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Second Primary Tumors Involving
Non-small Cell Lung Cancer*
Prevalence and Its Influence on Survival
Christianne S.J. Duchateau, MD; and Marcel P.M. Stokkel, PhD
Objectives: Patients with lung cancer have a relative high risk for second primary cancers. We
studied the prevalence of second primary tumors in patients with a diagnosis of non-small cell
lung cancer (NSCLC) in their history or at follow-up. Furthermore, we studied survival in
subgroups of those patients.
Methods and patients: Retrospectively, 860 patients with NSCLC that had been diagnosed in the
period from January 1, 1990, to December 31, 1999, were evaluated for second primary cancers
either in their history or in the follow-up period. The patients were divided into the following four
groups: group I, patients with another primary tumor detected in the follow-up period (n ⴝ 44);
group II, patients with another primary tumor in their history (n ⴝ 148); group III, patients with
no other primary tumor found in their history or at follow-up (n ⴝ 634); and group IV, patients
with more than one other primary tumor in found in their history or at follow-up (n ⴝ 34).
Results: The most frequently diagnosed double tumors were located in the lungs, the head and
neck region, and the urinary tract. The interval between another malignancy as the first tumor
(group II, 83 months) and NSCLC as the second malignancy was significantly longer than vice
versa (group I, 14.5 months; p < 0.05). In > 80% of patients, the second primary tumors were
diagnosed within 1 year after NSCLC was diagnosed. The 5-year survival rate is significantly
better for patients with more than two primary malignancies compared to patients without two
primary malignancies and patients with one other tumor in their history (p ⴝ 0.004 and 0.012,
respectively). The 5-year survival rate in patients with a second tumor in the follow-up period was
better than in patients without any other second tumor (p ⴝ 0.029). As the TNM stage and
therapy were comparable in all subgroups, it could not be used as explanation for the difference
in survival rates.
Conclusion: In 25% of patients, additional tumors that were NSCLC were diagnosed either in
their history or in the follow-up period. The majority of second tumors following NSCLC are
diagnosed within 1 year. Nevertheless, patients with a second tumor tend to have an overall
better survival rate than patients without second primaries, suggesting different growth habits.
(CHEST 2005; 127:1152–1158)
Key-words: follow-up; non-small cell lung cancer; prognosis; second primary tumors
Abbreviations: NSCLC ⫽ non-small cell lung carcinoma
cancer is, after coronary heart disease, the
L ung
second leading cause of death in men in the
Netherlands. Due to advanced diagnostic tools for
detecting a malignancy in an earlier stage and to
better treatment of other diseases, more than one
primary tumor in one single person is becoming
*From the Department of Nuclear Medicine, Leiden University
Medical Center, Leiden, the Netherlands.
Manuscript received February 5, 2004; revision accepted November 29, 2004.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:
[email protected]).
Correspondence to: M.P.M. Stokkel, PhD, Department of Radiology, Division of Nuclear Medicine, Leiden University Medical
Centre, PO Box 9600, 2300 RC Leiden, the Netherlands; e-mail:
[email protected]
more and more prominent. An increased use of
cytostatic drugs may increase the overall risk for a
new primary malignancy.1 However, Rheingold et al2
have suggested that when cancer is not associated
with mortality and is equally distributed throughout
the population, approximately 33% of the population
(one in three persons) will develop a malignancy,
11% (one in nine persons) will develop a second
primary tumor, and so on. In this respect, there are
several cancers with the same etiology that are
known to occur more frequently than may be expected from cancer statistics (eg, breast cancer with
ovarian cancer, and head and neck cancer with lung
malignancies). From this point of view, it is interesting to know whether prognosis and survival are
different in subgroups of patients with a second
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Clinical Investigations
tumor either preceding or following a non-small cell
lung carcinoma (NSCLC) compared with patients
with a NSCLC as a solitary tumor.
In the literature, only a few studies3,4 have been
published on patients with an NSCLC as a secondary
or tertiary primary tumor and the influence on
survival in these patient groups. However, as far as
we know, no study has been published that compares
the clinical outcomes among patients with another
primary malignancy in their history, patients with
another tumor found in the follow-up period, patients with more than one other tumor in their
history, and patients without any other tumor. The
aim of the present study was to describe the patient
and tumor characteristics of patients with second
primary malignancies in association with NSCLC
and to investigate whether NSCLC patients with
another primary tumor, either in their history or in
the follow-up period, have a comparable survival rate
to patients without another primary tumor. In addition, we wanted to study the intervals between the
primary and second primary tumors to assess the
effect on follow-up strategies.
period of follow-up of at least 29 months for each patient. As end
points, we used death irrespective of cause or survival at the
census date.
Definition of a Second Primary Lung Tumor
To divide the tumors between synchronous tumors and metachronous tumors, we used the criteria defined by Martini and
Melamed,7 which are in agreement with most of the studies in
the literature describing second primary lung cancers. If tumors
are present at the same time, they must be separated and the
histology must be different. If both tumors have the same
histology, they are located in different lungs, lobes, or segments,
they have no common lymphatics, and there are no distant
metastases present, they are considered to be two independent
primary tumors. If these criteria are not met, the two tumors are
considered to be a primary tumor with a metastasis (stage IV
tumor). Tumors with the same histology must have an interval of
at least 2 years, originating from carcinoma in situ (CIS) or
without common lymphatics to be considered as metachronous.
Statistical Analysis
Quantitative variables were summarized with their mean or
median and SD. One-way analysis of variance and the ␹2 test
were performed where appropriate. Multivariate analysis with
respect to survival was performed with the Cox regression model.
Finally, survival curves of the different subgroups are presented
according to the Kaplan-Meier method. Throughout, a p value of
ⱕ 0.05 was considered to be statistically significant.
Materials and Methods
Retrospectively, we reviewed all NSCLC patients who received their diagnoses at the Leiden University Medical Center
in the period between January 1, 1990, and December 31, 1999.
We used the hospital information system and medical records to
collect data about these patients and their tumors. The database
we used was tumor related, and if more than one tumor was
diagnosed in one single patient, each tumor was registered
separately. In the database, the following parameters were
registered: (1) patient characteristics (ie, date of birth and
gender); (2) NSCLC characteristics (ie, date of diagnosing the
NSCLC, TNM classification, histology, therapy [surgery, radiation therapy, or chemotherapy]), and follow-up; (3) other malignancies with their characteristics (ie, date of diagnosis, histology,
TNM classification, site of the tumor, and therapy). The TNM
classification that was used for staging the NSCLC was according
to the revised criteria from the International System for Staging
Lung Cancer described by Mountain5,6 in 1997. The nonmelanoma skin cancers (ie, squamous cell carcinoma and basocellular
carcinoma) were not registered as a second primary tumor as these
were not supposed to have influence on prognosis and survival.
The patients were divided into four groups. The first group (I)
included patients with NSCLC as the first tumor and with a
second primary tumor in the follow-up period. The second group
(II) included patients with another primary tumor in their history
in whom the second primary tumor was NSCLC. The third group
(III) contained patients with the NSCLC as the only tumor, and
the fourth group (IV) contained patients with more than two
primary tumors in their history and/or in the follow-up period.
Patients with another tumor detected at the same time as the
NSCLC (simultaneous tumors) were added to group 2. To be
sure that two tumors were second primaries and not a primary
tumor with a metastasis, the tumors must have fulfilled the
criteria described in the next section.
We used May 1, 2002, as the census date, revealing a minimum
Results
During the previously described period, 860 new
NSCLCs were diagnosed at the Leiden University
Medical Center. A total of 316 patients had a history
of another malignancy or developed a secondary
primary in the follow-up period. In 90 patients, the
malignancy concerned a nonmelanoma skin cancer,
and, as described before, these tumors were not
registered as a secondary primary tumor. As a result,
a second primary tumor developed in 44 patients
(5.1%) during the follow-up period (group 1), 148
patients (17.2%) had another malignancy in their
history (group 2), and 634 patients (73.7%) had
NSCLC as their only malignancy (group 3). In 34
patients (4.0%), more than one other primary tumor
was found (group 4); 30 patients had three primary
tumors, and four patients had four primary tumors.
Five patients moved to another country 1,991,
822, 594, 18, and 348 days after the diagnosis of
NSCLC, and one patient was lost to follow-up 17
days before the census date. The patient characteristics of each group are summarized in Table 1. In
groups I and II, the second primary tumors were
most frequently located in the lungs, the head and
neck region, and the urinary tract (Table 2). In 64%
and 56%, respectively, the second tumor was located
in the organ systems mentioned above. In 10% of the
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Table 1—Patients’ Characteristics Related to the Subgroups Studied*
Characteristics
Group I
Group II
Group III
Group IV
Patients
Gender
Men
Women
Age at time of diagnosis NSCLC, yr
Age range, yr
Histology
Squamous cell carcinoma
Adenocarcinoma
Large cell carcinoma
Adenosquamous carcinoma
Others
Initial treatment
Surgery
Radiation therapy
Chemotherapy
Combination therapy
Surgery and chemotherapy
Surgery and radiation therapy
Radiation therapy and chemotherapy
All modalities
No treatment
Interval between two tumors, %
⬍ 1 mo
1–6 mo
6 mo–1 yr
1–2 yr
2–5 yr
5–10 yr
⬎ 10 yr
Overall interval,† mo
5-yr survival
Deceased after diagnosis of NSCLC, %
⬍ 1 mo
1–6 mo
6 mo–1 yr
1–2 yr
2–5 yr
5–10 yr
⬎ 10 yr
44 (5.1)
148 (17.2)
634 (73.7)
34 (4.0)
37 (84)
7 (16)
69
(52–82)
123 (83)
25 (17)
71
(27–97)
489 (77)
145 (23)
66
(28–87)
30 (88)
4 (12)
67
(47–82)
16
16
4
2
6
66
37
17
4
24
237
169
151
13
64
20
6
2
1
5
10
16
4
35
56
3
122
217
49
13
10
1
0
2
1
0
11
1
7
5
0
41
5
30
23
2
186
0
1
0
0
9
72.7
4.6
4.5
2.3
6.8
6.8
2.3
14.5 (1–131)
7 (15.9)
5.4
4.1
2.7
10.1
16.2
28.4
33.1
83 (1–402)
10 (6.8)
44 (6.9)
7 (20.5)
6.8
15.9
11.4
22.7
13.6
6.8
0
4.7
22.3
23.0
19.6
11.5
3.4
0
7.4
25.6
23.0
18.3
11.8
1.7
0.2
8.8
17.6
20.6
8.8
11.8
5.9
0
*Values given as No. (%), unless otherwise indicated.
†Values in parentheses are ranges.
patients (n ⫽ 15) with another malignancy preceding
NSCLC, the malignancy concerned a lymphoma,
leukemia, or myeloma.
Comparing the NSCLC tumor stage between
groups I and II, no significant difference was found
(p ⫽ 0.41) [Fig 1]. Even when the stages were
grouped into low stages (stage I and II) and high
stages (stage III and IV), we did not find a significant
difference (p ⫽ 0.32). Approximately half of the
patients with a NSCLC as the primary tumor had a
low-stage lung carcinoma (stage I or II) compared
with 42% for patients with a NSCLC as the second
primary tumor. In addition, in the group of patients
with no other tumor found either in their history or
during the follow-up period (group 3) 29% had
NSCLC as the second primary tumor. On the other
hand, ⬎ 65% of patients with a NSCLC as the
second primary tumor and a time interval between
the two tumors of ⬎ 10 years had a stage III/IV
tumor. Regarding the histologic data, a slightly significant difference was found between the groups
studied (p ⫽ 0.04). In group III, more large cell
carcinomas were found (24%) compared with the
other groups (group I, 9%; group II, 12%; group IV,
6%). In group IV, more squamous cell carcinomas
(59%) and fewer adenocarcinomas (18%) were seen,
whereas the prevalence of adenocarcinoma and
squamous cell carcinoma was equal in group I.
The time interval between the diagnoses of the
second primary tumor was significantly different
(p ⬍ 0.05) between group I (NSCLC as the first
tumor) and group II (NSCLC as the second tumor)
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Clinical Investigations
Table 2—Locations of Other Cancers Preceding or Following NSCLC*
Cancer Locations
Lung Cancer First (n ⫽ 44)
Other Cancer First (n ⫽ 148)
Total (n ⫽ 192)
Another lung cancer
Head and neck cancer
Uroepithelium
Prostate cancer
Colorectal cancer
Gastric cancer
Esophagus
Tracheal cancer
Breast cancer
Lymphoma/leukemia/myeloma
Sarcoma
Cervical cancer
Brain-hypophysis tumors
Melanoma
Pancreas tumor
Testis carcinoma
Thyroid cancer
Paraganglioma
Not further specified
14 (31.8)
9 (20.4)
5 (11.4)
2 (4.5)
2 (4.5)
0
1 (2.3)
2 (4.5)
2 (4.5)
1 (2.3)
0
0
2 (4.5)
1 (2.3)
1 (2.3)
0
1 (2.3)
1 (2.3)
0
39 (26.0)
30 (20.0)
15 (10.0)
9 (6.1)
7 (4.7)
3 (2.0)
1 (0.6)
1 (0.6)
7 (4.7)
15 (10.0)
4 (2.7)
5 (3.4)
5 (3.4)
3 (2.0)
0
2 (1.4)
0
1 (0.6)
1 (0.6)
53 (27.6)
39 (20.3)
20 (10.4)
11 (7.4)
9 (4.7)
3 (1.6)
2 (1.0)
3 (1.6)
9 (4.7)
16 (8.3)
4 (2.1)
5 (2.6)
7 (3.6)
4 (2.1)
1 (0.5)
2 (1.0)
1 (0.5)
2 (1.0)
1 (0.5)
*Values given as No. (%).
[Table 1]. The time interval between the two tumors
in group I was 14.5 months (range, 1 to 131 months)
[the simultaneous tumors excluded], and in group II
it was 83 months (range, 1 to 402 months). In
general, more than 80% of second primary tumors
were diagnosed within 1 year after the diagnosis of
NSCLC. In group II, 12.2% of the patients had an
interval ⬍ 1 year.
With respect to NSCLC treatment, we found no
statistically significant differences among the four
subgroups (p ⫽ 0.179). In this study, 29% of the
patients were not treated anymore, but the prevalence of nontreatment was equal in the subgroups
(Table 1).
Figure 2 shows the Kaplan Meier curves for
survival after the diagnosis of NSCLC in the four
different groups. Patients with NSCLC as the first
malignancy and another in the follow-up period
(group I) had a significantly (p ⫽ 0.011) better survival rate than patients without any other tumor
(group III). We also found a significantly better
survival rate for patients with more than one tumor
in their history (group IV), compared to patients with
no other tumors (group III) [p ⫽ 0.012]. In addition,
patients with another malignancy in their history
were found to have a significantly better 5-year
survival rate than patients without another tumor
(p ⫽ 0.029), whereas patients with more than two
primary tumors had a significantly better 5-year
survival rate compared with patients with another
tumor in their history (p ⫽ 0.004). In conclusion,
patients with a primary NSCLC as the solitary tumor
and no other tumors had the worst survival rate of
those in the groups studied.
Discussion
Figure 1. TNM classification of NSCLC presenting as a first or
second primary tumor, demonstrating no significant differences
between both groups (p ⫽ 0.41).
In the present study, we evaluated the prevalence
of second primary tumors in patients with NSCLC.
In this group consisting of 860 patients, approximately 1 in every 4 patients with NSCLC had
another primary tumor in their history, or developed
one or more second primary tumors during the
follow-up period. General patient characteristics, as
the percentage of men and the age at the time of the
diagnosis of NSCLC, were comparable in all groups.
The most frequent sites of the second primary tumor
were (in order of frequency) the lungs, the head and
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Figure 2. Survival curves of patients with NSCLC as a solitary tumor, as the first or second primary
tumor or patients with multiple tumors, demonstrating significant differences between subgroups
(p ⫽ 0.011).
neck region, and the uroepithelium. The time interval between the two primary tumors was significantly
shorter in patients with NSCLC as the first tumor
than in patients with NSCLC as the second tumor.
The poorest outcome was found in patients with
NSCLC as a solitary tumor, and this differed significantly from patients with a tumor found in the
follow-up period (group I) as well as from patients
with more than two primary tumors (group IV).
The prevalence of two or more malignancies in
one patient has increased over the past decades.
Several explanations can be given for the fact that
multiple primary tumors are being diagnosed more
and more, and are nowadays not an exception anymore. Due to better treatment options for other
diseases, such as heart and vessel diseases, the life
expectancy in men has increased, which definitely
affects the prevalence of malignancies in general. In
addition, the increased use of radiation therapy
and/or chemotherapy for the first tumor also seems
to increase the number of secondary cancers. Finally, an important theory often used to explain
multiple malignancies is the “field cancerization
theory,” which states that organ systems exposed to
the same carcinogenic agents have a greater chance
of transforming into a malignancy.8 For example, the
coincidence of lung cancer with head and neck
cancer and/or cancer of the bladder has been welldescribed. In this respect, smoking plays an important role as a carcinogenic agent in the etiology of
malignancies at these sites.9,10 Another example is
alcohol, a well-known risk factor for cancer of the
oral cavity and stomach.9 Beside the environmental
factors, hereditary factors also play an important role
in the genesis of cancer. More than 30 genes are
currently known to have potential roles in the development of a malignancy. The genes that are related
to an increased risk of (multiple) cancer are tumor
suppressor genes and DNA-repair genes.11
With respect to the prevalence of secondary cancers, percentages ranging from 1 to 4.6% are found
in the literature.1,12–14 The high prevalence in the
present study can be explained by the fact that
NSCLC was used as a primary selection criterion. In
the studies by Aydiner et al12 and Kaneko and
Yamaguchi,13 the prevalence of multiple cancers in
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general was reported, whereas Teppo et al1 and Levi
et al14 described the prevalence of second primary
tumors during the follow-up of patients with NSCLC
as being the first tumor. In the present study, the
percentage of secondary tumors diagnosed after
NSCLC was 5.1%, and this is more in agreement
with the percentages (range, 3 to 13.4%) cited in the
literature.15
In our data, ⬎ 50% of the second primary tumors
either preceding NSCLC (group II) or following
NSCLC (group I) were located in the lungs (27.6%),
the head and neck area (20.3%), or the urinary tract
(10.4%). These are all smoking-related tumors, and
the combination of these tumor sites is described
earlier in the scope of the field-cancerization theory.
Regarding all patients studied (n ⫽ 860 [groups I, II,
III, IV]), a second primary tumor was found in the
lungs in only 6.1% of the patients, either preceding
or following NSCLC, which is more in agreement
with previously published data.16 –18
The Kaplan-Meier curves show a significantly
better survival rate for patients with another tumor
in the follow-up period (group II) compared to
patients without any other secondary primary tumor
(group III) [p ⫽ 0.011]. Also, patients with more
than two primary tumors (group IV) were found to
have a significantly better survival rate than patients
with NSCLC as the single tumor (group III)
[p ⫽ 0.012]. Our results are in contrast to those of
Koppe et al,19 who did not find any difference in
survival between patients with NSCLC and another
tumor in their history, and patients with a second
primary tumor found in follow-up period after
NSCLC, measured from the date of the thoracotomy. However, in that study, only patients were
selected who had undergone surgery for NSCLC.
One of the limitations of the present study is that we
were not able to register the cause of death in the
subgroups. Due to its retrospective character, risk
factors such as smoking, alcohol intake, and cardiovascular disease were not consistently recorded or
available. Nevertheless, as the number of resected
cancers is comparable in all groups, our results
suggest that patients with two or more cancers have
a predisposition to have tumors with a rather slow
progression.
In the present study, in approximately 40% of the
patients in group II NSCLC was diagnosed as a
second primary tumor within 5 years after the diagnosis of the first tumor. In contrast, in patients in
whom a new malignancy developed after the diagnosis of NSCLC, approximately 90% of malignancies
were diagnosed within the first 5 years, and even
81.8% were diagnosed within the first year of the
follow-up period. The different time intervals between the subgroups are probably related to differ-
ent mechanisms inducing second primary tumors.
Although the field-cancerization concept cannot be
ruled out, it seems that the rather long mean interval
between the diagnoses of the two primary tumors in
subgroup II may be related to the cancer treatment
for the first tumor. Indeed, many studies have
pointed to a relation between lung cancer following
chemotherapy and radiotherapy.20 –23 In these studies, a statistically significant increase in lung cancer
was found, which appears 1 to 4 years after chemotherapy and 5 years after radiotherapy. An overall
27.3-fold increased risk of developing lung cancer
was reported in patients treated with radiotherapy.
In addition, the reported median time to the diagnosis of lung cancer in these series was approximately 26 years. The hypothesis of therapy-related
NSCLC is supported by the increasing incidence of
second tumors during the follow-up period, as shown
in Table 1. As in group I, the incidence of second
primary tumors per year is relatively constant during
the follow-up period, so the field-cancerization concept may fit better. The continuous stimulation by
tobacco and alcohol seems to induce an expanding
preneoplastic field as the first and critical step in the
epithelial carcinogenesis. It has been shown by Braakhuis and colleagues8,24 that clonal divergence in this
field leads to the development of one or multiple
tumors with a rather constant rate over years. In this
respect, our results are in agreement with the data
published by Liu et al.25 They also found that the
time interval in the group with NSCLC as the second
tumor is significantly longer (46 months) compared
to the group with NSCLC as the primary tumor (10
months; p ⬍ 0.001).
A parameter that was expected to be important for
the prevalence of secondary primaries was the stage
of the primary tumor, derived from the TNM criteria. However, we did not find a significant difference
in distribution in the tumor stages between the
groups. In our population, 52% of the patients with
NSCLC as the first presenting tumor had a low-stage
carcinoma (stage I or II), compared to 42% in group
II. In the group of patients without any other tumor
(group III), it was only 29%. In contrast to our
results, Liu et al25 found a significant difference in
tumor stages, as 53% of the patients with NSCLC as
the first primary tumor had a stage I/II tumor, and
only 25% of the patients with NSCLC as the second
primary tumor had a stage I/II tumor.
Finally, regarding the histologic data, we found a
significant difference between the groups studied
(p ⫽ 0.04). Regarding the data found in the literature, however, it is hard to draw any conclusion. In
an article by Travis et al,22 describing lung cancer
following treatment for Hodgkin disease, they found
a prevalence of squamous cell carcinoma, adenocar-
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1157
cinoma, large cell tumors, and other carcinomas of
39.2%, 21.6%, 9%, and 14%, respectively. It was
concluded that following therapy with alkylating
agents, the risk of squamous cell lung cancer was
only statistically elevated. Regarding radiation therapy, significantly increased risks for all designated
morphologic groups occurred. With respect to the
risk of new primary tumors following lung cancer,
Teppo et al1 found a larger excess of new primary
tumors among patients with adenocarcinoma than
those with squamous cell carcinoma. In contrast,
however, Levi et al14 suggested that the increased
risk was comparable for patients with both tumors. It
has to be realized that in both studies, small cell lung
cancer was included, whereas in the study by Teppo
et al1 a high percentage of patients was included with
cytologic confirmation of malignancy but without
histology (30%).
It can be concluded that second or multiple
primary tumors are commonly seen in patients with
NSCLC, either preceding or following its occurrence. As approximately 80% of the second primary
tumors following NSCLC are diagnosed within the
first year, a thorough workup protocol is recommended that should focus on both the staging of
NSCLC as well as on the detection of other related
tumors (eg, smoking-related tumors), such as head
and neck tumors, lung tumors, and urinary tract
tumors. Further studies are required to assess the
role of more sophisticated imaging techniques, such
as fluorodeoxyglucose positron emission tomography, in the early detection of second primary tumors
in relation to the costs and consequences for treatment and survival. Moreover, as the present study
suggests a difference in the growth habits of NSCLC
between patients with and without second primary
tumors, studies should focus on this aspect to get a
better understanding of this possible prognostic feature.
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