Radiation therapy dose is associated with improved survival for
unresected anaplastic thyroid carcinoma: Outcomes from the
National Cancer Data Base
Todd A. Pezzi, BS
1
, Abdallah S. R. Mohamed, MD, Msc
2,3
, Tommy Sheu, MD, MPH
2
, Pierre
Blanchard, MD, PhD
2
, Vlad C. Sandulache, MD, PhD
4
, Stephen Y. Lai, MD, PhD
5
, Maria E.
Cabanillas, MD
6
, Michelle D. Williams, MD
7
, Christopher M. Pezzi, MD
8
, Charles Lu, MD
9
,
Adam S. Garden, MD
2
, William H. Morrison, MD
2
, David I. Rosenthal, MD
2
, Clifton D. Fuller,
MD, PhD
2
, and G. Brandon Gunn, MD
2
1
Baylor College of Medicine, Houston TX
2
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center,
Houston, TX
3
Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Alexandria
University, Alexandria, Egypt
4
Bobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of
Medicine, Houston, TX
5
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center,
Houston, TX
6
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD
Anderson Cancer Center, Houston, TX
7
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
8
Department of Surgery, Abington Hospital-Jefferson Health, Abington, PA
9
Department of Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer
Center, Houston, TX
Abstract
Background—We assessed the outcomes of patients with unresected anaplastic thyroid
carcinoma (ATC) in the National Cancer Data Base (NCDB) and explored potential relationships
between radiation therapy (RT) dose and overall survival (OS).
Corresponding author: G. Brandon Gunn, MD, Department of Radiation Oncology, The University of Texas MD Anderson Cancer
Center, 1515 Holcombe Boulevard, Unit 97, Houston, Texas, USA, 77030; Telephone: 713-563-2562; Fax: 713-563-2366;
gbgunn@mdanderson.org.
Funding & Conflicts: The authors have no conflicts of interest or funding to disclose
Author Contributions: All authors assisted in study design, drafting, and final approval of the manuscript. Authors T Pezzi, A
Mohamed, T Sheu, P Blanchard, CD Fuller, and GB Gunn also assisted in statistical analysis.
HHS Public Access
Author manuscript
Cancer
. Author manuscript; available in PMC 2018 May 01.
Published in final edited form as:
Cancer
. 2017 May 01; 123(9): 1653–1661. doi:10.1002/cncr.30493.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
Methods—The study group was composed of patients who received either no surgery or grossly
incomplete resection. Correlates of OS were explored using univariate and multivariable analysis
(MVA) analyses.
Results—A total of 1,288 patients were analyzed. Mean age was 70.2 years; 59.7% were female;
and 47.6% received neck RT. Median OS was 2.27 months, with 11% alive at one year. A positive
RT dose-survival relationship was seen for the entire study cohort, for those who received systemic
therapy, and for those with stage IVA/IVB and IVC disease. On MVA, older age (HR: 1.317, CI:
1.137–1.526), ≥1 comorbidity (HR: 1.587, CI: 1.379–1.827), distant metastasis (HR: 1.385, CI:
1.216 –1.578), receipt of systemic therapy (HR: 0.637, CI: 0.547–0.742), and receipt of RT as
compared with no RT (HR <45 Gy: 0.843, CI: 0.718–0.988; HR 45-59.9 Gy: 0.596, CI: 0.479–
0.743; HR 60-75 Gy: 0.419, CI: 0.339 – 0.517) correlated with OS. The RT dose-survival
relationship for those who received higher (60-75 Gy) vs. lower (45-59.9 Gy) therapeutic dose was
confirmed by propensity score matching.
Conclusions—Survival was poor in this cohort of patients with unresected ATC and more
effective therapies are needed. However, the association of RT dose with OS highlights the
importance of identifying patients with unresected ATC who may still yet benefit from multi-
modal local-regional treatment incorporating higher dose RT.
Keywords
Anaplastic thyroid carcinoma; Radiation therapy; National Cancer Data Base; Head and Neck;
Propensity-score matching
Introduction
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies in the head
and neck. While numerically rare, comprising 1-2% of all thyroid cancers, it has a grim
prognosis, as ATC accounts for approximately 40% of all thyroid cancer-related deaths.
1,2,3
Median survival ranges from 3-10 months, with long-term survival rates of <20%, as
patients routinely present with advanced disease.
4,5
Patients with ATC often present with
rapidly growing and immediately threatening local tumor not amenable to meaningful
resection. There are as yet no standard, highly effective treatment regimens for ATC, but
treatment is generally multi-modal.
6–8
Fit patients presenting without sign of distant
metastases are evaluated for surgery and adjuvant therapy, to provide the best chance for a
favorable outcome. However, since complete surgical resection is rarely feasible in ATC,
radiation therapy (RT), often with concurrent chemotherapy, is considered in an attempt to
induce local tumor regression (and achieve interim local control), to avoid or delay local
progression, preventing or deferring airway obstruction, severe dysphagia, and/or death
secondary to overwhelming local tumor burden, scenarios unfortunately common in these
patients, despite prompt tracheostomy.
9–13
Because presentation with or development of subsequent distant metastases is also common,
clinicians are faced with the challenge of how to prioritize local therapies and their intent or
aggressiveness.
14,15,16
At our center, the presence of distant metastases does not necessarily
preclude the use of upfront locally palliative therapy to either treat or prevent impending
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symptoms or death from tracheal or esophageal compromise, as medically fit patients with
smaller volume distant disease may still benefit from more durable local tumor control
through the use of RT.
Despite the poor overall prognosis of patients with unresected/unresectable local or distant
metastatic disease and the palliative nature of treatment in these scenarios, we hypothesize
those treatment regimens incorporating higher doses of neck RT may at least delay local
tumor progression and thus translate to improved patient survival, given the rapidity of
mortality for progressive disease. Given the rarity of this disease, and thus the inability of
any single-center (even a high-volume tertiary center) to accrue sufficient numbers for
statistical validity, we evaluated the survival of patients with unresected ATC within the
National Cancer Data Base (NCDB).
The specific goals of the present study are to:
1.
Characterize survival outcomes for patients with unresected ATC (i.e. those who
received either no surgery or had grossly incomplete resection);
2.
Explore patient, tumor, and treatment specific correlates of overall survival;
3.
Assess RT dose-survival relationships, and define clinical subgroups of interest
for future analyses
Methods
Dataset
The NCDB is a joint program of the Commission on Cancer (CoC) of the American College
of Surgeons and the American Cancer Society. The NCDB, established in 1989, is a
nationwide, facility-based, comprehensive clinical surveillance resource oncology data set
that captures 70% of all newly diagnosed malignancies in the United States annually,
including 92% of all thyroid cancers.
17
These cases come from approximately 1,500 CoC-
accredited cancer programs. It is the world’s largest oncology outcomes database and
contains over 30 million historical records. The data used in the study is derived from a de-
identified NCDB file. Access to this Health Insurance Portability and Accountability
(HIPAA)-compliant data was provided to the author CP as part of the NCDB’s Participant
Use File (PUF) program.
Clinical variables of patients with ATC reported to the NCDB from 1998 to 2012 were
retrieved from the NCDB using the International Classification of Disease, 3
rd
edition (ICD-
O-3) code 8021/3. Those diagnosed after 2011 were excluded due to lack of available
survival data at the time of data extraction and this analysis. As the purpose of this study was
to focus on ATC patients with locally advanced or unresected/unresectable tumors, patients
with tumor size <1cm and those who underwent complete surgical resection of macroscopic
disease (classified as either a “R0” or “R1” resection) were excluded. Those who had gross
residual tumor following attempted surgery (classified as a “R2” resection), or who did not
undergo surgery were included.
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Specific data examined included patient age at diagnosis, gender, race/ethnicity, presence of
comorbidities, tumor size, lymph node involvement, evidence of distant metastasis, AJCC
TNM category and stage grouping, type of surgery performed, surgical margin status, receipt
of chemotherapy as part of the first course of treatment, and patient survival. RT details
collected were: treatment site, modality, dose, number of fractions, overall treatment time,
and interval from surgery to RT start. Details regarding type of systemic therapy and patterns
of disease recurrence (local, regional or distant relapse) are not available within the NCDB.
Overall survival (OS) was compared by patient, tumor, and treatment groups of interest,
including by neck RT dose. In order to explore the neck RT dose-survival relationship, we
considered those who received 60-75 Gy to have received a higher therapeutic dose and
those 45-59.9 Gy a lower, potentially therapeutic dose. Those who received <45 Gy were
considered to have received palliative intent RT and are described here for completeness.
Those who received >75 Gy were excluded from survival comparison analyses as they were
considered to have received doses beyond the usual therapeutic range for this disease and
anatomic site.
Statistical analysis
ANOVA and Pearson chi-square tests were used for continuous and categorical data. Median
follow-up for surviving patients was calculated using the reverse Kaplan-Meier estimate.
Survival curves were generated using the Kaplan-Meier product-limit method and were
compared using the log-rank test. Time-to-event was indexed to the date of diagnosis.
Correlates of OS were explored using univariate and multivariable analyses (MVA) via Cox
proportional hazards approach for non-matched comparison. Propensity score matching was
subsequently performed using 1:1 nearest neighbor method without replacement, for patients
receiving higher versus lower therapeutic dose of neck RT.
18
Balance was assessed using
mean standardized differences. Univariate Weibull parametric survival analysis using the
propensity match score as a stratifier was implemented to calculate the β-coefficient and
hazard ratio of death as a function of RT dose. Propensity score adjusted p-value < 0.05 was
considered significant. Analyses were performed using SPSS 23.0 (IBM Corp., Armonk,
NY).
Results
Patients
Of the 355,028 cases of thyroid malignancy registered in the NCDB from 1998-2012, 3,266
(0.92%) were ATC. Of these, 2,987 were diagnosed between 1998 and 2011 and were also
≥1cm in size. 1,727 of these did not receive any surgery or had grossly incomplete surgical
resection (i.e. R2 resection). Of these, 439 patients were excluded: 202 for having no
documented target of RT, 110 for having a distant RT target, and 127 for incomplete RT dose
information. The most common distant RT targets were documented as, “Other NOS,”
“Lung/Chest,” and “Brain.” The 1,288 remaining patients who had either received
documented RT to the neck, or received no RT, comprised the final study cohort. Of these,
674 (52.3%) received no neck RT, 294 (22.8%) <45 Gy, 134 (10.4) 45–59.9 Gy, 178 (13.8%)
60–75Gy, and 8 (0.6%) received >75 Gy (Figure 1). Of the 614 patients who received RT,
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details regarding dose per fraction were available for 544 (88.6%), and of these, 80 (14.7%)
received ≤1.5Gy/fraction, a dose per fraction commonly used in hyperfractionation
schedules. However, details RT fractionation schedules are not specifically recorded in the
NCDB.
Patient, tumor, and treatment characteristics by neck RT dose group are shown in Table 1.
For the study cohort, treatment was provided at 627 unique institutions. The mean number of
cases treated per institution over the study period was 2.0 and the maximum at any single
facility was 21 cases. Overall, 47.2% had distant metastases at the time of diagnosis, 45.8%
regional lymph node involvement (N+), and 52.6% T4b tumors. When considering the neck
RT groups of interest, the group that received 45–59.9 Gy, in comparison to the group that
received 60–75 Gy was no different in mean age, gender, ethnicity, comorbidities, mean
tumor size, lymph node involvement, receipt of surgery, and receipt systemic therapy, but
were more likely to have had distant metastasis at diagnosis (48% vs. 34%, p = 0.011) and to
have received intensity modulated radiation therapy technique (43.8% vs. 27.6%, p = 0.003).
Of the 674 that received no neck RT, 582 (84%) also received no systemic therapy.
Survival Analyses
Median follow-up for surviving patients was 5.5 years. The median survival for the cohort
overall was 2.27 months (standard error [SE] +/- 0.102), with 11.29% and 6.55% of patients
alive at one and two years, respectively (see Supplementary Figure). The survival curves by
neck RT group for the study cohort overall, those who received systemic therapy, and those
with stage IVA/IVB and IVC disease are shown in Figure 2. A positive dose-survival
relationship was demonstrated for each aforementioned group of interest on this univariate
analysis, although differences for those with stage IVC disease were small. For those
receiving systemic therapy and RT and for those with stage IVA/IVB disease, visible
separation in the tail region of the curve shows extended survival in the higher RT dose
group, with relative plateau of the curve after 2 years. For the cohort overall, median survival
in months (+/- SE) was 1.31 (+/- 0.08) for those who did not receive neck RT, 1.97 (+/-
0.127) for the 1-44.9 Gy group, 4.240 (+/- 0.355) for the 45-59.9 Gy group, and 6.77 (+/-
0.391) for the 60-75 Gy group.
Correlates of survival
Results from the univariate and multivariable analysis are shown in Table 2. Variables
included in the multivariable model were those statistically significant on univariate
analysis, or established as a clinically important prognostic factor. The only variable
included in the MVA that was not statistically significant on univariate testing was presence
of nodal metastases, an established AJCC staging variable. On MVA, advanced age (HR:
1.317, CI: 1.137–1.526), ≥1 comorbidity (HR: 1.587, CI: 1.379 –1.827), distant metastasis
(HR: 1.385, CI: 1.216 –1.578), receipt of systemic therapy (HR: 0.637, CI: 0.547–0.742),
and receipt of RT as compared with no RT group (HR <45Gy: 0.843, CI: 0.718–0.988; HR
45–59.9Gy: 0.596, CI: 0.479–0.743; HR 60-75Gy: 0.419, CI: 0.339 – 0.517) correlated with
patient survival.
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