Phase III Randomized Study of Concurrent Chemotherapy and Pelvic Radiation Therapy With or Without Adjuvant Chemotherapy in High-Risk Patients With Early-Stage Cervical Carcinoma Following Radical Hysterectomy
Phase: PHASE3
Conditions: Cervical Cancer
Sponsor: Radiation Therapy Oncology Group

NRG ONCOLOGY 
Radiation Therapy Oncology Group 
RTOG 0724/GOG-0724 
(ClinicalTrials.gov NCT #: 00980954) 
PHASE III RANDOMIZED STUDY OF CONCURRENT CHEMOTHERAPY AND 
PELVIC RADIATION THERAPY WITH OR WITHOUT ADJUVANT CHEMOTHERAPY 
IN HIGH-RISK PATIENTS WITH EARLY-STAGE CERVICAL CARCINOMA 
FOLLOWING RADICAL HYSTERECTOMY 
 
Amendment 7: September 21, 2022 

RTOG 0724; version date September 21, 2022 
1 
                                                     NRG ONCOLOGY 
 
RTOG 0724/GOG-0724 
 
PHASE III RANDOMIZED STUDY OF CONCURRENT CHEMOTHERAPY AND 
PELVIC RADIATION THERAPY WITH OR WITHOUT ADJUVANT CHEMOTHERAPY 
IN HIGH-RISK PATIENTS WITH EARLY-STAGE CERVICAL CARCINOMA 
FOLLOWING RADICAL HYSTERECTOMY 
 
This trial is part of the national NCI Clinical Trials Network (NCTN) program which is sponsored by the 
National Cancer Institute (NCI). The trial will be led by NRG Oncology with the participation of the network 
of NCTN organizations: the Alliance, ECOG-ACRIN, and SWOG 
 
 
 
Study Chairs (21-SEP-2022) 
Principal Investigator/Radiation Oncology 
Anuja Jhingran, MD 
M.D. Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030 
713-563-2347/FAX 713-563-2366 
ajhingra@mdanderson.org  
 
Gynecology Oncology 
Heidi Gray, MD 
University of Washington 
Division of Gynecologic Oncology 
Department of OB/GYN, Box 356460 
Seattle, WA  98195 
206-543-3669/206-543-3915 
hgray@u.washington.edu  
 
Translational Research 
Joanne Weidhaas, MD, PhD 
UCLA / Jonsson Comprehensive Cancer Center 
Department of Radiation Oncology 
200 UCLA Medical Plaza 
Suite B265 
Los Angeles, CA 90095-6951 
310-825-5037 
jweidhaas@mednet.ucla.edu   
Quality of Life  
Rachel Hirschey, MD 
The University of North Carolina at Chapel Hill 
School of Nursing 
Carrington Hall, CB#7460 
919-843-9468 
hirschey@unc.edu  
 
Medical Physics 
Mohammad R. Salehpour, PhD 
U.T. M.D. Anderson Cancer Center 
Unit 1210 
1155 Pressler Street 
Houston, TX 77030 
713-563-2636/FAX 713-563-6895 
msalehpour@mdanderson.org 
 
Senior Statistician 
Kathryn Winter, MS 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3198/FAX 215-928-0153 
winterk@nrgoncology.org  
 
    

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2 
NRG ONCOLOGY  
 
RTOG 0724/GOG-0724 
 
PHASE III RANDOMIZED STUDY OF CONCURRENT CHEMOTHERAPY AND 
PELVIC RADIATION THERAPY WITH OR WITHOUT ADJUVANT CHEMOTHERAPY 
IN HIGH-RISK PATIENTS WITH EARLY-STAGE CERVICAL CARCINOMA 
FOLLOWING RADICAL HYSTERECTOMY 
                                                              
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
Carboplatin 
Commercial 
N/A 
Exempt 
Cisplatin 
Commercial 
N/A 
Exempt 
Paclitaxel 
Commercial 
N/A 
Exempt 
 
 
Participating Sites 
 U.S. Only 
 Canada Only 
 U.S. and Canada 
 Approved International Member Sites 
 
 
                                                                    Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 7 
September 21, 2022 
N/A 
Amendment 6 
February 04, 2022 
N/A 
Update 
September 22, 2014 
September 22, 2014 
Amendment 5 
August 21, 2014 
September 15, 2014 
Update 
August 30, 2012 
August 30, 2012 
Amendment 4 
December 29, 2010 
January 11, 2011 
Amendment 3 
October 22, 2010 
November 4, 2010 
Update 
September 21, 2010 
September 21, 2010 
Amendment 2 
August 12, 2010 
September 21, 2010 
Amendment 1 
July 9, 2010 
September 21, 2010 
Activation 
September 2, 2009 
September 16, 2009 
 
 
NRG Oncology 
1-800-227-5463, ext. 4189 
 
  
 
 
This protocol was designed and developed by the NRG Oncology.  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 NRG Oncologynor does 
NRG Oncology assume any responsibility for unauthorized use of this protocol. 

RTOG 0724; version date September 21, 2022 
3 
NRG ONCOLOGY  
 
RTOG 0724/GOG-0724 
 
PHASE III RANDOMIZED STUDY OF CONCURRENT CHEMOTHERAPY AND 
PELVIC RADIATION THERAPY WITH OR WITHOUT ADJUVANT CHEMOTHERAPY 
IN HIGH-RISK PATIENTS WITH EARLY-STAGE CERVICAL CARCINOMA 
FOLLOWING RADICAL HYSTERECTOMY 
 
 
CONTACT INFORMATION ((21-SEP2022) 
For regulatory requirements: 
For patient enrollments:  
For study data 
submission: 
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal. 
(Sign in at https://www.ctsu.org, 
and select the Regulatory > 
Regulatory Submission.)  
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU 
Regulatory Office immediately 
by phone or email: 1-866-651-
CTSU (2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) for regulatory 
assistance. 
Refer to the patient enrollment section of 
the protocol for instructions on using the 
Oncology Patient Enrollment Network 
(OPEN). OPEN is accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions by phone or 
email: 1-888-823-5923, or 
ctsucontact@westat.com. 
 
 
Submit data electronically 
via the NRG 
Oncology/RTOG web 
site, www.rtog.org 
 
Do not submit study data 
or forms to CTSU Data 
Operations. Do not copy 
the CTSU on data 
submissions. 
   
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website (https://www.ctsu.org).  Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires log in with a CTEP-IAM 
username and password.  
 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).   
 
For patient eligibility or treatment-related questions: Contact the Study PI of the Lead Protocol 
Organization”. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative. 

RTOG 0724; version date September 21, 2022 
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For imaging data submission questions: 
IROCimagearchive@acr.org; please include trial number in the email subject line 
 
For TRIAD access and installation support: 
TRIAD-Support@acr.org 
Triadhelp.acr.org 
 
TRIAD Software Installation: 
https://triadinstall.acr.org/triadclient/ 
 
 
 
 
 

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TABLE OF CONTENTS 
 
SCHEMA ....................................................................................................................................................... 7 
 
ELIGIBILITY CHECKLIST ............................................................................................................................. 8 
 
1.0 
INTRODUCTION ............................................................................................................................. 11 
1.1 
Assessments for Quality of Life, Neuropathy, and Diarrhea ....................................................... 12 
 
2.0 
OBJECTIVES .................................................................................................................................. 14 
2.1 
Primary ........................................................................................................................................ 14 
2.2 
Secondary ................................................................................................................................... 14 
 
3.0 
PATIENT SELECTION .................................................................................................................... 14 
3.1 
Conditions for Patient Eligibility ................................................................................................... 14 
3.2 
Conditions for Patient Ineligibility ................................................................................................ 15 
 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT...................................................................... 16 
4.1 
Required Evaluations/Management ............................................................................................ 16 
 
5.0 
REGISTRATION PROCEDURES ................................................................................................... 16 
5.1  
Pre-Registration Requirements for IMRT Treatment Approach .................................................. 16 
5.2 
Pre-Registration Requirements for Standard RT Treatment Approach ...................................... 16 
5.3 
Pre-Registration Requirements for Brachytherapy Treatment Approach ................................... 16 
5.4 
Digital Radiation Therapy Data Submission Using Transfer of Images and Data ...................... 17 
5.5 
Registration, Study Entry Procedures ......................................................................................... 17 
5.6 
Patient Enrollment ....................................................................................................................... 22 
 
6.0 
RADIATION THERAPY ................................................................................................................... 23 
6.1 
Standard External Beam Radiation Therapy .............................................................................. 23 
6.2 
IMRT  ........................................................................................................................................... 25 
6.3 
Intracavitary Radiotherapy Technique and Dose Specifications ................................................ 31 
6.4 
Compliance Criteria for Brachytherapy ....................................................................................... 32 
6.5 
R.T. Quality Assurance Reviews ................................................................................................. 32 
6.6 
Radiation Therapy Adverse Events............................................................................................. 32 
6.7 
Radiation Therapy Adverse Event Reporting .............................................................................. 32 
6.8  
Weekly Portal Images ................................................................................................................. 32 
 
7.0 
DRUG THERAPY ............................................................................................................................ 33 
7.1 
Treatment .................................................................................................................................... 33 
7.2 
Cisplatin Agent Information ......................................................................................................... 35 
7.3 
Carboplatin Agent Information .................................................................................................... 36 
7.4 
Paclitaxel Agent Information ....................................................................................................... 37 
7.5 
Dose Modifications   .................................................................................................................... 38 
7.6 
Modality Review .......................................................................................................................... 42 
7.7        Adverse Events .......................................................................................................................... 42 
7.8 
CTEP-AERS  Expedited Reporting Requirements ..................................................................... 43 
 
8.0 
SURGERY ....................................................................................................................................... 45 
 
9.0 
OTHER THERAPY .......................................................................................................................... 45 
9.1 
Permitted Supportive Therapy .................................................................................................... 45 
9.2 
Non-Permitted Supportive Therapy............................................................................................. 46 

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9.3 
Additional Considerations ........................................................................................................... 46 
 
10.0 
TISSUE/SPECIMEN SUBMISSION ................................................................................................ 46 
10.1 
General Information .................................................................................................................... 46 
10.2 
Fixed Tissue Specimen Collection for Banking and Translational Research ............................. 46 
10.3 
Peripheral Blood Collection for Banking and Translational Research ........................................ 47 
10.4 
Storage Conditions ...................................................................................................................... 48 
10.5 
Submission Address ................................................................................................................... 48 
10.6 
Specimen Collection Summary ................................................................................................... 48 
10.7 
Reimbursement ........................................................................................................................... 49 
10.8 
Confidentiality/Storage ................................................................................................................ 49 
 
11.0 
PATIENT ASSESSMENTS ............................................................................................................. 49 
11.1 
Study Parameters ....................................................................................................................... 49 
11.2 
Efficacy Outcome Definitions ...................................................................................................... 50 
11.3 
Criteria for Discontinuation of Protocol Treatment ...................................................................... 50 
11.4 
Assessments for Quality of Life, Neuropathy, and Diarrhea) ...................................................... 50 
 
12.0 
DATA COLLECTION ....................................................................................................................... 51 
12.1 
Summary of Data Submission ..................................................................................................... 51 
12.2 
Summary of Dosimetry Digital Data Submission ........................................................................ 52 
 
13.0 
STATISTICAL CONSIDERATIONS ................................................................................................ 53 
13.1 
Study Endpoints .......................................................................................................................... 53 
13.2 
Sample Size ................................................................................................................................ 53 
13.3 
Patient Accrual) ........................................................................................................................... 56 
13.4 
Analysis Plan ............................................................................................................................... 56 
13.5 
Inclusion of Minorities .................................................................................................................. 59 
 
REFERENCES ............................................................................................................................................ 60 
 
APPENDIX I ................................................................................................................................................ 62 
APPENDIX II ............................................................................................................................................... 65 
APPENDIX III .............................................................................................................................................. 66 
APPENDIX IV .............................................................................................................................................. 68 
APPENDIX V ............................................................................................................................................... 69 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

RTOG 0724; version date September 21, 2022 
7 
NRG ONCOLOGY  
 
 
RTOG 0724 
PHASE III RANDOMIZED STUDY OF CONCURRENT CHEMOTHERAPY AND PELVIC RADIATION 
THERAPY WITH OR WITHOUT ADJUVANT CHEMOTHERAPY IN HIGH-RISK PATIENTS WITH 
EARLY-STAGE CERVICAL CARCINOMA FOLLOWING RADICAL HYSTERECTOMY 
 
 
SCHEMA (8/21/14) 
 
S 
T 
R 
A 
T 
I 
F 
Y 
 
 
 
Intention To Use Brachytherapy 
1. No 
2. Yes 
 
RT Modality 
1. Standard RT 
2. IMRT 
 
Radiation Therapy Dose 
1. 45 Gy 
2. 50.4 Gy 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
Arm 1 
Concurrent weekly cisplatin and RT ± 
brachytherapy 
 
Versus 
 
Arm 2 
Concurrent weekly cisplatin and 
RT ± brachytherapy 
 
FOLLOWED BY 
 
Carboplatin and paclitaxel 
 
 
See Section 5.0 for credentialing requirements for radiation therapy. 
See Section 6.0 for radiation therapy details. 
See Section 7.0 for drug regimen details. 
 
 
 
Patient Population:  (See Section 3.0 for Eligibility) (8/12/10) 
Patients with clinical stage IA2, IB or IIA squamous, adenosquamous, or adenocarcinoma of the cervix 
who have any/all of the following high-risk features after surgery (this corresponds to surgical TNM 
staging of T1-T2, N1, M0): 
 
Positive pelvic nodes 
 
Positive parametrium 
 
Positive para-aortic nodes- completely resected, PET/CT negative (PET only required if positive para-
aortic nodes during surgery) 
 
 
 
Required Sample Size:  285 patients 
  

RTOG 0724; version date September 21, 2022 
8 
ELIGIBILITY CHECKLIST (12/29/10) 
 
(page 1 of 3) 
 
NRG Oncology Institution #   
 
RTOG 0724 
Case #  
 
 
 
 
        (Y)  1. 
Did the patient have a radical hysterectomy (open, laparoscopically, robotic) and staging 
including pelvic node sampling for cervical carcinoma within 70 days of study entry? 
         (Y/N)    Did the patient undergo para-aortic lymph node sampling/dissection at the 
time of surgery? 
  
 
          (Y)/N) If no, did the patient have a dissection of the common iliac nodes 
and the nodes were negative? 
         Y) If no, did the patient have a negative para –aortic  PET scan or PET-CT 
scan pre-or post-operatively? 
 
        (Y)  2.  
Does the patient have histologic proof of squamous, adenocarcinoma or adenosquamous 
carcinoma of the cervix? 
 
        (Y)  3.  
Is the FIGO stage IA2, Ib or IIA? 
 
        (Y)  4.  
Does the patient have any/all of the following high-risk features post surgery: positive 
pelvic nodes; positive parametrium; or positive para-aortic nodes-completely resected 
and PET/CT negative (required if + PA nodes during surgery) 
 
        (Y)  5.  
Is the Zubrod performance score 0-1? 
 
        (Y)  6.  
Has the patient had a history and physical within 56 days of study entry? 
 
        (Y)  7.  
Has the patient met all the lab requirements as described in Section 3.1.6 and 3.1.7.? 
 
        (Y)  8. 
Has the patient had a chest x-ray, chest CT, or whole body PET-CT within 70 days of 
study entry? 
 
        (Y)  9.  
Has the patient had a contrast-enhanced CT or MRI of the abdomen and pelvis OR 
whole-body PET-CT (with or without contrast) within 90 days of study entry? 
 
        (Y/N)  10. Has the patient had a prior invasive malignancy (except non-melanomatous skin 
cancer)? 
 
        (Y)  11. 
If yes, has the patient been disease free for a minimum of 3 years? 
 
         (N) 12. 
Has the patient had prior systemic chemotherapy for the current cervical 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 unstable angina and/or congestive heart failure requiring 
hospitalization within the last 6 months? 
 
         (N) 15. 
Has the patient had a transmural myocardial infarction within the last 6 months? 
 
         (N) 16. 
Does the patient have an acute bacterial or fungal infection requiring intravenous 
antibiotics at the time of study entry? 
 
 

RTOG 0724; version date September 21, 2022 
9 
 
 
ELIGIBILITY CHECKLIST (12/29/10) 
 
(page 2 of 3) 
 
NRG Oncology Institution #   
 
RTOG 0724 
Case #  
 
 
 
 
 
         (N) 17. 
Does the patient have chronic obstructive pulmonary disease exacerbation or other 
respiratory illness requiring hospitalization or precluding study therapy at the time of 
study entry? 
 
       (N) 18. 
Does the patient have known coagulation defects? 
 
___(Y/N) 19.  Is the patient known to be HIV positive? (NOTE: HIV testing is not required) 
 
 
(Y/NA)  If the patient is known to be HIV positive, has the patient had a CD4 cell 
count of ≥ 350 cells/mm3 obtained within 14 days of study entry?  
 
         (N) 20. 
Has the patient had prior allergic reaction to carboplatin, paclitaxel, and/or cisplatin? 
 
         (N) 21. 
Does the patient have gross residual disease?  
 
         (N) 22. 
Does the patient have distant metastatic disease other then + PA nodes that were 
completely resected and PET/CT negative? 
 
 
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 consent prior to study entry 
 
 
         
5. 
Patient’s Initials (First Middle Last)  [May 2003; If no middle initial, use hyphen] 
 
 
         
6. 
Verifying Physician 
 
 
         
7. 
Patient’s ID Number 
 
 
         
8. 
Date of Birth 
 
 
         
9. 
Race 
 
 
         
10. 
Ethnic Category (Hispanic or Latino; Not Hispanic or Latino; Unknown) 
 
 
         
11. 
Gender 
 
 
         
12. 
Patient’s Country of Residence 

RTOG 0724; version date September 21, 2022 
10 
ELIGIBILITY CHECKLIST (12/29/10) 
 
(page 3 of 3) 
NRG Oncology Institution #   
 
RTOG 0724 
Case #  
 
 
 
 
 
         
13. 
Zip Code (U.S. Residents) 
 
 
         
14. 
Patient’s Insurance Status 
 
 
         
15. 
Will any component of the patient’s care be given at a military or VA facility? 
 
 
         
16. 
Calendar Base Date 
 
 
         
17. 
Registration/randomization date: This date will be populated automatically. 
 
 
         
18. 
Medical oncologist  
 
              (Y/N) 19. 
Have you obtained the patient's consent for his or her tissue to be kept for use in 
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 20.  
Have you obtained the patient's consent for his or her blood to be kept for use in  
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 21. 
Have you obtained the patient's consent for his or her tissue to be kept for use in  
research about other health problems (for example: causes of diabetes, 
Alzheimer's disease, and heart disease)?   
 
              (Y/N) 22. 
Have you obtained the patient's consent for his or her blood to be kept for use in  
research about other health problems (for example: diabetes, Alzheimer's 
disease, or heart disease).  
 
              (Y/N) 23 
Have you obtained the patient's consent to allow someone from this institution to 
contact   
him or her in the future to take part in more research? 
 
              (Y/N) 24.  
Did the patient agree to participate in the quality of life component?” 
 
 
 
         
 
If no, please specify the reason from the following: 
 
 
 
 
1. Patient refused due to illness 
 
 
 
 
2. Patient refused for other reason: specify _____________ 
 
 
 
 
3. Not approved by institutional IRB 
 
 
 
 
4. Tool not available in patient’s language 
 
 
 
 
5. Other reason: specify_________________ 
 
 
              (Y/N) 25. 
Is use of brachytherapy intended?  
 
              (Standard RT/IMRT) 
26. 
Radiation modality to be used  
 
              (45 GY or 50.4GY) 
27. 
Indicate prescribed EBRT dose to be used. 
 
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 patient’s study file and will be evaluated 
during an institutional NCI/NRG Oncology audit. 
 
Completed by  
 
 
 
 
 
Date 
 
 
 
 
 

RTOG 0724; version date September 21, 2022 
11 
 
 
 
1.0 
INTRODUCTION 
Cervical carcinoma is the third most common gynecologic cancer in the United States, with a 
projected 11,150 cases and 3,670 deaths in 2007 (American Cancer Society 2007). The 
incidence of cervical carcinoma is higher in underdeveloped countries. It has been well 
documented that early-stage patients have survival rates of approximately 90%, whether treated 
with radical hysterectomy or radiation therapy alone. However, in 15% to 20% of patients with 
early-stage disease, the disease has either spread to nodes or there is involvement of the 
parametrium or surgical margins at the time of radical hysterectomy. When one or more of these 
factors is found, the 5-year survival rate drops to 50% to 70% (Delgado 1990).  Patients who 
receive pelvic radiation therapy because of these risk factors still have an approximately 34% 
recurrence rate, with 17% of patients experiencing recurrence in the radiated field only and 4% 
experiencing recurrence in the radiated field along with distant metastasis (Peters 2000). 
 
In 1999, after 5 positive trials, the NCI sent out an alert stating that concurrent cisplatin-based 
chemotherapy plus radiation therapy in patients with cervical cancer was better than radiation 
therapy alone (Peters 1990; Rose 1999; Morris 1999). In one of these trials (Peters 1990), 
patients with cervical carcinoma after a radical hysterectomy with positive nodes, parametrium, or 
surgical margins were randomized to concurrent cisplatin and 5-fluorouracil (5-FU) chemotherapy 
plus radiation versus radiation alone. In this trial concurrent chemotherapy and radiation therapy 
significantly improved progression-free and overall survival compared with radiation therapy 
alone. However, patients received different amounts of chemotherapy and, although not part of 
the randomization, the amount of chemotherapy was evaluated for recurrence rates. The patients 
were to receive 2 courses of chemotherapy with the radiation and 2 more courses of 
chemotherapy after the radiation. The investigators found that patients who received ≤ 2 courses 
of chemotherapy had a 31% recurrence rate compared with 13% of patients who received 3 or 4 
courses of chemotherapy. This trial suggests that adjuvant chemotherapy in addition to 
concurrent chemotherapy may be beneficial. The update of this trial, published in 2005, continued 
to show improvement with chemotherapy. However, there was a smaller absolute benefit when 
only one node was positive or when the tumor size was < 2 cm (Monk 2005). 
In addition to platinum, there are other chemotherapy agents that have demonstrated activity in 
cervical cancer. In the Peters trial (1990), cisplatin and 5-FU were used. However, another 
Gynecologic Oncology Group (GOG) trial found greater toxicity with concurrent cisplatin and 5-FU 
versus cisplatin alone; therefore, concurrent weekly cisplatin is the considered standard in the 
United States. Paclitaxel is a biologically active agent in gynecologic malignancies, used most 
abundantly in ovarian cancer. In other primary squamous malignancies such as head and neck 
cancer, paclitaxel has demonstrated activity (Forsatiere 1993). In cervical cancer, single-agent 
paclitaxel has demonstrated a 17% to 25% response rate in recurrent and advanced tumors 
(McGuire 1996; Kudelka 1997).  
The recently closed protocol GOG 204 is evaluating multiple arms of chemotherapy regimens, 
including paclitaxel and cisplatin in one arm, in patients with advanced or recurrent cervical 
cancer. The results were recently presented at ASCO. The investigators found no significant 
advantage of any arm over the control arm of cisplatin and paclitaxel (Monk, 2008). The quality of 
life data of this study was also presented. The investigators found that no doublet was clinically or 
statistically different from cisplatin and paclitaxel in quality of life or pain. The conclusions stated 
that there may be a clinical advantage to cisplatin and gemcitabine and cisplatin and topotecan in 
regards to neurotoxicity over the other two arms. However, the power was too low to detect a 
significant advantage (Wenzel,2008).  Because of the concern of toxicity, especially neurotoxicity, 
with cisplatin, there has been interest in using carboplatin as a less toxic regimen. A trial 
published in 2005 looked at the combination of carboplatin and paclitaxel in advanced and 
recurrent cervical carcinomas and found a 20% partial response rate and a 20% complete 
response rate in 25 patients. They investigators concluded that carboplatin-paclitaxel is an active 
combination in advanced and recurrent cervical cancer (Tinker, 2005).   

RTOG 0724; version date September 21, 2022 
12 
Recently, a multi-institutional retrospective study reported on experience with paclitaxel and 
carboplatin versus paclitaxel and cisplatin in advanced-stage or recurrent cervix cancer. Moore et 
al (2007) found objective responses of 53% in the carboplatin group compared with 29% in the 
cisplatin group, with significantly less toxicity. Internationally, there has been a trend towards 
using carboplatin in cervical cancer, especially in patients previously treated with radiosensitizing 
cisplatin.  Therefore, there is mounting evidence that the combination of paclitaxel and 
carboplatin is an effective and less toxic regimen in cervical cancer.  The added benefit of ease of 
administration as an outpatient treatment makes this regimen an ideal choice to study in this 
population. 
Preliminary data from the ongoing protocol GOG 209, treating advanced or recurrent endometrial 
cancer with either paclitaxel, doxorubicin and cisplatin or paclitaxel and carboplatin, showed 
increased hematologic toxicities when patients were previously irradiated.  This finding led to a 
protocol dose reduction to paclitaxel 135 mg/m2 and carboplatin AUC 5 for women who have 
previously undergone pelvic irradiation.  Consequently, we have modeled our starting doses in 
the treatment arm of paclitaxel and carboplatin to reflect these data.   
The goal of the current study is to evaluate the addition of systemic adjuvant therapy with 
paclitaxel and carboplatin following radical surgery and chemoradiation in early-stage, high-risk 
patients for the reduction in recurrence risk and improvement in disease-free survival and overall 
survival. Toxicity will also be evaluated, and the trial will include a quality of life (See Section 1.1) 
and transitional research component (see Sections 10.2 and 10.3.)  
Radiation therapy will be the standard in both arms. Intensity modulated radiation therapy will be 
allowed at the discretion of the treated radiation oncologist. In 2002, Mell et al. performed a 
nationwide survey and found that 15% of the IMRT users in the United States had treated at least 
one gynecologic patient with IMRT (Mell,2003). In the follow-up survey done in 2004, this 
percentage had increased to 35%, making gynecology the fourth most common site treated with 
IMRT and the most rapidly growing IMRT site overall in the United States (Mell,2005). RTOG 
recently completed a phase II trial evaluating the transportability of IMRT to multiple institutions in 
the post-operative setting in patients with both cervical and endometrial cancer. The results for 
the endometrial arm were recently presented at ASTRO in Boston and found IMRT was feasible 
across multiple institutions in the post-operative setting (Jhingran, 2008). Vaginal brachytherapy 
also will be allowed at the discretion of the treating physician which was not done in the Peters 
trial. Several retrospective studies have shown that vaginal brachytherapy in addition to external 
beam radiation therapy is safe and effective and the addition of it may reduce vaginal recurrence 
further than external beam therapy alone.   
 
1.1 
Assessments for Quality of Life, Neuropathy, and Diarrhea 
A meta-analysis of 19 randomized controlled trials totaling 4,580 patients verified that the 
addition of chemotherapy to radiation therapy improved progression-free and overall 
survival. Five large randomized clinical trials demonstrated a significant survival benefit 
for patients treated with concurrent chemoradiotherapy, using a cisplatin (CDDP)-based 
regimen, with a 28%-50% relative reduction in the risk of death. In addition, the results of 
a meta-analysis of 19 randomized controlled trials of concurrent chemoradiotherapy 
(1981-2000) involving 4580 patients showed that concurrent chemoradiotherapy 
significantly improved overall survival [hazard ratio (HR) 0.71; P < 0.0001], as well as 
progression-free survival (HR 0.61; P < 0.0001). In line with these results, concurrent 
chemoradiotherapy is currently recommended as standard therapy for advanced cancer 
(stage III/IVA) in the United States. However, much less is known about the toxicity and 
quality of life impacts of chemoradiation. (Goonatillake 2009) 
 
The Southwest Oncology Group (SWOG) Protocol 8797/Gynecologic Oncology Group 
(GOG) Protocol 109 addressed the role of adjuvant radiation and chemotherapy after 
radical hysterectomy and lymphadenectomy. This study evaluated women found to have 
positive pelvic lymph nodes (as in the current case) and/or microscopic involvement of 
the parametrium and/or positive surgical margins, who were randomly allocated to 

RTOG 0724; version date September 21, 2022 
13 
receive either pelvic radiation alone or radiation in combination with chemotherapy 
(intravenous bolus cisplatin 70 mg/m2 and a 96-hour infusion of fluorouracil 1,000 mg/m2 
every 3 weeks for 4 cycles). However, in another study by the GOG, it was felt that the 
combination of cisplatin and 5-FU was equally effective as weekly cisplatin and more 
toxic; therefore, weekly cisplatin has become the standard chemotherapy regime with 
radiation therapy. Additionally, the recently closed protocol GOG 204 is currently 
evaluating multiple combinations of chemotherapy, including cisplatin and paclitaxel, in 
the treatment of locally advanced cervical cancer. The combination of paclitaxel and 
cisplatin was generally felt to be the most active regimen of these three choices, 
increasing the response rate to 37% as well as prolonging the progression-free survival). 
However, because of the lack of a clear survival advantage, increased neuropathy, 
increased cytopenia, and associated alopecia, this combination can not be routinely 
recommended. (Monk 2007)  
 
An additional study explored the role of carboplatin in the treatment of cervical cancer 
patients. Forty-three patients staged as IB2–IIIB were treated with three 21-day courses 
of carboplatin (area under the time–concentration curve 6 mg•min/ml) and paclitaxel at 
175 mg/m2 by 3-h infusion both on day 1 followed by radical type III hysterectomy and 
adjuvant radiation concurrent with 6-weekly doses of cisplatin at 40 mg/m2. Response 
rate, resectability, toxicity, and survival were evaluated. Induction chemotherapy was well 
tolerated. A total of 129 cycles were administered, of which only two were delayed for 1 
week. The most common toxicities were nausea/vomiting and neuropathy and occurred in 
48% and 38%, respectively. There were no cases of leukopenia, but neutropenia was 
present in 12% and 3% of courses, respectively. Other toxicities were mild and 
uncommon. (Dueñas-Gonzales 2003) 
 
A meta-analysis of 18 trials was conducted to assess effects of chemoradiation therapy 
and chemoradiotherapy plus chemotherapy. Chemotherapy use was also sub-divided by 
platinum-based and non-platinum. This meta-analysis differed from others in that it was 
conducted using individual patient data and examined both acute and late toxicity data 
(Meta-Analysis Group, 2008). Gastrointestinal and acute hematologic toxicities were the 
most commonly reported toxicities, with a significant increase in gastrointestinal toxicities 
for groups using both platinum-based chemoradiation plus chemotherapy and additional 
radiotherapy (control arm). Gastrointestinal toxicities were not noted in trials using non-
platinum-based chemotherapy. Other data (Nagy 2007; Tormo Ferrero 2009) further 
validate the presence of gastrointestinal toxicities in platinum-based chemoradiation 
treatment for cervical cancer. These data corroborate the gap in knowledge for adverse 
profiles of diarrhea in cervical cancer patients receiving concurrent cisplatin and 5-
fluorouracil chemotherapy plus radiation versus radiation alone. The exploration of these 
adverse event profiles will provide an investigation of the quality of life for this patient 
population and allow for the development of appropriate treatment protocols. Missing 
from these analyses were data on neuropathy, further underscoring the need for the 
current trial.  
 
Quality of life, chemotherapy-induced neuropathy, and diarrhea will be assessed using 
the FACT-Cx, FACT-GOG/NTX4, and the FACIT-D respectively, all of which are patient-
reported questionnaires.  The FACT-Cx version 4 is comprised of 27 general items 
including the four domains of physical well-being, social and family well-being, emotional 
well-being, and functional well-being, as well as 15 additional items specific for symptoms 
and problems related to cervical cancer. The FACT-GOG/NTX4 is a patient-reported tool 
developed by the GOG to assess neuropathy.  It is comprised of 4 items related to 
numbness or tingling in patients’ extremities.  The diarrhea-specific portion of the FACIT-
D is comprised of 11 items.  For all patients participating in this portion of the trial, these 
tools will be collected at the following time points: baseline; end of concurrent 
chemoradiation; and 6, 12, and 24 months after the end of chemoradiation. 
 

RTOG 0724; version date September 21, 2022 
14 
The FACT-Cx, FACT-GOG/NTX4 and FACIT-D are derivatives of the FACT, a family of 
measures first developed in the early 1990’s. The core portion of the FACT, referred to as 
FACT-G, is comprised of four components of quality of life measured across 27 items. 
The FACT-Cx includes 15 additional items specific to cervical cancer; the FACT-
GOG/NTX4 has an additional 4 items specific to peripheral neuropathy; and the FACIT-D 
has an additional 11 items specific to diarrhea.  
 
The FACT-CX has been translated into 14 languages; the FACT-GOG/NTX has been 
translated into 40 languages; and the FACIT-D is available in 17 languages. All are 
available free of charge to institutions with the completion of an agreement to share data, 
accessible  http://www.facit.org/translation/licensure.aspx.  
 
 
2.0 
OBJECTIVES 
2.1 
Primary (8/12/10) 
To determine if adjuvant systemic chemotherapy following chemoradiation therapy will 
improve disease-free survival compared to chemoradiation therapy alone in patients with 
high-risk early-stage cervical carcinoma found to have positive nodes and/or positive 
parametria after a radical hysterectomy.  
 
2.2 
Secondary 
2.2.1 
To evaluate adverse events 
2.2.2 
To evaluate overall survival 
2.2.3 
To evaluate quality of life 
2.2.4 
To evaluate chemotherapy-induced neuropathy 
2.2.5 
To perform a post-hoc dose-volume evaluation between cases treated with standard 
RT and cases treated with IMRT with respect to toxicity and local control 
2.2.6 
To collect fixed tissue to identify tumor molecular signatures that may be associated 
with patient outcomes, such as adverse events, disease-free survival, and overall 
survival 
2.2.7 
To collect blood to: 
 
Identify secreted factors from serum and plasma that may be associated with 
adverse events or outcome, and 
 
Identify SNPs in genes from buffy coat that may be associated with a genetic 
predisposition to tumor formation itself or a response to cytotoxic therapy 
 
 
3.0 
PATIENT SELECTION 
 
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED  
3.1 
Conditions for Patient Eligibility (8/21/14) 
For questions concerning eligibility, please contact the study data manager. 
 
3.1.1 
Patients must have undergone radical hysterectomy (open, laparoscopically or robotic) 
and staging including pelvic node sampling or dissection for cervical carcinoma within 70 
days prior to study entry. [NOTE: If the patient did not have a para-aortic lymph node 
sampling/dissection, but had common iliac node dissection that was negative, a PET-CT 
is recommended, but not required. A negative pre or post-operative PET scan or PET-CT 
scan of the para–aortic nodes is required if the patient did not undergo para-aortic or 
common iliac nodal sampling/dissection] 
3.1.2 
Patients with clinical stage IA2, IB or IIA squamous, adenosquamous, or adenocarcinoma 
of the cervix who have any/all of the following high-risk features after surgery: 
 
Positive pelvic nodes 
 
Positive parametrium 
 
Positive para-aortic nodes- completely resected, PET/CT negative (PET only 
required if positive para-aortic nodes during surgery) 

RTOG 0724; version date September 21, 2022 
15 
3.1.3 
No distant metastases, based upon the following minimum diagnostic workup [NOTE: 
Patients with positive para-aortic nodes- completely resected, PET/CT negative are 
eligible]: 
 
History/physical examination within 56 days prior to study entry 
 
Contrast-enhanced imaging of the abdomen and pelvis by either CT, MRI, or 
whole body PET-CT (with or without contrast) within 90 days prior to registration. 
(NOTE: whole body PET-CT is preferred)  
 
Chest x-ray (PA and lateral) or chest CT within 70 days prior to study entry 
(except for those who have had whole body PET-CT per Section 3.1.3.).  
3.1.4 
Zubrod performance status 0-1. 
3.1.5 
Age ≥ 18 
3.1.6 
CBC/differential obtained 14 days prior to study entry, with adequate bone marrow 
function defined as follows: 
 
Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3  
 
 Platelets ≥ 100,000 cells/mm3  
 
Hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other intervention to 
achieve Hgb ≥ 10.0 g/dl is acceptable.) 
 
White blood cell count ≥ 4000 cells/mm3  
3.1.7 
Adequate hepatic and renal function defined as follows: 
 
Serum creatinine  1.5 mg/dL within 14 days prior to study entry 
 
Bilirubin  1.5 times normal 14 days prior to study entry 
 
Alkaline phosphatase within upper limits of institutional normal within 14 days prior 
to study entry  
 
ALT/SGPT and/or AST/SGOT within upper limits of institutional normal within 14 
days prior to study entry  
 
Patients with known HIV positive must have a CD4 cell count be ≥ 350 cells/mm3 
within 14 days prior to study entry (note, however, that HIV testing is not required 
for entry into this protocol.)  Excluding HIV positive patients with invasive cervical 
cancer and low CD4 cell counts is necessary because the treatments involved in 
this protocol may be significantly immunosuppressive. 
3.1.8 
Patient must provide study-specific informed consent prior to study entry. 
 
 
3.2 
Conditions for Patient Ineligibility 
3.2.1 
Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free 
for a minimum of 3 years (For example, carcinoma in situ of the breast, oral cavity, or 
cervix are all permissible) 
3.2.2 
Patients can not have any neuroendocrine histology in pathology. 
3.2.3 
Prior systemic chemotherapy for the current cervical cancer; note that prior 
chemotherapy for a different cancer is allowable. See section 3.2.1.  
3.2.4 
Prior radiation therapy to the pelvis that would result in overlap of radiation therapy 
fields  
3.2.5 
Severe, active co-morbidity, defined as follows: 
 
Unstable angina and/or congestive heart failure requiring hospitalization within the 
last 6 months 
 
Transmural myocardial infarction within the last 6 months 
 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
study entry 
 
Chronic obstructive pulmonary disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy at the time of study entry  
 
Coagulation defects; note, however, that coagulation parameters are not required 
for entry into this protocol.  
3.2.6 
Prior allergic reaction to carboplatin, paclitaxel, and/or cisplatin.  
3.2.7  
Patients who have gross residual disease or distant metastatic disease.  
 

RTOG 0724; version date September 21, 2022 
16 
 
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 
Required Evaluations/Management 
4.1.1 
Serum calcium, magnesium, sodium, potassium, chloride, CO2, BUN, and glucose. 
4.1.2 
Audiogram when there is a history of hearing loss. 
 
 
5.0 
REGISTRATION PROCEDURES (8/21/14) 
Access requirements for OPEN and TRIAD 
Site staff will need to be registered with CTEP and have a valid and active CTEP Identity and 
Access Management (IAM) account. This is the same account (user id and password) used for 
the CTSU members' web site. To obtain an active CTEP-IAM account, go to https://eapps-
ctep.nci.nih.gov/iam 
 
NOTE:    Only physicians who have completed the Knowledge Assessment Questionnaire 
(for ALL radiation treatment modalities) available from the Imaging and Radiation 
Oncology Core(IROC) Houston website (http://irochouston.mdanderson.org) may 
enter patients onto this study. 
 
NOTE:   See below for information on installing TRIAD for submission of digital RT data   
prior to enrolling patients. 
 
5.1  
Pre-Registration Requirements for IMRT Treatment Approach (8/21/14) 
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 
IROC 
Houston 
web 
site. 
Visit 
http://irochouston.mdanderson.org 
and 
select 
“Credentialing” and “Credentialing Status Inquiry”. 
5.1.1  
An IMRT phantom study with the IROC Houston must be successfully completed (if the 
institution has not previously met this credentialing requirement using IMRT on a Head 
and Neck or Pelvis phantom). Instructions for requesting and irradiating the phantom 
are available on the IROC Houston web site at http://irochouston.mdanderson.org; 
select “Credentialing” and “RTOG”. Upon review and successful completion of the 
phantom irradiation, the IROC Houston will notify both the registering institution and 
IROC Philadelphia that the institution has completed this requirement. Subsequently, 
IROC Houston will notify the institution that the site can enroll patients on the study. 
IROC Philadelphia will notify CTSU that the institution is credentialed. 
5.1.2 
The institution or investigator must complete a Facility Questionnaire and Credentialing 
Status 
Inquiry 
Form 
found 
on 
the 
IROC 
Houston 
website: 
http://irochouston.mdanderson.org and must set up a TRIAD account for digital data 
submission.  
 
5.2 
Pre-Registration Requirements for Standard RT Treatment Approach (8/21/14) 
The Facility Questionnaire and Credentialing Status Inquiry Form must be completed it is 
available on the  IROC Houston web site at http//irochouston.mdanderson.org Institutions must 
set up a TRIAD account for digital data submission.  IROC Houston will notify the institution when 
all requirements have been met. IROC Philadelphia will notify CTSU that the institution is 
credentialed. 
 
5.3 
Pre-Registration Requirements for Brachytherapy Treatment Approach (8/21/14) 
Upon review and successful completion of brachytherapy requirements per the IROC Houston 
website (http://irochouston.mdanderson.org)  IROC Houston will notify both the registering 
institution and IROC Philadelphia.  IROC Houston will then notify the institution. IROC 
Philadelphia will notify CTSU when all requirements have been met.  

RTOG 0724; version date September 21, 2022 
17 
 
5.4 
Digital Radiation Therapy Data Submission Using Transfer of Images and Data  
(21-SEP-2022)  
Transfer of Images and Data (TRIAD) is the American College of Radiology’s (ACR) 
image exchange application. TRIAD provides sites participating in clinical trials a secure 
method to transmit images. TRIAD anonymizes and validates the images as they are 
transferred. 
TRIAD Access Requirements: 
 
A valid Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) (CTEP-IAM) account.  
 
Registration type of: Associate (A), Associate Plus (AP), Non-Physician 
Investigator (NPIVR), or Investigator (IVR). Refer to the CTEP Registration 
Procedures section for instructions on how to request a CTEP-IAM account and 
complete registration in RCR. 
 
TRIAD Site User role on an NCTN or ETCTN roster. 
All individuals on the Imaging and Radiation Oncology Core provider roster have access 
to TRIAD and may submit images for credentialing purposes, or for enrollments to which 
the provider is linked in OPEN. 
TRIAD Installation: 
To submit images, the individual holding the TRIAD Site User role will need to install the 
TRIAD application on their workstation. TRIAD installation documentation is available at 
https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM account and RCR 
registration. 
For questions, contact TRIAD Technical Support staff via email TRIAD-Support@acr.org 
or 1-703-390-9858. 
5.5 
Registration, Study Entry Procedures (21-SEP-2022) 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account at 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr .  RCR utilizes five person registration types. 
 
IVR — MD, DO, or international equivalent; 
 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD); 
 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications  such 
as the Roster Update Management System [RUMS], OPEN, Rave,acting as a primary site 
contact, or with consenting privileges; 
 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; and 
 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with limited 
access to NCI-supported systems. 
 
 
 

RTOG 0724; version date September 21, 2022 
18 
RCR requires the following registration documents: 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
 
 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
 
Addition to a site roster; 
 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
 
Act as the site-protocol Principal Investigator (PI) on the IRB approval. 
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB approval), 
consenting/treating/drug shipment investigator in OPEN, must be rostered at the enrolling site with 
a participating organization.  
 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 
5.5.1    Cancer Trials Support Unit Registration Procedures  
            This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval  
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if the 
study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office 
following country-specific regulations.  

RTOG 0724; version date September 21, 2022 
19 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) 
for Local Context to the CIRB using IRBManager to indicate their intent to open the study 
locally. The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU 
Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the 
CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
 
Local IRB documentation; 
 
IRB-signed CTSU IRB Certification Form; and/or 
 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration 
of Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
 
Holds an active CTEP status; 
 
Active status at the site(s) on the IRB/REB approval  on at least one participating 
organization’s roster; 
 
If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s)record; 
 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile;  
 
Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in 
the RCR profile; and 
 
Holds the appropriate CTEP registration type for the protocol.  
              
 
Additional Requirements  
Additional site requirements to obtain an approved site registration status include: 
 
An active Federal Wide Assurance (FWA) number; 
 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
 
An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
 
Compliance with all protocol-specific requirements (PSRs). 
 
IRB/REB Approved Informed Consent (International sites only: English and native 
language versions*) 
*Note: International and Canadian Institutions must provide                
certification/verification of IRB/REB IEC consent translation to NRG Oncology 
(described below).  
 
Protocol Specific Requirements for RTOG 0724 site registration: 
 CTSU RT Facilities Inventory Form (if applicable) 
 
 
 
 
 

RTOG 0724; version date September 21, 2022 
20 
Non-English Speaking Canadian and Non-North American Institutions: 
*Translation of documents is critical. The institution is responsible for all translation 
costs. All regulatory documents, including the IRB/REB approved consent, must be 
provided in English and in the native language. Certification of the translation is optimal 
but due to the prohibitive costs involved NRG Oncology will accept, at a minimum, a 
verified translation. A verified translation consists of the actual REB approved consent 
document in English and in the native language, along with a cover letter on 
organizational/letterhead stationery that includes the professional title, credentials, and 
signature of the translator as well as signed documentation of the review and 
verification of the translation by a neutral third party. The professional title and 
credentials of the neutral third party translator must be specified as well. 
 
This is a study with a radiation and/or imaging (RTI) component and the enrolling site 
must be aligned to an RTI provider. To manage provider associations or to add or 
remove associated providers, access the Provider Association page from the Regulatory 
section on the CTSU members’ website at https://www.ctsu.org/RSS/RTFP 
roviderAssociation. Site must be linked to at least one Imaging and Radiation Oncology 
Core (IROC) provider to participate on trials with an RTI component. Enrolling sites are 
responsible for ensuring that the appropriate agreements and IRB approvals are in place 
with their RTI provider. An individual with a primary role on a treating site roster can 
update the provider associations, though all individuals at a site may view provider 
associations, though all individuals at a site may view provider associations. To find who 
holds primary roles at your site, view the Person Roster Browser under the RUMS 
section on the CTSU website. 
 
IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC Houston 
to verify credentialing status or to begin a new modality credentialing process.  
 
To complete protocol-specific credentialing the RTI provider or enrolling site should follow 
instructions in the protocol to submit documentation or other materials to the designated 
IROC Quality Assurance (QA) center. Upon the IROC QA center approving the RTI 
provider for the study modality, IROC will automatically send the approval to the 
Regulatory Support System (RSS) to comply with the protocol-specific requirement, 
unless otherwise noted at the bottom of the IROC Credentialing Approval notification.  
IROC will continue to copy the provider and/or enrolling site on modality approvals. 
 
Upon site registration approval in RSS, the enrolling site may access OPEN to complete 
enrollments. The enrolling site will select their credentialed provider treating the subject in 
the OPEN credentialing screen and may need to answer additional questions related to 
treatment in the eligibility checklist.    
 
5.5.2 
Downloading Site Registration Documents  
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to institutions and its associated investigators and 
staff on a participating roster. To view/download site registration forms:   
 Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; 
 Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol 
tree, or 
o Click on the By Lead Organization folder to expand, then select NRG and 
protocol number [NCI Protocol #]. 

RTOG 0724; version date September 21, 2022 
21 
Click on Documents, Protocol Related Documents, and use the Document 
Type filter and select Site Registration to download and complete the forms 
provided. (Note: For sites under the CIRB, IRB data will load automatically to 
the CTSU.)  
 
      Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, 
go to the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately by phone or email: 1-866-
651-CTSU (2878), or CTSURegHelp@coccg.org in order to receive further instruction 
and support. 
 
 
Checking Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.  
 
Click on Regulatory at the top of the screen; 
 
Click on Site Registration; and 
 
Enter the site’s 5-character CTEP Institution Code and click on Go: 
o 
Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
 
                     Pre-Registration Requirements FOR CANADIAN INSTITUTIONS 
 
In addition to the requirements above, Canadian institutions must complete and fax 
to 
the 
CTSU 
Regulatory 
Office 
(215-569-0206) 
or 
e-mail 
(CTSURegulatory@ctsu.coccg.org) the following forms:  
 
Health Canada’s Therapeutic Products Directorates’ Clinical Trial Site 
Information Form,  
 
Qualified Investigator Undertaking Form, and  
 
Research Ethics Board Attestation Form. 
 
5.5.3 
Pre-Registration Requirements FOR INTERNATIONAL INSTITUTIONS 
 
For institutions that do not have an approved LOI for this protocol: 
International sites must submit an LOI to NRG Oncology to receive approval to 
participate 
in 
this 
trial. 
For 
more 
details 
see 
link 
below: 
http://www.rtog.org/Researchers/InternationalMembers/LetterofIntent.aspx  
 
 
For institutions that have an approved LOI for this protocol: 
 
All requirements indicated in your LOI Approval Notification must be fulfilled prior to 
enrolling patients to this study. 
 
 
 

RTOG 0724; version date September 21, 2022 
22 
5.6 
Patient Enrollment (21-SEP-2022) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
Requirements for OPEN access:   
 
A valid CTEP-IAM account; 
 
To perform enrollments or request slot reservations: Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role of 
Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
 
Have an approved site registration for the protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. 
Prior to accessing OPEN, site staff should verify the following: 
 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
 
All patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA) authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com 
 
 
5.6.1  
OPEN Registration Instructions 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
 
All site staff will use OPEN to enroll patients to this study.  OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ web site 
https://www.ctsu.org. 
 
Prior to accessing OPEN site staff should verify the following: 
 
All eligibility criteria have been met within the protocol stated timeframes. Site 
staff should use the registration forms provided on the group or CTSU web site 
as a tool to verify eligibility. 
 
All patients have signed an appropriate consent form and HIPPA 
authorization form (if applicable).  
 
Access requirements for OPEN: 
 
See Section 5.0 for obtaining a CTEP-IAM account.  
 
To perform registrations, the site user must have been assigned the 'Registrar' 
role on the relevant Group or CTSU roster.  

RTOG 0724; version date September 21, 2022 
23 
 
To perform registrations on protocols for which you are a member of NRG 
Oncology, you must have an equivalent 'Registrar' role on the NRG Oncology 
roster.  Role assignments are handled through the Groups in which you are a 
member.  
 
To perform registrations to trials accessed via the CTSU mechanism (i.e., non-
Lead Group registrations) you must have the role of Registrar on the CTSU 
roster. Site and/or Data Administrators can manage CTSU roster roles via the 
new Site Roles maintenance feature under RSS on the CTSU members' web 
site. This will allow them to assign staff the "Registrar" role. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
Further instructional information is provided on the CTSU members' web site OPEN tab 
or within the OPEN URL. For any additional questions contact the CTSU Help Desk at 1-
888-823-5923 or ctsucontact@westat.com.  
 
In the event that the OPEN system is not accessible, participating sites can contact web 
support for assistance with web registration: websupport@acr.org or call the Registration 
Desk at (215) 574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. The registrar 
will ask the site to fax in the eligibility checklist and will need the registering individual’s e-
mail address and/or return fax number. This information is required to assure that 
mechanisms usually triggered by the OPEN web registration system (e.g. drug shipment 
and confirmation of registration) will occur. 
 
 
6.0 
RADIATION THERAPY (8/21/14) 
PRIOR TO ENROLLING PATIENTS, please see Section 5.4 for information on installing 
TRIAD for submission of digital RT data. 
 
Note: Intensity Modulated RT (IMRT) Is Allowed (See Section 6.2) 
Treatment planning CT scans with treatment planning dose information will be required for both 
IMRT and standard RT, and must be digitally submitted  to TRIAD. The CT scans should be 
scans from at least L3 to mid femur. The thickness of the slices depends on the type of treatment: 
For IMRT, the slice thickness should not be more than 3 mm; for standard RT, slice thickness up 
to 5 mm is allowed. For standard RT, no contouring is required; for IMRT requirements are per 
section 6.2.  
 
A rapid review of first enrolled case from each site will be conducted prior to RT treatment 
(see section 6.5) 
 
Protocol treatment must begin within 70 days after surgery. 
 
6.1 
Standard External Beam Radiation Therapy (See Section 6.2. for IMRT) ( 8/21/14) 
6.1.1 
Dose Specifications  
 
All patients will be treated with external beam radiation therapy with standard therapy 
or IMRT treatment plans. If using IMRT, please see Section 6.2 for dose specifications 
and requirements. All patients will be treated to either 45 Gy in 25 fractions or 50.4 Gy 
in 28 fractions (1.8 Gy/fraction). Patients will be treated once per day, 5 days per week. 
If using 6 MV or 10 MV photon energy, the patient must be treated with a 4-field 
technique using anterior/posterior and 2 lateral fields.  
 
The specification of the target dose is in terms of a dose to a point at or near the center 
of the target volume. For all field arrangements the dose specification point is the 
common isocenter of all beams. 
 
 
Radiation Treatment Interruption 

RTOG 0724; version date September 21, 2022 
24 
 
If interruption of 7 consecutive days or fewer occurs, radiation should be completed to 
the prescribed total dose.  
 
 
When therapy interruptions of more than 7 consecutive days occur, resumption of 
therapy will be at the discretion of the radiation oncologist but will be considered a 
deviation unacceptable. (See Section 6.1.8 for compliance criteria.) Follow-up must 
continue regardless of radiation treatment received.  
 
 
6.1.2 
Technical Factors 
 
A megavoltage beam of 6 MV or greater must be used, with a minimum source-axis 
distance of 100 cm. 
6.1.3 
Localization, Simulation, and Immobilization 
Treatment planning CT is required and must be digitally submitted to TRIAD All fields 
treated require simulation and portal verification on the treatment unit. Contouring of 
normal tissues as well as tissues at risk are not required; fields may be drawn using 
boney landmarks.  
6.1.4 
Whenever possible, patient should be treated with full bladder daily to reduce the 
amount of small bowel in the field.  The patient should be instructed to drink 32 oz 
starting 30 to 60 minutes before each treatment. 
6.1.5 
Radiation Treatment Fields  
 
Pelvic Portal (AP-PA) 
 
Superior border: A transverse line between L4-L5. 
 
Lateral border: 1-2 cm lateral to the widest true pelvic diameter. 
 
Inferior border: A transverse line below the obturator foramen and at least 4 cm 
beyond the vaginal cuff. A radio-opaque marker in the vagina to mark the 
vaginal cuff will help to facilitate proper placement of the lower border.  
 
Custom blocking to shield small bowel and femoral heads should maintain a 
margin of at least 1 cm from common iliac nodes and should not shield the 
obturator foramina However, contouring of nodes and normal structures is not 
required; fields may be drawn using boney landmarks. 
 
Pelvic Portal (lateral fields) 
 
Superior border: Identical to AP/PA fields. 
 
Anterior border: A line drawn through the symphysis pubis and at least 1 cm 
anterior to common iliac nodes at L4/L5 
 
Posterior border: Care should be taken to include at S3-S4. 
 
Inferior border: Identical to AP/PA fields. 
 
Custom blocking should be used to shield anterior small bowel if possible, 
maintaining a margin of at least 1 cm from common and external iliac nodes. 
Blocking may split the L4/L5 vertebral body to shield posterior soft tissue and 
split the sacrum to provide adequate margin for pre-sacral nodes. Posterior 
rectum may be blocked. 
 
Para-aortic Field (only if positive common iliac nodes or para-aortic nodes –AP/PA) 
 
Superior border: If common iliac nodes only positive and definitive negative 
para-aortic nodes – L1/L2 interspace; if positive para-aortic nodes – T11/T12 
interspace. 
 
Inferior border: Identical to pelvic field. 
 
Lateral border: Just outside the transverse processes. 
 
Custom blocking to shield the kidneys and bowels, and in the pelvic area, 
should be identical to pelvic portal. 
 
Para-aortic Field (lateral fields) 
 
Superior border: Identical to AP/PA fields 
 
Anterior border: At least 2 cm anterior to the vertebral body and/or 1 cm anterior 
to the para-aortic nodes region contoured. 
 
Posterior border: At least 1 cm posterior to contoured para-aortic nodal region 
and/or 1-1.5 into the vertebral body. 

RTOG 0724; version date September 21, 2022 
25 
 
Inferior border: Identical to pelvic fields. 
 
Custom blocking should block the small bowel and kidneys. Kidneys and spinal 
cord should be contoured, and doses to the kidneys and spinal cord need to be 
determined. 
6.1.6 
Documentation Requirements 
Field outlines are required for all treatment fields.  This information should be displayed 
on Digitally Reconstructed Radiographs (DRRs) produced with the institution’s 
treatment planning computer.  The images should include an outline of the field shape 
for each treatment portal, and must be obtained as a “screen capture” in standard jpg 
format. These images must be sent to TRIAD along with corresponding portal images 
obtained before the start of the first day’s treatment.  The portal images can be 
obtained with either EPID or film.  Radiographic film images must be converted to a 
digital format by the institution using a film scanner so that jpg images can be sent  via 
TRIAD.  The portal imaging process should be repeated every five days.  One set of 
portal images should be sent from the middle of the patient’s fractionated treatment, 
and images from the final portal imaging process should also be forwarded TRIAD 
using the jpg image format.  For data submission, please refer to Section 12.2. 
6.1.7 
Critical Structures 
 
The dose to kidneys and spinal cord should be considered when doing extended 
field radiation therapy; these structures should be contoured on the CT scan and 
dose should be calculated. The following dose criterion should be observed: 
 
Kidneys: 2/3 of each kidney should not receive more than 18 Gy 
 
Spinal cord: no more than 0.03 cc of spinal cord should receive a dose higher than 
45 Gy 
6.1.8 
Compliance Criteria for Standard Radiation Therapy 
 
Per Protocol: See Section 6.1. 
 
Variation Acceptable 
 
Interruption of external beam RT of less than 7 consecutive days 
 
The minimum dose to the dose specification point is greater than or equal to 
43.2 Gy for those patients for whom the intended dose was 45 Gy and greater 
than or equal to 48.6 Gy for those patients for whom the intended dose was 50.4 
Gy.   
 
Maximum dose to a volume of 0.03 cc of tissue within the convergence of the 
treatment fields should not exceed 107% of the prescription dose 
 
Deviation Unacceptable 
 
Field of RT is other than what is outlined in protocol  
 
Interruption of external beam RT of more than 7 consecutive days 
 
The minimum delivered dose to the dose specification point is less than 43.2 Gy 
for patients for whom the intended dose was 45 Gy or less than 48.6 Gy for 
patients for whom the intended dose was 50.4 Gy 
 
Maximum dose to a volume of 0.03 cc of tissue within the convergence of the 
treatment fields exceeds 107% of the prescription dose 
 
6.2 
IMRT (8/21/14) 
Please refer to the Gynecological Atlas for volume specifications.  The Atlas may be 
accessed at:  http://www.rtog.org./CoreLab/ContouringAtlases/GYN.aspx 
6.2.1 
Dose Specifications 
 
Prescription dose will be according to the following specifications:  
 
 
 
The vaginal planning target volume (PTV) (ITV with 7.0 mm margin) and nodal 
PTV will receive either 45 Gy in 25 fractions or 50.4 Gy in 28 fractions.  
Treatment will be delivered once daily, 5 fractions per week, over 5 to 5.5 weeks.  
All targets will be treated simultaneously with the same dose.  Breaks in 
treatment should be minimized.   
 
 
 
 
 
The dose is prescribed to cover 97% of the vaginal PTV and nodal PTV.  A 
volume of at least 0.03 cc within any PTV should not receive > 110% of the 

RTOG 0724; version date September 21, 2022 
26 
prescribed dose.  No volume within the PTV that is 0.03 cc or larger can receive 
a dose that is < 93% of its prescribed dose.  Any contiguous volume of 0.03 cc or 
larger of the tissue outside the PTVs  must not receive > 110% of the dose 
prescribed to the composite PTV.  
6.2.2 
Technical Factors 
 
Megavoltage equipment capable of delivering static intensity modulation with a 
multileaf collimator or dynamic intensity modulation (using a multileaf collimator or 
tomotherapy) is required.  The use of custom made compensators or partial 
transmission blocks is also acceptable as long as dose specifications and 
constraints are satisfied.  
 
 
A megavoltage beam of 6 MV or greater must be used, with a minimum source-axis 
distance of 100 cm.  The exception is the use of the Tomotherapy unit that uses 80 
cm. 
6.2.3 
Localization, Simulation, and Immobilization 
 
Prior to simulation, it is recommended that small radiopaque marker seeds be 
inserted into the vaginal apex to help identify the vaginal apex on the CT scan.   
 
Radiopaque markers that distend or otherwise alter the vaginal anatomy should not 
be used.  
 
 
Patients will be immobilized in the supine position in an immobilization device.   
 
Patients should, at least, be immobilized in a cradle that fixes the position of the 
upper body, trunk and proximal legs.  Patients will be treated in the immobilization 
device.  
 
 
Treatment planning CT scans will be required to define tumor, clinical and planning 
target volumes. The treatment planning CT scan should be acquired with the patient 
in the same position and immobilization device as for treatment 
6.2.4 
Treatment Planning/Target Volumes 
 
Two separate treatment planning CT scans (full bladder and empty bladder CT scans, 
as described below) are required (must be submitted) and then should be fused 
together prior to outlining target volumes. If two CT scans can not be performed, then 
IMRT will not be allowed and the patient must be treated with standard radiation 
therapy. The patient will be instructed to drink 32 ounces of fluid 30-60 minutes before 
simulation:  
 
A CT scan simulation will be performed with the full bladder, and  
 
A second CT will be performed after the patient has voided for the empty 
bladder scan. 
 
Both CT scans must be submitted (see Section 12.2)  
 
In this study, which is used for post-operative patients with no gross disease, there 
should not be a GTV.  
 
 
The Clinical Target Volume (CTV) is defined as areas considered to contain 
potential microscopic disease, delineated by the treating physician.  The overall CTV 
includes both the vaginal/parametrial ITV and the nodal CTV.  Please refer to 
Section 6.2.4.  
for details.  
 
 
Internal Target Volume (ITV) is defined as the volume of the vagina that is in both 
the empty and full bladder CT scans that are done at the time of simulation and 
fused together (the combined volume).  This volume accounts for internal organ 
motion. Institutions who are unable to do an ITV will not be allowed to do IMRT and 
should treat their patients with standard radiation therapy. Institutions that can not 
acquire two CT scans (full and empty bladder scans) should treat the patient with 

RTOG 0724; version date September 21, 2022 
27 
standard RT and not IMRT. It will be considered deviation unacceptable if the 
institution is unable to do two scans but uses IMRT. 
 
 
The Planning Target Volume (PTV) will provide a margin around the ITV to 
compensate for the variability of treatment setup.  Careful consideration should be 
made when defining the superior and inferior margins in three dimensions.  
 
 
Planning of the IMRT will be done on the full bladder scan with full heterogeneity 
correction enabled in the treatment planning system.  
 
 
The treatment plan used for each patient will be based on an analysis of the 
volumetric dose, including dose volume histogram (DVH) analyses of the PTV (CTV 
with a 7 mm margin) and critical normal structures. The treatment aim will be the 
delivery of radiation to the PTVs and the exclusion of non-involved tissues.  
 
 
Planning Priorities 
 
Dose to nodal PTV and vaginal ITV are the most important planning priorities, 
followed by the dose to critical structures prescription goals.  
 
The priorities in addressing the protocol aims and constraints are in Critical 
Structures (See Section 6.2.5).  
 
 
The nodal CTV should include lymph nodes that drain the involved site and adjacent 
perinodal soft tissue.  This should include the internal (hypogastric and obturator), 
external, and common iliac lymph nodes; presacral lymph nodes and soft tissues 
should be included as well, down to the level of S3.  Identification of the CTV usually 
begins with the identification of the iliac vessels.  The nodal CTV will include the 
vessel , perinodal tissue (on the pelvic wall side, the margin will exclude psoas and 
piriformis muscle) and pertinent clips.  The average margin will be 7 mm.  Bone and 
intraperitoneal small bowel should be excluded from the CTV; also, iliopsoas muscle 
that lies adjacent to clinically negative lymph nodes should also be excluded from 
the CTV.  Approximately 1-2 cm of tissue anterior to the S1, S2 and S3 sacral 
segments is usually added to the CTV for patients with cervical carcinoma in order 
to include the presacral lymph nodes and uterosacral ligaments.  The most antero-
lateral external iliac lymph nodes that lie just proximal to the inguinal canal should 
be excluded from the CTV (i.e., nodal CTV should stop right at the level of the 
femoral head).  The CTV of the nodes should end 7 mm from L4/L5 interspace to 
account for the PTV. The PTV for nodes to stop at L4/L5 interspace.  If the para-
aortic nodes for patients with positive common iliacs are treated, then PTV must end 
at the top of L2; for patients with positive para-aortic nodes, the PTV must end at the 
top of T12 (therefore, the CTV must end several slices below these endpoints). (See 
GYN 
atlas 
for 
examples:  
http://www.rtog.org./CoreLab/ContouringAtlases/GYN.aspx.)  
 
 
The vaginal and parametrial CTV should actually be an ITV, which will account for 
internal organ motion.  The ITV is drawn after the full and empty bladder scans are 
fused together, and it should encompass the vagina and paravaginal soft tissues 
from both scans.  This is because patients are not able to maintain constant levels 
of bladder filling, despite careful counseling.  Patients should, however, be treated 
with a full bladder, because full bladder pushes the small bowel up and out of the 
field.  The inferior limit is usually around the level of the upper third of the symphysis 
pubis but can be individualized based on inferior spread of the patient’s tumor on 
prior pre-operative physical examination and post-operative pathology reports.  The 
lateral margin of the vaginal PTV should be to the obturator muscle.  However, at 
least 3 cm of the vagina needs to be treated or at least 1 cm below the obturator 
foramen.  

RTOG 0724; version date September 21, 2022 
28 
 
PTV will provide a 7-mm margin (anteriorly, posteriorly, laterally, as well as in the 
superior and inferior directions) around the nodal CTV.  The vaginal PTV will be 7.0 
mm around the vaginal ITV anteriorly, superiorly, inferiorly, laterally, and posteriorly.  
 
 
The definition of volumes will be in accordance with the 1993 ICRU Report #50:  
Prescribing Recording and Reporting Photon Beam Therapy and 1999 ICRU Report 
#62:  Prescribing, Recording and Reporting Photon Beam Therapy (Supplement to 
ICRU Report 50).  
6.2.5 
Critical Structures 
 
Normal structures will be contoured using the full-bladder CT scan.  
 
Bladder – will be outlined on every slice, including the portion inferior to the planning 
target volume.  The contour includes the bladder contents. 
 
Rectum – will be outlined on every slice, including the portion inferior to the planning 
target volume and superior to the level that it leaves the posterior pelvis around the 
region of the rectosigmoid.  The contour includes the rectum contents. 
 
Bowel – will be outlined on every slice, including up to 2 cm above the planning 
target volume and no more.  It includes the volume surrounding loops of small bowel 
out to the edge of the peritoneum because the bowel may lie within this space at 
any time throughout the course of treatment.  
 
The femoral heads and the sacrum should be contoured in all slices.  
 
The dose constraints for critical structures are as follows: 
 
Bowel: no more than 30% of the volume of the bowel to receive a dose that 
is greater than 40 Gy 
 
Rectum: no more than 60% of the volume of the rectum to receive a dose 
that is greater than 45 Gy  
 
Bladder: no more than 35% of the volume of the bladder to receive a dose 
that is greater than 45 Gy  
 
Kidneys: 2/3 of each kidney to receive ≤18 Gy  
 
Spinal cord: no more than 45 Gy at any point with a volume of 0.03 cc or 
greater 
 
 
IV contrast may be used during simulation to help better define the vessels; 
however, it is not required.  Oral or rectal contrast is not allowed, because it will 
interfere with the planning process and may possibly cause anatomical distortion.  
 
 
All tissues to be irradiated must be included in the CT scan.  CT scan thickness 
should be 3 mm or smaller through the region that contains the primary target 
volumes plus critical structures requiring Dose-Volume Histogram analysis.  
Anatomy inferior and superior to this region, can be imaged with a greater slice 
thickness that does not exceed 5 mm.  The superior limit will be at least at the T10 
interspace and inferior limit will be below the perineum.  
 
 
The ITV and CTV and normal tissues must be outlined on all CT slices in which the 
structures exist on the full-bladder scan.  ITV contours will be drawn to include the 
excursion of target tissues as demonstrated on the empty bladder scan (ITV).  Using 
the full bladder scan, all normal tissues will be outlined on all CT slices in which the 
CTV and ITV exist and on at least 7 slices (21 mm) above and below the target.  
(See Section 6.2.4 for more detailed definitions.)  
 
 
Lymph node groups at risk including the following:  
 
The lower common iliac nodes – the superior limit of the contoured common iliac 
will be at the top of L5 vertebral body – the PTV should be at the top of L5; 
therefore, the CTV should be contoured up to 7 mm from the top of L5  
 
Internal iliac (obturator and hypogastric) nodes  
 
External iliac nodes up to the level of the top of the femoral heads  
 
The presacral nodes down to the level of S3  

RTOG 0724; version date September 21, 2022 
29 
 
The obturator nodes – inferiorly to upper 1/3 of the obturator fossa 
 
If positive common iliacs: PTV must be to top of L2; if positive para-aortic nodes: 
PTV must be to top of T12  
6.2.6 
Documentation Requirements 
Verification orthogonal films or images are required.  For all forms of IMRT dose 
delivery, orthogonal films or images that localize the isocenter placement shall be 
obtained.  The length of the treatment field shall be indicated on these films (images).  
These films (images) will not be collected but should be held by the institution and 
available for review if requested. For data submission, please refer to Section 12.2. 
6.2.7 
Compliance Criteria 
 
Per Protocol: Interruption of 0 days 
 
Variation Acceptable: Interruption of 1-7 consecutive days  
 
Deviation Unacceptable: Interruption of ≥ 8 consecutive days 
 
Volumes 
PTV vagina 45 or 50.4 Gy 
 
Per protocol: The prescription criteria in Section 6.2.1 are fulfilled. 
 
Variation Acceptable: The 0.03cc volume of overdose for the PTV exceeds 
110% of the prescribed dose but remains below 115%. No volume within this 
PTV that is 0.03 cc or larger receives a dose that is  < 91% of its prescribed 
dose. 
 
Deviation Unacceptable: A total of 0.03 cc of the PTV receives a dose that is 
over 115% of the prescribed dose. A volume within this PTV that is 0.03 cc or 
larger does receive a dose that is  < 91% of its prescribed dose. 
PTV nodal 
 
Per Protocol: The prescription criteria in section 6.2.1 are fulfilled. 
 
Variation Acceptable: The 0.03 cc volume of overdose for the PTV exceeds 
110% of the prescribed dose but remains below 115%.No volume within this 
PTV that is 0.03 cc or larger receives a dose that is  < 91% of its prescribed 
dose. 
 
Deviation Unacceptable: A total of 0.03 cc of the PTV receives a dose that is 
over 115% of the prescribed dose. A volume within this PTV that is 0.03 cc or 
larger does receive a dose that is < 91% of its prescribed dose. 
6.2.8 
Critical Structures 
 
Per Protocol 
 
Bowel: no more than 30% of the volume of the bowel to receive a dose that is 
greater than 40 Gy. No volume within bowel that is 0.03 cc or larger receives a 
dose that is > 110% of the prescription dose.  
 
Rectum: no more than 60% of the volume of the rectum to receive a dose that is 
greater than 45 Gy. No volume within rectum that is 0.03 cc or larger receives a 
dose that is > 110% of the prescription dose.  
 
Bladder: no more than 35% of the volume of the bladder to receive a dose that 
is greater than 45 Gy. No volume within bladder that is 0.03 cc or larger receives 
a dose that is > 110% of the prescription dose.  
 
Kidneys: 2/3 of each kidney to receive ≤18 Gy  
 
Spinal cord: no more than 45 Gy at any point with a volume of 0.03 cc or greater 
 
Variation Acceptable 
 
Bowel: A volume of 30% of the bowel does receive a dose that exceeds 40 Gy 
but does not exceed 45 Gy.  A volume of 0.03 cc or larger of bowel exceeds 
110% of the prescribed dose but remains at or below 115%. 
 
Rectum: A volume of 60% of the rectum does receive a dose that exceeds 45 
Gy but does not exceed 50 Gy.  A volume of 0.03 cc or larger of rectum exceeds 
110% of the prescribed dose but remains at or below 115%. 
 
Bladder: A volume of 35% of the bladder does receive a dose that exceeds 45 
Gy but does not exceed 50 Gy.  A volume of 0.03 cc or larger of bladder 
exceeds 110% of the prescribed dose but remains at or below 115%. 
 
Deviation Unacceptable 

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30 
 
Bowel: A volume of 30% of the bowel does receive a dose that is > 45 Gy.  A 
volume of 0.03 cc or larger of bowel exceeds 115% of the prescribed dose.  
 
Rectum: A volume of 60% of the bowel does receive a dose that is > 50 Gy.  A 
volume of 0.03 cc or larger of rectum exceeds 115% of the prescribed dose. 
 
Bladder:  A volume of 35% of the bladder does receive a dose that is > 50 Gy.  
A volume of 0.03 cc or larger of bladder exceeds 115% of the prescribed dose. 
 
Note: All required structures must be labeled for digital RT data submission as listed in the table 
below. Resubmission of data may be required if labeling of structures does not conform to the 
standard DICOM name listed. 
 
The 
following 
table 
outlines the 
naming of 
the various 
normal and 
critical 
structures 
for 
submission 
to TRIAD. 
 
STANDARD 
STRUCTURE NAMES for TRIAD SUBMISSION 
 
 
Structure 
DICOM name 
Description 
ITV 
ITV 
The volume of the 
vagina that is in both 
the empty and full 
bladder CT scans that 
are done at the time 
of simulation and 
fused together (the 
combined volume).   
CTVLN 
CTVn 
Nodal CTV 
PTVLN 
PTVn 
 
CTV VAG 
CTVp 
Vaginal CTV 

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31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3 
Intracavitary Radiotherapy Technique and Dose Specifications (optional treatment) 
6.3.1 
If vaginal brachytherapy boost is given, it must follow the external beam irradiation and 
be started within 7 days of completion of the pelvic irradiation. If high-dose rate 
applications are to be used, the insertions should be given in such a way to allow 
completion of the insertion prior to the beginning chemotherapy. More than one 
insertion may be performed per week. External beam radiation and intracavitary 
treatment should not be given on the same day. Iridium or cesium sources are to be 
used for intracavitary application with vaginal applicators for the after-loading applicator 
system.  
6.3.2 
It is preferable to treat the vaginal cuff only (treatment of the entire length of the vagina 
is discouraged and may increase morbidity). Not more than 2/3 of the vagina should be 
included in the treatment volume. Colpostats/ovoids or cylinders may be used. 
6.3.3 
For low-dose rate applications, 20-25 Gy (depending on the final external beam dose) 
to the vaginal surface in a single application will be given. For high-dose rate 
applications, 12-18 Gy to the vaginal surface in 2 to 3 applications (depending on the 
final external beam dose as described below) will be given. 
 
For low-dose rate applications: A dose of 20-25 Gy will be prescribed to the vaginal 
surface at a dose rate of 0.8 to 1.2 Gy per hour (see Appendix IV). Final dose is 
determined by the final dose of the external beam; if 45 Gy if given, then 25 Gy to 
the vaginal surface should be delivered and if 50.4 Gy is given, then the dose 
delivered should be 20 Gy. Colpostats or cylinders may be used. The largest 
possible cylinder diameter should be selected. Colpostats should be secured with 
maximal packing to minimize dose to the adjacent bladder and rectum.  
 
 
For high-dose rate applications: Two to three applications of 6 Gy each will be 
prescribed to the vaginal surface, for a total of 12-18 Gy. Dose will be prescribed at 
PTV VAG 
PTVp 
Vaginal PTV 
Bladder 
Bladder 
 
Rectum 
Rectum 
 
Left  Femur 
Femur_L 
 
Right Femur 
Femur_R 
 
Small Bowel 
BowelSpace 
It includes the volume 
surrounding loops of 
small bowel out to the 
edge of the 
peritoneum 
Left Kidney 
Kidney_L 
 
Right Kidney 
Kidney_R 
 
Spinal Cord 
SpinalCord 
 
Unspecified Tissue 
External 
 

RTOG 0724; version date September 21, 2022 
32 
the vaginal surface (see Appendix IV). If treating to a pelvic dose of 45 Gy, the dose 
to the vaginal surface should be 18 Gy in 3 fractions; if treating to a dose of 50.4, the 
dose to the vaginal surface should be 12 Gy in 2 fractions.  
6.3.4 
A Gynecological Brachytheraphy Protocol Compliance Form report on the source 
specifications, strengths, spacing relative to the applicators, size of applicator, and 
dosimetry calculations for all points is MANDATORY. The source employed must be in 
the directory used by IROC Houston. Dwell times and dwell positions for all HDR 
insertions are also required. For all films that are submitted, the points of dose 
calculations should be marked on the film (vaginal surface points) as well as bladder 
and rectal points if calculated. If cylinders are used and source specification and 
applicator size does not change, dose distributions may be made on only the first 
cylinder if desired. Dose to the vaginal surface from ovoid (colpostat) should include 
contribution from both ovoids. 
 
Vaginal surface dose may be calculated at the vaginal surface lateral to the 
midpoint of the surface of the ovoid or cylinder. See Appendix IV.  
 
If a cylinder is used, the dose at the apex of the cylinder should be calculated to be 
as close as possible (within +/- 25%) to the lateral vaginal surface dose. Dose 
points 0.5 cm posterior and anterior to the cylinder or colpostat should be 
calculated.  
 
6.4 
Compliance Criteria for Brachytherapy 
6.4.1 
Per Protocol: See Section 6.3.1 
6.4.2 
Variation Acceptable: Brachytherapy starting within 7 days from the completion of 
external beam RT.  
6.4.3 
Deviation Unacceptable: Brachytherapy starting after 14 days from the completion of 
external beam RT.  
 
6.5 
R.T. Quality Assurance Reviews (8/21/14) 
The Radiation Oncology Chair, Anuja Jhingran, MD (or NRG Oncology approved designee), will 
perform RT Quality Assurance Rapid Reviews on the first case from each site before the start of 
treatment. The next four cases submitted within one-week of RT planning will be performed as 
“Timely Reviews” (RT may begin and accrual continue before review feedback on these timely 
reviews).  The remaining cases will be reviewed on an ongoing basis. 
 
 
6.6 
Radiation Therapy Adverse Events 
Adverse effects expected from radiotherapy include tiredness near the end of treatment, diarrhea, 
nausea and vomiting, rectal irritation, urinary frequency and dysuria, loss of pubic hair, reddening 
and irritation of the skin in the irradiated field, and depression of blood counts. Long-term side 
effects, although uncommon, may include chronic malabsorption, rectal ulcer, bleeding, or 
stricture, dysuria, hematuria, bowel obstruction, shortening of the vagina, dyspareunia, vaginal 
vault necrosis and fistula formation between pelvic tissues. If the para-aortic nodes are treated, 
additional side effects include possible long-term kidney damage leading to dialysis and spinal 
cord damage leading to paralysis. 
 
 
6.7 
Radiation Therapy Adverse Event Reporting 
See Section 7.0. 
 
 
6.8  
Weekly Portal Images 
All participating institutions in either IMRT or Standard arm of the trial must digitally submit the 
first set of weekly portal images (every five treatment fractions) of all treatment films, a set taken 
in the middle of the external beam course, and the final set of weekly portal images in JPEG 
format. These images can come either from EPIDs or scanned Portal films.  For data submission 
please refer to section 12.2 
 

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33 
7.0 
DRUG THERAPY 
Protocol treatment must begin within 70 days after surgery. 
 
7.1 
Treatment (8/21/14) 
All patients will receive concurrent chemotherapy with weekly cisplatin intravenously during 
external beam radiation therapy for a total of 6 cycles.  Patients randomized to the 
chemotherapy treatment arm (Arm 2) will receive paclitaxel and carboplatin once every 21 days 
for 4 cycles, to start 4 to 6 weeks following completion of chemoradiation.   
 
7.1.1 
Concurrent Chemoradiation 
 
Drug 
Dose 
Schedule 
Arm 1 
Cisplatin 
40 mg/m2, 
maximum dose 70 
mg 
IV weekly over 1 hour, during 
external beam radiation x 5-6 
weeks (see Section 7.1.1.3 for 
administration details) 
 
Arm 2 
Cisplatin 
40 mg/m2, 
maximum dose 70 
mg 
IV weekly over 1 hour, during 
external beam radiation x 5-6 
weeks (see Section 7.1.1.3 for 
administration details) 
 
 
Dose Calculation: The dose will be calculated using actual body weight. The dose 
will be recalculated if there is a weight change of >10% from baseline.   
 
Preparation: Patients will receive pre- and post-hydration per institutional guidelines.  
Pre-medications can be given at the discretion of the treating physician.  Cisplatin 
injection should be further diluted in 0.9% sodium chloride or 5% dextrose and 
0.25% to 0.5% sodium chloride injection (Do not dilute in just 5% Dextrose Injection) 
and administered within 24 hours.   
 
 
Administration: Cisplatin will be administered once a week (starting on Monday or 
Tuesday, day 1 or 2) during external beam therapy (days 1, 8, 15, 22, 29, 36 or days 
2, 9, 16, 23, 30, 37). Cisplatin can be given before or after radiation.   
7.1.2 
Adjuvant Chemotherapy 
Patients randomized to the chemotherapy arm should start chemotherapy 4-6 weeks 
following completion of radiation therapy. 
 
Drug 
Dose 
Schedule 
Arm 1 
No treatment 
No treatment 
No treatment 
 
Arm 2 
Paclitaxel  
135 
mg/m2, 
maximum dose at 
BSA 2.0 m2 
 
IV over 3 hours, every 21 days 
x 4 (see Section 7.1.2. for 
administration details) 
 
 
Carboplatin 
AUC 5 
IV over 30 mins, every 21 days 
x 4 (see Section 7.1.2. for 
administration details) 
 
 
Paclitaxel  
 
Dose Definition 
 
The dose of paclitaxel is 135 mg/m2, with maximum body surface area (BSA) of 
2.0 m2.  The dose will be recalculated if there is a weight change of ≥10% from 
baseline.   
 
Preparation 
The regimen can be administered in an outpatient setting. Paclitaxel will be 
administered in a 3-hour infusion followed by carboplatin over 30 minutes. 
Paclitaxel will be administered via an infusion control device (pump) using non-

RTOG 0724; version date September 21, 2022 
34 
PVC tubing and connectors, such as the IV administration sets (polyethylene or 
polyolefin)which are used to infuse parenteral Nitroglycerin. Nothing else is to be 
infused through the line where paclitaxel is being administered. An antiemetic 
regimen is recommended. The antiemetic regimen used should be based on 
peer-reviewed consensus guidelines per institutional protocol. It is recommended 
that a preparative regimen be employed to reduce the risk associated with 
hypersensitivity reactions. This regimen should include dexamethasone (either IV 
or PO), anti-histamine H1 (such as diphenhydramine) and anti-histamine H2 
(such as cimetidine, ranitidine, or famotidine) given prior to administration of 
paclitaxel. 
 
 
Administration 
Paclitaxel 135 mg/m2, 3-hour infusion, Day 1, q 21 days, administered prior to 
carboplatin 
 
Patients randomized to the chemotherapy arm should start treatment within 4, 
but no longer than 6, weeks following completion of radiation therapy. 
 
 
Carboplatin  
 
Dose Definition 
The dose of carboplatin is area under the curve (AUC) 5. The dose will be 
calculated to reach a target area under the curve (AUC) of concentration x time 
according to the Calvert formula using an estimated glomerular filtration rate 
(GFR) from the Cockcroft-Gault formula.  
 
The initial dose of carboplatin must be calculated using GFR. In the absence of 
new renal obstruction or other renal toxicity greater than or equal to CTCAE v. 
4.0 grade 2 (serum creatinine >1.5 x ULN), the dose of carboplatin will not be 
recalculated for subsequent cycles, but will be subject to dose modification as 
noted.  
 
Carboplatin doses will be based on the subject’s weight at baseline and will 
remain the same throughout the study. However, the doses will be recalculated if 
the patient has a weight change of ≥ 10% from baseline. 
 
In patients with an abnormally low serum creatinine (less than or equal to 0.7 
mg/dl), due to reduced protein intake and/or low muscle mass, the creatinine 
clearance should be estimated using a minimum value of 0.7 mg/dl. If a more 
appropriate baseline creatinine value is available within 4 weeks of treatment that 
may also be used for the initial estimation of GFR. When concerned about the 
safety in a specific patient, measure GFR. 
 
 
Calvert Formula: Carboplatin dose (mg) = target AUC × (GFR +25). 
 
Note: the GFR in the Calvert formula should not exceed 125ml/min 
 
 
Maximum carboplatin dose (mg) = target AUC (mg/ml) x 150 ml/min. 
 
 
The maximum allowed doses of carboplatin in the study are: 
 
 
AUC 5 = 750 mg 
 
AUC 4 = 600mg 
 
 
For the purposes of this protocol, the GFR is considered equivalent to the 
creatinine clearance.  The creatinine clearance (Ccr) is estimated by the method 
of Cockcroft-Gault using the following formula: 
 

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35 
Creatinine Clearance (mL/min) = [140-Age(years)] x Weight (kg) x 0.85                                    
 
 
 
 
 
       72 x serum creatinine (mg/dl) 
NOTES:  
 
1).Weight in kilograms:  
In general, actual weight should be used for estimation of GFR.  However it is 
also acceptable to utilize ideal weight, when concerned about safety in a specific 
patient, in accordance with local institutional policy. An example of a commonly 
employed ideal weight calculation is:  
Ideal weight (kg) = (Height (cm)/2.54) – 60) x 2.3) + 45.5 
2) The Cockcroft-Gault formula above is specifically for women (it includes the 
0.85 factor) 
3) Conversion of IDMS creatinine levels to “non-IDMS” values will no longer be 
performed. 
 
Preparation  
Carboplatin will be reconstituted in 5% dextrose in water or 0.9% sodium chloride 
to produce a carboplatin concentration of 10 mg/ml.   
 
NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss 
of potency; therefore, needles or intravenous sets containing aluminum parts that 
may come in contact with the drug must not be used for the preparation or 
administration of carboplatin.  
 
Unopened vials of carboplatin are stable for the life indicated on the package 
when stored at controlled room temperature and protected from light. 
 
Administration 
Carboplatin AUC of 5 over 30 minutes, Day 1, q 21 days for 4 cycles, 
administered after paclitaxel. 
 
Patients randomized to the chemotherapy arm should start treatment within 4, 
but no longer than 6, weeks following completion of radiation therapy. 
 
7.2 
Cisplatin Agent Information 
Refer to the package insert for comprehensive pharmacologic and safety information. 
7.2.1 
Description, Packaging, and Storage 
Cis-diamminedichloroplatinum (cisplatin) is a heavy metal complex and is water 
soluble. It mechanism of action is a bifunctional alkylating agent.  Cisplatin is packaged 
as a sterile aqueous solution, each mL containing 1 mg cisplatin and 9 mg sodium 
chloride. Cisplatin is supplied in multidose vials with 50 mg and 100 mg of cisplatin. 
Store at 15-20°C. Do not refrigerate. Protect unopened container from light. The 
cisplatin remaining in the amber vial following initial entry is stable for 28 days 
protected from light or for 7 days under fluorescent room light.   
 
NOTE: Aluminum reacts with cisplatin causing precipitation formation and loss of 
potency; therefore, needles, or intravenous sets containing aluminum parts that may 
come in contact with the drug must not be used for the preparation or administration of 
cisplatin. 
7.2.2 
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.  
7.2.3 
Adverse Effects 
Allergy: Allergic reactions 
Gastrointestinal: Nausea and vomiting 
Hematologic: Myelosuppression, anemia, thrombocytopenia 

RTOG 0724; version date September 21, 2022 
36 
Metabolic: Electrolyte imbalance, hypocalcemia, hypomagnesemia 
Neurologic: Peripheral neuropathy 
Ocular/Visual: Ocular toxicity 
Ototoxicity: Aminoglycoside ototoxicity 
 
 
(Infrequent) 
Acute myeloid leukemia 
Dermatologic: Rash 
Gastrointestinal: Anorexia 
Hepatic: Elevated SGOT 
Renal: hemolytic uremic syndrome 
Other: Alopecia, Metallic taste 
 
Severe renal toxicity can be largely avoided by induction of a diuresis before, during, 
and after treatment.  Mild renal dysfunction is a common complication (10%) of chronic 
therapy and may require discontinuation of therapy if BUN > 30 mg/dl or creatinine > 
2.0 mg/dl develop. Mild or severe electrolyte abnormalities may occur (5%) as acute or 
chronic complications, especially hypokalemia or hypomagnesemia. Monitoring of 
electrolytes and electrolyte replacement will usually correct these abnormalities. Rarely, 
severe hypomagnesemia and hypocalcemia may require replacement therapy and 
discontinuation of treatment with cisplatin.  Allergic reactions are rare. If accompanied 
by respiratory symptoms, allergic reactions require discontinuation of treatment. Patch 
or skin tests are recommended for patients with suspected allergy to cisplatin. An 
emergency set for the treatment of allergic reactions should be available in the 
treatment area. Local necrosis and thrombophlebitis can be avoided by careful 
administration.  Neurotoxicity is related to cumulative dose and severe toxicity can be 
largely avoided by careful monitoring for evidence of paresthesias and timely 
discontinuation of treatment. Ataxia has been described. Ototoxicity may occur. 
NOTE: Eighth (VIII) nerve toxicity resulting in hearing loss and (less commonly) 
vestibular symptoms, is a well-documented complication of cisplatin treatment and is 
usually related to total cumulative dose.  It is advised that patients placed on cisplatin, 
whether as a single agent therapy or combination, be questioned concerning hearing 
loss. Patients with a history of hearing loss should be considered for pre-treatment 
audiometry with follow-up audiometry as clinically indicated. It is recommended that 
patients be queried concerning hearing loss before each course of cisplatin. 
 
7.3 
Carboplatin Agent Information 
Refer to the package insert for comprehensive pharmacologic and safety information. 
7.3.1 
Description, Packaging, and Storage 
Carboplatin is supplied as a sterile lyophilized powder available in single-dose vial 
containing 50 mg, 150 mg, and 450 mg of carboplatin for administration by intravenous 
infusion. Each vial contains equal parts by weight of carboplatin and mannitol. 
Immediately before use, the content of each vial must be reconstituted with either 
sterile water for injection, USP, 5% dextrose in water, or 0.9% sodium chloride 
injection, USP, according to the following schedule: 
Vial Strength Diluent Volume 
50 mg 5 ml 
150 mg 15 ml 
450 mg 45 ml 
These dilutions all produce a carboplatin concentration of 10 mg/ml. When prepared as 
directed, carboplatin solutions are stable for eight hours at room temperature, since no 
antibacterial preservation is contained in the formulation it is recommended that 
carboplatin solutions be discarded eight hours after dilution. 
 
NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss of 
potency, therefore, needles, or intravenous sets containing aluminum parts that may 

RTOG 0724; version date September 21, 2022 
37 
come in contact with the drug must not be used for the preparation or administration of 
carboplatin.  Unopened vials of carboplatin are stable for the life indicated on the 
package when stored at controlled room temperature and protected from light. 
7.3.2 
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. 
7.3.3 
Adverse Effects 
Allergy: Allergic reaction 
Gastrointestinal: Nausea and vomiting 
Hematologic: Myelosuppression 
Hepatic toxicity: Mild elevations in bilirubin, SGOT, and alkaline phosphatase levels. 
Metabolic: Electrolyte imbalance, hypomagnesemia, hypocalcemia 
Neurologic: Peripheral neuropathy 
Ototoxicity  
Ocular/Visual: Ocular toxicity 
 
7.4 
Paclitaxel Agent Information 
7.4.1 
Refer to the package insert for comprehensive pharmacologic and safety information. 
Description, Packaging, and Storage 
Paclitaxel is a poorly soluble plant product from western yew, Taxus brevifolia. 
Improved solubility requires a mixed solvent system with further dilutions of either 0.9% 
sodium chloride or 5% dextrose in water.  A sterile solution concentrate, 6 mg/ml in 5 
ml vials (30 mg/vial) in polyoxyethylated castor oil (Cremophor EL) 50% and 
dehydrated alcohol, USP, 50%. The contents of the vial must be diluted just prior to 
clinical use. It is also available in 100 and 300mg vials.  Paclitaxel, at the appropriate 
dose, will be diluted in 500-1000 cc of 0.9% Sodium Chloride injection, USP or 5% 
Dextrose injection, USP (D5W) (500 cc’s is adequate if paclitaxel is a single agent). 
Paclitaxel must be prepared in glass or polyolefin containers due to leaching of 
diethylhexlphthalate (DEHP) plasticizer from polyvinyl chloride (PVC) bags and 
intravenous tubing by the Cremophor vehicle in which paclitaxel is solubilized. 
 
NOTE: Formation of a small number of fibers in solution (within acceptable limits 
established by the USP Particulate Matter Test for LVPs) has been observed after 
preparation of Taxol. Therefore, in-line filtration is necessary for administration of 
paclitaxel solutions. In-line filtration should be accomplished by incorporating a 
hydrophilic microporous filter of pore size not greater than 0.22 microns (e.g. IVEX-II, 
IVEXHP or equivalent) into the IV fluid pathway distal to the infusion pump. Although 
particulate formation does not indicate loss of drug potency, solutions exhibiting 
excessive particulate matter formation should not be used. The intact vials can be 
stored in a temperature range between 2-25oC (36-77°F). Commercially available 
paclitaxel will be labeled with an expiration date. All solutions of paclitaxel exhibit a 
slight haziness directly proportional to the concentration of drug and the time elapsed 
after preparation, although when prepared as described above, solutions of paclitaxel 
(0.3-1.2 mg/ml) are physically and chemically stable for 27 hours. 
7.4.2 
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. 
7.4.3 
Adverse Effects   
Allergy: Anaphylactoid and urticarial reactions (acute), flushing, rash, pruritus 
Blood pressure: Hypotension, hypertension (possibly related to concomitant 
medication--dexamethasone)  
Gastrointestinal: Nausea and vomiting, diarrhea, stomatitis, mucositis, 
pharyngitis, typhlitis, ischemic colitis, neutropenic enterocolitis 
Heart: arrhythmia, heart block, ventricular tachycardia, myocardial infarction(MI), 
bradycardia,  atrial arrhythmia 
Hematologic: Myelosuppression 

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38 
Liver: Increased SGOT, SGPT, bilirubin and alkaline phosphatase, hepatic failure, 
hepatic necrosis 
Neurologic: Sensory (taste), peripheral neuropathy, seizures, mood swings, hepatic 
encephalopathy, encephalopathy 
Pulmonary: Pneumonitis 
Skin: Infiltration: erythema, induration, tenderness, rarely ulceration, radiation recall 
reactions 
Other: Alopecia, fatigue, arthralgia, myalgia, light-headedness, myopathy 
Other, Vision: Sensation of flashing lights, blurred vision, scintillating scotomata 
 
7.5 
Dose Modifications  (8/30/12) 
7.5.1  
Chemoradiation Therapy with Weekly Cisplatin 
No chemotherapy will be given until all drug-related toxicities, except anemia, > grade 2 
have resolved to grade 1.  There will be no dose escalations in this study.  
Chemotherapy will not be administered during a radiation therapy delay.  Radiotherapy 
will not be omitted or delayed for chemotherapy-related toxicities unless the 
investigator considers the patient too ill to be treated.   
 
Initial treatment modifications will consist of cycle delay and/or dose reduction as 
directed.  Treatment decision will be based on absolute neutrophil count (ANC) not total 
white blood cell count (WBC).  No cisplatin will be administered or resume until ANC is 
≥1500 cells/m3 and/or platelet count is ≥ 75,000 cells/m3.  Chemotherapy will be 
delayed week-by-week until these levels are exceeded. External radiation should 
continue while cisplatin is being held.  Patients who fail to recover from toxicities within 
21 days will not receive further protocol-directed therapy.  Only one dose reduction is 
allowed for cisplatin.   
 
Table A.  Dose Level Modifications 
 
Drug 
Starting dose level 
Dose level -1 
Cisplatin 
40 mg/m2 (70 mg maximum) 
30mg/m2 (60 mg 
maximum) 
 
CONCURRENT TREATMENT 
TOXICITY 
PARAMETER 
MODIFICATION 
 
Febrile neutropenia/ANC  
1st occurrence febrile 
neutropenia (≥ grade 3) 
or ANC <500 mm3 lasting 
>7 days 
Hold for that week. Repeat CBC. If ANC 
resolves to grade 1, resume at 1 dose 
level reduction. If ANC does not resolve 
to grade 1, discontinue chemotherapy. 
 
Febrile neutropenia/ANC  
2nd occurrence 
Discontinue cisplatin. 
 
ANC 
Uncomplicated (no 
fever/infection) <500 mm3 
lasting <7 days 
 
No dose reduction. 
Platelets 
1st occurrence grade 4 
thrombocytopenia or 
bleeding associates w/ 
grade 3 
thrombocytopenia 
Hold for that week. Repeat blood work. If 
platelets >75,000 cells/mm3, resume at 1 
dose level reduction. If platelets do not 
resolve to grade 1, discontinue cisplatin. 
 
 
2nd occurrence 
Discontinue cisplatin. 
 
 
Grade 3 – uncomplicated 
Hold until platelets > 75,000 cells/mm3. 

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39 
(absence of associated 
bleeding) 
Resume at current dose level (no dose 
modification).  
Nausea/vomiting 
Grade 4 
Once resolved to grade 1 with supportive 
therapy, resume and reduce by 1 dose 
level. 
 
 
2nd occurrence 
Discontinue cisplatin. 
 
Serum creatinine 
>2.0 mg/dl 
Hold 1 week. Repeat blood work. 
Resume if creatinine resolves to less 
than institutional ULN within 1 week.  
Discontinue if not recovered after 1 
week. 
 
Neurotoxicity-peripheral 
neuropathy 
 
Grade 2 
Hold cisplatin until neuropathy resolves 
to grade 1, then resume at 1 dose level 
reduction. If neuropathy does not resolve 
to grade 1, discontinue chemotherapy. 
 
 
≥ Grade 3 
Hold until grade 1. Resume at 1 dose 
level reduction. 
 
Hearing loss 
Symptomatic 
Discontinue cisplatin. 
 
Fatigue 
Any grade 
No dose reduction. 
 
Other non-hematologic 
toxicity  
 
≥ Grade 3 
Hold until grade 1. If delayed >21 days, 
discontinue cisplatin. 
 
 
7.5.2 
Adjuvant Chemotherapy with Paclitaxel and Carboplatin 
The adjuvant treatment course will not begin until all toxicities, except anemia, ≥ grade 
2 have resolved to grade 0 or 1. There will be no dose escalations in this study.   
 
Initial treatment modifications will consist of cycle delay and/or dose reduction as 
directed.  Treatment decisions will be based on absolute neutrophil count (ANC) not the 
total white blood cell count (WBC).  No treatment course will begin or resume until ANC 
is ≥ 1500 cells/mm3 (CTCAE grade 1) and platelet count is ≥ 100,000/mm3.  Treatment 
will be delayed for a maximum of 21 days until values are achieved.  A patient who fails 
to recover adequate counts in the 21-day period will not receive protocol-directed 
chemotherapy.  Exceptions to the above statement are patients who received G-CSF 
prior to the current cycle; these patients will be allowed to receive chemotherapy with 
ANC ≥ 1000 cells/mm3.  Also, patients who are delayed more than 7 days for 
hematologic toxicity may begin with ANC ≥1000 cells/mm3, as they will receive G-CSF 
during the subsequent therapy (See Section 9).  
 
 
 
Delayed Hematologic Recovery 
If ANC is less than 1,500 cells/mm3 (CTCAE grade 2 or worse) within 24 hours prior 
to chemotherapy, or 1000 cells/mm3 if the patient received G-CSF during the 
previous cycle, therapy will be delayed.  If platelet count is less than 100,000 
cells/mm3 within 24 hours prior to chemotherapy, therapy will be delayed.  Patients 
who have a >7 day delay in recovery of ANC to greater than 1000 cells/m3 will 
receive G-CSF with the next cycle.  Treatment will be delayed for a maximum of 21 

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40 
days until values are achieved.  Patients who fail to recover adequate counts in the 
21-day period will not receive protocol-directed chemotherapy. 
 
 
Paclitaxel Hypersensitivity Reaction  
Hypersensitivity reactions during administration of paclitaxel usually occur in the first 
few minutes of infusion.  Appropriate symptomatic therapy should be given per the 
treating physician institution’s protocol.  Consideration for continued treatment 
should be given if the reaction is not considered life threatening.  If the patient 
decides to continue treatment, it is preferable to re-treat that same day.  A 
suggested re-treatment would be to administer the drug first with 1 cc of the original 
IV solution diluted in 100 cc over 1 hour, then 5 cc in 100 cc over 1 hour, then 10 cc 
in 100 cc over 1 hour and finally the original solution at the normal speed.  Patients 
who elect not to have immediate (same day) re-treatment of paclitaxel may be given 
just carboplatin only that day, but they would be candidates for paclitaxel 
hypersensitivity rechallenge at the next cycle per their institution’s protocol.   
 
Table B.  Dose Level Modifications 
 
Drug 
Starting dose level 
Dose Level -1 
Paclitaxel 
135 mg/m2 
110 mg/m2 
Carboplatin 
AUC 5 (750 mg or less) 
AUC 4 (600 mg or less) 
 
ADJUVANT TREATMENT 
 
TOXICITY 
PARAMETERS 
MODIFICATION 
Refer to Section 7.5.2 for 
resumption details 
Febrile neutropenia/ 
ANC and platelets 
1st febrile neutropenia or ANC 
<500 mm3 lasting >7 days AND 
grade 4 thrombocytopenia or 
grade 3 thrombocytopenia 
associated with bleeding 
 
Reduce carboplatin 1 dose level  
 
2nd 
Reduce paclitaxel 1 dose level and 
add G-CSF  
 
3rd 
Discontinue protocol therapy.  
 
Febrile neutropenia/ 
ANC only 
1st occurrence febrile 
neutropenia or ANC<500 mm3 
lasting >7 days 
 
Reduce carboplatin 1 dose level  
 
2nd occurrence  
Reduce paclitaxel 1 dose level and 
add G-CSF  
 
3rd occurrence 
Discontinue protocol therapy. 
 
Neutropenia 
Grade 4 uncomplicated (no 
fever/infection) lasting <7 days 
 
No dose modifications. 
Platelets only 
1st occurrence grade 4 
Reduce carboplatin 1 dose level  
 
 
2nd  
Reduce paclitaxel 1 dose level  
 
 
3rd 
Discontinue protocol therapy. 
 
 
1st occurrence grade 3 
Reduce carboplatin 1 dose level  

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41 
associated with bleeding 
 
 
2nd 
Reduce paclitaxel 1 dose level  
 
 
3rd 
Discontinue protocol therapy. 
 
 
Grade 3 uncomplicated 
(absence of associated 
bleeding) 
No dose modifications. 
 
GI 
Any grade 
No dose modifications. 
 
Serum creatinine 
≥Grade 2 (less than 2.0 mg/dl) 
 
 
 
Hold treatment; when recovered to 
grade 1, resume, reducing 
carboplatin 1 dose level. If not 
recovered to ≤grade 1 within 21 
days, discontinue protocol therapy. 
 
 
>2.0 mg/dl 
Hold treatment. Calculated 
creatinine clearance must be 
obtained. If <50 ml/min, hold 
treatment and get weekly CalCcr 
until level is >50 ml/min. Then 
resume treatment, reducing 
carboplatin 1 dose level. If after 21 
days the CalCcr is still <50 ml/min 
or serum creatinine is >2.0 mg/dl, 
discontinue protocol therapy and 
notify study chair. 
 
 
≥Grade 3 
Notify study chair. 
 
Neurotoxicity-peripheral 
neuropathy 
≥Grade 3 
Reduce paclitaxel and carboplatin 
1 dose level and delay subsequent 
therapy for up to 21 days until 
recovered to grade 1. If not 
recovered within 21 days, 
discontinue protocol therapy. 
 
 
2nd occurrence 
Discontinue protocol therapy. 
 
SGOT/SGPT/alkaline 
phosphatase  
≥Grade 3 
Hold treatment; when recovered to 
≤grade 1 resume, reducing 
paclitaxel 1 dose level. If not 
recovered to ≤grade 1 within 21 
days, discontinue protocol therapy. 
 
Bilirubin 
≥Grade 3 
Hold treatment; when recovered to 
≤grade 1 resume, reducing 
paclitaxel 1 dose level. If not 
recovered within 21 days, 
discontinue protocol therapy. 
 
Alopecia, fatigue, 
myalgias 
Any grade 
No modification. 
 
Other non-hematologic 
toxicity 
≥Grade 3 
Hold treatment until recovered to 
grade 1. If not recovered to ≤grade 

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42 
1 within 21 days, discontinue 
protocol therapy. 
 
 
7.6 
Modality Review 
The Medical Oncology Co-Chair, Heidi Gray, 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. Gray will perform a Quality Assurance Review after complete data for the first 20 cases 
enrolled has been received at NRG Oncology. Dr. Gray will perform the next review after 
complete data for the next 20 cases enrolled has been received at NRG Oncology. 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 has been received at NRG Oncology, whichever occurs 
first. 
 
7.7        Adverse Events (8/21/14) 
 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 for adverse event (AE) reporting. The CTCAE version 4.0 is located on the CTEP website at                              
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below will be 
reported via the CTEP-AERS (CTEP Adverse Event Reporting System) application accessed via 
either the CTEP web site (https://eapps-
ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613). 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 
the RTOG Operations Office at 1-800-227-5463, ext. 4189, for instances when Internet fails. 
Once internet connectivity is restored, an AE report submitted by phone must be entered 
electronically into CTEP-AERS. 
 
7.7.1 
Adverse Events (AEs)  
 
Definition of an AE: Any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related.  Therefore, an AE can be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product (attribution 
of unrelated, unlikely, possible, probable, or definite). (International Conference on 
Harmonisation [ICH], E2A, E6). [CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements. February 29, 2012; 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.ht
m]  
 
7.7.2 
Serious Adverse Events (SAEs) — Serious adverse events (SAEs) that meet expedited 
reporting criteria defined in the table in section 7.8 will be reported via CTEP-AERS.  
SAEs that require 24 hour CTEP-AERS notification are defined in the expedited 
reporting table.  Contact the CTEP-AERS Help Desk if assistance is required. 
 
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that 
results in any of the following outcomes: 
 Death; 

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43 
 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, 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.  
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited 
manner.  
7.7.3 
Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) 
 
AML or MDS that is diagnosed as a secondary malignancy during or subsequent to 
treatment in patients on NCI/CTEP-sponsored clinical trials must be reported via the 
CTEP-AERS system within 30 days of AML/MDS diagnosis. 
 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g., treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event: 
 
 Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
 Myelodysplastic syndrome (MDS) 
 Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine reporting via CDUS unless otherwise specified.  
 
  
7.8 
CTEP-AERS Expedited Reporting Requirements (8/21/14) 
All serious adverse events that meet expedited reporting criteria defined in the reporting table 
below will be reported via CTEP-AERS, the CTEP Adverse Event Reporting System, accessed 
via the CTEP web site, 
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
     
 
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG 
Oncology requirements for expedited adverse event reporting. 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve 
radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only 
pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 
the NRG Oncology at 1-800-227-5463, ext. 4189, for instances when Internet fails. Once internet 

RTOG 0724; version date September 21, 2022 
44 
connectivity is restored, an AE report submitted by phone must be entered electronically into 
CTEP-AERS. 
 
 
CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour notification is 
electronically submitted within 24 hours of learning of the adverse event. Each CTEP-
AERS 24-hour notification must be followed by a CTEP-AERS 5 Calendar Day 
Report. Serious adverse events that require 24 hour CTEP-AERS notification are 
defined in the expedited reporting table below. 
 
Supporting source document is not mandatory.  However, if the CTEP-AERS report 
indicates in the Additional Information section that source documentation will be 
provided, then it is expected.  If supporting source documentation accompanies an 
CTEP-AERS report, include the protocol number, patient ID number, and CTEP-
AERS ticket number on each page, and fax supporting documentation to the NRG 
Oncology dedicated SAE FAX, 215-717-0990. 
 
A serious adverse event that meets expedited reporting criteria outlined in the 
following table but is assessed by the CTEP-AERS System as “expedited reporting 
NOT required” must still be reported to fulfill RTOG safety reporting obligations. Sites 
must bypass the “NOT Required” assessment; the CTEP-AERS System allows 
submission of all reports regardless of the results of the assessment.  
 
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials as described 
in the table below. Important: All AEs reported via CTEP-AERS also must be reported 
on the AE section of the appropriate case report form (see Section 12.1). 
 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies utilizing a Commercial Agent within 30 Days of the 
Last Administration of the Commercial Agent  
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether 
or not they are considered related to the commercial agent (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 

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45 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 
hours of learning of the AE, followed by a complete expedited report within 5 calendar days 
of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite require 
reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half lives, rounded UP to the nearest whole day, after the agent/intervention was last 
administered.  Footnote “1” above applies after this reporting period. 
Effective Date: May 5, 2011 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements 
for Phase 2 and 3 Trials Utilizing a Commercial Agent: 
None 
 
8.0 
SURGERY 
All patients will undergo surgery for their cancer prior to enrolling in this protocol 
 
 
9.0 
OTHER THERAPY 
9.1 
Permitted Supportive Therapy  
 
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 on each site’s source documents as concomitant medication.  
9.1.2 
Antiemetics should be given prior to and immediately after chemotherapy per the 
treating institution’s protocol. 
9.1.3 
Anticoagulants: Patients may receive anticoagulation therapy as a prophylaxis 
treatment for venous thromboembolism. 
9.1.4 
Antidiarrheals may be administered per the treating institution’s protocol. 
9.1.5 
Analgesics may be administered per the treating institution’s protocol. 
9.1.6 
Hematopoietic Growth Factors and Protective Agents: (NOTE: See Section 9.2.2 for 
non-permitted hematopoietic growth factors and protective agents) 
Patients may receive erythropoietin (EPO) for management of anemia AFTER 
documentation of hemoglobin less than 10g/dl (CTCAE grade 2).  Patients may receive 
transfusion or iron supplements as clinically indicated.  Patients may receive filgrastim 
(G-CSF) or PEG-filgrastim (Neulasta) if they demonstrate hematologic toxicity as 
outlined in Section 7.6.    

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46 
9.1.7 
Herbal Products: may be administered per the treating institution’s protocol. 
9.1.8 
Nutritional Supplementation: may be administered per the treating institution’s protocol. 
 
9.2 
Non-Permitted Supportive Therapy  
9.2.1 
Aminoglycoside antibiotics given before, with, or after cisplatin may potentiate renal 
toxicity and should be avoided whenever possible.  
9.2.2 
Hematopoietic Growth Factors and Protective Agents: (NOTE: See Section 9.1.6 for 
permitted hematopoietic growth factors and protective agents) 
Patients will NOT receive prophylactic filgrastim (G-CSF), PEG –filgrastim (Neulasta), 
or sargramostim (GM-CSF).  Patients will NOT receive prophylactic thrombopoietic 
agents.  Patients will NOT receive amifostine or other protective agents.  [NOTE: If 
patients experience delays due to hematologic toxicity, hematopoietic growth factors 
are allowed as indicated as outlined in Section 7.6.]   
 
9.3 
Additional Considerations 
Please see Section 7.2.3 for additional supportive care considerations related to cisplatin 
administration. 
 
 
10.0 
TISSUE/SPECIMEN SUBMISSION  
NOTE: Patients must be offered the opportunity to participate in the tissue/specimen 
submission portion of the protocol. If the patient consents to participate in this component of 
the study, the site is required to submit the patient’s specimens as specified below.  
 
Sites are not permitted to delete the tissue/specimen component from the protocol or from the 
sample consent. 
 
10.1 
General Information  
The NRG Biospecimen Bank at the University of California San Francisco acquires and maintains 
high quality specimens from NRG Oncology trials. Tissue from each block is preserved through 
careful block storage and processing. NRG Oncology encourages participants in protocol studies 
to consent to the banking of their tissue. The NRG Biospecimen Bank 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 
NRG Biospecimen Bank 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 NRG Biospecimen Bank for the purpose of tissue 
banking and translational research (recommended but not mandatory). 
 
10.2 
Fixed Tissue Specimen Collection for Banking and Translational Research ( 8/21/14) 
For patients who have consented to participate in the tissue/blood component of the study  
 
In this study, from FFPE tumor tissue we will isolate RNA and DNA to allow us to perform tumor 
tissue microarrays. We will also obtain FFPE tumor cores and create tissue arrays to allow us to 
perform immunohistochemistry for gene expression. Evaluation of tumor specimens and the 
possibility of creating a tissue array allows for easy simultaneous staining for proteins of interest 
and TUNEL staining for apoptosis. MicroRNA and gene expression utilizing microarray 
technology has been evaluated in a wide variety of neoplasms. Microarray technology allows for 
the simultaneous evaluation of hundreds of microRNAs and thousands of genes, creating a “snap 
shot” of the pathways activated in the tumor. The ultimate goal of these studies will be to identify 
tumor signatures that predict for patient outcomes such as toxicity, disease-free survival and 
overall survival. Better predictors of these factors before the initiation of treatment in the future 
could help guide treatment and create a “genetically tailored’ treatment approach. 
 
The following must be provided in order for the case to be evaluable for the Biospecimen Bank:  

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47 
10.2.1 
One H&E stained slide (slide can be a duplicate cut stained H&E of the diagnostic slide 
(block); it does not have to be the diagnostic slide itself) 
10.2.2 
A corresponding paraffin-embedded tissue block of the tumor the block must match the 
H&E being submitted) or three 2-mm diameter cores of tissue, punched from the tissue 
block containing the tumor with a punch tool and submitted in a plastic tube labeled 
with the surgical pathology number. NOTE: A kit with the punches, tubes, and 
instructions can be obtained free of charge from the NRG Oncology Biospecimen Bank. 
Block or core must be clearly labeled with the pathology identification number and 
block ID that corresponds to the Pathology Report. 
10.2.3 
A Pathology Report documenting that the submitted block or core contains tumor. The 
report must include the NRG Oncology protocol number and patient’s case number. 
The patient’s 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. 
10.2.4 
A Specimen Transmittal (ST) Form clearly stating that tissue is being submitted for the 
NRG Oncology Biospecimen Bank; if for translational research, this should be stated 
on the form. The form must include the NRG Oncology protocol number and patient’s 
case number.  
 
10.3 
Peripheral Blood Collection for Banking and Translational Research (8/30/12) 
In this study from serum and plasma we will be able to measure levels of secreted 
factors, antibodies, microRNAs, tumor cells etc., giving insight into both initial levels of 
these factors as well as levels at the end of treatment, to determine if levels determine 
toxicity or outcome at either timepoint. Whole blood analysis will allow us to have the 
patient normal DNA to perform studies such as SNP (single nucleotide polymorphism) 
studies in each patient. SNPs are inherited differences in a person’s DNA. There is 
mounting evidence that SNPs in genes important in DNA repair (oncogenes etc.) might 
either predict for a genetic predisposition to tumor formation itself or response to cytotoxic 
therapy.  
 
Serum and plasma for consenting subjects will be taken prior to treatment and at 
completion of chemoradiotherapy. Whole blood for DNA can be taken prior to treatment 
OR at completion of treatment. 
10.3.1 
Serum 
 
Use a Red top blood tube for serum collection.  
 
Keep serum collection tubes at 4° C until processing (tubes may be on ice up to 
2 hrs).   
 
Centrifuge specimens at 1000 x g (approximately 2500 RPM for standard clinical 
centrifuge) at 4°C for 10 minutes. 
 
Using sterile techniques to avoid contamination, aliquot 0.5 mL serum into 5-10 
1.0 mL cryovials and freeze at -80° C until ready to ship on dry ice. 
 
Take great care to collect only serum and avoid collecting any solid particulate 
matter into the cryovials.  
10.3.2 
Plasma  
 
Collect blood into one 3–5 mL purple-topped tubes (containing EDTA), using a 
19–21 gauge needle to minimize hemolysis.  
 
Store blood tubes vertically at 4°C, avoiding any kind of agitation. Ideally these 
should be processed within 30 minutes. 
 
Centrifuge specimens at 1000 x g (approximately 2500 RPM for standard clinical 
centrifuge) at 4°C for 10 minutes. 
 
Take the top two-thirds of supernatant and aliquot to a 0.5 mL/vial into 5-10 mL 
cryovials. The tip of the transfer pipette should be kept far away (at least 0.5 cm) 
from the buffy coat (this is very important in order to avoid platelet 
contamination).  
 
Label each aliquot with study protocol and case numbers, the date and time of 
collection, and the time point taken, before or after treatment. 

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48 
 
Place specimens in -80° C freezer until ready to ship on dry ice. 
 
10.3.3 
Whole Blood 
 
Collect blood into one 5 mL purple-topped tubes (containing EDTA), using a 19–
21 gauge needle to minimize hemolysis.  
 
Invert tubes to mix the whole blood and aliquot 1.0mL into up to 3-5 1mL 
cryovials. 
 
Store at -80° C until ready to ship on dry ice. 
 
10.3.4 
The above materials must be provided to the NRG Oncology Biospecimen Bank: 
A Specimen Transmittal (ST) Form documenting the date and time of collection 
of the specimen; the NRG Oncology protocol number, the patient’s case number, 
and method of storage, for example, stored at -80° C, must be included. 
 
Collection 
Kits 
may 
be 
requested 
from 
the 
Biospecimen 
Bank 
at 
RTOG@ucsf.edu 
 
10.4 
Storage Conditions (8/12/10) 
Store at –80 C (-70C to -90C) until ready to ship. If a -80C Freezer is not available:  
 Samples can be stored short term in a -20 C freezer (non-frost free preferred) for 
up to one week (please ship out Monday-Wednesday only- Canada: Mon-Tues). 
OR: 
 Samples can be stored in plenty of dry ice for up to one week, replenishing daily 
(ship out Monday-Wednesday only- Canada: Mon-Tues). 
OR: 
 Samples can be stored in liquid nitrogen vapor phase (ship out Monday-
Wednesday only- Canada: Mon-Tues). 
 
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and 
time stored. 
 
10.5 
Submission Address (8/21/14) 
Submit materials for banking and translational research as follows: 
 
Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
UCSF Box 1800 
2340 Sutter St, Room S341 
San Francisco, CA 94143-1800 
 
Courier Address (FedEx, UPS, etc.): For Trackable FFPE and ALL Frozen 
Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter St, Room S341 
San Francisco, CA 94115 
 
Questions: 415-476- 7864/FAX 415-476-5271; RTOG@ucsf.edu 
 
10.6 
Specimen Collection Summary ( 8/21/14) 
Specimens taken from 
patient: 
Collected when: 
Submitted as: 
 
Shipped: 
Representative H&E 
stained slide of the 
At surgery 
H&E stained slide 
Slide shipped ambient 

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49 
primary tumor  
A paraffin-embedded 
tissue block of the 
primary tumor or three 2 
mm diameter core of 
tissue, punched from the 
tissue block with a punch 
tool  
At surgery 
Paraffin-embedded 
tissue block or punch 
biopsy (must match the 
H&E slide being 
submitted)   
 
Block or punch shipped 
ambient 
 
SERUM: 5-10 mL of 
whole blood in 1 red-top 
tube and centrifuge 
Pre-treatment and at 
completion of 
chemotherapy 
Frozen serum samples 
containing 0.5 mL per 
aliquot in 1 mL 
cryovials (five to ten) 
Serum sent frozen on 
dry ice via overnight 
carrier 
PLASMA: 5-10 mL of 
anticoagulated whole 
blood in EDTA tube #1 
(purple/lavender top) 
and centrifuge 
Pre-treatment and at 
completion of 
chemotherapy 
Frozen plasma samples 
containing 0.5 mL per 
aliquot in 1 mL 
cryovials (five to ten) 
Plasma sent frozen on 
dry ice via overnight 
carrier 
DNA: 5-10 mL of 
anticoagulated whole 
blood in EDTA tube #2 
(purple/ lavender top) 
and mix 
Pre-treatment OR at 
completion of 
chemotherapy. NOTE 
if site missed the 
collection site may 
collect this specimen 
at any timepoint or 
follow-up but this must 
be noted on the ST. 
Frozen whole blood 
samples containing 1 
ml per aliquot in 1ml 
cryovials (three to five).  
Whole blood sent 
frozen on dry ice via 
overnight carrier 
 
 
10.7 
Reimbursement (8/21/14) 
 
NCI funds for reimbursement for protocol-specified biospecimen materials will be distributed per 
the requirements/methods specified by the new NCTN Program. This information will be made 
available with the other registration materials in the Oncology Patient Enrollment Network (OPEN) 
portal system. OPEN will serve as the registration system for all patient enrollments onto NCI-
sponsored NCTN trials, including this study, which will be transitioned into the new Program from 
the NCI-sponsored Cooperative Group Clinical Trials Program. 
 
10.8 
Confidentiality/Storage (8/30/12) 
 
(See the Patient Tissue Consent Frequently Asked Questions,  
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspx 
for 
further details.) 
10.8.1 
Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the 
patient’s case number only. The NRG Oncology Biospecimen Bank 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. 
10.8.2 
Specimens will be stored for an indefinite period of time. If at any time the patient 
withdraws consent to store and use specimens, remaining material will be returned to 
the institution that submitted it. 
 
11.0 
PATIENT ASSESSMENTS (12/29/10) 
11.1 
Study Parameters: See Appendix I for a summary of assessments and time frames. Details 
and exceptions appear below  
11.1.1 
Audiogram will be performed for patients with a history of hearing loss and for patients 
who start to complain about ringing in the ear or hearing loss during treatment. 

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50 
11.1.2 
Pap smear should be performed at least yearly during follow-up but should follow the 
standard guidelines of the institution. 
11.1.3 
Chest x-ray/chest CT will be performed yearly during follow-up unless there is reason 
to perform it sooner. 
11.1.4 
A PET Scan or PET-CT will be performed pre or post-operatively for patients who do 
not undergo para-aortic lymph node or common iliac lymph node sampling/dissection 
or who have positive common iliac nodes during surgery but no para-aortic sampling 
(See section 3.1.1 of the protocol for details). 
 
11.2 
Efficacy Outcome Definitions 
11.2.1 
Local Failure: Cervical cancer recurrence; biopsy confirmation is required. 
11.2.2 
Regional Failure: Appearance or recurrence of pelvic nodes; biopsy confirmation is 
required. 
11.2.3 
Para-Aortic Nodal Failure: Appearance or recurrence of para-aortic nodes; biopsy 
confirmation is required. 
11.2.4 
Distant Metastases Failure: Appearance of distant metastases other than para-aortic 
nodes. 
11.2.5 
Disease-Free Survival Failure: Local, regional, para-aortic, distant metastases failure, 
or death due to any cause. 
11.2.6 
Overall Survival Failure: Death due to any cause. 
 
11.3 
Criteria for Discontinuation of Protocol Treatment 
11.3.1 
Appearance of recurrent disease. 
11.3.2 
Adverse events that require discontinuation of protocol treatment per protocol-specified 
dose modifications. 
 
If protocol treatment is discontinued, follow-up and data collection will continue as specified in the 
protocol. 
 
11.4 
Assessments for Quality of Life, Neuropathy, and Diarrhea (8/12/10) 
NOTE: Patients must be offered the opportunity to participate in the Quality of 
Life/Neuropathy/Diarrhea portion of the study. If the patient consents to participate in this 
component of the study, the site is required to submit the patient’s specimens as specified below.  
 
Sites are not permitted to delete the Quality of Life/Neuropathy/Diarrhea portion from the protocol 
or from the sample consent. 
 
For all patients participating in this portion of the trial, these tools will be collected at the following 
time points: baseline; end of concurrent chemoradiation; and 6, 12, and 24 months after the end 
of chemoradiation. 
 
The FACT-CX has been translated into 14 languages; the FACT-GOG/NTX has been translated 
into 40 languages; and the FACIT-D is available in 17 languages. All are available free of charge 
to 
institutions 
with 
the 
completion 
of 
an 
agreement 
to 
share 
data, 
accessible  
http://www.facit.org/translation/licensure.aspx.  
 
If a non-English form is used, it must be transcribed onto the English version of the form and 
submitted to NRG Oncology per Section 12. Both copies must be kept in the patient’s files. 

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51 
11.4.1 
FACT-GOG/NTX4 
The FACT-GOG/NTX4 is a patient-reported tool developed by the GOG to assess 
neuropathy.  It is comprised of 4 items related to numbness or tingling in patients’ 
extremities. 
11.4.2 
FACT-Cx 
The FACT-Cx version 4 combines the components of the FACT-G (27 general items 
including the four domains of physical well-being, social and family well-being, 
emotional well-being, and functional well-being), with 15 additional items specific for 
symptoms and problems related to cervical cancer. 
11.4.3 
FACIT-D 
The diarrhea-specific portion of the FACIT-D is comprised of 11 items. 
 
 
12.0 
DATA COLLECTION (04-FEB-2022) 
Data should be submitted to: 
NRG Oncology* 
50 South 16th Street, Suite 2800 Philadelphia, PA  19102 
 
*If a data form is available for web entry, it must be submitted electronically. 
 
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 (8/21/14) 
 
 
Item 
Due 
Demographic Form (A5) 
Within 2 weeks of study entry 
 
Initial Evaluation Form (I1) 
Within 2 weeks of study entry 
 
Treatment Form (TF) 
Within 1 week of Chemo/RT completion 
 
Treatment Form (SF)- ARM 2 Patients Only 
 
Within 1 week of Adjuvant Chemo completion 
 
Follow-Up Form (F1) 
Every 3 months for the first 2 years, then 
every 6 months for 3 years, then annually. 
Also at progression/relapse and at death. 
 
Surgical Operative Report (S2)  
 
Within 2 weeks of study entry 
Surgical Pathology Report (S5) 
 
Within 2 weeks of study entry 
Autopsy Report (D3) 
As applicable 
 
Quality of Life (QL) 
 
Pre-treatment, at the end of concurrent 
treatment, and then at 6,12 and 24 months 
after concurrent treatment 
 
Final Dosimetry Information:  
 
Radiotherapy Form (T1) (copy to HQ) 
 
1 week after RT 
Complete Daily Treatment Record (T5) (copy 
to HQ) 
 

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52 
 
12.2 
Summary of Dosimetry Digital Data Submission (Submit TRIAD; see Section 5.0 for account 
access and installation instructions) (8/21/14) 
 
Item 
Due 
Preliminary Dosimetry Information (DD) 
 
Digital Data Submission – Treatment Plan submitted to TRIAD via TRIAD in 
DICOM format exported from treatment planning machine by Physicist 
Within 1 
week of 
start of 
RT 
Digital data submission includes the following: 
 
DICOM CT data,  
 
DICOM Structure critical normal structures, all GTV, CTV, and PTV 
contours 
 
DICOM Plan 
 
DICOM Doses  
 
Digital DVH data for all required critical normal structures, GTV, CTV, and 
PTVs for total dose plan  
 
All required structures MUST be labeled per the Table in Section 6.2. 
 
The “RTOG 0724 Datasheet” is available in the Forms section of the of the 
NRG Oncology/RTOG web site, 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0724 
Submit via TRIAD with the digital data listed above. 
Upon submission of the digital data via TRIAD, complete an online digital 
data transmission form (DT) located in the Forms section on the NRG 
Oncology/RTOG web site at    
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0724 
 
 
 
Final Dosimetry Information 
Within 1 
week of 
RT end 
Radiotherapy Form (T1) [copy to HQ] 
Daily Treatment Record (T5) [copy to HQ] 
Modified digital patient data as required through consultation with Image-Guided 
Therapy QA Center 
NOTE: 
Three sets of portal or isocenter verification images (beginning, middle of 
fractionated treatment and end) should be sent via TRIAD in jpg format. 
Institutions using Tomotherapy or relying on IGRT are required to send “screen 
captures” of the images used for verifying the patient’s position. 
 
 
*Optional Brachytherapy data (see section 6.3)  
 
Submit to IROC Houston: Complete brachytherapy treatment planning data including 
digital images or films INCLUDING AP and LATERAL views. 
 
Send by mail or FedEx to: 
IROC Houston QA Center 
8060 El Rio Street 
Houston, TX 77054 
 

RTOG 0724; version date September 21, 2022 
53 
 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Study Endpoints 
13.1.1 
Primary Endpoint 
Disease-free Survival (DFS) (failure: local, regional or distant metastases failure or 
death due to any cause) 
13.1.2 
Secondary Endpoints 
 
Adverse events 
 
Overall survival 
 
Chemotherapy-induced neuropathy as measured by FACT-GOG/NTX4 
 
QOL as assessed by FACT-Cx & FACIT-D 
 
Associations between tumor molecular signatures, from fixed tissue, and outcomes 
such as adverse events, disease free survival and overall survival 
 
Associations between secreted factors from serum and plasma with adverse 
events or outcome 
 
Associations between SNPs in genes from buffy coat and a genetic predisposition 
to tumor formation itself or a response to cytotoxic therapy 
 
13.2 
Sample Size (04-FEB-2022) 
13.2.1 
Stratification  
Patients will be stratified before randomization with respect to intention to use 
brachytherapy (no vs. yes) and radiation therapy modality (standard RT vs. IMRT), and 
radiation therapy dose (45 vs. 50.4 Gy). The treatment allocation scheme described by 
Zelen (1974) will be used because it balances patient factors other than institution. 
Patients will be randomized to radiation given concurrently with weekly cisplatin and 
optional brachytherapy  4 additional cycles of carboplatin and paclitaxel.  
13.2.2 
Sample Size Derivation 
The sample size calculations are based on the primary hypothesis that the addition of 4 
cycles of carboplatin and paclitaxel following concurrent radiation and weekly cisplatin 
will increase 4-year disease-free survival from 80% to 90% for patients with cervical 
carcinoma with positive nodes and/or positive margins after a radical hysterectomy. 
The 4-year disease-free survival rate of 80% for the control arm is based on the Peters 
et al study. (2000) 
 
Previous studies’ including GOG-0109 suggest a significant proportion of patients on 
this study will be cured. Therefore, the control arm is assumed to follow the Gompertz ~ 
(,) survival probability distribution with initial hazard  and hazard dissipation [2-
4]. Equations [1,] [2,] and [3] list survival, hazard, and cure rate functions respectively 
under the Gompertz ~ (,) survival probability distribution assumption. 
 
 
 












elsewhere
0
0
for 
)
exp(
1
exp
)
(
t
t
t
S



 
 
[1] 
 





elsewhere
0
0
for 
)
exp(
)
(
t
t
t
h


 
 
 
[2] 
 
 
 
 
 








exp
  
 
 
 
 
[3] 
 
The parameter estimates 
MLE
ˆ
 and 
MLE
ˆ
 were derived using the outcome data of the 

RTOG 0724; version date September 21, 2022 
54 
GOG-0109 CRT arm, since this historic information came from patients whose disease 
and treatment profiles best mimics the control arm. As a result, the anticipated 
performance (primary endpoint) of this study’s control arm was estimated by 
substituting the calculated 
MLE
ˆ
 and 
MLE
ˆ
 into equation [1] at several time points.  
Similarly, using equation [3] the expected cure rate (
MLE
ˆ
) for the control arm was 
deduced.  
 
Derived parameter estimates and expected cumulative probability of recurrence 
(ECPR) for the control arm at 36, 48, and 60 months are listed in below:  
 
 
 
Historic Data 
(GOG-0092 RT arm) 
       Control Arm   
 
 
 
Time (months) 
36 
48 
60 
96 
120 
0.0072 -0.0212 0.7120 
ECPR 
0.1658 0.195 0.2169 
0.2557 
0.2687 
 
Figure 1 shows superimposed plots of the expected and empirical cumulative 
probability of disease recurrence consistent with the estimated Gompertz model (solid 
curve) and the outcome data from GOG-0109 CRT arm (dash curve), respectively.  
 
 
                Figure 1 
 
The required sample size for the primary endpoint of disease-free survival is based on 
the following conditions: 
 
Survival times follow the Gompertz distribution with (at least approximately) 
constant hazards in both treatment arms 
 
The control arm (Arm 1) will have a 4-year disease-free survival of 80% 
 
The experimental arm (Arm 2) will have a 4-year disease-free survival of 90%, 
which corresponds to a hazard ratio (λ2/ λ1) = 0.4722 

RTOG 0724; version date September 21, 2022 
55 
 
1-sided test at  = 0.05 
 
Statistical power of 80% 
 
5.5 years of accrual with 4 years of follow-up 
 
2 interim significance tests and a final test are planned using the Lan-DeMets 
spending function (Lan 1983) for rejecting the null hypothesis (efficacy) and Rule C 
in Freidlin and Korn, (Freidlin 2002) for rejecting the alternative hypothesis (futility) 
 
Using the group sequential design method (Pocock 1997) with 2 interim analyses, 50 
disease-free survival failure events are required to detect an absolute disease-free 
survival benefit of 10%, translating into a hazard ratio of 0.47 (experimental/control). 
Given the conditions above, 272 evaluable patients will be required to be accrued 
uniformly over 5.5 years with an additional 4 years of follow-up. Guarding against an 
ineligibility or lack-of-data rate of up to 5%, the final targeted accrual for this study will 
be 285 patients. 
 
Revised Targeted Accrual 
Due to the slower than projected accrual, the required 50 DFS events will be able to be 
reached with a final targeted sample size of 235 patients.  There are no changes being 
made to the parameters driving the primary statistical design.   
 
13.2.3 
Statistical Power Information for Secondary Endpoints 
 
Overall Survival 
The 4-year overall survival rate for the control arm is expected to be approximately 
85%.  The overall survival will be compared between the two arms.  The final 
targeted sample size of 235 patients with the longer accrual time, will provide 64% 
and 78%  power to detect an increase in overall survival to 92% and 93% 
respectively, with a 1- sided alpha of 0.05. 
 
 
 
Patient-Reported Outcomes 
Overall quality of life, chemotherapy-induced neuropathy, and diarrhea will be 
assessed using the FACT-Cx, FACT-GOG/NTX4, and the FACIT-D respectively, all 
of which are patient-reported questionnaires.  The FACT-Cx version 4 is comprised 
of 27 general items including the four domains of physical well-being, social and 
family well-being, emotional well-being, and functional well-being, as well as 15 
additional items specific for symptoms and problems related to cervical cancer. The 
FACT-GOG/NTX4 is a patient-reported tool developed by the GOG to assess 
neuropathy.  It is comprised of 4 items related to numbness or tingling in patients’ 
extremities.  The diarrhea-specific portion of the FACIT-D is comprised of 11 items.   
 
The FACT-Cx, FACT-GOG/NTX4, and the FACIT-D will be collected at 6, 12 and 24 
months following completion of concurrent chemoradiation.  While participation is 
strongly encouraged, patients are not required to participate in these endpoints.  It is 
anticipated that at least 80% of patients will agree to participate .  With 188 
evaluable patients, there will be at least 85% power to address the hypotheses listed 
below.   
 
FACT-Cx 
The primary hypothesis for the FACT-Cx is that there is no difference 
between the treatment arms in cervical cancer–specific QOL at 12 months. 
Cervical cancer-specific QOL at 6 and 24 months after the end of 
chemoradiation will also be evaluated. 
 
FACT-GOG/NTX4 
The primary hypothesis for neuropathy is that four additional cycles of 
chemotherapy following concurrent chemoradiation will not significantly 
adversely affect the chemotherapy-induced neuropathy at 12 months after 

RTOG 0724; version date September 21, 2022 
56 
the end of chemoradiation.  Neuropathy at 6 and 24 months after the end of 
chemoradiation will also be evaluated. 
 
FACIT-D 
The primary hypothesis for the FACIT-D is that there is no a difference 
between the treatment arms in diarrhea at 12 months. Diarrhea at 6 and 24 
months after the end of chemoradiation will also be evaluated. 
 
13.3 
Patient Accrual (8/21/14) 
Given that there will not be any major phase III studies competing for this patient population and 
participation from other cooperative groups through the CTSU mechanism, the patient accrual is 
projected to be 6 cases per month, with 3 cases per month expected in the first 3 “ramp-up” 
months following activation. The accrual is projected to be complete in 5.5 years. The total 
duration of the study is expected to be 9 years from the time the first patient is entered to the 
overall survival analysis.  If the average monthly accrual rate during months 12-18 following 
activation is below 2 cases per month, the study statistician will recommend closure of the study 
to the RTOG Data Monitoring Committee (DMC), per the NCI guidelines for slowly accruing trials.  
 
Revised Accrual (8/21/14) 
The projected monthly accrual is being reduced to 3 cases per month.  This accrual rate will be 
monitored and reassessed with NCI 1 year after this amendment is released. 
 
13.4 
Analysis Plan (8/21/14) 
13.4.1 
Statistical Methods 
Disease-Free Survival: FS will be estimated by the Kaplan-Meier method (Kaplan 
1958). The distribution of DFS estimates between the two arms will be compared using 
the log rank test. (Mantel 1966)  DFS time will be measured from the date of 
randomization to the first date of DFS failure (local, regional or distant metastases 
failure or death due to any cause) or last follow-up.  The Cox proportional hazard 
regression model will be used to analyze the effects of factors, in addition to treatment, 
that may be associated with DFS. (Cox 1972)  
 
Overall Survival: OS will be estimated by the Kaplan-Meier method. (Kaplan 1958) The 
distribution of OS estimates between the two arms will be compared using the log rank 
test. (Mantel 1966)  Survival time will be measured from the date of randomization to 
the date of death or last follow-up.  The Cox proportional hazard regression model will 
be used to analyze the effects of factors, in addition to treatment, that may be 
associated with OS. (Cox 1972)  
13.4.2 Interim Analysis to Monitor the Study Progress 
Interim reports with statistical analyses will be prepared twice a year until the initial 
treatment results have been presented/published.  In general, the interim reports will 
contain the following information: 
 
patient accrual rate with a projected completion date (while the study is still 
accruing) 
 
total patients accrued  
 
distributions of important pretreatment and prognostic baseline variables  
 
the frequencies and severity of adverse events by treatment arm. 
 
compliance rates of treatment delivery 
 
The interim reports will not contain the results from the treatment comparisons with 
respect to the primary endpoint, DFS, or any secondary endpoints. 
13.4.3 
Significance Testing for Early Termination and/or Reporting 
 
Primary Endpoint: Disease-Free Survival 
A group sequential test with 2 planned interim analyses and a final analysis will be 
performed. The timing of the interim analyses will be based on primary endpoint 
events as defined in 13.1.1.  The maximum number of DFS failure events required 
for the trial is 50. Under the alternative hypothesis that the an additional 4 cycles of 

RTOG 0724; version date September 21, 2022 
57 
carboplatin and paclitaxel will increase disease-free survival from 80% to 90% at 4 
years, the projected numbers of DFS failure events and the nominal significance 
levels for rejecting the H0 or the H1 at each of these interim analyses, along with the 
projected timing and accrual, are shown in the table below:   
 
Table 1: Nominal Significance Levels for Interim Analyses 
 
Interim 
Analysis 
Efficacy: 
Reject H0 if 
p (H0) ≤ 
Futility: 
Reject 
H1 if 
Z  (H1) ≤ 
# Events  
 
#1 
≤ 0.0.0056 
-0.69 
25 
#2 
≤ 0.0.0229 
 -0.26 
38 
 
At each planned interim analysis, the 1-sided p-value from the log-rank test 
assessing treatment efficacy with respect to disease-free survival will be compared 
to the nominal significance levels in Table 1.  These levels are based on the Lan-
DeMets alpha spending function (Lan 1983) that behaves like the O’Brien-Flemming 
boundary. (O’Brien 1979)  If the computed p-value for efficacy is less than or equal 
to the nominal significance level boundary for rejecting the H0 (efficacy), then 
accrual to the trial will be stopped (if applicable), it will be concluded that the DFS 
rate of the experimental arm (Arm 2) is higher than that of the control arm (Arm 1), 
and the results will be reported.  For futility, the alternative hypothesis will be tested 
using Rule C from Freidlin and Korn (Freidlin 2002) at the critical values stated in the 
above table. If the critical value is less than or equal to the nominal value boundary 
for rejecting the H1 (futility), then accrual to the trial will be stopped (if applicable) 
and it will be reported that it cannot be concluded that the disease-free survival rate 
of the experimental arm (Arm 2) is higher than that of the control arm (Arm 1).  If 
neither of these boundaries is crossed, accrual (if applicable) and follow-up will 
continue until the next interim or final analysis.  
 
In addition to reporting results as listed in Section 13.4.2, at the first NRG Oncology 
DMC meeting following the required number of disease-free survival events for each 
planned interim analysis, blinded efficacy results will be reported to the NRG DMC.   
13.4.4 
Analysis for Patient-Reported Outcome Endpoints 
The distributions of quality of life data collection patterns over all collection points in 
each treatment arm will be described.  To inspect the missing data mechanism for each 
tool, at least a graphical method will be used.  A missing completely at random (MCAR) 
mechanism exists when missing values are randomly distributed across all 
observations. A missing at random (MAR) mechanism exists when values are not 
randomly distributed across all observations, rather than one or more sub-samples.  
 
If the cause of missing data is MCAR, listwise deletion (complete case analysis) will be 
done. If the MAR assumption is supported by the data, then an imputation method such 
as multiple imputation will be applied to impute missing data.  
  
If the MAR assumption is not supported by the data, then adjusting for covariates (such 
as the baseline quality of life score) might reduce the conditional association between 
outcomes and missing values. If missing data patterns look similar when stratified by 
such covariate(s), then an analysis that adjusts for such covariate(s) will be conducted 
and an imputation method such as multiple imputation will be applied.  If approximate 
conditional independence cannot be obtained with any set of covariates, then MNAR 
(missing not at random) must be addressed by an explicit model for the missing data 
mechanism and then an imputation method such as multiple imputation will be applied. 
All results from the imputed analysis using the multiple imputation will be compared to 
the complete case analysis results to assess any potential biases. 

RTOG 0724; version date September 21, 2022 
58 
 
FACT-Cx 
The 15 cervical cancer specific items on the FACT-Cx are scored from 0 to 4.  More 
than half of the items must be answered to provide a valid score.   Analysis of 
covariance, using the baseline FACT-Cx cervical cancer–specific score as a 
covariate, will be used to determine if there is a difference in cervical cancer–
specific quality of life between the treatment arms. 
 
 
FACT-GOG/NTX4 
If the neuropathy score for the 4 additional cycles of chemotherapy is at least 2 
standard errors of measure higher than for the control arm, it will be considered to 
significantly adversely affect the chemotherapy-induced neuropathy. The 4 items on 
the FACT-GOG/NTX4 are scored from 0 (none) to 4 (quite a bit).  At least 3 of the 
items must be answered to provide a valid score.  Analysis of covariance, using the 
baseline FACT-GOG/NTX4 score as a covariate, will be used to determine if the 
chemotherapy-induced neuropathy is significantly worse for the patients on the 4 
additional cycles of chemotherapy treatment arm. 
 
 
FACIT-D 
The 11 diarrhea-specific items on the FACIT-D are scored from 0 to 4. More than 
half of the items must be answered to provide a valid score. Analysis of covariance, 
using the baseline FACIT-D diarrhea-specific score as a covariate, will be used to 
determine if there is a difference in diarrhea between the treatment arms. 
13.4.5 
Analysis for Reporting the Initial Treatment Results   
The primary objective of this study is to determine whether the addition of 4 cycles of 
carboplatin and paclitaxel following concurrent radiation therapy and weekly cisplatin 
will increase 4-year disease-free survival from 80% to 90% for patients with cervical 
carcinoma with positive nodes and/or positive margins after a radical hysterectomy. 
This major analysis will occur after at least 50 total failures have been observed, unless 
an early stopping rule is satisfied. It will include: 
 tabulation of all cases entered and those excluded from the analyses with the 
reasons for exclusion given 
 distributions of important prognostic baseline variables  
 the frequencies and severity of adverse events by treatment arm 
 compliance rate of treatment delivery 
 observed results with respect to the primary and secondary endpoints 
 
All eligible patients randomized will be included in the comparison and will be grouped 
by assigned treatment in the analysis.  The primary hypothesis of treatment benefit will 
be tested using the log-rank statistic with a 1-sided significance level of 0.0424, given 
that the 2 interim analyses were carried out per Section 13.4.3..  Additional analyses of 
treatment effect will be performed using the Cox proportional hazard model with the 
stratification factor of intention to use vaginal cuff boost included as a fixed covariate, 
as well as other possible modifying factors, such as age, gender, race, and other 
patient characteristics that are imbalanced between the treatment arms.  If feasible, 
treatment comparisons with respect to the primary endpoint (disease-free survival) will 
be compared within each ethnic and racial category. 
13.4.6 
CDUS Monitoring 
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. 
13.4.7 
Post-Hoc Dose-Volume Analysis 
The collection of 3D volume data sets for all patients will allow for a central contouring 
of the vagina and pelvic lymph nodes.  If the distribution of patients being treated with 
standard RT and IMRT allows, this data will then be used to perform a post-hoc dose-
volume analysis comparing standard RT and IMRT with respect to toxicity and local 
control.  

RTOG 0724; version date September 21, 2022 
59 
 
13.5 
Inclusion of Minorities (21-SEP-2022) 
Women of all races and ethnic groups are eligible for this study.  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 also considered the possible interaction between 
race/ethnicity and treatment. Based on the Peters study (2000), it is projected that 14% will be of 
Hispanic or Latino ethnicity; racial distribution are projected to be 73% White, 23% are Black or 
African American and 4% Asian.  The following table lists the projected accrual by ethnic and 
racial categories.   
 
DOMESTIC 
 
 
 
 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
 Male  
Female 
 Male  
American Indian or Alaska Native 
2 
0 
0 
0 
2 
Asian 
6 
0 
0 
0 
6 
Native Hawaiian or other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African American 
22 
0 
4 
0 
26 
White 
93 
0 
25 
0 
118 
More than one race 
1 
0 
2 
0 
3 
TOTAL 
124 
0 
31 
0 
155 
FOREIGN 
 
 
 
 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
 Male  
Female 
 Male  
American Indian or Alaska Native 
0 
0 
0 
0 
0 
Asian 
72 
0 
0 
0 
72 
Native Hawaiian or other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African American 
0 
0 
0 
0 
0 
White 
8 
0 
0 
0 
8 
More than one race 
0 
0 
0 
0 
0 
Not Reported 
0 
0 
0 
0 
0 
TOTAL 
80 
0 
0 
0 
80 
 

RTOG 0724; version date September 21, 2022 
60 
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American Cancer Society: Cancer Statistics, 2007. Atlanta, GA: American Cancer Society, 2007.  
http://www.cancer.org/docroot/stt/stt_0.asp  
 
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Dueñas-Gonzalez A, López-Graniel C, González-Enciso A, et al. A phase II study of 
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Forsatiere AA. Use of Taxol in squamous carcinomas of the head and neck. Semin Oncol. 20:56-
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Freidlin B, Korn EL. A comment on futility monitoring. Controlled Clinical Trials. 23:355-66, 2002. 
 
Goonatillake S, Khong R, Hoskin P. (ePub ahead of print: 2009). Chemoradiation in 
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Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Stat Assoc. 
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Kudelka AP, Winn R, Edwards CL, et al. An update of a phase II study of paclitaxel in advanced 
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Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. 
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Mell LK, Roeske JC, Mundt AJ. A survey of intensity-modulated radiation therapy use in the 
United States. Cancer. 98 :204-211, 2003. 
Mell LK, Mehrotra AK, Mundt AJ. Intensity-modulated radiation therapy use in the U.S., 2004. 
Cancer.104 :1296-1303, 2005. 
 
Meta-Analysis Group. Reducing uncertainties about the effects of chemoradiotherapy for cervical 
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trials. Journal of Clinical Oncology, 26:5802-12, 2008. 
Monk BJ, Wang J, Im S, et al. Rethinking the use of radiation and chemotherapy after radical 
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February 
9, 
2008. 
From 
http://www.nccc-
online.org/patient_info/cervical_cancer/chemo.html 
 

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Monk, BJ, Sill M, McMeekin, et al. A randomized phase III trial of four cisplatin (CIS) containing 
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Nagy V, Todor N, Coza O, et al. Quality of life and treatment related toxicity in 335 patients with 
locally advanced cervical carcinoma treated by two chemoradiation regiments. J BUON. 12:389-
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RTOG 0724; version date September 21, 2022 
62 
 
APPENDIX I (9/22/14) 
STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS 
 
Assessment 
Time Points 
 
≤ 90 days prior to 
study entry 
≤ 70 days prior 
to study entry 
≤ 56 days 
prior to study 
entry 
≤ 14 days 
prior to 
study entry 
Radical hysterectomy/ 
node sampling 
 
X 
 
 
History/physical 
 
 
X 
 
Height, weight, BSA 
 
 
X 
 
Pelvic exam 
 
 
X 
 
Performance status 
 
 
X 
 
Contrast-enhanced CT or 
MRI of the abdomen and 
pelvis (if whole body 
PET-CT not done) 
 
X 
See section 11.1 
 
 
 
Chest x-ray/CT (if whole 
body PET-CT not done) 
 
 
X 
See section 11.1 
 
 
Whole-body PET-CT 
scan (optional) 
X 
 
 
 
CBC w/ diff & ANC, plt, 
Hgb 
 
 
 
X 
Serum creatinine, 
bilirubin, alk phos plus 
AST/SGOT and/or 
ALT/SGPT 
 
 
 
X 
Serum calcium, 
magnesium, Na,K, CL, 
CO2, BUN, creatinine, 
glucose 
 
 
 
X 
Audiogram 
 
 
 
X 
See section 
11.1 
CD4 count (for patients 
known to be HIV positive) 
 
 
 
X 
Informed Consent 
Prior to study entry 
Quality of Life (for 
consenting patients) 
 
 
X 
 
Tissue (for consenting 
patients) 
 
X 
 
 
Blood for serum and 
plasma (for consenting 
patients) 
 
X 
 
 
Whole Blood for DNA (for 
consenting patients) 
 
X  
See section 10.6 
 
 

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APPENDIX I 
STUDY PARAMETER TABLE: ASSESSMENTS DURING TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment 
Time Points 
 
Day 1-56: Weekly 
Day 57-140: 
q Course 
≤ 14 days of 
patient-
reported 
symptoms 
At end of 
concurrent 
chemoRT 
History/physical 
X 
X 
 
X 
Height, weight, BSA 
X 
X 
 
 
Pelvic exam 
 
 
 
X 
Performance status 
X 
X 
 
 
CBC w/ diff & ANC, plt, 
Hgb 
X 
X 
 
 
Serum calcium, 
magnesium, Na,K, CL, 
CO2, BUN, creatinine, 
glucose 
X 
X 
 
 
Audiogram 
 
 
X 
See section 
11.1 
 
Adverse event eval 
X 
X 
 
 
Quality of Life (for 
consenting patients) 
 
 
 
X 
Tissue (for consenting 
patients) 
 
 
 
X 
Blood for serum and 
plasma (for consenting 
patients) 
 
 
 
X 

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APPENDIX I 
STUDY PARAMETER TABLE: ASSESSMENTS IN FOLLOW UP 
 
 
Assessment 
Time Points 
 
q 3 mo X 2 yrs, q 6 
mo x 3 yrs & then 
yrly from treatment 
start 
Yrly from 
treatment start 
At 6, 12, & 24 mos from 
completion of concurrent 
chemoRT 
History/physical 
X 
 
 
Height, weight, BSA 
X 
 
 
Pelvic exam 
X 
 
 
Performance status 
X 
 
 
Contrast-enhanced CT or 
MRI of the abdomen and 
pelvis (if whole body PET-
CT not done) 
 
X 
 
Chest x-ray/CT (if whole 
body PET-CT not done) 
 
X 
See section 11.1 
 
CBC w/ diff & ANC, plt, 
Hgb 
X 
 
 
Serum calcium, 
magnesium, Na,K, CL, 
CO2, BUN, creatinine, 
glucose 
 
X 
 
 
Audiogram 
X 
 
 
Adverse event eval 
X 
 
 
Quality of Life (for 
consenting patients) 
 
 
X 

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APPENDIX II 
ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry work of a light or sedentary nature.  For example, light 
housework, office work. 
 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours. 
 
3 
Capable of only limited self-care, confined to bed or chair 50% or more 
of waking hours. 
 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed. 
 
5 
Death. 
 

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66 
APPENDIX III 
STAGING FOR CERVICAL CANCER 
(AJCC, 6th Edition, 2002) 
 
Primary Tumor (T) 
TNM 
Categories 
FIGO 
Stages 
 
TX 
 
Primary tumor cannot be assessed 
T0 
 
No evidence of primary tumor 
Tis 
0 
Carcinoma in situ (preinvasive carcinoma) 
T1 
I 
Cervical carcinoma confined to uterus (extension to corpus should be 
disregarded) 
   T1a 
   IA 
Invasive carcinoma diagnosed only by microscopy. All macroscopically 
visible lesions – even with superficial invasion – are T1b/IB. Stromal 
invasion with a maximal depth of 5.0 mm measured from the base of the 
epithelium and a horizontal spread of 7.0 mm or less. Vascular space 
involvement, venous or lymphatic, does not affect classification. 
T1a1 
IA1 
Stromal invasion no greater than 3.0 mm in depth and 7.0 mm or less in 
horizontal spread 
T1a2 
IA2 
Stromal invasion more than 3.0 mm and not more than 5.0 mm with a 
horizontal spread 7.0 mm or less* 
   T1b 
   IB 
Clinically visible lesion confined to the cervix or microscopic lesion 
greater than IA2/T1a2 
T1b1 
IB1 
Clinically visible lesion 4.0 cm or less in greatest dimension 
T1b2 
IB2 
Clinically visible lesion more than 4.0 cm in greatest dimension 
T2 
II 
Tumor invades beyond the uterus but not to pelvic wall or to lower third of 
the vagina 
T2a 
IIA 
Without parametrial invasion 
T2b 
IIB 
With parametrial invasion 
T3 
III 
Tumor extends to pelvic wall and/or involves lower third of vagina and/or 
causes hydronephrosis or non-functioning kidney 
T3a 
IIIA 
Tumor involves lower third of vagina no extension to pelvic wall 
T3b 
IIIB 
Tumor extends to pelvic wall and/or causes hydronephrosis or non-
functioning kidney 
T4 
IVA 
Tumor invades mucosa of bladder or rectum and/or extends beyond true 
pelvis* 
M1 
 
Distant metastasis 
 
 
 
*Note: The depth of invasion should not be more than 5 mm taken from the base of the epithelium, either surface or 
glandular, from which it originates.  The depth of invasion is defined as the measurement of the tumor from the epithelial-
stromal junction of the adjacent most superficial epithelial papilla to the deepest point of invasion. Vascular space 
involvement, venous or lymphatic, does not affect classification. 
*Note: The presence of bullous edema is not sufficient to classify a tumor as T4. 
 
Regional Lymph Nodes (N) 
 
NX – Regional lymph nodes cannot be assessed 
 
N0 – No regional lymph node metastasis 
 
N1 – Regional lymph node metastasis 
 
Distant Metastasis (M) 
 
MX – Distant metastasis cannot be assessed 
 
M0 – No distant metastasis 
 
M1 – Distant metastasis 
 
(Continued on Next Page) 

RTOG 0724; version date September 21, 2022 
67 
 
STAGE GROUPING 
FIGO 
Stage 
UICC 
 
 
T 
N 
M 
0 
Tis 
N0 
M0 
IA1 
T1a1 
N0 
M0 
IA2 
T1a2 
N0 
M0 
IB1 
T1b1 
N0 
M0 
IB2 
T1b2 
N0 
M0 
IIA 
T2a 
N0 
M0 
IIB 
T2b 
N0 
M0 
IIIA 
T3a 
N0 
M0 
IIIB 
T1 
N1 
M0 
 
T2 
N1 
M0 
 
T3a 
N1 
M0 
 
T3b 
Any N 
M0 
IVA 
T4 
Any N 
M0 
 
 
 
 
 

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APPENDIX IV 
 
DEFINITION OF BLADDER AND RECTAL POINTS 
 
 
 
 
 
Vaginal Cylinder 
 
 
Points of Calculation 
 

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APPENDIX V ( 8/21/14) 
 
Appendices for NRG Oncology Biospecimen Collection (as specified by the protocol). 
 
NRG Oncology FFPE Specimen Plug Kit Collection 
NRG Oncology Blood Collection Kit Instructions 
 
Shipping Instructions: 
U.S. Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
UCSF Box 1800 
2340 Sutter St, room S341  
San Francisco, CA 94143-1800 
Courier Address (FedEx, UPS, etc.): For ALL Frozen or Trackable Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter St, room S341  
San Francisco, CA 94115 
 
 
Include all NRG Oncology paperwork in pocket of biohazard bag.  
 
Check that the Specimen Transmittal Form (ST) has the consent boxes checked off.  
 
Check that all samples are labeled with the NRG Oncology study and case number, and include 
date of collection as well as collection time point (e.g., pretreatment, post-treatment). 
 
 
FFPE Specimens: 
o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top 
of the container. If you can hear the slides shaking it is likely that they will break during 
shipping.  
o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do 
not wrap blocks with bubble wrap or gauze. Place padding in top of container so that if you 
shake the container the blocks are not shaking. If you can hear the block shaking it might break 
during shipping.   
o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States 
Postal Service (USPS) to the USPS address (94143) or by Courier to the Street Address 
(94115). Do NOT ship on Dry Ice. 
 
 
Frozen Specimens:  
o Multiple cases may be shipped in the same cooler, but make sure each one is in a separate 
bag and clearly identified. If possible keep Serum, Plasma and Whole Bloods in separate bags 
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at 
least 7 lbs). There should be plenty of dry ice under and above the specimens. If the volume of 
specimens is greater than the volume of dry ice then ship in a larger Styrofoam box, or two 
separate boxes. Any Styrofoam box can be used, as long as it is big enough. 
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and 
the site will be notified.  
o Send frozen specimens on dry ice via overnight courier to the address above. Specimens 
should only be shipped Monday through Wednesday (Monday-Tuesday for Canada) to prevent 
thawing due to delivery delays. Saturday or holiday deliveries cannot be accepted. Samples 
can be stored frozen at -80 C until ready to ship. 
 
 
For Questions regarding collection/shipping please contact the NRG Oncology 
Biospecimen Bank by e-mail: RTOG@ucsf.edu or phone: 415-476- 7864or Fax: 415-476-
5271. 

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APPENDIX V (8/21/14) 
NRG Oncology FFPE SPECIMEN PLUG KIT INSTRUCTIONS 
 
This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology Biospecimen 
Bank. The plug kit contains a shipping tube and a punch tool.   
 
Step 1 
If the block is stored cold, allow it to equilibrate for 30 minutes at 
room temperature. Place the punch tool on the paraffin block over 
the selected tumor area.  (Ask a pathologist to select area with 
tumor.) Push the punch into the paraffin block.  Twist the punch tool 
once around to separate the plug from the block.  Then pull the 
punch tool out of the block.  The punch should be filled with tissue 
sample. 
 
 
Step 2 
Label punch tool with proper specimen ID.  DON’T remove 
specimen from the punch. 
 
Use a separate punch tool for every specimen. Call or email us if 
you have any questions or need additional specimen plug kits. 
 
 
 
 
 
Step 3 
Once punch tool is labeled, place in shipping tube and mail to 
address below. Please do not mix specimens in the same tube.    
 
 
 
 
 
We will remove core specimen from the punch, embed in a paraffin block, and label with specimen ID. 
 
*NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please 
send the entire block to the NRG Oncology Biospecimen Bank and we will sample a plug from the block 
and return the remaining block to your facility.  Please indicate on the submission form the request to 
perform the plug procedure and return of the block. 
Ship:  Specimen plug kit, specimen in punch tool, and all paperwork to the address below: 
 
US Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
UCSF Box 1800 
2340 Sutter St, Room S341 San Francisco, CA 94143-1800 
Courier Address (FedEx, UPS, etc.): For ALL Frozen Specimens or Trackable 
shipments 
NRG Oncology Biospecimen  Bank 
University of California San Francisco 
2340 Sutter St, Room S341 San Francisco, CA 94115 
Questions: 415-476- 7864/FAX 415-476-5271; RTOG@ucsf.edu 

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APPENDIX V (8/21/14) 
NRG Oncology BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
This Kit is for collection, processing, storage, and shipping of serum, plasma, or blood (as 
specified by protocol): 
 
Kit contents: (one collection timepoint) 
 
One  Red Top for serum (A) 
 
One Purple Top EDTA tube for plasma (B) 
 
One Purple Top EDTA tube for Whole Blood (C) 
 
Twenty-five (25) 1 ml cryovials 
 
Biohazard bags (3) and Absorbent shipping material (3) 
 
Styrofoam container (inner) and  Cardboard shipping (outer) box 
 
Pre-paid shipping label(s) 
 
UN1845 DRY Ice and UN3373 Biological Substance Category B Stickers 
 
Specimen Transmittal (ST) Form and Kit Instructions 
 
(A) Serum (if requested): Red Top Tube 
 
Label as many 1ml cryovials (5-10) as serum collected. 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 4C (preferred). If sites 
are unable to process samples at 4C then spinning at room temperature is acceptable if 
done within 2 hours of draw but must be noted on the ST. 
3. Aliquot 0.5 ml serum into as many cryovials as are necessary for the serum collected (5 to 
10) labeled with NRG Oncology study and case numbers, collection date/time, protocol time-
point collected (e.g. pretreatment, post-treatment), and clearly mark specimen as “serum”. 
4. Place cryovials into biohazard bag and immediately freeze at -70 to -90 C, and store frozen 
until ready to ship. See below for storage conditions. 
5. Store serum at -70 to -90 C until ready to ship on dry ice. See below for storage conditions 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point 
on the ST Form.. 
 
(B) Plasma (If requested): Purple Top EDTA tube #1 
 
Label as many 1ml cryovials (5 to 10) as necessary for the plasma collected. Label them with 
the RTOG study and case number, collection date, time, and time point, 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 4C (preferred). If sites are unable to process samples at 4C then 
spinning at room temperature is acceptable if done within 2 hours of draw but must be noted 
on the ST. 
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 0.5 ml plasma into each cryovial (5-10) labeled  
with NRG Oncology study and case numbers, collection date/time, time point 
collected and clearly mark specimen as “plasma”.   
5. Place cryovials into biohazard bag and immediately freeze at -70 to -90C 
6. Store frozen plasma until ready to ship on dry ice.  
 
7. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point 
on the ST.  
(Continued on next page) 

RTOG 0724; version date September 21, 2022 
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APPENDIX V (8/21/14) 
 
NRG Oncology BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
 
 
(C) Whole Blood For DNA (if requested): Purple Top EDTA tube #2 
                          
 
Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected. Label them with 
the NRG Oncology study and case number, collection date/time, and time point, and clearly mark 
cryovials “blood”. 
 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can 
also be mixed for 5 minutes on a mixer at room temperature. 
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the 
blood collected (3 to 5) labeled with NRG Oncology study and case numbers, collection 
date/time, time point collected and clearly mark specimen as “blood”. 
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80 Celsius. 
4. Store blood samples frozen until ready to ship on dry ice.  
5. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point 
on ST. 
 
Freezing and Storage 
 Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen. 
 
Store at –80C (-70C to -90C) until ready to ship.  
If a -80C Freezer is not available,  
 
Samples can be stored short term in a -20C freezer (non-frost free preferred) for 
up to one week (please ship out Monday-Wednesday only; Canada: Monday-
Tuesday only). 
OR: 
 
Samples can be stored in plenty of dry ice for up to one week, replenishing daily 
(please ship out on Monday-Wednesday only; Canada: Monday-Tuesday only). 
OR: 
 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-
Wednesday only; Canada: Monday-Tuesday only). 
 
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored. 
 
 
Shipping/Mailing: 
 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to 
prevent thawing due to delivery delays.  Saturday and holiday deliveries cannot be accepted.  

RTOG 0724; version date September 21, 2022 
73 
 
Include all NRG Oncology 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 whole bloods 
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 plenty of dry ice (7-10 lbs/3.5kg 
minimum).  Add padding to avoid the dry ice from breaking the tubes.  
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and 
UN1895 stickers to outer cardboard box. 
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag 
and that there is enough room for plenty of dry ice. Add padding to avoid the dry ice from 
breaking the tubes. 
 
For questions regarding collection, shipping or to order a Blood Collection Kit, please Email 
RTOG@ucsf.edu or call (415)476-7864 
 
Shipping Address : 
Courier Address (FedEx, UPS, etc.): For ALL Frozen Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
For questions, call 415-476-7864or e-mail: RTOG@ucsf.edu