Neuroendocrine Cervical Carcinomas: Genomic Insights, Controversies in Treatment Strategies, and Future Directions: A NeCTuR Study

Neuroendocrine cervical carcinomas are rare, aggressive tumors with a high risk of early metastasis and poor survival outcomes. Despite existing therapies, over half of patients experience recurrence or progression after primary treatment, and survival after recurrence remains limited. Survival rates have not significantly improved over the past several decades, underscoring an urgent need for better therapeutic options. The rarity of neuroendocrine cervical carcinoma has precluded randomized trials, leaving treatment strategies to be guided by small retrospective studies or adapted from protocols for small cell lung cancer. However, as we gain a deeper understanding of its unique origin, genomic landscape, and biological characteristics, it has become clear that neuroendocrine cervical carcinoma requires distinct management strategies. Key questions in managing neuroendocrine cervical carcinoma remain unanswered: does adjuvant radiation therapy improve outcomes for early-stage disease? Should neoadjuvant chemotherapy be considered for patients with bulky, localized tumors? Can immunotherapy improve outcomes when added to chemoradiation in locally advanced cases? Should immunotherapy be a standard option for recurrent disease? Addressing these questions requires a thorough understanding of the unique molecular and biological characteristics of neuroendocrine cervical carcinoma and its clinical behavior. This review aims to provide an updated summary of the molecular landscape of neuroendocrine cervical carcinoma, highlighting features that distinguish it from small cell lung cancer and align with other types of cervical cancer. We discuss current treatment approaches, identify gaps in knowledge, and examine paradigm-shifting clinical trials that have significantly impacted survival outcomes in cervical cancer and small cell lung cancer, translating these insights into potential strategies for neuroendocrine cervical carcinoma. By focusing on the unique aspects of neuroendocrine cervical carcinoma, this review emphasizes the need for specialized treatment strategies for this challenging disease.