The Importance of Quality Assurance in

Radiation Oncology Clinical Trials

Thomas J. FitzGerald,* Maryann Bishop-Jodoin,* Fran Laurie,* Matthew Iandoli,*
Koren Smith,* Kenneth Ulin,* Linda Ding,* Janaki Moni,* M. Giulia Cicchetti,* Michael Knopp,y
Stephen Kry,z Ying Xiao,x Mark Rosen,x Fred Prior,║ Joel Saltz,{ and Jeff Michalski#

Clinical trials have been the center of progress in modern medicine. In oncology, we are
fortunate to have a structure in place through the National Clinical Trials Network
(NCTN). The NCTN provides the infrastructure and a forum for scientific discussion to
develop clinical concepts for trial design. The NCTN also provides a network group struc-
ture to administer trials for successful trial management and outcome analyses. There are
many important aspects to trial design and conduct. Modern trials need to ensure appropri-
ate trial conduct and secure data management processes. Of equal importance is the quality
assurance of a clinical trial. If progress is to be made in oncology clinical medicine, investigators
and patient care providers of service need to feel secure that trial data is complete, accurate,
and well-controlled in order to be confident in trial analysis and move trial outcome results into
daily practice. As our technology has matured, so has our need to apply technology in a uniform
manner for appropriate interpretation of trial outcomes. In this article, we review the impor-
tance of quality assurance in clinical trials involving radiation therapy. We will include important
aspects of institution and investigator credentialing for participation as well as ongoing
processes to ensure that each trial is being managed in a compliant manner. We will provide
examples of the importance of complete datasets to ensure study interpretation. We will
describe how successful strategies for quality assurance in the past will support new initiatives
moving forward.
Semin Radiat Oncol 33:395−406 Ó 2023 Published by Elsevier Inc.

Introduction now in our daily inpatient and outpatient work scope and
reported on a daily basis. Outcomes in oncology are increas-

Q uality has become an important and elemental metric in

modern clinical medicine. Senior leadership groups in
ingly measured by regulatory agencies and insurance pro-
viders for performance analysis. Processes in all aspects of
modern hospital systems participate in daily reviews of pro- medical care have been adjusted to ensure that quality and
cesses and performance. Metrics for quality and safety are safety indicators remain a priority in the modern workplace.
While this aspect of workplace behavior has accelerated in
*
Department of Radiation Oncology, UMass Chan Medical School, Worces- the past decade, the National Cancer Institute (NCI)-led tri-
ter, MA.
y als including the current National Clinical Trial Network
Department of Radiology, University of Cincinnati, Cincinnati, OH.
z
Department of Radiation Physics, MD Anderson Cancer Center, Houston, (NCTN) have had quality assurance (QA) for more than 5
TX. decades. Changing clinical trial environments and moderni-
x
Department of Radiation Oncology, University of Pennsylvania, Philadel- zation of therapy technology demand process improvements
phia, PA. in the QA centers.1-5
║
Department of Biomedical Informatics, University of Arkansas for Medical
Sciences, Little Rock, AR.
In the mid-1960s, early pioneers in oncology practice saw
{
Department of Biomedical Informatics, Stony Brook University, Stony the worth of being able to share information about patient
Brook, NY. management and outcome. Collaborative meetings were
#
Department of Radiation Oncology, Washington University in St Louis, St held in common venues to have conversations and create
Louis, MO. protocols that could be shared among institutions to evaluate
Conflict of interest: none.
Address reprint requests to Thomas J. FitzGerald, Department of Radiation and test clinical concepts in patient care management. Clini-
Oncology, UMass Chan Medical School, Worcester, MA 01655. E-mail: cal trials established to test hypotheses of management and
tj.fi[email protected] outcomes were reviewed periodically at biannual meetings.

https://doi.org/10.1016/j.semradonc.2023.06.005 395
1053-4296/© 2023 Published by Elsevier Inc.
396 T.J. FitzGerald et al.

The process of trial development and outcome analysis service functions for the NCTN. This provides an opportu-
became an important vehicle because trial outcomes would nity to harmonize protocol review for each group and align
potentially influence standards of care. As clinical trial devel- data management and acquisition pathways for translational
opment broadened, it was recognized that an administrative research. As the pathways for data management become
structure would need to be established to generate clinical transparent, the data can be reformatted for upload to
trials and simultaneously collect and collate information for national archives including The Cancer Imaging Archive
study analysis. The NCI established a network for participa- (TCIA) for secondary analyses research, and development in
tion in what was called the cooperative groups now the artificial intelligence (AI).7,8 If the trials are well designed
NCTN. The cooperative groups became an extraordinary and the data acquired are in standard formats, the data pro-
vehicle to develop management strategies and test the vide an extraordinary opportunity to not only support and
hypotheses in a national and international venue. Prior to validate primary clinical trial endpoints but also serve to be
2014, there were 10 cooperative groups participating in all re-purposed for secondary analyses by site and study investi-
aspects of liquid and epithelial oncology.6 Many of the gators. Upload to archives such as TCIA make the data avail-
groups had strengths in most adult and pediatric disease dis- able for analyses by scientists worldwide.
ciplines and others had strengths in individual disease areas For confidence in the primary and secondary analyses, the
(Gynecologic Oncology Group [GOG]) and specific therapy data need to be adherent to trial guidelines and as uniform as
disciplines (Radiation Therapy Oncology Group [RTOG]). possible so that the results of the analysis can be applied to
The NCI serves multiple purposes including supporting the science of patient care. This is why QA of the clinical trial
phase 1 activity when required and validating potential new matters. In the next section, we will review the history of QA
advances in care through a phase 3 randomized approach. and how processes have matured over the past 5 decades.
The groups were supported by individual group data/statisti-
cal centers and tissue banks. In 2014, the cooperative system
was consolidated into 5 groups, 1 pediatric group, and 4 History of QA in Radiation Oncology
adult groups. The NCI consolidated all the QA review cen-
ters in imaging and radiation oncology into 1 group called
Clinical Trials
the Imaging and Radiation Oncology Core (IROC). IROC When the first patient was treated in the United States on a
includes the former Radiological Physics Center (RPC, IROC linear accelerator by Henry Kaplan in 1956, radiation oncol-
Houston), the Quality Assurance Review Center (QARC, ogy was introduced as a maturing discipline in medical sci-
IROC Rhode Island [RI]), The University of Ohio (IROC ence. With increasing technology changes generated from
Ohio), and the core labs for the American College of Radiol- post-World War II repurposed radar systems, compact linear
ogy Imaging Network (ACRIN) and RTOG, now IROC Phila- accelerators were developed for patient care.9,10 During the
delphia.1-5 The current schema is listed in Figure 1. Each 1960s, linear accelerator technology had developed to a
IROC QA Center has individual strengths, and the consoli- degree that daily treatment could be delivered in a reliable
dation has provided an opportunity to leverage these and consistent manner, and academic centers and commu-
strengths to support imaging and radiation oncology core nity hospitals were able to acquire the equipment for patient

Figure 1 NCTN Schema. This image is in the public domain and is courtesy of the National Cancer Institute (NCI).
(Color version of figure is available online.) https://www.cancer.gov/research/infrastructure/clinical-trials/nctn.
Seminars in Radiation Oncology 397

care. With advances in radiation oncology coupled with the known as QARC. The RTOG established an internal RT QA
evolving specialty of medical oncology, early oncology inves- process. In parallel the RPC established dose computation
tigators were committed to sharing patient treatment strate- validation processes for RT facilities participating in NCI tri-
gies and developing protocols for treatment. Commitments als. The development of these organizations confirmed the
were made by investigators to meet twice yearly, to review importance of QA in the clinical trials process. The QA
protocol progress and design strategies for the next iteration organizations provided an economy of scale for the coopera-
of trials. Initially, the commitments were informal, however, tive group process as each group could use services by the
the potential strength of collaboration to move clinical care individual QA centers.12,13
forward was recognized by the newly formed NCI and a net- As processes of clinical care matured, so did the QA pro-
work of cooperative groups was established over the ensuing cess. Fluoroscopic RT planning was only able to provide vol-
years to create protocols for clinical trials, collect data, assess umetric data at a rudimentary level. Volumetric-based
the outcome, and help standardize and improve clinical treatment planning with computer tomography (CT)-based
care.11 systems reshaped the planning process and workflow within
Over time, 10 cooperative groups were established in radiation oncology. Physicians, physics staff, dosimetrists,
both pediatric and adult diseases to address disease areas and therapists all adapted to volume-based planning. Physi-
and technology disciplines. Radiation therapy (RT) was con- cian workflow now required skill in contouring tumor tar-
sidered an important partner in clinical trial development. gets using CT tools and therapy was planned to a volume,
Strategies for protocol development were finalized by discus- not a point, with metrics applied to constrain dose to normal
sions within specific RT committees. Although desired, ini- tissue. In 2-dimensional fluoroscopic planning, the majority
tially there was no vehicle or mechanism to collate and of work required of the physician was completed at the time
collect RT treatment data for each trial. However, when a of the simulation. With volumetric planning, the work of the
limited number of completion notes were reviewed by the physician changed, and contours were drawn after digital
committee, it was recognized by committee members there imaging was processed by physics well after the patient left
was significant variance within the RT community in treat- the department. This would alter patient care as the planning
ment plans with respect to both radiation dose and volume effort could only begin once the contours were complete and
of treatment. Because there was limited commercialization of impose delays from the time of simulation to the patient ini-
RT planning systems at that time, variances in dose computa- tiating therapy. For patients on clinical trials requiring data
tion and calculation were likewise identified by reviewing submission, the process of forwarding digital planning infor-
objects and planning information.12 A decision was made mation became a challenge.14,15
within committees to acquire information on patient treat- A pivotal moment facilitating RT data transmission for
ment which included dose computation data and RT treat- clinical trials was provided with the introduction of RTOG
ment fields obtained at the time of fluoroscopic imaging data exchange. This permitted planning information to be
during simulation and megavoltage portal images obtained forwarded in a digital package to QA centers for protocol
from accelerators each week on treatment. Initially, there review. For targets thought to be well seen on RT 3-dimen-
was resistance to the data submission process, however, the sional systems including prostate, the data submission evalu-
groups supported data acquisition and within a year, sub- ating the image and the proposed plan could be completed
mission rates improved to 95% from 30% as institutions with a review of the objects. Drs. James Purdy (Washington
became more familiar with the data submission process. In University) and James Deye (NCI) were instrumental in pro-
the early phase of data acquisition, the materials were viding this form of digital data exchange to the cooperative
reviewed in retrospect often at trial completion. Despite the group community and the QA centers were able to align the
presence of RT guidelines in the study, deviation rates data acquisition process centered on digital exchange of
remained significant. Because the data acquisition process data.16
was proving to be successful, a decision was made by the As volumetric planning became more standard practice in
committee to require an on-treatment review of the planned radiation oncology, computational tools in radiation oncol-
treatment to ensure that the goals and objectives of the trial ogy for treatment planning evolved from an institution-
were being met. Cases were to be reviewed by day 3 of treat- driven practice towards alignment with commercial systems.
ment to provide what was then thought as a reasonable time Therefore, credentialing and benchmark analysis of treat-
frame to make an adjustment in the care plan to meet proto- ment plans for qualification of activity in clinical trials
col guidelines. The RT committee had multiple roles includ- became standardized as departments adopted more consis-
ing protocol development, protocol management, and the tent procedures.17-20 Although metrics for dose computation
new role of directing QA for the trial. In 1980, the pediatric became more uniform, the role of diagnostic imaging in
divisions of the Cancer and Leukemia Group B (CALGB) and defining target volumes for RT became the next important
Southwest Oncology Group (SWOG) separated from their step for protocol alignment among radiation oncologists.
respective group to form the Pediatric Oncology Group This became a focal point for radiation oncology clinical tri-
(POG). At that time, the QA program for data acquisition als managed through QARC.21,22 Imaging was needed to val-
and management for the CALGB, Intergroup Rhabdomyosar- idate the RT target volume and for assessing response to
coma Group (IRSG), National Wilms Tumor Study Group therapy and treatment outcome. As imaging became Digital
(NWTS), and POG became independently funded and Imaging and Communications in Medicine (DICOM)
398 T.J. FitzGerald et al.

Figure 2 Protocol patient digital file. Image courtesy of IROC RI. (Color version of figure is available online.)

compliant, digital transfer tools matured, and imaging was development or execution.23 The QA centers, now known as
acquired through similar mechanisms previously established IROC, house information from nearly 1000 NCI-sponsored
for radiation oncology. As institutions became more familiar and associated clinical trials with millions of images and thou-
with these processes, the volume of imaging acquired for sands of RT treatment objects all managed in a uniform format
clinical trial management began to include imaging associ- consistent with clinical trial processes. With bridges built into
ated with chemotherapy including response assessment clinical outcome data and tissue banks, the information
imaging. Because QA centers were collecting imaging and RT becomes a powerful vehicle for additional research including
treatment objects on the same patient for response assess- program development for processes in AI. Figure 2 represents
ment and review of RT treatment plans, a unique relation- imaging and RT objects archived side by side in the integrated
ship matured between the imaging and radiation oncology database at IROC RI.
committees of each group. Since response assessment imag- With the infrastructure in place and processes aligned for
ing was needed to design RT treatment objects, diagnostic enterprise function in data management, we need to examine
imaging, and radiation oncology committee members devel- why the processes came to be of importance to the clinical
oped a working relationship with increasing respect for each trials community.
other’s discipline as patient care became more interdependent.
As each discipline gained more familiarity with each other’s
work and expertise, radiologists were able to identify disease
progression more readily from the therapy effect. As the digital
Why QA Matters
world expanded, objects could be reviewed in real-time on a Although it is acknowledged that clinical trials remain a cor-
simultaneous basis by site and study investigators using web- nerstone in the improvement of clinical care for oncology
based tools. This moved QA processes and clinical trials to a patients, the processes involved in data management and
new level. Clinical trials were written to accommodate adap- clinical trial investigation for site investigators can be chal-
tive endpoints with RT treatment guidelines written for an lenging for even seasoned investigators. Internal review
adaptive clinical and radiographic response. Therefore, mod- board (IRB) approvals, consent, data management and
ern QA processes include site credentialing for participation in patient care before, during and after the time of study can be
clinical trials, data acquisition and management, real-time demanding and may limit perceived clinical productivity
review of protocol data including imaging and RT objects, when measured in relative value units (RVU). At times the
data analysis, and research including secondary clinical trial data management and submission processes can be a per-
objectives not necessarily anticipated at the time of trial ceived barrier to protocol participation. This can influence
Seminars in Radiation Oncology 399

how protocols are written and what data are collected, man- intermediate and low-risk HL. Each study incorporated RT
aged, and archived by QA centers. If data submission is per- for consolidation management with the intent to include all
ceived as a barrier to participation, often the compromise is soft tissue and bone sites of disease at presentation with
to limit the data acquisition process in order to encourage response-adapted titration of mediastinal adenopathy where
accrual to study. This can result in a decrease in submitted disease extended into pulmonary parenchyma. COG 9426,
imaging, elimination of the real-time review process, and no the low-risk study, also included response-adaptive titration
oversight into trial management. This has both strengths and of chemotherapy following a review of imaging after 2 cycles
weaknesses. The perceived immediate strength is the goal of of chemotherapy. The trial was conducted in the predigital
meeting study accrual objectives. However, for every per- era; however, the consensus was the review of RT objects
ceived strength there is a consequence and often limiting prior to the treatment was feasible because the RT would be
data acquisition can potentially decrease confidence in the executed after chemotherapy, therefore offering time for the
outcome of the clinical trial. The experience at QARC, now data to be submitted and reviewed. The response imaging,
IROC RI, in Hodgkin lymphoma (HL) typifies how processes however, was performed in retrospect. The pretreatment
in clinical trials have matured with the commensurate need review process proved to be a success with nearly 100% data
for optimal clinical trial management.24 submission pretherapy and significant improvement in study
Pediatric Oncology Group clinical trial 8725 would today compliance. However, what was unanticipated was the 50%
be classified as a study of patients with intermediate and discordance in the assessment of therapy response between
early high-risk HL. The trial design was a point of randomi- local and central reviews. This prompted an additional
zation to determine if RT after 8 cycles of hybrid chemother- review of the process, and a decision was made in concert
apy including MOPP and ABVD was of benefit. RT was with the imaging committee to review imaging objects in
designed to treat all initial sites of disease after completion of real-time to ensure the studies were conducted in a manner
chemotherapy with response-adapted blocking approved for consistent with trial objectives. The QA centers were devel-
the mediastinum to limit radiation dose to pulmonary paren- oping digital acquisition; therefore, it was an uncomplicated
chyma. CT images of the disease at presentation and comple- process to include digital imaging review with the review of
tion of chemotherapy were collected in order to confirm the RT treatment objects. Intermediate risk COG AHOD0031
volume of therapy to be treated. Response, not the rapidity became the first study to integrate real-time review of imag-
of response, was not intentionally reviewed for protocol ing and RT objects into the protocol schema (Fig. 3). The
management. In this era, digital information was not avail- study was designed to identify patients with rapid and slow
able, and all RT information was performed by study investi- early responses to chemotherapy and separate these popula-
gators as a retrospective process after the patient completed tions into different treatment strata as a secondary point of
therapy. There was no real-time review of information by randomization. There was a third randomization in patients
study investigators, or the QA centers. In the original publi- who were deemed both a rapid early responders to chemo-
cation,25 there appeared to be no benefit to the addition of therapy who in addition had a complete response after 4
RT after chemotherapy for this patient population.
A secondary analysis of the RT information on this study
was performed to determine why the deviation rate was in
excess of 30% and what could be done to improve the process
for the next iteration of Hodgkin studies. What was uncovered
was the following: the deviation rate was driven exclusively by
radiation investigators titrating the volume of therapy and
excluding segments of the original disease at the presentation
from the RT fields due to the perception that titrating volumes
limited the late sequelae. Therefore, in this study, the optimal
outcome was achieved when all sites of the original disease
were included in the RT treatment field and RT added no sta-
tistical benefit when original disease was excluded in the ther-
apy field.1-5 The findings were important at several levels. It
was clear to POG leadership that investigator-driven applica-
tion of RT in HL was variable and had the likely potential of Figure 3 Protocol schema for COG Hodgkin Lymphoma protocol
influencing trial outcomes. It was likewise clear that RT object AHOD0031 including time points for real time interventional
review done in a retrospective manner had importance how- review for imaging and radiation oncology. Ó 2013 FitzGerald,
Bishop-Jodoin, Bosch, Curran, Followill, Galvin, Hanusik, King,
ever the process was going to have to be adjusted if RT was
Knopp, Laurie, O'Meara, Michalski, Saltz, Schnall, Schwartz, Ulin,
going to have a meaningful impact in clinical trials involving
Xiao and Urie. This is an open-access article distributed under the
HL. After consideration by the RT committee, a decision was terms of the HYPERLINK http://creativecommons.org/licenses/by/3.0/
made to move forward with pretreatment approval of RT Creative Commons Attribution License, which permits use, distribution
treatment objects in the next generation of studies. and reproduction in other forums, provided the original authors and
Children’s Oncology Group (COG) Studies 9425 and source are credited and subject to any copyright notices concerning any
9426 were clinical trials designed to address trials in third-party graphics etc.
400 T.J. FitzGerald et al.

cycles of chemotherapy. In order to conduct the trial with Problems with Incomplete Data or
real-time review of multiple image sets including RT treat- Limitations in the QA Process
ment objects, QA data management and information services
(IS) teams developed a digital data transfer system with If AI models are going to be useful in clinical care, they need
reminders to sites about what data was due and when. The to be built on comprehensive datasets which are accurate
study was complex and included both anatomic and meta- and complete. One of the purposes of QA programs is to
bolic imaging for response assessment and digital RT objects ensure the completeness and accuracy of datasets to make
for preplan review. Nearly 1800 patients were accrued to certain the datasets provide all of the necessary information
study with data sets on each patient reviewed on multiple to draw accurate conclusions for primary and secondary
occasions for each patient to ensure that the data collected translational science. This is important in radiomic and
was study compliant including outcome images. The process pathomic research and just as vital in research involving radi-
was highly successful and led to several important publica- ation oncology. In a similar manner, if our trials and trial
tions on the study process and outcome. In submitting a results are to be accepted by colleagues for clinical practice,
paper evaluating the pattern of failure of patients relative to there must be full confidence in the process of the clinical
the RT treatment fields, the reviewers each commented on trial for the outcome to be believed and subsequently
the importance of the QA process and indicated that the pro- accepted as a standard of care.
cess provided trust to the reviewers that the study outcome The HeadSTART trial was designed to address the role of
could be believed. Today, real-time review of objects has Tirapazamine in patients with locally advanced nonmeta-
become standard in the pediatric and adult clinical trials static squamous cell carcinoma of the head and neck. The
community. This has led to successful studies in very lim- trial was conducted in an era where there was limited infor-
ited-stage HL and studies evaluating volume titration with mation about the role of human papillomavirus (HPV) in
RT after more comprehensive chemotherapy for advanced- tumor development. Successful phase 2 data from a single
stage patients.24,26 institutional trial generated significant enthusiasm for a
The current status of clinical trials for HL represents the phase 3 randomized trial evaluating Tirapazamine as a hyp-
growth and development of QA processes that have matured oxic sensitizer to RT. Trial accrual crossed 6 continents and
in parallel with technology development in radiation oncology with more than 800 patients enrolled. The trial committee
and diagnostic imaging. Radiation oncology has extraordinary wanted QA as part of the trial charter due to the global
technology which can now be applied with precision and nature of the study. Digital transfer tools at that time were
accuracy. QA programs have likewise matured with the tech- embryonic and data was accepted through multiple media in
nology improvements and can move/share data in real time order to facilitate imaging and radiation oncology data trans-
between site and study investigators. As digital data transfer fer. The data was acquired and managed through QARC. In
systems became available for use within institutions, they discussions before the trial charter was completed, the deci-
were readily repurposed for use at an enterprise level by sion was made by the trial management committee to have
the clinical trial community. This provided a mechanism an on-treatment review of objects at QARC and not a pre-
for study and site investigators to communicate in real treatment review. This decision was made because of the per-
time over issues with specific patients and their appropri- ception of delay in data transfer and response. The
ateness for the specific trial in a manner that could not management committee required an on-treatment review
occur in the era of hard copy data transfer. The ability to within the first 3 days. This was a time when radiation oncol-
perform real-time interactions optimized the placement of ogy was transitioning to volumetric treatment planning. Up
the patient on study and more importantly, applied the until this time, most radiation oncology investigators used
correct care plan to the right patient. fluoroscopy for treatment planning and the use of CT 3-
The HL treatment community worldwide recognizes the dimensional planning tools, digital data transfer, and tumor
need to perform clinical trials with real-time data manage- disease contouring was nascent in the global radiation oncol-
ment strategies including a collection of outcome imaging to ogy community.31,32
validate outcomes, recurrence patterns, and normal tissue During the course of the study, adjustments were
injury.27-30 The progress being made in our understanding requested in defining the tumor volume in 211 patients,
of therapeutic titration and therapy augmentation is driven greater than 25% of the study population. This was due to
in part by our ability to acquire complete datasets and re- under-contouring the tumor target resulting in nonprotocol
purpose them for primary and secondary study analysis. coverage of disease in both primary and nodal regions. Of
Nimble query tools permit us to ask questions not antici- the 211 patients requested to have adjustments in targeting,
pated at the time of trial design, for example, treatment 95 patients had plans resubmitted during treatment and 116
response velocity coupled with the need for RT. Providing patients did not have adjustments made. There was a signifi-
the datasets are complete without flaws, data interpretation cant difference in survival between patients who had a com-
can be secure. However, in circumstances where data are pliant plan at the time of review and those who had a
incomplete, at times the flaws and gaps of information can protocol-compliant review after plan adjustments were
bring investigators and the research community to conclu- made. The trial management committee was blinded to the
sions that may not be accurate. In the following section, sev- interventional review comments and on re-review of each
eral examples of the limitations of this issue are presented. case were in 100% compliance with all cases deemed study
Seminars in Radiation Oncology 401

Figure 5 Time to locoregional failure by deviation status. The 4

Figure 4 Overall survival by deviation status: (1) compliant from cohorts are (1) compliant from the outset (n = 502), (2) made com-
the outset (n = 502), (2) made compliant following a review by the pliant following a review by the Quality Assurance Review Center
Quality Assurance Review Center (n = 86), (3) noncompliant but (n = 86), (3) noncompliant but without predicted major adverse
without predicted major adverse impact on tumor control impact on tumor control (n = 105), and (4) noncompliant with pre-
(n = 105), and (4) noncompliant with predicted major adverse dicted major adverse impact on tumor control (n = 87). Overall p <
impact on tumor control (n = 87). Overall p < 0.001. Pair-wise 0.001. Pair-wise tests were not statistically significant except for
tests: not statistically significant except for cohort 1 versus cohort 4 cohort 1 versus cohort 4 (p < 0.001), cohort 2 versus cohort 4
(p < 0.001), cohort 2 versus cohort 4 (p = 0.041), and cohort 3 ver- (p = 0.004), and cohort 3 versus cohort 4 (p = 0.006). TCP, tumor
sus cohort 4 (p = 0.006). TCP, tumor control probability; RT, radio- control probability; RT, radiotherapy.31 Image courtesy of Wolters
therapy.31 Image courtesy of Wolters Klower Health, Inc. (Color Klower Health, Inc. (Color version of figure is available online.)
version of figure is available online.)

deviations, therefore there was QA on the on-treatment needed for trial management. The study demonstrated the
review process. At the closure of the study, the trial manage- need for pretreatment intervention, similar to the experience
ment committee asked QARC to review all study deviations in HL. It was interesting to note that even those patients with
and determine whether or not they were clinically meaning- adjusted plans on treatment review had an 8% statistically
ful. For example, at that time and even today, computer algo- significant decrease in survival even though the adjusted
rithm systems cannot accurately define dose to and beyond plan was study compliant. This indicates that every treat-
the dermal surface. If the nodal contour unintentionally ment mattered, and dose-volume relationships could not be
extended to the skin, the dose volume histogram would not secure in validation until one could ensure that the correct
be consistent with 95% coverage to 95% of the volume. volume was treated accurately every day. One of the primary
Therefore, unless there was unambiguous evidence of dermal goals of modern daily image guidance is to ensure this objec-
involvement, this was considered a deviation that would not tive. This study established a tone for developing a strategy
be clinically meaningful. The exclusion of tumor from the to ensure compliance to study for all future industry and
protocol dose was considered clinically meaningful. As seen NCI clinical trials. The data was collected and collated in a
in Figure 4, patient survival for those with deviations not timely and protocol-compliant manner, however, a greater
considered clinically meaningful had survival near identical effort in pretreatment review would have addressed what
to patients who had protocol-compliant adjustments in their proved to be an important study weakness. This will be espe-
care plan during treatment. Those who were scored as devia- cially important as we initiate protocols asking important
tions clinically meaningful had survival significantly worse questions for both dose and volume titration for head and
than other groups. Similar data were seen for local control neck patients.
seen in Figure 5. The cost of QA is largely driven by building the infra-
The phase 3 study failed to confirm the highly favorable structure to acquire and manage data in a secure digital man-
data from the phase 2 trial and the deviations in the study ner and training staff as data managers. It is a misperception
likely overwhelmed the ability to demonstrate benefit from that cost is driven by data acquisition. Once the infrastruc-
the study as the deviations had influence on study outcome. ture is in situ and data security systems are in place, it can be
RT was not the study question; however, RT became an used in a nimble manner to collect all RT data and imaging,
unintended focal point of the protocol as seen in the publica- including outcome imaging in a study-compliant manner.
tion. The study called attention to the fact that the quality of Institutions can develop internal strategies for data submis-
RT matters and can negatively impact trial performance if sion which become facile for data management staff as
not managed in a proactive manner. Although trial design patients are entered into clinical trials. It has proven to be a
seemingly addressed this point, in execution a more compre- mistake to limit data submission under the impression of
hensive approach would be required to maintain the rigor cost, especially for outcome imaging which serves to validate
402 T.J. FitzGerald et al.

outcome and pattern of failure, both essential components to remains a point of debate among colleagues in a tumor board
modern clinical trial management. Despite decades of clinical and breast cancer management group environment which
trial management in the delivery of RT for breast cancer, we influences current clinical trials as investigators need to per-
have not yet learned enough from the clinical trial experience mit diversity in approach to make certain study accrual
to indicate with measurable confidence which nodal basins objectives are met. Positron emission tomography studies are
to treat in node-negative or positive breast cancer manage- now obtained in a more commonplace manner as part of
ment. The former CALGB managed a series of breast cancer breast cancer management for patients with the triple nega-
trials testing the incorporation and dose density application tive disease before consideration for surgery and studies are
of chemotherapy to node-positive breast cancer patients. revealing occasional different locations of lymph nodes
These trials were highly successful and met accrual which may/may not have been included in traditional com-
objectives.33,34 Because RT was not thought to influence prehensive regional fields as defined by anatomical loca-
patient survival, information about radiation treatment tion.39 Therefore, more work is needed to re-address these
including volume treated and dose were intentionally not points which we did not define as part of the QA process
collected. When publications defined the significant survival when the opportunity was available. Patients are currently
benefit associated with RT in breast cancer, the information treated off-study in a nonuniform manner without the bene-
arrived mid-study, therefore amendments could not be intro- fit of comprehensive failure pattern data to support the
duced to alter study management. An effort was made to regional clinical application of RT.
acquire RT information and treatment objects by QARC as Management of patients with nonsmall cell lung carci-
part of a retrospective analysis, however, information could noma (NSCLC) has undergone considerable change in the
only be collected on approximately one-third of patients in past 2 decades. Volumetric planning has provided the infra-
the study as many institutions required an amendment to structure for defining dose-volume constraints for multiple
the institutional IRB to permit this information to be for- critical structures in the thorax including pulmonary and car-
warded to the QA center. The data that could be acquired diac volumes. This has helped put structure to clinical trials
was reviewed and published by Carolyn Sartor, MD and col- and provide a framework for treatment planning on proto-
leagues at QARC.35 The information revealed a vast asymme- cols managed by the NCTN and industry. RTOG protocol
try in both radiation dose and volume treated without the 0617 was a 2-tiered randomization study designed to evalu-
use of protocol guidelines and review of objects. The data ate the use of cetuximab in patients being treated for NSCLC
suggested there was a tendency for those patients who with 2 different RT treatment schedules of 60 Gy and 74 Gy.
received Taxol to also be irradiated, however no further RTOG 0617 revealed no benefit to the higher dose RT. Pro-
information could be gained from data acquisition and ponents point to the changing molecular landscape in the
review in this manner. This was disappointing because more treatment of lung carcinoma including the increasing use of
than 3000 patients were treated in these trials and the collec- immune and targeted therapies. The study has had a signifi-
tion of objects with patterns of local regional relapse would cant influence on the direction of lung cancer clinical trials
have been an invaluable addition to our clinical acumen and both in industry and the NCTN over the past decade, espe-
would have served to influence an important aspect of clini- cially with the increasing use of immunotherapy. Most
cal care for the radiation oncology community. The lack of industry and NCTN clinical trials, including those involving
data acquisition in this regard also influenced the interpreta- immunotherapy, limit the dose delivered to lung cancer to
tion of ACOSOG trial Z0011. This trial was designed to test 60 Gy under the assumption that “less is better” to improve
titration of surgical and RT to the axilla with the hypothesis tumor control, meet protocol-defined normal tissue metrics,
that early-stage and limited-volume patients would benefit and limit toxicity.40
from a clinical perspective without vigorous attention to axil- While these are reasonable conclusions with available
lary volumes. In the trial management of this study, guide- data, a closer evaluation of the data reveals that for the first
lines were indicated in the protocol however the decision few years of study, the local control in the high-dose arm
was made not to acquire objects as part of the study. The ini- was statistically inferior to the low-dose arm as seen in
tial publication suggested that therapy titration was reason- Table 1. This would be counterintuitive as one would
able for this group of patients, however, a retrospective assume that local control would be equivalent if not superior
review of limited data acquired by QARC revealed that a sig- in the high-dose arm. The QA process for this study col-
nificant number of patients thought to be of high risk actu- lected RT data sets and compliance standards were estab-
ally had comprehensive regional nodal RT, therefore raising lished by dose to volume on the data set. Other groups
a question concerning the role of limited volume routinely collect diagnostic images to validate the targeting
therapy.36,37 In traditional tangential RT to the breast, of tumor as part of the data management process. In this pro-
approximately 60% of the axillary contents and likely the tocol, it was generally assumed the tumor contours were
greater majority of level one are included in the therapy study appropriate. This may explain why in the initial phase
field.38 However, with tangential therapy, levels 2 and 3 are of the study, local control was inferior on the high-dose arm,
not intentionally included. Therefore, the asymmetry associ- suggesting that tumor contours possibly undertreated areas
ated with the volume of therapy treated makes it challenging of disease. Although local control balanced between the arms
for applying the results of Z0011 to real-world management in later analysis, if this did not occur in the early part of the
of the patients and, accordingly, management of the axilla study, would the narrative of “less is better” remain valid?
Seminars in Radiation Oncology 403

Table 1 RTOG Pulmonary Protocol 0617 local failure rate unintentionally increase pulmonary V20 and V5. Therefore,
for the initial three years on the study: High dose 36%, Low one has to prioritize constraints and ask harder questions as
dose 24%. Reprinted with permission from Bradley JD RT is not a drug and needs to be carefully applied for optimal
et al.40
normal tissue outcome.41
Quality assurance processes can review diagnostic imag-
ing and evaluate tumor targeting and normal tissue dose to
ensure compliance to study objectives. When patients are
treated per protocol, outcomes can be trusted and more
readily applied to clinical practice without the caveat of
doubt created by ambiguity of incomplete data, deviation
from the standard, or limitations in the processing of data. It
will also be important to have a better understanding of pre-
existing conditions prior to initiation of protocol therapy.
Oncologists need to apply treatment to clinical situations
and often have limited tools before treatment is applied a pri-
ori. Moving forward for clinical trials and toxicity assess-
ment, it will be important to have a nimble functional tool
for pretherapy normal tissue assessment before applying pro-
tocol therapy. There are imbedded processes for audiology
function in the delivery of cisplatin and similar processes
will need to be imbedded in clinical trials for normal tissue
function for cardiac, pulmonary, and additional targets to
optimize assessment of function post therapy and devise
We will not know the answer to this question as diagnostic strategies to mitigate decrease in function. This will require
imaging was not collected. large datasets which can only be generated from clinical trial
In the initial phase of applying new technology into clini- data management centers with a QA review of the data to
cal trials including review of tumor contours, there is uni- ensure completeness and accuracy of the dataset. QA pro-
formly a growth phase in the RT clinical community as to cesses can ensure this information is made available to inves-
how the technology and change are applied to patient care. tigators as part of the clinical trial process.
This is a vulnerable time as site investigators are adjusting to Recent studies in the application of postoperative RT for
protocol language more familiar to the investigators who resected lung cancer also point to the need for accurate data-
wrote the study. Questions will be asked by site investigators sets with QA review. One of these studies indicated a 20%
that may have not been anticipated at the time of initiating improvement in local control; however, the study also sug-
the study and challenges of meeting normal tissue con- gested the advantage was negatively influenced by a signifi-
straints due to target size and tumor location require real- cant increase in toxicity. It was also noted that nearly 90% of
time communication between investigators and QA centers the patients treated with RT were treated with 3-dimensional
to ensure study compliance. Sites will be opening trials at therapy, not intensity modulation and volumes were not
varied time points during the study, and each will experience reviewed. Postoperative patients have a decrease in func-
similar issues, perhaps to a lesser degree as the QA centers tional pulmonary volume; therefore, radiation oncologists
would be familiar with issues and may better anticipate need to be cognizant that metrics such as V20 and V5 have
issues de novo to educate those new to the study. Neverthe- different meanings in surgical patients as the denominator
less, the education of sites on study remains an exercise of has changed, therefore QA processes need to reflect this mat-
self-renewal and this is where the QA centers can have a sig- ter and guidelines for care require a thoughtful approach to
nificant impact in the success of a clinical trial by maintain- ensure benefits of therapy without the consequence.42
ing protocol standards during the study. Working with COG standard risk medulloblastoma protocol ACNS0331
study investigators, QA centers maintain the consistency of was a study with Jeff Michalski MD as principal investigator
trial conduct which will serve to strengthen and validate asking important radiation oncology questions in this disease
study conclusions.1-5 including volume titration of the boost field to an image-
Study 0617 also raised important questions about normal guided target volume and titration of the spine dose in age-
tissue tolerance and toxicity. Since the initiation of the study, appropriate patients. The protocol required 189 sites to meet
there have been considerable advances in technology for accrual objectives. A retrospective diagnostic imaging review
conformal avoidance of normal tissues and AI is supporting revealed more than 10% of patients entered into the study
contouring of normal tissue and tumor anatomy. Treatment were not eligible due to more than 1.5 cm3 residual disease
planning for lung patients remains challenging as optimal postsurgery in the posterior fossa or evidence of intramedul-
planning requires a balance of constraints as cardiac, pulmo- lary lesions on spine imaging. This is important for many
nary, esophageal, and spinal cord constraints can compete reasons including that these patients who unintentionally
and place emphasis on one can place unintended dose to entered the standard risk trial had a statistically significant
another structure. For example, a hard cardiac constraint can decrease in survival compared to the primary study
404 T.J. FitzGerald et al.

population. The RT components of the study were reviewed acquisition and management to support the success of the
in real-time, however, imaging by study investigators was trial. The HL QA process evolution led investigators to ask
performed in retrospect and the time of the final review of more modern questions in protocol format including
RT objects for RT volume compliance. Adjustments in response-driven adaptive RT and therapy titration. The abil-
approach are planned for the next series of studies which ity to acquire and share information worldwide on a real-
include real-time review by QA centers with referral to study time basis opens doors to pathways previously hidden. The
neuro-radiologist for challenging and ambiguous cases. QA future of clinical trials is bright with processes in place to
performed in real-time can ensure that the correct patient is ensure the acquisition and management of complete and
entered into the correct study to ensure optimal protocol accurate data.
management.43 We have much to learn. We need to optimize our target-
ing and dose to primary brain tumors relative to advanced
technology imaging. Can we titrate radiation dose and vol-
ume to selected head and neck patients, optimize function,
Summary and maintain local control? Can we adjust RT to gross tumor
Fairchild and colleagues performed a literature review of only for molecular-driven targets in primary lung cancer to
multiple clinical trials involving RT and noted that protocol- optimize cardio-pulmonary tolerance? Can we optimize tar-
compliant RT was associated with a decrease in failure rates geting for gastrointestinal volumes and limit toxicity to nor-
and an increase in survival.44 The investigators concluded mal tissue? Metabolic imaging is suggesting a higher number
that study compliance contributed to the ability of the col- of node-positive patients in advanced cervix cancer than was
lected data to answer the study question. Limitations and fac- previously recognized. Can we define the correct dose for
tors contributing to the ability to comply with protocol nodal targets, and do we need to adjust for size and meta-
management included misinterpretation of ambiguities writ- bolic activity? Can we dose paint image-defined targets in
ten in the study, institutional differences in problem-solving the prostate and consider the prostate gland a clinical target
and approach to patient care, inter-physician variation in volume, not a gross tumor volume? Can we limit toxicity for
interpretation of the target volume, and intentional changes our pediatric populations?45-60 These important questions
in approach due to the perception of acute and late toxicity. and others can only be answered in the context of a trial
While these reasons have merit, most if not all, can be with large datasets. The quality of the data provided by QA
addressed through real-time dialogue to determine if proto- has a direct bearing on the answers.
col guidelines can be met. The interactions can center on
study appropriateness for the individual patient and where Acknowledgments
compromises can be met in targeting to meet trial objectives Supported in part by the Imaging and Radiation Oncology
and needs of the patient. These exchanges can help secure Core (IROC) Grant, CA180803.
study compliance and meet study objectives. QA processes
have matured as our technology has evolved. Processes today
can function at an enterprise level not anticipated by our References
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