Future therapeutic strategies in the treatment of extrapulmonary neuroendocrine carcinoma: a review

Abstract

Neuroendocrine neoplasms (NENs) are rare malignancies arising most commonly in the gastrointestinal and bronchopulmonary systems. Neuroendocrine carcinomas (NECs) are a subgroup of NENs characterised by aggressive tumour biology, poor differentiation and dismal prognosis. Most NEC primary lesions arise in the pulmonary system. However, a small proportion arise outside of the lung and are termed extrapulmonary (EP)-, poorly differentiated (PD)-NECs. Patients with local or locoregional disease may benefit from surgical excision; however, this is often not an option, due to late presentation. To date, treatment has mirrored that of small-cell lung cancer, with platinum–etoposide forming the basis of first-line treatment. There is a lack of consensus in relation to the most effective second-line treatment option. Low incidence, an absence of representative preclinical models and a lack of understanding of the tumour microenvironment all present challenges to drug development in this disease group. However, progress made in elucidating the mutational landscape of EP-PD-NEC and the observations made in several clinical trials are paving the way towards improving outcomes for these patients. The optimisation and strategic delivery of chemotherapeutic interventions according to tumour characteristics and the utilisation of targeted and immune therapies in clinical studies have yielded mixed results. Targeted therapies that complement specific genetic aberrations are under investigation, including AURKA inhibitors in those with MYCN amplifications, BRAF inhibitors in those with BRAFV600E mutations and EGFR suppression, and Ataxia Telangiectasia and Rad3-related inhibitors in patients with ATM mutations. Immune checkpoint inhibitors (ICIs) have conferred promising results in several clinical trials, particularly with dual ICIs and in combination with targeted therapy or chemotherapy. However, further prospective investigations are required to elucidate the impact of programmed cell death ligand 1 expression, tumour mutational burden and microsatellite instability on response. This review aims to explore the most recent developments in the treatment of EP-PD-NEC and contribute towards the requirement for clinical guidance founded on prospective evidence.

Extrapulmonary Neuroendocrine Carcinomas: Current Management and Future Perspectives

“…The small sample size and retrospective design of the study hinder reliable conclusions. The NEONEC trial is currently investigating the activity of adjuvant platinum-based chemotherapy in patients who underwent surgery for digestive NECs, and the results are eagerly awaited (NCT04268121) [8].…”

“…On the other hand, single-agent pembrolizumab, another PD-1 inhibitor, failed to improve survival in an unselected population enrolled in a small phase II trial [97,101]. Given the interest in investigating the efficacy of ICIs, especially for the novel PD-(L)1-CTLA-4 dual inhibitors, a phase II trial of cadonilimab, a bispecific anti-PD-1/CTLA-4 inhibitor, is ongoing for the second-and third-line setting in recurrent NECs of the cervix (NCT05063916) [8,102].…”

“…Besides the lung, which is the most common primary site, NECs that arise outside of this location are referred to as extrapulmonary NECs (EP-NECs), and these are most commonly found in the gastroenteropancreatic (GEP) tract (about 37% of cases), followed by the genitourinary (GU) tract (about 17%) and gynecological (GY) tract (about 10%) [8,9]. EP-NECs are generally non-functioning: their clinical presentation is often the result of a combination of site-specific symptoms and the typical symptoms of advanced/metastatic cancers (weight loss, weakness, etc.)…”

Progress in immunotherapy for neuroendocrine neoplasm of the digestive system

“…However, PD-L1 expression appears quite heterogeneous across different studies[ 57 ], even though some studies revealed no relevance between the effectiveness of ICIs and PD-L1 expression[ 30 , 31 , 40 ]. Reasons for these results may be subject to limitations due to factors such as different methods of analysis, defined cutoffs, and the freshness of biopsy tissue obtained[ 58 ]. Therefore, based on identifying the expression of PD-L1, investigate the content of other predictive biomarkers to provide patients with the best immunotherapy prediction possible.…”

Development and Validation of a Novel Machine Learning Model to Predict the Survival of Patients with Gastrointestinal Neuroendocrine Neoplasms

“…Lymphadenectomy is suggested to be performed with surgical resection if suspected lymph nodes metastasis exist [3,27]. Platinum-based chemotherapy with etoposide and cisplatin is the first-line treatment for NECs, while irinotecan and cisplatin are found to be not inferior to etoposide and cisplatin [28][29][30][31][32]. Radiotherapy is commonly used as the secondline treatment of NETs.…”