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Brain photodiagnosis (PD), fluorescence guided resection (FGR) and photodynamic therapy (PDT): Past, present and future
Photodiagnosis and Photodynamic Therapy (2008) 5, 29—35
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REVIEW
Brain photodiagnosis (PD), fluorescence guided resection (FGR) and photodynamic therapy (PDT): Past, present and future M. Sam Eljamel MD, FRCSIr&ED(SN) ∗ Department of Neurosurgery, South Block, Level 6, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK
KEYWORDS Brain tumours; Gliomas; Photodynamic detection; Photodynamic resection
∗
Summary Intracranial tumours are an excellent target for photodiagnosis (PD), fluorescence guided resection (FGR) and photodynamic therapy (PDT), because the tumour to brain ratio of photosensitizers’ concentration is very high. However, several attempts of proving the value of PDT in the most malignant type of brain tumours, gliobastoma multeforme (GBM) failed to demonstrate any significant worthwhile survival advantage in the past because of the very nature of this cancer and several compounding factors that led to this apparent disappointing outcome; variations in the photosensitizer and light dosages, variations in the photosensitizer administration to treatment time-intervals, and variations in photosensitizers used are just few to mention in this article. However, after a very long gestation period of brain PD, FGR and PDT, three randomized controlled trials (RCT) in brain PD, FGR and PDT were concluded by 2007. The first trial demonstrated that time to tumour progression (TTP) was significantly longer in patients who had PD and FGR compared to standard surgical resection but this difference did not translate into survival advantage in GBM due to the variability in the management of recurrent tumours and significant residual tumour cells left after FGR in about a third of patients leading to GBM relapse. The second trial compared single shot PDT in GBM and standard therapy. Neither the treatment nor the control group received PD or FGR. Again this RCT did not provide any survival advantage in patients who had had PDT due to the fact that standard surgical resection had left significant residual tumour in a large number of patients canceling any potential benefit from PDT. The last trial compared combined PD, FGR and repetitive PDT and standard therapy and confirmed that TTP was significantly longer in the treatment group and demonstrated that the treatment group had significant survival advantage in GBM. In conclusion, PD, FGR and PDT need to be combined to be effective in brain tumours and in the future, we will see more and more scientific evidence accumulating in support of brain PD, FGR and PDT. The next decade will see further refinement and evolution of the techniques and technology employed and expansion of the indications of brain PD, FGR and PDT. © 2008 Elsevier B.V. All rights reserved.
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30
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Contents Brain PD, FGR and PDT, the past........................................................................................... Brain PD, FGR and PDT, the present ....................................................................................... Brain PD, FGR and PDT, the future......................................................................................... Appendix A ................................................................................................................ References ................................................................................................................
Brain PD, FGR and PDT, the past ‘‘Whoso neglects learning in his youth, loses the past and is dead for the future.’’ Euripides Brain photodiagnosis (PD) and photodynamic therapy (PDT) began in the early seventies with its first application in the laboratory using glioma cell cultures [1—8] and animal models of gliomas and gliosacaromas [9—18]. The primary endpoints of these experimental laboratory studies were to prove the concept of PD and PDT, that these tumour cells can preferentially uptake and retain the photosensitizers and to prove that these agents were not toxic or carcinogenic. The overall conclusion of this early pioneering work was that both PD and PDT had consistent anti-tumour effects and that glioma cells preferentially taken-up and retained the photosensitizers making these tumour cells potential targets for PD and PDT treatment. These experimental endeavours paved the way to phase I/II studies in brain tumours. In 1980, one of the early pioneering researchers in brain PDT had reported their series of post-resection glioma cavity PDT and predicted that future refinement of the technique may produce better tissue penetration and more radical glioma cell-kill [19]. Five years later an Australian group led by Andrew Kaye [20] reported a phase I/II trial involving 23 patients, of which there were 13 newly diagnosed glioblastomas (GBM), 6 recurrent GBM, 2 newly diagnosed anaplastic astrocytomas (AA) and 1 recurrent AA. These authors used hematoporphyrin derivative (HPD) administered 24 h before treatment at a dose of 5 mg/kg body weight. PDT treatment was administered following tumour debulking. The tumour cavity was irradiated with 630 nm laser light without a balloon-diffuser. Two different lasers were used to deliver the light and the light-dose varied from 70 to 230 J/cm2 . Sixty-eight percent of their patients developed new tumours and underwent radiotherapy (20 Gy). Fifty-seven percent of the recurrent gliomas developed further recurrences 12—16 weeks after PDT and 13% of the newly diagnosed gliomas developed recurrences at 3 and 13 weeks from PDT. Fifteen patients had no recurrences at a mean follow up of 7 months. These authors concluded that PDT can be used as an adjuvant therapy in these patients. In 1988, an Austrian group led by Herwig Kostron [21] reported their series of 20 patients including 18 GBM treated with a wavelength of 630 nm and 40—120 J/cm2 . This was followed immediately by a single dose of radiation. Conventional radiotherapy followed in eight patients. The median survival of three recurrent GBM was 5 months and four of the newly diagnosed
30 31 32 33 34
GBM died because of tumour recurrence with a median survival of 5 months. However, six of their patients were still alive 12 months after PDT and six patients were still alive at 22 months. This was a very encouraging outcome, considering that the mean survival of these patients at the time was less than 12 months and the 2-year survival was less than 7.5%. The Canadian experience was reported in 1991 (Muller and Wilson) [22], that included 49 patients treated with PDT. These were young patients (mean age of 41) with a mean KPS of 79, who had recurrent malignant gliomas. Thirty-two were GBM, 14 were AA, 6 were mixed and 4 were malignant ependymomas. The total light-dose in this series varied from 440 to 4500 J (median 1800 J) and the energy density varied from 8 to 110 J/cm 2 . The median survival of recurrent GBM was 30 weeks with a 1-year survival of 18%. The 1-year survival of GBM from first diagnosis was 82% and at 2 years the survival was 57%, which was significantly better than the 2-year survival of less than 7.5% following standard treatment. For recurrent AA, the median survival was 44 weeks and the 1-year and 2-year survival was 43% and 36%, respectively. In 1993 another group [23] reported their experience using image-guided computer assisted protocol to improve treatment volume coverage and pointed out that treatment failure was often due to lack of tumour coverage by the treatment and limited tissue penetration of the laser light. These authors had demonstrated that combining intracavity photo-illumination with peritumoral interstitial PDT was possible and could achieve better tumour-volume coverage. By 1996 [24], over 310 patients with newly diagnosed or recurrent malignant gliomas were treated with PDT after tumour resection (Fig. 1). Though there was wide variation in the light-dose, the photosensitizer dose, the completeness of surgical resection, the patients’ age, the KPS and the number of treatments received, meta-analysis of these data indicated that PDT significantly increased the survival of patients with malignant gliomas and that brain PDT was well tolerated. However, there were several compounding factors that led to inconsistency and variability of the outcome of brain PDT. 1. The volume of residual tumour after surgical resection in those patients treated by PDT was significantly large for PDT to cope with. 2. The uniformity of light illumination of the post-resection cavities was not possible due to: i. Variable geometry of the post-resection cavities and that not all cavities were spherical. ii. Infolding of the walls of these post-surgical cavities creating shadows.
Brain PD, FGR and PDT, past, present and future
Figure 1 The average survival of GBM treated with PDT in phase I/II trials before 1996 compared to standard treatment (the Y-axis represents survival in weeks).
iii. Significant and variable light scatter from the medium within these cavities. 3. The variability of the Laser fibres, Laser types and Laser dosages used. 4. The variability of the photosensitizers’ types and dosages.
Brain PD, FGR and PDT, the present ‘‘IF we open a quarrel between the past and the present, we shall find that we have lost the future.’’ Sir Winston Churchill Reviewing what had been done in the two decades prior to 1996 (the past), summarised in the aforementioned section, it was apparent that a number of improvements had to be made if brain PD, fluorescence guided resection (FGR) and PDT have any chance of competing for their rightful place among the surgical armamentarium against these tumours. Therefore, it seems logical that the first and foremost step in this field should be to find a way to achieve more radical tumour resection of these unpleasant locally malignant cancers of the brain for PDT to work. However, the most limiting factor to achieve complete surgical resection safely is the inability of the surgeons’ eyes to distinguish normal brain from tumour cells under normal surgical microscopy at the periphery of the tumour. In 1998, a group of investigators in Germany led by Walter Stummer [25] reported the utilization of PD and FGR to achieve maximum tumour removal safely with 100% specificity and 85% sensitivity. In more than 60% of 52 consecutive patients, the surgeons managed to completely excise the enhancing tumour on MRI scans [25]. Coupling this technology with the surgical microscope, had led to improved completeness of the resection of these tumours. In 2005, the Royal Melbourne Hospital’s experience including 375 patients was published [26]. There were 138 newly diagnosed GBM, 140 recurrent GBM, 41 newly diagnosed AA and 46 recurrent AA. Long-term analysis was available for 145 patients: 31 newly diagnosed GBM, 55 recurrent GBM, 30 newly diagnosed AA and 29 recurrent AA [26]. These patients received 5 mg HPD/kg body weight 24 h before surgery and the light-dose was 70—260 J/cm2 using a bare fibre inserted in the middle of the tumour cav-
31 ity without a balloon-diffuser. Twenty-nine percent of these patients received adjuvant chemotherapy. The mean survival of newly diagnosed GBM was 14.3 months and 28% survived more than 2 years. The mean survival of newly diagnosed AA was 76.5 months and 73% survived more than 36 months. The mean survival of recurrent GBM was 14.9 months with 2- and 3-year survival of 41% and 37%, respectively. The mean survival of recurrent AA was 66.6 months and the 2- and 3-year survival was 61% and 57%, respectively. The complication rate was 1.4% cerebral infarction, 6.2% cerebral oedema and 1.4% sunburns. The HPD tumour uptake varied from 2 to 13 g/g of wet tissue. The HPD uptake correlated to GBM outcome (p < 0.01) and the higher the dose of light, the better the outcome was (p < 0.03). However, a North American prospective randomized trial of patients between 40 and 120 J/cm2 found that the survival of the high dose (48 patients) was 10 months compared to 9 months in the low dose group (49 patients). This difference did not reach statistical significance at 0.05. However, the light-dose used was half the dose used by the Melbourne group, which would explain the difference in the responsedose relationship. In 2006 Kostron et al. [27] reported their experience of combining PD, FGR and PDT using FOSCAN® (meta-tetrahydroxyphenylchlorin—–mTHPC) in 26 patients. They used 0.15 mg Foscan per kg body weight and intraoperative 20 J/cm2 at 652 nm laser. The PD sensitivity was 87.9%, and the specificity was 95.7% with complete resection rate of the enhancing tumour in 75% compared to 52% in matched controls. The median survival of these 26 patients was 9 months compared to merely 3.5 months of matched controls. In recent years, three PD, FGR and PDT randomized controlled trials (RCT) were completed in brain tumours. In 2006, the ALA-study group in Germany [28] reported the results of a multicentre prospective randomized controlled trial using ALA-induced FGR and a two centre randomised controlled study [29] was reported using adjuvant Photofrin® PDT in the study group and in 2007, Eljamel et al. (2007) [30] reported a single centre prospective randomized controlled study using ALA and Photofrin® . All these three trials were performed in the most difficult tumour type to eradicate, the GBM. The ALA-study group reported PD and FGR led to complete removal of the enhancing tumour on MRI in 65% (90/139) of patients compared to 36% when standard microscopic techniques were used (p < 0.001) [28]. This trial had also demonstrated that the time to tumour progression (TTP) of the PD and FGR group was much better than that of the control group; 5.1 months in the PD and FGR group compared to 3.6 months in the controls (p < 0.001). Sadly, this difference in tumour-free survival did not translate into any significant difference in the overall survival. There were a number of possible compounding and mitigating factors that led to no significant difference in survival between the study and control groups. The trial’s primary endpoint was completeness of resection and TTP meant that the trial could be stopped prematurely once there was TTP advantage in any arm of the trial; that was what actually happened in this trial when the study arm was found to have achieved TTP advantage, the data monitoring committee had no choice but to stop the trial prematurely. There was no control for postresection adjuvant therapy upon tumour recurrence meant that therapy after tumour recurrence was not equivalent in the two groups. Finally not all tumour cells enhance on
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Figure 2 Comparison of recent treatment developments in GBM treatment with standard therapy (S: surgery alone, S + RT: surgery and radiotherapy, TZD: temazolamide treatment in addition to S and RT, Gl: Gliadel (carmustine) implants in addition to S + RT, PD: 5-ALA PD in addition to S and RT, PDT: Photofrin® PDT in addition to S + RT and PD/PDT: 5-ALA and fractionated PDT in addition to S and RT). All bars represent percent of overall survival except those marked * which represent tumour-free survival.
MRI scans and therefore relapses may still occur even when post-operative MRI demonstrated complete resection. The single Photofrin® PDT treatment study [29] demonstrated that more patients survived for 12 months of the group who received adjuvant PDT (17/43, 39.5%) compared to those who had not had PDT (9/33, 27.3%). Sadly, the survival curves crossed over at 15 months. Nevertheless the quality of survival in the treatment group was better than that in the controls. Again this trial was well designed but because the resection was performed without PD or FGR, realistically maximum tumour resection could have been achieved in only 25—35% of the patients in the study. This significant residual tumour was sufficient to cancel any potential gain from PDT. Furthermore, the light-dose was relatively low. The last study [30] combined the techniques of ALA and Photofrin® induced fluorescence assisted surgical resection (PD, FGR), PpIX spectroscopy and repetitive PDT up to a total dose of 500 J/cm2 divided into five fractions demonstrated that patients in the study group had significant survival, quality of life improvement and time to tumour progression advantages compared to the control group (p < 0.01). Therefore, the outcome of adjuvant PD, FGR and PDT techniques in GBM is in favour of brain PD/PDT (Fig. 2). Two of the aforementioned prospective randomized controlled trials demonstrated that TTP in GBM was significantly prolonged (p < 0.01) with PD and FGR compared to standard neurosurgical resection under white light microsurgery [28,30]. Phase I/II studies on PDT in malignant brain tumours were in favour of PDT on the basis of prolonging survival. However, the results of PD/PDT randomized controlled trials in GBM were divided regarding long-term survival. The ALA-study group [28] was not designed to look ahead for the overall survival. The authors did not control for adjuvant therapy following recurrence such as chemotherapy and further surgery. The second trial, conducted in North America, demonstrated that the initial survival advantage with single shot PDT was lost at 15 months. There were several reasons for this: a light-dose of 120 J/cm2 may not be sufficient, light-dose distribution may not have been uniform, the use of KTP pumped dye laser with a wavelength of 532 nm (ideally for Photofrin® a wavelength of 630 nm is preferred) and lastly the Photofrin® was injected 12—36 h prior
M.S. Eljamel to surgery. All these factors may have contributed to the failure of this trial to demonstrate survival advantage in the study group despite all phase I/II trials having demonstrated significant survival advantages in both newly diagnosed and recurrent GBM. However, the most likely compounding factor for the negative result of this particular study is the fact that significant residual tumour would have been left in the majority of patients as none of the groups had their tumour resected using PD/FGR techniques. Combining PD and PDT was shown in none randomised study to be beneficial [27]. The last study [30] demonstrated significant prolongation of the TTP in the study group and significant good quality survival in the study group, the critics pointed out that the study was single centre and used two photodynamic techniques and one cannot be sure which part of the technique (PD or PDT) was more significant. However, the fact that the study was performed in a single centre was a strength as the most difficult variable to control for in any surgical trial is patient selection and the surgical technique itself. It is less likely that there was significant variation in the equipoise for randomization or the surgical technique in a single centre study. The reason that the two techniques were tested together is also important as the efficacy of PDT would be dependant on the amount of residual tumour left behind. PD, FGR and PDT therefore go hand in hand. PD, FGR has already been shown to help in removing the residual tumour in 65% compared to only 36% using conventional techniques [28]. Combining both ALA and Photofrin® enhances PD and FGR as tumour fluorescence was more obvious to the extent it could be visualised by the naked eye. Similarly both photosensitizers have PDT effect. Furthermore, the use of spherical/cylindrical balloon-diffuser prevents shadows by preventing tumour cavity from infolding and the presence of the intralipid led to uniform illumination of the tumour walls [31]. The details of combining PD, FGR and repetitive PDT in brain tumours currently in use at Ninewells Hospital and Medical School, Dundee, Scotland, are summarised in Appendix A.
Brain PD, FGR and PDT, the future ‘‘The present is the ever moving shadow that divides yesterday from tomorrow. In that lies hope.’’ Frank Lloyd Wright (1867—1959) There is enough categories I/II evidence in support of PD, FGR and PDT in brain tumours and it is only a matter of time before PD, FGR and PDT becomes widely available to these patients as an option of management. As patients become aware of its existence and availability, patients and their families will demand it and undergo it in preference of its competitive therapies. I had patients come from farther a field seeking this target specific modality of treatment in preference to chemotherapy and radiotherapy. However, there is still a long road ahead in brain PD, FGR and PDT and many questions remain unanswered; How does PD, FGR and PDT interacts with other therapies, e.g. intraoperative radiotherapy? How can we reduce systemic photosensitivity and phototoxicity? How can we deliver a uniform homogeneous light-dose such as using implanted light emitting diodes of the correct bandwidth or metronomic PDT to
Brain PD, FGR and PDT, past, present and future improve the results? What is the role of PD, FGR and PDT in brain using other photosensitizers such as mTHPC, Hyperycin, Phtalocyanin, clorin e6 and boronated porphyrins? What is the role of PD, FGR and PDT in other intracranial and spinal indications such as pituitary adenomas, brain metastasis, skull base tumours and other intracranial tumours? All these questions are being investigated in several centres around the globe and discussion of early work in these areas of brain PD, PDT and PDT is beyond the scope of this article. Finally the future of PD, FGR and PDT in brain is dependent on further improvements and refinements of current technology and its wider availability at a reasonable cost.
Appendix A
33 Table 1 tumours
Timeline of PD, FGR and repetitive PDT in brain
Time to surgery
Tasks to be completed
48 h before surgery
2 mg/kg body weight Photofrin® is given via slow IV injection.
24 h before surgery
Preoperative planning MRI scan is performed for neuronavigation with skin fiducial-markers in place. The surgeon plans the surgical approach and rehearses the surgical approach on the workstation.
3 h before surgery
20 mg/kg body weight ALA in 30 ml of non-fizzy orange juice is given orally.
0 h time of surgery
Patient anaesthetised.a Cefruxime 1.5 g IV—–antibiotic prophylaxis. Dexamethazone 4 mg IV is given. The location of craniotomy is marked using neuronavigation. Perform craniotomy using image guidance. 100 ml of 20% mannitol is given over 20 min IV. Remove the easily recognisable bulk of the tumour using microscope, ultrasonic dissector and suction. Remove the rest of the tumour using PD and FGR techniques till no more tumour fluorescence is observedb . Inflate a balloon-diffuser—–using 0.32% intralipid solution till the balloon fills the resection cavity. Measure the diameter of the balloon-diffuser. Calculate the time required to provide 100 J/cm2 using Table 2. Recover the patient from anaesthesia. First dose of PDT 100 J/cm2 .
24 h post surgery 48 h post surgery 72 h post surgery
Second dose of PDT 100 J/cm2 . Third dose of PDT 100 J/cm2 . Fourth dose of PDT 100 J/cm2 .
96 h post surgery
Fifth dose of PDT 100 J/cm2 . Remove the balloon-diffuser.
Patient selection It is very important that PD, FGR and PDT are only offered to patients who are likely to benefit from this therapy. Patients undergoing PD, FGR and PDT brain must fulfill all the following inclusions criteria and none of the following exclusion criteria.
Inclusion criteria • Diagnosis of high grade glioma (HGG, including GBM and anaplastic astrocytomas, anaplastic oligodendroglioma, ependymomas, and primary cerebral lymphoma, recurrent HGG, brain metastasis). • Male or female subjects undergoing debulking of tumour via craniotomy. • Eighteen years of age or older. • Karnofsky performance status score over 60. • Able to give informed consent.
Exclusion criteria • Any history of photodermatosis such as erythropoietic protoporphyria. • History of disorders of the hepatic, or renal system. • Major medical or psychiatric illness. • Female who is pregnant or breast feeding. • Patients unable to give informed consent.
Surgical technique Preoperative screening A patient diagnosed on MRI and MRI spectroscopy with malignant brain tumour is counseled, and management options including the benefits and the risks of each option are discussed. If surgical resection was agreed to be the treatment plan, adjuvant PD, FGR and PDT is discussed including the risk of skin and retinal photosensitivity and essential photoprotection requirement. If the patients accepted PD, FGR and PDT as part of their treatment the following timeline is followed (Table 1).
a During anaesthesia most anaesthetists of today routinely monitor oxygen saturation during the craniotomy and thereafter. After ALA and Photofrin® administration it is essential that oxygen saturation is performed intermittently to avoid skin burns from the LED of the pulse-oxymeter. b PD and FGR is performed by attaching Olympus blue light source (370—440 nm) to 0 degree rigid Storz endoscope with a longpass observation filter (440 nm) and PDD camera system (Olympus).
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Table 2 PDT grid to calculate light-dose according to the size of the balloon-diffuser and the Laser fibre diffuser to give 100 J/cm2 Balloon-diffuser diameter (cm)
Laser fibre length (cm)
Laser power (mW)
Irradiance (mW/cm2 )
PDT duration (s)
0.5 0.75 1 1.25 1.5 1.75 2 2.25 2.5 3
1 1 1 1 1.5 1.5 1.5 1.5 2.5 2.5
400 400 400 400 600 600 600 600 1000 1000
509 226 127 81 85 62 48 38 51 35
196 442 785 1227 1178 1604 2094 2651 1963 2827
References [1] Tsai JC, Hsiao YY, Teng LJ, Chen CT, Kao MC. Comparative study on the ALA photodynamic effects of human glioma and meningioma cells. Lasers Surg Med 1999;24:296—305. [2] Stummer W, Stocker S, Novotny A, et al. In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid. J Photochem Photobiol 1998;45: 160—9. [3] Sreenivasan R, Muruganandham M, Sharma M, Joshi PG, Joshi NB. Binding of monometric and oligomeric porphyrins to human glioblastoma (U-87MG) cells and their photosensitivity. Cancer Lett 1997;120:45—51. [4] Abernathey CD, Anderson RE, Kooistra KL, Laws Jr ER. Activity of phthalocyanine against human Glioblastoma in vitro. Neurosurgery 1987;21:468—73. [5] Powers SK, Wlastad DL, Brown JT, Detty M, Watkins PJ. Photosensitization of human glioma cells by chalcogenapylium dyes. J Neurol Oncol 1989;7:179—88. [6] Sharma M, Joshi PG, Joshi NB. MC540 induced photosensitization of glioma and neuroblastoma cells. Ind J Med Res 1994;99:124—8. [7] Leach MW, Higgins RJ, Autry SA, Boggan JE, Lee SJ, Smith KM. In vitro photodynamic effects of lysyl chlorine p6; cell survival localization and ultrastructural changes. Photochem Photobiol 1993;58:653—60. [8] Wharen Jr RE, So S, Anderson RE, Laws Jr ER. Hematoporphyrin derivative photocutotoxicity of human Glioblastoma in cell culture. Neurosurgery 1986;19:495—501. [9] Lilge L, Olivo MC, Schatz SW, MaGuire JA, Wilson BC. The sensitivity of normal brain and intracranially implanted ZX2 tumor to interstitial photodynamic therapy. Br J Cancer 1996;73:332—43. [10] Whelan HT, Schmidt MH, Segura AD, et al. The role of photodynamic therapy in posterior fossa brain tumors, a preclinical study in a canine glioma model. J Neurosurg 1993;79:568—82. [11] Ji Y, Walstad D, Brown JT, Powers SK. Improved survival from intracavitary photodynamic therapy of rat glioma. Photochem Photobiol 1992;46:385—90. [12] Leach MW, Higgins RJ, Boggan JE, Lee SJ, Autry S, Smith KM. Effectiveness of a lysyl chlorine p6/chlorine p6 mixture in photodynamic therapy of the subcutaneous 9L glioma in the rat. Can Res 1992;52:1235—9. [13] Powers SK, Beckman Jr WC, Brown JT, Kolpack LC. Interstitial laser photochemotherapy of rhodamine 123 sensitized rat glioma. J Neurosurg 1987;67:889—94. [14] Kostron H, Swartz MR, Miller DC, Martuza RL. The interaction of hematoporphyrin derivative, light and ionizing radiation in a rat glioma model. Cancer 1986;57:964—70.
[15] Kaye AH, Morstyn G, Ashcroft RG. Uptake and retention of hematoporphyrin derivative in an in vivo/in vitro model of cerebral glioma. Neurosurgery 1985;17:883—90. [16] Cheng MK, McKean J, Mieke B, Tulip J, Boisvert D. Photoradiation therapy of 9L gliosarcoma in rats; hematoporphyrin derivative (type I & II) followed by laser energy. J Neuroncol 1985;3:217—28. [17] Rounds DE, Doiron DR, Jacques DB, Shelden CH, Olson RS. Phototoxicity of brain tissue in hematoporphyrin derivative treated mice. Prog Clin Biol Res 1984;170:613—28. [18] Boggan JE, Edwards MS, Bolger CA, Berns MW, Walter RJ. Hematoporphyrin derivative photoradiation therapy of the rat 9L gliosarcoma brain tumor model. Lasers Surg Med 1984;4:99—105. [19] Perria C, Capuzzo T, Cavagnaro G, et al. Fast attempts at the photodynamic treatment of human gliomas. J Neurosurg Sci 1980;24:119—29. [20] Kaye AH, Morstyn G, Brownbill D. Adjuvant high-dose photoradiation therapy in the treatment of cerebral glioma, a phase I/II study. J Neurosurg 1987;67:500—5. [21] Kostron H, Fritsch E, Grunert V. Photodynamic therapy of malignant brain tumors; a phase I/II trial. Br J Neurosurg 1988;2:241—8. [22] Muller P, Wilson B. Photodynamic therapy of brain tumourspostoperative field fractionation. J Photochem Photobiol 1991;9:117—9. [23] Origitano TC, Reichman OH. Photodynamic therapy for intracranial neoplasms; development of an image-based computer assisted protocol for photodynamic therapy of intracranial neoplasms. Neurosurgery 1993;32:587—95. [24] Kostron H, Obwegeser A, Jakober R. Photodynmaic therapy in neurosurgery, a review. J Photochem Photobiol Biol 1996;36:157—68. [25] Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen HJ. Fluorescence guided resection of Glioblastoma multiforme by using 5-aminolevulenic acid induced porphyrins; a prospective study in 52 consecutive patients. J Neurosurg 2000;93:1003—13. [26] Stylli SS, Kaye AH, MacGregor L, Howes M, Rajendra P. Photodynamic therapy of high grade glioma—–long term survival. J Clin Neurosci 2005;12:389—98. [27] Kostron H, Fiegele T, Akatuna E. Combination of FOSCAN® mediated fluorescence guided resection and photodynamic treatment as new therapeutic concept for malignant brain tumors. Med Las Appl 2006;21:285—90. [28] Stummer W, Pitchimeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomized controlled multicentre phase III trial. Lancet Oncol 2006;7:392—401.
Brain PD, FGR and PDT, past, present and future [29] Muller P. Photodynamic therapy in brain tumors, work in progress. In: Proceedings of the International Photodynamic Therapy Symposium. October 2006. [30] Eljamel M, Goodman C, Moseley H. ALA and photofrin fluorescence guided resection and repetitive PDT in glioblastomas multiforme: a single centre Phase III randomized controlled
35 trial. Lasers Med Sci 2007;October 10:DOI 10:1007/s10103-0070494-2. [31] Moseley H, Mclean C, Hockaday S, Eljamel M. In vitro light distributions from intracranial PDT balloons. Photodiag Photodyn Therapy 2007;4:213—20.
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journal homepage: www.elsevier.com/locate/pdpdt
REVIEW
Brain photodiagnosis (PD), fluorescence guided resection (FGR) and photodynamic therapy (PDT): Past, present and future M. Sam Eljamel MD, FRCSIr&ED(SN) ∗ Department of Neurosurgery, South Block, Level 6, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK
KEYWORDS Brain tumours; Gliomas; Photodynamic detection; Photodynamic resection
∗
Summary Intracranial tumours are an excellent target for photodiagnosis (PD), fluorescence guided resection (FGR) and photodynamic therapy (PDT), because the tumour to brain ratio of photosensitizers’ concentration is very high. However, several attempts of proving the value of PDT in the most malignant type of brain tumours, gliobastoma multeforme (GBM) failed to demonstrate any significant worthwhile survival advantage in the past because of the very nature of this cancer and several compounding factors that led to this apparent disappointing outcome; variations in the photosensitizer and light dosages, variations in the photosensitizer administration to treatment time-intervals, and variations in photosensitizers used are just few to mention in this article. However, after a very long gestation period of brain PD, FGR and PDT, three randomized controlled trials (RCT) in brain PD, FGR and PDT were concluded by 2007. The first trial demonstrated that time to tumour progression (TTP) was significantly longer in patients who had PD and FGR compared to standard surgical resection but this difference did not translate into survival advantage in GBM due to the variability in the management of recurrent tumours and significant residual tumour cells left after FGR in about a third of patients leading to GBM relapse. The second trial compared single shot PDT in GBM and standard therapy. Neither the treatment nor the control group received PD or FGR. Again this RCT did not provide any survival advantage in patients who had had PDT due to the fact that standard surgical resection had left significant residual tumour in a large number of patients canceling any potential benefit from PDT. The last trial compared combined PD, FGR and repetitive PDT and standard therapy and confirmed that TTP was significantly longer in the treatment group and demonstrated that the treatment group had significant survival advantage in GBM. In conclusion, PD, FGR and PDT need to be combined to be effective in brain tumours and in the future, we will see more and more scientific evidence accumulating in support of brain PD, FGR and PDT. The next decade will see further refinement and evolution of the techniques and technology employed and expansion of the indications of brain PD, FGR and PDT. © 2008 Elsevier B.V. All rights reserved.
Tel.: +44 1382 660111x35712; fax: +44 1382 496202. E-mail address: [email protected]. URL: http://www.dundee.ac.uk/neurosurgery.
1572-1000/$ — see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.pdpdt.2008.01.006
30
M.S. Eljamel
Contents Brain PD, FGR and PDT, the past........................................................................................... Brain PD, FGR and PDT, the present ....................................................................................... Brain PD, FGR and PDT, the future......................................................................................... Appendix A ................................................................................................................ References ................................................................................................................
Brain PD, FGR and PDT, the past ‘‘Whoso neglects learning in his youth, loses the past and is dead for the future.’’ Euripides Brain photodiagnosis (PD) and photodynamic therapy (PDT) began in the early seventies with its first application in the laboratory using glioma cell cultures [1—8] and animal models of gliomas and gliosacaromas [9—18]. The primary endpoints of these experimental laboratory studies were to prove the concept of PD and PDT, that these tumour cells can preferentially uptake and retain the photosensitizers and to prove that these agents were not toxic or carcinogenic. The overall conclusion of this early pioneering work was that both PD and PDT had consistent anti-tumour effects and that glioma cells preferentially taken-up and retained the photosensitizers making these tumour cells potential targets for PD and PDT treatment. These experimental endeavours paved the way to phase I/II studies in brain tumours. In 1980, one of the early pioneering researchers in brain PDT had reported their series of post-resection glioma cavity PDT and predicted that future refinement of the technique may produce better tissue penetration and more radical glioma cell-kill [19]. Five years later an Australian group led by Andrew Kaye [20] reported a phase I/II trial involving 23 patients, of which there were 13 newly diagnosed glioblastomas (GBM), 6 recurrent GBM, 2 newly diagnosed anaplastic astrocytomas (AA) and 1 recurrent AA. These authors used hematoporphyrin derivative (HPD) administered 24 h before treatment at a dose of 5 mg/kg body weight. PDT treatment was administered following tumour debulking. The tumour cavity was irradiated with 630 nm laser light without a balloon-diffuser. Two different lasers were used to deliver the light and the light-dose varied from 70 to 230 J/cm2 . Sixty-eight percent of their patients developed new tumours and underwent radiotherapy (20 Gy). Fifty-seven percent of the recurrent gliomas developed further recurrences 12—16 weeks after PDT and 13% of the newly diagnosed gliomas developed recurrences at 3 and 13 weeks from PDT. Fifteen patients had no recurrences at a mean follow up of 7 months. These authors concluded that PDT can be used as an adjuvant therapy in these patients. In 1988, an Austrian group led by Herwig Kostron [21] reported their series of 20 patients including 18 GBM treated with a wavelength of 630 nm and 40—120 J/cm2 . This was followed immediately by a single dose of radiation. Conventional radiotherapy followed in eight patients. The median survival of three recurrent GBM was 5 months and four of the newly diagnosed
30 31 32 33 34
GBM died because of tumour recurrence with a median survival of 5 months. However, six of their patients were still alive 12 months after PDT and six patients were still alive at 22 months. This was a very encouraging outcome, considering that the mean survival of these patients at the time was less than 12 months and the 2-year survival was less than 7.5%. The Canadian experience was reported in 1991 (Muller and Wilson) [22], that included 49 patients treated with PDT. These were young patients (mean age of 41) with a mean KPS of 79, who had recurrent malignant gliomas. Thirty-two were GBM, 14 were AA, 6 were mixed and 4 were malignant ependymomas. The total light-dose in this series varied from 440 to 4500 J (median 1800 J) and the energy density varied from 8 to 110 J/cm 2 . The median survival of recurrent GBM was 30 weeks with a 1-year survival of 18%. The 1-year survival of GBM from first diagnosis was 82% and at 2 years the survival was 57%, which was significantly better than the 2-year survival of less than 7.5% following standard treatment. For recurrent AA, the median survival was 44 weeks and the 1-year and 2-year survival was 43% and 36%, respectively. In 1993 another group [23] reported their experience using image-guided computer assisted protocol to improve treatment volume coverage and pointed out that treatment failure was often due to lack of tumour coverage by the treatment and limited tissue penetration of the laser light. These authors had demonstrated that combining intracavity photo-illumination with peritumoral interstitial PDT was possible and could achieve better tumour-volume coverage. By 1996 [24], over 310 patients with newly diagnosed or recurrent malignant gliomas were treated with PDT after tumour resection (Fig. 1). Though there was wide variation in the light-dose, the photosensitizer dose, the completeness of surgical resection, the patients’ age, the KPS and the number of treatments received, meta-analysis of these data indicated that PDT significantly increased the survival of patients with malignant gliomas and that brain PDT was well tolerated. However, there were several compounding factors that led to inconsistency and variability of the outcome of brain PDT. 1. The volume of residual tumour after surgical resection in those patients treated by PDT was significantly large for PDT to cope with. 2. The uniformity of light illumination of the post-resection cavities was not possible due to: i. Variable geometry of the post-resection cavities and that not all cavities were spherical. ii. Infolding of the walls of these post-surgical cavities creating shadows.
Brain PD, FGR and PDT, past, present and future
Figure 1 The average survival of GBM treated with PDT in phase I/II trials before 1996 compared to standard treatment (the Y-axis represents survival in weeks).
iii. Significant and variable light scatter from the medium within these cavities. 3. The variability of the Laser fibres, Laser types and Laser dosages used. 4. The variability of the photosensitizers’ types and dosages.
Brain PD, FGR and PDT, the present ‘‘IF we open a quarrel between the past and the present, we shall find that we have lost the future.’’ Sir Winston Churchill Reviewing what had been done in the two decades prior to 1996 (the past), summarised in the aforementioned section, it was apparent that a number of improvements had to be made if brain PD, fluorescence guided resection (FGR) and PDT have any chance of competing for their rightful place among the surgical armamentarium against these tumours. Therefore, it seems logical that the first and foremost step in this field should be to find a way to achieve more radical tumour resection of these unpleasant locally malignant cancers of the brain for PDT to work. However, the most limiting factor to achieve complete surgical resection safely is the inability of the surgeons’ eyes to distinguish normal brain from tumour cells under normal surgical microscopy at the periphery of the tumour. In 1998, a group of investigators in Germany led by Walter Stummer [25] reported the utilization of PD and FGR to achieve maximum tumour removal safely with 100% specificity and 85% sensitivity. In more than 60% of 52 consecutive patients, the surgeons managed to completely excise the enhancing tumour on MRI scans [25]. Coupling this technology with the surgical microscope, had led to improved completeness of the resection of these tumours. In 2005, the Royal Melbourne Hospital’s experience including 375 patients was published [26]. There were 138 newly diagnosed GBM, 140 recurrent GBM, 41 newly diagnosed AA and 46 recurrent AA. Long-term analysis was available for 145 patients: 31 newly diagnosed GBM, 55 recurrent GBM, 30 newly diagnosed AA and 29 recurrent AA [26]. These patients received 5 mg HPD/kg body weight 24 h before surgery and the light-dose was 70—260 J/cm2 using a bare fibre inserted in the middle of the tumour cav-
31 ity without a balloon-diffuser. Twenty-nine percent of these patients received adjuvant chemotherapy. The mean survival of newly diagnosed GBM was 14.3 months and 28% survived more than 2 years. The mean survival of newly diagnosed AA was 76.5 months and 73% survived more than 36 months. The mean survival of recurrent GBM was 14.9 months with 2- and 3-year survival of 41% and 37%, respectively. The mean survival of recurrent AA was 66.6 months and the 2- and 3-year survival was 61% and 57%, respectively. The complication rate was 1.4% cerebral infarction, 6.2% cerebral oedema and 1.4% sunburns. The HPD tumour uptake varied from 2 to 13 g/g of wet tissue. The HPD uptake correlated to GBM outcome (p < 0.01) and the higher the dose of light, the better the outcome was (p < 0.03). However, a North American prospective randomized trial of patients between 40 and 120 J/cm2 found that the survival of the high dose (48 patients) was 10 months compared to 9 months in the low dose group (49 patients). This difference did not reach statistical significance at 0.05. However, the light-dose used was half the dose used by the Melbourne group, which would explain the difference in the responsedose relationship. In 2006 Kostron et al. [27] reported their experience of combining PD, FGR and PDT using FOSCAN® (meta-tetrahydroxyphenylchlorin—–mTHPC) in 26 patients. They used 0.15 mg Foscan per kg body weight and intraoperative 20 J/cm2 at 652 nm laser. The PD sensitivity was 87.9%, and the specificity was 95.7% with complete resection rate of the enhancing tumour in 75% compared to 52% in matched controls. The median survival of these 26 patients was 9 months compared to merely 3.5 months of matched controls. In recent years, three PD, FGR and PDT randomized controlled trials (RCT) were completed in brain tumours. In 2006, the ALA-study group in Germany [28] reported the results of a multicentre prospective randomized controlled trial using ALA-induced FGR and a two centre randomised controlled study [29] was reported using adjuvant Photofrin® PDT in the study group and in 2007, Eljamel et al. (2007) [30] reported a single centre prospective randomized controlled study using ALA and Photofrin® . All these three trials were performed in the most difficult tumour type to eradicate, the GBM. The ALA-study group reported PD and FGR led to complete removal of the enhancing tumour on MRI in 65% (90/139) of patients compared to 36% when standard microscopic techniques were used (p < 0.001) [28]. This trial had also demonstrated that the time to tumour progression (TTP) of the PD and FGR group was much better than that of the control group; 5.1 months in the PD and FGR group compared to 3.6 months in the controls (p < 0.001). Sadly, this difference in tumour-free survival did not translate into any significant difference in the overall survival. There were a number of possible compounding and mitigating factors that led to no significant difference in survival between the study and control groups. The trial’s primary endpoint was completeness of resection and TTP meant that the trial could be stopped prematurely once there was TTP advantage in any arm of the trial; that was what actually happened in this trial when the study arm was found to have achieved TTP advantage, the data monitoring committee had no choice but to stop the trial prematurely. There was no control for postresection adjuvant therapy upon tumour recurrence meant that therapy after tumour recurrence was not equivalent in the two groups. Finally not all tumour cells enhance on
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Figure 2 Comparison of recent treatment developments in GBM treatment with standard therapy (S: surgery alone, S + RT: surgery and radiotherapy, TZD: temazolamide treatment in addition to S and RT, Gl: Gliadel (carmustine) implants in addition to S + RT, PD: 5-ALA PD in addition to S and RT, PDT: Photofrin® PDT in addition to S + RT and PD/PDT: 5-ALA and fractionated PDT in addition to S and RT). All bars represent percent of overall survival except those marked * which represent tumour-free survival.
MRI scans and therefore relapses may still occur even when post-operative MRI demonstrated complete resection. The single Photofrin® PDT treatment study [29] demonstrated that more patients survived for 12 months of the group who received adjuvant PDT (17/43, 39.5%) compared to those who had not had PDT (9/33, 27.3%). Sadly, the survival curves crossed over at 15 months. Nevertheless the quality of survival in the treatment group was better than that in the controls. Again this trial was well designed but because the resection was performed without PD or FGR, realistically maximum tumour resection could have been achieved in only 25—35% of the patients in the study. This significant residual tumour was sufficient to cancel any potential gain from PDT. Furthermore, the light-dose was relatively low. The last study [30] combined the techniques of ALA and Photofrin® induced fluorescence assisted surgical resection (PD, FGR), PpIX spectroscopy and repetitive PDT up to a total dose of 500 J/cm2 divided into five fractions demonstrated that patients in the study group had significant survival, quality of life improvement and time to tumour progression advantages compared to the control group (p < 0.01). Therefore, the outcome of adjuvant PD, FGR and PDT techniques in GBM is in favour of brain PD/PDT (Fig. 2). Two of the aforementioned prospective randomized controlled trials demonstrated that TTP in GBM was significantly prolonged (p < 0.01) with PD and FGR compared to standard neurosurgical resection under white light microsurgery [28,30]. Phase I/II studies on PDT in malignant brain tumours were in favour of PDT on the basis of prolonging survival. However, the results of PD/PDT randomized controlled trials in GBM were divided regarding long-term survival. The ALA-study group [28] was not designed to look ahead for the overall survival. The authors did not control for adjuvant therapy following recurrence such as chemotherapy and further surgery. The second trial, conducted in North America, demonstrated that the initial survival advantage with single shot PDT was lost at 15 months. There were several reasons for this: a light-dose of 120 J/cm2 may not be sufficient, light-dose distribution may not have been uniform, the use of KTP pumped dye laser with a wavelength of 532 nm (ideally for Photofrin® a wavelength of 630 nm is preferred) and lastly the Photofrin® was injected 12—36 h prior
M.S. Eljamel to surgery. All these factors may have contributed to the failure of this trial to demonstrate survival advantage in the study group despite all phase I/II trials having demonstrated significant survival advantages in both newly diagnosed and recurrent GBM. However, the most likely compounding factor for the negative result of this particular study is the fact that significant residual tumour would have been left in the majority of patients as none of the groups had their tumour resected using PD/FGR techniques. Combining PD and PDT was shown in none randomised study to be beneficial [27]. The last study [30] demonstrated significant prolongation of the TTP in the study group and significant good quality survival in the study group, the critics pointed out that the study was single centre and used two photodynamic techniques and one cannot be sure which part of the technique (PD or PDT) was more significant. However, the fact that the study was performed in a single centre was a strength as the most difficult variable to control for in any surgical trial is patient selection and the surgical technique itself. It is less likely that there was significant variation in the equipoise for randomization or the surgical technique in a single centre study. The reason that the two techniques were tested together is also important as the efficacy of PDT would be dependant on the amount of residual tumour left behind. PD, FGR and PDT therefore go hand in hand. PD, FGR has already been shown to help in removing the residual tumour in 65% compared to only 36% using conventional techniques [28]. Combining both ALA and Photofrin® enhances PD and FGR as tumour fluorescence was more obvious to the extent it could be visualised by the naked eye. Similarly both photosensitizers have PDT effect. Furthermore, the use of spherical/cylindrical balloon-diffuser prevents shadows by preventing tumour cavity from infolding and the presence of the intralipid led to uniform illumination of the tumour walls [31]. The details of combining PD, FGR and repetitive PDT in brain tumours currently in use at Ninewells Hospital and Medical School, Dundee, Scotland, are summarised in Appendix A.
Brain PD, FGR and PDT, the future ‘‘The present is the ever moving shadow that divides yesterday from tomorrow. In that lies hope.’’ Frank Lloyd Wright (1867—1959) There is enough categories I/II evidence in support of PD, FGR and PDT in brain tumours and it is only a matter of time before PD, FGR and PDT becomes widely available to these patients as an option of management. As patients become aware of its existence and availability, patients and their families will demand it and undergo it in preference of its competitive therapies. I had patients come from farther a field seeking this target specific modality of treatment in preference to chemotherapy and radiotherapy. However, there is still a long road ahead in brain PD, FGR and PDT and many questions remain unanswered; How does PD, FGR and PDT interacts with other therapies, e.g. intraoperative radiotherapy? How can we reduce systemic photosensitivity and phototoxicity? How can we deliver a uniform homogeneous light-dose such as using implanted light emitting diodes of the correct bandwidth or metronomic PDT to
Brain PD, FGR and PDT, past, present and future improve the results? What is the role of PD, FGR and PDT in brain using other photosensitizers such as mTHPC, Hyperycin, Phtalocyanin, clorin e6 and boronated porphyrins? What is the role of PD, FGR and PDT in other intracranial and spinal indications such as pituitary adenomas, brain metastasis, skull base tumours and other intracranial tumours? All these questions are being investigated in several centres around the globe and discussion of early work in these areas of brain PD, PDT and PDT is beyond the scope of this article. Finally the future of PD, FGR and PDT in brain is dependent on further improvements and refinements of current technology and its wider availability at a reasonable cost.
Appendix A
33 Table 1 tumours
Timeline of PD, FGR and repetitive PDT in brain
Time to surgery
Tasks to be completed
48 h before surgery
2 mg/kg body weight Photofrin® is given via slow IV injection.
24 h before surgery
Preoperative planning MRI scan is performed for neuronavigation with skin fiducial-markers in place. The surgeon plans the surgical approach and rehearses the surgical approach on the workstation.
3 h before surgery
20 mg/kg body weight ALA in 30 ml of non-fizzy orange juice is given orally.
0 h time of surgery
Patient anaesthetised.a Cefruxime 1.5 g IV—–antibiotic prophylaxis. Dexamethazone 4 mg IV is given. The location of craniotomy is marked using neuronavigation. Perform craniotomy using image guidance. 100 ml of 20% mannitol is given over 20 min IV. Remove the easily recognisable bulk of the tumour using microscope, ultrasonic dissector and suction. Remove the rest of the tumour using PD and FGR techniques till no more tumour fluorescence is observedb . Inflate a balloon-diffuser—–using 0.32% intralipid solution till the balloon fills the resection cavity. Measure the diameter of the balloon-diffuser. Calculate the time required to provide 100 J/cm2 using Table 2. Recover the patient from anaesthesia. First dose of PDT 100 J/cm2 .
24 h post surgery 48 h post surgery 72 h post surgery
Second dose of PDT 100 J/cm2 . Third dose of PDT 100 J/cm2 . Fourth dose of PDT 100 J/cm2 .
96 h post surgery
Fifth dose of PDT 100 J/cm2 . Remove the balloon-diffuser.
Patient selection It is very important that PD, FGR and PDT are only offered to patients who are likely to benefit from this therapy. Patients undergoing PD, FGR and PDT brain must fulfill all the following inclusions criteria and none of the following exclusion criteria.
Inclusion criteria • Diagnosis of high grade glioma (HGG, including GBM and anaplastic astrocytomas, anaplastic oligodendroglioma, ependymomas, and primary cerebral lymphoma, recurrent HGG, brain metastasis). • Male or female subjects undergoing debulking of tumour via craniotomy. • Eighteen years of age or older. • Karnofsky performance status score over 60. • Able to give informed consent.
Exclusion criteria • Any history of photodermatosis such as erythropoietic protoporphyria. • History of disorders of the hepatic, or renal system. • Major medical or psychiatric illness. • Female who is pregnant or breast feeding. • Patients unable to give informed consent.
Surgical technique Preoperative screening A patient diagnosed on MRI and MRI spectroscopy with malignant brain tumour is counseled, and management options including the benefits and the risks of each option are discussed. If surgical resection was agreed to be the treatment plan, adjuvant PD, FGR and PDT is discussed including the risk of skin and retinal photosensitivity and essential photoprotection requirement. If the patients accepted PD, FGR and PDT as part of their treatment the following timeline is followed (Table 1).
a During anaesthesia most anaesthetists of today routinely monitor oxygen saturation during the craniotomy and thereafter. After ALA and Photofrin® administration it is essential that oxygen saturation is performed intermittently to avoid skin burns from the LED of the pulse-oxymeter. b PD and FGR is performed by attaching Olympus blue light source (370—440 nm) to 0 degree rigid Storz endoscope with a longpass observation filter (440 nm) and PDD camera system (Olympus).
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M.S. Eljamel
Table 2 PDT grid to calculate light-dose according to the size of the balloon-diffuser and the Laser fibre diffuser to give 100 J/cm2 Balloon-diffuser diameter (cm)
Laser fibre length (cm)
Laser power (mW)
Irradiance (mW/cm2 )
PDT duration (s)
0.5 0.75 1 1.25 1.5 1.75 2 2.25 2.5 3
1 1 1 1 1.5 1.5 1.5 1.5 2.5 2.5
400 400 400 400 600 600 600 600 1000 1000
509 226 127 81 85 62 48 38 51 35
196 442 785 1227 1178 1604 2094 2651 1963 2827
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