Clinical trial NCT00973778: A Study for Short Preoperative Chemoradiotherapy for Resectable Rectal Carcinoma
Official title: A Phase II Study for Short Preoperative Chemoradiotherapy Utilizing Intensity Modulated Radiation Therapy (IMRT) in Combination With Capecitabine in Patients With Resectable Rectal Carcinoma
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Chemoradiotherapy
Keywords: Intensity Modulated Radiation Therapy
Capecitabine
Resectable Rectal Carcinoma
Lead sponsor: Shanghai Jiao Tong University School of Medicine
Sponsor class: OTHER
Collaborators: name: Ruijin Hospital
First posted: 2009-09-09
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Intensity modulated radiotherapy (IMRT)-based radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Investigators initiated a prospective study to evaluate the efficacy and toxicity of short course preoperative chemoradiotherapy utilizing Intensity Modulated Radiation Therapy (IMRT) in combination with capecitabine in patients with resectable rectal carcinoma.

Detailed description: Preoperative chemoradiotherapy has become a standard part of treatment protocols in stage II and III rectal cancer. Compared to postoperative chemoradiotherapy, the advantage of preoperative application of chemotherapeutics and irradiation includes improved compliance, reduced toxicity, and downstaging of the tumor in a substantial number of patients. The latter may enhance the rate of curative surgery, permit sphincter preservation in patients with low-sited tumors, and have a positive impact on the quality of life of these patients (Sauer et al, 2004).

The most widely used chemotherapeutic agent in colorectal cancer has been 5-fluorouracil (5-FU), and numerous attempts have been made to improve its efficacy, including biomodulation and protracted infusion. It has been demonstrated that biomodulation with leucovorin or levamisole was not effective in rectal cancer (Tepper et al, 2002), and protracted infusion of 5-FU was superior to bolus injection (O'Connell et al, 1994). New oral chemotherapeutic agents including capecitabine have been introduced and tried in colorectal cancer. Capecitabine is a tumor-selective fluoropyrimidine carbamate designed to achieve a higher intratumoral 5-FU level with lower systemic toxicity than intravenous administration of 5-FU (Shimma et al, 2000). It passes intact through the intestinal mucosa and is converted to 5-FU, preferentially in tumor tissue by thymidine phosphorylase (Schuller et al, 2000 ; Ishikawa et al, 1998 ; Miwa et al, 1998). Theoretically, oral capecitabine mimics the effect of protracted infusion of 5-FU without complications accompanying intravenous delivery (Liu et al, 1997). Moreover, experimental data using human cancer xenografts demonstrated up-regulation of thymidine phosphorylase by radiation (Sawada et al, 1999), constituting a synergistic effect. In two randomized Phase III trials, capecitabine showed a superior overall response rate and safety profile compared with 5-FU/lecovorinin for metastatic colorectal cancer (Van Cutsem et al, 2001; Hoff et al, 2001; Twelves, 2002). Intensity modulated radiotherapy (IMRT)-based radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. (Ballonoff et al, 2008)

With such encouraging outcomes, investigators initiated a prospective study to evaluate the efficacy and toxicity of short course preoperative chemoradiotherapy utilizing Intensity Modulated Radiation Therapy (IMRT) in combination with capecitabine in patients with resectable rectal carcinoma.

Eligibility criteria: Inclusion Criteria:

* Pathologically confirmed diagnosis of adenocarcinoma of the rectum by biopsy technique that does not completely excise the lesion (e.g., fine needle aspiration, core needle biopsy)
* Located up to 15 cm from the anal verge with no extension of malignant disease into the anal canal
* Stage IIIB-IIIC disease (T3-T4, N0-2, M0)(i.e., without evidence of distant metastases) tumor as determined by the following assessments:Colonoscopy and biopsy within the past 8 weeks; History/physical examination (including medication history screen for contraindications) within the past 8 weeks; Contrast-enhanced imaging of the abdomen and pelvis either by CT, MRI, or PET-CT (whole body preferred) within the past 8 weeks
* Chest x-ray (or CT) of the chest within the past 8 weeks to exclude distant metastases (except for patients who have had whole body PET-CT)
* Transrectal ultrasound (TRUS) within the past 8 weeks required to establish tumor stage
* TRUS not required if clinical exam, CT of the pelvis, and/or MRI demonstrates T4 lesion
* No synchronous primary colon carcinoma
* No evidence of distant metastases (M1)
* ANC ≥ 1,800/mm³
* Platelet count ≥ 100,000/mm³
* Hemoglobin ≥ 8.0 g/dL (transfusion or other intervention to achieve hemoglobin ≥ 8.0 g/dL allowed)
* AST \< 2.5 times upper limit of normal (ULN)
* Alkaline phosphatase \< 2.5 times ULN
* Bilirubin ≤ 1.5 times ULN
* Creatinine clearance \> 50 mL/min
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No prior invasive malignancy except nonmelanoma skin cancer unless disease free for a minimum of 3 years

Exclusion Criteria:

* Severe, active comorbidity, defined as follows:
* Unstable angina and/or congestive heart failure requiring hospitalization within the past 12 months
* Transmural myocardial infarction within the past 6 months
* Acute bacterial or fungal infection requiring intravenous antibiotics
* Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within the past 30 days
* Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
* AIDS
* 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
* Known, existing uncontrolled coagulopathy, unless clinically stable on anticoagulation therapy for ≥ 2 weeks
* Evidence of peripheral neuropathy ≥ grade 2
* Prior allergic reaction to capecitabine
* Lack of physical integrity of the gastrointestinal tract (i.e., severe Crohn disease that results in malabsorption; significant bowel resection that would make one concerned about the absorption of capecitabine) or malabsorption syndrome that would preclude feasibility of oral chemotherapy (i.e., capecitabine)

Primary outcomes:
measure: To evaluate if downstaging of tumor is observed after preoperative chemoradiotherapy: pathological T stage of disease in surgical specimen will be compared with preoperative T stage.
timeFrame: Every 21 days
Secondary outcomes:
measure: To evaluate survival after preoperative chemoradiotherapy.
timeFrame: Every 3 months
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Department of General Surgery, Shanghai Ruijin Hospital
city: Shanghai
country: China
facility: Department of Oncology, Shanghai Ruijin Hospital
Study officials:
affiliation: Ruijin Hospital
name: Weiguo Cao, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ruijin Hospital
name: Ren Zhao, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: