Advanced Large Cell Neuroendocrine Carcinoma Research Articles

MTE16.01 Proper Treatment of LCNEC; Chemotherapy or Targeted Therapy

Neuroendocrine Tumors of the Lung consisted of two subtypes which is small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC). Both subtypes represent around 15% of all Lung Cancer. The incidence of LCNEC was quite low as compare to SCLC. However both are aggressive and poor prognosis. The treatment of LCNEC was usually followed the SCLC. In early stages (I-II-III), surgery is recommended but does not seem to be sufficient. Platinum-based adjuvant chemotherapy may be useful while the role of neoadjuvant chemotherapy is still not well defined. In patients with advanced stage LCNEC, the chemotherapy regimens used in SCLC which is cisplatin plus etoposide remain the standard of treatment, but results are not satisfactory. Due to their peculiar clinical and biological features and the lack of literature data, there is an emerging need for a consensus on the best treatment strategy for LCNEC and for the identification of new therapeutic options. In this review, we will discuss the key aspects of LCNEC management and the possibility of using the gene sequencing to clarify the selection of chemotherapy regimen. large cell neuroendocrine carcinoma, lung

Amrubicin monotherapy may be an effective second-line treatment for patients with large-cell neuroendocrine carcinoma or high-grade non-small-cell neuroendocrine carcinoma.

There is no standard chemotherapy for pulmonary large-cell neuroendocrine carcinoma (LCNEC) and this type of cancer is difficult to diagnose using biopsy specimens. At the Shizuoka Cancer Center, when small biopsy specimens are used, they are diagnosed as high-grade non-small-cell neuroendocrine carcinoma (HNSCNEC) and the patients are treated according to the small-cell lung cancer (SCLC) guidelines. Amrubicin is an effective second-line treatment for patients with SCLC, although it remains unclear whether amrubicin monotherapy is effective for patients with LCNEC or HNSCNEC. Between September, 2004 and December, 2013, 18 patients with advanced LCNEC or HNSCNEC received amrubicin monotherapy in the second-line setting. The efficacy and toxicity of this treatment were retrospectively assessed. A total of 6 patients had LCNEC and 12 patients had HNSCNEC. The patients included 13 men, and the median age was 66 years (range, 57-82 years). A total of 16 patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. All the patients had received platinum-based chemotherapy as first-line treatment, and the median number of amrubicin cycles per patient was 4 (range, 1-9). The overall response rate was 11.1%. The median progression-free and overall survival were 4.0 and 9.1 months, respectively. Grade 3 or 4 neutropenia was observed in 44% of the patients, and grade 3 febrile neutropenia occurred in 17% of the patients. One patient developed pneumonia and succumbed to the disease. Non-hematological toxicities were generally mild and manageable. Therefore, the efficacy of amrubicin in the second-line setting for patients with LCNEC or HNSCNEC is limited. Development of new drugs and/or treatment strategies is warranted.

Evaluation of the efficacy of cisplatin-etoposide and the role of thoracic radiotherapy and prophylactic cranial irradiation in LCNEC.

In small-cell lung cancer (SCLC), the role of chemotherapy and radiotherapy is well established. Large-cell neuroendocrine carcinoma (LCNEC) shares several clinicopathological features with SCLC, but its optimal therapy is not defined. We evaluated clinical response and survival outcomes of advanced LCNEC treated in first-line therapy compared with SCLC.72 patients with stage III–IV LCNEC (n=28) and extensive-stage SCLC (ES-SCLC) (n=44) received cisplatin–etoposide with/without thoracic radiotherapy (TRT) and prophylactic cranial irradiation (PCI).Comparing LCNEC with SCLC, we observed similar response rates (64.2% versus 59.1%), disease control rates (82.1% versus 88.6%), progression-free survival (mPFS) (7.4 versus 6.1 months) and overall survival (mOS) (10.4 versus 10.9 months). TRT and PCI in both histologies showed a benefit in mOS (34 versus 7.8 months and 34 versus 8.6 months, both p=0.0001). LCNEC patients receiving TRT showed an improvement in mPFS and mOS (12.5 versus 5 months, p=0.02 and 28.3 versus 5 months, p=0.004), similarly to ES-SCLC. PCI in LCNEC showed an increase in mPFS (20.5 versus 6.4 months, p=0.09) and mOS (33.4 versus 8.6 months, p=0.05), as in ES-SCLC.Advanced LCNEC treated with SCLC first-line therapy has a similar clinical response and survival outcomes to ES-SCLC.

Case report from a study investigating everolimus combined with paclitaxel and carboplatin in patients with advanced large cell neuroendocrine carcinoma of the lung (LCNEC)

Targeted therapies are discussed as an approach to improve outcome in neuroendocrine tumors of the lung. With current treatment options like platinum derivates and etoposide, large cell neuroendocrine carcinoma of the lung (LCNEC) patients have a poor prognosis.

Combination Chemotherapy with Irinotecan and Cisplatin for Large-Cell Neuroendocrine Carcinoma of the Lung: A Multicenter Phase II Study

We conducted a phase II study of combination chemotherapy with irinotecan (CPT) and cisplatin (CDDP) in patients with advanced large-cell neuroendocrine carcinoma (LCNEC) of the lung. Patients received irinotecan (60 mg/m², days 1, 8, and 15) and cisplatin (60 mg/m², day 1) every 4 weeks for up to four cycles. The primary endpoint was the response rate. Expected and threshold values for the primary endpoint were 50% and 30%. Forty-four patients were enrolled between January 2005 and November 2011. The response rate (RR) was 54.5% (95% confidence interval [CI], 38.8-69.6%). The median progression-free survival time was 5.9 months (95% CI, 5.5-6.3), and the median survival time was 15.1 months (95% CI, 11.2-19.0). A central pathological review of specimens from 41 patients demonstrated that 30 patients had LCNEC but that 10 patients had small-cell lung cancer (SCLC) and one had non-small-cell lung cancer with a neuroendocrine structure. The RR was 46.7% (95% CI, 28.3-65.7%) in the LCNEC group and 80% (95% CI, 44.4-97.5%) in the SCLC group (p = 0.0823). The median survival time was 12.6 months (95% CI, 9.3-16.0) in the LCNEC group and 17.3 months (95% CI, 11.2-23.3) in the SCLC group (p = 0.047). Combination chemotherapy with irinotecan and cisplatin was active in patients with LCNEC, but the RR and the overall survival period among the patients with LCNEC seemed to be inferior to those among the patients with SCLC. Small numbers of patients were a major limitation in this study.

Multicentre phase II study of cisplatin–etoposide chemotherapy for advanced large-cell neuroendocrine lung carcinoma: the GFPC 0302 study

BackgroundThe optimal treatment of large-cell neuroendocrine carcinoma (LCNEC) of the lung remains unclear. Here, our primary objective was to assess the efficacy of cisplatin–etoposide doublet chemotherapy in advanced LCNEC. Accuracy of the pathological diagnosis and treatment toxicity were assessed as secondary objectives. Patients and methodsProspective, multicentre, single-arm, phase II study with a centralised review of treatment-response and pathological data. Patients had untreated performance status (PS) 0/1 stage IV/IIIB LCNEC and received cisplatin (80 mg/m22 d1) and etoposide (100 mg/m22 d1-3) every 21 days. ResultsEighteen centres included 42 patients (mean age, 59 ± 9 years; 69% men; median of four cycles/patient). At least one grade-3/4 toxicity occurred in 59% of patients (neutropaenia, thrombocytopaenia, and anaemia in 32%, 17%, and 12%, respectively). The median progression-free survival (PFS) and overall survival (OS) were 5.2 months (95% confidence interval, CI, 3.1–6.6) and 7.7 months (95% CI, 6.0–9.6), respectively. The centralised pathologist review reclassified 11 of 40 (27.5%) patients: 9 as small-cell lung cancer, 1 as undifferentiated non-small-cell lung cancer, and 1 as atypical carcinoid. Survival data were not significantly changed by excluding the reclassified patients. ConclusionsThe pathological diagnosis of LCNEC is difficult. The outcomes of advanced LCNEC treated with cisplatin–etoposide doublets are poor, similar to those of patients with advanced small-cell lung carcinoma (SCLC).

Combination chemotherapy with irinotecan and cisplatin (IP) for advanced large-cell neuroendocrine carcinoma (LCNEC) of the lung: A multicenter phase II study.

8037 Background: LCNEC and small cell lung cancer (SCLC) are recognized as high-grade neuroendocrine carcinoma of the lung. A differential diagnosis between LCNEC and SCLC using a tiny biopsy specimen is frequently difficult. Consequently, prospective clinical trials examining chemotherapy for advanced LCNEC have seldom been reported. We conducted a phase II study of combination chemotherapy with IP in patients (pts) with advanced LCNEC. Methods: The eligibility criteria included a chemotherapy-naïve status, a histological diagnosis of advanced LCNEC, an age of 20-75 years, and an ECOG PS of 0-1. Pts received I (60 mg/m2, days 1, 8, and 15) and P (60 mg/m2, day 1) every 4 weeks for up to 4 cycles. The primary endpoint was the response rate (RR). The sample size was determined to be 44, with a one-sided alpha of 0.1, a beta of 0.2, and expected and threshold values for the primary endpoint of 50% and 30%. Results: 44 pts from 11 institutes were enrolled between Jan 2005 and Nov 2011. The median age was 62.5 years; 21 pts had a PS of 0, and 35 pts were male. 5 pts had stage IIIB, 28 had stage IV, and 11 had recurrences after surgical resection. The RR was 54.5% (95% CI, 38.8-69.6). Grade 3 or 4 neutropenia was observed in 24 pts, but only 3 pts experienced febrile neutropenia. Other toxicities were mild and manageable. The median progression-free survival (PFS) was 5.9 months (95%CI, 5.5-6.3), and the median survival time (MST) was 15.1 months (95%CI, 11.2-19.0). Pathological specimens for a pre-planned central review were available for 41 pts. 30 pts were diagnosed as having LCNEC, whereas 10 pts were diagnosed as having SCLC, and 1 patient was diagnosed as having non-SCLC with a neuroendocrine morphology. Subgroup analyses were shown in the Table. Conclusions: Combination chemotherapy with IP was active in pts with advanced LCNEC, but the RR and the overall survival period in pts with LCNEC seemed to be inferior to those in pts with SCLC. Clinical trial information: UMIN000004796. [Table: see text]

Large Cell Neuroendocrine Carcinoma of the Lung: Is it Possible to Diagnose from Biopsy Specimens?

We have recently proposed new diagnostic criteria for high-grade non-small cell neuroendocrine carcinoma, i.e. possible large cell neuroendocrine carcinoma, in biopsy specimens and have started a clinicopathological comparative study of high-grade neuroendocrine carcinomas in an advanced stage. This study aimed to elucidate the usefulness of our diagnostic criteria for inoperable advanced large cell neuroendocrine carcinoma and to know the true incidence of large cell neuroendocrine carcinoma among lung cancers. We reviewed all cancer lesions (1040 specimens) obtained by transbronchial lung biopsies in our hospital from 2002 to 2009 and selected 38 biopsy specimens that satisfied our diagnostic criteria for high-grade non-small cell neuroendocrine carcinoma. All 38 cases were clinicopathologically investigated and all biopsy specimens were precisely studied for their morphological characteristics. Clinicopathological information about the selected 38 cases was very similar to the clinicopathological characteristics of large cell neuroendocrine carcinoma reported. Of 38 cases, six were at Stage I, II or IIIA, underwent surgery, and the diagnosis was confirmed to be large cell neuroendocrine carcinoma using surgical tumor specimens. In the 38 biopsy specimens, features of neuroendocrine morphology such as organoid nesting, peripheral palisading and rosette formation were not frequent histological features and the majority of tumor cells contained nuclei with a fine chromatin pattern. Mitoses were difficult to find; however, immunohistochemical Ki-67/MIB1 labeling indices were quite useful for evaluating proliferative activity, which ranged from 43.4 to 99.0%. Our study showed the diagnostic potential of using biopsy specimens for large cell neuroendocrine carcinoma, and we herein proposed more simplified diagnostic criteria for possible large cell neuroendocrine carcinoma in practical diagnostic use.

MIS2-2 - Chemotherapy for Pulmonary Large Cell Neuroendocrine Carcinoma: Similar to that for Small Cell Lung Cancer or Non-Small Cell Lung Cancer?

ABSTRACT Background There is controversy regarding palliative chemotherapy for large cell neuroendocrine carcinoma (LCNEC). We evaluated whether advanced LCNEC should be treated similarly as small-cell lung cancer (SCLC) or non-small-cell lung cancer (NSCLC). Methods The clinical reports and tumor specimens of 45 consecutive patients who were diagnosed with advanced LCNEC were reviewed. They were divided into SCLC (n = 11) and NSCLC regimen groups (n = 34) according to first-line chemotherapeutic regimens. Results Most patients were male (96%) and smokers (93%) with a median age of 64 years. Neuroendocrine differentiation was established in 42 (93%) tumors by immunohistochemical analyses. Regarding the efficacy of first-line chemotherapy in the SCLC and NSCLC regimen group, the response rates were 72.7% and 50% (P = 0.19), and the median progression-free survival times were 6.1 and 4.9 months (P = 0.41), respectively. The difference in overall survival between the two treatment groups was 7.3 months (16.5 versus 9.2 months, P = 0.10). There was also a contrasting difference in the type and efficacy of salvage chemotherapeutic regimens between the two groups: salvage regimens with irinotecan, platinum, or taxanes were commonly used with relatively high objective responses in the SCLC regimen group, whereas frequently used agents in the NSCLC regimen group such as pemetrexed, gefitinib, or erlotinib were associated with no objective response. Conclusions Regarding palliative chemotherapy, advanced LCNEC should be treated similarly as SCLC rather than NSCLC.

Chemotherapy for pulmonary large cell neuroendocrine carcinoma: Similar to that for small cell lung cancer or non-small cell lung cancer?

BackgroundThere is controversy regarding palliative chemotherapy for large cell neuroendocrine carcinoma (LCNEC). We evaluated whether advanced LCNEC should be treated similarly to small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Patients and methodsThe clinical reports and tumor specimens of 45 consecutive patients who were diagnosed with advanced LCNEC were reviewed. They were divided into SCLC (n=11) and NSCLC regimen groups (n=34) according to first-line chemotherapeutic regimens. ResultsMost patients were male (96%) and smokers (93%) with a median age of 64 years. Neuroendocrine differentiation was established in 42 (93%) tumors by immunohistochemical analyses. Regarding the efficacy of first-line chemotherapy in the SCLC and NSCLC regimen groups, the response rates were 73% and 50% (P=0.19), and the median progression-free survival times were 6.1 and 4.9 months (P=0.41), respectively. The difference in overall survival between the two treatment groups was 7.3 months (16.5 vs. 9.2 months, P=0.10). There was also a considerable difference in the type and efficacy of salvage chemotherapeutic regimens between the two groups: salvage regimens with irinotecan, platinum, or taxanes were commonly used with relatively high objective responses in the SCLC regimen group, whereas frequently used agents in the NSCLC regimen group such as pemetrexed, gefitinib, or erlotinib were associated with no objective response. ConclusionRegarding palliative chemotherapy for advanced LCNEC, treatment similar to SCLC is more appropriate than NSCLC.

Amrubicin Monotherapy for Patients with Previously Treated Advanced Large-cell Neuroendocrine Carcinoma of the Lung

No standard chemotherapy has been established yet for large-cell neuroendocrine carcinoma of the lung. Amrubicin is active for both small cell and non-small cell lung cancers, but its activity for large-cell neuroendocrine carcinoma is still unknown. From January 2002 to December 2009, 18 patients with previously treated advanced large-cell neuroendocrine carcinoma received amrubicin monotherapy. The efficacy and toxicity of the treatment were analyzed retrospectively. The patients comprised 17 males and one female with a median age of 62 years (range, 51-77). Fourteen and four patients had a performance status of 0-1 and 2, respectively. Thirteen (72%) patients had received one prior chemotherapy, while the others had received two or more chemotherapies. All the patients had received platinum-based chemotherapy before the amrubicin treatment. A total of 63 cycles of amrubicin chemotherapy was administered in the 18 patients, with a median number of cycles per patient of 2.5 (range, 1-10). The median dose of amrubicin in the 63 cycles was 40 (range, 30-45) mg/m(2)/day for 3 days. Grades 3-4 neutropenia, thrombocytopenia and anemia were seen in 89, 17 and 22% of the patients, respectively. Grade 3 febrile neutropenia occurred in 33% of the patients. Non-hematological toxicity was generally mild and manageable. There were five cases of partial response, six of stable disease and six of progressive disease among the 18 patients, yielding an objective response rate of 27.7%. The median progression-free and overall survivals of the patients were 3.1 and 5.1 months, respectively. Amrubicin was potentially active against previously treated large-cell neuroendocrine carcinoma.

Multicentric phase II trial of cisplatin/etoposide chemotherapy in advanced large-cell neuroendocrine carcinoma of the lung (LCNEC): Study GFPC 03-02 from the Groupe Francais de Pneumo-cancerologie.

e18018 Background: A few prospective studies concerning diagnosis and treatment of large cell neuroendocrine lung cancer have been published. After the new World Health Organization classification of lung tumours in 1999, results of previous or retrospective studies based on the old classification seemed unexplainable. So the GFPC started a prospective study, to establish the efficiency of cisplatinum/etoposide chemotherapy for patients with LCNE lung cancer, diagnosed on the basis of the Travis's criteria. 50 patients were planned. Methods: Patients with stage IV and stage III B (with neoplasic pleural effusion) were selected; treatment was three cycles of cisplatinum 80 mg/m2 d1/etoposide 100 mg/m2 d1d2d3 and two more cycles in case of objective response or stable disease. The primary objective is the efficiency, in term of objective response and survival rate, the secondary objectives, the improvement of the pathologic diagnosis, with validation of the paranuclear granular expression of a large spectru...

Long-term disease-free survivor of metastatic large-cell neuroendocrine carcinoma of the lung treated with amrubicin and irinotecan

Large-cell neuroendocrine carcinoma (LCNEC) is a relatively uncommon variant of non-small cell lung cancer. Since the biological characteristics of LCNEC are similar to those of small cell lung cancer, LCNEC is usually treated with chemotherapy regimens used for small cell lung cancer. However, the outcomes are usually dismal. Here, we report a patient with LCNEC (a metastasis to the brain). After whole brain irradiation, he received a combination of amrubicin and irinotecan chemotherapy, and has been relapse-free for two years. This treatment regimen may be beneficial for patients with advanced LCNEC.

A long-term survivor with pulmonary large-cell neuroendocrine carcinoma

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) has been characterized by highly aggressive behavior, with early spread to both regional lymph nodes and distant sites and a rapidly fatal course. In fact, no reports have described an advanced pulmonary LCNEC patient who has had long-term survival. A patient with large-sized pulmonary LCNEC, who is free of disease 11 years after surgery and postoperative chemotherapy, was reported.

PD4-3-7: Multicentric phase II trial of Cisplatin plus Etoposide chemotherapy in advanced Large-Cell Neuro Endocrine Carcinoma of the Lung (LCNEC): preliminary results. Study 03-02 from the “Groupe Francais de Pneumo-Cancerologie (GFPC)

PD4-3-7: Multicentric phase II trial of Cisplatin plus Etoposide chemotherapy in advanced Large-Cell Neuro Endocrine Carcinoma of the Lung (LCNEC): preliminary results. Study 03-02 from the “Groupe Francais de Pneumo-Cancerologie (GFPC)

P1-169: Multicentric phase II trial of Cisplatin plus Etoposide chemotherapy in advanced Large–Cell Neuro Endocrine Carcinoma of the Lung (LCNEC): preliminary results. Study 03–02 from the “Groupe Francais de Pneumo–cancerologie” (GFPC)

A few prospective studies concerning diagnosis and treatment of large cell neuroendocrine lung cancer were published, as this tumor seems relatively rare. The objectives of GFPC 03-02 prospective study were to establish the efficiency of Cisplatinum /Etoposide chemotherapy and to valid value of large spectrum cytokeratins in the diagnosis of neuro-endocrine differnciation. Patients with stage IV and stage III B (with neoplasic pleural effusion) were included; treatment consisted in three cycles of Cisplatinum 80mg/m2 d1 / Etoposide 100mg/m2 d1d2d3 and two more cycles in case of objective response or stable disease. The primary objective is the efficiency of this chemotherapy, secondary objective the validation of the paranuclear granular expression of a large spectrum cytokeratin, as a characteristic of neuro-endocrine differentiation. Slides were controlled by a panel of pathologists. Diagnoses were based on Travis’s criterias. 27 patients were included since May 2004. The slides of 21 cases were reviewed. 14 cases were confirmed as LCNEC. 4 were excluded on the basis of the nuclear criteria or cell size, and classified as small-cell carcinomas (SCC). One was excluded, because immunohistochemistry was not available. Two other patients were excluded because of the misinterpretation of the pathologic report by the clinicians (one SCC, one Large cell Carcinoma). Among the 14 cases, two sub-types were observed: –8 LCNEC with neuroendocrine features and positive immunohistochemistry–6 undifferentiated carcinomas with immunohistochemical neuroendocrine differentiation. None case was diagnosed as large-cell carcinoma with neuroendocrine pattern and negative immunohistochemistry. In all cases, at least two of the three neuroendocrine markers (chromogranin A, synaptophysin, CD56) were positive. Interobserver variability is not observed on the criterias of neuroendocrine immunohistochemical differentiaton, but only on the criterias of size. Some small scratched samples led to difficulties to distinguish small-cell carcinoma from large-cell carcinoma, especially when neuroendo-crine morphology (rosettes, trabecular growth pattern,_) was not present. It seems necessary to definite how many of the Travis’s crite-rias are necessary to accept the diagnosis of LCNEC (cell size, chromatin, nucleoli, nuclear-to-cytoplasmic ratio, large and eosinophilic or granular cytoplasm) when neuroendocrine differentiation is proved. This interobserver variability is described in the literature (1). Value of the paranuclear granular expression with Cytokeratins must be evaluated on cases not yet tested. Panel of pathologists is useful to diagnose LCNEC. Disagrements were on cell size, some LCNEC were reclassified as SCC. Usefulness of cytokeratins needs some more patients tested.

Paclitaxel and carboplatin for large cell neuroendocrine carcinoma of the uterine cervix

The prognosis of large cell neuroendocrine carcinoma (LCNEC) of the uterine cervix is generally poor despite multimodality of treatments. We report a case of advanced stage cervical LCNEC that showed definite response to paclitaxel/carboplatin, resulting in years of survival. The patient was referred to our institution after undergoing a simple hysterectomy with bilateral salpingo-oophorectomy in her local hospital because of a ruptured metastatic ovarian mass. She declined pelvic radiation treatment, so adjuvant chemotherapy (six cycles of paclitaxel/carboplatin) was given for the residual pelvic nodal diseases. Clinical complete remission was obtained, with a disease-free period of 19 months. Systemic recurrent diseases also showed partial response to the same drug regimen for months with only minimal toxicity. However, she subsequently had progressive diseases in the liver and brain and finally died at 44 months after primary diagnosis and 19 months after recurrent diseases.

P-523 Multicentric phase II trial of cisplatin plus etoposidechemotherapy in advanced large-cell neuro endocrine carcinoma of the lung (LCNEC): Preliminary results. Study 03-02 from the “Groups Francais de Pneumo-cancerologie (GFPC)”

P-523 Multicentric phase II trial of cisplatin plus etoposidechemotherapy in advanced large-cell neuro endocrine carcinoma of the lung (LCNEC): Preliminary results. Study 03-02 from the “Groups Francais de Pneumo-cancerologie (GFPC)”