Malignant mesothelioma (MM) is an uncommon

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 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/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. (CHEST 2001; 120:1167 1174) Key words: extrapleural pneumonectomy; light dosimetry; malignant pleural mesothelioma; meta-tetrahydroxyphenylchlorin; photodynamic therapy Abbreviations: IPDT intraoperative photodynamic therapy; MM malignant mesothelioma; MPM malignant pleural mesothelioma; mthpc meta-tetrahydroxyphenylchlorin; PDT photodynamic therapy Malignant mesothelioma (MM) is an uncommon disease, although its incidence has increased throughout the western world during the last decades. 1 3 In 1998, about 5,000 deaths were attributed to this disease in Western Europe. 3 MM develops long after asbestos exposure (ie, 20 to 50 years). Therefore, the abundant use of asbestos in the 1960s, and to a lesser extent in the 1970s, still leads *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. This study was partly supported by the Dutch Cancer Society (grant No. NKI 97-1446) and by Scotia Pharmaceuticals Ltd, Surrey, England. Manuscript received November 30, 2000; revision accepted April 16, 2001. 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@nki.nl CHEST / 120 / 4/ OCTOBER, 2001 1167

to increasing numbers of newly diagnosed MM patients, numbers that are predicted to rise until at least the year 2010. Treatment with surgery, radiotherapy, or chemotherapy has not resulted in successful local control of the disease or in sufficient response rates to influence survival significantly. 4 7 Numerous reports conclude that new treatment modalities or combinations must be investigated. One of the newer combined modality treatments available is the use of adjuvant intraoperative photodynamic therapy (IPDT) with second-generation photosensitizers. Ris et al 8 were the first to use the very potent second-generation photosensitizer metatetrahydroxyphenylchlorin (mthpc) for patients with pleural malignancies. In 1997, we reported on the feasibility of this approach in combination with integral chest illumination and real time light dosimetry. 9 It was concluded that the use of mthpcmediated photodynamic therapy (PDT) offered advantages over that of less potent sensitizers, since the light doses required are much lower. Consequently, the additional time for the IPDT was limited to 1 h. The integral illumination of the entire chest cavity with real-time monitoring of the cumulative fluence also ensured uniform illumination and accurate estimation of the total fluence. This feasibility study was continued as a phase I/II study, on which we are reporting herein. The main objective of the treatment combination was to achieve local control of the disease. We report on the dose-limiting toxicity, the site of recurrence, and the long-term follow-up of 26 patients treated with surgery and IPDT. Patients Materials and Methods Patients with a histologically confirmed diagnosis of malignant pleural mesothelioma (MPM) were informed about the combination therapy of surgical resection and IPDT. Most of the patients were referred to one of the participating institutions for preoperative assessment. An extensive preoperative workup was performed to select patients who were able to undergo an extrapleural pneumonectomy. The workup consisted of a CT scan, cardiologic analysis (including ultrasound), mediastinoscopy, and thoracoscopy for optimal staging of the tumor. Staging was based on the new criteria of the International Mesothelioma Interest Group. 10 Other inclusion criteria were a World Health Organization score of 2, age 70 years; weight loss of 10% in the preceding month, and a calculated postoperative FEV 1 40% of predicted. The local ethics committees approved the study, and patients were asked for written informed consent. Twenty-five patients were treated in the Netherlands Cancer Institute, and 3 patients were treated in the Daniel den Hoed Kliniek, using the same procedures and the same equipment. Study Design the dose levels of mthpc used were 0.075, 0.1, and 0.15 mg/kg. In phase I of the study, four patients were treated on each dose level, with surgical resection and illumination at 4 days after IV injection of mthpc. Significant perioperative morbidity and/or mortality was considered to be the dose-limiting toxicity level, and a dose level below that was considered to be the maximum tolerable dose. An additional group was created who received a dosage level at dose-limiting toxicity (ie, 0.15 mg/kg) with a longer interval between drug administration and illumination of 6 days, assuming that this would be less toxic than the same drug dose with illumination after 4 days. Once the maximum tolerable dose had been defined (ie, 0.1 mg/kg mthpc with illumination at 4 days), this group was expanded to include 15 more patients as a phase II study. Surgical Procedure The surgical and IPDT procedure used has been described previously. 9 In short, patients were intubated selectively by a double-lumen endotracheal tube and were placed in a lateral decubitus position. A posterolateral thoracotomy was performed, and previous entrance ports were excised. In selected cases, a Cavitron ultrasound surgical aspirator (ValleyLab; Boulder, CO) was used to limit blood loss and to facilitate the resection of the tumor. The aim was to remove all macroscopic sections of the tumor. Small residues of 5 mm of the tumor were accepted, if they could not be removed without disrupting normal anatomic boundaries like the diaphragm and the pericardium, in order to avoid local tumor spread. Staples were used to close the bronchial stump, and an ipsilateral mediastinal lymph node dissection was performed. After this procedure, the IPDT was performed (see below), followed by closure of the thoracotomy and immediate extraction of the breathing tube. The patients were monitored in the ICUs. Oxygen saturation was measured for only a few minutes every hour during the patient s stay in the ICU, to avoid skin burn lesions induced by the light of the oximeter. Digoxin was started the day before the operation, and oral anticoagulants were given postoperatively for a period of 3 months. After discharge from the ICU, patients stayed in the hospital until they had recovered sufficiently. Patients were monitored six times during the first year and three times per year thereafter with physical examinations, standard laboratory tests, chest radiographs, and CT scans of the thorax and upper abdomen. IPDT Procedure According to the protocol, doses of 0.075, 0.1, or 0.15 mg/kg of mthpc (Foscan; Scotia Pharmaceuticals Limited; Surrey, UK) were administered to the patient 4 or 6 days before illumination. Twenty milligrams of the drug was dissolved in 5 ml of a solvent containing ethanol, polyethylene glycol, and water. The solution was shaken vigorously for 5 min, and this procedure was repeated once more after 1 h, before slow-push IV administration of mthpc (4 mg/ml). Patients were nursed in subdued light for 2 weeks. After the extrapleural pneumonectomy, the chest cavity was extensively inspected and bleeding lesions were coagulated. Isotropic light probes (Cardiofocus; West Yarmouth, MA) that were inserted into sterile transparent tubes 1 to 2 mm in size (Vygon; Ecouen, France) were sutured onto strategic sites in the cavity (ie, apex, posterior diaphragmatic sinus, pericardium or anterior chest wall, and near the esophagus). These isotropic probes measure the fluence rate delivered to the tissue, including both direct incident and scattered light from the tissue (Fig 1). The isotropic probes were connected to photodiodes (Photop UDT-455; Graseby Electronics; Orlando FL). These signals were 1168 Clinical Investigations

and were calibrated for measurements in saline solution (ie, correction of the refractory index induced by the saline solution). Further details on the calibration have been reported by Marijnissen and Star. 11 Results Figure 1. Schematic setup of the IPDT procedure. Crosssectional view (top) and frontal view (bottom) of the situation after pleuropneumonectomy, with a light-emitting bulb fiber and four isotropic light detectors placed in their treatment positions. From January 1996 to December 1999, 28 patients entered this study. Four patients on whom we had reported previously were included in this study. 9 Patient characteristics, major complications, and the duration of hospital stays are shown for the three different mthpc dose groups in Tables 1, 2. All patients had negative results of mediastinoscopy and had no contraindications for the combined procedure. In two patients who had already been injected with mthpc, large quantities of tumor remained even after extensive diaphragmatic or pericardial resections. IPDT was not performed in these patients because the risk of damage due to direct illumination of adjacent organs was considered to outweigh any possible improvement in local control of disease. Definitive staging was recorded after surgical resection. The average total operation time was 6.5 h (range, 5 to 9 h), and the average time required for light delivery was 27 min (range, 16 to 54 min). In 14 of the 26 illuminated patients, the integral illumination was uneventful and a uniform total fluence of 10 J/cm 2 could be delivered to the entire cavity. Additional illumination was required in 12 patients because of a relative protrusion of the diaphragm and the consequent shielding of the diaphragmatic sinus. Examples of optimal illumination, and one example in which additional illumination of the diaphragmatic sinus was required, are shown in Figure 2. In Figure 2, the total fluence is shown as a function of the illumi- transmitted to a personal computer for data recording and real-time display. A transparent sterile plastic bag (Steri-Drape; 3M Corp; St. Paul, MN) was placed in the cavity and filled with sterile saline solution (2.5 to 4 L) at body temperature for better expansion of the diaphragm and mediastinal folds. The surgical wound was approximated, and a spherical bulb fiber 3 mm in diameter (Cardiofocus) was inserted into the center of the bag. Laser light of 652 nm was obtained from a 6-W diode laser (Applied Optronics; South Plainfield, NJ). Integral illumination of the chest cavity was achieved by positioning the bulb fiber so that the isotropic detectors indicated comparable fluence rates. After integral illumination, the plastic bag filled with saline solution was removed from the chest cavity. If one of the measured locations was insufficiently illuminated, one or two of the isotropic detectors were moved to the vicinity of this location and additional illumination was subsequently given by a handheld microlens or spherical diffuser. The total fluence delivered to the tissues was approximately 10 J/cm 2. Before and after the procedure, all isotropic detectors were checked for their performance Characteristics Table 1 Patient Characteristics 0.075 (n 4) mthpc Dose, mg/kg 0.1 (n 19) 0.15 (n 5) All Groups (n 28) Mean age, yr 57 56 62 57 Age range, yr 46 62 37 66 55 68 37 68 Right-sided disease, No. 4 13 2 19 Female, No. 0 2 0 2 Pathology, No. Epithelial 2 12 3 17 Sarcomatous 0 0 1 1 Mixed 2 7 1 10 Stage, No. I 0 2 2 4 II 1 4 0 5 III 1 8 1 10 IV 2 5 2 9 CHEST / 120 / 4/ OCTOBER, 2001 1169

Table 2 Major Complications* mthpc Dose, mg/kg Complications 0.075 (n 4) 0.1 (n 19) 0.15 (n 5) All Groups (n 28) Atrial fibrillation 3 4 0 7 Diaphragmal rupture 0 2 0 2 Empyema 0 2 0 2 Perforation esophagus 0 1 0 1 Bleeding stump of 0 1 0 1 pulmonary artery Fluid retention 3 2 0 5 Mucus impaction 0 1 0 1 Depression 1 1 0 2 Wound infection 2 3 2 7 Spinal cord injury 0 0 1 1 Perioperative death 0 1 2 3 Mean hospital stay, d 20 26 57 28 *Values represent No. unless otherwise noted. nation time. In the patient represented in Figure 2, bottom, additional illumination was selectively aimed at the diaphragmatic sinus between 8 and 16 min into the illumination period. The mean total fluence per patient varied between 9.2 and 12.9 J/cm 2. Details of light dosimetry are shown in Table 3. The patient group receiving 0.15 mg/kg mthpc with a 4-day illumination interval was closed prematurely after three patients had been entered. One death occurred, and one patient experienced severe toxicity (see below). An additional two patients received illumination therapy 6 days after receiving a 0.15 mg/kg dose of mthpc, but when one of these patients also died, this drug dose level was abandoned. Postoperative Treatment Mortality The first serious adverse event resulting in death occurred in a 69-year-old man injected with 0.15 mg/kg mthpc 4 days before his operation. A large fibrotic tumor mass hampered complete tumor resection. Hypotension developed due to blood loss, and the patient was transfused with 15 U packed RBCs. The light delivery was uneventful. On the first day after surgery, a myocardial infarction was diagnosed. The patient died on day 6 postoperatively, despite extensive supportive measures. At the postmortem examination, severe generalized vascular atherosclerosis was observed as well as a large anterior myocardial infarction. Necrotic tumor nests were found in the dorsal sinuses without viable tumor cells, indicating that PDT had been effective. The second patient who died was a 56-year-old man with a right-sided pleural mesothelioma, who died 13 days after treatment with 0.15 mg/kg mthpc and a 6-day interval before IPDT. Surgery Figure 2. Two examples of the light dosimetry measurements. The total light dose is shown as a function of time for four different locations of the inner chest cavity. Top: the recorded fluence was similar for all locations. Bottom: the recorded fluence in the dorsal diaphragm was insufficient, and this location then was given additional illuminated with a microlens. and IPDT passed without obvious problems. Leftsided pleural fluid (an exudate) was drained 7 days after treatment. Eleven days after the operation, a sudden deterioration of his clinical condition occurred. Bronchoscopy revealed a right bronchopleural fistula. A rethoracotomy was proposed but was refused by the patient. He died on day 12 after treatment. At autopsy, the bronchopleural fistula was confirmed with diffuse inflammation and extensive formation of debris in the right chest cavity. A culture of tissue from the cavity showed Klebsiella pneumonia and several Streptococcus species. The third death was in a patient treated with 0.1 mg/kg mthpc with a 4-day interval before illumi- 1170 Clinical Investigations

Table 3 Light Dosimetry of 26 Patients Treated With IPDT* Variables 0.075 (n 3) mthpc Dose, mg/kg 0.1 (n 18) 0.15 (n 5) All Doses (n 26) Lowest light dose, J/cm 2 9 7 10 7 Highest light dose, J/cm 2 10.8 15.6 14.8 15.6 Mean light dose, J/cm 2 10.1 12.9 12.1 9.17 Boosts, No. of patients 1 10 1 12 *Boosts additional light given to the diaphragmatic sinus after integral illumination. nation. In this case, the illumination was not performed strictly according to the protocol. This was due to an abnormal geometry of the left chest cavity. One isotropic detector was placed in the apex of the cavity, and three probes were placed on and around the diaphragm. This resulted in an overdose in the region of the esophagus and the heart. The patient developed an esophageal fistula after 7 days, which was corrected with placement of an omentum flap and the construction of a Clagett thoracotomy. On day 12, bleeding occurred in the chest cavity. In this patient, no anticoagulant therapy was administered. Despite intensive supportive treatment, the patient died. A postmortem examination revealed diffuse bleeding from multiple sites and necrosis in the margins of the esophageal fistula. Typical PDTinduced necrosis was observed in the epicardia reaching into the myocardium without coronary artery occlusion. Postoperative Morbidity The mean hospital stay was 28 days, ranging from 18 to 61 days (Table 2). The majority of patients (23 patients; 82%) had one or more postoperative complications, varying from pain in the surgical scar to diaphragmatic rupture or myocardial infarction. Congestive heart failure and atrial fibrillation were the most frequent side effects. Empyema occurred in four patients 3 to 6 months after the procedure. One of these patients had only been resected and not treated with IPDT. In some cases, complications such as excessive intrathoracic fluid accumulation could be attributed to the IPDT. In others, complications such as atrial fibrillation might have been elicited by the pleuropneumonectomy. In the majority of cases, it was difficult to attribute complications specifically to either modality. However, no further patients were enrolled in the 0.15 mg/kg dose group after the second fatality. The 0.1 mg/kg group was subsequently expanded. One of the two female patients (0.1 mg/kg dose group) had two major complications. She suffered from a diaphragmatic rupture with displacement of the stomach into the chest cavity on day 14 after treatment, which required surgical intervention. Tissue samples taken during the rethoracotomy showed a very thin muscle layer without evidence of PDTinduced necrosis. This patient subsequently developed a cardiac tamponade on day 14 during anticoagulant therapy. A pericardial drain was inserted. The hemorrhagic effusion revealed no malignant cells. This patient recovered successfully. Another patient (0.15 mg/kg mthpc with 4-day interval before IPDT) experienced a perioperative myocardial infarction and, subsequently, a spinal cord infarction due to hypotension caused by severe blood loss. The tumor had grown into the subclavian artery wall and into the myocardium. A vascular prosthesis had to be inserted in the resected subclavian artery. This patient was discharged on day 60 to a rehabilitation center. Skin phototoxicity was not a significant clinical problem in our study, and no sunlight-induced skin toxicity was observed. Skin burn effects were seen most frequently in the 0.15 mg/kg dose group (2 of 5 patients). This was induced by the surgical theater lights despite the covering of the wound edges with green surgical drapes. Site of Recurrence During follow-up, the following three types of recurrences could be identified: local; in the surgical scar; and distant. Recurrence was established in 20 patients. There were eight patients with local recurrences, four patients with recurrences in the surgical scar, and eight patients with distant recurrences (Table 4). Local disease control at 9 months was achieved in 13 of the 26 patients treated with surgery and IPDT. Table 4 Site of Recurrence of 26 Patients Treated With IPDT Sites 0.075 (n 3) mthpc Dose, mg/kg 0.1 (n 18) 0.15 (n 5) All Groups (n 26) Recurrence sites, No. Local 1 6 1 8 Surgical scar 0 4 0 4 Distant* 1 7 0 8 None 1 2 3 Perioperative death 0 1 2 3 *Lymph node (n 2), liver (n 2), contralateral lung, abdominal, and skeleton (numbers do not total 8, because total distribution is unknown). CHEST / 120 / 4/ OCTOBER, 2001 1171

Disease-Free Survival Time and Total Survival Time The median follow-up of the patients was 31 months (range, 9 to 53 months) Actuarial diseasefree survival time and total survival time are shown in Figure 3 for the 26 patients treated with surgery plus IPDT. The median disease-free survival time after surgery and IPDT was 9 months, and median total survival time was 10 months. These data for all patients were comparable with the results in the 0.1 mg/kg dose group alone with 7 months of disease free survival time and 10 months of overall survival time. Discussion Treatment for MPM is still unsuccessful in terms of cure and survival. Several investigators have tried to improve local control of the disease by incorporating surgery into their treatment strategy. Multimodality therapy with chemotherapy, radiotherapy, or both after tumor resection has been advocated. 5 However, these combination therapies have not managed to achieve local control of disease in the majority of patients. 12 PDT might have a role to play in increasing local control, since it has proven to be successful in the treatment of superficial malignancies. Enthusiasm following the initial promising results on the use of PDT in patients with MPM 8,13,14 has been tempered somewhat by a randomized study by Pass et al 15 that was published in 1997. They observed no advantage to the addition of Photofrinmediated IPDT (Axcan Pharma; Mount-Saint Hilaire, Quebec, Canada) to a regime of surgery and immunochemotherapy in a total of 25 patients. The median survival time did not exceed 14 months in Figure 3. Kaplan-Meier curves for disease-free survival times and total survival times of the 26 patients treated with surgery and IPDT. this study, which does not compare favorably with current alternative treatment options. Probably the most optimistic phase II results were those from the study of Moskal et al. 16 They reported that several long-term survivors were observed after the combination of surgery and PDT with Photofrin. However, patients who died perioperatively (3 of 40 patients who had been treated) were excluded from analysis in this study. In our study, we have tried to optimize one of the treatment parameters, drug dose, using a new delivery procedure for IPDT in patients with MPM. It is nearly impossible to analyze all PDT factors (ie, drug dose, light dose, and drug/light interval) adequately in one study. We focused on varying the drug dose, while maintaining both the light dose and the drug/ light interval. The differences in the extent of the surgical procedure also significantly influenced the final result and toxicity. Despite careful preoperative screening, some patients were found to have an nonresectable tumor during the surgical procedure. In three patients with extensive resections of tumor invading vasculature or the chest wall, IPDT was given according to the protocol. These patients had significant perioperative and postoperative complications, as mentioned above. Such patients should, therefore, probably be excluded from IPDT, and more stringent attempts should be made to identify patients with nonresectable tumors preoperatively. MRI, 17 19 three-dimensional tumor volume estimation, 20 and standardized uptake values of fluorodeoxyglucose positron emission tomography scanning 21,22 may improve the selection of patients for surgically based therapy. Until recently, MPM was thought to be primarily a local disease. 23 If this is true, successful local control should significantly improve survival times. However, autopsy reviews have indicated that 50% of patients with MPM develop distant metastases, 24,25 and Sugarbaker et al 26 also have demonstrated the prognostic importance of local (mediastinal) lymph node involvement. We have routinely incorporated a mediastinoscopy into the preoperative assessment of our patients in order to exclude those patients with mediastinal lymph node metastases. Rusch and Venkatraman 27 showed that one quarter of mediastinal lymph nodes in patients with MPM were not accessible to cervical mediastinoscopy. In comparison with patients with non-small cell lung cancer, a relatively large number of MPM patients have nodal disease confined to areas such as the peridiaphragmatic area or internal mammary chains. Improvements in local control of disease therefore should be integrated with effective systemic therapy to obtain a better prognosis for this disease in general. 1172 Clinical Investigations

Phase I of our study demonstrated that a dose of 0.1 mg/kg mthpc given 4 days before IPDT is the maximum tolerable dose. The IPDT could be given in a short period of time, which is one of the advantages of a potent photosensitizer such as mthpc. The treatment, however, did still lead to considerable morbidity. An analysis of the toxicities in this study is complicated by the multimodality approach. Pleuropneumonectomy alone leads to significant toxicity, with a mortality rate of about 10 to 15%, 28 which is comparable to that seen in the present combined-modality study. Right-sided resections carry the greatest surgical risk, and the majority of our patients (19 of 28) had right-sided disease. This might have influenced the results in a negative way. Large-surface PDT alone also would be expected to be associated with significant toxicity. In our study, the perforation of the esophagus clearly was related to the IPDT procedure. This fatal complication illustrates the importance of light dosimetry on more than one location. Temeck and Pass 29 have reported this complication as a dose-limiting factor in Photofrin-mediated IPDT in two MM patients. With respect to the IPDT-induced cardiac damage, a side study was initiated measuring T-troponin levels and performing cardiac examinations during surgery and after. No significant myocardial damage was observed in five patients treated with 0.1 mg/kg mthpc 4 days before IPDT, 30 when the illumination procedure was performed in a standard way. Our study addressed the influence of the sensitizer dose on IPDT-related toxicity. With the exception of two patients treated 6 days after injection of mthpc, the drug/light interval was kept constant at 4 days and only limited variations in total fluence were allowed. These choices were based on reports in the literature and our own experience. 31,32 The light delivery system used in this study is now thoroughly tested and is, in our opinion, an important improvement for the application of PDT in general. Other investigators 13 have used photodiode light detectors, which measure only incident light fluence, and not scattered and reflected light. Such detectors clearly give an underestimation of the total fluence delivered to the tissue surface. 33 The use of only four detectors placed on strategic sites in the chest cavity and a single spherical bulb fiber placed in the center of a fluid-filled transparent bag in the chest cavity allowed adequate integral illumination of the entire cavity in most cases. In view of the patient who was overdosed with light, we stress that it remains critical that detectors are placed with care and kept in their positions during the full procedure. Some sites, like the diaphragm, can be shielded from the light, but they are easily detected by this system using real-time dosimetry. Additional illumination can be administered with the isotropic bulb or lens fiber after completing the integral treatment. A possible disadvantage of our system is the pressure on surrounding tissue induced by the fluid-filled bag. Pressure against malignant and healthy tissue could perhaps reduce PDT efficacy due to decreased tissue perfusion accompanied by decreased oxygenation. 34,35 In conclusion, the combination of extensive surgical resection and IPDT was too toxic to be advocated as a widespread treatment option for patients with MPM. The use of intraoperative dosimetry devices is considered to be a prerequisite. Further studies should be performed with more limited surgical resections. Light doses of 10 J/cm 2 at 4 days after the administration of 0.1 mg/kg mthpc resulted in significant toxicity in this patient group. 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