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A novel risk-based treatment strategy evaluated in pediatric head and neck non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) patients: a survival analysis from the Children's Oncology Group study...
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A novel risk-based treatment strategy evaluated in pediatric head and neck non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) patients: a survival analysis from the Children's Oncology Group study...
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1
A Novel Risk-based Treatment Strategy Evaluated in Pediatric Head and Neck Non-
Rhabdomyosarcoma Soft Tissue Sarcomas (NRSTS) Patients: A survival analysis from the
Children’s Oncology Group study ARST0332
by
Xin Ma
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the Requirements for the Degree
MASTER OF SCIENCE
APPLIED BIOSTATISTICS AND EPIDEMIOLOGY
May 2018
2
Table of Contents
Acknowledgements ........................................................................................................ 3
List of Figures ................................................................................................................ 4
List of Tables .................................................................................................................. 5
Abstract .......................................................................................................................... 6
Introduction .................................................................................................................... 9
Methods........................................................................................................................ 11
Participants ........................................................................................................... 11
Risk classification and Treatment ........................................................................ 11
Outcome assessment ............................................................................................ 14
Statistical analysis ................................................................................................ 14
Results .......................................................................................................................... 16
Discussion .................................................................................................................... 29
Reference ..................................................................................................................... 32
3
Acknowledgements
I would like to express my sincere gratitude to my mentor Dr. Don Barkauskas for his patient
guidance, motivation and enormous help throughout the whole process of research and writing of
this thesis. I would like to thank my committee members Dr. Todd Alonzo and Dr. Meredith
Franklin for their support and insightful comments. I thank the Children’s Oncology Group for
providing such high-quality data. Finally, I would like to thank my family and friends for
supporting me spiritually all the time.
4
List of Figures
Figure 1 Experimental Design Schema……………………………………………......13
Figure 2 Treatment Regimens…………………………………………………............14
Figure 3 Estimated overall survival for all patients by tumor site and risk group…….24
Figure 4 Estimated event-free survival for all patients by tumor site and risk group....25
5
List of Tables
Table 1 Demographic and tumor characteristics of NRSTS pediatric patients………...17
Table 2 Critical events of overall survival by risk group……………………………....19
Table 3 Critical events of event-free survival by risk group……………………….......20
Table 4 Univariate Log-rank tests among patients with NRSTS Head & Neck……….21
Table 5 Univariate analysis of risk group among head and neck NRSTS patients…….22
Table 6 Five -year survival rates for OS stratified by tumor site and risk group…........24
Table 7 Five -year survival rates for EFS stratified by tumor site and risk group..........25
6
Abstract
Background
Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) are a rare and heterogeneous group of
malignancies among children and adolescents. Approximately 7% to 18% of childhood NRSTS
have primary tumors in the head and neck region, and these patients have not been extensively
studied, especially in pediatric oncology research.
Methods
The analysis data was from ARST0332, a groupwide Phase 3 study from the Children’s Oncology
Group which evaluated a novel risk-based treatment strategy for NRSTS in patients under 30 years
old. All study patients were assigned into four treatment arms and were categorized into low-,
intermediate-, and high-risk groups. This thesis focuses on 53 pediatric head and neck NRSTS
patients, while the comparison population is the 475 patients on the study with NRSTS at other
sites. Demographic and tumor features at baseline were summarized and compared between target
and comparison patients. Overall survival and event-free survival stratified by tumor site and risk
group among total 528 patients were evaluated by log-rank test. Stepwise Cox proportional hazard
regression was conducted to select potential predictors for survival time among the head and neck
patients.
Results
There were 53 patients with head and neck NRSTS. The age of patients and tumor size were
7
statistically significantly different in patients with head and neck NRSTS compared to patients
with NRSTS at other sites (p=0.0338 for continuous age variable; p<0.0001 for continuous tumor
size). The estimated five-year overall survival rates for patients with head and neck NRSTS were
100% in the low-risk group, 67.7% in the intermediate-risk group (95% CI: 43.7%–83.2%) and
25.0% in the high-risk group (95% CI: 0.9%–66.5%); the estimated five-year event-free survival
rates for these patients were 80.8% in the low-risk group (95% CI: 59.8%–91.5%), 53.9% in the
intermediate-risk group (95% CI: 30.8%–72.2%), and 0% in the high-risk group. All survival rates
were lower compared to patients with NRSTS at other sites except for overall survival of the low-
risk group. There was no selected potential predictor for survival under 5% significance level.
Among patients with head and neck NRSTS, the risk of death for patients in the high-risk group
was 2.66 times than those in the intermediate-risk group (95% CI: 0.68–10.33). In regard to event-
free survival, the risk of failure for patients in the high-risk group was 2.87 times than those for
intermediate-risk patients (95% CI:0.89–9.24), while patients in the low-risk group experienced
statistically significantly lower risk of developing events than intermediate-risk patients (HR=0.33,
95% CI: 0.11–0.96). Age, FNCLCC grade, categorical tumor size, invasiveness, unresectable
tumors and margin status were statistically significantly associated with treatment arm and risk
group.
Conclusion
In this study, the pediatric head and neck NRSTS patients experienced worse survival compared
8
to patients with NRSTS at other sites, but the results were not statistically significant. The survival
rates were statistically significantly different among three risk groups for head and neck NRSTS
patients and for other NRSTS patients.
Key Words: Non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), overall survival (OS), event-
free survival (EFS), pediatric cancer, head and neck.
9
Introduction
Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) are a rare and heterogeneous group of
malignancies, which includes an assorted group of tumors accounting for approximately 4% of
childhood malignancies. Nearly 500 children under 20 years old in the United States (US) suffer
from NRSTS each year
[1]
. Pediatric head and neck primary tumors represent 7% to 18% of NRSTS
among children
[2–5]
. However, these tumors have not been systematically studied, particularly in
clinical trials in the US. Surveillance Epidemiology, and End Results (SEER) data shows that the
survival of patients between 15 and 44 years old with sarcoma experienced the least improvement
over the past few decades
[6]
. Therefore, clinical trials for children, adolescents and young adults
with NRSTS require greater efforts to lead to more improvements in outcomes.
An important strategy in recent decades has been risk adaptive therapy in pediatric oncology.
The main purpose of therapy is to improve survival in high-risk patients. Patients of low risk have
better survival, so the therapy is aimed to minimize toxicities of therapy. This method had
succeeded in several pediatric tumors
[7, 8]
. Related studies suggested that the most important
prognostic factors in pediatric NRSTS are the extent of disease at diagnosis (localized vs.
metastatic), extent of tumor resection (resected vs. unresectable), maximal tumor diameter (≤5 cm
vs. >5 cm), and tumor grade (low vs. high)
[2, 3, 9–11]
. A study that enrolled patients treated at St.
Jude Children’s Research Hospital
[2]
identified three distinct risk subgroups: 1) patients with
grossly resected non-metastatic tumors (5-year estimated survival 89%); 2) patients with initially
10
unresected non-metastatic tumors (5-year estimated survival 56%); 3) patients with metastatic
tumors (5-year estimated survival 15%). In addition, other studies indicated that patients with
grossly resected non-metastatic high-grade tumors with maximal diameters greater than 5 cm were
at higher risk of treatment failure and death than other patients with non-metastatic grossly resected
tumors, the prognosis of which is similar to those with unresectable tumors
[12, 13]
. Based on these
results, patients in this study were divided into high, intermediate and low risk groups, which are
described below in the methods section. Low-risk patients were expected to have an excellent
survival exceeding 90%, while long-term survival for intermediate-risk patients was expected to
be about 50% and for those of high-risk survival was lower than 15%.
This study focused on evaluating survival of a defined risk-based strategy for treating pediatric
patients with NRSTS of the head and neck. Based on tumor status, patients were assigned to four
treatment arms. The survival outcomes were compared among risk groups.
11
Methods
Participants
All participants’ information in the study were from ARST0332, which was a group-wide Phase 3
clinical trial from the Children’s Oncology Group. Patients under 30 years old at the time of
diagnosis with NRSTS were eligible for the study. Gross total resection of the primary tumor for
patients was required except for: 1) non-metastatic high-grade tumor greater than 5 cm in maximal
diameter for which gross or microscopic residual tumor was anticipated following resection; 2)
tumor of either high or low grade that could not be grossly excised without unacceptable morbidity;
3) high grade tumor with metastases. Patients who experienced tumor recurrence after a gross total
tumor resection were excluded. Patients who were enrolled in treatment Arm C or D could have
no prior anthracycline or ifosfamide chemotherapy. All females of childbearing age on Treatment
Arm B, C and D needed a negative pregnancy test prior to enrollment. Sexually active patients of
childbearing age had to agree to use effective contraception during and for at least one month after
treatment was completed. Lactating females on treatment Arm C and D could not breastfeed during
treatment and for one month after the completion of treatment.
Risk classification and Treatment
In this study, the clinical features being evaluated included site of primary tumor, disease extent at
diagnosis (metastatic vs. non-metastatic), tumor size (maximal original diameter of primary tumor
(≤5cm vs. >5 cm), tumor depth (superficial vs. deep), tumor invasiveness (neurovascular and/or
12
bone), extent of resection of the primary tumor and metastases, microscopic surgical margins (for
patients whose tumor is resected prior to study entry), and histologic grade.
There are various tumor grading systems available for soft tissue sarcomas. The French
Federation of Cancer Centers (FNCLCC) Sarcoma Group grading system is one of the most widely
used for adult sarcomas
[14–18]
. Meanwhile, in children, the Pediatric Oncology Group (POG) Non-
rhabdomyosarcomatous Soft Tissue Sarcoma Grading System is routinely used
[18]
. These two
systems both use grades 1 through 3. Grades 1 and 2 were categorized as low grade while 3 was
high grade. Based on all above tumor features, the patients were assigned to four different
treatment arms and were evaluated as the following three risk groups (Figure 1 and Figure 2):
Low risk: patients with non-metastatic, grossly resected low-grade tumors, and those with
non-metastatic grossly resected high-grade tumors which were less than or equal to 5 cm in
maximal diameter.
Intermediate risk: patients with non-metastatic tumor that were both high grade and greater
than 5 cm in maximal diameter, and patients with non-metastatic unresectable tumors,
regardless of grade or size.
High risk: patients with metastatic tumors no matter the tumor grade and whether they were
unresectable or not.
This risk classification has been validated by Waxweiler et al (2015) using the NCI-SEER
database
[19]
. Low-risk patients underwent surgery with or without adjuvant radiotherapy
13
depending on the histologic grade of tumor and surgical margin status. Intermediate- and high-risk
patients whose primary tumor were not excised received neoadjuvant combined
chemoradiotherapy prior to definitive tumor resection, whereas those whose tumor was excised
received adjuvant chemotherapy and radiotherapy.
Figure 1 Experimental Design Schema
14
Figure 2 Treatment Regimens
Outcome assessment
Overall survival (OS) time: the time period from the date of enrollment to the date of death (event)
or last contact (censored), whichever occurred first.
Event-free survival (EFS) time: the time period from the date of enrollment to the date of relapse,
second malignancy, death (events) or last contact (censored), whichever occurred first.
Statistical analysis
Summary statistics were computed for demographic characteristics and baseline features of the
tumors. Continuous variables were displayed with mean and standard deviation. All categorical
variables were shown by the number of patients in each category with their corresponding
15
proportions. All variables were stratified by primary tumor site into two groups: NRSTS of the
head and neck, and others. The comparison between groups were conducted using independent
two-sample t-tests for continuous variables and Fisher’s exact tests for categorical variables.
Among the head and neck patients, two-way comparisons were conducted for all baseline
variables using Fisher’s exact test. Overall survival and event-free survival analyses were
performed on patients whose primary tumor sites were head and neck. Each baseline covariate was
tested for univariate association with overall survival and event-free survival using the Log-rank
test, stratified by risk group. Variables with p-values less than 0.2 were selected as potential
predictors in the final multivariate stepwise Cox regression model, in which entry and exit level
was 0.05.
A 0.05 significance level was considered statistically significant when reporting the results.
All analyses were done using SAS software (Version 9.4; SAS Institute Inc, Cary, NC).
16
Results
A total 528 patients were evaluated in the analysis, among which there were 53 patients with
NRSTS of the head and neck. The median follow-up time for all patients who were alive at last
contact was 5.7 years. The median follow-up time was 6.2 years for head and neck NRSTS patients
and 5.6 years for patients with NRSTS at other sites. Descriptive characteristics for all patients
stratified by tumor sites are summarized in Table 1. There was a statistically significant difference
in age between patients with NRSTS head and neck and other primary sites (p=0.0338 for
continuous age variable, p=0.0160 for categorized age variable). The average age of pediatric
NRSTS head and neck patients was 11.5 years old, while other patients were 13.2 years old. 41.5%
of patients with head and neck tumors were less than 10 years old, and 52.8% of them ranged from
10 to 18 years old. Among patients with tumors on other sites, 57.5% of them were between 10
and 18 years old, and 16.6% of them were 18 years or older. The majority of patients enrolled in
the study were white and not Hispanic or Latino. There were no statistically significant differences
of gender, race, or ethnicity between patients with head and neck and other sites tumors. The
average maximal diameter of head and neck tumors was 4.7 cm, and the mean value was 8.2 cm
for tumors at other sites (p<0.0001). 58.5% of patients with head and neck NRSTS had tumors
whose maximum diameters were less than or equal to 5 cm, while 65.5% of patients whose tumors
at other sites had tumors greater than 5 cm (p=0.0009). There were no statistically significant
differences on other baseline variables between patients with NRSTS of the head and neck and
17
patients with NRSTS at other sites. 79.3% of head and neck tumors were high POG grade, and
83.0% of them were deep. Among 53 patients with head and neck tumors, 49 of them (92.5%) had
non-metastatic tumors. Prior experience in NRSTS had proportions of participants in the low-,
intermediate- and high-risk groups of 50%, 35% and 15%, respectively
[2]
, fairly similar to our
study, where 49.1% of patients with head and neck tumors were enrolled in the low-risk group,
and 43.4% of them were intermediate risk, while only 7.6% were high risk.
Table 1 Demographic and tumor characteristics of NRSTS pediatric patients
Characteristics Head & Neck Others p-value
(n=53) (n=475)
Follow-up time for patients 5.7 (2.6) —
alive at last contact (years) 6.2 (2.7) 5.6 (2.5) 0.2063
Age at enrollment (years) 11.5 (5.3) 13.2 (5.6) 0.0338
Age at enrollment 0.0160
0–<10 22 (41.5%) 123 (25.9%)
10–<18 28 (52.8%) 273 (57.5%)
18–30 3 (5.7%) 79 (16.6%)
Sex 0.1121
Male 19 (35.9%) 226 (47.6%)
Female 34 (64.2%) 249 (52.4%)
Race 0.3077
White 42 (79.3%) 332 (69.9%)
Black or African American 6 (11.3%) 74 (15.6%)
Other — 24 (5.1%)
Unknown 5 (9.4%) 45 (9.5%)
Ethnicity 0.6354
Hispanic or Latino 10 (18.9%) 70 (14.7%)
Not Hispanic or Latino 41 (77.4%) 388 (81.7%)
Unknown 2 (3.8%) 17 (3.6%)
Primary tumor size (cm) 4.7 (2.9) 8.2 (5.6) <0.0001
18
Primary tumor size <0.0001
0–5 31 (58.5%) 164 (34.5%)
5.1–10 20 (37.7%) 147 (31.0%)
10.1–15 1 (1.9%) 105 (22.1%)
≥15.1 1 (1.9%) 59 (12.4%)
Tumor size 0.0009
≤5 31 (58.5%) 164 (34.5%)
>5 22 (41.5%) 311 (65.5%)
Tumor POG grade 0.2613
Low 11 (20.8%) 135 (28.4%)
High 42 (79.3%) 340 (71.6%)
Tumor FNCLCC grade 0.4444
Low 26 (49.1%) 266 (56.0%)
High 27 (50.9%) 208 (43.8%)
Indeterminate — 1 (0.2%)
Primary tumor depth 1.0
Superficial 9 (17.0%) 83 (17.5%)
Deep 44 (83.0%) 392 (82.5%)
Invasiveness 0.3064
Non-invasive 19 (35.9%) 210 (44.2%)
Invasive 34 (64.2%) 265 (55.8%)
Metastases 0.1544
Yes 4 (7.6%) 76 (16.0%)
No 49 (92.5%) 399 (84.0%)
Treatment arm 0.0897
A 21 (39.6%) 184 (38.7%)
B 5 (9.4%) 12 (2.5%)
C 9 (17.0%) 101 (21.3%)
D 18 (34.0%) 178 (37.5%)
Unresectable 0.8804
Yes 18 (34.0%) 169 (35.6%)
No 35 (66.0%) 306 (64.4%)
Margin status 0.2582
Positive 21 (39.6%) 137 (28.8%)
Negative 14 (26.4%) 161 (33.9%)
Not applicable 18 (34.0%) 177 (37.3%)
Risk group 0.2296
Low 26 (49.1%) 196 (41.3%)
Intermediate 23 (43.4%) 203 (42.7%)
19
High 4 (7.6%) 76 (16.0%)
Note: the follow-up time in above table are shown as median time and standard deviation.
Other continuous variables are displayed as mean (standard deviation); Categorical variables are displayed
as number of patients (percentage).
Independent two-sample t-tests were performed for continuous variables, while Fisher’s exact tests were
used for categorical variables.
Among 53 patients with head and neck NRSTS, there was no deceased patients in the low-
risk group. 7 patients (30.4%) died in the intermediate-risk group, and 75.0% patients in the high-
risk group died (Table 2). For event-free survival, 80.8% patients in the low-risk group didn’t
experience events. 4 patients in the low-risk group relapsed, and one had secondary malignant
neoplasms (SMN). In the intermediate-risk group, 56.5% patients had no events, whereas the rest
of them relapsed. All patients in the high-risk group experienced events, which included three
patients relapsed and one had SMN (Table 3).
Table 2 Critical events of overall survival by risk group
Head & Neck patients Comparison patients
(n=53) (n=475)
Risk group Alive Dead Alive Dead
Low 26 (100%) 0 188 (95.9%) 8 (4.1%)
Intermediate 16 (69.6%) 7 (30.4%) 157 (77.3%) 46 (22.7%)
High 1 (25.0%) 3 (75.0%) 27 (35.5%) 49 (64.5%)
Note: Number (percentage).
20
Table 3 Critical events of event-free survival by risk group
Risk group Low Intermediate High
Head & Neck
patients
(n=53)
Comparison
patients
(n=475)
No event 21 (80.8%) 13 (56.5%) 0
Relapse 4 (15.4%) 10 (43.5%) 3 (75.0%)
SMN 1 (3.8%) 0 1 (25.0%)
No event 175 (89.3%) 132 (65.0%) 16 (21.1%)
Relapse 20 (10.2%) 64 (31.5%) 58 (76.3%)
SMN 1 (0.5%) 5 (2.5%) 1 (1.3%)
Death 0 2 (1.0%) 1 (1.3%)
Note: Number (percentage); SMN=Secondary Malignant Neoplasms.
Each baseline covariate was tested for univariate association with overall survival and event-
free survival among pediatric patients with head and neck NRSTS. All tests were stratified by risk
group. The log-rank tests showed that there was no variable statistically significantly associated
with overall survival. However, for event-free survival, ethnicity, categorical tumor size and tumor
margin status had p-values less than 0.20 (Table 4), which were selected as potential predictors in
the final multivariate stepwise Cox model. Since the risk group was an important studied variable,
it was forced in the Cox model.
21
Table 4 Univariate Log-rank tests among patients with head and neck NRSTS
Overall survival Event-free Survival
Baseline
Covariates
Stratified Log-rank
p-value
Stratified Log-rank
p-value
Age at enrollment 0.9504 0.6208
Gender 0.8180 0.4012
Ethnicity 0.7252 0.0461*
Race 0.8284 0.7970
POG grade 0.4073 0.2150
FNCLCC grade 0.7647 0.9666
Tumor size 0.2147 0.0737*
Tumor depth 0.9654 0.7324
Invasiveness 0.8869 0.5099
Treatment arm 0.8957 0.8913
Unresectable 0.9688 0.5877
Margin status 0.8957 0.1937*
Note: Log-rank tests were performed for each categorical variable; all tests were stratified by risk group.
*: the variables were selected into multivariate stepwise Cox regression model.
Multivariate stepwise Cox regression results indicated that there was no covariate statistically
significantly associated with failure events (ethnicity p=0.0548; tumor size p=0.0516; margin
status p=0.3331). None of them significantly predicted the failures when entry and exit level was
0.05 in stepwise selection process. Since the study was risk-based, hazard ratios (HR) of risk group
were calculated for both overall and event-free survival.
The estimated risk of death for patients in the high-risk group was 2.66 times than those in the
22
intermediate-risk group (95% CI: 0.68–10.33), but the result was not statistically significant. There
was no patient died in the low-risk group. For event-free survival, a total of four patients in the
high-risk group experienced events. The estimated risk for patients in the high-risk group was 2.87
times that of intermediate-risk patients (95% CI:0.89–9.24), while patients in the low-risk group
experienced statistically significantly lower risk of developing events than intermediate-risk
patients (HR=0.33, 95% CI: 0.11–0.96) (Table 5).
Table 5 Univariate analysis of risk group among head and neck NRSTS patients
Overall Survival Event-free Survival
Risk group Hazard Ratio
(95% CI)
p-value Hazard Ratio
(95% CI)
p-value
Low 0.00 0.9935 0.33 (0.11–0.96) 0.0427
Intermediate 1.00 (reference) — 1.00 (reference) —
High 2.66 (0.68–10.33) 0.1578 2.87 (0.89–9.24) 0.0778
Note: HRs were calculated using Cox proportional hazard regression; 95% confidence intervals were
calculated based on Wald test.
For all eligible patients (Figure 3 and Table 6), the best survival was seen for patients with
head or neck NRSTS and in the low-risk group, giving 5-year survival 100%, while the worst was
seen for patients with head or neck NRSTS and in the high-risk group, giving 5-year survival
25.0%. In addition, the best event-free survival (Figure 4 and Table 7) was observed for patients
with NRSTS at other sites in the low-risk group, giving 5-year event-free survival 90.0%. However,
all 4 patients in the high-risk group and with head or neck tumors experienced failures. There was
23
no statistically significant difference in overall and event-free survival rates between two groups
of patients (Log-rank test p=0.6183 and p=0.6169, respectively). Overall, patients in the low-risk
group had the best overall and event-free survival, and the patients with tumors at other sites had
better survival than head and neck NRSTS patients, except for overall survival in the low-risk
group.
24
Figure 3 Estimated overall survival for all patients by tumor site and risk group
Table 6 Five -year survival rates for OS stratified by tumor site and risk group
Head & Neck patients Comparison patients
Risk group Probability (95% CI) Probability (95% CI)
Low 100%
—
95.6%
(91.0%–97.9%)
Intermediate 67.7%
(43.7%–83.2%)
79.8%
(73.2%–84.9%)
High 25.0%
(0.9%–66.5%)
37.0%
(25.9%–48.1%)
25
Figure 4 Estimated event-free survival for all patients by tumor site and risk group
Table 7 Five -year survival rates for EFS stratified by tumor site and risk group
Head & Neck patients Comparison patients
Risk group Probability (95% CI) Probability (95% CI)
Low 80.8%
(59.8%–91.5%)
90.0%
(84.6%–93.6%)
Intermediate 53.9%
(30.8%–72.2%)
64.9%
(57.7%–71.2%)
High 0%
—
23.4%
(14.5%–33.4%)
26
The pairwise comparison among demographic characteristics, baseline tumor features and risk
groups were performed for head and neck patients. Among those patients, there was a statistically
significant association between age and treatment (p=0.0084). Among patients who were less than
10 years old, 45.5% of them were assigned to treatment Arm D, and 22.7% of them were in Arm
C; 60.7% of patients between 10 to 18 years old were treated in Arm A, and 25.0% of them were
in Arm D. Two of the three patients who were 18 years or older were treated in Arm C, and one
was in Arm D. Age was also significantly associated with risk group (p=0.0041). More than half
(54.6%) of patients who were less than 10 years old were categorized in the intermediate-risk
group; all 28 patients who were between 10 to 18 years old were in the intermediate- or low-risk
group, 67.9% of them were low risk. One of the three patients who were 18 years or older was
high risk, and the other two were intermediate risk.
Tumor grades including POG grade and FNCLCC grade, were statistically significantly
associated with treatment arm (p=0.0188 and 0.0006, respectively). All 14 patients in treatment
Arm B and C had tumors with high POG grade; 88.9% of patients in Arm D had high POG grade
tumors; and 57.1% of patients in Arm A had tumors of high POG grade. As for FNCLCC grade,
the majority of patients in Arms B, C, D had high FNCLCC grade tumors, which included 60.0%
of patients in Arm B, 88.9% in Arm C and 66.7% in Arm D; while 80.95% patients in Arm A had
tumors with low FNCLCC grade. In addition, there was significant association between FNCLCC
grade and risk group (p=0.0009). 19 out of 26 (73.1%) patients with low FNCLCC grade tumors
27
were in the low-risk group, and the rest of them were evaluated as intermediate risk. For patients
with high FNCLCC grade tumors, 14.8% of them were high risk, and 59.3% of them were
intermediate risk. In regard to tumor features, FNCLCC tumor grade was marginally statistically
significantly associated with unresectable tumors and margin status (p=0.0418 and 0.0461,
respectively). 80.8% of low grade tumors were resectable, while 51.9% high grade tumors were
resectable. 42.3% low grade tumors had negative margin, while 34.6% of them had positive margin.
Among patients with high grade tumors, 44.4% of them had tumors with positive margin, and 44.4%
of them had tumors which margin status were not applicable.
In addition, there was statistically significant association between invasiveness and treatment
arm (p=0.0168) and risk group (p=0.0288). 68.4% of patients with non-invasive tumors were
treated in Arm A, and 73.7% of them were assigned into the low-risk group. Among 34 patients
with invasive tumors, 44.1% of them were assigned into treatment Arm D, and 23.5% were in Arm
A, 20.6% in Arm C. More than half of these patients (55.9%) were evaluated in the intermediate-
risk group. Margin status was also statistically significantly associated with risk group (p=0.0099).
All 14 patients with negative margin tumors were in the low-risk group. One of 18 patients with
tumors of not application margins was assigned in the high-risk group, and the rest of them were
all in the intermediate-risk group. 57.1% of patients with positive margin tumors were in the low-
risk group, and 28.6% of them in the intermediate-risk group.
Categorical tumor size was statistically significantly associated with invasiveness (p=0.0011)
28
and margin status (p=0.0097). When the maximum diameter of tumors was greater than 5 cm, 90.9%
of these tumors were invasive, and 50.0% of them had positive margin; however, as for the
maximum tumor diameter smaller or equal to 5 cm, only 45.2% of them were invasive, and 32.3%
of them had positive margin. A total of 31 patients had tumors sized less than or equal to 5 cm.
Tumor depth was statistically significantly associated with invasiveness and unresectable tumors
(p=0.0006 and 0.0206, respectively). Among 9 patients with superficial tumors, 8 patients had non-
invasive tumors, and all 9 patients had resectable tumors. Among 44 patients with deep tumors, 33
(75.0%) had invasive tumors, and 26 (59.1%) were resectable. There was also statistically
significant association between invasiveness and margin status (p=0.0001). 63.2% of tumors
which were non-invasive had negative margins; while 50% of invasive tumors had positive
margins, and the margin status of 44.1% of invasive tumors were not applicable.
29
Discussion
Baseline characteristics showed statistically significant differences between patients with head and
neck NRSTS and patients with NRSTS at other sites on age and tumor size. In the target population
which included 53 patients with head and neck primary tumors,58.5% of them had tumors whose
maximum diameters were less than 5cm. 79.3% of them had tumors with high POG grade. 92.5%
of them had tumors which were non-metastatic. These results are consistent with the conclusion
of Federico’s study
[20]
, which summarized that small, high grade and non-metastatic were features
of most head and neck NRSTS among young patients. In addition, a majority of patients with head
and neck NRSTS were no greater than 18 years old, and most of patients enrolled in the study were
white and not Hispanic or Latino. The demographics of this study were consistent with reported
findings that pediatric NRSTS had increasing incidence in adolescents and similar incidence
between male and female
[1, 21]
.
The overall survival of patients in the low-risk group was 100%, but the 5-year survival rates
in the intermediate- and high-risk group were slightly lower in patients with head and neck NRSTS
compared to those with tumors at other sites, although there was no statistically significant
difference of survival rates between two groups of patients (Log-Rank test p=0.6183). For event-
free survival, all survival rates were lower in patients with head and neck NRSTS than in patients
with tumors of other sites (Log-Rank test p=0.6169). The survival rates showed that the outcome
of head and neck NRSTS is poor compared to NRSTS at other sites, which was also reported by
30
St. Jude Children’s Hospital researchers
[20]
. The stepwise selection of multivariate Cox models
indicated that there was no statistically significant prognostic factor associated with survival
outcome, this result may have been due to small sample size.
The two-way comparison results showed several statistically significant associations among
baseline variables. Since assigning treatment arm and categorizing risk group were based on tumor
features, there was statistically significant correlation between treatment arm and risk group. As a
result, age, FNCLCC grade, categorical tumor size, invasiveness, unresectable, and margin status
were statistically significantly associated with treatment arm as well as risk group, while POG
grade was only associated with treatment arm. All three patients who were 18 years or older in
NRSTS head and neck study received Arm C or D treatment, and they were all evaluated as non-
low risk.
There were also statistically significant associations between some tumor feature variables.
Low FNCLCC grade tumors were more likely to be resectable and have negative margin. The
smaller tumor size whose maximum diameter were less than 5 cm in this study tended to be non-
invasive and have negative margin status. The statistically significant association between
invasiveness, unresectable tumors and tumor depth indicated that deep tumors had higher
probability being invasive and unresectable. The majority of invasive tumors had positive margin,
or the margin status of tumors were not applicable.
This study evaluated survival outcomes of patients with head and neck NRSTS who received
31
a novel risk-based treatment. However, few definite conclusions could be drawn, which could be
due to small sample size.
32
Reference
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Ma, Xin
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A novel risk-based treatment strategy evaluated in pediatric head and neck non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) patients: a survival analysis from the Children's Oncology Group study...
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Keck School of Medicine
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