Systematic review of case reports of Japanese esophageal neuroendocrine cell carcinoma in the Japanese literature

Abstract

Esophageal neuroendocrine cell carcinoma (NEC) is extremely rare, and its treatment strategy has not been established. Systematic review and meta-analysis were carried out to assess the treatment and prognosis of patients with esophageal NEC in Japan. The Ichushi-Web database was searched from January 1964 to May 2018. In total, 141 cases of esophageal NEC were included in the analysis. The survival of the chemotherapy group with stage II/III esophageal NEC was better than that of the surgery group. Meanwhile, the survival of the adjuvant treatment group with stage II/III esophageal NEC was significantly better than that of the surgery alone group. In patients with stage IV esophageal NEC, no significant differences were observed in terms of treatment response from the three regimens: irinotecan/platinum and etoposide/platinum compared with 5-fluorouracil/platinum. Moreover, no significant differences were observed in the survival of patients who received the chemotherapy regimens. However, the 2-year survival rates of the irinotecan/platinum (26%) group and etoposide/platinum (27%) group were higher than that of the 5-fluorouracil/platinum (0%) group. In esophageal NEC, chemotherapy may be used as the first-line treatment. Irinotecan/platinum or etoposide/platinum can be the first-line regimen for chemotherapy. However, the additive effects of surgery remain unclear.

Introduction

Esophageal neuroendocrine cell carcinoma (NEC) was first reported by McKeown [1]. In Japan, more than 90% of esophageal carcinomas are squamous cell carcinoma (SCC); thus, esophageal NEC only accounts for 0.3% of the cases [2]. The standard therapy for stage II/III esophageal SCC is neoadjuvant chemotherapy, followed by radical surgery. Meanwhile, the standard regimen of neoadjuvant chemotherapy for esophageal SCC is 5-fluorouracil plus cisplatin (FP) [3].

Only few reviews on esophageal NEC have been reported [4–6], and they did not suggest a preferred treatment strategy. The Japanese treatment guideline for NEC [7] showed that the standard chemotherapy regimens for pancreatic and gastrointestinal NEC were irinotecan plus platinum (CP) or etoposide plus platinum (EP). However, neither the standard treatment nor the standard regimen of chemotherapy for esophageal NEC has been established.

Previously, we evaluated the treatment strategy for the several types of rare carcinomas via systematic review and meta-analysis of Japanese case reports in the Ichushi-Web database [8–11]. These articles were referred to practice. Therefore, we performed a systematic review and meta-analysis of Japanese case reports to evaluate the treatment strategy and chemotherapy regimens for esophageal NEC.

Materials and methods

Materials

Between January 1964 and May 2018, we screened case reports in the Ichushi-Web database using the following key words: “esophageal small cell carcinoma” or “esophageal neuroendocrine cell carcinoma.” We identified a total of 170 cases from 140 Japanese case reports on esophageal NEC [12–151]. Among these reports, we excluded 6 patients with unverified age [12–17], 5 with indefinite staging [18–22], 1 with recurrence [96], 2 with unclear survival time [23, 24], 4 who underwent radiation alone without surgery [25–28], 1 who received the best supportive care [62], and 10 who underwent chemotherapy, excluding FP, CP, and EP in stage IV [29–36, 48] (Fig. 1). After excluding more than 29 cases, we analyzed 141 cases to assess for treatment options and chemotherapy regimens.

Fig. 1.

Study profile

Statistical analysis

The Kaplan–Meier survival curves were obtained using the survival time from the start of treatment, as described in the reports. Differences in the survival time were evaluated using the log-rank test. Meanwhile, differences in the response rate were evaluated using the Mann–Whitney U test. Differences in the rate of second-line chemotherapy were valuated using the Fisher’s exact probability test. All statistical analyses were performed with StatMate V for Win&Mac Hybrid (ATMS Co., Ltd., Tokyo, Japan). P values < 0.05 were considered statistically significant.

Results

The median age of the 141 patients was 64 (range: 38–88) years. Of the patients, 111 were men and 30 were women. There were 21, 69, and 51 cases of stage I, II/III, and IV esophageal NEC, respectively. In total, 6, 68, and 67 cases were treated with endoscopic therapy, surgery ± adjuvant chemotherapy, and chemotherapy ± radiation, respectively (Table 1).

Table 1.

Baseline characteristics of the patients

	Number (n = 141)
Median age (years)	64 (38–88)
Gender
Male	111
Female	30
Clinical stage
I	21
Endoscopic therapy	6 (0)
Surgery alone	6 (0)
Surgery plus adjuvant therapy	7 (0)
Chemotherapy ± radiation	2 (1)
II/III	69
Surgery alone	10 (0)
Surgery plus adjuvant therapy	13 (1)
Surgery plus neoadjuvant therapy	18 (4)
Chemotherapy ± radiation	28 (12)
IV	51
Surgery alone	4 (0)
Surgery plus adjuvant therapy	6 (0)
Surgery plus neoadjuvant therapy	4 (0)
Chemotherapy ± radiation	37 (8)
Therapy
Endoscopic therapy	6
Endoscopic submucosal dissection	5 (0)
Endoscopic submucosal dissection	1 (0)
Surgery	68
Surgery alone	20 (0)
Surgery plus adjuvant therapy	26 (1)
Surgery plus neoadjuvant therapy	22 (4)
Chemotherapy	67
5-Fluoropyrimidine plus platinum ± radiation	16 (11)
Irinotecan plus platinum ± radiation	31 (2)
Etoposide plus platinum ± radiation	20 (8)

(): Cases of combination therapy with radiation

The median survival time (MST) of the patients with stage I and II/III esophageal NEC was 25 months. Meanwhile, the MST of patients with stage IV esophageal NEC was 13 months. No statistically significant difference was observed in the overall survival between patients with stage I and II/III esophageal NEC (P = 0.854). Although the difference was not statistically significant, patients with stage IV esophageal NEC showed a poorer survival than those with stage II/III esophageal NEC (P = 0.053). The 5-year survival rates of patients with stage I, II/III, and IV esophageal NEC were 34.1%, 35.8%, and 27.9%, respectively (Fig. 2).

Fig. 2.

Overall survival curves according to each staging

The MST of the surgery alone, adjuvant, and neoadjuvant groups with stage I/II/II esophageal NEC were 9, 31, and 25 months, respectively (Fig. 3). The postoperative adjuvant group showed a significantly higher overall survival than the surgery alone group (P = 0.002). Similarly, the neoadjuvant group showed a significantly higher overall survival than the surgery alone group (P = 0.018). However, no significant difference was observed between the postoperative adjuvant and neoadjuvant groups (P = 0.792). Moreover, no significant difference was found between the chemotherapy ± radiation and neoadjuvant groups (P = 0.895) (Fig. 3).

Fig. 3.

Overall survival curves of patients with stage I/II/III esophageal NEC according to each treatment

The radiation combination rate was 57.1% (4/7) in the FP group, 4.7% (1/21) in the CP group, and 33.3% (3/9) in the EP group with stage IV esophageal NEC. The MST of the FP, CP, and EP groups were 13, 13, and 15 months, respectively (Fig. 4). No significant difference was observed in the survival rate of the CP, EP, and FP groups with stage IV esophageal NEC. However, the CP and EP groups showed a higher 2-year survival rate than the FP group (0%, 26%, and 27%, respectively) (Fig. 4).

Fig. 4.

Overall survival curves of patients with stage IV esophageal NEC according to each treatment

We summarized the efficacy of chemotherapy in patients with stage IV esophageal NEC (Fig. 5). The treatment responses of the FP group were as follows: CR, 4 cases; PR, 1 case; SD, 1 case; and unknown, 1 case. The treatment responses of the CP group were as follows: CR, 3 cases; PR, 15 cases; PD, 2 cases; and unknown, 1 case. The treatment responses of the EP group were as follows: CR, 3 cases; PR, 3 cases; and unknown, 3 cases (Fig. 5). We compared the response rates of the treatment groups. No significant difference was observed between the FP and CP groups (P = 0.078). Moreover, no significant difference was found between the FP and EP groups (P = 0.855). The CP and EP groups did not significantly differ (P = 0.970).

Fig. 5.

Overall response of patients with stage IV esophageal NEC according to each treatment

Then, we summarized the second-line chemotherapy (Fig. 6). In the first-line FP group, 2 of 6 patients were treated with chemotherapy as the second-line treatment. In the other three patients, two were treated with radiation and one did not receive any second-line treatment. In the CP group, 13 of 20 patients were treated with chemotherapy as second-line treatment. In the other 7 patients, 4 were treated with radiation and 2 underwent endoscopic treatment. In the EP group, 2 of 9 patients were treated with chemotherapy as second-line treatment. In the other 7 patients, 3 were treated with radiation and 4 did not receive any second-line treatment. Therefore, the rate of the second-line chemotherapy after FP was 50% (3/6). Meanwhile, the rates after CP and EP were 65% (13/20) and 22.2% (2/9), respectively. Thus, the first-line EP group less likely received second-line treatment than the first-line CP group (P = 0.044).

Fig. 6.

Number of second-line chemotherapy enforcements according to each treatment for individuals with stage IV esophageal NEC

Discussion

We found 141 cases of esophageal NEC in the Ichushi-Web database. Based on the systematic review and meta-analysis of such database, chemotherapy may be used as the first-line treatment for individuals with stage I/II/III esophageal NEC. CP or EP therapy may be used as the first-line chemotherapy for stage IV esophageal NEC.

The 5-year survival rate of patients with stage I esophageal squamous cell carcinoma was 76.8% [3]. However, in the present study, the 5-year survival rate of patients with stage I esophageal NEC was as low as 34.1%. Therefore, patients with stage I esophageal NEC must be strictly followed up.

Neoadjuvant chemotherapy, followed by radical surgery, was a standard treatment for patients with stage II/III esophageal squamous cell carcinoma in Japan [3]. Similarly, according to our results, adjuvant chemotherapy may improve the survival of patients with stage I/II/II esophageal NEC. The best timing for adjuvant chemotherapy was not clearly presented in the current study. Moreover, the significance of surgery was not clear because there was no significant difference between the surgery plus neoadjuvant chemotherapy group and the chemotherapy ± radiation group.

Sugiura et al. have summarized several case reports between 1980 and 2002, and they have reported that the 5-year survival rate and MST were only 2% and 6 months in individuals with stage IV esophageal NEC [68]. Our present data showed a significantly better prognosis than that in the report of Sugiura. Such discrepancy may be explained by the frequency of chemotherapy in patients with stage IV esophageal NEC. After 2003, 80% (33/41) of patients with stage IV esophageal NEC were treated with chemotherapy. The treatment response rate for CPT-11-based therapy for lung carcinoma was significantly higher in patients with extensive small cell carcinoma than those with non-small cell carcinoma (more than 60% versus 40%, respectively) [152–156]. Similarly, because esophageal NEC was also sensitive to CPT-11, the improvement of patients’ survival might be reflected by the use of CPT-11.

Noda et al. have reported that patients who received CP showed a significantly higher survival than those who received EP for extensive small cell lung carcinoma [155]. After this report, CP was generally used for NEC of various types of carcinoma in Japan. However, EP therapy is often used in western countries because two reports have shown that there was no significant difference in the survival of individuals who received CP and EP for small cell lung carcinoma [156, 157]. Similarly, Yamaguchi et al. have also reported that the response rates of CP and EP were similar in patients with gastrointestinal NEC [158]. Thus, the first-line chemotherapy regimen for esophageal NEC should be determined in the future. One of the proposals on how to determine the first-line chemotherapy could be based on adverse events. Because Yamada et al. have reported that CPT-11 when combined with radiation therapy causes 28.3% of grade 2 or higher pneumonitis [159], CP therapy should not be used with radiation therapy. We proposed a treatment algorithm on how to select the first-line regimen in Fig. 7. EP + radiation therapy might be selected for cases where primary tumor needs radiotherapy. And CP therapy might be selected for cases where the primary tumor does not require radiotherapy.

Fig. 7.

Treatment algorithm model

Regarding the second-line chemotherapy regimen, topotecan or amrubicin is generally used as second-line treatment for lung NEC [160]. von Pawel et al. have reported that patients with refractory lung NEC who received amrubicin treatment had a statistically significant survival benefit than those who received topotecan [161]. However, the second-line regimen for esophageal NEC remains controversial.

The present study had a limitation. That is, the study was a meta-analysis based on case reports in the Ichushi-Web database. Therefore, the collected cases may have some selection biases. In particular, it could have included more good responders and/or long-time survivors. Thus, consecutive cases based on a large-scale multicenter study must be assessed.

In conclusion, chemotherapy should be the first-line treatment for esophageal NEC. Irinotecan/platinum or etoposide/platinum may be used as the first-line regimen. However, the additive effects of surgery remain unclear.

Abbreviation

NEC

Neuroendocrine cell carcinoma

Conflict of interest

The authors have no conflicts of interest associated with this manuscript.

Ethical statement

This article does not contain any studies with human participants or animals performed by any of the authors.

Ethical approval

Ethical approval is not required because all data in this study uses Ichushi-Web database.

Informed consent

Informed consent is not required because all data in this study uses Ichushi-Web database.