Salvage camrelizumab plus apatinib for relapsed esophageal neuroendocrine carcinoma after esophagectomy: a case report and review of the literature

ABSTRACT

The current evidence regarding immunotherapy plus targeted therapy in esophageal neuroendocrine carcinoma (NEC) is lacking. Camrelizumab is a programmed cell death protein 1 inhibitor. Apatinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2. A 50-year-old female was initially diagnosed as primary esophageal NEC. Neoadjuvant chemotherapy and Ivor Lewis esophagectomy were performed (ypT3N0M0, stage Ⅱ). Twenty months after the surgery, an isolated mediastinal lymph node recurrence of NEC was recorded. The specimen revealed a positive expression of vascular endothelial growth factor and programmed cell death ligand 1. The diseased lymph node was slightly enlarged after two cycles of first-line paclitaxel liposome and S-1. Second-line apatinib and S-1 for 2 months also resulted in progressive disease. Subsequently, third-line camrelizumab plus apatinib was continued for 5 months. The patient demonstrated a progression-free status for more than 10 months following the combination therapy. Meanwhile, relevant studies of camrelizumab in gastric or esophageal cancer were briefly reviewed. Based on the current evidence, camrelizumab is a promising agent for esophageal cancer. More prospective trials are warranted before a definite recommendation could be drawn.

Introduction

Esophageal cancer is among the deadliest neoplasms around the world and ranks sixth cancer-related mortality.¹ Esophageal neuroendocrine cell carcinoma (NEC) is extremely rare, accounting for approximately 1% of esophageal cancer.² The treatment strategy for this uncommon disease has not been well established. A review of 141 esophageal NEC cases in Japan showed that chemotherapy provided better survival in stage I/II esophageal NEC patients than surgery;³ meanwhile, adjuvant treatment was also beneficial to stage II/III cases as compared with surgery alone. Therefore, the authors concluded that chemotherapy (irinotecan/etoposide and platinum) may be the first-line treatment option in esophageal NEC, whereas the additive effect of surgery remains unclear.

The newly emerged immunotherapy and antiangiogenic agents are expected to be effective in esophageal NEC. In terms of immunotherapy, a programmed cell death protein 1 (PD-1) inhibitor pembrolizumab has been approved for second-line treatment of PD ligand 1 (PD-L1)-positive esophageal squamous cell carcinoma (ESCC) and adenocarcinoma. Although 90% of esophageal cancer patients show up-regulated epidermal growth factor receptor (EGFR), anti-EGFR therapy has not been proved to improve the survival; therefore, better treatment options are urgently needed.⁴ Camrelizumab (SHR-1210), a PD-1 inhibitor, has been approved in China on 29 May 2019 for the treatment of relapsed or refractory classical Hodgkin lymphoma.⁵ This agent is also being investigated in esophageal and gastric cancer. Apatinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor-2. The first human phase 1 trial in Australian population (NCT02492789) showed that camrelizumab had manageable toxicity and encouraging preliminary activity in advanced solid tumors.⁶

To date, there are no guidelines or consensus on the optimal therapeutic regimen for relapsed esophageal NEC patients who cannot endure chemoradiotherapy (CRT) or reoperation. Herein a relapsed esophageal NEC in an isolated lymph node after esophagectomy treated by third-line camrelizumab plus apatinib was presented. The patient demonstrated a progression-free survival for more than 10 months (5 months after the discontinuation of immunotherapy). Meanwhile, the related reports in terms of camrelizumab for advanced gastric or esophageal cancer patients were reviewed.

Case presentation

A 50-year-old female nonsmoker was referred to the hospital in May 2016 due to gradually aggravated dysphagia and body weight loss in the preceding 2 months. Her previous medical history was unremarkable. Physical examination showed that the superficial supraclavicular lymph nodes were not obviously enlarged. The laboratory findings reported normal serum tumor marker levels including carcinoembryonic antigen, carbohydrate antigen 19–9, squamous cell carcinoma antigen, and neuron-specific enolase. Computed tomography (CT) and x-ray of the chest revealed wall thickening and stenosis of the middle and lower thoracic esophagus, respectively, indicating esophageal tumor (Figure 1). Endoscopy revealed that the upper margin of tumor was about 27 cm away from the incisors, and well-differentiated primary esophageal NEC was confirmed by pathology. The cells in the specimen were stained for chromogranin A and synaptophysin. No evidence of distant metastases was detectable in contrast-enhanced CT images.

Figure 1.

The esophageal tumor (indicated by arrows) before esophagectomy. a. X-ray on admission revealed stenosis of esophagus; b. CT images showed almost obstruction of the middle esophagus; c. After 2 cycles of irinotecan and cisplatin, the lesion was slightly shrunk

Neoadjuvant treatment followed by surgery with curative intent was scheduled according to the multidisciplinary consultation. After 2 cycles of irinotecan (65 mg/m² of body surface area) and cisplatin (75 mg/m² of body surface area) in a 21-d schedule, partial remission of the esophageal lesion (Figure 1) was indicated according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). However, the patient developed grade 4 leukocytopenia and thrombocytopenia according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Granulocyte colony-stimulating factor was administered until her blood cell counts recovered into normal range.

Additional preoperative chemotherapy and radiotherapy were not conducted. Three weeks after the induction therapy, a hybrid minimally invasive Ivor Lewis esophagectomy with two-field lymph node dissection and gastric tube reconstruction was performed. A total of 27 lymph nodes were harvested. The postoperative recovery was mainly uneventful. R0 resection was achieved, and lymph node metastasis was not observed. The postoperative diagnosis was primary esophageal NEC (ypT3N0M0, Stage Ⅱ) according to the 8th edition of staging system for esophageal cancer.⁷ Prophylactic thoracic radiotherapy (46 Gy/23 fractions) was conducted because the lymph node status before the induction chemotherapy was unknown.

Twenty months after the operation, the patient was readmitted in May 2018 because of fatigue and poor appetite. Her Eastern Cooperative Oncology Group score was 2. The serum tumor biomarkers were in normal range. The CT images revealed an isolated enlarged mediastinal lymph node about 12 mm in diameter (Figure 2a), in suspicious of tumor recurrence. An endoscopic ultrasonography-guided biopsy confirmed local recurrence of NEC, with positive expression of VEGF and PD-L1. Other metastasis was excluded by cranial magnetic resonance and bone emission CT.

Figure 2.

The images of the relapsed lymph node (indicated by arrows). a. CT showed an enlarged, isolated lymph node. b. The lymph node was slightly enlarged after 2 cycles of first-line paclitaxel liposome and S-1. c. The lymph node showed a progressive disease after 2 months of second-line apatinib and S-1. d. The diseased lymph node was significantly shrunk after 3 months of camrelizumab and apatinib. e. The target lymph node remained stable 5 months after discontinuation of therapy

The patient refused reoperation for lymphadenectomy or radiotherapy. Therefore, first-line paclitaxel liposome (135 mg/m² of body surface area every 21 d) and S-1 (60 mg, twice daily for 4 weeks with a 2-week interval) was administered because of the severe hematologic toxicities associated with irinotecan and platinum. However, the lymph node showed stable disease after two cycles of chemotherapy (Figure 2b). Grade 2 thrombocytopenia, elevated serum aspartate aminotransferase and alanine aminotransferase, and grade 3 diarrhea were reported and controlled efficiently. Second-line oral apatinib (250 mg, once daily) plus S-1 (40 mg, twice daily for 4 weeks with a 2-week withdrawal) was given since August 2018. However, after two cycles of treatment, the diseased lymph node was obviously enlarged in November 2018 (Figure 2c). Meanwhile, hypertension and impaired hepatic function were recorded. S-1 was then discontinued due to grade 4 leukocytopenia and grade 3 diarrhea. Subsequently, salvage camrelizumab (200 mg once, every 2 weeks) plus apatinib (250 mg, once daily) was initiated since December 2018. Encouragingly, this regimen demonstrated efficacy 3 months later (Figure 2d). Grade 3 rashes were resolved spontaneously. No grade 4 toxicity was observed. This therapeutic regimen was discontinued for financial reasons in May 2019. However, the diseased lymph node remained stable after camrelizumab interruption for another 5 months in October 2019 (Figure 2e). The patient reported a progression-free survival (PFS) of more than 10 months since the initiation of immunotherapy plus antiangiogenic therapy.

Discussion

The histotypes of esophageal NEC include high-grade small and large cell carcinomas and low-grade carcinoid tumors.⁸ The optimal treatment strategy for esophageal NEC has not been established, partly due to its rarity. The investigation of neoadjuvant or adjuvant immunotherapy is needed. It is reported that neoadjuvant chemoradiotherapy (elective nodal irradiation or involved-field irradiation) combined with surgery might be the optimal treatment for resectable esophageal cancer;⁹ however, although the addition of radiotherapy to neoadjuvant chemotherapy resulted in a higher R0 resection rate and pathologic complete response rate, it did not obviously impact the survival.¹⁰ For the present case, besides chemotherapy and immunotherapy, some reasonable local therapeutic options including cyberknife and stereotactic body radiotherapy could also be considered for the solitary lymph node with recurrent NEC.

To date, with the exception of ramucirumab, evidence for the efficacy of palliative treatments for esophageal and gastroesophageal cancer is lacking.¹¹ The role of surgery in esophageal NEC and the selection of patients who might benefit from surgery remain unclear. A retrospective analysis of 72 patients with resectable limited esophageal NEC showed a median survival time of 21.5 months.¹² On the other hand, the optimal management of locoregional recurrence of esophageal cancer is still controversial.¹³ Salvage cervical lymphadenectomy could achieve locoregional disease control with prolonged survival of the patients.^14,15 Furthermore, elective lymph node irradiation might also be feasible.¹⁶ Intensity-modulated radiotherapy and elective nodal irradiation might be superior to involved-field irradiation.¹⁷

We searched PubMed, Web of Science, Scopus, Embase, Europe PMC, Cochrane Library, and Google Scholar for reported trials of camrelizumab for the treatment of esophageal or gastric cancer up to June 2020. Keywords and MeSH terms in title or abstract including “esophageal” or “oesophageal” or “esophagus” and “camrelizumab” or “SHR-1210” were used. No restriction was made regarding the publication language. Finally, a total of seven trials and one case report were retrieved. The features of these reports are summarized in Table 1. The sample size in the treatment group of the trials was 19 ~ 228 patients. Among them, 6 studies involving 385 esophageal or gastric cancer patients presented a definite objective response rate (ranging from 17.4% to 73.1%) using camrelizumab. Huang et al. enrolled 30 chemotherapy-refractory ESCC patients receiving camrelizumab, and 10 patients (33.3%) had an objective response while the median PFS was 3.6 months.¹⁹ Xu et al. reported that camrelizumab (200 mg every 2 weeks) plus apatinib (125–500 mg once daily) demonstrated manageable toxicity, whereas the recommended dosage for apatinib was 250 mg.²¹ Wang et al. found that the elevated serum lactate dehydrogenase might be a prognostic factor.²² Furthermore, Huang et al. randomly assigned 228 ESCC patients to camrelizumab (200 mg every 2 weeks) group and 220 cases to chemotherapy (docetaxel or irinotecan) group;²⁴ and the median overall survival was significantly prolonged in the camrelizumab group as compared with the control (8.3 months vs 6.2 months); meanwhile, serious treatment-related adverse events and treatment-related deaths occurred in 37 (16%) and 7 (3%) patients, respectively, in the camrelizumab group. Based on the current evidence, only a small proportion of patients with advanced ESCC could benefit from camrelizumab; in addition, the reliable efficacy biomarkers have not been identified. Well-designed trials are warranted to elucidate the criteria of patient selection, biomarkers for efficacy prediction, optimal dosage, and treatment duration. The registered trials of camrelizumab for esophageal or gastroesophageal cancer are listed in Table 2.

Table 1.

Previous clinical studies of camrelizumab for the treatment of gastric or esophageal cancer

First author (year)	Study design (identifier)	Tumor type and stage	No. of patients	PD-L1 positive (≥1%), n (%)	Treatment lines	Regimen	Treatment duration	Objective response rate	Median PFS (95% CI)	Median OS (95% CI)	Adverse events ≥grade 3
Mo (2018)18	Phase 1 study	Advanced ESCC/GC	19	NA	≥ 2nd	60 mg with escalation to 200 and 400 mg	3.2 (0.5–19.3) months	NA	NA	NA	NA
Huang (2018)19	Phase I trial (NCT02742935)	Recurrent or metastatic ESCC	30	5 (16.7%)	2nd and beyond	60 mg with escalation to 200 and 400 mg	18.1 (2.0–38.1) weeks	33.3% (10/30)	3.6 (0–7.2) months	NA	2 pneumonitis; 1 increased cardiac troponin I
Huang (2019)20	Phase 1 trial (NCT02742935)	Recurrent or metastatic gastric/GEJ adenocarcinoma	30	15 (50.0%)	2nd and beyond	60 mg with escalation to 200 and 400 mg	11.2 (2.0–73.9) weeks	23.3% (7/30) with 1 CR	8.0 (7.9–8.1) weeks	NA	1 pruritus; 1 interstitial lung disease
Xu (2019)21	Phase 1 trial (NCT02942329)	GC, GEJ cancer	25	NA	2nd and beyond	200 mg every 2 weeks plus apatinib	5.1 (1.3–15.7) months	17.4% (4/23)	2.9 (2.5 − 4.2) months	11.4 (8.6-not reached) months	NA
Wang (2019)22	Phase I trial	Advanced ESCC	43	NA	2nd and beyond	60 mg with escalation to 200 and 400 mg	NA	25.6% (11/43) with 1 CR	2.0 (0–4.1) months	8.0 (7.2–8.8) months	NA
Zhang (2019)23	Phase II study	Advanced or metastatic ESCC	29	NA	1st	200 mg; plus paclitaxel/nedaplatin + apatinib	6–9 cycles	73.1% (19/26)	not reached	not reached	Leukopenia; neutropenia
Huang (2020)24	Phase III trial (NCT03099382, ESCORT)	Advanced or metastatic ESCC	228	93 (40.8%)	2nd	200 mg, d 1	NA	20.2% (46/228) with 1 CR	1.9 (1.9–2.4) months	8.3 (6.8–9.7) months	6 anemia; 4 impaired hepatic function
Wang (2020)25	Case report (CTR20170307)	ESCC	1	PD-L1 negative; EGFR exon 2–28 duplication	2nd	400 mg, d 1	4 weeks	Hyperprogression; liver metastasis	NA	NA	NA

PD-L1, programmed cell death protein ligand 1; ESCC, esophageal squamous cell carcinoma; GC, gastric cancer; GEJ, gastroesophageal junction; PFS, progression-free survival; OS, overall survival; CR, complete remission; CI, confidence interval; NA, not available.

Table 2.

The registered trials of camrelizumab for the treatment of esophageal or gastroesophageal junction cancer

Identifier	Year	Study design	Tumor type	Treatment lines	Regimen	Estimated enrollment	Primary outcomes	Status	Country
NCT03691090	2018	Double-blinded RCT	Esophageal cancer	1st	Carelizumab + paclitaxel + cisplatin	548	PFS, OS	Recruiting	China
NCT03603756	2018	Non-randomized, parallel assignment	ESCC	1st	Carelizumab + apatinib + irinotecan/paclitaxel liposome + nedaplatin	30	PFS	Recruiting	China
NCT04208347	2019	Parallel RCT	Gastric/gastroesophageal junction adenocarcinoma	Perioperative	Camrelizumab + apatinib + SOX	Total: 258	Major pathological response	Recruiting	China
NCT04390945	2020	Single-arm	Recurrence after esophageal cancer surgery	1st	Camrelizumab + chemoradiotherapy	57	PFS	Not yet recruiting	China
NCT04286958	2020	Single-arm	ESCC	Consolidation therapy	Camrelizumab	40	PFS	Not yet recruiting	China
NCT04342910	2020	Parallel RCT	Gastric/gastroesophageal junction adenocarcinoma	2nd	Carelizumab + apatinib	Total: 550	OS	Not yet recruiting	China
NCT04426955	2020	Parallel RCT	ESCC	1st	Camrelizumab + paclitaxel + cisplatin + radiotherapy	Total: 390	PFS	Not yet recruiting	China
ChiCTR1900028349	2019	Parallel RCT	Gastric/gastroesophageal junction adenocarcinoma	Neoadjuvant	Camrelizumab + apatinib + SOX	86	Major pathological response	Not yet recruiting	China
ChiCTR1900027275	2019	Single-arm	Esophageal cancer	NA	Camrelizumab	150	PFS	Recruiting	China
ChiCTR2000033252	2020	Single-arm	ESCC	1st	Camrelizumab + docetaxel + carboplatin	30	pCR	Recruiting	China
ChiCTR2000032189	2020	Single-arm	Gastrointestinal malignancies	1st	Camrelizumab	500	ORR, PFS	Recruiting	China
ChiCTR2000032093	2020	Non randomized control	ESCC	1st	Camrelizumab + lactobacillus paracasei	20	PFS	Recruiting	China
ChiCTR2000029807	2020	Single-arm	ESCC	Neoadjuvant	Camrelizumab + albumin paclitaxel/capecitabine	47	pCR	Recruiting	China
ChiCTR2000028900	2020	Single-arm	ESCC	Neoadjuvant	Camrelizumab + albumin paclitaxel + carboplatin	20	Safety	Recruiting	China
ChiCTR2000033761	2020	Single-arm	ESCC	Neoadjuvant	Camrelizumab + paclitaxel + nedaplatin	70	pCR	Not yet recruiting	China
ChiCTR2000032284	2020	Single-arm	ESCC	Neoadjuvant	Camrelizumab + docetaxel + nedaplatin	20	pCR, R0 resection	Not yet recruiting	China
ChiCTR2000030610	2020	Parallel RCT	Gastric/gastroesophageal junction adenocarcinoma	Neoadjuvant	Camrelizumab + FLOT	30	pCR, R0 resection	Not yet recruiting	China
ChiCTR2000029419	2020	Parallel RCT	ESCC	Neoadjuvant	Camrelizumab + DCF	33	R0 resection, PFS	Not yet recruiting	China
ChiCTR2000033622	2020	Single-arm	Esophageal cancer	NA	Camrelizumab + radiotherapy	116	OS	Not yet recruiting	China
ChiCTR2000033308	2020	Parallel RCT	ESCC	1st	Camrelizumab + radiotherapy	85	ORR	Not yet recruiting	China
ChiCTR2000032372	2020	Single-arm	ESCC	1st	Camrelizumab + nedaplatin + S-1	30	DFS	Not yet recruiting	China
ChiCTR2000032038	2020	Single-arm	Gastric/gastroesophageal adenocarcinoma	2nd	Camrelizumab + irinotecan + apatinib	85	OS	Not yet recruiting	China
ChiCTR2000031077	2020	Single-arm	ESCC	1st	Camrelizumab + chemoradiotherapy	20	PFS	Not yet recruiting	China
ChiCTR2000029717	2020	Single-arm	HER2-positive gastric/gastroesophageal junction adenocarcinoma	1st	Camrelizumab + pyrotinib maleate + oxaliplatin/carboplatin	40	Maximal tolerable dose, PFS	Not yet recruiting	China
ChiCTR2000028857	2020	Single-arm	ESCC	2nd	Camrelizumab + apatinib + irinotecan	65	PFS	Not yet recruiting	China

ESCC, esophageal squamous cell carcinoma; pCR, pathological complete remission; DFS, disease-free survival; PFS, progression-free survival; OS, overall survival; SOX, S-1 + oxaliplatin; DOX, docetaxel + oxaliplatin + carboplatin; FLOT, docetaxel + oxaliplatin + calcium folinate + fluorouracil; DCF, docetaxel + cisplatin + fluorouracil; ORR, objective response rate; DCR, disease control rate; HER2, human epidermal growth factor receptor-2; NA, not available.

Antiangiogenic drugs offer a modest survival benefit and rare durable responses while immunotherapy relies on the accumulation and activity of the immune effector cells within the tumor microenvironment; therefore, antiangiogenic therapy plus immune checkpoint inhibitors might increase the antitumor effect.²⁶ A preclinical experiment in mouse models demonstrated that low-dose VEGF receptor 2 inhibitor apatinib can enhance the efficacy of PD-1/PD-L1 blockade through modulating the tumor immunosuppressive microenvironment.²⁷ A pooled analysis showed that camrelizumab-activated multiple antigen-specific cellular therapies combined with apatinib could further improve the objective response rate and the PFS of the patients with advanced solid tumor.²⁸ For instance, ramucirumab plus apatinib is viable in esophagogastric cancer; nevertheless, this treatment regimen provides a limited benefit for unselected patients.²⁹ It is noteworthy that the immune checkpoint inhibitors are associated with several immune-related adverse events due to the disruption of self-tolerance.³⁰ Although most of the toxic effects are reversible, deaths due to myocarditis, pneumonitis, colitis, and neurologic events can occur.³¹ Additionally, Wang et al. reported a case of hyperprogression to camrelizumab.²⁵ The patient with EGFR exon 2–28 duplication demonstrated rapid progression of the primary ESCC and newly emerged liver metastasis after 4 weeks of camrelizumab; therefore, the ongoing trials should be conducted with regular CT restaging under strict supervision.

Conclusions

The promising efficacy and manageable safety profile of camrelizumab in gastric and esophageal cancer have been primarily established according to the current published trials; furthermore, we reported the first responded case of lymph node recurrence from NEC treated by this anti-PD-1 agent plus apatinib. More and better evidence are warranted to confirm this occasional finding.

Funding Statement

This study was supported by the Innovative and Entrepreneurial Talent Introduction Plan of Jiangsu Province (No. 2-2016SC01).

Disclosure of potential conflicts of interest

All authors have declared no potential conflicts of interest.

Ethical statement

This report was approved by the Institutional Review Board and the Medical Ethics Committees of Xuzhou Central Hospital. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. The clinical data were presented anonymously.