Study Chairs (3/30/10) Principal Investigator/Radiation Oncology Surgical Oncology

RADIATION THERAPY ONCOLOGY GROUP
RTOG 0822
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 Chairs (3/30/10)
Principal Investigator/Radiation Oncology
Michael C. Garofalo, MD
University of Maryland Medical Center
22 South Greene Street, Rm GGK39
Baltimore, MD 21201
410-328-6080/FAX 410-328-5279
mgarofalo@umm.edu
Surgical Oncology
Adam C. Berger, MD
Thomas Jefferson Medical Center
1100 Walnut Street, Suite 500
Philadelphia, PA 19107
215-955-1622/FAX 215-923-8222
adam.berger@jefferson.edu
Radiation Oncology
Theodore Hong, MD
Massachusetts General Hospital
55 Fruit St.
Boston, MA 02114
617-726-5866/FAX : 617-726-3603
tshong1@partners.org
Medical Physics
Fritz Lerma, PhD
University of Maryland Medical Center
22 South Greene Street
Baltimore, MD 21201
410-328-7159/FAX 410-328-2618
flerma@umm.edu
Medical Oncology
Johanna Bendell, MD
Sarah Cannon Research Institute
250 25th Avenue North
Nashville, TN 37203
615-329-7274/FAX 615-340-2902
jbendell@tnonc.com
Pathology
Sunil Krishnan, MD
MD Anderson Cancer Center
1515 Holcombe Boulevard, Box 097
Houston, TX 77030
713-563-2377/FAX 713-563-2366
skrishnan@mdanderson.org
Amendment 1
Update
Closure
Activation
Document History
Version/Update Date
August 17, 2011
April 17, 2008
April 17, 2008
Broadcast Date
August 25, 2011
March 30, 2010
November 13, 2009
April 29, 2008
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RTOG Headquarters/Department of Statistics

215-574-3189
1-800-227-5463, ext. 4189
This protocol was designed and developed by the Radiation Therapy Oncology
Group (RTOG) of the American College of Radiology (ACR). It is intended to be
used only in conjunction with institution-specific IRB approval for study entry.
No other use or reproduction is authorized by RTOG nor does RTOG assume
any responsibility for unauthorized use of this protocol.
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INDEX
Schema
Eligibility Checklist
1.0
Introduction
2.0
Objectives
3.0
Patient Selection
4.0
Pretreatment Evaluations/Management
5.0
Registration Procedures
6.0
Radiation Therapy
7.0
Drug Therapy
8.0
Surgery
9.0
Other Therapy
10.0
Tissue/Specimen Submission
11.0
Patient Assessments
12.0
Data Collection
13.0
Statistical Considerations
References
Appendix I
Appendix II
Appendix III
Appendix IV
Appendix V
Appendix VI
Appendix VII
- Sample Consent Form

- Study Parameters
- Performance Status Scoring
- Staging System
- Capecitabine BSA Dose Calculation Tables
- Pathologic Assessment of a Rectal Cancer Specimen
- Blood Collection Kit Instructions
RTOG 0822
RADIATION THERAPY ONCOLOGY GROUP

RTOG 0822
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
SCHEMA
Radiation Therapy
Pelvic IMRT: 45 Gy in 25 fx
3D-CRT boost: 5.4 Gy in 3 fx to total dose of 50.4 Gy in 28 fx
R
E
G
I
S
T
E
R*
PLUS
Concurrent Preoperative Chemotherapy
Capecitabine, Oxaliplatin
(4-8 wks)
Surgery
(4-8 wks)
Postoperative Chemotherapy
FOLFOX
* See Section 5.0 for pre-registration requirements.

See Section 6.0 for radiation therapy details.
See Section 7.0 for drug therapy details.
See Section 8.0 for surgery details.
Patient Population: (See Section 3.0 for Eligibility)
Pathologically proven diagnosis of adenocarcinoma of the rectum (located up to 12 cm from the anal
verge on flexible endoscopy) within 8 weeks of registration
Clinically determined to be T3 or T4 and N0-2, M0
Required Sample Size: 75 patients
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RTOG Institution #
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Case #
ELIGIBILITY CHECKLIST (4/29/08)

(page 1 of 4)
(Y)
1. Does the patient have pathologically confirmed adenocarcinoma of the rectum (located
up to 12 cm from the anal verge on flexible endoscopy) within 56 days of registration?
(N)
2. Does the malignant disease extend into the anal canal?
(Y)
3. Is the clinical T stage 3-4, N stage 0-2, and M0?
(Y/N)
4. Is the clinical T stage T3?

(Y)
If yes, was transrectal ultrasound performed within 56 days of registration?
(Y)
5. Has the patient had within 56 days prior to registration: (a) a colonoscopy; (b) biopsy; (c)
FNA; (d) history and physical; (e) contrast-enhanced CT, MRI, or PET-CT of the
abdomen and pelvis; and (f) chest x-ray or chest CT (if whole-body PET-CT not done)?
(Y)
6. Is the patients Zubrod performance status 0-2?
(Y)
7. Is the patient 18 years of age?
(Y)
8. Has a CBC/differential been obtained within 14 days prior to registration that meets the
requirements as specified in Section 3.1?
(Y)
9. Has a metabolic panel been obtained within 28 days prior to registration that meets the
requirements as specified in Section 3.1?
(Y/NA)
10. Has a serum pregnancy test been performed within 14 days prior to registration on study
(for female patients of childbearing potential)?
(Y/N)
11. Did the patient have a prior invasive malignancy (with the exception of nonmelanomatous skin cancer?
(Y)
If yes, has the patient been disease free for 3 years?
(N)
12. Has the patient had prior systemic chemotherapy for colorectal cancer?
(N)
13. Has the patient had prior radiation therapy to the region of the study cancer that would
result in overlap of radiation therapy fields?
(N)
14. Does the patient have evidence of grade 2 peripheral neuropathy?
(N)
15. Has the patient had major surgery within 28 days of registration (other than diverting
colostomy as specified in Section 9.1)?
(N)
16. Does the patient have synchronous primary colon carcinomas?
(N)
17. Does the patient have lack of physical integrity of the GI tract or malabsorption syndrome
that would preclude feasibility of oral chemotherapy?
(N)
18. Has the patient participated in any investigational drug study within 28 days of
registration?
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RTOG Institution #
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Case #

(page 2 of 4)
(N)
19. Has the patient had a prior allergic reaction to oxaliplatin or capecitabine?
(N)
20. Has the patient had a transmural myocardial infarction within the last 6 months?
(N)
21. Does the patient have an acute bacterial or fungal infection requiring intravenous
antibiotics at the time of registration?
(N)
22. Does the patient have chronic obstructive pulmonary disease exacerbation or other
respiratory illness requiring hospitalization or precluding study therapy within 30 days
prior to registration?
(N)
23. Does the patient have hepatic insufficiency resulting in clinical jaundice and/or
coagulation defects?
(N)
24. Does the patient have acquired immune deficiency syndrome (AIDS) based upon current
CDC definition?
(N)
25. Does the patient have evidence of uncontrolled seizures, central nervous system
disorder, or psychiatric disability judged by the investigator to be clinically significant,
precluding informed consent, or interfering with compliance of oral drug intake?
(N)
26. Does the patient have known existing uncontrolled coagulopathy?
(Y/N)
27. Is the patient on anticoagulation medication?

(Y)
If yes, has the patient been clinically stable for at least 2 weeks?
(Continued on the next page)
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RTOG Institution #
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Case #

(page 3 of 4)
The following questions will be asked at Study Registration:

IMRT CREDENTIALING IS REQUIRED BEFORE REGISTRATION
1.
Name of institutional person registering this case?
(Y) 2.
Has the Eligibility Checklist (above) been completed?
(Y) 3.
Is the patient eligible for this study?
4.
Date the patient provided study-specific, signed consent prior to study entry?
5.
Patients Initials (First Middle Last)
6.
Verifying Physician
7.
Patients ID Number
8.
Date of Birth
9.
Race
10.
Ethnic Category (Hispanic or Latino; Not Hispanic or Latino; Unknown)
11.
Gender
12.
Patients Country of Residence
13.
Zip Code (U.S. Residents)
14.
Patients Insurance Status
15.
Will any component of the patients care be given at a military or VA facility?
16.
Calendar Base Date
17.
Registration/randomization date: This date will be populated automatically.

(Continued on the next page)
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RTOG Institution #
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Case #
18.

(page 4 of 4)
Medical oncologist
(Y/N) 19.
Tissue/Blood kept for cancer research?
(Y/N) 20.
Tissue/Blood kept for medical research?
(Y/N) 21.
Allow contact for future research?
(T3/T4) 22.
Clinical T stage
The Eligibility Checklist must be completed in its entirety prior to web registration. The completed, signed, and
dated checklist used at study entry must be retained in the patients study file and will be evaluated during an
institutional NCI/RTOG audit.
Completed by
Date
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1.0
INTRODUCTION
1.1
Background
Preoperative chemoradiotherapy is currently considered standard therapy for patients with locally
advanced rectal cancer. Several important historical trials helped to establish trimodality therapy
as the standard treatment for locally advanced rectal cancer almost 20 years ago.1-3 The results
of a recent large randomized trial comparing preoperative chemoradiation versus postoperative
chemoradiation have clearly demonstrated that the toxicity is reduced and local control is
improved with a neoadjuvant approach, thus representing the prevailing paradigm for treatment at
this time.4
Historically, 5-fluorouracil (5-FU) has most commonly been employed concomitantly with external
beam radiation as a radiosensitizer. However, in part because of patient convenience, it has
become displaced in modern therapy by capecitabine, an orally active prodrug of 5-FU that has
been shown to be equally efficacious in randomized studies.5,6 Toward the improvement of
results seen with capecitabine or 5-FU based chemoradiation, several institutions have explored
the feasibility and efficacy of adding a second chemotherapeutic agent concurrent with
capecitabine and radiation in the neoadjuvant treatment of locally advanced rectal cancer.
Foremost among these have been oxaliplatin and irinotecan, owing to their proven success in the
metastatic setting. Based on the early results in several pilot studies, these drugs appeared to be
reasonably well tolerated when added to 5-FU and radiation therapy. These results, in part, led
the Radiation Therapy Oncology Group (RTOG) to design and conduct a phase II randomized
trial comparing capecitabine/oxaliplatin/radiation versus capecitabine/irinotecan/radiation in the
neoadjuvant treatment of locally advanced rectal cancer (RTOG 0247).
Due to unexpectedly high grade 3-4 non-hematologic toxicity observed in both arms of the trial,
accrual to RTOG 0247 was temporarily suspended. The toxicity experienced during neoadjuvant
treatment was largely gastrointestinal and appeared to be consequent to excess cumulative
gastrointestinal toxicity from both chemotherapy and radiation. In the irinotecan arm, 7/18
patients experienced grade 3-4 diarrhea. In the oxaliplatin arm, 5 patients had grade 3 diarrhea
and 1 patient had grade 5 diarrhea. The trial was ultimately re-opened, but only after the
capecitabine and oxaliplatin doses were decreased (825 mg/m2 bid and 50 mg/m2, respectively).
1.2
Rationale for Intensity Modulated Radiation Therapy in Rectal Cancer

Given that the dose-limiting toxicity in RTOG 0247 was gastrointestinal (not hematologic), modern
highly conformal radiation therapy planning and delivery techniques could potentially reduce the
radiation dose to the bowel and, consequently, reduce gastrointestinal side effects. The small
bowel has been estimated to have a 5% risk of late toxicity at 5 years with doses of between 45
and 50 Gy.7,8 The risk of grade 3 or greater bowel toxicity has been shown to increase with both
total dose and with the volume of bowel irradiated to higher doses. Gallagher et al9 have
suggested that the absolute volume of small bowel irradiated to 45 Gy or higher is associated
with an increased risk of late gastrointestinal toxicity. Intensity modulated radiation therapy
(IMRT) has previously been demonstrated to be effective in reducing small bowel dose and
resultant gastrointestinal toxicity in patients with other pelvic malignancies (cervical, endometrial,
prostate).10-12
Research into the potential benefits of IMRT in the treatment of rectal cancer have only recently
been undertaken.13,14 In one study, Urbano et al14 conducted a dosimetric analysis comparing
three dimensional conformal radiation therapy (3D-CRT) and both forward and inverse planned
IMRT with anywhere from 3 to 9 fields. They found that IMRT improved small bowel sparing
when compared with 3D-CRT as much as by a 64% reduction in the amount of small bowel
receiving 45 Gy. The differences in improvement between 5-, 7- and 9-field IMRT plans in
sparing volume of bowel getting high doses was minimal, but they were all significantly better at
sparing small bowel than the 3-field IMRT plan. The authors therefore concluded that the 5-field
custom segmented IMRT plan appeared to be clinically promising.
The primary aim of this protocol is to test the feasibility of delivering IMRT concurrent with
multiagent chemotherapy in a multi-institutional setting for the treatment of rectal cancer in the
neoadjuvant setting. We hypothesize that by effectively reducing radiation to the small bowel,
RTOG 0822
there will be a consequent reduction in side effectsparticularly acute gastrointestinal side

effects, which have been prohibitory to higher doses of capecitabine and oxaliplatin in the
recently completed RTOG 0247 study. If effective in reducing overlapping gastrointestinal toxicity
through reductions in small bowel toxicity, IMRT would re-open research avenues such as dose
escalation of chemotherapy and/or radiation therapy in the neoadjuvant setting, paving the way
toward improving local control, pathologic complete response rates, and, ultimately, overall
survival for our patients.
2.0
OBJECTIVES
2.1
Primary
2.1.1 To determine whether the incidence of acute (preoperative) grade 2-5 gastrointestinal toxicity
associated with preoperative chemoradiotherapy is reduced by inverse-planned IMRT-based
radiation treatment (when compared with conventionally delivered radiation treatment as was
utilized in the capecitabine and oxaliplatin arm of RTOG 0247).
2.2
2.2.1
2.2.2
2.2.3
2.2.4
2.2.5
2.2.6
3.0
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 preoperative period, the postoperative period, and overall.
To estimate the pathologic complete response rate following preoperative 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 preoperative chemoradiation therapy for rectal cancer.
To evaluate the rate of abdominoperineal resections (APR).
PATIENT SELECTION
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED

3.1
3.1.1
3.1.2
3.1.2.1
3.1.2.2
3.1.2.3
3.1.2.4
3.1.2.5
3.1.3
3.1.4
3.1.5
3.1.5.1
3.1.5.2
3.1.5.3
3.1.6
Conditions for Patient Eligibility

Pathologically proven diagnosis of adenocarcinoma of the rectum (located up to 12 cm from the
anal verge on flexible endoscopy) within 56 days of registration.
Diagnosis of rectal adenocarcinoma must be obtained by biopsy technique that does not
completely excise the lesion (e.g., fine needle aspiration, core needle biopsy).
Clinically determined to be stage T3 or T4,N0-N2, and M0, based upon the following minimum
diagnostic workup:
Colonoscopy 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 CT, MRI, or PET-CT (whole
body) within 56 days prior to registration. (NOTE: whole body PET-CT is preferred).
Chest x-ray (or CT) of the chest within 56 days prior to registration to exclude distant
metastases (except for those who have had whole body PET-CT per Section 3.1.2.3).
Transrectal ultrasound (TRUS) within 56 days prior to registration is required to establish T
stage, unless clinical exam, CT of the pelvis, and/or MRI demonstrates T4 lesion; in these
cases TRUS is not required
Zubrod Performance Status 0-2
Age 18
CBC/differential obtained within 14 days prior to registration on study, with adequate bone
marrow function defined as follows:
Absolute neutrophil count (ANC) 1,800 cells/mm3
Platelets 100,000 cells/mm3
Hemoglobin 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb
8.0 g/dl is acceptable.)
Metabolic panel within 28 days prior to registration on study, with adequate liver and renal
function defined as follows:
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3.1.6.1
3.1.6.2
3.1.6.3
3.1.7
3.1.8
AST and alkaline phosphatase < 2.5 x upper limit of normal (ULN)
Bilirubin 1.5 ULN
Calculated creatinine clearance (CrCl) > 50 ml/min using Cockcroft-Gault formula as below:
CrCl male = (140 -age) x (wt. in kg) / (Serum Cr) x 72
CrCl female = 0.85 x (CrCl male)
Serum pregnancy test within 14 days prior to registration on study (for female patients of
childbearing potential) (See also Section 4.1.2)
Patient must provide study-specific informed consent prior to study entry.
3.2
3.2.1
Conditions for Patient Ineligibility

Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a
minimum of 3 years
3.2.2
Prior systemic chemotherapy for colorectal cancer; note that prior chemotherapy for a different
cancer is allowable. See Section 3.2.1.
3.2.3
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation
therapy fields
3.2.4
Severe, active comorbidity, defined as follows:
3.2.4.1
Unstable angina and/or congestive heart failure requiring hospitalization within the last 12
months
3.2.4.2
Transmural myocardial infarction within the last 6 months
3.2.4.3
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
3.2.4.4
Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring
hospitalization or precluding study therapy within 30 days prior to registration.
3.2.4.5
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
3.2.4.6
Acquired immune deficiency syndrome (AIDS) based upon current CDC definition; note,
however, that HIV testing is not required for entry into this protocol. The need to exclude
patients with AIDS from this protocol is necessary because the treatments involved in this
protocol may be significantly immunosuppressive.
3.2.4.7
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.
3.2.4.8
Known, existing uncontrolled coagulopathy. Patients on therapeutic anticoagulation may be
enrolled provided that they have been clinically stable on anti-coagulation for at least 2
weeks.
3.2.4.9
Evidence of grade 2 or greater peripheral neuropathy
3.2.4.10
Major surgery within 28 days of study enrollment (other than diverting colostomy per Section
9.1)
3.2.5
Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception; this exclusion is necessary
because the treatment involved in this study may be significantly teratogenic
3.2.6
Prior allergic reaction to oxaliplatin or capecitabine
3.2.7
Any evidence of distant metastases (M1)
3.2.8
A synchronous primary colon carcinoma
3.2.9
Extension of malignant disease into the anal canal
3.2.10
Lack of physical integrity of the gastrointestinal tract (i.e., severe Crohns 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 (capecitabine)
3.2.11
Participation in any investigational drug study within 28 days of study enrollment
4.0
PRETREATMENT EVALUATIONS/MANAGEMENT
Note: This section lists baseline evaluations needed before the initiation of protocol treatment that do not
affect eligibility.
4.1
4.1.1
Required Evaluations/Management
See Appendix II; note that failure to perform these tests may result in assessment of a protocol
violation:
Serum CEA
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4.1.2
5.0
If serum pregnancy test per Section 3.1 was performed more than 14 days from the intended start
of radiation therapy, another serum pregnancy test must be performed and confirmed negative
within 14 days prior to radiation start.
REGISTRATION PROCEDURES
5.1
Pre-Registration Requirements for IMRT Treatment Approach
5.1.1
In order to utilize IMRT on this study, the institution must have met specific technology
requirements and have provided baseline physics information. Instructions for completing these
requirements or determining if they already have been met are available on the Radiological
Physics Center (RPC) web site at http://rpc.mdanderson.org/rpc/.
5.1.2
5.1.3
An IMRT phantom study with the RPC must be successfully completed (if the institution has not
previously met this credentialing requirement on another RTOG IMRT study). Instructions for
requesting and irradiating the phantom are available on the RPC web site at
http://rpc.mdanderson.org/rpc/; select Credentialing Status Inquiry and RTOG.
The institution or investigator must complete a new IMRT facility questionnaire and/or set up an
SFTP account for digital data submission, both of which are available on the Image-Guided
Center (ITC) web site at http://atc.wustl.edu.
Each institution must submit and successfully complete a protocol-specific Dry-Run Test (the
treatment plan for the first patient to be treated at the site on this protocol), and a Rapid Review
will be performed PRIOR TO DELIVERING ANY PROTOCOL TREATMENT. The DryRun
Test will be reviewed and the Rapid Review will be conducted by the ITC. Suggestions
regarding protocol compliance will be forwarded to the participating institution by the ITC.
The treatment plans for subsequent patients enrolled at a site will not be required to be
reviewed prior to treatment, but a review will be performed for protocol compliance at a later
date. Instructions for submitting the dry run can be found on the Advanced Technology
Consortium (ATC) web site, http://atc.wustl.edu.
Upon review and successful completion of the Dry-Run QA test, the ITC will notify both the
registering institution and RTOG Headquarters that the institution is eligible to enter patients
onto this study. Notification will then be given to the institution from the RTOG RT Quality
Assurance Department that the institution is eligible to enter patients onto this study.
5.2
5.2.1
5.2.2
Pre-Registration Requirements
U.S. sites and Canadian sites must fax copies of the documentation below to the CTSU
Regulatory Office (215-569-0206) prior to registration of the institutions first case:
IRB approval letter;
IRB assurance number;
Health Canadas TPD forms.
Note: International sites must receive written approval of submitted LOI forms from RTOG
Headquarters prior to submitting documents to their local ethics committee for approval. See
http://www.rtog.org/Researchers/InternationalMembers.aspx .
Approved international sites fax copies of the documentation below to RTOG Headquarters
(215-574-0300) prior to registration of the institutions first case:
IRB approval letter;
Federalwide Assurance (FWA) number.
5.3
Online Registration
Patients can be registered only after eligibility criteria are met.
Each individual user must have an RTOG user name and password to register patients on the
RTOG web site. To get a user name and password:
The investigator and research staff must have completed Human Subjects
Training and been issued a certificate (Training is available via
http://phrp.nihtraining.com).
A representative from the institution must complete the Password Authorization

Form at www.rtog.org/members/webreg.html (bottom right corner of the screen),
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and fax it to 215-923-1737. RTOG Headquarters requires 3-4 days to process

requests and issue user names/passwords to institutions.
An institution can register the patient by logging onto the RTOG web site (http://www.rtog.org),
going to Data Center Login" and selecting the link for new patient registrations. The system
triggers a program to verify that all regulatory requirements (OHRP assurance, IRB approval)
have been met by the institution. The registration screens begin by asking for the date on which
the eligibility checklist was completed, the identification of the person who completed the
checklist, whether the patient was found to be eligible on the basis of the checklist, and the
date the study-specific informed consent form was signed.
Once the system has verified that the patient is eligible and that the institution has met
regulatory requirements, it assigns a patient-specific case number. The system then moves to a
screen that confirms that the patient has been successfully enrolled. This screen can be
printed so that the registering site will have a copy of the registration for the patients record.
Two e-mails are generated and sent to the registering site: the Confirmation of Eligibility and
the patient-specific calendar. The system creates a case file in the studys database at the
DMC (Data Management Center) and generates a data submission calendar listing all data
forms, images, and reports and the dates on which they are due.
If the patient is ineligible or the institution has not met regulatory requirements, the system
switches to a screen that includes a brief explanation for the failure to register the patient. This
screen can be printed.
Institutions can contact RTOG web support for assistance with web registration:
websupport@phila.acr.org or 800-227-5463 ext. 4189 or 215-574-3189.
In the event that the RTOG web registration site is not accessible, participating sites can
register a patient by calling RTOG Headquarters, at (215) 574-3191, Monday through Friday,
8:30 a.m. to 5:00 p.m. ET. The registrar will ask for the sites user name and password. This
information is required to assure that mechanisms usually triggered by web registration (e.g.,
drug shipment, confirmation of registration, and patient-specific calendar) will occur.
6.0
RADIATION THERAPY
Note: Intensity modulated radiation therapy (IMRT) is mandatory for all patients for the initial
pelvic field encompassing the gross tumor and at-risk lymph nodes in the pelvis.
For specific questions or concerns regarding this section, please contact Dr. Michael Garofalo
(see cover page for contact information).
Protocol treatment (chemotherapy and radiation therapy) should be initiated simultaneously on a
Monday or Tuesday 21 days after protocol registration, with 5 days of consecutive treatment per
treatment week strongly encouraged.
6.1
6.1.1
Dose Specifications
Treatment plans for patients on this protocol will consist of 2 phases: 1) the first phase will
consist of inverse-planned IMRT-based treatment to the pelvis (rectum and draining lymphatics
at risk) for a total of 45 Gy in 1.8 Gy daily fractions, and 2) the second phase will consist of a 3dimensional conformal boost (a 3-field technique is suggested) to gross disease + a minimum 2
cm margin including all of the presacral space for an additional 5.4 Gy in 1.8 Gy daily fractions.
6.1.2
IMRT Dose Specifications
6.1.2.1
Inverse planning is required for the IMRT portion of treatment and planning constraints are
provided in this section for both the planning target volume (PTV) as well as critical normal
structures to be spared. Acceptable treatment plans will be established from a DVH-based
analysis of the volumetric dose to both the PTV and critical normal structures to ensure that
minimally acceptable constraints for each volume of interest have been met.
6.1.2.2
IMRT treatment to the pelvis will be planned to deliver a total of 45 Gy to the PTV in 25
fractions of 1.8 Gy over 5 consecutive weeks.
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6.2
6.2.1
6.2.2
6.3
6.3.1
6.3.2
6.4
6.4.1
6.4.2
6.4.3
6.4.3.1
6.4.3.2
6.4.3.3
6.4.3.4
6.5
6.5.1
6.5.2
Technical Factors
Megavoltage equipment (minimum acceptable energy is 6 MV) capable of delivering static
intensity modulation with a multileaf collimator or dynamic intensity modulation (using a
multileaf collimator or tomotherapy) is required.
Inverse-planning capable software is required.
Localization, Simulation, and Immobilization
A custom immobilization device (such as Alpha Cradle or vac-loc bag) for supine patients is
suggested to minimize setup uncertainty.
CT-based simulation (maximum 5 mm slice thickness) is required for this protocol and bowel
exclusion techniques should be used when possible. Patients may be simulated supine or prone
(if a belly board is utilized). Patients should be simulated in the arms up position whether prone
or supine and with a full bladder.
Treatment Planning/Target Volumes
The definition of volumes will be in accordance with the 1993 ICRU Report #50: Prescribing,
Recording and Reporting Photon Beam Therapy.
The Gross Tumor Volume (GTV) is defined as all known gross disease as determined from a
combination of physical exam, colonoscopy, ultrasound, CT (and MRI or PET-CT if performed).
The Clinical Target Volume (CTV) is defined as the GTV plus areas considered at significant risk
of harboring microscopic disease. The CTV for a T3 tumor should include all gross disease
(rectal and nodal) as well as the internal iliac lymph nodes and the mesorectum (perirectal fat and
the presacral space). The CTV for a T4 tumor will include the same structures as for a T3 tumor
but will include the external iliac lymph nodes as well.
The Planning Target Volume (PTV) will provide a margin around the CTV to compensate for the
inter- and intra-fraction uncertainty consequent to daily setup uncertainty and to potential internal
organ motion. By definition, the PTV will consist of a symmetrical 5 mm expansion around the
CTV. In the event that PTVs extend outside of the skin surface, the clinician should manually trim
the PTV contours to be 3-5 mm inside the outer skin (unless there is direct skin involvement).
The following are guidelines for generating CTV and a unified PTV.
Rectal GTV (+1.5 cm radially, +2.5 cm craniocaudally) = CTV
Nodal GTV + 1.5 cm symmetrical expansion = CTV
Uninvolved iliac vessels + 1.0 cm = CTV (include external iliac if T4)
Presacral lymphatic CTV is generated by contouring from mid S1-S5 and 8 mm tissue
anterior to the anterior border of the sacral bone
The mesorectum and perirectal lymphatics CTV is generated by utilizing anatomic
landmarks:
o Posterior Border: anterior border of the sacrum and gluteus maximus
o Lateral Border: ileum, piriformis and obturator muscles
o Anterior Border: should overlap by 1 cm into the bladder, vagina or prostate
The PTV is generated by expanding all of the above structures by 0.5 cm symmetrically and
unifying them into one 3-dimensional volume for planning purposes.
Examples of contoured patients are available for review on the RTOG website at
http://www.rtog.org/CoreLab/ContouringAtlases/Anorectal.aspx. These examples are an excellent
resource for the contouring of normal structures as well as GTV, CTV and PTV design.
PTV planning dose-volume constraints:
98% of the PTV receives 93% of the prescribed dose
None of the PTV is to receive 115% of the prescribed dose
Critical Structures (IMRT Planning Constraints)
Small bowel:
No more than 180 cc above 35 Gy
No small bowel volume should receive 50 Gy
Femoral heads:
No more than 40% volume above 40 Gy
RTOG 0822
6.5.3
6.5.4

No femoral head volume should receive 50 Gy
Bladder:
No bladder volume should receive 50 Gy
Unspecified Tissue:
No specific constraints, however a DVH will be generated for unspecified tissue which
consists of any tissue within the skin but not contoured as a part of any of the normal
structures above and/or the PTV
6.6
Documentation Requirements
Orthogonal films or images are required for isocenter verification. The length of the treatment
field shall be indicated on these films.
6.7
6.7.1
Compliance Criteria
The ITC will display (and compare with hard copies) isodose distributions through the planning
target volume to verify correct digital submission and conversion.
The ITC will compare the submitted digital dose-volume histograms (DVHs) for the PTVs, the
designated critical structures, and unspecified tissues with DVHs calculated by the ITC.
Each treatment will be remotely reviewed for Quality Assurance of target volumes and critical
structures. The following criteria will be utilized to assess compliance and/or deviation:
PTV
Per protocol if the prescription criteria in Section 6.4.3.4 are fulfilled
Variation acceptable if you fail to meet Section 6.4.3.4 constraints but can meet the
following constraints:
o 98% of the PTV receives 90% of the prescribed dose
Deviation unacceptable if you fail to meet any of the above criteria.
Small Bowel
Per protocol if the prescription criteria in Section 6.5.1 are fulfilled
Variation acceptable if you fail to meet Section 6.5.1 constraints but can meet the
following constraints:
o No more than 230 cc above 35 Gy
Femoral Heads
following:
No femoral head volume should receive 50 Gy
Bladder
following
No bladder volume should receive 50 Gy
6.7.2
6.7.3
6.7.3.1
6.7.3.2
6.7.3.3
6.7.3.4
6.8
R.T. Quality Assurance Reviews

The Radiation Oncology Co-Investigator, Michael Garofalo, MD, will perform a remote RT Quality
Assurance Review after ITC has received complete data for the first 20 cases enrolled. Dr.
Garofalo will perform the next remote review after ITC has received complete data for the next 20
RTOG 0822
cases enrolled. The final cases will be reviewed remotely within 3 months after this study has
reached the target accrual or as soon as complete data for all cases enrolled have been received,
whichever occurs first. These reviews will be ongoing and performed remotely.
6.9
6.9.1
6.9.2
Radiation Treatment Interruptions

Treatment interruptions are discouraged; however, they may be necessitated by uncontrolled
diarrhea or other acute complications. The reason for and length of any such interruption must
be documented. If the sum total of such interruptions exceeds 5 normally scheduled treatment
days, this would constitute a major treatment violation.
A minimum of 4 daily radiation therapy treatments are required in any given week. Any missed
radiation treatments will be made up at the end of the treatment schedule, such that the total
number of delivered 1.8 Gy fractions remains 28.
If chemotherapy is held, radiation therapy will continue.
Toxicity
XRT Dose
Grade 2 thrombocytopenia
Continue at current dose
Hold until recovery to grade 1, then resume.
Hold until recovery to grade 1 (platelets 75

x109/L), then resume.
Grade 3 neutropenia
Hold until recovery to grade 1 , then resume.
Grade 4 neutropenia
Hold until recovery to grade 1, then resume.
Grade 3 febrile neutropenia
Hold until resolution of fever and neutropenia to

grade 1. Hold until the ANC 1,500/mm3 and
fever has resolved. Then resume treatment.
See Section 7.3.2.1 for dose modifications for diarrhea and Section 7.3.2.2 for dose modifications
for nausea/vomiting.
7.0
6.10
Radiation Adverse Events

Side effects expected from radiation therapy include fatigue, rectal frequency, diarrhea, urinary
frequency, dysuria, loss of pubic hair, hyperpigmentation of the skin in the treatment field, lower
blood counts. Rare but possible side effects include small bowel obstruction, fistula, small bowel
ulceration, wet desquamation, infection, and urethral obstruction.
6.11
Adverse Events (AEs) and Serious Adverse Events (SAEs) Reporting Requirements
See Section 7.
DRUG THERAPY
Institutional participation in chemotherapy studies must be in accordance with the Medical
Oncology Quality Control guidelines stated in the RTOG Procedures Manual.
Radiation and chemotherapy should be initiated on a Monday or Tuesday 21 days of study
enrollment, with 5 days of consecutive treatment strongly encouraged. For the first week of
treatment, the capecitabine should be started the evening before the first radiation dose.
7.1
7.1.1
Treatment
Concurrent preoperative chemotherapy will begin on the first day of radiotherapy and
continue until the completion of radiation therapy. Capecitabine (825 mg/m2) will be
administered orally twice daily, and oxaliplatin (50 mg/m2) will be administered intravenously
weekly x 5 weeks. Dose calculations should be based upon actual body weight and not
modified for obesity. Dose calculations that deviate from the use of actual body weight will be
considered a major protocol violation. A summary of preoperative chemotherapy is provided in
table form below:
RTOG 0822
Agent
Dose
Capecitabine
Route
825 mg/m q12 hours
Schedule
st
oral
5 days per week during radiotherapy. The 1

dose will begin the evening prior to day 1 of RT.
Begin all subsequent weekly courses on Sunday
night, and end with Friday morning dose. Final
dose of capecitabine is administered on the
morning of the final radiation dose. If radiotherapy
is held for administrative reasons (i.e., weekday
holiday), capecitabine dose for that day will also
be held.
IV over 2
hours
Weekly x 5; days 1, 8, 15, 22, 29
(1650 mg/m /day)

Please refer to
capecitabine dosing
table in Appendix V
for capecitabine
dosing.
Oxaliplatin
50 mg/m
If any chemotherapy dose is missed, it should be documented as such and no effort will be made to make
up the missed dose.
7.1.2
Postoperative chemotherapy will be administered to all patients who have a complete

resection of rectal cancer with negative surgical margins and will begin no earlier than 4 and no
later than 8 weeks following surgical resection. Patients with unresectable disease or involved
margins will discontinue protocol therapy.
Postoperative chemotherapy will consist of a total of 9 cycles (each cycle = 14 days) of 5fluorouracil, leucovorin, and oxaliplatin (FOLFOX). The dose, route, and schedule of FOLFOX
delivery is summarized for ease of reference in table form below.
7.1.3
Agent
Dose
Oxaliplatin*
85 mg/m
Leucovorin*
400 mg/m
5-fluorouracil bolus*
400 mg/m
5-fluorouracil
infusion*
2400
mg/m
Route
Schedule
IV over 2 hours
Day 1, every 14 days
IV over 2 hours
IV push
IV continuous infusion over 46
Beginning day 1, every 14
hours
days
*Administer sequentially as written, except oxaliplatin and leucovorin may be administered

concurrently
If any chemotherapy dose is missed, it should be documented as such and no effort will be made to
make up the missed dose.
7.2
7.2.1
7.2.1.1
7.2.1.2
7.2.1.3
7.2.1.4
Study Agents
Drug accountability records must be maintained at all sites according to good clinical
practices and NCI guidelines.
Capecitabine: Refer to package insert for additional information.
Other names
Xeloda
Classification
Antimetabolite, cytotoxic.
Mode of action
Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally
administered systemic prodrug of 5-deoxy-5-fluorouridine (5-DFUR) that is converted to 5fluorouracil.
Storage and stability
RTOG 0822
7.2.1.5
7.2.1.6
7.2.1.7
7.2.1.8
7.2.1.9
7.2.2
7.2.2.1
7.2.2.2
7.2.2.3
Capecitabine should be stored at room temperature, excursions permitted to 15 to 30C (59

to 86F), with container tightly closed.
Administration
Tablets should be swallowed with water 30 minutes after the end of a meal (breakfast and
dinner). If necessary, tablets can be crushed.
Availability
Capecitabine is supplied as a biconvex, oblong film-coat tablets for oral administration. Each
light-peach colored tablet contains 150 mg capecitabine, and each peach colored tablet
contains 500 mg capecitabine.
Supply
Commercially available. The use of drug(s) or combination of drugs in this protocol meet the
criteria described under Title 21 CFR 312.2(b) for IND exemption.
Adverse Events
Blood: neutropenia, coagulation disorder, idiopathic thrombocytopenic purpura,
pancytopenia
Cardiac: angina pectoris, cardiomyopathy
Constitutional Symptoms: Fatigue
Dermatologic: Hand-foot syndrome (painful erythema and swelling of the hands and/or feet),
increased sweating, photosensitivity, radiation recall syndrome, skin pigmentation changes
(hyperpigmentation), alopecia, dry skin
Gastrointestinal: Diarrhea, nausea, vomiting, anorexia, stomatitis, intestinal obstruction,
rectal bleeding, GI hemorrhage, esophagitis, gastritis, colitis, duodenitis, hematemesis,
necrotizing enterocolitis, taste changes
Hepatobiliary: hepatic fibrosis, cholestatic hepatitis, hepatitis
Infections: fever, oral candidiasis, upper respiratory tract infection, urinary tract infection,
bronchitis, pneumonia, sepsis, bronchopneumonia, gastroenteritis, gastrointestinal
candidiasis, laryngitis, esophageal candidiasis
Immune System: drug hypersensitivity
Hepatobiliary: hepatic fibrosis, cholestatic hepatitis, hepatitis
Metabolism: cachexia, hypertriglyceridemia
Musculoskeletal: bone pain, joint stiffness
Neurological: ataxia, encephalopathy, depressed level of consciousness, loss of
consciousness
Ophthalmic: eye watering, eye irritation
Psychiatric: confusion
Renal and Urinary: nocturia
Respiratory: dyspnea, epistaxis, bronchospasm, respiratory distress
Vascular: hypotension, venous phlebitis and thrombophlebitis, deep venous thrombosis,
lymphoedema, pulmonary embolism, cerebrovascular accident
Drug Interactions
Sorivudine and brivudin: A metabolite of these investigational antiviral agents, 5bromovinyluracil, is a potent inhibitor of dihydropyrimidine dehydrogenase, the enzyme that
catabolizes 5-FU. Patients should not receive concurrent therapy with either of these
antiviral agents while receiving capecitabine.
Phenytoin: Increased phenytoin plasma concentrations have been reported during
concomitant use of capecitabine with phenytoin, suggesting a potential interaction.
Patients taking phenytoin concomitantly with capecitabine should be regularly monitored for
increased phenytoin plasma concentrations and associated clinical symptoms
Oxaliplatin: Refer to package insert for additional information.
Other Names
Eloxatin,
trans-l-diamino
cyclohexane
oxaliplatin,
cis-[oxalato(trans-l-1,2-diamino
cyclohexane)platinum(II)]/-OHP, Eloxatine , Dacplat, SR96669.
Classification
Alkylating agent. Cytotoxic.
Mode of Action
10
RTOG 0822
The mechanism of action of oxaliplatin is similar to cisplatin. The main site of action is
intrastrand cross-linking, therefore inhibiting DNA replication and transcription.
7.2.2.4 Storage and Stability
Oxaliplatin vials are stored at room temperature between 20 and 25C. Reconstituted solution
in sterile water or 5% dextrose may be stored and will remain stable for 24 hours at 2-8C
(36-46F).
7.2.2.5 Preparation
Reconstitute with 10 mL for 50 mg and 20 mL for 100 mg product sterile water or 5% dextrose
to provide an initial concentration of 5 mg/mL. Subsequent dilution with 250-500 mL 5%
Dextrose.
7.2.2.6 Administration
The diluted solution of oxaliplatin in 250 ml 5% dextrose is administered IV by an infusion pump
over 2 hours.
7.2.2.7 Incompatibilities
Do not mix or administer with saline or other chloride containing solutions. Oxaliplatin is
unstable in the presence of chloride. Oxaliplatin may be administered simultaneously with
leucovorin by the same infusion line, provided that they are reconstituted in D5W. Do not mix
with alkaline solutions. Oxaliplatin is unstable under alkaline conditions. Do not use
components containing aluminum for the preparation of oxaliplatin administration. There is a
risk of drug degradation when in contact with aluminum.
7.2.2.8 Availability
Freeze-dried powder for IV infusion in vials containing 50 mg or 100 mg of oxaliplatin. The
powder is a white to off-white cake or powder contained in clear glass vials, sealed with an
elastomeric stopper and aluminum seal with a flip-off cover. The excipient is lactose
monohydrate, 450 mg and 900 mg respectively.
7.2.2.9 Supply
Commercially available. The use of drug(s) or combination of drugs in this protocol meet the
criteria described under Title 21 CFR 312.2(b) for IND exemption.
7.2.2.10 Adverse Events
Allergy/Immunology: Allergic/Hypersensitivity reactions (including drug fever)
Auditory: Middle ear/hearing (ototoxicity, mild), inner ear/hearing (mild hearing loss)
Blood/Bone Marrow: decreased hemoglobin, hemolysis (e.g. immune hemolytic anemia,
drug-related hemolysis), decreased leukocytes, decreased platelets, neutropenia
Cardiovascular (Arrhythmia): Sinus tachycardia, supraventricular arrhythmias (SVT/atrial
fibrillation/flutter),
ventricular
arrhythmias
(PVCs/
bigeminy/trigeminy/ventricular
tachycardia)
Edema,
hypertension,
phlebitis
(superficial),
Cardiovascular
(General):
thrombosis/embolism (including pulmonary embolism)
Coagulation: DIC (Disseminated intravascular coagulation)
Constitutional Symptoms: Fever (in the absence of neutropenia), weight loss, fatigue
(lethargy, malaise, asthenia)
Dermatology/Skin: Erythema or skin eruptions, alopecia, injection site reaction,
rash/desquamation
Endocrine: Hot flashes/flushes
Gastrointestinal: Anorexia, constipation, dehydration, dysphagia, diarrhea, esophagitis,
odynophagia (painful swallowing), gastrointestinal reflux, enteritis, ascites (NOS), intestinal
obstruction, stomatitis/pharyngitis (oral/pharyngeal mucositis), taste disturbance
(dysgeusia), nausea, vomiting, colitis, ileus (or neuroconstipation), typhilitis
Hepatic: Increased alkaline phosphatase, increased bilirubin, increased GGT (gammaglutamyl-transpeptidase), hepatic enlargement, increased AST (AST) (serum glutamic
oxaloacetic transaminase), increased SGPT (ALT) (serum glutamic pyruvic transaminase).
Veno-occlusive disease of the liver has been reported with the administration of the
combination of 5-FU and oxaliplatin.
Hemorrhage: CNS hemorrhage/bleeding, hemoptysis, hemorrhage/bleeding with grade 3 or
4 thrombocytopenia, melena/GI bleeding, rectal bleeding/hematochezia, other (hemorrhage
NOS)
11
RTOG 0822
7.2.3
7.2.3.1
7.2.3.2
7.2.3.3
7.2.3.4
7.2.3.5
7.2.3.6
7.2.3.7
7.2.3.8
7.2.3.9
Infection/Febrile Neutropenia: Febrile neutropenia (fever of unknown origin without clinically

or microbiologically documented fever (ANC < 1.0 x 10e9/L, fever > 38.5C) infection
(documented clinically or micro-biologically with grade 3 or 4 neutropenia (ANC < 1.0 x
10e9/L), infection without neutropenia
Metabolic/Laboratory: Acidosis (metabolic or respiratory) hyperuricemia, hypokalemia,
hypophosphatemia, hyponatremia, hypocalcemia, hypomagnesemia, hyponatremia
Musculoskeletal: Involuntary muscle contractions
Neurology: Ataxia (incoordination, including abnormal gait) insomnia, mood alteration
(depression, anxiety) neuropathy cranial (ptosis), vertigo, neuropathy sensory (including
acute laryngeo-pharyngeal dysesthesias, LHermittes sign, paresthesia)
Ocular/Visual: Conjunctivitis, vision abnormalities (including blindness, optic neuritis,
papilledema, hemianopsia, visual field defect, transient blindness
Pain: abdominal pain or cramping, arthralgia (joint pain), bone pain, chest pain (non-cardiac
and non-pleuritic), headache (including migraine), myalgia (muscle pain including cramps
and leg cramps)
Pulmonary: Pulmonary fibrosis, cough, dyspnea (shortness of breath), hiccoughs (hiccups,
singultus), pneumonitis/pulmonary infiltrates (including eosinophilic pneumonia, interstitial
pneumonitis, and interstitial lung disease), laryngospasm
Renal/Genitourinary: Increased creatinine, renal failure, urinary retention
5-Fluorouracil: Refer to package insert for additional information.

Other Names
5-FU, Adrucil, Efudex.
Classification
Antimetabolite.
Mode of Action
Fluorouracil is a pyrimidine antagonist that interferes with nucleic acid biosynthesis. The
deoxyribonucleotide of the drug inhibits thymidylate synthetase, thus inhibiting the formation of
thymidylic acid from deoxyuridylic acid, thus interfering in the synthesis of DNA. It also
interferes with RNA synthesis.
Storage and Stability
Stable for prolonged periods of time at room temperature, if protected from light. Inspect for
precipitate; if apparent, agitate vial vigorously or gently heat to not greater than 140F in a
water bath. Do not allow to freeze.
Administration
5-FU will be administered as an IV bolus and as a 46-hour infusion.
Availability
Available in 500 mg/10 ml ampules and vials, and 1 gm/20 ml, 2.5 gm/50 ml, and 5 gm/100 ml
vials.
Supply
Commercially available.
Adverse Events
Cardiac: Angina, noted with continuous infusion
Constitutional: Fatigue
Dermatologic: Dermatitis, nail changes, hyperpigmentation, Hand-Foot Syndrome with
protracted infusions, alopecia
Gastrointestinal: Nausea, vomiting, anorexia, diarrhea, can be dose limiting; mucositis, more
common with 5-day infusion, occasionally dose limiting; severe, cholera-like diarrhea which
can be fatal when given with leucovorin; taste changes
Hematologic: Leukopenia, thrombocytopenia, anemia, can be dose limiting; less common
with continuous infusion
Hepatic: Hepatitis with hepatic infusion
Veno-occlusive disease of the liver has been reported with the administration of the
combination of 5-FU and oxaliplatin.
Neurologic: Cerebellar Syndrome (headache and cerebellar ataxia)
Ophthalmic: Eye irritation, nasal discharge, watering of eyes, blurred vision
Drug Interactions
12
RTOG 0822
Allopurinol: Oxypurinol, a metabolite of allopurinol, can potentially interfere with 5-FU

anabolism via orotate phosphoribosyltransferase. Although this was originally used as a
strategy to protect normal tissues from 5-FU-associated toxicity, further laboratory studies
suggested possible antagonism of the anticancer activity of 5-FU in some tumor models. If a
patient is receiving allopurinol, the need for taking this medicine should be ascertained. If
possible, allopurinol should be discontinued prior to starting on this regimen, and another
agent substituted for it.
Cimetidine: Because cimetidine can decrease the clearance of 5-FU, patients should not
enter on this study until the cimetidine is discontinued. Ranitidine or a drug from another antiulcer class can be substituted for cimetidine, as necessary.
7.2.4
7.2.4.1
Leucovorin Calcium: Refer to package insert for additional information.

Other Names
Leucovorin, Wellcovorin citrovorum factor, folinic acid, 5-formyl tetrahydrofolate, LV, LCV.
7.2.4.2 Classification
Tetrahydrofolic acid derivative.
7.2.4.3 Mode of Action
Leucovorin acts as a biochemical cofactor for 1-carbon transfer reactions in the synthesis of
purines and pyrimidines. Leucovorin does not require the enzyme dihydrofolate reductase
(DHFR) for conversion to tetrahydrofolic acid. The effects of methotrexate and other DHFRantagonists are inhibited by leucovorin. Leucovorin can potentiate the cytotoxic effects of
fluorinated pyrimidines (i.e., fluorouracil and floxuridine). After 5-FU is activated within the cell, it
is accompanied by a folate cofactor, and inhibits the enzyme thymidylate synthetase, thus
inhibiting pyrimidine synthesis. Leucovorin increases the folate pool, thereby increasing the
binding of folate cofactor and active 5-FU with thymidylate synthetase.
7.2.4.4 Storage and Stability
All dosage forms are stored at room temperature. The reconstituted parenteral solution, 10
mg/ml, is stable for at least 7 days at room temperature. At concentrations of 0.5-0.9 mg/ml the
drug is chemically stable for at least 24 hours at room temperature under normal laboratory
light.
7.2.4.5 Preparation
The 50 and 100 mg vials for injection are reconstituted with 5 and 10 ml of sterile water or
bacteriostatic water, respectively, resulting in a 10 mg/ml solution. The 350 mg vial is
reconstituted with 17 ml of sterile water resulting in a 20 mg/ml solution.
7.2.2.6 Compatibilities
Leucovorin (0.5-0.9 mg/ml) is chemically stable for at least 24 hours in normal saline, 5%
dextrose, 10% dextrose, Ringer's injection or lactated Ringer's injection. Leucovorin is also
compatible with fluorouracil and oxaliplatin.
7.2.4.7 Availability
Available in parenteral formulations (3 and 5 mg ampule; 50 mg, 100 mg and 350 mg vial).
7.2.4.8 Supply
Commercially available.
7.2.4.9 Adverse Events
Allergy/Immunology: Allergic/hypersensitivity reaction, urticaria
7.2.4.10 Drug Interactions: Leucovorin may potentiate the toxic effects of fluoropyrimidine therapy,
resulting, for example, in increased hematologic and gastrointestinal (diarrhea, stomatitis)
adverse effects.
7.3
PREOPERATIVE Dose Modifications
7.3.1 Hematologic Toxicity (Preoperative)
7.3.1.1 All adverse events should be graded according to the Common Terminology Criteria for Adverse
Events (Version 3.0). The final dose modification according to the following tables should be
based upon the worst grade of adverse event experienced.
7.3.1.2 If any of the treatment agents is held or discontinued for toxicity or intolerance, patients may
continue on study with the remaining agents unless otherwise specified.
7.3.1.3 Held doses of capecitabine and/or oxaliplatin will not be made up at a later date. If more than
one dose reduction applies, then use the most stringent (i.e., the greatest dose reduction). Doses
that are reduced at any point during a cycle will not be re-escalated.
7.3.1.4 Grade 1 toxicities will not result in dose modifications
13
RTOG 0822
7.3.1.5 Preoperative dose levels are as follows:

Capecitabine*
Oxaliplatin
1650 mg/m2/day
50 mg/m2/week
Start Level
2
1237 mg/m /day
40 mg/m2/week
Level -1
2
825 mg/m /day
32 mg/m2/week
Level -2
*Refer to capecitabine dosing table in Appendix V for capecitabine reduction doses.
If the patient requires dose reductions lower than level -2 protocol therapy should be
discontinued.
7.3.1.6 For hematologic toxicities listed below, in the case where there are concurrent toxicities, dose
modification should follow the most stringent management (dose levels as defined earlier in this
section). Patients who have capecitabine held should have oxaliplatin held until capecitabine is
restarted. Patients may continue on radiation treatment as clinically indicated. (See Section 6.9
for XRT Dose Modifications)
Toxicity
Grade 2
thrombocytopenia
Grade 3
thrombocytopenia)
Grade 4
thrombocytopenia
Grade 3 neutropenia
Grade 4 neutropenia
Grade 3 febrile
neutropenia
Capecitabine Dose
Oxaliplatin Dose
Modification
Modification
Continue at current
dose
Hold until recovery
to grade 1, then
resume one dose
level lower.
Hold until recovery
to grade 1, then
resume one dose
level lower.
Hold until recovery
to grade 1, then
resume one dose
level lower.
Hold until recovery
to grade 1, then
resume one dose
level lower.
Hold until resolution
of fever and
neutropenia to
grade 1. Hold until
the ANC
1,500/mm3 and
fever has resolved.
Then resume at the
next lower dose
level.
Continue at current
dose
Hold until recovery
to grade 1, then
resume one dose
level lower.
Hold until recovery
to grade 1, then
resume one dose
level lower.
Hold until recovery
to grade 1, then
resume one dose
level lower.
Hold until recovery
to grade 1, then
resume one dose
level lower.
Hold until resolution
of fever and
neutropenia to
grade 1. Hold until
the ANC
1,500/mm3 and
fever has resolved.
Then resume at the
next lower dose
level.
7.3.1.7 Capecitabine-Induced Hyperbilirubinemia (Preoperative)

Capecitabine is known to cause hyperbilirubinemia. Please follow the table below for instructions
regarding management of hyperbilirubinemia. Patients with > grade 2 hyperbilirubinemia should
14
RTOG 0822
be evaluated with radiologic study for biliary obstruction. Patients who have capecitabine held for
hyperbilirubinemia may continue on radiation therapy and oxaliplatin as clinically indicated.
Hyperbilirubinemia Grade
Capecitabine Adjustment
Grade 1
Continue capecitabine
Grade 2
Hold capecitabine until grade <1, then restart

capecitabine at current dose
Grade 3

Grade 4

7.3.2 Nonhematologic Toxicity (Preoperative)

7.3.2.1 Diarrhea (Preoperative)
7.3.2.1.1 Capecitabine can cause diarrhea and must be stopped if diarrhea is grade 3. Diarrhea must
be managed symptomatically. IV hydration and use of loperamide, as well as close observation,
are recommended for diarrhea. For loperamide dosage recommendation and treatment start, see
below. If control takes longer than 2 days, medical evaluation including relevant diagnostic
procedures, alternative treatment, and possible investigation of DPD deficiency should be
considered. Capecitabine cannot be re-started until diarrhea has resolved to grade < 2 with the
last loperamide dose given at least 24 hours beforehand. The recommended dosage regimen for
loperamide: 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is
diarrhea free for at least 12 hours. During the night, the patient may take 4 mg of loperamide
every 4 hours. Note: This dosage regimen exceeds the usual dosage recommendations for
loperamide. Premedication with loperamide is not recommended.
7.3.2.1.2 The use of drugs with laxative properties should be avoided because of the potential for
exacerbation of diarrhea. Patients should be advised to contact their physician to discuss any
laxative use.
7.3.2.1.3 Patients with grade 3 diarrhea should also be evaluated for C. difficile colitis.
7.3.2.1.4 Patients with neutropenia and diarrhea should be considered for empiric use of prophylactic
antibiotics such as oral quinolones.
7.7.2.1.5 Dose modifications for diarrhea are summarized in table form below:
Grade Diarrhea (stool number
is over pretreatment number
of stools)
Capecitabine
Oxaliplatin
XRT
Grade 1
Maintain dose, institute

supportive care for
diarrhea
Maintain dose
Maintain dose
Grade 2
Maintain dose, institute

supportive care for
diarrhea if not already
instituted
Maintain dose
Maintain dose
15
RTOG 0822
Grade 3
Hold until Grade < 1, then

restart capecitabine one
dose level lower.
Hold until Grade < 1,

then restart
oxaliplatin one dose
level lower
If grade 3 diarrhea
for > 4 days, hold
until Grade < 1, then
restart.
Grade 4
Hold until Grade < 1, then

restart capecitabine one
dose level lower.

then restart
oxaliplatin one dose
level lower. .

then restart.
7.3.2.2 Nausea and/or Vomiting (Preoperative)

The prophylactic administration of 5-HT3 antagonists (granisetron, ondansetron or variants) with
corticosteroids (e.g. dexamethasone) is highly recommended for primary prevention and
treatment of oxaliplatin-induced emesis. The dose of each agent is left to the discretion of each
investigator.
Secondary treatment and prophylaxis: Patients must be supplied with antiemetics at the initiation
of study treatment. The choice and dose of anti-emetics will be determined by the treating
physician. Anti-emetics should be initiated at the onset of symptoms and continued as directed
by the treating physician until resolution of symptoms to grade 0-1. Additional supportive care
measures, e.g. oral or intravenous rehydration, etc., should be instituted as required by the
patients clinical condition. Additional medical evaluation is recommended for those patients with
continued nausea/vomiting > grade 2, lasting > 48 hours despite institution of optimal supportive
care measures. Secondary prophylaxis must be initiated once nausea or vomiting has occurred if
initial primary prophylaxis was not initially employed. Dose modification is not required if primary
prophylaxis was not initiated as recommended in the protocol. Recurrent episodes of > grade 2
nausea/vomiting despite institution of optimal supportive care and prophylaxis should receive
dose reductions as outlined below.
Grade Nausea and/or

Vomiting (despite
adequate prophylaxis)
Grade 1
Grade 2
Grade 3
Grade 4
Capecitabine
Oxaliplatin
XRT
Maintain dose
Maintain dose
Hold until grade < 1, then
restart one dose level lower
restart two dose levels lower
Maintain dose
Maintain dose
restart one dose level lower
restart two dose levels lower
Maintain dose
Maintain dose
Maintain dose
Maintain dose
7.3.2.3 Capecitabine-Induced Hand Foot Skin Reaction (Preoperative)

Capecitabine dose adjustments for hand-foot skin reaction are listed below
Toxicity
Grade
1
2
3
Capecitabine Dose Adjustment

Maintain dose
Interrupt until grade 1. May then restart capecitabine at full dose. For second
occurrence, hold capecitabine until grade 1, then restart capecitabine one dose
level lower.
Interrupt until grade 1. Then restart capecitabine one dose level lower.
16
RTOG 0822
7.3.2.4 Oxaliplatin-Induced Neuropathy (Sensory) [Preoperative]

The table below summarizes the assessment, classification and dose modifications to be made
for oxaliplatin induced neuropathy.
Neurological Toxicity Scale for Oxaliplatin Dose Adjustments

Duration of Toxicity
Grade
Grade 1
Grade 2
Grade 3
1-7 Days
Maintain dose
Maintain dose
Maintain dose
Grade 4
Hold until grade 1, then

reduce one dose level.
7.3.2.4.1
> 7 Days
Maintain dose
Maintain dose
Acute Oxaliplatin-Induced Laryngopharyngeal Dysesthesia
An unusual laryngopharyngeal dysesthesia (LPD), a loss of sensation of breathing without any

objective evidence of respiratory distress (laryngospasm, bronchospasm or hypoxia), has been
observed. This neurotoxicity may be induced or exacerbated upon exposure to cold and should
be distinguished from a hypersensitivity reaction. If a patient develops LPD, the patients oxygen
saturation should be evaluated via a pulse oximeter and, if normal, reassurance that the LPD will
resolve itself, a benzodiazepine or other anxiolytic agent should be considered and the patient
should be observed in the clinic until the episode has resolved. The oxaliplatin infusion may then
be continued at a reduced rate, 33% of the original rate. Because this syndrome may be
associated with the rapidity of oxaliplatin infusion, subsequent doses of oxaliplatin should be
administered as 6-hour infusions. To minimize the risk of LPD, patients will be instructed to avoid
ice and cold drinks the day of treatment
7.3.2.5 Oxaliplatin-Induced Hypersensitivity Reactions (Preoperative)
Oxaliplatin, as is the case with all platinum-containing compounds, is associated with a
measurable (approximately 11%) incidence of hypersensitivity reactions, usually after multiple
doses of treatment. This may present as bronchospasm, hypotension, and even hemolytic
anemia. Pretreatment with glucocorticoids and antihistamines may be useful for some patients
but may not always prevent the development of anaphylactoid reactions, especially in patients
with a prior history of hypersensitivity to this agent. For patients who have experienced a Grade 1
or 2 acute hypersensitivity reaction that is assessed as related to oxaliplatin administration, the
following premedication is recommended prior to each subsequent dose of oxaliplatin (patients
who have grade 3 or 4 acute hypersensitivity reactions should discontinue oxaliplatin therapy):
Dexamethasone 20 mg PO or IV, 12 and 6 hours prior to the oxaliplatin dose;
Dexamethasone 20 mg PO or IV, as well as diphenhydramine 50 mg IV, and one of the

following: ranitidine 50 mg IV, or famotidine 20 mg IV 30-60 minutes prior to oxaliplatin
administration.
If these prophylactic measures fail to prevent oxaliplatin-related hypersensitivity, therapy with

oxaliplatin should be discontinued. Patients may continue on capecitabine and XRT as clinically
indicated. Patients who have oxaliplatin held for uncontrollable hypersensitivity may not restart
oxaliplatin at any time.
17
RTOG 0822
7.3.2.6 Oxaliplatin-Induced Pulmonary Fibrosis (Preoperative)

Oxaliplatin can be associated with a low risk of pulmonary fibrosis. If pulmonary fibrosis is
suspected, hold oxaliplatin. If pulmonary fibrosis is ruled out, oxaliplatin may be restarted. If
pulmonary fibrosis is diagnosed, discontinue oxaliplatin indefinitely.
7.4
7.4.1
POSTOPERATIVE Dose Modifications

Hematologic Toxicity (Postoperative)
7.4.1.1
Grade 1 toxicities will not result in dose modifications.
7.4.1.2
Postoperative dose levels are as follows:

Oxaliplatin
Leucovorin
Bolus 5-FU
Infusion 5-FU
Start Level
85 mg/m2
400 mg/m2
400 mg/m2
2400 mg/m2
Level -1
65 mg/m2
400 mg/m2
300 mg/m2
1800 mg/m2
Level -2
45 mg/m2
400 mg/m2
200 mg/m2
1200 mg/m2
If the patient requires dose reductions lower than level -2 protocol therapy should be discontinued.
7.4.1.3
Dose modifications are provided below; in the case where there are concurrent toxicities, dose
modification should follow the most stringent management.
Toxicity
Grade 2
Thrombocytopenia
Grade 3
Thrombocytopenia
Grade 4
Thrombocytopenia)
Grade 3 Neutropenia
Grade 4 Neutropenia
Grade 3/4 febrile
neutropenia
7.4.2
5-FU/Leucovorin Dose
Modification
Oxaliplatin Dose Modification
Hold until recovery to grade

1, then resume one dose
level lower.
level lower.
level lower.
level lower.
Hold until resolution of fever
and neutropenia to grade 1.
Hold until the ANC
1,500/mm3 and fever has
resolved. Then resume at the
next lower dose level. At
third recurrence of febrile
neutropenia, discontinue 5FU/leucovorin.
Hold until recovery to grade 1, then

resume one dose level lower.

Hold until resolution of fever and
neutropenia to grade 1. Hold until the
ANC 1,500/mm3 and fever has resolved.
Then resume at the next lower dose level.
At third recurrence of febrile neutropenia,
discontinue oxaliplatin.
Nonhematologic Toxicity (Postoperative)
7.4.2.1 Diarrhea (Postoperative)

7.4.2.1.1 5-FU can cause diarrhea and must be stopped if diarrhea is grade 3. Diarrhea must be
managed symptomatically. IV hydration and use of loperamide, as well as close observation, is
recommended for diarrhea For loperamide dosage recommendation and treatment start, see
below. If control takes longer than 2 days, medical evaluation including relevant diagnostic
procedures, alternative treatment, and possible investigation of DPD deficiency should be
18
RTOG 0822
considered. 5-FU cannot be re-started until diarrhea has resolved to grade < 2 with the last
loperamide dose given at least 24 hours beforehand.
7.4.2.1.2 The recommended dosage regimen for loperamide is 4 mg at the first onset of late diarrhea
and then 2 mg every 2 hours until the patient is diarrhea free for at least 12 hours. During the
night, the patient may take 4 mg of loperamide every 4 hours. Note: This dosage regimen
exceeds the usual dosage recommendations for loperamide. Premedication with loperamide is
not recommended.
7.4.2.1.3 The use of drugs with laxative properties should be avoided because of the potential for
exacerbation of diarrhea. Patients should be advised to contact their physician to discuss any
laxative use.
7.4.2.1.4 Patients with grade 3 diarrhea should also be evaluated for C. difficile colitis
7.4.2.1.5 Patients with neutropenia and diarrhea should be considered for empiric use of prophylactic
antibiotics such as oral quinolones.
7.4.2.1.6 Dose modifications of 5-FU/leucovorin and oxaliplatin for diarrhea are listed below:
Grade Diarrhea
(stool number is
over pretreatment
number of stools)
5-FU/Leucovorin
Oxaliplatin
Grade 1
Maintain dose, institute supportive

care for diarrhea
Maintain dose
Grade 2
Maintain dose, institute supportive

care for diarrhea
Maintain dose
Grade 3
Hold until Grade < 1, then restart

5-FU/leucovorin one dose level
lower. .

oxaliplatin one dose level lower.
Grade 4

5-FU/leucovorin one dose level
lower.

oxaliplatin one dose level lower.
7.4.2.2 Nausea and/or Vomiting (Postoperative)

The prophylactic administration of 5-HT3 antagonists (granisetron, ondansetron or variants) with
corticosteroids (e.g., dexamethasone) is highly recommended for primary prevention and
treatment of oxaliplatin-induced emesis. The dose of each agent is left to the discretion of each
investigator.
Secondary treatment and prophylaxis: Patients must be supplied with antiemetics at the initiation
of study treatment. The choice and dose of antiemetics will be determined by the treating
physician. Anti-emetics should be initiated at the onset of symptoms and continued as directed
by the treating physician until resolution of symptoms to grade 0-1. Additional supportive care
measures (e.g., oral or intravenous rehydration, etc.) should be instituted as required by the
patients clinical condition. Additional medical evaluation is recommended for those patients with
continued nausea/vomiting > grade 2, lasting > 48 hours despite institution of optimal supportive
care measures. Secondary prophylaxis must be initiated once nausea or vomiting has occurred if
initial primary prophylaxis was not initially employed. Dose modification is not required if primary
prophylaxis was not initiated as recommended in the protocol. Patients with recurrent episodes
of > grade 2 nausea/vomiting despite institution of optimal supportive care and prophylaxis should
receive dose reductions as outlined below.
19
RTOG 0822
Grade Nausea and/or

Vomiting (despite
adequate prophylaxis)
Grade 1
Grade 2
Grade 3
Grade 4
5-FU/Leucovorin
Oxaliplatin
Maintain dose
Maintain dose
Hold until grade < 1, then restart one
dose level lower
Hold until grade < 1, then restart two
dose levels lower
Maintain dose
Maintain dose
Hold until grade < 1, then restart one dose
level lower
Hold until grade < 1, then restart two dose
levels lower
7.4.2.3 Oxaliplatin-Induced Neuropathy (Sensory) [Postoperative]

The table below summarizes the assessment, classification, and dose modifications to be made
for oxaliplatin-induced neuropathy during postoperative FOLFOX.
Neurological Toxicity Scale for Oxaliplatin Dose Adjustments
Grade
Grade 1
Grade 2
Duration of Toxicity
1-7 Days
> 7 Days
Maintain dose
Maintain dose
Maintain dose
Maintain dose
Grade 3
Maintain dose
Grade 4
Hold until grade

0-1, then reduce
one dose level.
Hold until grade

0-1, then reduce
one dose level.
Hold until grade
0-1, then reduce
one dose level.
Persistent
Between Cyclesa
Maintain dose
Hold until grade 01, then reduce one
dose level.
dose level.
dose level.
Not resolved by the beginning of the next cycle.

7.4.2.3.1
Acute Oxaliplatin-Induced Laryngopharyngeal Dysesthesia

An unusual laryngopharyngeal dysesthesia (LPD), a loss of sensation of breathing
without any objective evidence of respiratory distress (laryngospasm, bronchospasm or
hypoxia), has been observed. This neurotoxicity may be induced or exacerbated upon
exposure to cold and should be distinguished from a hypersensitivity reaction. If a patient
develops LPD, the patients oxygen saturation should be evaluated via a pulse oximeter
and, if normal, reassurance that the LPD will resolve itself, a benzodiazepine or other
anxiolytic agent should be considered and the patient should be observed in the clinic
until the episode has resolved. The oxaliplatin infusion may then be continued at a
reduced rate, 33% of the original rate. Because this syndrome may be associated with
the rapidity of oxaliplatin infusion, subsequent doses of oxaliplatin should be administered
as 6-hour infusions. To minimize the risk of LPD, patients will be instructed to avoid ice
and cold drinks the day of treatment.
7.4.2.4 Oxaliplatin-Induced Hypersensitivity Reactions (Postoperative)

Oxaliplatin, as is the case with all platinum-containing compounds, is associated with a
measurable (approximately 11%) incidence of hypersensitivity reactions, usually after multiple
doses of treatment. This may present as bronchospasm, hypotension, and even hemolytic
anemia. Pretreatment with glucocorticoids and antihistamines may be useful for some patients
but may not always prevent the development of anaphylactoid reactions, especially in patients
with a prior history of hypersensitivity to this agent. For patients who have experienced a grade 1
or 2 acute hypersensitivity reaction that is assessed as related to oxaliplatin administration, the
following premedication is recommended prior to each subsequent dose of oxaliplatin (patients
who have grade 3 or 4 acute hypersensitivity reactions should discontinue oxaliplatin therapy):
20
RTOG 0822
Dexamethasone 20 mg PO or IV, 12 and 6 hours prior to the oxaliplatin dose;
Dexamethasone 20 mg PO or IV, as well as diphenhydramine 50 mg IV, and one of the

following: ranitidine 50 mg IV, or famotidine 20 mg IV 30-60 minutes prior to oxaliplatin
administration.
If these prophylactic measures fail to prevent oxaliplatin-related hypersensitivity, therapy with

oxaliplatin should be discontinued. Patients may continue on capecitabine and XRT as clinically
indicated. Patients who have oxaliplatin held for uncontrollable hypersensitivity may not restart
oxaliplatin at any time.
7.4.2.5 Veno-Occlusive Disease (VOD) [Postoperative]
Veno-occlusive disease is a very rare adverse event associated with the administration of the
combination of 5-FU and oxaliplatin. VOD disease is characterized by hepatomegaly, ascites, and
jaundice. Especially in patients without liver metastases, these signs and symptoms should
prompt consideration of VOD. A Doppler ultrasound showing reversal of portal blood flow or other
evidence of portal hypertension is suggestive of this diagnosis. In addition, standard clinical
practice for evaluation of VOD should include observation of liver and spleen size; history or
presence of gastrointestinal bleeding; and development of esophageal varices, ascites, bleeding,
or jaundice.
All patients on and off therapy who develop signs and symptoms suggestive of VOD should be
thoroughly evaluated and closely monitored/supported. If clinically warranted, 5-FU and
oxaliplatin should be discontinued.
7.4.2.6 Oxaliplatin-Induced Pulmonary Fibrosis (Postoperative)
Oxaliplatin can be associated with a low risk of pulmonary fibrosis. If pulmonary fibrosis is
suspected, hold oxaliplatin. If pulmonary fibrosis is ruled out, oxaliplatin may be restarted. If
pulmonary fibrosis is diagnosed, discontinue oxaliplatin indefinitely.
7.4.2.7 Other Nonhematologic Toxicities Not Mentioned Above (Postoperative)
If a toxicity is believed to be attributable to only one agent, then follow dose modifications below
for only that agent. If toxicity is thought to be attributable to more than one agent, then follow
dose modifications for all responsible agents as below. A dose modification chart is provided
below.
Nonhematologic
Toxicity*
Grade 0-1
Grade 2
Grade 3
Grade 4
5-FU/Leucovorin Dose Modification
Oxaliplatin Dose Modification
No change
If the toxicity is tolerable to the patient,
maintain the same dose. If the toxicity is
intolerable to patient, hold 5-FU/leucovorin
until recovery to grade 1, then
reintroduce at current dose.
If event returns to grade 2, hold 5FU/leucovorin until recovery to grade 1.
Then restart 5-FU/leucovorin at the next
lower dose level.
Hold until recovery to grade 1. Then
reintroduce 5-FU/leucovorin at the next
lower dose level.
reintroduce 5-FU/leucovorin at the two
dose levels lower.
No change
If the toxicity is tolerable to the patient,
maintain the same dose. If the toxicity is
intolerable to patient, hold oxaliplatin until
recovery to grade 1, then reintroduce at
current dose.
If event returns to grade 2, hold oxaliplatin until
recovery to grade 1. Then restart oxaliplatin
at the next lower dose level.
reintroduce oxaliplatin at the next lower dose
level.
reintroduce oxaliplatin at the two dose levels
lower. Can consider discontinuation of
oxaliplatin.
*Excluding alopecia, anorexia, and fatigue.
21
RTOG 0822
7.5
Modality Review
The Medical Oncology Co-Chair, Johanna Bendell, M.D., will perform a Chemotherapy
Assurance Review of all patients who receive or are to receive chemotherapy in this trial. The
goal of the review is to evaluate protocol compliance. The review process is contingent on timely
submission of chemotherapy treatment data as specified in Section 12.1. The scoring mechanism
is: Per Protocol/Acceptable Variation, Not Per Protocol, and Not Evaluable. A report is sent
to each institution once per year to notify the institution about compliance for each case reviewed
in that year.
Dr. Bendell will perform a Quality Assurance Review after complete data for 20 cases have been
received at RTOG Headquarters. Dr. Bendell will perform the next review after complete data for
the next 20 cases enrolled have been received at RTOG Headquarters. The final cases will be
reviewed within 3 months after this study has reached the target accrual or as soon as complete
data for all cases enrolled have been received at RTOG Headquarters, whichever occurs first.
7.6
Adverse Events (8/17/2011)

Beginning October 1, 2011 this study will utilize the Common Terminology Criteria for Adverse
Events (CTCAE) version 4.0 for AdEERS reporting of adverse events. A copy of the CTCAE v4.0
can be downloaded from the CTEP web site
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
All appropriate treatment areas should have access to a copy of the CTCAE v4.0. All AE
reporting on the study case report forms will continue to use CTCAE version 3.0.
All adverse events (AEs) as defined in the tables below will be reported via the AdEERs (Adverse
Event Expedited Reporting System) application accessed via the CTEP web site
(https://webapps.ctep.nci.nih.gov/openapps/plsql/gadeers_main$.startup).
Serious adverse events (SAEs) as defined in the tables below will be reported via AdEERs. Sites
also
can
access
the
RTOG
web
site
(http://www.rtog.org/ResearchAssociates/AdverseEventReporting.aspx) for this information.
In order to ensure consistent data capture, serious adverse events reported on AdEERs
reports also must be reported on an RTOG case report form (CRF). In addition, sites must
submit CRFs in a timely manner after AdEERs submissions.
7.6.1
Adverse Events (AEs)

Definition of an AE: Any unfavorable and unintended sign (including an abnormal laboratory
finding), symptom, or disease temporally associated with the use of a medical treatment or
procedure regardless of whether it is considered related to the medical treatment or procedure
(attribution of unrelated, unlikely, possible, probable, or definite). [CTEP, NCI Guidelines:
Expedited Adverse Event Reporting Requirements. December 2004.]
The following guidelines for reporting adverse events (AEs) apply to all NCI/RTOG research
protocols. AEs, as defined above, experienced by patients accrued to this protocol should be
reported on the AE section of the appropriate case report form (see Section 12.1). Note: AEs
indicated in the AdEERS Expedited Reporting Requirements in text and/or table in
Section 7.7 also must be reported via AdEERS.
NOTE: If the event is a Serious Adverse Event (SAE) [see next section], further reporting
will be required. Reporting AEs only fulfills Data Management reporting requirements.
7.6.2
Serious Adverse Events (SAEs)

All SAEs that fit any one of the criteria in the SAE definition below must be reported via
AdEERS within 24 hours of discovery of the event. Contact the CTEP Help Desk if
assistance is required.
22
RTOG 0822
Definition of an SAE: Any adverse drug experience occurring at any dose that results in any of
the following outcomes:
Death;
A life-threatening adverse drug experience;
Inpatient hospitalization or prolongation of existing hospitalization;
A persistent or significant disability/incapacity;
A congenital anomaly/birth defect.
Important medical events that may not result in death, be life threatening, or require
hospitalization may be considered an SAE drug experience, when, based upon medical
judgment, they may jeopardize the patient and may require medical or surgical intervention to
prevent one of the outcomes listed in the definition. [CTEP, NCI Guidelines: Expedited Adverse
Event Reporting Requirements. December 2004.]
Any late death (more than 30 days after last treatment) attributed to the protocol treatment
(possible, probable or definite) should be reported via AdEERS within 24 hours of discovery.
An expedited report, if applicable, will be required within 5 or 10 calendar days.
All supporting source documentation, if applicable or if being faxed to NCI, must be
properly labeled with the study/case numbers and the date of the adverse event and
must be faxed to the RTOG dedicated SAE FAX, 215-717-0990, before the five or tencalendar-day deadline to allow RTOG to comply with the reporting requirements of the
pharmaceutical company/companies supporting the RTOG trial. All forms (and supporting
source documentation) submitted to RTOG Headquarters must include the RTOG study/
case numbers; non-RTOG intergroup study and case numbers must be included, when
applicable. Submitted AdEERS Reports are forwarded to RTOG electronically via the AdEERS
system. Use the patients case number as the patient ID when reporting via AdEERS.
SAE reporting is safety related and separate and in addition to the Data Management
reporting requirements as outlined in the previous AE reporting section. Any event that
meets the above outlined criteria for an SAE but is assessed by the AdEERS System as
expedited reporting NOT required must still be reported for safety reasons and to fulfill
the obligations of RTOG to the pharmaceutical company/companies supporting the
RTOG trial. Sites must bypass the NOT Required assessment and complete and
submit the report. The AdEERS System allows submission of all reports regardless of
the results of the assessment. Note: Sites must print the AdEERS report and fax it to the
FDA, FAX 1-800-332-0178.
7.6.3
7.7
Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)

AML or MDS that is diagnosed during or subsequent to treatment in patients on NCI/CTEPsponsored clinical trials must be reported via the AdEERS system. If you are reporting in
CTCAE v 4, the event(s) may be reported as either: 1) Leukemia secondary to oncology
chemotherapy, 2) Myelodysplastic syndrome, or, 3) Treatment related secondary malignancy.
AdEERS Expedited Reporting Requirements
Phase 2 and 3 Trials Utilizing an Agent a Commercially Available Agent: AdEERS
Expedited Reporting Requirements for Adverse Events that Occur within 30 Days1 of the
Last Dose of the Investigational Agents in this Study
Grade 1
Grade 2
Grade 2
Unexpected
Unexpected
and
Expected
Expected
Unrelated
Unlikely
Not
Required
Not
Required
Grades
2
4&5
Grades
2
4&5
without
with
without
Hospitali- Hospitali- Hospitalization
zation
zation
Unexpected
Expected
10
Calendar
Days
10
Calendar
Days
10
Calendar
Days
Grade 3
Grade 3
Unexpected
Expected
with
Hospitalization
Not
10 Calendar
Required
Days
23
Not
Required
Not
Required
RTOG 0822
Possible
Probable
Definite
Not
Required
10 Calendar
Days
Not
10 Calendar
Required
Days
10
Calendar
Days
10
Calendar
Days
Not
Required
24-Hour;
5 Calendar
Days
10
Calendar
Days
Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of
treatment with a commercially available agent require reporting as follows:
AdEERS 24-hour notification followed by complete report within 5 calendar days for:
Grade 4 and Grade 5 unexpected events

AdEERS 10 calendar day report:
Grade 3 unexpected events with hospitalization or prolongation of hospitalization
Grade 5 expected events
Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full report is
required as outlined in the table.
Please see exceptions below under section entitled Additional Instructions or Exceptions.
March 2005
Note: All deaths on study require both routine and expedited reporting regardless of causality.
Attribution to treatment or other cause must be provided. On study is defined as during
or within 30 days of completing protocol treatment.
Expedited AE reporting timelines defined:
24 hours; 5 calendar days The investigator must initially report the AE via AdEERS within 24
hours of learning of the event followed by a complete AdEERS report within 5 calendar days
of the initial 24-hour report.
10 calendar days - A complete AdEERS report on the AE must be submitted within 10 calendar
days of the investigator learning of the event.
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or
prolongation of existing hospitalization) must be reported regardless of attribution and designation
as expected or unexpected with the exception of any events identified as protocol-specific
expedited adverse event reporting exclusions.
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or
birth defects must be reported via AdEERS if the event occurs following treatment with an agent
under a non-CTEP IND.
Use the NCI protocol number and the protocol-specific patient ID assigned during trial registration
on all reports.
Additional Instructions or Exceptions: None
8.0
SURGERY
8.1
Surgical Quality Assurance Reviews
A full surgical quality assurance review is required for this study. The review will be performed by
The Surgical Oncology Co-Chair, Adam Berger, M.D., after complete data for 20 cases have
been received at RTOG Headquarters. Dr. Berger will perform the next review after complete
data for the next 20 cases enrolled have been received at RTOG Headquarters. The final cases
will be reviewed within 3 months after this study has reached the target accrual or as soon as
complete data for all cases enrolled have been received at RTOG Headquarters, whichever
occurs first.
8.2
8.2.1
8.2.2
8.2.3
8.2.4
8.3
General Operative Evaluation

All patients will undergo surgery 4 to 8 weeks following the completion of radiation therapy. The
use and method of bowel preparation is at the discretion of the surgeon.
The surgeon will perform a thorough examination of the abdomen to detect for metastatic
disease, specifically in the liver, ovaries and peritoneal surfaces. Negative as well as positive
findings should be recorded in the operative report.
The finding at surgery of unexpected unresectable hepatic metastases or peritoneal seeding will
preclude radical resection of the primary unless at the discretion of the surgeon it is indicated for
local control and palliation.
If a patient has a solitary, unexpected liver metastasis that can be removed with a minimal
resection (i.e., wedge resection), this can be done at the surgeons discretion. Major
hepatectomy at the time of rectal resection is discouraged but not absolutely contraindicated.
Operative Procedure
24
RTOG 0822
8.3.1
8.3.2
8.3.3
8.3.4
8.3.5
8.3.6
8.3.7
8.4
8.4.1
8.4.2
8.4.3
9.0
The choice of procedure (abdominoperineal resection (APR), low anterior resection (LAR), or
LAR/coloanal anastomosis) is at the discretion of the surgeon. Total mesorectal excision (TME) is
strongly recommended and should be documented. En bloc hysterectomy, vaginectomy, and/or
multivisceral resection should be performed if felt to be indicated without violation of primary
tumor mass. The ureters should be identified bilaterally and preserved.
Techniques for anastomosis are at the discretion of the surgeon, as are use, placement, and
removal of pelvic drains.
APR will involve resection of the rectum and mesorectum from the perineum to the sacral
promontory. The distal left colon is divided with a linear stapler to prevent spillage of intraluminal
contents at a minimum of 5 cm proximal to the tumor mass in vivo (not required to be
documented ex vivo due to potential retraction). Closure of the perineum and use of pelvic
drain(s) is recommended.
For an LAR, the left colon is mobilized, with ligation of the inferior mesenteric artery and vein. The
distal left colon is divided with a linear stapler to prevent spillage of intraluminal contents at a
minimum of 5 cm proximal to the tumor mass in vivo (not required to be documented ex vivo due
to potential retraction). The rectum and mesorectum will be removed with a distal rectal margin of
at least 2 cm in vivo for sphincter preservation. Unirradiated colon from outside the pelvis should
be used for the anastomosis. If necessary, takedown of the splenocolic ligament should be
performed to ensure adequate length to reach the planned anastomosis without tension.
Diversion of fecal stream via ileostomy or colostomy in these patients will be left to the discretion
of the investigator.
If a LAR/coloanal anastomosis is performed, the entire left colon is mobilized, with ligation of the
inferior mesenteric artery and vein. The distal left colon is divided with a linear stapler to prevent
spillage of intraluminal contents at a minimum of 5 cm proximal to the tumor mass in vivo (not
required to be documented ex vivo due to potential retraction). A radical resection of the rectum
and mesorectum to the levators (distal rectal margin of at least 2 cm in vivo) is performed from
the abdominal incision. At the level of the anorectal ring, the muscular rectal wall is divided by
cautery and the specimen removed. The colon is brought into the anal canal and an anastomosis
performed to the dentate line with interrupted full-thickness sutures. Unirradiated colon from
outside the pelvis should be used for the anastomosis. If necessary, takedown of the splenocolic
ligament should be performed to avoid undue tension on the anastomosis. Use of pelvic drain(s)
is recommended. Temporary diversion of the fecal stream (through the formation of either an
ileostomy or transverse colostomy) should be performed. The temporary ostomy should not be
closed until at least 6-8 weeks after the completion of all cycles of postoperative chemotherapy.
Adequacy of bowel preparation (poor or adequate), presence or absence of liver/peritoneal
metastases, estimated proximal and distal in vivo surgical margins, use of TME, anastomotic
method, location of drains, need to takedown splenocolic ligament, and concomitant procedures
should be clearly documented in the operative report.
Laparoscopic rectal resection is allowed as long as all of the above mentioned criteria are met
and properly documented.
Surgical Pathology
The resected specimen is oriented for pathologic examination by placing a suture on the distal
anterior rectal wall. The pathologist should ink the specimen, prior to fixation, for radial margin
determination. See Appendix IV for specific details.
Separate biopsies of unresected tissue at the closest tumor margins may be taken to rule out
histologically residual tumor and submit in a separate bottle.
Biopsy of suspicious areas on the peritoneum, liver, or any other sites is recommended.
OTHER THERAPY
9.1
Permitted Supportive Therapy
9.1.1
A diverting colostomy without tumor resection is permitted prior to study entry when clinically
indicated.
9.1.2
All supportive therapy for optimal medical care will be given during the study period at the
discretion of the attending physician(s) within the parameters of the protocol and documented n
each sites source documents as concomitant medication.
Suggested supportive therapies are listed when appropriate in Sections 7 and 8.
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9.2
9.2.1
10.0
Non-Permitted Supportive Therapy

The use of cimetidine, amifostine and/or depot Sandostatin is not allowed on this protocol.
TISSUE/SPECIMEN SUBMISSION
10.1
Tissue/Specimen Submission
The RTOG Biospecimen Resource at University of California at San Francisco acquires and
maintains high quality specimens from RTOG trials. Tissue from each block is preserved through
careful block storage and processing. The RTOG encourages participants in protocol studies to
consent to the banking of their tissue. The RTOG Biospecimen Resource provides tissue
specimens to investigators for translational research studies. Translational research studies
integrate the newest research findings into current protocols to investigate important biologic
questions. The RTOG Biospecimen resource also collects tissue for Central Review of
pathology. Central Review of tissue can be for eligibility and/or analysis.
In this study, tissue will be submitted to the RTOG Biospecimen Resource for the purpose of
tissue banking (highly recommended).
10.2
Specimen Collection for Tissue Banking

For patients who have consented to participate in this component of the study (See
Appendix I).
The following must be provided in order for the case to be evaluable for the Tissue Bank:
10.2.1
Tissue
10.2.1.1 One H&E stained slide
10.2.1.2 A paraffin-embedded tissue block of the tumor or a 2 mm diameter core of tissue, punched from
the tissue block containing the tumor with a skin punch and submitted in a plastic tube labeled
with the surgical pathology number. NOTE: A kit with the punch, tube, and instructions can be
obtained free of charge from the Biospecimen Resource. Block or core must be clearly labeled
with the pathology identification number that corresponds to the Pathology Report.
10.2.1.3 A Pathology Report documenting that the submitted block or core contains tumor. The report
must include the RTOG protocol number and patients case number. The patients name and/or
other identifying information should be removed from the report. The surgical pathology
numbers and information must NOT be removed from the report.
10.2.1.4 A Specimen Transmittal Form clearly stating that tissue is being submitted for the RTOG
Biospecimen Resource.; if for translational research, this should be stated on the form. The
form must include the RTOG protocol number and patients case number.
10.2.1.5 Specimens should be taken from the original diagnostic biopsy ( 8 weeks prior to study entry)
and from surgical resection tissue
10.2.2
Blood
10.2.2.5 Peripheral blood will be collected at two time points: pre-treatment ( 28 days prior to study
entry) and on the last week of treatment and shipped using RTOG collection kits. Sites will
collect 5-10 mL of whole blood in a red-top tube and 5-10 mL of whole blood in EDTA tubes.
Red top tube is spun down for serum. EDTA tubes are spun for plasma and lymphocytes/buffy
coat cells. (See Appendix VII for detailed collection and shipping instructions). Collection kits
are available by contacting the RTOG Biospecimen Resource.(see contact information below).
Specimens should be sent with a Specimen Transmittal Form documenting the date of
collection of the serum; the RTOG protocol number, the patients case number, and method of
storage, for example, stored at -20 C, must be included. Questions regarding blood collection
or shipment should be directed to the RTOG Biospecimen Resource(see contact information
below). Ship by express overnight service, Monday through Thursday; avoid a weekend or
holiday arrival date, and DO NOT ship on Friday. Fedex labels will be supplied for sending
frozen materials.
26
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10.2.3 Summary of Specimens for Tissue Banking

Specimens taken from patient:
Collection Schedule:
Submitted as:
Shipped:
One H&E stained slide of the

primary tumor
From the original

diagnostic biopsy ( 8
weeks prior to study
entry) and from surgical
resection tissue
From the original
diagnostic biopsy ( 8
weeks prior to study
entry) and from surgical
resection tissue
H&E stained slide
Slide sent ambient
Paraffin-embedded
tissue block or punch
biopsy
Block or punch sent

ambient
5-10 mL of whole blood (red-top)

centrifuge for serum
28 days prior to study

entry and during the last
week of treatment
Serum samples into

four (4) 1 mL
cryovials
Frozen overnight
5-10 mL of anticoagulated blood

(EDTA) centrifuge for plasma
and buffy coat
28 days prior to study

entry and during the last
week of treatment
Plasma samples into

three (3) 1 mL
cryovials
Frozen overnight
A paraffin-embedded tissue
block of the primary tumor taken
before initiation of treatment or a
2 mm diameter core of tissue,
punched from the tissue block
with a skin punch
Buffy coat samples

into three (3) 1 mL
cryovials
10.2.4
Submit materials to:

USPS mailing address (all non-frozen specimens only)
RTOG Biospecimen Bank
University of California San Francisco
Campus Box 1800
San Francisco, CA 94143-1800
FedX/Courier address (all frozen samples)

RTOG Biospecimen Bank
University of California San Francisco
1657 Scott Street, Room 223
San Francisco, CA 94115
415-476-RTOG (7864)
Tel:
Fax:
415-476-5271
Email: RTOG@ucsf.edu
10.3
Reimbursement
RTOG will reimburse submitting institutions $300 per case for fresh or flash frozen tissue, serum
or plasma, and buffy coat cells; and $200 per case for a block or core of material. After
confirmation from the RTOG Biospecimen Resource that appropriate materials have been
received, RTOG Administration will prepare the proper paperwork and send a check to the
institution. Pathology payment cycles are run twice a year in January and July and will appear on
the institutions summary report with the institutions regular case reimbursement.
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10.4
Confidentiality/Storage
(See
the
RTOG
Patient
Tissue
Consent
Frequently
Asked
Questions,
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspx
for
further details.)
10.4.1
Upon receipt, the specimen is labeled with the RTOG protocol number and the patients case
number only. The RTOG Biospecimen Resource database only includes the following
information: the number of specimens received, the date the specimens were received,
documentation of material sent to a qualified investigator, type of material sent, and the date
the specimens were sent to the investigator. No clinical information is kept in the database.
10.4.2
Specimens for tissue banking will be stored for an indefinite period of time. If at any time the
patient withdraws consent to store and use specimens, the material will be returned to the
institution that submitted it.
11.0
PATIENT ASSESSMENTS
11.1
Study Parameters: See Appendix II for a summary of assessments and time frames.
11.2
Criteria for Evaluation and Endpoint Definitions
11.2.1
Measurement of the incidence of preoperative toxicity
11.2.1.1
Preoperative toxicity will be assessed based on CTCAE v3.0 criteria on a weekly basis
during preoperative chemoradiation and within 14 days prior to surgical resection (for
patients undergoing surgery) or 6-8 weeks from radiotherapy completion (for patients not
undergoing surgery).
11.2.2
Measurement of the incidence of postoperative toxicity
Postoperative toxicity will be assessed based on CTCAE v3.0 criteria in the postoperative
period following preoperative chemoradiation and surgical resection. Assessments will be
made as per the study schedule found in Appendix II.
11.2.3
Documentation of Tumor Response and Incidence and Patterns of Relapse
11.2.3.1
Pathologic complete response: No evidence of residual cancer histologically in the resection
specimen.
11.2.3.2
Local failure: recurrence or persistence of disease within radiation treatment volumes.
Persistent disease is defined as either: (1) micro- or macroscopic margins following surgery,
or (2) radiographically or intra-operatively unresectable at time of surgery as defined in
Section 8.2.
11.2.3.3
Regional failure: failure outside the treatment field on basis of direct and/or lymphatic spread
to include aortic nodes.
11.2.3.4
Distant failure: includes both peritoneal seeding and distant metastases to sites beyond
those described as locoregional per Sections 11.2.3.2 and 11.2.3.3.
11.2.3.5
Disease relapse: will be documented by biopsy whenever possible. When biopsy is
impossible or poses significant risk, clinical and radiographic evidence will be used to
document recurrence
11.3
Criteria for Discontinuation of Protocol Treatment

Progression of disease;
A delay in protocol treatment > 4 weeks;
Positive margin at time of surgery;
Unresectable disease at time of surgery.
If protocol treatment is discontinued, follow-up and data collection will continue as specified in the
protocol.
12.0
DATA COLLECTION
Data should be submitted to:
RTOG Headquarters*
1818 Market Street, Suite 1600
Philadelphia, PA 19103
*If a data form is available for web entry, it must be submitted electronically.
28
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Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will be
used (first-last). Last names with apostrophes will be identified by the first letter of the last name.
12.1
Summary of Data Submission
Item
Demographic Form (A5)
Initial Evaluation Form (I1)
Pathology Report (P1)
Slides/Blocks (P2)
Due
Within 2 weeks of study entry
Radiotherapy Form (T1) [Copy to ITC]

Daily Treatment Record (T5) [Copy to ITC]
Within 1 week of RT end
Preoperative Chemo/RT Treatment Form (TF)
At the end of concurrent preoperative therapy
Postoperative Chemo/RT Treatment Form (SF)
3 times during postoperative chemotherapy (once

every 3 cycles)
Surgical Form (S1)

Operative Report (S2)
Surgical Pathology Report (S5)
Submit for all patients either 2 weeks after surgery

or at the time that surgery is ruled out. In addition,
complete this form for all subsequent surgical
procedures. Submit with copies of an operative
(S2) note and pathology (S5) report.
Follow-up Form (F1)
Every 3 mos from the start of treatment x 2 yrs;

every 6 mos for yrs 3-5; then annually
12.2
Summary of Dosimetry Digital Data Submission (Submit to ITC; see Section 12.2.1)
(3/30/10)
Item
Preliminary Dosimetry Information (DD)
Digital Data Submission Treatment Plan
submitted to ITC via SFTP account exported
from treatment planning machine by Physicist.
Digital data submission includes the following:
CT data, critical normal structures, all
GTV, CTV, and PTV contours
Digital beam geometry for initial and
boost beam sets
Doses for initial and boost sets of
concurrently treated beams
Digital DVH data for all required critical
normal structures, GTV, CTV, and PTVs
for total dose plan (DV)
Due
Within 1 week of RT start
Digital Data Submission Information Form (DDSI)

Submitted online (Form located on ATC web
site, http://atc.wustl.edu/forms/ddsi/ddsi.html)
Hard copy isodose distributions for total dose
plan (T6)
29
RTOG 0822
NOTE: Sites must notify ITC via e-mail

(itc@castor.wustl.edu) after digital data IS
submitted. The e-mail must include study and
case numbers or, if the data is phantom, dry
run or benchmark.
Within 1 week of RT end
Final Dosimetry Information

Radiotherapy Form (T1) [copy to HQ and ITC]
Daily Treatment Record (T5) [copy to HQ and
ITC]
Modified digital patient data as required through
consultation with Image Guided Therapy QA
Center
12.2.1
Digital Data Submission to ITC

Digital data submission may be accomplished using media or the Internet.
For network submission: The SFTP account assigned to the submitting institution by the ITC
shall be used, and e-mail identifying the data set(s) being submitted shall be sent to:
itc@castor.wustl.edu
For media submission: Please contact the ITC about acceptable media types and formats.
Hardcopies accompanying digital data should be sent by mail or Federal Express and should
be addressed to:
Image-Guided Therapy Center (ITC)
ATTN: Roxana Haynes
4511 Forest Park, Suite 200
St. Louis, MO 63108
314-747-5415
FAX 314-747-5423
13.0
STATISTICAL CONSIDERATIONS
13.1
Study Endpoints
13.1.1
Primary Endpoint
13.1.1.1
Grade 2 treatment-related gastrointestinal adverse events per CTCAE v. 3.0, occurring
preoperatively
13.1.2
Secondary Endpoints
13.1.2.1
IMRT feasibility (per criteria in Section 6.7)
13.1.2.2
pCR rate
13.1.2.3
All treatment-related adverse events for the following time periods:
13.1.2.3.1
The preoperative period
13.1.2.3.2
The postoperative period, up to 3 months after the completion of postoperative
chemotherapy
13.1.2.3.3
Overall
13.1.2.4
Patterns of failure (per Section 11.2.3), including overall survival (failure is death due to any
cause)
13.1.2.5
Correlation of pre- and post-treatment serum cytokines with adverse events and efficacy
13.1.2.6
Abdominoperineal Resections (APR) rate
13.2
Study Design
13.2.1
Sample Size Derivation
The primary objective of this study is to determine if IMRT, given with concurrent chemotherapy
(capecitabine and oxaliplatin), reduces the rate of grade 2 treatment-related gastrointestinal
adverse events (per CTCAE v. 3.0) occurring preoperatively, compared to the rate with
conventional radiation.
The rate of these adverse events from the conventional
radiation/capecitabine/oxaliplatin arm of RTOG 0247 was 40%. Using a chi-squared test, a
30
RTOG 0822
13.2.2
sample size of 71 patients will ensure at least 80% probability of detecting a minimum reduction
of 12% in the adverse events described above at a significance level of 0.10 (1-sided).
Adjusting this figure by 5% to allow for patients determined to be ineligible or who do not start
protocol treatment, a total sample size of 75 patients will be required for this study.
Patient Accrual
It is projected that there will be a period of approximately 6 months with very slow accrual at the
beginning of this study to allow for both institutional IRB approval and IMRT approval by the
RTOG QA Center. Following this initial period, it is projected that the study will accrue 4
patients/month (based on the most recent RTOG rectal study, RTOG 0247) and that accrual
will be completed in approximately 18 months. If the average monthly accrual is less than 2
cases per month 12 months after it is opened, the study will be re-evaluated with respect to
feasibility.
13.3
Suspension of Accrual Due to Excessive Rate of Adverse Events or Abdominoperineal

Resections
13.3.1 Unacceptable Rate of Adverse Events
The rate of unacceptable adverse events related to protocol treatment (grade 3 and 4 nonhematologic adverse events, excluding nausea/vomiting controllable with antiemetics, and
alopecia) will be evaluated at two time points during accrual: after 24 and 48 patients have
been entered and are evaluable and again on all evaluable patients after the study has finished
accrual. The study chairs have determined that a rate of 40% or greater will be considered
unacceptable. According to Flemings method15 with a maximum overall significance level of
0.05 if there are:
11 or more unacceptable adverse events out of the first 24 evaluable patients, or
16 or more unacceptable adverse events out of the first 48 evaluable patients,
13.3.2
13.3.3
the study will have exceeded the limit for unacceptable adverse events. The final analysis will
use a rejection rule of 22 or more unacceptable adverse events out of 71 evaluable patients. If
the number of unacceptable adverse events crosses a boundary, as described in the rules
above, then the conclusion will be that the unacceptable adverse event rate is greater than
40%. If this occurs, the study chairs, the RTOG Gastrointestinal Cancer Committee chair, and
the statistician will review the adverse event data and make appropriate recommendations
about the study to the RTOG Executive Committee. These stopping rules provide 90% power
for concluding that the unacceptable adverse event rate is equal to or exceeds 40% when in
fact that is the true rate.
Fatal Treatment Morbidity
If a fatal adverse event occurs (1) within 30 days of protocol treatment completion, regardless
of relationship to protocol treatment, or (2) at any time and is related to protocol treatment, the
event will be reported to the study chairs and the RTOG Gastrointestinal Cancer Committee
chair for review. At this time it will be determined if accrual to the trial must be suspended
pending this review for patient safety. The data manager will, after requesting additional
supporting documentation if necessary, have all documents scanned and transmitted
electronically to the study chairs and the head of the RTOG Data Safety Monitoring Board
(DSMB) for their review. This will take place within 2 weeks of each reported adverse event if
at all possible.
Unacceptable Rate of Abdominoperineal Resections(APRs)
The rate of unacceptable APRs will be evaluated at two time points during accrual: after 24 and
48 patients have been entered and are evaluable and again on all evaluable patients after the
study has finished accrual. The study chairs have determined that an APR rate of 50% or
greater will be considered unacceptable. According to Flemings method15 with a maximum
overall significance level of 0.05 if there are:
14 or more unacceptable adverse events out of the first 24 evaluable patients, or
21 or more unacceptable adverse events out of the first 48 evaluable patients,
the study will have exceeded the limit for APRs. The final analysis will use a rejection rule of 29
or more unacceptable adverse events out of 71 evaluable patients. If the number of
31
RTOG 0822
unacceptable APRs crosses a boundary, as described in the rules above, then the conclusion
will be that the APR rate is greater than 50%. If this occurs, the study chairs, the RTOG
Gastrointestinal Cancer Committee chair, and the statistician will review the APR data and
make appropriate recommendations about the study to the RTOG Executive Committee. These
stopping rules provide 95% power for concluding that the unacceptable adverse event rate is
equal to or exceeds 50% when in fact that is the true rate.
13.4
Analysis Plan
13.4.1
Interim Reports
Interim reports will be prepared every 6 months until the primary endpoint has been accepted
for presentation or publication. In general, these reports include:
the patient accrual rate with projected completion date,
institutional accrual,
exclusion rates and reasons,
pretreatment characteristics,
compliance rates of treatment delivery with respect to the protocol prescription, and
the frequency and severity of adverse events.
13.4.2
CDUS Reports
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0.
Cumulative CDUS data will be submitted quarterly by electronic means. Reports are due
January 31, April 30, July 31, and October 31.
13.4.3
Data Safety Monitoring Board (DSMB) Review
To monitor the safety of this study, the RTOG DSMB will officially review this study twice per
year in conjunction with the RTOG semi-annual meeting and on an as needed basis in
between meetings.
13.4.4
Analysis for Reporting the Initial Treatment Results
The analysis for reporting the initial primary endpoint results of treatment will be undertaken
when each patient has been potentially followed for a minimum of 12 months. Only patients
that meet the eligibility requirements of this protocol and start protocol treatment will be
included. The usual components of this analysis are:
tabulation of all cases entered and any patients excluded from the analysis with reasons for
exclusion,
patient accrual rate,
institutional accrual,
distribution of important prognostic baseline and other pretreatment variables,
frequency and severity of adverse events,
compliance rates of treatment delivery with respect to the protocol prescription, and
observed results with respect to the endpoints described in Section 13.1.
Patterns of failure will be reported at least 2 years after the last patient has been entered. Time
to local, regional, and distant failure and time to progression will be estimated using the
cumulative incidence method.16 Overall survival rates will be estimated using the Kaplan-Meier
method.17
13.5
Gender and Minorities

In conformance with the National Institutes of Health (NIH) Revitalization Act of 1993 with regard
to inclusion of women and minorities in clinical research, we have considered differences in
prognosis by race, ethnicity and gender. If the distributions allow, an exploratory statistical
analysis will be performed to examine the possible differences between the genders and among
the race and ethnicity categories.
Projected Distribution of Gender and Minorities

Ethnic Category
Females
32
Gender
Males
Total
RTOG 0822
Females
Gender
Males
3
25
28
4
43
47
75
American Indian or Alaskan Native

Asian
Black or African American
Native Hawaiian or other Pacific Islander
White
0
1
2
0
25
0
1
3
1
42
0
2
5
1
67
Racial Category: Total of all subjects
28
47
75
Ethnic Category
Hispanic or Latino
Not Hispanic or Latino
Ethnic Category: Total of all subjects
Total
7
68
Racial Category
33
RTOG 0822
REFERENCES
1. Gastrointestinal Tumor Study Group. Prolongation of the disease-free interval in surgically treated rectal
carcinoma. N Engl J Med 1985;312:1465-72.
2. Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma.
N Engl J Med 1991;324:709-15.
3. NIH consensus conference: adjuvant therapy for patients with colon and rectal cancer. JAMA 1990;264:144450.
4. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal
cancer. N Engl J Med 2004;351:1731-40.
5. Twelves C, S. Gollins S, Grieve R, et al. A randomised cross-over trial comparing patient preference for oral
capecitabine and 5-fluorouracil/leucovorin regimens in patients with advanced colorectal cancer. Ann Oncol
2006;17(2):239-45.
6. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl
J Med 2005;352(26):2696-704.
7. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol
Biol Phys 1991;21:109-122.
8. Mak AC, Rich TA, Schultheiss TE, et al. Late complications of postoperative radiation therapy for cancer of
the rectum and rectosigmoid. Int J Radiat Oncol Biol Phys 1994;28:597-603.
9. Gallagher MJ, Brereton HD, Rostock RA, et al. A prospective study of treatment techniques to minimize the
volume of pelvic small bowel with reduction of acute and late effects associated with pelvic irradiation. Int J
Radiat Oncol Biol Phys 1986;12:1565-1573.
10. Nutting CM, Convery DJ, Cosgrove VP, et al. Reduction of small and large bowel irradiation using an
optimized intensity-modulated pelvic radiotherapy technique in patients with prostate cancer. Int J Radiat Oncol
Biol Phys 2000;48:649-656.
11. Portelance L, Chao KS, Grigsby PW, et al. Intensity-modulated radiation therapy (IMRT) reduces small
bowel, rectum, and bladder doses in patients with cervical cancer receiving pelvic and paraaortic irradiation. Int J
Radiat Oncol Biol Phys 2001;51:261-266.
12. Roeske JC, Lujan A, Rotmensch J, et al. Intensity-modulated whole pelvic radiation therapy in patients with
gynecologic malignancies. Int J Radiat Oncol Biol Phys 2000;48;1613-1621.
13. Duthoy W, De Gersem W, Vergote K, et al. Clinical implementation of intensity-modulated arc therapy
(IMAT) for rectal cancer. Int J Radiat Oncol Biol Phys 2004;60:794-806.
14. Urbano MTG, Henrys AJ, Adams EJ, et al. Intensity-modulated radiotherapy in patients with locally
advanced rectal cancer reduces volume of bowel treated to high dose levels. Int J Radiat Oncol Biol Phys
2006;65:907-916.
15. Fleming T. One-sample multiple testing procedure for phase II clinical trials. Biometrics 1982;38:143-151.
16. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. New York, John Wiley & sons,
1980.
17. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Stat Assoc 1958;53:457-481.
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APPENDIX I
Informed Consent Template for Cancer Treatment Trials
(English Language)
RTOG 0822
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
This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to
you. Clinical trials include only people who choose to take part. Please take your time to
make your decision about taking part. You may discuss your decision with your friends and
family. You can also discuss it with your health care team. If you have any questions, you can
ask your study doctor for more explanation.
You are being asked to take part in this study because you have rectal cancer.
As treatment for your rectal cancer, you will require radiation therapy and chemotherapy given
at the same time. Both radiation therapy and chemotherapy can cause side effects. When
given at the same time, they have a greater risk of causing side effects. Prior studies have
established that the most common side effects are gastrointestinal side effects (such as
diarrhea), which at times can be severe enough to require unplanned treatment breaks or
chemotherapy dose reductions (either of which can compromise the effectiveness of the
cancer treatment) or in rare cases require discontinuation of therapy. Modern radiation
therapy delivery techniques have the potential to reduce the risk of gastrointestinal side effects
when compared with standard radiation delivery techniques.
Why is this study being done?

It is possible to reduce the amount of radiation delivered to the normal tissues that surround
your cancer by using an advanced radiation therapy delivery technique called intensitymodulated radiation therapy (IMRT see description below). The purpose of this study is to
determine whether reducing the amount of radiation, given along with chemotherapy, to these
normal tissues will reduce the side effects associated with standard radiation and
chemotherapy treatment for rectal cancer.
Definition of IMRT: Several normal tissues in your pelvis (including the small and large bowel,
bladder, femoral heads and others) lie near the rectal tumor and regional lymph nodes.
Standard radiation techniques deliver radiation to the tumor target (rectal tumor and nearby
lymph nodes at high risk for spread), but in doing so also deliver some radiation dose to the
nearby normal tissues that we otherwise do not need to radiate. The higher the radiation dose
to these normal tissues, the greater the risk of developing side effects. IMRT is a more
sophisticated radiation planning and delivery technique that can lower the amount of radiation
35
RTOG 0822
dose that the normal tissues receive while maintaining effective treatment to the tumor target.
IMRT accomplishes this through the use of multiple computer-controlled radiation beams that
are optimized through computer planning to minimize the radiation dose to normal tissues
without compromising treatment to the tumor target.
How many people will take part in the study?
About 75 people will take part in this study.
What will happen if I take part in this research study?
Before you begin the study
You will need to have the following exams, tests, or procedures to find out if you can be in the
study. These exams, tests, or procedures are part of regular cancer care and may be done
even if you do not join the study. If you have had some of them recently, they may not need to
be repeated. This will be up to your study doctor.
A history and physical examination

A colonoscopy (examination of your rectum and colon with a lighted flexible
camera) and a biopsy (a piece of your tumor is taken for examination under the
microscope) these tests help to establish your cancers location in the rectum
and rule out other cancers in the rectum or colon
One of the following scans of the abdomen and pelvis to assess the size and
extent of the rectal tumor and assess the potential spread of the rectal tumor to
nearby lymph nodes or other organs such as the liver:
Computed tomography (CT) scan: An imaging study that uses x-rays to
look at one part of your body
Magnetic resonance imaging (MRI) scan: An imaging study that uses a
strong magnetic field to look at one part of your body
The combination of a positron emission tomography (PET) scan plus a
CT scan of your entire body (whole body PET-CT): A computerized image
that looks at the activity of tumor cells in your entire body and that
requires injection of a special marker in your vein, such as sugar
(glucose) combined with a low-dose radioactive substance (a tracer). A
camera records the tracers signal as it travels through your body.
CT scan or x-ray of the chest to assess whether the tumor may have spread to
the lungs or other areas in the chest (not needed if you have a whole body PETCT)
Transrectal ultrasound (a probe placed in the rectum to help image the tumor)
may be needed. Your study doctor can tell you whether or not you will need this
performed.
Blood tests
For women able to have children, a pregnancy test (blood test)
If your doctors are concerned that you are at significant risk of complete
obstruction of your rectum by the tumor, a diverting colostomy (re-routing your
bowel to a bag outside your body to prevent obstruction) may be performed. You
can discuss this with your study doctor.
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During the study

If the exams, tests, and procedures show that you can be in the study, and you chose to take
part, you will need the following tests and procedures. They are part of regular cancer care.
During the first 6 weeks of your treatment while you are receiving chemotherapy and radiation
at the same time:
Weekly history and physical examination
Weekly blood tests
After you have completed chemotherapy and radiation but before you have surgery to remove
your tumor:
A PET-CT scan (optional your doctor will let you know if this is recommended)
CT or MRI scan of the abdomen and pelvis (not needed if you have a PET-CT
scan)
A CT scan or x-ray of the chest (not needed if you have a PET-CT scan)
Blood tests
During the chemotherapy that is given after you have surgery:
A history and physical examination before each cycle of chemotherapy (every 14
days)
Blood tests before each cycle of chemotherapy (every 14 days)
When you are finished taking the study treatment.
You will be seen in follow-up every 3 months for the first 2 years following treatment
completion, every 6 months for the next 3 years, and then annually. During these visits you
will need the following exams, tests, and procedures:
Blood to assess your bone marrow, kidney and liver function as well as your
tumor marker (CEA)
A CT or MRI scan of the abdomen and pelvis if needed (your study doctor will
let you know if this is required)
A PET-CT scan (optional your doctor will let you know if this is recommended)
A colonoscopy (at your 12 month follow-up visit only if negative, then every 2
years thereafter)
You will receive the following treatments
CHEMOTHERAPY PLUS RADIATION THERAPY
Radiation: You will receive radiation treatments once per day, 5 days per week, for a
total of 28 treatments as an outpatient. This will take approximately 5 weeks.
Chemotherapy: You will receive two drugs.

o (1) You will receive capecitabine in pill form as an outpatient during the time you
are receiving radiation. The first dose will be given to you the evening before your
first radiation treatment. You will then receive it twice daily through Thursday,
with a final weekly dose on Friday morning.
37
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o (2) You will receive oxaliplatin intravenously (through a needle in a vein) once per
week as an outpatient during each of the 5 weeks of radiation treatments. The
treatment will last approximately 2 hours per time.
SURGERY
After you have recovered from the chemotherapy and radiation (about 4 to 8 weeks), you will
have surgery to remove your rectal tumor and the at-risk lymph nodes. Prior to the surgery,
you will be put to sleep with anesthesia.
If it is found after your surgery that you may have residual cancer that was surgically left
behind at the time of your resection, you will discontinue protocol therapy.
POSTOPERATIVE CHEMOTHERAPY
After you have recovered from the surgery (about 4 to 8 weeks), you will receive additional
chemotherapy. You will receive three drugs for nine cycles, with each cycle being 14 days.
(1) You will receive oxaliplatin intravenously as an outpatient once at the beginning of
each cycle. It will last approximately 2 hours.
(2) You will receive leucovorin intravenously as an outpatient once at the beginning of
each cycle. It will last approximately 2 hours.
(3) You will receive 5-fluorouracil (5-FU) intravenously as an outpatient once at the
beginning of each cycle. You will receive one dose once quickly (an intravenous
push), followed by a continuous intravenous infusion that will last approximately 46
hours. Your doctor will discuss with you whether you receive this as an inpatient or at
home.
How long will I be in the study?
Treatment will last 8 to 9 months. You will receive radiation therapy and chemotherapy for 5 to
6 weeks. You will then be given time to adequately recover prior to surgery. Surgery will be
performed 4 to 8 weeks after completion of radiation therapy. You will then be given time to
adequately heal and recover from your surgery. Four to 8 weeks after your surgery you will
receive additional chemotherapy for about 4 and a half months.
After you are finished all study treatments, the study doctor will ask you to visit the office for
follow-up exams every 3 months for the first 2 years, then every 6 months for the next 3 years,
and after that once every year. We would like to keep track of your medical condition for the
rest of your life. Keeping in touch with you and checking on your condition every year helps us
look at the long-term effects of the study.
Can I stop being in the study?
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about
stopping or decide to stop. He or she will tell you how to stop safely.
It is important to tell the study doctor if you are thinking about stopping so that he/she can
evaluate any risks from the treatment. Another reason to tell your study doctor that you are
thinking about stopping is to discuss what follow-up care and testing could be most helpful for
you.
The study doctor may stop you from taking part in this study at any time if he/she believes it is
in your best interest; if you do not follow the study rules; or if the study is stopped.
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What side effects or risks can I expect from being in the study?
You may have side effects while on the study. Everyone taking part in the study will be
watched carefully for any side effects. However, researchers dont know all the side effects
that may happen. Side effects may be mild or very serious. Your health care team may give
you medicines to help lessen side effects. Many side effects go away soon after you stop
taking the treatment. In some cases, side effects can be serious, long lasting, or may never go
away. There also is a risk of death.
You should talk to your study doctor about any side effects that you have while taking part in
the study.
Risks and side effects related to the radiation include those that are:
Likely
Skin irritation in the treatment area

More frequent bowel movements
Diarrhea
Tiredness
Loss of pubic hair (temporary)
Rectal discomfort
Sterility in pre-menopausal women. Hormones may be given orally to replace
hormones normally produced by the ovaries
Less Likely
More frequent urination
Urinary discomfort
Skin peeling
Rare but Serious
Narrowing or blockage of the bowel (which may be serious enough to require
surgery)
A hole forming in the intestine (perforation) which may require surgery to repair
Development of an abnormal path or connection between organs called a fistula
(which typically requires a surgical repair)
Permanent sterility (men)
Sores and bleeding from the bowel (these side effects may occur late after
treatment and be serious enough to require surgery)
Hip fracture
Risks and side effects related to capecitabine include those that are:
Likely
Diarrhea
Nausea/vomiting
Loss of appetite
Fatigue
Mouth sores
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Risks and side effects related to capecitabine continued:
Less Likely
Hand-foot syndrome (painful redness and swelling of the hands and/or feet)
Hair loss
Dry skin
Changes in skin coloring
Increased sensitivity to sunlight
Eye watering, eye irritation
Fever
Taste changes
Decrease in blood counts that may cause infection, bleeding, and bruising
Inflammation of the colon
Increased sweating
Laryngitis (irritation or swelling of the voice box that may cause voice changes or
temporary voice loss)
Bone pain
Joint stiffness
Increased urination at night
Rare but Serious

Coagulation disorder (problems with your bodys ability to clot blood)
Heart disease
Bowel perforation (a hole forming in the bowel wall)Rectal and/or gastrointestinal
bleeding
Inflammation of the esophagus
Inflammation of the lining of the stomach
Inflammation/infection of the intestine and intestinal tissue, which can be severe
enough to destroy it (necrosis)
Blood in vomit
Severe infection of the bloodstream
Pneumonia
Severe allergic reaction
Formation of scar tissue in the liver
Liver disease
High level of triglycerides in the blood, which can increase your risk for heart
disease
Problems with coordination
Brain disease
Loss of consciousness or reduced level of consciousness
Confusion
Respiratory distress
Low blood pressure
Blood clots/inflammation of veins
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Risks and side effects related to capecitabine continued:
Stroke
Radiation recall (redness, peeling, or blistering of skin in area where you
received radiation)
Fungal infection in the mouth or digestive tract
Respiratory tract infection
Urinary tract infection
Bronchitis (inflammation of the air tubes leading to the lung)
General wasting of the body caused by malnutrition
Shortness of breath
Nose bleed
Contractions of the bronchi muscles
Accumulation of fluid in the intestines, causing swelling of the body, especially of
the arms and legs
Risks and side effects related to oxaliplatin include those that are:
Likely
Fatigue
Decreased appetite
Nausea/vomiting
Diarrhea
Numbness, tingling, or change in sensations in the arms and legs
Less Likely
Decrease in blood counts that may cause infection, bleeding, and bruising
Decrease in electrolyte levels that may cause muscle twitching, weakness,
cramps
Involuntary muscle contractions
Weight loss
Hair loss
Injection site reaction
Dehydration
Taste disturbance
Inflammation of the intestine
Heartburn
Inflammation of the esophagus
Vision abnormalities, eye infection
Abdominal pain/cramping
Headache
Shortness of breath
Vocal cord spasm
Rash/skin peeling
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Risks and side effects related to oxaliplatin continued:
Fever
Constipation
Difficulty/pain with swallowing
Mouth sores
Cough
Hiccups
Insomnia
Dizziness
Changes in mood
Joint pain
Muscle pain
Bone pain
Rare but Serious

Allergic reaction
Mild hearing loss
Abnormal heart beat
Swelling
High blood pressure
Blood clots, problems with clotting, hemorrhage, bleeding
Inflammation of veins
Hot flashes/flushes
Bowel perforation (a hole forming in the bowel wall)
Inflammation of the intestine and intestinal tissues that is severe enough to
destroy the tissue
Coughing of blood
Liver disease (with a possible increased risk when combined with 5-FU)
Scar tissue in the lung
Inflammation of lung tissue
Decreased electrolyte levels, which may cause kidney problems, make you
disoriented
Risks and side effects related to 5-fluorouracil (5-FU) include those that are:
Likely
Diarrhea
Nausea/vomiting
Loss of appetite
Mouth sores
42
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Risks and side effects related to 5-fluorouracil (5-FU) continued:
Less Likely
Loss of appetite
Skin inflammation that causes redness, swelling, blistering, oozing, and itching
Nail changes
Hair loss
Taste changes
Low blood counts
Darkening of skin
Hand-foot syndrome (painful redness and swelling of the hands and/or feet)
Eye irritation, watering of the eyes, blurred vision
Nasal discharge
Rare but Serious

Chest pain
Liver disease (with a possible increased risk when combined with oxaliplatin)
Severe, cholera-like diarrhea
Risks and side effects related to leucovorin include those that are:
Less Likely
Hives
Rare but Serious
Severe allergic reaction
Reproductive risks: You should not become pregnant or father a baby while on this study
because the drugs in this study can affect an unborn baby. Pregnancy testing will be required
before you can enroll. Women should not breastfeed a baby while on this study. It is important
you understand that you need to use birth control while on this study. Check with your study
doctor about what kind of birth control methods to use and how long to use them. Some
methods might not be approved for use in this study. When receiving radiation therapy, there is
a possibility that permanent sterility may result.
For more information about risks and side effects, ask your study doctor.
Are there benefits to taking part in the study?
Taking part in this study may or may not make your health better. While researchers hope that
delivering radiation therapy with modern techniques (IMRT) will be as effective but with less
side effects compared to the usual treatment for this cancer, there is no proof of this yet. We
do know that the information from this study will help researchers learn more about the use of
IMRT as a treatment for rectal cancer. This information could help future cancer patients.
What other choices do I have if I do not take part in this study?
Your other choices may include:
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Getting treatment or care for your cancer without being in a study

Taking part in another study
Getting no treatment
Talk to your study doctor about your choices before you decide if you will take part in this
study.
Will my medical information be kept private?
Data are housed at RTOG Headquarters in a password-protected database. We will do our
best to make sure that the personal information in your medical record will be kept private.
However, we cannot guarantee total privacy. Your personal information may be given out if
required by law. If information from this study is published or presented at scientific meetings,
your name and other personal information will not be used.
Organizations that may look at and/or copy your medical records for research, quality
assurance, and data analysis include:
Your hospital or universitys institutional review board (IRB)
The National Cancer Institute (NCI) and other government agencies, like the Food and
Drug Administration (FDA), involved in keeping research safe for people
The Radiation Therapy Oncology Group
What are the costs of taking part in this study?
You and/or your health plan/insurance company will need to pay for some or all of the costs of
treating your cancer in this study. Some health plans will not pay these costs for people taking
part in studies. Check with your health plan or insurance company to find out what they will
pay for. Taking part in this study may or may not cost your insurance company more than the
cost of getting regular cancer treatment.
You will not be paid for taking part in this study.
For more information on clinical trials and insurance coverage, you can visit the National
Cancer Institutes Web site at http://cancer.gov/clinicaltrials/understanding/insurancecoverage. You can print a copy of the Clinical Trials and Insurance Coverage information
from this Web site.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them
to send you a free copy.
What happens if I am injured because I took part in this study?
It is important that you tell your study doctor, __________________ [investigators name(s)], if
you feel that you have been injured because of taking part in this study. You can tell the study
doctor in person or call him/her at __________________ [telephone number].
You will get medical treatment if you are injured as a result of taking part in this study. You
and/or your health plan will be charged for this treatment. The study will not pay for medical
treatment.
What are my rights if I take part in this study?
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Taking part in this study is your choice. You may choose either to take part or not to take part
in the study. If you decide to take part in this study, you may leave the study at any time. No
matter what decision you make, there will be no penalty to you and you will not lose any of
your regular benefits. Leaving the study will not affect your medical care. You can still get
your medical care from our institution.
We will tell you about new information or changes in the study that may affect your health or
your willingness to continue in the study.
A Data Safety Monitoring Board will be regularly meeting to monitor safety and other data
related to phase II RTOG clinical trials. The Board members may receive confidential patient
information, but they will not receive your name or other information that would allow them to
identify you by name.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek
payment by signing this form.
Who can answer my questions about the study?
You can talk to your study doctor about any questions or concerns you have about this study.
Contact your study doctor __________________ [name(s)] at __________________
[telephone number].
For questions about your rights while taking part in this study, call the
________________________ [name of center] Institutional Review Board (a group of people
who review the research to protect your rights) at __________________ (telephone number).
[Note to Local Investigator: Contact information for patient representatives or other individuals
in a local institution who are not on the IRB or research team but take calls regarding clinical
trial questions can be listed here.]
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Please note: This section of the informed consent form is about additional research
that is being done with people who are taking part in the main study. You may take
part in this additional research if you want to. You can still be a part of the main study
even if you say no to taking part in this additional research.
You can say yes or no to the following study. Below, please mark your choice.
Use of Tissue for Research
[The following example of tissue consent has been taken from the NCI Cancer Diagnosis
Programs model tissue consent form found at the following URL
http://www.cancerdiagnosis.nci.nih.gov/specimens/model.pdf
Consent Form for Use of Tissue for Research
About Using Tissue for Research
You are going to have a biopsy (or surgery) to see if you have cancer. Your doctor will remove
some body tissue to do some tests. The results of these tests will be given to you by your
doctor and will be used to plan your care.
As a result of your participation on this study, you will also have a biopsy 4 to 8 weeks after
you have completed radiation therapy. This biopsy will be done to evaluate whether the
treatment is affecting your cancer.
We would like to keep some of the tissue that is left over from these biopsies to use for future
research. If you agree, this tissue will be kept and may be used in research to learn more
about cancer and other diseases. Please read the information sheet called "How is Tissue
Used for Research" to learn more about tissue research. This information sheet is available to
all at the following web site: http://www.rtog.org/tissue%20for%20research_patient.pdf
As a result of your participation in this study, you will also have blood tests done at the
following times: before you begin study treatment and during the last week of treatment. When
we take the blood at these times, we would also like to take some blood to use for future
research. If you agree, this blood will be kept and may be used in research to learn more about
cancer and other diseases.
The research that may be done with your tissue and blood is not designed specifically to help
you. It might help people who have cancer and other diseases in the future.
Reports about research done with your tissue and blood will not be given to you or your doctor.
These reports will not be put in your health record. The research will not have an effect on your
care.
Things to Think About
The choice to let us keep the tissue and blood for future research is up to you. No matter what
you decide to do, it will not affect your care or your participation in the main part of the study.
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If you decide now that your tissue and blood can be kept for research, you can change your
mind at any time. Just contact us and let us know that you do not want us to use your tissue
and blood. Then any tissue that remains will no longer be used for research. Any remaining
tissue will be returned to the institution that submitted it, and any remaining blood will be
destroyed.
In the future, people who do research may need to know more about your health. While the
doctor/institution may give them reports about your health, your name, address, phone
number, or any other information that will let the researchers know who you are will not be
disclosed.
Sometimes tissue and blood are used for genetic research (about diseases that are passed on
in families). Even if your tissue and blood are used for this kind of research, the results will not
be put in your health records.
Your tissue and blood will be used only for research and will not be sold. The research done
with your tissue and blood may help to develop new products in the future.
Benefits
The benefits of research using tissue and blood include learning more about what causes
cancer and other diseases, how to prevent them, and how to treat them.
Risks
The greatest risk to you is the release of information from your health records. We will do our best to
make sure that your personal information will be kept private. The chance that this information will be
given to someone else is very small.
Making Your Choice
Please read each sentence below and think about your choice. After reading each sentence,
circle "Yes" or "No". If you have any questions, please talk to your doctor or nurse, or call our
research review board at IRB's phone number.
No matter what you decide to do, it will not affect your care.
1. My tissue/blood may be kept for use in research to learn about, prevent, or treat cancer.
Yes
No
2. My tissue/blood may be kept for use in research to learn about, prevent or treat other health
problems (for example: diabetes, Alzheimer's disease, or heart disease).
Yes
No
3. Someone may contact me in the future to ask me to take part in more research.
Yes
No
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Where can I get more information?

You may call the National Cancer Institute's Cancer Information Service at:
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615
You may also visit the NCI Web site at http://cancer.gov/
For NCIs clinical trials information, go to: http://cancer.gov/clinicaltrials/
For NCIs general information about cancer, go to http://cancer.gov/cancerinfo/
You will get a copy of this form.

your study doctor.
If you want more information about this study, ask
Signature
I have been given a copy of all _____ [insert total of number of pages] pages of this form. I
have read it or it has been read to me. I understand the information and have had my
questions answered. I agree to take part in this study.
Participant ________________________________
Date _____________________________________
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APPENDIX II: STUDY PARAMETER TABLE (3/30/10)

Pre-Treatment
56 days
28 days
14 days
prior to study
prior to
prior to
entry
study
study
entry
entry
History and physical exam

Medication history screen for
contraindications
Zubrod performance status
assessment
Diagnostic biopsy/FNA
Colonoscopy
Transrectal US (for T4, optional)
Contrast-enhanced CT or MRI of
the abdomen and pelvis
CXR/CT chest
Whole-body PET-CT scan of
body (optional)
CBC w/ diff & ANC, plt, HgB
CMP including LFTs
CrCl assessment
Serum pregnancy test
CEA
Informed consent
Tumor response eval
X
X
Weekly
(during
preoperative
chemoRT)
During Treatment
14 days
Prior to each
prior to
cycle of
surgical
postresection
operative
FOLFOX
q3 months
following
postoperative
FOLFOX
(for yrs 1-2)
X
X
X
X
X*
X
X
X*
X*
Follow-Up (Postoperative)
1 yr
q6 months
following
following
postpostoperative
operative
FOLFOX; if
FOLFOX
negative q 2
(for yrs 3yrs
5)
thereafter
X
X
X
X
X
X
X
(as indicated)
(as indicated)
(as
indicated)
X
X
X
X
X
X
X
X
X
X
X
(pathologic
assessment
at the time
of surgery)
Adverse event eval

Tissue for banking (optional)
Blood for banking (optional)
X
X
X
X
X
(last week
of treatment
only)
*If whole-body PET-CT done postoperatively, CT, MRI and CXR do not need to be done.
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q yr
following
postoperative
FOLFOX
(for yrs 6
and
beyond)
APPENDIX III
ZUBROD PERFORMANCE SCALE
0
Fully active, able to carry on all predisease activities without restriction

(Karnofsky 90-100).
Restricted in physically strenuous activity but ambulatory and able to carry

work of a light or sedentary nature. For example, light housework, office
work (Karnofsky 70-80).
Ambulatory and capable of all self-care but unable to carry out any work
activities. Up and about more than 50% of waking hours (Karnofsky 50-60).
Capable of only limited self-care, confined to bed or chair 50% or more of

waking hours (Karnofsky 30-40).
Completely disabled. Cannot carry on self-care. Totally confined to bed or

(Karnofsky 10-20).
Death (Karnofsky 0).

KARNOFSKY PERFORMANCE SCALE
100
Normal; no complaints; no evidence of disease
90
Able to carry on normal activity; minor signs or symptoms of disease
80
Normal activity with effort; some sign or symptoms of disease
70
Cares for self; unable to carry on normal activity or do active work
60
Requires occasional assistance, but is able to care for most personal

needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled; hospitalization is indicated, although death not

imminent
20
Very sick; hospitalization necessary; active support treatment is necessary
10
Moribund; fatal processes progressing rapidly
Dead
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APPENDIX IV
AJCC STAGING
COLON AND RECTUM, 6TH EDITION
DEFINITION OF TNM
The same classification is used for both clinical and pathologic staging.
Primary Tumor (T)
TX
T0
Tis
T1
T2
T3
T4
Primary tumor cannot be assessed

No evidence of primary tumor
Carcinoma in situ: intraepithelial or invasion of lamina propria*
Tumor invades submucosa
Tumor invades muscularis propria
Tumor invades through the muscularis propria into the subserosa, or into non-peritonealized pericolic or
perirectal tissues
Tumor directly invades other organs or structures, and/or perforates visceral peritoneum**, ***
* Note: Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria
(intramucosal) with no extension through the muscularis mucosae into the submucosa.
** Note: Direct invasion in T4 includes invasion of other segments of the colorectum by way of the serosa; for
example, invasion of the sigmoid colon by a carcinoma of the cecum.
***Note: Tumor that is adherent to other organs or structures, macroscopically, is classified T4. However, if no tumor
is present in the adhesion, microscopically, the classification should be pT3. The V and L substaging should
be used to identify the presence or absence of vascular or lymphatic invasion.
Regional Lymph Nodes (N)
NX
NO
N1
N2
Regional lymph nodes cannot be assessed

No regional lymph node metastasis
Metastasis in 1 to 3 regional lymph nodes
Metastasis in 4 or more regional lymph nodes
Note:
A tumor nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic
evidence of residual lymph node in the nodule is classified in the pN category as a regional lymph node
metastasis if the nodule has the form and smooth contour of a lymph node. If the nodule has an irregular
contour, it should be classified in the T category and also coded as V1 (microscopic venous invasion) or as
V2 (if it was grossly evident), because there is a strong likelihood that it represents venous invasion.
Distant Metastasis (M)

MX
MO
M1
Distant metastasis cannot be assessed

No distant metastasis
Distant metastasis
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APPENDIX IV (continued)
AJCC STAGING
COLON AND RECTUM, 6TH EDITION
STAGE GROUPING
Stage
Stage
Stage
T
Tis
N
N0
M
M0
Dukes*
-
MAC*
-
T1
T2
N0
N0
M0
M0
A
A
A
B1
Stage
IIA
IIB
T3
T4
N0
N0
M0
M0
B
B
B2
B3
Stage
IIIA
IIIB
IIIC
T1-2
T3-4
Any T
N1
N1
N2
M0
M0
M0
C
C
C
C1
C2/C3
C1/C2/C3
Stage
IV
Any T
Any N
M1
*Dukes B is a composite of better (T3 N0 M0) and worse (T4 N0 M0) prognostic groups, as is Dukes C (Any TN1
M0 and Any T N2 M0). MAC is the modified Astler-Coller classification.
Note: The y prefix is to be used for those cancers that are classified after pretreatment, whereas the r prefix is to
be used for those cancers that have recurred.
52
RTOG 0822
APPENDIX V
CAPECITABINE DOSING TABLE BASED UPON BODY SURFACE AREA CALCULATION
Dosing Table Based Upon Body Surface Area Calculation:
Capecitabine Starting Dose
AM
AM
Dose level 1650 mg/m2/d
150 mg 500 mg
BSA (m2)
Total Daily Dose (mg)
<1.24
2000
0
2
1.25-1.36
2150
1
2
1.37-1.51
2300
1
2
1.52-1.64
2600
2
2
1.65-1.76
2800
1
3
1.77-1.91
3000
0
3
1.92-2.04
3150
1
3
2.05-2.17
3300
1
3
>2.18
3600
2
3
PM
150 mg
PM 500 mg
0
0
1
2
1
0
0
1
2
2
2
2
2
2
3
3
3
3
Capecitabine 25% Dose Reduction: Dosing Table Based Upon Body Surface Area Calculation
AM
AM
PM
150 mg 500 mg 150 mg
Dose 1237 mg/m2/d
PM 500 mg
BSA (m2)
<1.24
1500
0
2
0
1
1.25-1.36
1650
1
2
0
1
1.37-1.51
1800
1
2
1
1
1.52-1.64
1950
2
2
1
1
1.65-1.76
2150
1
2
0
2
1.77-1.91
2300
1
2
1
2
1.92-2.04
2450
2
2
1
2
2.05-2.17
2500
0
3
0
2
>2.18
2650
1
3
0
2
Capecitabine 50% Dose Reduction: Dosing Table Based Upon Body Surface Area Calculation
AM
AM
PM
Dose level 825 mg/m2/d
150 mg 500 mg 150 mg PM 500 mg
BSA (m2)
<1.24
1000
0
1
0
1
1.25-1.36
1150
1
1
0
1
1.37-1.51
1150
1
1
0
1
1.52-1.64
1300
1
1
1
1
1.65-1.76
1450
2
1
1
1
1.77-1.91
1500
0
2
0
1
1.92-2.04
1650
1
2
0
1
2.05-2.17
1650
1
2
0
1
>2.18
1800
1
2
1
1
53
RTOG 0822
APPENDIX VI
PATHOLOGICAL ASSESSMENT OF A RECTAL CANCER SPECIMEN
When possible, specimens should be received fresh and opened by the pathologist. If this is not possible, then
the surgeon should open the bowel in the way described below and pin it out on a cork board for fixation.
The rectum should be opened anteriorly apart from the area 2 cm above and below the tumor where the anterior
part of the rectum is left intact. Below the peritoneal reflection the surgeon can usually remove between 0.5 and
1.0 cm anteriorly; thus tumors involving this area are at greater risk of circumferential resection margin (CRM)
involvement. In tumors above the peritoneal reflection, involvement of the peritoneal surface can occur; it is best
to avoid destroying this area and the pathologists ability to sample it by avoiding opening the site of the tumor. If
possible, a macroscopic photograph of the posterior and anterior sides of the specimen is valuable.
The opened specimen should then be pinned to a cork board and fixed for 48-72 hours. After fixation, the
specimen should be removed from the board and the non-peritonealized surfaces painted with ink by the method
in use locally.
The macroscopic description of the specimen is then performed. Failing to open the specimen does cause a
problem with recording the tumor characteristics. However, the length, width, and area of the tumor are not
prognostic, whereas CRM and peritoneal involvement are. The macroscopic description should assess the quality
of the mesorectum on the specimen. There are 3 grades:
3/Good: Intact mesorectum with only minor irregularities of a smooth mesorectal surface. No defect is
deeper than 5 mm. No coning on the specimen. Smooth CRM on slicing.
2/Moderate: Moderate bulk to mesorectum but irregularity of the mesorectal surface. Moderate coning of
the specimen towards the distal margin. At no site is the muscularis propria visible, with the exception of
the area of the insertion of levator muscles. Moderate irregularity of CRM.
1/Poor: Little bulk to mesorectum with defects down onto muscularis propria and/or very irregular CRM.
The area of the tumor that has been left intact is now sectioned transversely as thinly as possible. If the specimen
is not well fixed (i.e., 48-72 hours in formalin), then this process is more difficult.
The fixed slices are laid out under good light and photographed (if possible) and then inspected macroscopically.
Measurements include: i) the maximum depth of extension of the tumor from the muscularis propria; and ii) the
distance from the CRM to the tumor. If the tumor is within 1 mm on histological sections, then CRM involvement is
said to have occurred. If any lymph nodes abut the CRM, then these should be taken in continuity with the CRM
so that involvement by this route can be identified; similarly, if there is any evidence of isolated deposits or
thickening/fibrosis in this area, the area should be sampled. Again, if tumor is less than 1 mm from the CRM, the
CRM is said to be involved. Any peritumoral lymph nodes will be collected at this time. If the tumor approaches
the peritoneal surface, this must also be sampled to exclude malignant cells on the surface or ulceration of the
serosa by tumor. Four blocks of the primary tumor must be taken to assess the peritoneum and tumor
characteristics. These may be the same blocks as those for the CRM, if there is adequate tumor represented.
After assessing the primary tumor, attention should be turned to the lymph nodes. All lymph nodes should be
identified and embedded. If any lymph nodes lie against the circumferential margin, they should be taken in
continuity with the margin to exclude CRM involvement. The distal margin should then be sampled and the
doughnuts examined. The proximal margin does not need to be examined unless within 5 cm of the tumor. Any
mucosal lesions seen should be sampled. The status of the background mucosa can be obtained from the distal
margin.
Standard histological examination of the hematoxylin and eosin sections should then be performed. If tumor is
within 1 mm of the CRM, then it should be deemed to be involved. This measurement should be made on the
glass slide using the Vernier scale. If tumor is close to the margin but greater than 1 mm, then deeper levels
should be cut to exclude involvement. If fibrosis has led to a mistaken impression of the depth of invasion from the
muscularis propria, then this measurement should be corrected from the slide.
54
RTOG 0822
APPENDIX VII
BLOOD COLLECTION KIT INSTRUCTIONS
Instructions for use of serum, plasma, or buffy coat collection kit (collected as required by protocol):
This kit includes:
Ten (10) 1 ml cryovials
Biohazard bags
Absorbent shipping material
Styrofoam container (inner)
Cardboard shipping (outer) box
Pre-paid shipping label(s)
Serum (if requested):
Using four (4) or more 1 ml cryovials, label them with the RTOG study and case number, collection
date and time, and clearly mark cryovials serum.
Process:
1. Allow one red top tube to clot for 30 minutes at room temperature.
2. Spin in a standard clinical centrifuge at ~2500 RPM for 10 minutes at room temperature.
3. Aliquot a minimum of 0.5 ml serum (optimal 1ml) into each cryovial labeled with RTOG study and
case numbers, collection date/time, timepoint collected, and clearly mark specimen as serum.
4. Place cryovials into biohazard bag and immediately freeze at 70 to 80 Celsius.
5. Store serum at 70 to 80 Celsius until ready to ship.
6. Ship on dry ice.
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED.
Plasma (If requested):
Using three (3) or more 1 ml cryovials, label them with the RTOG study and case number, collection
date and time, and clearly mark cryovials plasma.
Process:
1.
After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA.
2.
Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500
RPM for 10 minutes at room temperature.
3.
If the interval between specimen collection and processing is anticipated to be greater than one
hour, keep specimen on ice until centrifuging is performed.
4.
Carefully pipette and aliquot a minimum of 0.5 ml plasma (optimal 1 ml) into each cryovial labeled
with RTOG study and case numbers, collection date/time, timepoint collected and clearly mark
specimen as plasma.
5.
Place cryovials into biohazard bag and immediately freeze at 70 to 80 Celsius.
6.
Store plasma at 70 to 80 Celsius until ready to ship.
7.
Ship on dry ice.
Buffy coat (if requested):
For a visual explanation of Buffy coat, please refer to diagram below.
55
RTOG 0822
Using one (1) or more 1 ml cryovials, label them with the RTOG study and case number, collection date
and time, and clearly mark cryovial(s) buffy coat.
Process:
1. Centrifuge EDTA (purple top) tube within one hour of collection in a standard clinical centrifuge at ~2500
RPM for 10 minutes at room temperature.
2. If the interval between specimen collection and processing is anticipated to be greater than one hour,
keep specimen on ice until centrifuging is performed.
3. Carefully remove plasma close to the buffy coat and set plasma aside (can be used to send plasma
samples see above instructions).
4. Remove the buffy coat cells carefully and place into cryovials labeled buffy coat (it is okay if a few
packed red cells are inadvertently collected in the process). Clearly mark the tubes with date/time of
collection and timepoint collected.
5. Place cryovials into biohazard bag and freeze immediately at -70 to -80 Celsius.
6. Store buffy coat samples frozen (-70 to -80 Celsius) until ready to ship.
7. Ship on dry ice.
Shipping/Mailing:
Ship specimens overnight Monday-Wednesday to prevent thawing due to delivery delays. Saturday and
holiday deliveries will not be accepted.
Include all RTOG paperwork in a sealed plastic and tape to the outside top of the Styrofoam box.
Wrap frozen specimens of same type (i.e., all serum together, plasma together and buffy coats together)
in absorbent shipping material and place each specimen type in a separate biohazard bag. Place
specimen bags into the Styrofoam cooler and fill with dry ice (4-5lbs/2-2.5kg minimum). Ship ambient
specimens in a separate envelope/cooler. Place Styrofoam coolers into outer cardboard box, and attach
shipping label to outer cardboard box.
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag.
For questions regarding collection, shipping or to order a Blood Collection Kit, please Email
RTOG@ucsf.edu or contact the RTOG Biospecimen Resource by phone 415-476-7864 or Fax at 415476-5271.
56
RTOG 0822

Study Chairs (3/30/10) Principal Investigator/Radiation Oncology Surgical Oncology

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What is the purpose of this study protocol?

What is the purpose of this study protocol?

What chemotherapy regimen is being evaluated in this study?

What chemotherapy regimen is being evaluated in this study?

RADIATION THERAPY ONCOLOGY GROUP

RTOG Headquarters/Department of Statistics

- Sample Consent Form

RADIATION THERAPY ONCOLOGY GROUP

* See Section 5.0 for pre-registration requirements.

Required Sample Size: 75 patients

ELIGIBILITY CHECKLIST (4/29/08)

2. Does the malignant disease extend into the anal canal?

3. Is the clinical T stage 3-4, N stage 0-2, and M0?

4. Is the clinical T stage T3?

If yes, was transrectal ultrasound performed within 56 days of registration?

6. Is the patients Zubrod performance status 0-2?

7. Is the patient 18 years of age?

If yes, has the patient been disease free for 3 years?

14. Does the patient have evidence of grade 2 peripheral neuropathy?

16. Does the patient have synchronous primary colon carcinomas?

ELIGIBILITY CHECKLIST (4/29/08)

26. Does the patient have known existing uncontrolled coagulopathy?

27. Is the patient on anticoagulation medication?

ELIGIBILITY CHECKLIST (4/29/08)

The following questions will be asked at Study Registration:

Name of institutional person registering this case?

Has the Eligibility Checklist (above) been completed?

Is the patient eligible for this study?

Patients Initials (First Middle Last)

Ethnic Category (Hispanic or Latino; Not Hispanic or Latino; Unknown)

Patients Country of Residence

Zip Code (U.S. Residents)

Patients Insurance Status

Will any component of the patients care be given at a military or VA facility?

Calendar Base Date

Registration/randomization date: This date will be populated automatically.

ELIGIBILITY CHECKLIST (4/29/08)

Tissue/Blood kept for cancer research?

Tissue/Blood kept for medical research?

Allow contact for future research?

Rationale for Intensity Modulated Radiation Therapy in Rectal Cancer

there will be a consequent reduction in side effectsparticularly acute gastrointestinal side

NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED

Conditions for Patient Eligibility

Conditions for Patient Ineligibility

A representative from the institution must complete the Password Authorization

and fax it to 215-923-1737. RTOG Headquarters requires 3-4 days to process

No more than 25% volume above 45 Gy

R.T. Quality Assurance Reviews

Radiation Treatment Interruptions

Continue at current dose

Hold until recovery to grade 1, then resume.

Hold until recovery to grade 1 (platelets 75

Hold until recovery to grade 1 , then resume.

Hold until recovery to grade 1, then resume.

Grade 3 febrile neutropenia

Hold until resolution of fever and neutropenia to

Radiation Adverse Events