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Association of Definitive Radiotherapy for Esophageal Cancer and the Incidence of Secondary Head and Neck Cancers: A SEER Population-Based Study

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Background Impact of radiotherapy (RT) for esophageal cancer (EC) patients on the development of secondary head and neck cancer (SHNC) remains equivocal. The objective of this study was to investigate the link between definitive RT used for EC treatment and subsequent SHNC. Methods This study was conducted using the Surveillance, Epidemiology, and End Results (SEER) database to collect the data of primary EC patients. Fine-Gray competing risk regression and standardized incidence ratio (SIR) and propensity score matching (PSM) method were used to match SHNC patients with only primary head and neck cancer (HNC) patients. Overall survival (OS) rates were applied by Kaplan-Meier analysis. Results In total, 14,158 EC patients from the SEER database were included, of which 9,239 patients (65.3%) received RT and 4,919 patients (34.7%) received no radiation therapy (NRT). After a 12-month latency period, 110 patients (1.2%) in the RT group and 36 patients (0.7%) in the NRT group experienced the development of SHNC. In individuals with primary EC, there was an increased incidence of SHNC compared to the general US population (SIR = 5.95, 95% confidence interval (CI): 5.15 - 6.84). Specifically, the SIR for SHNC was 8.04 (95% CI: 6.78 - 9.47) in the RT group and 3.51 (95% CI: 2.64 - 4.58) in the NRT group. Patients who developed SHNC after RT exhibited significantly lower OS compared to those after NRT. Following PSM, the OS of patients who developed SHNC after RT remained significantly lower than that of matched patients with only primary HNC. Conclusion An association was discovered between RT for EC and increased long-term risk of SHNC. This work enables radiation oncologists to implement mitigation strategies to reduce the long-term risk of SHNC in patients who have received RT following primary EC.
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Original Article World J Oncol. 2024;000(000):000-000
Association of Definitive Radiotherapy for Esophageal
Cancer and the Incidence of Secondary Head and
Neck Cancers: A SEER Population-Based Study
Qian Qian Guoa, i, Shi Zhou Mab, i, De Yao Zhaob, i, Narasimha M. Beerakac, d, e, Hao Gua,
Yu Fei Zhenga, Rui Wen Zhaoa, Si Ting Lia, Vladimir N. Nikolenkod, Kirill V. Bulygind,
Basappa Basappaf, Rui Tai Fana, g, h, j, Jun Qi Liua, g, j
Abstract
Background: Impact of radiotherapy (RT) for esophageal cancer (EC)
patients on the development of secondary head and neck cancer (SHNC)
remains equivocal. The objective of this study was to investigate the link
between definitive RT used for EC treatment and subsequent SHNC.
Methods: This study was conducted using the Surveillance, Epidemi-
ology, and End Results (SEER) database to collect the data of primary
EC patients. Fine-Gray competing risk regression and standardized
incidence ratio (SIR) and propensity score matching (PSM) method
were used to match SHNC patients with only primary head and neck
cancer (HNC) patients. Overall survival (OS) rates were applied by
Kaplan-Meier analysis.
Results: In total, 14,158 EC patients from the SEER database were
included, of which 9,239 patients (65.3%) received RT and 4,919 pa-
tients (34.7%) received no radiation therapy (NRT). After a 12-month
latency period, 110 patients (1.2%) in the RT group and 36 patients
(0.7%) in the NRT group experienced the development of SHNC.
In individuals with primary EC, there was an increased incidence of
SHNC compared to the general US population (SIR = 5.95, 95% con-
fidence interval (CI): 5.15 - 6.84). Specifically, the SIR for SHNC
was 8.04 (95% CI: 6.78 - 9.47) in the RT group and 3.51 (95% CI:
2.64 - 4.58) in the NRT group. Patients who developed SHNC after
RT exhibited significantly lower OS compared to those after NRT.
Following PSM, the OS of patients who developed SHNC after RT
remained significantly lower than that of matched patients with only
primary HNC.
Conclusion: An association was discovered between RT for EC and
increased long-term risk of SHNC. This work enables radiation on-
cologists to implement mitigation strategies to reduce the long-term
risk of SHNC in patients who have received RT following primary
EC.
Keywords: Radiation therapy; Esophageal cancer; Secondary head
and neck cancer; SEER database
Introduction
Esophageal cancer (EC) ranks as the seventh most prevalent
form of cancer worldwide and there were 604,100 new cases
and approximately 544,000 deaths in 2020 due to esophageal
malignancies [1-3]. Radiotherapy (RT) serves as a therapeutic
intervention for various malignancies and effectively offers pal-
liative relief to patients experiencing tumor-related symptoms
[4]. It is recommended as a selective therapeutic modality for
patients who are diagnosed with localized or advanced EC [5-7].
The long-term risks associated with RT should be studied
closely as the improvements in cancer increase survival among
cancer patients with RT [3, 8, 9-14]. During RT, the DNA of tu-
mor cells is damaged by irradiation [15, 16]. At the same time,
tissues surrounding the tumor cells are injured by RT due to the
nonselective nature of RT [16]. Hence, the advantages of RT
concerning tumor control need to be carefully considered in
relation to the potential risks of side effects [15, 17]. Moreover,
Manuscript submitted February 17, 2024, accepted May 6, 2024
Published online June 18, 2024
aDepartment of Oncology, The First Affiliated Hospital of Zhengzhou Univer-
sity, Zhengzhou 450000, Henan, China
bDepartment of Radiation Oncology, The First Affiliated Hospital of Zheng-
zhou University, Zhengzhou 450000, Henan, China
cRaghavendra Institute of Pharmaceutical Education and Research (RIPER),
Anantapuramu, Chiyyedu, Andhra Pradesh 515721, India
dDepartment of Human Anatomy and Histology, I.M. Sechenov First Moscow
State Medical University (Sechenov University), Moscow 119991, Russian
Federation
eHerman B. Wells Center for Pediatric Research, Department of Pediatrics,
Indiana University School of Medicine, Indianapolis, IN 46202, USA
fLaboratory of Chemical Biology, Department of Studies in Organic Chemis-
try, University of Mysore, Mysore, Karnataka 570006, India
gCancer Center, The First Affiliated Hospital of Zhengzhou University, Zheng-
zhou 450000, Henan, China
hCollege of Medicine, Zhengzhou University, Zhengzhou 450052, Henan, China
iThese authors contributed equally to this article.
jCorresponding Author: Rui Tai Fan, Cancer Center, The First Affiliated Hos-
pital of Zhengzhou University, Zhengzhou 450000, Henan Province, China.
Email: fccfanrt@zzu.edu.cn; Jun Qi Liu, Department of Radiation Oncology,
The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000,
Henan Province, China. Email: fccliujq@zzu.edu.cn
doi: https://doi.org/10.14740/wjon1834
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several recent studies pertinent to cancers have suggested that
RT could elevate the risks of long-term adverse consequences
including the incidence of secondary primary malignancies
(SPMs) [18-20].
Abundant evidence has been reported that there is an as-
sociation with an increased risk of secondary thoracic cancers
in patients who have received RT for EC [21-23]. Zhu et al de-
scribed that RT for young-onset head and neck cancer (HNC)
patients increased second cancer risk for the head and neck [18].
However, the implications of RT following EC diagnosis on the
development and prognosis of secondary head and neck cancer
(SHNC) remain equivocal. Insights gained are crucial for devel-
oping personalized treatment strategies and improving predic-
tions of disease progression in comparison to secondary thoracic
cancers. For this reason, we performed this study to determine
the risk of SPMs occurrence when the EC patients received RT
by analyzing the patient data acquired from US Surveillance,
Epidemiology, and End Results (SEER)-9 database.
Materials and Methods
Database and participants
SEER database, encompassing a total of 28% of the entire US
population, stands as the publicly accessible collection of cancer
data. Individuals with a primary diagnosis of EC were identi-
fied through nine registries within the SEER database, spanning
from January 1, 1975 to December 31, 2018. The utilization of
SEER data did not require obtaining informed consent from pa-
tients, as the data and information had been anonymized before
being released. This study was performed as per Strengthening
the Reporting of Observational Studies in Epidemiology guide-
lines. This study does not involve any animal or human experi-
mental models. Hence, ethical approval is not required.
Tumor sites were coded as per the third edition of the
ICD-O-3. Patients included in this study had a diagnosis of EC
(C15.0-15.9). Cases associated with the following criteria were
excluded: 1) patients for whom EC was not their initial primary
cancer; 2) unknown race, treatment, cause of death, or follow-
up data; 3) age < 20 years or survival time less than 12 months.
Treatment interventions
We collected information about demographic characteristics of
cancer patients and cancer incidence rates, age, sex, race, year
of diagnosis, tumor stage, tumor grade, clinicopathological data,
survival data, second primary cancer, and treatment. Based on
the initial treatment approach for primary EC, the patients were
divided into two groups: the RT group consisted of primary EC
patients who received RT, and the no radiation therapy (NRT)
group consisted of patients who were treated with no RT (Fig. 1).
Survival reports
The primary objective of this study was to evaluate the risk of
Figure 1. Flow diagram depicting the study population obtained from SEER database. PSM: propensity score matching; RT:
radiotherapy; NRT: no radiation therapy.
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Guo et al World J Oncol. 2024;000(000):000-000
SHNC, encompassing any form of HNC that developed more
than 12 months after EC treatment. The SEER program can
differentiate SPMs from recurrent diseases in accordance with
the ICD-O-3 guidelines. Another aim was to calculate the fol-
low-up of SHNC, commencing with the diagnosis of EC and
concluding at the date of all-cause death or the last follow-up
time.
Statistical analysis
R statistical computing (version 4.3.1) was used to execute
the statistical analysis. Fine-Gray competing risk regression
was implicated to calculate the cumulative incidence function
(CIF), which could show the probability of developing SHNC.
There were three kinds of events: SHNC (end event), alive (no
event), and death (competing event). The Chi-squared 2) test
was executed to perform the comparison of categorical data
and the Fisher’s exact test was selected when frequencies fell
below 5. The Mann-Whitney test was utilized to analyze con-
tinuous variables, considering normal and non-normal distri-
butions, respectively.
Furthermore, we calculated the SIR and its associated 95%
confidence interval (CI) through Poisson regression analysis.
The SIR represents the ratio of observed (O) malignancies to
the expected (E) number of malignancies (SIR = O/E). The
expected number was calculated based on a reference SEER
population aligning with the calendar year, age, race, and sex
characteristics of the examined population. The SIRs were cal-
culated using SEER*Stat software (version 8.4.2).
To evaluate the prognosis of SHNC, a five-to-one pro-
pensity score matching (PSM) between the patients with pri-
mary HNC and SHNC after RT for EC was performed with a
caliper of 0.02. Survival analysis was conducted for an effec-
tive comparison of overall survival (OS) between the SHNC
and adjusted cohorts, with P-values calculated using log-rank
test.
Results
Patient characteristics
All 39,225 patients diagnosed with primary EC from 1975 to
2018 were identified in this study. After excluding the patients
with nonmatched case criteria, we enrolled 14,158 patients in
total. Whites (n = 11,752, 83.0%), males (n = 10,887, 76.9%),
and elderly (n = 12,940, 91.4%) constituted most of the cases.
According to the therapeutic modalities, the baseline features
of all the patients diagnosed with ECs are described in Table
1 and the patients who developed SHNC are depicted in Ta-
ble 2. As described in Table 1, the RT group comprised 9,239
patients (65.3%), whereas the NRT group consisted of 4,919
patients (34.7%). Patients in the RT group exhibited a higher
proportion of upper and middle EC, squamous cell carcino-
ma, regional diseases, and larger tumor size (≥ 2 cm) when
compared to NRT group. Most of the patients received chemo-
therapy in RT group whereas, more patients opted for surgi-
cal treatment in the NRT group. A total of 36 patients (0.7%)
in the NRT group and 110 patients (1.2%) in the RT group
developed SHNC after 12 months latency. In SHNC patients,
the median follow-up time was 82 months (interquartile range,
42.5 - 117.8) in the RT group, and 151 months (interquartile
range, 73.5 - 203.0) in the NRT group (Table 2). Among the
cohort of patients diagnosed with SHNC, histological classi-
fication revealed 138 cases of head and neck squamous cell
carcinoma (HNSCC), one case of head and neck adenocarci-
noma (HNAC), and seven cases of other types of SHNC. Spe-
cifically, within the HNSCC subgroup, 117 cases were initially
identified as esophageal squamous cell carcinoma (ESCC), 13
as esophageal adenocarcinoma (EAC), and eight as other his-
tological subtypes of EC. Notably, all instances of HNAC and
other types of SHNC originated from ESCC (Table 3). The
additional baseline characteristics related to the patients who
developed SHNC are described in Supplementary Material 1
(www.wjon.org).
Cumulative incidence and risk of SHNC
Cumulative incidences were 1.3% in patients receiving RT,
whereas 0.5% in the patients with NRT in 10 years after EC di-
agnosis. Cumulative incidence rate was 1.6% in the RT group
and 1.1% in the NRT group in 20 years. The RT group had a
higher probability of incidence rate when compared to the NRT
group (P < 0.005, Fig. 2). The cumulative incidence of SHNC
in patients with primary ESCC was higher in the RT group than
in the NRT group (P < 0.001). Among secondary HNSCC pa-
tients with primary ESCC, the cumulative incidence rate was
higher in the RT group compared to the NRT group (P < 0.001,
Fig. 3). In patients who opted for surgery after EC diagnosis,
no statistically significant difference was observed between
RT group and the NRT group (P = 0.321). Among patients who
did not undergo surgery, the cumulative incidence was higher
in the RT group (P < 0.001) (Supplementary Material 2, www.
wjon.org). Additionally, within the subset of patients who re-
ceived chemotherapy, the RT group exhibited a higher cumu-
lative incidence than the NRT group (P < 0.001). Conversely,
among those who did not receive chemotherapy, the cumula-
tive incidence was higher in the NRT group (Supplementary
Material 3, www.wjon.org). Moreover, we used subgroup
analyses to calculate the risk of SHNC incidence with compet-
ing risk regression. Risk of developing SHNC associated with
RT was noticed in some patient subgroups depending on the
factors such as age of EC diagnosis (50 - 74), female, year of
EC diagnosis (1985 - 1994, 2005), grade (unknown), stage
(localized), tumor size (unknown), chemotherapy (yes) and
surgery (no) group (Fig. 4). These subgroups exhibited hazard
ratios (HRs) greater than 1.0.
Dynamic risk and incidence evaluation for SHNC
SIR was determined to ascertain the incidence risk of develop-
ing SHNC. For patients who have primary EC, more SHNC
incidence was observed than the general population of USA
(SIR = 5.95, 95% CI: 5.15 - 6.84). The SIR of SHNC was
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Table 1. Baseline Characteristics of Patients With EC Depending on RT or NRT and Their Comparison
Characteristics NRT (N = 4,919) RT (N = 9,239) P-value
Race < 0.001
Black 432 (8.8%) 1,184 (12.8%)
White 4,239 (86.2%) 7,513 (81.3%)
Other 248 (5.0%) 542 (5.9%)
Sex < 0.001
Female 1,040 (21.1%) 2,231 (24.1%)
Male 3,879 (78.9%) 7,008 (75.9%)
Age of EC diagnosis 0.002
20 - 49 462 (9.4%) 756 (8.2%)
50 - 74 3,454 (70.2%) 6,741 (73.0%)
≥ 75 1,003 (20.4%) 1,742 (18.9%)
Year of EC diagnosis 0.004
1975 - 1984 551 (11.2%) 1,037 (11.2%)
1985 - 1994 960 (19.5%) 1,580 (17.1%)
1995 - 2004 1,271 (25.8%) 2,433 (26.3%)
≥ 2005 2,137 (43.4%) 4,189 (45.3%)
Tumor stage of EC < 0.001
Distant 722 (14.7%) 1,513 (16.4%)
Localized 2,150 (43.7%) 2,416 (26.2%)
Regional 1,053 (21.4%) 3,603 (39.0%)
Unknown 994 (20.2%) 1,707 (18.5%)
Tumor histology of EC < 0.001
Adenocarcinoma 2,963 (60.2%) 4,227 (45.8%)
Squamous carcinoma 1,347 (27.4%) 4,263 (46.1%)
Others 609 (12.4%) 749 (8.1%)
Tumor grade of EC < 0.001
Grade I/II 1,956 (39.8%) 3,631 (39.3%)
Grade III/IV 1,545 (31.4%) 3,702 (40.1%)
Unknown 1,418 (28.8%) 1,906 (20.6%)
Tumor primary site of EC < 0.001
Upper esophagus 188 (3.8%) 981 (10.6%)
Middle esophagus 700 (14.2%) 1,911 (20.7%)
Lower esophagus 3,187 (64.8%) 5,119 (55.4%)
NOS 723 (14.7%) 827 (9.0%)
Overlapping 121 (2.5%) 401 (4.3%)
Tumor size of EC < 0.001
< 2 cm 360 (7.3%) 214 (2.3%)
≥ 2 cm 771 (15.7%) 2,430 (26.3%)
Unknown 3,788 (77.0%) 6,595 (71.4%)
Chemotherapy of EC < 0.001
No/unknown 3,763 (76.5%) 1,666 (18.0%)
Ye s 1,156 (23.5%) 7,573 (82.0%)
Surgery of EC < 0.001
No surgery 1,824 (37.1%) 5,542 (60.0%)
Surgery performed 3,095 (62.9%) 3,697 (40.0%)
Patients who developed SHNC 36 (0.7%) 110 (1.2%) 0.011
Median age of EC diagnosis (IQR), years 65 (57.0 - 73.0) 65 (57.0 - 72.0) 0.397
Median year of EC diagnosis (IQR) 2,002 (1,992.0 - 2,010.0) 2,003 (1,993.0 - 2,011.0) 0.006
Median latency between esophagus cancer and SHNC (IQR), months 93.5 (41.5 - 156.0) 45.5 (25.3 - 84.3) < 0.001
Median follow-up time of patients with EC (IQR), months 36 (19.0 - 91.5) 27 (17.0 - 56.0) < 0.001
EC: esophageal cancer; IQR: interquartile range; NRT: no radiation therapy; RT: radiotherapy; SHNC: secondary head and neck cancer.
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Guo et al World J Oncol. 2024;000(000):000-000
Table 2. Baseline Characteristics of EC Patients Who Experienced SHNC Categorized by Therapeutic Modalities Including RT and
NRT
Characteristics NRT (N = 36) RT (N = 110) P-value
Race 0.576
Black 8 (22.2%) 34 (30.9%)
White 26 (72.2%) 68 (61.8%)
Other 2 (5.6%) 8 (7.3%)
Year of EC diagnosis 0.052
1975 - 1984 12 (33.3%) 16 (14.5%)
1985 - 1994 8 (22.2%) 32 (29.1%)
1995 - 2004 12 (33.3%) 34 (30.9%)
≥ 2005 4 (11.1%) 28 (25.5%)
Age of EC diagnosis 0.929
20 - 49 5 (13.9%) 13 (11.8%)
50 - 74 29 (80.6%) 90 (81.8%)
≥ 75 2 (5.6%) 7 (6.4%)
Sex 0.226
Female 9 (25.0%) 41 (37.3%)
Male 27 (75.0%) 69 (62.7%)
Tumor stage of EC 0.148
Distant 2 (5.6%) 8 (7.3%)
Localized 21 (58.3%) 42 (38.2%)
Regional 7 (19.4%) 41 (37.3%)
Unknown 6 (16.7%) 19 (17.3%)
Tumor histology of EC 0.094
Adenocarcinoma 6 (16.7%) 7 (6.4%)
Squamous carcinoma 27 (75.0%) 98 (89.1%)
Others 3 (8.3%) 5 (4.5%)
Tumor grade of EC 0.630
Grade I/II 21 (58.3%) 53 (48.2%)
Grade III/IV 7 (19.4%) 27 (24.5%)
Unknown 8 (22.2%) 30 (27.3%)
Tumor primary site of EC 0.002
Upper esophagus 1 (2.8%) 34 (30.9%)
Middle esophagus 9 (25.0%) 25 (22.7%)
Lower esophagus 19 (52.8%) 31 (28.2%)
NOS 6 (16.7%) 15 (13.6%)
Overlapping 1 (2.8%) 5 (4.5%)
Tumor size of EC 0.461
< 2 cm 0 (0%) 1 (0.9%)
≥ 2 cm 3 (8.3%) 18 (16.4%)
Unknown 33 (91.7%) 91 (82.7%)
Chemotherapy of EC < 0.001
No/unknown 31 (86.1%) 18 (16.4%)
Ye s 5 (13.9%) 92 (83.6%)
Surgery of EC < 0.001
No surgery 9 (25.0%) 75 (68.2%)
Surgery performed 27 (75.0%) 35 (31.8%)
Median age of EC diagnosis (IQR), years 59 (56.0 - 65.3) 59 (54.0 - 66.0) 0.969
Median year of EC diagnosis (IQR) 1,991 (1,983.8 - 2,000.5) 1,996 (1,989.0 - 2,004.8) 0.063
Median follow-up time of patients with EC (IQR), months 151 (73.5 - 203.0) 82 (42.5 - 117.8) < 0.001
EC: esophageal cancer; IQR: interquartile range; NRT: no radiation therapy; RT: radiotherapy; SHNC: secondary head and neck cancer.
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8.04 (95% CI: 6.78 - 9.47) in the RT group and 3.51 (95%
CI: 2.64 - 4.58) in the NRT group (Table 4). In addition, we
established three dynamic SIR plots for primary EC patients
treated with RT or not treated with RT to evaluate the dynamic
incidence risk for developing SHNC based on the year of EC
diagnosis, age at the time of EC diagnosis, and latency period.
In the dynamic diagnosis year-SIR plot, there was a slightly
increased risk of SHNC after RT in the years from 1980 to
1990, but there was an overall downward trend during the pe-
riod of 1990 - 2010 (Fig. 5a). In the dynamic age-SIR plot,
the risk of SHNC decreased as the age increases regardless of
whether the RT group or the NRT group. The risk of SHNC in
older EC patients (50 - 74 years old) was less than the younger
ones (20 - 49 years old) in the RT group (Fig. 5b). The risk of
developing SHNC exhibited a gradual increase, reaching its
peak during late latency in the NRT group, as evident in the
dynamic latency-SIR plot. Conversely, in the RT group, the
risk of SHNC increased during early latency but decreased in
the late latency period (Fig. 5c).
Survival outcome of SHNC
We used Kaplan-Meier survival analysis to compare the prog-
nosis of the patients with SHNC after RT or NRT. The OS of
patients who developed SHNC after RT was generally inferior
in comparison to patients who underwent NRT (Fig. 6). Moreo-
ver, we matched only primary HNC as a control group in the
PSM. The findings indicated that the 10-year OS of patients who
developed SHNC after RT was notably reduced compared to the
matched individuals with solely primary HNC (10-year OS,
6.43% vs. 28.35%, P < 0.001) (Fig. 7a). Significant differences
were not observed between patients who experienced SHNC
without RT and the matched individuals with exclusively prima-
ry HNC (Fig. 7b). Information on matched only primary HNC
was shown in Supplementary Materials 4, 5 (www.wjon.org).
Figure 2. Comparisons of cumulative incidence related to SHNC between the patients who received RT and patients who
did not receive RT. EC: esophageal cancer; SHNC: secondary head and neck cancer; RT: radiotherapy; NRT: no radiation
therapy.
Table 3. Pathological Origins of Primary Tumors in Patients With SHNC
ESCC EAC Other histological types of EC Total
Secondary HNSCC 117 13 8 138
Secondary HNAC 1 0 0 1
Other histological types of SHNC 7 0 0 7
Total 125 13 8 146
EAC: esophageal adenocarcinoma; EC: esophageal cancer; ESCC: esophageal squamous cell cancer; HNAC: head and neck adenocarcinoma;
HNSCC: head and neck squamous cell cancer; SHNC: secondary head and neck cancer.
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Guo et al World J Oncol. 2024;000(000):000-000
Discussion
RT is considered the effective therapeutic modality for patients
diagnosed with localized or advanced EC [5-7]. However, the
implications of RT are constrained by the adverse effects on
patients due to its nonspecific toxic effect [16, 24, 25]. This
study, based on SEER data, explores the RT influence on the
development of SHNC in patients surviving more than 1 year
after the diagnosis of primary EC. Additionally, the progno-
sis of patients with SHNC is compared between the RT and
NRT groups. Notably, this large-scale population-based study
represents the first comprehensive investigation into the inci-
dence of SHNC in a cohort of EC patients treated with RT and
NRT. Importantly, RT is identified as one of the risk factors
for the occurrence of SHNC as a second primary malignancy
in individuals with EC. Furthermore, the occurrence of SHNC
after RT was typically higher when compared to the general
population in the USA. Third, after RT, the risk of developing
SHNC decreased with age and diagnosis time (1990 to 2010).
However, during the early latency period (36 to 90 months),
the risk increased, while it decreased during the late latency
period (90 to 180 months) in the RT group. Fourth, SHNC
patients after RT for primary EC showed a worse prognosis
than the patients who were on NRT. The prognosis of SHNC
patients who have primary EC after RT was also worse when
compared to the matched patients with only primary HNC.
Hence, RT can be considered a crucial risk factor for SHNC
development, and can negatively influence long-term OS of
SHNC patients.
Previous reports described that RT is the risk factor for de-
veloping SPMs [26, 27]. Patients diagnosed with prostate can-
cer who received RT were more likely to develop SPMs than
patients who were not treated with RT [19, 24, 28]. Guan et al
found an association between RT for treating rectal cancer and
the likelihood of developing second gynecological malignant
neoplasms [29]. Specific reports pertinent to the assessment
of SHNC incidence risk after RT for treating primary thoracic
and head cancer patients bestowed equivocal results. Hashibe
et al analyzed the SEER database to assess the impact of RT
to mitigate oral cancer in the risk of SPM development when
comparing the patients who received RT alone or radiation
with surgery, and they found that patients treated with radia-
tion only (relative risk (RR): 1.64, 95% CI: 1.18 - 2.29) or ra-
diation with surgery (RR: 1.49, 95% CI: 1.07 - 2.06) [30]. Fur-
thermore, Zhu et al elucidated that the long-term risk of SPM
among young patients with HNCs was higher than the older
Figure 3. Comparisons of cumulative incidence rates of SHNCs of different pathological origins between patients who received
RT and those who did not. (a) Cumulative incidences of SHNC originated from ESCC. (b) Cumulative incidences of SHNC origi-
nated from EAC. (c) Cumulative incidences of secondary HNSCC originated from ESCC. EAC: esophageal adenocarcinoma;
EC: esophageal cancer; ESCC: esophageal squamous cell cancer; HNSCC: head and neck squamous cell cancer; NRT: no
radiation therapy; RT: radiotherapy; SHNC: secondary head and neck cancer.
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SEER Study for SHNC Incidence After RT of EC World J Oncol. 2024;000(000):000-000
patients [18]. It has also been reported that RT could result
in increased risks of SPM in patients diagnosed with thyroid
cancer [31, 32]. However, a few research reports concluded
an opposite opinion that RT could reduce the risk of head and
neck second primary cancers [33]. Meanwhile, there was no
research reported to assess the association between RT for EC
and the incidence of SHNCs.
Fine-gray competing risk regression was utilized to deter-
mine the risk of SHNC in this study. The occurrence of all-
cause death of non-SHNC, which is seen as a competing risk
event prevents the occurrence of events of interest. By using
Fine-Gray competing risk regression, potential bias could be
avoided, and the risk of developing SHNC could be evaluated
adequately. The incidence rate of SHNC in patients with pri-
mary EC was compared to the general population of the USA,
elucidating the specific association between RT and the risk of
SHNC development.
In our study, the dynamic risk of SHNC was determined
by establishing three dynamic plots. Our results suggested that
the SIR of SHNC was higher in younger patients than in the
older patients in the RT group and NRT group, respectively.
Younger EC patients would have a higher longevity and the
older EC patients would suffer higher competing risk events
because of death. In the dynamic diagnosis year-SIR analysis,
the incidence risk of SHNC after RT increased in the years
from 1980 to 1990, but the overall trend was downward dur-
ing 1990 - 2010. This trend might indicate that the RT influ-
ence on the long-term risk of EC patients is minimal. Such
Figure 4. Subgroup analyses of competing risk regression for the risk of developing SHNC. CI: confidence interval; EC: esopha-
geal cancer; HR: hazard ratio; NRT: no radiation therapy; RT: radiotherapy; SHNC: secondary head and neck cancer.
Articles © The authors | Journal compilation © World J Oncol and Elmer Press Inc™ | www.wjon.org 9
Guo et al World J Oncol. 2024;000(000):000-000
a phenomenon might be associated with the development of
imaging techniques and highly conformal RT technology. The
highest incidence risk for the development of SHNC is typi-
cally associated with RT after a latency within 5 to 10 years,
but for NRT-associated SHNC, the risk is progressively higher
and peaks at late latency. NRT-associated factors may become
evident with longer latency. These inferences concluded that
long-term follow-up is important for primary EC patients who
were treated with RT.
The prognosis of RT-associated SHNC may present great
Table 4. Standardized Incidence Ratio Related to the SHNC
Total (n = 14,158) NRT (n = 4,919) RT
All 5.95 (5.15 - 6.84)* 3.51 (2.64 - 4.58)* 8.04 (6.78 - 9.47)*
Race
White 4.33 (3.60 - 5.16)* 2.56 (1.78 - 3.56)* 5.95 (4.77 - 7.32)*
Black 16.74 (12.77 - 21.55)* 13.96 (8.13 - 22.36)* 18.17 (13.15 - 24.47)*
Other 13.43 (7.34 - 22.53)* 4.17 (0.51 - 15.07) 21.31 (11.01 - 37.22)*
Sex
Female 18.18 (13.87 - 23.40)* 8.71 (4.50 - 15.22)* 24.95 (18.40 - 33.08)*
Male 4.60 (3.87 - 5.44)* 3.00 (2.16 - 4.06)* 6.01 (4.87 - 7.34)*
Age
20 - 59 9.13 (7.45 - 11.09)* 5.69 (3.84 - 8.13)* 12.20 (9.55 - 15.37)*
60 - 74 4.82 (3.85 - 5.95)* 2.62 (1.62 - 4.01)* 6.64 (5.11 - 8.47)*
≥ 75 2.47 (1.23 - 4.42)* 1.43 (0.30 - 4.19) 3.40 (1.47 - 6.70)*
Year of EC diagnosis
1975 - 1984 9.41 (6.59 - 13.02)* 7.86 (4.58 - 12.58)* 11.42 (6.88 - 17.84)*
1985 - 1994 7.66 (5.78 - 9.94)* 2.81 (1.35 - 5.16)* 12.26 (8.97 - 16.35)*
1995 - 2004 6.11 (4.73 - 7.78)* 4.07 (2.48 - 6.28)* 7.83 (5.73 - 10.44)*
≥ 2005 3.53 (2.52 - 4.81)* 1.48 (0.60 - 3.05) 4.99 (3.44 - 7.01)*
Tumor grade
Grade I/II 7.92 (6.50 - 9.57)* 5.01 (3.42 - 7.07)* 10.50 (8.27 - 13.14)*
Grade III/IV 4.00 (2.89 - 5.38)* 2.55 (1.22 - 4.69)* 4.82 (3.32 - 6.77)*
Unknown 5.23 (3.83 - 6.97)* 2.40 (1.24 - 4.19)* 8.95 (6.20 - 12.51)*
Tumor stage
Distant 3.74 (1.79 - 6.87)* 3.00 (0.36 - 10.83) 3.98 (1.72 - 7.84)*
Localized 5.32 (4.26 - 6.57)* 3.01 (2.03 - 4.30)* 9.03 (6.82 - 11.72)*
Regional 6.09 (4.66 - 7.83)* 4.70 (2.43 - 8.21)* 6.57 (4.86 - 8.68)*
Unknown 9.27 (6.65 - 12.58)* 4.56 (2.18 - 8.38)* 13.91 (9.45 - 19.75)*
Surgery
Ye s 3.94 (3.14 - 4.88)* 3.18 (2.25 - 4.36)* 4.92 (3.60 - 6.56)*
No 9.53 (7.86 - 11.45)* 4.69 (2.68 - 7.62)* 11.46 (9.30 - 13.97)*
Chemotherapy
Ye s 7.59 (6.33 - 9.02)* 3.84 (1.41 - 8.36)* 7.97 (6.62 - 9.52)*
No 4.27 (3.33 - 5.39)* 3.48 (2.56 - 4.61)* 8.48 (5.31 - 12.84)*
Latency
12 - 59 5.26 (4.25 - 6.44)* 2.23 (1.27 - 3.62)* 7.31 (5.77 - 9.12)*
60 - 119 7.20 (5.53 - 9.21)* 3.47 (1.94 - 5.72)* 10.83 (7.99 - 14.36)*
120 - 239 7.13 (5.12 - 9.67)* 7.22 (4.58 - 10.84)* 7.01 (4.16 - 11.08)*
≥ 240 0.00 (0.00 - 4.10) 0.00 (0.00 - 5.45) 0.00 (0.00 - 16.45)
*P < 0.05. EC: esophageal cancer; NRT: no radiation therapy; RT: radiotherapy; SHNC: secondary head and neck cancer.
Articles © The authors | Journal compilation © World J Oncol and Elmer Press Inc™ | www.wjon.org
10
SEER Study for SHNC Incidence After RT of EC World J Oncol. 2024;000(000):000-000
heterogeneity compared with NRT-associated SHNC. Further-
more, we observed that RT-associated SHNC patients have
poor survival when compared to NRT-associated SHNC pa-
tients and matched only primary HNC patients. Due to the di-
verse genetic signaling pathways modulated by the RT and the
genetic phenotype of RT-related SHNC, the efficacy of stand-
ard treatment was reduced, consequently leading to a poorer
prognosis for RT-associated SHNC.
Studies have demonstrated that ionizing radiation alters
cancer cell metabolism, inducing DNA damage and activat-
ing multiple signaling pathways associated with DNA damage
response, signal transduction, and cell survival. These altera-
tions can influence the cellular phenotype, potentially leading
to modified responses to treatments and affecting prognosis.
Both canonical and non-canonical Wnt pathways are involved
in cancer cell behavior, and disruptions in these pathways
resulting from genetic mutations or external factors such as
radiation exposure can contribute to cancer progression and
resistance to therapy [34, 35]. Nevertheless, there are no
available genomic data in the SEER database. Therefore, fu-
ture studies are required to elucidate the correlation between
genetic features and RT-associated risk for the development
of SHNC.
A near-complete follow-up period, a higher number of
enrolled patients, and potential prediction of SHNC in the pa-
tients diagnosed with ECs were the major strengths observed
from this study. However, several limitations of this study
should be noticed. Potential bias cannot be excluded due to the
absence of randomization in the initial treatment for EC. The
lack of detailed data on RT limited us to elucidate the associa-
tion between the suitable RT dosage and the development of
SHNC. Furthermore, information on smoking history, alcohol
consumption, and family history of cancer is also lacking, yet
various lifestyle and biological factors play a significant role
in promoting secondary tumors in NRT cancer patients [36].
Hence, attaining balance among all confounders between the
two treatment types is difficult. SEER database was reported
with unmeasured confounders and intrinsic selection bias. For
example, the SEER database exclusively documented the ini-
tial RT information relevant to patients with EC; however, it is
unclear whether those patients underwent subsequent delayed
RT.
Figure 5. Dynamic standardized incidence ratio of SHNC. (a) Year of EC diagnosis. (b) Age at EC diagnosis (years). (c) Latency
after EC diagnosis (months). EC: esophageal cancer; NRT: no radiation therapy; RT: radiotherapy.
Articles © The authors | Journal compilation © World J Oncol and Elmer Press Inc™ | www.wjon.org 11
Guo et al World J Oncol. 2024;000(000):000-000
Conclusion
RT for treating EC was associated with a higher incidence risk
of SHNC. Our results concluded that long-term surveillance
for these patients is potentially required, particularly those
young patients who were diagnosed with ECs.
Supplementary Material
Suppl 1. Comparisons of baseline characteristics of SHNC
patients by therapeutic modality types include NRT and RT.
SHNC: secondary head and neck cancer; RT: radiation thera-
py; NRT: no radiation therapy.
Figure 7. Comparison of overall survival between EC patients who developed SHNC and matched only primary HNC. (a) SHNC
after RT and matched only primary HNC. (b) SHNC after NRT and matched only primary HNC. EC: esophageal cancer; NRT: no
radiation therapy; RT: radiotherapy; SHNC: secondary head and neck cancer.
Figure 6. Comparison of overall survival between EC patients who developed SHNC after RT and NRT. EC: esophageal cancer;
NRT: no radiation therapy; RT: radiotherapy; SHNC: secondary head and neck cancer.
Articles © The authors | Journal compilation © World J Oncol and Elmer Press Inc™ | www.wjon.org
12
SEER Study for SHNC Incidence After RT of EC World J Oncol. 2024;000(000):000-000
Suppl 2. Comparisons of the cumulative incidence rate of
SHNC with or without surgery following primary EC diag-
nosis between the RT group and the NRT group. (a) Cumula-
tive incidences of SHNC with surgery following primary EC
diagnosis. (b) Cumulative incidences of SHNC without sur-
gery following primary EC diagnosis. EC: esophageal cancer;
SHNC: secondary head and neck cancer; RT: radiation thera-
py; NRT: no radiation therapy.
Suppl 3. Comparisons of the cumulative incidence rate of
SHNC with or without chemotherapy following primary EC
diagnosis between the RT group and the NRT group. (a) Cu-
mulative incidences of SHNC with chemotherapy following
primary EC diagnosis. (b) Cumulative incidences of SHNC
without chemotherapy following primary EC diagnosis. EC:
esophageal cancer; SHNC: secondary head and neck cancer;
RT: radiation therapy; NRT: no radiation therapy.
Suppl 4. Patient characteristics of SHNC treated with RT and
matched only primary head and neck cancer. SHNC: second-
ary head and neck cancer; RT: radiation therapy.
Suppl 5. Patient characteristics of SHNC treated with NRT
and matched only primary head and neck cancer. SHNC: sec-
ondary head and neck cancer; NRT: no radiation therapy.
Acknowledgments
Authors thank the supporting staff of the Cancer Center, The
First Affiliated Hospital of Zhengzhou University.
Financial Disclosure
This study was supported by the National Natural Science
Foundation of China (No. 81703158). The funder has no role,
if any, in the writing of the manuscript or the decision to sub-
mit it for publication.
Conflict of Interest
The authors declare no conflict of interest.
Informed Consent
Not applicable.
Author Contributions
Qian Qian Guo (QQG), Shi Zhou Ma (SZM), De Yao Zhao
(DYZ), Narasimha M. Beeraka (NMB), Hao Gu (HG), Yu
Fei Zheng (YFZ), Rui Wen Zhao (RWZ), Si Ting Li (STL),
Vladimir N. Nikolenko (VNN), Kirill V. Bulygin (KVB), Ba-
sappa Basappa (BB), Rui Tai Fan (RTF), and Jun Qi Liu (JQL)
designed the concept. RTF, JQL, SZM, DYZ, STL, and NMB
analyzed figures, study design, data collection, data analysis,
data interpretation, writing the manuscript. JQL, DYZ, SZM,
NMB, and RTF performed study design, data collection, data
analysis, data interpretation, writing, proofread, edited and
analyzed the content of the article. All authors reviewed the
manuscript and approved it before submission.
Data Availability
The data can be found at Surveillance, Epidemiology, and End
Results (SEER) database (https://seer.cancer.gov/).
Abbreviations
EAC: esophageal adenocarcinoma; EC: esophageal cancer;
ESCC: esophageal squamous cell cancer; HNAC: head and
neck adenocarcinoma; HNSCC: head and neck squamous cell
cancer; NRT: no radiation therapy; OS: overall survival; RT:
radiotherapy; SEER: SurveillanceEpidemiology, and End Re-
sults; SHNC: secondary head and neck cancer; SIR: standard-
ized incidence ratio; SPMs: secondary primary malignancies
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... miRNA-145-5p acting as both an oncogene and a tumour suppressor Esophageal cancer. Esophageal cancer ranks seventh among cancers worldwide; it has a high mortality with an estimated 544,000 esophageal cancer deaths in 2020 (85). Fan et al (40) found that miRNA-145-5p was negatively related to ABRA C-terminal like (ABRACL). ...
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