J. Photo&em.
Photobid.
B: Bid.,
9 (1991)
117
117-125
News and Views
Photodynamic fractionation”
therapy
of brain tumours
-
post-operative
“field
Paul Muller St. Michael’s
Hospital,
University
of Toronto, Toronto, Ontario (Canada]
Brian Wilson Ontario Cancer Foundation,
Hamilton,
Ontario (Canada.
Malignant primary cerebral tumours account for 3% of the cancer burden and constitute the most common solid tumour in the paediatric age group. In spite of the advances in the surgical treatment, radiation therapy and chemotherapy of these tumours, the prognosis remains very poor. Patients with glioblastoma multiforme, the most common primary cerebral glioma, have a median survival of less than 1 year and a 2 year survival rate of less than 20%. Malignant primary cerebral gliomas cause disability and death as the consequence of local effects. Their invasion and destruction of brain tissue results in neurological disability and the associated increase in intracranial pressure eventually leads to coma and death. Most malignant primary cerebral tumours do not metastasize. Therefore, these tumours represent an excellent example of a highly malignant solid tumour where local tumour control should be of survival value. However, patients with malignant glial brain tumours tend to present clinically with sizable tumours. In a series of 100 consecutive patients with malignant cerebral astrocytic tumours, computed tomography (CT) scan assessment showed the median tumour mass to be 35 g (not including tumour-associated cerebral oedema) [l]. This mass is within two or three doublings of the lethal mass of 100 g. The penetration depth of 630 nm light in brain tumour tissue in vivo is limited to approximately 3 mm [2, 31; the killing distance might thus be estimated to be 8-12 mm. By assuming a spherical geometry, the mass of tissue destroyed with a 1 cm killing radius is estimated to be only 4 g when a point source is used for interstitial photoillumination. A diffusion fibre with a 2 cm cylindrical tip might destroy 6-10 g of tumour tissue if the killing radius is 1 cm. By creating a spherical cavity with a radius of 2 cm within the solid tumour by surgical means and then using intracavitary photoillumination with a 1 cm killing radius, a much larger tumour mass of 80 g of tissue could be destroyed. Thus a combination of intraoperative intracavitsry photoillumination and multiple interstitially placed diffusion fibres may result in a substantial volume of tissue photoillumination and destruction. Elsevier Sequoia/Printed in The Netherlands
118
NEWS AND VIEWS
We have used intracavitary photoillumination in the treatment of 56 patients with brain tumours [4, 51. There were 49 patients with malignant gliomas and seven with metastatic brain tumours. In 39 cases the tumour was recurrent. The age range was 17-73 (mean = 48) years with a male to female ratio of 1.33:1. Patients received a porphyrin photosensitizer 18-24 h pre-operatively. An argon dye pump laser, tuned to 630 run, was used to photoilluminate a tumour cavity created by radical tumour resection and/or tumour cyst drainage. The total light energy delivered ranged from 440 to 4500 J and the cavitary light energy density ranged from 8 to 175 J cm-‘. In some patients a line fibre(s) was used to administer interstitial light as a supplement to the cavitary photoillumination. The additional light dose ranged from 60 to 945 J cme2. In the whole series an operative mortality and serious morbidity rate of 9% was observed. There were two post-operative deaths from intracerebral haemorrhage and three patients who had a permanent post-operative pecline in neurological function. In the 49 patients with gliomas the death rate per observation year was 0.9 for the interval between photodynamic therapy (PDT) and death. The median survival was 8.5 months with a 1 and 2’ year actuarial survival rate of 33% and 14% respectively. We concluded that the PDT of malignant brain tumours could be carried out with acceptable risk and that PDT was active against some gliomas. In their series of malignant brain tumours, Kaye et al. [6] observed that those patients who received a greater light dose survived longer than patients who received a lower light dose. We have also identified a relationship between light dose administered and survival. In our series those patients with malignant primary brain tumours who received a total light dose of less than 1000 J, 1000-1999 J or more than 2000 J had a median survival of 6.6, 8.5 and 9.9 months respectively and a 1 year actuarial survival of 18%, 34% and 42% respectively. We have come to recognize the need for high light doses in the treatment of brain tumours. However, even with the combined use of intracavitary and interstitial photoillumination techniques, the intraoperative illumination of the whole tumour has not been practical at times. The time required to deposit adequate light dose may be limited because of restrictions in safe intracranial tumour exposure time and anaesthetic time. Limited laser power and the need to run the laser over extended irradiation times are also major practical problems: 100 J crnp2 delivered to the tissue surface of a cavity of 2 cm radius takes 83 min at a laser power of 1 W. In order to overcome these problems we have implanted fibres intraoperatively into residual post-resection malignant astrocytic tumours and externalized the fibres through small skin wounds. At various times during the first three post-operative days, patients have been returned to the laser where the fibres are recoupled and further photoillumination is carried out. At each post-operative session a different volume or field of the tumour is treated. This has allowed us to photoilluminate a much greater volume of photosensitized tissue after the initial intraoperative exposure.
119
NEWS AND VIEWS
It is important to emphasize that, although the fractionation permits a larger total light energy to be administered, the fractionation is not a dose fractionation, but rather a “field” fractionation, since the purpose is not to re-illuminate tissues for which the threshold of the photodynamic effect has been reached or exceeded, but rather to photoillmate a greater volume of tissue. Preliminary experience in five patients to date has shown that this additional procedure is practical, easily tolerated by the patient and cost effective in the use of operating room facilities and staff. Furthermore, since the patient is conscious during the photoillumination, continuous neurological monitoring is possible. The use of implanted fibres for the post-operative photoillumination of brain tumours may significantly improve the practicality of brain tumour PDT. 1 2
3 4
5 6
P. J. Muiler and R. Lamond, unpublished data, 1984. B. Wilson, P. J. Muller and JI C. Yanche, Instrumentation and light dosimetry for intraoperative photodynamic therapy (PDT) of malignant brain tumours, Phys. Med. BioZ., 32 (1986) 125-133. P. J. Muller and B. C. Wilson, An update on the penetration depth of 630 nm light in normal and malignant human brain tissue in wivo, Phys. Med. Biol., 31 (1986) 1295-1297. P. J. Muiler and B. C. Wilson, Photodynamic therapy of malignant primary brain tumours: chnicai effects, post-operative intracranial ICP, and light penetration of brain, Photo&em. Photobiol., 46 (1987) 729-732. P. J. Muller and B. C. Wilson, Photodynamic therapy in the treatment of brain tumours - a report of 50 cases, Can. J. Neural. Sci., 17 (1990) 193-198. A. H. Kaye, G. Morstyn and D. Brownbill, Admvant high dose photoradiation therapy for the treatment of malignant glioma: a phase l-2 study, J. Neurosurg., 67 (1987) 500-505.
Photodynamic
therapy for ocular tumors
Robert W. Lingua+ hm Linda,
Linda University Eye Medical CA 92354 (U.S.A.)
Jean-Marie
Group, 11370 Anderson
Street,
Suite 1800, Lama
Pare1
Department of Ophthalmology, Boscom Palmer School of Medicine, Miami, FZ (U.S.A.)
Eye Institute,
University
of Miami
1. Introduction
The two most common primary ocular malignancies, retinoblastoma (pediatric) and choroidal melanoma (adult), are particularly vascular and are easily visualized for diagnosis and laser light, making photodynamic therapy ?Author to whom correspondence should be addressed.
Photobid.
B: Bid.,
9 (1991)
117
117-125
News and Views
Photodynamic fractionation”
therapy
of brain tumours
-
post-operative
“field
Paul Muller St. Michael’s
Hospital,
University
of Toronto, Toronto, Ontario (Canada]
Brian Wilson Ontario Cancer Foundation,
Hamilton,
Ontario (Canada.
Malignant primary cerebral tumours account for 3% of the cancer burden and constitute the most common solid tumour in the paediatric age group. In spite of the advances in the surgical treatment, radiation therapy and chemotherapy of these tumours, the prognosis remains very poor. Patients with glioblastoma multiforme, the most common primary cerebral glioma, have a median survival of less than 1 year and a 2 year survival rate of less than 20%. Malignant primary cerebral gliomas cause disability and death as the consequence of local effects. Their invasion and destruction of brain tissue results in neurological disability and the associated increase in intracranial pressure eventually leads to coma and death. Most malignant primary cerebral tumours do not metastasize. Therefore, these tumours represent an excellent example of a highly malignant solid tumour where local tumour control should be of survival value. However, patients with malignant glial brain tumours tend to present clinically with sizable tumours. In a series of 100 consecutive patients with malignant cerebral astrocytic tumours, computed tomography (CT) scan assessment showed the median tumour mass to be 35 g (not including tumour-associated cerebral oedema) [l]. This mass is within two or three doublings of the lethal mass of 100 g. The penetration depth of 630 nm light in brain tumour tissue in vivo is limited to approximately 3 mm [2, 31; the killing distance might thus be estimated to be 8-12 mm. By assuming a spherical geometry, the mass of tissue destroyed with a 1 cm killing radius is estimated to be only 4 g when a point source is used for interstitial photoillumination. A diffusion fibre with a 2 cm cylindrical tip might destroy 6-10 g of tumour tissue if the killing radius is 1 cm. By creating a spherical cavity with a radius of 2 cm within the solid tumour by surgical means and then using intracavitary photoillumination with a 1 cm killing radius, a much larger tumour mass of 80 g of tissue could be destroyed. Thus a combination of intraoperative intracavitsry photoillumination and multiple interstitially placed diffusion fibres may result in a substantial volume of tissue photoillumination and destruction. Elsevier Sequoia/Printed in The Netherlands
118
NEWS AND VIEWS
We have used intracavitary photoillumination in the treatment of 56 patients with brain tumours [4, 51. There were 49 patients with malignant gliomas and seven with metastatic brain tumours. In 39 cases the tumour was recurrent. The age range was 17-73 (mean = 48) years with a male to female ratio of 1.33:1. Patients received a porphyrin photosensitizer 18-24 h pre-operatively. An argon dye pump laser, tuned to 630 run, was used to photoilluminate a tumour cavity created by radical tumour resection and/or tumour cyst drainage. The total light energy delivered ranged from 440 to 4500 J and the cavitary light energy density ranged from 8 to 175 J cm-‘. In some patients a line fibre(s) was used to administer interstitial light as a supplement to the cavitary photoillumination. The additional light dose ranged from 60 to 945 J cme2. In the whole series an operative mortality and serious morbidity rate of 9% was observed. There were two post-operative deaths from intracerebral haemorrhage and three patients who had a permanent post-operative pecline in neurological function. In the 49 patients with gliomas the death rate per observation year was 0.9 for the interval between photodynamic therapy (PDT) and death. The median survival was 8.5 months with a 1 and 2’ year actuarial survival rate of 33% and 14% respectively. We concluded that the PDT of malignant brain tumours could be carried out with acceptable risk and that PDT was active against some gliomas. In their series of malignant brain tumours, Kaye et al. [6] observed that those patients who received a greater light dose survived longer than patients who received a lower light dose. We have also identified a relationship between light dose administered and survival. In our series those patients with malignant primary brain tumours who received a total light dose of less than 1000 J, 1000-1999 J or more than 2000 J had a median survival of 6.6, 8.5 and 9.9 months respectively and a 1 year actuarial survival of 18%, 34% and 42% respectively. We have come to recognize the need for high light doses in the treatment of brain tumours. However, even with the combined use of intracavitary and interstitial photoillumination techniques, the intraoperative illumination of the whole tumour has not been practical at times. The time required to deposit adequate light dose may be limited because of restrictions in safe intracranial tumour exposure time and anaesthetic time. Limited laser power and the need to run the laser over extended irradiation times are also major practical problems: 100 J crnp2 delivered to the tissue surface of a cavity of 2 cm radius takes 83 min at a laser power of 1 W. In order to overcome these problems we have implanted fibres intraoperatively into residual post-resection malignant astrocytic tumours and externalized the fibres through small skin wounds. At various times during the first three post-operative days, patients have been returned to the laser where the fibres are recoupled and further photoillumination is carried out. At each post-operative session a different volume or field of the tumour is treated. This has allowed us to photoilluminate a much greater volume of photosensitized tissue after the initial intraoperative exposure.
119
NEWS AND VIEWS
It is important to emphasize that, although the fractionation permits a larger total light energy to be administered, the fractionation is not a dose fractionation, but rather a “field” fractionation, since the purpose is not to re-illuminate tissues for which the threshold of the photodynamic effect has been reached or exceeded, but rather to photoillmate a greater volume of tissue. Preliminary experience in five patients to date has shown that this additional procedure is practical, easily tolerated by the patient and cost effective in the use of operating room facilities and staff. Furthermore, since the patient is conscious during the photoillumination, continuous neurological monitoring is possible. The use of implanted fibres for the post-operative photoillumination of brain tumours may significantly improve the practicality of brain tumour PDT. 1 2
3 4
5 6
P. J. Muiler and R. Lamond, unpublished data, 1984. B. Wilson, P. J. Muller and JI C. Yanche, Instrumentation and light dosimetry for intraoperative photodynamic therapy (PDT) of malignant brain tumours, Phys. Med. BioZ., 32 (1986) 125-133. P. J. Muller and B. C. Wilson, An update on the penetration depth of 630 nm light in normal and malignant human brain tissue in wivo, Phys. Med. Biol., 31 (1986) 1295-1297. P. J. Muiler and B. C. Wilson, Photodynamic therapy of malignant primary brain tumours: chnicai effects, post-operative intracranial ICP, and light penetration of brain, Photo&em. Photobiol., 46 (1987) 729-732. P. J. Muller and B. C. Wilson, Photodynamic therapy in the treatment of brain tumours - a report of 50 cases, Can. J. Neural. Sci., 17 (1990) 193-198. A. H. Kaye, G. Morstyn and D. Brownbill, Admvant high dose photoradiation therapy for the treatment of malignant glioma: a phase l-2 study, J. Neurosurg., 67 (1987) 500-505.
Photodynamic
therapy for ocular tumors
Robert W. Lingua+ hm Linda,
Linda University Eye Medical CA 92354 (U.S.A.)
Jean-Marie
Group, 11370 Anderson
Street,
Suite 1800, Lama
Pare1
Department of Ophthalmology, Boscom Palmer School of Medicine, Miami, FZ (U.S.A.)
Eye Institute,
University
of Miami
1. Introduction
The two most common primary ocular malignancies, retinoblastoma (pediatric) and choroidal melanoma (adult), are particularly vascular and are easily visualized for diagnosis and laser light, making photodynamic therapy ?Author to whom correspondence should be addressed.
