Combination carboplatin and nab-paclitaxel as a first-line treatment for advanced thymic carcinoma

Thymic carcinoma is a very rare neoplasm for which no optimal chemotherapeutic regimen has been established to date. Hence, we performed this study to investigate the efficacy and safety of carboplatin plus nanoparticle albumin-bound (nab)-paclitaxel as a first-line regimen for patients with advanced thymic carcinoma. We conducted this multi-institutional retrospective cohort study of patients with advanced thymic carcinoma who had received carboplatin plus nab-paclitaxel as a first-line chemotherapy between August 2013 and December 2021. Twelve patients were included in this study and were subjected to efficacy and safety analysis. Their median age was 62 years (range, 47–74 years), and all had an Eastern Cooperative Oncology Group performance status score of 0 or 1. After a median follow-up time of 19.7 months, the overall response rate was 50%; the median progression-free and overall survival times were 8.8 months and 23.3 months, respectively. Chemotherapy-related peripheral neuropathy was observed in 2 patients (16%; each with grade 1). Other toxicities were manageable, and there were no treatment-related deaths. Carboplatin plus nab-paclitaxel as a first-line chemotherapy regimen showed good efficacy and safety in patients with advanced thymic carcinoma.


Introduction
Thymic carcinomas are rare malignant tumors that occur in the anterior mediastinum; they arise from the thymic epithelium and account for 12-36% of all thymic epithelial tumors [1][2][3]. Thymic carcinoma is highly aggressive and tends to metastasize and invade surrounding tissues more frequently than thymoma. As such, its prognosis is poor, with a 5-year survival rate of only 30-50% [3,4]. Approximately half of the patients with thymic carcinoma have advanced-stage disease at initial presentation [3][4][5].
While systemic chemotherapy is a critical treatment for thymic carcinoma, it is often administered only to patients with advanced disease. Owing to its rarity, a standard chemotherapy regimen for thymic carcinoma has not yet been established. Presently, platinum combination chemotherapy with or without anthracycline is a widely used first-line regimen; moreover, the combination of carboplatin plus solvent-based paclitaxel (sb-paclitaxel) has been reported to be effective against advanced thymic carcinoma [6][7][8][9] and is recommended by the National Comprehensive Cancer Network (NCCN) Guidelines [10].
Nanoparticle albumin-bound (nab)-paclitaxel, where paclitaxel is bound to 130 nm albumin particles, is a promising novel agent for the treatment of non-small cell lung cancer (NSCLC) as well as breast and gastric cancers [11,12]. A previous preclinical study found that nab-paclitaxel exhibited greater antitumor activity than equitoxic doses of sb-paclitaxel in xenograft models based on lung (H522), breast (MX-1), ovarian (SK-OV-3), prostate (PC-3) and colon (HT29) cancer cell lines [13]. The same study reported that the intratumor concentrations of paclitaxel in MX-1 xenograft mice were 33% higher in animals administered nab-paclitaxel than in those that received equivalent doses of sb-paclitaxel [13]. Whereas some case reports previously have previously indicated the efficacy of combination carboplatin plus nab-paclitaxel in patients with advanced thymic carcinoma [14][15][16], no cohort studies have been performed to validate these claims, and little is known about the efficacy and safety of this combination regimen against this disease.
Hence, we conducted this study to evaluate the efficacy of carboplatin and nab-paclitaxel combination chemotherapy for patients with advanced thymic carcinoma.

Patients and methods
This was a multi-institutional retrospective cohort study of consecutive patients with histologically or cytologically confirmed thymic carcinoma treated between August 2013 and December 2021. All patients had unresectable advanced-stage disease as defined by the Masaoka classification [17]; some subjects were not eligible for curative treatments. The inclusion criterion was a measurable target lesion as observed on chest radiography, computed tomography (CT) of the chest and abdomen, or other imaging modalities (magnetic resonance imaging of the head, positron emission tomography [PET], or PET/CT). The data acquisition cut-off date was March 2022. The ethical review boards of Kitasato University and Kanagawa Prefectural Federation of Agricultural Cooperatives for Health and Welfare Sagamihara Kyodo Hospital approved the study and permitted the use of the opt-out method in lieu of written informed consent.
All patients received nab-paclitaxel infusion at the dose of 100 mg/m 2 on days 1, 8, and 15 as well as carboplatin at an area under the concentration-time curve of 6.0 on day 1; this treatment cycle was repeated every 4 weeks, with the maximum number of platinum doublet chemotherapy cycles limited to 6. Before the start of treatment, the patients were required to have an absolute neutrophil count of ≥ 1500/mm 3 , a platelet count of ≥ 100,000/mm 3 , serum aspartate aminotransferase and alanine aminotransferase levels less than threefold the upper limit of the normal range, and serum total bilirubin and creatinine levels less than 1.5-fold the upper limit of the normal range. Subsequent doses were modified based on any hematological and non-hematological toxicities at the discretion of the attending doctor.

Evaluation of response and toxicity
Tumor response was classified using the Response Evaluation Criteria for Solid Tumors, version 1.1; the best overall response and maximum tumor control were noted. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (version 5); all treatment courses were included in the toxicity analysis. Recombinant human granulocyte colony-stimulating factor was administered as permitted by the National Health Insurance of Japan. Treatment was discontinued in the event of disease progression, unacceptable toxicity, patient refusal of further treatment, or a decision by the attending doctor to terminate treatment.

Statistical analysis
Progression-free survival (PFS) was defined as the interval between the date of carboplatin and nab-paclitaxel therapy initiation and that of disease progression or death; if neither occurred, the patient was censored on the date of the last follow-up examination. Overall survival (OS) was measured from the first day of treatment to the date of death or final followup visit. All statistical analyses were performed using SPSS version 28.0 for Windows (IBM Corp., Armonk NY, USA).

Patient characteristics
The characteristics of the 12 patients enrolled in this study are listed in Table 1. The median patient age was 62 years; 7 of them were men, and all had a performance status score of 0 or 1. Most of the patients had squamous cell carcinoma and 4 had experienced postoperative recurrence. In total, 49 cycles of carboplatin and nab-paclitaxel were administered, with a median of 4 cycles per patient.

Adverse events
The highest levels of hematological and non-hematological toxicities in the 12 patients are summarized in Table 2. Nine patients experienced leukopenia and/or neutropenia of grade 3 or greater severity (75%) and two patients experienced peripheral neuropathy of grade 1. There were no treatment-related deaths.

Response and survival
Among the 12 patients, 6 experienced partial response, 5 had stable disease, and 1 had progressive disease; as such, the overall response rate was 50% (95% confidence interval  Fig. 2b), respectively. Eight of the 10 patients who experienced disease progression after carboplatin and nab-paclitaxel therapy received second-line chemotherapy; 4 received amrubicin monotherapy, 2 received S-1, 1 received carboplatin plus nab-paclitaxel as a rechallenge therapy, and 1 received carboplatin plus amrubicin (Supplemental Table 1). We showed a swimmer's plot chart regarding the clinical courses for the twelve patients (Supplemental Fig. 1).

Discussion
Our retrospective study analyzed the efficacy and safety of combined carboplatin plus nab-paclitaxel therapy in 12 previously untreated patients with advanced thymic carcinoma. While previous case reports have indicated the efficacy of this combination regimen for patients with this disease [14][15][16], no cohort studies have been performed to validate these claims. To the best of our knowledge, ours is the first study to evaluate the efficacy of combination carboplatin plus nab-paclitaxel in patients with advanced thymic carcinoma.
Owing to its rarity, there is limited information regarding the efficacy of chemotherapy in patients with advanced thymic carcinoma. The cisplatin-doxorubicin-cyclophosphamidevincristine (ADOC) regimen, which is an anthracycline-based multidrug treatment, is widely used as a first-line chemotherapy in clinical practice [10,[18][19][20]. However, the adverse effects of anthracycline-based regimens, particularly hematological toxicities, are reportedly more severe than those of platinumdoublet regimens [18,[21][22][23]. Recently, the Japanese NEJ023 multi-institutional retrospective study revealed that carboplatin plus sb-paclitaxel produces similar outcomes as ADOC in patients with advanced thymic carcinoma [24]. While there have been no prospective trials comparing ADOC to carboplatin/sb-paclitaxel, the NCCN guidelines currently recommend carboplatin/sb-paclitaxel as a first-line chemotherapy for patients with advanced thymic carcinoma [10]. Carboplatin plus nab-paclitaxel is a frequently used regimen for the treatment of advanced NSCLC in clinical practice as such its application for the treatment for thymic carcinoma would be relatively straightforward. Additionally, administering this combined regimen would certainly be more convenient than delivering ADOC, as it is available on an outpatient basis.
A global phase III study revealed that nab-paclitaxel plus carboplatin yielded a significantly higher overall response rate than carboplatin plus sb-paclitaxel in patients with NSCLC [25]. The authors of the study noted that patients with squamous cell histology responded remarkably well to nab-paclitaxel, suggesting that this agent is ideal for treating patients with that histological subtype [25]. The most common histologic type of thymic carcinoma in Japan is squamous cell carcinoma; as such, Japanese patient populations   ought to respond well to nab-paclitaxel [3]. Based on the results of our study, carboplatin plus nab-paclitaxel therapy produced a high response rate, with PFS and OS comparable to those of patients with thymic carcinoma who received carboplatin plus sb-paclitaxel (Table 3). It was previously found that carboplatin plus nab-paclitaxel therapy resulted in a significantly lower incidence rate of peripheral neuropathy among patients with NSCLC than did carboplatin plus sb-paclitaxel therapy [25]; this was further supported when using the FACT-Taxane tool, which showed a significant reduction in the development of neuropathy symptoms including neuropathic pain in the hands and feet [25]. Moreover, we found that the proportion of patients experiencing peripheral neuropathy owing to carboplatin plus nab-paclitaxel therapy appeared to be lower than that reported in patients receiving carboplatin plus sb-paclitaxel (Table 3). Hence, carboplatin plus nab-paclitaxel therapy appears to be at least as beneficial in patients with thymic carcinoma as in those with NSCLC not only in terms of good efficacy but also the low frequency of sensory neuropathy.
A previous multi-institutional retrospective study that evaluated the efficacy of second-line chemotherapy for patients with advanced thymic carcinoma in which 57.6% of the subjects received second-line platinum-based doublets, 13.6% received other multidrug regimens (e.g., ADOC), and 28.8% received monotherapy found that the median OS from the start of second-line chemotherapy was 22.4 months while the response rate was 20.0% [26]. Another multicenter, phase 2 trial of the vascular endothelial growth factor receptor kinase inhibitor lenvatinib [27,28] found that this agent is effective and safe in patients with advanced thymic carcinoma in a second-line setting [29]. Such findings suggest that second-line chemotherapy is valuable for patients with advanced thymic carcinoma. Of the 10 patients in our study who experienced disease progression while on carboplatin plus nab-paclitaxel, 8 (80%) received second-line chemotherapy given that their performance status did not deteriorate during first-line therapy. The preservation of performance status during first-line therapy is generally required for patients to be eligible for second-line therapy, which in turn may prolong survival time; our data indicate that carboplatin plus nab-paclitaxel is a reasonable option in this regard.
A limitation of our study is its retrospective design and small sample size; as such, our results cannot be considered definitive without additional validation.
In conclusion, carboplatin plus nab-paclitaxel showed favorable efficacy and safety as a first-line chemotherapy for patients with advanced thymic carcinoma. Given that this disease is rare, a multi-institutional non-randomized phase II study of the efficacy of this combination regimen is warranted.
Author contributions All authors contributed to the study conception and design. Data collection was performed by all authors, and analysis was performed by SI and MH. The first draft of the manuscript was written by SI and MH. All authors commented on versions of the manuscript. All authors read and approved the final version of the manuscript.

Data availability
The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Declarations
Ethical approval and informed consent The ethical review board of Kitasato University and its affiliated hospitals approved the study and permitted the use of the opt-out method in lieu of written informed consent.

Conflicts of interest
The authors have no relevant financial or nonfinancial interests to disclose.