Sun Jianhai is the Director of the Oncology Department at Hubei Provincial Third People’s Hospital, affiliated with Jianghan University; a master’s supervisor at Wuhan University, Wuhan University of Science and Technology, Jianghan University, and Hubei College of Pharmaceutical Sciences; and the Deputy Director of the Jianghan University Tumor Research Institute. He is recognized as a leading mid-career professional in Wuhan and an expert in oncology listed in the National Science and Technology Expert Database. Clinically, he specializes in comprehensive treatment of malignant tumors, hyperthermia, and standardized diagnosis and management of cancer pain. He spearheaded the establishment of a “Demonstration Ward for Standardized Cancer Pain Management” within his department and implemented patient-controlled analgesia (PCA) techniques. Currently, he serves as Deputy Chairperson of the CSCO Committee on Hyperthermia, Deputy Chairperson of the China–Japan Medical Association Committee on Hyperthermia, Executive Committee Member of the Head and Neck Oncology Committee of the China Health Promotion Foundation, Deputy Chairperson of the Committee on Hyperthermic Perfusion Therapy of the Chinese Anti-Cancer Association, Standing Committee Member of the Asia-Pacific Society of Biological Immunotherapy, Member of the CRPC Study Group under the Chinese Anti-Cancer Association’s Committee on Cancer Rehabilitation and Palliative Care, Deputy Chairperson of the Oncology Committee of the Wuhan Physicians Association, Deputy Chairperson of the Oncology Committee of the Wuhan Association of Traditional Chinese Medicine, Deputy Chairperson of the Committee on Hyperthermia of the Hubei Anti-Cancer Association, Standing Committee Member of the Oncology Professional Committee of the Wuhan Medical Association, Standing Committee Member of the Hubei Microcirculation Society, and an expert reviewer for medical malpractice cases at both municipal and provincial levels. He has presided over or participated in one project funded by the National Natural Science Foundation, one research project supported by the China International Medical Exchange Foundation, and one CSCO research project, as well as nine provincial- and municipal-level research initiatives in Hubei Province. He has published more than 100 papers in core domestic and international journals, including over 20 SCI-indexed articles with a maximum impact factor of 21.34, and has served as chief editor of five medical monographs. In recent years, he has formulated or co-formulated the “2020 CSCO Expert Consensus on Hyperthermia in Oncology,” the “CACA Guidelines for the Application of Hyperthermia in China,” and authored chapters on new advances in intracavitary hyperthermic perfusion therapy for the CSCO’s “2024 Advances in Clinical Oncology in China” and on new developments in pharmacologic treatment via intracavitary hyperthermic perfusion for the CSCO’s “2025 Advances in Clinical Oncology in China,” as well as contributing to the national 863 Series publications.

Advances in the application of hyperthermic intrathoracic chemotherapy for the treatment of malignant thoracic tumors

Sheng Jinjin, Yan Fei, Ma Yanling, Sun Jianhai, Li Li

Progress of Hyperthermic Intrathoracic Chemotherapy in Treatment of Thoracic Malignant Tumors

SHENG Jinjin, YAN Fei, MA Yanling, SUN Jianhai, LI Li

Department of Oncology, The Third People's Hospital of Hubei Province, Jianghan University, Wuhan 430033, China

Corresponding Authors: MA Yanling, E-mail: 1904227737@qq.com; SUN Jianhai, E-mail: sunjian.hai@163.com

Date of receipt: 2025-12-08; Date of revision received: 2026-04-01

Author’s affiliation: Department of Oncology, Hubei Provincial Third People’s Hospital, Affiliated to Jianghan University, Wuhan 430033

Corresponding authors: Ma Yanling, female, Master’s degree, Chief Physician; primarily engaged in comprehensive anti-tumor therapy. E-mail: 1904227737@qq.com, ORCID: 0000-0001-6640-3636; Sun Jianhai, male, Master’s degree, Chief Physician; primarily engaged in comprehensive treatment of malignant tumors, hyperthermia, and standardized diagnosis and treatment of cancer pain. E-mail: sunjian.hai@163.com, ORCID: 0000-0002-8982-1205.

Author biography: Sheng Jinjin, female, Master’s degree, resident physician, primarily engaged in comprehensive anti-tumor therapy; ORCID: 0009-0001-6951-0434.

Abstract: Hyperthermic intrathoracic chemotherapy (HITHOC) is a localized treatment that combines hyperthermia with medications such as chemotherapy, anti-angiogenic agents, targeted therapy, or immunotherapeutic agents. It has advanced clinical progress for conditions such as malignant pleural mesothelioma, pleural metastasis of lung cancer, and pleural dissemination of thymic tumors. Systematic analyses indicate that as an adjuvant therapy to cytoreductive surgery, HITHOC improves patient survival and effectively controls pleural effusion and pleural metastasis. It exerts antitumor effects by enhancing drug penetration through thermal effects, inducing apoptosis, and modulating the immune microenvironment. HITHOC combined with systemic therapies (e.g., chemotherapy, targeted therapy, and immunotherapy) demonstrates synergistic potential, but its role as a local treatment should be clearly defined as adjunctive within the comprehensive management of advanced-stage patients. Further research is needed to clarify its indications, standardized protocols, and long-term efficacy and to explore optimized regimens and personalized combination treatment strategies. This review delves into the key bottlenecks hindering the development of hyperthermia therapy, such as the lack of high-level evidence-based medicine and the absence of standardized diagnostic and efficacy evaluation criteria, and proposes potential solutions.

Key words: Hyperthermic intrathoracic chemotherapy; Thoracic malignant neoplasm; Malignant pleural mesothelioma; Lung cancer pleural metastasis; Combination therapy

Competing interests: The authors declare that they have no competing interests.

Abstract: Hyperthermic intrathoracic chemotherapy (HITHOC) is a localized treatment modality that combines hyperthermia with pharmacologic agents—such as chemotherapeutics, anti-angiogenic drugs, targeted therapies, or immunotherapeutics—and has recently demonstrated clinical progress in conditions including malignant pleural mesothelioma, pleural metastases from lung cancer, and pleural dissemination of thymic tumors. As an adjuvant to cytoreductive surgery, HITHOC can improve patient survival and effectively control pleural effusions and pleural metastases; it exerts antitumor effects by enhancing drug penetration through thermal effects, inducing apoptosis, and modulating the immune microenvironment. Combination therapy integrating HITHOC with systemic treatments—including chemotherapy, targeted therapy, and immunotherapy—shows promise for synergistic benefits. However, as a local therapeutic approach, its role within the comprehensive management of advanced-stage patients should be clearly defined as adjunctive. Further research is needed to establish appropriate indications, standardize protocols, and evaluate long-term efficacy, while also exploring regimen optimization and individualized combination strategies. This article provides an in-depth analysis of key barriers hindering advances in hyperthermia, such as the lack of high-level evidence-based medical data and the absence of standardized diagnostic and efficacy assessment criteria, and proposes corresponding solutions.

Keywords: Intrathoracic hyperthermic perfusion chemotherapy; malignant thoracic tumors; malignant pleural mesothelioma; pleural metastases from lung cancer; combination therapy

0 Introduction

Malignant thoracic tumors (such as malignant pleural mesothelioma, lung cancer with pleural metastasis, and thymic tumors) have a poor prognosis and pose a serious threat to patients’ lives. These tumors often exhibit diffuse growth or are accompanied by malignant pleural effusion, presenting significant challenges to clinical treatment [1]. Recurrent malignant pleural effusions severely impair quality of life and prognosis; conventional surgery, chemotherapy, and radiotherapy offer limited control over pleural lesions and effusions, while targeted and immunotherapies may also encounter resistance or prove ineffective [2]. Hyperthermic intrathoracic chemotherapy (HITHOC), as a local therapeutic technique, has emerged in response to these needs. This method involves circulating warmed chemotherapeutic agents within the pleural cavity, leveraging the synergistic effects of hyperthermia and chemotherapy to eradicate tumor cells and manage effusion. Hyperthermia enhances drug penetration, inhibits DNA repair, and increases the sensitivity of tumor tissues to chemotherapy [3].

Patients who develop malignant pleural effusion or pleural metastases are, in the vast majority of cases, already at an advanced stage, and their treatment should be anchored in systemic therapies (chemotherapy, targeted therapy, immunotherapy, etc.). As the primary local treatment for pleural effusion and pleural metastases today, HITHOC’s core value lies in its crucial supportive role: it can rapidly and effectively control pleural effusions and alleviate compressive symptoms such as dyspnea, thereby significantly improving patients’ quality of life. Moreover, by eliminating free cancer cells and micrometastases from the pleural cavity, it reduces the local tumor burden, creating more favorable conditions for subsequent systemic therapies and potentially delaying local recurrence. Therefore, HITHOC is not a stand-alone therapy but rather a key component of a multidisciplinary comprehensive treatment approach, aiming to synergize with systemic therapies to enhance efficacy and ultimately improve patients’ overall survival.

HITHOC was initially used primarily for malignant pleural mesothelioma in combination with cytoreductive surgery; in recent years, its applications have gradually expanded to other thoracic malignancies. This paper systematically summarizes advances in its mechanisms, clinical applications, technical parameters, and combination therapies, which is of great significance for promoting the standardization and optimization of this technique. The aim of this review is to synthesize the latest research findings, thoroughly analyze the current difficulties and challenges facing the field of hyperthermic therapy, and outline future directions, thereby providing a reference for clinical practice.

1 Combined application of hyperthermic intrathoracic chemotherapy and surgery

Pleural recurrent thymoma (PRT) and malignant pleural mesothelioma (MPM) are aggressive thoracic malignancies that pose significant challenges to treatment. Minimally invasive surgical approaches, particularly robot-assisted thoracic surgery (RATS) and video-assisted thoracic surgery (VATS), combined with adjuvant therapies such as HITHOC, are offering new treatment options and potential prognostic improvements for these patients [4]. For patients with pleural recurrent thymoma and early-stage MPM, the safety and efficacy of minimally invasive surgery in combination with HITHOC represent a current research focus.

Different minimally invasive surgical approaches exert varying degrees of influence on the operative space and the final perfusion outcome of HITHOC. While conventional VATS is less invasive, its instrument flexibility is limited when addressing complex pleural adhesions or performing thorough pleural decortication, potentially leaving behind small residual lesions or forming localized encapsulations that compromise the uniform distribution of subsequent hyperthermic perfusate. In contrast, RATS, with its three-dimensional high-definition visualization and multi-degree-of-freedom robotic arms, enables more precise dissection and more complete cytoreduction within the narrow and intricate thoracic anatomical spaces, thereby creating a broader, dead‑space‑free operative field for HITHOC and ensuring adequate contact between the hyperthermic perfusate and all pleural surfaces. Furthermore, the 3D thoracoscopy system, by providing depth perception, not only reduces intraoperative bleeding but also helps the surgeon place perfusion drainage tubes more accurately, optimizing fluid dynamics and enhancing the overall efficacy of hyperthermic perfusion.

A retrospective study analyzed data from nine patients with recurrent thymoma or MPM who underwent robotic surgery combined with HITHOC. Three patients underwent resection of recurrence, and six underwent pleurectomy; all procedures were performed using a four-port totally robotic technique. Results showed no intraoperative complications in any case and no infusion-related renal complications were recorded. Only one patient who underwent pleurectomy for MPM experienced a Clavien-Dindo grade II postoperative complication. These findings preliminarily suggest that robotic surgery combined with HITHOC is safe for treating patients with pleural recurrence of thymoma and early-stage MPM. However, given the small sample size, this conclusion requires validation by further large-scale studies [5]. HITHOC, as a local therapeutic modality, aims to enhance drug penetration, boost antitumor activity, and reduce systemic toxicity by directly instilling chemotherapeutic agents into the pleural cavity and circulating them at elevated temperatures [6]. It has been successfully applied in the treatment of pleural metastatic diseases; for example, the safety and efficacy of HITHOC are being investigated in patients with Masaoka-Koga stage IVa thymoma, and some studies indicate its potential to improve local control and prolong survival [4].

In the treatment of MPM, the combined use of surgical resection and HITHOC has also shown promise. A prospective, randomized, three-center pilot trial compared the efficacy of VATS talc pleurodesis (Group A) with that of VATS pleurectomy/decortication (P/D) combined with HITHOC (Group B) in patients with MPM. The study enrolled 27 MPM patients with a median age of 68 years. Results showed that at 20 months, the median overall survival began to diverge between the two groups, with Group A at 19 months (95% CI : 12~25), while group B was 28 months (95% CI : 0–56). Although this is a preliminary study, these findings suggest that VATS P/D combined with HITHOC may prolong survival in MPM patients undergoing surgery [7].

Minimally invasive surgical techniques such as VATS and RATS offer significant advantages in the treatment of thoracic tumors, including reduced surgical trauma, shorter recovery times, and lower rates of postoperative complications [8]. A meta-analysis incorporating 10 studies showed no significant difference in 1-year overall survival (OS) between VATS and open thoracotomy ( HR =1.30, 95% CI : 0.96~1.76, P =0.09), while the 3-year OS for VATS was even better ( HR =1.26, 95% CI : 1.12~1.42, P =0.0002). Intraoperative blood loss was significantly reduced in the VATS group (WMD=−61.43 ml, 95% CI : −87.69~−35.18, P <0.001), and both drainage time and hospital stay were shorter ( P <0.05)[9].

In terms of surgical technique, 3D thoracoscopy systems offer advantages in training surgeons. One study compared the use of 2D VATS and 3D VATS in lung cancer surgery and found that intraoperative blood loss was significantly reduced in the 3D VATS group (mean 34 ml). versus . 76 ml, P =0.0007), although the difference in operative time was not statistically significant (mean 225 min versus . 240 min, P =0.072) [10]. Pleurodesis with talc is one of the effective methods for managing malignant pleural effusion. However, a comparative study of efficacy and cost-effectiveness between VATS-assisted partial pleurectomy and talc pleurodesis in patients with MPM (the MesoVATS trial) found no significant difference in overall survival between the two procedures. Although VATS-assisted partial pleurectomy did not improve survival, its complication rate was higher than that of talc pleurodesis, suggesting that patient-specific factors and risk–benefit considerations should be comprehensively evaluated when selecting a surgical approach [9].

Given the potential advantages of minimally invasive surgical techniques, such as VATS and RATS, and HITHOC in the treatment of malignant pleural tumors, future research should focus on larger-scale, rigorously designed clinical trials to clarify their long-term efficacy, survival benefits, and optimal indications. Furthermore, exploring the combined use of HITHOC with other local therapies, such as photodynamic therapy, or systemic therapies, such as immunotherapy, may also offer patients greater therapeutic hope [10].

2 Clinical Research Progress of HITHOC in Various Malignant Thoracic Tumors

HITHOC was initially used primarily for malignant pleural mesothelioma in combination with cytoreductive surgery, but in recent years its application has gradually expanded to other thoracic malignancies [11–12]. Currently, clinical HITHOC mainly employs two perfusion modes: open-loop and closed-loop. Open-loop perfusion is relatively simple to perform, allowing the surgeon to directly visualize and adjust the position of the perfusion catheter to ensure uniform delivery throughout the pleural cavity; however, it results in rapid heat loss and poses occupational exposure risks due to drug aerosolization. Closed-loop perfusion, on the other hand, creates a sealed pleural space by suturing the incision to maintain circulation, thereby better sustaining a constant perfusion temperature and significantly reducing healthcare workers’ risk of drug exposure. This approach, however, places higher demands on the initial placement of intrathoracic catheters, and if drainage becomes obstructed, timely intraoperative adjustments are difficult to achieve.

As a localized therapy, HITHOC is primarily indicated for tumors prone to pleural dissemination or malignant pleural effusion. Its core applications include malignant pleural mesothelioma, lung cancer with pleural metastasis, and thymic tumors with pleural implantation.

2.1 Malignant Pleural Mesothelioma

Decade-long research has shown that HITHOC combined with cytoreductive surgery, primarily using cisplatin (50–225 mg/m² administered via hyperthermic perfusion at 42°C for 60 minutes), can extend the median overall survival of MPM patients to 20–30 months, significantly surpassing historical controls [10]. A systematic review indicated that HITHOC plus cytoreductive surgery improves survival in patients with malignant pleural mesothelioma (median OS, 18 months), highlighting its potential as an adjuvant therapy to surgery; however, the review also noted that this conclusion is limited by small sample sizes and heterogeneity [10]. Although most studies are retrospective or phase II trials lacking high-quality RCTs, a multicenter RCT in 2023 confirmed its superiority in increasing the objective response rate without increasing adverse events. The latest systematic review likewise concludes that this technique is safe, feasible, and improves survival [13].

The latest review indicates that HITHOC can safely and feasibly improve overall survival and recurrence-free survival in patients with malignant pleural mesothelioma, showing promising prospects; however, its efficacy still requires definitive validation through multicenter randomized controlled trials to establish a standardized treatment protocol [14]. Consequently, the academic community widely recognizes its potential and strongly advocates for additional phase III trials to conclusively confirm its efficacy and advance treatment standardization.

2.2 Pleural Metastasis from Lung Cancer (Malignant Pleural Effusion/Pleural Spread)

Research on HITHOC in malignant pleural effusion (MPE) associated with lung cancer started relatively later than that for MPM, and most evidence comes from retrospective studies, case series, and small-sample prospective studies. Some literature reports that, for patients with non–small cell lung cancer complicated by MPE, pleurodesis combined with HITHOC may help control pleural effusion symptoms and prolong survival [15]. Subsequently, several studies have reported the preliminary efficacy of HITHOC; Hu et al. performed video-assisted thoracoscopic pleural biopsy and HITHOC in 54 patients with lung cancer–induced MPE, achieving a median survival of 21.7 months, a 1-year survival rate of 74.1%, and significant control of pleural effusion [16].

A 2023 study retrospectively analyzed 33 patients with advanced lung cancer and symptomatic malignant pleural effusion (MPE) at initial diagnosis, comparing the efficacy of HITHOC (lobaplatin/Endu, 43°C) with that of simple indwelling pleural catheter drainage (IPCD). The results showed that at one month, the MPE control rates were similar between the two groups (HITHOC 95.7% versus . IPCD 90%), but at 3 months, the HITHOC group had a significantly higher MPE control rate (69.6%) versus . 30%, P =0.035). In the subgroup receiving tyrosine kinase inhibitor (TKI) therapy, patients treated with HITHOC in combination with TKI had significantly longer progression-free survival (PFS) and overall survival (OS) for pleural MPE compared with those receiving IPCD plus TKI [17]. This suggests that HITHOC may synergize with systemic therapy in specific lung cancer subgroups, such as TKI-sensitive populations.

2.3 Thymic tumor with pleural implantation

Most of the literature on HITHOC treatment for thymic tumors with pleural dissemination consists of small-sample retrospective studies or case reports. 2021 Annals of Translational Medicine A study provided a detailed review of the use of HITHOC in treating thymoma, including 15 years of experience from that center. The research demonstrated that for patients with thymoma pleural recurrence (TPR) or stage IVA primary thymoma, surgery combined with HITHOC is a safe and feasible treatment option, with a low complication rate, negligible systemic toxicity, and effective control of local disease, particularly in prolonging locoregional disease-free survival. For example, their study compared 27 patients with recurrent thymoma who underwent surgery plus HITHOC (cisplatin 80 mg/m² + epirubicin 25 mg/m², 42°C, 1 hour) to 13 patients treated with surgery alone. The two groups had similar perioperative complication rates, no treatment-related deaths, and comparable cumulative survival; however, the HITHOC group showed a trend toward a longer time to disease recurrence [18]. Yellin et al. previously reported on 27 patients with various tumors (including 7 cases of thymoma) who received HITHOC (cisplatin 60–200 mg/m², approximately 41°C, 1 hour), with thymoma patients achieving favorable long-term survival [19].

A 2024 systematic review and meta-analysis concluded that, for patients with thymic tumors—particularly thymomas—cytoreductive surgery combined with HIPEC generally carries a low risk of perioperative mortality and renal injury, demonstrating reasonable feasibility and safety. However, recurrence remains the primary challenge, and long-term efficacy requires validation through additional high-quality studies [20].

2.4 Other Malignant Thoracic Tumors

In addition to its primary indications, HITHOC has also been preliminarily explored in rare scenarios such as metastatic sarcoma, pleural metastases from breast or ovarian cancer, and pleural dissemination of pseudomyxoma peritonei. However, the available evidence largely consists of case reports, which are of low quality. Therefore, its use must be carefully evaluated by a multidisciplinary team, strictly limited to highly selected patients with refractory disease, and preferably administered within the framework of clinical studies.

3 Advances in the Application of Intrathoracic Hyperthermic Perfusion Chemotherapy Combined with Other Therapies

As previously mentioned, for patients with advanced malignant pleural tumors, when tolerable, a “dual‑route chemotherapy” approach combining HITHOC with systemic therapy, or a multimodal combination treatment strategy, represents the preferred option for enhancing efficacy and improving overall survival. The core principle of this strategy is to use HITHOC to efficiently eradicate local pleural lesions while relying on systemic therapies—such as chemotherapy, targeted therapy, and immunotherapy—to control the primary tumor and distant metastases, thereby achieving synergistic local and systemic anti‑tumor effects.

However, it is important to be vigilant, as “dual‑route chemotherapy” or multimodal combination therapy inevitably carries the risk of additive toxicity. Local HITHOC itself may cause chest pain, fever, gastrointestinal reactions, and transient renal impairment; when used concurrently with or sequentially after systemic chemotherapy, targeted therapy, or immunotherapy, it can markedly exacerbate bone marrow suppression (e.g., severe neutropenia and thrombocytopenia), increasing the risks of infection and bleeding. Furthermore, thermotherapy–induced alterations in the immune microenvironment, when combined with immune checkpoint inhibitors, could theoretically elevate the incidence of immune‑related adverse events (IRAEs), such as immune‑mediated pneumonitis or myocarditis. Therefore, when implementing combination therapies, patients must undergo rigorous baseline assessments, close monitoring of organ function, and well‑defined plans for managing adverse reactions.

3.1 Combined Application of Intrathoracic Hyperthermic Perfusion Chemotherapy and Targeted Therapy

Intrathoracic hyperthermic perfusion increases local tissue exposure to drugs, while combining it with targeted agents can control the progression of primary lesions and metastatic cancer cells systemically. The heat‑shock effects of hyperthermic chemotherapy may also promote tumor antigen presentation and immune system activation, providing a more favorable immune microenvironment [21]. The use of targeted therapies (such as EGFR‑TKIs and ALK inhibitors) has expanded in patients with lung cancer or related pleural diseases. Studies indicate that hyperthermic perfusion enhances tumor target exposure and reduces drug resistance, thereby producing a synergistic effect with molecularly targeted agents [22]. Combination therapy trials have shown that NSCLC patients with EGFR mutations treated with HITHOC plus EGFR‑targeted therapy achieved higher PFS and OS [23]. When intrathoracic hyperthermic chemotherapy is combined with first‑ or third‑generation EGFR‑TKI targeted therapy, compared with systemic EGFR‑TKI monotherapy, the combination regimen achieves MPE control rates of 80%–90%, along with significantly improved pathological response rates and survival times [3]. A multicenter study demonstrated that the HITHOC plus bevacizumab treatment modality can markedly reduce the rate of thoracic tumor recurrence by leveraging the dual action of localized hyperthermia and chemotherapeutic agents, together with vascular endothelial growth factor (VEGF) blockade to inhibit angiogenesis, resulting in a synergistic effect. This strategy is particularly suitable for patients with newly diagnosed limited lesions, with 5‑year survival rates improving by 20%–30% compared with chemotherapy alone [24]. Additionally, research involving elderly patients with extensive thoracic metastases showed that combining localized targeted drug delivery with hyperthermic perfusion effectively reduced postoperative complication rates. In a study of over 200 patients with advanced NSCLC, the combination therapy extended PFS to 10–15 months, demonstrating a significant advantage over single‑agent treatments [25].

3.2 Combined Application of Intrathoracic Hyperthermic Perfusion Chemotherapy and Immunotherapy

Intrathoracic hyperthermic perfusion uses localized heat and chemotherapeutic agents to increase vascular permeability in the tumor region, enhancing drug penetration into the tumor while exerting multiple effects on the tumor microenvironment. These effects include: promoting tumor cell apoptosis; inducing the release of tumor antigens, thereby triggering a host immune response and boosting the cytotoxic activity of immune cells against the tumor. Immune checkpoint inhibitors (such as PD-1/PD-L1 inhibitors) used in immunotherapy can further act on the heat-perfused, reprogrammed microenvironment by inhibiting the tumor’s immune evasion, thereby amplifying and sustaining local immune responses. In NSCLC patients with EGFR or ALK mutations, HITHOC combined with immune checkpoint blockade therapy (e.g., atezolizumab) has demonstrated significant efficacy. Overall survival in these patients was extended from 16 months with targeted therapy alone to more than 24 months [6].

A study found that loading immunotherapeutic agents into hyperthermic perfusion can improve their release rate and therapeutic efficacy. Combining immunotherapeutics, such as IL-2, with cisplatin in a gel formulation for local delivery demonstrated higher tumor control rates and enhanced immune activity [26]. A thermosensitive hydrogel loaded with esculentoside A (EA) was used in patients with advanced malignant pleural effusion, achieving significant results when combined with concurrent PD-1/PD-L1 immune checkpoint inhibitor therapy. During hyperthermic perfusion, the hydrogel gradually releases broad-spectrum antitumor drugs, while its temperature-responsive properties ensure stable drug efficacy. Meanwhile, the immune checkpoint inhibitors’ reshaping of the systemic microenvironment further enhances the local antitumor effects [27]. Another study established a murine model of pleural mesothelioma treated with intrapleural hyperthermic chemotherapy and found that this approach improves tumor control and survival by enhancing cytotoxic immune responses and promoting T-cell tumor infiltration, thereby remodeling the tumor immune microenvironment. Further results showed that intrapleural hyperthermic chemotherapy upregulates immune checkpoint expression on T cells and synergizes with dual PD-1 and CTLA-4 immune checkpoint inhibition, leading to additional survival benefits [28]. Groundbreaking research conducted in 2025 by Professor Sun Chaoyang’s team confirmed that hyperthermia can significantly ameliorate the immunosuppressive tumor microenvironment, reduce immunosuppressive cell subsets, and enhance T-cell infiltration [29]. Additionally, to further advance HITHOC combination therapies, several novel approaches are under investigation. For example, combining HITHOC with tumor vaccines, oncolytic viruses, or personalized antigen-based tumor vaccines leverages hyperthermic perfusion to activate immune mechanisms and further boost treatment outcomes. The use of intrapleural hyperthermic therapy in conjunction with local immune cell therapies—such as directly infusing immune cells (e.g., CAR-T cells or NK cells) into the modified pleural microenvironment following hyperthermic perfusion to strengthen specific antitumor responses—is an experimental strategy that holds promise for overcoming tumor resistance [18].

3.3 Combined Application of Intrathoracic Hyperthermic Perfusion Chemotherapy and Anti-Angiogenic Drugs

Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor A (VEGF‑A). By blocking the binding of VEGF‑A to its receptor, it inhibits tumor angiogenesis, thereby “starving” the tumor [30]. Bevacizumab has demonstrated significant efficacy in the treatment of various cancers, particularly metastatic colorectal cancer (MCC) and advanced hepatocellular carcinoma (HCC) [31]. In combination with intrathoracic chemohyperthermia (ICHT), hyperthermia itself can suppress tumor angiogenesis by disrupting tumor vasculature and inhibiting endothelial cell proliferation and migration [32]. When used together, hyperthermia and bevacizumab may exert a synergistic anti‑angiogenic effect, enhancing their ability to damage tumor vessels. In a study on colorectal cancer, the combined use of bevacizumab and anlotinib significantly inhibited tumor cell proliferation and induced apoptosis, exerting antitumor effects through downregulation of VEGF and p‑AKT expression [33].

Regarding the dosing of intrapleural bevacizumab, a study by Chen et al. enrolled 71 patients, with 31 in the low-dose group and 40 in the high-dose group; results showed that the incidence of adverse events was significantly lower in the low-dose group than in the high-dose group. Three patients in the high-dose treatment group died following intrapleural bevacizumab administration. Although overall survival (OS) was longer in the low-dose group and progression-free survival (PFS) was longer in the high-dose group, these differences were not statistically significant, suggesting that reducing the dose while maintaining efficacy may help decrease toxicity [22].

Endostar, a recombinant human vascular endothelial inhibitor, blocks tumor angiogenesis by inhibiting the migration and proliferation of endothelial cells, thereby cutting off the tumor’s nutrient supply and suppressing tumor growth or metastasis, ultimately controlling the progression of MPE. A meta-analysis by Rong et al. demonstrated that Endostar combined with chemotherapy is more effective than intrapleural chemotherapy alone for MPE, suggesting that Endostar may be an effective agent for managing MPE. Its unique mechanism of action confers significant adjunctive value in the treatment of MPE, particularly when used in combination with chemotherapeutic agents [34].

4 Challenges and Solutions in Advancing Standardization of Intrathoracic Hyperthermic Perfusion Chemotherapy

Hyperthermia, a “green therapy” that uses physical energy to treat tumors, offers advantages such as minimal adverse effects, a low likelihood of drug resistance, and compatibility with various treatment modalities [32]. However, while both the current NCCN guidelines for pleural mesothelioma and the 2024 Chinese Expert Consensus on the Diagnosis and Treatment of Malignant Pleural Effusion mention hyperthermic chemotherapy, no formal recommendations have been issued, and it is noted that the benefits of intrathoracic adjuvant therapies like HITHOC remain unclear. To date, there is no standardized management protocol—whether surgical or involving hyperthermic chemotherapy—for primary or secondary malignant pleural tumors, which significantly hinders the widespread adoption of intrathoracic hyperthermic perfusion. This limitation may stem partly from the diversity of tumor treatments and approaches, which restricts the application of HITHOC, and partly from restrictive eligibility criteria for HITHOC as well as individual physician and center preferences. Ultimately, its clinical implementation is constrained by a core dilemma: a lack of high-level evidence-based medicine, particularly large-scale, multicenter randomized controlled trials (RCTs). Underlying this challenge are a series of specific difficulties inherent in conducting high-quality clinical research.

4.1 Difficulties and Challenges in Conducting RCT Studies

The lack of precise, quantitative diagnostic methods remains a challenge. Assessing diffuse pleural disease and malignant pleural effusion poses the primary difficulty. The traditional RECIST criteria for evaluating solid tumor response are inadequate for accurately assessing irregular, plaque-like pleural thickening. CT imaging has limitations in distinguishing neoplastic thickening from inflammatory reactions or fibrosis, resulting in a lack of objectivity and reproducibility in baseline assessments and efficacy evaluations. Although some researchers have adapted the Peritoneal Cancer Index (PCI) to propose the concept of the Pleural Malignancy Index (PMI), intended to quantify pleural disease burden through intraoperative exploration, consensus and standardization have yet to be established [32].

There is a lack of simple, reliable intrathoracic temperature‑measurement techniques. The efficacy of hyperthermia is closely linked to temperature, and the optimal therapeutic window—typically 41°C to 43°C—is very narrow. However, the thoracic cavity has a complex anatomy, with multiple compartments and obstructions such as the lungs, heart, and diaphragm, making uniform heating and accurate, real-time multipoint temperature monitoring extremely challenging. Currently, clinical practice often relies on single‑point or limited‑point temperature measurement, which cannot accurately reflect the temperature distribution throughout the entire thoracic cavity. This prevents quantification and standardization of “thermal dose,” directly compromising the reliability and comparability of research findings.

Reliable methods for evaluating treatment efficacy are lacking. Current evaluation metrics primarily focus on pleural effusion control rates, cytology conversion rates, and survival outcomes (PFS, OS). However, effusion control can be influenced by multiple factors, cytology may yield false negatives, and using survival as the “gold standard” requires long-term follow-up and large sample sizes. How should the response of solid lesions on the pleura be assessed? How can treatment‑induced pathological changes be distinguished from residual tumor? To date, there is no standardized, reliable approach to address these questions.

4.2 Strategies and Prospects for Addressing Challenges in the Field of Hyperthermia

4.2.1 Establishing a Standardized System for Assessing Disease Burden and Treatment Efficacy

(1) Promote and refine PMI. Organize multicenter collaborations to validate and optimize the PMI scoring system, transforming it into a standardized intraoperative assessment tool—similar to the Peritoneal Cancer Index (PCI)—for patient selection and prognostic stratification. (2) Explore novel imaging techniques. Actively employ functional imaging modalities, such as PET-CT, to assess tumor burden via metabolic activity, which may be more sensitive than morphological assessment alone. Additionally, developing tumor-specific contrast agents targeting pleural neoplasms represents an important direction for future research.

(3) Development of composite efficacy endpoints. Future clinical trials should adopt composite endpoints that encompass not only OS and PFS, but also objective response rate (ORR, based on standardized PMI or imaging assessments), symptom control scores (e.g., dyspnea index), quality-of-life scales (QoL), and dynamic changes in pleural fluid cytology and molecular biomarkers (such as ctDNA), enabling a multidimensional comprehensive evaluation.

4.2.2 Innovating and Standardizing Temperature Monitoring Technologies

(1) Develop multi-point, wireless temperature measurement systems. There is an urgent need to create flexible, multi-point, wireless temperature sensors suitable for the complex thoracic environment, enabling real-time, precise monitoring of the temperature field within the perfusion region to ensure treatment efficacy and safety. Real-time thermal imaging under magnetic resonance guidance (MRgRT-compatible probes): Magnetic resonance imaging offers superior soft-tissue contrast; when combined with real-time thermal imaging capabilities, it allows for accurate visualization and dynamic monitoring of the intrathoracic temperature field during HITHOC. Developing temperature-sensing probes compatible with MRgRT systems will facilitate precise control of hyperthermia dosing and enable assessment of actual temperatures in tumor regions, thereby guiding personalized treatment. (2) Establish the concept and standards for “thermal dose.” Drawing on the concept of “absorbed dose” in radiotherapy, explore the development of a “thermal dose” (TD) model based on the integration of “temperature–time,” such as Cumulative Equivalent Minutes (CEM). This approach would parameterize and standardize hyperthermia protocols, providing a basis for comparing results across different studies.

4.2.3 Designing High-Quality, Innovative Clinical Research Studies

After addressing the aforementioned issues of standardization in diagnosis, temperature measurement, and evaluation, academic institutions or professional associations should take the lead in organizing large-scale, multicenter RCTs to clarify the precise efficacy and clinical role of HITHOC in specific cancer types and patient populations. For example, a study could be designed for patients with EGFR-mutant lung cancer and pleural metastases, comparing the outcomes of “targeted therapy” alone versus “targeted therapy plus HITHOC.” Given the challenges of conducting RCTs, it would be feasible to establish a high-quality prospective registry database and conduct large-scale real-world studies, thereby providing valuable evidence for clinical decision-making and offering guidance for the design of future RCTs.

5 Limitations and Future Prospects

HITHOC still faces significant challenges: its clinical positioning needs to be clearly defined; the existing clinical evidence is of low quality, and high-quality RCTs are urgently needed to validate its value; standardized protocols are lacking for technical procedures—particularly temperature control, disease assessment, and efficacy evaluation—which severely hinders its standardized development and widespread adoption. Looking ahead, advancing HITHOC will require addressing standardization issues in diagnosis, temperature measurement, and outcome assessment; conducting large-scale, multicenter randomized controlled trials to generate high-level evidence-based medicine; leveraging biomarkers to guide personalized treatment strategies; optimizing therapeutic parameters and developing novel drugs and intelligent delivery systems, especially precise temperature‑monitoring and thermal‑dose‑control technologies; and, guided by the “dual‑path chemotherapy” concept, integrating HITHOC with cutting-edge approaches such as immunotherapy and targeted therapy. By overcoming current challenges and fostering continuous innovation, HITHOC holds promise to assume an increasingly pivotal role in the individualized, precision treatment of malignant thoracic tumors.

Conflict of Interest Statement: All authors declare that no conflict of interest exists.

Author Contributions:

Sheng Jinjin: Literature Review, Data Collection, and Paper Writing

Yan Fei, Ma Yanling: participated in literature screening and data analysis

Sun Jianhai: Proposed the research concept, supervised thesis writing, and reviewed and revised the manuscript.

Li Li: Article Proofreading

Editor: Qiu Yinghui; Proofreader: You Tingting

References

[1] Petrella F. Malignant Pleural Effusion: Diagnosis and Treatment-Up-to-Date Perspective[J]. Curr Oncol, 2024, 31(11): 6867-6878.

[2] Addala DN, Kanellakis NI, Bedawi EO, et al. Malignant pleural effusion: Updates in diagnosis, management and current challenges[J]. Front Oncol, 2022, 12: 1053574.

[3] Zhao Y, Yu L, Wang L, et al. Current status of and progress in the treatment of malignant pleural effusion of lung cancer[J]. Front Oncol, 2023, 12: 961440.

[4] Vandaele T, Van Slambrouck J, Proesmans V, et al. Hyperthermic Intrathoracic Chemotherapy (HITHOC) for Pleural Disseminated Thymoma: A Systematic Literature Review[J]. Ann Surg Oncol, 2023, 30(1): 543-560.

[5] Romano G, Zirafa CC, Ceccarelli I, et al. Update in the Treatment of Pleural Tumors: Robotic Surgery Combined with Hyperthermic Intrathoracic Chemotherapy[J]. Cancers (Basel), 2024, 16(9): 1691.

[6] Zhao ZY, Zhao SS, Ren M, et al. Effect of hyperthermic intrathoracic chemotherapy on the malignant pleural mesothelioma: a systematic review and meta-analysis[J]. Oncotarget, 2017, 8(59): 100640-100647.

[7] Migliore M, Fiore M, Filippini T, et al. Comparison of video-assisted pleurectomy/decortication surgery plus hyperthermic intrathoracic chemotherapy with VATS talc pleurodesis for the treatment of malignant pleural mesothelioma: A pilot study[J]. Heliyon, 2023, 9(6): e16685.

[8] Rintoul RC, Ritchie AJ, Edwards JG, et al. Efficacy and cost of video-assisted thoracoscopic partial pleurectomy versus talc pleurodesis in patients with malignant pleural mesothelioma (MesoVATS): an open-label, randomised, controlled trial[J]. Lancet, 2014, 384(9948): 1118-1127.

[9] Li X, Huang K, Deng H, et al. Feasibility and oncological outcomes of video-assisted thoracic surgery versus thoracotomy for pathologic N2 disease in non-small cell lung cancer: A comprehensive systematic review and meta-analysis[J]. Thorac Cancer, 2022, 13(21): 2917-2928.

[10] Markowiak T, Larisch C, Hofmann H, et al. Hyperthermic intrathoracic chemotherapy (HITHOC): narrative review of the current literature, recommendations and future studies[J]. Ann Transl Med, 2021, 9(11): 955.

[11] Mennander AA. Commentary: A synthetic adeno-associated viral vector as a means of future precision treatment[J]. J Thorac Cardiovasc Surg, 2021, 164(6): e445-e446.

[12] Layer JP, Fischer P, Dejonckheere CS, et al. Safety and efficacy of helical tomotherapy following lung-sparing surgery in locally advanced malignant pleural mesothelioma[J]. Strahlenther Onkol, 2024, 200(7): 605-613.

[13] Liu L, Zhang T, Song X, et al. Hyperthermic intrathoracic/intraperitoneal chemotherapy versus conventional intrapleural/intraperitoneal chemotherapy for the malignant effusion: a multicenter randomized clinical trial[J]. Int J Hyperthermia, 2023, 40(1): 2241689.

[14] Elsayed HH, Elanany MEE, Elsayegh MT, et al. Hyperthermic intrathoracic chemotherapy in patients with malignant pleural mesothelioma after cytoreductive surgical procedures: a systematic review[J]. World J Surg Oncol, 2025, 23(1): 132.

[15] Migliore M, Nardini M. Does cytoreduction surgery and hyperthermic intrathoracic chemotherapy prolong survival in patients with N0-N1 nonsmall cell lung cancer and malignant pleural effusion?[J]. Eur Respir Rev, 2019, 28(153): 190018.

[16] Hu R, Jiang H, Li H, et al. Intrapleural perfusion thermo-chemotherapy for pleural effusion caused by lung carcinoma under VATS[J]. J Thorac Dis, 2017, 9(5): 1317-1321.

[17] Li Z, Deng J, Yan F, et al. Efficacy of hyperthermic intrathoracic chemotherapy for initially diagnosed lung cancer with symptomatic malignant pleural effusion[J]. Sci Rep, 2023, 13(1): 12071.

[18] Aprile V, Bacchin D, Korasidis S, et al. Hyperthermic Intrathoracic Chemotherapy (HITHOC) for thymoma: a narrative review on indications and results[J]. Ann Transl Med, 2021, 9(11): 957.

[19] Yellin A, Simansky DA, Paley M, et al. Hyperthermic pleural perfusion with cisplatin[J]. Cancer, 2001, 92(8): 2197-2203.

[20] da Nobrega Oliveira REN, de Andrade Pontual Peres C, Oliveira AC, et al. Efficacy of Cytoreductive Surgery and Hyperthermic Intrathoracic Chemotherapy (HITHOC) in Thymic Neoplasia: A Systematic Review and Single-Arm Meta-analysis[J]. Ann Surg Oncol, 2024, 32(3): 1670-1678.

[21] Hassan M, Zimmermann J, Schmid S, et al. Outcome after cytoreductive surgery combined with hyperthermic intrathoracic chemotherapy in patients with secondary pleural metastases[J]. Front Oncol, 2023, 13: 1259779.

[22] Chen M, Huang R, Rong Q, et al. Bevacizumab, tislelizumab and nab-paclitaxel for previously untreated metastatic triple-negative breast cancer: a phase Ⅱ trial[J]. J Immunother Cancer, 2025, 13(4): e011314.

[23] Pan X, Hou Z, Zhang T, et al. Efficacy and safety of intrapleural perfusion with hyperthermic chemotherapy for malignant pleural effusion: A meta-analysis[J]. J Cardiothoracic Surgery, 2024, 19(1): 278.

[24] Yi E, Kim D, Cho S, et al. Clinical outcomes of cytoreductive surgery combined with intrapleural perfusion of hyperthermic chemotherapy in advanced lung adenocarcinoma with pleural dissemination[J]. J Thorac Dis, 2016, 8(7): 1550-1560.

[25] Shen B, Tan M, Wang Z, et al. The Meta-Analysis of Bevacizumab Combined with Platinum-Based Treatment of Malignant Pleural Effusions by Thoracic Perfusion[J]. J Oncol, 2022, 2022: 1476038.

[26] Danuzzo F, Sibilia MC, Vaquer S, et al. The Role of Hyperthermic Intrathoracic Chemotherapy (HITHOC) in Thoracic Tumors[J]. Cancers (Basel), 2024, 16(14): 2513.

[27] You J, Shi K, Yang X, et al. Thoracic perfusion of Esculentoside A-loaded thermosensitive hydrogel for the treatment of malignant pleural effusion in lung cancer[J]. Chem Eng J, 2025, 512: 162404.

[28] Hao Y, Gkasti A, Managh AJ, et al. Hyperthermic Intrathoracic Chemotherapy Modulates the Immune Microenvironment of Pleural Mesothelioma and Improves the Impact of Dual Immune Checkpoint Inhibition[J]. Cancer Immunol Res, 2025, 13(2): 185-199.

[29] Hu X, Kang X, Zhao F, et al. Heterogeneous cellular responses to hyperthermia support combined intraperitoneal hyperthermic immunotherapy for ovarian cancer mouse models[J]. Sci Transl Med, 2025, 17(789): eadp2124.

[30] Laengsri V, Nantasenamat C, Schaduangrat N, et al. TargetAntiAngio: A Sequence-Based Tool for the Prediction and Analysis of Anti-Angiogenic Peptides[J]. Int J Mol Sci, 2019, 20(12): 2950.

[31] Fang X, Zhu N, Zhong C, et al. Sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line therapy in RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer: An open-label, single-arm, phase Ⅱ trial[J]. EClinicalMedicine, 2023, 62: 102123.

[32] Ranieri G, Ferrari C, Di Palo A, et al. Bevacizumab-Based Chemotherapy Combined with Regional Deep Capacitive Hyperthermia in Metastatic Cancer Patients: A Pilot Study[J]. Int J Mol Sci, 2017, 18(7): 1458.

[33] Yan M, Yang R, Li Q, et al. Anti-angiogenic and antitumor effects of anlotinib combined with bevacizumab for colorectal cancer[J]. Transl Oncol, 2024, 41: 101887.

[34] Rong B, Yang S, Li W, et al. Systematic review and meta-analysis of Endostar (rh-endostatin) combined with chemotherapy versus chemotherapy alone for treating advanced non-small cell lung cancer[J]. World J Surg Oncol, 2012, 10: 170.