A Randomized Phase III Trial of Cisplatin and Tumor Volume Directed Irradiation Followed by Carboplatin and Paclitaxel vs. Carboplatin and Paclitaxel for Optimally Debulked, Advanced Endometrial Carcinoma
Phase: PHASE3
Conditions: Endometrial Clear Cell Adenocarcinoma, Endometrial Serous Adenocarcinoma, Stage IA Uterine Corpus Cancer AJCC v7, Stage IB Uterine Corpus Cancer AJCC v7, Stage II Uterine Corpus Cancer AJCC v7, Stage IIIA Uterine Corpus Cancer AJCC v7, Stage IIIB Uterine Corpus Cancer AJCC v7, Stage IIIC Uterine Corpus Cancer AJCC v7, Stage IVA Uterine Corpus Cancer AJCC v7
Sponsor: Gynecologic Oncology Group

 
i 
TO: 
 
ALL PRINCIPAL INVESTIGATORS/NURSES/DATA MANAGERS 
 
FROM: 
 
 
PROTOCOL SECTION 
 
DATE: 
APRIL 28, 2014 
 
RE: 
 
GOG-0258 - REVISION #11 
 
Protocol Title:  A RANDOMIZED PHASE III TRIAL OF CISPLATIN AND TUMOR 
VOLUME DIRECTED IRRADIATION FOLLOWED BY CARBOPLATIN AND 
PACLITAXEL VS. CARBOPLATIN AND PACLITAXEL FOR OPTIMALLY DEBULKED, 
ADVANCED ENDOMETRIAL CARCINOMA  NCI Version Date 04/04/2014 
 
Study Chair: DANIELA MATEI, M.D.;
 
  
 
IRB Recommendations 
 
(  ) No review required 
(X) Expedited review; however, site IRB requirements take precedence 
(  ) Full board review recommended because there have been changes to the 
eligibility and/or informed consent 
 
Please direct questions about the recommended level of IRB review and/or re-consenting patients 
to your local IRB. The local IRB will make this determination. If your local IRB does not agree 
with the GOG’s recommended level of review, please document the IRB’s decision and the 
rationale for the decision in your study files 
________________________________________________________________________ 
 
The following changes have been made and become effective April 28, 2014: 
 
SUMMARY OF CHANGES 
 
For Protocol Revision #11 to: 
 
NCI Protocol #: GOG-0258 
Local Protocol #: GOG-0258 
 
NCI Version Date: 04/04/2014 
Protocol Date: 04/28/2014 
 
 

NCI Protocol #: GOG-0258 
Version Date: 04/04/2014 
ii 
# 
Section 
Page(s) 
Change 
1 
Title 
Pages 
 
 NCT #00942357 has been added. 
 NCI Version Date is now 04/04/2014. 
 Includes Revisions #1-11. 
 Lead and Participating Organizations have been added. 
 NCTN/CTSU Information has been updated. 
 To reflect date of revision. 
2 
4.55 
 
 References to Radiological Physics Center (RPC) have been changed to IROC 
Houston. 
 “Once data has been submitted to TRIAD, complete a DDSI contact information 
form at http://www.rtog.org/CoreLab/TRIAD.aspx” has been added. 
3 
4.62 and 
4.64 
 
References to Radiological Physics Center (RPC) have been changed to IROC 
Houston. 
4 
4.641 
 
“Rapid Review Data Submission for IMRT via TRIAD” has been added. 
5 
4.67 
 
“See Section 5.14 for instructions to set up TRIAD for digital submissions” has 
been added. 
 
6 
4.673, 
4.674 
 
 All plans will now be submitted via TRIAD. 
 References to Radiological Physics Center (RPC) have been changed to IROC 
Houston. 
 
7 
4.613 
 
RPC is now IROC Houston. 
8 
5.0 
 
The lead paragraph regarding CTSU submissions has been deleted. 

NCI Protocol #: GOG-0258 
Version Date: 04/04/2014 
iii 
9 
5.1, 5.11, 
5.12, 
5.13 
 
References to Radiological Physics Center (RPC) have been changed to IROC 
Houston. 
10 
5.14 
 
“Digital RT Data Submission Using TRIAD” has been added. 
11 
5.2 and 
subsectio
ns 
 
This section is now labeled “Registration Procedures,” and updated NCTN/CTSU 
Registration procedures have been inserted.  The remaining sections, (now 5.3 and 
5.4) have been renumbered. 
12 
5.3 
 
This section has been updated to reflect current NCTN/CTSU Registration 
procedures. 
 
5.433 
 
This section now references the GOG General Chemotherapy Guidelines appendix, 
Appendix IV. 
13 
Section 
10.1 and 
subsectio
ns 
 
References to the “Adverse Event Expedited Reporting System (AdEERS)” have 
been changed to “CTEP Adverse Event Reporting System (CTEP-AERS)” 
throughout the protocol. 
14 
10.2 
 
 Knowledge Assessment has been added to the forms table. 
 RT Treatment Plans will be submitted via TRIAD. 
15 
Appendix 
II 
 
Has been removed; CTSU information and instructions are now contained in the 
body of the protocol document.  The remaining appendices have been renumbered. 
16 
Appendix 
IV 
 
The fifth bullet now reads:  “Chemotherapy doses are required to be recalculated if 
the patient has a weight change of greater than or equal to 10%.  Patients are 
permitted to have chemotherapy doses recalculated for <10% weight changes.” 
17 
IC 
 
The NCI Version Date has been updated. 

NCI Protocol #: GOG-0258 
Version Date: 04/04/2014 
- 1 - 
PROTOCOL GOG-0258 
A RANDOMIZED PHASE III TRIAL OF CISPLATIN AND TUMOR VOLUME DIRECTED 
IRRADIATION FOLLOWED BY CARBOPLATIN AND PACLITAXEL VS. 
CARBOPLATIN AND PACLITAXEL FOR OPTIMALLY DEBULKED, ADVANCED 
ENDOMETRIAL CARCINOMA (NCT #00942357) (04/28/2014) 
NCI Version Date: 04/04/2014 
Includes Revisions #1-11 
POINTS: 
PER CAPITA - 20 
MEMBERSHIP – 6 
TRANSLATIONAL RESEARCH – Award based on specimen submission with 1.0 point for the submission of 
archival formalin-fixed, paraffin-embedded primary or metastatic tumor tissue and 0.5 points for whole blood. 
Lead Organization: NRG / NRG Oncology (04/28/2014) 
 
 
 
 
 
 
STUDY CHAIR  
 
 
 
STUDY CO-CHAIRS 
 
 
 
DANIELA MATEI, M.D.  
 
 
MARCUS E. RANDALL, M.D. 
 
See GOG Website Directory 
 
  
 
 
 
 
 
 
DAVID MUTCH, M.D. 
  
 
 
 
See GOG Website Directory 
 
 
 
 
 
 
 
 
QUALITY OF LIFE CO-CHAIR 
URSULA A. MATULONIS, M.D. 
RTOG CO-CHAIR (12-14-10) 
 
 
See GOG Website Directory 
I-CHOW HSU, M.D. 
 
 
 
See GOG Website Directory 
 
 
TR CO-CHAIR 
 
 
 
 
 
 
MICHAEL J. BIRRER, M.D., PH.D. 
NURSE CONTACT                    
 
 
See GOG Website Directory 
NANCY MENNING, MSN, ANP-C 
 
 
 
 
 
STUDY PATHOLOGIST 
 
MARGARET STEINHOFF, M.D. 
 
See GOG Website Directory 
    
  
 
 
 
STATISTICIAN                                                    
 
 
 
              GINNY FILIACI, PH.D. 
 
See GOG Website Directory  
   
QUALITY OF LIFE STATISTICIAN   
TRANSLATIONAL RESEARCH SCIENTIST 
HELEN Q. HUANG, M.S.  
HEATHER A. LANKES, PH.D., M.P.H. 
See GOG Website Directory  
See GOG Website Directory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
OPEN TO PATIENT ENTRY JUNE 29, 2009; REVISED AUGUST 12, 2009; REVISED OCTOBER 13, 2009  
REVISED JUNE 7, 2010; REVISED JANUARY 3, 2011; REVISED MARCH 14, 2011; REVISED JUNE 13, 
2011; REVISED SEPTEMBER 26, 2011; REVISED JUNE 25, 2012; REVISED JANUARY 13, 2014; REVISED 
APRIL 28, 2014 
This protocol was designed and developed by the Gynecologic Oncology Group (GOG).  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 GOG nor does GOG assume any responsibility for unauthorized use of this protocol. 
Participating Organizations (04/28/2014) 
 
ALLIANCE / Alliance for Clinical Trials in Oncology 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
SWOG / SWOG

NCI Protocol #: GOG-0258 
Version Date: 04/04/2014 
- 2 - 
PROTOCOL GOG-0258 
A RANDOMIZED PHASE III TRIAL OF CISPLATIN AND TUMOR VOLUME DIRECTED 
IRRADIATION FOLLOWED BY CARBOPLATIN AND PACLITAXEL VS. CARBOPLATIN AND 
PACLITAXEL FOR OPTIMALLY DEBULKED, ADVANCED ENDOMETRIAL CARCINOMA 
NCI Version Date: 04/04/2014 
Includes Revisions #1-11 
CONTACT INFORMATION (04/28/2014) 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Email: 
CTSURegulatory@ctsu.coccg.
org (for submitting regulatory 
documents only) 
Please refer to the patient 
enrollment section of the 
protocol for instructions 
on using the Oncology 
Patient Enrollment 
Network (OPEN) which 
can be accessed at 
https://www.ctsu.org/OPE
N_SYSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help 
Desk with any OPEN-
related questions at 
ctsucontact@westat.com. 
 
 
Use the SDC Electronic Data Entry System 
(SEDES) online application found at the 
GOG Web Menu page, to view and print a 
copy of each form along with instructions, 
and to submit forms electronically.  All 
amendments to forms submitted through 
SEDES must also be submitted through 
SEDES.  The original form and required 
copies for forms NOT submitted online must 
be mailed to the GOG SDC. 
 
 
 
 
 
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 Web page of the CTSU Member Web site located at 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 user log on with 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 RSS. 
For clinical questions (i.e. patient eligibility or treatment-related) 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.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please review 
the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website   
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU Regulatory 
and Monitoring Policy 
The CTSU Website is located at https://www.ctsu.org. 
 
 
 
OPEN TO PATIENT ENTRY JUNE 29, 2009; REVISED AUGUST 12, 2009; REVISED OCTOBER 13, 2009; 
REVISED JUNE 7, 2010; REVISED JANUARY 3, 2011; REVISED MARCH 14, 2011; REVISED JUNE 13, 
2011; REVISED SEPTEMBER 26, 2011; REVISED JUNE 25, 2012; REVISED JANUARY 13, 2014; REVISED 
APRIL 28, 2014 

NCI Protocol #: GOG-0258 
Version Date: 04/04/2014 
- 3 - 
 
SCHEMA  
 
Enroll patients with either FIGO 2009 surgical Stage III or IVA endometrial carcinoma or 
patients with FIGO 2009 Stage I or II serous (UPSC) or clear cell endometrial carcinoma and 
positive cytology. (01/03/2011) 
 
TREATMENT RANDOMIZATION 
 
REGIMEN I:  
Cisplatin 50 mg/m2 IV Days 1 and 29 (06/07/2010) 
plus Volume-directed radiation therapy 
followed by Carboplatin AUC 5* plus Paclitaxel 175 mg/m2 q 21 days for 4 cycles 
 with G-CSF support  
(08/12/09) 
or 
 
REGIMEN II: Carboplatin AUC 6 plus Paclitaxel 175 mg/m2 q 21 days for 6 cycles 
 
* first dose of Carboplatin will be at AUC of 5, in subsequent cycles the dose will be escalated 
to AUC 6, as described in Section 6.2.  (06/07/2010) 
 
Translational Research (See Section 7.3) 
 Archival formalin-fixed, paraffin-embedded primary or metastatic tumor tissue 
 Whole blood 
Quality of Life Assessment (See Section 7.4) 
 At baseline (within 14 days prior to starting protocol therapy ) 
 6 weeks from start of protocol treatment (1 week post-completion of RT for Regimen I or 
three weeks post completion of 2 cycles of chemotherapy for Regimen II) 
 18 weeks from start of protocol treatment (three weeks after completion of protocol therapy) 
 70 weeks from start of protocol treatment (1 year from completion of protocol therapy) 
 
 
 
 
 
 

NCI Protocol #: GOG-0258 
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TABLE OF CONTENTS 
PAGE 
1.0 
OBJECTIVES 
- 6 - 
1.1 
Primary Objective: 
- 6 - 
1.2 
Secondary Objectives: 
- 6 - 
1.3 
Translational Research Objective 
- 6 - 
2.0 
BACKGROUND AND RATIONALE 
- 7 - 
2.1 
Introduction, hypothesis and significance: 
- 7 - 
2.2 
Prior Experience with Chemotherapy and Radiotherapy in Endometrial Cancer 
- 8 - 
2.3 
Inclusion of Women and Minorities 
- 12 - 
3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS 
- 13 - 
3.1 
Eligible Patients 
- 13 - 
3.2 
Ineligible Patients 
- 14 - 
4.0 
STUDY MODALITIES 
- 15 - 
4.1 
Cisplatin (Platinol®-AQ) (NSC #119875) 
- 15 - 
4.2 
Carboplatin (Paraplatin®) (NSC # 241240) 
- 15 - 
4.3 
Paclitaxel (Taxol®) NSC#673089 
- 16 - 
4.4 
Filgrastim (G-CSF) or Pegfilgrastim 
- 18 - 
4.5 
Radiation Therapy 
- 19 - 
4.6 
Radiation Therapy Volumes and Technique 
- 21 - 
4.7 
Pathology Requirements 
- 34 - 
4.8 
Quality of Life Surveys 
- 34 - 
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE (04/28/2014) - 
36 - 
5.1 
IROC Houston (formerly the Radiological Physics Center [RPC]) Credentialing 
Requirements (04/28/2014) 
- 36 - 
5.2 
Registration Procedures (04/28/2014) 
- 37 - 
5.3 
Patient Entry and Registration  (04/28/2014) 
- 40 - 
5.4 
Treatment Plan 
- 41 - 
6.0 
TREATMENT MODIFICATIONS 
- 46 - 
6.1 
Radiation Therapy 
- 46 - 
6.2 
Chemotherapy-Hematological Toxicity 
- 46 - 
6.3 
Systemic Chemotherapy:  Non-Hematologic Toxicity 
- 48 - 
6.4 
Discontinuation from protocol 
- 50 - 
7.0 
STUDY PARAMETERS 
- 51 - 
7.1 
Observations and Tests (06/07/2010) (01/03/2011) (01/13/14) 
- 51 - 
7.2 
Stained Pathology Slides for Central Pathology Review to Confirm Eligibility 
- 52 - 
7.3 
Translational Research (01/13/14) 
- 52 - 
7.4 
Quality of Life 
- 53 - 
8.0 
EVALUATION CRITERIA 
- 56 - 

NCI Protocol #: GOG-0258 
Version Date: 04/04/2014 
- 5 - 
8.1 
Parameters of Response – GOG RECIST Criteria 
- 56 - 
9.0 
DURATION OF STUDY 
- 57 - 
9.1 
Patients will continue on protocol for a maximum of six cycles of chemotherapy or until 
disease progression or adverse effects necessitate removal from protocol therapy. 
- 57 - 
9.2 
Patients will be followed every three months for two years, then every six months for 
the next three years.  After five years follow-up information will be obtained annually. All 
subsequent anti-cancer therapies will be reported. (08/31/2009) 
- 57 - 
9.3 
A patient is considered off study therapy when the patient has either completed the 
prescribed number of cycles or fractions of study therapy, has progressed or died prior to 
completion of study therapy, a non-protocol drug or therapy (directed at the disease) is 
initiated, or all study therapy is totally discontinued.  Report all chemotherapy treatment 
received on Form D2R, radiation therapy received on Form G, HDRV or LDRV and adverse 
events on Form T until the patient qualifies as being off study therapy. (08/12/09) 
- 57 - 
10.0  STUDY MONITORING AND REPORTING PROCEDURES 
- 58 - 
10.1 
ADVERSE EVENT REPORTING FOR ALL REGIMENS (COMMERCIAL 
AGENTS AND RADIATION THERAPY ADMINISTRATION) (04/28/2014) 
- 58 - 
10.2 
GOG DATA MANAGEMENT FORMS (09/21/2009) (01/03/2011) (01/13/14) - 61 - 
11.0  STATISTICAL CONSIDERATIONS 
- 65 - 
11.1 
Overview, Study Registration and Randomization: 
- 65 - 
11.2 
Relevant data: 
- 65 - 
11.3 
Accrual rate, sample size and study duration: 
- 66 - 
11.4 
Hypotheses, planning parameters, method of analysis and sample size justification: - 
66 - 
11.5 
Interim analysis: 
- 70 - 
11.6 
Planned gender, minority and ethnic inclusion: 
- 71 - 
12.0  BIBLIOGRAPHY 
- 72 - 
APPENDIX I 
- 77 - 
APPENDIX II (04/28/2014) 
- 78 - 
APPENDIX III (04/28/2014) 
- 83 - 
APPENDIX IV (04/28/2014) 
- 85 - 
 
 

NCI Protocol #: GOG-0258 
Version Date: 04/04/2014 
- 6 - 
1.0 
OBJECTIVES  
 
1.1 
Primary Objective: 
 
1.11 
To determine if treatment with cisplatin and volume-directed radiation 
followed by carboplatin and paclitaxel for 4 cycles (experimental arm) 
reduces the rate of recurrence or death (i.e., increases recurrence-free 
survival) when compared to  chemotherapy consisting of  carboplatin and 
paclitaxel for 6 cycles (control arm) in patients with Stages III-IVA 
endometrial carcinoma (<2 cm residual disease) or patients with FIGO 
2009 Stage I or II serous (UPSC) or clear cell endometrial carcinoma and 
positive cytology. (01/03/2011) 
 
1.2 
Secondary Objectives:  
 
1.21 
To determine if treatment with cisplatin and volume-directed radiation 
followed by carboplatin and paclitaxel for 4 cycles (experimental arm) 
reduces the rate of death (i.e., increases survival) when compared to  
chemotherapy consisting of  carboplatin and paclitaxel for 6 cycles 
(control arm) in patients with Stages III-IVA endometrial carcinoma (< 2 
cm residual disease) or patients with FIGO 2009 Stage I or II serous 
(UPSC) or clear cell endometrial carcinoma and positive cytology. 
(01/03/2011) 
 
1.22 
To compare the regimens with respect to acute and late adverse effects of 
therapy. 
 
1.23 
To determine the impact on patient-reported Quality of Life during and 
following treatment for up to 1 year with the two treatment regimens. 
 
1.3 
Translational Research Objective 
 
1.31 
To bank formalin-fixed, paraffin-embedded (FFPE) tumor tissue and 
whole blood specimens for future research. 
 

NCI Protocol #: GOG-0258 
Version Date: 04/04/2014 
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2.0 
BACKGROUND AND RATIONALE 
 
2.1 
Introduction, hypothesis and significance: 
 
Advanced endometrial cancer (Stages III and IVA) comprises a heterogeneous 
group of patients, whose survival remains generally poor.  Improved surgical 
therapy and staging (including lymph node assessment and/or dissection) has 
given clinicians a better understanding of prognostic groups, risk factors, and 
patterns of recurrence.  The survival of patients with Stage III endometrial 
carcinoma is influenced by several prognostic factors: extent of abdominal/pelvic 
disease, histological subtype, nodal involvement, presence of extra-nodal disease, 
and completeness of surgical resection.1-5 Because of these parameters, which 
cause wide variability in the pool of patients selected for enrollment in clinical 
trials, there is a wide range of reported five-year survival for this group of patients 
(between 40% and 80%).6-8   
 
The optimal adjuvant treatment strategy for these patients is still not well defined.  
In the past surgical resection has been followed by pelvic or whole abdomen 
radiotherapy.  Unfortunately, systemic failures outside the treatment field have 
limited the impact of radiation on long-term survival.  In recent years, 
chemotherapy has demonstrated significant activity in patients with advanced 
endometrial cancer and has become the standard treatment.  Its benefits rely in the 
sterilization of systemic foci of metastatic disease.  However, if chemotherapy is 
given alone, the crude proportion of patients with pelvic recurrences is high 
(18%) and can lead to systemic recurrence and death.9   
Therefore, it is reasonable to hypothesize that a combined approach 
(chemotherapy and radiotherapy) may provide better disease control, by 
preventing both local/pelvic recurrences (radiation), as well as failure at distant 
sites, as opposed to chemotherapy alone.  Such approach has been tested in 
promising Phase II protocols, but has not been validated in a randomized fashion.  
The purpose of this trial is to test this hypothesis by utilizing modern tumor 
volume-directed radiotherapy administered with cisplatin and followed by 
systemic chemotherapy. 
 
This trial is significant as it could set a new standard of care for women with 
optimally cyto-reduced Stage III and IVA endometrial cancer.  The study builds 
on the previous experience of the Gynecologic Oncology Group (GOG) and of the 
Radiation Therapy Oncology Group (RTOG).  It is now clear that systemic 
chemotherapy should be part of the treatment for this patient population (GOG-
0122).  It is also predicted that radiotherapy would decrease the rate of local 
failure.  However, it is not known whether addition of volume-directed chemo-
radiation to chemotherapy alters recurrence-free survival (RFS) and overall 
survival (OS) in a significant manner.  This trial is the logical follow-up to the 
previous research questions addressed by GOG protocols (0122, 0177, 0184, and 
0209).  The trial will answer critical questions regarding 1) the impact of chemo-

NCI Protocol #: GOG-0258 
Version Date: 04/04/2014 
- 8 - 
radiation in this setting, 2) the tolerability of this approach compared to the 
standard of care, and 3) the short- and long-term impact on the quality of life. 
   
A positive trial would lead to a new standard treatment that could easily be 
adopted in the community practice.  Furthermore, if this regimen proves to be 
active and is feasible, future research could adopt it as a backbone for treatments 
incorporating molecularly driven therapies.  Based on the known pattern of 
disease recurrence in endometrial cancer and the role of radiotherapy in 
preventing local recurrence, it is highly predictable that this will be a positive 
trial.  However, in the event that the results of this trial are negative, a long-term, 
lingering question will be answered definitively.  A negative trial would provide 
the basis for limiting the role of radiotherapy in this setting and the rationale for 
focusing future research efforts on exploration of biological pathways important 
to progression of endometrial carcinoma. 
 
2.2 
Prior Experience with Chemotherapy and Radiotherapy in Endometrial Cancer 
 
2.21 
Review of the role of chemotherapy in advanced endometrial carcinoma   
The benefits of chemotherapy in patients with endometrial carcinoma have 
been recognized during the past decade.  Cisplatin, doxorubicin, and 
paclitaxel are all active agents in the treatment of metastatic or recurrent 
endometrial cancer.10-20  More recently, multi-agent chemotherapy 
emerged as an active therapeutic modality in patients with advanced 
endometrial cancer, with response rates as high as 70%.21  The GOG 
studied the combination of doxorubicin and cisplatin in protocols GOG-
0107 and GOG-0163.  In both protocols, the overall response rate to 
cisplatin/doxorubicin was at least 40%, with a complete response observed 
in approximately 20% of patients. 21 The toxicity profile of the 
combination arm was acceptable.  
  
A recent randomized Phase III clinical trial conducted by the GOG 
demonstrated a survival advantage for combination chemotherapy over 
whole abdominal irradiation (WAI) in patients with advanced endometrial 
cancer.9 GOG-0122, a randomized comparison between WAI and 
combination chemotherapy (AP), showed that combination 
doxorubicin/cisplatin (AP) improved overall and disease-free survival 
over whole abdominal radiotherapy in patients with optimally resected 
advanced endometrial cancer.  With a median 74 months of follow-up, the 
hazard ratio for PFS (HR=0.71) and OS (HR=0.68) favored the 
chemotherapy arm.  This trial set a new standard for patients with 
advanced endometrial cancer.  Importantly, the proportion of patients with 
an initial pelvic failure in this protocol was 18%, which suggests that 
despite good systemic control, local control is also needed in this patient 
population9.  Other retrospective analyses have also indicated that in the 
absence of radiotherapy, patients treated with systemic chemotherapy 
alone experience a high rate (20-30%) of pelvic recurrences.22-23 

NCI Protocol #: GOG-0258 
Version Date: 04/04/2014 
- 9 - 
 
To further improve treatment outcome, three subsequent trials followed: 
GOG-0177, 0184 and 0209.  All these trials addressed changes in the 
systemic regimen and did not focus on improving local control. GOG-
0177 and GOG-0184 looked at further improving the efficacy of 
combination chemotherapy by adding a third active agent (paclitaxel). 
 
In GOG-0177, the combination doxorubicin/cisplatin (AP) was compared 
to the triplet doxorubicin/cisplatin/paclitaxel (TAP) in women with 
measurable metastatic or recurrent endometrial cancer.24 The triplet was 
more active.  Response rates were 57% for TAP (22% CR, 35% PR) 
versus 34% for AP (7% CR, 26% PR); p<0.001 and the hazard ratio for 
progression or death for TAP relative to AP was 0.60 (95% CI 0.46-0.78, 
p<0.001).  This translated into a median progression-free survival (PFS) of 
8.3 for TAP versus 5.3 months for AP, and a median overall survival of 
15.3 for TAP versus 12.3 months for AP (p=0.037).24  However, the 
toxicity of the regimen was high and growth factor support was 
mandatory.  The proportion of patients with a maximum of Grade 2, 3, and 
4 neuropathy was 27%, 12%, and 0%, respectively.  Interestingly, when 
the TAP regimen was taken to the adjuvant setting, following volume-
directed RT in stage III-IVA endometrial cancer (GOG-0184), preliminary 
results of mature data suggest that there was no disease-free survival 
benefit noted compared to AP (unpublished results).  Furthermore, the 
crude proportion of patients with acute Grade 3-4 GI toxicity was 13% in 
the AP arm and 18.3% in the TAP arm, and 80% of all patients completed 
the planned six cycles of systemic treatment.  In the TAP arm, protocol 
therapy was discontinued in 14% of patients due to toxicity and an 
additional 4.6% due to patient refusal.  The crude proportion of patients 
with late Grade 3-4 GI toxicity, including bowel obstruction and fistula, in 
both doxorubicin containing regimens was 6-8% (this estimate does not 
account for competing risks).  These results suggest that although highly 
active in the metastatic setting, the triplet TAP regimen is not superior and 
is too toxic to be administered after RT in the adjuvant setting.  The long-
term adverse effects of chemotherapy on quality of life in these studies 
have not yet been analyzed, but an adverse impact due to neurotoxicity is 
expected to emerge.  These considerations led to a well justified interest in 
developing a less toxic regimen for this patient population.  This objective 
is addressed by protocol GOG-0209, designed to compare the commonly 
used and popular regimen carboplatin/paclitaxel (CT) vs. TAP.  The CT 
regimen had been tested in several Phase II studies, with encouraging 
preliminary results.25, 26 Hoskins and co-workers reported a 78% response 
rate in patients with advanced non-serous endometrial cancer, and a 
response rate of 51% in patients with serous papillary uterine cancer.25  
The three-year survival for patients with advanced non-serous papillary 
endometrial cancer was 62%, whereas patients with advanced papillary 
serous endometrial carcinoma had a 39% three-year overall survival 

NCI Protocol #: GOG-0258 
Version Date: 04/04/2014 
- 10 - 
probability.  Nakamura reported a complete response rate to CT of 
45.5%.26 Similarly, Price reported a 63% response rate in their series of 20 
patients.27 Lastly, a randomized Phase II trial suggested that the 
combination carboplatin/paclitaxel is at least as active as 
doxorubicin/cisplatin, with response rates of 44% (CT) versus 26% 
(AP).28 The results of GOG-0209 are not yet available. However, because 
of its ease of administration and reduced toxicity, in face of significant 
short- and long-term toxicity with the doxorubicin containing regimens, 
carboplatin/paclitaxel has been selected as the regimen for the control arm 
in the current protocol. 
 
2.22 
The role of radiation therapy in Stage III endometrial carcinoma   
 
Traditionally, radiation therapy has been employed in patients with 
endometrial carcinoma to improve local control after surgery.29  Its role 
has been established in patients with early-stage intermediate and high risk  
endometrial cancer.30  Although pelvic radiotherapy is commonly used in 
patients with advanced uterine carcinoma,31 to date a survival advantage 
with adjuvant radiotherapy has not been proven by a randomized study.  
Several retrospective case series have reported the impact of adjuvant 
radiotherapy in this setting, but most cohorts of patients are small and non-
homogenous.  In general, these studies suggest a modest benefit from 
adjuvant radiotherapy after complete surgery in this setting, with the 
majority of patients relapsing systemically.32-34 These studies also reflect 
the fact that Stage III endometrial cancer is often a systemic disease, 
where disease control requires effective systemic therapy. 
 
2.23 
Role of combined chemotherapy and radiation therapy in advanced 
endometrial cancer 
 
Based on these considerations, it is compelling to hypothesize that a 
strategy combining chemotherapy and radiotherapy would yield better 
results in this patient population by controlling both systemic and local 
recurrences.  It is important to note that 30% of patients included in GOG-
0122 treated with systemic chemotherapy recurred in the pelvis and in the 
abdomen.  This observation suggests that patients treated with systemic 
chemotherapy experience a significant rate of local failure, which leads to 
compromise in overall survival.  Inclusion of tumor volume-directed 
radiotherapy could prevent local recurrences and potentially would lead to 
an improvement in overall survival.  This is a crucial question that to date 
has not been addressed relative to this patient population in a randomized 
trial.  Several small studies have suggested that combination therapy can 
indeed yield survival benefit.  Onda reported that among 30 patients with 
Stage IIIC endometrial cancer treated with combination WAI and 
chemotherapy, the five-year OS was 84%.35 A recent study reported by 
Bruzzone notes DFS of 30% and OS of 53% among 45 poor-prognosis 

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patients with Stages III and IV uterine cancer treated with pelvic 
radiotherapy and chemotherapy (cisplatin, epidoxorubicin and 
cyclophosphamide).36   
 
The Phase II trial run by the RTOG (Protocol 9708) demonstrated 
feasibility and high efficacy of a  combined chemo-radiation approach in 
endometrial cancer patients at high risk of recurrence.37  The regimen 
studied here involved cisplatin given together with pelvic radiation (45Gy) 
followed by four cycles of cisplatin and paclitaxel.  At four years the 
cumulative proportions of patients with pelvic, regional and distant 
recurrence are 2%, 2%, and 19%, respectively.  The percent of patients 
alive or alive and disease free at 4 years are 85% and 81%, respectively.  
For Stage III patients, four-year OS and DFS was 77% and 72%, 
respectively.  These compelling results provide a preliminary basis 
suggesting the feasibility of this approach and also support studying this 
regimen in a randomized fashion.  Successful combination of a chemo-
radiation approach in high risk endometrial cancer has been suggested in 
another Italian pilot study using paclitaxel with EBRT.38  The combined 
modality approach has demonstrated efficacy and feasibility in many other 
tumor types,39-42 including cervical cancer.43-46 
 
Finally, the recently reported results of GOG-0184 suggest that a 
combined radiotherapy and chemotherapy approach in this setting yields 
three-year DFS of 62-64%.  In this protocol, women with optimally 
debulked Stage III and IVA endometrial cancer were randomized to pelvic 
radiotherapy followed by systemic chemotherapy.  The two arms of the 
trial compared outcomes with TAP vs. AP chemotherapy, the primary 
endpoint being DFS.  There was no statistically significant difference in 
DFS with the addition of paclitaxel to the AP regimen. The overall 
survival data is not yet reported.  The results of the trial further support 
feasibility of the approach.47 
 
The advantages of administering up-front chemotherapy with radiation are 
several: 1) synergistic, anti-tumor activity and modulation of the effects of 
radiation by cisplatin;40, 41 2) administration of the systemic agent up-front, 
which circumvents concern related to possible systemic relapses during 
the delay imposed by delivery of radiotherapy; 3) good track record and 
experience with this approach from the cervical cancer studies.43-46 
 
2.23 
Measurement of Quality of Life (QOL) in Endometrial cancer 
Little information exists on the impact of initial treatment on patients’ 
QOL as well as the long term QOL implications, and these QOL 
assessments may be crucial in help deciding treatment plans when 
treatments may offer comparable results.   QOL domains that are 
particularly important during platinum-based chemotherapy and 

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radiotherapy include neuropathy, overall general well being, fatigue, and 
gastrointestinal toxicity, and these will be the focus of this current study.  
 
QOL was measured during GOG study 0122, and newly diagnosed 
patients with either stage III or IV cancer were randomized to whole 
abdominal radiation versus doxorubicin and cisplatin (60 mg/m2 IV and 50 
mg/m2, resp., IV once every 3 weeks for 8 cycles).9,48  QOL measures 
used in this study included Functional Assessment of Cancer Therapy 
(General) (FACT-G), Fatigue Scale, Assessment of Peripheral neuropathy, 
and Functional Alterations due to Changes in Elimination (FACE).  
FACT-G scores were not different between the two treatment arms, but 
peripheral neuropathy was higher amongst patients receiving 
chemotherapy, and fatigue and FACE scores were worse in those patients 
receiving whole abdominal radiotherapy.   
 
In this current study, the following QOL measures will be used:  FACT-G 
(physical and functional well being), 49 FACT-Endometrial which remains 
exploratory, a four-item subscale of FACT-GOG neuropathy, and two 
questions from FACT-C (FACT-colon cancer). 50  These questions will 
answer both short-term as well as long-term side effect impact of therapy.     
 
2.3 
Inclusion of Women and Minorities 
 
The Gynecologic Oncology Group and GOG participating institutions will not 
exclude potential subjects from participating in this or any study solely on the 
basis of ethnic origin or socioeconomic status.  Every attempt will be made to 
enter all eligible patients into this protocol and therefore address the study 
objectives in a patient population representative of the entire endometrial cancer 
population treated by participating institutions. 
 

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3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS 
 
3.1 
Eligible Patients 
 
3.11 
All patients with Surgical Stage III or IVA endometrial carcinoma per 
FIGO 2009 staging criteria, including clear cell and serous papillary and 
undifferentiated carcinomas. (06/07/2010)(01/03/2011) 
 
 
Surgical Stage III disease includes those patients with positive adnexa, 
parametrial involvement, tumor invading the serosa, positive pelvic and/or 
para-aortic nodes, or vaginal involvement.  (01/03/2011) 
 
 
Surgical Stage IVA includes patients with bladder or bowel mucosal 
involvement, but no spread outside the pelvis.  
 
3.12 
Patients with FIGO 2009 surgical Stage I or II endometrial clear cell or 
serous carcinoma and with positive peritoneal cytology. (01/03/2011) 
 
3.13 
Surgery must have included a hysterectomy and bilateral salpingo-
oophorectomy.  Pelvic lymph node sampling and para-aortic lymph node 
sampling are optional.   
 
3.14 
Patients with a GOG Performance Status of 0, 1, or 2. 
 
3.15 
Patients with adequate organ function, reflected by the following 
parameters: 
 
WBC ≥ 3000/mcl 
Absolute neutrophil count (ANC) ≥ 1500/mcl  
 
Platelet count ≥ 100,000/mcl 
 
SGOT, SGPT, and alkaline phosphatase ≤ 2.5 X upper limit of normal 
 
(ULN)  (06/07/2010) 
 
Bilirubin ≤ 1.5 X ULN  (06/07/2010) 
Creatinine ≤ institutional ULN  (06/07/2010) 
 
3.16 
Patients who have met the pre-entry requirements specified in Section 7.0; 
testing values/results must meet eligibility criteria specified in Section 3.1. 
 
3.17 
Patients who have signed an approved informed consent and authorization 
permitting release of personal health information. 
 
3.18 
Patients must be 18 years of age or older. 
 
3.19 
 Entry into the study is limited to no more than 8 weeks from the date of 
surgery. (06/07/2010) 
 

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3.2 
Ineligible Patients  
 
3.21 
Patients with carcinosarcoma. 
 
3.22 
Patients with recurrent endometrial cancer. 
 
3.23 
Patients with residual tumor after surgery (any single site) exceeding 2 cm 
in maximum dimension. 
 
3.24 
Patients who have had pelvic or abdominal radiation therapy. 
 
3.25 
Patients with positive pelvic washings as the only extra-uterine disease are 
NOT eligible if the histology is other than clear cell or papillary serous 
carcinoma.  
 
3.26 
Patients with a history of other invasive malignancies, with the exception 
of non-melanoma skin cancer, are excluded if there is any evidence of 
active malignancy within the last five years.  Patients are also excluded if 
their previous cancer treatment contraindicates this protocol therapy. 
 
3.27 
Patients with a history of serious co-morbid illness or uncontrolled 
illnesses that would preclude protocol therapy. 
 
3.28 
Patients with an estimated survival of less than three months. 
 
3.29 
Patients with FIGO 2009 Stage IVB endometrial cancer. (01/03/2011) 
 
3.210 Patients with parenchymal liver metastases. 
 
3.211 Patients who have received prior chemotherapy for endometrial cancer. 
 
3.212 Patients with a history of myocardial infarction, unstable angina, or 
uncontrolled arrhythmia within 3 months from enrollment. 
 
 
 

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4.0 
STUDY MODALITIES 
 
4.1 
Cisplatin (Platinol®-AQ) (NSC #119875) 
 
4.11 
Formulation: Cisplatin is a sterile aqueous solution, each mcl containing 1 
mg cisplatin and 9 mg sodium chloride. Cisplatin is supplied in multidose 
vials with 50 mg and 100 mg of cisplatin. 
 
NOTE: Aluminum reacts with Platinol® 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 Platinol®. 
 
4.12 
Storage: Store at 15 to 25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. 
 
4.13 
Adverse effects: leukopenia, thrombocytopenia, anemia, nausea, vomiting, 
nephrotoxicity, ototoxicity, peripheral neuropathy, electrolyte imbalance, 
hypocalcemia, hypomagnesemia, aminoglycoside ototoxicity, ocular 
toxicity, and allergic reactions. Infrequent: Cardiac abnormalities, 
anorexia, elevated SGOT, rash, alopecia, and acute myeloid leukemia. 
 
NOTE:  Aminoglycoside antibiotics given before, with, or after cisplatin 
may potentiate renal toxicity and should be avoided whenever possible. 
 
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. 
 
4.14 
Supplier: Commercially available from Bristol Laboratories Oncology 
Products. 
 
 
 
 
*Refer to Package Insert for additional information. 
 
4.2 
Carboplatin (Paraplatin®) (NSC # 241240) 
 
4.21 
Formulation:  Paraplatin 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. 
 

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4.22 
Preparation:  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, Paraplatin solutions are stable for eight hours 
at room temperature, since no antibacterial preservation is contained in the 
formulation it is recommended that Paraplatin solutions be discarded eight 
hours after dilution. 
 
NOTE:  Aluminum reacts with Paraplatin 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 Paraplatin. 
 
4.23 
Storage:  Unopened vials of Paraplatin are stable for the life indicated on 
the package when stored at controlled room temperature and protected 
from light. 
 
4.24 
Adverse effects:  Myelosuppression, nausea, vomiting, peripheral 
neuropathy, ototoxicity, hepatic toxicity, electrolyte imbalance, 
hypomagnesemia, hypocalcemia, and allergic reaction. 
 
4.25 
Supplier:  Commercially available from Bristol-Myers Oncology. 
 
4.26 
Administration:  See Section 5.3. 
 
4.27 
Dose Calculations: See Appendix IV for current instructions. (01/03/2011) 
 
 
*Refer to Package Insert for additional information. 
 
4.3 
Paclitaxel (Taxol®) NSC#673089 
 
4.31 
Formulation: Paclitaxel is a poorly soluble plant product from the 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. 
 

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4.32 
Supplier/How Supplied:  Commercially available from Bristol-Myers 
Oncology. A sterile solution concentrate, 6 mg/ml available in 5 ml 
(30mg/vial), 16.7 ml (100mg/vial) and 50 ml (300mg/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.  
 
4.33 
Solution Preparation:  Paclitaxel, at the appropriate dose, will be diluted in 
500 – 1000 ml 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 LVP’s) 
has been observed after preparation of paclitaxel.  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, IVEX-HP 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. 
 
4.34 
Storage: The intact vials should be stored between 200-250C (680-770F), in  
original package.  Neither freezing nor refrigerator adversely affects the 
stability of the product. 
 
4.35 
Stability: 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 at ambient temperature (~250C) .  
 
4.36 
Administration of Paclitaxel:  Paclitaxel, at the appropriate dose and 
dilution, will be given as a continuous IV infusion.  Paclitaxel will be 
administered via an infusion control device (pump) using non-PVC tubing 
and connectors, such as the IV administration sets (polyethylene or 
polyolefin), which are used to infuse parenteral Nitroglycerin.  Nothing 
else other than 0.9% sodium chloride is to be infused through the line 
where paclitaxel is being administered. 
 
 
 

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4.37 
Adverse Effects: 
 
 
 
Hematological:  Myelosuppression 
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 
Pulmonary: Pneumonitis 
Blood Pressure: Hypotension, hypertension (possibly related to 
concomitant medication--Dexamethasone) 
Neurological: Sensory (taste), peripheral neuropathy, seizures, mood 
swings, hepatic encephalopathy, encephalopathy 
Skin:  Infiltration: erythema, induration, tenderness, rarely ulceration, 
radiation-recall reactions, erythema multiforme (e.g., Stevens-Johnson 
syndrome, toxic epidermal necrolysis) 
Allergy:  Anaphylactoid and urticarial reactions (acute), flushing, rash, 
pruritus 
Liver:  Increased SGOT, SGPT, bilirubin and alkaline phosphatase, 
hepatic failure, hepatic necrosis 
Other:  Alopecia, fatigue, arthralgias, myalgias, light-headedness, 
myopathy 
Other, Vision: Sensation of flashing lights, blurred vision, scintillating 
scotomata 
 
 
*Refer to Package Insert for additional information 
 
4.4 
Filgrastim (G-CSF) or Pegfilgrastim  
 
 
4.41 
Formulation: Filtrate (G-CSF) is available at a concentration of 300 
mcg/ml in 1.0 and 1.6 single-use glass vials.  It is formulated as a sterile, 
clear, colorless liquid in a 10 mm sodium acetate buffer at pH 4.0.  The 
quantitative composition (per ml) is: 
 
Filgrastim (G-CSF) 
 
300 mcg 
Acetate 
 
 
               0.59 mg 
Mannitol* 
 
              50.0 mg 
Tween 80TM 
 
 
0.004% 
Sodium 
 
 
 
0.035 mg 
Water for injection to 1 ml 
 
* Beginning in 1997, Mannitol will be replaced by sorbitol.  
Because Sorbitol improves product stability, it will be permissible 
to use Sorbitol-containing Filgrastim if it becomes accidentally 
frozen in transit for < 24 hours. 
 
4.42 
Preparation:  For this protocol, filgrastim will be given subcutaneously.  It 
can be used directly from the vial. 

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4.43 
Storage:  The intact vials of filgrastim should be stored under refrigeration 
(2o to 8o C).  
 
4.44 
Adverse Effects:  The adverse effects associated with G-CSF are usually 
mild and include bone pain and, rarely, splenomegaly.  Laboratory effects 
include increases in alkaline phosphatase, LDH, WBC, and uric acid.  G-
CSF should not be used in patients with known hypersensitivity to E. Coli-
derived drug preparations. 
 
4.45 
Supplier:  Commercially available from Amgen. 
 
4.46 
Administration:  G-CSF will be given as a subcutaneous injection. (See 
Section 6.241.)  The appropriate volume of G-CSF should be withdrawn 
and injected subcutaneously daily.  Injection sites should be rotated.  If the 
volume to be injected is greater than 1.5 ml, the dose should be divided in 
half, and both doses should be given at the same time in two sites. 
 
 
 
*Refer to Package Insert for additional information. 
 
 
 
4.47 
Pegfilgrastim (G-CSF) may be used as an alternative to Filgrastim and 
should be administered as a single subcutaneous dose of 6 mg on Day 2, 
24 hours after administration of the chemotherapy.  Pegfilgrastim should 
not be administered within 14 days of subsequent chemotherapy. 
 
4.5 
Radiation Therapy   
 
Patients randomized to Regimen I will receive concomitant chemo-radiation 
therapy followed by systemic chemotherapy.  Radiation Therapy will be given to 
the pelvis or pelvis and para-aortic fields (extended field RT), as described below.  
Given that nodal staging is optional for this study, it is the intention of the study 
that some flexibility be given to the treating physicians regarding the extent of the 
radiation therapy fields (See below.)  Adequate hematological parameters as 
evidenced by WBC≥3000/mcl, ANC≥1500/mcl, platelet count ≥ 100000/mcl are 
required prior to initiating chemo-radiotherapy. 
 
4.51 
Treatment will be randomized after enrollment to either chemo-radiation 
therapy followed by systemic chemotherapy or to chemotherapy alone.  
 
4.52 
Chemotherapy will be administered concomitantly with the radiation 
therapy.  Cisplatin (50 mg/m2) will be given on Days 1 and 29 of the 
course of external beam radiation therapy.  (See Chemotherapy section.) 
(06/07/2010) 
 
4.53 
Physical Factors: All treatment will be delivered by megavoltage 
equipment ranging from 6 MV to a maximum of 25 MV photons.  Cobalt-

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60 equipment will not be acceptable for treatment on this protocol.  
Tomotherapy is allowed. 
 
 
4.54 
Localization and Simulation Methods: Localization images taken on the 
conventional or CT-simulator will be necessary in all cases.   
 
4.55 
Treatment Plan and Dose Specification: Patients may be treated with 
either conventional radiation therapy approaches or with IMRT.  (See 
Sections 4.62, 4.64 and 5.1 for credentialing requirements.)  For patients 
treated with a conventional 4 field approach, it is highly recommended 
that each patient swallow a dilute solution of an appropriate contrast 
material at least 30 minutes before simulation so that the small bowel can 
be identified on the simulator films.  The use of individualized custom 
blocking is required. (06/07/2010) 
 
Before ANY patient is enrolled on this study, each treating radiation 
oncologist must complete on-line a Knowledge Assessment Questionnaire 
found on the IROC Houston (formerly known as the Radiologic Physics 
Center [RPC]) website (http://irochouston.mdanderson.org).  For patients 
treated with IMRT, the treatment plan for the first patient to be treated by 
each radiation oncologist on this protocol must be digitally submitted to 
TRIAD where it will be processed in preparation for rapid review. A rapid 
review will be performed PRIOR TO DELIVERING ANY PROTOCOL 
TREATMENT. The rapid review will be conducted by IROC Houston 
(RPC), and suggestions regarding protocol compliance will be forwarded 
to the participating institution’s radiation oncologist.  Instructions for 
electronically submitting the patient case can be found on the IROC 
Houston web site: http://irochouston.mdanderson.org.  The treatment plans 
for the subsequent patients enrolled at a site will not be required to be 
reviewed prior to treatment, but a review will be performed. Once data has 
been submitted to TRIAD, complete a DDSI contact information form at 
(06/07/2010) (04/28/2014) 
 
4.56 
Daily Tumor Dose, Total Dose, and Overall Treatment Time: A daily 
tumor dose of 180 cGy per day will be given to a total dose of 4500 cGy 
(180 cGy x 25 treatments) in approximately five weeks.  Treatment will 
be given 5 days a week, from Monday through Friday 
 
4.57 
Dose Distribution (Site):  Dose to the CTV should not vary by more than 
+/- 5% from the prescribed dosage for 3D conformal plans.  The use of 
tissue wedges and/or compensating filters may be necessary to accomplish 
this goal.  Isodose distributions shall be obtained and submitted for 
review. 
 
4.58 
As a general rule, only pelvic radiation therapy will be given, unless there 
is imaging, intra-operative, histologic, or other evidence of para-aortic 

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node involvement.  However, the treating radiation oncologist may 
reasonably elect to treat with extended-field radiation therapy in the 
setting of positive pelvic nodes in the absence of adequate surgical staging 
data indicating the para-aortic lymph nodes are negative.  Similarly, the 
treating radiation oncologist might elect not to treat the para-aortic field 
(only in the absence of proven metastatic disease in this region) to 
improve the patient’s acute tolerance to RT.  In general these treatment 
decisions will not be deemed protocol violations, given sufficient 
information regarding the decision-making process. 
 
4.59 
If there is tumor extension into the vagina, the external beam fields will be 
modified to include the disease volume with at least a 2 cm margin. For 
involvement of the distal 1/3 of the vagina, inguino-femoral nodes should 
also be covered in the external beam RT ports. If the patient’s tumor 
extends into the cervix, or invades deeply and extends into the lower 
uterine segment, or if there is lymph-vascular space invasion by tumor, or 
if the tumor has extended into the vagina, such a patient will receive 
intravaginal boost brachytherapy (HDR or LDR) at the discretion of the 
radiation oncologist. Patients with residual gross disease in the vagina 
following surgery are eligible as long as the maximum dimension is no 
greater than 2 cm by physical exam and imaging studies, if indicated. 
 
4.6 
Radiation Therapy Volumes and Technique 
 
4.61 
Pelvic field: 3D Conformal 
 
 
Portal and Treatment Volume Definition:  
 
The boundaries are as follows: 
 
AP/PA Fields:  Cephalad Border: 
 
A transverse line drawn within 2 cm of the L5-S1 interspace, or higher if 
necessary to include known areas of lymph node involvement by tumor. 
 
AP/PA Fields:  Caudal Border: 
 
The mid-portion of the obturator foramen or a minimum of 4 cm margin 
on the vaginal cuff, preferably defined by marker seed placement or by 
placement of a vaginal swab at the time of simulation. 
 
Lateral Borders: 
 
>1 cm beyond the lateral margin of the true pelvis at its widest points.  
Alternatively, use of a CT scan to outline the target vessels with a border 
of at least 1 cm is acceptable. 

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Lateral Pelvic Fields: 
 
The cephalad and caudal borders are same as above. 
 
Anterior Border: 
 
A horizontal line drawn anterior to the symphysis pubis.  When extended 
in the cephalad direction, this line should pass at least 1 cm anterior to 
known nodal regions or, in the absence or radiographic documentation, the 
line should pass at least 1.5 cm anterior to the L5 vertebral body.  
Individualized custom blocks can be used to achieve this goal. 
 
Posterior Border: 
 
A cephalo-caudal line passing through the third sacral vertebra.  Every 
effort should be made to include the upper vaginal stump with a margin of 
at least 3 cm. 
 
4.62 
Pelvic Radiation Therapy: IMRT 
 
In addition to the rapid review requirements for all radiation oncologists 
treating on this protocol (see Section 4.55), please note that all institutions 
that are considering the use of IMRT MUST be credentialed by IROC 
Houston (RPC) at M.D. Anderson Cancer Center before entering any 
patient on this study. (See Section 5.1). A pre-treatment review will be 
performed PRIOR TO DELIVERING ANY PROTOCOL TREATMENT.  
The rapid review will be conducted by IROC Houston  , and suggestions 
regarding protocol compliance will be forwarded to the participating 
institution – radiation oncologist. Instructions for electronically submitting 
the patient case can be found on the IROC Houston web site 
  Institutions that have been previously 
credentialed for IMRT by RTOG or GOG via the head and neck phantom 
or the pelvic phantom can determine what additional requirements must be 
completed by filling out the “Credentialing Status Inquiry” form on the 
IROC Houston website.  IROC Houston will issue credentials for this 
protocol to the institution and notify the GOG Statistical and Data Center. 
(06/07/2010) (04/28/2014) 
 
Institutions that have not been credentialed by GOG or RTOG must apply 
for IMRT credentialing. See Section 5.1 for credentialing requirements.   
 
Portal and Treatment Volume Definition: 
 
4.621 Patient Immobilization:  Prior to simulation, it is recommended 
that radiopaque marker seeds be inserted into the vaginal apex to 

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help to identify the area by CT scan.  Patients are to be 
immobilized in the supine position in an immobilization device 
such as Vac-lok or alpha-cradle, with fixation of the upper body, 
trunk, and proximal thighs. Patients are to be treated in the 
immobilization device.  CT scan thickness should be 3 mm or 
smaller through the region that contains the PTV, extending from 
at least L3-4 level to below the perineum. 
 
4.622 Simulation:  CT simulation is required to define clinical target 
volume (CTV) and planning target volume (PTV).  The CT scan 
should be acquired in the same position and immobilization device 
as for treatment.  The use of IV contrast and bowel prep-contrast 
are highly recommended for better delineation of the contrast-
enhanced pelvic vessels used as a surrogate for regional nodal 
delineation, as well as small bowel contouring, respectively.   
 
 
4.623 Contouring the Target volumes: 
 
 
4.6231 Please refer to the RTOG Gynecological Atlas for volume 
specification.  The atlas may be accessed on the RTOG 
website at: 
 
 
4.6232 The Clinical Target Volume (CTV) is defined as the 
vaginal apex with margins as given in Section 4.6, in 
addition to pelvic nodal regions lying within the field 
borders given in Section 4.61. 
 
If gas/stool distends the rectum, the CTV is to be expanded 
to include the anterior half of the rectum to account for 
evacuation of the rectum.  (03/14/2011) 
 
4.6233 The nodal portion of the CTV should include the internal 
(hypogastric and obturator), and external iliac lymph node 
regions.  The CTV should be delineated using the contrast-
enhanced (preferably IV contrast administered) iliac 
vessels, in addition to the perinodal soft tissue (minimum of 
6 mm axial margin around the vessels).  Bone and 
intraperitoneal small bowel should be excluded from the 
CTV as much as possible (leaving at least 6 mm margin 
around the vessels).  
 
 
Approximately 1-2 cm of tissue anterior to the sacrum (S1-
S3) may be added to the CTV for adequate coverage of pre-
sacral nodes, although this is optional and at the discretion 
of the treating radiation oncologist.  In addition the most 
antero-lateral margin of the external iliac nodes that lie just 

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proximal to the inguinal canal should be excluded from the 
CTV (nodal CTV should stop at the femoral head).  
Proximally, the CTV should end 7 mm from the L5-S1 
interspace to account for the PTV.  
 
 
The CTV should include the inguino-femoral nodes if the 
distal one-third of the vagina is involved with tumor.  
 
4.6234 The PTV should provide a 7 mm-1 cm margin in all 
directions around the CTV.  
 
4.6235 The definitions of volumes will be in accordance with the 
1993 ICRU report #50.  Prescribing, recording and 
reporting photon beam therapy and 1999 ICRU report #62.  
 
 
4.6236 Critical normal surrounding structures:  
 
 
4.62361   Bladder will be contoured in each slice in which 
it appears. 
 
 
4.62362   Rectum will be contoured in each slice in which 
it appears.  As a general guideline, the radiation 
oncologist can consider the maximum caudal 
extent of the rectum to lie 1.5-2.0 cm from the 
bottom of the ischial tuberosities.  Superiorly, 
judgment will be required to establish where the 
rectum ends and the sigmoid colon begins.  The 
transition to the sigmoid colon is marked by 
increased curvature and tortuosity in its path. 
 
 
4.62363   Small bowel will be contoured in each slice in 
which it appears, including at least 2 cm above 
the PTV.  The small bowel will be contoured in 
its entirety within these parameters, including 
adipose and mesentery. 
 
4.62364  Femoral heads will be contoured in all the slices 
in which they appear.  
 
4.624 Constraints:  Participants are strongly encouraged to respect the 
following limits, whether 3-D conformal or IMRT approaches are 
used. 
 
 
 
4.6241 Small bowel: <30% to receive ≥ 40Gy, Dmax <46 Gy 
 

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         4.6242 Rectum: < 80% to receive ≥ 40Gy, Dmax <55 Gy 
(03/14/2011) 
 
         4.6243 Bladder: < 50% to receive ≥ 45Gy, Dmax <60 Gy 
 
         4.6244 Femoral heads: < 50% to receive ≥ 40Gy, Dmax <50 Gy. 
 
 
4.6245 Unspecified tissue (tissue contained within the skin or any 
other normal structure not delineated above and outside the 
PTV, not included within any other structure):  No more 
than 1% or 1 cc (whichever is smaller) of the tissue outside 
the PTV will receive > 110% of the dose prescribed to the 
PTV.  
 
4.63 
Extended Field Radiation Therapy: 3D Conformal 
 
Portal and Treatment Volume:  The boundaries are as follows: 
 
AP/PA Fields:  Cephalad Border: 
 
A transverse line drawn within 2 cm of the T11-T12 interspace. 
 
AP/PA Fields:  Caudal Border: 
 
The mid-portion of the obturator foramen or a minimum of 4 cm margin 
on the vaginal cuff, preferably defined by marker seed placement or by 
placement of a vaginal swab at the time of simulation. 
 
Lateral Borders: 
 
In the pelvis >1 cm beyond the lateral margin of the true pelvis at its 
widest points.  Alternatively, use of a CT scan to outline the target vessels 
with a border of at least 1 cm is acceptable.  Moving superiorly, the width 
of the field will taper to the lateral aspects of the spinal transverse 
processes at L4 and superior to L4.  The approximate field width for the 
para-aortic portion of the field should be 8 cm, although some variation is 
expected. 
 
Lateral Pelvic Fields: 
 
The cephalad and caudal borders are same as above. 
 
Anterior Border: 
 
A horizontal line drawn anterior to the symphysis pubis.  When extended 
in the cephalad direction, this line should pass at least 1 cm anterior to 

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known nodal regions or, in the absence or radiographic documentation, the 
line should pass at least 1.5 cm anterior to the L5 vertebral body.  
Individualized custom blocks can be used to achieve this goal.  Moving 
superiorly, the anterior border of the para-aortic field should remain a 
minimum of 1.5-2 cm anterior to the anterior border of the vertebral body. 
Again, some variation is expected, particularly in patients who have 
positive PA nodes or in patients who kidneys are located more anteriorly 
than normal.  The overall width of the PA field should be at least 5 cm. 
 
Posterior Border: 
 
A cephalo-caudal line passing through the third sacral vertebra.  Every 
effort should be made to include the upper vaginal stump with a margin of 
at least 3 cm.  Moving superiorly, the posterior border of the PA field 
should extend back approximately 50% of the width of each vertebral 
body. 
 
Suggested technique:  Different techniques have been used to deliver 
extended field radiation therapy.  The suggested technique for this study is 
to treat the pelvic and para-aortic fields in continuity, as opposed to 
splitting fields, or treating the para-aortic portion with AP-PA fields only.  
Treating in continuity, it is suggested that the AP-PA fields be weighted 
70:30 in relation to the lateral fields, in terms of isocenter dose.  This 
technique strikes an appropriate balance, in most cases, between small 
bowel dose and kidney dose.  Other techniques or beam weightings are 
potentially permissible, if appropriate dose distributions to PTV and 
organs at risk (OAR’s) are obtained.  Should there be questions, the 
treating radiation oncologist is encouraged to contact the Radiation 
Oncology Co-Chair. 
 
4.64 
Extended Field Radiation Therapy: IMRT  (04/28/2014) 
 
In addition to the rapid review requirements for all radiation oncologists 
treating on this protocol (see Section 4.55), please note that all institutions 
that are considering the use of IMRT MUST be credentialed by IROC 
Houston before entering any patient on this study.  (See Section 5.1.)  
(06/07/2010) 
 
Please note that ALL institutions, when IMRT is to be used, must submit 
and successfully complete a plan for the first patient to be treated by each 
radiation oncologist treating on this protocol.  A rapid review will be 
performed PRIOR TO DELIVERING ANY PROTOCOL TREATMENT.  
The rapid review will be conducted by IROC Houston, and suggestions 
regarding protocol compliance will be forwarded to the participating 
institution – radiation oncologist. Instructions for electronically submitting 
the patient case Via TRIAD can be found on the IROC Houston web site: 

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  The treatment plans for the 
subsequent patients enrolled at a site will not be required to be reviewed 
prior to treatment, but a review will be performed. (06/07/2010)  
 
4.641 Rapid Review Data Submission for IMRT via TRIAD: 
(04/28/2014) 
 
For Submission via TRIAD, the structure names must match the 
following list exactly or resubmission will be required.  After 
submission is completed submit a DDSI contact information form.  
The DDSI can be found at 
 
                           
Structure Name 
Description 
CTV_4500 
CTV 
Required 
CTVn 
Nodal CTV portion 
Required
PTV_4500 
PTV 
Required
Bladder 
Bladder 
Required
Femurs 
Femoral Heads 
Required
Kidneys 
Kidneys 
Required
Rectum 
Rectum 
Required
BowelSpace 
Bowel  
Required
SpinalCord 
Spinal Cord 
Required
NonPTV 
Unspecified tissue (External minus PTV) 
Required
External 
External Skin 
 Required
 
Portal and Treatment Volume Definition: 
 
 
4.641  Patient Immobilization: 
   
Prior to simulation, it is recommended that radiopaque marker 
seeds are inserted into the vaginal apex to help to identify the area 
by CT scan.  Patients are to be immobilized in the supine position 
in an immobilization device such as Vac-lok or alpha-cradle, with 
fixation of the upper body, trunk, and proximal thighs.  Patients are 

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to be treated in the immobilization device.  CT scan thickness 
should be 3 mm or smaller through the region that contains the 
PTV, extending from at least L3-4 level to below the perineum. 
 
4.642  Simulation:   
 
CT simulation is required to define clinical target volume (CTV) 
and planning target volume (PTV).  The CT scan should be 
acquired in the same position and immobilization device as for 
treatment.  The use of IV contrast and bowel prep-contrast are 
highly recommended for better delineation of the contrast-
enhanced pelvic vessels used as a surrogate for regional nodal 
delineation, as well as small bowel contouring, respectively.   
 
4.643 Contouring the Target volumes:  Contouring in the pelvis is 
identical to that described in Sections 4.61- 4.63. (06/14/2010) 
 
4.6431 The Clinical Target Volume (CTV) is defined as the 
vaginal apex with margins as given in Section 4.6 in 
addition to pelvic and para-aortic nodal regions lying 
within the field borders given in Sections 4.61- 4.63. 
 
4.6432 The nodal portion of the CTV should include the internal 
(hypogastric and obturator), external iliac lymph node, and 
para-aortic regions.  The CTV should be delineated using 
the contrast-enhanced (preferably IV contrast administered) 
iliac vessels, in addition to the perinodal soft tissue 
(minimum of 6 mm axial margin around the vessels).  Bone 
and intraperitoneal small bowel should be excluded from 
the CTV as much as possible (leaving at least 6 mm margin 
around the vessels).  
 
 
Approximately 1-2 cm of tissue anterior to the sacrum (S1-
S3) may be added to the CTV for adequate coverage of 
presacral nodes, although this is optional and at the 
discretion of the treating radiation oncologist.  In addition, 
the most antero-lateral margin of the external iliac nodes 
that lie just proximal to the inguinal canal should be 
excluded from the CTV (nodal CTV should stop at the 
femoral head.  Proximally, the CTV should end 7 mm from 
the T11-T12 interspace to account for the PTV.  
 
4.6433 The PTV should provide a 7 mm-1 cm margin in all 
directions around the CTV.  
 

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4.6434 The definitions of volumes will be in accordance with the 
1993 ICRU report #50.  Prescribing, recording and 
reporting photon beam therapy and 1999 ICRU report #62.  
 
 
4.6435 Critical normal surrounding structures: (06/14/2010) 
 
4.64351 Bladder will be contoured in each slice in which 
it appears. 
 
4.64352 Rectum will be contoured in each slice in which 
it appears.  As a general guideline, the radiation 
oncologist can consider the maximum caudal 
extent of the rectum to lie 1.5-2.0 cm from the 
bottom of the ischial tuberosities.  Superiorly, 
judgment will be required to establish where the 
rectum ends and the sigmoid colon begins.  The 
transition to the sigmoid colon is marked by 
increased curvature and tortuosity in its path. 
 
4.64353 Small bowel will be contoured in each slice in 
which it appears, including at least 2 cm above 
the PTV.  The small bowel will be contoured in 
its entirety within these parameters, including 
adipose and mesentery. 
 
4.64354 Femoral heads will be contoured in all the slices 
in which they appear.  
 
4.6436 Constraints: Participants are strongly encouraged to respect 
the following limits, whether 3-D conformal or IMRT 
approaches are used. (06/14/2010) 
 
 
4.64361 Small bowel: <30% to receive ≥ 40Gy, Dmax <46 
Gy 
 
 
 
4.64362 Rectum: < 60% to receive ≥ 40Gy, Dmax <55 Gy 
 
 
 
4.64363 Bladder: < 50% to receive ≥ 45Gy, Dmax <60 Gy 
 
 
4.64364 Femoral heads: < 50% to receive ≥ 40Gy, Dmax 
<50Gy. 
 
4.64365 Kidney volume (combined right and left): <40% 
to receive >15 Gy (06/07/2010) 
 

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4.64366 Spinal cord:  <10% to receive >40 Gy, Dmax <45 
Gy (06/07/2010) 
 
4.64367 Unspecified tissue (tissue contained within the 
skin or any other normal structure not delineated 
above and outside the PTV, not included within 
any other structure):  No more than 1% or 1 ml 
(whichever is smaller) of the tissue outside the 
PTV will receive > 110% of the dose prescribed 
to the PTV.  
 
4.65 
Boosts to Gross Disease 
 
4.651 
As reflected in the eligibility and ineligibility criteria, otherwise 
eligible patients with up to 2 cm of residual disease (single site) are 
eligible. For these patients, it is permissible to deliver a 
radiotherapy boost to these areas provided that they are clearly 
definable by standard imaging modalities, allowing the radiation 
boost to be accurately targeted. 
 
4.652 Dose 
A further 10-15 Gy in 5-8 fractions can be delivered at the 
discretion of the radiation oncologist. The boost dose can be 
delivered to the initial volume of gross disease as identified on the 
initial imaging studies.  Should the initial chemo-radiation 
treatment result be a partial or complete response of the 
identifiable gross disease, the boost dose should be limited to 10 
Gy. 
 
4.653 Margin and Definition of Volume 
 
The original gross disease with a 1.0-1.5 cm margin should be 
targeted. 
 
4.654 Technique 
 
Either 3-D conformal or IMRT techniques can be used.  However, 
as noted in Section 4.62, it is NOT acceptable to treat initially with 
3-D conformal treatment and then switch to IMRT for the boost.   
 
The actual treatment technique is expected to vary considerably 
due to the location of the targeted area, surrounding radiosensitive 
structures, and dose distribution of the initial treatment. 
 
4.66 
Treatment Plan, Dose Specification, and Distribution 
 

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4.661 The volume irradiated with the whole pelvic fields will include the 
CTV and PTV as defined above. 
 
4.662 The whole pelvis will receive a total dose of 4500 cGy in 25 
fractions at 180 cGy/fx.  For patients treated with IMRT, the 
prescription dose is the isodose that encompasses at least 97% of 
the PTV.  No more than 20% of any PTV should receive >110% of 
the prescribed dose.  No more than 1% of the PTV should receive 
<93% of the prescribed dose.  No more than 1% or 1 cc (whichever 
is smaller) of the tissue outside the PTV will receive >110% of the 
dose prescribed to the PTV. However, with respect to this last 
constraint, it is recognized that there may be patients in which, due 
to obesity or other factors, this constraint may not be obtainable if 
other constraints, e.g. rectum, are met.  In these cases it is 
recommended that the OAR constraints be favored to the extent 
possible that is consistent with good radiotherapy practice. 
 
4.67 
Documentation requirements 
 
See Section 5.14 for instructions to set up TRIAD for digital submissions. 
(04/28/2014) 
 
4.671 
For 3-D conformal treatments, digital reconstructed radiographs 
(DRR) of the treatment fields with the three-dimensional 
reconstruction of the CTV are to be obtained and submitted for 
evaluation. 
 
4.672 
For 3-D conformal plans, localization or block-check images of 
virtually simulated fields are to be obtained in the simulator and/or 
treatment machine for all the treatment fields independently, 
whether cerrobend blocks or multi-leaf collimators are used. 
 
4.673 
For 3-D conformal plans, all plans must be submitted 
electronically via TRIAD. See IROC Houston (RPC) website for 
details:  
(04/28/2014) 
 
4.674  For IMRT plans, all plans must be submitted electronically via 
TRIAD for review, in addition to what is required from IROC 
Houston (RPC) in Section 10.2. (04/28/2014) 
 
4.675 
For IMRT plans, Dose-Volume Histograms (DVHs) are to be 
obtained for each one of the target volumes defined above, as well 
as the critical surrounding structures, and need to be submitted for 
evaluation.  For detailed description of radiation pelvic fields, 
please see Section 4.62. 
 

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4.68 
Therapy Interruptions:  If interruption of two weeks or less occurs, 
radiation should be completed to the prescribed total dose.  Therapy 
interruptions of more than two weeks will be considered a major or minor 
deviation from the protocol, depending on clinical circumstances, and 
resumption of therapy will be at the discretion of the radiation oncologist.  
Follow-up must continue regardless of radiation treatment received. 
 
4.69 
Expected Toxicity: Toxicity will vary depending upon tolerance of 
individual patient, daily dose, total dose, overall treatment time, associated 
illness, etc.  The following toxicity criteria may be used: 
 
Gastrointestinal: Nausea and vomiting is unusual, but may be seen after 
pelvic radiation.  Antiemetics may be used during treatment or may be 
given prophylactically the night prior to treatment.  Intractable nausea or 
vomiting is rarely seen with pelvic radiation alone and is usually the result 
of another process, i.e., bowel obstruction.  Increased bowel activity with 
diarrhea usually can be controlled with low- fiber, low-fat, bland diets, and 
anti-diarrhea medications.  Should G.I. toxicity become severe, 
hospitalization may be required, at which time the treatment is interrupted 
temporarily until the patient’s condition improves. 
 
Hematological: Hematological toxicity is seen infrequently, unless pelvic  
radiation is accompanied by chemotherapy.   A CBC should be obtained 
weekly during radiotherapy.  If the ANC falls below 1,000 /mcl or the 
platelet count below 50,000/mcl, the CBC should be obtained twice 
weekly. Radiotherapy should be stopped when ANC < 500 and/or platelets 
< 25,000. Radiotherapy should be temporarily halted if on successive 
measurements the platelet count declines rapidly below 50,000.   
Radiotherapy may be resumed when ANC > 500/mcl and platelets > 
50,000/mcl.  (06/22/09) 
 
4.610 Brachytherapy:  If a vaginal brachytherapy boost is to be given based on 
the criteria given in Section 4.59, it should commence within 2 weeks of 
completion of the external beam RT.  It should be delivered with a vaginal 
cylinder (HDR or LDR) or colpostats (LDR), and in the absence of gross 
residual disease following surgery the treating physician must choose one 
of the following: 
 
 
A)  HDR:  600 cGy x 2-3, weekly, prescribed at the vaginal surface.  Dose 
optimization should be used in an effort to create reasonable homogeneity 
of dose around the surface of the applicator.  A minimum of 4 cm of 
vaginal length should be treated. 
 
 
B)  LDR 2000-3500 cGy prescribed at the vaginal surface in 1 insertion at 
a dose rate of 40-100 cGy/hr.  A minimum of 4 cm of vaginal length 
should be treated. 

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In cases where the patient has small volume (<2 cm) residual disease in 
the vagina following surgery, the patient may have intra-cavitary treatment 
as described above only if the residual thickness following external RT is 
less that 0.5 cm.  If the residual lesion is greater than 1 cm in thickness, a 
low dose-rate interstitial implant is recommended to deliver approximately 
3500 cGy to the residual volume. 
 
4.611 Physical Factors (06/14/2010) 
 
If an intravaginal boost is to be used, it should be delivered with an 
intravaginal cylinder (HDR or LDR).  Acceptable isotopes include cobalt 
or iridium for HDR, radium or cesium for LDR. 
 
 
 
4.612 Expected Toxicity (06/14/2010) 
 
 
 
 
4.6121 Gastrointestinal:  Nausea and vomiting may occur after extended 
field (PAN) treatments, but can be effectively treated with an 
appropriate antiemetic in most cases.  Intractable nausea and 
vomiting beyond the first few days should arouse suspicion of 
recurrent tumor or other causes of bowel obstruction, as it is not 
commonly seen as a result of radiation alone. 
 
Increased bowel activity with diarrhea can be expected fairly 
routinely after the first two weeks of pelvic radiation.  It is 
recommended that instructions be given to patients for low-fiber, 
low-fat, bland diet.  Most patients will require anti-diarrheal 
medications such as diphenoxylate HCL with atropine sulfate 
(Lomotil) or loperamide HCL to control diarrhea. 
 
4.6122 Hematological toxicity of a mild nature will be seen frequently 
with a decline in WBC and platelet count. 
 
 
 
 
 
4.613 Radiation Therapy Quality Control and Documentation   (06/14/2010) 
IROC Houston is funded by the NCI to support clinical trials employing 
radiation therapy and will supervise the dosimetry quality control for this 
clinical trial.  To participate in the trial, the institutions must demonstrate 
the ability to achieve an accuracy of ±3% in measuring the output of their 
sources and ±5% in delivering the prescribed dose. (04/28/2014) 
 
 
4.614 Radiation Therapy – ECOG and RTOG Institutions   (06/14/2010) 
Please follow the Radiation Therapy instructions as detailed above and in 
Section 4.5.  All films and calculations should be sent directly to GOG 
Statistical and Data Center unless otherwise specified: (06/07/2010) 
 

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4.7 
Pathology Requirements 
 
4.71 
Eligible Patients: All patients with FIGO 2009 Surgical Stage III or IVA 
endometrial carcinoma, including clear cell and serous papillary and 
undifferentiated carcinomas.   Patients with FIGO 2009 Stage I and II 
clear cell or serous papillary uterine cancer with positive peritoneal 
cytology are eligible. (01/03/2011) 
 
4.72 
Ineligible Patients:   
4.721 Patients with carcinosarcoma. 
 4.722 Patients with recurrent endometrial cancer. 
4.723 Patients with Stage I and II endometrioid cancer with positive 
peritoneal cytology   (01/03/2011):   
4.724 Patients with Stage IVB endometrial cancer   (01/03/2011):   
 
4.73 
Stained pathology slides are required for central review by the GOG 
Pathology Committee to confirm eligibility.  At least one representative 
H&E stained slide (or slides) demonstrating primary site and histologic 
cell types will be required. At least one representative H&E stained slide 
documenting the most advanced stage of disease will be required. See 
Section 7.2 and 10.2 for additional instructions for submitting the stained 
pathology slides to the GOG Statistical and Data Center in Buffalo, NY. 
 
4.8 
Quality of Life Surveys 
 
Four instruments will be used to assess QOL changes during the treatment plan 
and one year post-treatment.   
 
4.81 
FACT-G:  FACT-G is a general QOL instrument that has been developed 
by David Cella and includes the following domains:  physical well being, 
social/family wellbeing, treatment satisfaction, emotional well-being, and 
fulfillment and contentment.  In this study, physical and functional well 
being, the areas most likely to be impacted by treatment, will be measured.   
 
4.82 
FACT-En:   This will represent a compilation of additional concerns that 
patients with endometrial cancer receiving treatment have, and this was 
piloted in GOG 209.    
 
4.83 
Four (4)-item subscale of FACT GOG neuropathy:  Patient reported 
neurotoxicity will be assessed using a four-item subscale embedded in 
FACT GOG neuropathy.  Based upon data collected in both GOG-0177 

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and 0209, the first four questions on the subscale (NTX 1-4) were able to 
classify best the majority of patients and this will greatly shorten the 
number of questions patients will have to answer.   The specific questions 
are:  I have numbness or tingling in my hands, I have numbness or tingling 
in my feet, I have discomfort in my hands, and I have discomfort in my 
feet.   
 
 
The summation of these first three QOL surveys represents the Trial 
Outcome Index that was piloted in GOG 209.   
 
4.84 
FACT-C (2 items):   Two questions will be used from this survey and they 
are as follows (C3, C5):  “I have control of my bowels”; “I have diarrhea.” 
 
 

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5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE (04/28/2014) 
 
5.1 
IROC Houston (formerly the Radiological Physics Center [RPC]) Credentialing 
Requirements (04/28/2014) 
 
5.11 
Credentialing for this protocol will be handled by IROC Houston.  All 
information regarding credentialing can be found on the IROC Houston 
website
 by selecting “Credentialing”, 
then “GOG.”  
 
5.12 
Before ANY patient is enrolled on this study, the treating radiation 
oncologist must complete on-line a Knowledge Assessment Questionnaire 
found on the IROC Houston (RPC) website. 
 
5.13 
IMRT credentialing requirements when IMRT is planned: 
 
Institutions must be credentialed for IMRT by IROC Houston for this 
protocol prior to enrolling patients into this study when IMRT is planned.  
Each institution must successfully irradiate a standardized phantom 
available from IROC Houston. Instructions for requesting and irradiating 
the phantom are available at the IROC Houston web site.  The treatment 
plan for irradiation of the phantom must be submitted electronically via 
TRIAD.  (See Section 5.14.)  Institutions that have been previously 
credentialed for IMRT via the head and neck phantom or the pelvic 
phantom can determine what additional requirements must be completed 
by filling out the “Credentialing Status Inquiry” form on the IROC 
Houston website.  IROC Houston will issue credentials for this protocol to 
the institution and notify the GOG Statistical and Data Center. 
 
 
Each Institution must complete the IMRT Facility Questionnaire available 
on the RPC web site by selecting “Protocol GOG-0258.”  Each institution 
must submit the completed IMRT Facility Questionnaire online.  
 
Institution and/or peer-reviewed documentation of target position 
reproducibility [planning treatment volume (PTV) and clinical target 
volume (CTV)] must be consistent with Section 4.643. 
 
5.14 
Digital RT Data Submission Using TRIAD (04/28/2014) 
 
TRIAD is the American College of Radiology’s (ACR) image exchange 
application and it is used by IROC Houston. TRIAD provides sites 
participating in clinical trials a secure method to transmit DICOM RT and 
other objects. TRIAD anonymizes and validates the images as they are 
transferred. The following process must be completed prior to enrolling 
patients on the trial. 
 

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TRIAD Access Requirements: 
 
Site physics staff who will submit images through TRIAD will need to be 
registered with The Cancer Therapy Evaluation Program (CTEP) and have 
a valid and active CTEP Identity and Access Management (IAM) account.  
To submit images, the site physics user must have been assigned the 
'TRIAD site user' role on the relevant Group or CTSU roster, and should 
follow their procedures for assignment of roster roles.  
 
TRIAD Installations: 
 
When a user applies for a CTEP-IAM account with proper user role, 
he/she will need to have the TRIAD application installed on his/her 
workstation to be able to submit images. TRIAD installation 
documentation can be found on the IROC- Houston web site.    
 
This process can be done in parallel to obtaining your CTEP-IAM account 
username and password.  
 
If you have any questions regarding this information, please send an e-
mail to the TRIAD Support mailbox at TRIAD-Support@acr.org. 
 
5.2 
Registration Procedures (04/28/2014) 
 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all investigators participating in any NCI-sponsored clinical 
trial to register and to renew their registration annually. 
 
Registration requires the submission of: 
 
 
a completed Statement of Investigator Form (FDA Form 1572) with an 
original signature 
 
a current Curriculum Vitae (CV) 
 
a completed and signed Supplemental Investigator Data Form (IDF) 
 
a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website 
at <http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  
For questions, please contact the CTEP Investigator Registration Help Desk by 
email at <pmbregpend@ctep.nci.nih.gov>. 
 
5.21 
CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) application is a web-based application intended for 
use by both Investigators (i.e., all physicians involved in the conduct of 

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NCI-sponsored clinical trials) and Associates (i.e., all staff involved in the 
conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial 
registration and annual re-registration) with CTEP and to obtain a user 
account. 
 
Investigators will use the CTEP-IAM application to obtain a user account 
only. (See CTEP Investigator Registration Procedures above for 
information on registering with CTEP as an Investigator, which must be 
completed before a CTEP-IAM account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and 
CTSU (Cancer Trials Support Unit) websites and applications, including 
the CTSU members’ website. 
 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For 
questions, please contact the CTEP Associate Registration Help Desk by 
email at <ctepreghelp@ctep.nci.nih.gov>. 
 
5.22 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
5.221 IRB Approval:   
 
Each investigator or group of investigators at a clinical site must 
obtain IRB approval for this protocol and submit IRB approval and 
supporting documentation to the CTSU Regulatory Office before 
they can be approved to enroll patients.  Study centers can check 
the status of their registration packets by querying the Regulatory 
Support System (RSS) site registration status page of the CTSU 
members’ website by entering credentials at https://www.ctsu.org.  
For sites under the CIRB initiative, IRB data will automatically 
load to RSS. 
 
5.222 Downloading Site Registration Documents:   
 
Site registration forms may be downloaded from the GOG-0258 
protocol page located on the CTSU members’ website.  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 RSS. 
 

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Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
Click on the Protocols tab in the upper left of your screen 
Click on the NCTN NRG link to expand, then select trial protocol # 
0258 
Click on the Site Registration Documents link 
 
5.223 Requirements For GOG-0258 Site Registration: 
 
• 
CTSU IRB Certification (for sites not participating via the NCI 
CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not 
participating via the NCI CIRB)  
• 
CTSU RT Facilities Inventory Form   
NOTE:  Per NCI policy all institutions that participate on protocols 
with a radiation therapy component must participate in IROC 
Houston monitoring program.  If this form has been previously 
submitted to CTSU it does not need to be resubmitted unless 
updates have occurred at the RT facility 
 
5.224 Submitting Regulatory Documents:  
 
Submit completed forms along with a copy of your IRB Approval 
and Model Informed Consent to the CTSU Regulatory Office, 
where they will be entered and tracked in the CTSU RSS.  
 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
Fax: 215-569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory 
document submission only) 
 
5.225 Checking Your Site’s Registration Status: 
 
Check the status of your site’s registration packets by querying the 
RSS site registration status page of the members’ section of the 
CTSU website.  (Note: Sites will not receive formal notification of 
regulatory approval from the CTSU Regulatory Office.) 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
Click on the Regulatory tab at the top of your screen 
Click on the Site Registration tab 
Enter your 5-character CTEP Institution Code and click on Go  
 

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5.3 
Patient Entry and Registration (04/28/2014) 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN).  OPEN is a web-based registration system available on a 24/7 
basis.  To access OPEN, the site user must have an active CTEP-IAM account 
(check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role 
on either the LPO or participating organization roster. 
 
All site staff will use OPEN to enroll patients to this study.  It is integrated with 
the CTSU Enterprise System for regulatory and roster data.  OPEN can be 
accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members’ 
side of the website at https://www.ctsu.org. 
 
All site staff will use OPEN to enroll patients to this study.  OPEN can be 
accessed on the GOG web menu page by clicking on the OPEN link.  
  
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 web site as a tool to 
verify eligibility. 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
  
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.   Please print this confirmation for your 
records.  
 
Access requirements for OPEN: 
  
 
Site staff will need to be registered with CTEP and have a valid and active 
CTEP-IAM account. This is the same account (user id and password) used 
for the CTSU members' web site.  
 
To perform registrations, the site user must have been assigned the 
'Registrar' role on the GOG or CTSU roster.  
 
To perform registrations you must have an equivalent 'Registrar' role on 
the Lead Group roster.  Role assignments are handled through the Groups 
in which you are a member.  
  
Note:  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 

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contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com.  
 
5.4 
Treatment Plan 
 
5.41 
Patients can be registered when eligibility criteria have been met and 
informed consent obtained.  Upon registration, each participant’s protocol 
treatment will be randomized to one of the following two arms: 
(06/07/2010) 
 
Regimen I:  Cisplatin 50mg/m2 IV on Day 1 and Day 29 (2 doses) 
given concomitantly with volume-directed RT, followed by 
Carboplatin/Paclitaxel given intravenously for 4 cycles at 3-week 
intervals. (06/07/2010) 
 
OR 
 
Regimen II: Carboplatin/Paclitaxel given intravenously for 6 cycles at 
3-week intervals. 
 
Protocol treatment will start within 4 weeks from study entry. 
(06/07/2010) 
 
 
 
5.42 
Treatment Schema (06/07/2010) 
 
 
Surgical debulking; optimal 
Stage III and IVA 
Register and randomize
ARM 1 
ARM 2
XRT 45Gy 
Cisplatin 50mg/m2 D1 and D29 
Vaginal brachytherapy 
Carboplatin AUC 6 
Paclitaxel 175 mg/ m2 q3 weeks X6 
Carboplatin AUC 5* 
Paclitaxel 175mg/ m2 q3 weeks X4 

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*First dose of carboplatin will be at AUC of 5, in subsequent cycles the dose will be escalated to 
AUC 6, as described in Section 6.2.  G-CSF use is required in Regimen I along with the four 
cycles of carboplatin/paclitaxel.  (08/12/09) (06/07/2010) 
 
 
5.43 
Methods of chemotherapy administration: 
 
5.431  Regimen I 
 
 
5.4311 Treatment Sequence:   
Day 1 and Day 29 Cisplatin 50 mg/m2 IV, two doses.  For 
reporting purposes Day 1 of cisplatin will be referred to as 
Cycle 1 and Day 29 will be referred to as Cycle 2.  Drug 
will be diluted in 250 ml 0.9% sodium chloride and 
administered at a rate no more than 1 mg/minute.  Details 
of pre- and post-hydration are left to the discretion of the 
treating physician, but at least cisplatin can be administered 
with hydration and supportive medications per institutional 
guidelines.  One suggested regimen is 1000 ml 0.9% 
sodium chloride administered prior to cisplatin and another 
1000 ml 0.9% sodium chloride administered following 
cisplatin are suggested.  Mannitol may also be mixed with 
cisplatin at the discretion of the treating physician.  
Electrolyte monitoring and replacement will be done based 
on individual assessment. (06/07/2010) 
 
5.4312 BSA Calculation:  Maximum body surface area used for 
dose calculations will be 2.0 m2 as per GOG Chemotherapy 
Procedures Manual.  
 
5.4313 Antiemetic therapy is indicated.  Details are left to the 
discretion of the treating physician.  However, a suggested 
regimen would include dexamethasone and a 5HT3 
antagonist (ondansetron or granisetron).  Suggested 
prophylaxis for delayed nausea induced by cisplatin 
consists of dexamethasone and metoclopramide. 
 
5.4314 Radiotherapy will be administered as detailed in Section 
4.6.   
 
 
Patients with pathologically negative para-aortic lymph 
nodes will be treated with pelvic irradiation.  If any para-
aortic lymph node is positive, the patient will receive 
extended field pelvic/para-aortic radiotherapy.  As 
described in Section 4.58, patients are allowed to receive 

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para-aortic RT in the absence of para-aortic nodal staging 
information if pelvic lymph nodes are positive. 
 
If there is tumor extension into the vagina, the external 
beam fields will be modified to include the disease volume 
with a 2 cm margin.  If the patient’s tumor extends into the 
cervix, or invades deeply and extends into the lower uterine 
segment, or if the tumor has extended into the vagina, such 
a patient will receive intra-vaginal boost brachytherapy 
(HDR or LDR) at the discretion of the radiation oncologist. 
 
After volume-directed concurrent chemo-radiation is 
completed, patients randomized to this arm will receive 
four additional cycles of chemotherapy 
(carboplatin/paclitaxel).  Use of G-CSF support for the last 
part of treatment is recommended.   
 
5.4315 Post-radiation chemotherapy: 
 
 
Chemotherapy will be initiated once all radiation-related 
toxicity recovered to less or equal to Grade 1 toxicity.  A 
maximum of 8 weeks is allowed between the end of 
chemo-radiation therapy and re-initiation of chemotherapy.  
Patients who do not recover organ function to the required 
parameters will be discontinued from protocol. 
 
 
Systemic chemotherapy will be administered after the 
completion of concurrent chemo-radiation and will consist 
of four cycles of carboplatin and paclitaxel.  (See Section 
5.332 regarding administration and specific 
recommendations for preparative regimen for this 
regimen.)   
 
 
Because of the high risk for myelosuppression following 
chemo-radiotherapy, the recommended starting dose for 
carboplatin will be calculated for an AUC of 5 (see Section 
5.3323 for dose calculation) and the recommended starting 
dose of paclitaxel will be 175 mg/m2.  (See Section 6.2 
regarding dose levels and treatment modification 
recommendations)  
 
5.4316 Prophylactic G-CSF will be administered to patients 
randomized to Regimen I during the post-radiation 
chemotherapy portion of the study.  Prophylactic G-CSF 
should not be administered during radiotherapy. 
 

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Filgrastim (Neupogen) can be administered at a dose of 5 
mcg/kg subcutaneously Days 2-11, at the discretion of the 
treating physician. Rounding of the G-CSF dose to the 
nearest vial size is acceptable.  Longer periods of G-CSF 
administration beyond 10 days are accepted at the 
discretion of the treating physician.  G-CSF must be 
discontinued at least 24 hours prior to administration of 
subsequent doses of chemotherapy.  For convenience, 
package insert recommendations regarding G-CSF use are 
printed below.  These are not, however, protocol 
requirements, and clinical judgment as to duration (or re-
institution of) G-CSF use should be exercised.  Some 
investigators prefer to discontinue G-CSF after nadir and 
two successive ANC measurements over 1500/mcl.  
(08/12/09) 
 
Filgrastim should be administered daily for up to two 
weeks until the ANC has reached 10,000/mcl following the 
expected chemotherapy-induced neutrophil nadir.  The 
duration of Filgrastim therapy should be discontinued if the 
ANC surpasses 10,000/mm3 after the expected 
chemotherapy-induced neutrophil nadir. (08/12/09) 
 
Peg-filgrastim (Neulasta) may be used as an alternative to 
Filgrastim and should be administered as a single 
subcutaneous dose of 6 mg on Day 2, 24 hours after 
administration of the chemotherapy. Pegfilgrastim should 
not be administered within 14 days of subsequent 
chemotherapy. (08/12/09) 
 
5.4317 Treatment interval:  Treatments are administered every 21 
days.  A maximum of four cycles will be administered.   
 
5.432 Regimen II- Paclitaxel/Carboplatin 
 
5.4321 Paclitaxel: 175 mg/m2, 3-hour infusion, Day 1, q 21 days 
followed by Carboplatin: dosed to an AUC of 6.0, Day 1, q 
21 days for 6 cycles. 
 
5.4322 BSA calculation:  Maximum body surface area used for 
dose calculations will be 2.0 m2 as per GOG Chemotherapy 
Procedures Manual.  
  
5.4323 Dosing of Carboplatin – See Appendix IV for current dose  
calculation instructions. (01/03/2011) 

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Note that carboplatin dose will be recalculated if patient has 
weight change of greater than or equal to 10% from 
baseline. (03/14/2011) 
 
5.4324 Sequence of Chemotherapy Administration:  Paclitaxel will 
be administered in a three-hour infusion followed by 
carboplatin.  An antiemetic regimen is recommended.  The 
antiemetic regimen used should be based on peer-reviewed 
consensus guidelines and is left up to the discretion of the 
treating physician.  Additionally, for all cycles where 
paclitaxel is to be administered, 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). 
 
5.4325 For patients randomized to Regimen I, prophylactic 
filgrastim (or peg-filgrastim) will be used during 
administration of carboplatin/paclitaxel. Filgrastim will not 
be used during radiotherapy, for patients randomized to 
Regimen I.  For patients randomized to Regimen II, use of 
filgrastim should follow published ASCO guidelines59.  
Erythropoietin should be used according to published 
ASCO guidelines.60 
 
5.433 Chemotherapy Guidelines 
 
See Appendix IV for General Chemotherapy Guidelines. 
(04/28/2014) 
 

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6.0 
TREATMENT MODIFICATIONS   
 
Early and late toxicities encountered during treatment will be evaluated and graded 
according to the NIH common toxicity criteria outlined in CTCAE v3.0. 
 
6.1 
Radiation Therapy 
 
6.11 
GI Toxicity:  Gastrointestinal toxicity greater than Grade 2 requires 
temporary discontinuation of treatment until toxicity resolves to Grade 1 
or less. 
 
6.12 
Hematological Toxicity:  CBC should be obtained weekly during radiation 
therapy.   If the ANC falls below 1,000 /mcl or the platelet count below 
50,000/mcl, the CBC should be obtained twice weekly.  If the ANC falls 
below 500/mcl or the platelet count below 25,000/mcl, then treatments 
should be stopped temporarily to allow recovery to ANC > 500/mcl and 
platelet count > 50,000/mcl.  Radiotherapy should be temporarily halted if 
on successive measurements the platelet count declines rapidly below 
50,000.  (06/22/09) 
 
6.13 
Recurrent Disease:  Treatment will be discontinued in patients with 
progressive disease.  Consideration for other therapies should be given.  
 
6.2 
Chemotherapy-Hematological Toxicity 
 
            6.21 
REGIMEN I: Cisplatin dose modifications (06/07/2010) 
 
 
6.211 Dose reduction levels: (06/07/2010) 
 
DRUG 
INITIAL DOSE 
Dose Reduction 
UNITS 
Cisplatin 
50 
40 
Mg/m2 
 
 
6.212 Treatment modifications will be based on the absolute neutrophil 
count (ANC) rather than the total white blood cell count (WBC).  
Administration of the second dose of cisplatin on Day 29 will be a 
dose Level 1 if the ANC is > 1,500 cells/mcl and the platelet count 
is > 100,000 cells/mcl, or at dose Level 2 if ANC 1,000 to 1,500 
cells/mcl and/or platelet count is 70,000-100,000 cells/mcl.  The 
second dose on Day 29 will be held until Day 36 if these 
parameters are not met.  If on Day 36, the hematological 
parameters are not met, the second dose of cisplatin will be 
omitted. (06/07/2010) 
 

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6.213 G-CSF and erythropoietin should not be used during chemo-
radiation treatment.  Transfusions can be administered at the 
discretion of the treating physician.  
 
6.22 
REGIMENS I and II: Carboplatin and paclitaxel dose modifications: 
(06/07/2010) 
 
6.221 Dose reduction levels: (06/07/2010) 
 
DRUG 
INITIAL DOSE 
1ST DOSE 
REDUCTION 
2ND DOSE 
REDUCTION 
UNITS 
Carboplatin 
6.0* 
5.0 
4.0 
AUC 
Paclitaxel 
175 
175 
135 
Mg/m2 
 
* For patients randomized to Regimen I, the initial dose of carboplatin will 
start at an AUC of 5.  The first dose reduction for patients receiving 
carboplatin at an AUC of 5 will correspond to the second dose reduction 
described in the table above.  Subsequent carboplatin doses will be 
escalated to an AUC of 6 as outlined below in Section 6.229. (06/07/2010) 
 
6.222 Treatment modifications will be based on the absolute neutrophil 
count (ANC) rather than the total white cell count (WBC).  
Subsequent cycles of therapy will not begin until the ANC is ≥ 
1,500/mcl and the platelet count is ≥100,000/mcl.  Therapy will be 
delayed on a week-by-week basis until these values are achieved.    
 
6.223 Treatment modifications will be employed in a sequential manner 
using cycle delay and dose reduction.   
 
6.224 Patients who experience Grade 4 thrombocytopenia (≤10,000 
plts/mcl) will have a 1-level dose reduction of carboplatin, without 
a change in paclitaxel dosage.   
 
6.225 There will be no dose modifications based on uncomplicated ANC 
nadirs. (06/07/2010) 
 
6.226 On Regimen II, patients who experience febrile neutropenia will 
receive G-CSF with subsequent cycles according to ASCO 
guidelines and no dose reduction.  As all patients in Regimen I will 
receive G-CSF with systemic chemotherapy, if febrile neutropenia 
occurs despite the use of G-CSF, then dose reduction will be 
necessary. (08/12/09) 
 
6.227 Patients who require a delay of > 7 days will receive a dose 
reduction of one level in accordance with the table above and 
without addition of G-CSF.   

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6.228 Protocol therapy will be discontinued in patients who require a 
delay of > 21 days.  
 
6.229 There will be no dose re-escalations in the study, except the 
following: Patients randomized to Regimen I will be started at a 
reduced dose of carboplatin after radiotherapy (AUC 5).  Their 
subsequent carboplatin dose will be escalated to an AUC of 6, 
provided that these patients do not develop any of the following: 
Grade 4 thrombocytopenia; greater than Grade 3 neutropenia that 
does not recover to Grade 1 by Day 21 of the first cycle; or other 
Grade 3 or higher non-hematological toxicity that does not recover 
to Grade 1 by Day 21 of the first cycle (except alopecia).  
Individual assessment by the treating physician is recommended 
prior to dose escalation of patients randomized to Regimen I after 
the first cycle of carboplatin and paclitaxel. (06/07/2010) 
 
6.2210 Transfusions and erythropoietin can be administered at the 
discretion of the treating physician. 
 
6.3 
Systemic Chemotherapy:  Non-Hematologic Toxicity  
 
 
6.31 
Paclitaxel hypersensitivity reaction:  If hypersensitivity reactions to 
paclitaxel or its vehicle (Cremophor) occur, it will usually be during the 
first few minutes of infusion.  Appropriate symptomatic therapy should be 
given.  Continued treatment may be considered if the reaction is not life 
threatening; however, patients must be cautioned about potential 
recurrences of the reaction.  Should the patient decide to continue with 
treatment, it is preferable that this be done on the same day of the 
occurrence.  A suggested procedure would be to administer the drug first 
with 1 ml of the original IV solution diluted in 100 ml over one hour, then 
5 ml in 100 ml over one hour, then 10 ml in 100 ml over one hour, and 
finally, the original solution at the original speed.  Patients who elect not 
to have continued treatment with paclitaxel after experiencing a 
hypersensitivity reaction may continue on protocol therapy with 
carboplatin only.  
 
6.32 
Cardiac arrhythmias:  Asymptomatic bradycardia associated with 
paclitaxel treatment is not an indication to discontinue therapy.  For 
symptomatic arrhythmia, paclitaxel infusion should be discontinued, and 
the arrhythmia managed according to standard practice.  The patient will 
be removed from protocol treatment and will require further cardiac 
assessment. 
 
 

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6.33 
Ototoxicity 
 
For clinically significant hearing loss or tinnitus, cisplatin will be 
discontinued.  Audiograms are indicated in patients with pre-treatment 
hearing loss. 
 
 
6.34 
Myalgias 
 
Myalgias can occur during the several days following paclitaxel treatment 
and may be severe.  They should receive aggressive symptomatic 
treatment, including NSAIDs, narcotics, or steroids, as deemed 
appropriate by the treating physician.  Myalgias are not an indication for 
dose reduction. 
 
6.35 
Neurological toxicity 
 
Grade 2 or greater peripheral neuropathy requires delaying therapy until 
symptoms resolve to  Grade 1.  When treatment is resumed, paclitaxel 
dose should be reduced one dose level to 135mg/m2. Recurrent Grade 2 
neurotoxicity will require delay of treatment until neuropathy resolves to 
Grade 1.  A delay exceeding three weeks for neurological function 
recovery will require discontinuation of protocol treatment.  Patients will 
be removed from protocol therapy for recurrent Grade 3 or for Grade 4 
neurological toxicity.  (10/13/09)(01/03/2011) 
 
6.36 
Renal toxicity  
 
Serum creatinine will be obtained at enrollment and with each cycle of 
treatment. 
 
For creatinine levels ≥1.6 mg/dl prior to treatment, cisplatin will be held.  
Patient may remain on protocol therapy with the omission of cisplatin at 
the discretion of the treating physician.  If the creatinine level 
subsequently returns to < 1.6 mg/dl, cisplatin may be reinstated in 
subsequent cycles.  Hydration before and after cisplatin infusion is 
recommended for all patients (2 liters of fluid).  Use of mannitol is 
optional. 
 
Selective renal tubular defects are observed with cisplatin.  Hypocalcemia, 
hypomagnesemia, and hypokalemia are common and potentially severe.  
Replacement of calcium, magnesium, and potassium is usually effective.  
Severe defects, although uncommon, may require chronic replacement 
therapy.   Discontinuation from protocol in cases of severe renal tubular 
dysfunction resulting in dyselectrolemia can be done at the discretion of 
the treating physician. 

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6.37 
Gastrointestinal toxicity   
 
 
 
Nausea and Vomiting:  Increased antiemetic support, sedation, and 
prophylactic hospitalization should be performed.  Dose reductions are 
generally not needed for nausea and vomiting.  Stomatitis or diarrhea: If 
any grade mucositis is present on Day 21 of a cycle, the next cycle of 
treatment should be withheld until the mucositis has cleared.  Grades 3 or 
4 mucositis or diarrhea require one dose level reduction for paclitaxel. 
 
 
 
6.38 
Hepatic Toxicity 
 
 
 
Liver function tests will be obtained prior to treatment and before each 
cycle of therapy (Bilirubin, SGOT and SGPT). 
 
Bilirubin must return to ≤1.5 ULN prior to further therapy. (10/13/09) 
 
Transaminases (AST and ALT) should be ≤ 2.5 times ULN prior to each 
cycle of treatment. 
 
6.39 
Other toxicities:  For any other Grade 3 or 4 toxicities not mentioned 
above, protocol treatment should be withheld until patients recover 
completely or to Grade 1 toxicity status.  The next dose of the agent 
believed responsible for the adverse event will be given at a one dose level 
reduction.  In general, unusual toxicities should be discussed with the 
Study Chair. 
 
6.4 
Discontinuation from protocol 
 
6.41 
Patients may withdraw from the protocol at any time for any reason. 
 
6.42 
Patients whose treatment is delayed over three consecutive weeks because 
of any toxicity should be removed from protocol therapy. 
 
6.43 
At the discretion of the treating physician, protocol treatment may be 
withdrawn because of serious toxicity or lack of compliance. 
 
 
 

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7.0 
STUDY PARAMETERS   
 
7.1 
Observations and Tests (06/07/2010) (01/03/2011) (01/13/14) 
 
The following observations and tests are to be performed and recorded on the 
appropriate form(s). See Section 7.3 for a description of the specimen 
requirements for translational research for this study.  See Sections 4.7, 7.2, 
and 10.2 for a description of the stained pathology slides that are required 
for central review by the GOG Pathology Committee to confirm eligibility 
and for instructions for shipping that material to the GOG Statistical and 
Data Center. 
 
 
1.      Must be obtained within 28 days of initiating protocol therapy. 
2.      Must be obtained within 14 days of initiating protocol therapy. 
3.      Must be obtained within 4 days of re-treatment with protocol therapy. 
4. 
Every 3 months for first 2 years, then every 6 months until 5 years post  
treatment. 
5. 
Weekly, and twice a week if ANC  1,000 or platelet count  50,000 mcl. 
6. 
Must be obtained at the end of therapy, then every 6 months for first 2 years, and then annually for an 
additional 3 years (01/03/2011)  
 7. 
Every other cycle of chemotherapy, or as clinically indicated.  
 
 8.      Within 3 days from Day 29 cisplatin (06/07/2010) 
9.      Must be obtained after surgery and within 28 days prior to initiating protocol therapy. (01/03/2011) 
 10.     Must be obtained if Chest x-ray is abnormal.  Chest CT is acceptable in place of CXR for baseline 
Tests & Observations 
Prior to  
study 
During radiation 
therapy weekly 
 
At the end of 
radiotherapy, 
 prior to starting 
combination 
chemotherapy 
(Regimen I only) 
Prior to each 
 cycle of 
chemo- 
therapy 
Follow-up 
Within 4 
weeks of 
completion 
of protocol 
therapy 
History 
1 
 
X 
X 
4, 12 
X 
Physical Examination 
1 
 
X 
X 
4 
X 
Toxicity assessment 
1 
X 
X 
X 
14 
X 
Pelvic Examination 
1 
 
X 
7 
4 
X 
HGB or HCT 
2 
X 
X 
3 
13 
X 
ANC 
2 
5 
X 
3 
13 
X 
Differential 
2 
X 
X 
3 
13 
X 
Platelets 
2 
5 
X 
3 
 
X 
Creatinine 
2 
8 
X 
3 
 
X 
Bilirubin 
2 
 
X 
3 
13 
X 
SGOT, SGPT 
2 
 
X 
3 
13 
X 
Alkaline Phosphatase 
2 
 
X 
 
13 
X 
Chest X-ray 
9 
 
 
 
6 
 
Urinalysis 
2 
 
 
 
 
 
Abdomen and  
pelvis CT 
9 
 
 
 
6 
 
Chest CT scan 
10 
 
 
 
10 
 
Quality of Life 
Assessments 
 
11 
 
 
11 
 
 
 
 
11 
 

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screening; however, the same modality that was used for baseline imaging studies must be used for all 
follow-up studies. (06/07/2010) 
11.    The QOL assessments to be administered are as follows:  FACT-G Physical Well-being (PWB) and   
          Functional Well-being (FWB) subscales (14 items), FACT-En additional concerns subscale (16 
items),  FACT/GOG-NTX-4 subscale (4 items), and items C3 and C5 from the FACT-C.  
  
 Patients will complete the QOL assessments at 4 times: 
   1) At baseline (within 14 days prior to starting protocol therapy) 
   2) 6 weeks from start of protocol treatment (1 week post completion of RT for Regimen I or three 
weeks post completion of 2 cycles of chemotherapy for Regimen II) 
   3) 18 weeks from start of protocol treatment (three weeks after completion of protocol therapy) 
   4) 70 weeks from start of protocol treatment (1 year from completion of protocol therapy) 
    NOTE: QOL assessments should be administered at ALL 4 assessment times, regardless of whether 
the patient progresses or is removed from the study for any reason.  
12.   After 5 years, information about survival will be obtained yearly by phone calls. (08/12/09) 
13.   At the end of protocol-directed therapy and yearly for the first 5 years. (06/07/2010) 
      If abnormal, evaluate with appropriate diagnostic testing to exclude the presence of systemic 
metastatic  disease. (01/03/2011) 
 14.   Every 6 months for 3 years (report on Form TLC). (01/03/2011)  
 
7.2 
Stained Pathology Slides for Central Pathology Review to Confirm Eligibility 
 
Stained pathology slides are required for central review by the GOG Pathology 
Committee to confirm eligibility for the protocol.  At least one representative 
stained slide (or slides) documenting the primary site, histologic cell type, grade, 
and one slide to show the most advanced stage of disease.  Peritoneal cytology 
slides are required for those patients with stage I and II clear cell or serous 
papillary uterine carcinoma, enrolled on the basis of positive cytology. 
(01/03/2011) 
 
When submitting pathology material to the GOG SDC, individual slides must be 
labeled with GOG Patient ID, patient initials and the surgical / pathology 
accession number (e.g., S08-2355) and block identifier (e.g., A6).  Don’t not 
label with disease site or collection date.  Pack the labeled slides into plastic slide 
cassette(s).  Tape plastic slide cassettes shut and wrap in bubble wrap or another 
type of padded material prior to shipping.  Please include the GOG Patient ID, 
patient initials, and protocol number on all pages of the pathology report and 
black out the patient’s name.  Ship pathology slides, three copies of both the 
Pathology Form F and the official pathology report directly to the Pathology 
Materials Coordinator at the GOG Statistical and Data Center, 
 
 
  The GOG Upload 
Application in SEDES is an alternative method for submitting pathology reports 
and Form F.  Please see sec. 4.7 and 10.2 for additional requirements and 
instructions. 
 
7.3 
Translational Research (01/13/14) 
 
7.31 
Specimen Requirements 
 

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If the patient gives permission for her specimens to be collected and used 
for this optional translational research component, then participating 
institutions within the United States are required to submit the patient’s 
translational research specimens as outlined below (unless otherwise 
specified). 
 
 
A detailed description of the translational research specimen procedures 
can be found in Appendix III.   
 
Required Specimen 
(Specimen Code) 
 
Collection Time Point 
Ship To 
FFPE Primary or Metastatic  
(FT011)* 
1st Choice: block 
2nd Choice: 15 unstained slides 
(charged, 5µm) 
Prior to all treatment 
GOG Tissue Bank within 8 
weeks of registration2 
Whole Blood (WB01) 
7-10mL drawn into purple-top 
(EDTA) tube(s) 
Prior to or after starting study 
treatment 
GOG Tissue Bank the day the 
blood is collected2 
* A copy of the corresponding pathology report must be shipped with all tissue specimens sent to the GOG Tissue Bank 
1 If submitting both, label primary as FT01 and metastatic as FT02. If only metastatic is submitted, it should be labeled 
FT01. 
2 GOG Tissue Bank / Protocol GOG-0258, Nationwide Children’s Hospital,
 
 
7.32 
Laboratory Testing 
 
The GOG Tissue Bank will coordinate with the GOG Committee on 
Experimental Medicine and the GOG Statistical and Data Center to 
distribute appropriate specimens to approved laboratories for approved 
projects.   
 
Investigators must submit a GOG concept or a GOG Tissue Bank 
Application to access GOG-0258 specimens and resources.  If approved, a 
GOG-8000 series protocol will be developed for review and approval.  
 
7.33    Future Research 
 
Details regarding the banking and use of translational research specimens 
for future research can be found in Appendix III. 
 
7.4 
Quality of Life 
 
7.41 
Patients will complete the QOL Survey at four times:  
1) At baseline (within 14 days prior to starting protocol therapy) 
2) 6 weeks from start of protocol treatment (1 week post completion of RT 
for Regimen I or three weeks post completion of 2 cycles of chemotherapy 
for Regimen II) 

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3) 18 weeks from start of protocol treatment (three weeks after completion 
of protocol therapy) 
4) 70 weeks from start of protocol treatment (1 year from completion of 
protocol therapy) 
 
NOTE:  QOL assessments should be administered at ALL four 
assessments times, REGARDLESS of whether the patient progresses 
or is removed from study for any reason.  
 
7.42 
The QOL survey is available in Spanish and French and has been 
translated into Korean for use on this study as of March 2010 (full 
validation of the Korean translation of En1 and En2 are pending).  
Requests for non-English versions should be made to the Statistical and 
Data Center. (06/07/2010) 
  
7.43 
Whenever possible, the QOL survey should be administered at the clinic 
visit before the patient is seen by the physician, before evaluations are 
performed, and before test results are shared with her.  In the event that the 
questionnaires are not administered at the clinic visit, the QOL data can be 
collected by telephone or mail as back-up methods, with telephone data 
collection being the preferred back-up method.   
  
7.44 
The Quality of Life Liaison (GOG Nurse/Data Manager) at each 
institution has overall responsibility for the administration of the study 
questionnaire. 
  
7.45 
The GOG Nurse/Data Manager should read the instructions printed on the 
questionnaire to the patient and ensure that the patient understands the 
instructions.  It is important to assure the patient that all material on the 
questionnaire is confidential and will not be shared with the health care 
team, and that it will not become part of the medical record. 
  
7.46 
Assistance in reading the questionnaire is permitted if the patient is unable 
to complete the questionnaire on her own (e.g., difficulty in reading, 
elderly).  It is important not to influence the response of the patient.  Note 
why the patient required assistance and what assistance was given.   
  
7.47 
Patients should be instructed to answer all the questions regardless of 
whether the symptoms or conditions asked about are related to the cancer 
or cancer treatment.  Discourage family members from being present 
during questionnaire completion or from influencing the patient's 
response.   
  
7.48 
Review the questionnaire for completeness before the patient leaves.   
  
7.481 If the patient has marked more than one answer per question, ask 
the patient which answer best reflects how she is feeling.    

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7.482 If the patient has skipped a question or questions, assure that she 
noted in the space provided that she has chosen not to answer those 
questions.   
  
7.49 
It is essential that the questionnaires be completed according to the 
schedule described in Section 7.41.   
  
7.410 If the patient refuses or cannot complete the questionnaire at any time, she 
should be asked to do so at the next scheduled administration time.   
  
7.411 Prior to submitting the QOL Scantron to the GOG Statistical and Data 
Center, be sure the following information is recorded and coded in: 
 
   
 
 
a) patient's complete GOG number 
b) date of form completion 
   
 
 
c) study time point for which the form is being completed 
 
 
 

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8.0 
EVALUATION CRITERIA   
 
8.1 
Parameters of Response – GOG RECIST Criteria 
 
8.11 
Measurable disease is defined as at least one lesion that can be accurately 
measured in at least one dimension (longest dimension to be recorded).  
Each lesion must be  20 mm when measured by conventional techniques, 
including palpation, plain x-ray, CT, and MRI, or  10 mm when 
measured by spiral CT.   
 
8.12 
Baseline documentation of “Target” and “Non-Target” lesions 
 
All measurable lesions, up to a maximum of 5 lesions per organ and 10 
lesions in total representative of all involved organs, should be identified 
as target lesions and will be recorded and measured at baseline.  Target 
lesions should be selected on the basis of their size (lesions with the 
longest dimension) and their suitability for accurate repetitive 
measurements by one consistent method of assessment (either by imaging 
techniques or clinically).  A sum of the longest dimension (LD) for all 
target lesions will be calculated and reported as the baseline sum LD.  The 
baseline sum LD will be used as reference to further characterize the 
objective tumor response of the measurable dimension of the disease. 
 
All other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not 
required, and these lesions should be followed as “present” or “absent.” 
 
All baseline evaluations of disease status should be performed as close as 
possible to the start of treatment and never more than four weeks before 
the beginning of treatment. 
 
8.13 
Recurrence (non-measurable disease studies) is defined as increasing 
clinical, radiological, or histological evidence of disease since study entry.  
CA125 rise, if measured, will not count as recurrence, unless there is 
clinical or radiological evidence of disease recurrence. 
 
 
 
 
8.14 
Survival is the observed length of life from entry into the study to death or 
the date of last contact. 
 
8.15 
Recurrence-Free Survival (non-measurable disease studies) is the period 
from study entry until disease recurrence, death, or date of last contact. 
 
8.16 
Subjective Parameters including performance status, specific symptoms, 
and side effects are graded according to CTCAE v3.0. 
 
 

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9.0 
DURATION OF STUDY    
 
9.1 
Patients will continue on protocol for a maximum of six cycles of chemotherapy 
or until disease progression or adverse effects necessitate removal from protocol 
therapy. 
 
9.2 
Patients will be followed every three months for two years, then every six months 
for the next three years.  After five years follow-up information will be obtained 
annually. All subsequent anti-cancer therapies will be reported. (08/31/2009) 
 
9.3 
A patient is considered off study therapy when the patient has either completed 
the prescribed number of cycles or fractions of study therapy, has progressed or 
died prior to completion of study therapy, a non-protocol drug or therapy 
(directed at the disease) is initiated, or all study therapy is totally discontinued.  
Report all chemotherapy treatment received on Form D2R, radiation therapy 
received on Form G, HDRV or LDRV and adverse events on Form T until the 
patient qualifies as being off study therapy. (08/12/09) 
 
 
 

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10.0 
STUDY MONITORING AND REPORTING PROCEDURES   
 
10.1 
ADVERSE EVENT REPORTING FOR ALL REGIMENS (COMMERCIAL 
AGENTS AND RADIATION THERAPY ADMINISTRATION) (04/28/2014) 
 
10.11 Definition of Adverse Events (AE) 
 
An adverse event (AE) is any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease that occurs in a 
patient administered a medical treatment, whether the event is considered 
related or unrelated to the medical treatment.  
 
10.12 Reporting Expedited Adverse Events 
 
Depending on the phase of the study, the use of investigational or 
commercial agents, and the role of the pharmaceutical sponsor, an AE 
report may need to reach multiple destinations.  For patients participating 
on a GOG trial, all expedited AE reports should be submitted by using the 
CTEP Adverse Event Reporting System (AERS).  All CTEP-AERS 
submissions are reviewed by GOG.  Submitting a report through CTEP-
AERS serves as notification to GOG and satisfies the GOG requirements 
for expedited AE reporting.  All adverse reactions will be immediately 
directed to the Study Chair for further action. 
 
The requirement for timely reporting of AEs to the study sponsor is 
specified in the Statement of Investigator, Form FDA-1572.  In 
compliance with FDA regulations, as contained in 21 CFR 312.64, AEs 
should be reported by the investigator. 
 
10.13 Phase 2 and 3 Trials Utilizing a Commercial Agent:  CTEP-AERS 
Expedited Reporting Requirements for Adverse Events That Occur Within 
30 Days of the Last Dose of Any Commercial Study Agent  
 
Reporting Requirements for Adverse Events that occur within 30 Days¹ of 
the Last Dose of the Commercial Agent on Phase 2 and 3 Trials 
 
From the period of protocol activation through September 30, 2011, 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 
(CTCAE v3.0) are utilized for defining and grading specific adverse 
events reported through the CTEP-AERS system. (09/26/11) 
 
 

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Beginning October 1, 2011, the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) v 4.0 will be utilized for AE reporting through 
the CTEP-AERS system. CTCAE v 4.0 is located on the CTEP website at 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.h
tm.  All appropriate treatment areas should have access to a copy of this 
Version of CTCAE.  CTCAE v 4.0 definition is also available on the GOG 
member web site 
. 
(09/26/11) 
 
 
 
Grade 1 
 
Grade 2 
 
Grade 2
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected  
and Expected 
 
 
Unexpected 
 
 
Expected
Unexpected 
Expected 
Unexpected Expected
With  
Hospitali-
zation 
Without 
Hospitali-
zation 
With  
Hospitali- 
zation 
Without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required
7 Calendar 
Days 
Not 
Required 
7 Calendar 
Days 
Not 
Required 
7 Calendar 
Days 
7 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
7 Calendar 
Days 
Not 
Required
7 Calendar 
Days 
7 Calendar 
Days 
7 Calendar 
Days 
Not 
Required 
24-Hrs; 
3 Calendar 
Days 
7 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of 
treatment with a commercial agent require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 3 calendar days for: 
 Grade 4 and Grade 5 unexpected events  
      CTEP-AERS 7 calendar day report: 
 Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
 Grade 5 expected events 
 
2 Although a CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full 
report is required as outlined in the table. 
 
 Please see exceptions below under the section entitled, “Additional Instructions or Exceptions to CTEP-AERS 
Expedited Reporting Requirements for Phase 2 and 3 Trials Utilizing a Commercial Agent.”  March 2005 
 
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality. Attribution to treatment or other cause must be provided. 
 
 
Expedited AE reporting timelines defined: 
 “24 hours; 3 calendar days” – The investigator must initially report the AE via CTEP-
AERSwithin 24 hours of learning of the event followed by a complete CTEP-AERS 
report within 3 calendar days of the initial 24-hour report. 
“7 calendar days” – A complete CTEP-AERS report on the AE must be submitted 
within 7 calendar days of the investigator learning of the event. 
 
 
Any medical event equivalent to CTCAE Grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported, regardless of 

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attribution and designation as expected or unexpected, with the exception of any 
events identified as protocol-specific exclusions for expedited adverse event reporting. 
 
 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported to GOG via CTEP-AERS if the event occurs 
following treatment with a commercial agent. 
 
 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
Additional Instructions or Exceptions to CTEP-AERSExpedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing a Commercial Agent: 
 
There are no additional instructions or exceptions to CTEP-AERS expedited reporting 
requirements for this protocol. 
 
10.14 Procedures for Expedited Adverse Event Reporting: 
 
10.141 CTEP-AERS Expedited Reports: Expedited reports are to be 
submitted using CTEP-AERS available at http://ctep.cancer.gov. 
The CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements for expedited adverse event reporting requirements 
are also available at this site.  
 
AML/MDS events must be reported via CTEP-AERS (in addition 
to your routine AE reporting mechanisms). In CTCAE v4.0, the 
event(s) may be reported as either: 1) Leukemia secondary to 
oncology chemotherapy, 2) Myelodysplastic syndrome, or 3) 
Treatment-related secondary malignancy.  (03/14/2011) 
 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made to NCI by telephone at: 301-897-
7497.  An electronic report MUST be submitted immediately upon 
re-establishment of internet connection. Please note that all paper 
CTEP-AERS forms have been removed from the CTEP website 
and will NO LONGER be accepted. (01/03/2011) 
 
 
 

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10.2 
GOG DATA MANAGEMENT FORMS (09/21/2009) (01/03/2011) (01/13/14) 
 
The following forms must be completed for all patients registered and submitted 
to the GOG Statistical and Data Center (SDC) in accordance with the schedule 
below.  Protocol forms and instructions can be submitted through or printed from 
the SDC Electronic Data Entry System (SEDES) online application found at the 
GOG Web Menu page.  All amendments to forms submitted through SEDES 
must also be submitted through SEDES.  The original form and required copies 
for forms NOT submitted online must be mailed to the GOG SDC. Note: 
Pathology materials (Form F, path report, and slides) may be submitted 
together via postal mail or by using the upload feature of SEDES. Stained 
slides must be submitted via postal mail.  See 7.2 for additional mailing 
instructions. Additionally, radiation materials (forms, copies, films, reports, 
etc) must be submitted together via postal mail. (09/21/2009) (03/14/2011) 
 
Form 
Due within 
Copies* 
Comments 
Weeks 
Event 
Knowledge Assessment 
(04/28/2014) 
0 
Prior to Registration 
1 
Available at 
http://irochouston.mdanderson.org 
under ‘Credentialing.’   
Form R (Registration 
Form) 
2 
 
Registration 
 
1 
 
Mandatory submission via SEDES 
Specimen Consent 
Application 
1 
Registration 
NA 
Complete Online 
Form OSU (Uterine Cancer 
On-Study Form) 
2 
Registration 
1 
Mandatory submission via SEDES 
Form DR (Pre-Treatment 
Summary Form) 
2 
 
Registration 
 
1 
 
Mandatory submission via SEDES 
 
Form D2M (Solid Tumor 
Reporting Form) - baseline 
2 
Registration 
1 
Mandatory submission via SEDES 
Form C (Surgical Reporting 
Form) 
Operative report 
Discharge summary 
6 
 
6 
6 
Registration 
 
Registration 
Registration 
1 
 
2 
2 
Mandatory submission via SEDES 
 
Submit via postal mail to SDC or 
upload via SEDES 
 
Quality of life: ***   
Scantron Form – baseline 
Scantron Form – 6 weeks 
Scantron Form – 18 weeks 
Scantron Form – 70 weeks 
 
2 
10 
22 
74 
 
Treatment Start 
Treatment Start 
Treatment Start 
Treatment Start 
 
1 
1 
1 
1 
 
Submit Scantron form via postal 
mail  to SDC***  
Pathology requirements 
Primary diagnosis: 
Form F (Pathology 
Form) 
Pathology Report 
Stained path slides to 
confirm eligibility 
 
 
6 
 
6 
6 
 
 
 
Registration 
 
Registration 
Registration 
 
 
 
2 
 
2 
** 
 
 
 
Submit together via postal mail to 
GOG SDC in Buffalo, NY, or 
submit using the report upload 
feature of SEDES** 

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Cytology Report 
Positive cytology slides 
6 
6 
Registration 
Registration 
2 
** 
Radiation Materials: 
External beam: 
- daily treatment reports 
- CT/MRI showing 
relevant target volume  ∆ 
- simulation films or 
digitally reconstructed 
radiograph  
- portal films 
- dosimetry calculation 
- Isodose distribution       
curves 
- Form G (Radiation 
Treatment Form) 
- 3D Plan electronically 
submitted to ITC. 
Brachytherapy: 
   - Treatment record for  
    HDR 
- orthogonal simulation 
films for each 
intracavitary placement 
- dosimetry calculation 
- isodose distribution 
curves for the first 
intracavitary implant 
and each subsequent 
intracavitary implant if 
different from earlier 
implants 
- Form HDRV (Vaginal 
HDR Intracavitary 
Radiation Oncology 
Form) or Form LDRV 
(Vaginal LDR 
Intracavitary Radiation 
Oncology Form) 
IMRT Plan electronically 
submitted to ITC 
-  DDSI 
-  Digital treatment    
planning data 
-  Color isodose 
distribution 
4 
Completion of  
radiation therapy 
 
 
2 
1 
 
1 
 
 
1 
2 
2 
 
2 
 
 
 
 
1 
 
1 
 
 
2 
2 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
Form G, HDRV and LDRV must 
be submitted via SEDES.  Paper 
copies should also be submitted 
with radiation materials via postal 
mail. 
 
 
 
 
 
 
 
 
 
Submitted electronically  via 
TRIAD (04/28/2014) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Submitted electronically via 
TRIAD (04/28/2014) 
Form D2R (Cycle Dose 
Drug Form) 
2 
Completion of each 
cycle of combination 
chemotherapy and each 
cycle of cisplatin 
1 
Mandatory submission via SEDES 

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Form T (Common Toxicity 
Form) 
2 
Start of each 
subsequent cycle of 
chemotherapy and 
cycle of cisplatin and 3 
weeks after last cycle 
of chemotherapy 
1 
 
Mandatory submission via SEDES 
 
Form D2M (Solid Tumor 
Evaluation Form) 
2 
Each disease evaluation 
1 
Mandatory submission via SEDES 
At completion of study therapy,  
semi-annually for 2 years, annually 
for 3 years or until disease 
progression is documented. 
Form TLC (Follow-Up 
Period Adverse Event 
Reporting Form) 
2 
Each follow-up toxicity 
assessment following 
completion of study 
therapy  
1 
Mandatory submission via SEDES 
until non-protocol therapy is 
initiated or disease progression is 
documented.  Every 6 months for 3 
years. 
Form SP-FT01-0258*****  
FFPE primary or metastatic 
tumor 
8 
Registration 
NA 
Submit via SEDES 
 
Form SP-FT02-0258***** 
2nd FFPE primary or 
metastatic tumor (optional)  
8 
Registration 
NA 
Submit via SEDES 
 
Form SP-WB01-0258 
whole blood  
26 
Treatment Start 
NA 
Submit via SEDES 
 
Form QO (Treatment 
Completion Form) 
2 
Completion of study 
treatment 
1 
Mandatory submission via SEDES 
Form Q (Follow-Up Form) 
 
2 
Disease progression; 
death; normal  
follow-up 
1 
Mandatory submission via SEDES 
quarterly for 2 years, semi-
annually for 3 more years, 
annually thereafter for 5 years. 
Report cause of death. 
* 
The number of required copies including the original form, which must be sent to the Statistical and Data 
Center (SDC).  No copies are required for forms submitted through SEDES.  Additionally, forms submitted 
through SEDES should not be sent through postal mail or fax, with the exception of Form G, Form HDRV, 
and Form LDRV. 
** 
Stained pathology slides are required for central review by the GOG Pathology Committee to confirm 
eligibility.    See Sections 4.7 and 7.2 for additional requirements and mailing instructions. 
*** 
QOL assessments should be administered at ALL four assessments times, REGARDLESS of whether the 
patient progresses or is removed from study for any reason.  Use only Scantron forms with the header of  
“GOG Protocol #258.”  Quality of life forms will be provided by the SDC upon request.  A form must be 
submitted whether or not the assessment is performed.  Please note: A QOL coversheet will not be 
collected. The coversheet questions have been included on the Scantron Form 
****       For all patients assigned to the treatment arm with radiation, Regimen I, the brachytherapy materials and 
forms will appear on the patient form schedule.  Forms HDRV and LDRV are both required to be 
submitted through SEDES for all patients whether or not brachytherapy is given and no matter what dose 
rate is used.  The materials will be addressed based on these completed treatment forms.  (06/07/2010) 
***** 
A copy of the corresponding pathology report must be shipped with all tissue specimens sent to the GOG 
Tissue Bank. 
 
Form SP must be submitted via SEDES regardless of whether the specimen is submitted for research.  
∆ 
CT/MRI showing relevant target volume is from the treatment planning system.  A print-out of one of the 
following will show the relevant tumor volume:  CT/MRI slices with volumes on them (can obtain this with 
the isodose lines also on the slices), the DRR (Digital Reconstructed Radiograph - where all the slices are 

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put together. Looks like an x-ray of the body, except it includes volumes and is from a CT/MRI scanner) or 
BEV (Beams Eye View – this shows the tumor volume from the perspective of each beam given, as well as 
the blocking used).  Best to submit the CT/MRI slices, but the others are fine. (01/03/2011) 
   
This study will be monitored by the Abbreviated Clinical Data System (CDUS) Version 3.0.  
CDUS data will be submitted quarterly to CTEP by electronic means. 
 
This study utilizes the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE 
v3.0) for defining and grading adverse events to be reported on GOG case report forms. A GOG 
CTCAE v3.0 Manual is available on the GOG member web site 
 
 and can be mailed to the institution registering a patient to this study if requested. 
(09/26/11) 
 
 
 

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11.0 
STATISTICAL CONSIDERATIONS  
 
11.1 
Overview, Study Registration and Randomization: 
 
This study is a two-arm, open-label, randomized Phase III trial.  The control arm 
for this trial is combination chemotherapy consisting of six, cycles of paclitaxel 
and carboplatin.  This regimen will be compared to a regimen of tumor-directed 
radiation with concurrent cisplatin followed by four cycles of paclitaxel and 
carboplatin combination chemotherapy.  The treatment regimens will be allocated 
so that the same number of patients will be treated with each treatment regimen.  
All patients will be registered centrally at the GOG Statistical and Data Center.  
The randomized treatment assignment will be revealed following patient 
registration.  Reports and publications will include a complete accounting of all 
patients registered to this study. 
 
11.2 
Relevant data: 
 
The principal items to be collected analyzed and reported to determine the 
therapeutic effect of treatment are outlined below. 
 
11.21 Outcome variables: recurrence-free survival (RFS), overall survival, 
cumulative incidence of local recurrence (limited to the pelvis or vagina) 
and cumulative incidence of distant metastases (beyond the pelvis and 
vagina). 
 
11.22 Tumor characteristics:  pelvic and para-aortic node status, FIGO surgical 
stage, maximum diameter of residual disease, cell type, depth of 
myometrial invasion and tumor grade. 
 
11.23 Patient characteristics: age, race, and performance status.  Race will be 
evaluated as a prognostic factor; however, no specific hypothesis test of an 
interaction between race and treatment is planned. 
 
11.24 Adverse effects of therapy:  the frequency and severity of acute and late 
adverse effects will be graded according to Common Terminology Criteria 
for Adverse Events (CTCAE) v3.0.  
 
11.25 Therapy administered: total amount in mg/m2 of each chemotherapy 
agent delivered, the number of cycles of chemotherapy completed, and the 
total dose and number of fractions of radiation delivered to the pelvis, 
extended field, and vagina.  The reason for discontinuation of study 
regimen will also be captured. 
 
11.26 Quality of life:  FACT-G Physical Well-being (PWB) and Functional 
Well-being (FWB) subscales (14 items), FACT-En additional concerns 
subscale (16 items), FACT/GOG-NTX-4 subscale (4 items) and items C3 
and C5 from the FACT-C. 

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11.3 
Accrual rate, sample size and study duration: 
 
The anticipated annual accrual is 180 patients.  This estimate is based upon the 
accrual to GOG-0184 and 0209.  The expected accrual period will be 54 months 
for a total of 804 patients.  This accrual duration accounts for a 5% ineligibility 
rate.  The post-accrual follow-up period for maturity of RFS and survival will 
require up to 12 months for RFS and 34 months for survival depending on the 
accrual rate and event rates in each arm. 
 
11.4 
Hypotheses, planning parameters, method of analysis and sample size 
justification:  
The primary hypothesis of this study is whether the addition of volume-directed 
radiation to adjuvant platinum and paclitaxel chemotherapy improves recurrence-
free survival in patients with optimally debulked Stage III or IVA endometrial 
adenocarcinoma.  Secondary endpoints include overall survival, cumulative 
incidence of local recurrence, cumulative incidence of distant metastases, acute 
and late adverse effects, and patient-reported quality of life. 
 
RFS and survival: For the purpose of planning this study, the death rate for 
survival and the recurrence or death rate for the RFS endpoint in the control 
regimen are estimated using the data from the doxorubicin and cisplatin arm of 
GOG-0122.  Data from that trial suggests that the hazard of first recurrence or 
death (RFS events) does not remain constant over time, but rather is greatest at 
the beginning of the study and decreases with time on study.  The hazard rates 
have been estimated assuming a Gompertz model (hazard function h(t)= αexp(βt) 
for t≥0).  The Gompertz model parameter estimates for RFS are, α=0.0196 per 
month (initial hazard) and β= –0.0217 (hazard decay factor).  The Gompertz 
model parameter estimates for survival are, α=0.0114 per month and β= –0.0120.  
These models assume that the recurrence or death rate is initially high, but 
declines rapidly over time, while the death rate starts lower and decays at a 
slightly slower rate. 
 
A 28.5% decrease (relative hazard=1.4) in the first recurrence or death rate would 
be considered clinically significant.  This relative decrease in recurrence or death 
rate translates into increasing the three-year recurrence-free survival from 61% to 
70% and the three-year survival from 72% to 79%.  This difference will require 
observing a total of at least 252 failures to permit at least 85% statistical power 
when the probability of Type I error for a one-tail comparison will be set at 
0.05.51 Overall Type I error is limited to 0.05 for RFS and survival separately.  
Independence between the two endpoints, RFS and survival, and randomized 
treatment will be assessed with a stratified logrank test for an intent-to-treat 
analysis of eligible patients.  The stratification will be defined by the covariates 
gross residual tumor (none or microscopic versus. gross) and age (65 and under 
versus over 65 years). 
 

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Toxicity:  The maximum grade over the entire course of therapy for any 
individual effect will be used as a summary of acute toxicity.  The Kruskal-Wallis 
test corrected for ties will be used to compare the maximum grade of acute 
adverse effects of therapy by treatment arm.  The CTCAE v3.0 grading system 
will be used (i.e., scale from 0 for none to 5 for death).  A significance level of 
0.01 will be used for each tested AE term or category.  No correction for multiple 
testing will be employed, since it is very important to identify moderate increases 
in the severity of toxicity at the risk of increasing the Type I error.  Since some of 
these toxicities are correlated, the overall Type I error is less than calculations 
would indicate when assuming complete independence.   
 
The maximum grade over the follow-up period (prior to initiation of subsequent 
therapy) for any individual effect will be used as summary of late adverse effects.  
The cumulative incidence of Grade 3 or higher bowel-related gastrointestinal 
adverse events will also be estimated using the date of onset and will account for 
competing events of death, progression, and non-protocol cancer treatment. 
 
Quality of Life:  The following assessment tools will be used to measure the 
quality of life prior to, during, and following treatment: 
 
FACT-G Physical Well-being (PWB) and Functional Well-being (FWB) 
subscales (14 items),  
 
FACT-En additional concerns subscale (16 items),  
 
FACT/GOG-NTX-4 subscale (4 items) and  
 
Items C3 and C5 from the FACT-C. 
 
Each tool will be evaluated at baseline (prior to therapy), 6 weeks from start of 
protocol therapy (1 week post completion of RT for Regimen I or three weeks 
post completion of 2 cycles of chemotherapy for Regimen II), 18 weeks from start 
of protocol therapy (three weeks after completion of protocol therapy), and then 
70 weeks from start of protocol therapy (1 year from completion of protocol 
therapy).   
 
Each item in the subscales listed above are scored using a five-point scale (0=not 
at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much).  Within an 
individual assessment, one or more items may not be answered.  A subscale score 
will be computed as long as more than 50% of subscale items have been 
answered.  A subscale score Si with Ni items will be calculated as:  
 









1
1
j
ij
j
ij
ij
i
i
s
N
S


 
 
Where ij is equal to 1 when the jth item has a valid response, otherwise it is equal 
to 0 and sij is the response score of the jth item.  The total score for the PWB and 
FWB is the sum of the two subscale scores if at least 80% of PWB and FWB 
items have been answered.  The total FACT-En TOI score is the sum of the 

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FACT-En PWB, FWB and FACT-En additional concerns subscale scores if at 
least 80% of TOI-En items have been answered. 
 
The QOL objectives in this study are to compare treatment regimens with respect 
to the patient-reported quality of life as measured with PWB+FWB score, TOI of 
FACT-En, and patient-reported neurotoxicity as measured with FACT/GOG-Ntx-
4 subscale.  A difference of 2~3 points is considered the minimally clinically 
important difference (MCID) for PWB and FWB respectively.52  For this study an 
observed difference of 4 points for the total score of PWB and FWB will be 
considered as the MCID in terms of QOL between the treatment groups.  This 
magnitude of difference is equivalent to an effect size of 0.38 assuming that the 
standard deviation (SD) is 10.4 for the total score of PWB and FWB as observed 
in GOG-0209.   
 
A difference of 1.5 points in FACT-GOG/Ntx-4 subscale (4 items) is considered 
the MCID between the treatment groups for this study.  This size of difference is 
equivalent approximately to an effect size of 0.35 assuming a SD of 4.3 as 
observed in GOG-0209.    
 
It has been suggested by the FACIT author53 that the Trial Outcome Index (TOI) 
which is the sum of the PWB, FWB, and “additional concerns” of a specific 
cancer is more responsive to change in QOL outcomes in cancer clinical trials.  
However, limited data are available on the validation of the TOI of FACT-En in 
terms of psychometric properties.  For the purposes of this study, the TOI of 
FACT-En will be assessed as an exploratory endpoint.  Currently the FACT TOI-
En scale is being used in GOG-0209 and will be validated once the study is 
completed.  By the time of the final QOL report, if the TOI of FACT-En is 
validated to be a reliable scale and sensitive to treatment and change over time, it 
will be assessed as a definitive endpoint in place of PWB+FWB to measure the 
quality of life. The TOI of FACT-En is computed by summating the FWB, PWB 
and En subscale if at least 80% of TOI-En items have been answered.  A 
difference of 6 points for TOI of FACT-En will be considered as the MCID in 
terms of QOL between the treatment groups. 52  
 
The treatment differences of QOL scores that are expected to be observed in this 
study and their corresponding effect sizes are listed in table below. 
 
 
Lower 
limit of 
MCID 
Estimated SD 
Effect size
Study or reference 
PWB+FWB 
4 
10.4 
0.38 
GOG-0209 
TOI of FACT-En 
6 
15.4 
0.39 
GOG-0209 
FACT-GOG/Ntx-4 
subscale 
1.5 
4.3 
0.35 
GOG-0209 
 

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With the multiple QOL measures, the Type I error is set at 0.017=1-(1-0.05)1/3 for 
each two-tail comparison between treatments to ensure the overall Type I error to 
be 0.05.  The sample size required for detecting an effect size of 0.35 with a 
statistical power of 90% is 220 eligible patients in each randomized group.  
Patient death, illness, noncompliance, and missed appointment can cause missing 
information that increases over time. In GOG-0209, approximately 68% of 
eligible patients who participated in QOL component completed the assessment at 
26 weeks post randomization. Assuming the completion rate for the QOL 
assessment at 70 weeks post start of protocol therapy in this trial is 65%, then the 
primary sample size of 766 eligible patients (383 per arm) will provide a 
statistical power of at least 93.5%.54 The statistical power will be higher if 
correlation among repeated measures exists.  
 
Linear mixed models adjusted for baseline score, age, and performance status at 
enrollment will be used to test the hypothesis of no difference in PWB+FWB 
scores and FACT-GOG/NTX-4 scores between assigned treatment arms in an 
intent-to-treat analysis of eligible patients.  These models will account for the 
correlation among scores measured over time.  The interaction between treatment 
and assessment time on QOL scores will be tested initially in each model.  If this 
interaction is found to be statistically significant (at level of 0.05), treatment 
comparisons for each assessment tool will be carried out individually at each 
point using the model parameter estimates.  If there is no evidence of an 
interaction, then a weighted average of estimates over the three points will be 
compared between assigned treatment arms.  The empirical sandwich variance 
will be used to estimate the precision of the parameter estimates.  Satterthwaite’s 
DF approximation will be used in significance testing to adjust the degrees of 
freedom for unequal group variances.  
 
An exploratory data analysis is planned to assess patient-reported gastrointestinal 
symptoms between the two groups using similar methods described above.  The 
gastrointestinal symptoms are evaluated with items C3 and C5 in combination 
with En1, O1, O3 and Cx6 in TOI of FACT-En.  A subscale score of 
gastrointestinal symptoms is computed using the same method described above 
for PWB and FWB subscales.  
 
One or more of the QOL assessments may be missing for an individual on any 
occasion. Missing information is troublesome, particularly in studies involving 
repeated patient assessments.  Data management procedures will be used to 
reduce missing data.  At selected semi-annual group meetings, the data managers 
and nurses will be given presentations that describe the goals of this study and 
stress the importance of obtaining complete assessment. A study contact person 
will be designated to answer questions that arise throughout the study.  A calendar 
of events that lists the dates of required QOL assessments for each patient will be 
made available to the patient’s health care provider as soon as the patient has been 
registered onto this study.  Also, the clinic staff will use the GOG Web-based 
forms tracking system to obtain reminders of the upcoming QOL assessments.  

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In case an assessment is missed, the reasons for missed QOL assessments will be 
collected.  The distribution of these reasons/missed assessments will be evaluated 
over time between the treatment arms for comparability.  Assessment completion 
rates will be summarized and monitored by the Quality of Life Committee every 6 
months. 
 
11.5 
Interim analysis: 
 
An initial interim analysis of RFS will be performed when there are at least 105 
events (recurrence or death) reported among all enrolled eligible patients.  It is 
projected that 105 events will be observed within 36 months of accrual.  The 
second planned interim analysis will be performed when there are at least 210 
events reported (estimated to occur at least 3 months after target accrual is 
reached).  Each interim analysis will be scheduled to coincide with the GOG Data 
Monitoring Committee (DMC) meetings that are held at each GOG semi-annual 
group meeting.  Overall survival, the accrual rate, adverse events of treatment, 
treatment compliance, and results of external studies will be included in the 
interim analysis report to the DMC to be taken into consideration when reaching a 
decision.  This planned interim analysis will include both an efficacy and a futility 
analysis.  The possibility of additional unplanned interim analyses of efficacy is 
taken into consideration in the plans below.   
 
Interim analysis for efficacy:  The previously described stratified logrank test 
will be used to compare recurrence-free survival distributions between the 
experimental regimen and the control regimen at each interim analysis.  If the null 
hypotheses can be rejected with p≤0.001 (one-tail test), terminating the accrual 
will be considered given that the study has not yet reached the target accrual goal.  
If the study is closed early, an additional period of follow-up for data maturity 
will also be considered prior to releasing the final report.  This will require 
evaluating the benefit of observing additional failures with the cost of postponing 
the release of the final report to observe these failures.  There will be no 
correction to the nominal p-value in the final report.  It has been shown that there 
is only a very small increase in Type I error associated with this type of interim 
analysis plan, even in the event of additional (unplanned) interim analyses using 
the 0.001 nominal p-value. 55 
 
Interim analysis for futility:  A futility analysis will be performed only at the first  
planned interim analysis.  If the observed rate of recurrence or death of the 
chemotherapy and radiation regimen is greater than the observed rate of 
recurrence or death of the chemotherapy-only arm when stratified by residual 
tumor and age, then accrual termination will be considered (if still active) with a 
conclusion that an advantage for the chemotherapy and radiation regimen has not 
been established.  The increase in Type II error due to this interim analysis is less 
than 1% if only one interim analysis is performed at 50% information time. 56   

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Under the null hypothesis, this procedure has a 50% chance of resulting in early 
termination.  
 
Safety monitoring:  The GOG Data Safety and Monitoring Board (DSMB) 
reviews accumulating summaries of adverse event reports and all serious adverse 
event (SAE) reports submitted during the interval between group meetings.  This 
committee also reviews deaths in which treatment may have contributed to the 
cause.   Based upon these reviews, the DSMB may recommend study 
amendments to the DMC pertaining to patient safety.   
 
Design assumptions:  Assumptions made to determine sample size will be 
checked prior to the planned time of closing the study to patient entry.  This will 
not involve a comparison of treatment arms but will be based upon aggregated 
data. 
 
11.6 
Planned gender, minority and ethnic inclusion: 
 
The following are the race and ethnicity distributions anticipated for this trial 
based upon historical data.  All patients in this study will be female by definition 
of disease.  Prior GOG studies in this population have not indicated that there is 
substantial heterogeneity of treatment effects among racial/ethnic subgroups. 
Therefore, the study design does not incorporate specific hypotheses concerning 
treatment interactions involving race or ethnicity. 
 
 
Ethnic Category 
Number of patients 
anticipated 
Hispanic or Latino 
    23 (   2.8%) 
Not Hispanic or Latino 
726 ( 90.3%) 
Undeclared 
   55 (   6.9%) 
Total 
804 (100.0%) 
 
Racial Category 
Number of patients 
anticipated 
American Indian/Alaskan Native 
2 (    0.3%) 
Asian 
16 (    2.0%) 
Native Hawaiian or Other Pacific Islander 
8 (    1.0%) 
Black or African American 
 42 (    5.2%) 
White 
732 (  91.0%) 
Undeclared 
 4 (    0.5%) 
Total 
804 (100.0%) 

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12.0 
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APPENDIX I 
CARCINOMA OF THE ENDOMETRIUM 
FIGO CLASSIFICATION 
2009 
 
 
 
Stage I* 
Tumor confined to the corpus uteri. 
IA* 
No or less than half myometrial invasion 
IB* 
Invasion equal to or more than half of the myometrium 
Stage II* 
Tumor invades cervical stroma, but does not extend beyond the uterus** 
Stage III* 
Local and/or regional spread of the tumor 
IIIA* 
Tumor invades the serosa of the corpus uteri and/or adnexae# 
IIIB* 
Vaginal and/or parametrial involvement# 
IIIC* 
Metastases to pelvic and/or para-aortic lymph nodes# 
IIIC1* 
Positive pelvic nodes 
IIIC2* 
Positive para-aortic lymph nodes with or without positive pelvic lymph         
nodes 
Stage IV* 
Tumor invades bladder and/or bowel mucosa, and/or distant metastases 
IVA* 
Tumor invasion of bladder and/or bowel mucosa 
IVB 
Distant metastases, including intra-abdominal metastases and/or inguinal 
lymph nodes 
 
*Either G1, G2, or G3. 
 
**Endocervical glandular involvement only should be considered as Stage I and no longer as 
Stage II. 
 
#Positive cytology has to be reported separately without changing the stage. 
 
 

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APPENDIX II (04/28/2014) 
 
Translational Research Specimen Procedures (01/13/14) 
 
I. 
Summary of Specimen Requirements 
 
If the patient gives permission for her specimens to be collected and used for this optional 
translational research component, then participating institutions within the United States are 
required to submit the patient’s specimens as outlined below (unless otherwise specified). 
 
Required Specimen 
(Specimen Code) 
 
Collection Time Point 
Ship To 
FFPE Primary or Metastatic  (FT011)* 
1st Choice: block 
2nd Choice: 15 unstained slides (charged, 
5µm) 
Prior to all treatment 
GOG Tissue Bank within 8 
weeks of registration2 
Whole Blood (WB01) 
7-10mL drawn into purple-top (EDTA) 
tube(s) 
Prior to or after starting study 
treatment 
GOG Tissue Bank the day the 
blood is collected2 
 
* 
A copy of the corresponding pathology report must be shipped with all tissue specimens sent to the GOG Tissue Bank 
If submitting both, label primary as FT01 and metastatic as FT02. If only metastatic is submitted, it should be labeled FT01. 
GOG Tissue Bank / Protocol GOG-0258, Nationwide Children’s Hospital,
 
 
II. 
Obtaining a GOG Bank ID for Translational Research Specimens 
 
Only one GOG Bank ID (# # # # - # # - G # # #) is assigned per patient. All translational research 
specimens and accompanying paperwork must be labeled with this coded patient number. A 
GOG Bank ID can be obtained online via the Tissue Bank Portal on the GOG website (under 
Tools on the Web Menu page). 
 
Obtain the patient’s study ID (GOG #) for all protocols with translational research specimen 
requirements before requesting a Bank ID from the Tissue Bank Portal. Be sure to indicate if 
the patient has a previous GOG # when registering. This will ensure the patient is only 
assigned one Bank ID. The GOG ID – Bank ID Lookup on the Tissue Bank Portal can be used to 
search for an existing Bank ID.  
 
Please contact GOG User Support if you need assistance or have assigned more than one Bank 
ID to a patient 
 
 
 III. 
Requesting Translational Research Specimen Kits 
 
Kits are not provided for this protocol. 
 
IV. 
Labeling Translational Research Specimens 
 
A waterproof permanent marker or printed label should be used to label each translational 
research specimen with: 

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GOG Bank ID (# # # # - # # - G # # #) 
GOG protocol number (GOG- # # # #) 
specimen code (see section I) 
collection date (mm/dd/yyyy) 
surgical pathology accession number (tissue specimens only) 
block number (tissue specimens only) 
 
Note: If labeling slides, only label on the top, front portion of the slide. Do not place a label on 
the back of the slide or over the tissue. The label must fit on the slide and should not be wrapped 
around the slide or hang over the edge. 
 
V. 
Submitting Formalin-Fixed, Paraffin-Embedded Tissue   
 
Formalin-fixed, paraffin embedded (FFPE) tissue should be the most representative of the 
specimen type (primary, metastatic). Primary and metastatic tumor should be collected prior to 
all treatment. Only one block may be submitted per tissue type. 
 
Primary tumor is the 1st choice and metastatic tumor is the 2nd choice. If submitting both, label 
primary tumor with the specimen code FT01 and metastatic tumor with the specimen code FT02. 
If only metastatic tumor will be submitted, it should be labeled FT01. 
 
Every attempt should be made to provide a FFPE block; however, if a block cannot be provided 
on a permanent basis, then 15 unstained slides (charged, 5µm) should be submitted. All tissue 
sections should be cut sequentially from the same block.  
 
Note: If stained slides (required to confirm patient eligibility by central pathology review) will be 
cut from the same block that will be submitted for translational research, your pathology 
department should cut the slides for staining prior to submitting the block for translational 
research. 
 
The type of specimen (block, slides) and the type of tumor tissue (primary, metastatic) should be 
specified on Form SP. 
 
All FFPE tissue should be submitted with the corresponding pathology report. 
 
VI. 
Submitting Whole Blood   
 
1.  
Label the lavender/purple top (EDTA) collection tube(s) as described above. Multiple 
tubes may be used to collect the required amount. 
 
2. 
Draw 7-10mL of blood into the labeled lavender/purple top tube(s). A minimum of 3mL 
is needed for processing. 
 
3.  
Immediately after collection, gently invert the tube 5-10 times to mix the blood and 
EDTA. 

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4. 
Whole blood specimens should be refrigerated (4°C) until the specimens can be shipped. 
Ship whole blood to the GOG Tissue Bank the day the specimen is collected. If the whole blood 
absolutely cannot be shipped the day it is collected, the tube(s) should be refrigerated (4°C) until 
the specimen can be shipped. 
 
VII. 
Submitting Form SP 
 
Form SP must be submitted via SEDES for each required specimen regardless of whether the 
specimen is submitted for research. 
 
A copy of the SEDES-completed Form SP must accompany each specimen shipped to the GOG 
Tissue Bank (or alternate laboratory). Handwritten forms will not be accepted. 
 
Note: A copy does not need to be sent if the specimen is not collected. 
 
Retain a printout of the completed form for your records. 
 
Please contact GOG User Support if you need assistance 
 
 
 
VIII. Shipping Translational Research Specimens 
 
A SEDES-completed copy of Form SP must be included for each translational research 
specimen. 
 
FFPE Tissue 
 
FFPE tissue and a copy of the corresponding pathology report should be shipped using your own 
container at your own expense to: 
 
 
 
 
 
 
 
 
Do not ship FFPE tissue for Saturday delivery. 
 
Whole Blood 
 
 
Whole blood specimens should be shipped to the GOG Tissue Bank (address above). 
 

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Whole blood can be shipped to the GOG Tissue Bank Monday through Friday for Tuesday 
through Saturday delivery. Do not ship whole blood the day before a holiday. Use your own 
shipping container to ship specimens via FedEx priority overnight. 
 
When shipping whole blood specimens, your institution must comply with IATA standards 
(www.iata.org). If you have questions regarding your shipment, contact the GOG Tissue Bank at 
 
 
 
To ship whole blood specimens you will need (1) a sturdy shipping container (e.g., a cardboard 
or styrofoam box), (2) a leak proof biohazard envelope with absorbent material*, (3) a puncture 
and pressure resistant envelope (e.g. Tyvek envelope), (4) an Exempt Human Specimen sticker, 
and (5) a pre-paid FedEx air bill. 
 
*If you will be shipping whole blood specimens from more than one patient, please put each 
specimen in a separate plastic zip-lock bag before placing the specimens in the shipping bag. 
You may include up to four different blood specimens in one biohazard envelope. 
 
If you do not have these materials available at your institution, you may order them from any 
supplier 
  
 
 
Shipping Whole Blood Using Your Own Shipping Container 
 
Place the whole blood specimen in a biohazard bag containing absorbent material. Expel as 
much air as possible before sealing the bag. 
  
Wrap the biohazard bag in bubble wrap or another padded material. 
 
Place the padded tube(s) into a Tyvek envelope. Expel as much air as possible before sealing the 
envelope. 
 
Place the Tyvek envelope in a sturdy shipping container (e.g., cardboard FedEx box). 
 
Insert a copy of Form SP for each specimen.  
 
Attach an Exempt Human Specimen Sticker to the outside of the shipping container. 
 
Print a pre-paid FedEx air bill using the Kit Management application (found under Data Entry on 
the Web Menu page). Attach the air bill. 
 
Make arrangements for FedEx pick-up through your usual institutional procedure or by calling 
 
 
IX. 
Distributing Translational Research Specimens 
 
The GOG Statistical and Data Center and Tissue Bank will coordinate the distribution of 
specimens to approved investigators. 

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Investigators will not be given access to any personal identifiers. 
 
Investigators will be responsible for the direct supervision and oversight of translational research 
and for keeping accurate records of all specimen testing. 
 
Investigators will ensure the results are linked to the appropriate specimen-specific identifiers 
and are responsible for transferring relevant laboratory data to the GOG Statistical and Data 
Center. 
 
At the discretion of the Chair of the Committee on Experimental Medicine and the Director of 
the GOG Tissue Bank, investigators may be required to ship any specimens (or by-products) 
remaining after the completion of the translational research to the GOG Tissue Bank. 
 
X. 
Banking Translational Research Specimens for Future Research 
 
Specimens will remain banked in the GOG Tissue Bank and made available for approved 
research projects if the patient has provided permission for the use of her specimens for future 
health research. The patient’s choices will be recorded on the signed informed consent document 
and electronically via the online Specimen Consent Application. (At the time of specimen 
selection for project distribution, the most recent consent information will be used. 
 
GOG institutions can amend a patient’s choices regarding the future use of her specimens 
at any time if the patient changes her mind. 
 
If the patient revokes permission to use her specimens, the GOG Tissue Bank will be instructed 
to destroy or return any remaining specimens. The patient’s specimens will not be used for any 
further research; however, any specimens distributed for research prior to revoking consent 
cannot be returned or destroyed. In addition, the patient cannot be removed from any research 
that has been done with her specimens distributed prior to revoking consent. 
 
Note: If return of specimens is requested, shipping will be at the institution’s expense. 
 
 
 

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APPENDIX III (04/28/2014) 
 
 CARBOPLATIN DOSE CALCULATION INSTRUCTIONS (03/14/11) 
 
1) The Cockcroft-Gault formula will be used in GOG trials (not the Jelliffe formula).  
 
2) Conversion of IDMS creatinine levels to “non-IDMS” values will not be permitted.  
 
3) The carboplatin calculation tool on the GOG website has been updated.  A legacy carboplatin 
calculator (using the Jelliffe formula and IDMS to “non-IDMS” conversion) is also available, if 
needed for dose modifications (see below). 
 
Dosing of Carboplatin: 
The carboplatin dose will be calculated to reach a target area under the curve (AUC) 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 renal toxicity 
greater than or equal to CTCAE Grade 2 (serum creatinine >1.5 x ULN) or toxicity requiring 
dose modification, the dose of carboplatin will not need to be recalculated for subsequent cycles, 
but will be subject to dose modification for toxicity as noted in the protocol. 
 
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 greater than or equal to 10% from baseline. 
 
In patients with an abnormally low serum creatinine (less than 0.7 mg/dl), the creatinine 
clearance should be estimated using a minimum value of 0.7 mg/dl.  If a patient is currently 
being dosed using a creatinine value less than 0.7 mg/dl, adjust dose with next planned treatment. 
 
For trials where patients enter and are treated within less than or equal to 12 weeks of surgery:  If 
a more appropriate (higher) baseline creatinine value is available from the pre-operative period 
(within 4 weeks of surgery date), that value may also be used for the initial estimation of GFR. 
 
CALVERT FORMULA: 
 
Carboplatin dose (mg) = target AUC x (GFR + 25) 
 
NOTE:  the GFR used in the Calvert formula should not exceed 125 ml/min. 
 
Maximum carboplatin dose (mg) = target AUC (mg/ml x min) x 150 ml/min. 
 
The maximum allowed doses of carboplatin are: 
 
AUC 6 = 900 mg 
AUC 5 = 750 mg 

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AUC 4 = 600 mg 
 
For the purposes of this protocol, the GFR is considered to be equivalent to the estimated 
creatinine clearance. The estimated creatinine clearance (ml/min) is calculated by the method of 
Cockcroft-Gault using the following formula: 
 
Creatinine Clearance (mL/min) =    [140-Age (years)] x Weight (kg) x 0.85  
                                                             
72 x serum creatinine (mg/dl)  
 
Notes: 
1) Weight in kilograms (kg): 
Body Mass Index (BMI) should be calculated for each patient.  A BMI calculator is available at 
the following link:  http://www.nhlbisupport.com/bmi/ 
Actual weight should be used for estimation of GFR for patients with BMI of less than 25.   
Adjusted weight should be used for estimation of GFR for patients with BMI of greater than 
or equal to 25. 
Adjusted weight calculation: 
Ideal weight (kg) = (Height (cm)/2.54) – 60) x 2.3) + 45.5 
 
Adjusted weight (kg) = ((Actual weight – Ideal weight) x 0.40) + Ideal weight 
 
If a patient with BMI of greater than or equal to 25 is currently being dosed using actual weight, 
adjust dose with next planned treatment. 
 
2) The Cockcroft-Gault formula above is specifically for women (it includes the 0.85 factor). 
 
At the time of a dose modification for toxicity:  
 
1) If the creatinine at the time of a dose modification is lower than the creatinine used to 
calculate the previous dose, use the previous (higher) creatinine; if the creatinine at the time of a 
dose modification is higher than the creatinine used to calculate the previous dose, use the 
current (higher) creatinine.  This will ensure that the patient is actually receiving a dose 
reduction.  
 
2) If the dose of carboplatin (mg) at the time of dose modification, is higher than the previous 
dose due to the use of the Cockcroft-Gault formula [when the previous dose was calculated using 
the Jelliffe formula and IDMS to “non-IDMS” conversion (if applicable)], use the same method 
that was used to calculate the previous dose [Jelliffe formula and IDMS to “non-IDMS” 
conversion (if applicable)], to calculate the dose of carboplatin (mg) at the time of dose 
reduction.  A legacy carboplatin calculator is available on the GOG website for this purpose.  
This will ensure that the patient is actually receiving a dose reduction.  

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APPENDIX IV (04/28/2014) 
General Chemotherapy Guidelines: 
 
 For 21 or 28 day cycles, a patient will be permitted to have a new cycle of 
chemotherapy delayed up to 7 days (without this being considered to be a 
protocol violation) for major life events (e.g., serious illness in a family member, 
major holiday, vacation which is unable to be re-scheduled).  Documentation to 
justify this decision should be provided. 
 It will be acceptable for individual chemotherapy doses to be delivered within a 
“24-hour window before and after the protocol-defined date” for “Day 1” 
treatment of 21 or 28 day cycles.  If the treatment due date is a Friday, and the 
patient cannot be treated on that Friday, then the window for treatment would 
include the Thursday (1 day earlier than due) through the Monday (day 3 past 
due). 
 For weekly regimens, it will be acceptable for individual chemotherapy doses to 
be delivered within a “24-hour window,” for example; “Day 8 chemotherapy” can 
be delivered on Day 7, Day 8, or Day 9 and “Day 15 chemotherapy” can be given 
on Day 14, Day 15, or Day 16. 
 Chemotherapy doses can be “rounded” according to institutional standards 
without being considered a protocol violation (most institutions use a rule of 
approximately +/- 5% of the calculated dose). 
 Chemotherapy doses are required to be recalculated if the patient has a weight 
change of greater than or equal to 10%.  Patients are permitted to have 
chemotherapy doses recalculated for <10% weight changes. (04/28/2014) 
 Maximum body surface area used for chemotherapy dose calculations will be 2.0 
m2.  For chemotherapy dose calculations that use mg/kg, there will be no 
maximum kilogram amount used (doses will be calculated on actual weight in 
kg).