DMH-Based Plan Evaluation and Inverse Optimization in Radiotherapy
Phase: NA
Conditions: Head and Neck Cancer, Lung Cancer, Prostate Cancer
Sponsor: University of Miami

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IRB # 20130751 
NCT02663817 
 
DMH-Based Plan Evaluation and Inverse Optimization in Radiotherapy 
 
 
PRINCIPAL INVESTIGATOR: 
 
 
Ivaylo Mihaylov, Ph.D. 
Associate Professor 
Department of Radiation Oncology 
1475 NW 12th Avenue 
Miami, FL  33136 
Phone:305-243-8223 
Fax: 305-243-5699 
Email: i.mihaylov@med.miami.edu 
 
 
 
 
 
 
 
 
 
VERSION #: 
4 
VERSION DATE: 
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TABLE OF CONTENTS 
 
SCHEMA 3DCT, IMRT, VMAT: .............................................................................................. 3 
SCHEMA SBRT: ................................................................................................................... 4 
HYPOTHESES: ..................................................................................................................... 5 
1.0 
BACKGROUND .......................................................................................................... 5 
1.1 
 Study Disease ......................................................................................................... 5 
1. 2          Rationale ................................................................................................................ 5 
1.3 
 Gender and Ethnicity ............................................................................................. 10 
2.0 
STUDY OBJECTIVES ............................................................................................... 10 
2.1 
 Primary objectives ................................................................................................. 10 
2.2           Secondary objectives ............................................................................................ 10 
3.0 
PATIENT SELECTION .............................................................................................. 10 
3.1 
 Inclusion Criteria.................................................................................................... 10 
3.2 
 Exclusion Criteria .................................................................................................. 11 
3.3 
 Enrollment and Withdrawal .................................................................................... 11 
4.0 
RESEARCH PLAN .................................................................................................... 11 
4.1 
 Assessment of Protocol Eligibility and Enrollment ................................................... 11 
4.2 
 Treatment Planning for Therapy Purposes .............................................................. 12 
4.3 
 CT Exam Specifications ......................................................................................... 12 
4.4 
 Other Imaging Studies ........................................................................................... 13 
4.5 
 Experimental Virtual Treatment Planning ................................................................ 13 
4.6 
 Duration of Study................................................................................................... 14 
5.0 
DOSE MODIFICATIONS ........................................................................................... 14 
6.0 
DATA ANALYSES PLAN .......................................................................................... 14 
7.0 
DATA AND SAFETY MONITORING PLAN ................................................................ 15 
8.0 
HUMAN SUBJECTS INSTRUCTIONS ....................................................................... 15 
9.0 
CRITERIA FOR DISCONTINUATION ........................................................................ 19 
10.0 DATA REPORTING................................................................................................... 19 
11.0 INVESTIGATOR’S RESPONSIBILITIES .................................................................... 19 
APPENDIX I: ....................................................................................................................... 31 
TABLE 1: STANDARD FRACTIONATION CALENDAR ......................................................... 31 
TABLE 2: SBRT CALENDAR ............................................................................................... 31 
  
 

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SCHEMA 3DCT, IMRT, VMAT:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT = computed tomography; MRI = magnetic resonance imaging; 
PET-CT = positron emission tomography; 3DCT = three-
dimensional conformal radiotherapy; IMRT= Intensity Modulated 
Radiotherapy; VMAT = Volumetric Modulated Arc Therapy; CT = 
Computed Tomography Imaging; OARs = Organs at Risk; 
 
Patient with head-and-
neck, lung, or prostate 
tumor
CT imaging for radiotherapy treatment planning. 
MRI and/or PET-CT imaging might also be 
available. All studies part of standard of care. 
Delineation of 
targets and OARs 
and radiotherapy 
treatment planning  
Radiation 
therapy 
Non-contrast CT imaging study midway (between 
fraction 10 and 20) through radiotherapy course. If 
ordered as standard of care will be used in this study 
Radiation 
therapy 
Non-contrast CT imaging study at follow up visit or at least 6 weeks 
post radiation treatment (whichever comes first). If ordered as 
standard of care will be used in this study. MRI and/or PET-CT may 

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SCHEMA SBRT:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SBRT = Stereotactic Body Radiotherapy; CT = Computed 
Tomography Imaging; OARs = Organs at Risk; 
 
Radiation 
therapy 
Radiation 
therapy 
Patient with head-and-
neck, lung, or prostate 
tumor 
Delineation of 
targets and OARs 
and radiotherapy 
treatment planning  
Non-contrast CT imaging study 
Midway (between fraction 3 and 4) 
through radiotherapy course 
CT imaging for radiotherapy treatment planning. 
MRI and/or PET-CT imaging might also be 
available. All studies part of standard of care. 
Non-contrast CT imaging study at follow up or at 
least 6 weekspost radiation treatment (whichever 
comes first). MRI and/or PET-CT may be included 
as standard of care. 

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HYPOTHESES: 
• Mass-based inverse optimization in radiotherapy treatment planning will result in 
a reduction of normal tissue and organs at risk (OAR) doses for desired 
prescription therapeutic doses to the targets. 
• Dose-mass histograms (DMHs) may be more relevant to radiotherapy treatment 
planning and treatment plan assessment than the standard of care, realized 
through dose-volume histograms (DVHs) 
 
1.0 
BACKGROUND 
1.1  Study Disease 
Lung cancer is the third most commonly occurring non-cutaneous cancer in the USA 
where the estimated number of new cases in 2013 was 228,190. Worldwide, it is the 
leading cancer in both incidence (1.61 million new cases annually) and mortality, 
(1.35 million deaths annually). In the USA alone lung cancer kills approximately 
160,000 individuals yearly – more people than breast, colon and prostate cancers 
combined.1-3 The 5-year actuarial survival estimate for non-small cell lung cancer 
(NSCLC) is approximately 15% for stages III-IV, and better for stages I-II. It has 
been shown that local disease control, using conventionally fractionated dose 
regimens, has not improved in more than a decade.4-14  
 
Approximately 53,000 new cases of head and neck cancers [mostly squamous cell 
carcinoma (HNSCC)] are diagnosed in the United States each year. About two thirds 
of those cases present with a locally advanced disease. HNSCC patients comprise 
another challenging therapeutic category.15-28  
 
Prostate cancer is the most commonly occurring non-cutaneous cancer in the USA 
with a reported incidence of about 238,000 new cases each year. Despite advances 
in early diagnosis and in treatment, its cure remains elusive. Local persistence of 
prostate cancer treated with radiation therapy is under-appreciated. Prostate cancer 
has a long natural history and persistent disease may not be realized for many 
years.29-38 
 
1.2  Rationale 
1.2.1 Standard of Care in Radiotherapy 

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Lung cancer is the most common cause of cancer-related deaths. The prevalent 
histological types are non-small cell (NSCLC) and small-cell (SCLC) lung 
carcinomas. 
Treatment 
options 
include 
surgery, 
chemotherapy, 
and 
radiotherapy. It has been demonstrated that radiotherapy dose of 70 Gy is a 
significant threshold in terms of survival benefits for NSCLC, while doses of ~85 
Gy are required to achieve 30 months of local progression-free survival. Phase I 
RTOG 0117 trial demonstrated that 74 Gy is the maximum tolerated dose in 
combined chemo-radiotherapy for that disease, indicating the detrimental effects 
of chemoradiotherapy which prohibit dose escalation. Single institution studies 
have reported on an improved local control with higher dose levels and/or higher 
doses per fraction, indicating that patients might benefit from radiotherapy dose 
escalation, realized by treatment planning and/or delivery techniques which 
minimize radiation doses to surrounding anatomical organs. In other words, if a 
technique which minimizes radiation dose to healthy tissue is developed, it will 
allow dose escalation (not to exceed an accepted level of healthy tissue toxicity) 
which might improve patient outcomes. Healthy tissue tolerance is very often the 
dose limiting factor for a successful definitive treatment. Symptomatic radiation-
induced lung injury (RILI) occurs in ~30% of the patients, while radiologic 
evidence for RILI occurs in ~50% of the NSCLC cases. Radiographic changes in 
lung (as function of regional dose) have almost linear relation with dose across 
the therapeutic range. Lung toxicity has been correlated with both mean lung 
dose (MLD) and local doses. Published data indicates that the rate of radiation 
pneumonitis (RP) is dependent on MLD and volume indices ranging from V5 to 
V30. The abovementioned data suggest that new strategies for a potential dose 
escalation, through innovative treatment planning and delivery techniques, where 
lower radiation doses are delivered to healthy tissue, need to be explored.10, 12, 14, 
34, 39-91  
 Another challenging group of cancer patients includes head-and-neck squamous 
cell carcinoma (HNSCC) cases. Radiotherapy combined with concurrent 
chemotherapy is commonly used for treatment of stages III-IV of these cancers 
(category 1 level of evidence in the recommendations of the National 
Comprehensive Cancer Network Head and Neck Pane). Although various meta-
analyses have clearly shown that delivering chemotherapy and radiotherapy 
concomitantly (chemoradiation) significantly boosts the effects of radiation alone, 
this approach raises a number of practical challenges, most of them resulting 
from poor treatment tolerance and reduced compliance to the prescribed dose 
levels 
of 
chemoradiation. 
Most 
HNSCC 
patients, 
receiving 
high-dose 
radiotherapy, are affected by severe acute side effects, including mucositis 
(stomatitis), dysphagia, and skin toxicity (radiation dermatitis). Chemoradiation is 

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associated with an even higher incidence of severe (grade 3/4) acute adverse 
events, indicating again the detrimental effects of chemo-radiotherapy 
combination for this treatment site. Although it has been repeatedly substantiated 
that combining radiotherapy with cisplatin and sometimes 5-FU yielded the best 
overall survival data, it can be claimed that the therapeutic potential of these 
drugs has been taken to its limit. An important avenue of research refers to 
advances in radiotherapy planning and delivery and, in particular, intensity-
modulated radiotherapy (IMRT). Compared with conventional techniques IMRT 
allows better sparing of unaffected tissues. The subsequent reduction in 
radiation-induced mucositis and xerostomia may help to decrease the morbidity 
of intensive concomitant chemoradiotherapy.16, 17, 19, 20, 22-25, 92-98  
Radical prostatectomy and radiotherapy are both viable treatment options for 
clinically localized prostate cancer. Both modalities have evolved over time, such 
that to maximize cancer-free survival, while minimizing health-related risks like 
urinary incontinence, bowel incontinence, and sexual dysfunction. However, to 
date there is still not one superior single treatment that is devoid of side effects. 
Notably, three recent randomized trials have shown a consistent improvement in 
biochemical 
failure 
when 
adjuvant 
radiotherapy 
is 
administered 
with 
prostatectomy. However, the price to be paid for the increased control is the 
increased risk for complications and side effects in the radiotherapy arm by a 
factor of two. Over the past decade, many publications have shown that high 
dose IMRT represents optimal form of external beam radiotherapy for localized 
prostate cancer. The combination of IMRT with image guidance has allowed an 
enhanced target precision together with the accompanying reduction in clinical 
target volumes and even perhaps reduction in the treatment related toxicity. 
Therefore, development and incorporation into clinical practices of novel 
advanced radiotherapy planning and delivery techniques will permit us to deliver 
radiation more safely and reduce treatment duration significantly for thousands of 
patients.29-33, 36, 38, 99-118 
Approximately 60% of all cancer patients require radiotherapy for local tumor 
control. Quite often radiotherapy is combined with other treatment modalities 
such as chemotherapy. The current state of the art radiotherapy treatment 
planning and treatment plan evaluation relies on the DVH paradigm, where 
doses to volumes of target and normal anatomical structures are employed.  
Recently however, it has been argued that the effects of delivered radiotherapy 
dose seem to be more closely related to healthy tissue toxicity (and thereby to 
clinical outcomes) when dose-mass-histograms (DMHs) are considered in 
treatment plan evaluation.119-121 So far, mass information has been utilized only 

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in evaluation of treatment plans and radiobiological modeling for NSCLC. DMHs 
were introduced for evaluation and review of thoracic treatment plans. Shortly 
thereafter, the analytic rationale for their application was outlined. Investigation of 
the difference between DVHs and DMHs and their effects on the treatment 
outcomes showed that the deviation range between them is large. It was 
concluded that “the effectiveness of the dose distribution delivered to the patients 
seems to be more closely related to the radiation effects when using the DMH concept”. 
An example figure from Mavroidis et. al., elucidating the grounds for that 
statement, is presented below.  
 
The figure presents DVH and DMH analyses for a breast patient treated with 
radiotherapy. The authors state that “It is shown that the DMH is lower than the 
corresponding DVH meaning that the lung actually receives a lower dose than what the 
DVH indicates. By interpreting these figures in terms of tissue response, it was found that 
the probability for lung complications was changed by 30% of its initial value closer to 
the clinically observed response rate” 
To date no investigation utilizing tissue mass (or density) effects explicitly in 
IMRT optimization process has been undertaken. We have incorporatd mass 
directly in the cost functions for inverse planning, and will study its potential for 
doses reduction to healthy tissue and the magnitude of the potentially achievable 
isotoxic dose escalation. For the first time tissue mass information is used for 

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treatment planning purposes, rather than academic plan review: that is, a shift 
from DVH- to a new, DMH-based, treatment planning paradigm. We will also look 
into the use of tissue density incorporation in the cost function, and optimize dose 
to density rather than dose to volume. Furthermore, we will study global energy 
minimization (as a fundamental physical principal) and its place in inverse 
optimization, since it can be readily incorporated in the development of the 
proposed novel treatment planning framework. From a conceptual stand point 
there is no difference between mass-based and volume based optimization cost 
functions when media with constant density is considered. However, human body 
comprises many different tissues which vastly differ in density, from air cavities to 
bones. Under those conditions the mathematical representation of the mass-
based optimization is more general than the representation of volume-based 
optimization. In other words, volume-based optimization is a special case of 
mass-based optimization in a media with a constant density. Therefore, we 
hypothesize, that applying the more general model (utilized through mass-based 
optimization) will be advantageous in certain situations and we want to explore 
what those situations are.32, 33, 42, 67, 73, 119-126 
 
1.2.2. Volumetric Imaging for Radiotherapy 
 
All patients receiving radiation therapy undergo a high resolution CT scan, which 
is a fundamental step in the current clinical radiotherapy planning process. 
Recently it has become a standard of care to also include complementary 
imaging modalities such as magnetic resonance imaging (MRI) and/or positron 
emission tomography (PET-CT), which helps delineate tumors and normal tissue. 
In addition, it has become quite common to perform MRI and/or PET-CT studies 
on follow-up visits after radiotherapy course completion in order to assess 
treatment outcome. 
 
1.2.3. Treatment Planning for Radiotherapy 
 
Cancer patients are treated according to the standard of care with either 
conformal radiotherapy (3DCRT), intensity modulated radiotherapy (IMRT), 
volumetric modulated arc therapy (VMAT), or a linear accelerator (linac) based 
stereotactic radiation therapy (SRT). Treatment planning is performed with any 
combination of coplanar or non-coplanar fields to deliver the prescribed dose, 
while restricting the dose to the normal tissues to empirically determined dose 
levels. Field arrangements and plan parameter optimization are determined by 

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experienced planners to produce the optimal plan in accordance with volume 
definitions and attending physician prescriptions and goals.86, 127-137  
 
1.3  Gender and Ethnicity 
It is estimated that the patient population who received radiation therapy at UMHC 
between 01/01/2003 and 12/31/2012 consists of 46% White, 10% African American, 
42% Hispanic, and 2% Other. 
 
2.0 
STUDY OBJECTIVES 
2.1  Primary objectives 
• To study and evaluate whether DMHs are better suited for predicting 
radiotherapy response and/or complication (toxicity) than standard of care realized 
through DVHs. 
• To investigate the time-trending changes between patient anatomy and DMH 
inverse radiotherapy optimization. 
2.2  Secondary objectives 
• To develop the conceptual framework for mass-based objective functions for 
inverse planning optimization of radiotherapy treatments. 
• To study different forms of mass-based objective functions. 
3.0 
PATIENT SELECTION 
3.1  Inclusion Criteria 
• Patients must have histologically confirmed head-and-neck, lung, or prostate 
tumors.  
• Patients who will be treated with radiation therapy or concurrent chemoradiation 
therapy. 
• Gross Tumor Volume (GTV) or resection cavity must be visible on CT such that it 
can be delineated as a target for radiotherapy.  
• Patients who are able to understand the investigational nature of this study and 
agree to sign a written informed consent document. 
 
 

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3.2  Exclusion Criteria 
• Pregnant or nursing women will not participate. Women of reproductive potential 
must be offered a pre-treatment pregnancy test and informed of the need to practice 
an effective contraceptive method during the therapy. 
• Patients younger than 18 years. 
• Patients whose size and weight would not allow CT scanning. 
 
No vulnerable populations (fetuses, pregnant women, children, prisoners) will be 
included in this study.   
3.3  Enrollment and Withdrawal 
3.3.1  Enrollment Guidelines 
Study enrollment, as used in this protocol, will be defined as the investigator’s 
confirmation of the subject’s eligibility by signing an eligibility checklist. 
 
3.3.2  Withdrawal Guidelines 
Patients can withdraw at any time if they decide to do so. If, for any reason, the 
attending radiation oncologist decides that patient participation in the study is not 
in their best interest the subject will be withdrawn from the study.  Furthermore, if 
the PI decides to discontinue the study, subjects’ participation will end.   Patients 
who are enrolled on study but not treated will be excluded from all analyses. 
4.0 
RESEARCH PLAN 
To support both currently planned and future investigations, a patient database will be 
established to manage the CT imaging data acquired through this protocol as well as 
other relevant data such as MRI and\or PET-CT studies. All analyses in this study will 
be based on this database. 
4.1  Assessment of Protocol Eligibility and Enrollment 
Eligible patients will be pre-screened by the attending physicians. If the patient is 
deemed suitable, informed consent will then be obtained.  

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4.2  Treatment Planning for Therapy Purposes 
This protocol is a non-therapeutic protocol. Therefore, patients enrolled in this 
protocol will be treated according to the standard of care for IMRT, VMAT, and 
SRT.29, 97, 138-144 Treatment planning will be performed with any combination of 
coplanar or non-coplanar IMRT fields or VMAT fields, to deliver the specified dose 
while restricting the dose to the normal tissues. Field arrangements will be 
determined to produce the optimal plan in accordance with volume definitions. The 
treatment plan used for each patient will be based on analyses of the volumetric 
dose, including DVH analyses of the planning target volumes (PTVs) and critical 
normal structures, as well as evaluation of isodose curves and isodose volumes. In 
addition to the abovementioned analyses (which is according current standard of 
care) our study will evaluate the pertinent DMHs and isomass volumes for all 
anatomical structures of interest. 
In addition to the planning CT scan and/or pre- and post-treatment MRIs and/or 
PET-CTs done routinely as part of standard of care, patients enrolled in this protocol 
will undergo two additional CT imaging studies at different times during the treatment 
course. CT studies are the primary data source for any type of external beam 
treatment planning. The information gained from the repetitive CT scans will be used 
to quantify the volumetric and mass changes of soft tissue (e.g. tumor shrinkage). 
Furthermore, the data will be used to assess the relation among soft tissue changes 
and radiographic features as well as dose-mass and dose-volume histograms, as 
well as the time-trends for DVHs and DMHs.  
All 
head-and-neck 
patients 
will 
be 
immobilized 
using 
custom-fabricated 
thermoplastic face masks affixed to the couch. Lung and prostate patients would be 
immobilized in body immobilization bags such as Alpha Cradles and vacuum 
immobilization bags (or vac-bags). Patients will be immobilized in the intended 
treatment position and imaged with a CT scanner in the same way as for standard 
3DCRT and IMRT/VMAT/SRT treatment planning. The final decision for treatment 
immobilization devices will be left to the discretion of the attending physician. 
4.3  CT Exam Specifications 
 All imaging studies for this protocol will be carried out at our Siemens 16 slice CT 
scanner in the Department of Radiation Oncology, Sylvester Cancer Center 
(SCCC)/SCCC_West/Deerfield Beach/new centers at the University of Miami. All 
subjects enrolled in this study will undergo four high-resolution CT scans. Head-and-
neck and prostate patients will undergo three-dimensional (3D) CT scans, while lung 
patients will undergo time-resolved four-dimensional (4D) CT scans. 4D CT scans 

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allow capturing of the anatomical changes due to human breathing. These studies 
are required for thoracic/abdominal cancers since patient’s anatomy changes 
significantly (on the order of 4-5 seconds) during a course of radiation. We will 
evaluate the effect of these changes on the calculated radiation dose. If applicable, 
i.e. requested by the attending radiation oncologist for therapeutic purposes 
according to the standard of care, the CT exam(s) may use the administration of 
radiocontrast. 
Note that if the attending physician orders a CT scan throughout the course of 
treatment and/or at the follow-up or at least 6 weeks after completion of therapy as a 
standard of care, this CT imaging would be used in our research instead of exposing 
the subjects to additional CT scan for the sole purpose of this protocol. If the midway 
scan or post treatment scan, as ordered by the attending physician, are performed in 
the Radiology Department we would transfer the imaging data from PACS to our 
research treatment planning system for the purposes of this research. 
4.4  Other Imaging Studies 
Complementary to the two additional CT scans proposed in this study all other 
patient imaging data will also be collected for our analyses. This data is part of the 
standard of care used in radiotherapy for cancer and they include MRI and PET-CT 
scans. MRIs and PET-CTs are very often ordered by the attending physicians for 
pre-treatment purposes, where they help delineate targets and OARs for treatment 
planning purposes. Furthermore, MRIs and PET-CTs can also be ordered by the 
treating doctors several weeks post-radiotherapy to assess tumor response, 
potential complications, and to assess treatment outcome. 
4.5  Experimental Virtual Treatment Planning 
The CT data acquired under this protocol will also be used for testing and 
development of our mass-based optimization methods. Those experimental plans 
will not be used for patient treatments. The plans used for patient treatment would 
be based on the standard of care described in section 4.3. Prospective data 
collection of 3D and 4D CT patient scans will be utilized for tallying DVH and DMH 
end-points and their relation to changes in pulmonary function, as well as studying 
interaction between tumor time-trending changes and DMH parameters in NSCLC, 
HNSCC, and prostate cases. All experimental mass-based treatment planning will 
be necessarily retrospective. Should a finding on one of the repetitive CT scans 
necessitate a change in plan or medical intervention, this will be at the discretion of 
the attending physician and will be performed according to the standard of care. 

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4.6  Duration of Study  
Several CT volumetric studies will be performed for each enrolled subject: one 
before the radiotherapy course for patient treatment planning purposes (as part of 
the standard of care), one during the radiotherapy treatment course (between 
fraction 10 and 20 for 3DCT, IMRT or VMAT patients and after fraction 3 for SBRT 
patients), and one at follow up visit or at least 6 weeks post-radiotherapy 
treatment(whichever comes first). The acquisition of these imaging data will require 
approximately 15 additional minutes of the patient time at those visits.  
5.0 
DOSE MODIFICATIONS 
There will be no immediate benefit to the patients from the performed research, since 
their course of treatment will not be affected by the proposed prospective data 
collection. However, an exception might occur if during the CT scans throughout the 
course of treatment a large tumor response (e.g. tumor regression) or normal tissue 
changes are discovered. Such a finding may prompt a radiotherapy treatment plan 
adaptation, which will be left at the discretion of the attending physician. 
6.0 
DATA ANALYSES PLAN  
This clinical imaging study will form a database for future research and development of 
3D and 4D treatment planning approaches for different anatomical sites treated with 
radiotherapy.  Statistical analyses will be used to assess the differences among 
standard of care, realized through DVHs, and our newly proposed mass-based 
optimizations and DMH evaluations.  Those statistical analyses are powered to detect 
clinically significant differences in dosimetry and estimated clinical outcome endpoints 
between various proposed simulated treatment techniques. Significant changes include:  
• 
Dosimetric: a dose variation between the different treatment planning 
approaches for normal tissue structures of more than 7%. 
• 
Estimated clinical outcome:  a ≥5% variation of normal tissue toxicity using the 
generalized equivalent uniform dose (gEUD) metric and isoeffect parameters and 
analyses tools developed by the NCI funded R01 CA163370 research grant.   
We will start with the null hypothesis that no difference between the treatment planning 
approaches is observed for the dosimetric and the estimated clinical outcome 
endpoints. Since patients are treated according to the standard of care and only their 
imaging information is used to estimate the potential outcome benefit of the new 
planning approaches, each patient serves as a control for themselves. Results will 
therefore be paired. The differences between the standard of care inverse optimization 

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and the proposed mass-based schemes for tumors will be tested using one-tailed 
paired t-tests, against a hypothesis that ±3% radiation dose differences in the tumors 
will not have an observable clinical significance The differences between the 
optimization results on the remaining parameters for all healthy anatomical structures 
(within the radiation field) will be tested using standard two-tailed t-tests with the null 
hypothesis set to 0%. We anticipate an enrollment period of five years. 
7.0 
DATA AND SAFETY MONITORING PLAN 
This study is a non-therapeutic study. As described in section 8.4 below the risks to the 
patients are very minimal, given that all of the enrolled individuals will receive radiation 
therapy as a standard of cancer care. No adverse events are expected within the scope 
of our work. Therefore, the data safety monitoring for this study would be performed by 
the PI and the co-investigators. The research team bears responsibility for suspending 
or terminating this study. 
8.0 
HUMAN SUBJECTS INSTRUCTIONS 
8.1  SUBJECT POPULATION 
Data would be utilized from all Department of Radiation Oncology at UM patients 
>18 year old with histologically proven head-and-neck, lung, and prostate cancers 
who will be treated with 3DCT, IMRT, VMAT, and SRT. 
8.2  RESEARCH MATERIAL 
Along with the CT imaging studies and the physical description of the radiotherapy, 
the following data will be collected as well from each subject:  
MRI studies (if any) 
 
 
Toxicities 
PET-CT studies (if any)  
 
Prior Surgery 
Age 
 
 
 
 
Tumor location 
Performance status 
 
 
Diagnostic CT/MRI/PET report 
Histology  
 
 
 
Tumor volume 
Disease stage   
 
 
Medication 
Patient weight           
 
 
Critical structures 
 
 
 
 
 
All of the data recorded will be entered into a database maintained by the principal 
investigator. Majority of that data for each patient is part of either our “record and 
verify” system or UChart. This data includes patient age, performance, histology, 
disease stage, patient weight, prior surgery, diagnostic report, medication. It will be 

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transcribed either by the PI or the study staff. For toxicity we will use CTCAE 4.0 
grading system (cf. Appendix II). Tumor volume and location as well as volumes and 
locations for all adjacent healthy anatomical structures within the radiation field 
would be determined form the radiotherapy treatment plans used for patient therapy. 
8.3  RECRUITMENT PLAN 
All eligible patients will be informed of the opportunity to participate in this study by 
the attending radiation oncologist.  Eligibility will be determined by a completion of 
an eligibility checklist. Specific details of the study, including a copy of the informed 
consent will be provided to all potential subjects. Informed consent can be obtained 
by the attending radiation oncologist, principal investigator, or study coordinator at 
initial consult or at any time prior to radiation therapy planning. The patient will have 
the opportunity to have any questions answered by any of the co-investigators or 
study staff involved.  Subjects must document their consent to participate by signing 
a written informed consent form that includes HIPAA authorization and has been 
approved by the University of Miami IRB. 
8.4  POTENTIAL RISKS 
The CT imaging studies proposed in this study do not subject patients to any 
therapeutic intervention beyond what is prescribed as part of their routine clinical 
care. A synopsis of radiation doses from the proposed imaging studies to be 
delivered to each subject enrolled in this protocol is presented in Table 1. The data 
outlines the CT imaging dose from a single CT scan. This data is for a 4D CT scan. 
4D CT scans deliver more radiation than much more commonly used 3D CT scans. 
Therefore, the presented dose estimates are effectively for upper dose limits. 4D CT 
scanning is relevant only for lungs patients. For head-and-neck and prostate patients 
standard 3D CT protocols will be used. As mentioned above, the 3D CT scans result 
in somewhat lower radiation doses than those outlined in Table 1.  
Table 2 presents the data for cone beam CT (CBCT) and on-board imagers (OBI), 
used on daily basis for patient positioning and pre-treatment localization. The 
cumulative doses in the table are calculated for a standard 35 session course of 
treatment, aiming to deliver radiation dose between 6600 cGy and 7000 cGy 
(depending on the fractional dose) to the tumor(s). In those 35 treatments there will 
be 7 CBCTs (once per week), while the remaining 28 treatments will utilize OBI for 
patient positioning. If a patient undergoes a SRT treatment, then all 3 to 5 fractions 
(which comprise this treatment) will require the use of CBCT. 

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The risk to the participants in our prospective CT data collection is very minimal. The 
therapeutic doses delivered to cancer patients are of the order of 200 cGy in each 
daily fraction. It is evident from Table 1 that imaging dose of ~4 cGy, delivered 
through a 4D CT scan, is ~ 2% of that daily dose. Notably, 2% daily variation in the 
radiation output is within the operational specifications of modern linear accelerators. 
In other words the added imaging dose per one CT scan will be no larger than the 
stochastic variation of the daily machine output. Furthermore, Table 2 demonstrates 
that the dose resulting from 7 CBCT and 28 OBI applications, used as standard of 
care for accurate patient daily localization, is equivalent to four 4D CT studies, i.e. 
one more study that the proposed number in this protocol (we will subject patients to 
one CT which is standard of care and two more for research purposes).  
In summary, the addition of three 3D or 4D CT scans in our prospective data 
collection will have a negligible dosimetric effect on the patients, given that it is only 
6% of a single fractional (daily) dose, or less than 0.2% of the total prescription dose 
over the course of treatment comprised by 35 fractions. 
 
Table 1:  Radiation Doses from CT Imaging 
 
 Scanning protocol  
Depth of 
measurement 
[cm]  
(corresponding 
anatomical 
structure)  
Dose [cGy]  
4D  
1  
(chest wall)  
3.5  
4D  
8  
(heart)  
2.2  
4D  
12  
(lung)  
1.7  
3D large chest  
1  
(chest wall)  
3.0  
 
 
 
 
 
 

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Table 2:  Radiation Doses from CBCT and OBI Imaging 
 
8.5  SAFEGUARDS IF ANY PARTICIPANTS WILL BE VULNERABLE 
Data will be anonymized.  
8.6  PRIVACY 
Once the patient name and medical record number is removed from the data, 
there is nothing in that data which could be used to identify patients. 
8.7  RISK/BENEFIT 
As discussed above, the risk of participating in this study is negligible, except for 
the inconvenience of spending extra time for additional CT imaging. This study is 
part of an effort to develop and investigate new methods for inverse radiotherapy 
plan optimization, which will significantly improve treatment plan quality and 
therefore reduce volumes and doses to normal tissue to be irradiated. Our 
studies will benefit future patients receiving radiation therapy for cancer 
treatment, but the patients enrolled in this study however will not directly benefit 
from the newly developed approaches. This is not a therapy study. Attending 
radiation oncologists may use this imaging data to improve the participating 
subject’s therapy, provided that all applicable FDA and IRB guidelines are 
followed. 
Type of 
imaging 
# of 
imaging 
sessions 
Estimated 
dose per 
session 
Estimated total 
dose 
CBCT 
7 
0.61 cGy 
(x2) 
8.54 cGy 
CBCT (SBRT) 
5 
0.61 cGy 
(x2) 
3.05 cGy 
OBI 
28 
0.08 cGy 
(x4) 
8.96 cGy 

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9.0 
CRITERIA FOR DISCONTINUATION  
• 
Attending physician finds it necessary for patient’s health or safety. 
• 
Patient decides to withdraw from the study. 
• 
The sponsor discontinues the study. 
• 
Administrative reasons require patient withdrawal. 
Although collecting new information about the subject will be stopped, the study team 
may still use the information they have already collected to evaluate the study results. 
10.0 DATA REPORTING 
Data will be submitted according to the protocol requirements for ALL patients 
registered. Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible. A computer based solution will be implemented to 
maintain a complete record of subject and study information and all processing. 
Additional files will be used to maintain a record of all subjects grouped within a single 
project. For the purposes of evaluating the mass-based effects on treatment planning 
and treatment plan assessment, we will add the following items in the data-
management system: (1) Images with outlined treatment volumes for targets and critical 
structures; (2) Images with outlined for targets and critical structures before, during, and 
after radiotherapy; (3) TCP, NTCP calculations, dose-volume histograms, dose-mass 
histograms, gEUDs, and mgEUDs; (4) isdose volumes and isodose masses; (5) 
Physician reports from follow-up exams. 
11.0 INVESTIGATOR’S RESPONSIBILITIES 
11.1 Investigator Responsibility/Performance 
The investigator will ensure that this study is conducted in accordance with all 
regulations governing the protection of human subjects.  
The investigator will ensure that all work and services described in, or associated 
with, this protocol will be conducted in accordance with the investigational plan, 
applicable regulations, and the highest standards of medical and clinical research 
practice. 
11.2  Confidentiality 
To safeguard confidentiality, imaging data for patient enrollees will be transferred to 
a computer workstation which is password-protected and kept in a locked room, 

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accessible only to institutional personnel.  Image data sets will be de-identified by a 
coding system that assures (a) subsequent image displays contain no patient 
identifiers and (b) file names are free of patient identifiers.  Patient-specific images 
and other data will be coded using three digit incrementing ID numbers (001, 002, 
etc.) assigned in order of accrual to the study. The master list documenting 
association between actual patient name and ID number will be accessible only to 
the PI. All data will be stored in secure locations on the University of Miami network 
(i.e., inside the University of Miami firewall). 
11.3  Informed Consent and Permission to Use Protected Health Information  
It is the responsibility of the investigator(s) to obtain written informed consent from 
each subject participating in this study after adequate explanation, in lay language, 
of the methods, objectives, anticipated benefits, and potential hazards of the study. 
The investigator(s) must also explain that the subject is completely free to refuse to 
enter the study or to discontinue participation at any time (for any reason).  Prior to 
study enrollment, each subject will sign an IRB approved informed consent form and 
receive a copy of it (and information leaflet, if appropriate). For subjects not qualified 
or able to give legal consent, consent must be obtained from a parent, legal 
guardian, or custodian. 
The investigator or designee must explain to the subject before enrollment into the 
study that for evaluation of study results, the subject’s protected health information 
obtained during the study may be shared with the study sponsor, regulatory 
agencies, and the IRB.  It is the investigator’s (or designee’s) responsibility to obtain 
permission to use protected health information per HIPAA from each subject, or if 
appropriate, the subjects’ parent or legal guardian. 
11.4  Source Documentation and Investigator Files 
The investigator must maintain adequate and accurate records to fully document the 
conduct of the study and to ensure that study data can be subsequently verified.   
11.5  Ethics 
The investigator agrees to conduct the study in compliance with the protocol, current 
good clinical practices, and all applicable (local, FDA) regulatory guidelines and 
standard of ethics. 
 

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the Art, Colorado Springs, Colorado, 2003 (unpublished). 
 
 
 
 

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APPENDIX I: 
TABLE 1: STANDARD FRACTIONATION CALENDAR 
 
 
 
 
 
 
 
 
 
 
TABLE 2: SBRT CALENDAR 
 
 
 
 
Assessment 
 
 
 
Prior to RT 
Between 
fractions 
10 and 20  
Follow up 
visit or 
atleast 6 
weeks post-
RT 
(whichever 
comes first) 
History & 
Physical Exam 
X 
 
X 
MRI and/or CT 
studies (if 
applicable) 
X 
 
X 
3D/4D CT scan 
X 
X 
X 
 
 
 
Assessment 
 
 
 
Prior to RT 
Between 
fraction 3 
and 
fraction 4 
of RT 
Follow up 
visit  or  at 
least 6 
weeks post-
RT 
(whichever 
comes first) 
History & 
Physical Exam 
X 
 
X 
MRI and/or CT 
studies (if 
applicable) 
X 
 
X 
3D/4D CT scan 
X 
X 
X