Photodiagnosis and Photodynamic Therapy (2004) 1, 303—310
REVIEW
Brain PDD and PDT unlocking the mystery of malignant gliomas M. Sam Eljamel MD, FRCS (Ed,Ire (SN)) ∗ Ninewells Hospital and Medical School, Department of Neurosurgery and The Scottish Photodynamic Centre, South Block Level 6, Dundee, Scotland DD1 9SY, UK Available online 8 March 2005 KEYWORDS Brain tumours; Photodynamic diagnosis; Photodynamic therapy
Summary Malignant brain tumours (MBTs) have one of the worst outcomes of human cancers today and their incidence is on the increase. Current treatment failure is usually due to local recurrence of the tumour rather than distant metastasis. In the last three decades we have seen many novel and potentially effective treatment strategies rise rapidly to the rescue. Sadly, however, the majority of these approaches were not good enough to withstand the harsh reality of the sceptical gaze of the scientific eye or the stringent health economics of this millennium. PDD and PDT, however, is one of the few therapies fighting back and still standing today. The results of its randomised controlled trials are eagerly awaited. To date the literature suggests that both PDD and PDT significantly prolong the time to tumour progression, reduce local recurrence, increase radical resection and prolong overall survival of MBTs. PDD and PDT are well tolerated by patients and worthwhile pursuing. © 2005 Elsevier B.V. All rights reserved.
Contents Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brain PDD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brain PDT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Malignant brain tumours (MBTs) are the second commonest cause of cancer death in children under 19 years of age and the third cause of cancer death * Tel.: +44 1382 660111x35712; fax: +44 1382 496202.
E-mail address: [email protected].
303 304 305 308
among young adults under the age of 35 years. They affect about 11 people in every 100,000 inhabitants and their incidence is on the rise. We are likely to see more than 100,000 new cases in the USA and over 50,000 new cases in the UK during the next 12 months and more than 90% of these new patients are likely to be dead within 2 years of diagnosis, a sobering statistical fact mak-
1572-1000/$ — see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(05)00008-6
304 ing MBTs one of the most lethal cancers facing humanity. Moreover, recent conceptual and technical advances in medicine and surgery had made great strides in screening, early detection and potential cure of many cancers outside the brain, the prognosis of MBTs remains dismal with a mean survival of 9 months and a meagre 2 year survival of 7.5% [1]. The present treatment of MBTs is multimodality; surgical resection (SR), external beam radiotherapy (EBR) and in some cases systemic chemotherapy (SCT) [2—4]. SR alone has not been subjected to a randomised controlled trial, but it is common sense that reducing the tumour burden would be more likely to increase the success of other therapies. For example SR combined with EBR had been shown to be more effective than SR alone in several randomised trials [5]. SCT on the other hand cannot reach the target in lethal concentrations because of the blood brain barrier (BBB) and the toxic side effects on normal organs. The response to SCT is at best 10—20% [6]. Therefore, the neurooncology community at large need to develop better weapons to defeat this common and increasing threat to human life. There is an urgent need to develop new ways of blowing tumour camouflage to reduce the residual tumour burden without increasing injury to the surrounding normal brain tissue [7,8]. There are several promising therapies currently under the scrutiny of the scientific eye with its sceptics on one hand and its health economics on the other. Over the last two decades several new novel and promising approaches have been developed in this battle-field with some limited success. Photodynamic assisted surgical resection (PDASR or PDD), photodynamic therapy (PDT), immunotherapy (IT), immunoradiotherapy (IRT), gene therapy (GT), intra-operative radiotherapy (IORT) and intraoperative chemotherapy (IOCT) are just few of the many approaches currently under investigation by several neuro-oncology groups around the world. There are several reasons, why these new novel and potentially effective approaches had not gained wide acceptance and support by neuro-oncologists, neurosurgeons and health care economists; the first and far most is the sceptical attitude introduced by lack of solid scientific evidence to proof a worthwhile health gain for sufferers compared to the additional cost. Secondly, the competing interests of the investigators and the commercial interests of the sponsoring companies added to the sceptical attitude. Thirdly, the stringent regulations of clinical governance led to premature stoppage of recruitment to trials. Finally the wide variation in the methodology used, particularly variation in the surgical technique and the surgeons’ judgement involved, which cannot be controlled for unless each
M.S. Eljamel individual surgeon enrols sufficient number of patients more or equivalent to the original sample size, which is currently impossible. However, there is still light at the end of the tunnel as I am sure that the combination of patients’ (the customers) demands for a cure and the enthusiasm of dedicated clinicians to find such cure will see this through till the end. Brain PDD and PDT is unique in that it combines reducing tumour burden to a minimum (PDD) and treating the residual tumour burden in the same sitting eliminating tumour recovery time and finishing the enemy off when it is most vulnerable. PDD and PDT takes advantage of the affinity and retention of the harmless photosensitizers; 5-aminolevulinic acid (5-ALA), porfimer sodium (photofrin) and temoporfin (foscan). After their administration, these agents are preferentially concentrated in malignant tumour cells [7] making them distinguishable from normal brain tissue and a target for therapy. The methodology of PDD and PDT has been developed and its feasibility, tolerability and practicability have already been published by several authors [8—11].
Brain PDD The survival of MBTs is dependant on the extent of surgical resection. In a surgical series of 645 patients, the median survival of patients who had gross total surgical resection was 11.3 months compared to 10.4 months of those who had partial surgical resection and 6.6 months for those who had just biopsy (p < 0.001) [12]. Another recent study of 102 anaplastic astrocytomas (AA) which evaluated the effect of residual post-surgical enhancement on the overall survival and time to tumour progression (TTP) had demonstrated that residual tumour enhancement on MRI adversely affected both the overall survival and the TTP (p < 0.002 and 19 times that in normal brain cells [20,26,35]. However, the reported tumour-to-brain ratio varies from 2:1 [60] to 50:1 [61] depending on the histological grade of the tumour. The higher the grade of the tumour (GBMs and AAs) was the higher the concentration of the photosensitizer in the tumour [20]. When the photosensitizing agents are exposed to light of particular wave length (635 nm for 5-ALA, 630 nm for Photofrin and 652 nm for Foscan), the light energy is absorbed and the Photosensitizer is activated. The outcome of this process is the accumulation of a highly active cytotoxic singlet oxygen 1 O2 [36—38]. This cytotoxic molecule leads to cell membrane damage [38,39] and influx of calcium [40], collapse of tumour microcirculation [41] and loss of tumour cell adhesiveness [42]. The net effect of all these cellular damage is necrosis of glioma cells [19,20,22—27,29,31—33]. The unwanted effect of this necrosis in a closed compartment
306
M.S. Eljamel
Figure 3 (a) MBT visualised by white light (tumour visible from 4 to 8 O’Clock position). (b) MBT visualised by violet—blue light (tumour visible from 4 to 11 O’Clock position). (c) MBT visualised by violet—blue light (small residual tumour nests only). (d) MBT visualised by violet—blue light (tumour completely resected).
such as the skull, is raised intracranial pressure (ICP) [43—46]. Therefore, it is very important that cytoreductive therapy is undertaken to reduce ICP. It had also been demonstrated that PDT can exert its anti-caner effects by programming tumour-cell death (apoptosis) [47], which would be a more welcome outcome in brain as it would not be associated with as much cerebral oedema and raised intracranial pressure. If a way could be found to increase apoptosis, decrease cell necrosis and enhance the beneficial anti-tumour effects of PDT, then it would be possible to deliver PDT stereo tactically, but for the present, PDT had to be given intra-cavity after tumour resection except in a very small tumour volume of less than 2 cm3 . The second important fact that makes intra-operative and immediate post-operative PDT an attractive option to exploit is the fact that PDT is a local treatment with light penetration of 8—20 mm. This allows photo-irradiation of the tumour margin, where more than 90% of tumour recurrence of MBTs occurs. A number of studies have been published in the literature over the last three decades on PDT in MBTs [7,11,48—56]. It would be, however, extremely difficult to compare these studies due to the small numbers of patients included, variation in techniques, entry criteria and photosensitizers,
publication bias and inadequate follow up information. However, all these studies have demonstrated the safely, tolerability, patient acceptance and potential benefits of PDT in MBTs. While these studies were neither randomised nor blinded, they all reported patient benefits in terms of time to tumour progression (TTP) and long-term survival (Table 1). Perria et al. [48] reported one of the earliest attempts to photo-irradiate post-resection glioma cavity in humans and predicted that future refinement of the technique may produce better tissue penetration and more extensive tumour kill. Kaye et al. [49] reported a phase I/II trial involving 22 patients, of which there were 13 new GBM, 6 recurrent GBM, 2 new AA and 1 recurrent AA. He used hematoporphyrin derivative administered 24 h before treatment at 5 mg/kg body weight. After radical tumour removal, the cavity was irradiated with 630 nm laser light. He used two different lasers to deliver the light and a dose variation from 70 to 230 J/cm2 . Sixty-eight percent of the patients developed new tumours and underwent radiotherapy (20 Gy). Fifty-seven percent of the recurrent gliomas developed further recurrence in 12—16 weeks and 13% of the new gliomas developed recurrence at 3 and 13 weeks. Fifteen patients had no recurrence at a mean follow up of 7 months
Brain PDD and PDT unlocking the mystery of malignant gliomas
Table 1
307
PDT in MBTs.
Authors
Year
MBTs breakdown
Main results
Perria et al. [48] Kaye et al. [49]
1980 1987
3 GBMs 19 GBMs, 3 AAs
Muller and Wilson [46]
1987
16 GBMs, 13 AAs
Kostron et al. [52] Perria et al. [53] Kostron et al. [11] Power et al. [50]
1987 1988 1988 1991
16 GBMs 2 GBMs, 3 AAs 18 GBMs 2 GBMs, 4 AAs
Muller and Wilson [51]
1995
56 GBMs and AAs recurrent
Popovic et al. [55]
1995
78 GBMs, 24 AAs
Muller and Wilson [54]
2000
32 GBMs, 14 AAs, 6 mixed
Olyushin et al. [56]
2003
10 GBMs, 3 AAs
Longest survival 44 weeks 13 patients survived 4—69 weeks, with only two recurrences in mean follow up of 30 weeks Recurrence free survival of 112 weeks in 36% of patients Survival of up to 52 weeks in six patients No recurrence on neuro-imaging at 39 weeks Survival of six cases exceeded 94 weeks Longest relapse free survival of 45 weeks in AAs and 27 weeks in GBMs Survival of recurrent GBMs and AAs was 30 and 44 weeks, respectively Mean life expectancy of GBMs (38 cases) was 105 weeks, recurrent GBMs (40 cases) was (38.5 weeks) for AAs was 86 weeks Mean survival for GBMs was 31 weeks, AAs was 50 weeks and mixed was 64 weeks Longest relapse free survival of GBMs was 77 weeks and for AAs was 116 weeks
GBMs, glioblastomas multiforme; AAs, anaplastic astrocytomas.
(1—16 months). The authors concluded that PDT can be used as adjuvant therapy to surgery and radiotherapy. By 1988, more than 64 MBTs treated patients with PDT were reported and although some of the initial results were disappointing, the majority of the treated patients had a low light dose and were of very poor prognosis [57]. Kostron et al. [11] reported his first 20 patients including 18 GBM treated with a wavelength of 630 nm and 40—120 J/cm2 . This was followed immediately with a single dose of radiation. Conventional radiotherapy followed in 8 patients. The median survival of 3 recurrent GBM was 5 months and 4 of newly diagnosed GBM died because of recurrence with a median survival of 5 months. However, 6 patients were still alive 12 months after PDT and 6 patients were still alive at 22 months. Origitano and Reichman [58] reported their experience using image guided computer assisted protocol to improve treatment volume coverage and pointed out that treatment failure is often due to lack of tumour coverage by the treatment and the limited tissue penetration of the laser light. They have demonstrated that combining intra cavity irradiation with peritumoral interstitial irradiation was possible and could achieve wider tumour volume coverage. Muller and Wilson [51] reported 56 patients treated with PDT. These were young (mean age of 41) with a mean Karnofsky performance score of 70, who had recurrent malignant gliomas. Thirty-two were GBM, 14 were AA, 6 were mixed
and 4 were malignant ependymomas. Treatment dose 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 survival of GBM from first diagnosis was 82% at 1 year and 57% at 2 years, which is significantly better than the 2 year survival of
REVIEW
Brain PDD and PDT unlocking the mystery of malignant gliomas M. Sam Eljamel MD, FRCS (Ed,Ire (SN)) ∗ Ninewells Hospital and Medical School, Department of Neurosurgery and The Scottish Photodynamic Centre, South Block Level 6, Dundee, Scotland DD1 9SY, UK Available online 8 March 2005 KEYWORDS Brain tumours; Photodynamic diagnosis; Photodynamic therapy
Summary Malignant brain tumours (MBTs) have one of the worst outcomes of human cancers today and their incidence is on the increase. Current treatment failure is usually due to local recurrence of the tumour rather than distant metastasis. In the last three decades we have seen many novel and potentially effective treatment strategies rise rapidly to the rescue. Sadly, however, the majority of these approaches were not good enough to withstand the harsh reality of the sceptical gaze of the scientific eye or the stringent health economics of this millennium. PDD and PDT, however, is one of the few therapies fighting back and still standing today. The results of its randomised controlled trials are eagerly awaited. To date the literature suggests that both PDD and PDT significantly prolong the time to tumour progression, reduce local recurrence, increase radical resection and prolong overall survival of MBTs. PDD and PDT are well tolerated by patients and worthwhile pursuing. © 2005 Elsevier B.V. All rights reserved.
Contents Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brain PDD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brain PDT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Malignant brain tumours (MBTs) are the second commonest cause of cancer death in children under 19 years of age and the third cause of cancer death * Tel.: +44 1382 660111x35712; fax: +44 1382 496202.
E-mail address: [email protected].
303 304 305 308
among young adults under the age of 35 years. They affect about 11 people in every 100,000 inhabitants and their incidence is on the rise. We are likely to see more than 100,000 new cases in the USA and over 50,000 new cases in the UK during the next 12 months and more than 90% of these new patients are likely to be dead within 2 years of diagnosis, a sobering statistical fact mak-
1572-1000/$ — see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(05)00008-6
304 ing MBTs one of the most lethal cancers facing humanity. Moreover, recent conceptual and technical advances in medicine and surgery had made great strides in screening, early detection and potential cure of many cancers outside the brain, the prognosis of MBTs remains dismal with a mean survival of 9 months and a meagre 2 year survival of 7.5% [1]. The present treatment of MBTs is multimodality; surgical resection (SR), external beam radiotherapy (EBR) and in some cases systemic chemotherapy (SCT) [2—4]. SR alone has not been subjected to a randomised controlled trial, but it is common sense that reducing the tumour burden would be more likely to increase the success of other therapies. For example SR combined with EBR had been shown to be more effective than SR alone in several randomised trials [5]. SCT on the other hand cannot reach the target in lethal concentrations because of the blood brain barrier (BBB) and the toxic side effects on normal organs. The response to SCT is at best 10—20% [6]. Therefore, the neurooncology community at large need to develop better weapons to defeat this common and increasing threat to human life. There is an urgent need to develop new ways of blowing tumour camouflage to reduce the residual tumour burden without increasing injury to the surrounding normal brain tissue [7,8]. There are several promising therapies currently under the scrutiny of the scientific eye with its sceptics on one hand and its health economics on the other. Over the last two decades several new novel and promising approaches have been developed in this battle-field with some limited success. Photodynamic assisted surgical resection (PDASR or PDD), photodynamic therapy (PDT), immunotherapy (IT), immunoradiotherapy (IRT), gene therapy (GT), intra-operative radiotherapy (IORT) and intraoperative chemotherapy (IOCT) are just few of the many approaches currently under investigation by several neuro-oncology groups around the world. There are several reasons, why these new novel and potentially effective approaches had not gained wide acceptance and support by neuro-oncologists, neurosurgeons and health care economists; the first and far most is the sceptical attitude introduced by lack of solid scientific evidence to proof a worthwhile health gain for sufferers compared to the additional cost. Secondly, the competing interests of the investigators and the commercial interests of the sponsoring companies added to the sceptical attitude. Thirdly, the stringent regulations of clinical governance led to premature stoppage of recruitment to trials. Finally the wide variation in the methodology used, particularly variation in the surgical technique and the surgeons’ judgement involved, which cannot be controlled for unless each
M.S. Eljamel individual surgeon enrols sufficient number of patients more or equivalent to the original sample size, which is currently impossible. However, there is still light at the end of the tunnel as I am sure that the combination of patients’ (the customers) demands for a cure and the enthusiasm of dedicated clinicians to find such cure will see this through till the end. Brain PDD and PDT is unique in that it combines reducing tumour burden to a minimum (PDD) and treating the residual tumour burden in the same sitting eliminating tumour recovery time and finishing the enemy off when it is most vulnerable. PDD and PDT takes advantage of the affinity and retention of the harmless photosensitizers; 5-aminolevulinic acid (5-ALA), porfimer sodium (photofrin) and temoporfin (foscan). After their administration, these agents are preferentially concentrated in malignant tumour cells [7] making them distinguishable from normal brain tissue and a target for therapy. The methodology of PDD and PDT has been developed and its feasibility, tolerability and practicability have already been published by several authors [8—11].
Brain PDD The survival of MBTs is dependant on the extent of surgical resection. In a surgical series of 645 patients, the median survival of patients who had gross total surgical resection was 11.3 months compared to 10.4 months of those who had partial surgical resection and 6.6 months for those who had just biopsy (p < 0.001) [12]. Another recent study of 102 anaplastic astrocytomas (AA) which evaluated the effect of residual post-surgical enhancement on the overall survival and time to tumour progression (TTP) had demonstrated that residual tumour enhancement on MRI adversely affected both the overall survival and the TTP (p < 0.002 and 19 times that in normal brain cells [20,26,35]. However, the reported tumour-to-brain ratio varies from 2:1 [60] to 50:1 [61] depending on the histological grade of the tumour. The higher the grade of the tumour (GBMs and AAs) was the higher the concentration of the photosensitizer in the tumour [20]. When the photosensitizing agents are exposed to light of particular wave length (635 nm for 5-ALA, 630 nm for Photofrin and 652 nm for Foscan), the light energy is absorbed and the Photosensitizer is activated. The outcome of this process is the accumulation of a highly active cytotoxic singlet oxygen 1 O2 [36—38]. This cytotoxic molecule leads to cell membrane damage [38,39] and influx of calcium [40], collapse of tumour microcirculation [41] and loss of tumour cell adhesiveness [42]. The net effect of all these cellular damage is necrosis of glioma cells [19,20,22—27,29,31—33]. The unwanted effect of this necrosis in a closed compartment
306
M.S. Eljamel
Figure 3 (a) MBT visualised by white light (tumour visible from 4 to 8 O’Clock position). (b) MBT visualised by violet—blue light (tumour visible from 4 to 11 O’Clock position). (c) MBT visualised by violet—blue light (small residual tumour nests only). (d) MBT visualised by violet—blue light (tumour completely resected).
such as the skull, is raised intracranial pressure (ICP) [43—46]. Therefore, it is very important that cytoreductive therapy is undertaken to reduce ICP. It had also been demonstrated that PDT can exert its anti-caner effects by programming tumour-cell death (apoptosis) [47], which would be a more welcome outcome in brain as it would not be associated with as much cerebral oedema and raised intracranial pressure. If a way could be found to increase apoptosis, decrease cell necrosis and enhance the beneficial anti-tumour effects of PDT, then it would be possible to deliver PDT stereo tactically, but for the present, PDT had to be given intra-cavity after tumour resection except in a very small tumour volume of less than 2 cm3 . The second important fact that makes intra-operative and immediate post-operative PDT an attractive option to exploit is the fact that PDT is a local treatment with light penetration of 8—20 mm. This allows photo-irradiation of the tumour margin, where more than 90% of tumour recurrence of MBTs occurs. A number of studies have been published in the literature over the last three decades on PDT in MBTs [7,11,48—56]. It would be, however, extremely difficult to compare these studies due to the small numbers of patients included, variation in techniques, entry criteria and photosensitizers,
publication bias and inadequate follow up information. However, all these studies have demonstrated the safely, tolerability, patient acceptance and potential benefits of PDT in MBTs. While these studies were neither randomised nor blinded, they all reported patient benefits in terms of time to tumour progression (TTP) and long-term survival (Table 1). Perria et al. [48] reported one of the earliest attempts to photo-irradiate post-resection glioma cavity in humans and predicted that future refinement of the technique may produce better tissue penetration and more extensive tumour kill. Kaye et al. [49] reported a phase I/II trial involving 22 patients, of which there were 13 new GBM, 6 recurrent GBM, 2 new AA and 1 recurrent AA. He used hematoporphyrin derivative administered 24 h before treatment at 5 mg/kg body weight. After radical tumour removal, the cavity was irradiated with 630 nm laser light. He used two different lasers to deliver the light and a dose variation from 70 to 230 J/cm2 . Sixty-eight percent of the patients developed new tumours and underwent radiotherapy (20 Gy). Fifty-seven percent of the recurrent gliomas developed further recurrence in 12—16 weeks and 13% of the new gliomas developed recurrence at 3 and 13 weeks. Fifteen patients had no recurrence at a mean follow up of 7 months
Brain PDD and PDT unlocking the mystery of malignant gliomas
Table 1
307
PDT in MBTs.
Authors
Year
MBTs breakdown
Main results
Perria et al. [48] Kaye et al. [49]
1980 1987
3 GBMs 19 GBMs, 3 AAs
Muller and Wilson [46]
1987
16 GBMs, 13 AAs
Kostron et al. [52] Perria et al. [53] Kostron et al. [11] Power et al. [50]
1987 1988 1988 1991
16 GBMs 2 GBMs, 3 AAs 18 GBMs 2 GBMs, 4 AAs
Muller and Wilson [51]
1995
56 GBMs and AAs recurrent
Popovic et al. [55]
1995
78 GBMs, 24 AAs
Muller and Wilson [54]
2000
32 GBMs, 14 AAs, 6 mixed
Olyushin et al. [56]
2003
10 GBMs, 3 AAs
Longest survival 44 weeks 13 patients survived 4—69 weeks, with only two recurrences in mean follow up of 30 weeks Recurrence free survival of 112 weeks in 36% of patients Survival of up to 52 weeks in six patients No recurrence on neuro-imaging at 39 weeks Survival of six cases exceeded 94 weeks Longest relapse free survival of 45 weeks in AAs and 27 weeks in GBMs Survival of recurrent GBMs and AAs was 30 and 44 weeks, respectively Mean life expectancy of GBMs (38 cases) was 105 weeks, recurrent GBMs (40 cases) was (38.5 weeks) for AAs was 86 weeks Mean survival for GBMs was 31 weeks, AAs was 50 weeks and mixed was 64 weeks Longest relapse free survival of GBMs was 77 weeks and for AAs was 116 weeks
GBMs, glioblastomas multiforme; AAs, anaplastic astrocytomas.
(1—16 months). The authors concluded that PDT can be used as adjuvant therapy to surgery and radiotherapy. By 1988, more than 64 MBTs treated patients with PDT were reported and although some of the initial results were disappointing, the majority of the treated patients had a low light dose and were of very poor prognosis [57]. Kostron et al. [11] reported his first 20 patients including 18 GBM treated with a wavelength of 630 nm and 40—120 J/cm2 . This was followed immediately with a single dose of radiation. Conventional radiotherapy followed in 8 patients. The median survival of 3 recurrent GBM was 5 months and 4 of newly diagnosed GBM died because of recurrence with a median survival of 5 months. However, 6 patients were still alive 12 months after PDT and 6 patients were still alive at 22 months. Origitano and Reichman [58] reported their experience using image guided computer assisted protocol to improve treatment volume coverage and pointed out that treatment failure is often due to lack of tumour coverage by the treatment and the limited tissue penetration of the laser light. They have demonstrated that combining intra cavity irradiation with peritumoral interstitial irradiation was possible and could achieve wider tumour volume coverage. Muller and Wilson [51] reported 56 patients treated with PDT. These were young (mean age of 41) with a mean Karnofsky performance score of 70, who had recurrent malignant gliomas. Thirty-two were GBM, 14 were AA, 6 were mixed
and 4 were malignant ependymomas. Treatment dose 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 survival of GBM from first diagnosis was 82% at 1 year and 57% at 2 years, which is significantly better than the 2 year survival of
