Outcomes of capecitabine plus temozolomide combination therapy in patients with advanced or metastatic pancreatic neuroendocrine tumors: a retrospective observational single-center study

Outcomes of capecitabine plus temozolomide combination therapy in patients with advanced or metastatic pancreatic neuroendocrine tumors: a retrospective observational single-center study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Outcomes of capecitabine plus temozolomide combination therapy in patients with advanced or metastatic pancreatic neuroendocrine tumors: a retrospective observational single-center study Yukiko Hibino, Susumu Hijioka, Chigusa Morizane, Daiki Agarie, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5073563/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 May, 2025 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Background : Treatment strategies for patients with unresectable or recurrent pancreatic neuroendocrine tumors (pNETs) have been investigated, and combination therapy with capecitabine plus temozolomide (CAPTEM) has demonstrated favorable outcomes. In response to these results, the CAPTEM regimen has been widely used in several countries, including Western nations. However, it is yet to be approved in Japan, and its efficacy and safety in the Japanese population remain unclear. In the present study, we examined the efficacy and safety of CAPTEM in Japanese patients with unresectable or recurrent pNETs. Methods : Data were retrospectivelycollected from the medical records of the National Cancer Center Hospital. Results : Fifteen patients with pNETs had received CAPTEM therapy, and 47% of the patients had WHO Grade 2 disease and 47% had WHO Grade 3 disease. The objective response rates and disease control rates were 26.7 and 66.7%, respectively. The median observation period was 20.8 months. The median progression-free survival was 5.3 months (95% confidence interval [CI]: 0.9–NA), and 1-year survival rate was 81.2% (95%CI: 41.5–95.2%). The most common adverse events (AEs) associated with CAPTEM therapy were hematologic and gastrointestinal toxicities. One patient experienced CTCAE grade 3 neutropenia, but no AE-related deaths were observed. Conclusions : This is the first study conducted to demonstrate CAPTEM is a valuable regimen also in the Japanese population, consistent with its established efficacy outside Japan. As reported previously, CAPTEM therapy was associated with high disease control rates, and it could be a valuable regimen in the Japanese population. capecitabine temozolomide CAPTEM pancreatic neuroendocrine tumors Japanese patients Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Neuroendocrine tumors (NETs) are epithelial neoplasms with predominantly neuroendocrine differentiation that can occur in any organ. Pancreatic NETs (pNETs) account for 3% of pancreatic malignancies, with an annual incidence of less than one per 100,000 individuals in the United States [1]. In Japan, the estimated prevalence is approximately 2.23 persons per 100,000, with an annual incidence of approximately 1.0 persons, although its per capita prevalence is higher than that in the United States [2]. Systemic therapies for advanced or recurrent pNETs include somatostatin analogs, molecular-targeted agents, cytotoxic anticancer agents, and peptide receptor radionuclide therapy (PRRT), all of which have demonstrated efficacy in phase 3 trials [3-6]. Among these treatments, 177 Lu-Dotatate demonstrated high efficacy in the NETTER-1 and NETTER-2 trials in combination with octreotide long-acting repeatable [6-7]. However, it faces challenges such as the limited 177 Lu-Dotatate supply and the long lead time from order to delivery. On the other hand, regimens containing cytotoxic anticancer agents, such as streptozotocin (STZ) and temozolomide, are readily available and reportedly efficacious against pNETs. STZ is an alkylating agent used in combination with 5-fluorouracil (5-FU) or as a single agent. Previous retrospective studies have revealed that the objective response rate (ORR) of STZ-containing regimens ranged from 6 to 39%, with a reported median progression-free survival (PFS) of 4 to 18 months [8-11]. Specifically, patients with Ki-67 levels greater than 5% exhibit favorable treatment responsiveness, thus indicating a pivotal role in the management of patients with WHO Grade 3 [11, 12]. Although the alkylating agent temozolomide was found to be efficacious and achieved an ORR of 33–45% in combination therapy with thalidomide and bevacizumab, it has been associated with CTCAE grade ≥3 lymphopenia and infections; therefore, its subsequent development has not been pursued [13, 14]. In 2022, combination therapy with capecitabine plus temozolomide (CAPTEM), which was efficacious in single-arm studies and retrospective studies, reported favorable outcomes in a randomized trial that prospectively compared CAPTEM with temozolomide monotherapy. The median PFS of the CAPTEM arm was 22.7 months, whereas that of the temozolomide monotherapy arm was 14.4 months (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.36–0.93, P = 0.022). Moreover, the disease control rate (DCR) of CAPTEM was 83.8%, and the median response duration was 16.6 months [15]. Treatment discontinuation due to treatment-related adverse events (AEs) occurred in 14.9% of the CAPTEM cohort, with hematological toxicity and gastrointestinal symptoms identified as primary CTCAE grade ≥3 AEs [15]. Several other retrospective studies have reported the efficacy and safety of CAPTEM therapy in patients with advanced or metastatic pNETs achieve an ORR of 38%, DCR of 77%, and median PFS of 13 months [16-19]. In response to these results, the CAPTEM regimen has been widely used in several countries, including Western nations. However, it is yet to be approved in Japan, and its efficacy and safety in the Japanese population remain unclear. In the current study, we retrospectively analyzed the experience of CAPTEM therapy for patients with advanced or recurrent pNETs who had applied for and received approval for off-label use to clarify the efficacy and safety of this combination in the Japanese population. Patients and Methods Study design and data collection This retrospective study included patients who received CAPTEM for advanced, defined as unresectable, or recurrent pNETs at our institution between January 2021 and November 2023. Based on the treatment outcomes reported in the United States, our department administers the CAPTEM regimen to patients with pNETs upon obtaining approval for off-label use (Approval ID: 2018-149). Additionally, the patient consent form explicitly included an explanation of the possibility of publishing treatment outcomes, and informed consent was obtained. The following clinicopathological features were extracted from the medical records: age, sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS), World Health Organization (WHO) 2019 classification grade, functional/non-functional status, concomitant use of somatostatin analog, somatostatin receptor expression 2 that is confirmed by somatostatin receptor scintigraphy, prior treatment history, history of STZ use, surgical history, liver tumor burden, and metastatic organs. The tumor response was evaluated using computed tomography imaging. Patients who could not visit our institution because of severe symptoms due to disease progression and were admitted to a local hospital were considered to have disease progression. The ORR was defined as the proportions of patients with complete responses (CR) and partial responses (PR). The PFS and the overall survival (OS) were defined as the period from the initiation of CAPTEM therapy to disease progression or clinical progressive disease (PD), including death event, and death due to any cause, respectively. AEs were recorded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Dosing regimen Each CAPTEM cycle was performed for 28 days. Patients received 750 mg/m ² capecitabine orally twice daily on Days 1–14 and 150–200 mg/m² temozolomide orally once daily on Days 10–14 [15, 20]. The initial temozolomide dose was determined comprehensively by experienced physicians based on the patient’s overall condition, physical examination results, and laboratory findings. Dose reductions due to adverse events were adjusted by the attending physicians based on previously reported methods and the dose reduction guidelines for temozolomide in the treatment of malignant gliomas, as established by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan [15]. Statistical analysis Categorical data are presented as patient count and percentage. Estimates of PFS and OS, along with their 95% CIs, were calculated using the Kaplan-Meier method. Using log-rank tests, we compared the PFS based on the presence or absence of prior use of the alkylating drug STZ. Statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics. Results Fifteen patients with pNETs received CAPTEM therapy during the study period, and their clinicopathological characteristics are summarized in Table 1. The median patient age was 62 years (range: 27–76 years), with an approximately equal sex distribution. ECOG PS was 0 in 67% of patients, PS 1 in 27%, and PS 2 in 7%. According to the 2019 WHO classification, 46% of the patients had WHO Grade 2 disease and 46% had WHO Grade 3 (well-differentiated NETs) disease. Functional NETs were detected in 27% of patients. The liver tumor burden was <10% in 7%, 10 to <25% in 40%, 25 to <50% in 13%, and ≥50% in 40% of patients. Regarding the line of therapy, CAPTEM was predominantly used in the late-line setting, with 73% of patients receiving it as a fourth-line or later therapy owing to its off-label use in Japan. Nine patients had received prior STZ treatment, and of these, six had received STZ in combination with 5-FU. The efficacy of CAPTEM therapy is shown in Table 2. The ORR of CAPTEM therapy was 26.7% (4/15), while the DCR was 66.7% (10/15). A representative case of CAPTEM therapy is shown in Fig. 1. The median observation period was 20.8 months. The median PFS was 5.3 months (95% CI: 0.9–NA), and the 6-month PFS rate was 45.8% (95% CI: 17.9–70.2) (Fig. 2). Five OS events occurred; four patients died from disease progression, while one death occurred due to an infection. The 1-year OS was 85.1% (95%CI: 52.3–96.1%), and the 2-year OS was 46.4% (95%CI: 16.3–72.3%) (Fig. 3). Ten patients had been previously treated with STZ, and their ORR and DCR were 30.0 and 60.0%, respectively. STZ was used either as a monotherapy or combined with 5-FU, resulting in DCRs of 75.0 and 50.0%, respectively, thereby demonstrating high disease control rates in both STZ-treated groups (Table 3). As shown in Fig. 4, we compared the PFS of CAPTEM therapy for patients previously treated or non-treated with STZ. The median PFS of CAPTEM therapy for patients previously treated with STZ was 4.3 months (95% CI: 0.3–12.0), whereas the median PFS for STZ-naïve patients was not reached (95% CI: 0.9–NA) (HR 4.47, 95% CI: 0.55–36.1, P = 0.16). Fig. 5 illustrates the treatment duration according to WHO grade using a swimmer plot. Although four WHO Grade 3 cases experienced early progressive disease, other two cases showed a response lasting longer than the median PFS, with patient 15 showing a response lasting over 4 years. Patient 5 discontinued CAPTEM therapy two months after initiation due to non-drug-induced pneumonia and had changed to 177 Lu-Dortatate therapy. However, after receiving four cycles of 177 Lu-Dotatate therapy, CAPTEM was resumed, resulting in a response duration of 20 months. Furthermore, among the seven patients with WHO Grade 2 tumors, three are currently continuing CAPTEM therapy. Table 4 presents the AEs observed during the study period. The most common AEs were hematological and gastrointestinal toxicities. Additionally, fatigue was observed in three patients. Among them, one patient with CTCAE grade 2 fatigue experienced disease progression simultaneously and subsequently transitioned to the next-line treatment. Another patient who developed CTCAE grade 1 fatigue continued treatment with temozolomide at a reduced dose of 150 mg/m² from 200 mg/m², in accordance with the patient’s preference. One patient experienced neutropenia, a CTCAE grade 3 event, and no AE-related deaths were observed. Discussion In the current study, we evaluated the efficacy and safety of CAPTEM therapy in Japanese patients with advanced or metastatic pNETs. The ORR and DCR were 26.7 and 66.7%, respectively, both of which are slightly lower than those reported previously (39.7% and 83.3%, respectively) [15]. The lower ORR and DCR may be attributable to factors such as racial difference, tumor proliferative potential and the timing of CAPTEM administration. Some studies have suggested that genetic polymorphisms and expression levels of O6-methylguanine-DNA methyltransferase (MGMT), which are thought to contribute to temozolomide sensitivity, may vary among different racial groups [21]. Although the impact of these differences on temozolomide sensitivity in Asian populations remains inconclusive, further research is warranted to clarify this potential association. In addition to racial differences, the tumor proliferation capacity may also explain the observed findings. Ki-67, which reflects the tumor proliferation capacity, is one of the indicators in the WHO grading system for pNETs. In the present study, three out of the four cases that developed progressive disease as the maximum response to CAPTEM therapy were WHO Grade 3 (Ki-67 > 20%). Certain drugs, including STZ, have been associated with high Ki-67 expression as a predictive marker of tumor response [20]; however, high Ki-67 expression could be associated with a lower response rate to CAPTEM therapy. Although a previous study by Kunz et al. on CAPTEM therapy did not include patients with WHO Grade 3 tumors, 47% of the patients in the current study were of WHO Grade 3 [15]. Limiting the analysis to patients with WHO Grade 2 tumors in our study, the ORR was 28.6%, and the DCR was 100%, which is consistent with previously reported results. However, this finding does not imply that CAPTEM therapy is inefficient in patients with WHO Grade 3. One of our patients with WHO Grade 3 responded to CAPTEM therapy for more than 4 years, and analysis in a larger cohort is required. Additionally, the observed lower ORR and DCR could be attributed to the timing of CAPTEM administration. A retrospective study supported poorer response to later-line CAPTEM therapy than front-line CAPTEM [17]. In our study, none of the patients had received CAPTEM as a first-line treatment, and 70% had used CAPTEM as their fourth or later-line therapy. The relationship between multiple prior treatments and lower response rates remains unclear, and further investigations are needed to clarify the optimal timing for CAPTEM therapy. Moreover, although based on a single case, as demonstrated in Figure 1, there was a case in which tumor shrinkage with CAPTEM therapy enabled curative surgery. This finding underscores the need for further exploration of CAPTEM therapy as a potential neoadjuvant treatment. Another finding in this study is a notable discrepancy between the median PFS (5.3 months, 95%CI: 0.9–NA) and the median OS (23.1 months, 95% CI: 12.9–NA). This discrepancy may be attributed to the effects of subsequent treatments. Among the nine patients who experienced PD following CAPTEM therapy, five received 177 Lu-Dotatate as the next-line treatment, two received sunitinib, and two transitioned to best supportive care. The median duration from the initiation of subsequent treatment to the end of the observation period was 15.7 months (95% CI: 5.8–NA) in the 177 Lu-Dotatate group. Of the two patients who changed to sunitinib, one was lost to follow-up due to transfer to another institution, while the remaining patient had a duration of 7.0 months. Based on these findings, we consider that the observed discrepancy between PFS and OS in this study was influenced by subsequent treatments. In Japan, STZ, an alkylating agent, is considered a standard treatment regimen, either as monotherapy or in combination with 5-fluorouracil (5-FU) [11]. In this study, we also evaluated the efficacy of CAPTEM therapy in patients with prior STZ treatment. Among the study population, four patients (26.7%) had received STZ monotherapy, and six (40.0%) had received STZ combined with 5-FU. Typically, drugs from the same drug class as those used previously are not administered, given the potential development of drug resistance. However, our study detected an ORR of 30% and a DCR of 60% in patients who had been previously treated with STZ, either with or without 5-FU. These findings suggest that CAPTEM therapy may exhibit antitumor activity even in patients who have undergone prior STZ monotherapy or STZ combined with 5-FU. Regarding PFS, although no statistically significant difference was observed between the STZ-pretreated and STZ-naïve groups (HR 4.47, 95% CI: 0.55–36.1), a trend toward shorter PFS was noted in patients with prior STZ treatment. One potential explanation for this finding is that 50% of patients in the STZ-pretreated group had WHO Grade 3 tumors, whereas the STZ-naïve group consisted exclusively of patients with WHO Grade 1 or 2 tumors. This suggests that the STZ-pretreated group included a higher proportion of tumors with greater proliferative potential, which may have contributed to the shorter PFS. Additionally, the STZ-pretreated group included patients who had received 5-FU, which shares a similar mechanism of action with capecitabine, raising the possibility that acquired resistance could have played a role. However, the median PFS in the six patients who had previously received STZ + 5-FU was 4.0 months (95% CI: 0.3–NA), compared with 5.3 months (95% CI: 2.0–NA) in the four patients who had received STZ monotherapy, with no statistically significant difference observed. Therefore, this study did not confirm an impact of prior 5-FU treatment on the sensitivity of CAPTEM therapy. Given the small sample size, these results should be interpreted with caution, and further studies with a larger cohort are warranted to validate these findings. Consistent with previous reports, AEs such as hematological and gastrointestinal toxicities were observed in the current study. In earlier reports, CTCAE grade ≥3 AEs were reported in 45% of the study cohort and led to treatment interruption in 14.9% of patients [15]. However, only one patient experienced grade 3 neutropenia in the present study. One possible explanation for this difference is the influence of racial variations. Hishinuma et al. reported that the frequency and types of DPYD gene polymorphisms, which play a crucial role in 5-FU metabolism, differ between Western and Asian populations [22]. In Western populations, approximately 3–5% of individuals carry DPYD gene mutations, which increase the risk of 5-FU toxicity. However, these mutations were not identified in Japanese individuals. Conversely, although the exact frequency remains unknown, rare Japanese-specific DPYD gene variants have been reported. To better understand these genetic influences, further studies with larger cohorts are warranted. Additionally, as this was a retrospective observational study, the frequency of patient visits was lower than in prospective trials, which may have resulted in insufficient toxicity monitoring. Furthermore, temozolomide's initial dosing and dose reductions were at the discretion of the attending physicians, potentially influencing the incidence of AEs. In this study, temozolomide was initiated at 150 mg/m² in five cases and 180 mg/m² in three cases. Due to liver dysfunction caused by liver metastases, six patients started treatment with a reduced dose of <150 mg/m². Patients who started at <150 mg/m² underwent dose escalation or continuation at the same dose based on tolerability assessments by the attending physicians. This individualized dosing strategy may have contributed to the lower incidence of AEs observed in this study. The limitations of this study include the use of single-center data and the small sample size. Furthermore, as this study retrospectively extracted data, the intervals between CT scans for evaluating treatment efficacy varied among attending physicians, making it challenging to accurately determine the best overall response. However, imaging assessments were carefully conducted by at least two physicians based on the principles of Response Evaluation Criteria in Solid Tumors (RECIST) to ensure reliability. Additionally, while tumor volume of liver metastases is recognized as an indicator of tumor progression, no standardized assessment method has been established. In this study, tumor volume was classified based on contrast-enhanced CT scans, with careful evaluation by medical oncologists. Nevertheless, this methodological limitation may have affected the analysis of the relationship between liver metastasis tumor volume and the efficacy of CAPTEM therapy. Moreover, this study extracted data retrospectively, and it is possible that AEs not recorded in the medical records were missing. Additional large-scale investigations involving multiple centers are necessary. Conclusion To the best of our knowledge, this is the first study conducted in Japan to demonstrate the efficacy and safety of CAPTEM in patients with advanced or recurrent pNETs. The study revealed a relatively high response rate despite the inclusion of patients with WHO Grade 3 tumors or those undergoing late-line treatment. Additionally, efficacy was observed in patients who had previously received STZ with or without 5-FU, suggesting that CAPTEM may play an important role in improving the prognosis of patients with advanced or metastatic pNETs. Declarations This study was approved by the Ethics Committee of the National Cancer Center Hospital (Approval ID: 2018-149). Conflict of Interests: Susumu Hijioka has received honoraria from Teijin Pharma and Novartis. The other authors declare no conflict of interests for this article. Data availability statement: Raw data were generated at National Cancer Center Hospital, Tokyo, Japan. Derived data supporting the findings of this study are available from corresponding author on request. References Oberg K, Eriksson B (2005) Endocrine tumours of the pancreas. Best Pract Res Clin Gastroenterol 19:753-781. https://doi.org/10.1016/j.bpg.2005.06.002 Ito T, Tanaka M, Sasano H et al (2009) Epidemiology of Pancreatic Endocrine Tumor in Japan. Pancreas 38:491. https://doi.org/10.1097/01.MPA.0000357057.19332.3a Raymond E, Dahan L, Raoul JL et al (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364:501-513. https://doi.org/10.1056/NEJMoa1003825 Yao JC, Shah MH, Ito T, et al (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514-523. https://doi.org/10.1056/NEJMoa1009290 Rinke A, Muller HH, Schade-Brittinger C et al (2009) Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 27:4656-4663. https://doi.org/10.1200/JCO.2009.22.8510 Strosberg J, El-Haddad G, Wolin E et al (2017) Phase 3 trial of 177 Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med 376:125-135. https://doi.org/10.1056/NEJMoa1607427 Singh S, Halperin D, Myrehaug S et al (2024) [ 177 Lu]Lu-DOTA-TATE plus long-acting octreotide versus high‑dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet 403:2807-2817. https://doi.org/10.1016/S0140-6736(24)00701-3 Kouvaraki MA, Ajani JA, Hoff P et al (2004) Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 22:4762-4771. https://doi.org/10.1200/JCO.2004.04.024 Cheng PN, Saltz LB (1999) Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma. Cancer 86:944-948. McCollum AD, Kulke MH, Ryan DP et al (2004) Lack of efficacy of streptozocin and doxorubicin in patients with advanced pancreatic endocrine tumors. Am J Clin Oncol 27:485-488. https://doi.org/10.1097/01.coc.0000135343.06038.eb Shibuya H, Hijioka S, Sakamoto Y et al (2018) Multi-center clinical evaluation of streptozocin-based chemotherapy for advanced pancreatic neuroendocrine tumors in Japan: focus on weekly regimens and monotherapy. Cancer Chemother Pharmacol 82:661-668. https://doi.org/10.1007/s00280-018-3656-y Ikeda M, Morizane C, Hijioka S et al (2020) Optimal strategy of systemic treatment for unresectable pancreatic neuroendocrine tumors based upon opinion of Japanese experts. Pancreatology 20:944-950. https://doi.org/10.1016/j.pan.2020.06.002 Kulke MH, Stuart K, Enzinger PC et al (2006) Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 24:401-406. https://doi.org/10.1200/JCO.2005.03.6046 Chan JA, Stuart K, Earle CC et al (2012) Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol 30:2963-2968. https://doi.org/10.1200/JCO.2011.40.3147 Kunz PL, Graham NT et al (2023) Randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors (ECOG-ACRIN E2211). J Clin Oncol 41:1359-1369. https://doi.org/10.1200/JCO.22.01013 Thomas K, Voros BA, Meadows-Taylor M et al (2020) Outcomes of capecitabine and temozolomide (CAPTEM) in advanced neuroendocrine neoplasms (NENs). Cancers 12:206. https://doi.org/10.3390/cancers12010206 Peixoto RD, Noonan KL, Pavlovich P et al (2014) Outcomes of patients treated with capecitabine and temozolamide for advanced pancreatic neuroendocrine tumors (PNETs) and non-PNETs. J Gastrointest Oncol 5:247-252. https://doi.org/10.3978/j.issn.2078-6891.2014.019 Strosberg JR, Fine RL, Choi J et al (2011) First‐line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 117:268-275. https://doi.org/10.1002/cncr.25425 Al-Toubah T, Pelle E, Valone T et al (2022) Efficacy and toxicity analysis of capecitabine and temozolomide in neuroendocrine neoplasms. J Natl Compr Canc Netw 20:29-36. https://doi.org/10.6004/jnccn.2021.7017 Fine RL, Gulati AP, Krantz BA et al (2013) Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: The Pancreas Center at Columbia University experience. Cancer Chemother Pharmacol 71:663-670. https://doi.org/10.1007/s00280-012-2055-z Chen C, Wang F, Cheng Y et al. Predictive value of MGMT promoter methylation status in Asian and Caucasian patients with malignant gliomas: a meta-analysis. Int J Clin Exp Med. 2015:8(4):6553-62 Hishinuma E, Narita Y, Obuchi K et al (2022) Importance of Rare DPYD Genetic Polymorphisms for 5-Fluorouracil Therapy in the Japanese Population. Frontiers in Pharmacology 13:930470. https://doi.org/10.3389/fphar.2022.930470 Tables Table 1 . Characteristics of included patients Total (N = 15) Median age, years (range) 62 (27-76) Sex, n (%) Male 7 (47) Female 8 (53) ECOG performance status, n (%) 0 10 (67) 1 4 (27) 2 1 (7) WHO Grade (2019) , n (%) 2 7 (47) 3 7 (47) Unknown 1 (7) Resection of primary tumor, n (%) Yes 8 (53) No 7 (47) Function, n (%) Non-functional 11 (73) Functional 4 (27) Liver tumor burden, n (%) <10% 1 (7) ≧10%, <25% 6 (40) ≧25%, <50% 2 (13) ≧50% 6 (40) Somatostatin Receptor 2, n (%) Positive 14 (93) Negative 1 (7) Concurrent use of lanreotide, n (%) Yes 6 (40) No 9 (60) Surgical resection, n (%) Yes 8 (53) No 7 (47) Metastatic site, n (%) Liver 15 (100) Bone 3 (20) Treatment lines prior to CAPTEM, n (%) 1 2(13) 2 2 (13) 3 5 (33) 4 6 (40) Previous treatment with STZ, n (%) n = 10 Monotherapy 4 (40) STZ+5-FU 6 (60) Abbreviations: CAPTEM, capecitabine plus temozolomide; STZ+5-FU, streptozotocin plus 5-fluorouracil Table 2. Efficacy of CAPTEM Maximum Response Number of Pt (%) Partial Response 4 (26.7) Stable Disease 6 (40.0) Progressive Disease 5 (33.3) ORR 26.7% DCR 66.7% Abbreviations: CAPTEM, capecitabine plus temozolomide; Pt, patients; ORR, objective response rate; DCR, disease control rate Table 3 . Efficacy of CAPTEM in patients who have used STZ in a prior line of therapy Max. Response Previous STZ treatment (n=10) STZ monotherapy (n=4) STZ+5-FU (n=6) Partial Response 3 (30.0%) 1 (25.0.%) 2 (33.3%) Stable Disease 3 (30.0%) 2 (50.0%) 1 (16.7%) Progressive Disease 4 (40.0%) 1 (25.0.%) 3 (50.0%) ORR 30.0% 25.0 % 33.3% DCR 60.0% 75.0 % 50.0% Abbreviations: CAPTEM, capecitabine plus temozolomide; STZ, streptozotocin; STZ+5-FU, streptozotocin plus 5-fluorouracil; ORR, objective response rate; DCR, disease control rate Table 4. Adverse events of CAPTEM therapy CTCAE Grade Grade 1 Grade 2 Grade 3 Number of patients (%) Neutrophil count decrease 7 (46.7%) 1 (6.7%) 1 (6.7%) Febrile neutropenia - - 0 Anemia 7 (46.7%) 4 (26.7%) 0 Platelet count decreased 6 (40.0%) 0 0 Oral mucositis 1 (6.7%) 0 0 Nausea 6 (40.0%) 2 (13.3%) 0 Malaise 1 (6.7%) 2 (13.3%) 0 Palmar-plantar erythrodysesthesia syndrome 1 (6.7%) 2 (13.3%) 0 Abbreviations: CAPTEM, capecitabine plus temozolomide Cite Share Download PDF Status: Published Journal Publication published 09 May, 2025 Read the published version in International Journal of Clinical Oncology → Version 1 posted Reviewers agreed at journal 30 Mar, 2025 Reviewers invited by journal 29 Mar, 2025 Editor assigned by journal 18 Mar, 2025 First submitted to journal 12 Mar, 2025 Editorial decision: Minor revisions 21 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5073563","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":435808388,"identity":"110a4f2c-80cf-4699-a579-2de506f75c4d","order_by":0,"name":"Yukiko Hibino","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAu0lEQVRIiWNgGAWjYFACHobDDAYMcjAuM9FajEnTAlKV2EC0swxu5B48XFBwJ307++EHjF8qGNjNCWvJSzg8w+BZ7s6eNANmmTMMzJaE7DO4kWNwmMfgcO6GG0AXSrYxMBscIFJLugHJWhJAWhg/EqNF8swbA6BfDhtuOJNmcJjhjARhv/AdzzH+XPDnsLzB8cMPH/6osEkmGGIKyM44zMMgkWxASIs8sjMYfzAw2BHUMgpGwSgYBSMOAAAZhkEnNxvf9wAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0004-6807-4142","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":true,"prefix":"","firstName":"Yukiko","middleName":"","lastName":"Hibino","suffix":""},{"id":435808389,"identity":"c3267f23-c771-4a54-bf06-088eedb2ef04","order_by":1,"name":"Susumu Hijioka","email":"","orcid":"https://orcid.org/0000-0002-0394-6876","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Susumu","middleName":"","lastName":"Hijioka","suffix":""},{"id":435808390,"identity":"1220ac4d-1155-41eb-8b98-f0cfe999ce53","order_by":2,"name":"Chigusa Morizane","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Chigusa","middleName":"","lastName":"Morizane","suffix":""},{"id":435808391,"identity":"cfbfb90d-f755-493b-bf2b-4fcebdbb19fc","order_by":3,"name":"Daiki Agarie","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Daiki","middleName":"","lastName":"Agarie","suffix":""},{"id":435808392,"identity":"03ca6427-52c8-45fb-b5e1-47ef76188fd4","order_by":4,"name":"Kohei Okamoto","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Kohei","middleName":"","lastName":"Okamoto","suffix":""},{"id":435808393,"identity":"bd706bb8-3741-423b-bd47-c3477b2603d9","order_by":5,"name":"Daiki Yamashige","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Daiki","middleName":"","lastName":"Yamashige","suffix":""},{"id":435808394,"identity":"d7de1c4d-ff81-4129-867f-c4249fcb716d","order_by":6,"name":"Shin Yagi","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Shin","middleName":"","lastName":"Yagi","suffix":""},{"id":435808395,"identity":"4ca74b3a-0091-4659-ac26-08e97b57f620","order_by":7,"name":"Soma Fukuda","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Soma","middleName":"","lastName":"Fukuda","suffix":""},{"id":435808396,"identity":"bc4bab41-f228-4a1a-871e-f5ca91a2fece","order_by":8,"name":"Masaru Kuwada","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Masaru","middleName":"","lastName":"Kuwada","suffix":""},{"id":435808397,"identity":"1cf74222-03fe-4620-b4d2-44242c13e934","order_by":9,"name":"Yasuhiro Komori","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Yasuhiro","middleName":"","lastName":"Komori","suffix":""},{"id":435808398,"identity":"0e57d34c-8c40-4c4e-9cd1-d75c7c7e3af1","order_by":10,"name":"Mao Okada","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Mao","middleName":"","lastName":"Okada","suffix":""},{"id":435808399,"identity":"fc22fccb-9b9e-4760-badc-20bf8f830b2d","order_by":11,"name":"Yuta Maruki","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Yuta","middleName":"","lastName":"Maruki","suffix":""},{"id":435808400,"identity":"e53507d5-5519-480b-ba65-4fc41d0944f8","order_by":12,"name":"Yoshikuni Nagashio","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Yoshikuni","middleName":"","lastName":"Nagashio","suffix":""},{"id":435808401,"identity":"cecc03ad-9fc1-415a-ab19-57fbefff7f6f","order_by":13,"name":"Hideki Ueno","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Hideki","middleName":"","lastName":"Ueno","suffix":""},{"id":435808402,"identity":"0f86319a-49df-4a92-9d25-bd702a03513e","order_by":14,"name":"Takuji Okusaka","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Takuji","middleName":"","lastName":"Okusaka","suffix":""}],"badges":[],"createdAt":"2024-09-11 21:39:47","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5073563/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5073563/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-025-02779-1","type":"published","date":"2025-05-09T15:57:39+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":81016859,"identity":"17fc1992-9802-4eb5-ac67-d51396d632ab","added_by":"auto","created_at":"2025-04-21 09:07:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":452249,"visible":true,"origin":"","legend":"\u003cp\u003eThe case of a 44-year-old female with pancreatic NET Grade 2 (Ki-67 8.6%) and multiple liver metastases. After progressing on sunitinib, she received four courses of CAPTEM therapy as second-line treatment. Tumor shrinkage was achieved, and she underwent resection of both the primary tumor and liver metastases. She has remained disease-free for 3 years and 2 months postoperatively.\u003c/p\u003e\n\u003cp\u003eAbbreviations: NET, neuroendocrine tumor; CAPTEM, capecitabine plus temozolomide;\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-5073563/v1/5f20c24ffb0d910ec9d837ab.png"},{"id":81016858,"identity":"9143d0f2-ef85-4b8d-86d4-3d737a6f9126","added_by":"auto","created_at":"2025-04-21 09:07:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":38791,"visible":true,"origin":"","legend":"\u003cp\u003eProgression-free survival for entire group of patients with advanced or metastatic pNET\u003c/p\u003e\n\u003cp\u003eAbbreviations: pNET, pancreatic neuroendocrine tumor; PFS, progression-free survival; NA, not achieved\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-5073563/v1/dabf8067ce7ebc2409b2d960.png"},{"id":81016857,"identity":"30224595-614d-4afb-832d-1113a18d1ad1","added_by":"auto","created_at":"2025-04-21 09:07:55","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":37622,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival for entire group of patients with advanced or metastatic pNET\u003c/p\u003e\n\u003cp\u003eAbbreviations: pNET, pancreatic neuroendocrine tumor; OS, overall survival; NA, not achieved\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-5073563/v1/51ae1188576566a52a772c6f.png"},{"id":81016861,"identity":"24577a01-98e7-4a68-922d-9c3c43280150","added_by":"auto","created_at":"2025-04-21 09:07:55","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":45151,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of progression-free survival based on prior streptozocin use\u003c/p\u003e\n\u003cp\u003eAbbreviations: mPFS, median progression-free survival; NA, not achieved; HR, hazard ratio\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-5073563/v1/827858071c983a9c14fa106f.png"},{"id":81018181,"identity":"366cc5f1-536e-4468-b0c5-0c8714dad9c8","added_by":"auto","created_at":"2025-04-21 09:15:55","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":66384,"visible":true,"origin":"","legend":"\u003cp\u003eSwimmer plot showing the difference of treatment duration and outcomes for each patient by WHO grades\u003c/p\u003e\n\u003cp\u003eAbbreviations: CAPTEM, capecitabine plus temozolomide; PD, progressive disease\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-5073563/v1/955b613d82e9e1c3b24e578e.png"},{"id":82537639,"identity":"324a6197-ace8-4e49-a73a-1d30381314b2","added_by":"auto","created_at":"2025-05-12 16:09:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1550935,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5073563/v1/517e70f1-1a31-4575-99b7-1ea376efa372.pdf"}],"financialInterests":"","formattedTitle":"Outcomes of capecitabine plus temozolomide combination therapy in patients with advanced or metastatic pancreatic neuroendocrine tumors: a retrospective observational single-center study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeuroendocrine tumors (NETs) are epithelial neoplasms with predominantly neuroendocrine differentiation that can occur in any organ. Pancreatic NETs (pNETs) account for 3% of pancreatic malignancies, with an annual incidence of less than one per 100,000 individuals in the United States [1]. In Japan, the estimated prevalence is approximately 2.23 persons per 100,000, with an annual incidence of approximately 1.0 persons, although its per capita prevalence is higher than that in the United States [2].\u003c/p\u003e\n\u003cp\u003eSystemic therapies for advanced or recurrent pNETs include somatostatin analogs, molecular-targeted agents, cytotoxic anticancer agents, and peptide receptor radionuclide therapy (PRRT), all of which have demonstrated efficacy in phase 3 trials [3-6]. Among these treatments, \u003csup\u003e177\u003c/sup\u003eLu-Dotatate demonstrated high efficacy in the NETTER-1 and NETTER-2 trials in combination with octreotide long-acting repeatable [6-7]. However, it faces challenges such as the limited \u003csup\u003e177\u003c/sup\u003eLu-Dotatate supply and the long lead time from order to delivery. On the other hand, regimens containing cytotoxic anticancer agents, such as streptozotocin (STZ) and temozolomide, are readily available and reportedly efficacious against pNETs. STZ is an alkylating agent used in combination with 5-fluorouracil (5-FU) or as a single agent. Previous retrospective studies have revealed that the objective response rate (ORR) of STZ-containing regimens ranged from 6 to 39%, with a reported median progression-free survival (PFS) of 4 to 18 months [8-11]. Specifically, patients with Ki-67 levels greater than 5% exhibit favorable treatment responsiveness, thus indicating a pivotal role in the management of patients with WHO Grade 3 [11, 12].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough the alkylating agent temozolomide was found to be efficacious and achieved an ORR of 33\u0026ndash;45% in combination therapy with thalidomide and bevacizumab, it has been associated with CTCAE grade \u0026ge;3 lymphopenia and infections; therefore, its subsequent development has not been pursued [13, 14]. In 2022, combination therapy with capecitabine plus temozolomide (CAPTEM), which was efficacious in single-arm studies and retrospective studies, reported favorable outcomes in a randomized trial that prospectively compared CAPTEM with temozolomide monotherapy. The median PFS of the CAPTEM arm was 22.7 months, whereas that of the temozolomide monotherapy arm was 14.4 months (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.36\u0026ndash;0.93, \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.022). Moreover, the disease control rate (DCR) of CAPTEM was 83.8%, and the median response duration was 16.6 months [15]. Treatment discontinuation due to treatment-related adverse events (AEs) occurred in 14.9% of the CAPTEM cohort, with hematological toxicity and gastrointestinal symptoms identified as primary CTCAE grade \u0026ge;3 AEs [15]. Several other retrospective studies have reported the efficacy and safety of CAPTEM therapy in patients with advanced or metastatic pNETs achieve an ORR of 38%, DCR of 77%, and median PFS of 13 months [16-19].\u003c/p\u003e\n\u003cp\u003eIn response to these results, the CAPTEM regimen has been widely used in several countries, including Western nations. However, it is yet to be approved in Japan, and its efficacy and safety in the Japanese population remain unclear. In the current study, we retrospectively analyzed the experience of CAPTEM therapy for patients with advanced or recurrent pNETs who had applied for and received approval for off-label use to clarify the efficacy and safety of this combination in the Japanese population.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy design and data collection\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e \u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study included patients who received CAPTEM for advanced, defined as unresectable, or recurrent pNETs at our institution between January 2021 and November 2023. Based on the treatment outcomes reported in the United States, our department administers the CAPTEM regimen to patients with pNETs upon obtaining approval for off-label use (Approval ID: 2018-149). Additionally, the patient consent form explicitly included an explanation of the possibility of publishing treatment outcomes, and informed consent was obtained.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe following clinicopathological features were extracted from the medical records: age, sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS), World Health Organization (WHO) 2019 classification grade, functional/non-functional status, concomitant use of somatostatin analog, somatostatin receptor expression 2 that is confirmed by somatostatin receptor scintigraphy, prior treatment history, history of STZ use, surgical history, liver tumor burden, and metastatic organs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe tumor response was evaluated using computed tomography imaging. Patients who could not visit our institution because of severe symptoms due to disease progression and were admitted to a local hospital were considered to have disease progression. The ORR was defined as the proportions of patients with complete responses (CR) and partial responses (PR). The PFS and the overall survival (OS) were defined as the period from the initiation of CAPTEM therapy to disease progression or clinical progressive disease (PD), including death event, and death due to any cause, respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAEs were recorded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDosing regimen\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach CAPTEM cycle was performed for 28 days. Patients received 750 mg/m \u0026sup2; capecitabine orally twice daily on Days 1\u0026ndash;14 and 150\u0026ndash;200 mg/m\u0026sup2; temozolomide orally once daily on Days 10\u0026ndash;14 [15, 20]. The initial temozolomide dose was determined comprehensively by experienced physicians based on the patient\u0026rsquo;s overall condition, physical examination results, and laboratory findings. Dose reductions due to adverse events were adjusted by the attending physicians based on previously reported methods and the dose reduction guidelines for temozolomide in the treatment of malignant gliomas, as established by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan [15].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCategorical data are presented as patient count and percentage. Estimates of PFS and OS, along with their 95% CIs, were calculated using the Kaplan-Meier method. Using log-rank tests, we compared the PFS based on the presence or absence of prior use of the alkylating drug STZ. Statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFifteen patients with pNETs received CAPTEM therapy during the study period, and their clinicopathological characteristics are summarized in Table 1. The median patient age was 62 years (range: 27\u0026ndash;76 years), with an approximately equal sex distribution. ECOG PS was 0 in 67% of patients, PS 1 in 27%, and PS 2 in 7%. According to the 2019 WHO classification, 46% of the patients had WHO Grade 2 disease and 46% had WHO Grade 3 (well-differentiated NETs) disease. Functional NETs were detected in 27% of patients. The liver tumor burden was \u0026lt;10% in 7%, 10 to \u0026lt;25% in 40%, 25 to \u0026lt;50% in 13%, and \u0026ge;50% in 40% of patients. Regarding the line of therapy, CAPTEM was predominantly used in the late-line setting, with 73% of patients receiving it as a fourth-line or later therapy owing to its off-label use in Japan. Nine patients had received prior STZ treatment, and of these, six had received STZ in combination with 5-FU.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe efficacy of CAPTEM therapy is shown in Table 2. The ORR of CAPTEM therapy was 26.7% (4/15), while the DCR was 66.7% (10/15). A representative case of CAPTEM therapy is shown in Fig. 1. The median observation period was 20.8 months. The median PFS was 5.3 months (95% CI: 0.9\u0026ndash;NA), and the 6-month PFS rate was 45.8% (95% CI: 17.9\u0026ndash;70.2) (Fig. 2). Five OS events occurred; four patients died from disease progression, while one death occurred due to an infection. The 1-year OS was 85.1% (95%CI: 52.3\u0026ndash;96.1%), and the 2-year OS was 46.4% (95%CI: 16.3\u0026ndash;72.3%) (Fig. 3).\u003c/p\u003e\n\u003cp\u003eTen patients had been previously treated with STZ, and their ORR and DCR were 30.0 and 60.0%, respectively. STZ was used either as a monotherapy or combined with 5-FU, resulting in DCRs of 75.0 and 50.0%, respectively, thereby demonstrating high disease control rates in both STZ-treated groups (Table 3). As shown in Fig. 4, we compared the PFS of CAPTEM therapy for patients previously treated or non-treated with STZ. The median PFS of CAPTEM therapy for patients previously treated with STZ was 4.3 months (95% CI: 0.3\u0026ndash;12.0), whereas the median PFS for STZ-na\u0026iuml;ve patients was not reached (95% CI: 0.9\u0026ndash;NA) (HR 4.47, 95% CI: 0.55\u0026ndash;36.1, P = 0.16).\u003c/p\u003e\n\u003cp\u003eFig. 5 illustrates the treatment duration according to WHO grade using a swimmer plot. Although four WHO Grade 3 cases experienced early progressive disease, other two cases showed a response lasting longer than the median PFS, with patient 15 showing a response lasting over 4 years. Patient 5 discontinued CAPTEM therapy two months after initiation due to non-drug-induced pneumonia and had changed to \u003csup\u003e177\u003c/sup\u003eLu-Dortatate therapy. However, after receiving four cycles of \u003csup\u003e177\u003c/sup\u003eLu-Dotatate therapy, CAPTEM was resumed, resulting in a response duration of 20 months. Furthermore, among the seven patients with WHO Grade 2 tumors, three are currently continuing CAPTEM therapy.\u003c/p\u003e\n\u003cp\u003eTable 4 presents the AEs observed during the study period. The most common AEs were hematological and gastrointestinal toxicities. Additionally, fatigue was observed in three patients. Among them, one patient with CTCAE grade 2 fatigue experienced disease progression simultaneously and subsequently transitioned to the next-line treatment. Another patient who developed CTCAE grade 1 fatigue continued treatment with temozolomide at a reduced dose of 150 mg/m\u0026sup2; from 200 mg/m\u0026sup2;, in accordance with the patient\u0026rsquo;s preference. One patient experienced neutropenia, a CTCAE grade 3 event, and no AE-related deaths were observed.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the current study, we evaluated the efficacy and safety of CAPTEM therapy in Japanese patients with advanced or metastatic pNETs. The ORR and DCR were 26.7 and 66.7%, respectively, both of which are slightly lower than those reported previously (39.7% and 83.3%, respectively) [15]. The lower ORR and DCR may be attributable to factors such as racial difference, tumor proliferative potential and the timing of CAPTEM administration. Some studies have suggested that genetic polymorphisms and expression levels of O6-methylguanine-DNA methyltransferase (MGMT), which are thought to contribute to temozolomide sensitivity, may vary among different racial groups [21]. Although the impact of these differences on temozolomide sensitivity in Asian populations remains inconclusive, further research is warranted to clarify this potential association.\u003c/p\u003e\n\u003cp\u003eIn addition to racial differences, the tumor proliferation capacity may also explain the observed findings. Ki-67, which reflects the tumor proliferation capacity, is one of the indicators in the WHO grading system for pNETs. In the present study, three out of the four cases that developed progressive disease as the maximum response to CAPTEM therapy were WHO Grade 3 (Ki-67 \u0026gt; 20%). Certain drugs, including STZ, have been associated with high Ki-67 expression as a predictive marker of tumor response [20]; however, high Ki-67 expression could be associated with a lower response rate to CAPTEM therapy. Although a previous study by Kunz et al. on CAPTEM therapy did not include patients with WHO Grade 3 tumors, 47% of the patients in the current study were of WHO Grade 3 [15]. Limiting the analysis to patients with WHO Grade 2 tumors in our study, the ORR was 28.6%, and the DCR was 100%, which is consistent with previously reported results. However, this finding does not imply that CAPTEM therapy is inefficient in patients with WHO Grade 3. One of our patients with WHO Grade 3 responded to CAPTEM therapy for more than 4 years, and analysis in a larger cohort is required.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdditionally, the observed lower ORR and DCR could be attributed to the timing of CAPTEM administration. A retrospective study supported poorer response to later-line CAPTEM therapy than front-line CAPTEM [17]. In our study, none of the patients had received CAPTEM as a first-line treatment, and 70% had used CAPTEM as their fourth or later-line therapy. The relationship between multiple prior treatments and lower response rates remains unclear, and further investigations are needed to clarify the optimal timing for CAPTEM therapy. Moreover, although based on a single case, as demonstrated in Figure 1, there was a case in which tumor shrinkage with CAPTEM therapy enabled curative surgery. This finding underscores the need for further exploration of CAPTEM therapy as a potential neoadjuvant treatment.\u003c/p\u003e\n\u003cp\u003eAnother finding in this study is a notable discrepancy between the median PFS (5.3 months, 95%CI: 0.9\u0026ndash;NA) and the median OS (23.1 months, 95% CI: 12.9\u0026ndash;NA). This discrepancy may be attributed to the effects of subsequent treatments. Among the nine patients who experienced PD following CAPTEM therapy, five received \u003csup\u003e177\u003c/sup\u003eLu-Dotatate as the next-line treatment, two received sunitinib, and two transitioned to best supportive care. The median duration from the initiation of subsequent treatment to the end of the observation period was 15.7 months (95% CI: 5.8\u0026ndash;NA) in the \u003csup\u003e177\u003c/sup\u003eLu-Dotatate group. Of the two patients who changed to sunitinib, one was lost to follow-up due to transfer to another institution, while the remaining patient had a duration of 7.0 months. Based on these findings, we consider that the observed discrepancy between PFS and OS in this study was influenced by subsequent treatments.\u003c/p\u003e\n\u003cp\u003eIn Japan, STZ, an alkylating agent, is considered a standard treatment regimen, either as monotherapy or in combination with 5-fluorouracil (5-FU) [11]. In this study, we also evaluated the efficacy of CAPTEM therapy in patients with prior STZ treatment. Among the study population, four patients (26.7%) had received STZ monotherapy, and six (40.0%) had received STZ combined with 5-FU. Typically, drugs from the same drug class as those used previously are not administered, given the potential development of drug resistance. However, our study detected an ORR of 30% and a DCR of 60% in patients who had been previously treated with STZ, either with or without 5-FU. These findings suggest that CAPTEM therapy may exhibit antitumor activity even in patients who have undergone prior STZ monotherapy or STZ combined with 5-FU. Regarding PFS, although no statistically significant difference was observed between the STZ-pretreated and STZ-na\u0026iuml;ve groups (HR 4.47, 95% CI: 0.55\u0026ndash;36.1), a trend toward shorter PFS was noted in patients with prior STZ treatment. One potential explanation for this finding is that 50% of patients in the STZ-pretreated group had WHO Grade 3 tumors, whereas the STZ-na\u0026iuml;ve group consisted exclusively of patients with WHO Grade 1 or 2 tumors. This suggests that the STZ-pretreated group included a higher proportion of tumors with greater proliferative potential, which may have contributed to the shorter PFS. Additionally, the STZ-pretreated group included patients who had received 5-FU, which shares a similar mechanism of action with capecitabine, raising the possibility that acquired resistance could have played a role. However, the median PFS in the six patients who had previously received STZ + 5-FU was 4.0 months (95% CI: 0.3\u0026ndash;NA), compared with 5.3 months (95% CI: 2.0\u0026ndash;NA) in the four patients who had received STZ monotherapy, with no statistically significant difference observed. Therefore, this study did not confirm an impact of prior 5-FU treatment on the sensitivity of CAPTEM therapy. Given the small sample size, these results should be interpreted with caution, and further studies with a larger cohort are warranted to validate these findings.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsistent with previous reports, AEs such as hematological and gastrointestinal toxicities were observed in the current study. In earlier reports, CTCAE grade \u0026ge;3 AEs were reported in 45% of the study cohort and led to treatment interruption in 14.9% of patients [15]. However, only one patient experienced grade 3 neutropenia in the present study. One possible explanation for this difference is the influence of racial variations. Hishinuma et al. reported that the frequency and types of \u003cem\u003eDPYD\u003c/em\u003e gene polymorphisms, which play a crucial role in 5-FU metabolism, differ between Western and Asian populations [22]. In Western populations, approximately 3\u0026ndash;5% of individuals carry \u003cem\u003eDPYD\u003c/em\u003e gene mutations, which increase the risk of 5-FU toxicity. However, these mutations were not identified in Japanese individuals. Conversely, although the exact frequency remains unknown, rare Japanese-specific \u003cem\u003eDPYD\u003c/em\u003e gene variants have been reported. To better understand these genetic influences, further studies with larger cohorts are warranted. Additionally, as this was a retrospective observational study, the frequency of patient visits was lower than in prospective trials, which may have resulted in insufficient toxicity monitoring. Furthermore, temozolomide\u0026apos;s initial dosing and dose reductions were at the discretion of the attending physicians, potentially influencing the incidence of AEs. In this study, temozolomide was initiated at 150 mg/m\u0026sup2; in five cases and 180 mg/m\u0026sup2; in three cases. Due to liver dysfunction caused by liver metastases, six patients started treatment with a reduced dose of \u0026lt;150 mg/m\u0026sup2;. Patients who started at \u0026lt;150 mg/m\u0026sup2; underwent dose escalation or continuation at the same dose based on tolerability assessments by the attending physicians. This individualized dosing strategy may have contributed to the lower incidence of AEs observed in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe limitations of this study include the use of single-center data and the small sample size. Furthermore, as this study retrospectively extracted data, the intervals between CT scans for evaluating treatment efficacy varied among attending physicians, making it challenging to accurately determine the best overall response. However, imaging assessments were carefully conducted by at least two physicians based on the principles of Response Evaluation Criteria in Solid Tumors (RECIST) to ensure reliability. Additionally, while tumor volume of liver metastases is recognized as an indicator of tumor progression, no standardized assessment method has been established. In this study, tumor volume was classified based on contrast-enhanced CT scans, with careful evaluation by medical oncologists. Nevertheless, this methodological limitation may have affected the analysis of the relationship between liver metastasis tumor volume and the efficacy of CAPTEM therapy. Moreover, this study extracted data retrospectively, and it is possible that AEs not recorded in the medical records were missing. Additional large-scale investigations involving multiple centers are necessary.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTo the best of our knowledge, this is the first study conducted in Japan to demonstrate the efficacy and safety of CAPTEM in patients with advanced or recurrent pNETs. The study revealed a relatively high response rate despite the inclusion of patients with WHO Grade 3 tumors or those undergoing late-line treatment. Additionally, efficacy was observed in patients who had previously received STZ with or without 5-FU, suggesting that CAPTEM may play an important role in improving the prognosis of patients with advanced or metastatic pNETs.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThis study was approved by the Ethics Committee of the National Cancer Center Hospital (Approval ID: 2018-149).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSusumu Hijioka has received honoraria from Teijin Pharma and Novartis. The other authors declare no conflict of interests for this article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRaw data were generated at National Cancer Center Hospital, Tokyo, Japan. Derived data supporting the findings of this study are available from corresponding author on request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eOberg K, Eriksson B (2005) Endocrine tumours of the pancreas. Best Pract Res Clin Gastroenterol 19:753-781. https://doi.org/10.1016/j.bpg.2005.06.002 \u003c/li\u003e\n\u003cli\u003eIto T, Tanaka M, Sasano H et al (2009) Epidemiology of Pancreatic Endocrine Tumor in Japan. Pancreas 38:491. https://doi.org/10.1097/01.MPA.0000357057.19332.3a \u003c/li\u003e\n\u003cli\u003eRaymond E, Dahan L, Raoul JL et al (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364:501-513. https://doi.org/10.1056/NEJMoa1003825 \u003c/li\u003e\n\u003cli\u003eYao JC, Shah MH, Ito T, et al (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514-523. https://doi.org/10.1056/NEJMoa1009290 \u003c/li\u003e\n\u003cli\u003eRinke A, Muller HH, Schade-Brittinger C et al (2009) Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 27:4656-4663. https://doi.org/10.1200/JCO.2009.22.8510 \u003c/li\u003e\n\u003cli\u003eStrosberg J, El-Haddad G, Wolin E et al (2017) Phase 3 trial of \u003csup\u003e177\u003c/sup\u003eLu-dotatate for midgut neuroendocrine tumors. N Engl J Med 376:125-135. https://doi.org/10.1056/NEJMoa1607427 \u003c/li\u003e\n\u003cli\u003eSingh S, Halperin D, Myrehaug S et al (2024) [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTA-TATE plus long-acting octreotide versus high‑dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet 403:2807-2817. https://doi.org/10.1016/S0140-6736(24)00701-3 \u003c/li\u003e\n\u003cli\u003eKouvaraki MA, Ajani JA, Hoff P et al (2004) Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 22:4762-4771. https://doi.org/10.1200/JCO.2004.04.024 \u003c/li\u003e\n\u003cli\u003eCheng PN, Saltz LB (1999) Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma. Cancer 86:944-948. \u003c/li\u003e\n\u003cli\u003eMcCollum AD, Kulke MH, Ryan DP et al (2004) Lack of efficacy of streptozocin and doxorubicin in patients with advanced pancreatic endocrine tumors. Am J Clin Oncol 27:485-488. https://doi.org/10.1097/01.coc.0000135343.06038.eb \u003c/li\u003e\n\u003cli\u003eShibuya H, Hijioka S, Sakamoto Y et al (2018) Multi-center clinical evaluation of streptozocin-based chemotherapy for advanced pancreatic neuroendocrine tumors in Japan: focus on weekly regimens and monotherapy. Cancer Chemother Pharmacol 82:661-668. https://doi.org/10.1007/s00280-018-3656-y \u003c/li\u003e\n\u003cli\u003eIkeda M, Morizane C, Hijioka S et al (2020) Optimal strategy of systemic treatment for unresectable pancreatic neuroendocrine tumors based upon opinion of Japanese experts. Pancreatology 20:944-950. https://doi.org/10.1016/j.pan.2020.06.002 \u003c/li\u003e\n\u003cli\u003eKulke MH, Stuart K, Enzinger PC et al (2006) Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 24:401-406. https://doi.org/10.1200/JCO.2005.03.6046 \u003c/li\u003e\n\u003cli\u003eChan JA, Stuart K, Earle CC et al (2012) Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol 30:2963-2968. https://doi.org/10.1200/JCO.2011.40.3147 \u003c/li\u003e\n\u003cli\u003eKunz PL, Graham NT et al (2023) Randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors (ECOG-ACRIN E2211). J Clin Oncol 41:1359-1369. https://doi.org/10.1200/JCO.22.01013 \u003c/li\u003e\n\u003cli\u003eThomas K, Voros BA, Meadows-Taylor M et al (2020) Outcomes of capecitabine and temozolomide (CAPTEM) in advanced neuroendocrine neoplasms (NENs). Cancers 12:206. https://doi.org/10.3390/cancers12010206 \u003c/li\u003e\n\u003cli\u003ePeixoto RD, Noonan KL, Pavlovich P et al (2014) Outcomes of patients treated with capecitabine and temozolamide for advanced pancreatic neuroendocrine tumors (PNETs) and non-PNETs. J Gastrointest Oncol 5:247-252. https://doi.org/10.3978/j.issn.2078-6891.2014.019 \u003c/li\u003e\n\u003cli\u003eStrosberg JR, Fine RL, Choi J et al (2011) First‐line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 117:268-275. https://doi.org/10.1002/cncr.25425 \u003c/li\u003e\n\u003cli\u003eAl-Toubah T, Pelle E, Valone T\u003cem\u003e \u003c/em\u003eet al\u003cem\u003e \u003c/em\u003e(2022) Efficacy and toxicity analysis of capecitabine and temozolomide in neuroendocrine neoplasms. J Natl Compr Canc Netw 20:29-36. https://doi.org/10.6004/jnccn.2021.7017 \u003c/li\u003e\n\u003cli\u003eFine RL, Gulati AP, Krantz BA et al (2013) Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: The Pancreas Center at Columbia University experience. Cancer Chemother Pharmacol 71:663-670. https://doi.org/10.1007/s00280-012-2055-z \u003c/li\u003e\n\u003cli\u003eChen C, Wang F, Cheng Y et al. Predictive value of MGMT promoter methylation status in Asian and Caucasian patients with malignant gliomas: a meta-analysis. Int J Clin Exp Med. 2015:8(4):6553-62\u003c/li\u003e\n\u003cli\u003eHishinuma E, Narita Y, Obuchi K et al (2022) Importance of Rare DPYD Genetic Polymorphisms for 5-Fluorouracil Therapy in the Japanese Population. Frontiers in Pharmacology 13:930470. https://doi.org/10.3389/fphar.2022.930470\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e Characteristics of included patients\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"352\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width: 22.6455%;\"\u003e\n \u003cp\u003eTotal (N = 15) \u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 16.6621%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian age, years (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 3.8068%;\"\u003e\n \u003cp\u003e62 (27-76)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 22.6455%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex, \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 1.426%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 5.9203%;\"\u003e\n \u003cp\u003e7 (47)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 1.426%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 5.9203%;\"\u003e\n \u003cp\u003e8 (53)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 22.6455%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eECOG performance status, \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 1.426%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 5.9203%;\"\u003e\n \u003cp\u003e10 (67)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 1.426%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 5.9203%;\"\u003e\n \u003cp\u003e4 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 1.426%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 5.9203%;\"\u003e\n \u003cp\u003e1 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 22.6455%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWHO Grade (2019) , \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 1.426%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 5.9203%;\"\u003e\n \u003cp\u003e7 (47)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 1.426%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 5.9203%;\"\u003e\n \u003cp\u003e7 (47)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 1.426%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 5.9203%;\"\u003e\n \u003cp\u003e1 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 22.6455%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResection of primary tumor, \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 1.426%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.4547%;\"\u003e\n \u003cp\u003e8 (53)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 1.426%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.4547%;\"\u003e\n \u003cp\u003e7 (47)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 26.3442%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFunction, \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 1.426%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003eNon-functional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 7.5055%;\"\u003e\n \u003cp\u003e11 (73)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 1.426%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003eFunctional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 7.5055%;\"\u003e\n \u003cp\u003e4 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 26.3442%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLiver tumor burden, \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 1.426%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003e\u0026lt;10%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 6.4547%;\"\u003e\n \u003cp\u003e1 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 1.426%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003e≧10%, \u0026lt;25%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 6.4547%;\"\u003e\n \u003cp\u003e6 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 1.426%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003e≧25%, \u0026lt;50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 6.4547%;\"\u003e\n \u003cp\u003e2 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 1.426%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003e≧50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 2.1766%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 6.4547%;\"\u003e\n \u003cp\u003e6 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 26.3442%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSomatostatin Receptor 2, \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 1.5011%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 2.1015%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 7.5805%;\"\u003e\n \u003cp\u003e14 (93)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 1.5011%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 2.1015%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 7.5805%;\"\u003e\n \u003cp\u003e1 (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 26.3442%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConcurrent use of lanreotide, \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 9.0816%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 9.2317%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 8.0308%;\"\u003e\n \u003cp\u003e6 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 9.0816%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 9.2317%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 8.0308%;\"\u003e\n \u003cp\u003e9 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 18.3133%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSurgical resection, \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 8.0308%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 9.0816%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 9.2317%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 8.0308%;\"\u003e\n \u003cp\u003e8 (53)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 9.0816%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 9.2317%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 8.0308%;\"\u003e\n \u003cp\u003e7 (47)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 26.3442%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetastatic site, \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 1.5011%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 2.1015%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 7.5805%;\"\u003e\n \u003cp\u003e15 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 1.5011%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003eBone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 2.1015%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 7.5805%;\"\u003e\n \u003cp\u003e3 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 26.3442%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment lines prior to CAPTEM, \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 1.5011%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 2.1015%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 7.5805%;\"\u003e\n \u003cp\u003e2(13)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 1.5011%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 2.1015%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 7.5805%;\"\u003e\n \u003cp\u003e2 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 1.5011%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 2.1015%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 7.5805%;\"\u003e\n \u003cp\u003e5 (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 1.5011%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 2.1015%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 7.5805%;\"\u003e\n \u003cp\u003e6 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 16.6621%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrevious treatment with STZ, \u003cem\u003en\u003c/em\u003e (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 9.682%;\"\u003e\n \u003cp\u003e\u003cem\u003en\u003c/em\u003e = 10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 1.5011%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003eMonotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 2.1015%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 7.5805%;\"\u003e\n \u003cp\u003e4 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 1.5011%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 15.2361%;\"\u003e\n \u003cp\u003eSTZ+5-FU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 2.1015%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 7.5805%;\"\u003e\n \u003cp\u003e6 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: CAPTEM, capecitabine plus temozolomide; STZ+5-FU, streptozotocin plus 5-fluorouracil\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Efficacy of CAPTEM\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"382\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 182px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMaximum Response\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of Pt (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 182px;\"\u003e\n \u003cp\u003ePartial Response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\"\u003e\n \u003cp\u003e4 (26.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 182px;\"\u003e\n \u003cp\u003eStable Disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\"\u003e\n \u003cp\u003e6 (40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 182px;\"\u003e\n \u003cp\u003eProgressive Disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\"\u003e\n \u003cp\u003e5 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 182px;\"\u003e\n \u003cp\u003eORR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\"\u003e\n \u003cp\u003e26.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 182px;\"\u003e\n \u003cp\u003eDCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\"\u003e\n \u003cp\u003e66.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: CAPTEM, capecitabine plus temozolomide; Pt, patients; ORR, objective response rate; DCR, disease control rate\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e. Efficacy of CAPTEM in patients who have used STZ in a prior line of therapy\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"558\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMax. Response\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrevious STZ treatment\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(n=10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSTZ monotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(n=4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSTZ+5-FU\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(n=6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003ePartial Response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e3 (30.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e1 (25.0.%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e2 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eStable Disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e3 (30.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e2 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e1 (16.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eProgressive Disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e4 (40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e1 (25.0.%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e3 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eORR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e30.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e25.0 %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e33.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003eDCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e60.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e75.0 %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e50.0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: CAPTEM, capecitabine plus temozolomide; STZ, streptozotocin; STZ+5-FU, streptozotocin plus 5-fluorouracil; ORR, objective response rate; DCR, disease control rate\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u003c/strong\u003e\u0026nbsp; Adverse events of CAPTEM therapy\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCTCAE Grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003e\u003cem\u003eNumber of patients (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003eNeutrophil count decrease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e7 (46.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1 (6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1 (6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003eFebrile neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e7 (46.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e4 (26.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003ePlatelet\u0026nbsp;count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e6 (40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003eOral mucositis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1 (6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e6 (40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2 (13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 226px;\"\u003e\n \u003cp\u003eMalaise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1 (6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2 (13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003ePalmar-plantar\u0026nbsp;erythrodysesthesia syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e1 (6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e2 (13.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: CAPTEM, capecitabine plus temozolomide\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"capecitabine, temozolomide, CAPTEM, pancreatic neuroendocrine tumors, Japanese patients","lastPublishedDoi":"10.21203/rs.3.rs-5073563/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5073563/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Treatment strategies for patients with unresectable or recurrent pancreatic neuroendocrine tumors (pNETs) have been investigated, and combination therapy with capecitabine plus temozolomide (CAPTEM) has demonstrated favorable outcomes. In response to these results, the CAPTEM regimen has been widely used in several countries, including Western nations. However, it is yet to be approved in Japan, and its efficacy and safety in the Japanese population remain unclear. In the present study, we examined the efficacy and safety of CAPTEM in Japanese patients with unresectable or recurrent pNETs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: Data were retrospectivelycollected from the medical records of the National Cancer Center Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Fifteen patients with pNETs had received CAPTEM therapy, and 47% of the patients had WHO Grade 2 disease and 47% had WHO Grade 3 disease. The objective response rates and disease control rates were 26.7 and 66.7%, respectively. The median observation period was 20.8 months. The median progression-free survival was 5.3 months (95% confidence interval [CI]: 0.9–NA), and 1-year survival rate was 81.2% (95%CI: 41.5–95.2%). The most common adverse events (AEs) associated with CAPTEM therapy were hematologic and gastrointestinal toxicities. One patient experienced CTCAE grade 3 neutropenia, but no AE-related deaths were observed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: This is the first study conducted to demonstrate CAPTEM is a valuable regimen also in the Japanese population, consistent with its established efficacy outside Japan. As reported previously, CAPTEM therapy was associated with high disease control rates, and it could be a valuable regimen in the Japanese population.\u003c/p\u003e","manuscriptTitle":"Outcomes of capecitabine plus temozolomide combination therapy in patients with advanced or metastatic pancreatic neuroendocrine tumors: a retrospective observational single-center study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-21 09:07:51","doi":"10.21203/rs.3.rs-5073563/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-03-31T03:12:25+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-29T22:43:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-18T14:09:16+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2025-03-13T01:20:34+00:00","index":"","fulltext":""},{"type":"decision","content":"Minor revisions","date":"2025-01-22T02:06:37+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d92d786a-63b4-4afc-97a3-f5c8884345c0","owner":[],"postedDate":"April 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-12T16:06:13+00:00","versionOfRecord":{"articleIdentity":"rs-5073563","link":"https://doi.org/10.1007/s10147-025-02779-1","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2025-05-09 15:57:39","publishedOnDateReadable":"May 9th, 2025"},"versionCreatedAt":"2025-04-21 09:07:51","video":"","vorDoi":"10.1007/s10147-025-02779-1","vorDoiUrl":"https://doi.org/10.1007/s10147-025-02779-1","workflowStages":[]},"version":"v1","identity":"rs-5073563","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5073563","identity":"rs-5073563","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}