Impact of a Contralateral Tumor Nodule on Survival in Non-Small-Cell Lung Cancer

Abstract

Introduction: Contralateral lung tumors in non-small-cell lung cancer (NSCLC) are classified as stage M1a yet may represent hematogenous metastases or synchronous primary tumors. The impact of these tumors on overall survival (OS) is poorly understood. Here, we aim to determine whether NSCLC patients with M1a disease due only to a contralateral tumor nodule exhibit a favorable prognosis relative to other M1a or M1b patients.

Methods: Retrospective evaluation of the impact of contralateral tumor nodules on OS in NSCLC stratified by primary tumor size and N stage attained from Surveillance, Epidemiology, and End Results database.

Results: Of 173,640 patients, 5161 M1a-contra patients were identified. Median and 3-year OS for these patients exceeded that of patients with M1b (p < 0.0001) or other M1a disease (p < 0.0001). Primary tumor size and N stage were strongly associated with OS in M1a-contra patients. Three-year OS demonstrated a delayed convergence between M1a-contra and other M1a patients with primary tumors greater than or equal to 3 cm or mediastinal lymph node involvement. Proportional hazard modeling indicated that T1-2N0-1M1a-contra patients exhibit OS not significantly different (p = 0.258) from that predicted with comparable T and N stage disease plus a second early-stage primary.

Conclusions: Contralateral tumors in NSCLC carry a more favorable prognosis than other M1a or M1b disease. Primary tumor size and N stage may help distinguish M1a-contra patients with hematogenous metastasis from those with a synchronous, second primary.

Figure 1. Overall survival of patients with NSCLC stratified by extent of disease

Patients from the SEER database with NSCLC were sub-divided as indicated based on extent of disease. Kaplan-Meier OS curves (solid lines) are shown with 95% confidence intervals (shaded) (log-rank p < 0.0001). Intergroup comparisons demonstrate that M1a-contra patients exhibit improved survival compared to those with other M1a or M1b disease but inferior survival compared to M0 patients (p < 0.0001 for all).

Figure 2. Overall survival of patients with NSCLC grouped by primary tumor size

Patients were sub-divided by extent of disease and grouped based on primary tumor size: A) ≤ 2 cm, B) 2.1 – 3 cm, C) 3.1 – 5 cm, D) 5.1 – 7 cm, E) > 7 cm. Kaplan-Meier OS curves (solid lines) are shown together with 95% confidence intervals (shaded), (log-rank p < 0.0001 for each graph). F) Regardless of primary tumor size, M1a-contra patients exhibit improved survival compared to those with other M1a and M1b disease and inferior survival compared to M0 patients (p < 0.0001 for all except primary tumor > 7 cm M1a-contra vs other M1a, p = 0.0033). Improved three year OS is observed for M1a-contra patients compared to other M1a patients for primary tumors ≤ 2cm or 2.1–3 cm (p < 0.0001 each) but not for larger primaries (3–5 cm p = 0.2450; 5–7 cm p = 0.5688; > 7 cm p = 0.1018).

Figure 3. Overall survival of patients with NSCLC grouped by N-stage

Patients were segregated by extent of disease and grouped based on N-stage: A) N0, B) N1, C) N2, or D) N3. Kaplan-Meier OS curves are shown (solid line) together with 95% confidence intervals (shaded) (log-rank p < 0.0001 for each graph). E) Regardless of N-stage, M1a-contra patients exhibit improved survival compared to patients with other M1a and M1b disease and inferior survival compared to patients with M0 disease (p < 0.0001 for all intergroup comparisons). Improved median survival translates to a durable improvement in three year OS for M1a-contra patients compared to those with other M1a disease in the context of N0 – N2 disease (N0 p = < 0.0001; N1 p = 0.0143; N2 p = 0.0034) but not with N3 disease (p = 0.2501).

Figure 4. Comparison of overall survival between NSCLC patients with N0-1M1a-contra and those with N3M0 disease

Patients with N0-1M1a-contra or N3M0 disease were grouped based on primary tumor size: A) ≤ 2 cm, B) 2.1 – 3 cm, C) 3.1 – 5 cm, D) 5.1 – 7 cm, E) > 7 cm. Kaplan-Meier OS curves are shown (solid line) together with 95% confidence intervals (shaded). Median OS was greater for patients with N0-N1M1a-contra disease compared to those with N3M0 disease for primary tumors ≤ 2 cm (28 vs 15 mo, p = 0.0004). This difference became non-significant and then reversed with increasing primary tumor size (2.1–3 cm, 19 vs 14 mo, p = 0.123; 3.1–5 cm, 13 vs 13 mo, p = 0.496; 5.1 – 7 cm, 11 vs 12 mo, p = 0.064; > 7cm, 7 vs 9 mo, p = 0.003).

Figure 5. Modeling of risk from a synchronous second primary tumor

Using a proportional hazards model we constructed a model of estimated OS for patients with concurrent independent primary tumors. Stratifying this model by T and N stage we observe no significant difference in predicted survival for patients with T1-2N0-1 disease and a second independent T1 primary as compared to SEER survival data for T1-2N0-2M1a-contra patients. p value refers to the comparison of OS between the estimated OS curve and that for patients with T1-2N1M1a-contra disease.