Prognostic Factor in Patients with Advanced, Inoperable Thymic Carcinoma: An Application of the Lung Immune Prognostic Index

Background: The prognostic implications of palliative chemotherapy for advanced or recurrent thymic carcinomas require full elucidation. The lung immune prognostic index (LIPI) is a novel prognostic index whose effectiveness has recently been reported in lung cancer patients. This study aimed to evaluate the LIPI’s clinical value in advanced or recurrent thymic carcinoma patients. Methods: We retrospectively analyzed 41 advanced or recurrent thymic carcinoma patients undergoing palliative chemotherapy between January 2001 and December 2020. Survival-time analysis was conducted using the Kaplan–Meier method and log-rank test. Multivariate analysis using the Cox proportional hazards model was performed to investigate the LIPI’s predictive and/or prognostic value. Results: Median progression-free survival (PFS) for rst line chemotherapy and overall survival (OS) were signicantly longer in the good-LIPI group (LIPI: 0) than in the intermediate/poor-LIPI group (LIPI: 1 or 2) (PFS: 13.4 vs. 6.8 months, p=0.0425; OS: 48.2 vs. 28.9 months, p=0.00506.). Multivariate analysis revealed that serum albumin <3.5 g/dL and an intermediate/poor LIPI were independent adverse prognostic factors for OS. Moreover, an intermediate/poor LIPI was the only adverse prognostic factor for PFS. Conclusions: Our study indicates that the LIPI is a potential prognostic marker in patients with advanced or recurrent thymic carcinoma undergoing palliative chemotherapy.


Introduction
Thymic carcinomas are rare neoplasms that arise in the anterior mediastinum, with a reported annual incidence of 0.29 per 100,000 population in Japan [1] . Thymic carcinoma is a highly progressive disease characterized by a poor survival rate, local invasion, and distant metastases often present at the time of diagnosis [2,3] . Patients with advanced (stage IVa and IVb according to the Masaoka-Koga stage classi cation) or recurrent thymic carcinoma are usually treated with palliative intent chemotherapy or radiotherapy. However, due to the rarity of this patient population, the optimal chemotherapeutic strategy and sequence of treatment are debatable. Thus, there are con icting ndings in previous reports regarding the prognostic implications of palliative intent chemotherapy for patients with advanced and/or recurrent thymic carcinoma.
In ammatory dynamics in the tumor microenvironment play a key role in carcinogenesis [4] . In recent years, the prognostic utility of hematological and biochemical parameters that can be routinely evaluated in daily clinical practice and that potentially re ect tumor in ammation have been validated. Typically, the neutrophil-to-lymphocyte ratio (NLR) and derived NLR (dNLR), comprising leukocyte fractions, are commonly used parameters [5,6] . In cancer patients, these parameters have been reported to act as predictive and/or prognostic biomarkers, indicating tumor in ammatory status re ected by alterations in peripheral blood leukocytes [6] . Furthermore, serum lactate dehydrogenase (LDH) is a well-known prognostic marker for various types of cancer. Elevated LDH levels have been reported to re ect tumor in ammation [7] and signi cant tumor growth potential [8] . Based on these perspectives, Mezquita et al. proposed the lung immune prognostic index (LIPI), a composite index comprising the dNLR and LDH, and demonstrated its prognostic and predictive value in non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) [9] . Since then, numerous reports on the clinical utility of the LIPI, especially in lung cancer, have been published [10][11][12] . However, the clinical value of the LIPI in thymic carcinoma remains uncertain, and its prognostic role is unclear. Therefore, we conducted this study to validate the clinical value of the LIPI in patients with advanced or recurrent thymic carcinoma undergoing palliative intent chemotherapy.

Patient characteristics
During the study period, data on 54 patients with thymic carcinomas were collected from their medical records. Ten patients with insu cient clinical data for analysis and three who had been administered curative treatment, including radiotherapy or salvage thoracic surgery, were excluded; therefore, a total of 41 eligible patients were enrolled (Fig. 1). The patient characteristics are presented in Table 1

Prognostic factors for PFS and OS
The results of univariate and multivariate analyses of PFS and OS using the Cox proportional hazards model are presented in Tables 4 and 5

Discussion
The present study demonstrated that pretreatment LIPI has prognostic potential for patients with thymic carcinoma treated exclusively with palliative intent chemotherapy. Pretreatment LIPI was also associated with PFS for rst line chemotherapy. The patients were divided into the following two groups according to LIPI score: the "good-LIPI group" and "intermediate/poor-LIPI group," based on the study by Mezquita L et al [9] . In the intermediate/poor-LIPI group, there were higher rates of poor PS, histological types other than squamous cell carcinoma, and multiple metastatic lesions, and these differences were not statistically signi cant. In the survival-time analysis, PFS and OS were both signi cantly shorter in the intermediate/poor-LIPI group. In the multivariate analysis, Alb < 3.5 g/dL and an intermediate/poor LIPI were independent adverse prognostic factors for OS. Notably, an intermediate/poor LIPI was also an independent adverse prognostic factor for PFS for the rst line treatment. To the best of our knowledge, this is the rst study to demonstrate the clinical utility of the LIPI in patients with advanced and metastatic thymic carcinoma.
Recently, a multicenter, retrospective study on advanced thymic carcinoma, involving a comparatively large sample size, was conducted in Japan [16][17][18] . The results of the study revealed no signi cant difference in OS between the rst-line chemotherapy regimens, whereas tumor staging (Masaoka-Koga stage IVa) was an independent prognostic factor for OS [16,17] . In addition, hypoalbuminemia was identi ed as an independent prognostic factor [16] . These ndings indicate that in patients with advanced or metastatic thymic carcinoma, clinical characteristics and laboratory ndings may have prognostic potential superior to that of chemotherapy regimen. Thus, in the present study, we applied the LIPI and evaluated its clinical utility as a novel prognostic marker in patients with thymic carcinoma.
LDH plays an unfavorable role in various cancers; it is reportedly associated with tumor invasion and proliferation [19] , metastatic potential [20] , and drug resistance [21] . Elevated dNLR indicates a preference for granulocytes and monocytes over lymphocytes, re ecting the promotion of in ammatory dynamics in the tumor microenvironment [6] . The LIPI is a novel clinical indicator initially proposed by Mezquita et al., who validated its prognostic value in NSCLC patients treated with ICIs [9] . In their seminal report, it was suggested that LIPI potentially strengthens the prognostic power of LDH and the dNLR and facilitates better strati cation of the patient population. Thereafter, its prognostic value was reported not only in ICIs but also in NSCLC patients treated with epidermal growth factor receptor tyrosine kinase inhibitors [11] and cytotoxic chemotherapy [10] as well as in patients with small-cell lung cancer [22] . In recent years, the LIPI has been applied not only in lung cancer but also in the analysis of other cancer types. In their retrospective analysis of 361 resected esophageal squamous cell carcinomas, Feng et al. reported that a good LIPI was signi cantly associated with a superior 5-year survival rate, and this was observable at any stage of the disease [23] . Daniel et al. retrospectively analyzed 578 solid-tumor patients, including 145 renal cell carcinoma patients treated with ICIs, and demonstrated that in the renal cell carcinoma cohort, an intermediate/poor LIPI was signi cantly associated with shorter PFS and OS [24] . Chen et al. also analyzed 108 patients with advanced hepatocellular carcinoma treated with ICIs and found that an intermediate/poor LIPI was signi cantly associated with a poor disease control rate as well as shorter PFS and OS [25] . To date, the clinical value of the LIPI for advanced thymic carcinoma has not been investigated. Only one observational study suggested that elevated serum LDH is an independent prognostic factor for advanced thymic carcinoma, although, unlike our patient population, it included patients who underwent curative surgical or radiological treatment [26] .
Our data revealed that hypoalbuminemia and an intermediate/poor LIPI were signi cantly associated with unfavorable survival outcomes. Serum albumin is a well-known prognostic marker for several cancer types [27] . In addition to being a nutritional indicator, albumin also acts as a parameter representing in ammatory dynamics, and it is affected by several factors, such as extracellular uid volume, dehydration status, and in ammatory dynamics. Our results corroborate those of a previous study by Okuma et al., in which hypoalbuminemia was found to be an adverse prognostic factor for OS in advanced thymic carcinoma [16] . Notably, the present study demonstrated that an intermediate/poor LIPI was an independent negative prognostic factor for both PFS and OS. Although there was no signi cant difference in response rate according to LIPI score, pretreatment LIPI was associated with longer PFS to rst line treatment, which might have better strati ed subsequent long-term survival. We believe that, in advanced thymic carcinoma, for which the optimal chemotherapeutic strategy is debatable, the LIPI, an easy strati cation tool, may be bene cial in clinical practice.
This study had certain limitations. First, the small sample size and retrospective nature of this study might have in uenced patient background and selection. Due to the small sample size, it was di cult to make a comparison between three LIPI groups, that is, good (0), intermediate (1), and poor (2), as in the previous studies. Second, in our study, patients who underwent curative radiotherapy or surgical resection during their clinical course were excluded, whereas those who received palliative radiotherapy were included. As the de nition of "palliative radiotherapy" is unclear, there might have been selection bias in the process of patient recruitment. Furthermore, we did not examine treatment beyond second-line chemotherapy; although there is no established strategy for chemotherapy beyond second-line therapy in advanced thymic carcinoma, the course of post-treatment may affect OS.
In conclusion, this is the rst study to suggest the clinical bene ts of the LIPI in the prognosis of advanced or recurrent thymic carcinoma. The results of the present study suggested that LIPI might be superior to Alb, a universal cancer prognostic marker; the intensity of tumor growth re ected by LDH and the in ammatory dynamics in the tumor microenvironment re ected by dNLR could have better strati ed the patients.

Patients and setting
The present study was conducted retrospectively at a single institution. All methods of this study were performed in accordance with the amended Declaration of Helsinki. The Institutional Review Board of Shinshu University School of Medicine approved the conduct of this study (approval number: 5155) and waived off the patient informed consent because this was a retrospective observational study. Instead, an opt-out document for this study has been posted on the website of Shinshu University School of Medicine. Analysis data were collected from paper-based or electrical medical records. We extracted data on patients diagnosed with thymic carcinoma at our institute between January 2001 and December 2020. Patients meeting the following criteria were included: histopathological diagnosis of thymic carcinoma based on the 2015 World Health Organization classi cation of thymic tumors [13] , unresectable and advanced-stage (Masaoka-Koga stage a or b) carcinoma or postoperative recurrence thereof, receiving at least one regimen of systemic chemotherapy with cytotoxic agents, and not receiving curative treatment other than chemotherapy (i.e., curative intent radiotherapy, salvage surgery, etc.).

Data collection
Data on patient characteristics included age, sex, smoking history, histology, and clinical stage according to the Masaoka-Koga stage classi cation for thymic tumors, metastatic lesions, and performance status (PS) as evaluated by the Eastern Cooperative Oncology Group. The laboratory data measured at the initiation of rst-line chemotherapy included serum albumin (Alb); peripheral complete blood count, including absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) to calculate the dNLR; and serum LDH to evaluate the LIPI. The LIPI was evaluated according to the dNLR (ANC/[WBC-ALC]) and serum LDH levels, with scores ranging from 0 to 2 and calculated as follows: dNLR < 3 and LDH < 223 U/L = 0, dNLR ≥ 3 and LDH < 223 U/L or dNLR < 3 and LDH ≥ 223 U/L = 1, and dNLR ≥ 3 and LDH ≥ 223 U/L = 2. In this study, the patients were divided into the following two groups according their LIPI scores: the "good-LIPI group," including patients with an LIPI score of 0, and "intermediate/poor-LIPI group," including those with LIPI scores of 1 or 2. Regarding clinical course, data on the types of rst line chemotherapy regimen, treatment response, palliative intent radiotherapy, and survival time were collected. The treatment response for rst line chemotherapy was evaluated according to the revised Response Evaluation Criteria in Solid Tumors guidelines (v.1.1) [14] . Overall survival (OS) was de ned as the period from initiation of chemotherapy to either a fatal event or censored observation. Progressionfree survival (PFS) for rst-line chemotherapy was de ned as the period from initiation of chemotherapy to death or disease progression.

Statistical analysis
Kaplan-Meier analysis was performed to plot the PFS and OS curves, and the log-rank test was employed for intergroup comparisons of PFS and OS. A Cox proportional hazards model was used to identify the prognostic factors for PFS and OS, with statistically signi cant variables used for the univariate model and clinically important variables further analyzed using multivariate analysis. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria), and statistical signi cance was set at P < 0.05 [15] .

Declarations Author contributions
The study was initially conceived by T.K. All authors contributed to the study conception and design. The rst draft of the manuscript was written by T.A., and all authors provided recommendations for the improvement of previous versions of the manuscript. All authors have read and approved the nal manuscript.

Competing interests
The authors declare no competing interests.

Data Availability Statement
The data that support the ndings of this study are available from the corresponding author, K.T., upon reasonable request.