Introduction: Neuroendocrine carcinoma (NEC) is characterized by a poor prognosis and is generally treated with platinum and etoposide combination therapy as first-line chemotherapy. However, it remains uncertain whether carboplatin and etoposide combination therapy (CE) and cisplatin and etoposide combination therapy (PE) have comparable treatment efficacy. In this retrospective analysis, we compared the efficacy and safety of CE and PE in patients with NEC. Methods: We retrospectively reviewed the patient’s clinical record from 2005 to 2022 at the Department of Medical Oncology, Tohoku University Hospital. Patients who received either CE or PE were included in the study. Statistical analyses were performed using JMP Pro 16.0 (SAS Institute Inc., Cary, NC, USA). Results: A total of 104 patients were enrolled, with 73 patients assigned to the CE group and 31 patients assigned to the PE group. Statistically, the response rate, progression-free survival time and overall survival time were 42.6%, 5.1 months (95% CI: 3.5–6.3) and 13.6 months (95% CI: 8.9–17.4), respectively, in the CE groups and 44.4%, 5.6 months (95% CI: 3.1–7.0) and 12.5 months (95% CI: 11.2–14.6), respectively, in the PE groups. There was no significant difference in treatment efficacy between the CE and the PE groups. However, the number of patients with elevated creatinine (3.35 mg/dL and 3.88 mg/dL in 2 patients, respectively) was significantly higher in the PE group than in the CE group. Conclusion: The efficacy of CE and PE in patients with NEC is comparable. However, the incidence of renal dysfunction was found to be significantly higher in the PE group than in the CE group.

Neuroendocrine tumors (NETs) are epithelial tumors that can arise in various organs: [1]. The grading of NETs involves the use of the Ki-67 index. Based on the Ki-67 index, NETs are classified into three grades. NETs with a Ki-67 index of less than 3% are classified as NET G1, those with a Ki-67 index of 3–20% are classified as NET G2, and those with a Ki-67 index of more than 20% are classified as NET G3 [1]. NETs with a Ki-67 index greater than 20% and histopathologic features such as poor differentiation, p53 overexpression, and Rb loss are neuroendocrine carcinomas (NECs). The prognosis of patients with NEC is reported to be worse than that of NET: [2]. Due to the rapid growth of the disease, patients diagnosed with NEC often present with distant metastases. Therefore, the primary treatment of NEC involves the administration of systemic anticancer drugs. Platinum and etoposide combination therapy has emerged as the first-line chemotherapy for patients with NEC [3‒7]. A previous meta-analysis reported similar therapeutic effects and different profile of adverse event (AE) profiles between carboplatin and etoposide combination therapy (CE) and cisplatin and etoposide combination therapy (PE) in patients with the small-cell lung cancer [8]. However, no previous prospective study has yet compared the efficacy of CE and PE, specifically for patients with NEC. Two retrospective studies have compared the efficacy of CE and of PE for patients with NEC [9, 10]. In one of these studies, the overall survival time (OS) of PE in patients with NEC was found to be significantly longer than that of CE; however, information on overall response rate (ORR), progression-free survival time (PFS), or AEs was lacking [10]. Conversely, the other study reported comparable treatment efficacy (PFS, OS, and ORR) between CE and PE, although without providing background information on the patients in each group [9]. Therefore, it remains unclear whether the previous study adequately compared the treatment efficacy of CE and PE between balanced patient groups [9]. Therefore, the suitability of the platinum regimens for patients with NEC remains uncertain, and a prospective comparative study is needed to clarify this issue. However, due to the rarity of NEC [11], conducting a prospective study comparing the efficacy and safety of CE and PE in these patients is challenging. Therefore, it is important to accumulate results from retrospective studies comparing the efficacy and safety of the CE and the PE in patients with NEC. In the present study, we retrospectively analyzed the efficacy and safety of CE and PE in patients with advanced NEC treated at the Department of Medical Oncology, Tohoku University Hospital.

Patients

We retrospectively reviewed the medical records between 2005 and 2022 at the Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan.

Inclusion criteria were as follows:

  • 1.

    Patients with a histopathologic diagnosis of NEC.

  • 2.

    Patients who received at least one course of either CE or PE.

Treatment Methods

The dosing and schedule for CE and PE are described below:

CE: intravenous administration of carboplatin area under the blood concentration-time curve 5) on day 1, and intravenous administration of etoposide 80 mg/m2 from day 1 to day 3. This regimen was repeated every 3 weeks [12].

PE: intravenous administration of cisplatin 80 mg/m2 on day 1, and intravenous administration of etoposide 100 mg/m2 from day 1 to day 3. This regimen was repeated every 3 weeks [13].

Evaluations and Statistical Analyses

Responses were evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1 [14]. Response rate and the disease control rate (DCR) were calculated as follows:

Response rate: (number of patients with complete response [CR] + partial response [PR])/(number of patients with CR + PR + stable disease [SD] + progressive disease [PD]).

Disease control rate: (number of patients with CR + PR + SD)/(number of patients with CR + PR + SD + PD).

PFS was defined as the period from the initiation of chemotherapy to confirmation of disease progression (radiological or clinical progression or death). OS time was defined as the period from the initiation of the chemotherapy to confirmation of patient death. Hematologic toxicities were assessed and graded according to the Common Terminology Criteria for Adverse Events version 5.0: [15].

Statistical Analyses

Fisher’s exact test was used to calculate p values for differences in number of patients between two groups, differences in response rate between two groups, and differences in the percentage of >grade 3 AEs between the CE group and the PE group. The Pearson χ2 test was used to calculate the 0.05 of p value for differences in age or Charlson’s comorbidity index between two groups. Median OS and median PFS were calculated using the Kaplan-Meier method. All statistical analyses in this study were performed using JMP Pro 16.0 (SAS Institute Inc., Cary, NC, USA).

Institutional Review Board Statement

This study protocol was approved by the Ethics Committee of Tohoku University Hospital (approval number: 2023-1-169). The Tohoku University Hospital Ethics Committee granted permission to conduct retrospective studies without obtaining informed consent statements from patients (opt-out system). All data in the current study were de-identified and kept confidential. The present study adhered to the tenets of the Declaration of Helsinki.

Patient’s Characteristics

A total of 104 patients were included in the present study, with 73 patients assigned to the carboplatin-etoposide-treated group (CE group) and 31 patients were assigned to the cisplatin-etoposide-treated group (PE group). The patient’s background is described in Table 1. The CE group included 48 patients (65.8%) with gastroenteropancreatic NEC and the PE group included 19 patients (61.3%) with gastroenteropancreatic NEC. In addition, the CE group included 10 patients (13.7%) and the PE group included 5 patients (16.1%) with mixed type neuroendocrine neoplasm (MiNEN), respectively. Over 70% of patients in both groups (86.3% in the CE group and 74.2% in the PE group) received platinum and etoposide combination therapy as the first-line chemotherapy. The mean Charlson comorbidity index was 2.65 (range 0–6) in the CE group and 2.48 (range 0–4) in the PE group. In addition, over 80% of patients in both groups had an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 [16]. No significant differences were observed between the two groups with regard to sex, age, primary organ, number of patients with MiNEN, line of chemotherapy, Charlson comorbidity index, and ECOG PS.

Table 1.

Patient’s characteristics

Carboplatin-etoposide (CE) (n = 73)Cisplatin-etoposide (PE) (n = 31)p value
Sex, n (%)   0.57 
 Male 45 (61.6) 18 (58.1)  
 Female 28 (38.4) 13 (41.9)  
Age    
 Mean (range) 65.7 (41–83) 59.2 (41–76) 0.24 
Primary organ, n (%) 
Gastroenteropancreatic system, n (%) 48 (65.8) 19 (61.3) 0.58 
 Pancreas 14 (19.2) 5 (16.1)  
 Esophagus 13 (17.8) 3 (9.7)  
 Stomach 12 (16.4) 5 (16.1)  
 Colorectum 5 (6.8) 5 (16.1)  
 Duodenum 3 (4.1) 1 (3.2)  
 Small intestine 1 (1.4) 0 (0.0)  
Non-gastroenteropancreatic system 25 (34.2) 11 (38.4) 0.53 
 CUP 11 (15.1) 6 (19.4)  
 Prostate 3 (4.1) 0 (0.0)  
 Bile duct 3 (4.1) 1 (3.2)  
 Kidney 2 (2.7) 0 (0.0)  
 Head and neck 2 (2.7) 2 (6.5)  
 Urinary bladder 1 (1.4) 0 (0.0)  
 Lung 1 (1.4) 2 (6.5)  
 Breast 1 (1.4) 0 (0.0)  
 Liver 1 (1.4) 0 (0.0)  
 Adrenal gland 0 (0.0) 1 (3.2)  
MiNEN, n (%) 10 (13.7) 5 (16.1) 0.56 
Ki-67, n (%) 
 ≥55% 49 (67.1) 24 (77.4) 0.31 
 <55% 24 (32.9) 7 (22.6)  
Line of chemotherapy, n (%) 
 1st 63 (86.3) 23 (74.2) 0.45 
 2nd 6 (8.2) 6 (19.4) 0.15 
 >3rd 4 (5.5) 2 (6.5) 0.88 
Charlsons’ comorbidity index 
 Mean (range) 2.65 (0–6) 2.48 (0–4) 0.87 
ECOG PS, n (%) 
 0 35 (47.9) 14 (45.2) 0.86 
 1 31 (42.5) 13 (41.9) 0.81 
 2 5 (6.8) 3 (9.7) 0.67 
 3 2 (2.7) 1 (3.2) 0.77 
Carboplatin-etoposide (CE) (n = 73)Cisplatin-etoposide (PE) (n = 31)p value
Sex, n (%)   0.57 
 Male 45 (61.6) 18 (58.1)  
 Female 28 (38.4) 13 (41.9)  
Age    
 Mean (range) 65.7 (41–83) 59.2 (41–76) 0.24 
Primary organ, n (%) 
Gastroenteropancreatic system, n (%) 48 (65.8) 19 (61.3) 0.58 
 Pancreas 14 (19.2) 5 (16.1)  
 Esophagus 13 (17.8) 3 (9.7)  
 Stomach 12 (16.4) 5 (16.1)  
 Colorectum 5 (6.8) 5 (16.1)  
 Duodenum 3 (4.1) 1 (3.2)  
 Small intestine 1 (1.4) 0 (0.0)  
Non-gastroenteropancreatic system 25 (34.2) 11 (38.4) 0.53 
 CUP 11 (15.1) 6 (19.4)  
 Prostate 3 (4.1) 0 (0.0)  
 Bile duct 3 (4.1) 1 (3.2)  
 Kidney 2 (2.7) 0 (0.0)  
 Head and neck 2 (2.7) 2 (6.5)  
 Urinary bladder 1 (1.4) 0 (0.0)  
 Lung 1 (1.4) 2 (6.5)  
 Breast 1 (1.4) 0 (0.0)  
 Liver 1 (1.4) 0 (0.0)  
 Adrenal gland 0 (0.0) 1 (3.2)  
MiNEN, n (%) 10 (13.7) 5 (16.1) 0.56 
Ki-67, n (%) 
 ≥55% 49 (67.1) 24 (77.4) 0.31 
 <55% 24 (32.9) 7 (22.6)  
Line of chemotherapy, n (%) 
 1st 63 (86.3) 23 (74.2) 0.45 
 2nd 6 (8.2) 6 (19.4) 0.15 
 >3rd 4 (5.5) 2 (6.5) 0.88 
Charlsons’ comorbidity index 
 Mean (range) 2.65 (0–6) 2.48 (0–4) 0.87 
ECOG PS, n (%) 
 0 35 (47.9) 14 (45.2) 0.86 
 1 31 (42.5) 13 (41.9) 0.81 
 2 5 (6.8) 3 (9.7) 0.67 
 3 2 (2.7) 1 (3.2) 0.77 

CUP, cancer of unknown primary; MiNEN, mixed neuroendocrine neoplasm; ECOG PS, Eastern Cooperative Oncology Group performance status.

Efficacies

The ORR of the CE group and the PE group in the present study were 42.6% and 44.4%, respectively (Table 2). The DCR of the CE and the PE group in the present study was 69.1% and 59.3%, respectively (Table 2). There were no significant differences in ORR and DCR between the two groups.

Table 2.

Response to platinum and etoposide combination therapy

Carboplatin-etoposide (CE) (n = 73)Cisplatin-etoposide (PE) (n = 31)p value
Complete response  
Partial response 27 10  
Stable disease 18  
Progression disease 21 11  
Not evaluated  
Response rate (%) 42.6 44.4 0.8732 
DCR (%) 64.4 59.3 0.3592 
Carboplatin-etoposide (CE) (n = 73)Cisplatin-etoposide (PE) (n = 31)p value
Complete response  
Partial response 27 10  
Stable disease 18  
Progression disease 21 11  
Not evaluated  
Response rate (%) 42.6 44.4 0.8732 
DCR (%) 64.4 59.3 0.3592 

The median PFS in the CE and the PE group was 5.1 months (95% confidence interval [CI]: 3.5–6.3) and 5.6 months (95% CI: 3.1–7.0), respectively (log-rank test: p = 0.781) (Fig. 1a). The median OS in the CE and the PE groups was 13.6 months (95% CI: 8.9–17.4) and 12.5 months (95% CI: 11.2–14.6), respectively (log-rank test: p = 0.593) (Fig. 1b). No significant difference was observed between the CE and the PE groups for both PFS and OS.

Fig. 1.

a The Kaplan-Meier curve of PFS in the CE group and the PE group. b The Kaplan-Meier curve of OS in the CE group and the PE group.

Fig. 1.

a The Kaplan-Meier curve of PFS in the CE group and the PE group. b The Kaplan-Meier curve of OS in the CE group and the PE group.

Close modal

Adverse Events

Severe AEs in the CE or PE group are described in Table 3. The number of patients with severe leukopenia, neutropenia, anemia, and thrombocytopenia were 43 (58.9%), 50 (68.5%), 9 (12.3%), and 2 (2.7%), respectively, in the CE group and 16 (51.6%), 21 (67.7%), 3 (9.7%), and 1 (3.2%), respectively, in the PE group. The proportion of patients who suffered from hematological toxicities was similar between the two groups. The number of patients with aspartate aminotransferase (AST) of alanine aminotransferase (ALT) elevations in the CE and PE groups was 2 (2.7%) and 1 (3.2%), respectively. There were no significant differences in the percentage of severe AST or ALT elevations between the two groups. The number of patients with severe creatinine elevation in the CE and PE group was 0 (0.0%) and 2 (6.5%), respectively.

Table 3.

Severe AEs

Carboplatin-etoposide (CE) (n = 73)Cisplatin-etoposide (PE) (n = 31)
grade 3grade 4>grade 3grade 3grade 4>grade 3p value (>grade 3)
Leukopenia, n (%) 32 (43.8) 11 (15.1) 43 (58.9) 13 (41.9) 3 (9.7) 16 (51.6) 0.5818 
Neutropenia, n (%) 14 (19.2) 36 (49.3) 50 (68.5) 6 (19.4) 15 (48.4) 21 (67.7) 0.87 
Anemia, n (%) 9 (12.3) 0 (0.0) 9 (12.3) 3 (9.7) 0 (0.0) 3 (9.7) 0.656 
Thrombocytopenia, n (%) 2 (2.7) 0 (0.0) 2 (2.7) 0 (0.0) 1 (3.2) 1 (3.2) 0.914 
Elevation of creatinine, n (%) 0 (0.0) 0 (0.0) 0 (0.0) 2 (6.5) 0 (0.0) 2 (6.5) 0.028 
Elevation of AST or ALT, n (%) 2 (2.7) 0 (0.0) 2 (2.7) 1 (3.2) 0 (0.0) 1 (3.2) 0.914 
Carboplatin-etoposide (CE) (n = 73)Cisplatin-etoposide (PE) (n = 31)
grade 3grade 4>grade 3grade 3grade 4>grade 3p value (>grade 3)
Leukopenia, n (%) 32 (43.8) 11 (15.1) 43 (58.9) 13 (41.9) 3 (9.7) 16 (51.6) 0.5818 
Neutropenia, n (%) 14 (19.2) 36 (49.3) 50 (68.5) 6 (19.4) 15 (48.4) 21 (67.7) 0.87 
Anemia, n (%) 9 (12.3) 0 (0.0) 9 (12.3) 3 (9.7) 0 (0.0) 3 (9.7) 0.656 
Thrombocytopenia, n (%) 2 (2.7) 0 (0.0) 2 (2.7) 0 (0.0) 1 (3.2) 1 (3.2) 0.914 
Elevation of creatinine, n (%) 0 (0.0) 0 (0.0) 0 (0.0) 2 (6.5) 0 (0.0) 2 (6.5) 0.028 
Elevation of AST or ALT, n (%) 2 (2.7) 0 (0.0) 2 (2.7) 1 (3.2) 0 (0.0) 1 (3.2) 0.914 

AST, aspartate aminotransferase; ALT, alanine aminotransferase.

Multivariate Analyses

Multivariate analyses were performed for the PFS and the OS in the present study (Fig. 2a, b). The results demonstrated that patients with PS ≥2, gastroenteropancreatic NEC, and those who received platinum plus etoposide combination therapy as a second or later line had a worse prognosis and shorter time to tumor progression. Importantly, the choice of platinum agent (carboplatin or cisplatin) in patients with NEC was not associated with the time to progression or OS. Other factors such as sex, age, Ki-67 index, and MiNEN or not were not associated with either time to progression or time to death.

Fig. 2.

a The forest plot of the multivariate analysis for PFS. b The forest plot of the multivariate analysis for OS.

Fig. 2.

a The forest plot of the multivariate analysis for PFS. b The forest plot of the multivariate analysis for OS.

Close modal

In the present study, we compared the efficacy and safety between the CE and the PE. Since the background of the two groups of the present study was well-balanced, it was considered that we could compare the efficacy and safety of CE and PE between two well-balanced two groups.

The overall ORR, the median PFS, and median OS were similar in the CE and PE groups. In addition, multivariate analyses controlling for confounders showed no significant difference in PFS and OS between the two groups. These results suggest that both CE and PE have comparable efficacy in terms of PFS and OS.

Regarding safety, the incidence of severe hematologic toxicities and elevation of AST or ALT was similar between the CE and PE groups in the present study. However, the incidence of severe creatinine elevation was significantly higher in the PE group than in the CE group. This suggests that PE was associated with a higher risk of severe renal AEs compared to CE.

Interestingly, our multivariate analyses revealed that patients treated with platinum and etoposide combination therapies (both PE and CE) as second or later line had shorter progression time and OS. This finding is consisting with previous reports in patients with small-cell lung cancer, which is classified as NEC according to the World Health Organization (WHO) classification [17]. The nature of NEC and of small-cell lung cancer is considered to be similar, suggesting that second-line platinum and etoposide combination therapy in the present study exhibited shorter PFS and OS compared to first-line therapy, similar to findings in small-cell lung cancer [18].

In a multivariate analysis of a previous study, patients with gastroenteropancreatic NEC showed a shorter OS when compared to patients with non-gastrointestinal NEC [10]. Consistently, a significant difference in both PFS and OS was observed between patients with the gastroenteropancreatic NEC and patients with the non-gastroenteropancreatic NEC in the present study. In particular, patients with gastroenteropancreatic NEC had a shorter OS, which was consistent with the results of the previous study [10]. Notably, our study provides a novel finding regarding platinum and etoposide combination therapy for patients with NEC as there are no previous reports suggesting a shorter PFS in gastroenteropancreatic NEC compared to non-gastroenteropancreatic NEC. In the previous study, poor PS was reported as an independent prognostic factor for poor prognosis [9]. In the present multivariate analysis, PS ≥2 is an independent poor prognostic factor, which is considered to support the previous study [9].

Our study has several limitations. First, this study is a retrospective study. Second, the present study included a small number of patients, which may limit the generalizability of our findings. Third, we could not include comprehensive information on AEs such as a nausea, fatigue, or neuropathy, which are commonly associated with platinum-based chemotherapy [19‒21]. These AEs were not consistently documented in the medical records, and therefore could not be included as objective data in our analysis. In order to more accurately compare the safety of CE and PE in patients with NEC, standardized methods for recording and reporting non-hematologic toxicities should be incorporated, to provide a more comprehensive assessment of treatment safety. Fourth, we could not evaluate the treatment efficacy of irinotecan-containing regimens as a first-line therapy. A previous prospective study compared the treatment efficacy between the PE and irinotecan and etoposide combination therapy as the first-line chemotherapy in patients with advanced NEC: [22]. This study has reported similar PFS and OS rates between the two treatment approaches: [22]. As irinotecan and etoposide combination therapy showed similar PFS and OS to EP therapy in this study, irinotecan has become one of the important anticancer drugs that should be used for patients with NEC. However, due to the lack of patients receiving carboplatin and irinotecan combination therapy in our institute, evaluating the treatment efficacy of this combination therapy for patients with NEC remains an important area for further investigation. Given that carboplatin and irinotecan combination therapy is generally used for patients with small-cell lung cancer: [23], it is believed to have potential efficacy for patients with NEC. Therefore, conducting a clinical trial to evaluate the treatment efficacy of carboplatin and irinotecan combination therapy for patients with NEC is warranted.

Based on our results, it can be concluded that the efficacy of CE and PE for patients with NEC appears to be comparable. However, it is important to note that the incidence of AEs, especially creatinine elevation, was higher with PE than with CE.

This study protocol was approved by the Ethics Committee of Tohoku University Hospital (approval number: 2023-1-169). The Ethics Committee of Tohoku University Hospital has approved to conduct retrospective studies without patients consent (opt-out system). Opt-out informed consent protocol was used for use of participant data for research purposes. Opt-out informed consent protocol was used for use of participant data for research purposes. This consent procedure was reviewed and approved by the Ethics Committee of Tohoku University Hospital (approval number: 2023-1-169). All data in the present study had no personal identifiers and were kept confidential. Consent for publication: not applicable.

Chikashi Ishioka received research funding from the Tokyo Cooperative Oncology Group. Chikashi Ishioka also received contributions from Chugai Pharmaceutical, Novartis Pharma K.K., Ono Pharmaceutical, MSD, Pfizer, AstraZeneca, Bristol Myers Squibb, Kyowa Kirin Co., Ltd., Janssen Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo Company, Limited, and Takeda Pharmaceutical, Merck Biopharma Co., Ltd, Eli Lilly Japan K.K, Bayer Yakuhin, Ltd, Incyte Biosciences Japan G.K. Chikashi Ishioka is a representative of Tohoku Clinical Oncology Research and Education Society, a specified nonprofit corporation. Dr. Masahiro Takahashi reports grants from Ono Pharmaceutical, Merck Biopharma Co., Chugai Pharmaceutical, MSD, outside the submitted work. The authors report no other conflicts of interest in this work.

This study was not funded by any sponsor.

Hiroo Imai designed this retrospective study and wrote the initial draft of the manuscript. Chikashi Ishioka is the corresponding author. Chikashi Ishioka also contributed to the analysis and interpretation of the data and assisted in drafting of the manuscript.

Hiroo Imai, Ken Saijo, Yoshifumi Kawamura, Shuto Kodera, Keigo Komine, Tomoyuki Iwasaki, Noriko Takenaga, Yuki Kasahara, Kota Ouchi, Hidekazu Shirota, Masanobu Takahashi, Chikashi Ishioka have contributed to data collection and interpretation and critically reviewed the manuscript. Hiroo Imai, Ken Saijo, Yoshifumi Kawamura, Shuto Kodera, Keigo Komine, Tomoyuki Iwasaki, Yuki Kasahara, Kota Ouchi, Hidekazu Shirota, Masanobu Takahashi, Chikashi Ishioka were the attending physician of 1 of the patients enrolled in the present study. All authors approved the final version of the manuscript and agreed to take responsibility for all aspects of the work to ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

The data used to support the findings are included as tables and figures in the manuscript of the present study. The detailed retrospective observational data used to support the findings of this study are available from the first author (Hiroo Imai, e-mail: hiroo.imai.d8@tohoku.ac.jp) upon reasonable request. All data in the current study had no personal identifiers and were kept confidential. Data are not publicly available due to ethical reasons. Further inquiries can be directed to the corresponding author.

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