Malignant pleural mesothelioma (MPM) is a devastating cancer. Survival of MPM changed a little in the last 20 years. In the last decade, the median overall survival reported in 12,168 patients with MPM improved only from 7.3 [1993–2003] to 8.9 [2004–2011] and 9.3 months from 2012 to 2018 (P<0.001). This unfortunate result confirms that the prognosis for MPM is still poor. Although the use of chemotherapy increased from 9.3% to 39.4%, most of the patients (62.2%) received no antitumor treatment due to poor performance status and patient preference (1).
Several surgical techniques which are considered radical have been popularized over the years. However, some randomized trials have repeatedly shown limited improvement in patient outcomes, with a considerable number of harmful postoperative consequences (2-5). In a few words, randomized clinical evidence to validate the different surgical approaches of extrapleural pneumonectomy (EPP), pleurectomy/decortication (P/D) and talc pleurodesis is very weak. Video-assisted thoracoscopic surgery (VATS) talc pleurodesis remains the most used treatment and is the only acceptable approach for many patients with MPM (3). Novel management approaches are necessary to prolong survival in these patients without devastating extirpative operations.
Although hyperthermic intraoperative thoracic chemotherapy (HITHOC) was introduced more than 20 years ago (6,7), it is still infrequently used and is not routinely performed in general thoracic surgical practice. Nevertheless, at present, the role of HITHOC in clinical practice is becoming more central, and its position in today’s world of oncology and surgical oncology is increasing (8).
In this article, we summarize the evidence taken from the recent literature and our surgical experiences on the role of HITHOC following cytoreductive surgery for MPM.
What is HITHOC
HITHOC is a type of adjuvant treatment which is performed in the operating room immediately after debulking surgery for extended thoracic cancers. After surgery, two to four drains (apical and basal) and two thermometers are inserted in the chest. The drains are connected to the extracorporeal machine, while the chest is closed (Figure 1). The chemotherapeutic drug (cisplatinum most of the time although other drugs or a combination of two has been assayed) is introduced in a bag containing 2–3 L of normal saline and when the intrathoracic temperature of 42.5 ℃ is reached, intrapleural cisplatin perfusion is started for 60–90 min. Advanced cardiac and hemodynamic monitoring is mandatory during the procedure (Figure 2).
Rationale for using HITHOC
The infusion of the drug into the pleural cavity leads to the direct exposure of tumour cells lining its surface, furthermore, the hyperthermia itself confers toxicity to malignant cells and amplifies the toxicity of the chemotherapeutic agent (9,10). Moreover, under ex vivo hyperthermic conditions, it has been found that cisplatin penetrated the human lung tissue with a depth of 3–4 mm (11). Mercifully, the systemic concentrations remain below toxic levels due to the limited absorption of the drug from the cavity. The original article of Larish et al. (12) demonstrated that decortication at 42 ℃ significantly increased the cisplatin concentration in the lung in comparison to non-decorticated tissue samples (P=0.005) with an overall maximum penetration depth of 7.5 mm. The authors also demonstrated that a temperature rise showed no effect on the cisplatin concentration in decorticated tissue samples (P=0.985) (11).
Guidelines for the use of HITHOC
Guidelines for the use of HITHOC for MPM do not exist and its absence could create confusion for patients, oncologists and surgeons (8,13-16). Nevertheless, in 2020, an expert recommendation paper has been published in Germany (17). Some may erroneously conclude that the procedure is still experimental, while the reality says that, despite its current limited use, HITHOC is more than 20 years old. We have recently published a study which demonstrated that HITHOC should be taken into consideration to be included in the guidelines for MPM (13). It is important to comprehend that in MPM, HITHOC was used when the tumour is at the initial stage (stage I–II), while in all other thoracic cancers HITHOC is used when the tumour has reached an advanced stage, and the pleura is a metastatic site (18-23).
The reported renal toxicity which was common in the early phase of use (24) is now rarely reported as it has been demonstrated that preoperative hydration is sufficient to avoid the development of renal failure. Although a recent paper from the United States (25) reported a high incidence of renal toxicity as acute kidney injury. It seems clear that renal toxicity and mortality developed in patients who underwent EPP, and not in those who underwent P/D (13-15). A retrospective, multicenter study of 700 patients who underwent cytoreductive surgery plus cisplatin based HITHOC reported significant postoperative morbidity related to HITHOC, particularly renal insufficiency (26,27) since it appeared in 41 patients (12%) and the risk for postoperative renal failure was dependent on the intrathoracic cisplatin dosage.
The treatment algorithm for MPM is still under constant development and adjustment. Surgical management, in particular, holds a huge controversy on how and when to do it. It is now accepted that implementing surgery alone will not be effective for the management of MPM. Surgery, alongside other modalities such as chemotherapy and radiation, has a more favourable outcome. Surgical management varies from performing minimally invasive excisions to more radical methods. Three surgical methods have been popular over the past decades to treat MPM such as P/D, extended pleurectomy/decortication (EPD), and extra-pleural pneumonectomy.
Pleurectomy/decortication involves total parietal and visceral pleurectomy that spares the pericardium and hemidiaphragm. It is usually recommended for the early stages of the disease; however, the risk of parenchymal air leak is high. EPD is the removal of parietal and visceral pleura as well as the pericardium and the hemidiaphragm (28-32). Extra-pleural pneumonectomy is the in-bloc resection of all the above tissue including the lung (33).
Several studies have concluded that EPP should no longer be used for MPM due to the rate of risks and high mortality associated with it (2,28,32). Several systematic reviews and meta-analyses have concluded that EPP was associated with more postoperative mortality and morbidity in comparison with P/D. It was also concluded that EPD decreased mortality and morbidity by 2.5 folds and that it improved survival (15,22,34-37).
Different clinical trials are still ongoing to study the treatment options of MPM, focusing on EPD to analyze the best use in MPM, and whether it could be a viable option in the first place. Also, VATS P/D is considered to manage MPM symptomatically; however, several studies observed that its surgical complications risks weigh more than the possible benefits and that VATS pleurodesis is a more effective and less invasive method (3) (Figure 3).
The role of cytoreductive surgery is to remove the macroscopic pathology with an extra margin around the MPM (Figure 4). However, any residual microscopic disease can lead to MPM progression. To try and overcome this, HITHOC is administered (Video 1) and is associated with a higher disease-free interval and overall survival especially when administered at a high dose (15). Our preferred surgical approach is a VATS via a mini-thoracotomy of 8–12 cm instead of large thoracotomies with/without rib resection (38).
The study was reviewed and approved by the Institutional Review Board at King Faisal Specialist Hospital in Riyadh, Saudi Arabia. Written informed consent was obtained from the patient.
Despite the innovations that have been incorporated into the management of the MPM over the years, the approach and the type of operative treatment is still controversial. The role of HITHOC with debulking surgery for the management of MPM has been heavily debated in the literature through different studies and trials.
In 1997, Shirakusa and Okabayashi reported for the first time the use of HITHOC via VATS for pleural disseminated lesions and malignant pleural effusions (6). In 2002, de Bree et al. (39) reported a series with 3 patients with pleural thymoma metastases and 11 patients with pleural mesothelioma showing acceptable morbidity rates and encouraging locoregional disease control.
In 2003, van Ruth et al. (7) reported on 20 patients who were operated on for stage I mesothelioma and HITHOC with a median follow-up of 14 months and a median survival of 11 months with a 1-year survival of 42%. The authors reported considerable morbidities such as bronchopleural fistula, diaphragm rupture, wound dehiscence, persistent air leakage, and chylous effusion.
In 2008, van Sandick reported a negative study (40). Fifteen MPM patients were treated with EPP plus radiotherapy (RT) versus 20 patients who underwent cytoreductive surgery—P/D or EPP—and HITHOC but operated on years before. The median overall survival was 29 months for EPP/RT patients and 11 months for HITHOC patients. The authors concluded the use of cytoreductive surgery in combination with HITHOC for MPM is not supported, and renal failure was common.
However, in the last 10 years, different surgical positive experiences have been reported in Europe, China and the United States, and the use of HITHOC for MPM has also been expanded. As a result of this increase, many systematic reviews have been recently published and all of them confirm a longer survival when HITHOC is added to P/D (35-37). In a recent systematic review and meta-analysis (8), 762 patients treated with HITHOC have been compared to the control group that did not receive HITHOC. The analysis showed an standardized mean difference (SMD) of 0.24, with a 95% CI of 0.06–0.41 in favour of the HITHOC group. The survival effect of HITHOC in epithelioid MPM vs. non-epithelioid MPM showed an SMD of 0.79 (95% CI: 0.48–1.10) in favour of epithelioid MPM.
Furthermore, we have recently demonstrated that HITHOC can offer a longer survival rate with fewer risks than before with good quality of life to patients affected by MPM. We have published as a pre-print a study comparing 12 patients with P/D and HITHOC to 13 patients with talc pleurodesis alone. The advantage for the HITHOC group is evident and the median survival for the epithelioid type is 45 months (41,42). In the HITHOC group, there was a patient who survived 8 years and received three operations including debulking surgery and HITHOC (43). Although all these studies are very encouraging, it is evident that more multi-center randomized control trials are necessary to give HITHOC its position in the decision-making process in the treatment of MPM (44).
Nevertheless, the future seems to integrate immunotherapy for the few patients for whom radical surgical therapy is intended. The recent publication of the Checkmate 743 trial (45) demonstrated a survival benefit of combination immunotherapy over standard chemotherapy in patients with MPM. Simultaneously, the CONFIRM trial (46) demonstrates a modest and significantly longer survival of second-line nivolumab versus placebo in patients who already received standard chemotherapy. We also are waiting for the results of the MARS2 trial which is a randomized multicentric trial comparing (extended) P/D versus standard P/D in patients with MPM (47).
Finally, the combination of the recent and future innovations in the treatment of MPM has a two-fold goals. The first is to realize the new paradigm of “precision (individualized) treatment” and the second is to achieve through the individualization of the treatment a better long-term survival (48,49).
In conclusion, the use of HITHOC as a perioperative adjuvant treatment for MPM will likely expand in specialized centers in the future. Nevertheless, as MPM is a rare tumour, a global effort is necessary to definitively prove its efficacy.
We would like to thank Mr. Baraa Helal, Mr. Mohammad Albalkhi and Mrs. Cristina Riera López for their technical support.
Provenance and Peer Review: This article was commissioned by the Guest Editor (Rahul Nayak) for the series “Management of Pleural Diseases in the 21st Century” published in Shanghai Chest. The article has undergone external peer review.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://shc.amegroups.com/article/view/10.21037/shc-22-22/coif). The series “Management of Pleural Diseases in the 21st Century” was commissioned by the editorial office without any funding or sponsorship. 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. The study was reviewed and approved by the Institutional Review Board at King Faisal Specialist Hospital in Riyadh, Saudi Arabia. Written informed consent was obtained from the patient.
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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Cite this article as: Migliore M, Albalkhi I, Alshammari A, Aldebakey H, Alashgar O, Calatayud Gastardi J, Santana-Rodríguez N. A glimpse into the role of debulking surgery and hyperthermic intrathoracic chemotherapy (HITHOC) in the management of malignant pleural mesothelioma. Shanghai Chest 2022;6:37.