Combination Chemotherapy and Intensity-Modulated Radiation Therapy in Treating Patients Undergoing Surgery for Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Specialized 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. Giving these treatments before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving chemotherapy after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying the side effects and how well giving combination chemotherapy together with intensity-modulated radiation therapy works in treating patients undergoing surgery for locally advanced rectal cancer.

Detailed Description
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OBJECTIVES: Primary To determine whether the incidence of neoadjuvant acute gastrointestinal toxicity (grade ≥ 2) associated with neoadjuvant chemoradiotherapy is reduced by inverse-planned intensity-modulated radiotherapy (IMRT)-based radiation treatment when compared with conventionally delivered radiotherapy, as was utilized in the capecitabine and oxaliplatin arm of RTOG-0247 (NCT00081289). Secondary To evaluate the feasibility of performing IMRT in a cooperative group setting for the treatment of rectal cancer. To estimate the incidence of all toxicity (hematologic and non-hematologic) associated with protocol treatment in the neoadjuvant period, the adjuvant period, and overall. To estimate the pathologic complete response rate following neoadjuvant IMRT-based chemoradiotherapy. To estimate the time to treatment failure and patterns of failure. To correlate pre- and post-treatment levels of serum cytokines with symptoms during and pathological outcomes following neoadjuvant chemoradiotherapy for rectal cancer. To evaluate the rate of abdominoperineal resections. OUTLINE: This is a multicenter study. Chemoradiotherapy: Patients undergo inverse-planned intensity-modulated radiotherapy to the pelvis once daily, 5 days a week, for 5 weeks (total of 45 Gy) and a 3-dimensional conformal radiotherapy boost to gross disease once daily for 3 days (total of 45 Gy). Beginning on the first day of radiotherapy and continuing through completion of radiotherapy, patients receive oral capecitabine twice daily, 5 days a week, for 5 weeks and oxaliplatin IV over 2 hours on days 1, 8, 15, 22, 29. Surgery: Within 4-8 weeks after completion of chemoradiotherapy, patients undergo resection of the rectal tumor. Adjuvant chemotherapy: Beginning 4-8 weeks after surgery, patients with completely resected disease and negative surgical margins receive leucovorin calcium IV over 2 hours and oxaliplatin IV over 2 hours on day 1 and fluorouracil IV bolus on day 1 and fluorouracil IV infusion continuously over 46 hours beginning on day 1 . Treatment repeats every 14 days for up to 9 courses in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months after the start of treatment for 2 years, every 6 months for years 3-5, and then annually thereafter.

Official Title
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A Phase II Evaluation of Preoperative Chemoradiotherapy Utilizing Intensity Modulated Radiation Therapy (IMRT) in Combination With Capecitabine and Oxaliplatin for Patients With Locally Advanced Rectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: capecitabine
* Drug: oxaliplatin
* Procedure: resection
* Radiation: radiation therapy
* Drug: FOLFOX


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: 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 12 cm from the anal verge with no extension of malignant disease into the anal canal Clinically determined to be stage T3 or T4,N0-N2, and M0 tumor as determined by the following assessments: Colonoscopy and biopsy within 56 days prior to registration History/physical examination (including medication history screen for contraindications) within 56 days prior to registration Contrast-enhanced imaging of the abdomen and pelvis either by computed tomography(CT), MRI, or Positron-emission tomography(PET)-CT (whole body preferred) within 56 days prior to registration Chest x-ray (or CT) of the chest within within 56 days prior to registration to exclude distant metastases (except for patients who have had whole body PET-CT) Transrectal ultrasound (TRUS) within 56 days prior to registration 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) PATIENT CHARACTERISTICS: Inclusion criteria: Zubrod performance status 0-2 Absolute neutrophil count (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) Aspartate aminotransferase (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 oxaliplatin or 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) Prior systemic chemotherapy for colorectal cancer (prior chemotherapy allowed provided it was for a cancer other than colorectal cancer) Prior radiotherapy to the region of the study cancer that would result in overlap of radiotherapy fields Major surgery within 28 days of study enrollment(other than diverting colostomy without tumor resection) Participation in any investigational drug study within 28 days of study enrollment. Concurrent cimetidine, amifostine, and/or depot Sandostatin

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: IMRT + Chemotherapy , Resection, Postoperative Chemotherapy<br>Radiation therapy (intensity modulated radiation therapy [IMRT] + three dimensional conformal radiation therapy [3D-CRT]) + neoadjuvant chemotherapy (capecitabine and oxaliplatin) followed by resection and postoperative chemotherapy (FOLFOX) | Drug: capecitabine<br>* 1650 mg/m^2/day orally 5 days/week during radiotherapy.<br>Drug: oxaliplatin<br> <br> * Other names: 50 mg/m^2 IV over 2 hours weekly for five weeks starting on day 1 of radiotherapy.;Procedure: resection<br>* All patients undergo surgery 4 to 8 weeks following the completion of radiation therapy. The choice of procedure (abdominoperineal resection (APR), low anterior resection (LAR), or LAR/coloanal anastomosis) is at the discretion of the surgeon.<br>Radiation: radiation therapy<br>* Pelvic intensity modulated radiation therapy (IMRT): 45 Gy in 25 fx Three dimensional conformal radiation therapy (3D-CRT) boost: 5.4 Gy in 3 fx to total dose of 50.4 Gy in 28 fx<br>Drug: FOLFOX<br>* Postoperative chemotherapy is administered to all patients who have a complete resection of rectal cancer with negative surgical margins and begins within 4-8 weeks following surgical resection, consisting of a total of 9 14-day cycles. Oxaliplatin 85 mg/m^2, IV over 2 hours, day 1. Leucovorin 400 mg/m^2, IV over 2 hours, day 1. 5-fluorouracil bolus 400 mg/m^2, IV push, day 1. 5-fluorouracil infusion 2400 mg/m^2, IV continuous infusion over 46 hours, day 1.<br>* Other names: Oxaliplatin, leucovorin, 5-fluorouracil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Patients Experiencing Treatment-related Gastrointestinal Adverse Events ≥ Grade 2 Per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v. 3.0, Occurring Preoperatively | The percentage of patients experiencing preoperative treatment-related gastrointestinal adverse events ≥ grade 2. If patient did not receive surgery, then such adverse events <= 90 days from the start of concurrent treatment are included. | From start of treatment to surgery or ≤ 90 days from the Start of Concurrent Treatment (for patients not undergoing surgery) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients in Protocol Adherence Categories for Intensity-modulated Radiotherapy (IMRT) Planning | Real-time quality assurance was performed remotely by the study chair or the radiation oncology co-chair prior to initiation of treatment for the first 40 cases. The final cases enrolled were reviewed within 3 months after accrual was completed. Review included evaluation of clinical target volume (CTV) and planning target volume (PTV), Organs at Risk (OARs), and treatment plan dosimetry. | Pretreatment | 
| Number of Patients With Pathologic Complete Response | Pathologic complete response is defined as no evidence of residual cancer histologically in the resection specimen. | At the time of surgery, which is 4-8 weeks after radiation therapy, approximately 9-13 weeks from treatment start. | 
| Percentage of Patients With Grade 3 or Higher Treatment-related Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 | Grade refers to the severity of the adverse event (AE). The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Adverse events were compiled in four different time periods: 1) Preoperative: Preoperatively or, if no surgery, then ≤ 90 days from the Start of Concurrent Treatment; 2) Postoperative#1: Postoperatively and ≤ 30 days from the Date of Surgery; 3) Postoperative#2: Postoperatively and ≤ 90 days from the End of Postoperative Chemotherapy; 4) Overall: From start of concurrent treatment to end of follow-up; | From study registration to end of follow-up. Maximum follow-up at time of analysis was 5.2 years. | 
| Local-regional Failure: 4-year Rate | Local failure is defined as: (1) any recurrence or surgery to the primary site after a complete response (CR) reported at surgery or reported after the end of protocol treatment; or (2) persistence [failure at one day post study entry], absence of CR after protocol treatment was completed and patient lived at least 90 days from the end of treatment. Regional failure is defined as: (1) any recurrence after a nodal CR reported at surgery or reported after the end of protocol treatment; or (2) persistence, absence of nodal CR after protocol treatment was completed and patient lived at least 90 days from the end of treatment. Local-regional failure time is defined as time from registration to local or regional failure, last known follow-up (censored), or death (competing risk). Local-regional failure rates are estimated by the cumulative incidence method. | From registration to four years | 
| Distant Failure: 4-year Rate | Distant failure is defined as the appearance of peritoneal seeding or distant metastases. Time to distant failure is defined as time from registration to the date of distant failure, last known follow-up (censored), or death (competing risk). Distant failure rates are estimated by the cumulative incidence method. | From registration to four years | 
| Overall Survival: 4-year Rate | Overall survival time is defined as time from registration to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. | From registration to four years | 
| Disease-free Survival: 4-year Rate | Disease is defined as local-regional failure or distant failure. Distant failure is defined as the appearance of peritoneal seeding or distant metastases. Local-regional failure is defined as: (1) any recurrence or surgery to the primary site after a complete response (CR) / any recurrence after a nodal CR - reported at surgery or reported after the end of protocol treatment; or (2) persistence [failure at one day post study entry], absence of primary/nodal CR after protocol treatment was completed and patient lived at least 90 days from the end of treatment. Disease-free survival time is defined as time from registration to the date of disease, death, or last known follow-up (censored). Disease-free survival rates are estimated using the Kaplan-Meier method. | From registration to four years | 
| Number of Patients Who Underwent Abdominoperineal Resection | All patients were to undergo surgery 4 to 8 weeks following the completion of radiation therapy. The choice of procedure (abdominoperineal resection (APR), low anterior resection (LAR), or LAR/coloanal anastomosis) was at the discretion of the surgeon. If more than 28 patients received abdominoperineal resection, this would result in a conclusion of an excessive number of abdominoperineal resections. | Surgery occurred 4 to 8 weeks following the completion of radiation therapy, approximately 9-13 weeks from start of treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III rectal cancer, adenocarcinoma of the rectum