Edited by: Alfredo Addeo, Geneva University Hospitals (HUG), Switzerland
Reviewed by: Dwight Hall Owen, The Ohio State University, United States; Monica Khunger Malhotra, University of Pittsburgh Medical Center, United States
*Correspondence: Weidong Hu,
This article was submitted to Thoracic Oncology, a section of the journal Frontiers in Oncology
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Research on patients with lung cancer as a second primary malignancy (LCSPM) remains limited. This study aims to determine the clinical characteristics, prognosis, and temporal relationship of other cancers to lung cancer in these patients.
This study retrospectively analyzed 3465 patients with dual primary cancers from the 5253 patients with LCSPM retrieved from the Surveillance, Epidemiology and End Results (SEER) database from 2010 to 2015.
2285 eligible patients were further analyzed in this study cohort with 59.3% of 1-year OS, 34.7% of 3-year OS, and 25.2% of 5-year OS. The most common first primary cancer (FPC) in dual primary cancer patients with LCSPM was prostate cancer, followed by female breast cancer and urinary bladder cancer. In the entire study population, the median interval between the two primary malignancies was 21 months (range: 3.5–52 months). Age, sex, FPC location, surgery, stage, and histology of lung cancer were regarded as independent prognostic factors for these patients. The prognosis of patients with urinary bladder cancer as FPC was the worst in the univariate (
Cancer patients still have the risk of developing a new primary lung cancer. Close, lifelong follow-up is recommended for all these patients. Early detection for surgical treatment will significantly improve the prognosis of dual primary cancer patients with LCSPM. The nomogram developed to predict 1-, 3-, and 5-year OS rates has relatively good performance.
Lung cancer poses a serious threat to public health due to its high morbidity and mortality. Nevertheless, little attention has been paid to multiple primary cancers (MPC) involving lung cancer. With the advancement of medical technology and the extension of survival time of cancer patients, more and more cancer patients develop one or more new primary malignant tumors in the same or other organs during follow-up. MPC involving lung cancer is common clinically. Depending on incomplete statistics, the incidence of MPC involving lung cancer ranges from 0.9% to 26.3% (
The clinical information of LCSPM patients was extracted from the SEER database between 2010 and 2015. We accessed the database using SEER*Stat 8.3.5 software (
Flow chart detailing the selection of the patients in this study.
In this study, overall survival (OS) was calculated from the diagnosis date of the second primary malignancy (lung cancer) to the date of the last follow-up or death in the SEER database. The OS of all variables were calculated using the Kaplan-Meier method. Survival curves were compared with the log-rank test. Simple random sampling was performed in version 3.6.0 of R software, and patients were randomly divided into a training cohort and a validation cohort at a ratio of 7 to 3. In the training cohort, the Cox proportional hazards model was utilized to estimate OS hazard ratio (HR) for prognostic factors, including age, sex, race, histology, location of FPC, the time interval between two primary cancers, AJCC stage, year of diagnosis, and surgery. All variables were first subjected to univariate Cox analysis, and then variables with
In total, 5253 patients with MPC involving lung cancer were extracted from the SEER database, and 3465 (66.0%) dual primary cancer patients with LCSPM were used to analyze FPC site distribution and the time interval between the two primary cancers. Furthermore, of the 3465 patients, 2285 had complete information and were randomly divided into a training cohort (
Demographic and clinicopathological characteristics of the training and validation cohorts.
Variables | Entire cohort (n=2285) (N, %) | Training cohort (n=1601) (N, %) | Validation cohort (n=684) (N, %) |
---|---|---|---|
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<65 | 622 (27.2) | 436 (27.2) | 186 (27.1) |
>= 65 | 1663 (72.8) | 1165 (72.8) | 498 (72.9) |
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Female | 877 (38.4) | 616 (38.4) | 261 (38.1) |
Male | 1408 (61.6) | 985 (61.6) | 423 (61.9) |
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White | 1862 (81.5) | 1303 (81.4) | 559 (81.7) |
Black | 252 (11.0) | 175 (10.9) | 77 (11.2) |
Other | 171 (7.5) | 123 (7.7) | 48 (7.1) |
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Adenocarcinoma | 863 (37.8) | 618 (38.6) | 245 (35.8) |
Squamous cell carcinomas | 510 (22.3) | 366 (22.9) | 144 (21.1) |
Small cell cancer | 213 (9.3) | 142 (8.8) | 71 (10.4) |
Others | 699 (30.6) | 475 (29.7) | 224 (32.7) |
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Prostate | 486 (21.3) | 331 (20.6) | 155 (22.6) |
Female Breast | 308 (13.5) | 210 (13.1) | 98 (14.4) |
Urinary Bladder | 238 (10.4) | 174 (10.9) | 64 (9.3) |
Others | 1253 (54.8) | 886 (55.4) | 367 (53.7) |
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Stage I | 843 (36.9) | 602 (37.6) | 241 (35.2) |
Stage II | 217 (9.5) | 159 (9.9) | 58 (8.5) |
Stage III | 414 (18.1) | 298 (18.7) | 116 (16.9) |
Stage IV | 811 (35.5) | 542 (33.8) | 269 (39.4) |
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No | 1511 (66.1) | 1048 (65.4) | 463 (67.6) |
Yes | 774 (33.9) | 553 (34.6) | 221 (32.4) |
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<24 | 1391 (60.9) | 986 (61.5) | 405 (59.2) |
24 - 47 | 695 (30.4) | 479 (30.0) | 216 (31.5) |
48 - 72 | 199 8.7) | 136 (8.5) | 63 (9.3) |
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2010 | 81 (3.5) | 59 (3.6) | 22 (3.3) |
2011 | 228 (10.0) | 166 (10.4) | 64 (9.3) |
2012 | 344 (15.1) | 239 (14.9) | 105 (15.4) |
2013 | 436 (19.1) | 301 (18.8) | 135 (19.7) |
2014 | 569 (24.9) | 394 (24.7) | 175 (25.6) |
2015 | 625 (27.4) | 442 (27.6) | 183 (26.7) |
Clinicopathological characteristics of dual primary cancers patients with LCSPM between 2010 and 2015.
Variables | 2010 (n = 81) | 2011 (n = 230) | 2012 (n = 344) | 2013 (n = 436) | 2014 (n = 569) | 2015 (n = 625) |
---|---|---|---|---|---|---|
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68.72 (11.44) | 70.50 (10.03) | 69.11 (10.60) | 70.18 (9.72) | 70.41 (9.60) | 70.53 (9.60) |
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Female | 37 (45.68) | 90 (39.13) | 127 (36.92) | 148 (33.94) | 212 (37.26) | 263 (42.08) |
Male | 44 (54.32) | 140 (60.87) | 217 (63.08) | 288 (66.06) | 357 (62.74) | 362 (57.92) |
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Adenocarcinoma | 28 (34.57) | 89 (38.70) | 128 (37.21) | 176 (40.37) | 208 (36.56) | 234 (37.44) |
Squamous cell carcinomas | 16 (19.75) | 53 (23.04) | 77 (22.38) | 93 (21.33) | 125 (21.97) | 146 (23.36) |
Small cell cancer | 8 (9.88) | 15 (6.52) | 37 (10.76) | 36 (8.26) | 52 (9.14) | 65 (10.40) |
Others | 29 (35.80) | 73 (31.74) | 102 (29.61) | 131 (30.05) | 184 (32.34) | 180 (28.80) |
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Prostate | 17 (20.99) | 46 (20.0) | 78 (22.67) | 92 (21.10) | 125 (21.97) | 128 (20.48) |
Female Breast | 17 (20.99) | 29 (12.61) | 39 (11.34) | 55 (12.61) | 72 (12.65) | 96 (15.36) |
Urinary Bladder | 7 (8.64) | 28 (12.17) | 34 (9.88) | 47 (10.78) | 67 (11.78) | 55 (8.80) |
Others | 40 (49.38) | 127 (55.22) | 193 (56.10) | 242 (55.50) | 305 (53.60) | 346 (55.36) |
|
4.11 (2.44) | 8.32 (4.99) | 14.93 (9.11) | 19.42 (12.34) | 24.21 (15.63) | 30.41 (19.84) |
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Stage I | 36 (44.44) | 89 (38.70) | 126 (36.63) | 150 (34.40) | 204 (35.85) | 238 (38.08) |
Stage II | 8 (9.88) | 25 (10.87) | 33 (9.59) | 44 (10.09) | 41 (7.21) | 66 (10.56) |
Stage III | 11 (13.58) | 45 (19.57) | 77 (22.38) | 71 (16.28) | 107 (18.80) | 103 (16.48) |
Stage IV | 26 (32.10) | 71 (30.87) | 108 (31.40) | 171 (39.22) | 217 (38.14) | 218 (34.88) |
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No | 47 (58.02) | 141 (61.3) | 213 (61.92) | 283 (64.91) | 395 (69.42) | 432 (69.12) |
Yes | 34 (41.98) | 89 (38.7) | 131 (38.08) | 153 (35.09) | 174 (30.58) | 193 (30.88) |
Continuous variables (age and interval) are presented as mean and standard deviation, and categorical variables are presented as numbers and percentages.
Among the 5253 LCSPM patients, 4437 were dual primary cancers, and 710 were triple primary cancers, 90 were four primary cancers, 14 were five primary cancers, and 2 were six primary cancers (
The site distribution of FPC. There were 76 sites of FPC, and the most common site was the prostate (722), followed by female breast (464), and urinary bladder (380) (excluding patients with the first primary cancer in the lung and bronchi). Only the location distribution of more than 40 cases was shown here.
Location of the first primary cancer (FPC) and median interval between two primary cancers.
Location of FPC | N (%) | Median interval (months) |
---|---|---|
Total | 3465 (100) | 21 |
Prostate | 722 (20.8) | 26 |
Female Breast | 464 (13.4) | 52 |
Urinary Bladder | 380 (11.0) | 24 |
Larynx | 137 (3.95) | 9.5 |
NHL - Nodal | 128 (3.69) | 17.5 |
Kidney | 127 (3.67) | 11 |
Melanoma of the Skin | 111 (3.20) | 40.5 |
Rectum | 87 (2.51) | 23 |
Corpus Uteri | 84 (2.42) | 11.5 |
Chronic Lymphocytic Leukemia | 84 (2.42) | 37.5 |
Tongue | 73 (2.11) | 18.5 |
Sigmoid Colon | 71 (2.05) | 24.5 |
Thyroid | 60 (1.73) | 29 |
Ascending Colon | 59 (1.70) | 31.5 |
NHL - Extranodal | 56 (1.62) | 18.5 |
Liver | 54 (1.56) | 30.5 |
Cecum | 50 (1.44) | 16 |
Stomach | 49 (1.41) | 15 |
Pancreas | 45 (1.30) | 3.5 |
Others | 625 (18.1) | 8.5 |
After a univariate Cox analysis of 1601 patients in the training cohort, the results showed that age, gender, histology, AJCC stage, FPC location, and surgery were all related to the survival prognosis of these patients (Log-rank test, all
Univariate and multivariate Cox analysis for these patients in the training cohort.
Variables | Univariate Cox analysis | P value | Multivariate Cox analysis | P value |
---|---|---|---|---|
HR (95% CI) | HR (95% CI) | |||
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<65 | Reference | Reference | ||
>= 65 | 1.18 (1.02-1.36) | 0.024 | 1.25 (1.08-1.45) | 0.003 |
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Female | Reference | Reference | ||
Male | 1.45 (1.27-1.65) | <0.001 | 1.28 (1.08-1.51) | 0.004 |
|
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White | Reference | — | ||
Black | 0.98 (0.80-1.20) | 0.865 | — | |
Other | 1.07 (0.85-1.35) | 0.558 | — | |
|
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Adenocarcinoma | Reference | Reference | ||
Squamous cell carcinomas | 1.21 (1.02-1.42) | 0.024 | 1.21 (1.03-1.43) | 0.022 |
Small cell cancer | 2.13 (1.73-2.62) | <0.001 | 1.34 (1.08-1.65) | 0.007 |
Others | 0.87 (0.74-1.02) | 0.089 | 1.13 (0.96-1.32) | 0.147 |
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Prostate | Reference | Reference | ||
Female Breast | 0.67 (0.53-0.84) | <0.001 | 1.21 (0.91-1.61) | 0.199 |
Urinary Bladder | 1.29 (1.03-1.61) | 0.024 | 1.53 (1.23-1.92) | <0.001 |
Others | 0.85 (0.72-0.99) | 0.046 | 1.35 (1.13-1.61) | <0.001 |
|
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Stage I | Reference | Reference | ||
Stage II | 1.74 (1.35-2.23) | <0.001 | 1.80 (1.44-2.32) | <0.001 |
Stage III | 2.70 (2.23-3.29) | <0.001 | 1.80 (1.46-2.21) | <0.001 |
Stage IV | 6.36 (5.39-7.51) | <0.001 | 3.90 (3.24-4.70) | <0.001 |
|
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No | Reference | Reference | ||
Yes | 0.22 (0.18-0.25) | <0.001 | 0.36 (0.30-0.44) | <0.001 |
|
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<24 | Reference | — | ||
24 - 47 | 1.08 (0.94-1.24) | 0.277 | — | |
48 - 72 | 0.86 (0.65-1.13) | 0.276 | — | |
|
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2010 | Reference | — | ||
2011 | 1.03 (0.74-1.45) | 0.852 | — | |
2012 | 1.06 (0.76-1.47) | 0.741 | — | |
2013 | 1.14 (0.83-1.58) | 0.424 | — | |
2014 | 1.06 (0.77-1.47) | 0.702 | — | |
2015 | 0.88 (0.63-1.22) | 0.441 | — |
Kaplan-Meier survival curves of overall survival based on age
Considering the great difference in biological behavior and prognosis between NSCLC and SCLC, we separately analyzed the survival of these patients. Age, gender, AJCC stage, FPC location, and surgery were all regarded as related to the survival prognosis of NSCLC patients (log-rank test, all
Kaplan-Meier survival curves of overall survival for NSCLC
A prognosis nomogram was developed to predict 1-, 3-, and 5-year OS rates on the basis of 1601 patients in the training cohort. The established nomogram included all statistically significant prognostic factors in the Cox proportional hazard model, involving age, gender, histology, AJCC stage, FPC location, and surgery (
Prognostic nomogram of overall survival in dual primary cancer patients with LCSPM. Nomogram to predict 1-, 3-, and 5-year OS rates of the patients. The factors of age, sex, histology, stage, location of FPC, and surgery were included in the model. Aden: adenocarcinoma; Squa: squamous cell carcinomas; SCLC: small cell lung cancer.
Evaluation of the prognostic nomogram. Calibration curves for 1-year
In recent years, with the continuous advancement of medical technology and the improvement of patient compliance, many cancer patients have been diagnosed with new primary malignant tumors in their lungs. In the past, a large number of studies have focused on single primary lung cancer or multiple primary lung cancer (MPLC), but there are few studies on lung cancer patients with other primary malignancies. To date, little is known about the regularity of the time interval between two primary malignancies and the prognosis of dual primary cancer patients with LCSPM. Thus, this study retrospectively analyzed the clinical characteristics of 3465 dual primary cancer patients with LCSPM extracted from the SEER database between 2010 and 2015, intending to improve the understanding of these diseases and provide a certain reference for future clinical work.
During the follow-up of cancer patients, clinicians tend to focus more on the organ where the primary tumor is located and other organs where the tumor is more likely to metastasize, which will inadvertently ignore the risk of developing a primary malignancy in other organs. Lung cancer, a malignant tumor with a high incidence rate and mortality rate, poses a serious threat to public health. Thus, it is of great clinical significance to clarify the common sites of FPC in LCSPM patients to improve the effectiveness of follow-up and vigilance of cancer patients. Through analysis of 185 patients with MPC involving lung cancer from Guangdong Lung Cancer Research Institute from 2005 to 2013, Li et al. found that colorectal cancer, esophageal cancer, and thyroid cancer were the tumors that most frequently accompanied lung cancer (
Definitely, understanding the time interval between two primary cancers can assist clinicians to develop better follow-up strategies for cancer patients. Li and his colleagues found that the median interval between two primary cancers in MPC patients was 41.2 months (
In this study, we observed that age, sex, histology, stage, and surgery were all closely related to the prognosis of these patients. Advanced age (> 65 years old) and being male were independent risk factors for patients. Compared with nonsurgical treatment, lung cancer-directed surgery could significantly improve OS of these patients, with 3-year OS rates of 18.0% and 66.0%, respectively. SCLC had the worst prognosis. The later the stage of lung cancer, the worse the prognosis. This was also in line with the findings of other studies (
Additionally, our study found that, since 2010, more and more cancer patients were diagnosed with another new primary tumor in their lungs. This trend was mainly related to the following points. First, the age of the population was prolonged. Second, more and more chemicals were coming into contact. The third was the influence of bad habits, such as cigarettes. The fourth were the advances in imaging technology and the increasing pace of life. Finally, an important factor was the increasing awareness of early lung cancer screening. Several studies (
Good prognosis evaluation is of great significance for the treatment and follow-up of cancer patients. Clinically, due to the lack of a relatively perfect scoring system, clinicians often make empirical judgments based on the patients’ age, AJCC stage and pathological results. As an emerging tool widely used in some clinical research (
Our study has the following advantages. First, we used the large sample size of the SEER database to determine the common sites of FPC and the median interval between the two primary malignancies in dual primary cancer patients with LCSPM, which was of great significance in improving the effectiveness of follow-up in cancer patients. Second, our study was the first attempt to use a nomogram to predict the survival of dual primary cancer patients with LCSPM, which included 2285 patients from the SEER database, and its data accuracy was up to 95% (
Admittedly, our study also has some shortcomings. First, the limitations of the SEER database widely discussed in previous studies (
In summary, dual primary cancer patients with LCSPM have approximately 59.3% of 1-year OS, 34.7% of 3-year OS, and 25.2% of 5-year OS, respectively. Systematic and periodic follow-up is recommended for all cancer patients, and other organs should not be ignored in the follow-up of cancer patients. Early detection for surgical treatment will significantly improve the prognosis of these patients.
Publicly available datasets were analyzed in this study. This data can be found here:
The present study was approved by the Institutional Research Committee of Zhongnan Hospital of Wuhan University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.
CS, WH, and SL: designed the study. CS, SL, and WH: reviewed relevant literature and drafted the manuscript. CS, QW, and YW conducted all statistical analyses. All authors contributed to the article and approved the submitted version.
This work was supported by Key Projects of Hubei Provincial Health and Family Planning Commission (WJ2017Z006) and Zhongnan Hospital of Wuhan University Science Technology and Innovation Cultivating Fund (cxpy2017041) and the 351 Talent Project of Wuhan University (Luojia Yong Scholars: SL).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This study used the Surveillance, Epidemiology, and End Results (SEER) database. We acknowledge the efforts of the National Cancer Institute in the creation of the database.
The Supplementary Material for this article can be found online at:
Evaluation of the prognostic nomogram. Calibration curves for 1-year
Univariate and multivariate Cox analysis for NSCLC and SCLC patients in the training cohort.
MPC, multiple primary cancers; MPLC, multiple primary lung cancers; LCSPM, lung cancer as a second primary malignancy; FPC, first primary cancer; SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer; OS, overall survival; HR, hazard ratio; SEER, Surveillance, Epidemiology, and End Results.