Cytoreductive surgery and post-operative heated pleural chemotherapy for the management of pleural surface malignancy

Figures & data

Figure 1. Heated pleural chemotherapy (HPC) protocol.

Figure 2. Correlation analysis between RF power and peri-pleural temperature in 160 patients with PICT.

Table I. Baseline characteristics of the patients.

	Disease
Characteristic	NSCLC (n = 101)	MPM (n = 25)	Thymoma (n = 12)	Metastatic^a(n = 22)	p-value
Age, mean (SD), years	58 (11.5)	58 (9.2)	50 (14.5)	48 (17.4)	0.001^b
Sex
Female	57	17	5	13	0.488^c
Male	44	8	7	9
Surgical approach
EPP	9	16	2	0	<0.0001^c
Pneumonectomy	4	0	0	0
Lobectomy	72	2	0	3
Sub-lobar resection	16	6	3	19
Pleurectomy	0	1	7	0
Category of resection
Major resection	13	16	2	0	<0.0001^c
Minor resection	88	9	10	22
N-status
N0, N1	76	18	11	22	0.015^d
N2	25	7	1	0
D, E-status
D0E0, D1E0, D0E1	58	1	7	14	<0.0001^d
D1E1, D2E0-2, D0-2E2	43	24	5	8
Max. RF power
Average (SD), W	684 (149.7)	713 (82.2)	656 (97.0)	639 (130.0)	0.262^b
Max. temperature
Average (SD), °C	41.9 (1.67)	42.2 (1.96)	40.6 (1.56)	41.1 (1.65)	0.007^b
Overall death
Alive	32	4	10	4	<0.0001^d
Death	69	21	2	18
Local recurrence
No recurrence	62	13	7	14	0.855^c
Recurrence	39	12	5	8
Follow-up
Median, months	37	17	68	21

NSCLC, non-small cell lung cancer; MPM, malignant pleural mesothelioma; EPP, extrapleural pneumonectomy.

^aTumours metastatic to the lung.

^bAnalysis of variance (ANOVA).

^cChi-square test.

^dFisher’s exact test.

Figure 3. Overall survival curves (A and B) and local PFS curves (C and D) for 101 NSCLC patients according to the grade of pleural malignancy.

Figure 4. Overall and local RFS curves of 101 NSCLC (A and C) patients and 25 MPM (B and D) patients according to the type of resection.

Table II. Adverse events related to postoperative heated pleural chemotherapy (HPC) (NCI-CTC version 2.0).

	Common toxicity criteria
Adverse event	0	1	≥2
Focal skin pain beneath the electrode	77	87 (53.0%)	0
Grade II burn beneath the electrode	162	2 (1.2%)	0
Formation of induration in the subcutaneous fat	162	2 (1.2%)	0
Anxiety during heating	163	1 (0.6%)	0
Vomiting	163	1 (0.6%)	0

Of 164 patients, two patients with focal skin pain and one with both pain and induration were excluded from the analysis because we had to control the RF power lower than 400 W to remove the pain.

Table III. Summary of studies concerning outcomes for the management of pleural surface malignancy arising from three different diseases.

					Survival (%) at
Study	Study design (identified period)	Median follow-up (months)	No. of patients	Treatment modalities	1 year	3 years	5 years	10 years	MST (months)	MRFS (months)	Other information as specified
Disseminated thymoma
Refaely et al.*^a 2001 [21]	Single institution retrospective, stage IVa (1995–2000)	34	14	Resection + thermo-chemo		90	70
Kondo et al. 2003 [22]	115 institutes retrospective, stage IVa (1990–1994)	NR	67	Not defined			70.6	45			Resectability rate of stage IV = 42%
Wright 2006 [23]	Single institution retrospective, stage IVa (1987–2003)	NR	5	Chemo + PP + RT			75	50	86		WHO B3 thymoma
Haung et al. 2007 [24]	Single institution retrospective, stage IVa (1996–2006)	32.2	18	Chemo + resection + hemi-thoracic RT		91	78	65
Ishikawa et al. 2009 [25]	Single institution retrospective, stage IVa. IVb (1988–2006)	NR	11	Chemo + EPP + RT			81	70
Lucchiet al. 2009 [26]	Single institution retrospective, stage II–III (1980–2006)	NR	20	Resection			43.1	25.8			From pleural recurrence resection
Siesling et al. 2012 [27]	RACECARE project, all stage (1978–2002)	NR	403	Not defined	85		65.6
Yellin et al.*^a 2013 [28]	Single  institution   retrospective  (since  1995)	62	DNT 17	Resection + HPCP			81	73			5-, 10-y PFS: 61%, 43%
			TPR 14			67	56				5-, 10-y PFS: 48%, 18%
			TC 4				0	0
Kodama et al. 2013	Single institution retrospective (1989–2010)	68	12	Resection + HPC		91	91	73			DNT 4 TPR 6 Others 2
Malignant pleural mesothelioma
Monneuse et al. 2003 [29]	Single institution retrospective, T1-4 (1990–2000)	89	17	Pleurectomy + chemo + hyperthermia	69	42	8		18
Xia et al. 2006 [12]	Single institution retrospective, T1-3 (1995–2005)	NR	11	RT + chemo + hyperthermia	63	26	26		27		No surgery
Richards et al.*^b 2006 [30]	Single institution prospective, epithelial type (1999–2002)	NR	24	Pleurectomy + chemo + hyperthermia	80	39					MST of 20 patients with epithelial tumour + high-dose cisplatin: 26 M
Rice et al. 2007 [31]	Single institution retrospective, stage I–IV (1995–2005)	NR	63	EPP + IMRT	21				14		In field recurrence: 5%
Tilleman et al. 2009 [32]	Single institution prospective, BWH stage I–III (2004–2006)	NR	121	EPP + chemo + hyperthermia					12.8		Ipsilateral recurrence: 17.4%. High % of patients with stage III
Tokunaga et al.*^c 2011 [33]	Single institution retrospective, stage III–IV (1995–2008)	19	11	EPP + PICT		63.6			19	17
Sugarbaker et al.*^b 2013 [34]	Single institution retrospective, epithelial, stage I–IV (2001–2009)	NR	72	EPP or P/D + HIOC					35.3	27.1	13% had biphasic histological findings on the final pathological analysis
Kodama et al.*^c 2013	Single institution retrospective, all stage (1990–2010)	17	25	EPP or P/D + HPC		21	16	8	18	21	20 cases had stage III or IV. 9 cases had epithelial type.
NSCLC with pleural surface malignancy
Sawabata et al. 2002 [35]	Single institution retrospective, c-stage I–III (1980–1994)	NR	40	Resection			9		13		Malignant minor pleural effusion detected on thoracotomy 13 cases had local relapse
Muraoka et al. 2006 [36]	Single institution retrospective	NR	25	Resection + intrapleural cisplatin		52.6	11.3		47		Positive pleural lavage cytology or malignant effusion
Seto et al. 2006 [37]	Multi-institutional phase II trial, stage IIIB–IV (1998–2002)	34	80	Intrapleural hypotonic cisplatin ± any other treatments	39				7.9		1-year effusion progression free survival rate: 31.8%
Lim et al. 2010 [1]	Meta-analysis, p-stage I–IV (submission before 2008)	39	511	Not defined		80		31			Pleural lavage cytology positive
Kodama et al. 2013	Single institution retrospective, c-stage I–III (1987–2010)	37	101	Resection + HPC		60	37	14	44	78	37 cases had positive finding (cluster cells) on pleural lavage cytology

MST: median survival time; MRFS: median relapse-free survival; NR: not reported; PP: parietal pleurectomy; RT: radiation therapy; EPP: extrapleural pneumonectomy; DNT: de novo stage IVa thymoma; TPR: thymoma with pleural relapse; TC, thymic carcinoma; HPCP, heated pleural chemoperfusion; HPC, heated pleural chemotherapy; BWH, Brigham and Women's Hospital; IMRT, intensity-modulated radiation therapy; PICT, post-operative intra-thoracic chemo-thermotherapy; P/D, pleurectomy/decortication; HIOC, hyperthermic intraoperative cisplatin chemotherapy; NSCLC, non-small cell lung cancer.

*Same institutions.

Refaely Y, Simansky DA, Paley M, Gottfried M, Yellin A. Resection and perfusion thermochemotherapy: A new approach for the treatment of thymic malignancies with pleural spread. Ann Thorac Surg 2001;72:366–70

 Google Scholar

Kondo K, Monden Y. Therapy for thymic epithelial tumors: A clinical study of 1,320 patients from Japan. Ann Thorac Surg 2003;76:878–85

 PubMed Web of Science ®Google Scholar

Wright CD. Pleuropneumonectomy for the treatment of Masaoka stage IVA thymoma. Ann Thorac Surg 2006;82:1234–9

 Google Scholar

Haung J, Rizk NP, Travis WD, Seahan VE, Bains MS, Dycoco J, et al. Feasibility of multimodality therapy including extended resections in stage IVa thymoma. J Thorac Cardiovasc Surg 2007;134:1477–84

 Google Scholar

Ishikawa Y, Matsuguma H, Nakahara R, Suzuki H, Ui A, Kondo T, et al. Multimodality therapy for patients with invasive thymoma disseminated into the pleural cavity: The potential role of extrapleural pneumonectomy. Ann Thorac Surg 2009;88:952–7

 Google Scholar

Lucchi M, Davini F, Ricciardi R, Duranti L, Boldrini L, Palmiero G, et al. Management of pleural recurrence after curative resection of thymoma. J Thorac Cardiovasc Surg 2009;137:1185–9

 Google Scholar

Siesling S, van der Zwan JM, Izarzugaza I, Jaal J, Treasure T, Foschi R, et al. Rare thoracic cancers, including peritoneum mesothelioma. Eur J Cancer 2012;48:949–60

 PubMed Web of Science ®Google Scholar

Yellin A, Simansky DA, Ben-Avi R, Perelman M, Zeitlin N, Refaely Y, et al. Resection and heated pleural chemoperfusion in patients with thymic epithelial malignant disease and pleural spread: A single-institution experience. J Thorac Cardiovasc Surg 2013;145:83–9

 Google Scholar

Monneuse O, Beaujard AC, Guibert B, Gilly FN, Mulsant P, Carry PY, et al. Long-term results of intrathoracic chemohyperthermia (ITCH) for the treatment of pleural malignancies. Br J Cancer 2003;88:1839–43

 Google Scholar

Xia H, Karasawa K, Hanyu N, Chang TC, Okamoto M, Kiguchi Y, et al. Hyperthermia combined with intra-thoracic chemotherapy and radiotherapy for malignant pleural mesothelioma. Int J Hyperthermia 2006;22:613–21

 PubMed Web of Science ®Google Scholar

Richards WG, Zellos L, Bueno R, Jaklitsch MT, Jänne PA, Chirieac LR, et al. Phase I to II study of pleurectomy/decortication and intraoperative intracavitary hyperthermic cisplatin lavage for mesothelioma. J Clin Oncol 2006;24:1561–7

 PubMed Web of Science ®Google Scholar

Rice DC, Stevens CW, Correa AM, Vaporciyan AA, Tsao A, Forster KM, et al. Outcomes after extrapleural pneumonectomy and intensity-modulated radiation therapy for malignant pleural mesothelioma. Ann Thorac Surg 2007;84:1685–93

 PubMed Web of Science ®Google Scholar

Tilleman TR, Richards WG, Zellos L, Johnson BE, Jaklitsch MT, Mueller J, et al. Extrapleural pneumonectomy followed by intracavitary intraoperative hyperthermic cisplatin with pharmacologic cytoprotection for treatment of malignant pleural mesothelioma: A phase II prospective study. J Thorac Cardiovasc Surg 2009;138:405–11

 PubMed Web of Science ®Google Scholar

Tokunaga T, Higashiyama M, Okami J, Maeda J, Fujiwara A, Kodama K. Intrathoracic chemo-thermotherapy with radiofrequency waves after extrapleural pneumonectomy for malignant pleural mesothelioma. Interact Cardiovasc Thorac Surg 2011;13:267–70

 Google Scholar

Sugerbaker DJ, Gill RR, Yeap BY, Wolf AS, DaSilva MC, Baldini EH, et al. Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection. J Thorac Cardiovasc Surg 2013;145:955–63

 Google Scholar

Sawabata N, Matsumura A, Motohiro A, Osaka Y, Gennga K, Fukai S, et al. Malignant minor pleural effusion detected on thoracotomy for patients with non-small cell lung cancer: Is tumor resection beneficial for prognosis? Ann Thorac Surg 2002;73:412–15

 PubMed Web of Science ®Google Scholar

Muraoka M, Oka T, Akamine S, Tagawa T, Morinaga M, Inoue M, et al. Modified intrapleural cisplatin treatment for lung cancer with positive pleural lavage cytology or malignant effusion. J Surg Oncol 2006;93:323–9

 Google Scholar

Seto T, Ushijima S, Yamamoto H, Ito K, Araki J, Inoue Y, et al. Intrapleural hypotonic cisplatin treatment for malignant pleural effusion in 80 patients with non-small-cell lung cancer: A multi-institutional phase II trial. Br J Cancer 2006;95:717–21

 PubMed Web of Science ®Google Scholar

International Pleural Lavage Cytology Collaborators. Impact of positive pleural lavage cytology on survival in patients having lung resection for non-small cell lung cancer: An international individual patient data meta-analysis. J Thorac Cardiovasc Surg 2010;139:1441–6

 Google Scholar