Does cytoreduction surgery and hyperthermic intrathoracic chemotherapy prolong survival in patients with N0–N1 nonsmall cell lung cancer and malignant pleural effusion?

Discussion

It is known that drug infusion into the pleural cavity leads to direct exposure of tumour cells lining the surface of the pleural cavity. Systemic absorption from the pleural cavity is lower when compared with absorption from the peritoneal cavity during intraperitoneal hyperthermic chemotherapy procedures [11]. The hyperthermia itself has a toxic effect on malignant cells [12] and modifies the toxicity of the chemotherapeutic agent [13]. However, systemic concentrations remain below toxic levels due to the limited absorption of the drug from the cavity. By attempting to “sterilise” the microscopic residual disease after surgical resection, HITHOC has been successfully used in the treatment of some thoracic tumours such as malignant pleural mesothelioma and thymomas [14–16]. Moreover, a recent well-designed study demonstrated that hyperthermia together with cisplatin is an effective treatment for epidermal growth factor receptor (EGFR) kinase domain mutation-positive lung cancer patients [17]. The authors of the study confirmed that hyperthermia and cisplatin, synergistically, downregulated the EGFR protein level, leading to quenching of the signal from EGFR and induction of apoptosis.

For the same reasons, the hypothesis that cytoreductive surgery and HITHOC could improve local pleural control and overall survival for selected patients with advanced NSCLC confined in the chest seems based on a good rationale. It is therefore fascinating that our systematic review, on the possible role of debulking surgery and HITHOC for selected stage IV NSCLC, confirms that something “new” should and could be done to prolong survival. A mean survival of 27 months, with 13 out of 21 (62%) patients alive at 1 year and 10 patients still alive at the time of the respective publication in the 21 patients included (table 1) are positive results for those who, on the basis of the present literature, have a poor prognosis, with a median overall survival of just 4 months, and 1- and 5-year survival rates of less than 16% and 2%, respectively [18]. Although we did not look at perioperative complications, there was no systemic toxicity or treatment-related mortality.

Of note, all 21 patients included in our systematic review had adenocarcinoma of the lung and all of them had also been treated with chemotherapy. Certainly, the appropriate indications for this type of surgery are mandatory to obtain longer survival. Surgical indications in this group of patients could be proposed as summarised in table 2. The exclusion of N2 and N3 patients is mandatory, and therefore correct histology of mediastinal nodes prior to surgery is obligatory. In the case of PET-positive N2 or N3, the standard protocol must include EBUS and/or video-mediastinoscopy to guarantee that no patient is denied surgery because of a false-positive PET scan or enlarged nodes on CT [19].

In 2003, Shigemura et al. [9] published a pilot study on HITHOC and panpleuropneumonectomy for patients with advanced carcinomatous pleuritis caused by lung cancer. Surgery was performed after HITHOC. The mean survival time was 19 months. Işık et al. [8] performed cytoreduction and HITHOC in 19 patients overall. The 1-year survival rate was 54.7% in the HITHOC group, while it was 0.6% and 0.8% in the two historical control groups (p<0.01 and p<0.05, respectively). Both of our patients who underwent this procedure were reported in 2015 [3], but have since died. The first died after 7 months because of sepsis following spinal surgery and the second died after 3 years because of tumour spread in the abdomen (the chest had minimal uptake on PET-CT).

Nevertheless, some other relevant publications not included in the systematic review (figure 1) confirmed a better survival of the study groups (table 3). Kimura et al. [20] demonstrated absence of death during a follow-up period of 9–35 months in seven patients who underwent HITHOC and debulking surgery for disseminated malignant pleural effusion for lung cancer. Matsuzaki et al. [21] performed HITHOC following resection of the lung primary tumour (no pleurectomy) in 11 consecutive patients with primary pulmonary adenocarcinoma and pleural effusions containing tumour cells but without distant metastasis. The median survival time for the patients receiving perfusion treatment was 20 months, while the median survival time for the control group was only 6 months [16]. Hu et al. [22] performed video-assisted thoracoscopic surgery pleural biopsy and HITHOC in 54 patients with malignant pleural effusion caused by lung carcinoma with a median survival of 21.7 months and a 1-year survival rate of 74.1%. Yi et al. [23] performed an interesting study on 23 patients with advanced lung adenocarcinoma who underwent debulking surgery alone versus debulking surgery with HITHOC, which was continued for only 30 min (compared with 60 min in our technique). The complication rate was 34.8% versus 40%, while the 3-year survival rate was 24.3% versus 0% (p=0.045), respectively. Kodama et al. [24] performed debulking surgery and HITHOC in 101 patients with pleural surface malignancy, obtaining a 37.4% survival rate at 5 years.

Of note, because all of the patients in our systematic review had adenocarcinoma, which presents high heterogeneity, other factors such as molecular biology indicators, classification and degree of infiltration could have had an impact on the therapeutic effect with a possible influence on long-term follow-up results [25]. Furthermore, on the basis of the survival obtained in our systematic review, which showed a mean survival of 27 months and a median survival of 18 months, we believe that there is a subgroup of lung cancer and pleural effusion/nodules confined in the chest that does not have the proper allocation in the tumour, node and metastasis classification. These tumours may be better downstaged to stage IIIB, and this is supported by the International Association for the Study of Lung Cancer Lung Cancer Staging Project that reported the survival for pathological stage IIIC and pathological stage IVA is about the same, with no statistically significant differences [26].

Furthermore, although the recent results of a prospective randomised study on the use of “solo” HITHOC or chemical talc pleurodesis in patients diagnosed with NSCLC and metastatic malignant pleural effusion have shown a dismal survival of only 8 months [27], the good results of our systematic review suggest that debulking surgery and HITHOC need to be investigated thoroughly with the intention to give hope, but not false hope, to the group of patients with advanced stage lung cancer.

In conclusion, although this systematic review shows that some encouraging evidence exists, the quality of evidence available concerning debulking surgery and HITHOC is still weak in order to confirm the effectiveness of this procedure for selected patients with advanced lung cancer. Therefore, better evidence, preferably in the form of randomised controlled trials, is necessary to evaluate clearly the benefit of this novel therapeutic approach. Setting standardised criteria for surgery is also mandatory. The positive results obtained in this systematic review can contribute to generating interest in this form of surgery for selected patients with stage IV lung cancer. This new interest could also drive further evidence supporting the prolongation of survival time while maintaining a good quality of life.