Photodiagnosis and Photodynamic Therapy (2005) 2, 135—147

REVIEW

Photodynamic therapy in the management of malignant pleural mesothelioma: A review Keyvan Moghissi, Kate Dixon BA (Hons) ∗ The Yorkshire Laser Centre, Goole & District Hospital, Woodland Avenue, Goole, East Yorkshire DN14 6RX, UK

KEYWORDS Photodynamic therapy; Malignant pleural mesothelioma; Pulmonary resection

Summary Background: In the past decade there have been sporadic publications on malignant pleural mesothelioma (MPM). In the present trend of multi-modal treatment for MPM we aim to evaluate the current status of photodynamic therapy (PDT) in the management of MPM through a review study. Methods: Original publications in English were the main source of the review and their material analysed in respect of patient and disease characteristics, PDT methods, mortality and morbidity and survival. Ten articles concerned with 230 patients were analysed and 35 other publications relevant to the study were used for reference. In every case PDT was used as an adjuvant to surgery whose role appeared to be a cyto-reductive procedure of debulking, pleurectomy and decortication (DPD) with/without pulmonary resection. PDT methods used two photosensitisers; PhotofrinTM [630 nm laser light] (6 series = 170 patients) or FoscanTM [652 nm laser light] (4 series = 60 patients). Results: Overall mortality and morbidity was 7.1% (4.9% for PhotofrinTM and 13.3% for FoscanTM PDT) and 48% (38% for PhotofrinTM and 70% for FoscanTM PDT) respectively. Better survival was achieved for DPD and early stage disease. Conclusions: Intra-operative (IOP) PDT in MPM is a safe procedure that requires more development and work regarding photosensitisers and light distribution systems for use in intra-pleural situations. The role of surgery in IOP-PDT appears to be cytoreduction to ≤5 mm residual tumour thickness in order for PDT to be used effectively. Curative intent may depend on the stage of MPM and completeness of cyto-reduction with/without pulmonary resection. © 2005 Elsevier B.V. All rights reserved.

Contents Introduction ..................................................................................................... Material and methods............................................................................................ Results........................................................................................................... ∗

Corresponding author. Tel.: +44 1724 290456; fax: +44 1724 290456. E-mail address: [email protected] (K. Dixon).

1572-1000/$ — see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(05)00059-1

136 137 137

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Clinical results ................................................................................................... Discussion........................................................................................................ Conclusion ....................................................................................................... Appendix A. Staging of malignant pleural mesothelioma according to the International Mesothelioma Interest Group 1995 [8] ...................................................................... References.......................................................................................................

Introduction Mesotheliomas are tumours of the serosal membranes of the pleura, peritoneum, pericardium, tunica vaginalis testis and ovaries. In the case of pleural disease, which forms over 80% of cases, diffuse and localised varieties are recognised. Of the localised variety, 10% are malignant and the remaining 90% are benign and are now classified under fibrous tumours of the pleura. The diffuse variety of pleural mesothelioma is always malignant and is referred to as malignant pleural mesothelioma (MPM). Characteristically the disease has an insidious evolution and is usually diagnosed in its advanced stage. It predominantly affects the male population (ratio 4—5 males to 1 female) over the age of 50 and has antecedent of exposure to asbestos. The link between MPM and asbestos first emerged in 1960 through observation of a high incidence amongst South African asbestos miners [1]. There is, however, a latent period of 30—40 years or even longer between exposure and clinical presentation. This is reflected in an increasing incidence of the disease in recent decades attributed to widespread use of asbestos after the end of World War II up to the 1970s [2]. It is expected that the incidence will peak sometime between 2010 and 2020 [3]. The cell origin of MPM was initially subject to debate and controversy between those who believed in an epithelial origin and others who suggested it to derive from mesothelial cells. The present consensus is that the tumour originates from mesothelial coelomic components. The current histological typing of MPM recognises three varieties based on leading cell population growth: namely epithelial, sarcomatoid and biphasic (mixed type) mesothelioma. The majority of MPM’s comprise of a mixture of epithelial and sarcomatous cells. It is, nevertheless, difficult to be unequivocally precise on the histology of a small biopsy sample, which may not be representative of the whole, that can be procured by surgical or autopsy material; serial section is usually required for detailed histological typing [4,5].

140 142 144 145 145

Both clinically and histologically the differential diagnosis between MPM and adenocarcinoma and its variants can be difficult in some 10—15% of cases [6]. It is relevant to emphasise that the definitive and reliable diagnosis of MPM and its differential from secondary tumours (e.g. pulmonary adenocarcinoma) affecting the pleura became possible in the1980s through availability of immuno/histochemistry methods. Evolution: The tumour arises from pleural mesothelial cells, which initially probably originate within the parietal pleura. Thereafter, it spreads locally in all directions to involve the whole of the costal, diaphragmatic, apical mediastinal pleurae and the chest wall. In many cases the visceral pleura is involved at an early stage. Distant metastases are uncommon. MPM is essentially a local disease and the cause of death usually relates to respiratory insufficiency. The characteristic gross appearance of the ‘‘en bloc’’ resected or postmortem pleuro-pulmonary specimen is one of encasement of a compressed lung beneath a thick and rigid sheet of tumour resembling a spongy cake (the lung) covered all round by thick layers of icing (pleural tumour). The mechanical effect of such encasement of the lung is to interfere with pulmonary inflation and deflation; the physiological consequence of restricted pulmonary ventilation. Staging: At least five different stage classifications have been proposed to group MPM, of which two have been most frequently used in recent years. These are the systems suggested by the Union Internationale Centre Cancer (UICC) [7] and the International Mesothelioma Interest Group (IMIG) [8] (see Appendix A) both of which use the tumour node metastases (TNM) system. Treatment: There is no generally agreed standard treatment for MPM. Treated by symptom relief and with supportive measures, the median survival for a patient with MPM is variously reported to be between 6 and 17 months [9—11], depending on the stage of the disease at presentation. Thus far, none of the standard cancer therapy methods, when used in their single modality protocol, have shown to significantly

Photodynamic therapy in the management of malignant pleural mesothelioma influence the outcome of the disease over and above its natural history and what is achieved through non-specific supportive treatment [11—16]. Therefore, effort is being made to develop multimodal regimes [17,18]. Surgical treatment of total or partial debulking form the fundamental part of multi-modal therapy. Extra pleural pleuro-pneuomonectomy was introduced in the early 1950s and was tried by many thoracic surgeons throughout the World [19—22]. It fell into disrepute since it did not achieve its objective of better survival, except for a very selected minority, compared with less extensive surgery [20]. However, surgical operation and adjuvant chemo/radiotherapy has shown to offer survival benefit [23—25]. Early in the development of photodynamic therapy (PDT), its potential to treat a wide variety of malignant tumours was investigated by Dougherty et al. [26]. Considering that MPM is essentially a localised disease and that, as PDT is also essentially a local treatment, it seems reasonable to use PDT for MPM specially following radical or even extensive debulking surgery. The aim of this review article is mainly to find answers to two questions: 1. What is the present role of PDT in the management of MPM? 2. In what capacity could PDT be usefully deployed, and what are the problem areas?

Material and methods A literature search was made through PubMed for listed articles on PDT in MPM and those in which PDT and MPM received a citation. Initially, the abstracts of all the listed articles were obtained. In addition, the search was extended to relevant journals that are not processed by PubMed. Moreover, some authors with personal experience in MPM were approached through personal contact. Inclusion criteria were: • Original articles concerned with the use of PDT in MPM as a sole modality treatment or within a multimodal protocol. • Articles (or their abstract) in English language. Exclusion criteria were: • Review articles in which there was no clinical material from the authors or their institutions. • Single case report articles. • Articles (and their Abstracts) in languages other than English.

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The articles included were studied and critically analysed with particular reference to: • • • • • •

• •

Number of patients; Protocol of the study; Pre-treatment investigations; Patient and tumour characteristics including staging; Treatments other than, or in addition to PDT; Details of PDT including photosensitising agent (drug), its dose and latent period (drug administration to illumination time) and illumination data; Mortality and morbidity; The conclusion of the authors.

Results The literature search identified a total of 46 articles in two categories. (a) Ten articles [27—36] were totally compatible with the inclusion criteria. They contained original material relevant to our review. They were, therefore, fully analysed (see Table 1); (b) A further 35 articles were either concerned with PDT or were considered as key publications on MPM and its treatment in some of which PDT was cited or discussed. These had useful information but contained no original material or method. They were studied and were used in the Discussion or other areas of this article as appropriate. A total of 230 patients with MPM in whom PDT was used were the subject of 10 articles [27—36]. These were reviewed and their series studied. In all cases PDT was used intra-operatively as adjuvant treatment after completion of the surgical procedure. Pre-operative/pre-treatment work up consisted of standard clinical, laboratory, radiological, biopsy and other investigations used for patients suffering from pleuro-pulmonary neoplasia. Bronchoscopy, mediastinoscopy, thoracoscopy (videoassisted thoracoscopic surgery) had been carried out in many prior to the surgery, however, tumour staging and, in some cases, histopathological confirmation were carried out at operation. Tumour staging used either the UICC or IMIG-TNM classification. • Treatment protocol: Patient selection: In all series patients had been selected for PDT amongst those with MPM confined to one hemithorax without extra pleural chest wall involvement or distant metastases. All

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Table 1 Number

1 2 3 4 5 6 7 8 9 10 Total

Summary of 10 articles in 230 patients undergoing surgery and IOP-PDT for MPM. First author (year)

Reference Number of Study number patients phase

Photosensitiser

Takita (1994) Pass (1994) Takita (1995) Ris (1996) Baas (1997) Pass (1997) Moskal (1998) Schouwink (2001) Friedberg (2003) Matzi (2004)

[27] [28] [29] [30] [31] [32] [33]

21 31 31 8 4 25 40

II I II I I III II

Ph Ph Ph F F Ph Ph

[34]

22

I and II F

[35]

26

I

F

[36]

22

III

PhP

230

5 × Ph, 1 × PhP, 4 × F

Pleurectomy + pulmonary resection Radical EPP 6 1 9 8 — — 7 —

Modified EPP

Pleurectomy/ lobectomy

Decortication/ Post cyto-reduction pleurectomy residual tumour DPD thickness

5

— 11 28

5 mm 5 mm 5 mm NS 5 mm NS 5 mm

—

—

5 mm

19

5 mm NS

7

5

4 14

—

22 7

15 18 22

—

—

—

22

31

54

10

135

Key: Ph, PhotofrinTM ; PhP, polyhaematorphyrin; F, FoscanTM (mTHPC); EPP, extra pleural pneumonectomy; DPD, debulking pleurectomy and decortication; and NS, not specified.

authors had taken account of the patient’s cardio/respiratory function, good performance status, as well as suitability for thoracotomy and pleuroectomy with/without pulmonary resection. Previous chemotherapy, other than within 30 days of operation, did not exclude a patient entering into the intra-operative PDT (IOP-PDT) protocol. Multi-disciplinary teams comprised of surgeons and oncologists knowledgeable in PDT and appropriate physicists who co-operated to plan and undertake the treatment. In every case treatment consisted of two parts: the surgical procedure followed, after its completion, by IOP-PDT. In practice, the patient had systemic administration of photosensitiser prior to surgery, followed by an appropriate latent period and then the operation, at the completion of which, illumination took place (see Box 1 ). Box 1: MPM surgery—–IOP-PDT protocol

Administration of photosensitising agent (drug) to patient ↓ Latent period (photosensitisation → illumination time) ↓ Operation ↓ - Surgical procedure ↓ - Illumination

• Surgical operation: A variety of operations were undertaken by the surgical teams in the 10 series. Table 1 shows the number of cases

treated in each of the 10 series and the distribution of cases per type of operation. These may be divided into two groups: Group I: Ninety-five patients (41.3%) had surgery which involved pleurectomy and some form of lung resection. A closer look at the surgery used in this group shows a considerable variation in the type of operation. A subset of patients underwent radical operation, which in thoracic surgical terminology, means en-bloc extra pleural pleuro-pneumonectomy, ipsilateral peri-cardectomy and ipsilateral excision of the diaphragm, referred to in this review as radical extra-pleural-pleuro-pneumonectomy (REPP). Another subset underwent a pleuropneumonectomy without excision of the diaphragm and/or pericardium referred to as modified pleuro-pneumonectomy (MPP). A third subset had pleuro-lobectomy or pleurectomy and non-anatomical lung resection. It is not clear whether complete clearance from tumour was achieved in all cases of REPP. Group II: In 135 other patients (58.7%), surgery was either an elective debulking pleurectomy and decortication (DPD) or was converted (by second intention) to some type of pleurectomy and tumour excision at exploratory thoracotomy. In thoracic surgical practice the term DPD refers to excision of the tumour-infiltrated parietal pleura and peeling off layers of tumour from the inner chest wall and over the visceral pleura and the lung. This is not a quantitative term and it neither conveys the volume of tumour that has been excised nor quantifies

Photodynamic therapy in the management of malignant pleural mesothelioma

Table 2

Details of photosensitising agents used in 11 series.

Sensitising agent Number of articles

Photofrin/PhP

Dose used mg/kg/bw (recommended)a

Nr = 6 (patients = 170) 2

Latent period [optimal]a

Light wavelength (nm)

Light dose [optimal]a (J/cm2 )

24—48 h

630

20 20—30 [30]

652

5—10 10

[24 h] Foscan

139

Nr = 4 (patients = 60)

0.075—0.2 (0.1)

4—6 days [6 days]

Latent period = time between photosensitisation and illumination. a This dose appears to have been determined by trial to be MTD.

the residual tumour left in situ. However, conscious of this fact, the majority of researchers and authors of the reviewed articles adopted a 5 mm thickness as the threshold level at which tumour residue could be ‘‘safely’’ left behind. This thickness of tumour was judged to be destroyable by PDT. Therefore, DPD was, in most series, carried out to such an extent as to leave a thickness of tumour ≤5 mm. • PDT method (Table 2): In ten of the reviewed studies, PDT was carried out according to standard methods consisting of administration of the photosensitising agent (drug) followed by a latent period and then illumination using a laser light of an appropriate wavelength to match the absorption band of the drug. In one series [36] the method entailed carrying out PDT under hyperbaric oxygen conditions. • Photosensitisation: Two types of photosensitising agent were used. In 6 series, comprising 170 patients, porphyrin formulation photosensitisers (Porfimer Sodium: PhotofrinTM or equivalent polyhematoporphyrin) were used at a uniform dose of 2 mg/kg/bw. In the remaining 4 series’ that comprised 60 patients, a chlorine derivative photosensitising agent (mTHPC—–FoscanTM ) was employed at a variable dose. In a Phase I study by Schouwink et al. [34] the patients were divided into three cohorts receiving Foscan at an escalating dose of 0.075 mg/kg/bw, 0.1 mg/kg/bw and 0.15 mg/kg/bw, respectively, in order to determine the maximum tolerating dose (MTD) which they found was 0.1 mg/kg/bw. • Illumination: In all series the power source was a laser emitting either 630 nm light for porphyrin base sensitising agents or 652 nm for mTHPC. Light delivery systems varied but in all cases the

aim was to deliver a pre-determined light dose calculated as J/cm2 to the target. In each case uniform light distribution throughout the chest cavity was ensured by calculating the total light power required to cover the surface area of the chest and then using appropriate delivery and applicator systems to illuminate each cm2 of the total area. This entailed: - A laser generator providing the appropriate wavelength to activate the administered photosensitising agent and emitting a light of sufficient power to achieve illumination of such a large surface area (the chest cavity). - Delivery and applicator devices suitable for the purpose. - Ensuring homogenous light distribution via a user-friendly diffuser (a system device which could be managed in an operating theatre setting). - Monitoring the light dose distribution. Fig. 1 illustrates schematically the light delivery system used by different authors. In one series Takita et al. [27] used a method that initially created a life-sized model of each patient’s thorax from enlarged CT scan films. By

Figure 1 Illumination methods for IOP-PDT in MPM.

140 employing a planimeter they then determined the overall surface area of the entire chest cavity and calculated the total light dose required for the whole of the chest. This was arrived at from the intended light dose (illumination) per cm2 multiplied by the surface area. For light delivery, they used four fibreoptic bulbs placed in the model of the chest and measured light distribution with detectors. In this way the overall light dose and its homogenous distribution was pre-determined using the model before applying it to the patient at operation. At the conclusion of surgical operation, the chest was closed and four delivery fibres and bulbs were placed in the location previously chosen in the model with the pre-determined dosimetry to achieve 20—25 J/cm2 of the area. In a subsequent publication Takita and Dougherty [29] used the same method and confirmed 20—25 J/cm2 light dose for IOP-PDT in 31 patients, 48 h after intravenous administration of 2 mg/kg/bw PhotofrinTM . Yet in a more recent study, the same institution [33] treated 40 patients with MPM using IOP-PDT following surgical operation of either EPP or DPD using their previously described method [27] for calculating the surface area of the chest and then giving a light dose of 20—30 J/cm2 of the area. Illumination was carried out 48 h after intravenous administration of PhotofrinTM and light delivery was achieved using four to six fibres with end-diffusers. A number of authors have used a liquid diffusing medium into which they introduced an appropriate number of optical fibres with end microlens or bulb delivering a light dose powerful enough, after diffusion through the medium, to illuminate each cm2 of the target chest cavity with the pre-determined light dose. Either 0.01% Intralipid (Kabi-vitrum) [28] or normal saline in a plastic container [34] was used as a diffusing medium. In all cases delivery of homogenous light was monitored by placing isotropic detectors at strategic points within the chest. Pass et al. [28] carried out a study in which 31 patients with MPM were treated by intra-operative PhotofrinTM PDT. Patients were divided into cohorts of three and given escalating intra-operative light doses of 15 J/cm2 rising by 2.5—35 J/cm2 48 h after intravenous administration of PhotofrinTM II. In the same study, in another cohort, they used a light dose of 30—32.5 J/cm2 delivered 24 h after administration of the photosensitising agent. They concluded that the best combination to achieve appropriate illumination (maximum tolerable dose—–MTD) was 30 J/cm2 delivered 24 h after

K. Moghissi, K. Dixon administration of PhotofrinTM II. The diffusing medium, in their cases, was a 0.01—0.02% solution of Intralipid. The chest cavity was filled with the solution and the light delivery devices were introduced into the solution, which was renewed every 5—7 min. The homogeneity and the desired light dose was monitored by a number of photodiodes. Three of the four series concerned with FoscanTM PDT in this review [30,31,34] used a light dose of 10 J/cm2 of the pleural space with a variable latent period between photosensitisation and illumination of 24 h or 6 days after drug administration. In the fourth series Friedberg et al. [35] in a Phase I study of 33 patients set out to determine the optimal light dose. They divided their patients into four cohorts after injection of 0.1 mg/kg/bw FoscanTM . They then carried out illumination after either 4 or 6 days with the light dose of 5 J/cm2 or 10 J/cm2 for each group. They showed that the most appropriate, with least toxicity, combination was 0.1 mg/kg/bw and light dose of 10 J/cm given 6 days after the photosensitiser administration. In these series, homogeneity of illumination was achieved by using a plastic container filled with normal saline solution acting as a diffusing medium, which was placed in the chest cavity. The light fibre with end bulb/microlens diffuser was placed in the fluid-filled container. Homogeneity of illumination in the chest cavity was assured by placing a number of isotropic light detectors in different areas of the chest.

Clinical results Overall mortality and morbidity of patients undergoing surgery and adjuvant PDT was 7.1% and 48%, respectively. Breakdown of the mortality and morbidity figures according to the type of operation was unachievable in this review because of lack of necessary data from which information could be derived in the majority of articles. Additionally, patients in most series had a variety of different operations, some of which could not be categorised into a standard or anatomically typical category. Furthermore, some of the series were concerned with Phase I trials with a varying dose of photosensitiser administered and/or differing light dose exposure, either or both of which, jeopardises the validity of the analysis. In some of the Phase II and III studies, with more homogenous types of surgery, the morbidity and mortality of different types of operations were evaluated.

Photodynamic therapy in the management of malignant pleural mesothelioma

Table 3

141

Mortality and morbidity rates of PhotofrinTM and FoscanTM in IOP-PDT for MPMa .

Photosensitising agent

Number patients treated

Mortality rate (%) (number)

Morbidity rate (%)

Photofrin/PhP Foscan Overall

162 60 222

4.9 (8) 13.3 (8) 7.1 (16)

38 70 48

a Note the discrepancy between the number of patients in this table and Table 1 which is due to a lack of information concerned with mortality and morbidity in 31 patients.

In Moskal et al. [33] series of 40 patients, 28 patients had DPD, 7 had EPP and 5 had lobectomy and pleurectomy, all combined with PDT. It is not clear what the indications were for each operation. They found that mortality for DPD and REPP was 3.6% and 28%, respectively, and that the rates of complications for pleurectomy and REPP were 39% and 71%, respectively. Matzi et al. [36] recently showed that there was no mortality in 22 patients who underwent extensive debulking and pleurectomy combined with IOP-PDT. Three patients (13.6%) had post-operative complications. In most of the other studies there was higher mortality and morbidity for EPP + IOP-PDT than for DPD + IOP-PDT. The mortality and morbidity for PhotofrinTM PDT and FoscanTM PDT in this review is presented on Table 3. This shows a significantly high mortality and morbidity for those having FoscanTM versus porphyrin based PDT. • Survival: Of the 10 series of patients included in this review, five were Phase I studies in which survival had not been an end point of the protocol of the study. Two of the remaining five had inadequate data to be included in our survival analysis. Therefore, three series could be considered for survival analysis. Takita et al. [27] in a Phase II study of 23 patients having surgery and IOP-PDT stratified survival by tumour stage. The overall estimated median survival was 12 months. Median survival for 16 patients with Stages III and IV disease was 7 months. Of the remaining seven patients with Stages I and II disease five were alive between 11 and 33 months after operation. Survival was not stratified by the type of operation but all living patients with Stages I or II disease had DPD. Pass et al. [32] reported the results of a Phase III trial in 63 patients; to receive maximum debulking surgery and post-operative Cisplatin, Interferon Alphet-2b and Tamoxifen (CIT), immuno-chemotherapy randomised with

or without intra operative PDT (IOP-PDT). The intent was to determine feasibility of such a multimodal therapy and to evaluate the impact of first generation (in their case PhotofrinTM II) PDT on local recurrence. Inclusion to the study was based on disease amenable to sub-total extirpation such that the maximum thickness after debulking at any intrathoracic site was 5 mm or less. Forty-eight patients qualified to enter the randomised study. The remaining 15 were excluded because they could not be decorticated to a minimum 5 mm residual thickness. Of the 48 who entered the study 25 were in the PDT arm (group) and 23 in the non-PDT group. There was a comparable number of EPP and DPD in each group. There were also reasonably comparable early Stages (I and II = number 4) and late Stages (III and IV = numbers 21 and 23). The results showed two bronchopleural fistulas in each group and one death in all. The median survival for 15 non-debulked patients was 7.2 months compared with 14 months for the other 48 patients on the protocol who could be decorticated to the required level. Survival for the PDT group (surgery + immunochemotherapy + PDT) was 14.4% versus 14.1% for the non-PDT group (surgery + immunochemotherapy without PDT). The study concluded that PDT added to surgery and immunochemotherapy did not influence mortality and morbidity. Nevertheless, there was no survival difference between PDT versus non-PDT group. However, it was not clear how many cases in each group had complete surgical clearance and, because of the relatively small numbers of patients, results could not be analysed for early Stages (I and II) and late Stages (III and IV) disease for each group separately. Since IOP-PDT had not shown any survival benefit in the study, the authors conducted another study of 47 patients. In this study [37], all patients had cyto-reductive surgery to 5 mm thickness tumour residue and post-operative immuno-chemotherapy. They were randomised to PDT or no PDT groups. The aims were to look at the possible association of volumetrics (bulk

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of the tumour) with survival and recurrence and volumetrics correlation with staging system. As a by-product they also reported on possible survival difference between DPD and REPP. Median survival for all patients was 14.4 months and a trend for longer survival was observed in those having DPD compared with patients having REPP (22 months versus 11 months). No conclusion can be drawn from the study on the influence of PDT on survival for either DPD or REPP since there is no indication as to whether the better survivors (DPD) were in the PDT or non-PDT group. However, the study shows a correlation between tumour volume and staging. It also predicts overall and disease-free survival both of which seems to relate with volumetrics. Furthermore, post resection residual tumour burden could seemingly predict outcome. Matzi et al. [36] carried out a non-randomised Phase III study of 34 patients with MPM. All patients had DPD for as much as could be achieved by the thoracic surgeon. Twenty-two of the patients had IOP-PDT under hyperbaric oxygen and 12 others had debulking pleurectomy and no PDT also under hyperbaric oxygen conditions. All gross disease up to 1200 g was removed by open surgery. One-year survival was 80 ± 12% for PDT group versus 28 ± 17% in the non-PDT group. Survival difference was significant (log rank test: P = 0.017) in favour of PDT group. • Quality of life: In ten of the reviewed studies no dedicated quality of life indicators were used although in

Table 4

B

Discussion This review of published literature on the use of PDT in MPM brings to the fore a number of important issues. It also highlights the existing deficiencies and practical difficulties that need to be addressed if further progress in this field is to be made. Intracavity (intra-pleural) PDT combined with thoracic surgery is a major and complex procedure that requires participation of a multi-disciplinary team to plan and undertake it. For all its complexity, based on this review, IOP-PDT does not seem to be attended by a higher mortality and morbidity than that which results from surgical procedures undertaken singly or part of multi-modal therapy for MPM. Table 4 includes some of the most recent publications using different surgical procedures without (Section A) [38—42] or with (Section B) [33,36] PDT and confirms this point.

Mortality and morbidity of surgical treatment of MPM without/with IOP-PDT.

First author (year)

A

all cases WHO Performance Status (PS) scale was used to evaluate patients pre-operatively. Only two groups in this review appear to have measured PS post-operatively (surgery + PDT). Matzi et al. measured dyspnoea, PS, pain and FEV1 prior to and 6 months after operation and found improvement in all parameters for patients who had undergone PDT compared to those with no PDT. However, the difference was not statistically significant.

Reference number

Number of patients

Treatment

Rusch (1994) Soysal (1997)

[38] [39]

27 100

DPD + chemotherapy DPD

3.7 1

40 22

Asiz (2002)

[40]

64 47

EPP DPD

9 0

n/k n/k

Sugarbaker (2004) Stewart (2005)

[41] [42]

328 74

EPP (trimodality) EPP + chemotherapy

3.4 6.7

60.4 63

Review of 230

EPP/DPD + PDT

7.1

48

3.6 28.6

39 71

Present review Moghissi (2005) Moskal (1998)

[33]

40

28 DPD 7 EPP

Matzi (2004)

[36]

22

DPD + PDT

Key: A = without PDT and B = with PDT.

Mortality (%)

0

Adverse events (%)

Photodynamic therapy in the management of malignant pleural mesothelioma Irrespective of any additional treatment (chemo/radiotherapy and/or PDT), significantly higher operative mortality and post-operative complications are attached to EPP than DPD [38—40]. It is, therefore, relevant to consider whether it is advantageous to use PDT in conjunction with EPP rather than DPD. Critical analysis of cases in different studies of this review shows that in the majority of patients the surgical operation, even in its most radical form, was carried out in order to prepare the pleural cavity so that PDT could be most effectively deployed. It seems that, based on previous studies, Potter et al. [43] and Takita et al. [27] first introduced the concept of 5 mm residual tumour thickness in DPD as a threshold for effective red light penetration and photodestruction when neoplastic tissue was pre-sensitised by the first generation photosensitising agents. The 1998 study carried out by Pass et al. [37] is interesting in that it shows a correlation between the T factor (as calculated by CT scan of the thorax) and volume of tumour prior to debulking decortication. It also shows correlation between residual volume thickness to be illuminated in the PDT process and the outcome in terms of survival. Extension of this idea leaves us with the hypothesis that in combined modality treatment of IOP-PDT the role of surgery, even in its radical EPP form, may be one of cyto-reduction or debulking of the tumour burden. The question arises as to whether radical EPP should be carried out only in the context of cyto-reductive surgery in advanced stage disease (Stages III and IV) and in order to have little or no tumour residue for the effective use of subsequent PDT. Conversely, it can be argued that the best results of IOP-PDT can be expected when PDT is combined with DPD in early stage disease (Stages I and II). The available publications do not provide convincing evidence of this. Nevertheless careful analysis of some of the reviewed articles provides interesting information. Moskal et al. [33] showed that survival was longer in Stages I and II than that of Stages III and IV, which is to be expected. However, the surgical procedure in the only five patients in Stages I and II amongst the long survivors was DPD + PDT and not EPP + PDT. Also, in their 1998 randomised study of cyto-reductive surgery with or without PDT, Pass et al. [37] showed that patients who had EPP had less survival benefit than those who had DPD. Nevertheless, it is not clear how many of the 28 patients who had DPD were amongst those who received PDT and how many had early Stages (I and II) MPM. It seems, therefore, that based on published studies there is no evidence that EPP per se is a

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determining factor on survival when it comes to surgery and IOP-PDT. It is also pertinent to point out that the 5 mm tumour thickness is relevant in the specific situation of the pleural cavity with a specific power setting and delivery system appropriate for intra-pleural surface illumination. With interstitial, intra-tumour illumination using a cylindrical diffuser a thicker bulk of tumour can be satisfactorily destroyed which has also been shown to be the case for advanced endobronchial/oesophageal tumours [44,45]. Theoretically, therefore, IOP-PDT could deploy both modes of illumination according to the volume of tumour residue after DPD. An appropriate photosensitising agent is crucial for the success of IOP-PDT. Most investigators accept that at the present time we do not possess an ideal agent for this purpose. The presence of so many vital structures within the thoracic cavity requires an agent with high selectivity of concentration in the neoplastic tissue compared with vital structures such as the lungs, oesophagus, heart and other vascular structures. Each of the two drugs in clinical use has strengths and weaknesses. The first generation Porphyrin-derived photosensitisers have stood the test of time with fairly safe dosimetry of 2 mg/kg/bw, which has been proved in many clinics. However, its yield of singlet oxygen is poor and its activation by 630 nm red light limits attraction/transmission to depth >1—1.5 cm. Second generation mTHPC has a much higher singlet oxygen yield but its dosimetry is subject to a much narrower margin of error. This is illustrated in the MPM setting by the work of Schouwink et al. [34] when, in a cohort of five patients who were administered 0.15 mg/kg/bw of mTHPC, two of the patients died and the other had spinal cord infarction. In another cohort of four patients, however, 0.75 mg/kg/bw was administered and there were no peri-operative deaths and no serious complications. The mortality and morbidity of the two agents, as presented on Table 2, would seem to confirm the view that FoscanTM PDT has not reached beyond a Phase I study. For now PhotofrinTM emerges as a safer drug. It may be argued that in future planning, if PhotofrinTM is chosen for PDT in the pleural cavity, one may consider twophase illumination or interstitial as well as surface illumination. • Illumination There are a number of essential requirements for intra-pleural illumination. - The source of energy needs to be capable of generating and emitting powerful light of an appropriate wavelength to the wide pleural space.

144 - The delivery device needs to be capable of transmitting light powerful enough (after diffusion) to activate the photosensitised tumour in all areas in order to illuminate every corner of the chest after EPP or following DPD. Whilst the problems associated with the light source and delivery fibres are essentially the concerns of the industry, those related to applicators and diffusers or diffusing medium will require input from thoracic surgeons. This review study shows that various teams have approached the problems of illumination through co-operation between surgeons and physicists. The use of standard microlens diffusers, usually at the tip of optical fibres, and centimetre-by-centimetre placement to cover the whole of the ‘‘empty chest’’ after pneumonectomy or the chest wall and visceral pleural surface of the lung after DPD is tedious and time consuming. The deployment of a grid as used by Matzi et al. [36] is practical only to put some order into illumination with more regularity and accuracy but it is still labour intensive. The use of multiple fibres with end diffusers and beam-splitters would be more helpful. Diffusing media, such as saline solution and intralipid, as used by some of the authors in this review, are useful in a number of ways since they ensure homogenous and integral light exposure. There remains the necessity of placing light detectors in strategic points such as the costodiaphragmatic sinuses and the apex of the chest and also removal of the fluid if this is not placed in a plastic container. Such plastic containers require pre-testing to assess the loss of light through the plastic in order to consider it in dosimetric calculations. Light dosimetry for PhotofrinTM PDT has been extensively tried. This needs re-evaluation for other photosensitisers.

Conclusion 1. What is the present role of PDT in the management of MPM?

K. Moghissi, K. Dixon The present role of PDT in MPM appears to be in association with surgical debulking procedures. • There is no evidence to suggest that a REPP (with IOP-PDT) presents any advantage over the simpler DPD in IOP-PDT situation. The role of EPP in complex IOP-PDT seems to be cytoreduction. The question may be asked as to whether medical EPP has any place in combination with PDT. • IOP-PDT in the treatment of MPM is a safe procedure. At this moment in time and based on the available data, PhotofrinTM IOP-PDT is safer than FoscanTM IOP-PDT in this situation. 2. In what capacity could PDT be usefully deployed in the future and what are the problem areas? We believe that in future studies there may be two indications for the use of PDT in mesothelioma: (a) To use the expertise gained in VATS minimal access surgery to carry out DPD to achieve minimal or no residual tumour and then employ intra-pleural PDT. Illumination may be repeated within the time constraints (drug effectiveness) imposed by the characteristic of the drug. (b) In conjunction with EPP in early Stage I disease. In such cases the role of PDT would be one of a ‘‘mopping-up’’ operation with curative intent. Problems of PDT for MPM relate to light delivery systems and distribution in the wide pleural space. Integral and uniform illumination with light of a specific wavelength and sufficient power are essential in order to secure efficient photodynamic effect. Light source delivery devices and applicators suitable for intra cavitary situations need to be re-assessed. It is also important to simplify the procedure of IOP-PDT in the thorax and make it more user-friendly. Coda: We do need more trials to sort out these problems and in order to advance.

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Appendix A. Staging of malignant pleural mesothelioma according to the International Mesothelioma Interest Group 1995 [8] T1

Scattered tumour foci in the ipsilateral pleura Only on the parietal pleura, the visceral not being involved Scattered foci also on the visceral pleura

a b

T2

Tumour involving each of the ipsilateral surfaces (parietal pleura including costal, mediastinal and diaphragmatic and the visceral pleura) with at least one of these features: • Involvement of the diaphragmatic muscle • Confluent visceral tumour or extension into the lung parenchyma

T3

Locally advanced tumour but potentially respectable with at least one of the following: • Involvement of the thoracic fascia • Extension to mediastinal fat • Solitary extension into the soft tissues of the chest wall • Non-transmural involvement of the pericardium

T4

Unresectable tumour, with at least one of the following: • Diffuse extension into the soft tissues of the chest wall with or without rib destruction • Direct extension of the tumour: - Into the peritoneum - Into contralateral pleura - Into one or more of the mediastinal organs - Into the spine

N

Lymph nodes Regional lymph nodes cannot be assessed No regional lymph node metastases Metastase(s) in ipsilateral peribronchial and/or hilar lymph nodes Metastase(s) in subcranial and/or ipsilateral mediastinal lymph nodes including ipsilateral internal mammillary lymph nodes Metastase(s) in contralateral mediastinal, contralateral internal mammillary, ipsilateral or contralateral supraclavicular lymph nodes

Nx N0 N1 N2 N3

M

Metastases Distant metastases cannot be assessed No distant metastases Distant metastases exist

Mx M0 M1

Clinical staging stage I

Ib II III IV

Ia

TNM T1a N0 M0 T1b N0 M0 T2 N0 M0 Every T3 M0 Every N1 M0 Every T4 Every N3 Every M1

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