SIRs for EC
A total of 44172 patients were diagnosed with EC in the SEER 18 Program database between 2000 and 2016. The characteristics of these patients with EC are shown in Figure 1. Of these cases with EC who were followed for a total of 85011.69 person-years at risk, 424 developed a SPLC. SIR was utilized to evaluate the incidence of SPLC. In comparison with the general population, higher rates of SPLC occurred among patients with EC (SIR = 1.86, 95% CI:1.69-2.05). The risk of developing SPLC was statistically significantly elevated in all subgroups when grouped cases with SPLC according to different standards.
Compared with male EC patients, female had the higher risk for a SPLC, with statistical significance. The risk of developing a SPLC was significantly lower in white patients (SIR 1.74, 95% CI: 1.56-1.93) than black patients (SIR 3.02, 95% CI: 2.31-3.87). For an analysis by latency, the risk (SIR) for a SPLC increased progressively with advancing latency, but with no significant difference. The maximum risk (SIR) was seen for EC patients younger than 50 years (SIR 4.97, 95% CI: 2.78-8.2), which was significantly higher than the risk for patients aged 60-69 years (SIR 2.11, 95% CI: 1.81-2.44) and older than 70 years (SIR 1.29, 95% CI: 1.08-1.51). We noted that there was no significantly increase on the risk (SIR) developing a SPLC during study periods by patient’s year of EC diagnosis.
Patient and Tumor Characteristics
Table 1 outlines the patient and EC characteristics for patients with SPLC at time of diagnosis of EC. Among the SPLC histological subtype groups, the distribution of sex, race, latency, age at EC diagnosis, year of EC diagnosis, stage of EC, site of EC and surgery for EC was similar. The SPLC histological subtypes were associated with histological subtype (P = 0.004) and grade (P = 0.005) of EC (Table 1 and Supplementary Table 1). Patients with secondary primary lung squamous carcinoma after EC (EC-LUSC) were more likely to have a history of esophageal squamous carcinoma (ESC) as 54.0% of them had a history of ESC (SAR = 3.1). Similarly, patients with secondary primary lung adenocarcinoma after EC (EC-LUAD) were more likely to have a history of esophageal adenocarcinoma (EAD) as 58.7% of them had a history of EAD (SAR = 2.6). Individuals with EC-LUAD tended to have a lower grade of EC (53.8%, SAR = 2.8), while individuals with EC-LUSC tended to have a higher grade of EC (68.6%, SAR = 2.9).
Table 2 outlines the baseline characteristics of EC-LUSC and LUSC-1 patients. There was a nonsignificant difference with regard to race, age at lung squamous carcinoma (LUSC) diagnosis and surgery for LUSC between the EC-LUSC and LUSC-1 patients. There was a significantly different distribution of year of LUSC diagnosis (P < 0.001) (Table 2 and Supplementary Table 2). SARs demonstrated that EC-LUSC were more prevalent than LUSC-1 in individuals diagnosed from 2010 to 2016. In addition, sex differed significantly depending on the type of LUSC (P = 0.010), with patients with EC-LUSC more likely to be male. We found a statistically significant difference with respect to grade of disease between the EC-LUSC and LUSC-1 patients (P = 0.008). In comparison with LUSC-1 patients, EC-LUSC patients were more likely to be diagnosed at the well differentiated grade (8.6%, SAR = 2.8). Conversely, LUSC-1 patients tended to be diagnosed at the poorly differentiated and undifferentiated grade (54.4%, SAR = 2.2). There was a significant relationship with regard to stage between the EC-LUSC and LUSC-1 patients (P < 0.001). Patients with EC-LUSC tended to be diagnosed at an earlier stage compared with patients with LUSC.
Table 2 outlines the baseline characteristics of EC-LUAD and LUAD-1 patients. There were no significant differences with regard to surgery for lung adenocarcinoma (LUAD) between the EC-LUAD and LUAD-1 patients, which were similar to the results in the LUSC cohorts (including EC-LUSC and LUSC-1 patients). We found a statistically significant difference with respect to sex, race, age at LUAD diagnosis, year of LUAD diagnosis, stage of LUAD, grade of LUAD, and surgery for LUAD between the EC-LUAD and LUAD-1 patients (Table 2 and Supplementary Table 3). Patients from other races in the EC-LUAD group were more prevalent than those in the LUAD-1 group. Patients with LUAD-1 were more likely to be diagnosed at a younger age than patients with EC-LUAD. Compared with LUAD-1, EC-LUAD were more prevalent in individuals diagnosed in recent years (2010 to 2016). There was a significantly different distribution of sex, with individuals with EC-LUAD tending to be male (P < 0.001). However, the male-female ratio approximately turned out equal for individuals with LUAD-1. In addition, we found that EC-LUAD was significantly more likely to be of lower grade compared with LUAD-1 (P = 0.028). SARs demonstrated that EC-LUAD patients with grade I (well differentiated grade) were more prevalent than LUAD-1 patients with grade I, while EC-LUAD patients with grade III/IV (poorly differentiated and undifferentiated grade) were less prevalent than LUAD-1 patients with grade III/IV. Moreover, The stage of LUAD differed significantly between the EC-LUAD and LUAD patients (P < 0.001). SARs showed that the prevalence of EC-LUAD patients with localized stage was higher, while that with distant stage was lower. Supplementary Table 4 outlines the baseline characteristics of secondary primary small cell lung cancer after EC (EC-SCLC) and the first primary small cell lung cancer (SCLC-1) patients. We did not find a statistically significant difference with regard to race, age, sex, grade and stage between the SCLC-1 and EC-SCLC patients. However, there was a significant difference with respect to year of diagnosis (P = 0.007) (Supplementary Table 4 and Supplementary Table 5). Compared with SCLC-1 patients, EC-SCLC patients were more prevalent in individuals diagnosed earlier this decade (2000 to 2004).
Survival
Supplementary Table 6 shows the comparisons of crude survival statistics between EC-LC and LC-1 patients. The leading cause of death among SPLC patients regardless of pathologic types was LC. In comparison with individuals with EC-LUSC, those with LUSC-1 experienced relatively fewer deaths from other cancers, with similar results in patients with other LC pathologic types.
KM methods were used to compute the survival analyses for LUSC and LUAD among survivors of EC and individuals with LC-1 (we did not conduct the survival analyse for SCLC because of sample limitations). A comparison of the unadjusted OS between LUSC-1 and EC-LUSC patients is shown in Table 3. For individuals with LUSC of localized, regional, and distant stage, the median OS of individuals with LUSC-1 was 40 months, 18 months and 7 months, while the median OS of individuals with EC-LUSC was 20 months, 14 months and 7 months, respectively. In comparison with LUSC-1 patients in localized stage, the survival rate of EC-LUSC patients in localized stage was significantly lower (P < 0.001). However, these differences in other stages were not found to be statistically significant (regional, P = 0.140; distant, P = 0.229). Six-month, one-year, two-year and three-year survival rates for EC-LUSC patients in localized stage were 81.0%, 55.3%, 46.7% and 29.5%, respectively. And six-month, one-year, two-year, three-year, five-year and ten-year survival rates for LUSC-1 patients in localized stage were 89.7%, 79.5%, 63.9%, 53.3%, 40.0% and 19.7%, respectively. A comparison of the unadjusted OS between LUAD-1 and EC-LUAD patients is shown in Table 3. For individuals with LUAD of localized, regional, and distant stage, the median OS of individuals with LUAD-1 was 81 months, 33 months and 8 months, while the median OS of individuals with EC-LUAD was 30 months, 34 months and 7 months, respectively. In comparison with the survival rate of LUAD-1 patients in localized stage, the one of EC-LUAD patients in localized stage was significantly lower (P < 0.001).
Then multivariable analysis was performed applying a Cox regression modeling to assess the effect of a history of EC in patients with localized stage. We applied this model adjusted for sex, race, age at LC diagnosis, year of LC diagnosis, grade of LC, and surgery for LC. For LUSC in localized stage, results are presented in Table 4 for the 19531 individuals with complete information on all variables as well as subsequently using multiple imputation method for all 24760 individuals. For LUAD in localized stage, results are presented in Table 4 for the 36100 individuals with complete information on all variables as well as subsequently using multiple imputation method for all 44615 individuals. A history of EC was found to be a poor-prognostic factor for LUSC and LUAD patients in localized stage. For LUSC in localized stage, the hazard ratio (HR) for a history of EC was 2.49 (95% CI, 1.75-3.54) in the analysis of the 19531 individuals with complete information and was 1.91 (95% CI, 1.48-3.05) in the analysis of the 24760 individuals by using multiple imputation method. For LUAD in localized stage, the HR for a history of EC was 2.63 (95% CI, 1.71-4.03) in the analysis of the 36100 individuals with complete information and was 2.13 (95% CI, 1.48-3.05) in the analysis of the 44615 individuals by using multiple imputation method. For purpose of reducing the error generating by misdiagnosis of synchronous primary cancers as SPLC and misclassification of metastatic disease as SPLC, we omitted cases with <one-year and <two-year latency to SPLC diagnosis. Whether in LUSC in localized stage or in LUAD in localized stage, results after omitting patients with <one-year and <two-year latency were not changed obviously.
Propensity score-matching analysis was performed to re-evaluate the effect of a history of EC in patients with localized stage. For LUAC in localized stage, a total of 205 patients (41 EC-LUSC patients and 164 LUSC-1 patients) were included after propensity matching. Subsequent KM analysis (Figure 2) and multivariate analysis redemonstrated that a history of EC was a poor-prognostic factor for LUSC (median OS, 20 versus 56 months; HR, 2.37 (95% CI, 1.56-3.60), P < 0.001). A similar result was found for LUAD in localized stage. A total of 192 patients (39 EC-LUAD patients and 153 LUAD-1 patients) were included after propensity matching. Subsequent analyses (Figure 2) showed again that a history of EC correlated with worse prognosis for localized stage LUAD (median OS, 29 versus 110 months; HR, 3.24 (95% CI, 1.84-5.69), P = 0.012).