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

Colorectal Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00613080
• Other study ID #: RTOG-0822
• Secondary ID: CDR0000586277
• Status: Completed
• Phase: Phase 2
• Start date: April 2008
• Est. completion date: December 2016

Study information

• Verified date: July 2018
• Source: Radiation Therapy Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 79
• Est. completion date: December 2016
• Est. primary completion date: January 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms
• Rectal Neoplasms

Intervention

Drug:
• capecitabine
1650 mg/m^2/day orally 5 days/week during radiotherapy.
• oxaliplatin

Procedure:
• resection
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.

Radiation:
• radiation therapy
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

Drug:
• FOLFOX
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.

Locations

Country	Name	City	State
Canada	London Regional Cancer Program at London Health Sciences Centre	London	Ontario
United States	Rosenfeld Cancer Center at Abington Memorial Hospital	Abington	Pennsylvania
United States	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio
United States	American Fork Hospital	American Fork	Utah
United States	Saint John's Cancer Center at Saint John's Medical Center	Anderson	Indiana
United States	Piedmont Hospital	Atlanta	Georgia
United States	Auburn Radiation Oncology	Auburn	California
United States	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland
United States	Barberton Citizens Hospital	Barberton	Ohio
United States	Eugene M. and Christine E. Lynn Cancer Institute at Boca Raton Community Hospital - Main Campus	Boca Raton	Florida
United States	Boston University Cancer Research Center	Boston	Massachusetts
United States	Dana-Farber/Brigham and Women's Cancer Center	Boston	Massachusetts
United States	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Maimonides Cancer Center at Maimonides Medical Center	Brooklyn	New York
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Radiation Oncology Centers - Cameron Park	Cameron Park	California
United States	Cancer Institute of Cape Girardeau, LLC	Cape Girardeau	Missouri
United States	Mercy Cancer Center at Mercy San Juan Medical Center	Carmichael	California
United States	Sandra L. Maxwell Cancer Center	Cedar City	Utah
United States	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Charles M. Barrett Cancer Center at University Hospital	Cincinnati	Ohio
United States	Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center	Columbus	Ohio
United States	John B. Amos Cancer Center	Columbus	Georgia
United States	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Northeast Radiation Oncology Center	Dunmore	Pennsylvania
United States	Dale and Frances Hughes Cancer Center at Pocono Medical Center	East Stroudsburg	Pennsylvania
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	Hudner Oncology Center at Saint Anne's Hospital - Fall River	Fall River	Massachusetts
United States	California Cancer Center - Woodward Park Office	Fresno	California
United States	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota
United States	University of Florida Shands Cancer Center	Gainesville	Florida
United States	Wayne Memorial Hospital, Incorporated	Goldsboro	North Carolina
United States	Wayne Radiation Oncology	Goldsboro	North Carolina
United States	Center for Cancer Care at Goshen General Hospital	Goshen	Indiana
United States	Penn State Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	St. Vincent Oncology Center	Indianapolis	Indiana
United States	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida
United States	CCOP - Kansas City	Kansas City	Missouri
United States	North Kansas City Hospital	Kansas City	Missouri
United States	Parvin Radiation Oncology	Kansas City	Missouri
United States	Research Medical Center	Kansas City	Missouri
United States	Saint Luke's Cancer Institute at Saint Luke's Hospital	Kansas City	Missouri
United States	St. Joseph Medical Center	Kansas City	Missouri
United States	Truman Medical Center - Hospital Hill	Kansas City	Missouri
United States	Kingsbury Center for Cancer Care at Cheshire Medical Center	Keene	New Hampshire
United States	Christine LaGuardia Phillips Cancer Center at Wellmont Holston Valley Medical Center	Kingsport	Tennessee
United States	Rebecca and John Moores UCSD Cancer Center	La Jolla	California
United States	Monter Cancer Center of the North Shore-LIJ Health System	Lake Success	New York
United States	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada
United States	University Medical Center of Southern Nevada	Las Vegas	Nevada
United States	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri
United States	Liberty Hospital	Liberty	Missouri
United States	Monmouth Medical Center	Long Branch	New Jersey
United States	CCOP - North Shore University Hospital	Manhasset	New York
United States	Don Monti Comprehensive Cancer Center at North Shore University Hospital	Manhasset	New York
United States	Minnesota Oncology Hematology, PA - Maplewood	Maplewood	Minnesota
United States	Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton	Marlton	New Jersey
United States	Riddle Memorial Hospital Cancer Center	Media	Pennsylvania
United States	Columbia Saint Mary's Hospital - Ozaukee	Mequon	Wisconsin
United States	Baptist-South Miami Regional Cancer Program	Miami	Florida
United States	Upper Delaware Valley Cancer Center	Milford	Pennsylvania
United States	Columbia-Saint Mary's Cancer Care Center	Milwaukee	Wisconsin
United States	Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin
United States	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota
United States	Providence Cancer Center at Providence Hospital	Mobile	Alabama
United States	Cancer Center at Ball Memorial Hospital	Muncie	Indiana
United States	Jon and Karen Huntsman Cancer Center at Intermountain Medical Center	Murray	Utah
United States	Long Island Jewish Medical Center	New Hyde Park	New York
United States	Southwest Virginia Regional Cancer Center at Wellmonth Health	Norton	Virginia
United States	Val and Ann Browning Cancer Center at McKay-Dee Hospital Center	Ogden	Utah
United States	Integris Oncology Services	Oklahoma City	Oklahoma
United States	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma
United States	Nebraska Medical Center	Omaha	Nebraska
United States	Integrated Community Oncology Network - Orange Park	Orange Park	Florida
United States	Menorah Medical Center	Overland Park	Kansas
United States	Saint Luke's Hospital - South	Overland Park	Kansas
United States	Bay Medical	Panama City	Florida
United States	Cancer Center of Paoli Memorial Hospital	Paoli	Pennsylvania
United States	Regional Cancer Center at Singing River Hospital	Pascagoula	Mississippi
United States	Frankford Hospital Cancer Center - Torresdale Campus	Philadelphia	Pennsylvania
United States	Kimmel Cancer Center at Thomas Jefferson University - Philadelphia	Philadelphia	Pennsylvania
United States	Rhode Island Hospital Comprehensive Cancer Center	Providence	Rhode Island
United States	Utah Valley Regional Medical Center - Provo	Provo	Utah
United States	Renown Institute for Cancer at Renown Regional Medical Center	Reno	Nevada
United States	Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota
United States	Radiation Oncology Center - Roseville	Roseville	California
United States	Mercy General Hospital	Sacramento	California
United States	Radiological Associates of Sacramento Medical Group, Incorporated	Sacramento	California
United States	Dixie Regional Medical Center - East Campus	Saint George	Utah
United States	Norris Cotton Cancer Center - North	Saint Johnsbury	Vermont
United States	Heartland Regional Medical Center	Saint Joseph	Missouri
United States	Barnes-Jewish West County Hospital	Saint Louis	Missouri
United States	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri
United States	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota
United States	Park Nicollet Cancer Center	Saint Louis Park	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Siteman Cancer Center at Barnes-Jewish St. Peters Hospital - St. Peters	Saint Peters	Missouri
United States	Cancer Care Center, Incorporated	Salem	Ohio
United States	LDS Hospital	Salt Lake City	Utah
United States	Utah Cancer Specialists at UCS Cancer Center	Salt Lake City	Utah
United States	Veterans Affairs Medical Center - San Diego	San Diego	California
United States	Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center	Savannah	Georgia
United States	St. Francis Cancer Center at St. Francis Medical Center	Shakopee	Minnesota
United States	Shawnee Mission Medical Center	Shawnee Mission	Kansas
United States	Cancer Institute at St. John's Hospital	Springfield	Illinois
United States	CCOP - Cancer Research for the Ozarks	Springfield	Missouri
United States	Hulston Cancer Center at Cox Medical Center South	Springfield	Missouri
United States	J. Phillip Citta Regional Cancer Center at Community Medical Center	Toms River	New Jersey
United States	Solano Radiation Oncology Center	Vacaville	California
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	Precision Radiotherapy at University Pointe	West Chester	Ohio
United States	Minnesota Oncology Hematology, PA - Woodbury	Woodbury	Minnesota
United States	Cancer Treatment Center	Wooster	Ohio
United States	CCOP - Main Line Health	Wynnewood	Pennsylvania
United States	Lankenau Cancer Center at Lankenau Hospital	Wynnewood	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
Radiation Therapy Oncology Group	National Cancer Institute (NCI), NRG Oncology

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.