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

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00613080
• Collaborator: National Cancer Institute (NCI) (NIH), NRG Oncology (Other)
• Enrollment: 79
• Locations: 120
• Arm: 1
• Duration (Months): 104
• Patients Per Site: 0.7
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: capecitabine; Drug: oxaliplatin; Procedure: resection; Radiation: radiation therapy; Drug: FOLFOX	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 79 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Apr 1, 2008
• Actual Primary Completion Date: Jan 1, 2010
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Other: IMRT + Chemotherapy , Resection, Postoperative Chemotherapy 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; 1650 mg/m^2/day orally 5 days/week during radiotherapy.; Drug: oxaliplatin; Other Names: 50 mg/m^2 IV over 2 hours weekly for five weeks starting on day 1 of radiotherapy. ; 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.; Other Names: Oxaliplatin, leucovorin, 5-fluorouracil

Outcome Measures

Primary Outcome Measures

1. 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 [From start of treatment to surgery or ≤ 90 days from the Start of Concurrent Treatment (for patients not undergoing surgery)]

   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.

Secondary Outcome Measures

1. Number of Patients in Protocol Adherence Categories for Intensity-modulated Radiotherapy (IMRT) Planning [Pretreatment]

   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.

2. Number of Patients With Pathologic Complete Response [At the time of surgery, which is 4-8 weeks after radiation therapy, approximately 9-13 weeks from treatment start.]

   Pathologic complete response is defined as no evidence of residual cancer histologically in the resection specimen.

3. 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 [From study registration to end of follow-up. Maximum follow-up at time of analysis was 5.2 years.]

   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;

4. Local-regional Failure: 4-year Rate [From registration to four years]

   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.

5. Distant Failure: 4-year Rate [From registration to four years]

   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.

6. Overall Survival: 4-year Rate [From registration to four years]

   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.

7. Disease-free Survival: 4-year Rate [From registration to four years]

   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.

8. Number of Patients Who Underwent Abdominoperineal Resection [Surgery occurred 4 to 8 weeks following the completion of radiation therapy, approximately 9-13 weeks from start of treatment.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Providence Cancer Center at Providence Hospital	Mobile	Alabama	United States	36608
2	Auburn Radiation Oncology	Auburn	California	United States	95603
3	Radiation Oncology Centers - Cameron Park	Cameron Park	California	United States	95682
4	Mercy Cancer Center at Mercy San Juan Medical Center	Carmichael	California	United States	95608
5	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010-3000
6	California Cancer Center - Woodward Park Office	Fresno	California	United States	93720
7	Rebecca and John Moores UCSD Cancer Center	La Jolla	California	United States	92093-0658
8	Radiation Oncology Center - Roseville	Roseville	California	United States	95661
9	Radiological Associates of Sacramento Medical Group, Incorporated	Sacramento	California	United States	95815
10	Mercy General Hospital	Sacramento	California	United States	95819
11	Veterans Affairs Medical Center - San Diego	San Diego	California	United States	92161
12	Solano Radiation Oncology Center	Vacaville	California	United States	95687
13	Eugene M. and Christine E. Lynn Cancer Institute at Boca Raton Community Hospital - Main Campus	Boca Raton	Florida	United States	33486
14	University of Florida Shands Cancer Center	Gainesville	Florida	United States	32610-0232
15	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida	United States	32207
16	Baptist-South Miami Regional Cancer Program	Miami	Florida	United States	33176
17	Integrated Community Oncology Network - Orange Park	Orange Park	Florida	United States	32073
18	Bay Medical	Panama City	Florida	United States	32401
19	Piedmont Hospital	Atlanta	Georgia	United States	30309
20	John B. Amos Cancer Center	Columbus	Georgia	United States	31904
21	Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center	Savannah	Georgia	United States	31403-3089
22	Cancer Institute at St. John's Hospital	Springfield	Illinois	United States	62702
23	Saint John's Cancer Center at Saint John's Medical Center	Anderson	Indiana	United States	46016
24	Center for Cancer Care at Goshen General Hospital	Goshen	Indiana	United States	46526
25	St. Vincent Oncology Center	Indianapolis	Indiana	United States	46260
26	Cancer Center at Ball Memorial Hospital	Muncie	Indiana	United States	47303-3499
27	Menorah Medical Center	Overland Park	Kansas	United States	66209
28	Saint Luke's Hospital - South	Overland Park	Kansas	United States	66213
29	Shawnee Mission Medical Center	Shawnee Mission	Kansas	United States	66204
30	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland	United States	21201
31	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
32	Dana-Farber/Brigham and Women's Cancer Center	Boston	Massachusetts	United States	02115
33	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
34	Boston University Cancer Research Center	Boston	Massachusetts	United States	02118
35	Hudner Oncology Center at Saint Anne's Hospital - Fall River	Fall River	Massachusetts	United States	02721
36	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
37	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota	United States	55433
38	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
39	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota	United States	55432
40	Minnesota Oncology Hematology, PA - Maplewood	Maplewood	Minnesota	United States	55109
41	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota	United States	55407
42	Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota	United States	55422-2900
43	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota	United States	55416
44	Park Nicollet Cancer Center	Saint Louis Park	Minnesota	United States	55416
45	United Hospital	Saint Paul	Minnesota	United States	55102
46	St. Francis Cancer Center at St. Francis Medical Center	Shakopee	Minnesota	United States	55379
47	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
48	Minnesota Oncology Hematology, PA - Woodbury	Woodbury	Minnesota	United States	55125
49	Regional Cancer Center at Singing River Hospital	Pascagoula	Mississippi	United States	39581
50	Cancer Institute of Cape Girardeau, LLC	Cape Girardeau	Missouri	United States	63703
51	Truman Medical Center - Hospital Hill	Kansas City	Missouri	United States	64108
52	Saint Luke's Cancer Institute at Saint Luke's Hospital	Kansas City	Missouri	United States	64111
53	St. Joseph Medical Center	Kansas City	Missouri	United States	64114
54	North Kansas City Hospital	Kansas City	Missouri	United States	64116
55	Parvin Radiation Oncology	Kansas City	Missouri	United States	64116
56	CCOP - Kansas City	Kansas City	Missouri	United States	64131
57	Research Medical Center	Kansas City	Missouri	United States	64132
58	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri	United States	64086
59	Liberty Hospital	Liberty	Missouri	United States	64068
60	Heartland Regional Medical Center	Saint Joseph	Missouri	United States	64506
61	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
62	Barnes-Jewish West County Hospital	Saint Louis	Missouri	United States	63141
63	Siteman Cancer Center at Barnes-Jewish St. Peters Hospital - St. Peters	Saint Peters	Missouri	United States	63376
64	CCOP - Cancer Research for the Ozarks	Springfield	Missouri	United States	65802
65	Hulston Cancer Center at Cox Medical Center South	Springfield	Missouri	United States	65807
66	Nebraska Medical Center	Omaha	Nebraska	United States	68198
67	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
68	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89106
69	Renown Institute for Cancer at Renown Regional Medical Center	Reno	Nevada	United States	89502
70	Kingsbury Center for Cancer Care at Cheshire Medical Center	Keene	New Hampshire	United States	03431
71	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756-0002
72	Monmouth Medical Center	Long Branch	New Jersey	United States	07740-6395
73	Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton	Marlton	New Jersey	United States	08053
74	J. Phillip Citta Regional Cancer Center at Community Medical Center	Toms River	New Jersey	United States	08755
75	Maimonides Cancer Center at Maimonides Medical Center	Brooklyn	New York	United States	11219
76	Monter Cancer Center of the North Shore-LIJ Health System	Lake Success	New York	United States	11042
77	CCOP - North Shore University Hospital	Manhasset	New York	United States	11030
78	Don Monti Comprehensive Cancer Center at North Shore University Hospital	Manhasset	New York	United States	11030
79	Long Island Jewish Medical Center	New Hyde Park	New York	United States	11040
80	Wayne Memorial Hospital, Incorporated	Goldsboro	North Carolina	United States	27534
81	Wayne Radiation Oncology	Goldsboro	North Carolina	United States	27534
82	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio	United States	44309-2090
83	Barberton Citizens Hospital	Barberton	Ohio	United States	44203
84	Charles M. Barrett Cancer Center at University Hospital	Cincinnati	Ohio	United States	45267
85	Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center	Columbus	Ohio	United States	43210-1240
86	Cancer Care Center, Incorporated	Salem	Ohio	United States	44460
87	Precision Radiotherapy at University Pointe	West Chester	Ohio	United States	45069
88	Cancer Treatment Center	Wooster	Ohio	United States	44691
89	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma	United States	73104
90	Integris Oncology Services	Oklahoma City	Oklahoma	United States	73112
91	Rosenfeld Cancer Center at Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
92	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania	United States	19010
93	Northeast Radiation Oncology Center	Dunmore	Pennsylvania	United States	18512
94	Dale and Frances Hughes Cancer Center at Pocono Medical Center	East Stroudsburg	Pennsylvania	United States	18301
95	Penn State Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
96	Riddle Memorial Hospital Cancer Center	Media	Pennsylvania	United States	19063
97	Upper Delaware Valley Cancer Center	Milford	Pennsylvania	United States	18337
98	Cancer Center of Paoli Memorial Hospital	Paoli	Pennsylvania	United States	19301-1792
99	Kimmel Cancer Center at Thomas Jefferson University - Philadelphia	Philadelphia	Pennsylvania	United States	19107-5541
100	Frankford Hospital Cancer Center - Torresdale Campus	Philadelphia	Pennsylvania	United States	19114
101	CCOP - Main Line Health	Wynnewood	Pennsylvania	United States	19096
102	Lankenau Cancer Center at Lankenau Hospital	Wynnewood	Pennsylvania	United States	19096
103	Rhode Island Hospital Comprehensive Cancer Center	Providence	Rhode Island	United States	02903
104	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina	United States	29425
105	Christine LaGuardia Phillips Cancer Center at Wellmont Holston Valley Medical Center	Kingsport	Tennessee	United States	37662
106	American Fork Hospital	American Fork	Utah	United States	84003
107	Sandra L. Maxwell Cancer Center	Cedar City	Utah	United States	84720
108	Jon and Karen Huntsman Cancer Center at Intermountain Medical Center	Murray	Utah	United States	84157
109	Val and Ann Browning Cancer Center at McKay-Dee Hospital Center	Ogden	Utah	United States	84403
110	Utah Valley Regional Medical Center - Provo	Provo	Utah	United States	84604
111	Dixie Regional Medical Center - East Campus	Saint George	Utah	United States	84770
112	LDS Hospital	Salt Lake City	Utah	United States	84103
113	Utah Cancer Specialists at UCS Cancer Center	Salt Lake City	Utah	United States	84106
114	Norris Cotton Cancer Center - North	Saint Johnsbury	Vermont	United States	05819
115	University of Virginia Cancer Center	Charlottesville	Virginia	United States	22908
116	Southwest Virginia Regional Cancer Center at Wellmonth Health	Norton	Virginia	United States	24273
117	Columbia Saint Mary's Hospital - Ozaukee	Mequon	Wisconsin	United States	53097
118	Columbia-Saint Mary's Cancer Care Center	Milwaukee	Wisconsin	United States	53211
119	Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin	United States	53226
120	London Regional Cancer Program at London Health Sciences Centre	London	Ontario	Canada	N6A 4L6

Sponsors and Collaborators

• Radiation Therapy Oncology Group
• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• Principal Investigator: Michael C. Garofalo, MD, University of Maryland Greenebaum Cancer Center
• Study Chair: Adam C. Berger, MD, Sidney Kimmel Cancer Center at Thomas Jefferson University
• Study Chair: Johanna Bendell, MD, Duke Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT00613080
• Other Study ID Numbers: RTOG-0822; CDR0000586277
• First Posted: Feb 12, 2008
• Last Update Posted: Sep 25, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by Radiation Therapy Oncology Group: stage III rectal cancer; adenocarcinoma of the rectum
• Additional relevant MeSH terms: Rectal Neoplasms; Leucovorin; Fluorouracil; Capecitabine; Oxaliplatin

Study Results

Participant Flow

Arm/Group Title	IMRT + Chemotherapy , Resection, Postoperative Chemotherapy
Arm/Group Description	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)
Period Title: Overall Study
STARTED	79
COMPLETED	68
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	IMRT + Chemotherapy , Resection, Postoperative Chemotherapy
Arm/Group Description	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)
Overall Participants	68
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	51
Sex: Female, Male (Count of Participants)
Female	30 44.1%
Male	38 55.9%

Outcome Measures

1. Primary Outcome

Title	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
Description	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.
Time Frame	From start of treatment to surgery or ≤ 90 days from the Start of Concurrent Treatment (for patients not undergoing surgery)

Outcome Measure Data

Analysis Population Description

Eligible subjects who started study treatment.

Arm/Group Title	IMRT + Chemotherapy , Resection, Postoperative Chemotherapy
Arm/Group Description	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)
Measure Participants	68
Number (90% Confidence Interval) [percentage of patients]	51

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMRT + Chemotherapy , Resection, Postoperative Chemotherapy
	Comments	This study was designed for a one-sided chi-square test to detect at least 12% reduction in the 40% rate of ≥ grade 2 treatment-related preoperative GI AEs from the conventional radiotherapy / capecitabine /oxaliplatin arm of study RTOG-0247 (NCT00081289) with 80% power and a one-sided type I error rate of 0.10.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.93
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Proportion (reported as percentage)
	Estimated Value	51
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Patients in Protocol Adherence Categories for Intensity-modulated Radiotherapy (IMRT) Planning
Description	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.
Time Frame	Pretreatment

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	IMRT + Chemotherapy , Resection, Postoperative Chemotherapy
Arm/Group Description	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)
Measure Participants	68
Per Protocol	58 85.3%
Acceptable variation	5 7.4%
Unacceptable variation	5 7.4%
Per Protocol	62 91.2%
Acceptable variation	6 8.8%
Unacceptable variation	0 0%
Per Protocol	59 86.8%
Acceptable variation	8 11.8%
Unacceptable variation	1 1.5%
Per Protocol	48 70.6%
Acceptable variation	17 25%
Unacceptable variation	3 4.4%

3. Secondary Outcome

Title	Number of Patients With Pathologic Complete Response
Description	Pathologic complete response is defined as no evidence of residual cancer histologically in the resection specimen.
Time Frame	At the time of surgery, which is 4-8 weeks after radiation therapy, approximately 9-13 weeks from treatment start.

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	IMRT + Chemotherapy , Resection, Postoperative Chemotherapy
Arm/Group Description	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)
Measure Participants	68
Count of Participants [Participants]	10 14.7%

4. Secondary Outcome

Title	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
Description	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;
Time Frame	From study registration to end of follow-up. Maximum follow-up at time of analysis was 5.2 years.

Outcome Measure Data

Analysis Population Description

For the four time periods reported, respectively: all registered patients; patients that had surgery; patients that had surgery and postoperative chemotherapy; all registered patients.

Arm/Group Title	IMRT + Chemotherapy , Resection, Postoperative Chemotherapy
Arm/Group Description	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)
Measure Participants	68
Preoperative	49 72.1%
Postoperative #1	7 10.3%
Postoperative #2	74 108.8%
Overall	78 114.7%

5. Secondary Outcome

Title	Local-regional Failure: 4-year Rate
Description	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.
Time Frame	From registration to four years

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	IMRT + Chemotherapy , Resection, Postoperative Chemotherapy
Arm/Group Description	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)
Measure Participants	68
Number (95% Confidence Interval) [percentage of participants]	7.4 10.9%

6. Secondary Outcome

Title	Distant Failure: 4-year Rate
Description	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.
Time Frame	From registration to four years

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	IMRT + Chemotherapy , Resection, Postoperative Chemotherapy
Arm/Group Description	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)
Measure Participants	68
Number (95% Confidence Interval) [percentage of participants]	29.7 43.7%

7. Secondary Outcome

Title	Overall Survival: 4-year Rate
Description	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.
Time Frame	From registration to four years

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	IMRT + Chemotherapy , Resection, Postoperative Chemotherapy
Arm/Group Description	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)
Measure Participants	68
Number (95% Confidence Interval) [percentage of participants]	82.9 121.9%

8. Secondary Outcome

Title	Disease-free Survival: 4-year Rate
Description	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.
Time Frame	From registration to four years

Outcome Measure Data

Analysis Population Description

Eligible patients who started study treatment

Arm/Group Title	IMRT + Chemotherapy , Resection, Postoperative Chemotherapy
Arm/Group Description	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)
Measure Participants	68
Number (95% Confidence Interval) [percentage of participants]	60.6 89.1%

9. Secondary Outcome

Title	Number of Patients Who Underwent Abdominoperineal Resection
Description	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.
Time Frame	Surgery occurred 4 to 8 weeks following the completion of radiation therapy, approximately 9-13 weeks from start of treatment.

Outcome Measure Data

Analysis Population Description

Eligible patients that had surgery

Arm/Group Title	IMRT + Chemotherapy , Resection, Postoperative Chemotherapy
Arm/Group Description	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)
Measure Participants	67
Count of Participants [Participants]	14 20.6%

Adverse Events

Adverse Event Reporting Description	Eligible patients with adverse event data are included. Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Arm/Group Title	IMRT + Chemotherapy , Resection, Postoperative Chemotherapy
Arm/Group Description	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)
All Cause Mortality
	IMRT + Chemotherapy , Resection, Postoperative Chemotherapy
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	IMRT + Chemotherapy , Resection, Postoperative Chemotherapy
	Affected / at Risk (%)	# Events
Total	23/68 (33.8%)
Blood and lymphatic system disorders
Hemoglobin decreased	4/68 (5.9%)
Cardiac disorders
Atrial fibrillation	1/68 (1.5%)
Atrial tachycardia	1/68 (1.5%)
Myocardial ischemia	1/68 (1.5%)
Sinus tachycardia	1/68 (1.5%)
Gastrointestinal disorders
Abdominal pain	2/68 (2.9%)
Colonic stenosis	1/68 (1.5%)
Diarrhea	10/68 (14.7%)
Dyspepsia	1/68 (1.5%)
Dysphagia	1/68 (1.5%)
Enteritis	1/68 (1.5%)
Esophageal hemorrhage	1/68 (1.5%)
Esophagitis	1/68 (1.5%)
Gastrointestinal disorder	1/68 (1.5%)
Ileus	1/68 (1.5%)
Mucositis oral	1/68 (1.5%)
Nausea	3/68 (4.4%)
Rectal hemorrhage	1/68 (1.5%)
Rectal pain	1/68 (1.5%)
Small intestinal obstruction	2/68 (2.9%)
Vomiting	3/68 (4.4%)
General disorders
Fatigue	3/68 (4.4%)
Fever	2/68 (2.9%)
Pain	1/68 (1.5%)
Infections and infestations
Peritoneal infection	1/68 (1.5%)
Pneumonia	1/68 (1.5%)
Sepsis	3/68 (4.4%)
Injury, poisoning and procedural complications
Intraoperative complications	1/68 (1.5%)
Rectal anastomotic leak	1/68 (1.5%)
Wound dehiscence	1/68 (1.5%)
Investigations
Alkaline phosphatase increased	1/68 (1.5%)
Aspartate aminotransferase increased	1/68 (1.5%)
Creatinine increased	1/68 (1.5%)
Leukopenia	5/68 (7.4%)
Lymphopenia	2/68 (2.9%)
Neutrophil count decreased	4/68 (5.9%)
Platelet count decreased	1/68 (1.5%)
Metabolism and nutrition disorders
Anorexia	1/68 (1.5%)
Dehydration	5/68 (7.4%)
Hyperglycemia	2/68 (2.9%)
Hypermagnesemia	1/68 (1.5%)
Hypoalbuminemia	2/68 (2.9%)
Hypocalcemia	2/68 (2.9%)
Hypokalemia	4/68 (5.9%)
Hypomagnesemia	1/68 (1.5%)
Hyponatremia	4/68 (5.9%)
Nervous system disorders
Dizziness	1/68 (1.5%)
Ischemia cerebrovascular	1/68 (1.5%)
Peripheral sensory neuropathy	1/68 (1.5%)
Psychiatric disorders
Insomnia	1/68 (1.5%)
Renal and urinary disorders
Renal failure	1/68 (1.5%)
Ureteric obstruction	1/68 (1.5%)
Urinary incontinence	1/68 (1.5%)
Reproductive system and breast disorders
Pelvic pain	1/68 (1.5%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/68 (1.5%)
Hypoxia	1/68 (1.5%)
Pneumonitis	1/68 (1.5%)
Skin and subcutaneous tissue disorders
Pruritus	1/68 (1.5%)
Rash desquamating	1/68 (1.5%)
Sweating	1/68 (1.5%)
Urticaria	1/68 (1.5%)
Vascular disorders
Hypertension	1/68 (1.5%)
Thrombosis	4/68 (5.9%)
Other (Not Including Serious) Adverse Events
	IMRT + Chemotherapy , Resection, Postoperative Chemotherapy
	Affected / at Risk (%)	# Events
Total	67/68 (98.5%)
Blood and lymphatic system disorders
Blood disorder	5/68 (7.4%)
Hemoglobin decreased	40/68 (58.8%)
Eye disorders
Vision blurred	4/68 (5.9%)
Gastrointestinal disorders
Abdominal distension	5/68 (7.4%)
Abdominal pain	25/68 (36.8%)
Anal pain	10/68 (14.7%)
Constipation	31/68 (45.6%)
Diarrhea	55/68 (80.9%)
Dyspepsia	9/68 (13.2%)
Dysphagia	7/68 (10.3%)
Fecal incontinence	6/68 (8.8%)
Flatulence	4/68 (5.9%)
Gastrointestinal disorder	11/68 (16.2%)
Mucositis oral	12/68 (17.6%)
Nausea	48/68 (70.6%)
Proctitis	7/68 (10.3%)
Rectal fistula	4/68 (5.9%)
Rectal hemorrhage	9/68 (13.2%)
Rectal pain	27/68 (39.7%)
Vomiting	25/68 (36.8%)
General disorders
Chest pain	8/68 (11.8%)
Chills	5/68 (7.4%)
Edema limbs	8/68 (11.8%)
Fatigue	54/68 (79.4%)
Fever	10/68 (14.7%)
Pain	12/68 (17.6%)
Immune system disorders
Hypersensitivity	5/68 (7.4%)
Injury, poisoning and procedural complications
Dermatitis radiation	13/68 (19.1%)
Radiation recall reaction (dermatologic)	12/68 (17.6%)
Vascular access complication	4/68 (5.9%)
Wound dehiscence	6/68 (8.8%)
Investigations
Alanine aminotransferase increased	24/68 (35.3%)
Alkaline phosphatase increased	17/68 (25%)
Aspartate aminotransferase increased	23/68 (33.8%)
Creatinine increased	6/68 (8.8%)
Hyperbilirubinemia	11/68 (16.2%)
Laboratory test abnormal	6/68 (8.8%)
Leukopenia	41/68 (60.3%)
Lymphopenia	23/68 (33.8%)
Neutrophil count decreased	34/68 (50%)
Platelet count decreased	34/68 (50%)
Weight loss	18/68 (26.5%)
Metabolism and nutrition disorders
Anorexia	27/68 (39.7%)
Dehydration	18/68 (26.5%)
Hyperglycemia	35/68 (51.5%)
Hyperkalemia	7/68 (10.3%)
Hypoalbuminemia	16/68 (23.5%)
Hypocalcemia	20/68 (29.4%)
Hypokalemia	17/68 (25%)
Hypomagnesemia	8/68 (11.8%)
Hyponatremia	18/68 (26.5%)
Musculoskeletal and connective tissue disorders
Back pain	10/68 (14.7%)
Bone pain	5/68 (7.4%)
Joint pain	5/68 (7.4%)
Muscle weakness	6/68 (8.8%)
Neck pain	4/68 (5.9%)
Pain in extremity	8/68 (11.8%)
Nervous system disorders
Dizziness	6/68 (8.8%)
Headache	13/68 (19.1%)
Neurological disorder NOS	5/68 (7.4%)
Peripheral motor neuropathy	8/68 (11.8%)
Peripheral sensory neuropathy	50/68 (73.5%)
Taste alteration	15/68 (22.1%)
Psychiatric disorders
Agitation	5/68 (7.4%)
Anxiety	9/68 (13.2%)
Depression	10/68 (14.7%)
Insomnia	22/68 (32.4%)
Renal and urinary disorders
Cystitis	6/68 (8.8%)
Urinary frequency	13/68 (19.1%)
Urinary incontinence	4/68 (5.9%)
Respiratory, thoracic and mediastinal disorders
Cough	12/68 (17.6%)
Dyspnea	11/68 (16.2%)
Hemorrhage nasal	6/68 (8.8%)
Skin and subcutaneous tissue disorders
Alopecia	14/68 (20.6%)
Dry skin	8/68 (11.8%)
Hand-and-foot syndrome	12/68 (17.6%)
Rash desquamating	10/68 (14.7%)
Skin disorder	5/68 (7.4%)
Sweating	6/68 (8.8%)
Vascular disorders
Hot flashes	6/68 (8.8%)
Hypotension	5/68 (7.4%)
Thrombosis	6/68 (8.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.