R. Damhuis

Clinical features of large cell neuroendocrine carcinoma : a population-based overview

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is an orphan disease and few data are available on its clinical characteristics. Therefore, we analysed LCNEC registered in the Netherlands Cancer Registry, and compared data with small cell lung carcinoma (SCLC), squamous cell carcinoma (SqCC) and adenocarcinoma (AdC). Histologically confirmed LCNEC (n=952), SCLC (n=11u200a844), SqCC (n=19u200a633) and AdC (n=24u200a253) cases were selected from the Netherlands Cancer Registry (2003–2012). Patient characteristics, metastasis at diagnosis (2006 or later), overall survival (OS) including multivariate Cox models and first-line treatment were compared for stage I–II, III and IV disease. The number of LCNEC cases increased from 56 patients in 2003 to 143 in 2012, accounting for 0.9% of all lung cancers. Stage IV LCNEC patients (n=383) commonly had metastasis in the liver (47%), bone (32%) and brain (23%), resembling SCLC. Median OS (95% CI) of stage I–II, III and IV LCNEC patients was 32.4 (22.0–42.9), 12.6 (10.3–15.0) and 4.0 (3.5–4.6)u2005months, respectively. Multivariate-adjusted OS of LCNEC patients resembled that of SCLC patients, and was poorer than those of SqCC and AdC patients. However, frequency of surgical resection and adjuvant chemotherapy resembled SqCC and AdC more than SCLC. Diagnosis of LCNEC has increased in recent years. The metastatic pattern of LCNEC resembles SCLC as does the OS. However, early-stage treatment strategies seem more comparable to those of SqCC and AdC. Outcome of LCNEC is poor and metastatic pattern resembles SCLC, yet stage I–II treatment corresponds more with NSCLC http://ow.ly/S37N9

Single organ metastatic disease and local disease status, prognostic factors for overall survival in stage IV non-small cell lung cancer: Results from a population-based study

PURPOSEnTo analyse the prognostic impact on overall survival (OS) of single versus multiple organ metastases, organ affected, and local disease status in a population based stage IV non-small cell lung cancer (NSCLC) cohort.nnnMETHODSnIn this observational study, data were analysed of all histologically confirmed stage IV NSCLC patients diagnosed between 1 January 2006 and 31 December 2012 registered in the Netherlands Cancer Registry. Location of metastases before treatment was registered. Multivariable survival analyses [age, gender, histology, M-status, local disease status, number of involved organs, actual organ affected] were performed for all patients and for an (18)fluorodeoxyglucose-positron emission tomography ((18)FDG-PET)-staged subgroup.nnnRESULTSn11,094 patients were selected: 60% male, mean age 65 years, 73% adenocarcinoma. Median OS for 1 (N = 5676), 2 (N = 3280), and ⩾ 3 (N = 2138) metastatically affected organs was 6.7, 4.3, 2.8 months, respectively (p < 0.001). Hazard ratio (HR) for 2 versus 1 organ(s) was 1.33 (p < 0.001), for ⩾ 3 versus 1 organ(s) 1.91 (p < 0.001). Results were confirmed in the (18)FDG-PET-staged cohort (N = 1517): patients with single organ versus 2 and ⩾ 3 organ metastases had higher OS (8.6, 5.7, 3.8 months, HR 1.40 and 2.17, respectively, p < 0.001). In single organ metastases, OS for low versus high TN-status was 8.5 versus 6.5 months [HR 1.40 (p < 0 .001)]. (18)FDG-PET-staged single organ metastases patients with low TN-status had a superior OS than those with high TN-status (11.6 versus 8.2 months, HR 1.62, p < 0.001).nnnCONCLUSIONnPatients with single organ metastases stage IV NSCLC have a favourable prognosis, especially in combination with low TN status. They have to be regarded as a separate subgroup of stage IV disease.

Chemotherapy for pulmonary large cell neuroendocrine carcinomas : Does the regimen matter?

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is rare. Chemotherapy for metastatic LCNEC ranges from small cell lung carcinoma (SCLC) regimens to nonsmall cell lung carcinoma (NSCLC) chemotherapy regimens. We analysed outcomes of chemotherapy treatments for LCNEC. The Netherlands Cancer Registry and Netherlands Pathology Registry (PALGA) were searched for patients with stage IV chemotherapy-treated LCNEC (2003–2012). For 207 patients, histology slides were available for pathology panel review. First-line platinum-based combined chemotherapy was clustered as “NSCLC-t”, comprising gemcitabine, docetaxel, paclitaxel or vinorelbine; “NSCLC-pt”, with pemetrexed treatment only; and “SCLC-t”, consisting of etoposide chemotherapy. A panel review diagnosis of LCNEC was established in 128 out of 207 patients. NSCLC-t chemotherapy was administered in 46% (n=60), NSCLC-pt in 16% (n=20) and SCLC-t in 38% (n=48) of the patients. The median (95% CI) overall survival for NSCLC-t chemotherapy was 8.5 (7.0–9.9)u2005months, significantly longer than patients treated with NSCLC-pt, with a median survival of 5.9 (5.0–6.9)u2005months (hazard ratio 2.51, 95% CI 1.39–4.52; p=0.002) and patients treated with SCLC-t chemotherapy, with a median survival of 6.7 (5.0–8.5)u2005months (hazard ratio 1.66, 95% CI 1.08–2.56; p=0.020). In patients with LCNEC, NSCLC-t chemotherapy results in longer overall survival compared to NSCLC-pt and SCLC-t chemotherapy. Treatment for pulmonary LCNEC is debated; we show favourable results for standard gemcitabine NSCLC chemotherapy http://ow.ly/2Xt730a0PK0

Molecular Subtypes of Pulmonary Large-cell Neuroendocrine Carcinoma Predict Chemotherapy Treatment Outcome

Purpose: Previous genomic studies have identified two mutually exclusive molecular subtypes of large-cell neuroendocrine carcinoma (LCNEC): the RB1 mutated (mostly comutated with TP53) and the RB1 wild-type groups. We assessed whether these subtypes have a predictive value on chemotherapy outcome. Experimental Design: Clinical data and tumor specimens were retrospectively obtained from the Netherlands Cancer Registry and Pathology Registry. Panel-consensus pathology revision confirmed the diagnosis of LCNEC in 148 of 232 cases. Next-generation sequencing (NGS) for TP53, RB1, STK11, and KEAP1 genes, as well as IHC for RB1 and P16 was performed on 79 and 109 cases, respectively, and correlated with overall survival (OS) and progression-free survival (PFS), stratifying for non–small cell lung cancer type chemotherapy including platinum + gemcitabine or taxanes (NSCLC-GEM/TAX) and platinum-etoposide (SCLC-PE). Results: RB1 mutation and protein loss were detected in 47% (n = 37) and 72% (n = 78) of the cases, respectively. Patients with RB1 wild-type LCNEC treated with NSCLC-GEM/TAX had a significantly longer OS [9.6; 95% confidence interval (CI), 7.7–11.6 months] than those treated with SCLC-PE [5.8 (5.5–6.1); P = 0.026]. Similar results were obtained for patients expressing RB1 in their tumors (P = 0.001). RB1 staining or P16 loss showed similar results. The same outcome for chemotherapy treatment was observed in LCNEC tumors harboring an RB1 mutation or lost RB1 protein. Conclusions: Patients with LCNEC tumors that carry a wild-type RB1 gene or express the RB1 protein do better with NSCLC-GEM/TAX treatment than with SCLC-PE chemotherapy. However, no difference was observed for RB1 mutated or with lost protein expression. Clin Cancer Res; 24(1); 33–42. ©2017 AACR.

Association of molecular status and metastatic organs at diagnosis in patients with stage IV non-squamous non-small cell lung cancer

OBJECTIVESnBiological predisposition for specific metastatic organs might differ between molecular subgroups of lung cancer. We aimed to assess the association between molecular status and metastatic organs at diagnosis in a nationwide stage IV non-squamous non-small cell lung cancer ((ns)-NSCLC) cohort.nnnMETHODSnAll ns-NSCLC from 2013 that were stage IV at diagnosis were identified from the Netherlands Cancer Registry, which records information on metastatic organs at diagnosis. Tumors were matched to the Dutch Pathology Registry (PALGA) from which data on molecular status established in routine practice was extracted. Four molecular subgroups (EGFR+, KRAS+, ALK+, triple-negative) were identified. For each metastatic organ, proportions of tumors metastasized to this organ were, per molecular subgroup, compared to triple-negative tumors by multivariable logistic regression analyses (adjusted odds ratios (OR) with 95% confidence intervals (CI)), taking clinicopathological variables into account.nnnRESULTSn160 EGFR+ (exon 19 del, exon 21 L858R), 784 KRAS+, 42 ALK+, and 1008 triple-negative tumors were identified. Most frequent metastatic organs were the bone (34%), pleura (24%), lung (23%), and brain (22%). Compared to triple-negatives, EGFR+ tumors had more often metastases to the bone (31.5 vs 53.8%; OR 2.55 (95% CI 1.80-3.62)) and pleura (24.1 vs 37.5%; OR 2.06 (1.42-2.98)), and less often to the brain (22.0 vs 12.5%; OR 0.53 (0.32-0.88)) and adrenal glands (19.1 vs 7.5%; OR 0.46 (0.28-0.75)). Compared to triple-negatives, KRAS+ and ALK+ tumors had at diagnosis metastasized more often to the lung (20.3 vs 26.7%; OR 1.40 (1.12-1.76)) and the liver (13.1 vs 23.8%; OR 2.07 (1.00-4.32)), respectively.nnnCONCLUSIONnNSCLC molecular status was associated with metastatic pattern at diagnosis. 54% of stage IV EGFR+ ns-NSCLC patients had bone metastases at diagnosis. These observational results are hypothesis generating, and call for a prospective study where EGFR+ patients are screened for bone metastases, and treated to prevent skeletal related events.

Why we should improve current practice of diagnosing and treating pulmonary large cell neuroendocrine carcinomas in patients with advanced disease

In response to our manuscript on first-line chemotherapy treatment for metastatic pulmonary large cell neuroendocrine carcinoma (LCNEC) [1], Rossi and co-workers raised their concerns about the validity of our results by questioning the accuracy of LCNEC diagnosis on a biopsy specimen. We would like to thank the authors for their critical appraisal, underscoring the need to increase awareness among pulmonologists, oncologists and pathologists of the diagnostic issues and consequences of metastatic LCNEC diagnosed on a biopsy specimen. Current criteria for LCNEC diagnosed on a biopsy specimen are in need of improvement http://ow.ly/lRP730fu552