Hyperthermic intrathoracic chemotherapy (HITHOC) in stage IVA thymomas: a narrative review

Introduction

Thymomas are rare neoplasms derived from thymic epithelial cells, accounting for the majority of anterior mediastinal tumors (1). Despite their generally indolent nature, advanced stage thymomas, particularly those classified as stage IVA, or recurrent disseminated disease, present significant therapeutic challenges. These cases are characterized by pleural or pericardial dissemination, complicating complete surgical resection and leading to frequent recurrences (2). Indeed, pleural dissemination is associated with high morbidity and poses a significant risk of progression, even in patients receiving multimodal therapy (3). More specifically, according to the latest tumor-node-metastasis (TNM) staging classification, stage IVA is defined by the presence of microscopically confirmed nodules, separate from the primary tumor, involving the visceral or parietal pleural surfaces, or the pericardial surfaces, in line with the definition proposed by the Masaoka-Koga classification system, though the former stands apart from the latter by comprising also the peri-thymic nodal involvement (4).

The surgical management of patients with advanced thymic epithelial tumors (TETs) at stage IVA has been extensively studied over the years. However, due to the rarity of these tumors, most studies are limited by small sample sizes. Current European Society for Medical Oncology (ESMO) guidelines recommend a multimodal treatment approach, including surgery, for stage IVA patients where complete resection is considered feasible (5). Data from international databases confirm that surgical removal of pleural tumor components in stage IVA can achieve effective local tumor control and improve overall survival (OS) (6). Despite these promising outcomes, pleural recurrences remain a significant challenge, limiting long-term survival.

Achieving complete macroscopic tumor resection is technically possible, though a safety margin cannot be maintained due to the diffuse nature of pleural tumor spread. Consequently, microscopic residual disease (R1) is often present, leading to pleural relapses caused by undetectable tumor implants or cell dissemination during surgery. To address these limitations, additional intracavitary therapies have been explored to enhance local tumor control, with hyperthermic intrathoracic chemotherapy (HITHOC) gaining increasing attention (7). This approach has shown potential in TET with pleural involvement, where it is combined with complete surgical resection to improve outcomes, either in case of first presentation or recurrent disease. Indeed, stage IVA thymoma should be considered as locally spread disease, rather than systemic, thus potentially benefiting from combined local therapies.

However, robust evidence supporting HITHOC in this context is still lacking, as most available data come from feasibility and small retrospective studies. This narrative review aims at providing a detailed examination of the mechanisms, indications, procedural aspects, and outcomes of HITHOC in pleural localizations of thymomas, as well as its future potential in thoracic oncology. We present this article in accordance with the Narrative Review reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-25-8/rc).

Methods

A comprehensive search was performed using the MEDLINE and Google Scholar databases, considering all articles published up to January 2025. All types of publications were included, such as original full-length articles, meta-analyses, review articles, and case reports. Non-English articles, preprints, as well as those without details on HITHOC applied to stage IVA thymomas, were excluded. A summary of our search strategy is presented in Table 1. The search terms included “HITHOC”, “HIOC”, “HITOC”, “ITCH”, “Stage IVA Thymoma”, “Hyperthermic Intrathoracic Chemotherapy”, and their various combinations.

HITHOC

Mechanisms of HITHOC

HITHOC is based on the principles of hyperthermia and localized chemotherapy to achieve enhanced cytotoxicity and improved control of residual microscopic disease after resection (8). The synergy between these two modalities is central to its therapeutic success, and is based on the following mechanisms:

• Thermal effects on tumor cells: hyperthermia, achieved by maintaining temperatures between 41 and 43 °C in the pleural cavity, disrupts several critical cellular processes in tumor cells (9):
  • DNA damage: heat impairs the ability of tumor cells to repair DNA breaks caused by chemotherapy, thereby amplifying its cytotoxic effects.
  • Protein denaturation: hyperthermia induces the denaturation of cellular proteins, leading to apoptosis and necrosis in cancer cells.
  • Enhanced lysosomal activity.
  • Increased vascular permeabilization.
• Enhanced chemotherapeutic uptake: elevated temperatures increase cell membrane fluidity, enhancing the penetration of chemotherapeutic agents into tumor cells, as extrapolated from studies focused on thymomas and pleural mesotheliomas (10). This is particularly beneficial for targeting residual microscopic disease in the pleural cavity, which is often inaccessible to intravenous chemotherapy.
• Immune modulation: heat shock proteins, released during hyperthermia, activate immune responses by promoting antigen presentation and stimulating dendritic cells (11). This may potentially enhance systemic anti-tumor immunity, providing theoretical benefits beyond localized disease control.
• Reduced systemic toxicity: by confining chemotherapy to the pleural cavity, HITHOC achieves high local drug concentrations while minimizing systemic absorption (10). This targeted delivery reduces the risk of adverse effects associated with systemic chemotherapy, such as myelosuppression and gastrointestinal toxicity.
• Drug-specific synergies with heat: certain chemotherapeutic agents, such as cisplatin and doxorubicin, exhibit enhanced efficacy at higher temperatures (12). These agents show increased binding to DNA and greater cytotoxicity when used in conjunction with hyperthermia, making them ideal candidates for HITHOC protocols.

Indications and patient selection

HITHOC has been utilized in thoracic surgery since the early 1990s, primarily for treating malignant pleural mesothelioma (MPM) (13), based on the encouraging results gained in peritoneal carcinosis treatment (14). Building on its success in MPM, HITHOC has gained attention as part of a multimodal approach for de novo or relapsing stage IVA thymomas, in combination with or following primary tumor resection (15). It has shown promising results in extending local disease-free survival and reducing recurrence rates.

Additionally, its application has been reported in cases of unilateral pleural carcinosis from lung cancer (16) and other rarer pleural neoplasms, such as solitary fibrous tumors.

A thorough preoperative assessment, including imaging studies, pulmonary function tests, cardiac safety and laboratory evaluations, is essential to determine a patient’s eligibility for HITHOC (17). Multidisciplinary discussions involving thoracic surgeons, oncologists, radiotherapists and anesthesiologists are crucial for tailoring the treatment plan (18).

Patients with systemic metastases or extra-thoracic disease, as well as those with severe organ dysfunction, including renal, hepatic, or cardiac impairment, should be excluded from the treatment (19). Furthermore, anatomical factors that compromise pleural integrity (e.g., large diaphragmatic defects, or contralateral pleural space opening) represent relative contraindications to HITHOC, due to increased risk of chemotherapeutic agent leakage (20). In addition, patients requiring extensive pericardium resection and reconstruction should be carefully evaluated for this treatment. Lastly, large-scale decortications may increase drug absorption leading to toxicities (20).

Procedure

HITHOC is typically performed intraoperatively under general anesthesia following the surgical procedure with deflated lung on lateral or supine decubitus. Perfusion begins after the surgical phase, which may involve resecting isolated implants, performing partial pleurectomy (PP), pleurectomy/decortication (P/D), or even extrapleural pneumonectomy (EPP), depending on the patient’s condition, tumor histology, and extent of disease. A specialized perfusion system is connected to the patient via pleural drains, and saline isotonic solution is circulated and heated to the target temperature, typically between 41 and 43 °C according to the different protocols adopted. Once the solution reaches the desired temperature, chemotherapeutic agents are introduced into the circuit through the inflow catheter. The drugs circulate for 60 to 90 minutes, targeting residual tumor cells, and are then flushed out via the outflow catheter by reversing the circuit flow (21). If the thorax is temporarily closed during HITHOC, target temperatures are reached within few minutes.

Chemotherapeutic regimens in HITHOC

The selection of chemotherapeutic agents for HITHOC is critical; commonly used agents include:

• Cisplatin: the most widely used agent in HITHOC due to its high efficacy against thymic epithelial cells and enhanced activity under hyperthermic conditions (22).
• Doxorubicin: often combined with cisplatin to enhance cytotoxicity (23). Doxorubicin exhibits strong anti-tumor activity and synergizes with hyperthermia to induce apoptosis. Doxorubicin might exert local cardiac toxicity.
• Mitomycin C: known for its tropism to target slow-growing tumor cells, mitomycin C complements cisplatin’s activity and is frequently included in combination regimens (22).
• Oxaliplatin: a newer agent and larger molecule with reduced nephrotoxicity compared to cisplatin (24,25). Its use in HITHOC is gaining attention due to its favorable safety profile, shorter exposure time (45 min) and strong activity in hyperthermic conditions.

Clinical outcomes

Numerous studies have investigated the safety and efficacy of HITHOC in managing stage IVA thymomas (pleural disease), highlighting its role as part of a multimodal treatment approach (19,22-40), as highlighted in Table 2.

Collectively, these studies demonstrate that HITHOC, when combined with cytoreductive surgery, improves local control and survival in advanced thymomas. Furthermore, the application of HITHOC seems not to exclude the possibility of perioperative radiation therapy (28). While variations in chemotherapy protocols and surgical approaches exist, evidence consistently supports its role in reducing recurrence and enhancing outcomes, particularly in well-selected patients.

In 2001, Yellin and colleagues (36) evaluated HITHOC in 7 patients affected by thymoma. Cisplatin was administered at doses ranging from 60 to 200 mg/m² at 41 °C for one hour. The procedure was complication-free, with only one patient experiencing thrombocytopenia. After a mean follow-up of 60.2 months, five patients remained disease-free, one died from systemic progression, and another from leukemia.

Refaely and colleagues (26) analyzed the outcomes of 10 patients with stage IVA thymoma. Complete resection was achieved in seven cases, while three had R1/R2 margins. Using cisplatin at 100–200 mg/m² at 43 °C for one hour, the authors reported no complications or platinum-related toxicity. Three-year survival for thymoma patients was 90%, decreasing to 70% at 5 years.

de Bree and colleagues (7) treated 3 patients with pleural recurrences from thymoma using cisplatin (80 mg/m²) and doxorubicin (15–25 mg/m²) at 40–41 °C for 90 minutes. While one patient developed nephrotoxicity, OS at 18 months was 100%.

In 2013, Ried and colleagues (41) analyzed 8 patients with stage IVA thymoma. All underwent P/D followed by HITHOC with cisplatin (100 mg/m² at 42 °C for 60 minutes). Severe postoperative morbidity occurred in two patients, but oncological outcomes were encouraging, with only two relapses reported during a 22-month follow-up. A subsequent study in 2014 by the same group (42) included 13 stage IVA thymomas, showing an 89% disease-free rate at the end of follow-up.

Yellin and colleagues (27) later expanded their cohort to 35 patients with thymic malignancies. They incorporated doxorubicin (50–60 mg/m²) alongside cisplatin (100 mg/m²). The procedure demonstrated excellent safety, with no perioperative complications, highlighting the potential of lung-sparing surgery with HITHOC to improve outcomes.

Maury and colleagues (29) investigated HITHOC in 19 patients with relapsing disease, using cisplatin (50 mg/m²) and mitomycin (25 mg/m²) at 42 °C for 60 minutes. Complications included bone marrow aplasia and reversible kidney failure. The study reported a median DFS of 53 months and OS of 63 months, with 1- and 5-year survival rates of 93% and 86%, respectively.

Aprile and colleagues (19) reported a mean OS of 153 months and a mean disease-free interval (DFI) of 88 months, with a 10-year OS rate of 77%, in a 12-year retrospective study of 40 patients with relapsing thymomas. These results were achieved using HITHOC with cisplatin (80 mg/m²) and epirubicin (25 mg/m²) at 42.5 °C for 60 minutes following PP. Multivariable analysis identified HITHOC and adjuvant therapy as key factors in improving DFS. This study reinforced the importance of combining radical surgery with HITHOC while prioritizing lung- and organ-sparing approaches to preserve patient eligibility for further treatments.

Chappuy and colleagues (33) documented a 5-year OS of 86% and a median DFI of 70 months in 40 patients with stage IVA thymomas. HITHOC was performed after subtotal pleurectomy using cisplatin (50 mg/m²) and mitomycin (25 mg/m²) at 42 °C over 90 minutes.

Kumar and colleagues (31) observed excellent outcomes with a 5-year OS and recurrence-free survival (RFS) of 100% in six patients following complete pleurectomy. Cisplatin (130–150 mg/m²) was administered at 41–43 °C for 60 minutes. Although five patients experienced minor complications, no operative mortality was reported.

Ried and colleagues (35) reported a 5-year OS of 77% and a 5-year RFS of 44%, with a median DFI of 43 months. This study included 22 patients with resected pericardium and 19 with resected diaphragm, all reconstructed as needed. HITHOC was performed with cisplatin (120 mg/m²) ± doxorubicin (35 mg/m²) at 42 °C for 60 minutes following lung-sparing P/D. It is worth to mention that in this study other 15 patients affected by thymic carcinoma were enrolled, reporting a surprising 5-year OS of 41% (43).

Dolan and colleagues (34) documented a 5-year OS of 80% and a 5-year DFS of 85% in 34 patients who underwent complete macroscopic resection. HITHOC utilized cisplatin (175 mg/m²) at 42 °C for 60 minutes.

A recent systematic review (25) reviewed outcomes in 171 patients who underwent HITHOC following cytoreductive surgery. The analysis reported a local recurrence rate of 31%, with DFI ranging from 7 to 88 months and 5-year OS rates between 70% and 92%. The overall mortality rate was 19%, with 35% of deaths attributed to disease progression. Adverse events associated with HITHOC included early postoperative acute kidney injury and bone marrow aplasia. No intraoperative morbidity or mortality was observed, except for a single case of transient right heart failure.

A more recent systematic review and meta-analysis (44) evaluated 248 patients undergoing HITHOC. The findings indicated low perioperative mortality (2.42%) and manageable morbidity, with an overall mortality rate of 8.32%. Reported complications included mild fever, pleuritic pain, and transient renal dysfunction, which were generally self-limiting. Severe complications, such as acute kidney injury (2.83%) and bone marrow suppression, were rare and reversible. The incidence of pneumonia was 1.96%, and the disease recurrence rate was 26%.

Challenges and future directions

Despite its promise, HITHOC faces several challenges (45,46):

• Standardization
  • Variability in HITHOC protocols, including differences in chemotherapy agents, dosages, and perfusion parameters, as well as variations in duration and temperature of the procedure, complicates the interpretation of outcomes across studies. Developing standardized guidelines is of paramount importance, more so after HITHOC has been included in the latest consensus document on the surgical management of thymomas from the Society of Thoracic Surgeons (47).
  • Regimen optimization: the ideal combination of agents and dosing protocols remains an area of active research. Factors such as tumor biology, patient characteristics, and institutional expertise influence regimen selection.
• Evidence base
  • Most available data are derived from retrospective analyses, underscoring the need for prospective, multicenter trials to validate HITHOC’s efficacy and safety.
• Access and cost
  • The resource-intensive nature of HITHOC, including specialized equipment and multidisciplinary expertise, may limit its availability to high-resource settings.
• Integration with novel therapies
  • Combining HITHOC with emerging modalities, such as immunotherapy and targeted agents, holds potential for improving outcomes further.

Conclusions

Complete resection remains the cornerstone of thymoma surgery and is recognized as the most critical prognostic factor, despite thymomas being sensitive to both chemotherapy and radiotherapy. However, for stage IVA tumors or recurrences involving unilateral pleural, pericardial, or diaphragmatic implants, achieving a complete resection is often impractical due to the likelihood of microscopic residual disease. Additionally, the radical procedures required, such as EPP, can be highly invasive and debilitating for patients.

To mitigate perioperative morbidity and mortality, with the aim to achieve complete macroscopic resection, lung-, pericardial-, and diaphragmatic-sparing P/D has been introduced as an alternative to EPP. While this approach carries a potential risk of incomplete resection (R1 or minimal R2), it offers a balance between oncological efficacy and patient safety. It has to be emphasized that most patients with thymoma with residual pleural disease can live long despite persistent disease, and this should be carefully discussed before embarking in any major therapeutic strategy associated with possible treatment-related risks. In this context, HITHOC has been developed as an adjunct to macroscopic radical pleural tumor resection. By enhancing local tumor control and lowering recurrence rates, HITHOC provides a valuable addition to the multimodal treatment of advanced thymomas. HITHOC may represent a significant improvement in the treatment of advanced thymomas with pleural dissemination. By combining cytoreductive surgery with localized hyperthermic chemotherapy, it may address the limitations of conventional therapies, potentially offering improved local disease control and survival. Nonetheless, randomized controlled trials investigating on HITHOC are still lacking, thus preventing to draw definitive conclusion on its real potential. While challenges remain, ongoing research and innovation promise to refine this technique and expand its role in thoracic oncology. With continued collaboration and standardization, HITHOC has the potential to become a cornerstone of multimodal therapy for advanced thymomas.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Malgorzata Szolkowska) for “The Series Dedicated to the 14th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2024)” published in Mediastinum. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-25-8/rc

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-25-8/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-25-8/coif). “The Series Dedicated to the 14th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2024)” was commissioned by the editorial office without any funding or sponsorship. P.M. serves as an unpaid editorial board member of Mediastinum from January 2025 to December 2026. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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