Phase II/III Clinical Trial of Intensity Modulated Radiation Therapy With Concurrent Cisplatin for Stage I-IVA Cervical Carcinoma
Phase: PHASE2
Conditions: Cervical Cancer
Sponsor: University of California, San Diego

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INTERNATIONAL EVALUATION OF RADIOTHERAPY TECHNOLOGY 
EFFECTIVENESS IN CERVICAL CANCER (INTERTECC): 
 
PHASE II/III CLINICAL TRIAL OF INTENSITY MODULATED  
RADIATION THERAPY FOR CERVICAL CANCER 
 
 
NCT 01554397 
 
Activation Date: May 1, 2011 
Version Date: June 16, 2016 
 
 

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INTERNATIONAL EVALUATION OF RADIOTHERAPY TECHNOLOGY 
EFFECTIVENESS IN CERVICAL CANCER (INTERTECC): 
 
PHASE II/III CLINICAL TRIAL OF INTENSITY MODULATED  
RADIATION THERAPY FOR CERVICAL CANCER 
 
 
 
Activation Date: May 1, 2011 
Version Date: June 16, 2016 
 
 
 
 
Center for Advanced Radiotherapy Technologies 
Attention: INTERTECC PI (lmell@ucsd.edu) 
3855 Health Sciences Drive #0843 
La Jolla, CA 92093-0843 
(858)822-5036 / Fax: (858)822-5568 
 
 
 
 
 
 
 
 
 
 
 
This protocol was designed and developed by the International Radiotherapy Technologies and Oncology 
Consortium (IRTOC) and is intended to be used only in conjunction with IRB approval for study entry. No 
other use or reproduction of this protocol is authorized or endorsed by IRTOC. 

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Principal Investigator 
Loren K. Mell, M.D. 
University of California San Diego 
 
Center for Advanced Radiotherapy Technologies 
3855 Health Sciences Drive #0843 
La Jolla, CA 92093-0843 
(858) 246-0471 / Fax: (858)822-5568 
lmell@ucsd.edu 
 
 
Medical Physics Co-Chair 
Kevin Moore, Ph.D.  
University of California San Diego 
Center for Advanced Radiotherapy Technologies 
3855 Health Sciences Drive #0843 
 
La Jolla, CA 92093-0843 
(858)822-5129  
kevinmoore@ucsd.edu 
 
 
 
 
Gynecologic Oncology Co-Chair 
Michael McHale, M.D. 
University of California San Diego 
Moores Cancer Center  
 
 
 
3855 Health Sciences Drive #0987 
 
 
La Jolla, CA 92093 
(858) 822-6275  
mtmchale@ucsd.edu 
 
 
 
Biostatistics Co-Chair 
Ronghui (Lily) Xu, Ph.D. 
University of California San Diego  
Department of Family and Preventive Medicine 
9500 Gilman Drive 
La Jolla, CA 92093-0112 
(858) 534-6380 
rxu@ucsd.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
1.0 
Schema 
2.0 
Eligibility Checklist 
3.0 
Registration Worksheet 
4.0 
Introduction 
5.0 
Objectives 
6.0 
Population and Eligibility Criteria 
7.0 
Pretreatment Evaluations/Management 
8.0 
Registration Procedures 
9.0 
Radiation Therapy 
10.0 
Drug Therapy 
11.0 
Surgery 
12.0 
Other Therapy 
13.0 
Pathology and Tissue/Specimen Submission 
14.0 
Patient Assessments, Follow-Up, and Data Collection Procedures 
15.0 
Patient Safety and Ethical Considerations 
16.0 
Statistical Considerations 
17.0 
References 
 
 
 

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1.0 SCHEMA 
 
Design: 
Phase II/III Clinical Trial 
 
Sample Size: 91 (Phase II); 415 (Phase III) 
 
Population / Eligibility (Section 6.0):  
 
 
• 
Biopsy-proven carcinoma of the cervix 
• 
No Prior Radiation or Chemotherapy 
• 
Medically Fit for Pelvic Chemoradiotherapy  
• 
No Evidence of Distant Metastasis 
• 
Does Not Require Para-aortic Radiotherapy 
• 
Willing and Able to Undergo PET/CT Imaging 
 
 
Radiation Therapy (Section 9.0):   
Phase III, Arm A:  
Image-Guided Bone Marrow-Sparing IMRT (IG-BMS-IMRT)  
 
Phase III, Arm B: 
Non-Bone Marrow Sparing Radiotherapy 
 
All Arms: 
 
Standard Chemotherapy** (Cisplatin 40 mg/m2 x 6 cycles) 
 
**Adjuvant Chemotherapy will not be given on this trial 
 
Stratification Factors: 
 
-Age (≥ 60 vs. < 60) 
-Stage (IB-IIA vs. IIB-IVA) 
 
 
 
 

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2.0 ELIGIBILITY CHECKLIST 
(Y) 1. Does the patient have stage IB-IVA biopsy-proven, invasive carcinoma of the cervix? 
(N) 2. Does the patient have clinical, radiographic, or pathologic evidence of para-aortic and/or 
distant metastasis? 
(Y) 3. Will the patient receive radiation to a field including the pelvic lymph nodes, with 
concurrent chemotherapy (only patients undergoing concurrent chemoradiotherapy are 
eligible)? 
(Y) 4. Can the patient undergo PET/CT or PET/CT simulation? 
(Y) 5. Has the patient had a pelvic examination within 42 days prior to registration? 
(Y) 6. Has the patient had an X-ray, CT scan, or PET/CT of the chest within 60 days prior to 
registration? 
(Y) 7. Has the patient had a CT scan, MRI, or PET/CT of the pelvis within 60 days prior to 
registration? 
(Y) 8. Is the patient’s Karnofsky Performance Status ≥ 60? 
(Y) 9. Is the patient ≥ 18 years of age? 
(Y) 10. Has the patient met all the lab requirements as described in Section 6.1.8? 
(Y) 11. If the patient is of child bearing potential, has she had a negative pregnancy test? 
(Y) 12. If the patient is of child bearing potential, did she agree to practice effective birth control 
throughout the treatment phase of the study? 
(N) 13. Is the patient pregnant or lactating? 
(Y/NA)14. If clinical suspicion of AIDS, must have CD4+ T cell count > 200 per µL of blood and 
>14% of all lymphocytes  
(Y/N) 15. Does the patient have a history of a prior different invasive malignancy (with the 
exception of non-melanomatous skin cancer)? 
(Y) If yes, has the patient been disease free for greater than three years? (Patients with 
recurrences of the primary malignancy following surgery alone, with no prior history of 
chemotherapy or radiation, are eligible) 
(N) 16. Has the patient had prior systemic chemotherapy? 
(N) 17. Has the patient had prior radiation therapy to the pelvis or abdomen that would result in 
overlap of radiation therapy fields? 
(N) 18. Has the patient had unstable angina and/or congestive heart failure requiring 
hospitalization within the last 6 months? 
(N) 19. Has the patient had a myocardial infarction within the last 6 months? 
(N) 20. Does the patient have an acute infection requiring antibiotics at the time of registration? 
(N) 21. Does the patient have a Chronic Obstructive Pulmonary Disease or other respiratory 
illness requiring hospitalization or precluding study therapy at the time of registration? 
(N) 22. Does the patient have hepatic insufficiency resulting in clinical jaundice and/or 
coagulation defects? 
(N) 23. Does the patient have uncontrolled diabetes? 
(N) 24. Does the patient have uncompensated heart disease or uncontrolled blood pressure per 
Section 6.2.6.7? 
(N) 25. Does the patient have a CD4+ T cell count < 200 per µL of blood or <14% of all 
lymphocytes? 
(N) 26. Does the patient have a history of organ transplant, chronic glucocorticoid use, or any 
other immunocompromised status that in the opinion of the investigator would preclude the 
patient from receiving protocol therapy? 
(Y) 27. Did the patient sign a study specific informed consent prior to study entry? 
 
IRTOC Institution #______________ 
 
Case # ________________________ 

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3.0 REGISTRATION WORKSHEET 
1. Name of person registering the case 
(Y) 2. Has the Eligibility Checklist been completed and the patient determined to be eligible? 
(Y) 3. Has the patient signed informed consent? 
4. Patient’s Initials (First Middle Last)  
5. Verifying Physician 
6. Patient’s ID Number 
7. Date of Birth 
8. Race  
9. Ethnic Category (Hispanic or Latino; Not Hispanic or Latino; Unknown)  
10. Patient’s Country of Residence 
11. Zip Code (U.S. Residents) 
12. Patient’s Insurance Status 
13. Calendar Base Date 
14. Registration date 
 (Y/N) 15. Does the patient consent to be contacted for future research? 
16. Gynecologic Oncologist’s Name 
17. Radiation Oncologist’s Name 
18. Age 
19. Stage 
 
The Eligibility Checklist must be completed in its entirety prior to registration. The completed, 
signed, and dated checklist used at study entry must be retained in the patient’s study file and 
will be evaluated during an audit. 
 
 
Completed by____________________________Date _______________________ 
 
*THIS FORM SHOULD BE TURNED IN AT THE TIME OF REGISTRATION 
 

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4.0 INTRODUCTION 
4.1 Background  
Gynecologic malignancies are a leading cause of morbidity and mortality in women 
worldwide [1-2]. Many of these malignancies are attributable to human papillomavirus 
(HPV), the primary cause of cancers of the cervix, vagina, vulva, and anus. In North 
America, endometrial cancer is the most common gynecologic malignancy in women, 
with over 50,000 new cases annually. Often these disease present in later stages where 
surgical treatment alone is insufficient, and either adjuvant chemoradiotherapy (CRT) or 
primary CRT is required. 
 
Locoregionally advanced gynecologic malignancies are frequently treated with primary 
CRT. Multiple clinical trials have established concurrent CRT as a standard treatment 
approach for locally advanced cervical cancer [3-8]. Increasingly, CRT has been used to 
treat advanced endometrial cancer as well. However, with this approach, acute and late 
toxicity are significant problems, while the incidence of locoregional failure, distant 
metastasis, and cancer mortality remain high [3-10]. Therefore, strategies to reduce 
toxicity and permit treatment intensification are needed. 
 
4.2 Efficacy and Toxicity of Chemoradiation for Pelvic Cancers 
Multiple studies have established that intensifying both concurrent and adjuvant CRT 
improves treatment outcomes for pelvic malignancies [9-12].   However, acute toxicity, 
particularly gastrointestinal (GI) and hematologic toxicity, are increased. Rates of high 
grade toxicity as high as 80% or more have been reported from multi-center trials [12].  
Methods to reduce toxicity of CRT, particularly gastrointestinal and hematologic toxicity, 
could reduce barriers to intensifying chemotherapy and improve the therapeutic ratio of 
CRT. 
 
 
4.3 Intensity Modulated Radiation Therapy 
Conventional pelvic RT techniques often employ opposed anterior-posterior / posterior-
anterior (AP/PA) and lateral fields, resulting in a box-shaped dose distribution that 
encompasses both targeted tissues (e.g. tumor, parametria, pelvic lymph nodes, etc.) 
and normal tissues (e.g., bowel, rectum, bladder, bone marrow, etc.). Field borders are 
frequently defined based on standard bone landmarks rather than by expressly defined 
targets.  
 
Intensity modulated radiation therapy (IMRT) is a modern RT technique that differs from 
conventional techniques in many ways. First, patients undergo computed tomography 
(CT) simulation so that customized target volumes can be defined 3-dimensionally. 
IMRT treatment planning involves multiple beam angles and uses computerized inverse 
treatment planning optimization algorithms to identify dose distributions and intensity 
patterns that conform dose to the target, reducing radiation dose to surrounding tissues. 
IMRT delivery is typically accomplished with the use of multileaf collimators, which 
involve small motorized leaflets (collimators) that move in and out of the beam path, 
modulating the dose intensity.  
 
Multiple studies in gynecologic cancer have shown that IMRT plans reduce dose to 
pelvic organs while maintaining acceptable target coverage [13-15]. Comparisons of 
IMRT to conventional treatments in patients have found reduced acute and late GI 
toxicity and hematologic toxicity with IMRT [16-18]. Studies have also shown that IMRT 
plans can be optimized to intensively reduce normal tissue dose [13-15] and have 
established evidence-based guidelines for dosimetric planning to reduce toxicity [19-21]. 

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Validated predictive models indicate that optimized IMRT plans are clinically feasible and 
can be expected to decrease the rates of acute toxicity by approximately two-fold [21-
22]. Retrospective studies have also indicated that IMRT is associated with low acute 
and late toxicity and favorable long-term outcomes [23-25]. Prospective clinical trials of 
IMRT, however, are still limited. A prospective trial of IMRT for gynecologic cancer 
showed that IMRT is feasible in the multi-institutional setting for post-operative patients 
[26], with low toxicity. A small randomized trial of IMRT in India also found that toxicity 
was reduced with IMRT [27].  
 
4.4 Quality of Life and Patient-Reported Outcomes 
Validated QOL measurements used in patients treated for cervical cancer have 
demonstrated that a considerable proportion of patients report debilitating functional 
compromise and psychosocial morbidity [28]. Studies have indicated that reducing pelvic 
radiation dose in women with endometrial cancer reduces urinary incontinence, diarrhea, 
and fecal leakage, leading to fewer limitations in daily activities [29-30]. However, 
detailed studies of the  effect of IMRT on QOL in gynecologic cancer patients are 
lacking, particularly in the international setting. Longitudinal assessments of QOL and 
key functions such as activities of daily living, bowel and urinary habits, psychosocial 
function, and sexual function are included as secondary end points of this study.  
 
We will explore the impact of IMRT on QOL using severalvalidated QOL instruments: the 
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 form 
and the disease site-specific module QLQ-CX24. The 30-item EORTC QOL 
questionnaire (QLQC30) is a psychometrically robust, cross-culturally accepted 
questionnaire that was designed to be applicable to a broad spectrum of cancer patients 
as a core questionnaire [31]. The form has been translated into many languages 
including English, Mandarin, Hindi, Thai, Portuguese, Czech, Dutch, Korean, Spanish, 
Turkish, and Vietnamese. Previous studies have shown that, despite regional variations 
in responses that need to be considered, the QLQ-C30 is suitable for use in a wide 
variety of countries and settings [32].  
 
The QLQ-CX24 is a validated and reliable psychometric module consisting of 3 multi-
item scales and 5 single-item scales. It is characterized by high internal consistency, 
good compliance and fast completion with no or minimal assistance [33]. Cross-cultural 
studies in Asian samples, for example, have found the module to be a reliable and valid 
measure of QOL [34-35]. The module has been translated into many languages 
including English, Mandarin, Hindi, Portuguese, Czech, Dutch, Korean, and Spanish.  
 
4.5 Image-Guided Bone Marrow-Sparing IMRT  
Hematologic toxicity (HT) is a key barrier to intensifying chemoradiotherapy in 
patients with pelvic malignancies. It is well-known that both radiation and chemotherapy 
are myelosuppressive, but the extent to which pelvic radiation contributes to HT in 
patients undergoing CRT is unknown. Radiation causes apoptosis of bone marrow (BM) 
and peripheral blood stem cells and BM stromal damage, resulting in myelosuppression 
and characteristic pathologic and radiographic BM changes [36-38]. BM stem cells are 
exquisitely sensitive to low doses of radiation [39]. Older clinical studies have shown that 
radiation BM injury depends on both radiation dose and volume of BM irradiated [40-42]. 
CT-based IMRT plans can be optimized to reduce BM irradiation [14-15], but the large 
avoidance volume constrains IMRT plan optimization. Refining IMRT plans to focus on 
sparing BM subregions may therefore be a more effective strategy. Previous studies 
have shown that functional imaging can help optimize IMRT plans to spare active BM 

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[43-47]. However, the locations of BM subregions most important for sparing remain 
unknown, and studies investigating functional BM imaging are needed to optimally 
design BM-sparing IMRT plans.  
We have implemented functional imaging to identify “active” BM subregions for 
avoidance. It is known from pathology and imaging studies that BM is comprised of 
subregions of hematopoeitically active, fat-poor, “red” BM and inactive, fat-rich, “yellow” 
marrow [48-52]. Red BM contains approximately 40% fat, 40% water, and 20% protein; 
yellow BM contains approximately 80% fat, 15% water, and 5% protein [48]. Up to 50% 
of the body’s red BM may be located in the pelvis and lumbar spine [53] and thus 
contained within conventional RT ports. These active and inactive regions cannot be 
distinguished on computed tomography (CT) [54-55], which is the principal imaging 
modality used for RT planning. Functional imaging studies indicate that active BM tends 
to be concentrated particularly in vertebral and ilial subregions [44-46,49]. These regions 
co-localize with regions which, by MRI studies, show longer T1 relaxation times and 
longer T2 indicative of red vs. yellow BM [48]. Reducing dose specifically to active 
subregions of pelvic BM may be beneficial, but the precise location of active BM 
subregions, variation in active BM distribution between individuals, and relationship 
between toxicity and radiation dose to these active BM regions are all unknown. 
 [18F]-deoxyfluorothymidine (18F-FLT) is an effective PET imaging tracer for 
proliferating BM. FLT is a DNA precursor that is phosphorylated and sequestered 
intracellularly by the enzyme thymidine kinase 1 [56], which is active during DNA 
synthesis, leading to specific tracer uptake in proliferating tissues [57]. Hayman et al. 
showed was useful for in vivo measurements of proliferating BM [58]. Several studies 
have noted decreased tracer uptake in BM after irradiation with doses as low as 2 Gy, 
and complete absence of uptake after 10-20 Gy [57,59-61]. 18F-FLT appears superior to 
18F-FDG for BM imaging, due to the inability of 18F-FDG to discriminate between 
proliferating cells and metabolically active non-proliferating cells [58,62-63].  Recently a 
study found that increased radiation to BM sub-regions with higher 18F-FDG-PET activity 
was associated with increased HT [64], supporting the hypothesis that reducing dose to 
active subregions could mitigate HT. In this protocol, we will test the hypothesis that BM-
sparing IMRT plans designed to avoid active subregions identified by PET can reduce 
HT. This technique could improve patients’ tolerance to chemotherapy and increase the 
therapeutic ratio of CRT for pelvic malignancies in general. 
 
4.6 Restriction Spectrum Imaging 
     Diffusion-weighted MRI (DW-MRI) has been intensively studied in cervical cancer for 
both diagnostic and prognostic utility. DW-MRI quantifies water diffusion within tissues, 
highlighting differences between normal tissue and tumors. Tumors generally have 
higher cellular density and higher N/C ratio, which restricts water diffusion more than in 
normal tissue. A measure called the apparent diffusion coefficient (ADC) is a commonly 
used indicator of water diffusion detected with DW-MRI, and the ADC is often lower in 
tumors than surrounding normal tissue. Multiple studies have shown the utility of DW-
MRI for diagnosis, prognosis, and evaluation of response to therapy. For example, Lin et 
al. showed that change in ADC was associated with reduced tumor size in response to 
therapy, showing the promise of DW-MRI as an imaging biomarker. An important 
limitation of standard DW-MRI, however, is its inability to distinguish tumor 
hypercellularity from other causes of altered water diffusion, such as inflammation or 
hemorrhage. Moreover, standard diffusion imaging can have poor contrast resolution, 
and all MR diffusion imaging is susceptible to large anatomic distortion from ever-
present inhomogeneity (or non-uniformity) in the MRI system’s magnetic field. As a 

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result, image quality is too poor to make DW-MRI useful for radiation therapy planning or 
for assessing response to therapy.  
     In contrast, Restriction Spectrum Imaging (RSI) is a highly novel MRI technique 
developed at UCSD for cancer imaging (Figure). The chief advantage of RSI over DW-
MRI is that it provides better functional information about tumors, particularly cellularity, 
with superior image contrast. Additionally, the anatomic distortion is removed from the 
RSI images by accounting for the magnetic field inhomogeneity, a critical step for 
accurately locating tumors. Unlike PET, the RSI technique delivers no ionizing radiation 
to patients, and may improve resolution over PET. Certain refractory tumors retain high 
cellularity after treatment. RSI is likely to be a useful technique to determine response to 
therapy, and to identify patients who are not responding well earlier in the course of 
treatment than can be done with standard imaging methods. The use of RSI in cervical 
cancer is completely novel, and there are no published studies of it in this context. 
 
Figure 4.1. RSI of a poorly differentiated squamous cell carcinoma of the cervix 
before treatment (LEFT) and mid-treatment (RIGHT) showing the reduction in 
tumor (orange/red colorwash) in response to therapy. Note these are the first ever 
RSI images in a patient with cervical cancer. 
 
A.  
B.  
C.  
D.  
E.  
 
 
 
 
 
 
 
 
 
4.7 Knowledge-Based Planning 
Our research group has developed mathematical models to detect sub-optimal 
IMRT plans with high sensitivity and specificity, using a process termed Knowledge-
Based Planning (KBP) [43]. This system is built to identify optimal plans amongst prior 
training cohorts, and use the resulting model to develop predictive dose-volume 
histograms (pDVH) for organs-at-risk (OARs) that give precise quantitative information 
on plan quality deficiencies. This approach will allow us to identify, quantify, and 
ultimately correct sub-optimal treatment plans, a process that is ideally suited for 
application to quality control in the multi-center clinical trial setting, particularly when new 
technologies or implementations are being introduced.  
 
4.8 Primary Hypothesis 
Compared to standard radiotherapy, IG-BMS-IMRT will improve progression-free 
survival for cervical cancer patients treated with concurrent chemotherapy. 
 
5.0 OBJECTIVES 
5.1 Primary 

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5.1.1 To test whether IG-BMS-IMRT improves progression-free survival (PFS) for 
cervical cancer patients treated with concurrent chemotherapy.  
 
5.2 Secondary 
5.2.1 To compare acute and long-term QOL in the study arms 
5.2.2 To compare acute and late hematologic and gastrointestinal (GI) toxicity in the 
study arms 
5.2.3 To compare total chemotherapy dose delivered in the study arms 
5.2.4 To compare locoregional (pelvic) failure, distant metastasis, and overall survival in 
the study arms 
5.2.5. To evaluate the quality of IMRT planning in the international cooperative group 
setting  
5.2.6 To quantify changes in tumor cellularity using Restriction Spectrum Imaging (RSI 
substudy) 
5.2.7 To compare hematologic toxicity of FLT-PET-based IG-BMS-IMRT vs. other 
treatment approaches (FDG-PET-based IG-BMS-IMRT and standard radiotherapy) 
 
6.0 POPULATION AND ELIGIBILITY CRITERIA 
6.1 Conditions for Patient Eligibility 
6.1.1 Biopsy-proven, unresected stage IB-IVA invasive carcinoma of the cervix.  
6.1.2 Candidate for pelvic or pelvic-inguinal radiotherapy and concurrent chemotherapy. 
Patients undergoing preoperative chemoradiotherapy are excluded.  
6.1.3 Able to undergo diagnostic PET/CT or PET/CT simulation 
6.1.4 History/physical examination within 42 days prior to registration to document 
cervical tumor size and stage 
6.1.5 CT, MRI, or PET/CT imaging of the chest, abdomen, and pelvic regions within 60 
days prior to registration (for stage I patients, PA and lateral chest x-ray is sufficient for 
chest imaging) 
6.1.6 Karnofsky Performance Status 60-100 
6.1.7 Age ≥ 18 
6.1.8 Laboratory data obtained ≤ 42 days prior to registration on study, with adequate 
bone marrow, hepatic and renal function defined as follows: 
• Absolute neutrophil count (ANC) ≥ 1500 cells/mm3; 
• Platelets ≥ 100,000 cells/mm3; 
• Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to 
achieve Hgb ≥ 8.0 g/dl is acceptable) 
• Creatinine clearance ≥ 50 mg/dl OR Serum Creatinine ≤ 1.5 x ULN 
• Bilirubin < 1.5 mg/dl 
• WBC ≥ 3,000/μl 
• ALT/AST < 3 x ULN 
• Negative pregnancy test for women of child-bearing potential 
6.1.9 Women of childbearing potential must agree to practice effective birth control 
throughout their participation in the treatment phase of the study. 
6.1.10 If there is clinical suspicion of AIDS, an HIV test must be done within 60 days 
prior to registration. Note: HIV positive patients with a CD4+ T cell count > 200 per µL of 
blood and >14% of all lymphocytes are eligible for this trial. 
6.1.11 Patients must sign informed consent prior to study entry. 
 
6.2 Conditions for Patient Ineligibility  
6.2.1 Prior invasive malignancy (except non-melanomatous skin cancer), unless disease 
free for a minimum of 3 years.) 

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6.2.2 Prior systemic chemotherapy  
6.2.3 Prior radiotherapy to the pelvis or abdomen that would result in overlap of radiation 
therapy fields. 
6.2.4 Para-aortic or inguinal metastasis.  
6.2.5 Distant metastasis 
6.2.6 Severe, active co-morbidity, defined as follows: 
6.2.6.1 Unstable angina and/or congestive heart failure requiring hospitalization 
within the past 6 months; 
6.2.6.2 Transmural myocardial infarction within the last 6 months; 
6.2.6.3 Acute bacterial or fungal infection requiring intravenous antibiotics at the 
time of registration; 
6.2.6.4 Chronic Obstructive Pulmonary Disease exacerbation or other respiratory 
illness requiring hospitalization or precluding study therapy at the time of 
registration; 
6.2.6.5 Hepatic insufficiency resulting in clinical jaundice and/or coagulation 
defects; 
6.2.6.6 Uncontrolled diabetes, defined as diabetes mellitus, which in the opinion 
of any of the patient’s physicians requires an immediate change in management; 
a patient may be considered eligible for the study if the physician managing the 
patient’s diabetes considers that the appropriate changes in management have 
resulted in adequate control. 
6.2.6.7 Uncompensated heart disease or uncontrolled high blood pressure, which 
in the opinion of any of patient’s physicians, requires immediate change in 
management; a patient may be considered eligible for the study if the physician 
managing the patient’s heart disease or blood pressure considers that the 
appropriate changes in management have resulted in adequate control.  
6.2.6.8 Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC 
definition; patients with AIDS will be ineligible for this protocol because the 
treatments involved may be significantly immunosuppressive. Patients with 
clinical suspicion of AIDS and who are unwilling to have an HIV test are not 
eligible for this trial. 
6.2.6.9 Uncontrolled infection 
6.2.6.10 Other immunocompromised status (e.g., a history of organ transplant, 
chronic glucocorticoid use, or any other immunocompromised status that in the 
opinion of the investigator would preclude the patient from receiving protocol 
therapy). 
6.2.7 Women who are pregnant or lactating are ineligible due to teratogenic effects on 
developing fetuses. Women who are of child-bearing potential need to practice effective 
methods of contraception including oral contraceptives, intrauterine device, diaphragm 
with spermicides, and/or abstinence.  
6.2.8 Prior history of hip, pelvic, or lumbosacral prosthesis or other implanted device. 
6.2.9 Patients undergoing preoperative chemoradiotherapy 
 
7.0 PRE-TREATMENT EVALUATIONS / MANAGEMENT 
7.1 History and physical examination including assessment of tumor size, height, 
weight and body surface area and performance status.  
7.2 Assessment of smoking and alcohol history (past and current) within 42 days prior to 
study entry. 
7.3 Assessment of race and ethnicity and comorbidity index within 42 days prior to study 
entry  

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7.4 Patients must not be allergic to iodinated contrast if undergoing a contrast enhanced 
CT scan of the pelvis. 
7.5 Pre-treatment MRI is not required but is encouraged to aid staging evaluation and 
target delineation.  
7.6 PET/CT and Study-Related Functional Imaging 
At baseline, all patients will undergo PET/CT or PET/CT simulation with a slice thickness 
of 3 mm and large field-of-view pelvic protocol.  Subjects imaged with FDG-PET will 
undergo intravenous administration of 200-400 MBq of 18F-FDG 60 minutes prior to 
imaging. Subjects imaged with FLT-PET will undergo intravenous administration of 4.5 
MBq/kg of 18F-FLT 60 minutes prior to imaging. These doses can be repeated for 
patients undergoing serial imaging. 
 
Patients on the functional MRI (RSI) and/or 18F-FLT will undergo serial imaging as 
described in section 14.2 
 
8.0 REGISTRATION PROCEDURES 
8.1 Pre-Registration Requirements 
8.1.1 Pre-Registration Requirements for IMRT 
In order to register patients on this study, the institution must provide baseline physics 
information and an anonymized case study, including all contours and a sample 
treatment plan (“Dry Run”). For instructions on pre-registration requirements, contact the 
study PI (lmell@ucsd.edu) or the Physics Chair (kevinmoore@ucsd.edu).  
An IMRT phantom study may be required to be eligible to register patients. Institutions 
will be notified with further instructions if they are required to submit a phantom study. 
Instructions for requesting and irradiating the phantom will be available at the 
Radiological Physics Center (RPC) at MD Anderson Cancer Center website 
(http://rpc.mdanderson.org/rpc)  
 
8.1.2 Central Review 
All external beam treatment plans will be centrally reviewed at UC San Diego to 
determine protocol compliance (section 9.9).  
 
8.2 Registration 
8.2.1 Screening Procedures 
Diagnostic or laboratory studies will be performed to determine eligibility. Studies or 
procedures that were performed for clinical indications or as standard of care (not 
exclusively to determine study eligibility) may be used for baseline values, even if the 
studies were done before informed consent was obtained, provided they occur within the 
proper window. 
 
8.2.2 Informed Consent  
Written informed consent will be obtained prior to any study procedures.. Each institution 
should customize the consent form according to their institutional requirements. The 
investigational nature and objectives of the trial, the procedures and treatments involved 
and their attendant risks and discomforts, and potential alternative therapies will be 
carefully explained to the subject and a signed informed consent will be obtained. 
Documentation of informed consent (e.g. scanned record) will be transmitted to UC San 
Diego via the secure FTP server.  
 
8.2.3 Recruitment 
Subjects will be recruited at participating centers by local investigators. 

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8.2.4 Registration Procedures 
Patients will be registered through UC San Diego’s Velos system.  Each participating 
site will be given a Velos account username and password. Eligible patients will be 
assigned a case number and study arm through this system.  Velos will contain the data 
submission calendar including all data forms, images, and reports and the dates on 
which they are due. 
 
 
9.0 RADIATION THERAPY 
9.1 General 
 
• 
Patients will be randomized to one of two arms: 
 
A. Image-guided bone marrow sparing IMRT (IG-IMRT) 
B. Non-Bone Marrow-Sparing Radiation Therapy 
 
• 
The total duration of concurrent chemoradiotherapy should be ≤ 60 days.  
 
• 
The patient’s baseline PET/CT, CT simulation, and external beam treatment plan(s) 
should be submitted within 45 days of completing treatment.  
 
Delivery Compliance Criteria 
 
Per Protocol 
Acceptable 
Variation  
Unacceptable 
Variation  
Overall Treatment 
time 
≤ 60 days 
≤ 66 days 
> 66 days 
 
 
9.2 Simulation 
All patients should be simulated according to the criteria below for this protocol. 
 
9.2.1 Bladder and Bowel Preparation 
The degree of bladder and rectal fullness should be made to duplicate that which 
is anticipated for daily treatment, i.e., if the patient is instructed to maintain a full 
bladder for treatment, she should be simulated as such. It is recommended to 
use a consistent bladder filling state (e.g. always full or always empty) for 
simulation and treatment. It is recommended for patients not to be simulated or 
treated with a full rectum as this may result in irreproducible setup. Bowel 
preparatory agents (enema, stool softeners, etc.) may be applied at the 
discretion of the physician. If a full rectum is noted on the simulation study it is 
recommended that the patient undergo a new simulation scan. 
 
9.2.2 Contrast and Markers 
Intravenous contrast is recommended unless medically contraindicated. Oral 
contrast is optional. A radio-opaque cervical marker may be placed in the apex of 
the vagina to assist with target delineation and is optional. Implanted fiducials are 
optional.  
 

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9.2.3 Position 
Simulation will be done in the supine position.  
 
9.2.4 Immobilization 
All subjects will have a customized immobilization device (e.g., Alpha Cradle or 
Vac-Lok) fabricated at the time of simulation.   
 
9.2.5 Imaging 
All subjects should undergo a CT (or PET/CT) simulation scan using a slice 
thickness of 2.5-3.0 mm and large field-of-view pelvic protocol.  CT scans should 
be obtained from the T12 vertebral body to 5 cm below the ischial tuberosities.  
 
9.2.6 Isocenter placement 
Isocenter placement is left to discretion of treating physician, however, it is 
recommended to place the isocenter along the patient’s midline 1.5 cm caudal to 
the inferior border of the sacroiliac joint. 
 
 
9.3 Normal Tissue Delineation   
 
9.3.1 General 
Normal tissues will be contoured on the simulation scan. The tissue within the skin 
surface and outside all other critical normal structures and the PTV is designated as 
unspecified tissue.  
 
 
All patients will have the following normal tissues delineated for this trial: 
 
9.3.2 Bowel 
The bowel will be contoured beginning from the axial slice situated 1 cm superior to the 
superior-most slice containing PTV (if bowel is not present at this level, the bowel 
contour will start from its most superior extent), and will continue to its most inferior 
extent in the pelvis.  The outermost extent of the bowel loops will be outlined on each 
axial CT slice, as described in the literature [22]. Individual loops of bowel should not be 
contoured separately. Rectum should be contoured separately from bowel. An 
instructional video can be viewed at https://healthsciences.ucsd.edu/som/radiation-
medicine/research/clinical-translational/clinical-
trials/intertecc/protocol/Pages/Videos.aspx.  
 
9.3.3 Rectum 
The outer rectal wall will be contoured and filled in, treating the organ as a solid 
continuous structure, and will be defined from the level of the sigmoid flexure to the 
anus.   
 
9.3.4 Bladder 
The outer bladder wall will be contoured and filled in, treating the organ as a solid 
continuous structure.    
 
9.3.5 Pelvic Bone Marrow (PBM) 
The outer bone contour will be delineated and filled in, treating the bone marrow as a 
solid continuous structure. The regions contoured will include the os coxae, L4 and L5 
vertebral bodies, entire sacrum, acetabulae, and proximal femora. The superior extent of 

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INTERTECC TRIAL 
 
the bone marrow contour should be at the level of the superior border of L4 or the iliac 
crest, whichever is more superior. The caudal-most extent of the bone marrow contour 
should be at the level of the ischial tuberosities. For examples see Mell et al. [20], Figure 
3. An instructional video can be viewed at https://healthsciences.ucsd.edu/som/radiation-
medicine/research/clinical-translational/clinical-
trials/intertecc/protocol/Pages/Videos.aspx. 
 
9.3.6 Femoral Heads 
The outer contours of the femoral heads will be delineated and filled in, treating each as 
a solid continuous structure. Do not include the femoral neck.   
 
9.3.7 Active Bone Marrow (ABM) 
Active BM (ABM) will be a subset of the entire Pelvic BM (PBM) volume (delineated in 
9.2.3.5).  ABM will be defined as the subregion with a standardized uptake value (SUV) 
greater than the mean value over the BM volume. Automatic segmentation using 
commercially available software can be used to define ABM. The functional imaging 
technique will be either FDG-PET or FLT-PET depending on availability of funding for 
FLT-PET. This volume can be generated locally or (for patients on Arm A) the ABM can 
be generated centrally at UCSD and supplied to the treating site after the DICOM data 
has been transmitted. 
 
9.4 Target Delineation 
9.4.1 General 
For patients treated with conventional techniques, 3-D planning with target delineation 
according to the criteria below is suggested, but not required. If target delineation is not 
performed, follow the guidelines for blocking outlined in section 9.5.3. 
 
9.4.2 Image fusion 
Pelvic MRI and/or PET fusion is encouraged to aid clinical target volume delineation. 
Fusion should be optimized to match the MRI / PET scan to the treatment position. The 
Gross Tumor Volume (GTV) and Clinical Target Volume (CTV) and normal tissues will 
be contoured on all CT slices in which the structures exist. The definition of all volumes 
will be in accordance with the 1993 ICRU Report #50: Prescribing, Recording and 
Reporting Photon Beam Therapy 
(http://www.icru.org/index.php?option=com_content&task=view&id=72).  
 
9.4.3 Definition of Target Volumes and Margins 
 
It is strongly recommended that investigators read guidelines for contouring target 
volumes [66-69]. A visual demonstration of target delineation procedure can also be 
viewed or downloaded from https://healthsciences.ucsd.edu/som/radiation-
medicine/research/clinical-translational/clinical-
trials/intertecc/protocol/Pages/Videos.aspx 
 
Standard 
Name 
 
Description 
 
Detailed Specification 
CTV_4500 
CTV to receive 45 Gy 
Required 
 
It is recommended to divide the CTV into 3 
sub regions: CTV1, CTV2, CTV3.  CTV1 
will consist of the gross tumor, cervix, and 
uterus. CTV2 will consist of the parametria 

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INTERTECC TRIAL 
 
and superior third of the vagina (or half of 
the vagina, if the vagina is clinically 
involved). CTV3 will include the common, 
external, and internal iliac and presacral 
lymph nodes. It is acceptable for CTV1, 
CTV2, and/or CTV3 to overlap each other. 
The upper border of the CTV3 should not 
extend above the confluence of the common 
iliac arteries with the aorta (i.e., aortic 
bifurcation), and should begin no lower than 
superior border of L5. The nodal CTV 
(CTV3) will be obtained by ensuring an 
approximately 7 mm margin around the 
vessels, plus extension to include any 
adjacent visible lymph nodes, lymphoceles, 
or pertinent surgical clips. The presacral 
nodes should be contoured until the superior 
border of the S3 vertebral body is reached; 
below this point the nodal volume can be 
separated into two structures. The external 
iliac nodes should be contoured to the 
superior aspect of the femoral head. CTV3 
should be modified to exclude bone, muscle, 
and bowel. The CTV should not extend 
inferior to the ischial tuberosities. 
CTV_4760 
(for SIB 
schemes 
only) 
CTV to receive 47.6 Gy 
Required 
  
Same as description of CTV_4500 above 
CTV_Boost 
(for SIB 
schemes 
only) 
CTV to receive 54.0-59.4 
Gy  
Required 
 
Gross pelvic lymph nodes 
ITV_4500 
 ITV to receive 45 Gy 
Contouring is required 
only when ITV 
approach is used. 
Patients should be simulated with both a full 
and empty bladder (i.e., 2 simulation scans). 
CTV1-CTV3 and PTV1-PTV3 should be 
delineated as described above on the plan 
used for treatment (either the full or empty 
bladder scan), and CTV1 should be 
delineated on both scans. The CTV1 from 
both scans should be fused together to 
generate ITV_4500. A 7 mm margin should 
be applied to generate PTV4.  
PTV_4500 
PTV to receive 45 Gy 
Required 
Around CTV1, a 15 mm uniform expansion 
should be used. Around CTV2, a 10 mm 
uniform expansion should be used. Around 
CTV3 (and CTV_boost, if applicable), a 5 
mm uniform expansion should be used. 
These expansions will generate PTV1, 
PTV2, and PTV3, respectively. PTV1-3 will 

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INTERTECC TRIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.5 Treatment Planning and Delivery 
9.5.0 General  
The experimental arm (Arm A) will be treated with image-guided bone marrow sparing 
IMRT (section 9.5.4.4.2). Standard radiation therapy (Arm B) will consist either of a 
conventional 4-field box technique (section 9.5.3) or non-bone marrow sparing IMRT 
(section 9.5.4.4.1). Bone marrow will not be used as an avoidance structure in 
treatment planning for patients assigned to Arm B.  
 
9.5.1 Photon Energy 
All treatment plans must use 6-18 MV photons. Heterogeneity corrections should be 
applied. 
 
9.5.2 Setup Verification 
For patients treated with conventional techniques, MV portal verification is required at 
least weekly. For patients treated with IMRT, skeletal imaging (e.g., kV imaging and/or 
CBCT) must be performed daily to verify setup accuracy.  
 
For patients undergoing CBCT with each fraction, at the time of simulation, the isocenter 
should be placed along the patient’s midline 1.5 cm caudal to the inferior border of the 
sacroiliac joint. Patients will undergo CBCT acquisition prior to each fraction, for a total 
of 25 scans. CBCTs should be obtained in half-fan mode, using 125kV, 80mA, and 
25ms/frame. If a marked discrepancy is observed between the patient’s imaged anatomy 
on the day of treatment versus the day of simulation, at the treating physician’s 
discretion, the patient may be taken down off the machine (e.g., to void the bladder or 
rectum) and may be treated later that same day. If the anatomical discrepancy is still 
present, the treating physician may elect to postpone treatment, and re-simulation 
be fused to generate the PTV. If the ITV 
approach is used,  PTV4 should be fused 
with PTV1-PTV3 to generate PTV_4500. 
PTV_4760 
(for SIB 
schemes 
only) 
PTV to receive 47.6 Gy  
Required 
 
Same as description of PTV_4500 above 
PTV_Boost 
(for SIB 
schemes 
only) 
PTV to receive 54.0-59.4 
Gy  
Required 
5 mm uniform expansion around CTV_Boost 

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INTERTECC TRIAL 
 
should be considered. 
 
9.5.3 Conventional Radiation Therapy (Arm B only) 
9.5.3.1 Field Arrangement 
Conventional RT consisting of a 4-field “box” arrangement using opposed AP/PA 
and lateral fields is allowed for patients randomized to Arm B. For conventional 
RT, it is permissible to use bone landmarks to draw field borders or to use 3-D 
planning with explicit targeting as outlined above, using customized blocking to 
encompass the PTV. If explicit targeting is used, follow the target coverage 
requirements in 9.5.3.4. If bone landmarks are used, use the following portals: 
 
 
 
• Superior border: L4-5 
 
 
• Lateral border: 1-2 cm lateral to the border of the true pelvis 
• Inferior border: Obturator foramen or 4 cm inferior to vaginal cuff,  
whichever is lower 
• Anterior border: line from pubic symphysis to 1 cm anterior to common  
iliac nodes at L4-5 
 
 
• Posterior border: draw border posterior to or splitting the sacrum from  
S1-S4 
• Custom blocking to shield femoral heads. Do not block the obturator foramen or 
within 1 cm of the common iliac nodes 
 
9.5.3.2 Prescription Dose 
The initial prescription dose will be 45.0 Gy in 1.8 Gy fractions to the PTV.  
PTV_boost (if defined) may receive an additional 9.0-14.4 Gy, either with 
conventional techniques or IMRT, at the discretion of the treating physician. 
 
9.5.3.3 Normal Tissue Constraints and Compliance Criteria 
No criteria for normal structure doses are applied for Conventional RT. 
 
9.5.3.4 Target Volume Constraints and Compliance Criteria 
If 3-D planning is used, create the volume CTV_4500 as the union of CTV1, 
CTV2, and CTV3, and use the following guidelines: 
 
 
 
9.5.4 General Intensity Modulated Radiation Therapy Criteria (Arm A or B) 
 
9.5.4.1 Beam arrangement 
IMRT plans may include static field arrangements (e.g. 5-9 fields), modulated arc 
therapy, or Tomotherapy. Pseudo-step wedge techniques are also permitted.  
 
9.5.4.2 Prescription dose 
For sequential boost plans or plans with no nodal boost, the initial prescription 
dose will be 45.0 Gy in 1.8 Gy fractions to the PTV.  PTV_boost (if defined) may 
receive an additional 9.0-14.4 Gy, with IMRT, at the discretion of the treating 
Name of 
Structure 
Dosimetric 
parameter 
Per Protocol 
Acceptable 
Variation  
Unacceptable 
Variation  
CTV_4500 
DMin (Gy) 
≥ 41.85 
≥ 40.5 
< 40.5 
DMax (Gy) 
≤ 48.15 
≤ 51.75 
> 51.75 

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physician.  
 
For simultaneous integrated boost technique, the primary PTV should be treated 
to 47.6 Gy in 1.7 Gy fractions (28 fractions) and PTV_boost should be treated to 
59.4 Gy in 2.12 Gy fractions (28 fractions). At the discretion of the treating 
radiation oncologist, the fraction size to PTV_boost may be reduced as low as 
1.93 Gy (i.e., total dose 54.0 Gy), in order not to overdose adjacent bowel or 
other critical normal structures.  
 
If a pseudo-step wedge technique is used, the central pelvis (i.e., PTV1) should 
receive 20 Gy, with the remainder of dose to the central pelvis delivered via 
brachytherapy. Cervical cancer primaries should be boosted using intracavitary 
brachytherapy (see section 9.6), unless the patient refuses or is otherwise unable 
to undergo brachytherapy or is treated at a center without access to 
brachytherapy (see section 9.8).   
 
9.5.4.3 Target Volume Constraints and Compliance Criteria 
 
 
 
 
 
 
 
 
*Minimum dose 
*Minimum dose is applied to a 54 Gy prescription and maximum dose to a 59.4 Gy 
prescription. 
 
 
9.5.4.4 Normal Tissue Volume Constraints and Compliance Criteria 
 
 
 
 
9.5.4.4.1 Non-Bone Marrow-Sparing IMRT (Arm B only)* 
 
*Note that Bone Marrow should not be used as an avoidance structure for patients 
treated on Arm B 
 
Name of 
Structure 
Dosimetric 
parameter 
Per Protocol Acceptable 
Variation  
Unacceptable 
Variation  
PTV_4500 
D95% (Gy) 
≥ 45 
≥ 43.65 
< 43.65 
D97% (Gy) 
≥ 43.65 
≥ 40.5 
< 40.5 
D99% (Gy) 
≥ 40.5 
≥ 39.6 
< 39.6 
DMax (Gy) 
≤ 51.75 
≤ 54 
> 54 
PTV_4760  
D95% (Gy) 
≥ 47.6 
≥ 45 
< 45 
D97% (Gy) 
≥ 46.17 
≥ 41.85 
< 41.85 
D99% (Gy) 
≥ 42.84 
≥ 40.5 
< 40.5 
DMax (Gy) 
≤ 68.31 
- 
> 68.31 
CTV_Boost* DMin (Gy) 
≥ 50.22 
≥ 43.65 
< 43.65 
DMax (Gy) 
≤ 63.56 
≤ 68.31 
> 68.31 
PTV_Boost* D95% (Gy) 
≥ 54 
≥ 51.75 
< 51.75 
D97% (Gy) 
≥ 52.38 
≥ 47.6 
< 47.6 
D99% (Gy) 
≥ 48.6 
≥ 45 
< 45 
DMax (Gy) 
≤ 68.31 
- 
> 68.31 
Dose maximum should occur within the PTV. 

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Name of Structure 
Dosimetric 
parameter 
Per Protocol 
Acceptable 
Variation  
Unacceptable 
Variation  
Bladder 
D50% (Gy) 
≤ 45 
≤ 55 
> 55 
DMax (Gy) 
≤ 50 
≤ 57.5 
> 57.5 
Rectum 
D50% (Gy) 
≤ 45 
≤ 54 
> 54 
D60% (Gy) 
≤ 30 
≤ 50 
> 50 
DMax (Gy) 
≤ 50 
≤ 55 
> 55 
Bowel 
D30% (Gy) 
≤ 40 
≤ 50 
> 50 
DMax (Gy) 
≤ 59.4 
≤ 62.1 
> 62.1 
V45 (cc) 
≤ 200 cc 
≤ 250 cc 
> 250 cc  
Femurs 
D15% (Gy) 
≤ 30 
≤ 50 
> 50 
DMax (Gy) 
≤ 50 
≤ 55 
> 55 
 
 
 
 
 
9.5.4.4.2 Image-Guided Bone Marrow-Sparing IMRT (Arm A only) 
 
Name of Structure 
Dosimetric 
parameter 
Per Protocol 
Acceptable 
Variation  
Unacceptable 
Variation  
Bladder 
D50% (Gy) 
≤ 45 
≤ 55 
> 55 
DMax (Gy) 
≤ 50 
≤ 57.5 
> 57.5 
Rectum 
D50% (Gy) 
≤ 45 
≤ 54 
> 54 
D60% (Gy) 
≤ 30 
≤ 50 
> 50 
DMax (Gy) 
≤ 50 
≤ 55 
> 55 
Bowel 
D30% (Gy) 
≤ 40 
≤ 50 
> 50 
DMax (Gy) 
≤ 59.4 
≤ 62.1 
> 62.1 
V45 (cc) 
≤ 200 cc 
≤ 250 cc 
> 250 cc  
Pelvic Bone 
Marrow 
 
DMean (Gy) 
≤ 27 
≤ 29 
> 29  
V10 (%) 
≤ 85.5% 
≤ 90% 
> 90%  
V20 (%) 
≤ 66% 
≤ 75% 
> 75%  
Active Bone 
Marrow 
DMean (Gy) 
≤ 28.5 
≤ 30 
> 30  
V10 (%) 
≤ 90% 
≤ 90% 
> 90%  
V20 (%) 
≤ 70% 
≤ 75% 
> 75%  
Femurs 
D15% (Gy) 
≤ 30 
≤ 50 
> 50 
DMax (Gy) 
≤ 50 
≤ 55 
> 55 
 
9.5.5 Parametrial Boost 
Parametrial boost is optional according to the discretion of the treating physician.  
In this case either brachytherapy or external beam radiotherapy (e.g., opposed anterior-
posterior field arrangements with appropriate blocking, to a total dose of 8.0-14.4 Gy in 
4-8 daily fractions) is acceptable. 
 
9.5.6 Re-planning 
Re-planning (such as to account for changes in tumor volume) is allowed. If re-planning 
is necessary, the new treatment plan should meet the same criteria as the initial plan, as 
if the new plan were delivered for the entire treatment course (i.e., 25 or 28 fractions). 
The new treatment plan should be submitted for central review according to the same 
process as the initial plan.  

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9.6 Brachytherapy 
9.6.1 General 
Either low dose rate (LDR) or high dose rate (HDR) brachytherapy is permitted 
according to each institution’s standard. Either standard (point-directed) or 
volume-directed brachytherapy techniques are permitted according to each 
institution’s standard. For institutions wishing to implement pulse dose rate 
(PDR), please contact the study P.I. Interstitial brachytherapy may be used to 
treat disease that cannot be adequately treated with intracavitary treatment. 
External beam radiation and brachytherapy may not be administered on the 
same day. It is recommended to start brachytherapy after delivery of at least 39.6 
Gy of external beam RT.  
 
Iridium-192 should be used for HDR brachytherapy and Cs-137 should be used 
for LDR brachytherapy.  
 
In general, HDR insertions should be separated by a minimum of 24 hours and 
no more than 3 insertions should be performed per week.  
 
For volume-directed brachytherapy, a pelvic MRI (≤ 5 mm slice thickness) should 
be acquired with either the first or second insertion. 
 
9.6.2 Target and Normal Tissue Delineation (for volume-directed brachytherapy) 
The following targets and organs at risk (OAR) will be contoured at each 
insertion, according to the GEC ESTRO Recommendations [81-82]. The MRI 
based target delineation can be reused by superimposition in the process of 
contouring on CT, if for subsequent fractions of brachytherapy only CT can be 
used with the applicator in place. No planning margins will be added to the CTV. 
 
• GTVB: Macroscopic tumor (if present) at time of brachytherapy  
 
• High risk target (HR-CTV): GTVB + whole cervix + presumed extra 
cervical tumor extension  
 
• Point-A (left and right) - Measure 2 cm along the intrauterine tandem 
from the cervical os or flange of the tandem and 2 cm laterally in the 
plane of the intracavitary system. 
 
• Bladder (the outer bladder wall is contoured) 
 
• Rectum (the outer rectal wall is contoured from above the anal sphincter 
to the level of transition into the sigmoid) 
 
• Sigmoid (the outer sigmoid wall is to be contoured from the recto-
sigmoid flexure to 2 cm superior to the parametria and the uterus  
 
• ICRU bladder point  
 
• ICRU rectal point  
 

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9.6.3 Prescription Dose and Fractionation 
For HDR, permissible dose/fractionation schemes are: 
 
• 5.5 Gy x 6 fractions 
• 5.5 Gy x 5 fractions 
• 6.0 Gy x 5 fractions 
• 6.0 Gy x 6 fractions 
• 7.0 Gy x 3 fractions 
• 7.0 Gy x 4 fractions 
• 7.0 Gy x 5 fractions 
• 7.5 Gy x 3 fractions  
 
 
For LDR, 35-40 Gy (80-85 Gy total in EQD2, α/β=3, T1/2 = 1.5 hours) will be 
delivered to point A in 1-2 insertions. If 2 insertions are used they should be 
separated by a minimum of 7 and maximum of 21 days. 
 
For volume-directed brachytherapy, the following dose-volume criteria for HR-
CTV should be met: 
 
EBRT + Volume-directed Brachytherapy 
Note: Dose to HR-CTV is cumulative EQD2 (α/β=3, T1/2 = 1.5 hours).  
 
9.6.4 Normal Tissue Dosimetric Criteria 
 
EBRT+ Brachytherapy 
Name of Structure 
Dosimetric 
parameter 
Per Protocol 
Acceptable 
Variation 
Unacceptable 
Variation 
LDR point-directed/HDR Volume-directed  
Bladder 
(ICRU reference point) 
DMax (Gy) 
≤ 85 
≤ 90 
> 90 
Rectum 
(ICRU reference point) 
DMax (Gy) 
≤ 80 
≤ 85 
> 85 
Vaginal_Surface* 
(reference point) 
DMax (Gy) 
≤ 150 
≤ 175 
> 175 
Sigmoid** 
DMax (Gy) 
≤ 75 
≤ 80 
> 80 
HDR Point-directed 
Bladder 
(ICRU reference point) 
DMax (Gy) 
≤ 80 
≤ 85 
> 85 
Rectum 
(ICRU reference point) 
DMax (Gy) 
≤ 75 
≤ 80 
> 80 
Vaginal_Surface 
(reference point) 
DMax (Gy) 
≤ 150 
≤ 175 
> 175 
*For point-directed 
**For volume-directed 
Name of 
Structure 
Dosimetric 
parameter 
Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
HR-CTV  
D90Min (Gy)  
≥ 75  
- 
< 75 
D90Max (Gy)  
≤ 90 
- 
> 90 

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Note: Doses to critical structures are cumulative EQD2 (α/β=3, T1/2 = 1.5 hours). If CT is used 
for planning it is recommended to keep the maximum bowel dose < 25% of the brachytherapy 
prescription dose.  
 
For point-directed brachytherapy, the dose to points A and B, the rectal reference point dose, 
bladder reference point dose, and vaginal surface reference point dose, and central axis isodose 
curve must be calculated and reported. Please follow the definitions in ICRB 38. 
 
For volume-directed brachytherapy, uniform dose volume reporting according to the GEC 
ESTRO guidelines is required. For each fraction the following parameters should be recorded:  
• TRAK  
• D100 for GTV, CTV  
• D90 for GTV, CTV  
• D50 for CTV  
• V100 for CTV 
• D2cc of the bladder, rectum and sigmoid, (converted to EQD2 doses per formula  
EQD2= D X [(d + α/β)/ (2 + α/β)]); use α /β=3. 
• ICRU bladder and ICRU rectal points  
 
9.7 Radical IMRT for boost therapy 
Use of fractionated IMRT in place of brachytherapy to boost gross cervical cancer is 
considered a protocol deviation and is strongly discouraged. If deemed necessary or 
essential for the patient’s care (e.g., if a patient refuses brachytherapy), please notify the 
study PI.  
 
9.8 Stereotactic Boost Radiotherapy 
Patients treated at centers without access to brachytherapy or who otherwise are poor 
candidates for brachytherapy (e.g., refusal, medical comorbidities, etc.) should undergo 
SBRT with 5 fractions of 6 Gy prescribed to the high-risk CTV, with dose constraints 
identical to those for high dose rate, volume-directed brachytherapy (see section 9.6.3). 
In this case it is recommended that the patient undergo arc therapy with a minimum of 
two arcs, and that on-line kV CBCT be used to verify the isocenter prior to each arc 
delivery. Patients should be resimulated for SBRT boost planning.  
 
9.9 Protocol Compliance and Quality Assurance Review 
Quality assurance to verify protocol compliance will be performed by the protocol review 
committee at the UC San Diego. For instructions on data transfer, contact the study PI 
(lmell@ucsd.edu) or the Physics Chair (kevinmoore@ucsd.edu). 
 
External beam treatment plans should be submitted no later than 45 days following 
completion of treatment. Criteria for IG-BMS-IMRT protocol compliance are listed below. 
 
9.9.1 Simulation 
9.9.1.1 Position 
• Per Protocol: supine 
• Deviation: not supine 
 
9.9.1.2 CT Slice Thickness 
• Per Protocol: ≤ 3.0 mm 
• Variation Acceptable: > 3.0 mm and ≤ 5.0 mm 

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• Deviation: > 5.0 mm 
 
9.9.1.3 CT Range 
• Per Protocol: T12 – 5.0 cm inferior to ischial tuberosity 
• Variation Acceptable: ≤ 2 cm deviation from protocol 
• Deviation: > 2 cm deviation from protocol 
 
9.9.2 Target Delineation (IMRT or 3-D planning) 
 
9.9.2.1 CTV_4500 / CTV_4760 
• Per Protocol: includes gross tumor, cervix, and uterus as 
described in section 9.4.3 
• Variation Acceptable: ≤ 1 cm deviation from volumes as 
described in section 9.4.3 
• Deviation: fails to include gross tumor, cervix, or uterus and/or 
any other deviation > 1 cm from volumes as stated in section 9.4.3 
 
9.9.2.2 PTV_4500 / PTV_4760 
• Per Protocol: Minimum 15 mm margin around 
tumor/cervix/uterus, 10 mm margin around upper 
vagina/parametria, 5 mm margin around nodal CTV 
• Deviation: Margins less than described above 
 
9.10 Treatment Modifications 
Modification of the radiotherapy protocol is admissible if necessary in the opinion of the 
treating physician in order to ensure patient safety, but the rationale should be 
documented and communicated to the study P.I. Physicians may consider holding 
treatment for ANC <500/mm3, platelets < 20,000 mm3, febrile neutropenia, or 
uncontrolled bleeding. No radiation dose reductions are allowed, however. Treatment 
may be resumed upon resolution of neutropenia (ANC ≥500/mm3), thrombocytopenia 
(platelets ≥ 20,000 mm3), and febrile neutropenia (temperature<38.0º C). 
 
9.11 Radiation Adverse Events 
Risks and side effects related to radiation therapy include:  
 
Likely (more than 10%)  
• Redness and skin irritation in the treatment area that may result in bleeding 
and/or infection, which may require hospitalization  
  
• Loss of pubic hair in the treated area, usually temporary  
  
• Tiredness  
  
• Nausea and/or vomiting  
  
• Sterility (inability to bear children) in fertile women  
  
• Sterility (inability to produce children) in men  
 
Less Likely (3-9%)  
  
• Diarrhea  
• Sores and bleeding from the bowel (these side effects may occur well after 
treatment and be serious enough to require surgery)  
• Narrowing and dryness of the vagina (birth canal) and genital area with painful 
or difficult intercourse and possibly bleeding  

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• Development of extra tissue (fibrosis) in the anal canal, which may result in 
decreased function  
  
• Long-term dryness of the skin  
 
• Hip, pelvic, or sacral fracture  
  
• Build up of fluid in ankles, feet, and/or legs  
 
Rare, but serious (less than 2%)  
• Narrowing or blockage of the bowel (these side effects may occur well after 
treatment and be serious enough to require surgery)  
  
• Blockage of the urinary tubes  
  
• Development of an abnormal path or connection between organs (fistulae)  
  
• Skin damage (tissue death), which may result in surgery  
• Narrowing of or persistent bleeding in the vagina (birth canal), which may result 
in surgery 
 
10.0 DRUG THERAPY 
10.1 Concurrent chemotherapy will be cisplatin 40 mg/m2 weekly x 6 cycles 
 
 
10.2  Source and Formulation: per institutional standard  
 
10.3 
Administration: Patients will be prehydrated per institutional guidelines. Drug 
preparation is per institutional standard. Supportive treatment will be given 
according to institutional policy. 
 
10.4  Storage and Stability: per institutional standard  
10.1.4  Adverse Events: Incidence rates of adverse events are provided in the 
product package insert.  
 
 
10.1.5  Supply: Drugs used in this protocol are commercially available. 
 
10.1.6  Timing of administration: It is recommended to start chemotherapy on day 
1 of external beam RT but it is acceptable to begin on days 1, 2, or 3 of 
external beam RT.   
 
10.5 Dose Modification 
 
10.5.1 Chemotherapy will be held for: 
• 
ANC < 500 /mm3. 
• 
Platelets < 50,000/mm3. 
• 
Febrile neutropenia or bleeding. 
• 
Persistent (>24 hours) grade 3 or 4 nausea and vomiting. 
• 
Renal Failure (creatinine > 2.0 mg% or creatinine clearance < 50 ml/min). 
 
10.5.2 Criteria for resumption of chemotherapy or holding for other toxicities is per 
institutional policy. 
 
10.5.3 For persistent renal insufficiency, neurotoxicity, or ototoxicity, it is acceptable to 
replace cisplatin with carboplatin per institutional policy. Otherwise, cisplatin 
should be discontinued. 
 

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10.5.4 Modifications from the chemotherapy protocol are admissible if necessary in the 
opinion of the treating physician in order to ensure patient safety, but the 
rationale for treatment modification should be documented and communicated to 
the study P.I.  
 
11.0 SURGERY 
Patients who have undergone hysterectomy are ineligible for the study. Planned radical 
surgery following preoperative chemoradiotherapy is not allowed. 
 
12.0 OTHER THERAPY 
 
12.1 Permitted Supportive Therapy/Procedures: 
12.1.1  Antiemetics 
12.1.2  Antidiarrheals 
12.1.3  Analgesics 
12.1.4  Nutritional and fluid supplementation 
12.1.5  Myeloid growth factors 
12.1.5  Packed red blood cell transfusions 
 
 
12.2 Non-permitted Supportive Therapy 
12.2.1  Erythropoieitic growth factors (e.g. epoetin alfa, epoetin beta, darbepoetin alfa, etc. 
 
13.0 PATHOLOGY AND TISSUE / SPECIMEN SUBMISSION 
13.1 Histologic Confirmation of Diagnosis 
All patients must have pathologically confirmed carcinoma by biopsy or surgical 
pathology. 
 
13.1 Specimen Submission 
No specimen submission is required for this protocol 
 
14.0 PATIENT ASSESSMENTS, FOLLOW-UP, AND DATA COLLECTION PROCEDURES  
 
14.1 General 
Data will be submitted electronically via secure FTP server using the Velos system and 
stored centrally at UC San Diego. For instructions for data transfer, contact the study PI 
(lmell@ucsd.edu). A case report form packet will be provided to participating sites 
including a demographic and health information form (DHIF), disease evaluation form 
(DEF), treatment information form (TIF), symptom and toxicity evaluation form (STEF), 
outcomes evaluation form (OEF), and quality of life (QOL assessments; EORTC QLQ-
C30 and CX24 forms).  
 
 

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14.2 Time Schedule for Assessment, Follow-Up and Data Collection 
 
Study 
Procedures 
Pre-
CRT 
Weekly 
During 
CRT 
Mid- 
Treat-
ment  
(Week 3) 
1 & 2 wks 
post- 
External 
Beam RT 
1 mo. 
post- 
CRTc 
Months 
post-CRTd 
Informed Consent 
X 
 
 
 
 
 
History and 
Physical 
X 
 
 
 
X 
6, 12, 24, 36 
CBC with 
Differentiala  
X 
X 
 
X 
X 
 
Comprehensive 
Metabolic Panelb 
X 
 
 
 
 
 
Cervical / vaginal 
cytology  
X 
 
 
 
 
6, 12, 24, 36 
Diagnostic chest 
x-ray, chest CT, or 
PET/CT 
X 
 
 
 
 
6, 12, 24, 36 
Diagnostic pelvic 
CT, MRI, or 
PET/CT 
X 
 
 
 
 
3-4e, 12, 24, 
36 
CT or PET/CT 
Simulation  
X 
 
 
 
 
 
Baseline Data 
(DHIF, DEF, TIF) 
X 
 
 
 
 
 
Evaluation for 
Toxicity (STEF) 
X 
X 
 
X 
X 
6, 12, 24, 36 
Outcomes Form 
(OEF) 
 
 
 
 
X 
6, 12, 24, 36 
QLQ-C30 form 
X 
 
 
 
X 
6, 12, 24, 36 
CX24 form  
X 
 
 
 
X 
6, 12, 24, 36 
RSI (MRI) 
(Substudy only) 
X 
 
X 
 
X 
3-4 
FLT-PET/CT 
(Substudy only) 
X 
 
X f 
 
X f 
3-4f 
     a CBC with differential should be collected weekly during treatment (patient is considered on 
     treatment until all radiation is complete). CBC with differential must be collected in weeks 1  
     and 2 following completion of external beam radiotherapy.  
       b Electrolytes including Mg and Ca, Creatinine, Bilirubin, SGOT, and SGPT  
       c Visit should occur 1 month post completion of all radiation +/- 14 days 
       d +/- 2 months (for initial post-treatment imaging, no earlier than 2 months) 
       e Post-treatment PET/CT at 3-4 months is strongly encouraged to assess for recurrence 
     f If FLT-PET/CT is done at 3-4 months post-treatment, FDG-PET/CT should not be done at  
       this time point. Serial FLT-PET/CT scans will be acquired conditional on funding. 
 
 
 
 
15.0 PATIENT SAFETY AND ETHICAL CONSIDERATIONS 
15.1 Informed Consent  

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Written informed consent will be obtained prior to any study procedures. 
 
15.2 Adverse Event Reporting 
All expected adverse events will be documented on the Symptom and Toxicity 
Evaluation Form (STEF). Any unsuspected or confirmed unanticipated adverse event 
should be reported immediately (within 24 hours) to the study principal investigator 
(lmell@ucsd.edu) and Data Safety Monitoring Committee via the INTERTECC main 
email (irtoc@ucsd.edu). This study will utilize the Common Terminology Criteria for 
adverse events (CTCAE) of the National Cancer Institute for reporting of unanticipated 
serious adverse events (SAE). A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP home page (http://ctep.cancer.gov/reporting/ctc.html). Unanticipated 
SAE information will be collected, documented, and reported comprehensively starting 
with entry into the study and continuing through 1 month post treatment. SAEs will be 
reported to the study principal investigator, the patient’s institution’s IRB, and the Data 
Safety and Monitoring Committee. This reporting will include a description of the event, 
the subject’s study identification number, severity of the event, and its suspected cause. 
This form will include timing, severity and perceived causation of the events and followed 
until they either stabilize or resolve.  
 
15.3 Steps to Determine If an Adverse Event is Reported in an Expedited Manner 
Step 1: Identify the type of adverse event using the CTCAE v4.  The CTCAE v4 provides 
descriptive terminology and a grading scale for each adverse event listed.  A copy of the 
CTCAE v4 can be downloaded from the CTEP home page 
(http://ctep.cancer.gov/reporting/ctc.html).  Additionally, if assistance is needed, the NCI 
has an Index to the CTCAE v4 that provides help for classifying and locating terms.   
 
 
Step 2:  Grade the adverse event using the NCI CTCAE v4. 
 
Step 3:  Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
Unrelated, Unlikely Related, Possibly Related, Probably Related, and Definitely 
Related. 
Note:  This includes all events that occur within 30 days of the last day of 
protocol treatment.  Any event that occurs more than 30 days after the last day of 
treatment and is attributed (possibly, probably, or definitely) to the treatment must 
also be reported according to the instructions above. 
 
Step 4:  Determine the prior experience of the adverse event.  Expected events are 
those that have been previously identified as resulting from administration of the 
treatment.  An adverse event is considered unexpected, for expedited reporting 
purposes only, when either the type of event or the severity of the event is not listed in: 
 
• the current known adverse events listed in the STEF of this protocol ; 
• the investigator’s brochure or the drug package insert  
 
 
Step 5:  Review Section 15.2 to determine if: 
• there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 
• there are any protocol-specific exceptions to the reporting requirements. 
 

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15.4 Reporting Requirements for Serious Adverse Events  
The investigator will report all unexpected SAEs that are determined to be possibly, 
probably or definitely related to the research within 10 working days of learning of the 
event to both the principal investigator (lmell@ucsd.edu) and the Data and Safety 
Monitoring Committee via the INTERTECC main email (irtoc@ucsd.edu).  
 
Toxicities from Experimental Treatment  
• 
Death on Study - regardless of cause: Written Report  
• 
Grade 4 anaphylaxis: Written report 
• 
All other expected toxicities, grades 1-4: Report in Continuing Review. 
 
15.5 Criteria for Removal from Protocol Therapy  
a) 
Unacceptable toxicity requiring removal from study. 
b) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
c) 
Physician determines it is in the subject’s best interest. 
d) 
Patient refusal of protocol therapy 
 
15.6 Criteria for Removal from Study 
a) 
Loss to follow-up. 
b) 
Withdrawal of consent for any further data submission. 
 
 
15.7 Data and Safety Monitoring Plan 
The INTERTECC Data and Safety Monitoring Board will assume the responsibility for 
the data and safety monitoring. Monitoring will be conducted remotely by review of 
electronically submitted eligibility forms, consents, primary endpoint data, and treatment 
plans. On-site audits by members of the DSMB will also be conducted at least once for 
each collaborating site, to review sample charts for registered subjects. All adverse 
events will be reported to the IRB in accordance with regulations. Confidentiality of data 
will be maintained through subject de-identified numbers, the use of locked cabinets to 
store paper records, and a secure database which is maintained at the Moores UC San 
Diego Cancer Center.  
 
Study data will be collected and managed using Velos electronic data capture tools 
hosted at the Clinical and Translational Research Institute at UC San Diego. Velos is a 
secure, web-based application designed exclusively to support data capture for research 
studies. Velos provides: 1) an intuitive interface for data entry (with data validation); 2) 
audit trails for tracking data manipulation and export procedures; 3) automated export 
procedures for seamless data downloads to common statistical packages (SPSS, SAS, 
Stata, R); 4) procedures for importing data from external sources; 5) tools for on-the-fly 
generation of plots, descriptive statistics, and reports for study monitoring and quality 
assurance; and 6) advanced features, such as branching logic and calculated fields. 
Creation of the forms via Velos web interface will be conducted by Dr. Mell in 
conjunction with the Clinical and Translational Research Institute (CTRI) Biostatistics 
team at UC San Diego. 
 
15.8 Confidentiality Procedures 

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All acquired data will be stored at UC San Diego on a secure password-protected server 
with access limited to the principal investigator, co-investigators, clinical trial coordinator, 
and authorized personnel (e.g., post-doctoral researchers, etc.). The database will be 
de-identified by removing subjects' names and only maintaining the subjects' medical 
record numbers as a unique identifier. Similarly, data acquired locally at each 
participating institution will be stored on a secure password-protected server with access 
limited to the site principal investigator, co-investigators, and authorized personnel. 
Deliberations and recommendations of the Data and Safety Monitoring Committee are 
strictly confidential. Each member of the Data and Safety Monitoring Committee must 
sign a statement of confidentiality.  
 
15.9 Oversight of Other Centers and Dissemination of Information 
 
 
Whenever there is an adverse event reported or a protocol amendment or change in the 
consent form or interim results or other information that may impact the risks to subjects 
or others, the study PI and/or coordinator at UC San Diego will notify all the institution’s 
PI’s and study coordinators via email. 
 
16.0 STATISTICAL CONSIDERATIONS 
16.1 Definition of Primary Endpoint 
 
The primary endpoint of this study is progression-free survival (PFS). Patients will be 
randomized in a 3:2 ratio favoring the experimental arm. Unequal randomization is justified 
based on the “learning curve” argument as described by Dumville et al. [76].  Event time 
is calculated as the time from randomization to the date of first evidence of disease 
progression or death due to any cause. Event times will be censored for surviving patients 
if there is no evidence of disease progression at the latest follow-up assessment or if the 
patient is lost to follow-up. If a new therapeutic course for cervical cancer is initiated after 
completing protocol therapy without documented evidence of progression, a progression 
event will be considered to have occurred at the time the therapeutic course is initiated.  
 
Prior data indicate that the median time to progression or death on the control treatment 
is 3.2 years, and that with better chemotherapy delivery, this may be extended to 5 years 
or more [12,75]. If the true median PFS times on the control and experimental 
treatments are 3.2 and 5 years, respectively, we will need to study 275 experimental 
subjects and 137 control subjects to be able to reject the null hypothesis that the 
experimental and control survival curves are equal with 80% power and alpha=0.05.    
 
16.2 Sample Size and Study Duration 
16.2.1 The primary aim of the study is to test whether treatment with IG-BMS-IMRT 
improves progression-free survival compared to treatment with standard of care. For this 
aim we consider a 2-arm group sequential design with progression-free survival as the 
primary endpoint. The sample size is based on testing the hazard ratio (HR) for 
Treatment A vs B. We test the two-sided hypothesis: 
 
 
 
Based on past data [12] we assume that median survival in the standard care group is 
3.2 years, and we power against the alternative that median survival in the IG-BMS-
IMRT group is 5 years, i.e. that the hazard ratio is as small as 0.64. The total sample 

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size is 415 patients and a total of 163 events is required for the final analysis. Planned 
recruitment duration is 5 years and the minimum follow-up planned is 1 year. Thus, the 
total expected study duration is 6 years. Enrollment is assumed to be constant at a rate 
of 83.0 patients per month. The assumed dropout rate is 5% per year. There is a single 
interim analysis planned after 82 events have accrued which is expected to occur after 
approximately 3.9 years. 
 
Timing, number of events, sample size, and boundaries (Z-values, nominal p-values, 
approximate hazard ratios) are shown in Table 16.1, as well as the probability of 
crossing study boundaries under the null and alternative hypotheses. Following are plots 
of the Z-values (Figure 16.1) and approximate hazard ratios (Figure 16.2) at the design 
bounds. Table 16.2 shows the effect of the drop-out rate and randomization ratio on the 
design. 
 
Table 16.1 Progression-free survival trial design with HR=0.64, 80% power and 
2.5% one-sided Type 1 error. P{Cross} is the probability of crossing the given 
bound (efficacy or futility) at or before the given analysis under the assumed 
hazard ratio (HR). 
 
 
 
Figure 16.1. Z-value Bound Plot 
 
 

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Figure 16.2. Hazard Ratio Bound Plot 
 
 
 
Table 16.2 
 
 
Secondary aims 
In secondary analyses, we will further test the effect of treatment on hematologic 
and gastrointestinal toxicities. Hematologic toxicity is typically measured with numeric 
biomarkers such as neutrophil count. Also of particular interest in this study are patient-
reported outcomes pertaining to health and quality of life. The EORTC QLQ-C30 and QLQ-
CX24 instruments will be used to measure gastrointestinal toxicity as experienced by 
patients. 
Specifically, a composite of QLQ-C30 item Q17 and CX-24 item Q32, which deal with 
diarrhea and bowel control, will be considered. Responses to each item are numeric with 
integer values from one to four. Both the hematologic biomarkers and the quality of life 
instruments yield quantitative outcomes. The mean response between treatment groups 
will be tested using two-sided, two-sample t-tests. Table 16.3 below gives the power of the 
tests based on the sample size from the primary outcome, correcting for multiple testing. 
 
Table 16.3: Power for the secondary analyses. The table shows the power for the two-
sample, two-sided t-test based on a sample size of 102 patients per group. The 
calculations assume that two tests are performed; a Bonferroni correction is used to 
maintain a family-wise type-1 error rate of 0.05. Since some outcomes are patient-
reported and subject to missing-ness, the columns index the effective sample size in 

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terms of the compliance rate. Rows index the effect size under the alternative 
hypothesis. 
 
 
 
FLT/RSI Imaging Substudy Aims 
 
Patients treated on the FLT/RSI substudy must have access to FLT-PET and RSI (i.e., 
be treated at UCSD or participating institutions with access to this technology). The 
primary aim of the imaging substudy is to compare the rate of acute grade ≥ 3 
hematologic toxicity with FLT-PET-guided BMS-IMRT vs. the other 2 arms. Based on 
prior institutional and published data [12,74] the probability of acute hematologic toxicity 
with multiagent concurrent chemoradiotherapy (institutional standard) is 45% or more. If 
the relative risk (RR) of toxicity for patients receiving experimental therapy (FLT-PET-
guided BMS-IMRT) is 0.5, we will be able to reject the null hypothesis that RR=1 with 
80% power, with a 1-sided Type I error of 15%, with 60 subjects (30 experimental, 30 
control). Based on prior accrual at our institution this is a feasible accrual goal, and 
based on prior published data this effect size is plausible. We will use an uncorrected 
chi-squared statistic to test the null hypothesis. At the conclusion of the trial, we will also 
compare hematologic toxicity for all patients treated with FLT-PET-guided BMS-IMRT 
vs. FDG-PET-guided BMS-IMRT vs. usual care.  
 
All 60 patients will undergo serial RSI imaging before (<4 weeks before treatment), 
during (at 3-4 weeks), immediately following (2-4 weeks after), and 3-4 months after 
chemoradiotherapy at the UCSD Multimodal Imaging Lab (MMIL). Regions of interest 
(ROIs) will be delineated on both MRI and PET/CT, and both cellularity indices (z-
scores) and standardized uptake values (SUV) will be collected, respectively, for each 
subject before and after treatment. ROIs will be defined and z-scores and SUVs 
calculated using commercially available software. We will compare the changes in mid-
treatment and post-treatment cellularity indices within the tumor on RSI to the change 
from baseline to 3-4-months using PET/CT. We expect to see inter-patient 
variation in the degree of response measured by change in cellularity and change in 
SUV. At the end of the study we will plot the distribution of observed changes in 
cellularity indices and the change in z-score vs. change in SUV for patients undergoing 
both FDG-PET/CT and FLT-PET/CT. Statistical tests will be performed using a rank 
correlation test (z-score versus SUV). 
 
 
16.2.2 The study duration will be 5 years (3 years for the imaging sub-study). The 
accrual period will be 4-5 years and the expected accrual rate is 3-4 patients per month. 
Subjects will be followed for long-term outcomes and toxicity for up to three years.  
 

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16.2.3 Patients will be randomized at the time of registration. Randomization will be 
done at UCSD with stratification on age and stage using randomized blocks of size 4. 
  
16.3 Plan for Data Analysis 
16.3.1 Time to recurrence will be defined as the time from study enrollment to the time of 
recurrence of disease, determined by biopsy or imaging. If biopsy is not obtained to 
confirm diagnosis of recurrence, treatment failure will be determined to have occurred 
only if the patient undergoes a change in management on the basis of the imaging 
results (e.g., salvage or palliative therapy or hospice referral). Local recurrence will be 
defined as persistence or recurrence of tumor at the cervix or vaginal cuff. Regional 
recurrence will be defined as recurrence of tumor elsewhere in the pelvis or para-aortic 
nodal region (if treated). Distant recurrence will be defined as recurrence of tumor 
outside of the treatment field, including the para-aortic nodal region. Time to locoregional 
recurrence will be defined as the shortest time to local or regional recurrence, whichever 
occurs first. Time to recurrence will be defined as the shortest time to locoregional or 
distant recurrence, whichever occurs first. The cumulative probability of recurrence will 
be estimated using cumulative incidence functions, considering other first events (such 
as deaths) as competing events.  
 
16.3.2 Disease-free survival will be defined as freedom from recurrence or death. 
Disease-specific survival will be defined as freedom from death due to cervical cancer. 
Overall survival will be defined as freedom from death due to any cause. These 
outcomes will be estimated using Kaplan-Meier survival curves with 95% confidence 
bands. Final outcomes will be assessed at the conclusion of the study, three years after 
enrollment of the last patient. 
 
16.3.3 Analysis of the phase III data will be according to intention to treat. If significant 
site-to-site variability is observed, we will plan to model this in phase III using frailty or 
mixed-effects models. 
 
16.3.4 Analysis of the phase III longitudinal QOL data will use linear random effects 
modeling, adjusting for important covariates such as the baseline QOL in addition to the 
treatment assignment. Nested random effects can also be used to model site-to-site 
variation. Non-informative missingness in the data is naturally accommodated by the 
random effects models. The QOL data at 1 month post treatment will be correlated with 
peak toxicities which occur during that month. 
 
16.3.5 Primary and secondary endpoints will be analyzed according to several factors, 
as listed in the schema (section 1.0). Differences in proportions will be tested using the 
chi square or t test. Differences in time to events will be analyzed using the log rank test 
or Gray’s test and/or inclusion as covariates in multi-variable Cox proportional hazards 
models. We will use Forest plots to analyze treatment effects within subgroups. 
 
16.3.6 Missing data 
Differences in baseline characteristics between those lost to follow-up and those 
completing the protocol will be assessed using chi-square or t-test. A worst-case 
sensitivity analysis will be conducted to assess whether findings are robust to the 
missing data. 
 
16.3.7 Site effects 

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We will use logistic and proportional hazards mixed-effects regression models to test for 
and, as necessary, model site effects on safety and efficacy outcomes [72-73]. 
 
17.0 REFERENCES 
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. 
CA Cancer J Clin 2011;61:69-90. 
2. WHO GLOBOCANdatabase: http://www-dep.iarc.fr/, accessed March 31, 2015. 
3. Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and adjuvant 
hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB 
cervical carcinoma. N Engl J Med 1999;340:1154-61. 
4. Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy 
compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J 
Med 1999;340:1137-43. 
5. Eifel PJ, Winter K, Morris M, et al. Pelvic irradiation with concurrent chemotherapy 
versus pelvic and para-aortic irradiation for high-risk cervical cancer: an update of 
radiation therapy oncology group trial (RTOG) 90-01. J Clin Oncol 2004;22:872-80. 
6. Peters WA 3rd, Liu PY, Barrett RJ 2nd, et al. Concurrent chemotherapy and pelvic 
radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after 
radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 
2000;18:1606-13. 
7. Whitney CW, Sause W, Bundy BN, et al. Randomized comparison of fluorouracil plus 
cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA 
carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology 
Group and Southwest Oncology Group study. J Clin Oncol 1999;17:1339-48.   
8. Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and 
chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144-53. 
9. Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant 
chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and 
meta-analysis. Lancet 2001;358:781-62. 
10. Green J, Kirwan J, Tierney J, et al. Concomitant chemotherapy and radiation therapy 
for cancer of the uterine cervix. Cochrane Database Syst Rev 2005;(3):CD002225. 
11. Dueñas-Gonzalez A, Cetina-Perez L, Lopez-Graniel C, et al. Pathologic response 
and toxicity assessment of chemoradiotherapy with cisplatin versus cisplatin plus 
gemcitabine in cervical cancer. Int J Radiat Oncol Biol Phys 2005;61:817-823. 
12. Dueñas-González A, Zarbá JJ, Patel F, et al. Phase III, open-label, randomized 
ctudy comparing concurrent gemcitabine plus cisplatin and radiation followed by 
adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients 
with stage IIB to IVA carcinoma of the cervix. J Clin Oncol 2011;29:1678-85. 
13. Roeske JC, Lujan A, Rotmensch J, Waggoner SE, Yamada D, Mundt AJ. Intensity-
modulated whole pelvic radiation therapy in patients with gynecologic malignancies. Int J 
Radiat Oncol Biol Phys. 2000;48:1613-21. 
14. Lujan AE, Mundt AJ, Yamada SD, et al. Intensity-modulated radiotherapy as a 
means of reducing dose to bone marrow in gynecologic patients receiving whole pelvic 
radiotherapy. Int J Radiat Oncol Biol Phys 2003;57:516–521. 
15. Mell LK, Tiryaki H, Ahn KH, Mundt AJ, Roeske JC, Aydogan B. Dosimetric 
comparison of bone marrow-sparing intensity-modulated radiotherapy versus 
conventional techniques for treatment of cervical cancer. Int J Radiat Oncol Biol Phys 
2008;71:1504-10. 
16. Mundt AJ, Lujan AE, Rotmensch J, et al. Intensity-modulated whole pelvic 
radiotherapy in women with gynecologic malignancies. Int J Radiat Oncol Biol Phys. 
2002;52:1330-7.  

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17. Mundt AJ, Mell LK, Roeske JC. Preliminary analysis of chronic gastrointestinal 
toxicity in gynecology patients treated with intensity-modulated whole pelvic radiation 
therapy. Int J Radiat Oncol Biol Phys 2003;56:1354-60.   
18. Brixey CJ, Roeske JC, Lujan AE, et al. Impact of intensity modulated radiotherapy on 
acute hematologic toxicity in women with gynecologic malignancies. Int J Radiat Oncol 
Biol Phys 2002;54:1388–1396. 
19. Roeske JC, Bonta D, Mell LK, Lujan AE, Mundt AJ. A dosimetric analysis of acute 
gastrointestinal toxicity in women receiving intensity-modulated whole-pelvic radiation 
therapy. Radiother Oncol 2003;69:201-7. 
20. Mell LK, Kochanski JD, Roeske JC, et al. Dosimetric predictors of acute hematologic 
toxicity in cervical cancer patients treated with concurrent cisplatin and intensity-
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