Clinical characteristics and survival of lung cancer patients associated with multiple primary malignancies
Clinical characteristics and survival of lung cancer patients associated with multiple primary malignancies
Shan Shan 1 2
Jun She 2
Zhi-qiang Xue 0 2
Chun-xia Su 2
Shen-xiang Ren 2
Feng-ying Wu 2
0 Department of Thoracic Surgery, PLA General Hospital , Shanghai , China , 4 Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine , Shanghai , China
1 Department of Respirology, Shanghai sixth people's hospital, Shanghai Jiaotong University , Shanghai , China , 2 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University , Shanghai , China
2 Editor: Rafael Rosell, Catalan Institute of Oncology , SPAIN
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: This work was supported by the National
Natural Science Foundation of China, Grant
number:81402381 (http://www.nsfc.gov.cn/) to
Fengying Wu. The funder had no role in study
design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Competing interests: The authors have declared
that no competing interests exist.
To investigate the characteristics and survival of lung cancer patients with additional malignant primary cancers.
Records of lung cancer patients newly diagnosed in Shanghai Pulmonary Hospital between
January 2000 and January 2010 were retrospectively reviewed. Patients with second pri
mary lung cancer and those with lung cancer only were included for detailed analysis.
Of 27642 newly diagnosed lung cancer patients, 283 patients (1.02%) suffered previous
additional primary cancers. Compared with single primary lung cancer, patients with
secondary lung cancer associated other primary cancers were more often women (female to
male ratio 1:1.72 vs 1:2.58, P = 0.018), older (64.2 vs 60.5 years old, P<0.001), more
squamous cell type (30.7% vs 20.5%, P = 0.004), less small cell (3.9% vs 15.5%, P<0.001) type,
at earlier stages (17.7% vs 11.0% for stage I, P = 0.014), and more frequently with family
history of cancers (7.8% vs 3.9%, P = 0.038). The most common previous primary cancers
observed were colorectal (22.0%), breast (18.4%), gastric (14.4%) and larynx cancers
(11.9%). Approximately 42.9% of patients were diagnosed with lung cancer 2 to 6 years
after diagnosis of initial primary cancers. The survival of patients with secondary lung cancer
associated other malignancies was not significantly different from those with single lung
cancer (P = 0.491), while synchronous multiple primary malignancies showed worse
prognosis compared with those with metachronous ones or single lung cancer (p = 0.012).
The possibility of second primary lung cancer should always be considered during the follow-up of related cancer types, especially those with family history of cancers. Patients with
secondary lung cancer associated other primary malignancies have non-inferior survival
than those with single lung cancer.
Multiple primary malignancies (MPMs) are defined as the formation of more than one
different tumors in the same or different organs synchronously or metachronously. Early detection
and improved treatments contribute to significantly prolonged survival time of cancer patients
and allow more cancer patients to live long enough to develop subsequent primary cancers[1±
3]. The occurrence of MPMs is related to genetic predisposition, exposure to same carcino
gens, chemotherapeutic agents and radiotherapy for previous primary cancers[
Investigation of MPMs may help us further understand risk factors for second primary cancers.
Lung cancer is the leading cause of cancer mortality in the world[5±7]. Prolonged survival
of cancer patients makes it possible to develop second primary lung cancer. Even though there
is adequate published data describing the clinical characteristics of patients with MPMs,
reports about lung cancer as a second primary cancer are rare. In the present study, we
identified possible risk factors of development to lung cancer as a secondary primary cancer in
MPMs and evaluated clinical characteristics and survival of patients with secondary lung cancer associated other MPMs.
Materials and methods
27642 lung cancer patients were newly diagnosed in Shanghai Pulmonary Hospital between
January 2000 and January 2010. All cancer diagnosis was confirmed by histopathological
examination. Of these patients, 283 cases were diagnosed other primary malignancies
previously. 283 patients with single lung cancer within the same period were randomly selected as
control group. We collected medical records and tumor registry information of these patients
after institutional review board approval (Medical Ethics Committee of Shanghai Pulmonary
Hospital). Epidemiological features, intervals and treatments for previous malignancies, family histories and prognosis were extracted and analyzed.
Second primary cancers diagnosed within 6 months after diagnosis of previous primary
cancers were termed as synchronous primary cancers, and diagnosed beyond6 months were
metachronous ones. Staging of lung cancer was determined by the seventh editions of the
TNM classification system of the Union for International Cancer Control. Patients were classi
fied into three groups according to the smoking status: never-smokers (0 pack year),
lightsmokers (<10 pack years), and smokers( 10 pack years, including former smokers and
current smokers). Family history of cancers was defined as cancer diagnosis in first-degree
relatives. Occupational history, including exposure to asbestos or other known carcinogens,
occupational exposure to dust or microscopic particles were also reviewed.
All data was shown as means or as percentage within groups. Differences of clinical characteristics were analyzed by two-sided Fisher's exact test. Categorical variables were analyzed by chi-square tests. Parameters included age, gender, smoking status, pathology, stage, and cancer history. The potential risk factors were analyzed with logistic regression models. Overall
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survival (OS) was calculated from the date of diagnosis to the date of death by Kaplan-Meier
method. It was considered statistically significant if p value was less than 0.05. Statistical
analyses were performed by SAS 9.3 (SAS Institute Inc., NC, USA) and SPSS 19.0 (IBM, NY, USA).
Among the27642 newly diagnosed lung cancer patients between January 2000 and January
2010, 283 (1.02%) patients had one or more additional previously diagnosed malignancies. As
shown in Table 1, clinical characteristics including mean age, gender, pathology, stage,
smoking status and family history were compared between lung cancer associated with other MPMs
group and single lung cancer group. The mean age of patients was 64.2 years old in MPMs
group and 60.5 years old in single lung cancer group, showing significant difference
(P<0.001). There were more female patients in MPMs group, with female to male ratio of
1:1.72 in MPMs group and 1:2.58 in single lung cancer group separately(P = 0.018). Regarding
pathological types, an obviously higher incidence of squamous carcinoma (30.7% vs 20.5%,
P = 0.004) and significantly lower incidence of small cell carcinoma (3.9% vs 15.5%, P<0.001)
were observed in MPMs group. Furthermore, there were more stage I patients in MPMs group
(17.7%)than in single groups (11%)(P = 0.014). Whereas no obvious difference was observed
in stage II (7.4% vs 5.7%, P = 0.384), stage III (29.3% vs 31.8%, P = 0.518) or stage IV (45.6% vs
51.6%, P = 0.124). Additionally, patients with MPMs were prone to have family history of
cancers (7.8% vs 3.9%, P = 0.038).Furthermore, no significant difference was found in smoking
status (43.5% vs 41.0%, P = 0.540) between two groups.
Additional primary malignancies in patients with lung cancer
Of 283 MPMs patients, 15 patients (5.3%) had synchronous tumors and 268 (94.7%) had meta
chronous tumors. All patients had one previous primary cancer in the synchronous group.
Whereas in the metachronous group, most of patients had one previous malignancy except 7
patients who had two previous primary cancers and 1 patient who had three previous
malignancies. Number and types of previous primary cancers were shown in Table 2 and Fig 1. It
was not surprising to find that colorectal (22.0%), breast (18.4%) and gastric (14.4%) cancer
were the most common primary cancers in the metachronous MPMs group, since these
cancers were of high morbidity in China. Interestingly, incidence of head and neck cancer
accounted for 20.9%,of which laryngeal cancer (11.9%), the morbidity of which was1.2%-1.6%
in China, presented to be fourth common cancer in lung cancer associated metachronous
MPMs. Melanoma, cervical and pancreatic cancers represented to be the least frequent cancer
types. Incidentally, none patients with prostate cancer and leukemia were observed in
metachronous MPMs. In the synchronous group, colorectal, bladder and liver cancers were
common cancers diagnosed synchronously with lung cancer. As for the small number of cases, we
couldn't conclude which cancers were more likely to accompany with lung cancer.
Intervals between lung cancer and additional primaries
In our study, the mean and median interval time between previous primary cancer and lung
cancer was 7.4±5.9 years and 6 years respectively, ranging from 0.75 to 40 years in
metachronous group. As shown in Table 3 and Fig 2, 42.9% of MPMs patients developed lung cancer 2
to 6 years after diagnosis of first primaries. Chances of developing lung cancer decreased as
time went by. The average intervals of different cancer types developing secondary lung cancer
were investigated. Result showed that gastric, thyroid and breast cancer presented to have
longest interval time, with the intervals of 9.3±3.0, 9.0±3.0 and 8.1±2.8 years separately, which was
obviously longer than cervical and liver cancer(3.9±1.9 and 3.2±1.8 years, P<0.05).
Treatments of previous malignant primaries
We analyzed treatments for previous primary cancers among metachronous MPMs patients.
In these 267 cases, 254 (95%), 91 (34%), 45 (17%) and 10 (4%) patients received surgery,
chemotherapy, radiotherapy and endocrine therapy respectively. Those who underwent
chemotherapy were more likely to be gastrointestinal cancer patients (47/91, 51.6%), and those who
underwent radiotherapy were more likely to be head and neck cancer patients (20/45, 44.4%)
and breast cancer patients (10/45, 22.2%). When we separated treatments into chemotherapy
alone, radiotherapy alone and chemo-radiotherapy, it was interesting that more squamous
cancer and less adenocarcinoma cell in radiotherapy alone group than in chemotherapy alone
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Cholecyst and Biliary ducts
Other intestinal tract
Synchronous n (%)
(n = 15), n (%)
group (37% vs 32% for squamous carcinoma, 42% vs 51% for adenocarcinoma separately,
P>0.05), but it failed to reach statistical significance.
Survival of patients with MPMs involving lung cancer
We further investigated the prognosis of lung cancer patients with previous primary cancers.
Survival data of 151 patients in metachronous group (calculated from diagnosis of lung
cancer), 9 patients in synchronous group and 254 patients in single lung cancer group were
analyzed separately. As shown in Fig 3, no significant difference was found in the overall survival
for patients in metachronous group when compared with single lung cancer group, with the
median survival of 14.32 months and 15.14months separately (P = 0.491). However, patients
with synchronous primary cancers had obvious inferior survival when compared with those
with metachronous primary cancers or single lung cancer (median OS: 7.78, 14.32 and 15.14
months, P = 0.012).
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Fig 1. Types of additional malignancies in patients with MPMs associated lung cancer.
Cancer survivors have a 14% increased risk of developing a second primary cancer compared
with the general population[
]. The incidence of MPMs has increased due to the prolonged
survival of cancer patients, increased awareness of the possibility of second malignancies, and
frequent use of sensitive screening procedures[
]. It was reported that the overall prevalence of
MPMs was between 0.73% and 11.7%[9±11]. But there were no reports addressed the incidence of lung cancer as a second primary malignancy. In the present study, we retrospectively
Fig 2. Proportion of patients with first primary cancer developed lung cancer within different
Fig 3. Survival of patients between metachronous group and synchronous group. Difference between
two groups was statistically significant (P = 0.001).
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analyzed the secondary lung cancer associated other MPMs in ten years and found that the
incidence of MPMs was 1.02%among all the lung cancer patients in Chinese patient
Characteristics of lung cancer involved MPMs
Previously, Watanabe et al reported that squamous cell carcinoma was the most frequent histo
logic type of lung cancer in patients with multiple primary malignancies between 1962 and
]. Liu et al. found that adenocarcinoma was the most frequent histologic type of lung
cancer with MPMs[
]. In our study, we found that adenocarcinoma presented to be the most
frequent histologic type, which was similar to Liu's study.
In terms of stage, stage I showed higher percentage in MPMs group, which may be attributed to the routine follow-up of previous malignancy and increased awareness of symptoms.
Possible risk factors for a second primary lung cancer associated with
Carcinogenesis is a multi-step and complex process. The development of MPMs might be
attributed to shared exposure to risk factors including environment, lifestyle, inherited genes,
or treatments of initial primary cancers. To investigate the possible risk factors for later
primary lung cancer, we analyzed age, gender, smoking status, genetic factors, previous cancer
types, occupational history, intervals and treatments for previous primary cancers in MPMs
Age is considered to be a risk factor for MPMs. The prevalence of MPMs was reported to be
5±12% for patients aged 50±64 years old, compared with 12±26% for those aged over 80 years
]. Geryk et al found that the highest burden of MPMs was among patients aged 50±69
]. In the present study, the average age of secondary lung cancer associated MPMs
was 64.2 years old, which was significantly higher than single lung cancer group (60.5 years
old), indicating that age added the risk of development of secondary lung cancer.
Tobacco smoking has been proved to increase the risk of MPMs. Cancer survivors with smoking history had a higher risk of MPMs compared with non-smokers[1, 15]. However, in our analysis, we didn't find any differences in smoking status between secondary lung cancer associated MPMs and single lung cancer patients.
It is well known that patients with family history of cancers would inherit genetic cancer
susceptibility, which increases the risk of MPMs[16±18]. For example, microsatellite instability
was noticed to more frequently occur in cases of MPMs than sporadic cancers[19±20].In the
present study, MPMs patients with secondary lung cancer were more often with history of
cancers. It was reported that impaired DNA damage repair contributed to the formation of
nonsmall cell lung cancer in MPMs patients since benzopyrene diol epoxide-induced DNA
damage were significantly higher in patients with MPMs[
]. It still needed further investigations
on specific genes involved in these processes.
Certain cancers might be associated with the increased risk of subsequent primary lung
cancer. Our results showed that patients who initially presented with colorectal, breast, gastric
and head and neck cancers were more liable to develop second primary lung cancer.
Furthermore, malignancies such as oral cavity, pharynx, larynx and lung cancers were reported in
patients previously diagnosed with similar malignancies because of smoking exposure[2, 21±
22]. Interestingly, head and neck cancer, especially laryngeal cancer, had strong association
with second primary lung cancer. Previously, Michael et al. found that patients with head and
neck squamous cell carcinoma were at high risk of developing second primary lung cancer,
with the risk of 5.8%, 11.4%, and 16.4% at 5, 10, and 15 years after diagnosis of head and neck
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cancer respectively. Smoking exposure and/or host factors may lead to obvious association
between these two cancer types[
]. Our recent data further validated these strong associations
and suggested that close monitoring should be carefully conducted in patients harboring these
Time intervals might be associated with the onset of secondary lung cancer. Liu et al
reported that about 59.9% of secondary lung cancer occurred within 5 years after the initial
diagnosis of the first cancer[
]. Scott et al reported that the risk for lung cancer may be elevated
within the first 4 years ofthe treatment of Hodgkin's disease[
], while others reported that the
increased risks is not apparent until the fifth year[
]. Our study showed that a big proportion
of secondary lung cancers were diagnosed within the 2nd to 6th years after the diagnosis of first
malignancy. Therefore, careful follow-up are necessary during this treatment interval.
Briefly, genetic predisposition, previous cancer treatments, smoking, lifestyles, and other aspects could act as risk factors in the developments of secondary lung cancer.
Survival of patients with multiple primary cancers varies depending on the method of
calculation and primary tumor types. Some studies reported no differences in survival when
comparing MPMs with single cancers[26±27], while some other reported worse prognosis for patients
with multiple primary cancers when calculating survival from the date of the second primary
]. For lung cancer as a second primary cancer, the 5-year survival for those with
metachronous primary cancers was 44% compared with 10% for those with synchronous
]. In the present analysis, survival of lung cancer associated with other MPMs
patients showed no significant difference with that of single lung cancer patients. However,
patients with synchronous cancers showed obviously worse survival than those with
metachronous cancers or single ones. Heavy tumor burden in synchronous lung cancer patients may
contribute to the worse prognosis.
In summary, secondary lung cancer associated other MPMs were more often women and
older, and those with family history of cancers. Second primary lung cancer was more likely to
develop in patients with initial primary cancers such as colorectal, breast, gastric and larynx
cancer, 2 to 6 years after the first primary malignancy diagnosis. Therefore, careful follow-up
are necessary during this treatment interval for patients with these cancers. Furthermore,
previously primary cancers did not seem to adversely impact the survival of patients with second
lung cancer, suggested that these patients should be treated appropriately and timely, especially
those with synchronous lung cancer patients.
S1 File. Original data of our study.
Conceptualization: Feng-ying Wu.
Data curation: Shan Shan, Jun She, Zhi-qiang Xue.
Formal analysis: Shan Shan, Jun She, Feng-ying Wu.
Funding acquisition: Feng-ying Wu.
Investigation: Shan Shan, Jun She, Chun-xia Su.
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Methodology: Shan Shan, Shen-xiang Ren, Feng-ying Wu.
Project administration: Feng-ying Wu.
Resources: Feng-ying Wu.
Software: Shan Shan, Jun She.
Supervision: Feng-ying Wu.
Validation: Shan Shan, Zhi-qiang Xue.
Visualization: Shan Shan, Feng-ying Wu.
Writing ± original draft: Shan Shan.
Writing ± review & editing: Shan Shan, Feng-ying Wu.
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