Postoperative Management of Multiple Primary Cancers Associated with Non-small Cell Lung Cancer

Discussion

Recent advances in less-invasive surgery, anesthesia, and perioperative management enable patients with lung cancer with preoperative comorbidities to achieve acceptable long-term survival (14). Because of carcinogens, environmental or hereditary factors, patients with a history of lung cancer are at risk for MPC (2, 7). Thus, it is necessary to follow lung cancer patients adequately to detect MPC.

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Figure 5.

Forest plot of hazard ratios (HR) for risk factors for patients with multiple primary cancers in the LCF group. COPD: Chronic obstructive pulmonary disease; IP: interstitial pneumonia; IPF: idiopathic pulmonary fibrosis; 95%CI: 95% confidence interval.

The emphasis of the present study was on the following points: First, the frequency of MPC was 15.2% in lung cancer patients who underwent surgery. The percentage of patients with MPC associated with lung cancer has recently increased, and several studies report similar percentages (>10%) of MPC (8, 15). Generally, patients with metachronous cancer have a better prognosis compared with those with synchronous tumors because of careful postoperative follow-up of the initially detected cancer (6). Moreover, Aguiló et al. (8) found that multiple cancers are not significantly associated with worse prognosis. Similarly, our present results do not indicate a significant difference between the prognosis of patients without MPC, metachronous cancer, or synchronous cancer. Therefore, thorough screening designed to diagnose MPC, at the earliest, may lead to increased long-term survival of these patients.

Second, advanced age and respiratory comorbidities, mainly COPD and sublobar resection for lung cancer, were risk factors for the occurrence of MPC. Further, our subgroup analysis reveals that patients with LCF with COPD had a 5-fold higher prevalence of MPC compared with those without COPD. There is a close association between COPD and the development of lung cancer (16), and smoking is the most important independent risk factor of cancer multiplicity (5, 8, 9, 17). Although patients with COPD patients had a history of smoking, our data reveal that only COPD was a risk factor for MPC.

This result may be explained as follows: Among the 97 patients with COPD studied here, the amount of tobacco use of 86 patients (88.7%) according to the Brinkman Index (BI) was analyzed. The BI of 71/86 patients (82.6%) was >400, indicating heavy smoking. Thus, COPD was likely the result of heavy smoking, indicating that this habit is a risk factor for MPC. In contrast, an emphysematous change may not always be recognized in patients with a history of smoking. Henschke et al. (18) found CT findings of emphysema in never smokers and that their emphysema could be caused by secondhand tobacco smoke. Therefore, never-smoking LCF patients who exhibit emphysematous changes should be carefully checked and CT should be used to detect MPC.

The identification of sublobar resection as a risk factor for MPC in the present study may be explained by the selection of patients with early-staged lung cancer who underwent this treatment. Moreover, 143/161 patients (88.8%) were diagnosed with pathological stage I NSCLC. Therefore, MPC may occur in long-term survivors of early-stage NSCLC, which supports the findings of a previous study, which shows that the probability of developing a second cancer depends on surviving a first cancer (8).

Third, the leading sites of MPC in synchronous and patients with OCF were digestive organs, consistent with findings from previous studies (5). Li et al. (6) found that lung cancer in Korean subjects is closely associated with digestive cancers because of smoking and that the most frequent sites (44.0%) of MPC are digestive organs such as the stomach and colorectum (15). In contrast, in this study the leading site of MPC in patients with LCF was the lung, which is consistent with previous reports (2, 5, 19). Thus, it is important to recognize that the major site of MPC differs between patients with OCF or LCF. Therefore, surgeons and oncologists should pay special attention to the incidence of cancers of digestive organs and the lung to optimize postoperative management.

Fourth, in patients with LCF, at least two primary lung cancers were detected within the first 5 years after surgery to treat the first detected lung cancer and thereafter, while primary cancers of other organs were detected within 5 years. Liu et al. (5) found that >50% of patients had multiple primary cancers within 1 year of diagnosis of the first lung cancer, and 83.4% of the patients experienced an occurrence within 5 years. Duchateau et al. (2) found that approximately 80% of second primary cancers identified after NSCLC are diagnosed within the first year. Reinmuth et al. (20) found that leading site of MPC in patients with LCF is the lung (56.2%), and the median interval between diagnosis of the first and secondary lung cancers is 72 months. Surapaneni et al. (7) found that the risk of developing a second lung cancer is highest during the first year and continues to occur at a high frequency 10 years after treatment of the first lung cancer. Further, there is an increased risk of gastrointestinal cancers such as esophageal cancer, gastric cancer, and colorectal cancer after the diagnosis of lung cancer during the first few years, which gradually decreases to that of the general population because of risk mitigation, including smoking cessation and occupational changes (7). These results are consistent with our present findings.

The National Comprehensive Cancer Network's guidelines recommend conducting surveillance for NSCLC as follows: medical history, physical examination (H&P), and chest CT every 6 to 12 months for the first 2 years, followed by annual H&P and chest CT. In the present study, the leading site of metachronous primary cancer was the lung; however, other organs were not excluded as metachronous sites. Our data indicate the requirement for careful long-term follow up, and it may be necessary to establish a thorough postoperative screening plan to examine the lungs as well as other organs.

Our retrospective results are valuable and informative for surgeons and oncologists. However, a limitation of the present study was that it was a retrospective study of patients treated at a single institution. Thus, large and multicenter clinical trials using adequate postoperative screening plans designed to detect MPC will be required.

In conclusion, a series of MPC were found to be associated with lung cancer. Patients of advanced age, those with COPD, or those who underwent sublobar resection for lung cancer may represent high-risk groups for MPC. Therefore, careful follow-up is recommended to detect MPC of the lung and other organs even as long as 5 years after treatment of the first cancer.