Phase II study of S‐1 plus cisplatin with concurrent radiotherapy for locally advanced thymic carcinoma: Results of the LOGIK1605/JART‐1501 study

Abstract Background Combination chemotherapy is used to treat advanced thymic carcinoma; however, the effects are insufficient. Methods Previously untreated patients with unresectable locally advanced thymic carcinoma received two cycles of 80 mg/m2/day S‐1 orally on days 1–14 plus 60 mg/m2/day cisplatin intravenously on day 1, and concurrent radiotherapy (60 Gy). Results Three patients were enrolled into the study. Toxicity and survival were assessable in all patients, but the treatment response was only assessable in one patient. The study was terminated because of poor case recruitment. The patients' characteristics were as follows: male/female = 2/1; PS 0/1 = 2/1; median age (range) = 59 (55–72); and stage III/IV = 2/1. The patient in which the treatment response was assessed exhibited SD (response rate: 0%). In both nonevaluable cases, the second course of chemotherapy was judged to be post‐protocol treatment because it was delayed by ≥14 days, but a CR and PR were achieved after the end of the study, respectively. G4 leukopenia/neutropenia and G3 febrile neutropenia occurred in one patient each (33%). The median time to tumor progression was 17.6 months, and the 1‐, 2‐, 3‐, and 4‐year survival rates were 67, 33, 33, and 33%, respectively. The median overall survival time was not reached, and the 1‐, 2‐, 3‐, and 4‐year survival rates were 100, 67, 67, and 67%, respectively. Conclusions Although it was difficult to recruit patients, there was a long‐term survivor >4 years who appeared to have achieved a CR, indicating that such chemoradiotherapy may be effective against locally advanced thymic carcinoma.

and 4-year survival rates were 67, 33, 33, and 33%, respectively. The median overall survival time was not reached, and the 1-, 2-, 3-, and 4-year survival rates were 100, 67, 67, and 67%, respectively. Conclusions: Although it was difficult to recruit patients, there was a long-term survivor >4 years who appeared to have achieved a CR, indicating that such chemoradiotherapy may be effective against locally advanced thymic carcinoma.

INTRODUCTION
Thymic epithelial tumors are derived from the thymus and include thymomas and thymic carcinomas. They are rare, but they are still the most common neoplasms of the anterior mediastinum. 1 They tend to be aggressive and infiltrate neighboring organs, which makes total resection very difficult. Thymic carcinoma has a poor prognosis compared with thymoma. 2 The incidence of thymic carcinoma is 1.5 per 1 million person-years. 3 Surgery is the mainstay of treatment in resectable cases, and multimodal approaches play an important role in advanced cases 4 ; however, few studies have evaluated third-generation drugs or the concurrent use of chemoradiotherapy as treatments for thymic carcinoma because of the rarity of such tumors.
Regarding chemotherapy, regimens that are similar to the cisplatin-based regimens used for thymoma are the main treatments for clinical stage IV or recurrent thymic carcinoma. A few studies that specifically examined the effects of chemotherapy on thymic carcinoma have also been reported, and the response rate was about 22%-38%, which indicated that it had some effect. [5][6][7] Therefore, it is recommended that chemotherapy is used in patients that are in a good general condition. Cisplatin/doxorubicin/cyclophosphamide, etoposide/cisplatin, and paclitaxel/carboplatin regimens are commonly used to treat thymic carcinoma. 8,9 S-1 (TS-1; Taiho Pharmaceutical Co. Ltd.) is a third-generation oral fluoropyrimidine antitumor agent, which combines tegafur, gimeracil, and oteracil potassium in a molar ratio of 1.0:0.4:1.0, and it was reported to be effective against various solid cancers, including gastric, colon, and non-small cell lung cancer (NSCLC). [10][11][12] Recently, a number of studies have indicated that S-1 treatment is effective against thymic carcinoma. 13-15 S-1 plus cisplatin with concurrent radiotherapy is a commonly used treatment for non-small cell lung cancer. Its safety has been confirmed, 16,17 and it has been reported to have a marked effect against thymic carcinoma. 18 Therefore, we conducted a phase II study of S-1 plus cisplatin with concurrent thoracic radiotherapy for locally advanced thymic carcinoma, 19 in which the overall response rate was employed as the primary endpoint. The secondary endpoints were overall survival, progression-free survival, and safety.

METHODS
The study protocol was reviewed and approved by the protocol committee of the Lung Oncology Group in Kyusyu (LOGiK) and The Clinical Research Review Board in Nagasaki University (CRB7180001) (registration number: jRCTs071180046). Written informed consent was obtained from all study participants. The study was performed by an independent collaborative (unsponsored) group. It has also been registered with the University Hospital Medical Information Network (UMIN) in Japan (registration number: UMIN000024643).

Study design and patients
The LOGIK1605/JART-1501 study was initially designed as a phase II, single-arm trial of S-1 plus cisplatin with concurrent radiotherapy as a first-line treatment for patients with locally advanced thymic carcinoma, involving two research groups, LOGiK and the Japanese Association for Research on the Thymus (JART).
The eligibility criteria for this study were as follows: a histologically and/or cytologically confirmed diagnosis of thymic carcinoma; not having previously undergone chemotherapy, radiotherapy, or surgery for thymic carcinoma; not being indicated for radical surgical resection; having locally advanced Masaoka stage III or IV disease with or without lymph node metastasis, without distant metastasis and/or dissemination; not experiencing postoperative recurrence; being eligible for radical irradiation according to the treatment plan developed by a radiotherapist; not having any other active malignancies; being aged ≥20 and ≤75 years old; having an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤1; having adequate bone marrow function (a leukocyte count of ≥3000/μl or a neutrophil count of ≥1500/μl, a hemoglobin level of ≥9.0 g/dl, and a platelet count of ≥10.0 Â 10 4 /μl); having alanine aminotransferase and aspartate transaminase levels of <100 IU/l; having a serum bilirubin level of ≤1.5 mg/dl; having a creatinine clearance rate of ≥60 ml/min; exhibiting arterial O 2 pressure of ≥60 Torr or SpO 2 of ≥90%; providing written informed consent; and having a life expectancy of >3 months. The exclusion criteria were as follows: having severe complications, such as uncontrolled angina; having suffered a myocardial infarction within the past 3 months; suffering severe heart failure or an infection; having uncontrolled diabetes or hypertension; having interstitial pneumonia, as determined by a chest x-ray; or having medical problems that were severe enough to prevent compliance with the protocol.

Assessment
Before treatment, each patient's complete medical history was taken, and all patients underwent a physical examination, assessments of complications, blood cell counts, blood biochemistry tests, a chest x-ray, chest and abdominal computed tomography (CT), a radionuclide bone scan or positron emission tomography (PET)-CT, brain magnetic resonance imaging, and electrocardiography. Treatment responses were determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. All adverse events were recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Treatment
The patients received chemotherapy with S-1 (80 mg/m 2 ) in two daily doses after meals on days 1-14 and 29-42, and cisplatin (60 mg/m 2 ) as an intravenous infusion on days 1 and 29. The dose of S-1 was determined according to the patient's body surface area (BSA) as follows: BSA: <1.25 m 2 , 80 mg per day; BSA: 1.25 m 2 to <1.50 m 2 , 100 mg per day; and BSA: ≥1.5 m 2 , 120 mg per day. As for the radiotherapy regimen, 2.0 Gy was administered once daily, 5 times a week, from day 1 until a total dose of 60 Gy had been administered. Intensity-modulated radiotherapy was not permitted. The method used to assess the area of the primary tumor on CT has been described in a previous study. 19

Pathological specimens and images
The initial pathological diagnosis was obtained at each facility and was confirmed by a central review committee after the treatment had been completed. Similarly, the initial imaging-based staging and response assessments were performed at each facility and were confirmed by a central review committee.

Statistical analysis
The primary endpoint of this study was the response rate, which was assessed by an independent review committee. The secondary endpoints included overall survival, progression-free survival, and safety. The estimated required number of patients for an accurate binomial test was determined to be >27 based on the following assumptions: threshold response rate P0 = 0.45, expected response rate P1 = 0.70, one-sided α = 0.05, and ß = 0.20. As some patients may be ineligible, the target sample size was set at 30. The enrollment period was set at 3 years, and the followup period was scheduled to last for 1.5 years.

RESULTS
Three patients from two institutions were enrolled in this trial between December 2016 and November 2019. Due to the difficulty of recruitment, case registration was terminated without extending the recruitment period. One patient received the planned treatment and underwent evaluations of the treatment response, toxicity, and survival. The remaining two patients also received the planned treatment; however, the start of the second cycle of chemotherapy was delayed by >14 days in these cases, which met the protocol treatment discontinuation criteria, and hence, the second cycles were judged to be post-protocol treatment regimens by an independent committee. Thus, these two patients underwent the evaluations of toxicity and survival, but not the treatment response evaluation.

Treatment administration
A total of four cycles of S-1 plus cisplatin were administered as protocol treatment to the three patients: one cycle was administered to two patients (cases 1 and 3) and two cycles were administered to one patient (case 2). In case 1, a second cycle of S-1 plus cisplatin was administered as postprotocol treatment 27 days later due to myelotoxicity, and a total of four cycles of S-1 plus cisplatin were eventually administered. In case 3, the patient developed severe nausea and weight loss and was considered to be cisplatin-intolerant. Therefore, S-1 plus cisplatin was terminated after one cycle, and S-1 alone was administered in the second cycle as a post-protocol treatment. The S-1 treatment was delayed 53 days because of leukopenia, neutropenia, febrile neutropenia, and weight loss. Sixty Gy of thoracic radiotherapy was administered to two patients (cases 1 and 2), and 40 Gy of thoracic radiotherapy was administered to one patient (case 3) due to a reduction in their PS.

Efficacy
The patient characteristics, treatments administered, and their efficacy are shown in Table 1. The treatment response was assessed in one patient (case 2), who exhibited stable disease (SD), resulting in an overall response rate of 0%. The treatment response was not evaluable in two patients (cases 1 and 3) because of the administration of early postprotocol treatment; that is, S-1 plus cisplatin (case 1) and S-1 (case 3), respectively. The median potential follow-up time was 41.1 months. Two patients survived, and the other patient died during the follow-up period. The median progression-free time of the three patients was 17.6 months, and the 1-, 2-, 3-, and 4-year progression-free survival rates were 67, 33, 33, and 33%, respectively. The median overall survival time was not reached, and the 1-, 2-, 3-, and 4-year overall survival rates were 100, 67, 67, and 67%, respectively. CT images of cases 1 and 3 are shown in Figures 1 and 2, respectively. In case 1, after one cycle of the protocol treatment with full radiotherapy and three cycles of postprotocol treatment the tumor continued to shrink, and after 56.9 months it was still asymptomatic and had not progressed. In case 2, the tumor shrank, but only by 27%; therefore, it was classified as SD. No exacerbation was observed until 17.6 months later when a new lesion appeared. Postprotocol treatment with carboplatin and paclitaxel was administered, and so far the patient has survived for 41.1 months. In case 3, the tumor shrank, as shown in Figure 2; however, a tumor developed in the neck outside of the irradiation field after 9.1 months. The patient's condition gradually deteriorated, and he died 13.9 months later.

Toxicities
The toxicities experienced during the protocol treatment are listed in Table 2. Toxicities were assessable in all three patients. Two (67%) patients experienced grade 3 or 4 hematological toxicities, and one (33%) developed grade 4 toxicities. The principal grade 3 or 4 hematological toxicity was leukopenia, which occurred in two (67%) patients, and the principal grade 4 toxicities were leukopenia and neutropenia, which occurred in one (33%) patient. Febrile   neutropenia occurred in one (33%) patient. The major nonhematological toxicity was nausea, which occurred in all three (100%) patients. Esophagitis was observed in two (67%) patients, but it was not severe. In case 3, the patient developed severe nausea and could not eat at all, resulting in a PS of 4. It was considered that she had experienced grade 3 nausea, weight loss, and fatigue.

DISCUSSION
As far as we are aware, the LOGIK1605/JART-1501 study is the first prospective study designed to evaluate the efficacy of third-generation cytotoxic agents plus cisplatin with concurrent radiotherapy for patients with locally advanced unresectable thymic carcinoma. Unfortunately, only three patients were enrolled, and the study was terminated because of poor case recruitment. In addition, the treatment response could only be evaluated in one case, which involved SD, and hence, the response rate was 0%. However, among the cases involving post-protocol treatment there was one long-term (>4 years) survivor, who seemed to achieve a complete response (CR) after S-1/cisplatin plus concurrent radiotherapy, indicating that chemoradiotherapy may be effective against locally advanced thymic carcinoma. One of the reasons why the case recruitment did not go well is that the eligibility criteria included unresectable cases in which preoperative induction chemoradiotherapy had not been performed. Cases in which surgical excision was planned after chemoradiotherapy were considered resectable, and hence were ineligible. Even locally advanced cases involving infiltration of the great vessels or the pericardium were considered resectable by the surgical researchers and hence, were ineligible. Further progression leads to pericarditis and pleuritis, and chemotherapy alone is used instead of chemoradiotherapy in such cases. Extended surgery including the heart, great vessels, and mediastinal lymph node metastasis was also performed for non-small cell lung cancer from 1970 to the 1990s; 20-22 however, its use has gradually decreased since prospective clinical trials demonstrated the long-term survival benefits of concurrent chemoradiotherapy. 23,24 Since thymic carcinoma is rare, it is difficult to conduct prospective clinical trials of treatments for the disease, especially for locally advanced cases. Nevertheless, it is necessary to continue to develop effective concurrent chemoradiotherapy regimens for thymic carcinoma.
Since we had no experience in conducting prospective trials of chemoradiotherapy for thymic carcinoma, unlike for lung cancer, it was difficult to determine the protocol rules with regard to the irradiation methods. 19 Although the case recruitment was unsuccessful this time, we believe that our experience with this prospective clinical trial will aid the development of treatments for this disease. If the investigators agree that the primary objective is to evaluate this chemoradiotherapy, it may be one way to conduct this as a clinical trial for preoperative induction treatment or stage III including resectable cases.
As for the effects of chemoradiotherapy on thymic carcinoma, Chen et al. retrospectively examined the cases of 29 patients who received concurrent chemoradiotherapy with a cisplatin combination regimen for unresectable thymic carcinoma. 25 The response rate was 50%, and half of the responders achieved a CR. In addition, the 3-and 5-year survival rates were 74.5 and 67.7%, respectively, and only mild adverse events were seen. Kashima et al. retrospectively examined the effects of chemoradiotherapy in 14 patients with thymic carcinoma and found a response rate of 57% (CR: n = 0; PR: n = 8), progression-free survival of 15.1 months, and median overall survival of 31.4 months. 26 Their 5-year survival rate of 25.7% was lower than that reported by Chen et al., and they mostly used cisplatin regimens, but they also used carboplatin regimens. Prospective studies of neoadjuvant chemoradiotherapy have also been conducted. Korst et al. conducted a prospective phase II trial of neoadjuvant chemoradiotherapy in 22 patients with locally advanced thymic tumors, including seven with thymic carcinoma, and a trend towards a greater radiographic response (as measured by tumor size) was seen. 27 In addition, we also experienced a case in which long-term recurrence-free survival was achieved after chemoradiotherapy-induced tumor shrinkage followed by complete resection. 28 In the current study, there was a long-term survivor who seemed to have achieved a CR, and the 4-year overall survival rate was 67%, suggesting the usefulness of chemoradiotherapy for locally advanced thymic carcinoma. Maintenance therapy with immune checkpoint inhibitors after concurrent chemoradiotherapy has been established as standard treatment in patients with locally advanced NSCLC. 29 We must therefore continue our efforts to develop chemoradiotherapy and chemoradiotherapy plus immune checkpoint inhibitors in future in the field of thymic carcinoma.
Regarding toxicities, severe nausea and weight loss developed in case 3 and the patient could not eat at all, resulting in a PS of 4. Occasionally, we encounter patients who are cisplatin-intolerant. Ueda et al. reported a female patient with advanced gastric cancer who suffered from lifethreatening adverse events, including severe myelosuppression during chemotherapy involving S-1 plus cisplatin. She was hospitalized because of weight loss and severe dehydration, which led to grade 4 leukopenia/neutropenia. 30 The latter case is similar to our case 3. Before treatment, the patient in case 3 was fine and had a PS of 0. Two weeks after treatment, grade 2 nausea, weight loss, and fatigue were observed together with grade 0 leukopenia and neutropenia. However, the nausea, weight loss, and fatigue continued for the next 2 weeks, and the leukopenia and nausea worsened to grade 4, and febrile neutropenia also developed and worsened, resulting in a PS of 4. The lack of sufficient chemotherapy and radiotherapy in case 3 also affected the efficacy of treatment, who was the only patient to experience short overall survival.
Hypersensitivity is a serious side effect of platinum agents, such as cisplatin and carboplatin, 31 but we do not think that our patients were affected by hypersensitivity. In case 1, myelotoxicity was prolonged and the start of the second course was delayed by 2 weeks, and the treatment deviated from the protocol treatment. However, the treatment was generally tolerated and, in case 2, the treatment was performed as planned. Considering that this treatment can be performed effectively in lung cancer patients, 16,17 and severe nausea and weight loss were only seen in case 3, it is probably tolerable for patients with locally advanced thymic carcinoma. Regarding age, only case 3 was over 70 years old, while cases 1 and 2 were under 60 years old. The occurrence of serious adverse events in case 3 may indicate that elderly patients have a higher incidence of adverse events in the current chemoradiotherapy treatment.
In conclusion, the LOGIK1605/JART-1501 study attempted to prospectively evaluate S-1 plus cisplatin chemotherapy with concurrent radiotherapy for locally advanced thymic carcinoma. Although case recruitment was difficult, there was a long-term survivor, and it was indicated that chemoradiotherapy may be effective against locally advanced thymic carcinoma.

CONFLICTS OF INTEREST
Dr Fukuda reports personal fees from AstraZeneca K.K., Bristol Myers Squibb, Chugai, Eli Lilly Japan, Kyowa Kirin, MSD K.K., Nippon Kayaku, Novartis, Pfizer Japan Inc., Taiho Pharmaceutical Co., and Takeda, grants from Astra-Zeneca K.K. and Eli Lilly Japan, outside the submitted work. Dr Mukae reports personal fees from MSD K.K., personal fees from Pfizer Japan Inc., grants and personal fees from Boehringer Ingelheim Japan, personal fees from Astellas Pharma Inc., personal fees from AstraZeneca K.K., grants and personal fees from Shionogi & Co., Ltd., grants and personal fees from Daiichi Sankyo Company, grants and personal fees from Taisho Pharma Co., Ltd, grants and personal fees from Meiji Seika Pharma Co., Ltd, personal fees from SRL, Inc, grants and personal fees from Asahi Kasei Pharma Corporation, personal fees from Eli Lilly Japan, personal fees from Ono Pharmaceutical Co. LTD., grants and personal fees from Kyorin Pharmaceutical Co., Ltd., grants and personal fees from Sumitomo Dainippon Pharma Co., Ltd, grants and personal fees from Taiho Pharmaceutical Co., personal fees from Mitsubishi Tanabe Pharma Corporation, grants and personal fees from Chugai Pharmaceutical Co, personal fees from Teijin Home Healthcare Limited, personal fees from Toa Shinyaku Co., Ltd, personal fees from Nihon Pharmaceutical Co. Ltd, personal fees from Janssen Pharmaceutical K.K., grants and personal fees from Fujifilm Toyama Chemical Co., Ltd, outside the submitted work; Dr Seto reports grants and personal fees from Astellas Pharma, grants and personal fees from AstraZeneca, grants and personal fees from Chugai Pharmaceutical, grants and personal fees from Eli Lilly Japan, grants and personal fees from Kissei Pharmaceutical, grants and personal fees from MSD, grants and personal fees from Nippon Boehringer Ingelheim, grants and personal fees from Novartis Pharma, grants and personal fees from Pfizer Japan, grants and personal fees from Takeda Pharmaceutical, personal fees from Bristol-Myers Squibb, personal fees from Kyowa Hakko Kirin, personal fees from Nippon Kayaku, personal fees from Ono Pharmaceutical, personal fees from Roche Singapore, personal fees from Taiho Pharmaceutical, personal fees from Thermo Fisher Scientific, personal fees from Yakult Honsha, grants from Bayer Yakuhin, grants from Daiichi Sankyo, grants from Eisai, grants from Loxo Oncology, grants from Merck Serono, outside the submitted work; The other authors have nothing to disclose.