Anlotinib plus camrelizumab achieved long‐term survival in a patient with metastatic esophageal neuroendocrine carcinoma

Abstract Background Esophageal neuroendocrine carcinoma (NEC) is a rare cancer with an extremely poor prognosis. The average overall survival of patients with metastatic disease is only 1 year. The efficacy of anti‐angiogenic agents combined with immune checkpoint inhibitors remains unknown. Case Presentation A 64‐year‐old man, initially diagnosed with esophageal NEC, underwent neoadjuvant chemotherapy and esophagectomy. Although the patient remained disease‐free for 11 months, eventually the tumor progressed and did not respond to three lines of combined therapy (etoposide plus carboplatin with local radiotherapy, albumin‐bound paclitaxel plus durvalumab, and irinotecan plus nedaplatin). The patient then received anlotinib plus camrelizumab, and a dramatic regression was observed (confirmed by positron emission tomography‐computed tomography). The patient has been disease‐free for over 29 months and has survived for over 4 years since diagnosis. Conclusion Combined therapy with anti‐angiogenic agents and immune checkpoint inhibitors may be a promising strategy for esophageal NEC, although more evidence is warranted to validate its efficacy.


| INTRODUCTION
Esophageal neuroendocrine carcinoma (NEC) is much rarer than typical esophageal carcinomas with a worse prognosis, and a median overall survival (OS) of 12-13 months in stage IV patients. [1][2][3] There are no standard therapeutic strategies for treating esophageal NEC. 4 For patients with stage IV or relapsed NEC, systemic and local treatment must be considered. Chemotherapy is the first choice of treatment, which is similar to small cell lung carcinoma (SCLC). 3 In recent years, anti-angiogenic agents, have exhibited potential for SCLC management. 5 Programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) inhibitors have also been widely studied for the treatment of extensive-stage SCLC (ES-SCLC). 6,7 Here, we report our experience with a patient with esophageal NEC, in whom several lines of chemotherapy-based treatment failed but complete disease regression was observed after treatment with anti-angiogenic therapy and PD-1 inhibitors, Lingxiao Zhou, Guanxin Xu, and Tianwei Chen contributed equally to this work. which may be a promising treatment strategy for this unique cancer.

| CASE DESCRIPTION
A 64-year-old Chinese man with no notable family history was admit- discovered that dual therapy could promote antitumor immunity in gastric cancer. PD-L1 could also be significantly upregulated in anlotinib-treated renal cell carcinoma cells. 16 Since NECs in the esophagus and lungs share similar pathologic and clinical manifestations, it is reasonable to propose that anti-angiogenic agents and immunotherapy might also benefit patients with esophageal NEC. In the case of resistance of multiple chemotherapy agents, we provided anti-angiogenic agents and immunotherapy for this patient. Our patient has already reached a remarkable PFS of over 29 months with anlotinib and camrelizumab combination therapy, which is much longer than the chemotherapy-based systemic treatment in other reported cases. However, there have been very few attempts at this combination treatment and the efficacy still requires more cases to confirm.

| CONCLUSION
We encountered a case of metastatic esophageal NEC in which complete regression and long survival were observed after treatment with combination of anlotinib and camrelizumab, which can be hardly achieved in routine treatment. Given the poor prognosis of the disease, this therapy should be considered for patients with unresectable esophageal NEC, especially for who who have developed chemoresistance.

AUTHOR CONTRIBUTIONS
All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analy-

ACKNOWLEDGMENTS
The case report has no financial support or funding.

CONFLICT OF INTEREST STATEMENT
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

DATA AVAILABILITY STATEMENT
Data will be made available on request.

ETHICS STATEMENT
Approval of the research protocol by an Institutional Reviewer Board: This study was reviewed and approved by Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine and it conforms to the provisions of the Declaration of Helsinki.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.