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Refined screening guidelines for radiation-related late effects in childhood cancer survivors: a dose-volumetric guided approach

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Refined screening guidelines for radiation-related late effects in childhood cancer survivors: a dose-volumetric guided approach

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Content Refined Screening Guidelines for Radiation-related Late Effects in Childhood Cancer Survivors:
A Dose-Volumetric Guided Approach
By
Sally Josephine Cohen-Cutler
A Thesis Presented to the
FACULTY OF THE USC KECK SCHOOL OF MEDICINE
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(CLINICAL, BIOMEDICAL AND TRANSLATIONAL
INVESTIGATIONS)
August 2020
Copyright 2020 Sally Josephine Cohen-Cutler
ii
Acknowledgements
I would like to acknowledge my incredible mentors and study team for their guidance and
collaboration in the creation of this work. First and foremost, I would like to thank Dr. David
Freyer, who has been an unwavering advocate and supportive mentor. His guidance directly led
to the success of this research and has been integral to my professional development. I am also
grateful to Dr. Arthur Olch and Dr. Kenneth Wong, who were invaluable contributors and
mentors in radiation oncology, and crucial to my understanding of the research question and
data. I would also like to thank Dr. Louis S. Costine at the University of Rochester, who has
served as an outside-institution mentor, and helped to put into perspective the findings of this
work, as well as Dr. Charles Gomer, who generously has served on my thesis committee and
has offered thoughtful insights into the implications and strengths of this research. This project
would not have been possible without the assistance in both planning and analyses from Dr.
Richard Sposto and Jemily Malvar Biostatistics/Bioinformatics Core of the Center for Cancer
and Blood Diseases at the Children's Hospital Los Angeles, and the careful review by Dr. Amit
Sura in the Department of Radiology. I would also like to recognize the hard work of our medical
student from the Keck School of Medicine, Pierre Kobierski, and the support, input, and advice
from my colleagues in the Pediatric Hematology-Oncology program at Children’s Hospital Los
Angeles.

iii
Table of Contents

Acknowledgements.......................................................................................................................ii
List of Tables................................................................................................................................iv
List of Figures...............................................................................................................................v
Abstract .......................................................................................................................................vi
Chapter 1: Radiation-related long-term follow-up practices for childhood cancer survivors:
a comparative study of volumetric dosimetry versus general radiation fields..............................1
Abstract............................................................................................................................1
Introduction......................................................................................................................3
Methods...........................................................................................................................4
Results.............................................................................................................................8
Discussion.......................................................................................................................17

References.................................................................................................................................22
Appendices.................................................................................................................................25
Appendix A: Organ or Anatomic Structure Association with Potential Late
Effect………………….....................................................................................................25
Appendix B: Recommended Screening Practice
Categories. …………………...........................................................................................27

iv
List of Tables
Table 1: Study Cohort Characteristics........................................................................................9

Table 2: Difference in Number of Recommended Screening Practices per Decade of
Follow-Up, per Patient................................................................................................................14

Table 3: Difference in Number of Recommended Screening Practices for Organs with
Radiation Dose-Specific Thresholds.......................…………………….………. ….....................16

Appendix A: Organ or Anatomic Structure Association with Potential Late
Effect…………………………………………………………………………………………………….25

Appendix B: Recommended Screening Practice Categories...................................................27

v
List of Figures
Figure 1: Difference in Number of Late Effects Flagged by LADDRS Compared with
GRF, by Patient..........................................................................................................................11
Figure 2: Number of Screening Practice Actions per Decade per Patient................................13
Figure 2a: All Patients...................................................................................................13
Figure 2b: By Cancer Type...........................................................................................13
Figure 2c: By Sex.........................................................................................................13
Figure 2d: By Age at End of Treatment........................................................................13
Figure 3: Number of Diagnostic Imaging and Procedures per Decade of Follow-Up, per
Patient.......................................................................................................................................15

vi
Abstract
The impact of childhood cancer is felt by survivors far beyond diagnosis and treatment.
Cancer therapy is a significant cause of long-term morbidity and chronic health conditions well
into adulthood for many patients. This has profound implications for patients and families,
impairing patient’s overall health and quality of life. Early detection of late effects of therapy
allows for intervention and may alleviate some of this impact.
Radiation therapy is a cornerstone of many pediatric oncology treatment regimens. While
an effective therapy, it is a well-known contributor to the development of many significant late
effects. Current guidelines for long term follow-up of pediatric cancer survivors recommend
screening based on general regions of the body that received treatment with radiation.
However, modern radiation treatment has evolved to be more specific in treatment of the target
while sparing other anatomic structures. Given this approach, there is less broad regional
exposure. Moreover, detailed data on exact doses to organs at risk of developing late effects is
readily available from treatment planning software by computing the volumetric dosimetry.
We investigated the use of more specific organ-dose information on the application of the
Children’s Oncology Group (COG) Long Term Follow-Up Guidelines, the standard for late effect
surveillance in North America. Using an innovative program to extract treatment data from
radiation planning software, we compared the late effects identified as needing surveillance and
corresponding screening recommendations when using volumetric dosimetry versus general
radiation fields.
The use of volumetric dosimetry to determine exposures significantly reduced late effect
and recommended screening practices. These findings were more dramatic with incorporation
of specific thresholds for organs. This exploratory study is the first to address this question and
will serve as a basis for further investigations into the optimization of long-term follow-up for
radiation therapy for survivors of childhood cancer.
1
Chapter One: Radiation-related long-term follow-up practices for
childhood cancer survivors: a comparative study of volumetric
dosimetry versus general radiation fields

ABSTRACT
Background: Late effects of childhood cancer have significant impact on survivor health and
quality of life, with known increased burden on patients who receive radiation therapy in the
course of treatment. Surveillance for these late effects relies on assessment of dose to general
areas of the body, but modern treatment protocols utilize organ-sparing techniques and are able
to determine exact doses to anatomic structures (volumetric dosimetry). This more specific data
offers a unique opportunity to refine the approach to late effect screening by incorporation of
detailed exposures into the application of long-term follow-up guidelines.
Objective: The objective is to utilize more specific exposure data to apply screening guidelines
in order to optimize long-term follow-up in survivors of childhood cancer by minimizing
unnecessary testing while maintaining adequate surveillance.
Methods: This retrospective, cross-sectional study evaluated childhood cancer survivors
enrolled in our institutional cancer survivorship clinical and research database who had received
radiation as part of their therapy. The Children’s Oncology Group Long-Term Follow-Up
Guidelines were applied using both general radiation fields and volumetric dosimetry, and
outcomes of late effects (Potential Late Effects) identified as necessary for surveillance and
ensuing screening practices (Recommended Screening Practices) were compared.
Results: In the cohort of 132, the majority (61%) of patients received radiation to the head/brain
region. There was significant disagreement between the late effects identified by each method,
with only 7 (5.3%) subjects having the exact same recommendations (p < 0.001). Use of
volumetric dosimetry as compared to general radiation fields significantly reduced Potential Late
Effects by 11.5% (p < 0.001) and Recommended Screening practices by 7.4% (p < 0.001).
2
Incorporation of dose-thresholds in application of volumetric dosimetry reduced Recommended
Screening Practices by 30-100%.
Conclusions: The use of volumetric dosimetry provides more specific treatment information
than general radiation fields, which allows for more tailored application of long-term follow-up
guidelines in survivors of childhood cancer. This approach significantly reduces the number of
late effects to be surveilled as well as the recommended screening practices.

3
INTRODUCTION
Treatment advances have greatly improved outcomes for children and adolescents
diagnosed with cancer, such that 5-year survival now exceeds 80%.1 Cure comes at a cost,
however, as the majority of long-term survivors develop late effects related to their cancer
treatment.1 In particular, radiation therapy causes or contributes to the development of many of
the most predictable and clinically significant late effects, including second malignancies,
neurocognitive deficits, cardiotoxicity, cerebrovascular disease, and musculoskeletal deformity.2
With their capacity to affect virtually any organ system, radiation-induced complications directly
compromise health and reduce quality of life.1,2 In many cases, early detection can mitigate or
prevent these complications through early intervention and risk-reduction strategies. For this
reason, effective screening for late effects of childhood cancer treatment is considered crucial
for improving the duration and quality of life for long-term survivors.1-3
In North America, surveillance for late effects of childhood cancer and its treatment is
based on the Children's Oncology Group (COG) Long-Term Follow-Up Guidelines for Survivors
of Childhood, Adolescent, and Young Adult Cancer.4 Based on a combination of published
evidence and expert consensus, the COG guidelines comprise comprehensive
recommendations for late effects screening and health promotion among cancer survivors
treated with chemotherapy, surgery, and/or radiation therapy.5 The recommendations are
organized by treatment modality with the type, initiation, frequency and duration of screening
measures determined according to individual risk using factors such as cumulative
chemotherapy dose and age at treatment. For survivors treated with radiation therapy, the
recommendations are organized by general radiation fields (GRF), i.e., anatomic regions that
encompass organs-at-risk (OAR), which are then screened as a result of presumed radiation
exposure within those fields. Use of GRF offers the distinct advantage of being readily
applicable to clinical practice, but it provides limited information concerning the actual radiation
dose delivered to the OAR.
4
In contrast, current radiation techniques utilize three-dimensional treatment planning to
provide volumetric dosimetry, i.e., organ-specific dose-volume data yielding more accurate
estimates of actual radiation dose given to the OAR.6-8 Compared with GRF, volumetric
radiation fields (VRF) could be expected to enable more accurate determination of risk for
developing late effects and need for screening.9 Such organ-specific dose-volume data is now
routinely given due consideration in radiation planning to reduce the risk of late effect
development.7 However, no studies have been published, to our knowledge, regarding
incorporation of volumetric dosimetry into guideline-driven surveillance for radiation-related late
effects. Such an effort would be responsive to the call for greater “precision survivorship.”10
To explore this possibility, we undertook this study to evaluate the feasibility and impact
of using VRF compared with GRF for determining COG guideline-recommended late effects
screening and health promotion practices in a cohort of childhood cancer survivors treated with
radiation therapy. The study was facilitated by an automated software system we developed for
importing volumetric radiation dosimetry into our institutional cancer survivorship clinical and
research database.11 The primary aim of our study was to determine and compare the type and
frequency of screening recommended by the COG Guidelines based upon general radiation
fields versus volumetric dosimetry. Our hypothesis was that more specific exposure data would
lead to a decrease in identified potential late effects and recommended screening practices. Our
overall objective was to examine a more nuanced application of well-established screening
guidelines in hopes of maximizing their yield for detecting early pathology while reducing the
burden of potentially unnecessary testing.

METHODS
Study Design and Participants
This was a retrospective, cross-sectional cohort study of childhood cancer
survivors previously treated with radiation therapy at Children’s Hospital Los Angeles
5
(CHLA) and identified using the LIFE Cancer Survivorship Research Database at CHLA. The
LIFE Database comprises cancer survivors who underwent evaluation in the LIFE Cancer
Survivorship Clinic at CHLA and contains patient-specific information concerning demographics,
cancer diagnosis, stage and previous treatment with chemotherapy, irradiation, and/or surgery;
and current health problems including clinical severity and attribution of cause. The LIFE
Database is a research resource approved by the CHLA Institutional Review Board (IRB) and
informed consent/assent is obtained for all participants.
Inclusion criteria for the current study included prior radiation treatment planned with
computerized tomography (CT) for a first diagnosis of cancer at CHLA between 2000 (when
volumetric CT planning of radiation therapy became standard at CHLA) and 2016. Exclusion
criteria included relapsed cancer and radiation treatment planning at other institutions.
Demographic, diagnosis and treatment-related data were recorded from the LIFE database and
supplemented where necessary by medical record abstraction. Cancer diagnoses were grouped
under three major categories reflecting historical clinical oncology team groupings at CHLA:
Bone and Soft Tissue Tumors (BSTT), Leukemia and Lymphoma (LL), and Neural Tumors (NT),
the latter encompassing central nervous system tumors, neuroblastoma, and retinoblastoma.
This retrospective study was approved by the CHLA IRB.
Late Effect Screening Guidelines
Late effects and screening recommendations referenced in this study were drawn from
the Children's Oncology Group (COG) Long-Term Follow-Up Guidelines for Survivors of
Childhood, Adolescent, and Young Adult Cancer, version 5.0.4 Briefly, the COG Guidelines were
introduced in 2004 and represent a combination of evidence and expert consensus-based
recommendations for improving early detection and reducing risk for development of treatment-
related complications. They contain 55 sections describing possible radiation-related late effects
in OAR, and their corresponding periodic evaluations and health counseling.
Determination of Organ Radiation Exposures
6
Radiation exposure was determined in two ways. To determine radiation
exposures consistent with the COG guidelines, radiation fields and their attendant OAR
were used as defined in the COG Guidelines; for purposes of this study, these were
designated “General Radiation Fields (GRF).” To determine organ-specific volumetric
dosimetry exposures, designated “Volumetric Radiation Fields (VRF),” the following
method was used. All patient organs visible on the radiation planning CT scan were
contoured using treatment planning software (Eclipse, Varian Medical Systems, Palo
Alto, CA). Approximately 30% of patients were contoured manually, a selection of which
were used to create a reference atlas in an auto-segmentation program (Velocity, Varian
Medical Systems, Palo Alto, CA) to apply to the remaining patients. Automated contours
were reviewed to ensure accuracy and consistency across the cohort and edited if
incorrectly contoured. For quality assurance, all contoured structures were reviewed by
an experienced radiologist and adjudicated, as needed, by the study team.
The organ contours from the CT scan enabled organ-specific volumetric dose
calculations from the patient’s treated plan. Values were then extracted and integrated
into the LIFE Research Database by the LIFE Clinic Automated Dose-Volume Retrieval
System (LADDRS), a web-based computer program developed at CHLA using the
Application Program Interface for extracting data from the Eclipse treatment planning
system and Microsoft SQL from the Aria database. This program exports organ-specific
volumetric doses, and using predetermined limits, is able to flag potentially toxic doses.11
For the purposes of this study, volumetric dosimetry limits were set as equivalent
to the COG Guideline thresholds for toxicity, which generally relate to whether the region
in question was irradiated or not. Each possible late effect corresponds to a specific
organ contained in the region (Appendix A). For the five organs or anatomic structures
that did have actual dose thresholds defined by COG Guidelines, the threshold to trigger
screening by volumetric dosimetry was set as 50% of the organ having received the
7
guideline-specified dose. For the remaining 50 organs or anatomic structures with no specific
dose limit specified by the COG Guidelines, the threshold to trigger screening by volumetric
dosimetry was set as 10% of the organ receiving a minimum of 5 Gy, a conservative
representation that the region was irradiated. Laterality was considered when applicable, and if
only one side surpassed threshold, late effect screening was triggered for the organ.
Study Procedures and Outcome Variables
For each patient, the study procedure consisted of two steps. First, radiation exposures
were determined by the two methods described above, GRF and VRF. Next, the COG
Guidelines were applied to generate and compare, as derived by each method, the (1) possible
late effects that could be incurred (designated “Potential Late Effects”) and (2) corresponding
recommended periodic evaluations and health counseling (designated “Recommended
Screening Practices"). In this fashion, patients served as their own controls. For purposes of this
study, Recommended Screening Practices were further categorized as History and Physical
Examination Elements, Laboratory Tests, Diagnostic Imaging and Procedures, Referrals to
Specialists, and Health Education and Counseling (Appendix B). In applying the COG
Guidelines, standard demographic and relevant treatment factors were accounted for, including
age at treatment, attained age at time of screening, sex, cumulative anthracycline exposure,
and maximum radiation dose in fields involving the heart. End of puberty was set at 16 years for
females and 18 years for males. To estimate lifetime screening burden, recommendations were
summed over an assumed life span of 80 years. When there was more than one indication for a
screening practice based on multiple organ exposures, only the one with the greater frequency
of screening was used. Data were managed using the Research Electronic Data Capture
(REDCap) platform (http://project-redcap.org/).12,13
Statistical Analysis
Descriptive statistics were used to enumerate the number and type of Potential Late
Effects and Recommended Screening Practices according to each method of determining
8
radiation exposure (VRF and GRF). Mean number of Potential Late Effects was computed for
each approach and compared using the two-sample t-test. Mean number of Recommended
Screening Practices per decade per patient was determined for each approach and the
difference between the two methods was computed and compared using a one-sample paired t-
test. Random effects repeated measures linear regression was utilized to assess differences in
combined Recommended Screening Practices while controlling for effects of sex and cancer
type and repeated for each of the Recommended Screening Practice categories. For the five
Potential Late Effects with dose-specific thresholds defined by COG Guidelines, the number of
patients to whom these applied was determined by GRF and VRF (designated as “at risk”);
corresponding Recommended Screening Practices were then calculated over the remainder of
the full cohort’s lifetime with a lifespan of 80 years. All analyses utilized two-sided tests with
significance level set at p < 0.05 and were completed using Stata statistical software.14

RESULTS
Patient Characteristics
A total of 509 patients were identified as having received radiation in the LIFE Research
Database. After excluding those who were treated before 2000 (n =160), did not undergo
complete CT planning (n=150), or relapsed (n = 67), 132 were eligible for inclusion in the study.
Key clinical and treatment characteristics for the cohort are shown in Table 1. Mean ages at
diagnosis and end of therapy were 9.6 and 10.6 years, respectively. Over 80% of the patients
were treated for solid tumors; CNS tumors accounted for almost half (n=59). Over 80% of
patients received 1-2 unique radiation fields; the maximum number of fields was 5 and the mean
was 1.8. Reflecting the distribution of cancer types, the three most common radiation fields were
head/brain (81/132, 61%), abdomen (29/132, 22%), and spine (20/132, 15%). Forty-one percent
of patients received anthracyclines with a mean cumulative doxorubicin-equivalent dose of 237
mg/m2.
9
n (%)
Clinical Characteristics
Age (y)
Diagnosis
Mean (SD)
Range
End of treatment
Mean (SD)
Range

9.6 (5.4)
0.3-19.8

10.6 (5.3)
1.4-20.4

Sex
Female
Male

52 (39)
80 (61)
Diagnosis type
Neural tumor
CNS tumor*
Neuroblastoma
Retinoblastoma

Bone and soft tissue
Rhabdomyosarcoma
Wilms tumor
Ewings Sarcoma
Other†

Leukemia/Lymphoma
Hodgkin’s lymphoma
Non-Hodgkin’s lymphoma
Leukemia

76 (58)
59 (45)
13 (10)
4 (3)

35 (27)
14 (11)
5 (4)
4 (3)
12 (9)

21 (16)
14 (11)
3 (2)
4 (3)
Radiation Exposure
Unique fields per patient (no.)
1
2
3
4
5

86 (65)
21 (16)
4 (3)
5 (4)
16 (12)
Dose (Gy)
Head/Brain
Mean (SD)
Median
Range
Abdomen
Mean (SD)
Median
Range
Chest
Mean (SD)
Median
Range
Spine
Mean (SD)
Median
Range

48.8 (13.5)
54
12-66.6

27.8 (12.4)
21.6
9-55.8

22.7 (13)
21
10.5-66

31.1 (13.6)
23.4
6-54

81 (61)

29 (22)

20 (15)

20 (15)

10
Neck
Mean (SD)
Median
Range

Pelvis
Mean (SD)
Median
Range
Extremity
Mean (SD)
Median
Range
Axilla
Mean (SD)
Median
Range

26.7 (10.6)
21
21-51.2

42.8 (14.4)
50.4
21-56

46.7 (18.1)
50.4
21.6-70

21 (0)
21
21
19 (14)

12 (9)

10 (8)

8 (6)
Anthracycline Exposure
Exposed 54 (41)
Cumulative dose (mg/m2)‡
0
<250
≥250

78 (59)
34 (26)
20 (15)
*CNS tumors included germ cell tumor (n=12), medulloblastoma (n=12),
ependymoma (n=12), craniopharyngioma (n=7), astrocytoma (n=4), glioma
(n=3), ATRT (n=2), PNET (n=2), chondrosarcoma (n=1), choroid plexus
carcinoma (n=1), giant cell glioblastoma (n=1), gliosarcoma (n=1), mixed tumor
(n=1)
†Other tumors included MPNST (n=2), nasopharyngeal carcinoma (n=2),
synovial sarcoma (n=2), acinar cell carcinoma (n=1), adenoid cystic carcinoma
(n=1), angiofibroma (n=1), chondrosarcoma (n=1), clear cell sarcoma (n=1),
pancreatoblastoma (n=1)
‡ Anthracycline dose expressed in doxorubicin equivalents

Table 1: Study Cohort Characteristics (n=132)

Potential Late Effects Flagged
As the first outcome, we evaluated and compared the number of Potential Late
Effects per patient flagged for surveillance by GRF and VRF. For the full cohort, the
mean number of late effects flagged by GRF and VRF was 24.4 versus 21.7,
respectively (mean difference -2.8 [-11.5%], p < 0.001). Comparing the number of late
effects flagged by VRF compared with GRF, 79 patients (59.8%) had fewer late effects
flagged, 40 (30.3%) had more, and 13 (9.8%) had no change (Figure 1). For those who
had fewer, the mean decrease was -6.5, and for those who had more, the mean
11
increase was 3.8. Only seven patients (5.3%) had the same number and combination of late
effects flagged by both methods but four of these had only radiation of an extremity with no
organ exposure, effectively reducing the number to 3 (2.3%).

Figure 1: Difference in Number of Late Effects Flagged by LADDRS Compared with GRF, by
Patient

Recommended Screening Practices Triggered
As the second outcome, we evaluated and compared the number and type of
Recommended Screening Practices triggered for surveillance of the Potential Late Effects
flagged. Taking all screening practices in aggregate, there was a tendency for patients to have
fewer screening practices triggered with VRF than with GRF, especially for patients needing
approximately 500-600 screening practices (Figure 2, Panel A). Using VRF, 90 (68.2%) patients
had fewer Recommended Screening Practices in comparison with GRF, and 8 (6.1%) had the
same number. When examining this tendency according to other patient characteristics, the
12
reduced number of Recommended Screening Practices with VRF appeared to be more
striking for neural tumors compared with other cancer types (Panel B), whereas the
reductions were relatively balanced for sex (Panel C) and age (Panel D).
13

Figure 2: Number of Screening Practice Actions per Decade per Patient
14

In quantifying these reductions and seeking to maximize their relevance for
clinical practice, we computed the mean number of Recommended Screening Practices
per patient per decade of follow-up and determined the difference between the two
methods. As shown in Table 2, the screening categories of History and Physical
Examination Elements and Health Education and Counseling accounted for the largest
number of Recommended Screening Practices under both approaches. With the use of
VRF the aggregate number of Recommended Screening Practices triggered was
significantly reduced compared with GRF (-7.4%, p < 0.001). By specific category of
screening practice, significant relative reductions of similar magnitude were noted for
History and Physical Examination Elements (-6.9%, p < 0.001), Referrals to Specialists
(-10%, p < 0.001), and Health Education and Counseling (-7.7%, p < 0.001). The most
substantial reduction was noted for Diagnostic Imaging and Procedures, where 37%
fewer tests per patient were triggered with use of VRF (Table 2, Figure 3; p < 0.001).
The number of Laboratory Tests triggered was also lower with VRF (-4.6%) but not
significantly so.

Table 2: Difference in Number of Recommended Screening Practices per Decade of Follow-Up,
per Patient
Screening Practice GRF
Mean
Range
VRF
Mean
Range
Absolute Change
(95% CI)
%
Change
p-value
All Screening
Practices
504.4
200-744.4
467.2
200-744.4
-37.2
(-49.2, -25.2)
-7.4% <0.001
History and Physical
Exam Elements
396
180-568.4
368.5
180-560
-27.5
(-36.2, -18.8)
-6.9% <0.001
Laboratory Tests 15.3
0-20.3
14.6
0-30.3
-0.7
(-1.8, 0.5)
-4.6% 0.265
Diagnostic Imaging
and Procedures
4.6
0-23
2.9
0-22.8
-1.7
(-2.3, -1.1)
-37% <0.001
Referrals to
Specialists
21.2
0-30.2
19.1
0-30.2
-2.1
(-3.2, -1.0)
-10% <0.001
Health Education and
Counseling
67.4
20-120.2
62.1
20-120.2
-5.2
(-8, -2.5)
-7.7% <0.001
15

Figure 3: Number of Diagnostic Imaging and Procedures per Decade of Follow-Up, per Patient

In the most recent version of the COG Guidelines (5.0), only five organs or anatomic
structures have radiation dose-specific thresholds specified for triggering health screening and
counseling. The lifetime impact of using GRF and VRF in these structures is shown in Table 3.
Without exception, for every Potential Late Effect and corresponding Recommended Screening
Practice, there was a reduction in the absolute number of interventions needed for this cohort
using VRF. Of the 15 Recommended Screening Practices, the percent reduction in testing for
the cohort was greater than 30% for 13 and greater than 50% for nine. More striking, using VRF
almost eliminated testing for two Recommended Screening Practices (osteoradionecrosis of
16
mandible and infectious risk counseling for functional asplenia). For cardiotoxicity, there
were 1,064 fewer (-66.8%) lifetime echocardiograms triggered using VRF in this cohort;
similarly, there were approximately 70% fewer EKGs and interactions for cardiac history
and health counseling. In contrast, somewhat lower percent reductions were noted for
focused endocrine history and Medical Alert bracelet counseling (central adrenal
insufficiency); and for blood pressure monitoring and focused cardiac exam
(cardiotoxicity) because for some patients these were triggered by other radiation
exposures without dose-specific thresholds.

17

Table 3: Difference in Number of Recommended Screening Practices for Organs with Radiation Dose-Specific Thresholds
18
DISCUSSION
In this exploratory study of methods to identify organ exposure to radiation, we found
significant differences in the organs identified to be at risk for late effects of radiation therapy for
childhood cancer treatment when using more specific volumetric dosimetry in comparison to
more general radiation fields as defined by the COG Guidelines. Consistent with our hypothesis,
use of volumetric dosimetry significantly reduced the number of identified Potential Late Effects
and corresponding Recommended Screening Practices. This reduction was more pronounced
with incorporation of any dose-specific threshold. These findings are of importance as they
indicate a need for more specific identification of radiation exposure, which may decrease both
the number of late effects discussed with patients and families as well as minimize
interventions, removing unnecessary anxiety and burden.15,16 This study is the first to our
knowledge to address the use of volumetric dosimetry in the application of follow-up guidelines,
and our findings indicate further work will be crucial on this topic.
The striking difference in anatomic structures triggered for surveillance when using VRF
and GRF is indicative of the broad and inexact nature of the general radiation fields. Complete
agreement of the two methods was rare: only 5.3% of the cohort had the exact same identified
Potential Late Effects using each method, with more than half of these patients having received
radiation exclusively to an extremity (i.e. with no organ exposures). This disagreement between
the methods indicates the lack of specificity in GRF, suggesting their utility in guiding necessary
late effects surveillance may be limited. On the whole, VRF recognized significantly less
Potential Late Effects as necessary for surveillance. However, 30.3% of patients did have an
increase in anatomic structures triggered for surveillance when applying the COG Guidelines
using VRF, indicating that GRF may not fully capture all radiation exposed structures. In
identifying the organs that actually received radiation, rather than just those in an adjacent area
of the body, VRF is more precise in its recognition of late effect risk. This has the potential to
increase the yield of late effect surveillance, which has been shown in prior research to be low
19
for many interventions.17 Patient adherence to recommendations has also been historically
poor, but increased yield and minimization of unnecessary surveillance may also improve
patient ability and willingness to follow recommendations.18,19
Consistent with the significant decrease in Potential Late Effects with VRF, the mean
number of Recommended Screening Practices per decade per patient was significantly reduced
as well. Of note, though the Diagnostic Imaging and Procedures had the fewest mean
Recommended Screening Practices per patient per decade, this category represents
colonoscopies, mammograms, echocardiograms, and similarly intensive procedures. The
approximately 40% reduction in recommendations for this category is even more impactful in
consideration of what tests can be avoided – those that are higher cost, may require anesthesia,
more frequently cause “scanxiety,” and may result in false positives.16
The impact of VRF in reduction of Potential Late Effects and Recommended Screening
Practices was most dramatic when a dose-specific threshold was included with the Potential
Late Effect, as it was for central adrenal insufficiency, ototoxicity, osteoradionecrosis of the jaw,
cardiotoxicity, and functional asplenia. These five anatomic structures required a minimum dose
for application of both GRF and VRF, but the incorporation of a dose threshold led to
consistently significant decreases in recommended screenings with VRF. We anticipate that the
magnitude of reduction in identified Potential Late Effects and Recommended Screening
Practices will be significantly greater with incorporation of dose thresholds. Research on
radiation dose thresholds for late effects in pediatric patients is ongoing,7 though similar limits
have been identified for adults.20
Of note, the effect of dose-specific thresholds is crucial in interpreting the findings of
those Potential Late Effects without any specified dose distinctions. Given the definition of
exposure for VRF had a very low threshold (10% organ dose of 5 Gy), some anatomic
structures were frequently triggered as at-risk despite likely clinically insignificant doses of
radiation. A clear example was craniospinal irradiation, where VRF frequently triggered
20
screening for lungs, liver, and pancreas-related late effects, due to these organs’ midline body
position, despite their exclusion when GRF was used to determine exposure. This may have
blunted the degree of reduction seen in Recommended Screening Practices in all categories,
and especially in Laboratory Tests, as the majority are recommended in response to the
radiation of the aforementioned midline structures.
A striking finding in this study was the sheer number of Recommended Screening
Practices by either method, with a range of 200 to almost 750 unique interventions per decade
for each patient. The bulk of these recommendations represent History and Physical Exam
Elements. While some of these are relatively benign and minimally time consuming, i.e.
focused ophthalmologic history or bilateral upper extremity blood pressure, others represent
distressing or invasive measures, i.e. detailed sexual history and breast exam. This extensive
screening regimen is recommended to persist throughout the patient’s lifetime, emphasizing the
ongoing impact of a childhood cancer diagnosis despite cure.
The study cohort represented varied diagnoses and body areas irradiated, allowing for
greater generalization of these results. Further strengths include the use of each patient as their
own control, minimizing bias and error, and the inclusion of automation, offering an avenue for
implementation at other institutions and on a larger scale. The exclusion of chemotherapy late
effect surveillance recommendations in this analysis is a limitation, as chemotherapy-associated
recommendations may impact the aggregate numbers due to overlap of screening practices.
Similarly, we recognize that exposure of an individual anatomic structures to radiation may not
represent the full risk of developing late effects, exemplified by hearing loss, a complex issue
with multiple contributing and often interacting etiologies, not solely cochlear radiation
exposure.21 The future incorporation of more comprehensive dose threshold information will
help address this limitation.
This study is a novel approach to the optimization of late effects surveillance. The COG
Guidelines represent carefully developed “risk-based, exposure-related clinical practice
21
guidelines for screening and management of late effects,”4 crafted with the best available
evidence and collective clinical experience. Though rigorously designed with concrete
standardized follow-up recommendations, when used for radiation, they are limited by the data
available about specific exposure. Much of the surveillance currently recommended is based
upon older treatment regimens that have been refined through treatment modifications based on
clinicopathological factors and to spare organs at risk of late effects. This type of personalization
will continue to increase the variety of treatment plans and actual organ exposures, along with
the subsequent range of potential late effects.10,22 Such evolution in cancer treatment is
inevitable and will further complicate using generalized representations of dose like radiation
fields. As cancer treatment becomes more sophisticated and precise, follow-up strategies will
need to likewise adapt.10 Utilizing patient-specific information about radiation treatment offers
refined screening that may improve the underlying challenges in late effects surveillance, and
ideally improve the lives of childhood cancer survivors. This innovative approach offers
significant potential to improve long-term follow-up for patients who receive radiotherapy, with
opportunity to further refine the methodology.

22
REFERENCES
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Survivors of Childhood Cancer: Results from the Childhood Cancer Survivor Study. Radiation
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organization of long-term follow-up care for childhood and adolescent cancer survivors: a report
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4. Children's Oncology Group. Long-Term Follow-Up Guidelines for Survivors of Childhood,
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5. Landier W, Bhatia S, Eshelman DA, et al. Development of risk-based guidelines for pediatric
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Children's Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol.
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6. Kaviarasu K, Nambi Raj NA, Hamid M, Giri Babu AA, Sreenivas L, Murthy KK. Verification of
Dosimetric Commissioning Accuracy of Intensity Modulated Radiation Therapy and Volumetric
Modulated Arc Therapy Delivery using Task Group-119 Guidelines. J Med Phys. 2017;42(4):258-
265.
7. Constine L, Hodgson D, Bentzen S. Pediatric Treatment Planning II: The PENTEC Report On
Normal Tissue Complications. Med Phys. 2014;41(6):419-+.
23
8. Constine LS, Ronckers CM, Hua CH, et al. Pediatric Normal Tissue Effects in the Clinic (PENTEC):
An International Collaboration to Analyse Normal Tissue Radiation Dose-Volume Response
Relationships for Paediatric Cancer Patients. Clin Oncol (R Coll Radiol). 2019;31(3):199-207.
9. Merchant TE, Hodgson D, Laack NNI, et al. Children's Oncology Group's 2013 blueprint for
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Precision Survivorship. Journal of clinical oncology : official journal of the American Society of
Clinical Oncology. 2018;36(21):2231-2240.
11. Olch AJ, Tan YJ, Wong K, Freyer D. A dose-volume approach to surveillance for radiation
therapy-related late effects. Int J Radiat Oncol Biol Phys. 2017;99(2):E542.
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(REDCap)--a metadata-driven methodology and workflow process for providing translational
research informatics support. J Biomed Inform. 2009;42(2):377-381.
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Child’s Treatment for Cancer Has Completed and Their Implications for Ongoing Support. Illness,
Crisis & Loss. 2020:1054137320919916.
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this”: adolescent and young adults’ perspectives on cancer survivorship. Journal of Psychosocial
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24
17. Landier W, Armenian SH, Lee J, et al. Yield of Screening for Long-Term Complications Using the
Children's Oncology Group Long-Term Follow-Up Guidelines. J Clin Oncol. 2012;30(35):4401-
4408.
18. Reppucci ML, Schleien CL, Fish JD. Looking for trouble: Adherence to late-effects surveillance
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19. Tonorezos ES, Henderson TO. Clinical Guidelines for the Care of Childhood Cancer Survivors.
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Radiat Oncol Biol Phys. 2010;76(3):S1-S2.
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25
Appendices

Appendix A: Organ or Anatomic Structure Association with Potential
Late Effect

Section
Number
Potential Late Effect Organ or Anatomic Structure
43 Secondary benign or malignant
neoplasm
Skin, soft tissue, bone
44 Dermatologic toxicity Skin
45 Brain tumor (benign or malignant) Brain
46 Neurocognitive deficits Brain
47 Clinical leukoencephalopathy Brain
48 Cerebrovascular complications Cerebrovasculature
49 Craniofacial abnormalities Face
50 Chronic sinusitis Frontal, ethmoid, sphenoid, and
maxillary sinuses
51 Overweight/obesity Hypothalamus, pituitary
52 Growth hormone deficiency Hypothalamus, pituitary
53 Precocious puberty (male) Hypothalamus, pituitary
54 Precocious puberty (female) Hypothalamus, pituitary
55 Hyperprolactinemia Hypothalamus, pituitary
56 Central hypothyroidism Hypothalamus, pituitary
57 Gonadotropin deficiency (male) Hypothalamus, pituitary
58 Gonadotropin deficiency (female) Hypothalamus, pituitary
59 Central adrenal insufficiency Hypothalamus, pituitary
60 Cataracts Lens
61 Ocular toxicity Orbit, optic nerve
62 Ototoxicity Cochlea
63 Xerostomia, salivary gland dysfunction Parotid, submandibular glands
64 Dental abnormalities/TMJ dysfunction Oral cavity
65 Osteoradionecrosis of the jaw Mandible
66 Thyroid nodules Thyroid
67 Thyroid cancer Thyroid
68 Hypothyroidism Thyroid
69 Hyperthyroidism Thyroid
70 Carotid artery disease Carotid arteries
71 Subclavian artery disease Subclavian arteries
72 Breast cancer Breasts
73 Breast tissue hypoplasia Breasts
26
74 Pulmonary toxicity Lungs
75 Lung cancer Lungs
76 Cardiac toxicity Heart
77 Functional asplenia Spleen
78 Esophageal stricture Esophagus
79 Impaired glucose metabolism Pancreas
80 Dyslipidemia Liver
81 Hepatic fibrosis/cirrhosis/FNH Liver
82 Cholelithiasis Liver
83 Bowel obstruction Bowel space
84 Chronic enterocolitis/fistula/strictures Bowel space
85 Colorectal cancer Colon
86 Renal toxicity, insufficiency, HTN Kidney
87 Urinary tract toxicity Ureter, bladder
88 Bladder malignancy Bladder
89 Testicular hormonal dysfunction Testes
90 Impaired spermatogenesis Testes
91 Ovarian hormone deficiencies Ovaries
92 Reduced ovarian follicular pool Ovaries
93 Uterine vascular insufficiency Uterus
94 Vaginal fibrosis/stenosis Vagina
95 Musculoskeletal growth problems Bones
96 Scoliosis/kyphosis male Spine
97 Radiation induced fracture Bones

27
Appendix B: Recommended Screening Practice Categories

Recommended Screening Practices
History and Physical Exam Element
Focused dermatologic history
Skin self-exam
Focused dermatologic exam
Assessment of bone pain and health
Palpation of bones in irradiated fields
Focused neurologic history
Focused neurologic exam
Focused educational history
Psychosocial assessment
Craniofacial exam
Focused sinus history
Focused sinus exam
Height/Weight/BMI
Assessment of nutritional status
Tanner staging
Height and weight
Testicular volume by Prader orchidometer
Sexual function history
History of galactorrhea
Menstrual history
Focused endocrine history
Focused hair exam
Focused exam for dermatologic evidence of endocrine
disorder
Thyroid exam
Detailed pubertal history
Regular growth monitoring
Focused vision history
Eye exam
Focused ophthalmologic symptomology assessment
Focused otic history
Otoscopic exam
Focused oral and dental exam
Comprehensive jaw history
Comprehensive jaw exam
28
Focused cardiac exam
Carotid exam
Bilateral upper extremity blood pressure monitoring
Perfusion exam
Brachial and radial pulses assessment
Breast exam
Focused pulmonary history
Pulmonary exam
Focused cardiac history
Blood pressure monitoring
Focused gastrointestinal history
Focused hepatic exam
Focused abdominal exam
Focused urologic history
Menopausal symptoms
Menstrual and pregnancy history
Pregnancy history
Focused genitourinary history
External genitalia exam
Limb lengths
Sitting height
Spine exam
Laboratory Test
Thyroid function tests
8 AM Cortisol level
Fasting blood glucose or HbA1c
Lipid profile
Liver function testing
Electrolyte panel
Diagnostic Imaging and Procedures
Complete audiological evaluation
Mammogram
Breast MRI
Pulmonary function tests
EKG
Echocardiogram
Colonoscopy
Health Education and Counseling
Promptly seek medical attention for bone pain, bone
mass, persistent fevers
29
Control health conditions known to increase
cardiovascular and stroke risk
Avoid obesity and management of obesity-related
health risks
Assess thyroid levels prior to attempting pregnancy
and throughout
Be aware spermatogenesis may occur years later
(male)
Use contraception regularly
Wear Medical Alert bracelet
Be aware of need for corticosteroid replacement
therapy and stress dosing
Teach breast self-exam and counsel to perform
monthly
Avoid tobacco and quit smoking if appropriate
Possibility of need for spiral CT with any suspicion for
lung pathology
Maintain appropriate weight, blood pressure, heart
healthy diet
Exercise counseling as appropriate
Be aware of risk of life threatening and malarial and
tick-borne disease
Promptly report dysuria or gross hematuria
Be aware recovery of fertility may occur years later
(female)
Be aware of adverse impact of hormone deficiencies
on growth, BMD, CV disease, and sexual dysfunction
Be aware of potential for shorter period of fertility
Avoid frequent contact with irritants
Be aware of Increased risk of fractures
Referral to Specialist
Referral for formal neuropsychological evaluation
Referral for ophthalmology evaluation
Referral for dental exam and cleaning

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Asset Metadata

Creator Cohen-Cutler, Sally Josephine (author)

Core Title Refined screening guidelines for radiation-related late effects in childhood cancer survivors: a dose-volumetric guided approach

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical, Biomedical and Translational Investigations

Publication Date 07/19/2020

Defense Date 07/17/2020

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag dose volumetrics,late effects,OAI-PMH Harvest,oncology,pediatric oncology,Pediatrics,radiation oncology,survivorship

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Freyer, David (committee chair), Gomer, Charles (committee member), Wong, Kenneth (committee member)

Creator Email cohencut@usc.edu,sally.cohencutler@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c89-335925

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