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Intraoperative Photodynamic Therapy After Pleuropneumonectomy in Patients With Malignant Pleural Mesothelioma^*

Dose Finding and Toxicity Results

Hugo Schouwink, MD; Emiel T. Rutgers, MD, PhD; Joost van der Sijp, MD, PhD; Hugo Oppelaar, Ing; Nico van Zandwijk, MD, PhD, FCCP; Robert van Veen, Ing; Sjaak Burgers, MD, PhD; Fiona A. Stewart, PhD; Frans Zoetmulder, MD, PhD and Paul Baas, MD, PhD, FCCP

^* From the Departments of Thoracic Oncology (Drs. Schouwink, Van Zandwijk, and Baas), Surgical Oncology (Drs. Rutgers and Zoetmulder), and Experimental Therapy (Dr. Stewart and Mr. Oppelaar), The Netherlands Cancer Institute, Amsterdam, the Netherlands; and the Departments of Thoracic Oncology (Dr. Burgers), Surgical Oncology (Dr. van der Sijp), and Clinical Physics (Mr. van Veen), University Hospital Rotterdam/Daniel, Rotterdam, the Netherlands. Currently at the Department of Pulmonary Diseases, Medisch Spectrum Twente, Enschede, The Netherlands.

Correspondence to: Paul Baas, MD, PhD, FCCP, Department of Thoracic Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; e-mail: p.baas{at}nki.nl

Objective: To determine the optimal administered dose of meta-tetrahydroxyphenylchlorin (mTHPC) for intraoperative photodynamic therapy (IPDT) in resected malignant pleural mesothelioma (MPM). The primary objective of this combination treatment was to improve local tumor control.

Design: Phase I/II dose escalation study.

Setting: Two Dutch cancer centers.

Patients: The study included 28 patients (2 women, 26 men), with pathologically confirmed MPM. The mean age was 57 years (age range, 37 to 68 years), and the World Health Organization performance score was 0 to 1. Epithelial mesotheliomas were found in 17 patients, a sarcomatous mesothelioma was found in 1 patient, and mixed epithelial sarcomatous mesotheliomas were found in 10 patients.

Methods: Patients were injected with 0.075 mg/kg (4 patients), 0.10 mg/kg (19 patients), or 0.15 mg/kg (5 patients) mTHPC 4 or 6 days before undergoing surgery and IPDT. Complete surgical resection (ie, pleuropneumonectomy) was followed by integral illumination with monochromatic light of 652 nm (10 J/cm²). The real-time fluence rate measurements were performed using four isotropic detectors in the chest cavity to calculate the total light dose.

Results: Dose-limiting toxicity was reached at the level of 0.15 mg/kg mTHPC. Three patients died in the perioperative period, and one death was directly related to photodynamic therapy. Real-time dosimetry identified 12 patients in whom additional illumination had to be given to the diaphragmatic sinuses, which were unavoidably shielded during integral illumination. In two patients, illumination was cancelled due to the insufficient resectability of the tumor. The median survival time for all 28 patients was 10 months. Local tumor control, 9 months after treatment, was achieved in 13 of the 26 patients treated with IPDT.

Conclusion: IPDT using mTHPC, combined with a pleuropneumonectomy, resulted in local control of disease in 50% of the treated cases. The considerable toxicity associated with the procedure, however, precludes its recommendation for widespread use. Stricter patient selection and improvements of the IPDT technique may reduce the toxicity.

Key Words: extrapleural pneumonectomy • light dosimetry • malignant pleural mesothelioma • meta-tetrahydroxyphenylchlorin • photodynamic therapy

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