Clinical trial NCT00613080: Combination Chemotherapy and Intensity-Modulated Radiation Therapy in Treating Patients Undergoing Surgery for Locally Advanced Rectal Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Cancer
Keywords: stage III rectal cancer
adenocarcinoma of the rectum
Lead sponsor: Radiation Therapy Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
name: NRG Oncology
First posted: 2008-02-12
Enrollment: 79
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: From start of treatment to surgery or ≤ 90 days from the Start of Concurrent Treatment (for patients not undergoing surgery)
Secondary outcomes:
measure: Number of Patients in Protocol Adherence Categories for Intensity-modulated Radiotherapy (IMRT) Planning
timeFrame: Pretreatment
measure: Number of Patients With Pathologic Complete Response
timeFrame: At the time of surgery, which is 4-8 weeks after radiation therapy, approximately 9-13 weeks from treatment start.
measure: 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
timeFrame: From study registration to end of follow-up. Maximum follow-up at time of analysis was 5.2 years.
measure: Local-regional Failure: 4-year Rate
timeFrame: From registration to four years
measure: Distant Failure: 4-year Rate
timeFrame: From registration to four years
measure: Overall Survival: 4-year Rate
timeFrame: From registration to four years
measure: Disease-free Survival: 4-year Rate
timeFrame: From registration to four years
measure: Number of Patients Who Underwent Abdominoperineal Resection
timeFrame: Surgery occurred 4 to 8 weeks following the completion of radiation therapy, approximately 9-13 weeks from start of treatment.
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Providence Cancer Center at Providence Hospital
state: Alabama
city: Auburn
country: United States
facility: Auburn Radiation Oncology
state: California
city: Cameron Park
country: United States
facility: Radiation Oncology Centers - Cameron Park
state: California
city: Carmichael
country: United States
facility: Mercy Cancer Center at Mercy San Juan Medical Center
state: California
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Fresno
country: United States
facility: California Cancer Center - Woodward Park Office
state: California
city: La Jolla
country: United States
facility: Rebecca and John Moores UCSD Cancer Center
state: California
city: Roseville
country: United States
facility: Radiation Oncology Center - Roseville
state: California
city: Sacramento
country: United States
facility: Radiological Associates of Sacramento Medical Group, Incorporated
state: California
city: Sacramento
country: United States
facility: Mercy General Hospital
state: California
city: San Diego
country: United States
facility: Veterans Affairs Medical Center - San Diego
state: California
city: Vacaville
country: United States
facility: Solano Radiation Oncology Center
state: California
city: Boca Raton
country: United States
facility: Eugene M. and Christine E. Lynn Cancer Institute at Boca Raton Community Hospital - Main Campus
state: Florida
city: Gainesville
country: United States
facility: University of Florida Shands Cancer Center
state: Florida
city: Jacksonville
country: United States
facility: Baptist Cancer Institute - Jacksonville
state: Florida
city: Miami
country: United States
facility: Baptist-South Miami Regional Cancer Program
state: Florida
city: Orange Park
country: United States
facility: Integrated Community Oncology Network - Orange Park
state: Florida
city: Panama City
country: United States
facility: Bay Medical
state: Florida
city: Atlanta
country: United States
facility: Piedmont Hospital
state: Georgia
city: Columbus
country: United States
facility: John B. Amos Cancer Center
state: Georgia
city: Savannah
country: United States
facility: Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center
state: Georgia
city: Springfield
country: United States
facility: Cancer Institute at St. John's Hospital
state: Illinois
city: Anderson
country: United States
facility: Saint John's Cancer Center at Saint John's Medical Center
state: Indiana
city: Goshen
country: United States
facility: Center for Cancer Care at Goshen General Hospital
state: Indiana
city: Indianapolis
country: United States
facility: St. Vincent Oncology Center
state: Indiana
city: Muncie
country: United States
facility: Cancer Center at Ball Memorial Hospital
state: Indiana
city: Overland Park
country: United States
facility: Menorah Medical Center
state: Kansas
city: Overland Park
country: United States
facility: Saint Luke's Hospital - South
state: Kansas
city: Shawnee Mission
country: United States
facility: Shawnee Mission Medical Center
state: Kansas
city: Baltimore
country: United States
facility: Greenebaum Cancer Center at University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber/Brigham and Women's Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Boston University Cancer Research Center
state: Massachusetts
city: Fall River
country: United States
facility: Hudner Oncology Center at Saint Anne's Hospital - Fall River
state: Massachusetts
city: Burnsville
country: United States
facility: Fairview Ridges Hospital
state: Minnesota
city: Coon Rapids
country: United States
facility: Mercy and Unity Cancer Center at Mercy Hospital
state: Minnesota
city: Edina
country: United States
facility: Fairview Southdale Hospital
state: Minnesota
city: Fridley
country: United States
facility: Mercy and Unity Cancer Center at Unity Hospital
state: Minnesota
city: Maplewood
country: United States
facility: Minnesota Oncology Hematology, PA - Maplewood
state: Minnesota
city: Minneapolis
country: United States
facility: Virginia Piper Cancer Institute at Abbott - Northwestern Hospital
state: Minnesota
city: Robbinsdale
country: United States
facility: Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center
state: Minnesota
city: Saint Louis Park
country: United States
facility: CCOP - Metro-Minnesota
state: Minnesota
city: Saint Louis Park
country: United States
facility: Park Nicollet Cancer Center
state: Minnesota
city: Saint Paul
country: United States
facility: United Hospital
state: Minnesota
city: Shakopee
country: United States
facility: St. Francis Cancer Center at St. Francis Medical Center
state: Minnesota
city: Waconia
country: United States
facility: Ridgeview Medical Center
state: Minnesota
city: Woodbury
country: United States
facility: Minnesota Oncology Hematology, PA - Woodbury
state: Minnesota
city: Pascagoula
country: United States
facility: Regional Cancer Center at Singing River Hospital
state: Mississippi
city: Cape Girardeau
country: United States
facility: Cancer Institute of Cape Girardeau, LLC
state: Missouri
city: Kansas City
country: United States
facility: Truman Medical Center - Hospital Hill
state: Missouri
city: Kansas City
country: United States
facility: Saint Luke's Cancer Institute at Saint Luke's Hospital
state: Missouri
city: Kansas City
country: United States
facility: St. Joseph Medical Center
state: Missouri
city: Kansas City
country: United States
facility: North Kansas City Hospital
state: Missouri
city: Kansas City
country: United States
facility: Parvin Radiation Oncology
state: Missouri
city: Kansas City
country: United States
facility: CCOP - Kansas City
state: Missouri
city: Kansas City
country: United States
facility: Research Medical Center
state: Missouri
city: Lee's Summit
country: United States
facility: Saint Luke's East - Lee's Summit
state: Missouri
city: Liberty
country: United States
facility: Liberty Hospital
state: Missouri
city: Saint Joseph
country: United States
facility: Heartland Regional Medical Center
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
state: Missouri
city: Saint Louis
country: United States
facility: Barnes-Jewish West County Hospital
state: Missouri
city: Saint Peters
country: United States
facility: Siteman Cancer Center at Barnes-Jewish St. Peters Hospital - St. Peters
state: Missouri
city: Springfield
country: United States
facility: CCOP - Cancer Research for the Ozarks
state: Missouri
city: Springfield
country: United States
facility: Hulston Cancer Center at Cox Medical Center South
state: Missouri
city: Omaha
country: United States
facility: Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: University Medical Center of Southern Nevada
state: Nevada
city: Las Vegas
country: United States
facility: CCOP - Nevada Cancer Research Foundation
state: Nevada
city: Reno
country: United States
facility: Renown Institute for Cancer at Renown Regional Medical Center
state: Nevada
city: Keene
country: United States
facility: Kingsbury Center for Cancer Care at Cheshire Medical Center
state: New Hampshire
city: Lebanon
country: United States
facility: Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Long Branch
country: United States
facility: Monmouth Medical Center
state: New Jersey
city: Marlton
country: United States
facility: Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton
state: New Jersey
city: Toms River
country: United States
facility: J. Phillip Citta Regional Cancer Center at Community Medical Center
state: New Jersey
city: Brooklyn
country: United States
facility: Maimonides Cancer Center at Maimonides Medical Center
state: New York
city: Lake Success
country: United States
facility: Monter Cancer Center of the North Shore-LIJ Health System
state: New York
city: Manhasset
country: United States
facility: CCOP - North Shore University Hospital
state: New York
city: Manhasset
country: United States
facility: Don Monti Comprehensive Cancer Center at North Shore University Hospital
state: New York
city: New Hyde Park
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: Goldsboro
country: United States
facility: Wayne Memorial Hospital, Incorporated
state: North Carolina
city: Goldsboro
country: United States
facility: Wayne Radiation Oncology
state: North Carolina
city: Akron
country: United States
facility: Summa Center for Cancer Care at Akron City Hospital
state: Ohio
city: Barberton
country: United States
facility: Barberton Citizens Hospital
state: Ohio
city: Cincinnati
country: United States
facility: Charles M. Barrett Cancer Center at University Hospital
state: Ohio
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
state: Ohio
city: Salem
country: United States
facility: Cancer Care Center, Incorporated
state: Ohio
city: West Chester
country: United States
facility: Precision Radiotherapy at University Pointe
state: Ohio
city: Wooster
country: United States
facility: Cancer Treatment Center
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma University Cancer Institute
state: Oklahoma
city: Oklahoma City
country: United States
facility: Integris Oncology Services
state: Oklahoma
city: Abington
country: United States
facility: Rosenfeld Cancer Center at Abington Memorial Hospital
state: Pennsylvania
city: Bryn Mawr
country: United States
facility: Bryn Mawr Hospital
state: Pennsylvania
city: Dunmore
country: United States
facility: Northeast Radiation Oncology Center
state: Pennsylvania
city: East Stroudsburg
country: United States
facility: Dale and Frances Hughes Cancer Center at Pocono Medical Center
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Cancer Institute at Milton S. Hershey Medical Center
state: Pennsylvania
city: Media
country: United States
facility: Riddle Memorial Hospital Cancer Center
state: Pennsylvania
city: Milford
country: United States
facility: Upper Delaware Valley Cancer Center
state: Pennsylvania
city: Paoli
country: United States
facility: Cancer Center of Paoli Memorial Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Kimmel Cancer Center at Thomas Jefferson University - Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Frankford Hospital Cancer Center - Torresdale Campus
state: Pennsylvania
city: Wynnewood
country: United States
facility: CCOP - Main Line Health
state: Pennsylvania
city: Wynnewood
country: United States
facility: Lankenau Cancer Center at Lankenau Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital Comprehensive Cancer Center
state: Rhode Island
city: Charleston
country: United States
facility: Hollings Cancer Center at Medical University of South Carolina
state: South Carolina
city: Kingsport
country: United States
facility: Christine LaGuardia Phillips Cancer Center at Wellmont Holston Valley Medical Center
state: Tennessee
city: American Fork
country: United States
facility: American Fork Hospital
state: Utah
city: Cedar City
country: United States
facility: Sandra L. Maxwell Cancer Center
state: Utah
city: Murray
country: United States
facility: Jon and Karen Huntsman Cancer Center at Intermountain Medical Center
state: Utah
city: Ogden
country: United States
facility: Val and Ann Browning Cancer Center at McKay-Dee Hospital Center
state: Utah
city: Provo
country: United States
facility: Utah Valley Regional Medical Center - Provo
state: Utah
city: Saint George
country: United States
facility: Dixie Regional Medical Center - East Campus
state: Utah
city: Salt Lake City
country: United States
facility: LDS Hospital
state: Utah
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists at UCS Cancer Center
state: Utah
city: Saint Johnsbury
country: United States
facility: Norris Cotton Cancer Center - North
state: Vermont
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
city: Norton
country: United States
facility: Southwest Virginia Regional Cancer Center at Wellmonth Health
state: Virginia
city: Mequon
country: United States
facility: Columbia Saint Mary's Hospital - Ozaukee
state: Wisconsin
city: Milwaukee
country: United States
facility: Columbia-Saint Mary's Cancer Care Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin Cancer Center
state: Wisconsin
city: London
country: Canada
facility: London Regional Cancer Program at London Health Sciences Centre
state: Ontario
Study officials:
affiliation: University of Maryland Greenebaum Cancer Center
name: Michael C. Garofalo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sidney Kimmel Cancer Center at Thomas Jefferson University
name: Adam C. Berger, MD
role: STUDY_CHAIR
affiliation: Duke Cancer Institute
name: Johanna Bendell, MD
role: STUDY_CHAIR
References: