Clinical trial NCT01535053
Conditions: Choriocarcinoma FIGO Stage I Gestational Trophoblastic Tumor FIGO Stage II Gestational Trophoblastic Tumor FIGO Stage III Gestational Trophoblastic Tumor Hydatidiform Mole
Sponsor: GOG Foundation
Start date: 2012-06-18; Completion date: 2020-07-17
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase III trial studies how well methotrexate works compared to dactinomycin in treating patients with low-risk gestational trophoblastic neoplasia. Drugs used in chemotherapy, such as methotrexate and dactinomycin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether methotrexate is more effective than dactinomycin in treating gestational trophoblastic disease.

Detailed description:
PRIMARY OBJECTIVES:

I. To test the hypothesis that treatment with multi-day methotrexate is inferior to treatment with pulse actinomycin-D (dactinomycin) in patients with low-risk gestational trophoblastic disease with respect to complete response.

SECONDARY OBJECTIVES:

I. To describe the frequency of post protocol surgical treatment for each arm. II. To describe the frequency of post protocol multi-agent chemotherapy treatment for each arm.

III. To compare multi-day methotrexate to actinomycin-D with respect to frequency and severity of adverse events in patients with low-risk gestational trophoblastic neoplasia.

IV. To investigate the impact of treatment on overall quality-of-life (QOL) and explore the influence of treatment on issues such as body image, sexual functioning, and patient-reported side effects and disruption.

V. To assess whether uterine artery pulsatility index (UAPI) can provide independent prognostic information predictive of single-drug resistance.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive dactinomycin intravenously (IV) over 15 minutes on day 1.

ARM II: Patients receive methotrexate intramuscularly (IM) on days 1, 3, 5, and 7 and leucovorin calcium orally (PO) on days 2, 4, 6, and 8 OR single agent methotrexate IV on days 1-5.

In both arms, treatment repeats every 14 days for up to 20 courses\* in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up monthly for 1 year and then every 3 months for 1 year.

NOTE: \* Patients will be treated for three courses after human chorionic gonadotropin (hCG) \< 5 mIU/mL or until evidence of treatment failure (biologic progression), disease progression, or unacceptable toxicity despite dose modifications. Upon normalization of hCG (\< 5 mIU/mL), patients will be treated with three additional courses.

Arms: arm 1: Patients receive dactinomycin IV over 15 minutes on day 1. arm 2: Patients receive methotrexate IM on days 1, 3, 5, and 7 and leucovorin calcium PO on days 2, 4, 6, and 8 OR single agent methotrexate IV on days 1-5.
Interventions: intervention 1: Dactinomycin intervention 2: Leucovorin Calcium intervention 3: Methotrexate intervention 4: Quality-of-Life Assessment
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO intervention 3: Given IV and IM intervention 4: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
Philip J. DiSaia, M.D. 
President 
 
Administrative Office 
Four Penn Center 
1600 John F. Kennedy Boulevard, Suite 1020 
Philadelphia, Pennsylvania 19103 
Phone: 215-854-0770 Fax: 215-854-0716 
 
Laura L. Reese 
Executive Director of Operations 
 
Larry J. Copeland, M.D. 
Vice President  
 
Finance/Development Office 
2127 Espey Court 
Suite 100 
Crofton, Maryland 21114 
Phone: 410-721-7126 Fax: 301-261-3972 
 
Mary C. Sharp 
Chief Financial Officer 
 
 
SUMMARY OF CHANGES 
 
For Protocol Revision #5 to GOG-0275 
 
NCI Protocol #: GOG-0275 
Local Protocol #: GOG-0275 
 
NCI Version Date: 03/25/2015 
Protocol Date:  
 
 
# 
Section 
Page(s) 
Change 
1. 
Title Pages 
1-3 
• The NCI Version Date is now 03/25/2015. 
• Includes Revisions #1-5. 
2. 
11.32 
40, 41 
Accrual rates have been revised. 
3. 
11.33 
41 
This section has been expanded to include information regarding revised 
accrual rates. 
4. 
IC 
 
The NCI Version Date is now 03/25/2015. 
 
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NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
PROTOCOL GOG-0275 
A PHASE III RANDOMIZED TRIAL OF PULSE ACTINOMYCIN-D VERSUS MULTI-DAY 
METHOTREXATE FOR THE TREATMENT OF LOW-RISK GESTATIONAL 
TROPHOBLASTIC NEOPLASIA NCT #01535053 (11/24/2014) 
NCI Version Date 03/25/2015 
Includes Revisions #1-5 
POINTS: 
PER CAPITA -20 
MEMBERSHIP -6 
Lead Organization: NRG / NRG Oncology (11/24/2014) 
 
 
 
 
 
 
STUDY CHAIR (11/24/2014) 
STUDY CO-CHAIR 
 
 
 
JULIAN C. SCHINK, M.D.  
 
RAYMOND J. OSBORNE, M.D. 
SPECTRUM MEDICAL GROUP 
 
TORONTO-SUNNYBROOK REGIONAL 
648 MONROE AVE NW, SUITE 115 
 
CANCER CENTER 
GRAND RAPIDS, MI 49503  
 
2075 BAY VIEW AVE. 
616-267-7095  
 
 
 
TORONTO, ON M4N3M5 CA 
FAX: 616-267-8887  
 
 
416-480-4026 
julian.schink@spectrumhealth.org  
 
ray.osborne@sunnybrook.ca   
 
NURSE CONTACT STUDY CO-CHAIR 
NANCY J. ANDERSON, RN, APN 
 
 
JOHN TIDY, M.D. 
NORTHWESTERN UNIVERSITY 
 
 
SHEFFIELD TEACHING HOSPITALS 
GYNECOLOGIC ONCOLOGY 
 
 
GLOSSOP ROAD 
675 N. ST. CLAIR ST. SUITE 21-200  
 
SHEFFIELD S10 2JF UK 
CHICAGO, IL 60611-3905 
 
 
 
44-114226857 
312-695-0990  
 
 
 
 
John.Tidy@sth.nhs.uk  
FAX: 312-695-6870 
nanderson@nmff.org    
 
 
 
QUALITY OF LIFE CHAIR 
 
 
 
 
 
 
 
JEANNE CARTER, Ph.D. 
PATHOLOGIST 
 
 
 
 
See GOG Website Directory 
HELEN E. MICHAEL, M.D. 
See GOG Website Directory  
 
 
STATISTICIANS 
 
 
 
 
 
 
 
VIRGINIA FILIACI, PH.D. 
STUDY COLLABORATOR 
 
 
 
HELEN HUANG, M.S. 
MICHAEL SECKL, MBBS., B.Sc., Ph.D., FRCP. See GOG Website Directory 
See GOG Website Directory 
 
 
 
 
 
 
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 (11/24/2014) 
ALLIANCE / Alliance for Clinical Trials in Oncology 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
SWOG / SWOG 
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NCI Protocol #: GOG-0275 
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PROTOCOL GOG-0275 
A PHASE III RANDOMIZED TRIAL OF PULSE ACTINOMYCIN-D VERSUS MULTI-DAY 
METHOTREXATE FOR THE TREATMENT OF LOW-RISK GESTATIONAL 
TROPHOBLASTIC NEOPLASIA 
NCI Version Date 03/25/2015 
Includes Revisions #1-5 
 
CONTACT INFORMATION 
To submit site 
registration documents: 
For patient enrollments:  
Submit study  
CTSU Regulatory Office 
1818 Market Street, Suite 
1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Email: CTSU 
REGULATORY@ctsu.co
ccg.org (for 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/OPEN_
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. 
 
GOG Statistical and Data Center at Roswell 
Park Cancer 
Institute 
Elm and Carlton Streets 
Buffalo, NY 14263 
Call GOG User support 716-845-7767 to 
obtain user name and password to submit 
electronic data 
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. 
 
Note:  Non-lead group institutions will order the following supplies from the CTSU Operations Office: hard 
copy GOG-0275 QOL scantron forms. 
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.  
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NCI Protocol #: GOG-0275 
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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 Web site is located at   https://www.ctsu.org 
 
OPEN TO PATIENT ENTRY JUNE 18, 2012 
REVISED MARCH 11, 2013 
REVISED MAY 28, 2013 
REVISED NOVEMBER 24, 2014 
REVISED 
 
 
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NCI Protocol #: GOG-0275 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients will be treated for three cycles after hCG <5mIU/ml or until evidence of 
biologic or disease progression or unacceptable toxicity despite dose modifications.  
Upon normalization of hCG (<5mIU/ml), hCG levels will then be monitored every 4 
weeks for 52 weeks beginning with the 1st day of the last chemotherapy cycle. 
 
 
 
 
 
 
 
 
 
 
Quality of Life surveys are to be obtained at 5 time-points: 
• Prior to cycle 1 
• Prior to cycle 3 (If off study therapy, 4 weeks after starting study treatment) 
• Prior to cycle 5 (If off study therapy, 8 weeks after starting study treatment) 
• Prior to cycle 7 (If off study therapy, 12 weeks after starting study treatment) 
• 26 Weeks after starting study treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hCG <  
5mIU/MI 
Treat 3 
cycles past 
first hCG 
<5mIU/MI 
hCG follow up 
for 1 year 
beginning 1st 
day of last cycle 
Eligible 
patients: 
Low-risk 
persistent 
GTN;  
FIGO Stage 
I, II, III; and 
WHO Score 
0-6 
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
Regimen 1:  Patients will receive IV pulse 
actinomycin-D (1.25mg/m2) every 14 days. (2mg max 
dose) 
 
Regimen 2: Patients will receive their institutional 
preference of either: 
• 
IV methotrexate (0.4 mg/kg) daily for 5 days 
every 14 days. (25mg max daily dose) 
OR 
• 
IM methotrexate (50mg) on Days 1, 3, 5, 7 
(4 doses per cycle) with Leucovorin (15mg) 
on Days 2, 4, 6, 8.  Repeat every 14 days. 
Prescribed 
Treatment 
Biologic or 
disease 
progression; 
unacceptable 
toxicity 
Discontinue 
study 
treatment, 
Restage 
Off study follow-up 
period; report 
subsequent treatment 
and outcome; total 
study duration of 2 years   
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TABLE OF CONTENTS 
 
1.0 
OBJECTIVES 
- 7 - 
1.1 
Primary Objectives 
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1.2 
Secondary Objectives 
- 7 - 
2.0 
BACKGROUND AND RATIONALE 
- 7 - 
2.1 
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 
Actinomycin-D 
- 15 - 
4.2 
Methotrexate 
- 15 - 
4.3 
Leucovorin 
- 16 - 
4.4 
Pathology Requirements 
- 17 - 
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE 
- 18 - 
5.1 
Registration Procedures 
- 18 - 
5.3 
Treatment Plan 
- 22 - 
5.4 
Criteria for Removal from Treatment 
- 24 - 
5.5 
Quality of Life Assessment 
- 24 - 
6.0 
TREATMENT MODIFICATIONS 
- 25 - 
6.1    Any patient whose treatment is delayed must be evaluated on a weekly basis until 
adequate hematologic and non-hematologic parameters have been met.  No dose 
escalation above the starting dose will be employed for either drug. 
- 25 - 
6.2  
The maximum permitted dose of actinomycin–D will be 2 mg per cycle.  The 
maximum permitted dose of daily IV methotrexate will be 25mg per day. (03/11/2013) - 
25 - 
6.3 
Dose Modifications (05/28/2013) 
- 25 - 
6.4 
Hematologic Toxicities 
- 25 - 
6.5 
Gastrointestinal and Other Toxicities 
- 26 - 
7.0 
STUDY PARAMETERS 
- 27 - 
7.1 
Observations and Tests 
- 27 - 
7.2 
Stained Pathology Slide Requirements for Central Review to Confirm Eligibility: - 
28 - 
7.3 
Translational Research 
- 29 - 
7.4 
Quality of Life 
- 29 - 
8.0 
EVALUATION CRITERIA 
- 31 - 
8.1 
Evaluability 
- 31 - 
8.2. 
Clinically Assessed Response 
- 31 - 
8.3 
Disease Progression is defined as new metastatic disease findings from clinical or 
radiological investigations or a sustained elevation in hCG levels above 5 mIU/ml after 
documentation of a complete response (two consecutive levels above 5mIU/ml taken at 
least one week apart). 
- 32 - 
8.4 
Other Objective Parameters 
- 32 - 
8.5  
Quality of Life Assessments 
- 32 - 
9.0 
DURATION OF STUDY 
- 34 - 
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10.0 
STUDY MONITORING AND REPORTING PROCEDURES 
- 35 - 
10.1 
ADVERSE EVENT REPORTING FOR A COMMERCIAL AGENT (  ) 
- 35 - 
10.2  GOG DATA MANAGEMENT FORMS 
- 38 - 
11.0 
STATISTICAL CONSIDERATIONS 
- 40 - 
11.1 
Study Design and Treatment Randomization: 
- 40 - 
11.2 
Efficacy and toxicity measures 
- 40 - 
11.3 
Statistical study design and planned analyses of therapeutic efficacy 
- 40 - 
11.4 
Safety analyses 
- 43 - 
11.5 
Quality of life analyses 
- 44 - 
11.6 
Uterine Artery Pulsatility Index Analysis 
- 45 - 
11.7 
Anticipated distribution of patients’ race and ethnicity (all are female) 
- 46 - 
12.0 
BIBLIOGRAPHY 
- 47 - 
APPENDIX I 
- 50 - 
APPENDIX II 
- 51 - 
APPENDIX III 
- 52 - 
APPENDIX IV (03/11/2013) 
- 53 - 
 
 
 
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NCI Protocol #: GOG-0275 
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1.0 
OBJECTIVES  
 
1.1 
Primary Objectives 
 
 
1.11 
To test the hypothesis that treatment with multi-day methotrexate is 
inferior to treatment with pulse actinomycin-D in patients with low-risk 
gestational trophoblastic disease with respect to complete response. 
 
1.2 
Secondary Objectives 
 
1.21 
To describe the frequency of post protocol surgical treatment for each arm. 
 
1.22 
To describe the frequency of post protocol multi-agent chemotherapy 
treatment for each arm. 
 
1.23 
To compare multi-day methotrexate to actinomycin-D with respect to 
frequency and severity of adverse events in patients with low-risk 
gestational trophoblastic neoplasia. 
 
1.24 
To investigate the impact of treatment on overall QOL and explore the 
influence of treatment on issues such as body image, sexual functioning, 
and patient reported side effects and disruption. 
 
1.25 
To assess whether uterine artery pulsatility index (UAPI) can provide 
independent prognostic information predictive of single-drug resistance. 
 
2.0 
BACKGROUND AND RATIONALE 
 
Prior Clinical Trial Evidence 
 
Both methotrexate and actinomycin-D are effective first-line drugs for persistent low-risk 
gestational trophoblastic disease.  There are several dosing/cycling options for each drug.  
When GOG-0174, a phase III randomized trial of bi-weekly IV actinomycin-D versus 
weekly IM methotrexate was initiated in 1999, the most commonly used North American 
regimen was low dose IM methotrexate.1,15   In a follow-up phase II dosing study, the 
GOG demonstrated that escalating the methotrexate dose up to 50mg/m2 did not 
significantly alter response when compared to the fixed dose of 30 mg/m2 in the previous 
study.16  Furthermore, Elit et al found that high dose methotrexate  did not demonstrate 
significant additional benefit over the study dosage.23  Single agent actinomycin-D was 
initially reported as a five-day parenteral regimen but it lost favor because of alopecia and 
nausea (Wong et al).24  More recently single-injection actinomycin-D was reported to be 
as effective first treatment as weekly methotrexate.19, 20, 22  
 
GOG-0174 demonstrated a higher complete response rate for bi-weekly actinomycin-D 
regimen than for the weekly IM methotrexate regimen.1 GOG-0174 included patients 
with a World Health Organization (WHO) risk score of 0-6 and patients with metastatic 
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disease or choriocarcinoma.  Of the 216 eligible patients, bi-weekly intravenous (IV) 
actinomycin-D at 1.25mg/m2 was statistically superior to weekly intramuscular (IM) 
methotrexate at 30 mg/m2 (complete response: 70 vs. 53%; p=0.01).  Similarly, in 
patients with low risk GTN as defined prior to the 2002 WHO risk score revisions (risk 
score of 0-4 and excluding choriocarcinoma) response was 58 and 73% in the 
methotrexate and actinomycin-D arms, respectively (p=0.03).  Both regimens were less 
effective if the WHO risk score was 5 or 6 or if the diagnosis was choriocarcinoma 
(complete response: 9 and 42%, respectively).  There were two potential recurrences; one 
at four months (actinomycin-D) and one at 22 months (methotrexate).  Not all patients 
completed follow-up.  Both regimens were well tolerated. 
 
While the results of GOG-0174 are compelling evidence that pulse actinomycin-D is the 
more effective single day regimen, many Trophoblastic Disease Centers continue to use 
multi-day methotrexate regimens because of a perception of higher complete response 
rates in the absence of a randomized controlled trial.  Controversy exists over the relative 
toxicity and efficacy of these commonly used regimens compared with the pulse 
actinomycin-D regimen.   
 
Rationale for Selected Approach and Trial Design 
 
The abrupt psychological shift experienced by a woman facing a diagnosis of gestational 
trophoblastic disease can be traumatic.4 The excitement and anticipation of a future child 
to the sadness associated with the loss of a viable pregnancy to the anxiety and fear 
connected with a potentially malignant and life-threatening condition is profound and 
certainly unique to this disease entity.5 However, low-risk gestational trophoblastic 
neoplasia (GTN) is a highly curable disease.   
 
There are many effective single-drug chemotherapy regimens; however, the choice of 
both the drug and regimen is highly institution specific.  There is no consensus on the 
best regimen for the primary treatment of GTN.  While the most important objective of 
treatment in these young reproductive-aged women is effectiveness and lower risk of 
exposure to multi-drug second-line regimen, other considerations, including short-term 
toxicity, side-effects and treatment issues (i.e., cost efficiency, administration, patient 
preference and compliance) and QOL become paramount and warrant investigation as 
targeted outcomes.  The goal would be to identify the most effective single agent 
chemotherapy, recognizing the significant negative impact of multi-agent chemotherapy 
on possible reproductive issues (early menopause),6 risk of secondary cancer7, 8 and 
ultimately QOL if multi-agent chemotherapy is required for cure. 
 
The GOG-0174 study conducted by members of this study team, as mentioned above, 
examined biweekly actinomycin-D and weekly methotrexate and both regimens were 
well tolerated.1 However, questions remain regarding differences in drug dosages, 
schedules, administration methods and length of therapy delivered after hCG 
normalization.9 These concerns have been addressed within the design of the proposed 
randomized clinical trial by clearly outlining the treatment modalities for each study arm.  
The proposed study will also include areas not formally assessed in previous studies 
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NCI Protocol #: GOG-0275 
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using patient reported outcomes (PROs) to prospectively examine patient’s overall QOL 
during the treatment process and immediate surveillance period.  This will enable us to 
examine to the influence of treatment factors, short-term toxicities, and side effects on 
QOL, which may be crucial when survival outcomes are both excellent and expected to 
be equivalent.  
 
This comparative effectiveness research has the potential to establish a new resource 
sensitive standard acceptable worldwide.  This study will compare pulse actinomycin-D 
with the standard therapies used at the expert centers around the world.  If the complete 
response rate for multi-day methotrexate is not better than bi-weekly pulse actinomycin-
D, women will have a clear option for a more convenient, less toxic treatment regimen.  
QOL assessment will also provide valuable information from the patient’s perception to 
be included in determining a worldwide standard.  
 
Upfront complete response is an important endpoint because approximately 25%1, 2 of 
women failing to achieve complete response with their initial chemotherapy regimen 
ultimately require surgery and/or multi-agent etoposide based chemotherapy.  In GOG-
0174 the complete response rate for pulse actinomycin-D was 71%.1  Lurain et al.2 
described the toxicity and efficacy of the 5 day methotrexate regimen noting 4.7% of 
patients experienced toxicity requiring a change from methotrexate to actinomycin-D and 
an 89.3% (226/253) complete remission rate to initial single-agent methotrexate 
(0.4mg/kg IV push qd x 5d qo week).  Berkowitz described the New England 
Trophoblastic Disease Center experience with the 8 day methotrexate with folinic acid 
rescue regimen with a 90% complete response rate.3  A recent Cochrane review 
concluded that the 8 day regimen did not offer an advantage in efficacy or adverse event 
profile over the 5 day regimen.   
 
While past research has described various treatment outcomes from chemotherapy and 
surgery, the health consequences and psychosocial aspects have been minimally explored 
and rarely in a prospective manner or with PROs.  Survey studies have shown quality of 
life to be negatively impacted by chemotherapy, regardless of the regimen.10,11  A trend 
of lower QOL exists between those requiring chemotherapy treatments to those who do 
not.10 In a cross-sectional survey study, women with active disease (n=11) demonstrated 
greater concerns, fear and threats to self-esteem than women in remission.11  Yet, another 
recent study described no significant effect of chemotherapy on QOL, but the number of 
patients surveyed during active treatment (out of n=54) was not provided.12  Formal 
assessment of QOL over the course of treatment will allow for a more thorough 
examination of possible treatment influences on QOL such as delivery, number of 
chemotherapy cycles, type of chemotherapy, compliance and life disruption.  
 
Attention to acute side-effects/short-term toxicities and their impact on QOL is an 
important area for consideration and noted need in the comparison of chemotherapy 
regimens.9  This is of particular relevance in a population with an excellent survival 
outcome of more than 98%.8  For example, the side-effects of alopecia is often under-
reported in oncology clinical trials,1 and has been coded as a dermatologic event in past 
studies.  Difficulty with body image (unattractive, feeling less of a woman) and sexuality 
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NCI Protocol #: GOG-0275 
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(difficulty with sex and fear that sex would worsen disease) have been described in 
women with active disease with greater levels of distress.11  Patient reported outcomes are 
needed to understand patient’s perception (i.e. body image) and the experience of 
treatment effects on QOL.   
 
It is recognized that overall QOL is a multi-faceted domain including physical, 
functional, social, and emotional factors.  We will examine these subcomponents within 
this study design based on the GTD/GTN literature.  Our goal is to determine which 
treatment is best tolerated with less negative impact on QOL while simultaneously 
assessing the effectiveness of the proposed chemotherapies.  Issues of social support, 
emotional well-being and gynecologic issues have been described as having influence on 
QOL in this population.  For example, studies investigating QOL after GTD have 
identified greater social support (p<.0001) and less disease specific distress (p<.0001) to 
be associated with high quality of life scores.5  In additional analyses, less gynecologic 
concerns (i.e., pain) were significant predictors of positive QOL.5  Other research in 
women with a history of molar pregnancies found issues of emotional well-being 
(anxiety, depression)10 and sexual dysfunction were experienced by participants.10,13 
While these studies highlight some significant psychosocial effects experienced by 
survivors of GTD, acute and short-term health consequences of newly diagnosed GTN 
patients requires further prospective investigation.  In particular, psychosocial distress has 
been noted to be more pronounced in the initial months of diagnosis.10 
  
This study will prospectively evaluate the effectiveness of two types of chemotherapy 
treatments and explore factors (social support/ emotional/ gynecologic issues) that may 
influence QOL.  In addition, we will determine if these findings may vary by type of 
chemotherapy treatment, number, or length of treatment and/or in surveillance.  Quality 
of life predictors of social support may also buffer distress in these women.14   As we 
measure QOL within this study, we will also examine for potential buffering effects. 
 
It should be noted that long-term toxicities have also been identified as an important area 
for future research.  However, difficulties arise when studying this population, as many 
women are not followed at cancer centers beyond the 6 months after hCG normalization 
due to low recurrence rates.1,8,9  Although it is recognized as important for further 
research, it is beyond the scope of this comparative effectiveness chemotherapy trial.  
 
Rationale for Optional Doppler Ultrasonography of the Uterine Artery  
 
Neo-angiogenesis, the formation of new blood vessels, is a critical step in 
tumorogenesis.27  Neo-angiogenesis is associated with increased tumor growth, 
acquisition of metastatic potential, drug resistance and poor prognosis in a number of 
solid tumocenters such as breast, lung and ovarian cancer.28,29,30,31  Histological 
asssessment of microvessel density (MVD) with CD34 immunostaining is used to assess 
angiogenesis in these tumors. In contrast, MVD assessment is not possible in GTN as 
biopsy is frequently contraindicated because of the risk of precipitating life-threatening 
hemorrhage in this highly vascular disease. Instead, the diagnosis is usually made on the 
basis of rising hCG levels post-molar pregnancy. Agarwal et al. previously proposed the 
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NCI Protocol #: GOG-0275 
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use of Doppler ultrasonography as a non-invasive alternative to assess tumor vascularity 
in GTN, using the uterine artery pulsatility index (UAPI).32 The UAPI is inversely 
proportional to tumor vascularity, and a low UAPI is indicative of increased 
arteriovenous shunting, a feature of the abnormal neo-angiogeneisis characteristic of 
tumors.  In that sudy of 164 patients with GTN, a UAPI of ≤1 was shown to be an 
independent predictor of methotrexate resistance (MTX-R) and in combination with the 
Charing Cross Hospital (CXH) scoring system improve prediction of MTX-R.  In 
particular, the risk of MTX-R in patients with medium-risk CXH scores of 6–8 with a 
UAPI of ≤1 was increased to 72.7% from a baseline risk of 56.3% in this group. These 
findings suggested that UAPI might be a useful additional variable to incorporate into the 
prognostic scoring systems to help refine which patients might be treated with EMA-CO 
chemotherapy upfront.  
 
To assess whether the UAPI could also contribute to the FIGO scoring system Agarwal et 
al. recently repeated this single center study. The results, published in 2012, confirm that 
UAPI is an independent predictor for MTX-R in low risk GTN patients (FIGO score 0-6) 
following a hydatidiform mole.33 In this study, 239 patients were assessable for both 
UAPI and MTX-R. The median UAPI was lower (higher vascularity) in MTX-R 
compared with MTX-sensitive patients (0.8 vs 1.4, p<0.0001). In multivariate logistic 
regression, UAPI≤1 predicted MTX-R, independent of both CXH and FIGO scores. The 
risk of MTX-R in patients with a FIGO score of 6 and UAPI ≤ 1 was 100% vs 20% in 
patients with UAPI ≤ 1 (chi-sq. p<0.0001).   
 
It was proposed that it might be helpful to consider adding the UAPI to the FIGO scoring 
system.  We believe it would be helpful to first prospectively validate these findings in a 
multicenter study. This would demonstrate the utility of the approach across centers in 
many countries.      
 
In the case of gestational trophoblastic tumors where nearly all patients are cured with 
existing therapies, the incorporation of UAPI into the scoring system would help to more 
accurately select patients for combination chemotherapy,  resulting in less total treatment 
time and toxicity.32  Based on these prior data, we are asking institutions to collect and 
report Doppler assessments of the uterine arteries, to further validate these findings in the 
context of a multi-center randomized prospective study, to determine if UAPI should be 
considered for incorporation in to FIGO scoring.  While this is an optional study and does 
not preclude institutions from participating in the main study, we strongly encourage 
centers to participate, as the Doppler assessment can be conducted rapidly at the time of 
baseline staging ultrasound scans prior to commencement of chemotherapy.
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NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
2.1 
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 population treated by 
participating institutions. 
 
 
 
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NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS  
 
3.1 
Eligible Patients  
 
3.11 
Patients who meet F.I.G.O. Stage I, II, or III criteria (See Appendix I-
F.I.G.O. Staging Criteria) for low-risk gestational trophoblastic neoplasia 
(GTN): post molar GTN or choriocarcinoma (as defined below).  Patients 
may have had a second curettage but must still meet GTN criteria below. 
 
3.111   Post Molar GTN 
For the purposes of this study, patients must have undergone 
evacuation of a complete or partial hydatidiform mole and then meet 
the criteria for GTN defined as:  
 
3.1111  A < 10% decrease in the hCG level using as a reference the 
first value in the series of 4 values taken over a period of 
3weeks  (>50 mIU/ml minimum). 
 
OR  
3.1112 A > 20% sustained rise in the hCG taking as a reference the 
first value in the series of 3 values taken over a period of 
2weeks  (>50 mIU/ml minimum). 
 
OR 
3.1113 A persistently elevated hCG level a period of  6 months or 
more following the initial curettage (>50 mIU/ml minimum).  
  
3.112   Choriocarcinoma 
 
3.1121 Histologically proven non-metastatic choriocarcinoma.  
 
 
OR  
3.1122 Histologically proven metastatic choriocarcinoma if the 
metastatic site(s) is restricted to one (or more) of the 
following: vagina, parametrium, or lung. 
 
 
3.12 
W.H.O. risk score 0-6 (See Appendix II-W.H.O. Risk Scoring Criteria). 
 
3.13 
Patients must be willing to practice effective contraception for the duration 
of the study.
 
3.14 
Patients must have normal hepatic, hematologic, and renal function: 
 
WBC ≥ 3,000 cells/mcl;  
Granulocytes ≥ 1500/mcl;  
Platelets ≥ 100,000/mcl;  
Creatinine ≤ 2.0 mg/dcl; Bilirubin ≤ 1.5x institutional normal;  
ALT, AST and alkaline phosphatase ≤ 3x institutional normal. 
 
3.15 
Patients who have met the pre-entry requirements specified in Section 7.0. 
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NCI Protocol #: GOG-0275 
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3.16 
Before enrolling a patient, the institution must verify the availability of an 
adequate supply of methotrexate for a full course of therapy. 
 
3.17 
Patients must have signed an approved informed consent and authorization 
permitting release of personal health information. 
 
3.18 
Patients must be 18 years of age and older. 
 
3.2 
Ineligible Patients  
 
3.21 
Patients who do not have GTN as defined in Section 3.11. 
 
3.22 
Patients with non-gestational choriocarcinoma. 
 
3.23 
Patients who have previously been treated with cytotoxic chemotherapy. 
However, patients who received prior low-dose methotrexate for treatment 
of an ectopic pregnancy will be eligible for this study. 
  
3.24 
Patients who have received prior pelvic radiation. 
 
3.25 
Patients with placental site trophoblastic tumor (PSTT) or epithelioid 
trophoblastic tumor (ETT). 
 
3.26 
Patients with GOG Performance status of 3 or 4. 
 
3.27 
Patients with a history of other invasive malignancies, with the exception 
of non-melanoma skin cancer, are excluded if there is any evidence of 
other malignancy being present within the last five years.  Patients are also 
excluded if their previous cancer treatment contraindicates this protocol 
therapy. 
 
3.28 
Patients whose circumstances at the time of study entry do not permit 
completion of the study or required follow-up.  
 
3.29 
Patients who wish to breast-feed during treatment. 
 
 
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NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
4.0 
STUDY MODALITIES   
 
4.1 
Actinomycin-D 
 
4.11 
Other Names:  DACTINomycin, DACT, or ACT-D, Cosmegen® 
 
4.12 
Description:  Injection of actinomycin-D is a lyophilized powder.  In the 
dry form, the compound is an amorphous yellow to orange powder.  
Injection of actinomycin-D is supplied in vials containing 0.5mg (500 
micrograms) of actinomycin-D and 20.0mg of mannitol. 
 
4.13   How Supplied:  Commercially available. 
 
4.14 
Storage and Stability:  Protect from light.  Store in a dry place between 200 
to 250 C (680 to 770 F) (86°F).  Cosmegen® (actinomycin-D for injection) 
has been found to maintain full activity for 24 hours, when stored both at 
room temperature or under refrigeration, if reconstituted as recommended.   
 
4.15 
Preparation:   Reconstitute actinomycin-D by adding 1.1 mL of sterile 
water for injection (without preservative) using aseptic precautions.  The 
resulting solution of actinomycin-D will contain approximately 500mcg or 
0.5mg per ml.  When reconstituted, the solution is clear and gold-colored. 
 
4.16 
Administration:  1.25 mg/m
2 (maximum dose 2mg) by slow IV push over 
15 minutes or institution standard (via running IV of 0.9NS with brisk 
blood return every 1/2mL).  Provide 75mL of 0.9NS flush prior to and 
after infusion.  If evidence of extravasation occurs during administration, 
the infusion should be stopped immediately and completed via another 
vein, preferably in opposite arm.  If extravasation is suspected, 
intermittent application of ice to the site for 15 minutes four times a day 
for 3 days is recommended. (03/11/2013) 
 
4.17     Adverse Effects:  Consult the package insert for the most current and 
complete information. 
 
4.2 
Methotrexate   
 
4.21    Other Names:  MTX, amethopterin 
 
4.22    Description:  Methotrexate is a folate antimetabolite.   
 
4.23    How Supplied:  Commercially available.  Injectable methotrexate is 
currently available in 25mg/mL injection in a 10mL vial. (03/11/2013) 
 
4.24  Storage and Stability: The drug will only be safe to use within 24 hours at 
room temperature. 
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NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
 
4.25 
Preparation:  
For IM administration, the methotrexate 25mg/mL is drawn up in a 
syringe with diluent. If necessary for patient comfort, the dose may be 
divided into two syringes. 
 
For IV administration, the methotrexate is prepared in a syringe with 
diluent of normal saline for a total volume of 5cc. 
 
4.26  Administration:  (11/24/2014) 
 
Intramuscular Administration:  Inject 50mg methotrexate deeply into the 
upper outer quadrant of the buttock or institution standard.  Aspirate prior 
to injection to avoid injection into a blood vessel. 
 
Intravenous administration:  0.4mg/kg methotrexate (maximum daily dose 
of 25mg) injected as a slow push via free-flowing IV infusion or via 25g 
butterfly needle with 3cc 0.9NS flush prior to and post administration of 
the drug with brisk blood return every 1cc or institution standard. 
 
4.27 
Adverse Effects: Consult the package insert for the most current and 
complete information.  
 
4.3 
Leucovorin  
 
4.31 
Other Names:  Calcium folinate, folinic acid, citrovorum factor, 5-formyl 
tetrahydrofolate 
 
4.32 
Description:  Leucovorin is a reduced folic acid.  Leucovorin is used in 
combination with other chemotherapy drugs to either enhance 
effectiveness, or as a “chemoprotectant”.  
 
4.33 
How Supplied:  Commercially available.  Tablet for oral administration in 
5 and 10 mg scored white tablets and also in 15 and 25mg scored yellow 
tablets. 
 
4.34 
Storage:  Store away from light, excess heat and moisture and at room 
temperature of 15°C to 30°C (59°F to 86°F). 
 
4.35  Administration:  This study will use oral administration of Leucovorin.  
Patients receiving IM methotrexate will be instructed to take Leucovorin 
PO between 24 -30 hours after the preceding injection. If a patient misses 
a dose of Leucovorin she should be instructed to take the pill as soon as 
she remembers it unless it is within 12 hours of the next scheduled 
methotrexate injection.  If it is 12 hours or closer to the next IM 
methotrexate injection, the patient should be instructed to skip that dose. 
 
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NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
4.36 
Adverse Effects:  Allergic reaction: rash, itching, facial flushing (rarely 
severe); Nausea and vomiting are rare.  Please consult the package insert 
for additional information 
 
4.4 
Pathology Requirements 
 
4.41 
Eligibility Criteria: Patients with histologically proven stage Stage I, II or 
III gestational trophoblastic disease (hydatidiform mole or 
choriocarcinoma) are eligible.  Patients with non-gestational 
choriocarcinoma, placental site trophoblastic tumor (PSTT) or epithelioid 
trophoblastic tumor (ETT) are not eligible. 
 
4.42 
Requirements:  Review of slides will be performed by the pathology 
committee at the semi-annual GOG business meetings.  Slides must be 
submitted to document the initial diagnosis of partial mole, complete 
hydatidiform mole, or choriocarcinoma.  If invasive or metastatic 
gestational trophoblastic disease is documented histologically, slides from 
those specimens must also be submitted for pathology committee review.  
Registration specimens will be classified histologically as either  
choriocarcinoma, partial mole or complete mole, if possible.  See Sections 
7.2 and 10.2 for additional instructions and requirements. 
 
 
 
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NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE     
 
5.1 
Registration Procedures (11/24/2014) 
 
 
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>. 
 
5.11 
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 
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>. 
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NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
 
5.12 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
5.121 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. 
 
5.122 Downloading Site Registration Documents:   
 
Site registration forms may be downloaded from the GOG-0275 
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. 
 
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 # 
0275 
Click on the Site Registration Documents link 
 
5.123 Requirements For GOG-0275 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 
 
 
 
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NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
5.124 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) 
 
5.125 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  
 
5.2 
Patient Entry and Registration (11/24/2014) 
 
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: 
  
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NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
• 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 
contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com.  
 
NOTE:  Each participating site must make a ONE TIME declaration of the 
methotrexate administration schedule to be used exclusively at their site. Prior to 
the registration of a site’s first patient, a representative must sign on to the GOG 
Web Menu and use the GOG methotrexate declaration application located under 
the Registration column. Sites will indicate the methotrexate administration 
schedule that will be used exclusively at the site for the duration of the study. The 
representative will choose the methotrexate schedule from a drop down list 
provided.  The site representative must be in the GOG roster with an active status at 
the site who is a DM1, DM2, PI1, or PI2.  The site must have approved IRB status to 
make the declaration.  Once a site registers their first patient, they will no longer be 
able to change the selected methotrexate administration schedule.  This schedule 
must be used for all other patients put on this study. (03/11/2013) 
 
 
 
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NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
The methotrexate administration choices are as follows: 
 
IV methotrexate daily for 5 days. 
 
OR 
 
IM  methotrexate on days 1,3,5,7. 
 
5.3 
Treatment Plan 
 
One of two treatment regimens will be randomly allocated in equal proportions 
within strata.  The strata are determined by the following factors: 
 
 
Country where treatment is given (US, Canada, Japan, Korea, Australia, 
United Kingdom, etc.) 
 
Multi-day methotrexate regimen (8- or 5-day) used by the participating 
site as stated on the one time methotrexate declaration form.   
 
5.31 
Study Regimens 
 
Eligible, consented patients will be randomized to one of the following 
two study regimens: 
 
Regimen 1:  Patients will receive IV pulse actinomycin-D (1.25 mg/m2) 
once every 14 days.  Maximum dose is 2 mg.  
 
 
Regimen 2:  Patients will receive their institutional preference of either IV 
methotrexate (0.4mg/kg) daily for 5 days every 14 days with a maximum 
daily dose of 25 mg.  
OR 
IM methotrexate (50mg) on Days 1,3,5,7 (4 doses per cycle) with 
Leucovorin (15mg) orally on Days 2, 4, 6, 8 within 24-30 hours of the 
preceding day’s injection.  Repeated every 14 days.    
 
Leucovorin Administration 
 
 
Patients receiving IM methotrexate will be instructed to take Leucovorin 
PO between 24 -30 hours after the preceding injection. If a patient misses 
a dose of Leucovorin she should be instructed to take the pill as soon as 
she remembers unless it is within 12 hours of the next scheduled 
methotrexate dose. If it is 12 hours or closer to the next IM methotrexate 
injection, the patient should be instructed to skip that dose. 
 
 
A medication calendar (Appendix IV) is provided for patients to record 
intake of Leucovorin. Completed calendars should be returned with empty 
bottles of drug. (03/11/2013) 
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NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
5.32 
Potential Drug Interactions 
 
 
It is anticipated that nausea and vomiting may be a side effect of both 
methotrexate and actinomycin-D.  Institutional guidelines for antiemetic 
administration should be followed.  It is suggested that NCCN guidelines 
be followed (see GOG-0275 webpage to download).  (03/11/2013) 
 
Supplements with a high folic acid level should not be taken while on 
study. 
 
In addition, patients should be advised to avoid taking NSAIDS while on 
treatment with methotrexate and to discuss with their physician.  
 
Use of sunscreen should be advised for all study patients as actinomycin-
D and methotrexate can cause skin reactions when exposed to sun.  
 
5.33 
Treatment Schedule 
 
A Cycle is 14 days.  The patient must receive her first cycle of treatment 
within 2 weeks of entry onto the study. 
 
 
A call (by site staff) will be placed to the patient prior to every other 
treatment cycle to (1) assess toxicity and (2) encourage compliance.   
 
 
Patients will be treated for three cycles after hCG<5mIU/ml or until 
evidence of treatment failure (biologic progression), disease progression 
or unacceptable toxicity despite dose modifications.  Upon normalization 
of hCG (<5mIU/ml), patients will be treated with three additional cycles.  
HCG levels will then be monitored every 4 weeks beginning with the 1st 
day of the last chemotherapy cycle, for the next 52 weeks to complete one 
full year of follow up.  QOL questionnaires are to be completed by all 
patients at 26 weeks.     
 
Patients will be treated for a maximum of 20 cycles if hCG remains 
elevated (above 5mIU/ml). (05/28/2013) 
 
5.34 
 Doppler Ultrasound to Measure UAPI 
 
At the time of the baseline pelvic ultrasound, centers participating in the 
optional UAPI component of the study should use Doppler ultrasound  to 
measure the left and right uterine artery pulsatility indices (UAPI).  UAPI 
can be calculated automatically by most machines using the autotrace 
functionality.  The PI value is calculated by the machine and appears on 
the report. 
 
A representative sample of 3 cardiac cycles (pulses) should be measured 
for the left artery as close to the uterus as possible.  Perform this 
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NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
measurement three separate times and record the lowest of the three PI 
values on the Pelvic Ultrasound GTN (PUG) form. Repeat this same 
process for the right uterine artery, recording the lowest PI value on the 
PUG. 
 
If Doppler ultrasonography is performed but the UAPI is not recorded, 
please mark “not specified” on the report.  If your site does not have 
access to Doppler ultrasonography, please record “not done” on the Pelvic 
Ultrasound Measurements Report. 
 
5.4 
Criteria for Removal from Treatment 
 
5.41 
Inability to tolerate the lowest dose because of toxicity (e.g., inability to 
tolerate the allocated treatment due to repeated grade 4 toxicity that does 
not respond to supportive measures). 
 
5.42 
Treatment failure (biologic progression) or disease progression that is 
defined in Section 8. 
 
5.43 
Treatment non-compliance that is defined to be less than 75% of planned 
or protocol-modified dose over 3 cycles. 
 
5.44 
Patients may refuse further intervention or completely withdraw consent 
from the study at any time for any reason.  If a patient elects to discontinue 
further study treatment and/or intervention prior to protocol specification 
and elects to receive alternate therapy, this information should be 
specifically documented as consent allows.  Additionally, if the patient 
withdraws from the treatment portion of the study, hCG levels should still 
be obtained per protocol schedule. 
 
5.45 
Pregnancy 
 
5.5 
Quality of Life Assessment 
 
Quality of Life surveys are to be obtained at 5 time points: 
 
Prior to cycle 1 
 
Prior to cycle 3 (If off study therapy, 4 weeks after starting study 
treatment) 
 
Prior to cycle 5 (If off study therapy, 8 weeks after starting study 
treatment) 
 
Prior to cycle 7 (If off study therapy, 12 weeks after starting study 
treatment) 
 
26 weeks after starting study treatment 
 
See Section 8.5 for complete overview of QOL study survey. 
 
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NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
6.0 
TREATMENT MODIFICATIONS    
 
6.1    Any patient whose treatment is delayed must be evaluated on a weekly basis until 
adequate hematologic and non-hematologic parameters have been met.  No dose 
escalation above the starting dose will be employed for either drug.  
 
6.2  
The maximum permitted dose of actinomycin–D will be 2 mg per cycle.  The 
maximum permitted dose of daily IV methotrexate will be 25mg per day. 
(03/11/2013) 
 
6.3 
Dose Modifications (05/28/2013) 
 
 
Study Drug  
2 Level reduction 
1 Level reduction 
Initial dose level 
 
Actinomycin-D  
0.75mg/m2 
1.0mg/m2 
1.25mg/m2 
Actinomycin-D for 
patients who are 
receiving the 
maximum dose (2mg) 
due to BSA 
1.28mg 
1.6mg 
2.0mg 
IV Methotrexate 
(0.4mg /kg) 
3 days only 
4 days only 
Daily for 5 days 
IM Methotrexate 
(50mg) 
Leucovorin 
 (15mg) 
Discontinue  
study treatment 
Increase Leucovorin 
dose to 30mg. 
50mg 
 
6.4 
Hematologic Toxicities  
 
6.41  Myelosuppression as demonstrated by pretreatment counts:  
 
6.411  Treatment will be delayed for 1week if the following parameters 
are not met on the day 1 of each cycle: 
   
Granulocytes ≥ 1500 cells/mcl and platelets ≥ 100,000/mcl 
 
If any course is delayed more than two weeks from the scheduled 
administration date, the dose of the start of the next cycle will be 
decreased by one dose level. 
  
6.412  In the event that a patient experiences Grade 4 myelosuppression, 
G-CSF may be used at the discretion of the investigator.  However, 
its use, including the duration and timing of administration and 
dosage, must be documented on Form D2R.  
 
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NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
6.5 
Gastrointestinal and Other Toxicities  
 
6.51  Nausea and emesis:  
 
6.511   Nausea and emesis are anticipated with all regimens but are not 
expected to be incapacitating.  Reassessment of IV and oral 
antiemetics for appropriate adjustments should be considered.  
Please refer to the NCCN guidelines (on the GOG-0275 webpage) 
for supportive care guidelines. (03/11/2013) 
 
6.512   No dose adjustment is to be made for nausea and emesis. 
 
6.513   Treatment will be delayed for Grade 3 toxicity until resolution to 
            Grade 2 or less is reached.  Protocol treatment will be discontinued 
for Grade 4 toxicity. 
    
6.52  Stomatitis and other GI, renal or hepatic toxicities:  
 
6.521 If a patient experiences Grade 2 stomatitis, treatment will be 
delayed until resolution to Grade 1.  Grade 3 stomatitis will 
require a one dose level reduction at the start of the next cycle 
once resolution to Grade 1 is reached.  Protocol treatment will be 
discontinued for Grade 4 stomatitis. 
 
6.522  Treatment will be delayed for Grade 3 gastrointestinal, renal or 
hepatic toxicity until resolution to Grade 2 or less is reached.  
Protocol treatment will be discontinued for Grade 4 toxicity  
 
6.53 
Pleuritis: 
 
6.531 For Grade 3 pleuritis, hold treatment until resolution to Grade 2 or 
lower. 
   
6.532 For Grade 4 toxicity the patient will be taken off study treatment.  
 
6.54 
Potential modifications for other non-hematologic toxicities not listed, 
with an impact on organ function of Grade 3 (or greater) require 
discussion with one of the study chairs. 
 
Applicable to all toxicities, study treatment should be discontinued if 
treatment is delayed longer than 2 weeks. 
 
 
 
 
 
- 26 - 


NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
7.0 
STUDY PARAMETERS   
 
7.1 
Observations and Tests 
The following observations and tests are to be performed and recorded on the 
appropriate form(s): 
 
 
Parameter 
 
 
Prior to 
Study 
Entry 
Prior 
to 
Each 
Cycle   
 
Prior to 
Every 
Other 
Cycle 
Following 
Completion of 
Treatment 
Weeks 1-26 
(Months 1-6)  
(03/11/2013) 
Following 
Completion of 
Treatment 
Beginning 
Week   
27 
(Month 7)  
(03/11/2013) 
At Diagnosis 
of Disease 
Progression or 
Treatment 
Failure 
(biologic 
progression) 
and Follow-up 
(03/11/2013) 
History & Physical,  
including concomitant 
medication tracking 
 
1 
 
X 
 
 
2 
 
 
X 
Pelvic Exam 
1 
 
 
 
 
 
 
CBC/Differential/Platelets 
 
 
3 
 
X 
 
 
 
 
X 
hCG Test 
3 
X 
 
4 
4 
X 
Serum chemistry 
(total bilirubin, creatinine,  
alkaline phosphate, 
SGOT(AST), 
SGPT(ALT), sodium, 
potassium, albumin, 
glucose,  BUN) 
 
3 
 
9 
 
 
 
 
 
X 
 
LDH 
 
10 
 
 
 
 
 
 
Toxicity Assessment 
 
1 
 
X, 7 
 
 
 
 
X 
 
Calculate WHO Score 
 
1 
 
 
 
 
 
X 
 
FIGO Staging 
 
1 
 
 
 
 
 
X 
 
Pelvic Ultrasound 
 
1,11 
 
 
 
 
 
X 
 
CXR for WHO Scoring 
 
1 
 
 
 
 
 
X 
CT or MRI of the brain, if 
abnormal CXR or if 
clinically indicated 
 
1 
 
 
 
 
 
X 
- 27 - 


NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
 
1. Must be obtained with 28 days prior to initiating protocol therapy. If the pelvic exam is abnormal, it 
should be repeated as needed. 
2. For patients who have responded to treatment; must be obtained  at 3 months and 6 months after 
completing treatment (week 12 and week 24) (+/- 7 days). (03/11/2013) 
3. Must be obtained with 14 days prior to initiating protocol therapy. 
4. For patients who have responded to treatment; must be obtained every 4 weeks (or monthly +/- 3 days) 
for 1 year after completing treatment. (03/11/2013) 
5. Prior to cycle 1, 3, 5, 7 and at 26 weeks (refer to section 7.42  if  pt off chemotherapy treatment) 
6. Call will be made if pt misses treatment or follow-up visit. 
7. 2-4 weeks after last cycle of study treatment. 
8. For patients discontinuing treatment due to treatment failure (biologic progression), disease progression, 
or unacceptable toxicity, report disease status, survival status and pregnancy status/outcome quarterly 
via the Q form for a period ending 2 years after study entry. (03/11/2013) 
9. Prior to cycle 1, 3, 5, and 7. 
10. Must be obtained within 14 days prior to study entry and if abnormal, repeat prior to each cycle. 
11. Doppler ultrasonography (optional sub-study) of both the left and right uterine arteries should be 
performed at the time of the pelvic ultrasound, to determine the uterine artery pulsatility index (UAPI). 
This is automatically calculated and should be included in the ultrasound report (see section 5.24). 
12. For patients who have responded to treatment, report disease status, survival status and pregnancy 
status/outcome quarterly via the Q form for a period ending 2 years after study entry.  (03/11/2013) 
 
7.2 
Stained Pathology Slide Requirements for Central Review to Confirm Eligibility:  
 
H&E stained glass slides to document the following: 1) the initial diagnosis of 
gestational trophoblastic disease (all patients) and 2) any invasive or metastatic 
tumor that is histologically proven. 
 
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).  Do not label 
with 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.  Ship pathology slides, 
two 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, 
Roswell Park Cancer Institute, Research Studies Center, Carlton and Elm Streets, 
Buffalo, New York, 14263; phone (716) 845-5702.  The GOG Upload 
Application in SEDES is an alternative method for submitting pathology reports 
and Form F.  Please see sections 4.4 and 10.2 for additional requirements. 
Follow-up phone call by 
site staff 
 
 
 
X 
 
6 
 
6 
 
QOL Assessments 
(FACT-G and FACIT) 
 
3 
 
5 
 
 
5 
 
 
5 
Report subsequent   
 treatment and outcome  
 
 
 
 
12 
(03/11/2013) 
 
12 
(03/11/2013) 
8 
 
- 28 - 


NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
 
7.3 
Translational Research 
 
Not Applicable 
 
7.4 
Quality of Life 
 
7.41 
Refer to sections 5.4; 7.1; 7.42; 8.6 and 10.2 for description and collection 
times of the QOL study assessments. 
 
7.42 
Timing of the Quality of Life Assessments 
 
To measure the difference in QOL following initiation of treatment on this 
study, the following time points for QOL assessments are planned:  
 
7.421 At baseline (prior to cycle 1) 
7.422 Prior to cycle 3 (4 weeks after starting study treatment if off study 
treatment prior to cycle 3) 
7.423 Prior to cycle 5 (8 weeks after starting study treatment if off study 
treatment prior to cycle 5) 
7.424 Prior to cycle 7 (12 weeks after starting study treatment if off study 
treatment prior to cycle 7) 
7.425 26 weeks after the start of study treatment.  
  
  
While still on study treatment, assessments will be completed as planned 
at initial treatment visits for appropriate cycles prior to obtaining 
knowledge of hCG value changes or treatment changes.   
 
7.43     Quality of life forms will be provided by the SDC upon request.  Requests 
for non-English versions should be made to the Statistical and Data 
Center.   
 
7.44     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.   
  
7.45     The Quality of Life Liaison (GOG Nurse/Data Manager) at each 
institution has overall responsibility for the administration of the study 
questionnaire. 
  
7.46     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 
- 29 - 


NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
questionnaire is confidential and will not be shared with the health care 
team, and that it will not become part of the medical record. 
  
7.47     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.   
  
7.48     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.   
  
7.49     Review the questionnaire for completeness before the patient leaves.   
  
7.491   If the patient has marked more than one answer per question, ask 
the patient which answer best reflects how she is feeling.    
  
7.492   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.   
  
7.410   It is essential that the questionnaires be completed according to the 
schedule described in Section 7.42.   
  
7.411   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.   
  
7.412   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 
 
 
- 30 - 


NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
8.0 
EVALUATION CRITERIA  
 
8.1 
Evaluability 
 
8.11 
Patients evaluable for response are those who have received one or more 
cycles of drug and have a sufficient number of bi-weekly test results to 
fulfill one of the response categories. 
 
8.12 
Patients are evaluable for assessment of adverse effects (toxicity) if they 
have received a minimum of one injection or infusion of treatment. 
 
8.2. 
Clinically Assessed Response 
 
 
 
Institutional hCG test results will be used to define the dichotomous primary 
clinical response measure and to evaluate the primary objective.  Reporting 
should be in terms of the best response achieved in a given case. 
 
8.21 
Complete Response will be defined as 3 consecutive bi-weekly values of 
hCG<5 over a minimum of 4 weeks of normal hCG values with no values 
greater than 5 mIU/ml on the BMR form.  Report best response as 
“Complete Response” on Form Q0 per Section 10.2  
 
8.22 
Treatment Failure (biologic progression) is defined as: 
 
8.221  A < 10% decrease in the hCG levels using as a reference first value 
in the series of 4 values taken over at least a 3-week period.  
 
 
OR  
 
8.222  A > 20% sustained rise in the hCG taking as a reference the first 
value in the series of 3 values taken over at least a 2-week period.  
 
OR  
 
8.223  Two consecutive hCG levels above 5 mIU/ml after the institutional 
normal has been reached taken at least one week apart. 
  
OR  
 
8.224 hCG levels remain elevated above 5 mIU/ml after 20 cycles of 
treatment. (05/28/2013) 
 
OR 
 
8.225  New metastatic disease based on either clinical findings or 
radiologic Investigations while on study treatment or during the 
follow-up period. 
 
If any of the criteria in 8.221-8.225 are met then report “Biologic 
Progression” as best response on Form Q0.   
- 31 - 


NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
 
8.23  Persistent disease is defined as 4 consecutive hCG values over 6 weeks 
that fluctuate within the range of 5 to 50 mIU/ml.  Special consideration is 
required for patients with persistent hCG levels as this may not reflect 
treatment failure. For patients that develop persistent disease with less 
than 50 IU/ml, steps need to be taken to rule out false positive hCG, 
quiescent hCG, or phantom hCG. You should contact the study chair for 
discussion.  
  
8.3 
Disease Progression is defined as new metastatic disease findings from clinical or 
radiological investigations or a sustained elevation in hCG levels above 5 mIU/ml 
after documentation of a complete response (two consecutive levels above 
5mIU/ml taken at least one week apart).   
 
8.4 
Other Objective Parameters  
 
8.41  A cycle is defined as planned treatment for a period of 14 days.  
 
8.42  The major toxicities of each regimen will be collected and compared using 
standard CTCAE version 4.0 toxicity criteria. 
 
8.5  
Quality of Life Assessments 
 
 
 
The measures selected to comprise the Quality of Life assessment will include: 1) 
an overall quality of life measure addressing: physical symptoms, functional well-
being, social well-being and emotional well-being, 2) supplemental items drawn 
from the FACIT scales addressing additional domains based on the GTN 
literature regarding potential toxicities, side-effects and treatment issues that can 
impact QOL and 3) two exploratory items about treatment factors.  The QOL 
assessment will be administered at medical appointments and take approximately 
15 to 20 minutes. 
 
8.51 
The Functional Assessment of Cancer Therapy (FACT-G) will be used to 
measure overall quality of life.  The FACT-G is a 27-item scale measuring 
QOL in patients with cancer.25 It includes four subscales: 1) physical 
well-being {FACT-PW subscale} with 7 items  (a=.82) - e.g., I have lack 
of energy; 2) functional well-being {FACT-FW subscale} with 7 items 
(a=.80), - e.g., I am able to work; 3) social well-being {FACT-SW 
subscale} with 7 items (a=.69) - e.g., I feel close to my friends; and 4) 
emotional well-being {FACT-EW subscale} with 6 items (a=.74) - e.g., I 
feel sad.  The total alpha coefficient is.89, supported by factor analysis.  
Participants rate on a 5-point Likert-type scale (0=not at all; 1=a little bit; 
2=somewhat; 3=quite a bit; 4=very much).  The subscales are summed for 
a total score ranging from 0-108, and a higher score  indicates better QOL.  
The mean in a population of mixed cancer patients was 82.06 +/- 15.86.  
The FACT-G is available in multiple languages. 
- 32 - 


NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
 
8.52 
FACIT Supplemental Items: have been added to the QOL assessment 
based on a review of previous GTD/ GTN studies and identified toxicities 
and side effects from actinomycin-D and methotrexate noted in the 
literature.  As the FACIT items are available in multiple languages, 
specific items were selected from the FACT disease specific subscales 
addressing potential factors that may influence the QOL of GTN patients 
undergoing chemotherapy treatment.  Three items from FACT-N 
(Neutropenia) addressing blood counts, energy and mouth sores; Three 
items from the FACT-O (ovarian) addressing hair loss, appearance; Three 
items from FACT-Cx (cervical) addressing body image & sexual function 
and two from FACT-En (endometrial) addressing fatigue and gyn concern 
(pain).  These items are also available in multiple languages. 
 
 
 
8.53 
Two exploratory items were created specific to treatment concerns: 1) 
Likert scale evaluation degree of life disruption from chemotherapy 
treatment and 2) rank item addressing factors associated with 
chemotherapy treatment (e.g. requirement per week and length of time per 
treatment).  These will be available for an exploratory analysis in English 
speaking patients. 
 
- 33 - 


NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
9.0 
DURATION OF STUDY    
 
 
Patients will be treated for three cycles after hCG <5mIU/ml or treatment failure 
(biologic progression), disease progression or unacceptable toxicity despite dose 
modifications.  All subjects will be followed for a period ending 2 years after study entry.  
Quality of life will be assessed for all study patients at 26 weeks from the start of 
treatment, regardless of treatment status.  
  
NOTE:  The Q0 form is due at treatment completion (See Section 10.2).  The Q form is 
due quarterly during the follow-up period.  HCG values will be reported every 4 weeks 
on the BMR form. 
 
 
- 34 - 


NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
10.0 
STUDY MONITORING AND REPORTING PROCEDURES   
 
10.1 
ADVERSE EVENT REPORTING FOR A COMMERCIAL AGENT 
(11/24/2014) 
   
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.  
 
The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have 
access to a copy of the CTCAE version 4.0.  A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov).  The CTCAE v4.0 Manual is also available on the 
GOG member web site (http://www.gog.org under MANUALS). 
 
10.12 Reporting Expedited Adverse Events 
 
Depending on the phase of the study, use of investigational or commercial 
agents, and 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 before final submission to CTEP-AERS.  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 signing the 
FDA-1572, the investigator assumes the responsibility for reporting AEs 
to the NCI.  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  
 
- 35 - 


NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
Reporting Requirements for Adverse Events that occur within 30 Days¹ of the Last Dose of the 
Commercial Agent on Phase 2 and 3 Trials 
 
 
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 aCTEP-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-
AERS within 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 
attribution and designation as expected or unexpected with the exception of any 
events identified as protocol-specific expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported to GOG via CTEP-AERS if the event occurs 
following treatment with a commercial agent. 
 
 
- 36 - 


NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited 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 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. 
 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made to GOG by telephone at: 215-854-0770.  
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. 
 
 
- 37 - 


NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
10.2  GOG DATA MANAGEMENT FORMS 
 
The following GOG forms must be completed for all patients registered and 
submitted to the GOG Statistical and Data Center (SDC) in accordance with the 
schedule below.  GOG 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.  Pathology material (Form F, pathology reports and slides) should be 
submitted together via mail.  The GOG Uploader Application in SEDES is an 
alternate method for submitting Form BDR, operative reports, Form F and 
pathology reports to the GOG SDC.  
Form∆ 
Due within 
Copies* 
Comments 
Weeks 
Event 
Form R (Registration Form) 
Form SCT - entry (WHO 
Scoring Form for GTT) 
2 
2 
 
Registration 
Registration 
 
N/A 
N/A 
 
Mandatory Submission 
via SEDES 
Form OST (Trophoblastic On 
Study Form) 
Form PUG (Pelvic Ultrasound 
GTN Form) 
2 
 
      2 
Registration 
 
Registration  
N/A  
Mandatory Submission 
via SEDES 
Ultrasound Report 
Chest X-ray Report 
Brain MRI or CT Report, if 
lung mets or clinically indicated 
4 
4 
4 
Registration 
Registration 
Registration 
1 
1 
1 
Submit via postal mail or 
upload online via 
SEDES labeled with 
patient identifier 
Operative report – initial 
curettage  
Operative report – second 
curettage, if applicable  
6 
6 
 
Registration 
Registration 
 
1 
1 
 
Submit via postal mail 
or upload online via 
SEDES labeled with 
patient identifier 
Pathology Material 
Initial curettage (all patients) 
and invasive/metastatic tumor 
(if histologically documented): 
Form F (Pathology Form) 
Pathology Report 
Slides  
 
 
 
 
6 
6 
6 
 
 
 
 
Registration 
Registration 
Registration 
 
 
 
 
2 
2 
** 
 
 
 
 
Submit together to SDC 
via postal mail 
 or upload online via 
SEDES** 
Form BMR (Biomarker 
Reporting Form) report 
required hCG values during 
treatment 
2 
Every 4 weeks 
 
N/A 
Mandatory Submission 
via SEDES 
Form BMR (Biomarker 
Reporting Form) report 
required hCG values during 
follow-up period 
2 
Every 4 weeks 
N/A  
Mandatory Submission 
via SEDES 
QOL Scantron Form*** 
Scantron Form prior to cycle 1 
Scantron Form prior to cycle 3 
Scantron Form prior to cycle 5 
Scantron Form prior to cycle 7 
Scantron Form for week 26 
 
2 
6 
10 
14 
28 
 
Treatment start 
Treatment start 
Treatment start 
Treatment start 
Treatment start 
 
1 
1 
1 
1 
1 
 
Submit the original 
Scantron form to the 
GOG SDC via postal 
mail 
- 38 - 


NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
Form D2R (Cycle Dose Drug 
Form) 
2 
Completion of each 
cycle of therapy 
N/A  
Mandatory Submission 
via SEDES 
Form T (Common Toxicity 
Reporting Form) 
2 
Beginning of each 
subsequent cycle 
N/A 
Mandatory Submission 
via SEDES 
Form SCT – treatment failure 
(WHO Scoring form for GTT) 
4 
Completion of study 
treatment 
N/A  
 
Mandatory Submission 
via SEDES 
Ultrasound Report 
 
Chest X-ray Report 
 
4 
 
4 
Treatment Failure  
 
Treatment Failure  
1 
 
1 
Submit via postal mail or 
upload online via 
SEDES labeled with 
patient identifier  
Form Q0 (Treatment 
Completion Form) 
2 
Completion of study 
treatment 
N/A  
Mandatory Submission 
via SEDES 
Form Q (Follow-Up Form) 
 
2 
Disease progression, 
death, normal follow-up  
N/A  
Quarterly for 2years 
 
* 
The number of required copies including the original form that must be sent to the Statistical and Data Center. 
** 
At least one representative H&E stained slide (or slides) documenting the initial diagnosis of gestational 
trophoblastic disease and any invasive or metastatic tumor that is histologically proven.  Please see sections 
4.4 and 7.2 for additional requirements and instructions.    
*** Quality of life Scantron forms may be ordered online via the GOG website under GOG Web 
Menu/Tools/Order forms.    
 
This study will be monitored by the Abbreviated Clinical Data System (CDUS) Version 3.0 
CDUS data will be submitted quarterly by the January 31, April 30, July 31 and October 31 due 
dates to CTEP by electronic means. 
 
 
 
- 39 - 


NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
11.0 
STATISTICAL CONSIDERATIONS   
 
11.1 
Study Design and Treatment Randomization: 
This study is designed as a two arm randomized phase III non-inferiority trial 
with a control arm using actinomycin-D (ACT-D) and an experimental arm using 
one of two multi-day methotrexate (MTX) regimen chosen by the participating 
site.  The design will provide a direct assessment of the null hypothesis that the 
efficacy attributed to multi-day methotrexate regimens is inferior to that of ACT -
D given every two weeks.  Each IRB-approved participating site will declare 
upfront which MTX regimen they will use for the duration of the trial.   
 
 
Prior to patient registration, eligibility will be reviewed by FFS verification.  The 
sequence of treatment assignments will be concealed from institutions and 
patients until registration with verification of eligibility.  Patients will be 
registered by the participating site through OPEN and randomization will be 
carried out centrally by the GOG Statistical and Data Center.  The randomization 
will be stratified by the country (a surrogate for health care system) where 
treatment is given and the multi-day methotrexate regimen to be used by the 
institution using a minimization procedure that tends to allocate two study arms in 
a ratio of 1 to 1 within strata. 
 
11.2 
Efficacy and toxicity measures                                                                                      
The principal observations for evaluating the therapeutic efficacy and safety of 
treatments are listed below (see Section 8 for definitions). 
 
11.21 Primary efficacy endpoint:  complete response vs, treatment failure 
 
11.22 Safety endpoints:  severity of adverse events 
 
11.23 Factors to be tested for association with treatment failure:  W.H.O. risk 
score, choriocarcinoma histology, uterine artery pulsatility index 
 
11.3 
Statistical study design and planned analyses of therapeutic efficacy 
 
11.31 Accrual goal: 384 patients 
The maximum target accrual includes an expected 5% of patients to be 
deemed ineligible after central review. 
 
11.32 Accrual rate: Originally, 80 patients per year was the expected accrual 
rate.  However during the first 3 years the accrual was much lower than 
anticipated.  Efforts to expand accrual to international sites were 
completed near the end of the third year of accrual.   
 
The following is a revised estimate of annual accrual rates over time.   
Year 1:  9 
Year 2:  14 
Year 3:  27  
Year 4+:  ≥ 60  
  
- 40 - 


NCI Protocol #: GOG-0275 
Version Date: 03/25/2015 
GOG accrual for protocol 174 averaged 31 patients per year.  We expected 
increased GOG site participation based on the flexibility in the 
experimental arm.  Assuming a 25% increase in accrual rate (40) from that 
observed on GOG 174 from GOG sites and additional accrual of 40 
patients per year from non-GOG sites that have expressed support for this 
study the expected annual accrual rate was 80 patients.  This accrual rate 
has been revised based on actual accrual through the first 2.5 years. (  ) 
 
11.33 Study duration: 60 months assuming an average annual accrual rate of 80.  
Assuming the revised accrual rates, the accrual duration is expected to be 
8.6 years or less.  A follow-up period of up to 6 months may be necessary 
to observe and report response in all patients.  Additional time may be 
necessary to obtain all required QOL assessments.  All required follow-up 
will end 24 months following the last enrollment.  (  ) 
 
11.34 Primary hypothesis 
The primary null hypothesis to be tested is that the complete response 
attributed to multi-day methotrexate treatment is inferior to that of 
actinomycin-D.  
 
 
H0:  pd - pm ≥ M1 vs. H1:  pd – pm < M1 
 
In this statistical representation of the primary hypothesis, pd represents the 
proportion of complete responses on ACT-D, pm represents the proportion 
of complete responses on multi-day methotrexate, and M1 represents the 
non-inferiority margin. 
 
11.341 Non-inferiority margin and effect of the active control: M1 = 0.05 
and pd = 0.70 
 
GOG 174, a randomized phase III clinical trial comparing weekly 
methotrexate to ACT-D, demonstrated a superior complete 
response rate to ACT-D over weekly methotrexate.  Hence, ACT-
D is considered the active control in this non-inferiority study.  The 
estimated difference in response rates was 0.15.  The response rate 
to ACT-D was 0.70.  The non-inferiority margin for this study is 
defined to be 0.05, 1/3 of the effect of ACT-D relative to weekly 
MTX.  
 
11.342 Type I error for non-inferiority:  0.05 
 
11.343 Type I error for superiority:  0.05 
 
11.344 Statistical power:  0.95 calculated under the alternative that pd = 
0.70 and pm = 0.80 
 
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NCI Protocol #: GOG-0275 
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11.35 Primary analysis 
This study design requires the assumption of a consistent effect size 
relative to ACT-D for both MTX regimens.  The statistical analysis plan 
will incorporate a stratified primary analysis comparing the binomial 
proportion of complete responses between the treatment arms among 
eligible patients.  A test of the difference in proportions responding will 
utilize a test statistic that does not pool the variance across treatment 
groups.  In the event that the null hypothesis of inferiority is rejected, a 
test of the superiority of the methotrexate regimen will be carried out and 
reported.  There will be approximately 80% power to detect an increase in 
response rate of 11% if the true response rate in the reference arm is 70%.  
Reports and publications will include a complete accounting of all patients 
registered to this study. 
 
Statistical test characteristics:  probabilities of accepting each regimen under different 
settings 
Methotrexate 
response 
pm 
ACT-D 
response 
Pd 
 
 
pd – pm 
P(accept MTX| pm, pd) 
P(accept ACT-D| pm, pd) 
0.80 
0.70 
-0.10 
0.95 
0.05 
0.70 
0.70 
0.00 
0.27 
0.73 
0.65 
0.70 
0.05 
0.05 
0.95 
 
 
U
n
d
e
r
 the null and alternative hypotheses, the average sample size is 277. 
 
11.351 Delta value to reject H0 at final analysis: pd – pm < -0.0252 
In this case, the observed response rate to methotrexate will need 
to be at least 2.52%  better than that of actinomycin-D at the final 
analysis to accept methotrexate with its associated intensive 
scheduling.   
 
11.352 Compliance monitoring: 
Compliance to protocol treatment will be monitored for early 
discontinuation or non-protocol based dose adjustments.  The total 
dose reported will be compared to the planned or protocol 
modified dose for each cycle. 
 
11.353 Exploratory analysis of treatment efficacy: 
An indirect comparison of the Multi-day regimens can be 
performed by assessing the relative effects across stratum of each 
methotrexate regimen against the control arm.  This would be 
Interim and final analysis plan details 
 
 
 
 
 
 
 
 
Boundary Crossing  
Look Info 
Sample 
Error Spent 
Boundaries 
Probabilities 
 
 # 
Fraction Size 
Alpha 
Beta 
H0+ 
H1+ 
H0+ 
H1+ 
 
1 
0.55 
201 
0.0082 
0.0082 
-2.399 0.071 
0.536   
0.536   
  
2 
1.00 
365 
0.0500 
0.0500 
-1.670 -1.670 
0.464   
0.464   
 
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considered an exploratory analysis and used to provide an 
approximate evaluation of the assumption of a constant effect size 
across multi-day regimens.   
 
11.36 Interim analysis 
An interim analysis plan is outlined above assuming the interim analysis 
occurs at exactly 55% of the information fraction.  The information 
fraction is estimated by the number of eligible patients evaluated for 
response at a given time divided by the target sample size of eligible 
patients.  However, the timing of the interim analyses will likely vary from 
this exact schedule for practical reasons.  At the interim analysis, the test 
statistic for the primary analysis will be compared with the critical 
boundaries defined by the statistical design parameters described above an 
O’Brien and Fleming alpha spending function as proposed by Lan and 
DeMets.  If a boundary is crossed, consideration will be given to 
terminating study accrual, if still active, and/or early release of data.  
Additional decisions may include recommendations on instructions for 
patients on study treatment. These rules are non-binding. 
 
The results of interim analyses are scheduled to be reviewed by the GOG 
Data Safety and Monitoring Board (DSMB) at its semi-annual meetings.  
This committee meets in January and July each year.  The precise dates for 
these meetings are set more than one year in advance by individuals who 
have no knowledge of efficacy results.  Approximately eight weeks prior 
to each of these meetings, the database is locked in order to prepare a 
progress report.  If the prerequisite number of patients evaluated for 
response has been attained, an interim analysis is also prepared and 
presented to the DSMB at their next scheduled meeting.  The decision to 
terminate accrual to any particular regimen includes consideration of 
adverse events, treatment compliance and results from external studies.  
Additionally, the GOG Safety Review Committee (SRC) reviews 
accumulating summaries of toxicities and all serious adverse event (SAE) 
reports on an ongoing basis (not efficacy results).  This committee also 
reviews those deaths in which the study treatment may have been a 
contributing cause.  The SRC reports to the DSMB and may recommend 
study amendments pertaining to patient safety. 
 
11.361 Delta value to reject H0: pd – pm < -0.0957; that is, pm is at least 
9.57% greater than pd. 
 
11.362 Delta value to reject H1: pd – pm >0.0457; that is, pm is at least 
4.57% less than pd. 
 
11.4 
Safety analyses 
Patients adverse events will be captured by individual adverse event terms and 
grade defined by the NCI Common Terminology Criteria for Adverse Events 
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version 4.  The maximum grade of any adverse event observed during active 
treatment period or within 4 weeks of completing study treatment for each eligible 
patient will be tabulated.  The proportion of patients with a serious adverse event 
or reported Grade 3 or worse adverse event, regardless of attribution, will be 
compared between the treatment regimens using a chi-square test.  Additionally, 
the frequency of any hospitalization while on study therapy, frequency of early 
study treatment discontinuation not due to complete response or treatment failure, 
number of patients who receive non-protocol therapy and number of patients who 
receive non-protocol multi-agent chemotherapy. 
 
11.5 
Quality of life analyses 
The QOL objective for this study is to measure the difference in QOL between 
patients in each randomized study arms.  The FACT-G scale will be used to 
measure the overall QOL and is considered the primary QOL endpoint.  The 
FACIT supplemental items will be used to measure treatment-related symptoms.  
Analysis of the FACIT supplemental items and treatment disruption will be 
treated as exploratory.   
 
The QOL assessment time points are scheduled with the intention to achieve 
maximum compliance; however, there is still a possibility of noncompliance 
especially for patients whose disease does not respond to study treatments.  These 
patients might seek other therapies that might interfere with their compliance to 
the QOL assessments.  In GOG #174, treatment with actinomycin-D was 
discontinued due to lack of response in about 5% of patients before 2 cycles of 
treatment ; another 14% before cycle 4 and 7% before cycle 6.  Thus we expect 
90% eligible patients will complete QOL assessment at 2nd assessment (prior to 
cycle 3), 80% at the 3rd assessment (prior to cycle 5), and 70% at the 4th 
assessment (prior to cycle 7).  With a sample size of 365 eligible patients, this 
study will achieve at least 88% statistical power to detect an effect size of 0.4 at a 
significance level of 5% using a two-sided two-sample test.  Assuming the 
standard deviation of the FACT-G score is 15.86 in both groups, an effect size of 
0.4 corresponds to a difference of 6.3 points between the two groups, which is 
considered clinically important (MID)26.  The statistical power could be higher 
than estimated if the correlations among the repeated measures are taken into 
account.  A linear mixed model that accounts for the correlation among the 
repeated measures will be fitted for the FACT-G score adjusting for baseline 
score and other covariates.  The patient-reported symptom measurement scores 
and treatment disruption on QOL will be summarized by treatment arms with the 
estimated means for continuous variables or frequency tables for categorical 
variables accompanied with 95% confidence intervals. 
 
The 6 month follow-up assessment will be considered non-definitive since at that 
time point the QOL will likely capture a mixture of effects not directly related to 
the study therapy, e.g. patients whose disease does not respond will be treated 
with surgery, single agent and/or multiple agent chemotherapy; some 
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NCI Protocol #: GOG-0275 
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reproductive-aged patients may get pregnant; or study treatment may continue for 
26 weeks. 
 
11.6 
Uterine Artery Pulsatility Index Analysis 
Investigators at Charing Cross Hospital have assessed the association of uterine 
artery pulsatility index with resistance to single agent methotrexate treatment and 
reported that patients with persistent GTN, FIGO score 0-6, treated with 
methotrexate and UAPI≤1 had increased risk of treatment resistance regardless of 
FIGO score (referred to as WHO score in this protocol) and this increased risk 
was more pronounced in patients with a score of 6.27, 28  In this study, the analysis 
of UAPI will focus initially on testing the statistical significance of UAPI (values 
≤ 1 vs. > 1) and an interaction factor of UAPI and WHO score (UAPI ≤ 1 and 
WHO score = 6 vs. UAPI >1 or WHO score < 6).  In the two previous studies 
46%-51% of patients had a UAPI of ≤ 1 and 2-4% of patients had UAPI ≤ 1 and 
WHO score = 6.  Given the small proportion of patients with UAPI ≤ 1 and WHO 
score = 6, statistical power for inference on the coefficient for the interaction term 
will be extremely limited for moderate effects.  The model of treatment resistance 
will also include an indicator for treatment and a treatment by UAPI interaction 
term.  The main effect term for WHO score is not expected to be related to 
resistance in univariate analyses since the range of scores is generally associated 
with similar risks of resistance but it will be included in the model, nonetheless, 
when the UAPI/WHO score interaction term is included.  The treatment/UAPI 
interaction term will only be kept in the model if significant at the 20% level (two 
sided). 
 
Additional analyses will report predictiveness curves 34 (with observed risk for 
assessing calibration) for UAPI with and without the interaction term, functions of 
sensitivity, specificity and risk, risk distribution by treatment outcome, and AUC 
from ROC analysis.  These analyses will help to evaluate the predictive accuracy 
of UAPI when predicting resistance to standard single agent therapy.   
 
Measurement of UAPI in this study will be optional since it requires use of 
Doppler ultrasonography.  At this time the degree of participation in this 
component is unknown.  This study does not specify a priori a threshold of risk to 
determine recommendation for treatment with single versus multi-agent 
chemotherapy. Given the optional nature of this secondary objective, this study 
will not provide a final recommendation on how to incorporate UAPI into the 
current prognostic index, but will either confirm or refute its prognostic 
significance.   
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11.7 
Anticipated distribution of patients’ race and ethnicity (all are female) 
 
Ethnic Category 
% 
Hispanic or Latino 
58 
15 
Not Hispanic or Latino 
326 
85 
Ethnic Category: Total of all subjects 
384 
100 
Racial Category 
 
American Indian or Alaskan Native 
8 
2 
Asian 
46 
12 
Black or African American 
65 
17 
Native Hawaiian or other Pacific Islander 
4 
1 
White 
261 
68 
Racial Category: Total of all subjects 
384 
100 
 
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12.0 
BIBLIOGRAPHY   
 
1. Osborne RJ, Filiaci G, Schink JC, et al.  A phase III trial of weekly methotrexate or pulsed 
dactinomycin for low risk gestational trophoblastic neoplasia: A Gynecologic Oncology 
Group study.  J Clin Oncol.  2011;19:825-831. 
 
2. Lurain JR, Elfstand EP.  Single-agent methotrexate chemotherapy for treatment of 
nonmetastatic gestational trophoblastic tumors.  Am J Obstet Gynecol. 1995;172:574-579. 
 
3. Berkowitz RS, Goldstein DP, Bernstein MR.  Ten year’s experience with methotrexate and 
folinic acid as primary therapy for gestational trophoblastic disease.  Gynecol Oncol.  1986; 
23:111-118. 
 
4. Flam F, Magnusson C, Lundstrom-Lindstedt V, et al.  Psychosocial impact of persistent 
trophoblastic disease.  J Psychosom Obstet Gynaecol.  1993;14:241-248.   
 
5. Wenzel L, Berkowitz RS, Newlands E, et al.  Quality of life after gestational trophoblastic 
disease.  J Reprod Med. 2002; 47:387-394. 
 
6. Bower M, Rustin GJS, Newlands ES et al. Chemotherapy for gestational trophoblastic tumors 
hastens menopause by 3 years.  Eur J Ca. 1998:34:1204-1207. 
 
7.  Rustin GJ, Newlands EZ, Lutz JM, et al. Combination but not single agent methotrexate 
chemotherapy for gestational trophoblastic tumors.  Am J Obstet Gyn. 172;574-579. 
 
8.  Seckl MJ, Sebire NJ, Berkowitz RS.  Gestational trophoblastic disease. Lancet. 
2010;376:717-729. 
 
9.  Aghajanian C.  Treatment of low-risk gestational trophoblastic neoplasia.  J Clin Onc. 786-
788. 
 
10. Petersen RW, Ung K, Holland C, et al. The impact of molar pregnancy on psychological 
symptomatology, sexual function, and quality of life. Gynecol Oncol. 2005; 97:535-542. 
 
11. Wenzel L, Berkowitz R, Robinson S et al. The psychological, social, and sexual 
consequences of gestational trophoblastic disease. Gyn Onc.1992;46:74-81. 
 
12. Ferreira EGV, Maesta I, Michelin OC, et al. Assessment of QOL and psychologic aspects in 
patients with gestational trophoblastic disease. J Reprod Med. 2009;54:239-244. 
 
13. Cagayan, MSFS. Sexual dysfunction as a complication of treatment of gestational 
trophoblastic neoplasia.  J Reprod Med. 2008;53(8):595-599. 
 
14. Wenzel L, Berkowitz RS, Habbal R, et al.  Predictors of quality of life among long-term 
survivors of gestational trophoblastic disease. J Reprod Med. 2004;49:589-594. 
 
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15. Homesley HD, Blessing JA, Rettenmaier M, et al. Weekly intramuscular methotrexate for 
nonmetastatic gestational trophoblastic disease. Obstet Gynecol. 1988;72:413-418. 
 
16. Homesley HD, Blessing JA, Schlaerth J, et al. Rapid escalation of weekly intramuscular 
methotrexate for nonmetastatic gestational trophoblastic disease: A Gynecologic Oncology 
Group study. Gynecol Oncol. 1990;39:305-308.  
 
17. Goldstein DP, Winig P, Shirley RL. Actinomycin D as initial therapy of gestational 
trophoblastic disease. Obstet Gynecol. 1972;39:341-345. 
 
18. Petrilli ES, Morrow CP. Actinomycin D toxicity in the treatment of trophoblastic disease: A 
comparison of the five-day course to single dose administration. Gynecol Oncol. 1980;9:18-
22. 
 
19. Twiggs LB.  Pulse actinomycin D scheduling in non-metastatic gestational trophoblastic 
neoplasia: cost-effective chemotherapy. Gynecol Oncol. 1983;16:190-195. 
 
20. Petrilli ES, Twiggs LB, Blessing JA, et al. Single-dose actinomycin D treatment for 
nonmetastatic gestational trophoblastic disease: A prospective phase II trial of gynecologic 
oncology. Cancer. 1987; 60:2173-2176. 
 
21. Osathanondh R, Goldstein DP, Pastorfide GB. Actinomycin D as the primary agent for 
gestational trophoblastic disease. Cancer. 1975;36:863-866. 
 
22. Schlaerth JB, Morrow CP, Nalick RH, et al. Single-dose actinomycin D in the treatment of 
postmolar trophoblastic disease. Gynecol Oncol. 1984;19:53-56. 
 
23. Elit L, Covens A, Osborne R, et al.  High-dose methotrexate for gestational trophoblastic 
disease. Gynecol Oncol. 1994;54:282-287. 
 
24. Wong LC, Ngan HY, Cheng DK, et al. Methotrexate infusion in low-risk gestational 
trophoblastic disease.  Am J Obstet Gynecol. 2000;183:1579-1582. 
 
25. Cella DF, Wiklund I, Shumaker SA, et al.  Integrating health-related quality of life into 
cross-sectional clinic trials. Qual Life Res. 1993;2:433-440. 
 
26. Yost KJ, Eton DT. Combining distribution-and anchor-based approaches to determing 
minimally important differences (the FACIT experience). Evaluation & the Health 
Professions. 2005:28:172-191. 
 
27. Hanahan D, Weinberg RA.  Hallmarks of cancer: the next generation. Cell. 2011;144: 646-
674. 
 
28. Weidner N. Tumor angiogenesis: review of current applications in tumor prognostication. 
Semin Diagn Pathol.  1993;10: 302-312. 
 
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29. Weidner N, Folkman J, Possa F, et al.  Tumor angiogenesis: a new significant and 
independent prognostic indicator in early-stage breast carcinoma.  J Natl Cancer Inst. 1992; 
84:1865-1887. 
 
30. Hollingsworth HC, Kohn EC, Steinberg SM, et al. Tumor angiogenesis in advanced stage 
ovarian carcincoma.  Am J Pathol. 1995;147:33-41. 
 
31. Siddiqui GK, Elmasry K, Wong Te Fong AC, et al. Prognostic significance of intratumoral 
vasclar endothelial growth factor as a marker of tumour angiogenesis in epithelial ovarian 
cancer.  Eur J Gynaecol Oncol. 2010; 31: 156-159. 
 
32. Agarwal R, Strickland S, McNeish I, et al.  Doppler ultrasonography of the uterine artery 
and the response to chemotherapy in patients with gestational trophobastic tumors. Clin 
Cancer Res. 2002;8:1142-1147. 
 
33. Agarwal R, Harding V, Short D, et al.  Uterine artery pulsaility index: a predictor of 
methotrexate resistance in gestational trophoblastic neoplasia.  Br J Cancer. 2012 Mar 
13;106(6):1089-94. doi: 10.1038/bjc.2012.65. Epub 2012 Feb 28. 
 
34. Pepe MS, Feng Z, Huang Y, Longton G, Prentice R, Thompson IA, Zheng Y. Integrating 
the Predictiveness of a Marker with its Performance as a Classifier.  Am J Epidemiol. 
2008;167(3):362-368. DOI: 10.1093/aje/kwm305. 
 
 
 
 
 
 
 
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APPENDIX I 
 
F.I.G.O. 2000 staging criteria for gestational trophoblastic neoplasia17 
 
A. 
Criteria for the diagnosis of post-hydatidiform mole trophoblastic neoplasia (GTN) based 
on the modified W.H.O. risk/prognosis scoring schema. 
 
 
1. 
GTN may be diagnosed* when the plateau of human chorionic gonadotrophin (hCG) 
lasts for four measurements over a period of 3 weeks or longer; that is, days 1, 7, 14, 
21. 
 
  
2. 
GTN may be diagnosed* when there is a rise of hCG of 3 weekly consecutive 
measurements or longer, over at least a period of 2 weeks or more; days 1, 7, 14. 
 
 
3. 
GTN is diagnosed when the hCG level remains elevated for 6 months or more.** 
 
 
4. 
GTN is diagnosed if there is a histologic diagnosis of choriocarcinoma. 
 
* 
The actual level of hCG or the amount of rise will be determined by the 
individual investigator. 
** This may not apply for patients with unexplained low-level hCG without 
clinical or imaging evidence of GTN. 
 
B. 
Investigative tools to diagnose metastases 
 
 
1. 
Chest x-ray is appropriate to diagnose lung metastases and it is chest x-rays that are 
used for counting the number of lung metastases to evaluate the risk score. 
 
 
2. 
Liver metastases may be diagnosed by ultrasound or CT scanning. 
 
 
3. 
Brain metastases may be diagnosed by MRI or CT scanning. 
 
C. 
F.I.G.O. staging schema for GTN 
 
 
Stage I 
Disease confined to the uterus 
 
 
Stage II 
GTN extends outside the uterus but is limited to the genital structures 
(adnexae, vagina, and broad ligament). 
  
 
Stage III 
GTN extends to the lungs with or without genital tract involvement. 
 
 
Stage IV 
All other metastatic sites. 
 
 
 
 
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APPENDIX II 
W.H.O. risk scoring criteria 
 
 
Modified W.H.O. prognostic scoring system as adopted by F.I.G.O. (2000)17 
 
 
Risk score 
0 
1 
2 
4 
 
 
 
 
 
Age 
< 40 
40 or older 
- 
- 
Antecedent pregnancy 
mole 
abortion 
term 
- 
Interval months from 
index pregnancy 
< 4 
4 to < 7 
7 to < 13 
13 or more 
Pre-treatment serum 
hCG (miu/ml) 
< 103   (1 
to 999) 
103 to < 104 
(1,000 to 
9,999) 
104 to < 105 (10,000 
to 99,999) 
105 or higher 
(100,000 and 
higher) 
Largest tumor size 
including uterus 
- 
3 to < 5cm 
5cm or larger 
- 
Sites of metastases 
lung 
spleen, kidney 
gastrointestinal 
liver, brain 
Number of metastases 
- 
1 to 4 
5 to 8 
> 8 
Previous failed 
chemotherapy 
- 
- 
single drug 
2 or more drugs 
 
 
 
 
 
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APPENDIX III 
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APPENDIX IV (03/11/2013) 
Leucovorin Calendar 
 
Patient Name: ______________________________  Patient Study ID __________________ Date: ______ /______ / _______  
 
This is a calendar to help you track when to take your Leucovorin pill and when you have taken it.  Each time you return to your 
treatment center or doctor’s office for the next injection, please bring this calendar with you.   
 
When should you take your Leucovorin pill? 
When taking Leucovorin, it should be taken between 24 & 30 hours after your injection of methotrexate.  For example, if you are 
injected on Monday at 10 am, then you should take 1 Leucovorin (15mg) pill on Tuesday between 10am & 4pm.   
 
What if you forget to take your pill? 
If you forgot to take your Leucovorin pill on Tuesday between 10 am & 4pm, you should take the missed pill as soon as you 
remember if there is at least 12 hours before your next scheduled injection time.  If there is less than 12 hours before your next 
injection time, then skip that pill. For example, you remembered your missed pill at 8 pm and you are scheduled to get your next 
methotrexate injection on Wednesday morning at 10 am.  Because there are more than 12 hours before your next injection, you should 
take the missed pill.   
 
 
 
Injection  
Day 1 
___/___/___ 
Leucovorin 
Day 2 
___/___/___ 
Injection  
Day 3 
___/___/___ 
Leucovorin 
Day 4 
___/___/___ 
Injection  
Day 5 
___/___/___ 
Leucovorin 
Day 6 
___/___/___ 
Injection  
Day 7 
___/___/___ 
Leucovorin 
Day 8 
___/___/___ 
Time Injected 
Window to Take 
Pill 
Time Injected 
Window to Take 
Pill 
Time Injected 
Window to Take 
Pill 
Time Injected 
Window to Take 
Pill 
                     
AM 
                     
PM 
 
 
 
 
____ - ____ 
                     
AM 
                     
PM 
 
 
 
____ - ____ 
                     
AM 
                     
PM 
 
 
 
____ - ____ 
                     
AM 
                     
PM 
 
 
 
____ - ____ 
 
Time Pill Taken 
 
Time Pill Taken 
 
Time Pill Taken 
 
Time pill taken 
 
 
AM 
  
PM 
 
AM 
  
PM 
 
AM 
  
PM 
 
AM 
  
PM 
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