Capecitabine and Temozolomide as a Promising Therapy for Advanced Thymic Atypical Carcinoid

Thymic neuroendocrine tumors are rare malignant tumors of the anterior mediastinum and lack standard treatment options. This report analyzes the efficacy and safety of the CAPTEM regimen in 9 patients with thymic atypical carcinoid.

Abstract

Background.

Thymic atypical carcinoid (TAC) is a rare thymic neuroendocrine tumor that originates in the neuroendocrine system and lacks a standardized treatment. The combination of capecitabine (CAP) and temozolomide (TEM) is associated with an extremely high and long‐lasting response rate in patients with metastatic pancreatic neuroendocrine tumors. However, there is little evidence showing that the CAPTEM regimen is effective for TAC. For patients with unresectable or metastatic atypical carcinoid of the thymus, few treatment options are available, and the treatment efficacy is not satisfactory. To explore the efficacy and safety of the CAPTEM regimen against TAC, we conducted a retrospective review.

Patients and Methods.

A total of nine patients with advanced atypical carcinoid of the thymus in the China‐Japan Friendship Hospital were treated with capecitabine (750 mg/m² twice daily, days 1–14) and temozolomide (200 mg/m² once daily, days 10–14) every 28 days between 2014 and 2018. The disease control rate (DCR), progression‐free survival (PFS), and adverse effects after treatment were analyzed. The DCR was calculated by RECIST version 1.1. Progression‐free survival was calculated by the Kaplan‐Meier survival method.

Results.

A total of nine patients (six male and three female) were included. The median age at CAPTEM initiation was 50 years (range, 26–58). The median number of CAPTEM cycles was 8 (range, 3–23). The DCR was 89% (8/9), with eight patients achieving stable disease. Only one patient (11%) showed progressive disease. The median PFS was 8 months. Because we applied vitamin B6 and ondansetron before administering the drugs, the side effects of this regimen were very small. Adverse reactions were all below grade 3 and included myelosuppression and digestive tract reaction.

Conclusion.

Our results suggest that the CAPTEM regimen may be effective and well tolerated for the treatment of TAC. More evidence is needed to validate the effectiveness of this regimen.

Implications for Practice.

Capecitabine and temozolomide regimen is effective and well tolerated in patients with advanced thymic atypical carcinoid.

Introduction

Thymic neuroendocrine tumors are rare thymic malignant tumors located in the anterior mediastinum. They only account for approximately 2% to 5% of thymic carcinomas [1], [2]. Thymic atypical carcinoid (TAC) accounts for approximately 40%–50% of all thymic neuroendocrine tumors [3]. Because of the rareness of this disease, there is a lack of standard treatment options, and few reports related to TAC have been published. Based on the mitotic count and the degree of necrosis, thymic neuroendocrine tumors are classified as low‐grade (typical carcinoid), intermediate‐grade (atypical carcinoid), or high‐grade (large‐cell neuroendocrine carcinoma, small‐cell carcinoma) tumors [4]. Compared with typical carcinoid, atypical carcinoid usually shows high levels of nuclear isoforms and higher mitotic activity (2~10/2 mm²), and this disease often shows central necrosis of the tumors [5].

There have been no large clinical trials on the treatment of TAC, which makes standardized treatment difficult. Surgical resection is believed to be the only curative method for resectable lesions. For patients with unresectable or metastatic tumors, chemotherapy with or without radiotherapy is recommended. However, its clinical use is limited because of its toxic side effects. For patients who have positive somatostatin receptor imaging, somatostatin analogues (SSAs) may be an option. Targeted therapeutic drugs, such as tyrosine kinase inhibitors (e.g., sunitinib) and mTOR inhibitors (everolimus), can be beneficial in the treatment of TAC, but neither has been shown to achieve significant tumor shrinkage. In China, the cost of targeted drugs and SSA treatment is expensive, resulting in limited clinical use. Therefore, there is an urgent clinical need for highly effective chemotherapy regimens with low toxicity.

Recently, the oral alkylating agent temozolomide (TEM) has been proven to be an active treatment option with or without a combination of thalidomide, bevacizumab or capecitabine (CAP) for neuroendocrine tumors [6], [7], [8], [9], [10].

The CAPTEM regimen has been shown to have significant activity in pancreatic NETs (neuroendocrine tumors) [11], but there are only a few reports on thymic NETs. Therefore, we retrospectively analyzed the efficacy and safety of the CAPTEM regimen in nine patients with TAC.

Subjects, Materials, and Methods

We retrospectively enrolled nine patients with metastatic TAC who failed to respond to previous therapy from September 2014 to April 2018 at the China‐Japan Friendship Hospital. Each patient received at least three cycles of the CAPTEM regimen. Patients were eligible if they had a diagnosis of TAC based on histological samples evaluated by pathologists accompanied by a mass on the chest shown in computed tomography (CT) imaging.

Dosing Regimen

The CAPTEM dosing regimen was as follows: capecitabine, 750 mg/m² by mouth twice daily on days 1–14, and temozolomide, 200 mg/m² by mouth once daily on days 10–14 every 28 days. While patients were on this regimen, 50 mg vitamin B6 tablets were given orally three times daily on days 1–14 to prevent capecitabine‐related hand‐foot syndrome, and 8 mg ondansetron tablets were taken orally once daily before temozolomide to prevent digestive tract reaction.

The patients received monthly complete blood counts and liver function tests. Each patient received radiological assessment every three cycles to evaluate the efficacy of the regimen.

Patient Demographics

Baseline demographics, tumor characteristics, and prior treatment were recorded for each patient. The side effects were collected from the patient records and categorized according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The disease control rate (DCR) was evaluated using RECIST version 1.1.

Statistical Analysis

Data were statistically analyzed using SPSS version 22.0 (IBM Corporation, Armonk, NY). The DCR and progression‐free survival (PFS) were calculated from the initiation of the CAPTEM regimen until disease progression, administration of alternative treatment, or death. PFS was calculated by the Kaplan‐Meier survival method.

Results

We selected nine (six male and three female) patients who were diagnosed with TAC and treated with at least three cycles of the CAPTEM regimen. The median age of the patients was 50 years (range, 26 to 58 years). The ratio of male to female patients was 2:1. The patient characteristics are listed in Table 1. The most common sites of TAC metastases were peripheral lymph nodes, bone, and lung. Only one patient showed liver metastases.

Table 1. Patient characteristics.

^aAge indicates age at time of presentation.

^bMasoka staging: stage I, completely encapsulated tumor and macroscopically no capsular invasion; stage II, macroscopic invasion into surrounding tissues; stage III, macroscopic invasion into neighboring organs, such as the pericardium or great vessels; stage IVa, pleural or pericardial dissemination; stage IVb, lymphogenous or hematogenous metastases.

^cYamakawa‐Masaoka TNM staging: T, tumor; T1, completely encapsulated; T2, macroscopic invasion to the surrounding tissue or invasion of the capsule; T3, invasion into neighboring organs; T4, pleural or pericardial dissemination; N, nodes; N0, no lymph node metastasis; N1, metastasis to anterior mediastinal lymph nodes; N2, metastasis to intrathoracic lymph nodes except anterior mediastinal lymph nodes; M, metastasis; M0, no hematogenous metastasis; M1, hematogenous metastasis.

Abbreviations: a, CAPTEM regimen with SSA; B, bone; C, chemotherapy; F, female; L, lung; Li, liver; LN, lymph nodes; M, male; PD, progressive disease; PFS, progression‐free survival; R, radiation therapy; RR, response rate; S [in pretreatment column], surgery; S [in metastases column], surrounding organs; SD, stable disease; SSA, somatostatin analogue treatment.

Five patients (56%) received surgical resection. Only two (22%) patients were previously treated with SSA, and seven (78%) patients underwent chemotherapy, most of which was cisplatin and etoposide or carboplatin and etoposide. Moreover, two (22%) patients accepted CAPTEM as the first‐line regimen, six (67%) as the second‐line regimen, and one (11%) as the third‐line regimen.

The median number of cycles of this regimen that patients received was 8, ranging from 3 to 23 cycles. The DCR was assessed using RECIST version 1.1 based on the patients' imaging studies during the follow‐up visit. Eight (89%) patients had stable disease, and one (11%) patient had progressive disease. The median PFS (mPFS) was estimated at 8 months (95% confidence interval, 6–28 months) from the beginning of the CAPTEM regimen, as shown in Figure 1.

Figure 1.

Progression‐free survival (PFS) from the date of the beginning of the CAPTEM regimen for the entire cohort. Median PFS for the entire cohort was 8 months.

Typical case (case 1): male, 58 years. The patient experienced pain in his left chest and increased pain during activities and coughs in December 2016. The chest CT examination (not in our hospital) showed anterior mediastinum occupancy, multiple bone metastases, and tumor embolism in the superior vena cava. A thoracic mass biopsy was performed, and the pathology was diagnosed by the China‐Japan Friendship Hospital: neuroendocrine tumors (two mitoses per 10 high power fields, Ki‐67 + 10%, considered atypical carcinoid). Then, the patient received five cycles of chemotherapy (cisplatin and etoposide), but because the fifth cycle of chemotherapy was associated with serious side effects, especially third‐degree myelosuppression, the use of this protocol was stopped. After that, the patient received the CAPTEM regimen from May 20, 2017, and he is still accepting this regimen. The chest CT was regularly reviewed. There was no increase in the tumor size. The patient is still followed up regularly, and no tumor progression has appeared. (Chest CT images of the patient at different times are shown in Figure 2.)

Figure 2.

Computed tomography scans of a patient (case 1). Scans were made in April 24, 2017 (upper left), July 21, 2017 (upper right), October 24, 2017 (lower left), and February 24, 2018 (lower right). Note: The medial mediastinum shows a large mass containing multiple necrotic areas invading the superior vena cava (arrows).

No patient underwent dose reduction because of adverse reactions. The most common minor adverse events were grade 1 or 2 fatigue (n = 4, 44%) and grade 1 or 2 nausea and vomiting (n = 3, 33%). Two (22%) patients experienced grade 1 anemia and leukopenia. Only one patient had abnormal liver function (grade 1 elevated AST) and hand‐foot skin reaction, which was mainly caused by capecitabine. No treatment‐related death occurred.

Discussion

Thymic neuroendocrine tumors were first described by Rosai and Higa [12]. These are extremely rare neuroendocrine tumors, and the little attention paid by doctors and patients makes early detection and treatment difficult. Men aged 55 years are more vulnerable to the disease than women [2], [13], [14]. According to our data, with nine patients, there were six men, and the median age of the patients was 47.5 years, which is consistent with the literature. TAC has high clinical invasiveness and lethality with nonspecific clinical symptoms. Tumors are usually identified on routine imaging examination. The typical clinical symptoms include cough, chest pain, and dyspnea due to superior vena cava syndrome [15]. Different symptoms also indicate different degrees of tumor malignancy. Chest tightness, cough, and other chest compression symptoms are due to large tumors of the chest; metastasis‐related symptoms (such as bone pain) suggest that metastases occur when the chest mass is too small to cause clinical symptoms, which indicates that TAC with metastasis‐related symptoms as the first symptoms may have increased malignancy. Our data show six patients with clinical manifestations of cough, chest pain, chest tightness, and shortness of breath were found to have a mass by the chest CT imaging. One patient was found to have TAC according to a left supraclavicular lymph node biopsy because of intermittent fever. Another patient with bone metastases visited the hospital with pain in the right shoulder and neck. The mass in the chest of one patient without any symptoms was found in a routine physical examination. Once the patient is diagnosed with TAC, it usually shows aggressive and metastatic characteristics. Unlike gastrointestinal pancreatic neuroendocrine tumors, which often have liver metastases, TAC often metastasizes to the lymph nodes, lung, pleura, and bone [2], [16], [17]. There were six cases of lymph node metastases, five cases of bone metastases, five cases of lung metastases, and only one case of liver metastases, which is consistent with the TAC characteristics of previous reports.

Thymic neuroendocrine tumors can produce many hormones. They are also associated with multiple endocrine neoplasia type 1 (MEN1), which is an autosomal dominant tumor caused by MEN1 gene mutations. Several findings strongly suggest that patients with MEN1 are susceptible to thymic neuroendocrine tumors [18], [19]. According to our data, one patient diagnosed with TAC associated with MEN1 developed progressive disease after 7 months of the CAPTEM regimen.

According to the National Comprehensive Cancer Network guidelines, TAC should be managed with a multidisciplinary collaborative treatment method. For localized tumors, surgical resection is the first choice; for the tumors that are not completely resected or have a positive margin, radiotherapy with or without the combination chemotherapy should be considered. For the patients who had positive somatostatin receptor imaging, SSAs, including octreotide and lanreotide, can be an option to this type of disease. For the tumors that cannot be excised locally or have distant metastases, SSA therapy alone or combined with targeted drugs (everolimus) or chemotherapy is recommended. Although there is no standard combination regimen, currently, chemotherapy is still recommended for TAC with high proliferation rates. Studies showed that cisplatin or temozolomide‐based chemotherapy regimens affect thymic neuroendocrine tumors [3]. Platinum‐containing protocols, such as cisplatin and etoposide or carboplatin and etoposide, are recommended for patients diagnosed with TAC. However, this regimen is sometimes limited by its toxicity.

In recent years, studies by American and Jordanian scholars have found that the CAPTEM protocol has a PFS ranging from 14.0 to 16.5 months in well‐differentiated NENs [20], [21]. Other studies have shown that the CAPTEM regimen is very effective for metastatic neuroendocrine tumors [22]. In a large cohort of 143 patients with pancreatic neuroendocrine tumors treated with CAPTEM chemotherapy [23], researchers reported an mPFS of 17 months. Only a few studies related to the treatment of TAC are available. One retrospective analysis included three patients with metastatic neuroendocrine tumors of the thymus treated with the CAPTEM regimen and showed that the combination of capecitabine and temozolomide may have a positive outcome for these rare and highly malignant tumors, with one patient achieving partial response and two patients achieving stable disease [24]. In our data, eight patients achieved stable disease, and only one patient experienced progressive disease. Five patients showed a response to the CAPTEM regimen even after experiencing progressive disease treated previously with other chemotherapies. The mPFS was 8 months, and no patient underwent drug decrement due to adverse reactions. Therefore, we assumed that the efficacy of the CAPTEM regimen for TAC disease is general, but for this malignant tumor, it is also meaningful to achieve an mPFS of 8 months. Furthermore, this regimen was very safe for the patients.

Mechanistic studies have shown that temozolomide is an oral alkylating agent that kills tumor cells by alkylating DNA. The lack of immunohistochemical O6‐methylguanine DNA methyltransferase may increase the sensitivity of neuroendocrine tumors to temozolomide [25]. And there is a certain synergy between capecitabine and temozolomide.

Limitations of this report include the small sample size and the lack of multicenter data. However, this retrospective report provides an alternative for the treatment of this rare tumor. Further research is required to confirm the clinical value of this regimen.

Conclusion

Many questions remain concerning the medical management of TAC, such as the sequence of chemotherapeutic drugs and the timing of treatment initiation. Our results demonstrate that the CAPTEM regimen is an alternative option with well‐tolerated side effects, which could be considered for use in patients with TAC, but its long‐term use still requires confirmation by further studies. Although prospective research is needed, there are abundant retrospective data indicating that this therapy may be beneficial for patients with TAC.

Author Contributions

Conception/design: Huangying Tan, Xin Wang

Provision of study material or patients: Huangying Tan, Yuanliang Li, Zhirong Qi

Collection and/or assembly of data: Xin Wang, Yingying Chen, Bing Yuan

Data analysis and interpretation: Xin Wang, Jianghui Duan, Zhirong Qi

Manuscript writing: Xin Wang

Final approval of manuscript: Xin Wang, Yuanliang Li, Jianghui Duan, Yingying Chen, Bing Yuan, Zhirong Qi, Huangying Tan

Disclosures

The authors indicated no financial relationships.