Debulking surgery and hyperthermic intrathoracic chemotherapy(HITHOC) for lung cancer

Marcello Migliore

Thoracic Surgery Unit, A.O.U. Policlinico-Vittorio Emanuele, Department of Surgery and Medical Specialities, University of Catania, Catania 95123, Italy

One hundred years ago, the first patients with lung cancer have been reported (1). Since then long term survival in patients with lung cancer remains disappointing, and this is not only due to the delayed diagnosis but also to the dismal survival of the 70%–75% inoperable patients.

Hyperthermic intrathoracic chemotherapy (HITHOC)has been successfully used alone in the treatment of malignant pleural effusion (2,3) or associated with debulking surgery in the treatment of some thoracic tumors such as malignant pleural mesothelioma (MPM) and thymomas (4-6). We know that hyperthermia has toxic effect on malignant cells (7), and modifies toxicity of the chemiotherapic agent (8) as the infusion of the agent into the pleural cavity leads to direct exposure of tumor cells adjacent to its surface. Another study proved that under ex vivo hyperthermic conditions, cisplatin diffused into human lung tissue with a median penetration depth of approximately 3–4 mm. The penetration of cisplatin into lung tissue may affect the local therapy of residual tumor cells on the lung surface using HITHOC perfusion in patients with malignant pleural tumors (9).

For the above mentioned reasons, the hypothesis that cytoreductive surgery and HITHOC could improve local pleural control and overall survival for selected patients with advanced non-small-cell lung cancer (NSCLC)confined in the chest seems to be based on an excellent rationale.

Already in 2003, Shigemura et al. (10) published a pilot study on HITHOC and panpleuropneumonectomy for advanced patients with carcinomatous pleuritis caused by lung cancer. Surgery was performed after HITHOC, and the mean survival time was 19 months. Recently Zhou et al.(11) performed a meta-analysis on the effect of debulking surgery and HITHOC on malignant pleural effusion for various primary cancers. They showed that patients who received HITHOC had a longer survival P<0.001. I??k et al. (12) performed cytoreduction and HITHOC in 19 patients. The 1-year survival was 54.7% in the HITHOC group 1 while it was 0.6% and 0.8% in the other groups,respectively (P<0.01 and P<0.05). Yi et al. (4) performed an interesting study on 23 patients with advanced lung adenocarcinoma who underwent debulking surgery alone vs. debulking surgery with HITHOC performed for 30 min. Complications rate was 34.8% vs. 40.0% while 3 years survival was 24.3% vs. 0% (P=0.045), respectively.Moreover, we have recently demonstrated in a systematic review a survival of 27 months in 21 collected patients with advanced lung adenocarcinoma (13) after debulking surgery and HITHOC; the fact that 10 patients were still alive at the time of the respective publication suggests that survival could be longer than 27 months.

In the Department of Surgery, University of Catania, the indications for debulking surgery and HITHOC for NSCLC are very strict as follows: good performance status,a disease confined in the hemithorax with parietal and/or visceral invasion, resectable lung tumor(s) in presence or not of pleural effusion, and finally absence of N2 or N3 disease. Although at the beginning this kind of surgery was performed through a thoracotomy, nowadays the operation could be performed via a uniportal or single incision technique reducing the postoperative complication due to the thoracotomy.

In conclusion, the evidence of more than a “few”successful experiences seems to confirm that new operations could be offered to prolong survival in selected patients with advanced stage lung cancer, and therefore it is fantastic to consider the possible role of debulking surgery and HITHOC for selected stage IV NSCLC. Caution is necessary, and therefore randomized controlled trials are mandatory to evaluate the real benefit of this promising novel therapeutic approach.

Acknowledgements

None.

Footnote

Conflicts of Interest: The author has no conflicts of interest to declare.

1.Spiro SG, Silvestri GA. One hundred years of lung cancer. Am J Respir Crit Care Med 2005;172:523-9.

2.Kimura M, Tojo T, Naito H, et al. Effects of a simple intraoperative intrathoracic hyperthermotherapy for lung cancer with malignant pleural effusion or dissemination. Interact Cardiovasc Thorac Surg 2010;10:568-71.

3.Hu R, Jiang H, Li H, et al. Intrapleural perfusion thermo-chemotherapy for pleural effusion caused by lung carcinoma under VATS. J Thorac Dis 2017;9:1317-21.

4.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 Thorac Dis 2016;8:1550-60.

5.Migliore M, Calvo D, Criscione A, et al.Cytoreductive surgery and hyperthermic intrapleural chemotherapy for malignant pleural diseases:preliminary experience. Future Oncol 2015;11:47-52.

6.Kodama K, Higashiyama M, Okami J, et al.Cytoreductive surgery and post-operative heated pleural chemotherapy for the management of pleural surface malignancy. Int J Hyperthermia 2013;29:653-62.

7.Crile G Jr. The effects of heat and radiation on cancers implanted on the feet of mice. Cancer Res 1963;23:372-80.

8.Barlogie B, Corry PM, Drewinko B. In vitro thermochemotherapy of human colon cancer cells with cis-dichlorodiamineplatinium (II) and mitomycin C. Cancer Res 1980;40:1165-8.

9.Ried M, Lehle K, Neu R, et al. Assessment of cisplatin concentration and depth of penetration in human lung tissue after hyperthermic exposure. Eur J Cardiothorac Surg 2015;47:563-6.

10.Shigemura N, Akashi A, Ohta M, et al. Combined surgery of intrapleural perfusion hyperthermic chemotherapy and panpleuropneumonectomy for lung cancer with advanced pleural spread: a pilot study. Interact Cardiovasc Thorac Surg 2003;2:671-5.

11.Zhou H, Wu W, Tang X, et al. Effect of hyperthermic intrathoracic chemotherapy(HITHOC) on the malignant pleural effusion: A systematic review and meta-analysis. Medicine(Baltimore) 2017;96:e5532.

12.I??k AF, ?anl? M, Y?lmaz M, et al. Intrapleural hyperthermic perfusion chemotherapy in subjects with metastatic pleural malignancies. Respir Med 2013;107:762-7.

13.Migliore M, Nardini M, Borrata F, et al. Systematic review on cytoreduction surgery and hyperthermic intrathoracic intraoperative chemotherapy(HITHOC) for adenocarcinoma of the lung confined to the heminthorax. Future Oncol 2017 (in press).