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Photodynamic therapy enhanced by hyperbaric oxygenation in palliation of malignant pleural mesothelioma: clinical experience
Photodiagnosis and Photodynamic Therapy (2004) 1, 57—64
Photodynamic therapy enhanced by hyperbaric oxygenation in palliation of malignant pleural mesothelioma: clinical experience Veronika Matzi a , Alfred Maier a , Oliver Sankin a , Jörg Lindenmann a , Michael Woltsche b , J. Smolle c , Freyja Maria Smolle-Jüttner, MD (Professor) a,* a
Division of Thoracic and Hyperbaric Surgery, Department of Surgery, University of Medicine, A-8036 Graz, Austria b Department of Pneumology, LKH Hörgas-Enzenbach, Austria c Department of Dermatology, University of Medicine, A-8036 Graz, Austria
KEYWORDS Pleural mesothelioma; Photodynamic therapy; Hyperbaric oxygenation
Summary Introduction: Surgical debulking followed by radiotherapy/chemotherapy are the standards in the palliative treatment schedule of malignant pleural mesothelioma. The aim of this study was to evaluate the additional effect of intraoperative photodynamic therapy (PDT) under hyperbaric oxygenation (HBO) if compared to decortication alone. Patients and methods: From January 1993 to August 2003, decortication was done in 34 patients (28 males, 6 females; mean age: 65 years) suffering from advanced malignant pleural mesothelioma. Twenty-two patients received additional intraoperative PDT under HBO. The surgery and PDT/HBO was done 48 h after photosensitization with a polyhematoporphyrin, 2 mg/kg BW using a diode laser delivering red light at 630 nm through a microlens. The light dose was calculated for 300 J at a distance of 1 cm from the tumour surface. Results: At 6-month follow-up the Karnofsky performance status showed no significant difference (P ≥ 0.05) between both groups. CT scans documented focal regrowth of the tumour after 6 months in 10/12 cases of the non-PDT group. However, in the PDT group tumour regrowth was detected in only 9/22 cases at 6-month follow-up. Survival analysis showed a significant advantage for the group with PDT (log-rank test: P = 0.0179). Conclusion: Although the study includes only a small number of patients, it indicates that additional PDT/HBO represents a safe and technically feasible approach in the palliative setting of advanced malignant mesothelioma of the pleura. © 2004 Published by Elsevier B.V.
Introduction ∗ Corresponding
author. Tel.: +43-31-63853302; fax: +43-31-63854679. E-mail address: [email protected] (F.M. Smolle-Jüttner). 1572-1000/$ – see front matter © 2004 Published by Elsevier B.V. doi:10.1016/S1572-1000(04)00009-2
Because of the long interval between the exposure to asbestos and its development an increasing incidence of malignant pleural mesothelioma is to be expected, creating a therapeutic challenge for any physician in the following 10—15 years.
58 Presently, there is no established curative approach for advanced malignant pleural mesothelioma. The results of extensive surgery i.e. pleuropneumonectomy, resection of the diaphragm and pericardium, carry high morbidity and/or mortality rates at a poor long-term survival. Nevertheless, surgical debulking followed by chemotherapy and external beam radiation increased the median survival to 11—22 months compared to 5—7 months with supportive care only [1,2]. Because of the lack of sufficient treatments, malignant pleural mesothelioma has become a model disease for the development of adjunctive treatment modalities. The efficacy of photodynamic therapy as a treatment protocol of malignant pleural mesothelioma has been described and established in several clinical studies [3—6]. Photodynamic therapy (PDT) is based on the illumination of malignant tissue after selective accumulation of photosensitizers in tumour cells. Photosensitizing agents can absorb photons of appropriate wavelength and become excited to a triplet species. The photon energy is transferred to ground state triplet oxygen producing the excited singlet oxygen (type II photo-oxygenation reaction). In the other type of photo-oxidative process (type I photo-oxygenation reaction) the excited sensitizer itself initiates a free radical reaction. Both types of reaction are associated with PDT. Potentially, they cause an acute necrosis of tumour in the illuminated tumour region [7]. In vitro experiments, however, have shown that oxygen is a key component in PDT. There is decreased cell sensitivity to PDT in the presence of low oxygen. Furthermore, animal tumour models have demonstrated an decreased and reduced effect to PDT under hypoxemic conditions [8,9]. The use of hyperbaric oxygenation (HBO) in this particular field of cancer treatment could be the key to obtaining high levels of molecular oxygen in tumour tissue in order to increase cytotoxicity. According to the experimental studies by Dong et al. [8], the use of HBO in PDT accelerates the photodynamic reaction by raising the transmission efficiency of light energy, increasing the quantum amount of oxygen and extending its radius of effective distance. In an experimental animal model, Jirsa et al. [9] studied the influence of HBO and PDT in tumour-bearing nude mice. They concluded that combining HBO and PDT improves the efficiency of PDT by increasing the depth of tumour cell damage, and/or by reducing the doses of sensitizers or–—potentially–—the duration of illumination. Especially in case of mesothelioma in which a large surface requires illumination during PDT a shorten-
V. Matzi et al. ing of the time of intervention by additional use of HBO would be desirable. The rationale of this clinical trial was to study both the technical feasibility and the efficacy of combined decortication of the pleura and intraoperative PDT under HBO. Main variables were considered as PDT associated side effects, morbidity/or mortality and survival time compared to debulking procedure alone.
Patients and methods In a prospective non-randomized clinical trial from January 1993 to August 2003, tumourectomy/decortication was done in 34 patients (28 males, 6 females; mean age: 65 years, range: 52—82 years), suffering from advanced malignant mesothelioma of the pleura. Twenty-two patients received additional intraoperative PDT under HBO. As there was no patient in whom a curative approach would have been possible, decortication combined with additional intracavitary PDT of residual tumour tissue was offered to all patients as an intention to treat on an experimental basis. However, since additional intracavitary PDT carries the disadvantage of long-lasting skin photosensitization (8—12 weeks) only 22 patients agreed to it. Therefore, patient selection for additional PDT was done according to signed informed consent.
Diagnostic work-up All patients suffered from dyspnea and chest pain caused by direct tumour expansion and pleural effusion associated to the tumour. Thirty-one patients had a history of asbestos exposure and 29 patients were heavy cigarette smokers. In presence of a tentative diagnosis made after initial radiological work-up including conventional chest roentgenograms and CT scan of the thorax, video-assisted diagnostic thoracoscopy (VATS) with pleural biopsy was done, confirming the diagnosis in all patients. Ipsilateral mediastinal lymphnode biopsy during the VATS procedure was performed, if technically feasible. Clinical staging revealed UICC III (T2 n = 22; T3 n = 12; N1 n = 14; N2 n = 20). Histological examination showed 21 epithelial, 11 biphasic and 2 sarcomatous subtypes. After establishing the definitive diagnosis CT scan of the abdomen and bone-scan completed the staging procedure. Additionally a PET scan was used in six patients.
Photodynamic therapy: clinical experience
59
Figure 1 Intraoperative view after tumourectomy/decortication and lymphadenectotomy of the upper mediastinum and the paracaval region.
Surgery In 34 patients, debulking and decortication was done through a posterolateral thoracotomy. All gross disease (up to 1200 g) was removed, leaving as little residual tumour as possible. Mediastinal lymph nodes were sampled routinely (Fig. 1). In two cases subtotal pericardiectomy followed by synthetic mesh reconstruction was done. In 22 cases, the treatment was completed by intraoperative PDT enhanced by HBO applied to all residual tumour surfaces (Fig. 2).
Figure 2
Pathological staging confirmed UICC stage III in all patients.
Intraoperative photodynamic therapy (PDT) under hyperbaric oxygenation (HBO) In order to achieve an optimum effect of the photosensitizer the operation was scheduled 48 h after intravenous application of 2 mg/kg BW of a polyhematoporphyrin (Photosan-3, Seehof Laboratory, Wesselburenkoog, Germany).
Intraoperative PDT under HBO in a walk-in hyperbaric chamber.
60
V. Matzi et al.
Figure 3
Six-months follow-up.
The operation was done in a hyperbaric chamber fully equipped as an operating theatre. After finishing decortication and lymphadenectomy, PDT was done by one surgeon, under hyperbaric oxygenation (100% oxygen, 2 ATA pressure). Transcutaneous pO2 -levels were used as an indirect indicator of the oxygen load. They rose from 59—77 mmHg (mean: 68 mmHg) under normobaric conditions to 500—750 mmHg (mean: 580 mmHg) tcpO2 -levels under 2 bar [10,11]. After a steady state of transcutaneous pO2 had been reached, PDT/HBO was started. Using a diode laser system (Ceramoptec® , Bonn, Germany) delivering red light at 630 nm through a microlens (PhotoDynamicTherapy® , Vienna, Austria), the light dose at the tumour surface was calculated as 300 J with a distance of 1 cm from the tumour surface. Illumination of the tumour area was done centimetre square per centimetre square of tumour surface using a microlens that was moved stepwise along a flexible sterile plastic grid. Depending on the topography and extent of the tumour area, the delivery time ranged from 40 to 60 min (median time: 50 min).
Follow-up Follow-up investigations were scheduled 3, 6 and 12 months after combined surgical resection ± intraoperative PDT/HBO comprising CT scans of the thorax and abdomen and assessment of changes in the quality of life, by using the Karnofsky index.
Statistical work-up The Chi-square test was used to compare paired values. Survival curves and their comparison were calculated with the help of the Kaplan—Meier survival table and the log-rank test.
Results At 6-months follow-up, dyspnea, pain, Kanofsky performance status, FVC1 and tumour regrowth were checked (Fig. 3). Comparison of CT scans 1 and 6 months postoperatively documented focal regrowth of the tumour in 10/12 cases of the non-PDT group. In the PDT group, tumour regrowth was detected in 9/22 patients. At 3-months follow-up, the overall subjective relief of symptoms such as dyspnea and pain was reported as substantial in 18/22 and in 4/22 as slight to moderate in the PDT group. In the non-PDT group relief of symptoms was reported as substantial in 7/12 and moderate in 5/12. At the time of admission the Karnofsky performance status showed a mean of 85.1 (range: 70—100) in the PDT group and 82.3 (range: 70—95) in the non-PDT group. At 3-months follow-up a significant improvement in both groups (P ≤ 0.05) with a mean of 95 (range: 90—100) in the PDT group and 92 (range 85—100) in the non-PDT group, respectively, could be achieved. In spite of the subjective relief of dyspnea and minimal recurrent pleural effusion, pulmonary function parameters (FVC, FVC1) before treatment, as well as at 6-months follow-up did not show any statistically significant differences (P ≥ 0.05) in either group.
Survival (Fig. 4) In the non-PDT group 10/12 patients died of their disease due to local tumour progression and distant metastases. Two patients are still alive 11 and 14 months after operation. In the PDT group 17/22 patients died from their disease, due to local tumour progression and/or distant metastases. Five patients are still alive at 9, 11, 12, 15 and 18 months, respectively, postoperatively.
Photodynamic therapy: clinical experience
61
Figure 4 Kaplan—Meier survival distribution of patients with pleural mesothelioma treated by decortication with and without PDT.
One-year survival rate was found to be 80 ± 12% in the PDT-treated group, compared to only 28 ± 17% in the non-PDT-treated group. Survival analysis showed a significant difference in favour of the PDT group (log-rank test: P = 0.0179).
Complications There were no major intra- or postoperative complications. The mean stay at the intensive care unit was 3 days (range from 1—7 days) and the mean estimated blood loss was 640 ml (range from 300—2400 ml). Nine patients required blood transfusions to maintain a haemoglobin of at least 12 g/l. Three patients needed mechanical respiratory support for more than 24 h (40 and 46 h). Air leaks could be observed in 28 patients, however, these closed spontaneously within 3—6 days. The patients were discharged from hospital between day 9 and day 20 (mean 14 days). In two cases with additional PDT a superficial dehiscence of the thoracotomy wound was present which, however, closed spontaneously under outpatient wound care. In one patient, re-admission, 4 weeks after discharge due to empyema became necessary. He could be successfully managed by open window thoracostomy. No major complications related to either to photosensitization, to PDT or to HBO were observed during or after the intervention.
Side effects included mild skin photosensensitivity in two patients who had neglected the instructions to avoid sunlight after PDT and to use a sun blocker for at least 12 weeks [10]. A single episode of fever up to 39 ◦ C in the afternoon after the PDT-procedure was observed in five patients. None of these effects required specific treatment.
Discussion Debulking and decortication are frequently used as palliative treatment in case of advanced malignant pleural mesothelioma. Local recurrences are almost unavoidable, as surrounding structures and the diffuse character of the tumour preclude an actually radical resection. Because of the low chemosensitivity of mesothelioma, and the difficulty of irradiating all areas, the additive use of radiotherapy and/or chemotherapy conveys little benefit [1,2]. Several reports suggested that malignant mesothelioma of the pleura would respond to PDT [3—6], an antitumour treatment characterized by high potential for selectivity, destroying tumour tissue along the path of monochromatic light, while sparing adjacent healthy structures. Therefore, it might be reasonable to use it in addition to debulking and/or pleuropneumonectomy to improve local control of the tumour. However, as mentioned in several reports [5,6], highly vulnerable structures
62 like the esophagus and the bronchial stump should be excluded from PDT to prevent fistula formation. PDT involves the interaction of photosensitizers, light and oxygen. Sensitizers–—originally in a low energy state–—are excited to a maximum by absorption of monochromatic light of appropriate wavelength and energy. In this energetic state, they react directly through a free radical mechanism, or indirectly via molecular oxygen which undergoes a spin-state transition to reactive singlet oxygen. The depth of penetration of monochromatic light–—about 5—7 mm–—limits the active range of the cytotoxic effect. Both pathways yield potentially cytotoxic compounds, although the singlet oxygen process is thought to be predominant in PDT [12,13] and oxygen has been shown to fuel the polyhematoporphyrin based photodynamic action in vitro [14]. Considering the interactions of photosensitizer, light and oxygen, with singlet oxygen as the final common mediator of photodynamic cytotoxicity, an enhanced tumouricidal effect may be achieved by increasing the amount of oxygen available for the photochemical reaction. This concept is of crucial importance, as PDT by itself induces reduced blood flow and causes a shutdown of tumour vessels resulting in hypoxia with decreased oxygen tension [15]. Therefore, a significant increase of oxygen by the use of hyperbaric oxygenation (HBO) in this concept seemed logical. Under HBO oxygen physically dissolves in all fluid components of the body, resulting in the fact that oxygenation is no longer dependent on the presence of red blood cells. Lambertson [16] determined that the arteriovenous oxygen gradient rises to 350 mmHg when 100% oxygen is breathed at 3 ATA in a typical tissue. Even in the presence of a 50% reduction of blood flow to the tissues, the corresponding values of capillary pO2 will be 288 mmHg. In spite of vasoconstriction and a bradycardia-induced reduction of the stroke volume which have been known as physiological side-effects of HBO, oxygenation is pushed to high levels of up to 1000—2000 pa O2 at 2 or 3 atm, respectively. In this context, HBO-induced vasoconstriction may be viewed as a regulatory mechanism to protect the healthy organs from exposure to excessive pO2 . A very important phenomenon in this concept is that the vasoconstrictor response does not take place in hypoxic tissue [17]. Transcutaneous pa O2 in our patients was lower than to be expected but it is a well known fact that the oxygen pressure recorded at the transcutaneous electrode tends to be lower than the true arterial pO2 due to the oxygen consumption of the skin itself [11]. Side effects of HBO may affect the central nervous system and the lung but they subside sponta-
V. Matzi et al. neously and are very rarely seen at pressures below 2 ATA and exposure times less than 90 min. Accordingly, we did not observe them in our patients. From the technical point of view, combined surgical treatment followed by PDT and HBO did not include any problems provided the laser light generator was positioned outside the hyperbaric chamber with only the fibre being exposed to the hyperbaric atmosphere. We did not observe any complications specifically related to intraoperative PDT and HBO. Even the most radical and aggressive surgical procedures could not serve the purpose of oncological success in patients with advanced malignant mesothelioma, whereas they are associated with severe morbidity and mortality. Therefore, PDT seems to be an additional option in palliative surgery of malignant mesothelioma to achieve an acceptable clinical outcome in at low morbidity. The statistically significant survival benefit as well as the longer interval to tumour recurrence in patients receiving additional PDT/HBO are explicable due to (a) the treatment of non-resected involved parts of the thoracic cavity i.e. the phrenic nerve, the pericardium, the diaphragm, the hilus and the lung, (b) the treatment of the mediastinum after systematic lymphadenectomy. In conclusion, the poor prognosis of advanced malignant mesothelioma of the pleura necessitates new treatment protocols. PDT represents a highly selective tumouricidal tool, whereby oxygen seems to be one of the keys to improve this additive therapy. Although the study includes only a small number of patients and hence does not allow definitive conclusions, it indicates that additional PDT under HBO represents a safe and technically feasible approach in the palliative setting of advanced malignant mesothelioma of the pleura and might improve the therapeutic result.
References [1] Aisner J. Current approach to malignant mesothelioma of the pleura. Chest 1995;107:332—44. [2] Sugarbaker D, Garcia J, Richards W. Extrapleural pneumonectomy in the multimodality therapy for malignant pleural mesothelioma: results in 120 consecutive patients. Ann Surg 1996;224:288—96. [3] Baas P, Murrer L, Zoetmulder FA. Photodynamic therapy as adjuvant therapy in surgically treated pleural malignancies. Br J Cancer 1997;76:819—26. [4] Pass HI, Temeck BK, Kranda K. Phase III randomized trial of surgery with or without intraoperative photodynamic therapy and postoperative immunochemotherapy for malignant pleural mesothelioma. Ann Surg Oncol 1997;4:628—33.
Photodynamic therapy: clinical experience [5] Ris H, Altermatt H, Nachbur B. Intraoperative photodynamic therapy with m-tetrahydroxypheylchlorin for chest malignancies. Lasers Surg Med 1996;18:39—45. [6] Friedberg JS, Mick R, Stevenson J, et al. A phase I study of foscan-mediated photodynamic therapy and surgery in patients with mesothelioma. Ann Thorac Surg 2003;75:952— 9. [7] Moan J, Peng Q, Sorensen R, Jani V, Nesland JM. Biophysical foundations of photodynamic therapy. Endoscopy 1998;30:387—91. [8] Dong GC, Hu SX, Zhao GY, Gao SZ, Wu LR. Experimental study on cytotoxic effects of hyperbaric oxygen and photodynamic therapy on mouse transplanted tumours. Chin Med J Engl 1987;100:697—702. [9] Jirsa Jr M, Pouckiva P, Dolezal J, Pospisil J, Jirsa M. Hyperbaric oxygen and photodynamic therapy in tumour bearing nude mice. Eur J Cancer 1991;27:109. [10] Maier A, Anegg U, Fell B, et al. Hyperbaric oxygen and photodynamic therapy in the treatment of advanced carcinoma of the cardia and the esophagus. Lasers Surg Med 2000;26:1—7. [11] Gray BJ, Heaton RW, Henderson A, Hutchinson DCS. In vivo calibration of a transcutaneous oxygen electrode in adult patients. In: Advances in experimental medicine and biology. New York and London: Plenum Press; 1987. p. 75—8. [12] Foote CS. Mechanism of photooxygenation. In: Doiron DR, Alan R, editors. Porphyrin localization and treatment of tumours. New York: Liss; 1984. p. 3. [13] Cortese DA, Kinsey GH. Endoscopic treatment of lung cancer with hematoporphyrin phototherapy. Mayo Clin Proc 1982;57:543—7. [14] Diamond I, Granelli SG, Mc Donough AF, Nielson S, Wilson CB, Jaenicke R. Photodynamic therapy of malignant tumours. Lancet 1972;2:117. [15] Wiemann TJ, Mang TS, Fingar VH. Effect of photodynamic therapy on blood flow in normal and tumour vessels. Surgery 1988;194:512—7. [16] Lambertson CJ. Effects of hyperoxygenation on organs and their tissues. In: Rubin E, editor. Extrapulmonary manifestation of respiratory disease. New York: Marcel Dekker; 1978. p. 239—303. [17] Jain KK. Textbook of hyperbaric medicine. 2nd rev. ed. Kirkland, WA, USA: Hogrefe & Huber Publishers.
Commentary by Professor Tom Treasure, MD, MS, Guy’s Hospital, London SE1 9RT, UK Malignant pleural mesothelioma is a cancer of the pleura which is in nearly all cases a direct consequence of exposure to asbestos. Because the relationship between the causative agent and the disease is so relatively tight, with asbestos exposure being almost an absolute requirement to get the disease, epidemiologists were able to predict the rise of this cancer from nearly 10 years ago with remarkable accuracy [1] by looking at the data for asbestos imports. When the figures were re-analysed for Europe 5 years ago the epidemic was very much on course as predicted [2] and the current estimates are that the number of UK mesothelioma deaths will peak at a level of between 1950 and 2450 deaths sometime between the year 2011 and 2015 [3] 50 years after the peak of the imports. The story in Eu-
63 rope is similar. The situation is better in the United States where asbestos imports were curtailed earlier, probably worse in Australia, and much worse in the third world where in many countries there is little or no control. So we will be seeing steadily more of this disease. Furthermore, as awareness increases we will see cases earlier and be expected to do more to help. In the 1960s when I was a student this was a rare disease with a hundred or so cases a year. It is now 20 times commoner and working in a thoracic unit we are seeing new patients with this cancer every week. It starts in the parietal pleura and creeps along, thickening the membranes and trapping the lung. It grows out invading the chest wall. It often interferes with the normal flow of pleural fluid so that what should be just sufficient fluid to moisten the lung and pleura as they move against each other, may become 2—3 l leaving little room to breath. Put together these cause the typical presenting features of worsening breathlessness and gnawing pain. Our goals in the treatment of cancer are to use whatever treatments we know are effective, in any combination tailored to that patient, with the paired objectives of getting the best we can for them in terms of quality and length of life. Applying these objectives in mesothelioma is a challenge. Our best treatments are only marginally effective. Even if used in combination the best results with combined chemotherapy, surgery and radiotherapy are modest and such trimodality therapy is only applicable to a few very selected cases [4]. We, therefore, welcome any advance or innovation with enthusiasm because what is on offer at present is not great. In that spirit the work of Smolle-Jüttner’s group is welcomed. Read their article for the technical details but in essence what they have been exploring is the use of photodynamic therapy under hyperbaric oxygenation to kill some of the cancer and reduce its volume; this is a strategy called ‘‘debulking’’. The principle is that the volume of the cancer is in itself a detrimental factor and that the greater the bulk the less impact chemotherapy can make. Surgical debulking of a cancer spreading in the chest wall is every bit as crude as it sounds and the bleeding and lung injury that ensue adds morbidity to an already sick patient. More selective or targeted strategies may have something to offer. Smolle-Jüttner’s and colleagues think it does and they seek to persuade us in this important contribution to the care of patients with mesothelioma. The start of a new journal, however, gives me an opportunity to lay down a challenge–—to subject your treatments to proper trials [5]. As surgeons we were mocked by the Editor of The Lancet when
64 he described in headlines our efforts in surgical research as ‘‘Comic Opera’’ [6]. In this paper a new treatment is compared with an alternative in a way that lends itself to serious scientific doubt about the claims made. There is said to be a survival advantage and yet the basic principle of a clinical trial has been breached; the allocation was not randomised. We know that very different survival can be seen in different groups of mesothelioma patients [7]. The course of the disease is very long and very varied. Unrecognised differences in stage at entry, rate of progression, and lead time bias can produce big survival differences at least as large as in this study. The randomisation of patients between treatment arms is not easy and requires scientific conviction and an honest presentation to the patient but that is what our patients deserve under all circumstances. In my view it is not an option; it is essential. Big break throughs are now improbable. Small gains are hard to recognise amongst the heterogeneity of the cases and the trade off of survival time versus its quality. Those involved in photodynamic therapy and its evaluation should all study the Medical Research Council’s publication on Health Technology Assessement [5] and if cancer surgeons are not prepared to accept what is said by a very serious group of clinical research workers, read one of the most cogent explanation of the importance trials in cancer, by John Diamond [8] a journalist who died very publicly from cancer. How else can we get evidence if we continue to engage in substandard research methods [9]? If it is deemed unethical to allocate patients by chance the counter argument is that it
V. Matzi et al. is utterly unethical not to; the consequence of erroneous claims is promulgating treatments that do more harm than good to some patients. These patients are in the last months of their lives. The next 2—3 months are probably the best and we should not use them up on ineffective treatments. Let me now at the debut of this new journal ask that these new technologies are evaluated as early as possible in their evaluation within scientifically constructed trials and that your new Journal makes that a hallmark of quality.
References [1] Peto J, Hodgson JT, Matthews FE, Jones JR. Continuing increase in mesothelioma mortality in Britain. Lancet 1995;345:535—9. [2] Peto J, Decarli A, La Vecohia C, Levi F, Negri E. The European mesothelioma epidemic. Br J Cancer 1999;79:666—72. [3] UK Health and Safety Executive data on asbestos. Available at: http://www.hse.gov.uk/statistics/causdis/ asbestos.htm. UK Health and Safety Executive; 2004. [4] Treasure T, Waller D, Swift S, Peto J. Radical surgery for mesothelioma. BMJ 2004;328:237—8. [5] Lilford R, et al. Health technology assessment in surgery. London: Medical Research Council; 2003. [6] Horton R. Surgical research or comic opera: questions, but few answers. Lancet 1996;347:984—5. [7] Tan C, Swift S, Gilham C, Shaeti S, Fountain SW, Peto J, et al. Survival in surgically diagnosed patients with malignant mesothelioma in current practice. Thorax 2002;57iii:iii36. [8] Diamond JC. Because cowards get cancer too. London: Vermilion; 1998. [9] Treasure T, Swift S, Tan C. Radical surgery for mesothelioma: how can we obtain evidence? World J Surg 2003;27:891—4.
Photodynamic therapy enhanced by hyperbaric oxygenation in palliation of malignant pleural mesothelioma: clinical experience Veronika Matzi a , Alfred Maier a , Oliver Sankin a , Jörg Lindenmann a , Michael Woltsche b , J. Smolle c , Freyja Maria Smolle-Jüttner, MD (Professor) a,* a
Division of Thoracic and Hyperbaric Surgery, Department of Surgery, University of Medicine, A-8036 Graz, Austria b Department of Pneumology, LKH Hörgas-Enzenbach, Austria c Department of Dermatology, University of Medicine, A-8036 Graz, Austria
KEYWORDS Pleural mesothelioma; Photodynamic therapy; Hyperbaric oxygenation
Summary Introduction: Surgical debulking followed by radiotherapy/chemotherapy are the standards in the palliative treatment schedule of malignant pleural mesothelioma. The aim of this study was to evaluate the additional effect of intraoperative photodynamic therapy (PDT) under hyperbaric oxygenation (HBO) if compared to decortication alone. Patients and methods: From January 1993 to August 2003, decortication was done in 34 patients (28 males, 6 females; mean age: 65 years) suffering from advanced malignant pleural mesothelioma. Twenty-two patients received additional intraoperative PDT under HBO. The surgery and PDT/HBO was done 48 h after photosensitization with a polyhematoporphyrin, 2 mg/kg BW using a diode laser delivering red light at 630 nm through a microlens. The light dose was calculated for 300 J at a distance of 1 cm from the tumour surface. Results: At 6-month follow-up the Karnofsky performance status showed no significant difference (P ≥ 0.05) between both groups. CT scans documented focal regrowth of the tumour after 6 months in 10/12 cases of the non-PDT group. However, in the PDT group tumour regrowth was detected in only 9/22 cases at 6-month follow-up. Survival analysis showed a significant advantage for the group with PDT (log-rank test: P = 0.0179). Conclusion: Although the study includes only a small number of patients, it indicates that additional PDT/HBO represents a safe and technically feasible approach in the palliative setting of advanced malignant mesothelioma of the pleura. © 2004 Published by Elsevier B.V.
Introduction ∗ Corresponding
author. Tel.: +43-31-63853302; fax: +43-31-63854679. E-mail address: [email protected] (F.M. Smolle-Jüttner). 1572-1000/$ – see front matter © 2004 Published by Elsevier B.V. doi:10.1016/S1572-1000(04)00009-2
Because of the long interval between the exposure to asbestos and its development an increasing incidence of malignant pleural mesothelioma is to be expected, creating a therapeutic challenge for any physician in the following 10—15 years.
58 Presently, there is no established curative approach for advanced malignant pleural mesothelioma. The results of extensive surgery i.e. pleuropneumonectomy, resection of the diaphragm and pericardium, carry high morbidity and/or mortality rates at a poor long-term survival. Nevertheless, surgical debulking followed by chemotherapy and external beam radiation increased the median survival to 11—22 months compared to 5—7 months with supportive care only [1,2]. Because of the lack of sufficient treatments, malignant pleural mesothelioma has become a model disease for the development of adjunctive treatment modalities. The efficacy of photodynamic therapy as a treatment protocol of malignant pleural mesothelioma has been described and established in several clinical studies [3—6]. Photodynamic therapy (PDT) is based on the illumination of malignant tissue after selective accumulation of photosensitizers in tumour cells. Photosensitizing agents can absorb photons of appropriate wavelength and become excited to a triplet species. The photon energy is transferred to ground state triplet oxygen producing the excited singlet oxygen (type II photo-oxygenation reaction). In the other type of photo-oxidative process (type I photo-oxygenation reaction) the excited sensitizer itself initiates a free radical reaction. Both types of reaction are associated with PDT. Potentially, they cause an acute necrosis of tumour in the illuminated tumour region [7]. In vitro experiments, however, have shown that oxygen is a key component in PDT. There is decreased cell sensitivity to PDT in the presence of low oxygen. Furthermore, animal tumour models have demonstrated an decreased and reduced effect to PDT under hypoxemic conditions [8,9]. The use of hyperbaric oxygenation (HBO) in this particular field of cancer treatment could be the key to obtaining high levels of molecular oxygen in tumour tissue in order to increase cytotoxicity. According to the experimental studies by Dong et al. [8], the use of HBO in PDT accelerates the photodynamic reaction by raising the transmission efficiency of light energy, increasing the quantum amount of oxygen and extending its radius of effective distance. In an experimental animal model, Jirsa et al. [9] studied the influence of HBO and PDT in tumour-bearing nude mice. They concluded that combining HBO and PDT improves the efficiency of PDT by increasing the depth of tumour cell damage, and/or by reducing the doses of sensitizers or–—potentially–—the duration of illumination. Especially in case of mesothelioma in which a large surface requires illumination during PDT a shorten-
V. Matzi et al. ing of the time of intervention by additional use of HBO would be desirable. The rationale of this clinical trial was to study both the technical feasibility and the efficacy of combined decortication of the pleura and intraoperative PDT under HBO. Main variables were considered as PDT associated side effects, morbidity/or mortality and survival time compared to debulking procedure alone.
Patients and methods In a prospective non-randomized clinical trial from January 1993 to August 2003, tumourectomy/decortication was done in 34 patients (28 males, 6 females; mean age: 65 years, range: 52—82 years), suffering from advanced malignant mesothelioma of the pleura. Twenty-two patients received additional intraoperative PDT under HBO. As there was no patient in whom a curative approach would have been possible, decortication combined with additional intracavitary PDT of residual tumour tissue was offered to all patients as an intention to treat on an experimental basis. However, since additional intracavitary PDT carries the disadvantage of long-lasting skin photosensitization (8—12 weeks) only 22 patients agreed to it. Therefore, patient selection for additional PDT was done according to signed informed consent.
Diagnostic work-up All patients suffered from dyspnea and chest pain caused by direct tumour expansion and pleural effusion associated to the tumour. Thirty-one patients had a history of asbestos exposure and 29 patients were heavy cigarette smokers. In presence of a tentative diagnosis made after initial radiological work-up including conventional chest roentgenograms and CT scan of the thorax, video-assisted diagnostic thoracoscopy (VATS) with pleural biopsy was done, confirming the diagnosis in all patients. Ipsilateral mediastinal lymphnode biopsy during the VATS procedure was performed, if technically feasible. Clinical staging revealed UICC III (T2 n = 22; T3 n = 12; N1 n = 14; N2 n = 20). Histological examination showed 21 epithelial, 11 biphasic and 2 sarcomatous subtypes. After establishing the definitive diagnosis CT scan of the abdomen and bone-scan completed the staging procedure. Additionally a PET scan was used in six patients.
Photodynamic therapy: clinical experience
59
Figure 1 Intraoperative view after tumourectomy/decortication and lymphadenectotomy of the upper mediastinum and the paracaval region.
Surgery In 34 patients, debulking and decortication was done through a posterolateral thoracotomy. All gross disease (up to 1200 g) was removed, leaving as little residual tumour as possible. Mediastinal lymph nodes were sampled routinely (Fig. 1). In two cases subtotal pericardiectomy followed by synthetic mesh reconstruction was done. In 22 cases, the treatment was completed by intraoperative PDT enhanced by HBO applied to all residual tumour surfaces (Fig. 2).
Figure 2
Pathological staging confirmed UICC stage III in all patients.
Intraoperative photodynamic therapy (PDT) under hyperbaric oxygenation (HBO) In order to achieve an optimum effect of the photosensitizer the operation was scheduled 48 h after intravenous application of 2 mg/kg BW of a polyhematoporphyrin (Photosan-3, Seehof Laboratory, Wesselburenkoog, Germany).
Intraoperative PDT under HBO in a walk-in hyperbaric chamber.
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Figure 3
Six-months follow-up.
The operation was done in a hyperbaric chamber fully equipped as an operating theatre. After finishing decortication and lymphadenectomy, PDT was done by one surgeon, under hyperbaric oxygenation (100% oxygen, 2 ATA pressure). Transcutaneous pO2 -levels were used as an indirect indicator of the oxygen load. They rose from 59—77 mmHg (mean: 68 mmHg) under normobaric conditions to 500—750 mmHg (mean: 580 mmHg) tcpO2 -levels under 2 bar [10,11]. After a steady state of transcutaneous pO2 had been reached, PDT/HBO was started. Using a diode laser system (Ceramoptec® , Bonn, Germany) delivering red light at 630 nm through a microlens (PhotoDynamicTherapy® , Vienna, Austria), the light dose at the tumour surface was calculated as 300 J with a distance of 1 cm from the tumour surface. Illumination of the tumour area was done centimetre square per centimetre square of tumour surface using a microlens that was moved stepwise along a flexible sterile plastic grid. Depending on the topography and extent of the tumour area, the delivery time ranged from 40 to 60 min (median time: 50 min).
Follow-up Follow-up investigations were scheduled 3, 6 and 12 months after combined surgical resection ± intraoperative PDT/HBO comprising CT scans of the thorax and abdomen and assessment of changes in the quality of life, by using the Karnofsky index.
Statistical work-up The Chi-square test was used to compare paired values. Survival curves and their comparison were calculated with the help of the Kaplan—Meier survival table and the log-rank test.
Results At 6-months follow-up, dyspnea, pain, Kanofsky performance status, FVC1 and tumour regrowth were checked (Fig. 3). Comparison of CT scans 1 and 6 months postoperatively documented focal regrowth of the tumour in 10/12 cases of the non-PDT group. In the PDT group, tumour regrowth was detected in 9/22 patients. At 3-months follow-up, the overall subjective relief of symptoms such as dyspnea and pain was reported as substantial in 18/22 and in 4/22 as slight to moderate in the PDT group. In the non-PDT group relief of symptoms was reported as substantial in 7/12 and moderate in 5/12. At the time of admission the Karnofsky performance status showed a mean of 85.1 (range: 70—100) in the PDT group and 82.3 (range: 70—95) in the non-PDT group. At 3-months follow-up a significant improvement in both groups (P ≤ 0.05) with a mean of 95 (range: 90—100) in the PDT group and 92 (range 85—100) in the non-PDT group, respectively, could be achieved. In spite of the subjective relief of dyspnea and minimal recurrent pleural effusion, pulmonary function parameters (FVC, FVC1) before treatment, as well as at 6-months follow-up did not show any statistically significant differences (P ≥ 0.05) in either group.
Survival (Fig. 4) In the non-PDT group 10/12 patients died of their disease due to local tumour progression and distant metastases. Two patients are still alive 11 and 14 months after operation. In the PDT group 17/22 patients died from their disease, due to local tumour progression and/or distant metastases. Five patients are still alive at 9, 11, 12, 15 and 18 months, respectively, postoperatively.
Photodynamic therapy: clinical experience
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Figure 4 Kaplan—Meier survival distribution of patients with pleural mesothelioma treated by decortication with and without PDT.
One-year survival rate was found to be 80 ± 12% in the PDT-treated group, compared to only 28 ± 17% in the non-PDT-treated group. Survival analysis showed a significant difference in favour of the PDT group (log-rank test: P = 0.0179).
Complications There were no major intra- or postoperative complications. The mean stay at the intensive care unit was 3 days (range from 1—7 days) and the mean estimated blood loss was 640 ml (range from 300—2400 ml). Nine patients required blood transfusions to maintain a haemoglobin of at least 12 g/l. Three patients needed mechanical respiratory support for more than 24 h (40 and 46 h). Air leaks could be observed in 28 patients, however, these closed spontaneously within 3—6 days. The patients were discharged from hospital between day 9 and day 20 (mean 14 days). In two cases with additional PDT a superficial dehiscence of the thoracotomy wound was present which, however, closed spontaneously under outpatient wound care. In one patient, re-admission, 4 weeks after discharge due to empyema became necessary. He could be successfully managed by open window thoracostomy. No major complications related to either to photosensitization, to PDT or to HBO were observed during or after the intervention.
Side effects included mild skin photosensensitivity in two patients who had neglected the instructions to avoid sunlight after PDT and to use a sun blocker for at least 12 weeks [10]. A single episode of fever up to 39 ◦ C in the afternoon after the PDT-procedure was observed in five patients. None of these effects required specific treatment.
Discussion Debulking and decortication are frequently used as palliative treatment in case of advanced malignant pleural mesothelioma. Local recurrences are almost unavoidable, as surrounding structures and the diffuse character of the tumour preclude an actually radical resection. Because of the low chemosensitivity of mesothelioma, and the difficulty of irradiating all areas, the additive use of radiotherapy and/or chemotherapy conveys little benefit [1,2]. Several reports suggested that malignant mesothelioma of the pleura would respond to PDT [3—6], an antitumour treatment characterized by high potential for selectivity, destroying tumour tissue along the path of monochromatic light, while sparing adjacent healthy structures. Therefore, it might be reasonable to use it in addition to debulking and/or pleuropneumonectomy to improve local control of the tumour. However, as mentioned in several reports [5,6], highly vulnerable structures
62 like the esophagus and the bronchial stump should be excluded from PDT to prevent fistula formation. PDT involves the interaction of photosensitizers, light and oxygen. Sensitizers–—originally in a low energy state–—are excited to a maximum by absorption of monochromatic light of appropriate wavelength and energy. In this energetic state, they react directly through a free radical mechanism, or indirectly via molecular oxygen which undergoes a spin-state transition to reactive singlet oxygen. The depth of penetration of monochromatic light–—about 5—7 mm–—limits the active range of the cytotoxic effect. Both pathways yield potentially cytotoxic compounds, although the singlet oxygen process is thought to be predominant in PDT [12,13] and oxygen has been shown to fuel the polyhematoporphyrin based photodynamic action in vitro [14]. Considering the interactions of photosensitizer, light and oxygen, with singlet oxygen as the final common mediator of photodynamic cytotoxicity, an enhanced tumouricidal effect may be achieved by increasing the amount of oxygen available for the photochemical reaction. This concept is of crucial importance, as PDT by itself induces reduced blood flow and causes a shutdown of tumour vessels resulting in hypoxia with decreased oxygen tension [15]. Therefore, a significant increase of oxygen by the use of hyperbaric oxygenation (HBO) in this concept seemed logical. Under HBO oxygen physically dissolves in all fluid components of the body, resulting in the fact that oxygenation is no longer dependent on the presence of red blood cells. Lambertson [16] determined that the arteriovenous oxygen gradient rises to 350 mmHg when 100% oxygen is breathed at 3 ATA in a typical tissue. Even in the presence of a 50% reduction of blood flow to the tissues, the corresponding values of capillary pO2 will be 288 mmHg. In spite of vasoconstriction and a bradycardia-induced reduction of the stroke volume which have been known as physiological side-effects of HBO, oxygenation is pushed to high levels of up to 1000—2000 pa O2 at 2 or 3 atm, respectively. In this context, HBO-induced vasoconstriction may be viewed as a regulatory mechanism to protect the healthy organs from exposure to excessive pO2 . A very important phenomenon in this concept is that the vasoconstrictor response does not take place in hypoxic tissue [17]. Transcutaneous pa O2 in our patients was lower than to be expected but it is a well known fact that the oxygen pressure recorded at the transcutaneous electrode tends to be lower than the true arterial pO2 due to the oxygen consumption of the skin itself [11]. Side effects of HBO may affect the central nervous system and the lung but they subside sponta-
V. Matzi et al. neously and are very rarely seen at pressures below 2 ATA and exposure times less than 90 min. Accordingly, we did not observe them in our patients. From the technical point of view, combined surgical treatment followed by PDT and HBO did not include any problems provided the laser light generator was positioned outside the hyperbaric chamber with only the fibre being exposed to the hyperbaric atmosphere. We did not observe any complications specifically related to intraoperative PDT and HBO. Even the most radical and aggressive surgical procedures could not serve the purpose of oncological success in patients with advanced malignant mesothelioma, whereas they are associated with severe morbidity and mortality. Therefore, PDT seems to be an additional option in palliative surgery of malignant mesothelioma to achieve an acceptable clinical outcome in at low morbidity. The statistically significant survival benefit as well as the longer interval to tumour recurrence in patients receiving additional PDT/HBO are explicable due to (a) the treatment of non-resected involved parts of the thoracic cavity i.e. the phrenic nerve, the pericardium, the diaphragm, the hilus and the lung, (b) the treatment of the mediastinum after systematic lymphadenectomy. In conclusion, the poor prognosis of advanced malignant mesothelioma of the pleura necessitates new treatment protocols. PDT represents a highly selective tumouricidal tool, whereby oxygen seems to be one of the keys to improve this additive therapy. Although the study includes only a small number of patients and hence does not allow definitive conclusions, it indicates that additional PDT under HBO represents a safe and technically feasible approach in the palliative setting of advanced malignant mesothelioma of the pleura and might improve the therapeutic result.
References [1] Aisner J. Current approach to malignant mesothelioma of the pleura. Chest 1995;107:332—44. [2] Sugarbaker D, Garcia J, Richards W. Extrapleural pneumonectomy in the multimodality therapy for malignant pleural mesothelioma: results in 120 consecutive patients. Ann Surg 1996;224:288—96. [3] Baas P, Murrer L, Zoetmulder FA. Photodynamic therapy as adjuvant therapy in surgically treated pleural malignancies. Br J Cancer 1997;76:819—26. [4] Pass HI, Temeck BK, Kranda K. Phase III randomized trial of surgery with or without intraoperative photodynamic therapy and postoperative immunochemotherapy for malignant pleural mesothelioma. Ann Surg Oncol 1997;4:628—33.
Photodynamic therapy: clinical experience [5] Ris H, Altermatt H, Nachbur B. Intraoperative photodynamic therapy with m-tetrahydroxypheylchlorin for chest malignancies. Lasers Surg Med 1996;18:39—45. [6] Friedberg JS, Mick R, Stevenson J, et al. A phase I study of foscan-mediated photodynamic therapy and surgery in patients with mesothelioma. Ann Thorac Surg 2003;75:952— 9. [7] Moan J, Peng Q, Sorensen R, Jani V, Nesland JM. Biophysical foundations of photodynamic therapy. Endoscopy 1998;30:387—91. [8] Dong GC, Hu SX, Zhao GY, Gao SZ, Wu LR. Experimental study on cytotoxic effects of hyperbaric oxygen and photodynamic therapy on mouse transplanted tumours. Chin Med J Engl 1987;100:697—702. [9] Jirsa Jr M, Pouckiva P, Dolezal J, Pospisil J, Jirsa M. Hyperbaric oxygen and photodynamic therapy in tumour bearing nude mice. Eur J Cancer 1991;27:109. [10] Maier A, Anegg U, Fell B, et al. Hyperbaric oxygen and photodynamic therapy in the treatment of advanced carcinoma of the cardia and the esophagus. Lasers Surg Med 2000;26:1—7. [11] Gray BJ, Heaton RW, Henderson A, Hutchinson DCS. In vivo calibration of a transcutaneous oxygen electrode in adult patients. In: Advances in experimental medicine and biology. New York and London: Plenum Press; 1987. p. 75—8. [12] Foote CS. Mechanism of photooxygenation. In: Doiron DR, Alan R, editors. Porphyrin localization and treatment of tumours. New York: Liss; 1984. p. 3. [13] Cortese DA, Kinsey GH. Endoscopic treatment of lung cancer with hematoporphyrin phototherapy. Mayo Clin Proc 1982;57:543—7. [14] Diamond I, Granelli SG, Mc Donough AF, Nielson S, Wilson CB, Jaenicke R. Photodynamic therapy of malignant tumours. Lancet 1972;2:117. [15] Wiemann TJ, Mang TS, Fingar VH. Effect of photodynamic therapy on blood flow in normal and tumour vessels. Surgery 1988;194:512—7. [16] Lambertson CJ. Effects of hyperoxygenation on organs and their tissues. In: Rubin E, editor. Extrapulmonary manifestation of respiratory disease. New York: Marcel Dekker; 1978. p. 239—303. [17] Jain KK. Textbook of hyperbaric medicine. 2nd rev. ed. Kirkland, WA, USA: Hogrefe & Huber Publishers.
Commentary by Professor Tom Treasure, MD, MS, Guy’s Hospital, London SE1 9RT, UK Malignant pleural mesothelioma is a cancer of the pleura which is in nearly all cases a direct consequence of exposure to asbestos. Because the relationship between the causative agent and the disease is so relatively tight, with asbestos exposure being almost an absolute requirement to get the disease, epidemiologists were able to predict the rise of this cancer from nearly 10 years ago with remarkable accuracy [1] by looking at the data for asbestos imports. When the figures were re-analysed for Europe 5 years ago the epidemic was very much on course as predicted [2] and the current estimates are that the number of UK mesothelioma deaths will peak at a level of between 1950 and 2450 deaths sometime between the year 2011 and 2015 [3] 50 years after the peak of the imports. The story in Eu-
63 rope is similar. The situation is better in the United States where asbestos imports were curtailed earlier, probably worse in Australia, and much worse in the third world where in many countries there is little or no control. So we will be seeing steadily more of this disease. Furthermore, as awareness increases we will see cases earlier and be expected to do more to help. In the 1960s when I was a student this was a rare disease with a hundred or so cases a year. It is now 20 times commoner and working in a thoracic unit we are seeing new patients with this cancer every week. It starts in the parietal pleura and creeps along, thickening the membranes and trapping the lung. It grows out invading the chest wall. It often interferes with the normal flow of pleural fluid so that what should be just sufficient fluid to moisten the lung and pleura as they move against each other, may become 2—3 l leaving little room to breath. Put together these cause the typical presenting features of worsening breathlessness and gnawing pain. Our goals in the treatment of cancer are to use whatever treatments we know are effective, in any combination tailored to that patient, with the paired objectives of getting the best we can for them in terms of quality and length of life. Applying these objectives in mesothelioma is a challenge. Our best treatments are only marginally effective. Even if used in combination the best results with combined chemotherapy, surgery and radiotherapy are modest and such trimodality therapy is only applicable to a few very selected cases [4]. We, therefore, welcome any advance or innovation with enthusiasm because what is on offer at present is not great. In that spirit the work of Smolle-Jüttner’s group is welcomed. Read their article for the technical details but in essence what they have been exploring is the use of photodynamic therapy under hyperbaric oxygenation to kill some of the cancer and reduce its volume; this is a strategy called ‘‘debulking’’. The principle is that the volume of the cancer is in itself a detrimental factor and that the greater the bulk the less impact chemotherapy can make. Surgical debulking of a cancer spreading in the chest wall is every bit as crude as it sounds and the bleeding and lung injury that ensue adds morbidity to an already sick patient. More selective or targeted strategies may have something to offer. Smolle-Jüttner’s and colleagues think it does and they seek to persuade us in this important contribution to the care of patients with mesothelioma. The start of a new journal, however, gives me an opportunity to lay down a challenge–—to subject your treatments to proper trials [5]. As surgeons we were mocked by the Editor of The Lancet when
64 he described in headlines our efforts in surgical research as ‘‘Comic Opera’’ [6]. In this paper a new treatment is compared with an alternative in a way that lends itself to serious scientific doubt about the claims made. There is said to be a survival advantage and yet the basic principle of a clinical trial has been breached; the allocation was not randomised. We know that very different survival can be seen in different groups of mesothelioma patients [7]. The course of the disease is very long and very varied. Unrecognised differences in stage at entry, rate of progression, and lead time bias can produce big survival differences at least as large as in this study. The randomisation of patients between treatment arms is not easy and requires scientific conviction and an honest presentation to the patient but that is what our patients deserve under all circumstances. In my view it is not an option; it is essential. Big break throughs are now improbable. Small gains are hard to recognise amongst the heterogeneity of the cases and the trade off of survival time versus its quality. Those involved in photodynamic therapy and its evaluation should all study the Medical Research Council’s publication on Health Technology Assessement [5] and if cancer surgeons are not prepared to accept what is said by a very serious group of clinical research workers, read one of the most cogent explanation of the importance trials in cancer, by John Diamond [8] a journalist who died very publicly from cancer. How else can we get evidence if we continue to engage in substandard research methods [9]? If it is deemed unethical to allocate patients by chance the counter argument is that it
V. Matzi et al. is utterly unethical not to; the consequence of erroneous claims is promulgating treatments that do more harm than good to some patients. These patients are in the last months of their lives. The next 2—3 months are probably the best and we should not use them up on ineffective treatments. Let me now at the debut of this new journal ask that these new technologies are evaluated as early as possible in their evaluation within scientifically constructed trials and that your new Journal makes that a hallmark of quality.
References [1] Peto J, Hodgson JT, Matthews FE, Jones JR. Continuing increase in mesothelioma mortality in Britain. Lancet 1995;345:535—9. [2] Peto J, Decarli A, La Vecohia C, Levi F, Negri E. The European mesothelioma epidemic. Br J Cancer 1999;79:666—72. [3] UK Health and Safety Executive data on asbestos. Available at: http://www.hse.gov.uk/statistics/causdis/ asbestos.htm. UK Health and Safety Executive; 2004. [4] Treasure T, Waller D, Swift S, Peto J. Radical surgery for mesothelioma. BMJ 2004;328:237—8. [5] Lilford R, et al. Health technology assessment in surgery. London: Medical Research Council; 2003. [6] Horton R. Surgical research or comic opera: questions, but few answers. Lancet 1996;347:984—5. [7] Tan C, Swift S, Gilham C, Shaeti S, Fountain SW, Peto J, et al. Survival in surgically diagnosed patients with malignant mesothelioma in current practice. Thorax 2002;57iii:iii36. [8] Diamond JC. Because cowards get cancer too. London: Vermilion; 1998. [9] Treasure T, Swift S, Tan C. Radical surgery for mesothelioma: how can we obtain evidence? World J Surg 2003;27:891—4.