Comprehensive Dissection of Treatment Patterns and Outcome for Patients With Metastatic Large-Cell Neuroendocrine Lung Carcinoma

Abstract

Background: Large-cell neuroendocrine lung carcinoma (LCNEC) is a rare pulmonary neoplasm with poor prognosis and limited therapeutic options.

Methods: We retrospectively analyzed all patients with metastatic LCNEC in the records of a large German academic center since 2010.

Results: 191 patients were identified with a predominance of male (68%) smokers (92%) and a median age of 65 years. The single most important factor associated with outcome was the type of systemic treatment, with a median overall survival (OS) of 26.4 months in case of immune checkpoint inhibitor administration (n=13), 9.0 months for other patients receiving first-line platinum doublets (n=129), and 4.0 months with non-platinum chemotherapies (n=17, p<0.01). Other patient characteristics independently associated with longer OS were a lower baseline serum LDH (hazard ratio [HR] 0.54, p=0.008) and fewer initial metastatic sites (HR 0.52, p=0.006), while the platinum drug type (cisplatin vs. carboplatin) and cytotoxic partner (etoposide vs. paclitaxel), patients' smoking status and baseline levels of tumor markers (NSE, CYFRA 21-1, CEA) did not matter. 12% (23/191) of patients forewent systemic treatment, mainly due to tumor-related clinical deterioration (n=13), while patient refusal of therapy (n=5) and severe concomitant illness (n=5) were less frequent. The attrition between successive treatment lines was approximately 50% and similar for platinum-based vs. other therapies, but higher in case of a worse initial ECOG status or higher serum LDH (p<0.05). 19% (36/191) of patients had secondary stage IV disease and showed fewer metastatic sites, better ECOG status and longer OS (median 12.6 vs. 8.7 months, p=0.030). Among the 111 deceased patients with palliative systemic treatment and complete follow-up, after exclusion of oligometastatic cases (n=8), administration of local therapies (n=63 or 57%) was associated with a longer OS (HR 0.58, p=0.008), but this association did not persist with multivariable testing.

Conclusions: Highly active systemic therapies, especially immunotherapy and platinum doublets, are essential for improved outcome in LCNEC and influence OS stronger than clinical disease parameters, laboratory results and other patient characteristics. The attrition between chemotherapy lines is approximately 50%, similar to other NSCLC. Patients with secondary metastatic disease have a more favorable clinical phenotype and longer survival.

Keywords: de novo metastatic; immunotherapy; large-cell neuroendocrine lung carcinoma; local therapies; overall survival; platinum chemotherapy; secondary metastatic.

Figure 1

Flowchart of study patients and the populations used in each analysis. FU, follow-up.

Figure 2

Overall survival of patients with metastatic LCNEC. (A) The median overall survival was 14.1 (95% confidence interval 7.9-20.3), 9.9 (8.6-11.2), 5.7 (4.3-7.1) and 1.1 (0.6-1.6) months (p < 0.001) for patients with 0, 1, 2 or 3 risk factors (lack of highly active systemic treatment with platinum and/or immunotherapy and/or TKI, baseline LDH ≥271 U/l, >1 initial metastatic sites; see Table 2 ). All patients with available values for all three parameters were included in this analysis (n = 135). (B) The median overall survival (OS) was 5.7 months (3.2-8.2) for patients with diagnosis of stage IV and serum LDH equal to or above the median for the entire study population (271 U/l, Table 1 ) vs. 10.9 months (9.9-11.9) for patients with diagnosis of stage IV and serum LDH below the median. (C) The median overall survival (OS) was 10.4 (8.5-12.3) months for patients with diagnosis of stage IV and ≤ 1 metastatic sites vs. 7.2 (5.3-10.0) months for patients with > 1 metastatic sites. (D) The median overall survival (OS) was 26.4 (6.4-46.5) months for patients who received immunotherapy in any treatment line vs. 9.0 (7.5-10.2) months for non-immunotherapy-treated patients, who received first-line platinum-based chemotherapy (logrank p=0.006 against immunotherapy) vs. 4.0 (1.6-6.4) months for patients who received other first-line chemotherapies (logrank p = 0.00033 against platinum-based chemotherapy). The rare (n = 2) TKI-treated patients were excluded from this analysis.

Figure 3

Factors associated with platinum-based first line in metastatic LCNEC. (A) The rate of platinum-based first-line treatment was 99% (65/66), 85% (64/75), 50% (1/2), and 0% (0/2) among patients with ECOG performance status (PS) 0, 1, 2, and ≥3 (chi-square p = 0.00004). (B) The rate of platinum-based first line treatment was 94% (79/84) among patients younger vs. 84% (141/158) among patients older than 65 years (median age, Table 1 , chi-square p = 0.038).

Figure 4

The clinical profile and survival of patients with secondary metastatic LCNEC. (A) The median overall survival from treatment start for stage IV disease was 12.6 (95% confidence interval [CI] 8.8-16.5) vs. 8.7 (6.9-10.4) months for patients with secondary vs. de novo metastatic LCNEC (logrank p = 0.030). (B) The median number of metastatic sites was 1.56 (standard error of the mean [SEM] 0.15) vs. 1.99 (SE 0.16, p = 0.041 with a t-test) for patients with secondary vs. de novo metastatic LCNEC. Error bars indicate SEM. (C) The percentage of cases with ECOG performance status (PS) 0 was 61% (20/33, CI 42-79) among patients with secondary vs. 41% (56/138, CI 32-49) among patients with de novo metastatic LCNEC (chi-square p = 0.038). Error bars indicate CI.

Figure 5

Flow of patients with metastatic LCNEC across treatment lines. This analysis was performed in the subset of patients who received palliative systemic treatment and have complete follow-up available until death ( Figure 1 ). ACO, adriamycin, cyclophosphamide, vincristine; TKI, tyrosine kinase inhibitors; immunotherapy: immune checkpoint inhibitors. The ALK-positive LCNEC patient has been published previously (26). * 4th and subsequent lines cumulated; ****p < 0.0001 with a chi-square test for the percentage of platinum-based vs. non-platinum-based therapies in the first vs. second and third line; p = 0.56 with a mixed linear model for the attrition rate after platinum-based vs. other chemotherapies across the first three treatment lines.

Figure 6

Baseline parameters at initial diagnosis associated with lack of subsequent treatment in metastatic LCNEC. This analysis was performed in the subset of patients who received palliative systemic treatment and have complete follow-up available until death ( Figure 1 ). (A) The percentage of patients who missed second-line treatment was 66% (29/44) among patients with metastatic LCNEC with a higher serum LDH at diagnosis (≥ 271 U/l, i.e. above the median value, Table 1 ) vs. 43% (23/54) among patients with lower serum LDH levels (chi-square p = 0.0214). The LDH cut-off was based on the median value of the entire study population ( Table 1 ). (B) The percentage of patients who missed second-line treatment was 68% (41/60) among patients with metastatic LCNEC and an ECOG performance status (PS) >0 at diagnosis vs. 48% (20/42) among patients with an ECOG PS 0 (chi-square p = 0.0357). The LDH and ECOG PS cut-offs were based on the median values of the entire study population ( Table 1 ).

Figure 7

Palliative local therapies and their association with survival in metastatic LCNEC. (A) 75% of patients (47/63) received palliative radiotherapy only, 8% of patients (5/63) received palliative surgery, and 17% of patients (11/63) received both ( Table 1 ). (B) The median overall survival (OS) was 8.1 (95% confidence interval 6.5-9.6) months for patients who received palliative local therapies during any treatment line vs. 6.9 (5.6-8.2) months for patients who did not (logrank p=0.007362).