the protocol for the duration of the study.

• History of allergic reactions, hypersensitivity reactions to aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or sulfonamides