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Clinical trial availability for adolescents and young adults with cancer
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Clinical trial availability for adolescents and young adults with cancer
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Content
Running Head: CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER
Clinical Trial Availability for Adolescents and Young Adults with Cancer
By
Stefanie M Thomas
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the Requirements for the Degree
MASTER OF SCIENCE (CLINICAL AND BIOMEDICAL INVESTIGATIONS)
May 2018
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 2
2
Table of Contents
Abstract ......................................................................................................................................................... 3
Chapter One: A Prospective Observational Cohort Study Comparing Cancer Clinical Trial
Availability and Enrollment between Early Adolescents/Young Adults and Children* .............................. 4
Abstract……… ...................................................................................................................................... 4
Background and Significance ................................................................................................................. 5
Methods……. ......................................................................................................................................... 6
Study Design, Setting and Case Ascertainment ............................................................................. 6
Determination of CCT Existence, Availability, and Enrollment Status ......................................... 7
Statistical Analysis ......................................................................................................................... 8
Results……….…. .................................................................................................................................. 9
Patient Characteristics .................................................................................................................... 9
CCT Existence, Availability, and Enrollment Proportions .......................................................... 10
Predictors of CCT Enrollment ...................................................................................................... 13
CCT Characteristics...................................................................................................................... 14
Discussion…… .................................................................................................................................... 15
Chapter Two: A Prospective Study of Cancer Clinical Trial Availability and Enrollment among
Adolescents/Young Adults Treated at a Children’s Hospital or Affiliated Adult Cancer Specialty
Hospital ....................................................................................................................................................... 19
Abstract…….… ................................................................................................................................... 19
Background and Significance ............................................................................................................... 20
Methods…….. ...................................................................................................................................... 21
Study Design, Setting and Case Ascertainment ........................................................................... 21
Determination of CCT Existence, Availability, and Enrollment Status ....................................... 22
Statistical Analysis ....................................................................................................................... 23
Results……….. .................................................................................................................................... 23
Patient Characteristics .................................................................................................................. 24
CCT Existence, Availability, and Enrollment Proportions .......................................................... 26
CCT Characteristics...................................................................................................................... 26
Discussion……. ................................................................................................................................... 28
References ................................................................................................................................................... 33
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 3
3
Abstract
Cancer is the leading cause of disease-related death for adolescents and young adults (AYA,
15-39 years old). Over the past thirty years, survival gains in AYAs have lagged significantly behind
those achieved in younger and older patients. Low participation in clinical trials is considered to be a
key contributor to this lack of progress. Several factors likely influence participation, but whether
appropriate trials are available for AYAs is as fundamental as it is under-studied. This comparative
prospective observational cohort study of clinical trial availability involved three subsets of newly-
diagnosed cancer patients: children <15 years at Children’s Hospital Los Angeles (CHLA), early
AYAs (15-20 years) at CHLA, and AYAs (18-39 years) at University of Southern California Norris
Cancer Hospital (NCH) over 13 months. For each patient, demographic and disease-related data was
collected and trial availability determined. Availability of clinical trials and final enrollment status
was compared between the children and AYA population at CHLA (Chapter 1) and the two AYA
populations (Chapter 2). We found that for the children and early AYAs at CHLA, clinical trial
availability was similar in the two groups, but a significantly lower proportion of early AYAs
enrolled onto CCTs. However, when comparing the early AYA cohort treated at CHLA and the older
AYA cohort treated at NCH, we found similar proportions of nationally existing cancer clinical trial,
but a significantly lower proportion of NCH AYAs having a locally available cancer clinical trial.
Our data shows distinct reasons for low trial enrollment depending on treatment site/patient age.
“Downstream” patient- and physician-level barriers to enrollment appear to more greatly impact the
early AYA population treated at CHLA, while “upstream” barriers to making trials available more
greatly impact the AYA population treated at NCH.
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 4
4
Chapter One: A Prospective Observational Cohort Study Comparing Cancer Clinical
Trial Availability and Enrollment between Early Adolescents/Young Adults and
Children*
Abstract
Background: Poor enrollment of adolescents and young adults (AYAs, 15-39 years) onto cancer
clinical trials (CCT) may contribute to inferior survival gains compared with children. This study
assessed whether differences in CCT availability explain lower CCT enrollment for early AYAs
(eAYAs, 15-21 years).
Methods: This prospective observational cohort study was conducted at a single academic children’s
hospital. For consecutive patients newly-diagnosed with cancer over a 13 month period, it was
determined whether an appropriate CCT existed nationally, was available locally, and whether
enrollment on that CCT occurred. The proportions of eAYAs versus children in each category were
compared using the χ
2
test. The impact of age and other factors on enrollment status was assessed
using logistic regression analysis.
Results: Among 216 patients, 58 were eAYAs and 158 were children. There was no difference in the
proportion of eAYAs versus children who had an existing (28/58 [48.3%] versus 85/158 [53.8%];
p=0.47) or available (23/58 [39.7%] versus 75/158 [47.5%]; p=0.31) CCT. However, significantly
fewer eAYAs were enrolled when a CCT was available (7/23 [30.4%] versus 50/75 [67.7%];
p=0.002). In multivariable analysis, eAYAs were significantly less likely than children to be enrolled
in an available CCT (adjusted odds ratio 0.22, 95% confidence interval 0.08, 0.62).
Conclusions: Equal proportions of children and eAYAs had CCTs available but significantly fewer
eAYAs were enrolled. This suggests that for eAYAs, factors other than CCT availability are
important enrollment barriers and should be addressed.
*This work was originally published in Cancer.
Thomas, S. M., Malvar, J., Tran, H., Shows, J., & Freyer, D. R. (2017). A prospective, observational
cohort study comparing cancer clinical trial availability and enrollment between early
adolescents/young adults and children. Cancer.
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 5
5
Background and Significance
Cancer remains the leading cause of disease-related death in the United States (US) for
adolescents and young adults (AYAs, 15-39 years old). Despite impressive survival gains achieved in
both younger and older populations over the past thirty years, AYAs have not experienced the same
improvements.(W. A. Bleyer et al., 1997) In 2006, the US National Cancer Institute (NCI) identified
AYAs as a health disparity population.(National Cancer Institute, 2006)
The lagging survival improvement of AYAs is multifactorial.(A. Bleyer et al., 2008; Butow et al.,
2010; Canner et al., 2013; Martin et al., 2007; Zebrack, 2011) One fundamentally important
contributor is the low participation of AYAs in NCI-sponsored cancer clinical trials (CCT).
Numerous studies of CCT enrollment indicate that 40-60% of children < 15 years of age participate in
CCTs compared with only 10-20% of early AYAs (eAYAs, 15-21 years old).(A. Bleyer, Montello,
Budd, & Saxman, 2005; W. A. Bleyer et al., 1997; Collins, Malvar, Hamilton, Deapen, & Freyer,
2015; Krailo, Bernstein, Sullivan-Halley, & Hammond, 1993; Parsons, Harlan, Seibel, Stevens, &
Keegan, 2011; Shaw & Ritchey, 2007) For AYAs older than 21 years, the proportion participating is
even lower.(Collins et al., 2015) This non-participation has serious consequences. Low CCT
enrollment of AYAs has been directly correlated with significantly lower annual survival
improvement compared with children.(A. Bleyer et al., 2005) Non-enrollment onto CCT also
prevents AYAs from gaining access to promising investigational therapies, providing biospecimens
essential for basic and translational research, and benefiting from studies of supportive care, quality
of life, cancer epidemiology, and other non-survival endpoints.(Freyer & Seibel, 2015)
Reasons for lower CCT enrollment of AYAs are not well understood. Studies suggest that AYA
enrollment barriers include suboptimal insurance, low socioeconomic status, distance to the cancer
center, older age, type of cancer specialist, and treatment by community-based providers who do not
participate in NCI-sponsored CCT.(Felgenhauer & Hooke, 2014; Parsons et al., 2015; Parsons et al.,
2011) Limited availability of CCTs for AYAs is another potential factor often asserted to be of major
importance.(Chuk, Mulugeta, Roth-Cline, Mehrotra, & Reaman, 2017; Jacob & Shaw, 2017; Parsons
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 6
6
et al., 2011; Shaw & Ritchey, 2007) However, published data regarding CCT availability are scant
and do not necessarily support this contention.(Seibel et al., 2014) Availability of CCTs is a crucial
consideration because other factors that could influence enrollment, such as patient/family- and
provider-level issues, presuppose availability of a CCT and are moot without one.(Freyer & Seibel,
2015) Yet assessment of CCT availability is challenging because it is difficult for retrospective
studies to ascertain eligibility of individual patients for CCTs that commonly open and close to
enrollment over time. Also, it is difficult for population-based studies to determine whether CCTs that
existed nationally were actually open at specific treatment sites. To overcome these challenges, we
undertook this prospective study of consecutive eAYAs and children newly-diagnosed with cancer to
evaluate potential age-related differences in CCT availability and enrollment. The primary study aim
was to compare the proportions of eAYAs and children for whom an appropriate CCT existed, was
available locally, and utilized for enrollment; secondary aims were to evaluate the effects of age and
other factors upon CCT enrollment. Our overall hypothesis was that both availability of and
enrollment onto CCTs would be significantly lower among eAYAs than children.
Methods
Study Design, Setting and Case Ascertainment
This was a prospective observational cohort study conducted at Children’s Hospital Los Angeles
(CHLA), an academic center located 6 miles from our affiliated adult-focused cancer hospital. CHLA
provides specialized cancer care from birth through young adulthood, typically 21 years of age for
newly-diagnosed patients.
To confirm the feasibility of our methods, we first conducted an informal pilot study of ten
children and eAYAs who were not included in this cohort. For this current study, all consecutive
pathology reports from patients aged 0-21 years were screened in real-time by collaborating pediatric
pathology fellows and transmitted to the principal investigator with name, medical record number,
and final pathology diagnosis. Pathology reports were reviewed by SMT and disregarded if they
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 7
7
represented pathology-only consultations for patients not receiving cancer care at CHLA, or
pathology specimens from second surgeries of patients already included in this study. The remaining
pathology reports were used to identify unique patients 0-21 years old with first diagnosis of cancer
and cancer treatment initiated at CHLA. Exclusion criteria were relapsed cancer, subsequent
malignant neoplasm (SMN), or transfers to CHLA having already starting cancer treatment
elsewhere.
For each patient meeting eligibility criteria for this study, pertinent demographic (age, sex, and
race/ethnicity) and disease-related (cancer diagnosis, stage, grade, risk group and relevant genomics)
information was abstracted from the medical record. For analytic purposes, cancer type was grouped
as leukemia/lymphoma and solid tumor. Patients were classified as children or eAYAs by age 0-14 or
15-21 years, respectively. This study was approved by the CHLA Institutional Review Board (IRB)
with a waiver for informed consent, as only anonymous data were collected and there was no patient
contact.
Determination of CCT Existence, Availability, and Enrollment Status
For purposes of this study, “clinical trial existence” was operationalized as a CCT appropriate for
the patient’s age, diagnosis, and stage/risk-group registered nationally on ClinicalTrials.gov and listed
as open and recruiting. “Clinical trial availability” was operationalized as an existing CCT that was
IRB-approved, activated and open to enrollment at CHLA at the time of that patient’s diagnosis.
“Clinical trial enrollment” was operationalized as the patient being successfully entered onto the CCT
according to standard procedures of the Clinical Trials Office for the CHLA Children’s Center for
Cancer and Blood Diseases. In regard to consenting procedures for CCTs, the CHLA IRB requires
written informed assent and parental permission for cognitively intact patients aged 7-17 years, and
written informed consent for patients 18 years and older. Regardless of patient age, permission for
CCT participation is obtained in accordance with these requirements by the disease-specific clinical
team.
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 8
8
For each patient, existence of a CCT was determined by SMT within two weeks of receiving the
diagnosis by searching ClinicalTrials.gov for a relevant CCT. The two-week timeframe was
established because trial sponsors are required to post updates on ClinicalTrials.gov within four
weeks of changes in enrolling status. The diagnosis was entered into the search term area with studies
limited to those “open and recruiting,” “interventional,” and available in the US. If a trial was so
identified, patient-specific clinical information (e.g., histology, stage, grade, risk group, genomic
status, and other characteristics) was employed to determine the patient’s specific eligibility for that
trial. Those confirmed as eligible were thus classified as having an existing CCT. Trial-specific data
available on ClinicalTrials.gov were recorded including the National Clinical Trial identification
number, phase, categorical type (e.g., National Clinical Trials Network [NCTN], other national
collaborative group, multi-center collaboration, industry, or institutional), the specific sponsor (e.g.,
Children’s Oncology Group [COG]), and the date the trial opened. Patients with an existing CCT
were then assessed for availability of, and enrollment upon, the CCT as described above.
For patients who had more than one applicable trial listed on ClinicalTrials.gov but none
available at CHLA, only one trial was recorded as existing using the following hierarchy: NCTN,
other national collaborative group, multi-center collaboration, industry-sponsored, or institutional.
Statistical Analysis
Descriptive statistics were used to characterize the sample. Differences in demographics, CCT
existence, CCT availability, and CCT enrollment among eAYAs versus children were evaluated using
the χ
2
test of proportions. The effects of demographics and disease characteristics on CCT enrollment
were analyzed using logistic regression. Predictor variables consisting of age, sex, race/ethnicity,
ethnicity, and cancer type were evaluated in univariable models. We tested for two-way interactions
between all predictors with none discovered. Two multivariable models were assessed, one including
ethnicity and the other including race/ethnicity, with both models including age, sex and cancer type
because of their clinical relevance. The model selected for reporting adjusted for ethnicity because its
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 9
9
effect was stronger than race/ethnicity in univariable analysis. All analyses were performed using 2-
sided tests with a p-value of < 0.05 defined as significant. Stata statistical software was used for all
analyses.(StataCorp.2009. Stata Statistical Software: Release 11).
Results
Between November 1, 2015 and December 1, 2016, a total of 277 unique patients were identified
and screened for eligibility (Figure 1). Of these, 61 were excluded for having relapsed disease (n=42;
24 children, 18 eAYAs), or already starting cancer treatment prior to transfer to CHLA (n=19; 13
children, 6 eAYAs). There were no patients with SMN.
Figure 1: CONSORT Diagram. Children = < 15 years old; early AYA = 15-21 years old.
Patient Characteristics
A total of 216 consecutive patients, 158 children and 58 eAYAs, constituted the analytic sample
(Table 1). The median ages of the childhood and eAYA groups were 6 years (range, 0-14) and 17
years (range, 15-20), respectively. Other demographic characteristics were similar except there was a
higher proportion of males in the eAYA group. In both groups, more than half the patients were
Hispanic, consistent with the population served by CHLA. A significantly higher proportion of
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 10
10
diagnoses were leukemia and brain tumors among children, whereas lymphoma and non-brain solid
tumors were more common among eAYAs.
Table 1: Patient Characteristics
1
Total (%) Children (%) Early AYA (%) p
Total 216 158 (73.1) 58 (26.9) --
Age (years)
Median 10 6 17
--
Range 0-20 0-14 15-20
Sex
Male 111 (51.4) 73 (46.2) 38 (65.5)
0.012
Female 105 (48.6) 85 (53.8) 20 (34.5)
Race/Ethnicity
Hispanic 120 (55.6) 84 (53.2) 36 (62.1)
0.53
White/Non-Hispanic 50 (23.1) 41 (25.9) 9 (15.5)
Asian 13 (7.4) 10 (6.3) 3 (5.2)
Black 12 (5.6) 9 (5.7) 3 (5.2)
Other 21 (9/7) 14 (8.9) 7 (12.1)
Diagnosis
Leukemia/lymphoma 114 (52.8) 81 (51.3) 33 (56.9)
0.0015
Leukemia 85 (39.4) 68 (43.0) 17 (29.3)
Lymphoma 29 (13.4) 13 (8.2) 16 (27.6)
Solid Tumor 102 (47.2) 77 (48.7) 25 (43.1)
Brain Tumor 25 (11.6) 21 (13.3) 4 (6.9)
Non-brain Solid Tumor 77 (35.6) 56 (35.4) 21 (36.2)
1
Children = < 15 years old; early AYA = 15-21 years old.
CCT Existence, Availability, and Enrollment Proportions
The proportions of CCT existence, availability, and enrollment were compared for eAYAs and
children (Figure 2). The proportions of eAYAs and children were similar for both having an existing
(28/58 [48.3%] versus 85/158 [53.8%], p=0.47) and having an available (23/58 [39.7%] versus
75/158 [47.5%], p=0.31) CCT. However, a significantly lower proportion of eAYAs than children
was enrolled onto CCT. Among those with an existing CCT, only 7/58 (12.1%) eAYAs enrolled
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 11
11
versus 50/158 (31.6%) children (p=0.004). Among patients who had an available CCT, 7/23 (30.4%)
eAYAs versus 50/75 (67.7%) children were enrolled (p=0.002). In seeking to localize the age where
enrollment declines, we found the enrollment proportions among both children < 10 years old and
children 10-14 years old with available CCT were significantly higher than eAYAs (34/49 [69.4%],
p=0.002; and 16/26 [61.5%], p=0.030, respectively). Additionally, we compared CCT enrollment
between younger eAYAs who gave informed assent (15-17 years old; n=45) and older eAYAs who
gave informed consent (18 years and older; n=13); among those with an available CCT, the
proportions enrolled were 4/16 (25.0%) and 3/7 (42.8%), respectively (p=0.39).
Figure 2: Cancer Clinical Trial Existence, Availability, and Enrollment by Age Group. Children = <
15 years (n=158); early AYA = 15-21 years old (n=58). See Methods for operational definitions of
cancer clinical trial existence, availability and enrollment.
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 12
12
As shown in Table 2, for both eAYAs and children a diagnosis of leukemia had the highest
proportion of existing and available CCTs, whereas a diagnosis of non-brain solid tumors had the
lowest. However, within diagnoses there were no compelling age-related differences in CCT
existence or availability. For our sample, most diagnoses without an available CCT occurred in both
children and eAYAs. These included astrocytoma, Ewing sarcoma (localized), germ cell tumors,
Hodgkin lymphoma (low stage), melanoma, mixed phenotypic acute leukemia, neuroblastoma, non-
Hodgkin lymphoma, osteosarcoma, rhabdomyosarcoma, and thyroid carcinoma. Among children,
diagnoses where CCTs were not available included chondrosarcoma, chordoma, hepatoblastoma,
glioblastoma multiforme, infantile fibrosarcoma, inflammatory myofibroblastic tumor, Langerhans
cell histiocytosis, rhabdoid tumor, renal cell carcinoma, retinoblastoma, solid pseudopapillary tumor
of the pancreas, synovial sarcoma, transitional liver cell tumor, and undifferentiated sarcoma. There
were no diagnoses encountered only among eAYAs where no CCT was available.
Table 2: Distribution of Patients Evaluated for Cancer Clinical Trials, by Patient and Trial
Characteristics (n=113 Patients)
Existence (%) Availability (%) Enrollment (%) Enrollment when Available (%)
2
Children
1
Early
AYA
1
Children Early AYA Children Early AYA Children Early AYA
Total 85 (75.2) 28 (24.8) 75 (66.4) 23 (20.4) 50 (44.3) 7 (6.2) 50 (66.6) 7 (30.4)
Sex
Male 37 (43.5) 18 (64.3) 35 (46.7) 14 (60.9) 22 (44.0) 3 (42.9) 22 (62.9) 3 (21.4)
Female 48 (56.5) 10 (35.7) 40 (53.3) 9 (39.1) 28 (56.0) 4 (57.1) 28 (70.0) 4 (44.4)
Cancer Type
Leukemia/Lymphoma 71 (83.5) 25 (89.3) 66 (88.0) 21 (91.3) 44 (88.0) 6 (85.7) 44 (66.7) 6 (28.6)
Leukemia 64 (75.3) 14 (50.0) 61 (81.3) 14 (60.9) 40 (80.0) 4 (57.1) 40 (65.6) 4 (28.6)
Lymphoma 7 (8.2) 11 (39.3) 5 (6.7) 7 (30.4) 4 (8.0) 2 (28.6) 4 (80.0) 2 (28.6)
Solid Tumor 14 (16.4) 3 (10.7) 9 (12.0) 2 (8.7) 6 (12.0) 1 (14.3) 6 (66.7) 1 (50.0)
Brain Tumor 10 (11.8) 1 (3.6) 7 (9.3) 1 (4.3) 5 (10.0) 1 (14.3) 5 (71.4) 1 (100)
Solid Tumor 4 (4.7) 2 (7.1) 2 (2.7) 1 (4.3) 1 (2.0) 0 1 (50.0) 0
Phase of Trial
Phase 1/2 3 (3.5) 0 0 0 0 0 -- --
Phase 2 6 (7.1) 5 (17.9) 3 (4.0) 0 3 (6.0) 0 3 (100) --
Phase 2/3 1 (1.2) 0 0 0 0 0 -- --
Phase 3 72 (84.7) 23 (82.1) 70 (93.3) 23 (100) 45 (90.0) 7 (100) 44 (62.9) 7 (30.4)
Phase 4 3 (3.5) 0 2 (2.7) 0 2 (4.0) 0 2 (100) --
Type of Trial
NCTN 73 (85.9) 25 (89.3) 73 (97.3) 23 (100) 48 (96.0) 7 (100) 48 (65.8) 7 (30.4)
Multi-Site 5 (5.9) 1 (3.6) 2 (2.7) 0 2 (4.0) 0 2 (100) --
Single Institution 7 (8.2) 2 (7.1) 0 0 0 0 -- --
1
Children = age < 15 years; early AYA = 15-21 years.
2
Proportions indicate the patient number enrolled over the patient number with available cancer clinical trials.
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 13
13
Predictors of CCT Enrollment
Logistic regression analysis was used to evaluate predictors for both overall CCT enrollment (i.e.,
among all patients included in the study [n=216]), as well as for CCT enrollment when the existing trial
was also available at CHLA (n=98). For overall CCT enrollment (Table 3), univariable analysis found
there was a significantly lower likelihood (OR [95%CI]) for eAYAs (0.30 [0.13, 0.70], p= 0.002) and
patients diagnosed with solid tumors (0.09 [0.04, 0.22], p= <0.001) to be enrolled, whereas there was a
significantly greater likelihood for Hispanic patients to be enrolled compared with non-Hispanic patients
(2.09 [1.10, 3.95], p= 0.021).
Table 3: Predictors of Enrollment onto Cancer Clinical Trials (n = 216)
Univariable Analysis Multivariable Analysis
Predictor Levels OR (95% CI) p OR (95% CI) p
Age group
1
Children (ref) 1
0.002
1
0.001
Early AYA 0.30 (0.13, 0.70) 0.23 (0.09, 0.58)
Sex Female (ref) 1
0.18
1
0.090
Male 0.66 (0.36, 1.22) 0.54 (0.26, 1.11)
Race/
Ethnicity
White/Non-Hispanic (ref) 1
0.067 Not included Hispanic 1.93 (0.87, 4.25)
Others 0.84 (0.30, 2.36)
Ethnicity Non-Hispanic (ref) 1
0.021
1
0.085
Hispanic 2.09 (1.10, 3.95) 1.89 (0.91 3.92)
Disease
category
Leukemia/lymphoma (ref) 1
<0.001
1
<0.001
Solid tumors 0.09 (0.04, 0.22) 0.08 (0.03, 0.19)
1
Children = < 15 years; early AYA = 15-21 years old.
In multivariable analysis adjusted for sex, ethnicity, cancer type and age, overall CCT enrollment was
significantly less likely to occur for both eAYAs (0.22 [0.09, 0.58], p= 0.001) and those with solid tumors
(0.07 [0.03, 0.18], p= <0.001). In contrast, among those for whom existing CCTs were available at CHLA
(Table 4), the only factor associated with CCT enrollment was age, where eAYAs were significantly less
likely to be enrolled in both univariable (0.22 [0.08, 0.60], p= 0.002) and multivariable (0.21 [0.07, 0.61],
p= 0.003) analysis. Predictors of enrollment within the eAYA group were unable to be assessed due to
small numbers.
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 14
14
Table 4: Predictors of Enrollment onto Cancer Clinical Trials when Available (n = 98)
Univariable Analysis Multivariable Analysis
Predictor Levels OR (95% CI) p OR (95% CI) p
Age group
1
Children (ref) 1
0.002
1
0.003
Early AYA 0.22 (0.08, 0.60) 0.22 (0.08, 0.62)
Sex Female (ref) 1
0.15
1
0.22
Male 0.55 (0.25, 1.25) 0.58 (0.24, 1.40)
Race/
Ethnicity
White/Non-Hispanic (ref) 1
0.10 Not included Hispanic 1.30 (0.43, 3.91)
Others 0.43 (0.12, 1.59)
Ethnicity Non-Hispanic (ref) 1
0.085
1
0.057
Hispanic 2.06 (0.90, 4.73) 2.37 (0.96, 5.81)
Disease
Category
Leukemia/lymphoma (ref) 1
0.69
1
0.64
Solid tumors 1.30 (0.35, 4.75) 1.39 (0.35, 5.52)
1
Children = < 15 years; early AYA = 15-21 years old.
CCT Characteristics
The characteristics of the CCTs that existed, were available, and were utilized for enrollment are
summarized in Table 2 and Table 5. Twenty-six unique trials existed for the patients in this study, 20 for
children and 12 for eAYAs; six spanned both age groups (leukemia=4, lymphoma=1, and solid tumor=1).
Of these, 13 were available locally compared with 7 for eAYAs. Target cancers addressed by these trials
were similar across both age groups except that children had more brain tumor studies available. Phase 3
trials accounted for the vast majority of available trials in both age groups. For both age groups, most
trials were sponsored by the NCTN; all of the available Phase 3 trials were sponsored by COG. Among
children, all five of the existing single-institution studies were sponsored by a single pediatric cancer
research hospital, whereas among AYAs both existing single institution studies were from adult-focused
cancer research centers. Within phases and types of CCT, the distribution of patients by age was not
appreciably different (Table 2).
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 15
15
Table 5: Number and Types of Cancer Clinical Trials (n=26)
Cancer Clinical Trials Among Children
1
Cancer Clinical Trials Among Early AYAs
Existed
2
Available
2
Utilized for
Enrollment
2
Existed
Available
Utilized for
Enrollment
Total 20 13 9 12 7 4
Target Cancer
Leukemia 6 5 3 4 4 2
Lymphoma 4 2 2 5 1 1
Solid Tumor 4 2 1 2 1 --
Brain Tumor 6 4 3 1 1 1
Phase
Phase 1/2 1 -- -- -- -- --
Phase 2 5 2 2 5 0 --
Phase 2/3 1 -- -- -- -- --
Phase 3 12 10 6 7 7 4
Phase 4 1 1 1 -- -- --
Sponsor
NCTN
12 12 8 9 7 4
Multi-site
3 1 1 1 -- --
Single Institution
5 -- -- 2 -- --
1
Children = age < 15 years; early AYA = 15-21 years old.
2
See Methods for operational definitions of cancer clinical trial existence, availability and enrollment.
Discussion
The overall objective of this study was to evaluate the relative importance of trial availability as a
cause of under-enrollment of eAYAs onto CCTs. Consistent with our hypothesis, we found that a
significantly lower proportion of eAYAs than children was enrolled onto CCTs that existed nationally.
However, contrary to our hypothesis, we found that there was no significant difference in CCT
availability among children and eAYAs. Importantly, we found that among patients who had a CCT
available, a significantly lower proportion of eAYAs was enrolled. To our knowledge, this is the first
study to evaluate potential differences in CCT availability and their impact on CCT enrollment for
eAYAs versus children. Our principal finding of lower eAYA enrollment in, but equivalent availability
of, CCTs is consequential because it indicates that factors other than CCT availability serve as barriers to
eAYA enrollment. This study addresses a clinically important issue because low CCT enrollment of
AYAs has been correlated with poorer cancer survival improvement.(A. Bleyer et al., 2005)
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 16
16
To date, explaining low AYA participation in CCTs has been the subject of considerable speculation
but limited research. In this study, we focused on potential differences in CCT availability. Several
authors have argued that there are an insufficient number and variety of CCTs available for the cancers
that are most common among AYAs, and that opening more trials should be a high priority.(Chuk et al.,
2017; Jacob & Shaw, 2017; Parsons et al., 2011) This is a crucial question because many factors that
influence enrollment become relevant only when a CCT is available. However, in this study we found
there was no difference in the proportion of eAYAs and children for whom a CCT either existed at the
national level or was available within our institution. On the other hand, the proportion of those eAYAs
actually enrolled onto available CCTs was less than half that of children. In adjusted multivariable
analysis, eAYAs were nearly 80% less likely to be enrolled. Few literature reports exist to provide a
context for these findings. A recent children’s hospital-based retrospective study reported that 62% of
eAYAs versus 47% of children lacked an available CCT, which had not improved from a previous
study.(Shaw & Ritchey, 2007)
,
(Jacob & Shaw, 2017) In a large, retrospective, case-linked study of CCT
enrollment performed in our cancer center that documented markedly lower CCT enrollment of AYAs
than children, we found that, for the top 10 diagnoses in each age group, AYAs had 8 available CCTs
compared with 10 for children.(Collins et al., 2015) In contrast to these two studies, a SEER-based study
of AYA CCT enrollment by the NCI estimated that actual enrollment exceeded expected enrollment for
several cancer types.(Seibel et al., 2014) All three of these studies reflect the difficulty of collecting
robust CCT enrollment data retrospectively. To our knowledge, no published study prior to this has used
prospective, case-linked methodology to assess the impact of CCT availability on AYA enrollment. This
approach offers substantial benefits. For example, we discerned that although fewer CCTs did, in fact,
exist for eAYAs than children (12 versus 20), the proportions of patients who had CCTs available were
equivalent. For discussions of CCT availability, this illustrates the importance of accounting for site and
patient characteristics in addition to the absolute number of existing trials.
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 17
17
The setting and design of our study afforded important strengths with some limitations. A significant
strength was prospective case ascertainment combined with real-time, patient-specific evaluation of CCT
existence and availability. This provided a level of accuracy that is difficult to achieve retrospectively.
The volume and heterogeneity of patients at CHLA made it feasible to conduct this study over a relatively
short period at a single institution, yet the sample was not large enough to assess definitively all
covariates of interest. For example, Hispanic ethnicity was suggestive of facilitating CCT enrollment in
our adjusted multivariable analysis, a finding consistent with our previous retrospective study,(Collins et
al., 2015) but did not reach statistical significance. Also, results obtained at a large, urban, academic
children’s hospital may be different from those obtained in either a community-based setting where many
AYAs are treated, or at an academic hospital serving the full AYA age spectrum.(Albritton, Wiggins,
Nelson, & Weeks, 2007; Tai, Buchanan, Westervelt, Elimam, & Lawvere, 2014; Yeager, Hoshaw-
Woodard, Ruymann, & Termuhlen, 2006) Similarly, our sample with a maximum age of 21 years may
not be reflective of CCT activity among older AYAs. Our focus on patients with first cancers limits our
ability to comment on the impact of CCT availability in relapsed cancer, which could be important for
AYAs who often have high-risk disease. Finally, we relied on pathology specimens to trigger case
ascertainment, which could have resulted in missing a small number of patients where diagnosis is based
on imaging, such as diffuse intrinsic pontine glioma.
Nonetheless, our study offers important insights concerning barriers and facilitators of CCT
enrollment among AYAs. What implications should be drawn from these data? First, it is clear that
factors other than CCT availability influence AYA enrollment and need further study. These
“downstream” factors may include provider-level choices not to present the CCT option due to medical
and perceived social circumstances, limited professional time, poor reimbursement, and lack of research
infrastructure.(Grunfeld, Zitzelsberger, Coristine, & Aspelund, 2002; Meropol, 2007) At the patient level,
several psychosocial factors may influence AYA enrollment, including coping status, perceptions of
clinical research, informed consent issues, and social relationships.(Barakat, Schwartz, Reilly, Deatrick,
& Balis, 2014; Buchanan, Block, Smith, & Tai, 2014; Read et al., 2009) Because our study was not
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 18
18
designed to capture such information, further research is needed to understand and address these factors.
Second, with our study showing that only about half of both children and eAYAs had existing CCTs,
there may indeed be opportunities to increase the number of CCTs for both age groups. Our data do not
provide a clear indication of where such efforts should be focused, as the diagnoses where CCTs were not
available spanned the spectrum of age, incidence and outcomes. Thus, for improving survival it seems
reasonable to maximize CCT availability for the more common, highest-risk cancers. However, this
seems unlikely to be an effective stand-alone strategy for improving AYA-specific CCT enrollment.
Similarly, with a high proportion of existing trials already being available locally, our results suggest that
broad efforts to increase CCT activation at the site level may not necessarily yield higher enrollment for
either age group. On the other hand, it must be acknowledged that some institutions may face substantial
resource limitations preventing activation of all CCTs. Also, the number of existing CCTs nationally may
fluctuate over time as they are individually launched and completed. Therefore, it is safe to assume that
maximizing both development and availability of impactful CCTs for AYAs will always be necessary and
appropriate. Finally, because this study reflects the CCT enrollment fate only of patients who “made it
through the door” at CHLA, it does not negate the importance of pre-hospital barriers that impede AYA
CCT participation.(Albritton et al., 2007; Parsons et al., 2011; Yeager et al., 2006) Thus, the most
important implication of this study is that for AYAs, future research should be focused on provider- and
patient/family-level factors affecting CCT enrollment. These factors are the subject of a funded study we
are now conducting.
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19
Chapter Two: A Prospective Study of Cancer Clinical Trial Availability and Enrollment
among Adolescents/Young Adults Treated at a Children’s Hospital or Affiliated Adult
Cancer Specialty Hospital
Abstract
Background: Low cancer clinical trial (CCT) enrollment may contribute to the poor survival improvement
for adolescents and young adults (AYAs, aged 15-39 years) with cancer. Treatment site is thought to
exacerbate this problem. This study evaluated whether differences in CCT availability explain lower CCT
enrollment depending on treatment site for AYAs.
Methods: This prospective, observational cohort study was conducted at an academic children’s hospital
and its affiliated adult cancer within a National Cancer Institute designated Comprehensive Cancer
Center. In consecutive AYA patients newly-diagnosed with cancer at both sites, it was determined
whether an appropriate CCT existed nationally, was available locally, and if enrollment occurred. The
proportions of AYAs in these categories were compared by site using the χ2 test.
Results: Among 152 consecutive AYA patients, 68 (aged 15-20 years) and 84 (aged 18-39 years) were
treated at the children’s hospital and adult cancer hospital, respectively. Although no difference in CCT
existence for AYAs was found between the two sites, (children’s hospital 36/68 [52.9%] versus adult
cancer hospital 45/84 [53.6%], p=0.938), the availability of CCTs for patients treated at the adult cancer
was significantly lower (14/84 [16.7%] versus 30/68 [44.1%], p<0.001). Enrollment percentages were
similarly low in both groups (8/68 [11.8%] versus 6/84 [7.1%], p=0.327). 8/14 (57.1%) existing CCTs
were available at the children’s hospital compared to 4/27 (14.8%) at the adult cancer hospital.
Conclusions: Significantly fewer AYAs treated at the adult hospital had a CCT available, but national
existence was similar at both sites. This suggests that institutional barriers to opening CCT have more
importance at adult centers.
*This work is currently being revised and prepared for publication.
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Background and Significance
Adolescents and young adults (AYA, aged 15-39 years) with cancer have been designated by the
United States (US) National Cancer Institute (NCI) as a health disparity population because their survival
improvement lags behind both younger and older patients.(W. A. Bleyer et al., 1997; National Cancer
Institute, 2006) The cause of this lower survival improvement is likely multifactorial, but low
participation of AYAs in NCI-sponsored cancer clinical trials (CCTs) is considered a key contributing
factor.(A. Bleyer et al., 2005) Low enrollment also prevents AYAs from gaining access to promising
investigational therapies, providing biospecimens essential for basic and translational research, and
offering their unique perspective in studies of supportive care, quality of life, and other non-survival
endpoints.(Freyer & Seibel, 2015)
Low CCT enrollment for AYAs has been consistently described in the literature with 40-60% of
children < 15 years of age participating in CCTs compared with 10-20% of early AYAs, 15-21 years old
and less than 10% for AYAs older than age 21.(A. Bleyer et al., 2005; W. A. Bleyer et al., 1997; Collins
et al., 2015; Krailo et al., 1993; Parsons et al., 2011; Shaw & Ritchey, 2007) Reasons for lower CCT
enrollment of AYAs are not well understood. Factors associated with low CCT enrollment include
suboptimal insurance, low socioeconomic status, distance to the cancer center, older age, type of cancer
specialist, and care provided by community-based clinicians who do not participate in NCI-sponsored
CCT.(Felgenhauer & Hooke, 2014; Parsons et al., 2015; Parsons et al., 2011) Limited availability of
CCTs for AYAs is another potential factor often asserted to be of major importance.(Chuk et al., 2017;
Jacob & Shaw, 2017; Parsons et al., 2011; Shaw & Ritchey, 2007) In theory, a lack of CCTs would be
decisive in that without a trial available enrollment is impossible.(Freyer & Seibel, 2015)
However, we recently conducted a prospective, observational cohort study of CCT availability
and enrollment among AYAs and reported that within our academic children’s hospital, CCT enrollment
but not availability was significantly lower for early AYAs aged 15-21 years compared with
children(Thomas, Malvar, Tran, Shows, & Freyer, 2017) . While in general agreement with a suggestive
retrospective study(Seibel et al., 2014), our prospective, case-level methodology offered the important
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21
advantage of real-time ascertainment of individual patient eligibility in relation to CCTs confirmed open
at our institution. Our findings indicated that in the setting of a children’s hospital, patient/family and
provider-level barriers were more important than CCT availability in explaining low AYA enrollment.
Because CCT availability and enrollment may differ between older and early AYAs and be
subject to influences related to older age and treatment site, we now report the results of our prospective
study comparing CCT availability and enrollment among AYAs consecutively diagnosed at either the
academic children’s hospital or the adult cancer specialty hospital within our NCI-designated
comprehensive cancer center. The primary study aim was to compare the proportions of AYAs at each
locations for whom an appropriate CCT existed, was available locally, and utilized for enrollment. Our
overall hypothesis was that both availability of and enrollment onto CCTs would be significantly lower
among AYAs at the adult cancer hospital.
Methods
Study Design, Setting and Case Ascertainment
This was a prospective, observational cohort study conducted at two sites encompassed by the
University of Southern California (USC) Norris CCC: Children’s Hospital Los Angles (an academic
children’s hospital, CHLA) and the adult-focused Norris Cancer Hospital (an adult cancer specialty
hospital, NCH). Though affiliated, these two sites are clinically and administratively distinct, located on
separate campuses about 6 miles apart. In general, AYAs 15-21 years of age are treated at CHLA, while
AYAs aged 18-39 years are treated at NCH. The two sites have a relationship as members of an over-
arching AYA Program, but a coordinated AYA CCT enrollment mechanism has not been developed.
We initially conducted a pilot study of 20 patients (10 at CHLA and 10 at NCH), who are
included in this cohort. Case ascertainment was site-specific to allow for prospective, real-time
identification of newly diagnosed patients. At CHLA, all consecutive pathology reports from patients
aged 15-21 years were screened in real-time by collaborating pediatric pathology fellows (HT, JS) and
transmitted to the principal investigator (SMT) with name, medical record number, and final pathology
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 22
22
diagnosis. Pathology reports were reviewed by SMT and disregarded if they represented pathology-only
consultations for patients not receiving cancer care at CHLA, or pathology specimens from second
surgeries of patients already included in this study. The remaining pathology reports were used to identify
unique patients 15-21 years old with first diagnosis of cancer and cancer treatment initiated at CHLA. At
NCH, newly diagnosed patients 15-39 years of age were identified by USC Norris Cancer Registry staff,
who notified SMT every two weeks of all newly diagnosed patients ages 15-39. SMT reviewed these
patients to identify unique patients aged 15-39 with a first diagnosis of cancer and cancer treatment
initiated at NCH. At both sites, patients with relapsed cancer, subsequent malignant neoplasm, or transfers
having already starting cancer treatment elsewhere were excluded from this study.
For each patient meeting eligibility criteria for this study, pertinent demographic (age, sex, and
race/ethnicity) and disease-related (cancer diagnosis, stage, grade, risk group and relevant genomics)
information was abstracted from the medical record. Patients were classified as either treated at CHLA or
NCH. This study was approved by the CHLA and USC Institutional Review Boards (IRB) with a waiver
for informed consent, as only anonymous data were collected and there was no patient contact.
Determination of CCT Existence, Availability, and Enrollment Status
At both sites, the following methods were applied to eligible patients at both sites. For purposes
of this study, “clinical trial existence” was operationalized as a CCT appropriate for the patient’s age,
diagnosis, and stage/risk-group registered nationally on ClinicalTrials.gov and listed as open and
recruiting. “Clinical trial availability” was operationalized as an existing CCT that was IRB-approved,
activated and open to enrollment at the site when the patient was diagnosed. “Clinical trial enrollment”
was operationalized as the patient being successfully entered onto the CCT.
For each patient, existence of a CCT was determined by SMT within two weeks of receiving the
diagnosis by searching ClinicalTrials.gov for a relevant CCT. The two-week timeframe was established
because trial sponsors are required to post updates on ClinicalTrials.gov within four weeks of changes in
enrolling status. The diagnosis was entered into the search term area with studies limited to those “open
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23
and recruiting,” “interventional,” and available in the US. If a trial was so identified, patient-specific
clinical information (e.g., histology, stage, grade, risk group, genomic status, and other characteristics)
was employed to determine the patient’s specific eligibility for that trial. Those confirmed as eligible were
thus classified as having an existing CCT. Trial-specific data available on ClinicalTrials.gov were
recorded including the National Clinical Trial identification number, phase, categorical type (e.g.,
National Clinical Trials Network [NCTN], other national collaborative group, multi-center collaboration,
industry, or institutional), the specific sponsor (e.g., Children’s Oncology Group [COG]), and the date the
trial opened. Patients with an existing CCT were then assessed for availability of, and enrollment upon,
the CCT as described above.
For patients who had more than one applicable trial listed on ClinicalTrials.gov but none
available at their treating hospital, only one trial was recorded as existing using the following hierarchy:
NCTN, other national collaborative group, multi-center collaboration, industry-sponsored, or institutional.
Statistical Analysis
Descriptive statistics were used to characterize the sample. Differences in demographics, CCT
existence, CCT availability, and CCT enrollment among AYAs treated at CHLA versus at NCH were
evaluated using the χ
2
test of proportions with a p-value of < 0.05 defined as significant. SPSS statistical
software was used for all analyses("IBM Corp. Released 2016. IBM SPSS Statistics for Windows,
Version 24.0. Armonk, NY: IBM Corp.,").
Results
Between November 1, 2015 and December 1, 2016, 238 AYA patients were screened for
eligibility (CHLA = 92; NCH=146). Of these, 86 were excluded (CHLA = 24; NCH = 62) for having
relapsed disease or starting treatment prior to referral (Figure 1). There were no patients with SMN.
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24
Figure 1: CONSORT diagram of the current study comparing cancer clinical trial availability
between adolescent and young adult cancer patients treated at a children’s hospital (CHLA) vs
adult cancer center (NCH).
Patient Characteristics
A total of 152 AYAs, 68 at CHLA and 84 at NCH, were included in this study (Table 1). The
median ages of the CHLA and NCH cohorts were 17 years (range, 15-20) and 31 years (range, 18-39),
respectively. There was little age overlap between the two sites, with 18 18-21 year olds being treated at
CHLA and 4 being treated at NCH. Distribution by sex and race/ethnicity were similar across groups, but
whereas leukemia was most common at CHLA, solid tumors, particularly carcinomas, predominated at
NCH.
Excluded (n=24)
Relapses (n=18)
Transfers on
therapy (n=6)
Excluded (n=62)
Relapses (n=62)
Assessed for eligibility
(n=238)
CHLA AYAs (n=68) NCH AYAs (n=84)
CHLA AYAs (n=92) NCH AYAs (n=146)
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25
Table 1: Clinical Characteristics of Adolescents/Young Adult Cohort (n=152)
CHLA
1
n (%)
NCH
2
n (%)
68 (43.9) 84 (56.1)
Age Distributions (years)
15-17 50 (73.5) 0 (0)
18-21 18 (26.5) 4 (4.8)
22-25 0 (0) 14 (16.7)
26-30 0 (0) 19 (22.6)
31-35 0 (0) 23 (27.4)
36-39 0 (0) 24 (28.6)
Sex
Male 43 (63.2)
53 (63.1)
Female 25 (36.8) 31 (36.9)
Race/Ethnicity
Hispanic 40 (58.8)
37 (44.0)
White/Non-Hispanic 12 (17.6)
20 (23.8)
Asian 4 (5.9)
13 (15.5)
Black 4 (5.9)
7 (8.3)
Other 8 (11.8)
7 (8.3)
Diagnosis
Leukemia/lymphoma
Acute Lymphoblastic Leukemia 16 (23.5)
5 (6.0)
Acute Myeloid Leukemia 7 (10.3)
4 (4.8)
Hodgkin Lymphoma 10 (14.7) 3 (13)
Non-Hodgkin Lymphoma 7 (10.3) 11 (13.1)
Solid Tumor
Brain Tumors 5 (7.4) 8 (9.5)
Extra-Cranial Germ Cell Tumor 12 (17.6) 15 (17.9)
Carcinoma
3 (4.4)
3
29 (34.5)
4
Sarcoma 7 (10.3) 7 (8.3)
Other Solid Tumor 1 (1.5)
5
2 (2.4)
6
1
CHLA: Children’s Hospital Los Angeles
2
NCH: Norris Cancer Hospital
3
Thyroid (3)
4
Breast (8), Colorectal (7), Cervical (4) Esophageal (2), Hepatocellular (1), Lung (1), Nasopharyngeal (1), Renal (4), and Thyroid
(1)
5
Melanoma (1)
6
Desmoplastic Small Round Cell Tumor (1), Gastrointestinal Stromal Tumor (1)
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26
CCT Existence, Availability, and Enrollment Proportions
The proportions of CCT existence, availability, and enrollment were compared for AYAs treated
at CHLA and NCH (Figure 2). The proportion of AYAs at CHLA and NCH were similar for having an
existing CCT (36/68 [52.9%] versus 45/84 [53.6%], p=0.938). However, a significantly higher proportion
of AYAs at CHLA had an available CCT compared with NCH (30/68 [44.1%] versus 14/84 [16.7%],
p<0.001). Despite this, enrollment proportions were similar between the two groups (8/68 [11.8%] versus
6/74 [7.1%], p=0.327).
Figure 2: Cancer Clinical Trial Existence, Availability, and Enrollment by Treatment Center.
Children’s Hospital Los Angeles (CHLA) (n=68); Norris Cancer Hospital (NCH) (n=84). See
Methods for operational definitions of cancer clinical trial existence, availability and enrollment.
CCT Characteristics
The characteristics of CCTs that existed, were available, and were utilized for enrollment at the
two sites are summarized in Table 4. Thirty-five unique trials existed nationally for AYAs in this study,
14 at CHLA and 27 at NCH; six of these existing trials were appropriate for patients treated at both sites.
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27
Of these six trials, three were available at CHLA, one was available at NCH, one was available at both
sites and one was available at neither. Of the trials that existed nationally, 8/14 (57.1%) were available at
CHLA while only 4/27 (14.8%) were available at NCH. The one trial available at both sites during this
study period was a COG study for patients with non-rhabdomyosarcoma opened at NCH via the Clinical
Trials Support Unit of the NCI. Diagnoses addressed by CCTs available at CHLA included both leukemia
and solid tumors, while all 4 of those at NCH were for solid tumors. For CHLA AYAs, all eight available
CCTs were Phase 3, and sponsored by an NCTN cooperative group (COG). In contrast, for NCH AYAs,
one each of the four available CCTs were phase 1, 2, 2/3, and 3, with three trials sponsored by NCTN
cooperative groups and one a multi-institutional collaboration. Notably, there were no pharma-sponsored
trials available at either site during the study period.
Table 2: Number and Types of Cancer Clinical Trials by Treatment Site (N=35)
Cancer Clinical Trials At CHLA
1
Cancer Clinical Trials At NCH
2
Existed
3
Available
3
Utilized for
Enrollment
3
Existed
Available
Utilized for
Enrollment
Total 14 8 4 27 4 3
Target Cancer
Leukemia 4 4 2 3 -- --
Lymphoma 6 1 1 8 -- --
Solid Tumor 3 2 -- 13 4 3
Brain Tumor 1 1 1 3 -- --
Phase
Phase 1 -- -- -- 4 1 1
Phase 1/2 -- -- -- 1 -- --
Phase 2 6 -- -- 14 1 1
Phase 2/3 1 1 -- 2 1 --
Phase 3 7 7 4 6 1 1
Sponsor
NCTN
10 8 4 12 3 2
Multi-site
2 -- -- 7 1 1
Investigator
Initiated
2 --
--
4 --
--
Pharmaceutical -- -- -- 4 -- --
1
CHLA: Children’s Hospital Los Angeles
2
NCH: Norris Cancer Hospital
3
See Methods for operational definitions of cancer clinical trial existence, availability and enrollment.
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In this study, there were five AYAs who had available CCTs for potential enrollment at the site
other than where they were actually treated. Four AYAs without available CCTs at NCH (acute
lymphoblastic leukemia = 3, Ewing sarcoma = 1) had available CCTs at CHLA. Conversely, one AYA at
CHLA (intermediate risk testicular cancer) had an available CCT at NCH.
Discussion
The overall objective of this study was to determine the existence of, availability of, and
enrollment upon CCTs by AYAs treated at either an academic children’s hospital (CHLA) or an affiliated
adult cancer specialty hospital (NCH). Our major findings are three-fold. First, the existence of CCTs at a
national level was similar for both groups of AYAs, at a little more than 50% of the patients at each site.
Second, the availability of CCTs was significantly lower for AYAs at the adult cancer specialty hospital
than at the children’s hospital, about 16% versus 44%, respectively. Third, enrollment proportions were
low for both groups of AYAs, about 10% of patients at each site. Viewed together, these findings shed
much-needed light on the pathway to low CCT enrollment for newly-diagnosed AYAs with cancer.
Although the end result of low enrollment onto CCTs across sites was not unexpected and is similar to
previous reports by our group and others(W. A. Bleyer et al., 1997; Collins et al., 2015; Jacob & Shaw,
2017; Sanford, Beaumont, Snyder, Reichek, & Salsman, 2017), our findings regarding national-level
similarity in CCT existence, but site-level disparity in CCT availability, are new. Further, they are of
direct clinical importance because they point to different major barriers, and therefore potential solutions
and research needed to address low CCT enrollment among older and younger AYAs treated in
contrasting settings. To our knowledge, this is the first study to evaluate prospectively the roles of CCT
existence and availability in explaining low CCT enrollment for AYAs treated at a pediatric or adult
cancer specialty hospital.
This study adds to the scant published research examining potential causes for low AYA
enrollment onto CCTs. Here, we focused on the existence and availability of CCTs for AYAs, comparing
them between AYAs treated at either a pediatric hospital (CHLA) or an adult cancer specialty hospital
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 29
29
(NCH). As potential “upstream” barriers to CCT enrollment, existence and availability are crucial factors
operating at the national and site levels, respectively, because patient- and physician-level barriers are
“downstream” to both and are not relevant without CCTs upon which patients can be enrolled. In our
recent study comparing CCT availability and enrollment for children versus early AYAs treated in an
academic children’s hospital, we found similar CCT availability but significantly lower enrollment of
early AYAs.(Thomas et al., 2017) Whereas that study suggested that patient- and provider-level barriers
were more important for younger AYAs in a children’s hospital, results of our current study indicate that
low CCT availability is currently the major barrier for AYAs in an adult cancer specialty hospital.
Therefore, distinctly different explanations exist for low CCT enrollment depending on the institution
type, age and diagnoses applicable to older versus younger AYAs. Worthy of note, national existence of
CCTs was the same at both sites, indicating this was not the explanation for lower CCT availability in the
adult cancer specialty hospital. We also were able to characterize the CCTs that existed and were
available to AYAs treated at both sites. We found that all available CCTs at the children’s hospital were
NCTN, specifically COG, studies. Available studies at the adult cancer specialty hospital were both
NCTN and multi-institutional studies. To our knowledge, no published study prior to this has used
prospective, case-linked methodology to assess the impact of CCT availability on AYA enrollment across
sites. Retrospective analyses that have been done have been unable to compare clinical trial availability
between sites.(Downs-Canner & Shaw, 2009) In a large, retrospective, case-linked study of CCT
enrollment performed in our cancer center that documented markedly lower CCT enrollment of AYAs,
we found that at the children’s hospital 60% of trials open were for one of the 10 most common diagnoses
in the AYA population but only 44% at the adult hospital, and only 8% encompassed the entire AYA age
range. But clinical trial availability for individual patients could not be determined. This further
illustrates the importance of utilizing a prospective, case-linked approach.
A significant strength of this study was the prospective, concurrent case ascertainment at two
affiliated sites combined with real-time, case-linked evaluation of CCT existence and availability. This
provided a level of accuracy that is difficult to achieve retrospectively because of the nature of CCTs
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 30
30
opening and closing to enrollment over time. The volume and heterogeneity of patients treated at our
CCC made it feasible to conduct this study over a short period of time at both sites. But, as a cancer
tertiary care center, NCH treats a higher volume of relapsed/refractory patients that did not meet inclusion
criteria for this study. Therefore, our focus on patients with first cancers limits our ability to comment on
the impact of CCT availability in relapsed cancer, which could be important for AYAs who often have
high-risk disease. Additionally, the AYA age constitutes a minority of patients cared for at adult cancer
hospitals and institutional research resources may be targeted to larger, older, patient populations.
Furthermore, results obtained at hospitals that are part of a CCC may be different from those obtained in
either a community-based setting where many AYAs are treated, or at an academic hospital serving the
full AYA age spectrum in one building.(Albritton et al., 2007; Alvarez et al., 2017; Tai et al., 2014;
Yeager et al., 2006)
Because of the lack of availability of CCTs at NCH, we were unable to perform planned
statistical analysis on predictors of enrollment onto CCTs. Because of this lower than anticipated sample
size, lack of CCT availability, and confounding of age, treatment center, and diagnosis with older patients
being treated at NCH and more commonly having carcinomas, determining predictors of enrollment was
not possible.
However, several insights can be gained from our data. First, clinical trial existence was similar
for patients treated at both sites. This indicates that trials exist for AYAs but are not reaching the patients
where they are being treated. Therefore, our cohort would not have been affected by simply opening
more trials at a national level, an often touted solution. (Chuk et al., 2017; Jacob & Shaw, 2017; Parsons
et al., 2011) Second, characteristics of the CCTs that were available differed at each site signifying local
factors impact which trials are opened. Only 25% (3/12) existing NCTN trials were available for patients
treated at NCH compared to 80% (8/10) for patients treated at CHLA (Table 2). This suggests that
institutional barriers exist making opening and activating cooperative group studies difficult.
Unfortunately, our study was not designed to capture this information, but some possible explanations do
exist. Cost is frequently cited as a reason for choosing not to open cooperative group studies as
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 31
31
reimbursement is lower than industry trials.(Seow et al., 2012) Although we did not have any industry
sponsored studies available in our cohort, it is possible that these studies were open for relapsed/refractory
patients. Related to cost, cooperative group studies are known to have sub-optimal accrual.(Bennette et
al., 2016; Stensland et al., 2014) This low accrual causes significant institutional expense,(Kitterman,
Cheng, Dilts, & Orwoll, 2011) which, in a time of decreased research funding, may lead site to prioritize
studies expected to have better accrual. Third, treatment location of individual patients even within a CCC
can affect CCT availability. Several patients could have accessed CCT if treated at the affiliated hospital
if a functional mechanism existed to do so; four of these were at NCH and 1 was at CHLA. This
illustrates the need for a means either to move patients between sites or open CCTs across sites. The
NCTN provides one option by allowing cross-group enrollment of patients onto cooperative group studies
though the CTSU. This mechanism has the potential to greatly impact the AYA age range as it can
overcome the additional barriers such as insurance coverage and local hospital policy,(Weiss, Nichols, &
Freyer, 2015) but not all studies are available as part of the CTSU. One study at NCH has been opened
through this mechanism making the trial available for one patient in our cohort, but the patient did not
enroll. If the study is not available through the CTSU, individual patients would need to be transferred to
the site where the trial is available. One means for improving clinical trial enrollment for AYAs by
developing an AYA program uniting the pediatric oncology and medical oncology departments with a
focus on trial participation. This mechanism has been reported to initially improve clinical trial
enrollment at another institution,(Shaw et al., 2012) but on reassessment several years later, enrollment
returned to lower rates again implying this needs to be an active process.(Jacob & Shaw, 2017) While we
have an AYA program uniting the two hospitals, we do not currently have a mechanism to quickly
identify newly diagnosed patients who have an available trial at the other site and transfer their care.
Additionally, medical insurance and hospital policies create additional barriers to treating patients over
the age of 21 years at our children’s hospital. Finally, because CCT availability was so low in this cohort,
it was not possible to develop a clear understanding of possible patient- and physician related barriers to
enrollment. It is possible that this may also contribute to low enrollment, but availability is likely of
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 32
32
greater relative importance. Future research should focus on regulatory and institutional barriers to
opening and activating CCT that exist nationally.
CLINICAL TRIAL AVAILABILITY FOR AYAS WITH CANCER 33
33
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Abstract (if available)
Abstract
Cancer is the leading cause of disease-related death for adolescents and young adults (AYA, 15-39 years old). Over the past thirty years, survival gains in AYAs have lagged significantly behind those achieved in younger and older patients. Low participation in clinical trials is considered to be a key contributor to this lack of progress. Several factors likely influence participation, but whether appropriate trials are available for AYAs is as fundamental as it is under-studied. This comparative prospective observational cohort study of clinical trial availability involved three subsets of newly- diagnosed cancer patients: children <15 years at Children’s Hospital Los Angeles (CHLA), early AYAs (15-20 years) at CHLA, and AYAs (18-39 years) at University of Southern California Norris Cancer Hospital (NCH) over 13 months. For each patient, demographic and disease-related data was collected and trial availability determined. Availability of clinical trials and final enrollment status was compared between the children and AYA population at CHLA (Chapter 1) and the two AYA populations (Chapter 2). We found that for the children and early AYAs at CHLA, clinical trial availability was similar in the two groups, but a significantly lower proportion of early AYAs enrolled onto CCTs. However, when comparing the early AYA cohort treated at CHLA and the older AYA cohort treated at NCH, we found similar proportions of nationally existing cancer clinical trial, but a significantly lower proportion of NCH AYAs having a locally available cancer clinical trial. Our data shows distinct reasons for low trial enrollment depending on treatment site/patient age. “Downstream” patient- and physician-level barriers to enrollment appear to more greatly impact the early AYA population treated at CHLA, while “upstream” barriers to making trials available more greatly impact the AYA population treated at NCH.
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Asset Metadata
Creator
Thomas, Stefanie M.
(author)
Core Title
Clinical trial availability for adolescents and young adults with cancer
School
Keck School of Medicine
Degree
Master of Science
Degree Program
Clinical and Biomedical Investigations
Publication Date
08/08/2018
Defense Date
01/21/2018
Publisher
University of Southern California
(original),
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Tag
Adolescents,cancer,clinical trials,OAI-PMH Harvest,oncology,Young adults
Language
English
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Electronically uploaded by the author
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Freyer, David R. (
committee chair
), Milam, Joel (
committee member
), Sposto, Richard (
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stefaniemariethomas@gmail.com,stthomas@chla.usc.edu
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