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VOLUME
26
䡠
NUMBER
7
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MARCH
1
2008
JOURNAL OF CLINICAL ONCOLOGY
S P E C I A L
A R T I C L E
Globalization of the Radiation Therapy Oncology Group:
Implementation of a Model for Service Expansion and
Public Health Improvement
Benjamin W. Corn, Isaiah D. Wexler, Mohan Suntharalingam, Moshe Inbar, and Walter J. Curran Jr
From the Department of Radiation
Oncology; Department of Oncology, Tel
Aviv Medical Center, Tel Aviv; Department of Pediatrics, Mount Scopus
Campus, Hadassah University Hospital,
Jerusalem, Israel; Department of Radiation Oncology, University of Maryland
Greenebaum Cancer Center, Baltimore,
MD; and the Radiation Oncology
Department, Thomas Jefferson University Hospital of the Jefferson Medical
College, Philadelphia, PA.
Submitted September 15, 2007;
accepted November 9, 2007.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Corresponding author: Benjamin W.
Corn, MD, Institute of Radiotherapy,
Aviv Medical Center, 6 Weizmann St,
Aviv, Israel 64239; e-mail: bencorn@
tasmc.health.gov.il.
© 2008 by American Society of Clinical
Oncology
0732-183X/08/2607-1160/$20.00
DOI: 10.1200/JCO.2007.14.3891
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The Radiation Therapy Oncology Group (RTOG) is part of the cooperative group network that is
overseen by the National Cancer Institute (NCI). Although the NCI is a US-based group, it has
empowered the cooperative groups to recruit foreign institutions to participate in collaborative
clinical trials. The RTOG undertook the challenge of globalizing its efforts in 2004. This article
describes the rationale for this decision and the tactics adopted by the first hospital outside of
North America to enroll patients onto RTOG trials. The challenges confronted by foreign
institutions seeking admission to the RTOG and the mechanism by which Tel Aviv Medical Center
(TAMC) met these challenges are described. Shortly after its acceptance, TAMC emerged as one
of the leading accruers of patients to RTOG studies. The public health implications of this
accomplishment are discussed.
J Clin Oncol 26:1160-1166. © 2008 by American Society of Clinical Oncology
INTRODUCTION
Motivated by the rapidly expanding incidence of
cancer, the US government established the cooperative cancer group network under the aegis of the
National Cancer Institute (NCI) in 1955.1 The rationale for forming large, multi-institutional groups
was based on the growing recognition that cancer
represented a taxonomy of clinically and pathologically diverse malignant processes.2 To develop effective therapies, it would be necessary to test a variety
of treatments on diverse populations. This required
a large number of subjects with identical cancers. To
accrue a sufficient number of patients, cancer centers had to pool their resources. A distinction of the
cooperative groups was that all centers adhered to
rigid and well-defined protocols that strengthened
the findings of the clinical trials. As a prototype, the
cooperative cancer group networks within the
United States greatly expanded in the ensuing decades, and served as a model for collaborative research in Europe and Canada.
As the concept of the cooperative cancer group
networks continued to evolve, there was a push to
focus on specific modes of cancer therapeutics. In
1972, Dr. Simon Kramer argued that radiation therapy, which was emerging as a curative modality in
the management of neoplastic disease, required a
cooperative group mechanism of its own to properly
assess its efficacy.3 As a result of the pioneering ef-
forts of Kramer and his colleagues, the Radiation
Therapy Oncology Group (RTOG) was founded.
The RTOG has been among the most successful entities within the NCI constellation of
cooperative groups. The success is manifest by an
increasing annual accrual of patients, a steady expansion of centers affiliated with the group, a
broadening of the number of disease sites studied,
and a decrease in the median time required to
complete studies.4-6 In a groundbreaking paradigm shift, in 2004, the Membership Committee
of the RTOG adopted a proposal that would make
global expansion of RTOG activities a strategic
priority. After approval by the Steering Committee of the RTOG, a tender inviting foreign centers
(outside North America) to apply for affiliate
membership was issued. Acceptance was contingent on the candidate center’s ability to document
adherence to the guidelines specified by the
RTOG.7 Affiliate membership was granted to Tel
Aviv Medical Center (TAMC; Tel Aviv, Israel) in
2005. Subsequently, centers from Peru, South Korea, and Australia were invited to join the RTOG.
This article will discuss the basis for globalization
of the RTOG’s clinical programs and enumerate
the benefits associated with expanded international membership from the perspective of both
the RTOG and the international affiliates (Table
1). The inclusion of non-US centers was not without challenges, and the experiences of one of the
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Globalization of the Radiation Therapy Oncology Group
Table 1. Advantages and Disadvantages Derived From Globalization of the Radiation Therapy Oncology Group
Group
Advantage
International center
RTOG
Disadvantage
Upgrade of medical standards for patients enrolled on study with
“spillover effect” to non-participants
External review and quality assurance from an established entity
Provision of medication without charge
Expanded “N” empowers clinical trials
Accelerated accrual
Verification of applicability of intervention being tested
Increased probability of adoption of clinical intervention
affiliates (TAMC) to meet the requirements set forth by the RTOG
will be discussed.
RTOG AND GLOBALIZATION
In 1971, then-President Richard Nixon and the US Congress declared
war on cancer. In the State of the Union address of that year, Nixon
argued for a national commitment in the fight against cancer, commenting that, “America has long been the wealthiest nation in the
world. Now it is time we became the healthiest nation in the world.”
Given this somewhat nationally self-centered goal, it would seem that
the expansion of the RTOG to include foreign centers would run
counter to this aim. Dispensing limited funds to nondomestic institutions means that there is less available to cancer centers in the United
States. More to the point, money spent on treating foreigners is money
not spent on treating US residents. Altruism may and should be part of
the motivation of expanding clinical research beyond the borders of
the United States.8 However, it is one thing for the United States
Centers for Disease Control to do onsite research and donate much
needed anti-HIV medications and research support to African countries as part of ongoing clinical research programs,9 and a totally
different undertaking to recruit foreign nationals to participate in
US-based clinical research and subsidize their treatment.
The decision of the RTOG to recruit international members was
motivated by a pragmatic approach related to cancer research. The
war on cancer needs to be waged on many fronts, and the outcome of
this war, similar to other wars, will most likely be determined by the
number of resources that can be brought to bear in the battle against
this modern-day scourge. The heterogeneity of cancer was already
thought to be complex in the 1950s, and today, with more advanced
understanding of cancer genetics and aberrant signal transduction, it
is axiomatic that single-agent approaches will be inadequate against
malignant disease. Multimodal treatment (eg, chemotherapy, surgery,
and radiotherapy) is now the rule, and the challenge for clinical cancer
research is to find the right balance of the constituent therapies. In
practical terms, this means that more studies involving larger and
diverse populations need to be performed.
For cooperative cancer groups to maintain a leadership role in
clinical cancer research, they would have to activate more protocols,
accrue a larger number of patients, and accelerate turnaround time so
that more protocols could be executed. Even so, the capacity of the
cancer groups would be exceeded if the number of centers was not
increased. The leadership of the RTOG recognized that, to attain such
goals, expansion should be done both domestically and internation-
Nonreimbursable management expenses
Need to dispatch reviewers to foreign country
ally. Previous limitations on international expansion such as geographic distance and differences in medical practice have been
ameliorated with improved global communications that facilitate not
only data transmission but also international harmonization of clinical practice and investigational drug development.10-13
There were other motives behind the RTOG’s effort to recruit
international centers. Extensive clinical cancer research is currently
being conducted in numerous countries. As a result, there is duplication of studies, which leads to the wasting of scarce fiscal resources.
Imperfect duplication of protocols and nonuniform standards can
have an impact on research findings. For example the treatment of
carcinoma of the cervix was stagnant for a prolonged period of time as
clinician-scientists struggled to agree on the optimal synthesis of
external-beam irradiation, brachytherapy regimens, and chemotherapy as reflected by the lack of uniformity among study protocols.14
With discrepant results, it is difficult for clinicians and/or patients to
decide whether a specific treatment modality is appropriate. Without
the resources and the commitment to quality control that have been
the hallmark of the RTOG, positive or negative findings of specific
studies might not meet the strict requirements demanded by
evidence-based medicine, with the possibility of tragic consequences if
scientifically unfounded therapies are disseminated. Consideration
also has to be given to the protection of human subjects involved in
studies. Indeed, in a policy statement adopted by the American Society
of Clinical Oncology (ASCO) in 2002, it was advocated that the protection afforded to participants in US-based trials be extended to
subjects recruited for international, multi-institutional clinical trials,
and that this can best be done in the framework of foreign institutions’
joining the cooperative cancer groups.15
The inclusion of more centers and patients with diverse ethnic,
socioeconomic, and cultural backgrounds would only strengthen the
conclusions of a given study. With more centers, there is less chance of
bias affecting the result. Unduly favorable results from one center will
not disproportionately affect the results of a trial, and the larger number of patients will allow for the use of multiple end points that
supplement the main finding and offer a greater chance for obtaining
statistically significant results and avoiding type 2 errors because of
insufficient numbers of enrollees. Moreover, the addition of centers
allows for a faster rate of accrual and the chance to systematically study
rare cancers.
Beyond the requirement for greater and more rapid accrual of
patients which frankly could be accomplished by recruiting more
centers in North America, there is a need to expand the patient base to
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include individuals from different ethnic backgrounds who are exposed to a variety of environmental factors (eg, diet, climate, pollutants, and so on) that could have an impact on outcome. There is also a
greater appreciation of the role that genetics of the host (eg, pharmacogenomics) has in determining susceptibility, prognosis, and
response to treatment, and these factors can best be analyzed
through evaluation of a diverse population.16,17 With a more varied pool of patients, study results would have greater universality
and applicability.
Foreign centers also have strong motivations to align themselves
with the RTOG. Smaller countries may not have the patient numbers
to execute either institutional studies or collaborative national studies.
By joining the RTOG, they can contribute to large-scale studies while
simultaneously benefiting from the data derived from these clinical
trials. In following the identical protocols used by the RTOG, study
results are more meaningful because the experimental conditions are
uniform at all sites. At another level, participation in the RTOG requires adhering to high quality control standards and making data
available for external audits. Patients receiving care at an RTOG affiliate, even if they are not enrolled in a specific protocol, can be assured
that they are receiving a high level of care. Finally, individuals with
cancer are afforded a chance to receive cutting-edge therapy that
might not otherwise have been accessible to them, either because of
the costs of treatment or the lack of availability of certain experimental
drugs or equipment.
CHALLENGES FACING FOREIGN INSTITUTIONS: A CASE STUDY
Despite the benefits of belonging to the RTOG, foreign radiotherapy
centers face considerable challenges in meeting the standards set forth
by the RTOG for affiliate membership (Fig 1). These include bearing
the costs involved in fulfilling RTOG prerequisites, changing clinical
RTOG assessment
practices, and adopting institutional practices such as institutional
review board (IRB) procedures so that they are compatible with the
human-experimentation practices of the RTOG. Language barriers
can be a major hurdle because patient documentation must be prepared in a language that can be understood by RTOG representatives.
Likewise, primary documents written in the vernacular of a foreign
institution must be translated to English so that monitoring can be
carried out by the RTOG. In the following section, we will describe the
challenges faced by TAMC and how these hurdles were surmounted
en route to joining the RTOG. The experiences of TAMC will be useful
to other centers outside North America seeking to join the RTOG and
demonstrate the benefits associated with broadening participation in
the RTOG.
TAMC AND THE RTOG: THE INSTITUTE OF RADIOTHERAPY
AT TAMC
TAMC is one of the primary teaching affiliates of the Tel Aviv University School of Medicine, and one of the largest inpatient facilities in
Israel. TAMC has a longstanding tradition of clinical and basic research and has been a participant in several European consortia such
as the European Organisation for the Research and Treatment of
Cancer (EORTC) and the Breast International Group (BIG). The
Institute of Radiotherapy at TAMC has been operational for more
than three decades and is now equipped with four linear accelerators,
two computed tomography simulators, and capabilities for radiosurgery, brachytherapy, intensity-modulated radiotherapy (IMRT), and
image-guided radiotherapy. On average, 170 patients with varied primary tumors are treated daily with either curative or palliative intent.
The strategic decision by TAMC to apply for RTOG membership
was primarily motivated by the desire to introduce standards practiced
by the RTOG and other cooperative cancer groups into the Israeli
oncologic community. By accepting the clinically rigorous standards
of the RTOG, it would be expected that not only patients enrolled into
RTOG protocols but also those who declined to participate in these
protocols or simply were deemed protocol-ineligible would derive
benefit from the enhanced standard of care.
• Adequacy of equipment (hardware, software)
• Institutional experience (credentials)
• Availability of chemotherapeutic agents
Institutional assessment
• Volume of patients (high: ≥ 100/year; low: < 100/year)
• Language barrier (translation of form; interpreter)
• Tissue blocks (approval from local IRB and Ministry of Health)
Monitoring
• Helsinki committee inspection
• RTOG audit process
Fig 1. Evolution of protocol implementation. RTOG, Radiation Therapy Oncology Group; IRB, institutional review board.
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MEETING THE REQUIREMENTS FOR RTOG MEMBERSHIP
The RTOG has established a set of prerequisites that must be met by
institutions to be considered for membership. Although the details are
enumerated on the RTOG website,7 several key requirements are
worth noting here in more detail. First, the physics staff must submit a
description of all equipment (eg, linear accelerators and simulators
and their characterizing features), software, calibration schedule, and
quality-assurance protocols. Second, physicians must provide a synopsis of all “clinical material” encountered (eg, number and type of
patients seen in consultation, quantification of total fields treated per
day, brachytherapy applications, and special procedures such as hyperthermia and radiosurgery). Third, all potential investigators (eg,
physicians, physicists, clinical research associates) must complete the
online course for the Human Participant Protections Education for
Research Teams, which is sponsored by the National Institutes of
Health (NIH; Bethesda, MD).18 To meet the prerequisites set forth by
the RTOG, TAMC began a comprehensive overhaul of its practices
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Globalization of the Radiation Therapy Oncology Group
that involved credentialing, translation of clinical materials, procedures for processing clinical specimens, data handling, internal review
monitoring, instituting changes in indemnification and informed
consent for patient participation, as well as the development of funding sources.
Credentialing
One of the challenges facing foreign institutions is ensuring that
both study personnel and equipment meet the requirements of the
RTOG. There are often differences between the United States and
other countries in terms of specialty training and certification. Standards of care vary, and protocols for maintenance of machinery may
not be sufficiently strict. To ensure that both TAMC personnel and
equipment met RTOG standards, an extensive credentialing process
was instituted. Institutional registries were accessed to determine the
absolute number of cancer cases treated per year and to categorize the
cases according to disease site and as a function of therapeutic intent
(definitive v palliative). Case logs were solicited from physicians to
establish the number of patients treated by each attending radiation
oncologist on an annual basis. The availability of modern apparatus
(eg, simulators, linear accelerators) and updated software (eg, treatment planning packages, record and verify systems) were documented. Phantom measurements and individualized test cases of
novel procedures (eg, radiosurgery, partial breast irradiation) were
submitted separately for review to the physics staff of RTOG. The
latter were transmitted electronically to expedite the credentialing
process and reduce expenditure.
Compliance With Cancer Therapy Evaluation Program
Guidelines for International Collaborating Institutions
The NCI Cancer Therapy Evaluation Program (CTEP) has developed guidelines for international institutions wishing to participate
in cooperative study groups. These guidelines, which are available
online (http://ctep.cancer.gov/guidelines/nci_clin_intl_guidelines
.pdf), detail specific requirements regarding protection of human
subjects, uniform handling of data, protocol development, appropriate conduct of the trial, investigational drug handling, and
external auditing. For institutions such as TAMC, in which participation in the RTOG involves receiving federal funds for per-case
reimbursement, the requirements are particularly stringent. For
example, TAMC must maintain a Federalwide Assurance (FWA)
for the protection of human subjects indicating that they are complying with the guidelines established by the Office of Human
Research Protection (OHRP) for institutions in countries other
than the United States. Use of investigational new drugs (INDs) or
commercially supplied trial drugs also is covered by CTEP and the
US Food and Drug Administration regulations. The NCI has recommended that international centers establish an international
source and distributor for INDs or commercial agents. This has
proven challenging because it often requires the cooperation of
pharmaceutical firms that, for various reasons (eg, liability, costs,
proprietary interests), may be reluctant to supply study drugs.
The CTEP strongly recommends that the NCI-sponsored collaborative group (in this case, RTOG) identify a principal investigator at
the foreign site who is responsible for effecting on-site protocol regulatory approval. The principal investigator also assumes responsibility
for all protocol patient accruals, delivery of protocol treatment, and
reporting of protocol-related toxicity and clinical data. In the case of
TAMC, the task of bringing the Institute of Radiotherapy into compliance with CTEP guidelines and recommendations was facilitated by
the fact that the principal investigator previously held leadership roles
in the RTOG.
Language Barriers
Barriers need to be overcome where English is not the primary
language. In Israel, all RTOG documents including protocols, consent
forms, and patients’ materials had to be translated into Hebrew. This is
often a difficult task, especially with regard to informed consent because nuances in the translation regarding risks and benefits could
lead to misunderstandings and impair the informed-consent process.
Fortunately, many of the ancillary materials (eg, quality-of-life tools)
had already been translated into Hebrew (as well as multiple other
languages) and validated within the vernacular. To ensure appropriate
informed consent, provision had to be made for interpreters who
would translate the informed consent form containing the description
of the study. In addition, patient documentation (eg, operative notes,
imaging reports, pathologic diagnoses) was translated from Hebrew to
English so that RTOG auditors would be able to verify the legitimacy
of the cases enrolled onto specific protocols.
Clinical Specimen Handling
A unique hurdle associated with RTOG membership involved
the handling of clinical specimens, especially tissue blocks. Tissue
blocks have become a precious resource in the era of translational
research because they can be processed to determine the impact of
biologic markers on patient outcome. At present, all of the brain
tumor protocols of the RTOG mandate submission of tissue blocks as
a prerequisite for protocol enrollment. No precedent existed, however, in the Israeli health care system for the extramural transfer of
human materials. To join the RTOG, the TAMC Institute of Radiotherapy had to obtain permission for tissue transfer from the
TAMC IRB (Helsinki Committee), the national IRB, and the Israeli
Ministry of Health. One difficulty encountered during the process
was the insistence by the IRBs that separate applications be made
for individual protocols, which represents a significant time expenditure (a three-step process that must be performed serially rather
than in parallel) and can cause a delay in patient recruitment for
new protocols.
Internal Review
A hallmark of large collaborative studies by the NIH is the requirement for external review and auditing. To prevent external audit
failures, a rigorous internal review system had to be instituted. This
involved weekly meetings with required attendance of physicians (radiation oncologists, medical oncologists, surgeons), physicists, clinical
pharmacists, and clinical research associates. In addition to prophylaxing against audit failure, these meetings provide a forum for the
review of interval progress on a per-patient basis, debugging of logistical obstacles, and refinement of strategic goals (eg, activating new
protocols, terminating old protocols).
Indemnification
Responsibility for the adverse effects of therapeutic RTOG protocol– based interventions is borne by the treating institution. To
minimize both the exposure of TAMC personnel and the RTOG to
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litigation, attorneys representing the hospital and the RTOG worked
together to ensure that the appropriate waivers were enforceable.
Data Handling
As of late, information technology is playing a larger role in the
RTOG and other cooperative cancer groups. Patient data, even information not currently required by the RTOG, needed to be recorded in
a systematic fashion that would allow for easy transferability to existing RTOG databases. As mentioned earlier herein, CTEP has also
established uniform methods for data recording and reporting that
must be followed by all participating collaborative group centers.
Databases used for the study had to be designed for forward compatibility in case the RTOG adapts new database software.
Funding
As stated in the introduction, there are numerous advantages for
a non–North American center’s allying itself with the RTOG. However, a major drawback is the cost of membership. The rigorous
standards of the RTOG, the need for an extensive infrastructure for
data management and record keeping, long-term patient tracking and
follow-up, the costs of treatment, and the increased labor costs (physicians, technologists, allied health personnel) make membership in
the RTOG an expensive proposition for any potential applicant
whether in the United States or abroad. In the case of TAMC, it was
necessary for the Institute of Radiotherapy to hire two additional data
managers, a half-time medical secretary, and a nurse. In addition, the
Institute’s medical administrator devotes 0.125 of his time to RTOGrelated procedures. Moreover, physician time per RTOG patient is
greater, so participating physicians had to reduce their patient loads.
The allocated RTOG reimbursement per protocol can defray
some of the costs inherent in the upkeep of an RTOG center, but this
reimbursement falls far short of covering the expenses encountered
and the expected costs accrued over the lifetime of a protocol. For
TAMC to join the RTOG, it was necessary to aggressively seek and
secure funding from a variety of sources that include seed money
invested by the TAMC administration and solicitations of philanthropic foundations. Our experiences are not unique, and the cost
issues that behoove procurement of external funding will remain a
significant challenge for any institute wishing to join the RTOG.
ACCEPTANCE INTO THE RTOG
In August 2005, the TAMC Institute of Radiotherapy was accepted
into the RTOG. Since joining the RTOG, the Institute of Radiotherapy
has devoted significant resources to initiating and maintaining RTOG
protocols as described in the following sections. Currently, a network
of nearly a dozen physicians participate in the recruitment and management of RTOG patients at TAMC. On a weekly basis, four to six
physicians (along with pharmacists, physicists, and research associates) participate in “RTOG Rounds.” Medical and surgical oncologists
are invited to these meetings, and RTOG protocols and cases are
discussed at institutional-wide tumor boards and grand rounds. To
encourage participation of all oncologic disciplines in RTOG-related
studies, the Institute of Radiotherapy has provided subsidies to enable
health care professionals to attend RTOG-sponsored meetings
and workshops.
1164
Selection of Feasible Research Targets
In surveying the clinical caseload at TAMC, it was clear that the
two most potentially fertile opportunities for accession of patients
were tumors of the breast and brain. Accordingly, protocols pertaining to these disease sites were the first to be submitted to the institutional Helsinki committee. This decision was deliberate because it was
readily apparent that the Helsinki committee could not be inundated
by multiple submissions of RTOG protocols. Moreover, it was understood that the learning curve for protocol participation could be more
confidently ascended by staff members (physicians, data managers,
research nurses, and so on) if only a limited number of studies were
being managed simultaneously. Similar logic was applied to the technologies selected at the outset. To wit, although TAMC possessed a full
complement of the resources needed to execute protocols predicated
on IMRT and adaptive treatment approaches, the decision was made
to concentrate on the more straightforward protocols (eg, conformal
treatment, palliative treatment) so as not to confound the goal of
efficient protocol enrollment and acquisition of momentum. Conversely, because a brisk radiosurgery program was extant at TAMC,
RTOG trial 03-20 (brain metastases from primary lung cancer treated
with whole-brain irradiation, radiosurgical boost, and varying chemotherapies) was activated.
Enrollment of Patients Onto RTOG Studies
Approval for accrual to five RTOG protocols (three brain protocols; one breast protocol; one lung protocol) was granted by the
Helsinki Committee in the latter part of 2005. During the course of the
ensuing calendar year, 28 patients were enrolled onto these respective
studies. Ten patients had breast cancer, and three had primary non–
small-cell lung cancer. The remainder suffered from malignancies of
the CNS. The 28 patients who enlisted ranked TAMC fourth in the
standing of the 213 “affiliate members” of the RTOG (Table 2). Figure
2 shows a steady increase in the rates of accrual observed at TAMC
during the first year and a half of active recruitment. Within the initial
Table 2. Radiation Therapy Oncology Group Top Institutional Accruers for 2006
Institution
Accrual
Full members
Arizona Oncology Services Foundation
McGill University
Mayo Clinic
Notre Dame Hospital/University of
Montreal
Medical College of Wisconsin
Affiliate members
University of Wisconsin
University of Utah
Yale Cancer Center
Tel Aviv Medical Center
Waukesha Memorial Hospital
CCOP members
Southeast Cancer Control Consortium
Christiana Care Health System
LIMR/MLH CCOP
Michigan Caner Research Consortium
Beaumont CCOP
150
81
75
73
73
52
45
31
28
27
115
50
26
24
20
Abbreviations: CCOP, Community Clinical Oncology Program; LIMR/MLH,
Lankenau Institute for Medical Research/Main Line Health.
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Globalization of the Radiation Therapy Oncology Group
16
14
Patients
12
10
8
6
4
2
0
Q1 2006
Q2 2006
Q3 2006
Q4 2006
Q1 2007
Q2 2007
Quarters
Fig 2. The number of patients accessed to the trials of the Radiation Therapy
Oncology Group by Tel Aviv Medical Center on a per-quarter basis.
half of 2007, TAMC was the lead accruer of all affiliate members.
What’s more, only seven full member institutions enrolled more patients onto RTOG trials between January and June 2007.
Compliance With Groupwide Standards
In February 2007, a random audit was conducted on seven of the
aforementioned patients. This exercise did not require the actual dispatching of auditors from RTOG headquarters in Philadelphia, PA,
but rather consisted of data exchange by electronic and postal mail.
The parameters assessed (Table 3) pertained to the IRB monitoring,
the informed consent process, the management of the investigative
agents studied, and a review of actual patient case material. In each of
the cases, no major violations were seen. Minor deviations from protocol guidelines were easily remedied.
DISCUSSION
As part of its agenda, the cooperative group mechanism was designed
to serve as a model for cancer clinical trials throughout the world.
From the outset, the leaders of the NCI recognized the limitations of
single institutions, irrespective of size, to consistently accrue adequate
Table 3. Parameters of Initial Audit of TAMC
Parameter
IRB
Investigative agent management
Patient cases
Components
IRB approval
Annual renewal of studies
Amendment approval
Update of safety reports
Drug accountability forms
Shipment labels
Return/discard of unused materials
Physician notes (H&P, follow-up
assessments)
Radiology reports
Laboratory reports
Administrative flow sheets
Pill diaries
Radiation treatment flow sheets
Informed consent
Abbreviations: TAMC, Tel Aviv Medical Center; IRB, institutional review
board; H&P, history and physical examination.
patient numbers for the conduct of trials that would answer meaningful questions. Subsequently, leaders of the NCI advocated the
fostering of greater international cooperation to speed technology
transfers.1 The internationalization of participants within the
RTOG is thus in synchrony with the strategic expansion of the
cooperative group system.
TAMC has directly benefited from its affiliate membership in the
RTOG by adopting the group’s rigorous standards for administering
radiotherapy,19 calibration and dosimetry,20 as well as quality assurance.21 There has been a commensurate enhancement in quality of
care among those patients who have enrolled onto RTOG trials.
Moreover, the guidelines established by the RTOG have extended
beyond the requirements of clinical investigation, and have found
application in the daily practice conducted at TAMC. In fact, the
major enticement to joining the RTOG lay in the mandatory adoption
of a set of quality-assurance guidelines set by the group that could then
also be applied to nonprotocol treatments. The RTOG standards,
which are reflective of a national consensus within the United States,
were utilized to raise the level of radiation treatment in Israel. The
measure of success of these efforts can be judged by the fact that other
radiation oncology centers in Israel are now exploring the possibility
of affiliating with the RTOG.
The cooperative cancer groups are rapidly evolving to ensure
their place at the forefront of the conduct of clinical trials during the
21st century. Incorporation of foreign centers will directly solidify the
standing of the cooperative groups while simultaneously upgrading
the clinical care administered to patients worldwide. Although it is too
soon to determine whether the addition of international sites will
accomplish all the goals described in this discussion, it is clear that the
globalization of cooperative cancer group trials will maintain the
United States’ leadership position in clinical cancer research and bring
about improved care and better decision making for patients, clinicians, researchers, and policy makers in the United States and abroad.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) indicated a financial or other interest that is relevant to the subject
matter under consideration in this article. Certain relationships marked
with a “U” are those for which no compensation was received; those
relationships marked with a “C” were compensated. For a detailed
description of the disclosure categories, or for more information about
ASCO’s conflict of interest policy, please refer to the Author Disclosure
Declaration and the Disclosures of Potential Conflicts of Interest section in
Information for Contributors.
Employment or Leadership Position: Walter J. Curran Jr, Radiation
Therapy Oncology Group (U) Consultant or Advisory Role: None Stock
Ownership: None Honoraria: None Research Funding: None Expert
Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Benjamin W. Corn, Isaiah D. Wexler, Mohan
Suntharalingam, Walter J. Curran Jr
Financial support: Moshe Inbar
Administrative support: Moshe Inbar
Provision of study materials or patients: Benjamin W. Corn,
Walter J. Curran Jr
1165
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192.114.23.18.
Copyright © 2008 by the American Society of Clinical Oncology. All rights reserved.
Corn et al
Collection and assembly of data: Benjamin W. Corn, Mohan
Suntharalingam, Walter J. Curran Jr
Data analysis and interpretation: Benjamin W. Corn, Isaiah D. Wexler,
Mohan Suntharalingam, Walter J. Curran Jr
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■ ■ ■
Acknowledgment
The authors wish to acknowledge Professor Gabriel Barbash who provided steadfast support to the RTOG program at Tel Aviv
Medical Center.
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