Incidence of second primary cancers in oral and pharyngeal cancer patients using a large medical claims database in Japan

Abstract

Background/purpose
As the occurrence of second primary cancers (SPCs) is strongly related to the survival rate of patients with oral and pharyngeal cancers, early detection and treatment are important. Therefore, this study aimed to clarify the incidence of SPCs and their risk factors in patients with oral and pharyngeal cancer.

Materials and methods
This observational study was conducted using data from the administrative claims database of 21,736 participants with oral and pharyngeal cancer from January 2005 to December 2020. We evaluated the cumulative incidence of SPCs among patients with oral and pharyngeal cancers using the Kaplan–Meier method. The Cox proportional-hazard model was used for multivariate analysis.

Results
Of the 1633 patients with oral and pharyngeal cancer who qualified for analysis, 388 developed SPCs (incidence rate, 7.994/1000 person-months). The multivariate analysis showed that the risk of developing SPCs was affected by age at diagnosis of oral and pharyngeal cancer, cancer treatment, and anatomical site of the primary cancer.

Conclusion
Patients with oral and pharyngeal cancers are at a high risk of developing SPCs. The data from this study may be useful in providing accurate information to patients with oral and oropharyngeal cancer.

Full text

Original Article
Incidence of second primary cancers in oral
and pharyngeal cancer patients using a large
medical claims database in Japan
Masanori Matsui
a,b
, Kahori Kawamura
b
*, Keita Kano
b
,
Hideki Yoshimatsu
b
, Takashi Doi
b
, Tatsuro Miyake
b
a
Graduate School of Dentistry (Department of Preventive and Community Dentistry), Osaka Dental
University, Hirakata, Osaka, Japan
b
Department of Preventive and Community Dentistry, Osaka Dental University, Hirakata, Osaka, Japan
Received 27 October 2022; Final revision received 24 November 2022
Available online 9 December 2022
KEYWORDS
Claims database;
Oral and pharyngeal
cancer;
Second primary
cancers
Abstract Background/purpose: As the occurrence of second primary cancers (SPCs) is
strongly related to the survival rate of patients with oral and pharyngeal cancers, early detec-
tion and treatment are important. Therefore, this study aimed to clarify the incidence of SPCs
and their risk factors in patients with oral and pharyngeal cancer.
Materials and methods: This observational study was conducted using data from the adminis-
trative claims database of 21,736 participants with oral and pharyngeal cancer from January
2005 to December 2020. We evaluated the cumulative incidence of SPCs among patients with
oral and pharyngeal cancers using the KaplaneMeier method. The Cox proportional-hazard
model was used for multivariate analysis.
Results: Of the 1633 patients with oral and pharyngeal cancer who qualified for analysis, 388
developed SPCs (incidence rate, 7.994/1000 person-months). The multivariate analysis showed
that the risk of developing SPCs was affected by age at diagnosis of oral and pharyngeal cancer,
cancer treatment, and anatomical site of the primary cancer.
Conclusion: Patients with oral and pharyngeal cancers are at a high risk of developing SPCs.
The data from this study may be useful in providing accurate information to patients with oral
and oropharyngeal cancer.
ª2022 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier
B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.
org/licenses/by-nc-nd/4.0/).
* Corresponding author. Department of Preventive and Community Dentistry, Osaka Dental University 8-1 Kuzuhahanazono-cho, Hirakata,
Osaka 573-1121, Japan
E-mail address: kawamura@cc.osaka-dent.ac.jp (K. Kawamura).
https://doi.org/10.1016/j.jds.2022.11.025
1991-7902/ª2022 Association for Dental Sciences of the Republic ofChina. Publishing servicesby Elsevier B.V. This isan open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
T
a
i
w
a
n
A
s
s
o
c
i
a
t
i
o
n
f
o
r
D
e
n
t
a
l
S
c
i
e
n
c
e
s
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.e-jds.com
Journal of Dental Sciences 18 (2023) 1047e1054

Introduction
Oral and pharyngeal cancers have been reported in more
than 700,000 cases and 380,000 deaths worldwide annu-
ally.
1
In Japan, more than 22,000 people are diagnosed with
oral and pharyngeal cancer per year, and in 2020, there
were approximately 7800 deaths; this figure is increasing
every year.
2,3
Patients with head and neck cancer may be
directly exposed to tobacco and alcohol carcinogens in
their oral and pharyngeal regions. These patients are at an
increased risk of local recurrence of head and neck, lung,
esophagus, and other cancers called second primary can-
cers (SPCs), according to the “field cancerization” phe-
nomenon.
4e6
In addition, the overall survival rate is lower
in patients with SPCs than in those without SPCs, especially
those with SPCs in the esophagus or lungs.
7e9
Studies have also been conducted on the incidence of
SPCs in relation to the age at diagnosis of head and neck
cancer using the Japanese Cancer Registry Database. The
cumulative incidence of secondary esophageal cancer is
significantly higher among younger (<65 years) than among
older individuals (65 years), whereas the cumulative inci-
dence of other cancers is significantly lower among younger
than among older individuals.
10
Another study on the risk of
SPCs of the hypopharynx and esophagus in patients with
primary oral and oropharyngeal cancer using mass screening
data and cancer registry data in Taiwan suggested that
compared with patients with lip cancer, those with cancer of
the oropharynx, oral floor, and hard palate are at a higher
risk for SPCs, and the risk varies by the anatomical site.
11
As SPCs are strongly related to the survival rate of pa-
tients with oral and pharyngeal cancers, early detection
and treatment are important. Detailed surveillance,
including regular follow-up, is emphasized for the early
diagnosis of SPCs; however, standard recommendations
have not yet been determined. Therefore, this study aimed
to clarify the incidence of SPC and its risk factors in pa-
tients with oral and pharyngeal cancer using a large medi-
cal claims database in Japan.
Materials and methods
Study design and data source
This retrospective study used the health insurance claims
database provided by the Japan Medical Data Center (JMDC)
Co., Ltd (Tokyo, Japan). The JMDC database consists of
medical, dental, and pharmacy claims, including specific
health checkup information from several health insurance
societies in Japan. As of April 2022, the cumulative dataset
comprises approximately 14 million employees of medium-
to-large companies and their dependents, excluding in-
dividuals aged 75 years. In addition, the JMDC claims
database is highly encrypted using irreversible anonymiza-
tion technology and does not allow the identification of in-
dividuals. Diagnoses were recorded using the International
Classification of Diseases 10th revision (ICD-10). The study
protocol was approved by the ethics committee of Osaka
Dental University (Number: 111163, May 31, 2021). The need
for additional informed consent was waived by the commit-
tee, according to the guidelines.
Study population
Data of patients diagnosed with oral and pharyngeal cancer
(ICD-10 codes C00-C14) from January 2005 to December 2020
were obtained from the JMDC database. The inclusion cri-
terion was that the patient had received at least one therapy:
surgery, radiotherapy, and chemotherapy. The exclusion
criteria were as follows: suspected oral and pharyngeal
cancer, diangosis within the first 6 months from the start of
the observation, and diagnosis of cancer in other sites before
oral and pharyngeal cancer treatment. This record included
information concerning the patient’s age, sex, insurance
codes, and tumor sites. We assessed comorbid conditions
before oral and pharyngeal cancer treatment, including hy-
pertension (I10-I15), diabetes mellitus (E10-E14), cerebro-
vascular disease (I60-I69), ischemic heart disease (I20-I25),
hyperlipidemia (E78), and renal disease (N00-N29). The
treatment was identified using the original Japanese pro-
cedure codes.
Outcomes
The primary outcome was the cumulative incidence of SPCs
(ICD-10 codes C15-C73) in patients with oral and pharyngeal
cancer. We separated the SPCs of the digestive system (ICD-
10 codes C15-25) from those of the respiratory system (ICD-
10 codes C30-C34). We excluded the suspected disease
codes for the diagnosis of SPCs. A synchronous SPC was
defined as one that was diagnosed within 6 months of the
initial primary oral and pharyngeal cancer, while a meta-
chronous SPC was defined as one that was diagnosed at 6
months after the primary oral and pharyngeal cancer, ac-
cording to the criteria of Warren and Gates.
12
We examined
whether the incidence of SPC differed according to age,
sex, working status, comorbidity, treatment of primary
cancer, and anatomical site of the primary cancer.
Statistical analysis
Continuous variables are presented as means and standard
deviations (SD) or as medians and ranges, depending on the
type of data. Categorical variables are presented as numbers
and percentages for analysis. The cumulative incidence of
SPCs was estimated using the KaplaneMeier method, and
differences among anatomical subsites of the primary cancer
were compared using the log-rank test. The Cox
proportional-hazard regression model was used to calculate
the hazard ratios (HRs) of SPCs in patients with oral and
pharyngeal cancer. We performed a sensitivity analysis: SPCs
were diagnosed after primary cancer and diagnosed 6
months after primary cancer. Data analysis was performed
using SPSS software version 28 (IBM, Armonk, NY, USA). A
two-sided value of P<0.01 was used to determine statistical
significance.
Results
Fig. 1 shows a flowchart of participant selection. We
identified 21,736 patients diagnosed with oral and pharyn-
geal cancer. After excluding 20,103 patients based on our
criteria, 1633 were eligible for analysis.
M. Matsui, K. Kawamura, K. Kano et al.
1048

Table 1 shows the sociodemographic data of patients
with oral and pharyngeal cancers divided into oral, sali-
vary gland, and pharyngeal cancers based on the site of
primary cancer. “Oral” includes the lip, tongue, gingiva,
oral floor, plate, and buccal mucosa. “Salivary grand” in-
cludes the parotid, submandibular, and sublingual glands.
“Pharynx” includes the nasopharynx, oropharynx, and
hypopharynx.
Figure 1 Flowchart of the inclusion and exclusion criteria for participation.
Table 1 The sociodemographic data of patients, based on the site of primary cancer.
Oral Salivary gland Pharynx
NZ830 N Z221 N Z582
Age 53 (44e60) 51 (42e60) 58 (51e63)
Age-grouping (years)
<45 217 (26.1) 64 (29.0) 60 (10.3)
45e54 234 (28.2) 66 (29.9) 152 (26.1)
55e64 274 (33.0) 72 (32.6) 259 (44.5)
65 105 (12.7) 19 (8.6) 111 (19.1)
Sex
Male 563 (67.8) 131 (59.3) 488 (83.8)
Female 267 (32.2) 90 (40.7) 94 (16.2)
Working status
Insured person 658 (79.3) 155 (70.1) 501 (86.1)
Family 172 (20.7) 66 (29.9) 81 (13.9)
Cancer treatment
With surgery 698 (84.1) 167 (75.6) 182 (31.3)
With chemotherapy 281 (33.9) 60 (27.1) 460 (79.0)
With radiation therapy 216 (26.0) 98 (44.3) 438 (75.3)
Comorbidity
Hypertension 220 (26.5) 48 (21.7) 184 (31.6)
Hyperlipidemia 180 (21.7) 36 (16.3) 122 (21.0)
Diabetes mellitus 153 (18.4) 26 (11.8) 121 (20.8)
Renal disease 46 (5.5) 13 (5.9) 38 (6.5)
Ischemic heart disease 37 (4.5) 11 (5.0) 31 (5.3)
Cerebrovascular disease 33 (4.0) 4 (1.8) 36 (6.2)
Age is expressed as median (interquartile range).
Categorical variables are presented as numbers (%).
Journal of Dental Sciences 18 (2023) 1047e1054
1049

Table 2 Second primary cancers (SPCs) by site of oral and pharyngeal cancer (including SPCs <6 months after initial cancer diagnosis).
Total
NZ1633
Lip
NZ16
Tongue
NZ590
Gingiva
NZ113
Oral
floor
NZ46
Palate
NZ18
Buccal
mucosa
NZ47
Parotid
gland
NZ157
Submandibular
grand/
Sublingual
grand
NZ64
Oro
pharynx
NZ233
Naso
pharynx
NZ81
Hypo
pharynx
NZ235
Others
NZ33
Age 55 (46e
62)
52 (36e
63)
51 (43e
59)
57 (51e
65)
58 (54e
64)
47 (43e
57)
58 (49e
63)
51 (41e
59)
53 (44e
61)
56 (50e
62)
51 (42e
60)
60 (55e
65)
59 (50e
63)
Male 1182 (72.4) 7 (43.8) 398 (67.5) 76 (67.3) 40 (87.0) 11 (61.1) 31 (66.0) 91 (58.0) 40 (62.5) 184 (79.0) 62 (76.5) 214 (91.1) 28 (84.8)
Cancer treatment
Surgery 1047 (64.1) 14 (87.5) 520 (88.1) 74 (65.5) 36 (78.3) 16 (88.9) 38 (80.9) 121 (77.1) 40 (71.9) 88 (37.8) 12 (14.8) 69 (29.4) 13 (39.4)
Chemotherapy 801 (49.1) 2 (12.5) 178 (30.2) 61 (54.0) 18 (39.1) 2 (11.1) 20 (42.6) 35 (22.3) 25 (39.1) 177 (76.0) 70 (86.4) 193 (82.1) 20 (60.6)
Radiation
therapy
752 (46.1) 2 (12.5) 127 (21.5) 50 (44.2) 18 (39.1) 5 (27.8) 14 (29.8) 75 (47.8) 23 (35.9) 152 (65.2) 64 (79.0) 197 (83.8) 25 (75.8)
Person-
months
at risk
48535 514 18001 2931 1279 432 1475 5266 2241 6564 3270 5620 942
Anatomic site of SPCs
Esophagus 146 3.01 0 0.00 16 0.89 6 2.05 4 3.13 2 4.63 2 1.36 0 0.00 0 0.00 26 3.96 0 0.00 87 15.48 3 3.18
Lung 58 1.20 0 0.00 15 0.83 6 2.05 0 0.00 0 0.00 1 0.68 4 0.76 4 1.78 11 1.68 1 0.31 14 2.49 2 2.12
Larynx 54 1.11 0 0.00 4 0.22 0 0.00 1 0.78 0 0.00 0 0.00 0 0.00 0 0.00 8 1.22 0 0.00 31 5.52 10 10.62
Stomach 47 0.97 0 0.00 12 0.67 3 1.02 3 2.35 0 0.00 3 2.03 1 0.19 1 0.45 11 1.68 0 0.00 9 1.60 4 4.25
Nasal,
paranasal sinus
30 0.62 0 0.00 0 0.00 15 5.12 0 0.00 2 4.63 2 1.36 2 0.38 1 0.45 3 0.46 4 1.22 1 0.18 0 0.00
Male
genital
organs
21 0.43 1 1.95 4 0.22 2 0.68 2 1.56 0 0.00 1 0.68 5 0.95 0 0.00 0 0.00 1 0.31 5 0.89 0 0.00
Large
intestine
20 0.41 0 0.00 2 0.11 3 1.02 2 1.56 0 0.00 0 0.00 0 0.00 1 0.45 5 0.76 0 0.00 4 0.71 3 3.18
Thyroid
gland
20 0.41 0 0.00 7 0.39 0 0.00 0 0.00 0 0.00 0 0.00 3 0.57 0 0.00 2 0.30 1 0.31 5 0.89 1 1.06
Bone,
articular
cartilage
and spinal
cord
16 0.33 0 0.00 2 0.11 7 2.39 1 0.78 1 2.31 2 1.36 0 0.00 0 0.00 0 0.00 2 0.61 1 0.18 0 0.00
Renal
urinary
tract
11 0.23 0 0.00 4 0.22 1 0.34 1 0.78 0 0.00 0 0.00 2 0.38 0 0.00 2 0.30 0 0.00 1 0.18 0 0.00
Pancreas 10 0.21 0 0.00 1 0.06 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 1 0.45 2 0.30 1 0.31 5 0.89 0 0.00
Mesothelium 10 0.21 0 0.00 1 0.06 2 0.68 0 0.00 0 0.00 3 2.03 0 0.00 0 0.00 1 0.15 1 0.31 1 0.18 1 1.06
M. Matsui, K. Kawamura, K. Kano et al.
1050

and soft
tissue
Breast 9 0.19 0 0.00 3 0.17 1 0.34 0 0.00 1 2.31 0 0.00 2 0.38 1 0.45 0 0.00 1 0.31 0 0.00 0 0.00
Liver 7 0.14 0 0.00 0 0.00 0 0.00 1 0.78 0 0.00 0 0.00 0 0.00 1 0.45 2 0.30 1 0.31 1 0.18 1 1.06
Skin 6 0.12 1 1.95 2 0.11 1 0.34 0 0.00 0 0.00 1 0.68 0 0.00 0 0.00 0 0.00 1 0.31 0 0.00 0 0.00
Gallbladder,
biliary
tract
5 0.10 0 0.00 2 0.11 0 0.00 0 0.00 0 0.00 1 0.68 0 0.00 0 0.00 0 0.00 0 0.00 2 0.36 0 0.00
Brain,
central
nervous
system
3 0.06 1 1.95 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 1 0.45 0 0.00 0 0.00 1 0.18 0 0.00
Small
intestine
2 0.04 0 0.00 0 0.00 0 0.00 1 0.78 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 1 0.18 0 0.00
Female
genital
organs
2 0.04 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 1 0.19 0 0.00 0 0.00 1 0.31 0 0.00 0 0.00
No. of
SPCs of
the
digestive
system
207 4.26 0 0.00 27 1.50 10 3.41 10 7.82 2 4.63 3 2.03 1 0.19 4 1.78 41 6.25 2 0.61 98 17.44 9 9.55
No. of
SPCs of
the
respiratory
system
137 2.82 0 0.00 19 1.06 21 7.16 1 0.78 2 4.63 3 2.03 6 1.14 5 2.23 20 3.05 5 1.53 43 7.65 12 12.74
No. of SPCs 388 7.99 3 5.84 66 3.67 40 13.65 13 10.16 5 11.57 10 6.78 18 3.42 10 4.46 61 9.29 13 3.98 131 23.31 18 19.11
Journal of Dental Sciences 18 (2023) 1047e1054
1051

In total, most patients were male (72.4%), 37.0% were
aged 55e64 years, and 80.5% were working during cancer
therapy. In addition, we indicated the percentages of
cancer treatment types and the prevalence of comorbid-
ities. Surgery (64.1%) was more common than chemo-
therapy (49.1%) or radiation therapy (46.1%). The most
common complication was hypertension (27.7%), followed
by hyperlipidemia (20.7%) and diabetes mellitus (18.4%).
Table 2 shows the incidence of SPCs by the anatomical
site of the primary oral and pharyngeal cancer. Of the 1633
patients with oral and pharyngeal cancer, 388 developed
SPCs (incidence rate, 7.99/1000 person-months). Of the
SPC sites, the esophagus (146 cases) was the most common
site, followed by the lungs (58 cases) and larynx (54 cases).
In the overall SPCs, the incidence was highest in the
hypopharynx (23.31), followed by the gingiva (13.65) and
palate (11.57). The parotid gland (3.42) had the lowest
incidence. In SPCs of the digestive system, the incidence
was highest in the hypopharynx (17.44), followed by the
oral floor (7.82) and oropharynx (6.25). In SPCs of the res-
piratory system, the incidence was highest in the hypo-
pharynx (7.65), followed by the gingiva (7.16) and palate
(4.63). The cumulative incidence of SPCs in patients whose
initial cancers were in different sites of oral and pharyngeal
cancer is presented in Fig. 2.
The univariate and multivariate Cox proportional-hazard
models for the risk of developing SPCs among patients with
oral and pharyngeal cancer are shown in Table 3. Multi-
variate analysis showed that age, cancer treatment, and
the anatomical site of the primary cancer affected the
development of SPCs. Age (55 years), chemotherapy, ra-
diation therapy, and development of primary cancer on the
oral floor, gingiva, or hypopharynx increased the risk of
SPCs. However, surgery and the development of primary
cancer of the tongue reduced the risk of SPCs.
Discussion
In this study, we examined the incidence of and factors
associated with SPCs among patients with oral and
pharyngeal cancer using an administrative claims database
in Japan. Patients with oral and pharyngeal cancers are at a
higher risk of developing SPCs. According to a systematic
review by Coca-Pelaz et al.,
13
the average morbidity rate of
second primary tumors, including synchronous and meta-
chronous tumors, in patients treated for head and neck
cancer was 13.2% (2.4e27.7%), with large discrepancies. In
the present study, the morbidity rate of SPCs, including
both synchronous and metachronous tumors, was 23.8%. In
addition, as shown in Supplementary Table 1, the morbidity
of metachronous tumors (SPCs) at 6 months after the pri-
mary cancer diagnosis was 9.3% (153 cases). We performed
a sensitivity analysis of the characteristics noted in the
claims data to confirm the occurrence of the outcome
(Supplementary Table 1). Although there is a wide range in
the incidence rate between immediately after the diagnosis
of the primary tumor and at 6 months after the diagnosis,
the results complement those of previous studies.
5,10
After adjusting for several covariates, the results showed
that the risk of developing SPCs was affected by age at
diagnosis of oral and pharyngeal cancer, cancer treatment,
and the anatomical site of the primary cancer. The same
trend was observed regarding the factors contributing to the
occurrence of second primary cancers between the inci-
dence immediately after the primary-tumor diagnosis and
that after 6 months (Supplementary Table 2).
It is generally believed that cancer morbidity increases
with age, as shown in a study by Hori et al. using the Jap-
anese cancer registry.
14
It has been reported that the
morbidity of SPC increases with age,
5,15
while there are also
reports that younger people are at an increased risk for
SPC,
16,17
with some studies reporting different results. In
this study, older age (55 years) resulted in a higher risk of
SPC. Younger and older patients were defined based on a
median age of 55 years, which is the median age of the
entire patient population. The database did not include
patients aged >75 years, which resulted in a relatively low
median age. Patients aged 55e64 years, which represented
37% of the total eligible population, were included in this
study as older adults. It is likely that the risk of developing
SPCs differs depending on the age used as the criterion for
defining younger and older patients.
To the best of our knowledge, no study to date has
examined the onset and comorbidity of SPCs using a large
claims database. Multivariate analysis showed that comor-
bidities were not associated with the risk of developing
SPC. The ability to obtain information on comorbidities
other than cancer is an advantage of using a health insur-
ance claims database.
In the treatment of primary cancer, radiation therapy has
been reported to increase the risk of SPCs by field cancer-
ization of the upper respiratory tract due to exposure-
induced DNA strand breaks, chromosomal aberrations, mu-
tations, and overall genetic instability.
18
Conversely, the
effect of radiation on the incidence of SPCs is much more
controversial, as studies of different designs and methods
have yielded conflicting results in the analysis of SPC risk in
patients treated with radiation therapy.
19,20
In this study,
multivariate analysis showed that patients treated with ra-
diation therapy or chemotherapy were at a higher risk of
developing SPC. However, the medical claims database lacks
information, such as radiation dose. Chemotherapy and
radiotherapy for the treatment of oral and pharyngeal can-
cers may only be applied in severe cases.
Figure 2 Cumulative incidence of second primary cancers
(SPCs) by site of oral and pharyngeal cancer.
M. Matsui, K. Kawamura, K. Kano et al.
1052

Previous studies have shown that patients with oropha-
ryngeal and hypopharyngeal primary cancers have an
increased incidence of SPCs compared with those with can-
cers at other sites.
21,22
In a study on the risk of a second
primary hypopharyngeal and esophageal cancer after an
initial primary oral and oropharyngeal cancer in Taiwan,
11
the oral cavity was subdivided by site, with the lips having
the lowest incidence as the criterion; the highest relative
risk was in the oropharynx (21.85), followed by the oral floor
(12.11) and palate (8.74). In the present study, compared
with the tongue, the highest risk was observed in the hypo-
pharyngeal region, followed by the gingiva, oral floor, pal-
ate, and oropharynx. Interestingly, the risk of developing
SPC depended on the anatomical site of the primary cancer.
To the best of our knowledge, this is the first study to
examine the incidence of SPCs and associated factors in a
large and diverse population of patients treated for oral and
pharyngeal cancer in Japan. The advantage of the health
insurance claims database that we used is that it can provide
information on diagnosis and treatment even if participants
switch to other healthcare providers.
23
However, our study
had several limitations. Owing to the nature of the admin-
istrative claims database, only medical and dental services in
health insurance could be included. Reports have shown that
the severity of oral and pharyngeal cancers affects the
development of SPCs.
4,24
However, tumor staging was not
performed in this study. Although alcohol consumption and
smoking have been reported to be factors associated with
the development of SPCs, alcohol consumption and smoking
status could not be ascertained.
10,25e27
In conclusion, patients with oral and pharyngeal cancer
are at a higher risk of developing SPCs. Age, cancer treat-
ment, and the anatomical subsite of the initial cancer may
influence its incidence. The data obtained in this study may
be useful to provide information on the risk of SPCs in pa-
tients with oral and oropharyngeal cancer.
Declaration of competing interest
None.
Acknowledgments
This research was supported by Grant-in-Aid for Young
Scientists (KAKENHI grant number: 21K17204). We would
like to thank Korenori Arai of Osaka Dental University for
providing us with valuable advice for our study.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.jds.2022.11.025.
References
1. Global Burden of Disease 2019 Cancer Collaboration,
Kocarnik JM, Compton K, et al. Cancer incidence, mortality,
years of life lost, years lived with disability, and disability-
Table 3 Cox proportional hazard model for risk of developing second primary cancers.
Variables Univariable Multivariable
HR 95%CI P-value HR 95%CI P-value
Age 55 years 2.141 1.734e2.644 <0.001 1.435 1.140e1.805 0.002
Sex Male 1.541 1.206e1.969 <0.001 0.932 0.641e1.355 0.712
Working status Working 0.905 0.794e1.033 0.139 1.065 0.719e1.579 0.752
Comorbidity Hypertension 1.561 1.267e1.923 <0.001 1.271 1.006e1.607 0.044
Hyperlipidemia 1.09 0.856e1.388 0.485 0.851 0.644e1.125 0.258
Diabetes mellitus 1.322 1.035e1.688 0.025 1.127 0.857e1.483 0.392
Renal disease 0.905 0.583e1.406 0.658 0.789 0.499e1.248 0.311
Ischemic heart disease 1.231 0.793e1.912 0.354 0.927 0.579e1.483 0.752
Cerebrovascular disease 1.515 1.003e2.291 0.049 1.100 0.703e1.721 0.676
Cancer treatment With surgery 0.349 0.285e0.427 <0.001 0.755 0.590e0.968 0.026
With chemotherapy 3.331 2.654e4.180 <0.001 1.703 1.280e2.265 <0.001
With radiation therapy 3.295 2.646e4.103 <0.001 1.644 1.243e2.173 <0.001
Anatomic site of the
primary cancer
Tongue 1.000 <0.001 1.000 <0.001
Parotid gland 1.005 0.597e1.693 0.984 0.906 0.532e1.544 0.717
Nasopharynx 1.324 0.730e2.401 0.356 0.626 0.335e1.173 0.144
Submandibular grand/
Sublingual grand
1.348 0.693e2.623 0.378 1.168 0.598e2.280 0.650
Lip 1.706 0.536e5.427 0.366 2.169 0.678e6.941 0.192
Buccal mucosa 2.072 1.065e4.030 0.032 1.547 0.790e3.030 0.203
Oropharynx 2.672 1.886e3.786 <0.001 1.392 0.949e2.040 0.090
Palate 2.823 1.137e7.009 0.025 3.086 1.229e7.754 0.016
Oral floor 2.930 1.616e5.313 <0.001 2.258 1.234e4.131 0.008
Gingva 4.086 2.756e6.059 <0.001 2.834 1.882e4.267 <0.001
Hypopharyngeal 7.508 5.567e10.127 <0.001 3.323 2.336e4.727 <0.001
HR, hazard ratio; CI, confidence interval.
Journal of Dental Sciences 18 (2023) 1047e1054
1053

adjusted life years for 29 cancer groups from 2010 to 2019: a
systematic analysis for the global burden of disease study 2019.
JAMA Oncol 2022;8:420e44.
2. Vital statistics Japan (Ministry of health, Labour and Welfare).
Available at: https://ganjoho.jp/reg_stat/statistics/index.
html. [Date accessed 31 July 2022.
3. Katanoda K, Hori M, Saito E, et al. Updated trends in cancer in
Japan: incidence in 1985e2015 and mortality in 1958e2018da
sign of decrease in cancer incidence. J Epidemiol 2021;31:
426e50.
4. Diaz DA, Reis IM, Weed DT, Elsayyad N, Samuels M,
Abramowitz MC. Head and neck second primary cancer rates in
the human papillomavirus era: a population-based analysis.
Head Neck 2016;38:E873e83.
5. Tabuchi T, Ito Y, Ioka A, Miyashiro I, Tsukuma H. Incidence of
metachronous second primary cancers in Osaka, Japan: update
of analyses using population-based cancer registry data. Can-
cer Sci 2012;103:1111e20.
6. Simple M, Suresh A, Das D, Kuriakose MA. Cancer stem cells and
field cancerization of oral squamous cell carcinoma. Oral Oncol
2015;51:643e51.
7. Chuang SC, Scelo G, Tonita JM, et al. Risk of second primary
cancer among patients with head and neck cancers: a pooled
analysis of 13 cancer registries. Int J Cancer 2008;123:2390e6.
8. Baxi SS, Pinheiro LC, Patil SM, Pfister DG, Oeffinger KC,
Elkin EB. Causes of death in long-term survivors of head and
neck cancer. Cancer 2014;120:1507e13.
9. Chen MC, Huang WC, Chan CH, Chen PT, Lee KD. Impact of
second primary esophageal or lung cancer on survival of pa-
tients with head and neck cancer. Oral Oncol 2010;46:249e54.
10. Iwatsubo T, Ishihara R, Morishima T, et al. Impact of age at
diagnosis of head and neck cancer on incidence of metachro-
nous cancer. BMC Cancer 2019;19:3.
11. Su WW, Chuang SL, Yen AM, et al. Risk for a second primary
hypopharyngeal and esophageal cancer after an initial primary
oral cancer. Oral Dis 2019;25:1067e75.
12. Warren S, Gates O. Multiple malignant tumors: a survey of
literature and statistical study. Am J Cancer 1932;16:1358e414.
13. Coca-Pelaz A, Rodrigo JP, Sua
´rez C, et al. The risk of second
primary tumors in head and neck cancer: a systematic review.
Head Neck 2020;42:456e66.
14. Hori M, Matsuda T, Shibata A, et al. Cancer incidence and inci-
dence rates in Japan in 2009: a study of 32 population-based
cancer registries for the Monitoring of Cancer Incidence in
Japan (MCIJ) project. Jpn J Clin Oncol 2015;45:884e91.
15. Mochizuki Y, Harada H, Ikuta M, et al. Clinical characteristics of
multiple primary carcinomas of the oral cavity. Oral Oncol
2015;51:182e9.
16. Chen MC, Chen PT, Chan CH, et al. Second primary esophageal
or lung cancer in patients with head and neck carcinoma in
Taiwan: incidence and risk in relation to primary index tumor
site. J Cancer Res Clin Oncol 2011;137:115e23.
17. Chen PT, Kuan FC, Huang CE, et al. Incidence and patterns of
second primary malignancies following oral cavity cancers in a
prevalent area of betel-nut chewing: a population-based cohort
of 26,166 patients in Taiwan. Jpn J Clin Oncol 2011;41:1336e43.
18. Hashibe M, Ritz B, Le AD, Li G, Sankaranarayanan R, Zhang ZF.
Radiotherapy for oral cancer as a risk factor for second primary
cancers. Cancer Lett 2005;220:185e95.
19. Min SK, Choi SW, Lim J, Park JY, Jung KW, Won YJ. Second
primary cancers in patients with oral cavity cancer included in
the Korea Central Cancer Registry. Oral Oncol 2019;95:16e28.
20. Ben Arie G, Shafat T, Belochitski O, El-Saied S, Joshua BZ.
Treatment modality and second primary tumors of the head
and neck. ORL J Otorhinolaryngol Relat Spec 2021;83:420e7.
21. Morris LG, Sikora AG, Patel SG, Hayes RB, Ganly I. Second
primary cancers after an index head and neck cancer: subsite-
specific trends in the era of human papillomavirus-associated
oropharyngeal cancer. J Clin Oncol 2011;29:739e46.
22. TiwanaMS, Hay J, Wu J, Wong F, CheungW, Olson RA. Incidence of
second metachronous head and neck cancers: population-based
outcomes over 25 years. Laryngoscope 2014;124:2287e91.
23. Tanaka S, Seto K, Kawakami K. Pharmacoepidemiology in
Japan: medical databases and research achievements. J Pharm
Health Care Sci 2015;1:16.
24. Rennemo E, Za
¨tterstro
¨m U, Boysen M. Impact of second pri-
mary tumors on survival in head and neck cancer: an analysis of
2,063 cases. Laryngoscope 2008;118:1350e6.
25. Tabuchi T, Ito Y, Ioka A, Nakayama T, Miyashiro I, Tsukuma H.
Tobacco smoking and the risk of subsequent primary cancer
among cancer survivors: a retrospective cohort study. Ann
Oncol 2013;24:2699e704.
26. Leo
´n X, Del Prado Venegas M, Oru
´s C, Kolan
˜czak K, Garcı
´aJ,
Quer M. Metachronous second primary tumours in the aero-
digestive tract in patients with early stage head and neck
squamous cell carcinomas. Eur Arch Oto-Rhino-Laryngol 2005;
262:905e9.
27. Day GL, Blot WJ, Shore RE, et al. Second cancers following oral
and pharyngeal cancers: role of tobacco and alcohol. J Natl
Cancer Inst 1994;86:131e7.
M. Matsui, K. Kawamura, K. Kano et al.
1054