Intraoperative photodynamic therapy after pleuropneumonectomy in patients with malignant pleural mesothelioma: dose finding and toxicity results.

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 (i.e., pleuropneumonectomy) was followed by integral illumination with monochromatic light of 652 nm (10 J/cm(2)). 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.

Photodynamic therapy for malignant mesothelioma: preclinical studies for optimization of treatment protocols.

Effective photodynamic therapy (PDT) depends on the optimization of factors such as drug dose, drug-light interval, fluence rate and total light dose (or fluence). In addition sufficient oxygen has to be present for the photochemical reaction to occur. Oxygen deficits may arise during PDT if the photochemical reaction consumes oxygen more rapidly than it can be replenished, and this could limit the efficacy of PDT. In this study we investigated the influence of the drug-light interval, illumination-fluence rate and total fluence on PDT efficacy for the photosensitizer meta-tetrahydroxyphenylchlorin (mTHPC). The effect of increasing the oxygenation status of tumors during PDT was also investigated. PDT response was assessed from tumor-growth delay and from cures for human malignant mesothelioma xenografts grown in nude mice. Tumor-bearing mice were injected intravenously with 0.15 or 0.3 mg.kg-1 mTHPC, and after intervals of 24-120 h, the subcutaneous tumors were illuminated with laser light (652 nm) at fluence rates of 20, 100 or 200 mW.cm-2. Tumor response was strongly dependent on the drug-light interval. Illumination at 24 h after photosensitization was always significantly more effective than illumination at 72 or 120 h. For a drug-light interval of 24 h the tumor response increased with total fluence, but for longer drug-light intervals even high total fluences failed to produce a significant delay in tumor regrowth. No fluence-rate dependence of PDT response was demonstrated in these studies. Nicotinamide injection and carbogen breathing significantly increased tumor oxygenation and increased the tumor response for PDT schedules with illumination at 24 h after photosensitizer injection.

Caelyx in malignant mesothelioma: a phase II EORTC study.

BACKGROUND: The use of doxorubicin has shown some activity in malignant mesothelioma but prolonged administration is hampered by cardiotoxicity. Caelyx, a new liposomal and pegylated form of doxorubicin has shown a better pharmacokinetic and toxic profile then doxorubicin. In a phase II study, the efficacy and toxicity of Caelyx was tested in previously untreated patients with malignant pleural mesothelioma. PATIENTS AND METHODS: Thirty-three patients who had measurable or evaluable histologically confirmed malignant pleural mesothelioma were included in the study. Caelyx (45 mg/m2) was given i.v. on outpatient base every four weeks for nine cycles or till progression or unacceptable toxicity occurred. RESULTS: Of the 33 patients, 32 were evaluable for toxicity and 31 for response. Two patients had a partial response (6%, 95% confidence interval: 0.2%-20.2%). The median survival was 13 months. Forty percent of the patients received >6 cycles. Toxicity was mild with palmar plantar erythrodysesthesia being most pronounced (62% grade 1-2, 6% grade 3) and of limited duration. Ten percent of patients had grade 3 anemia and 3% grade 3 thrombocytopenia. Two patients (6%) had grade 3 or 4 cardiac toxicity, which was not drug related. CONCLUSION: At the prescribed dose, single agent Caelyx is well tolerated but its activity in chemotherapy-naive mesothelioma patients does not warrant further investigation as a single agent.

Monitoring of impending myocardial damage after pleuropneumonectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma using biochemical markers.

In five patients who were treated for malignant pleural mesothelioma (MPM) with pleuropneumonectomy and intraoperative photodynamic therapy (IPDT), impending myocardial damage was monitored using ECG, the classical biochemical markers (creatine kinase [CK], total activity; CKMB, mass; and myoglobin), and the new cardiac markers troponin I (cTnI) and troponin T (cTnT). In the peroperative and postoperative period all classical markers were elevated, in contrast to cTnI and cTnT, because of the concomitant skeletal muscle damage. Sequential electrocardiogram monitoring showed no signs of myocardial damage. From this study in patients with MPM treated with pleuropneumonectomy and IPDT it can be concluded that measurement of cTnI and cTnT for the detection of myocardial damage is more suitable than measurement of the classical markers.

Prognostic value of the serum tumour markers Cyfra 21-1 and tissue polypeptide antigen in malignant mesothelioma.

In malignant mesothelioma, survival is claimed to be related to age, duration of symptoms, performance status, histological subtype, stage and platelet count. However the exact prognostic value of these factors is still a matter of debate. We studied the two cytokeratin markers, Cyfra 21-1 and Tissue polypeptide antigen (TPA) for their significance in predicting survival retrospectively in 52 patients. Cyfra 21-1 and TPA were elevated in 26 (50%) and 30 (58%) patients, respectively, and were highly correlated (r = 0.98). Univariate analysis of data from 51 patients, showed a relation with survival for performance status (P = 0.010), thoracic pain (P = 0.014), platelet count (P = 0.027), Cyfra 21-1 (P = 0.002) and TPA (P = 0.003). Multivariate analysis identified independent prognostic significance for performance status, platelet count and Cyfra 21-1. In addition to performance status ( < 80 vs. > 80) the cytokeratin markers identified patients with good prognosis in a log rank test. Values of Cyfra 21-1 and TPA are significantly correlated.

Acute pancreatitis in a case of Werner's syndrome with severe hyperlipidaemia.

A patient with Werner's syndrome and acute pancreatitis due to severe hyperlipidaemia is reported. Special attention is paid to early recognition of the syndrome and the prevention of complications of the several metabolic disorders that occur in this syndrome.