Locally advanced thymic tumors; does neoadjuvant chemotherapy make a difference?
Authors: Abdeljalil Riad , Abdallah Farah A. , Obeid Zeinab , Harb Ahmad Khaled , Chaar Mohamad K. Abou , Shannies Tariq Bassem , El-Edwan Ahed , Haddad Hussam , Ghraibeh Azza , Abu-Shanab Ahmad 
Published: April 2023

Abstract
Background: Thymomas, although rare, remain the most frequently encountered primary tumor of the anterior mediastinum comprising about 50% of all masses in the region. Surgical resection, via thymectomy, remains the mainstay treatment modality conventionally. In locally advanced and borderline resectable tumors, neoadjuvant chemotherapy may be utilized to increase the chance of R0 resection. Therefore, questions of efficacy and safety of the NACT arise.Methods: Data from 25 patients (10 NACT vs 15 primary surgery) who had undergone tumor resection (January 2015-October 2021) was collected from electronic medical records at the King Hussein Cancer Center. Both radiological and pathological tools used to assess the effect of neoadjuvant chemotherapy on tumor. CT scan was used to delineate clinical staging, tumor size and to detect post-therapeutic variations in tumor burden. The response evaluation criteria in solid tumors (RECIST) was used to classify the effect of neoadjuvant chemotherapy (NACT) on tumor burden as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). The pathological response was determined by measuring the percentage of necrotic tissue.Results: The majority of patients were male. Mean age 46.28 +-15.31 at diagnosis. Distribution among stages was as followed; stage I (4; 16%), stage II (7; 28%), stage III (7; 28%), stage IV (7; 28%). Patients who received NACT were evenly distributed among stages III and IV accounting for 71.4% each. Eleven patients underwent VATS tumor resection; one of them is in the NACT group (10%). Negative resection margins in 96%; 24 patients. Patients received 3–6 cycles of platinum-based NACT. A single patient who received definitive radiation and 12 cycles of chemotherapy outside our center developed chemotherapy induced heart failure and died immediately postoperatively. No other patients reported severe toxicity. The mean change in tumor volume and maximum diameter was 165 cm3 (p = 0.079) and 1.53 +- 1.49 cm (p < 0.01) respectively. Tumor diameter stratified according to stage showed a variation of 2.0+- 1.6 cm in stage IVa (p = 0.02) and 1+-1.35 cm in stage III (p = 0.08), respectively. The effect of NACT on tumor burden based on RECIST criteria was minimal as 80% (n = 8) of patients had SD and the remaining 2 patients had PR and PD. Based on pathological findings, the average necrotic portion of the tumor was 39.5%.; 23% in stage III and 56% in stage IVa (p = 0.152). The overall survival rate is 91.2%, mean survival was 115 months (4-125). Recurrence occurred in 28% (n = 7). The NACT group had a higher risk for recurrence (5; 50%) with a mean survival of 43.8 months compared to 59.6 months in those who did not receive induction therapy.Conclusions: The exact role of induction chemotherapy in locally advanced thymoma patients theoretically to increase the chance of R0 resection remains controversial. Though our study group number is small but we combined both radiological and pathological tools for better assessment of neoadjuvant chemotherapy effect on tumor burden, we found that the radiographic and histopathological effect of NACT on thymic tumors is minimal especially on stage III with the greatest variation in tumor burden is in Stage IVa. However, NACT was not found to significantly improve oncological outcomes compared to upfront surgery in locally advanced disease. To further demonstrate the impact of induction chemotherapy, we recommend multicentric collaborative studies.