Late-stage esophageal neuroendocrine carcinoma in a patient treated with tislelizumab combined with anlotinib: a case report

Abstract

Esophageal neuroendocrine carcinoma (ENEC) is an extremely rare tumor with highly malignant potential, rapid growth, and a poor prognosis. Advanced extrapulmonary neuroendocrine carcinoma should be treated with chemotherapeutic regimens suitable for small cell lung cancer. However, ENEC has no clear second-line treatment options. The clinical application of immunotherapy and targeted therapy in small cell lung cancer has produced good therapeutic effects. We describe the case of an elderly woman with multiple metastatic advanced ENEC treated with tislelizumab combined with anlotinib as second-line therapy, achieving complete remission in a short period and long-term survival. In total, 21 cycles of tislelizumab combined with anlotinib were given to this patient. After two cycles, the patient’s neuron-specific enolase level decreased from 181.8 to 22.9 µg/L and remained at normal levels throughout treatment. Progression-free survival and overall survival were 16 and 21 months, respectively, in this patient. No obvious side effects were observed. Thus, tislelizumab and anlotinib could represent a novel therapeutic option for advanced ENEC.

Introduction

Esophageal neuroendocrine carcinoma (ENEC) is an extremely rare tumor first reported by Mckeown in 1952 with highly malignant potential, rapid growth, and a poor prognosis.^1–2 More than 90% of esophageal cancers (ECs) are squamous cell carcinoma (SCC), whereas ENEC accounts for only 0.05% to 2.4% of cases. ³ Standard management and prognostic factors for ENEC have not been established because of the small number of cases and its poor prognosis.

ENEC mainly includes small cell and large cell variants. Neuroendocrine carcinoma (NEC) is generally the small cell type. Small cell carcinoma of the esophagus (SCCE) and small cell lung cancer (SCLC) are categorized as small round cell tumors because of their similar histological manifestations, genetic changes, and highly aggressive biological characteristics. Therefore, the standard treatment regimen for SCCE is mainly based on the treatment mode of SCLC.^4–5

For patients with resectable stage I to III ENEC, surgical resection plus adjuvant chemotherapy is recommended. The preferred chemotherapy regimens are etoposide plus platinum (EP) and irinotecan plus platinum (IP). ⁶ However, the optimal second-line treatment strategy for NEC remains to be determined. We urgently need to identify effective adjuvant and neoadjuvant strategies for this disease. Along with the discovery of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and associated antibodies, we have entered the era of immunotherapy. The clinical application of immunotherapy and targeted therapy in SCLC has achieved good therapeutic effects. ⁷ To date, there are few reports on the efficacy of immune checkpoint inhibitors combined with targeted therapy for gastrointestinal NEC. In this study, we describe a case of multiple metastatic advanced ENEC treated with tislelizumab combined with anlotinib as second-line therapy, achieving complete remission in a short period and long-term survival.

Case presentation

A 66-year-old woman was first admitted to our hospital with abdominal pain for 1 month. Our physical examination revealed multiple palpable swollen right supraclavicular lymph nodes with poorly defined borders that fused into a mass of approximately 4.0 × 3.0 cm² in size. The patient was previously healthy, and she had no personal or family history of hypertension, heart disease, or diabetes. The patient underwent painless gastroscopy on 26 October 2020, and the esophageal tumor was located 20 to 38 cm from the incisors with erosion and bleeding on the surface of the lesions, poor elasticity, and smooth cardiac mucosa without stenosis. A surface ulcer of approximately 3.0 × 3.0 cm² was present in the gastric fundus mucosa with poor elasticity. The results of gastroscopy indicated EC, gastric fundus tumor, and chronic superficial atrophic gastritis (Figure 1). The patient underwent contrast-enhanced computed tomography (CT) of the chest and whole abdomen, which revealed uneven thickening of the esophagus. Because of the possibility of EC, and it was recommended to perform endoscopy. Because multiple lymph nodes were swollen in the mediastinum, neck, abdominal cavity, and retroperitoneum, lymphoma was first considered, and multiple metastases were not excluded (Figure 2a1–4) on 27 October 2020. We also performed needle biopsy of the right supraclavicular lymph nodes. The pathological report of gastroscopy on 28 October 2020 indicated the presence of cancerous tissue in the esophageal mucosa and gastric fundus mucosa. Combined with immunohistochemical markers, the findings were consistent with small cell NEC. Immunohistochemistry revealed high expression of Ki-67 (>90%). Tumor cells were positive for synaptophysin, chromogranin A, and CD56 and negative for cytokeratin 7, P40, villin, and leukocyte common antigen. Pathological examination of right cervical lymph node tissue strips disclosed metastasis of small cell NEC on 29 October 2020. The neuron-specific enolase (NSE) level was significantly elevated (180 µg/L) on 31 October 2020.

Figure 1.

Results of initial endoscopy for the patient. (a, b) Digestive endoscopy revealed a space-occupying lesion in the esophagus, and the lumen was obviously narrowed and (c) Digestive endoscopy revealed a tumor-occupying site in the gastric fundus.

Figure 2.

Results of CT before and after chemotherapy. (a1) Enhanced CT revealed the enlargement of multiple right supraclavicular lymph nodes. (a2) CT illustrated that the esophageal wall of the esophagus was significantly thickened with unequal enhancement. (a3) CT revealed multiple enlarged lymph nodes on the lesser curvature side of the stomach that fused into a mass. (a4) CT revealed multiple lymphadenopathy in the abdominal cavity and retroperitoneum. (b1–4) CT of the chest and whole abdomen revealed that the thickness of the esophageal wall was significantly reduced compared with the previous examination, multiple lymph nodes in the mediastinum, neck, abdominal cavity, and retroperitoneum were enlarged, and the tumor volume was significantly lower than that in the prior examination.

Figure 3.

The results of CT in the patient before and after immunotherapy combined with targeted therapy. (a1–b1) Enhanced CT of the chest and whole abdomen revealed that the lymph nodes in the abdominal cavity and retroperitoneum had increased in number and size. (a2–b2) After two cycles of tislelizumab plus anlotinib, the lymph nodes in the liver and stomach space had shrank, and the lymph nodes next to the middle abdominal artery were enlarged but weakened. (a3–b3) After four cycles of treatment, some of the metastases had completely disappeared, and the other metastases had shrank and (a4–b4) After eight cycles of treatment, repeated CT revealed that the lymph nodes in the abdominal cavity and retroperitoneum had shrank.

Figure 4.

NSE levels in the patient over the course of tislelizumab plus anlotinib therapy.

This patient received six cycles of EP combination chemotherapy (cisplatin 40 mg on days 1–3 and etoposide 0.1 g on days 4–7 of each 21-day cycle) starting on 1 November 2020. This patient developed myelosuppression and mild gastrointestinal reactions during chemotherapy. We repeated chest and abdomen enhanced CT every two cycles to evaluate the curative effect. After two cycles of EP, all primary and metastatic lesions had shrank, and the NSE level returned to normal (11.2 µg/L). The patient had no discomfort, and her diet and life improved significantly. After four cycles of treatment, most of the primary and metastatic lesions had completely disappeared (Figure 2b1–4). After six cycles, the patient’s level NSE had increased (34.8 µg/L), and repeat CT on 20 March 2021 revealed enlargement of the lymph nodes in the abdominal cavity and retroperitoneum. Conversely, the remaining lesions were largely unchanged (Figure 3a1–b1). During hospitalization, the patient had obvious abdominal pain accompanied by nausea, vomiting, and anorexia. The re-examination of biochemical indicators revealed hypoalbuminemia and electrolyte imbalance. We gave the patient symptomatic and supportive pain medication. Her general state was poor, and she could not tolerate systemic chemotherapy.

On 7 April 2021, we discussed this case in our department and formulated a new treatment plan to combine tislelizumab with anlotinib (tislelizumab 200 mg on day 1 and anlotinib 10 mg on days 1 to 14 of each 21-day cycle). The patient and her family members agreed to the treatment plan after consultation. During the course of treatment, the skin and sclera of the patient obviously yellowed, and thus, we improved the relevant examinations on 10 April 2021. The total bilirubin level was significantly elevated at 96.1 µmol/L, and both direct and indirect bilirubin levels were elevated. Color Doppler ultrasound revealed a mixed echo of approximately 8.5 × 6.1 cm² in the left liver lobe, and the bile ducts inside and outside the liver were significantly dilated. On repeat examination, the NSE level was significantly elevated (181.8 µg/L). Because the patient refused to undergo liver biopsy because of her poor general condition, oral anlotinib and liver-protecting and bilirubin-lowering symptomatic drug treatment were continued. The symptoms of the patient were gradually relieved, her general state gradually improved, the yellowing of the skin and sclera gradually resolved, her total bilirubin level in the re-examination had normalized (24.9 µmol/L), and the other biochemical indicators were basically normal on 28 April 2021. In the subsequent examination, the patient’s NSE level had significantly declined (35.1 µg/L). Then, we continued treatment with tislelizumab plus anlotinib. In total, 21 cycles of tislelizumab combined with anlotinib were completed. We repeated enhanced CT every two cycles to evaluate the curative effect according to the Response Evaluation Criteria in Solid Tumors version 1.1. The patient received tislelizumab 200 mg on day 1 and anlotinib 10 mg on days 1 to 14 of the first five 21-day cycles. The patient experienced chest tightness, suffocation, and chills after the fifth cycle. There was no obvious discomfort after symptomatic treatment. However, the patient refused tislelizumab treatment in the sixth cycle. In cycles 6 to 8, the patient received anlotinib alone at an increased dose of 12 mg. The patient restarted immunotherapy in cycle 9 and continued to receive tislelizumab combined with anlotinib in cycles 9 to 21 (tislelizumab 200 mg on day 1 and anlotinib 12 mg on days 1–14). No liver metastases were detected after two cycles. The lymph nodes in the liver and stomach had shrank, and those next to the middle abdominal artery were enlarged but weakened (Figure 3a2–b2). After four cycles of treatment, some of the metastases had completely disappeared, and the other metastases had shrank (Figure 3a3–b3). After eight cycles, repeated illustrated that the lymph nodes in the abdominal cavity and retroperitoneum had shrank, and the curative effect was stable (Figure 3a4–b4). The patient’s NSE level gradually returned to normal, and it has remained low (Figure 4). We continued the original treatment plan starting in cycle 13. Fortunately, there was no change in CT findings, and the patient experienced no discomfort through 13 cycles of treatment. This patient has received immunotherapy combined with targeted therapy for more than 1 year. Her tumor markers have remained normal on re-examination, and her condition has remained stable on enhanced CT. During treatment, the patient’s thyroid function and levels of cortisol, aldosterone, adrenocorticotropic hormone, and other indicators were not significantly abnormal. The patient tolerated the treatment, and follow-up is ongoing.

We obtained written informed consent for publication from the patient, and the reporting of this study conforms to the CARE guidelines. ⁸ The treatment protocol for this case was approved by the ethics review committee of Dezhou People’s Hospital (ethics batch number: 2022077).

Discussion

ENEC is a relatively rare tumor characterized by obvious invasiveness, easy metastasis, and a somewhat poor prognosis. Given the rarity of ENEC, there has been no systematic description of its clinical features or proposed treatment strategies. ⁹ In prior research, 44% of patients were found to have distant organ metastases, especially liver and lymph node metastases. Histologically, NEC is often associated with SCC or adenocarcinoma. ¹⁰ In this case, enhanced CT at the initial diagnosis revealed multiple lymph node metastases throughout the body, and lymphoma was considered possible. However, gastroscopy and pathology of cervical lymph node tissue obtained via puncture biopsy confirmed the diagnosis of ENEC. Therefore, the possibility of NEC should be considered when we encounter tumors with these macroscopic manifestations. If the histological diagnosis is not NEC, then additional detailed histological examinations such as immunohistochemistry and re-biopsy should be performed. ¹¹ For limited-stage ENEC, surgery combined with postoperative adjuvant chemotherapy is the preferred treatment option. Neoadjuvant chemotherapy and radiotherapy are also under investigation. Advanced extrapulmonary NEC should be treated with chemotherapy regimens suitable for SCLC. Therefore, systemic chemotherapy (with or without radiotherapy) featuring platinum-containing regimens such as EP or IP is the main treatment strategy.^12–13 This patient had a good response to the EP regimen, and although complete remission was initially achieved, rapid progression occurred after six cycles of treatment. However, ENEC has no clear second-line treatment options, thereby complicating this case.

Immune checkpoint inhibitors including PD-1, PD-L1, and CTLA-4 inhibitors have emerged as promising therapeutic options for multiple malignancies, enabling the use immunotherapy in clinical cancer treatment. Monoclonal antibodies against PD-1 and its ligands PD-L1 and PD-L2 have many potential advantages versus chemotherapy such as a long duration of response, low adverse event rates, and efficacy in patients who cannot tolerate or who refuse chemotherapy. ¹⁴ Because of the high incidence of SCLC and large number of clinical studies, the treatment of ENEC can be based on that for SCLC.^4–5 Double-blind, randomized, multicenter, phase III trials demonstrated that atezolizumab (IMpower-133) or durvalumab (CASPIAN) in combination with cisplatin or carboplatin plus etoposide chemotherapy improved overall survival (OS) in patients with extensive-stage SCLC. In the IMpower-133 trial, OS and progression-free survival (PFS) were significantly prolonged by atezolizumab plus combination. Median OS was 12.3 months in the experimental group, versus 10.3 months in the placebo group (hazard ratio [HR] = 0.70; 95% confidence interval [CI] = 0.54–0.91, P = 0.007), whereas median PFS was 5.2 months in the atezolizumab group, compared with 4.3 months in the placebo group (HR = 0.77; 95% CI = 0.62–0.96, P = 0.02). ¹⁵ The CASPIAN trial also had good results. Durvalumab plus chemotherapy significantly improved median OS compared with that in the chemotherapy group. Median OS was 13.0 months in the experimental group, versus 10.3 months in the placebo group (HR = 0.73, 95% CI = 0.59–0.91, P = 0.0047). Median PFS was 5.1 months (95% CI = 4.7–6.2) in patients treated with durvalumab plus EP, compared with 5.4 months (95% CI = 4.8–6.2) in patients treated with EP alone. ¹⁶ For recurrent SCLC, immunotherapy can be used in addition to conventional chemotherapy. The phase I/II CheckMate-032 study recorded objective response rates of 10% in patients with retreated SCLC receiving nivolumab (3 mg/kg) monotherapy, 23% in patients treated with nivolumab (1 mg/kg) combined with ipilimumab (3 mg/kg), and 19% in patients receiving nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg). ¹⁷ In the present case, the patient’s general condition was poor after marked progression on EP chemotherapy, and thus, she could not tolerate chemotherapy. We then considered the use of immunotherapy. Tislelizumab is a humanized IgG4 monoclonal antibody that binds with high affinity to PD-1. The Fc segment of tislelizumab has been genetically engineered to minimize binding to Fc receptors in macrophages and maximize the number and function of effector T cells, thereby increasing its antitumor activity. At the same time, the antibody-binding fragment (Fab fragment) of tislelizumab can specifically bind to PD-1 with higher affinity. In both Asian and non-Asian populations, intravenous monotherapy with tislelizumab at the recommended dose of 200 mg was generally well tolerated, and antitumor activity was achieved regardless of PD-L1 expression. In addition, tislelizumab has been approved for indications in major tumor types. ¹⁸ The efficacy of immunotherapy alone is relatively low, and therefore, we wanted to add targeted therapy based on immunity to increase its efficacy. Anlotinib hydrochloride is a small-molecule multitarget tyrosine kinase inhibitor that can effectively inhibit vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor, c-Kit, and other kinase receptors. Both benign and malignant cells must secrete growth factors to achieve tumor cell growth. Multitarget receptor tyrosine kinases play an inhibitory role in the production of various growth factor receptor kinases in blood vessels, thereby delaying and inhibiting the further spread and metastasis of tumor cells. Therefore, anlotinib inhibits angiogenesis and tumor growth. In a double-blind, randomized, multicenter, phase II trial (ALTER 1202), anlotinib had good clinical efficacy as the third-line or higher treatment for SCLC. Median PFS was 4.3 months in the anlotinib group, versus 0.7 months in the placebo group (HR = 0.19, P < 0.0001). Median OS was 7.3 months in the anlotinib group, compared with 4.9 months in the placebo group. The disease control rate was also superior for the anlotinib group (71.6% vs. 13.2%). ¹⁹ Although targeted therapy produces significant and rapid clinical responses in most patients, acquired resistance typically develops rapidly within months, leading to tumor recurrence. By contrast, immunotherapy can achieve long-term disease control, albeit with limited response rates. Increasing numbers of preclinical studies and clinical trials have demonstrated that targeted drugs can synergize the functions of immune cells and the immune microenvironment. The possible molecular mechanisms include promoting the expression of tumor cell differentiation antigens, stimulating T cell infiltration into the tumor microenvironment, and eliminating immune suppression of the tumor microenvironment.^20–21 In this case, the patient’s disease rapidly progressed after chemotherapy with the EP regimen, after which she received immunotherapy combined with targeted therapy (tislelizumab plus anlotinib). Her condition changed rapidly a few days after the initiation of this treatment, and she developed hyperbilirubinemia. Color Doppler ultrasound revealed a liver mass and intrahepatic and extrahepatic bile duct dilatation, and the patient’s tumor marker levels were elevated. The patient insisted on continuing oral anlotinib treatment. Her symptoms gradually resolved, and her liver function returned to normal after two cycles of monotherapy. No liver mass and bile duct dilatation were found on enhanced CT. Considering that anlotinib alone was effective, the patient has completed 21 cycles of tislelizumab combined with anlotinib. The long-term efficacy of immunotherapy might play a more critical role in the treatment, as indicated by PFS of 16 months. The patient’s OS has reached 21 months, which is rare for advanced ENEC. Moreover, the safety of the treatment regimen has been excellent, and the patient’s tolerance and compliance have been good. The use of immunotherapy combined with targeted therapy has obvious benefits. The results of this case could inform future treatment plans for advanced ENEC, and immunotherapy combined with targeted therapy could represent a new treatment option for this disease.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605231187942 - Supplemental material for Late-stage esophageal neuroendocrine carcinoma in a patient treated with tislelizumab combined with anlotinib: a case report

Supplemental material, sj-pdf-1-imr-10.1177_03000605231187942 for Late-stage esophageal neuroendocrine carcinoma in a patient treated with tislelizumab combined with anlotinib: a case report by Yanqi Zhang, Xiaoyu Liu, Honglu Liang, Weihua Liu, Haiyan Wang and Tao Li in Journal of International Medical Research