Malignant pleural mesothelioma treated with cytoreductive video-assisted thoracic surgery plus hyperthermic intrathoracic chemotherapy: a case report

Introduction

Malignant pleural mesothelioma (MPM) is a rare malignant tumor originating in the pleura, and its incidence has increased in some regions in recent years (1). Generally, early-stage MPM is treated with a combination therapy based on lung pleurectomy. However, after lung pleurectomy, many patients with MPM experience a significant reduction in lung function and a deterioration in quality of life (2). As MPM is difficult to detect in the early stage and is highly invasive locally, most patients with MPM are diagnosed at an advanced stage and often have persistent pleural effusion, which lowers the possibility of surgery substantially and leads to a poor prognosis (3).

Patients with late-stage MPM are primarily treated with pemetrexed combined with platinum-based chemotherapy. However, chemotherapy does not appreciably improve patient survival and is associated with significant adverse reactions (4,5). Due to the presence of refractory pleural effusion and continuous tumor progression, patients with MPM have a short survival time and poor quality of life. Therefore, effective refractory pleural effusion control might be the first step in improving the long-term survival of these patients. Cytoreductive surgery plus hyperthermic chemotherapy is commonly used for primary or metastatic tumors for controlling the accumulation of thoracoabdominal or pleural fluid and facilitating subsequent systemic antitumor treatment (6-8). Moreover, the means to curtailing continuous tumor progression is critical to improving long-term outcomes in patients with MPM. The combination of pemetrexed and platinum-based chemotherapy has been considered the standard treatment for MPM (9). However, the overall survival (OS) of patients advanced with MPM receiving this therapy is only 8 to 14 months, and the 5-year survival rate is low, at 5.5% (10,11). Therefore, there remains an urgent need for more effective therapy to be developed that can improve the therapeutic outcomes of these patients with MPM.

Immunotherapy is being increasingly applied to a larger array of cancer types, and research has shown that immunotherapy has good efficacy and safety as a form of systemic therapy for MPM (12-16). However, there have been no reports on whether the combination immunotherapy with cytoreductive video-assisted thoracic surgery (VATS) can improve the prognosis and quality of life of patients with advanced MPM. Here, we report the first case in which cytoreductive VATS plus hyperthermic intrathoracic chemotherapy was applied as a local treatment and was followed by chemo-immunotherapy as systemic treatment to achieve high-quality, long-term survival. This regimen may hold potential as therapeutic option for patients with MPM and concomitant pleural effusion. We present this case in accordance with the CARE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1700/rc).

Case presentation

In February 2017, a 63-year-old male patient was admitted to the Department of Thoracic surgery, The Third Affiliated Hospital of Chongqing Medical University for coughing for 1 month and experiencing chest tightness and chest pain for 2 days. Chest computed tomography (CT) revealed multiple nodules on the left pleura and encapsulated fluid accumulation in the left chest and between the lobes of the lung (Figure 1). Subsequent positron emission tomography-computed tomography (PET-CT) confirmed MPM characterized by multiple nodules on the left pleura, with some nodules demonstrating invasion into the diaphragm and aorta. After admission, the patient underwent thoracic puncture drainage of 2,500 mL of bloody pleural effusion. The carcinoembryonic antigen test result for pleural effusion was normal, and the routine examination of pleural fluid indicated exudative effusion. Tuberculosis tests on pleural fluid and blood yielded negative results. Therefore, this patient was diagnosed with a malignant pleural tumor based on clinical symptoms, imaging results, and pleural fluid analysis, and was staged as IIIb (c-T4NXM0) according to the 7th edition of the tumor-node-metastasis (TNM) staging system jointly formulated by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC).

Figure 1 Timeline of patient treatment. VATS, video-assisted thoracic surgery; CT, computed tomography.

After a thorough discussion with the patient about the diagnosis and treatment options, the patient underwent left pleural biopsy under single-port thoracoscopy, followed by cytoreductive surgery plus hyperthermic intrathoracic chemotherapy as a local adjuvant treatment. Intraoperative findings revealed hemorrhagic effusion in the left thoracic cavity with extensive tumor distribution on both the visceral and parietal pleura. The largest tumor, approximately 4 cm in diameter, was adherent to the diaphragm and aorta, and was removed. Further pathological results confirmed MPM (epithelioid type), and immunohistochemistry findings indicated cytokeratin (CK)(+), epithelial membrane antigen (EMA)(+), cytokeratin high (CKH)(+), cytokeratin low (CKL)(+), vimentin (VIM)(+), calretinin (CR)(+), WT-1(+), mesothelial cells (MC)(+), Ki67 15%, CK7(−), TTF1(−), P40(−), synaptophysin (SYN)(−), chromogranin A (CgA)(−), CDX-2(−), CD34(−). The tumor in the visceral and parietal pleura was extensively removed with an electric knife and argon knife to achieve tumor reduction. Subsequently, after completion of the surgical procedure, 200 mL of sterile water at 48 ℃ mixed with cisplatin 100 mg was instilled into the pleural cavity, which was followed by instillation with 120 mg of doxorubicin, as hyperthermic chemotherapy, which lasted for 30 minutes (Figure 2). Postoperatively, according to the National Comprehensive Cancer Network (NCCN) Guidelines for Pleural Malignant Mesothelioma (version 3.2016), the patient received 1 cycle of adjuvant chemotherapy with pemetrexed 800 mg and cisplatin 120 mg. After that, the patient declined to proceed with additional adjuvant chemotherapy. At a postoperative follow-up in October 2017, we found that he had recurrent MPM with multiple nodules in the left pleura. Despite this, the patient declined further antitumor treatment.

Figure 2 Cytoreductive video-assisted thoracic surgery of the pleural tumor. (A) Visceral pleural and costophrenic angle tumor. (B) Aortic surface tumor. (C) Parietal pleural tumor. (D) Costophrenic angle after electrocoagulation debulking. (E) Lung surface and aorta after tumor debulking. (F) Electrocoagulation debulking of the parietal pleura.

In April 2020, the patient was readmitted to The Third Affiliated Hospital of Chongqing Medical University for left-sided chest pain and was observed to have an enlarged tumor in the left pleural on further imaging examination. Fortunately, pleural effusion was not observed again since then. In accordance with the 2020 NCCN guidelines for MPM (Version 1.2020), the combination of pemetrexed disodium with nivolumab plus ipilimumab, or monotherapy with pembrolizumab is the preferred treatment option. However, due to financial difficulties, the patient was administered a combination of sintilimab (200 mg, day 1) and cisplatin (75 mg/m², day 2)-pemetrexed (500 mg/m², day 2) chemotherapy as systemic therapy for six cycles and subsequent maintenance therapy with sintilimab (200 mg, day 1) alone for three additional cycles. As a result, the left pleural tumor shrank significantly, and according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (14), the patient achieved partial remission (Figure 3). However, due to the patient’s irregular treatment adherence, the patient returned with respiratory distress in November 2021 and was found with mild enlargement of the left pleural lesion on CT imaging. As a result, sintilimab (200 mg, day 1) was resumed for four cycles, and a slight reduction of the pleural tumor was achieved suggesting stable disease. Once again, the patient discontinued treatment until he experienced left-sided chest pain and partial tumor enlargement in February 2023. Another three cycles of sintilimab (200 mg, day 1) were administered, but the pleural tumor continued to grow. In June 2023, the patient succumbed to respiratory failure caused by a pulmonary infection. Overall, the patient’s survival time was 76 months, far exceeding the average survival time for patients with MPM (3). Notably, the absence of pleural effusion contributed significantly to the patient’s high quality of life.

Figure 3 Post-treatment radiographic alterations. (A) February 2017: left pleural tumor diagnosed. (B) February 2017: thoracoscopy and hyperthermic chemotherapy initiated. (C) March 2017: pleural effusion cleared post-surgery. (D) October 2017: recurrence of malignant pleural mesothelioma detected. (E) April 2020: enlarged left pleura without treatment. (F) October 2020: tumor reduction with chemoimmunotherapy. (G) November 2021: recurrence triggered by treatment interruption. (H) January 2022: disease stabilized via immunotherapy. (I) February 2023: pleural tumor recurrence due to irregular treatment. (J) April 2023: gradual progression of tumor post-immunotherapy.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

International multidisciplinary team (iMDT) discussion

Discussion among doctors from The Third Affiliated Hospital of Chongqing Medical University

Department of Thoracic Surgery

The two principal surgical approaches for MPM employed to achieve this goal are extrapleural pneumonectomy which entails the en bloc removal of the lung, pleura, pericardium, and diaphragm, and extended pleural decortication (17). The objective of radical intent surgery is to accomplish a macroscopic complete resection, which means the removal of all visible and palpable tumors within the hemithorax. However, the efficacy and safety benefits of surgical radical intent surgery has remained questioned. In the mesothelioma and radical surgery 1 (MARS1) randomized feasibility study, there was a significant increase in mortality rates associated with extrapleural pneumonectomy as opposed to no surgical intervention (18). Although it’s important to consider patient selection criteria and heterogeneity across trials in meta-analyses, the findings from this study led to a shift away from extrapleural pneumonectomy in favor of lung-preserving extended pleural decortication (19). However, the MARS2 phase 3 clinical trial has recently reported an elevated mortality risk when extended pleural decortication is combined with chemotherapy [hazard ratio (HR) =1.28, P=0.15] (20). These results strongly suggest that radical surgery should not be recommended for patients with disease that is potentially resectable.

Pleural effusion in MPM is a leading contributor to poor prognosis and low quality of life (21). Effective control of pleural effusion is a fundamental prerequisite for achieving long-term survival in patients with MPM. Currently, patients with late-stage MPM and pleural effusion are typically treated with systemic treatment, and there is a lack of effective localized treatment options for controlling pleural effusion. Nevertheless, some studies suggest that surgical debulking of pleural tumors combined with intraoperative hyperthermic chemotherapy and subsequent postoperative intrathoracic hyperthermic chemotherapy may become an effective method of local treatment for controlling pleural effusion in MPM (7,8). This may be because malignant tumor cells are intolerant to high temperatures.

During surgery, energy instruments such as electric knives and argon knives can be used to extensively treat both visceral and parietal pleural tumors, with the aim of eradicating as many tumor cells as possible. Compared to traditional pleuropneumonectomy, these surgical techniques are minimally invasive and more effective in preserving the patient’s lung function and quality of life while allowing for better coordination with subsequent systemic antitumor treatments. However, it is evident that surgery alone cannot eradicate tumor cells, especially those deep-seated tumor cells within the pleura. Therefore, hyperthermic intrathoracic chemotherapy is necessary. This procedure involves circulating heated chemotherapy drugs within the pleural cavity, achieving the goal of killing pleural tumor cells (22,23).

Localized hyperthermic chemotherapy allows chemotherapy drugs to penetrate deep-seated tumor cells more easily under heated conditions. Compared to systemic chemotherapy, this approach results in higher drug concentrations in the targeted area, leading to more thorough tumor cell destruction with lower systemic side effects. Previous clinical studies have confirmed that hyperthermic intrathoracic chemotherapy can effectively control pleural effusion in patients with MPM (21,24). In this case, the patient underwent only cytoreductive VATS plus hyperthermic intrathoracic chemotherapy for effective control of pleural effusion. Fortunately, no recurrence of pleural effusion was observed during the 6-year follow-up. This combination strategy for controlling pleural effusion caused by MPM might provide the possibility of long-term effects for subsequent systemic treatment. Furthermore, it may help to delay tumor recurrence if combined with postoperative adjunct hyperthermic intrathoracic chemotherapy.

We believe that some lessons might be learned from these MPM patients in the future (1). The primary aim of thoracoscopic tumor debulking is to remove as much of the visible tumor tissue as possible, but achieving macroscopic complete resection with VATS cytoreduction is quite challenging. The tumor cells that are not discernible to the naked eye and potentially left behind during surgery. As we cannot guarantee the absence of residual tumor cells, we make subsequent adjuvant hyperthermic intrathoracic chemotherapy (HITHOC) therapy for improving patient survival (2). Pleuropneumonectomy encompassing pleurectomy/decortication or extrapleural pneumonectomy, is primarily for patients with stage I to IIIA MPM for achieving radical objective. However, this approach significantly affects lung function. On the other hand, VATS cytoreduction combined with HITHOC can aimed at more advanced-stage patients for maximally reducing tumor burden, controlling postoperative pleural effusions, and improving the overall condition of the patient for further systemic treatment. Besides, our department has initiated a clinical trial (Project approval number: CSTB2023NSCQ-MSX1106) investigating on the efficacy of tumor debulking combined with hyperthermic intrathoracic chemotherapy as an adjuvant therapy for malignant pleural tumors, including MPM.

Department of Oncology

In addition to effectively controlling pleural effusion, systemic treatment for MPM can also ensure long-term survival. Traditionally, systemic treatment for MPM has focused on chemotherapy and anti-angiogenesis. However, patients often experience severe adverse reactions, leading to unsatisfactory treatment outcomes. Moreover, the use of the antiangiogenic drug bevacizumab in patients with MPM has not been approved by regulatory authorities (25,26). Recently, the demonstrated efficacy and safety of immunotherapy for MPM has provided the possibility of long-term survival. The KEYNOTE-028 trial was first to report the use of pembrolizumab monotherapy in the first-line treatment of PD-L1-positive patients with MPM. The study showed a disease control rate of 72%, with a median progression-free survival and OS of 5.4 months and 18 months, respectively (12). The open-label, multicenter, phase III clinical CheckMate-743 trial aimed to evaluate the efficacy and safety of nivolumab in combination with ipilimumab and those of standard chemotherapy with cisplatin or carboplatin in the first-line treatment of MPM. The median OS was 18.1 months for patients in the nivolumab + ipilimumab group and was 14.1 months for those in the standard chemotherapy group (HR =0.74, 96.6% confidence interval: 0.60–0.91; P=0.0020) (13).

After about 3 years, the patient was readmitted to our hospital for left-sided chest pain and was observed to have an enlarged tumor in the left pleural on further imaging examination. Fortunately, pleural effusion was not observed again since then. In accordance with the 2020 NCCN guidelines for MPM (version 1.2020), the combination of pemetrexed disodium with nivolumab plus ipilimumab, or monotherapy with pembrolizumab is the preferred treatment option. In our case, due to economic considerations, the patient did not choose nivolumab in combination with ipilimumab but opted for a combination therapy approach with sintilimab and cisplatin-pemetrexed. In the initial stage of systemic treatment of this case, chemo-immunotherapy achieved effective and prolonged tumor inhibition. Unfortunately, the patient did not regularly adhere to the systemic treatment, leading to inconsistencies in the efficacy of antitumor treatment. Overall, chemo-immunotherapy appears to be a potentially effective systemic treatment option to improve the prognosis of those with MPM.

In this case, thoracoscopy-assisted cytoreduction combined with HITHOC followed by systemic chemo-immunotherapy may be a potentially effective approach for the treatment of advanced MPM. However, the overlapping risk of pulmonary injury from intrathoracic hyperthermic chemotherapy and immune-related pneumonitis should be carefully monitored. Good adherence is another essential problem for ensuring treatment efficacy and improving patient survival. In this patient, chemotherapy combined with immunotherapy resulted in significant tumor reduction. If the treatment been administered more consistently, a longer survival time might have been achieved. Additionally, other combination therapies with immunotherapy, such as radiation or dendritic cell-based therapy with immunotherapy, may have the potential to improve the prognosis of these patients (24,27,28).

Several issues regarding the diagnosis and treatment of patients with MPM were further discussed as follows

Question 1: How can the combination of cytoreductive VATS and hyperthermic intrathoracic chemotherapy be optimized to further improve outcomes in patients with MPM?

Expert opinion: Dr. Francesco Petrella

The combination of induction chemo-immunotherapy and HITHOC could lead to a dose-reduction of chemotherapeutic agents and could allow a faster and less aggressive pleurectomy.

Question 2: What are the potential benefits and risks of integrating immunotherapy with conventional chemotherapy in the treatment of advanced-stage MPM?

Expert opinion: Dr. Francesco Petrella

As learned from non-small cell lung cancer experience, induction immunotherapy can effectively contribute to reduce tumor volume, thus allowing a parenchyma sparing procedure; in pleural mesothelioma surgery, it could prevent pericardium or diaphragm resection, thus shifting form extended pleurectomy/decortication to limited pleurectomy, in particular if associated to hyperthermic intrathoracic chemotherapy (29). On the other hand, induction immunotherapy could make a bit harder tissue dissection.

Question 3: Given the irregular treatment adherence observed in the case, how can patient compliance be better managed to enhance the efficacy of long-term MPM treatment?

Expert opinion: Dr. Francesco Petrella

Among all the advantages of HITHOC—including limitation of side effects to extrathoracic organs—a one-shot intraoperative delivery of cytotoxic agents could be appropriate in patient with low adherence, avoiding or at least reducing long lasting treatments, thus reducing treatment failure due to low adherence of the patient.

Question 4: In light of this case, what are the implications for future clinical practice in balancing aggressive local treatment and systemic therapy for MPM?

Expert opinion: Dr. Francesco Petrella

According to the state of the art and the present knowledge about systemic treatment of PM, induction chemo-immunotherapy, (extended) pleurectomy decortication + HITHOC and adjuvant postoperative immunotherapy might represent the new multimodality approach.

Conclusions

Cytoreductive VATS plus hyperthermic intrathoracic chemotherapy represents an effective local treatment for controlling pleural effusion caused by MPM, and chemo-immunotherapy may serve as an effective systemic treatment for controlling tumor progression in MPM. This novel therapeutic strategy may have considerable potential for ensuring the long-term, high-quality survival of patients with MPM.

Acknowledgments

The authors appreciate the great support from Dr. Wickii T. Vigneswaran (James A Haley Veterans’ Hospital, USA) in improving the quality of this paper.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1700/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1700/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1700/coif). The authors have no 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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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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