Hyperthermic intrathoracic chemotherapy in thoracic surgical oncology: future challenges of an exciting procedure

The effect of hyperthermia on human neoplastic cells was understood in the 1970s. It has also been demonstrated that there is a synergism between hyperthermia and chemotherapy drugs such as Adriamycin [1,2]. In this context, hyperthermic intrathoracic chemotherapy (HITHOC), sometimes referred to as HIOC or HITOC, was developed. HITHOC is a type of adjuvant treatment performed in the operating room immediately after debulking surgery for extensive thoracic cancers when the surgical treatment is thought to be noncurative [3,4]. The methodology of HITHOC varies according to different centers and experiences, although it should be consistent worldwide [5], as it is not uncommon for different valuation methods to produce different results even in the same group of patients. Furthermore, excluding American Society of Clinical Oncology guidelines, HITHOC as an adjunct to surgery in malignant pleural mesothelioma has not been cited in recently published guidelines [6].

Therefore, the question arises, why should we discuss HITHOC if the procedure is not common? We try to answer this question not only by addressing the rationale with regard to the hesitancy of physicians to use HITHOC but also by emphasizing the reasons why HITHOC should be used and developed more.

Research evidence

Intracavitary hyperthermic chemotherapy following debulking surgery was initially applied to peritoneal carcinomatosis and only successively performed in thoracic oncology when surgical resection alone was felt to be macroscopically or microscopically incomplete. Following the early phase of its use, HITHOC was abandoned because of complications, renal toxicity and unsatisfactory long-term survival.

However, as a result of a better understanding of the procedure, improved patient selection and increased personalization of therapy, it has recently been shown that HITHOC could be of benefit to some patients [7,8]. The most important indicators to select patients for HITHOC include good functional status, no significant comorbidities (including renal failure) and cancer that is confined to the ipsilateral hemithorax as determined by a CT scan and PET scan. The type of cytoreduction surgery now favored to be performed prior to HITHOC is pleurectomy/decortication. In fact, massive extirpative surgery such as extrapleural pneumonectomy plus HITHOC has demonstrated poor early- and long-term results [8].

Nevertheless, after performing a simple search of all National Center for Biotechnology Information databases on July 10, 2021, for evidence of ‘hyperthermic intrathoracic chemotherapy,’ 262 publications were found. The same search in the PubMed database showed 72 results, with an evident increase in publication rate over the last two years (2019–2020). This increase demonstrates that the procedure is being used and investigated more frequently. This positive increase could be due to the expansion of indications: HITHOC is now not only used in malignant pleural mesothelioma (stage I–II) or advanced thymoma but also in advanced metastatic cancer of the pleura, such as selected M1a lung cancer and pleural dissemination of pseudomyxoma peritonei.

Experimental evidence

Combining intrapleural injection of cytotoxic drugs with hyperthermic perfusion may offer an additional benefit, in that the tumor cells are directly exposed to a higher concentration of chemotherapy agents, such as cisplatin or mitomycin c, with a lower incidence of systemic side effects. The infusion of the drug into the pleural cavity leads to direct exposure of tumor cells lining its surface, and the hyperthermia conveys toxicity to malignant cells and amplifies the effects of the chemotherapy agent. The pharmacokinetics of cytotoxic agents during HITHOC have been extensively studied. It has been shown that 41% of mitomycin C and 72% of doxorubicin were absorbed by thoracic cavity, and that there was a persistence of higher concentration of intrapleural drugs as compared to plasma concentrations when HITHOC has been used [9]. Ried et al. reported that the mean concentration of cisplatin in the perfusate is 55–58 times greater than in the serum and also found that increasing the dose of cisplatin to 150 mg/m² does not lead to a higher serum concentration [10]. Moreover, at “ex vivo” hyperthermic exposure experiment (cisplatin: 0.05 mg/ml, 60 min, 42°C) performed in 12 wedge resection, the penetration of cisplatin in the lung parenchima was approximately 3–4 mm [8]. In a recent second experiment, the same group of authors [11] demonstrated that decortication at 42°C significantly increases cisplatin concentration in the lungs in comparison to no-decorticated tissue samples (p = 0.005), with an overall maximum penetration depth of 7.5 mm. The authors also reported that a rise in temperature showed no effect on cisplatin concentration in decorticated tissue samples (p = 0.985). The proved penetration of cisplatin in the lungs after decortication permits a wider oncologic sterilization that cannot be obtained in another way after pleurectomy/decortication.

Clinical evidence

To fully understand the state of the art and to support clinical evidence, two recent systematic reviews and a meta-analysis were reviewed. Interestingly, all of them showed good results when HITHOC was added to debulking surgery for mesothelioma or malignant pleural effusion. A mean survival of 27 months and a median survival of 18 months, with 62% of patients alive at 1 year and 28.5% alive at 2 years, have been reported for malignant pleural effusion due to lung cancer confined to the chest [12–14]. The authors of these studies proposed that selected patients with non-small-cell lung cancer, pleural effusion and carcinomatosis undergo surgical treatment with debulking surgery and HITHOC. Furthermore, Li et al., in describing the management of selected stage IV lung cancer patients, confirmed that HITHOC could control symptoms and prolong survival of non-small-cell lung cancer patients with malignant pleural effusion [15]. Finally, the results of the systematic reviews and meta-analysis have been confirmed by recent experiences, which have reported very encouraging results, with improved long-term survival in malignant pleural mesothelioma, M1a lung cancer and advanced thymoma [16–21]. In the event that thymic cancer spreads into the thorax, surgery is often avoided. By contrast, Ambrogi et al. demonstrated that in advanced thymic cancer with pleural recurrence of thymoma, surgical resection followed by HITHOC was feasible and safe in 13 prospectively collected patients, with a disease-free interval of 47.2 months [17]. Taken together, these reports suggest that although the role of surgery in advanced chest cancer is still largely unknown, there is some evidence that adding HITHOC to pleurectomy/decortication could enhance surgery in selected patients with lung or metastatic cancer confined to the chest.

We have seen improved survival rates in recent clinical scenarios when HITHOC is performed following debulking surgery. There is substantial reason for patients with advanced malignant disease confined to the chest to see a light at the end of the tunnel. So, why is HITHOC still only used in a few centers? Moreover, as the clinical results are encouraging and the scientific rationale is well demonstrated, why is HITHOC used so little, to the point that guidelines for mesothelioma do not even mention it [6,22]?

We will try to answer these observations by identifying at least three different reasons. The first is the reported high perioperative complication and mortality rate of the procedure. In the initial cases, HITHOC was added to extended extirpative operations such as extrapleural pneumonectomy performed via a thoracotomy, often with rib resection, and the rate of complications and death was often unacceptable [23]. The trend today is for video-assisted thoracoscopic surgery with mini-thoracotomy using a 10-12-cm skin incision to perform extended debulking of chest tumors, such as pleurectomy and decortication [15,19]. The minimal invasiveness decreases perioperative complications and could serve to stimulate the immune system.

The second factor that may have contributed to the delay in wide use of HITHOC is the reported renal toxicity and subsequent renal failure. Nevertheless, although common in early experiences with HITHOC, renal toxicity is now rarely reported [24] for debulking surgery, as it has been demonstrated that preoperative hydration is sufficient to avoid the development of renal failure. By contrast, extrapleural pneumonectomy should be avoided before HITHOC,as a high risk of acute kidney injury has been demonstrated [8].

The final reason is the influential 2013 ‘in vitro’ study by Camerun and Hou [25]. The authors, in an experiment using different cell lines, suggested that the practice of pleural perfusion at 42°C for 1 h, often with single-agent cisplatin, was likely ineffective, and that the optimal mixture for intraoperative hyperthermic chemotherapy perfusion would use combinations of chemotherapy agents, such as cisplatin and pemetrexed or cisplatin and gemcitabine, at 45°C or greater for 60 min or more. We are pleased to be corrected but although ‘in vitro’ methods that use human cells in a laboratory provide a controlled environment for an experiment, they occur outside of a living organism, where other factors come into play, such as the fact that hyperthermia induces inflammatory cascades, immune responses and vascular permeability. Furthermore, the recent good clinical results obtained by many researchers [16–21] and the ‘ex vivo’ experiments of Ried et al. and Larish et al [10,11] contradict the ‘in vitro’ results obtained by Cameron and Hou, and therefore the latter results must be considered carefully and reevaluated. Taken together, these data not only justify the current practice of HITHOC but also increase the confidence in the more positive trend in the evidence. Certainly, as suggested by Molnar and Drogyik [28], further studies and randomized data are needed to strongly confirm the strength of the recommendation to use HITHOC [26,27], and to give it a position in the decision-making process with regard to the treatment of advanced malignant chest tumors [28].

In the clinical setting, the use of HITHOC as an adjunct to surgery is employed in a few centers in Europe (Germany, Hungary, Italy and Spain), the USA (Boston and Miami) and China [12,13,15,29]. As the field of application of HITHOC continues to rapidly evolve, specialization and dedication need to evolve together with this emerging practice. Furthermore, it is evident that a multidisciplinary approach is needed to evaluate the feasibility of HITHOC in such a way that it will be possible to individualize treatment in patients with advanced chest tumors [30]. We are convinced that this positive trend in the evidence will not only overcome the existing described obstacles but also stimulate the launch of an international randomized controlled trial in specialized centers to define the definitive role of this exciting ‘adjuvant’ treatment in thoracic surgical oncology.