5
Section of Oncology
53
A part coming from the blood plasma due to Mathiew (1939) American Journal Obstetrics & Gynecology 37, 654 systemic tumour and part by more direct export Newman J, Josephson A S,of Cacatian A & Tsang A into cerebral ECF. Calculations can be made to (1974) Lancet ii, 756 P, Vandenheuvel F A & Fumnagalli R subtract from the CSF HCG value the component Paoletti (1969) Neurology (Minneapolis) 19, 190 attributable to diffusion from plasma and it Pavel S Journal ofClinical Endocrinology and Metabolism 31, 369 remains to be determined whether this provides a (1970) Rushwrth A G J, Orr A H & Bagshawe K D better guide than plasma/CSF ratio. (1968) British Journal of Cancer 22, 253 Shuttleworth E C Evidence that other intracranial tumours can (1972) in Experimental Tumor Research 17, 276 be detected in this way is scanty, but it may be TaismaProgress C K, Timberger R, Burdick It, Leavy M & Rawson R W noted that thyroxine (Hansen & Siersbaek- (1965) Journal Qf Clinical Endocrinology and Metabolism 25, 1493 J F, Ransohofi J & Kayden H J Nielsen 1969), arginine vasotocin (Pavel. 1970) Weiu (1972) Neurology (Minneapolis) 22, 187 and growth hormone (Linfoot et al. 1970) have Wilde C E, Orr A H & Bagshawe K D been measured in CSF. In the case of growth (1967) Journal of Endocrinology 37, 23 hormone the CSF values reported for 3 patients with suprasellar extensions of pituitary tumours were higher than the plasma concentrations. Surprisingly, the authors attributed this to a breakdown of the blood/brain barrier. These observations therefore raise the question of the operation of the blood/brain barrier with respect to products secreted by tumours. We have Mr J S Garfield no information about the route of entry of HCG (Wessex Neurological Centre, from blood into CSF and vice versa, but our Southampton General Hospital, evidence suggests that this is determined by Shirley, concentration gradients, possibly across the Southampton, S09 4XY) capillary endothelium. In the case of cerebral tumours, if the lesion is located on or very close Neurosurgical Aspects of Supratentorial to the ventricular or meningeal surfaces there may Malignant Gliomas be direct secretion into the CSF. In the case of lesions deep in the cerebral structure, the tumour The starting point of any discussion of manageproducts are presumably secreted into the small ment must be the natural history of the disease. extracellular fluid (ECF) compartment. Presum- Whether the natural history of any intracranial ably they may gain access from the ECF into the tumour can be ascertained is indeed doubtful, CSF since the reverse route from CSF into because without histological verification diagcerebral ECF, has been demonstrated by Bright- nosis cannot be assumed, while the very process man et al. (1970) for horseradish peroxidase of obtaining material for histological examination which has a molecular weight of 43 000 com- by burr hole biopsy or by craniotomy may signifiparable with that of HCG (40 000). In any case cantly influence the patient's progress either the fact that tumour products may be found in favourably or adversely. The subsequent course higher concentrations in CSF than in plasma cannot, therefore, be described as natural. rules out breakdown of the blood/brain barrier The long-accepted management of the patient as the sole mechanism for their presence in CSF. with a supratentorial mass, demonstrated radioThe detection and measurement of tumour logically, has been the establishment of pathology products in CSF may have a wide application and the removal of the tumour if benign. If when more of these substances have been malignant, and if access would not produce characterized. unacceptable deficit, the object of surgery has been to reduce tumour mass and thereby relieve pressure and distressing symptoms intracranial REFERENCES such as severe headache and failing visual Bagshawe K D, Orr A H & Rushworth A,G J (1968) Nature (London) 217,950 acuity. It might improve level of consciousness, Barone A (1948) Acta neurologica italiana 3, 434 but was not expected to improve focal neuroBrightman M W, Klatzo I, Olsson Y & Reese T S logical deficit. Decisions about ease of access (1970) Journal of the Neurological Sciences 10, 215 Currie G A (1974) Cancer and the Immune Response. were not difficult, in that frontal pole, occipital Edward Arnold, London pole and temporal lobe (particularly nonEhrhardt K (1931) Medizinische Klinik 27,426 Hansen J M & Siersbaek-Nielsen K dominant) masses were readily accessible. Mid(1969) Journal of Clinical Endocrinology and Metabolism 29, 1023 parietal or posterior parietal lesions were less Linfoot J A, Garcia J F, Wei W, Fink R, Sarin R & Born J L (1970) Journal of Clinical Endocrinology and Metabolism 31, 230 accessible in that surgery was likely to produce Long D M (1970) Journal of Neurosurgery 32, 127 unacceptable deficit, while deep lesions, particuMason D Y & Roberts-Thomson P larly thalamic and callosal, were not accessible (1974) Lancet ii, 938
54 Proc. roy. Soc. Med. Volume 69 January 1976
6
and the feasibility of internal decompression at craniotomy without producing unacceptable neurological deficit. The more accessible the The immediate results of this type of surgical site, the easier is the decision in favour of cranioapproach were satisfactory in terms of relief of tomy. The less accessible the site the more difficult raised intracranial pressure and rapid improve- is the decision because as the hazards of burr ment in level of consciousness. Unfortunately the hole biopsy are greater, so are the hazards of further results are generally dismal with average meddlesome surgery. overall survival of 2.2 months and average survival after craniotomy of 3.3 months. Indication for Internal Decompression Internal decompression by removal of tumour Needfor Histological Verification tissue is done either as part of a life-saving or It is still a reasonable dictum, that no patient distress-relieving procedure and/or as part of the should be allowed to die without histological establishment of the pathology, and the results verification. Accepting the constraints of site in the former circumstances can be dramatic. already mentioned, there is little problem, there- However, it remains very doubtful whether infore, when we are faced with a patient who is ternal decompression achieves more than this, steadily and rapidly deteriorating and is likely and there is very little evidence to suggest that it to die within hours or days. The decision is far improves the natural history of the disease more difficult in the patient who is neither beyond the temporary relief, at least in the astroseriously disabled nor dying, because biopsy cytomas of Kernohan Grade 3 or 4 malignancy. itself may produce deficit and hasten demise and If this is so, an ethical question arises: Is it right because verification of an astrocytoma of Grade to save the dying patient in the knowledge that he 3 or 4 malignancy will not generally lead to and his family will inevitably have to face his treatment which will improve prognosis. Carotid decline again, probably within the next three or angiography is of great value in showing con- six months? At the time the decision has to be clusively meningiomas and gliomas by the pre- made after balancing this defeatist view against sence of the appropriate type of pathological the more optimistic that the lesion might not be circulation. But both meningiomas and gliomas malignant, that it might be encephalitic rather may be avascular masses as also may cerebral than neoplastic and that even if malignant the abscess. Conversely, both meningiomas and patient may be one of the few who will survive abscess may have a pathological circulation for many years. Provided the patient's quality of which is hard to distinguish from that of malig- survival is not distressing (such as aphasia and nant glioma and to allow a patient to die with hemiplegia) most neurosurgeons will pursue an either an accessible meningioma or an abscess is aggressive course and save life by craniotomy, a disaster. It is this fear of occasional disaster but we should continue to be aware that our which leads to the neurosurgeon's unease at not treatment frequently does not provide the happiest obtaining histological verification. The use of the result for the patient and his family, whereas burr EMI scan has greatly improved the accuracy of hole biopsy might have done so. intracranial diagnosis, but has not removed the need for histological verification. In addition the Extent of Tumour Removal accurate assessment of methods of treatment such The typical supratentorial glioma lacks any clear line of demarcation macroscopically, and histoas chemotherapy demands histological diagnosis. logically the change from normal brain to tumour is gradual and, therefore, truly total Method of Histological Verification The two surgical methods are burr hole biopsy removal of the tumour is impossible. Whether and craniotomy and often the choice of which to removal of tumour beyond the point that is use is difficult. The advantages of burr hole necessary to achieve an internal decompression biopsy are that it is rapid, cheap, prevents improves length of survival is unproven. In an meddlesome surgery, and provides the correct attempt to determine the advantages of extensive therapy for the unexpected cerebral abscess. Its removal we are examining the wall of the residual disadvantages are failure of diagnosis, the pre- cavities by multiple biopsies, and will later seek cipitation of hemorrhage which cannot be correlation between these histological appearcontrolled, and deterioration in the patient's ances and length of survival. neurological state. Craniotomy is more likely to Extent of tumour removal and thereby achieve diagnosis without hemorrhage or deterioration, producing at the same time an reduction of volume of malignant tissue probably internal decompression. The choice of method improves the effectiveness of radiotherapy and will depend upon the likelihood of malignancy chemotherapy. although the evidence is by no
and were neither biopsied nor was more extensive removal attempted.
7
Section of Oncology
55
means conclusive. Weir (1973) found that total Nonsurgical Management compared with subtotal removal did not improve The use of dexamethasone has made decisions long-term survival in irradiated and non- about surgical management more difficult. irradiated groups. Taveras et al. (1962) found that Whereas radiotherapy and conventional chemopartial removal followed by irradiation produced therapy are not usually started without histobetter survival at six months than biopsy and logical verification, there are often grounds for irradiation, but only in those patients who sur- giving dexamethasone without it. The remarkable vived for 30 days postoperatively, suggesting and long-lasting response of some patients to that extent of tumour removal only affected dexamethasone makes it unlikely that the effect is immediate postoperative survival and did not only to reduce surrounding cerebral cedema. influence radiotherapy. Hitchcock & Sato (1964) did not find any statistically significant difference Therefore dexamethasone encourages the surin immediate survival between external de- geon to defer histological verification in patients compression with radiotherapy and tumour whose investigations are consistent with. a maligremoval with radiotherapy; The better prognosis nant glioma particularly in sites to which surgical of frontal pole tumours treated by surgery and access is hazardous, a course that accepts radiotherapy recorded by Ramsey & Brand (1973) possible error in diagnosis. may be a reflection of their suitability for more radical excision. Similar problems arise in the Unfortunately the widespread use of dexaassessment of the apparently encouraging results methasone makes the interpretation of the results of chemotherapy, particularly using BCNU and of other forms of chemotherapy and radiotherapy CCNU in continuation with irradiation following difficult. Chemotherapeutic trials which disregard these effects and particularly those in surgery as described by Walker (1973). which steroids are given in doses necessary to Our own work on intracavitary chemotherapy, maintain the patient in a reasonable neurological first using methotrexate (Garfield & Dayan 1973) state are of limited value. Provided the dosage and and later BCNU, assumed that reduction of use of dexamethasone is standardized its use may tumour mass would improve the effect of any be acceptable in other trials, although tumours chemotherapeutic agent. The studies were limited show a remarkable variation in response. to assessing the feasibility and duration of the REFERENCES method of drug administration, neurological Garfield J & Dayan A D complications, systemic toxicity, maximal dosage (1973) Journal of Neurosurgery 39, 315-322 and tumour pathology at operation and autopsy. Hitchcock E & Sato F (1964) Journal of Neurosurgery 21, 497 Neither radiotherapy nor steroids were given. Ramsey R G & Brand W N The simple catheter system was left in position (1973) Journal of Neurosurgery 39, 197 J M, Thompson H G & Pool J L for up to 44 days. Immediate neurological Taveras (1962) American Journal of Roentgenology 87, 473-479 complications were due to volume and position Walker M D of catheter tip and only to concentration with (1973) Cancer Chemotherapy Reports (Part 3) 4, No. 3, 21-26 BCNU above 10 mg/mi. System toxicity occurred Weir B (1973) Journal of Neurosurgery 38, 448-452 with methotrexate but not with BCNU despite maximum dosages of up to 1000 mg in 12 days. Methotrexate produced a zone of necrosis and cedema around the walls of the operation cavity and any residual tumour but this was impossible to quantify. BCNU produced a zone of acute necrosis in the wall of the cavity to a depth of The following paper was also read: 0.8-1.5 cm and a noticeable increase in the extent of pleomorphism in the tumours from long- Diagnostic Methods, in particular survival patients, but length of survival did not the EMI Scanner differ from that obtained with conventional Dr J A E Ambrose methods of treatment, there being one patient (Atkinson Morley's Hospital, alive and well 4j years after BCNU therapy. Wimbledon, London SW20)
Section of Oncology
53
A part coming from the blood plasma due to Mathiew (1939) American Journal Obstetrics & Gynecology 37, 654 systemic tumour and part by more direct export Newman J, Josephson A S,of Cacatian A & Tsang A into cerebral ECF. Calculations can be made to (1974) Lancet ii, 756 P, Vandenheuvel F A & Fumnagalli R subtract from the CSF HCG value the component Paoletti (1969) Neurology (Minneapolis) 19, 190 attributable to diffusion from plasma and it Pavel S Journal ofClinical Endocrinology and Metabolism 31, 369 remains to be determined whether this provides a (1970) Rushwrth A G J, Orr A H & Bagshawe K D better guide than plasma/CSF ratio. (1968) British Journal of Cancer 22, 253 Shuttleworth E C Evidence that other intracranial tumours can (1972) in Experimental Tumor Research 17, 276 be detected in this way is scanty, but it may be TaismaProgress C K, Timberger R, Burdick It, Leavy M & Rawson R W noted that thyroxine (Hansen & Siersbaek- (1965) Journal Qf Clinical Endocrinology and Metabolism 25, 1493 J F, Ransohofi J & Kayden H J Nielsen 1969), arginine vasotocin (Pavel. 1970) Weiu (1972) Neurology (Minneapolis) 22, 187 and growth hormone (Linfoot et al. 1970) have Wilde C E, Orr A H & Bagshawe K D been measured in CSF. In the case of growth (1967) Journal of Endocrinology 37, 23 hormone the CSF values reported for 3 patients with suprasellar extensions of pituitary tumours were higher than the plasma concentrations. Surprisingly, the authors attributed this to a breakdown of the blood/brain barrier. These observations therefore raise the question of the operation of the blood/brain barrier with respect to products secreted by tumours. We have Mr J S Garfield no information about the route of entry of HCG (Wessex Neurological Centre, from blood into CSF and vice versa, but our Southampton General Hospital, evidence suggests that this is determined by Shirley, concentration gradients, possibly across the Southampton, S09 4XY) capillary endothelium. In the case of cerebral tumours, if the lesion is located on or very close Neurosurgical Aspects of Supratentorial to the ventricular or meningeal surfaces there may Malignant Gliomas be direct secretion into the CSF. In the case of lesions deep in the cerebral structure, the tumour The starting point of any discussion of manageproducts are presumably secreted into the small ment must be the natural history of the disease. extracellular fluid (ECF) compartment. Presum- Whether the natural history of any intracranial ably they may gain access from the ECF into the tumour can be ascertained is indeed doubtful, CSF since the reverse route from CSF into because without histological verification diagcerebral ECF, has been demonstrated by Bright- nosis cannot be assumed, while the very process man et al. (1970) for horseradish peroxidase of obtaining material for histological examination which has a molecular weight of 43 000 com- by burr hole biopsy or by craniotomy may signifiparable with that of HCG (40 000). In any case cantly influence the patient's progress either the fact that tumour products may be found in favourably or adversely. The subsequent course higher concentrations in CSF than in plasma cannot, therefore, be described as natural. rules out breakdown of the blood/brain barrier The long-accepted management of the patient as the sole mechanism for their presence in CSF. with a supratentorial mass, demonstrated radioThe detection and measurement of tumour logically, has been the establishment of pathology products in CSF may have a wide application and the removal of the tumour if benign. If when more of these substances have been malignant, and if access would not produce characterized. unacceptable deficit, the object of surgery has been to reduce tumour mass and thereby relieve pressure and distressing symptoms intracranial REFERENCES such as severe headache and failing visual Bagshawe K D, Orr A H & Rushworth A,G J (1968) Nature (London) 217,950 acuity. It might improve level of consciousness, Barone A (1948) Acta neurologica italiana 3, 434 but was not expected to improve focal neuroBrightman M W, Klatzo I, Olsson Y & Reese T S logical deficit. Decisions about ease of access (1970) Journal of the Neurological Sciences 10, 215 Currie G A (1974) Cancer and the Immune Response. were not difficult, in that frontal pole, occipital Edward Arnold, London pole and temporal lobe (particularly nonEhrhardt K (1931) Medizinische Klinik 27,426 Hansen J M & Siersbaek-Nielsen K dominant) masses were readily accessible. Mid(1969) Journal of Clinical Endocrinology and Metabolism 29, 1023 parietal or posterior parietal lesions were less Linfoot J A, Garcia J F, Wei W, Fink R, Sarin R & Born J L (1970) Journal of Clinical Endocrinology and Metabolism 31, 230 accessible in that surgery was likely to produce Long D M (1970) Journal of Neurosurgery 32, 127 unacceptable deficit, while deep lesions, particuMason D Y & Roberts-Thomson P larly thalamic and callosal, were not accessible (1974) Lancet ii, 938
54 Proc. roy. Soc. Med. Volume 69 January 1976
6
and the feasibility of internal decompression at craniotomy without producing unacceptable neurological deficit. The more accessible the The immediate results of this type of surgical site, the easier is the decision in favour of cranioapproach were satisfactory in terms of relief of tomy. The less accessible the site the more difficult raised intracranial pressure and rapid improve- is the decision because as the hazards of burr ment in level of consciousness. Unfortunately the hole biopsy are greater, so are the hazards of further results are generally dismal with average meddlesome surgery. overall survival of 2.2 months and average survival after craniotomy of 3.3 months. Indication for Internal Decompression Internal decompression by removal of tumour Needfor Histological Verification tissue is done either as part of a life-saving or It is still a reasonable dictum, that no patient distress-relieving procedure and/or as part of the should be allowed to die without histological establishment of the pathology, and the results verification. Accepting the constraints of site in the former circumstances can be dramatic. already mentioned, there is little problem, there- However, it remains very doubtful whether infore, when we are faced with a patient who is ternal decompression achieves more than this, steadily and rapidly deteriorating and is likely and there is very little evidence to suggest that it to die within hours or days. The decision is far improves the natural history of the disease more difficult in the patient who is neither beyond the temporary relief, at least in the astroseriously disabled nor dying, because biopsy cytomas of Kernohan Grade 3 or 4 malignancy. itself may produce deficit and hasten demise and If this is so, an ethical question arises: Is it right because verification of an astrocytoma of Grade to save the dying patient in the knowledge that he 3 or 4 malignancy will not generally lead to and his family will inevitably have to face his treatment which will improve prognosis. Carotid decline again, probably within the next three or angiography is of great value in showing con- six months? At the time the decision has to be clusively meningiomas and gliomas by the pre- made after balancing this defeatist view against sence of the appropriate type of pathological the more optimistic that the lesion might not be circulation. But both meningiomas and gliomas malignant, that it might be encephalitic rather may be avascular masses as also may cerebral than neoplastic and that even if malignant the abscess. Conversely, both meningiomas and patient may be one of the few who will survive abscess may have a pathological circulation for many years. Provided the patient's quality of which is hard to distinguish from that of malig- survival is not distressing (such as aphasia and nant glioma and to allow a patient to die with hemiplegia) most neurosurgeons will pursue an either an accessible meningioma or an abscess is aggressive course and save life by craniotomy, a disaster. It is this fear of occasional disaster but we should continue to be aware that our which leads to the neurosurgeon's unease at not treatment frequently does not provide the happiest obtaining histological verification. The use of the result for the patient and his family, whereas burr EMI scan has greatly improved the accuracy of hole biopsy might have done so. intracranial diagnosis, but has not removed the need for histological verification. In addition the Extent of Tumour Removal accurate assessment of methods of treatment such The typical supratentorial glioma lacks any clear line of demarcation macroscopically, and histoas chemotherapy demands histological diagnosis. logically the change from normal brain to tumour is gradual and, therefore, truly total Method of Histological Verification The two surgical methods are burr hole biopsy removal of the tumour is impossible. Whether and craniotomy and often the choice of which to removal of tumour beyond the point that is use is difficult. The advantages of burr hole necessary to achieve an internal decompression biopsy are that it is rapid, cheap, prevents improves length of survival is unproven. In an meddlesome surgery, and provides the correct attempt to determine the advantages of extensive therapy for the unexpected cerebral abscess. Its removal we are examining the wall of the residual disadvantages are failure of diagnosis, the pre- cavities by multiple biopsies, and will later seek cipitation of hemorrhage which cannot be correlation between these histological appearcontrolled, and deterioration in the patient's ances and length of survival. neurological state. Craniotomy is more likely to Extent of tumour removal and thereby achieve diagnosis without hemorrhage or deterioration, producing at the same time an reduction of volume of malignant tissue probably internal decompression. The choice of method improves the effectiveness of radiotherapy and will depend upon the likelihood of malignancy chemotherapy. although the evidence is by no
and were neither biopsied nor was more extensive removal attempted.
7
Section of Oncology
55
means conclusive. Weir (1973) found that total Nonsurgical Management compared with subtotal removal did not improve The use of dexamethasone has made decisions long-term survival in irradiated and non- about surgical management more difficult. irradiated groups. Taveras et al. (1962) found that Whereas radiotherapy and conventional chemopartial removal followed by irradiation produced therapy are not usually started without histobetter survival at six months than biopsy and logical verification, there are often grounds for irradiation, but only in those patients who sur- giving dexamethasone without it. The remarkable vived for 30 days postoperatively, suggesting and long-lasting response of some patients to that extent of tumour removal only affected dexamethasone makes it unlikely that the effect is immediate postoperative survival and did not only to reduce surrounding cerebral cedema. influence radiotherapy. Hitchcock & Sato (1964) did not find any statistically significant difference Therefore dexamethasone encourages the surin immediate survival between external de- geon to defer histological verification in patients compression with radiotherapy and tumour whose investigations are consistent with. a maligremoval with radiotherapy; The better prognosis nant glioma particularly in sites to which surgical of frontal pole tumours treated by surgery and access is hazardous, a course that accepts radiotherapy recorded by Ramsey & Brand (1973) possible error in diagnosis. may be a reflection of their suitability for more radical excision. Similar problems arise in the Unfortunately the widespread use of dexaassessment of the apparently encouraging results methasone makes the interpretation of the results of chemotherapy, particularly using BCNU and of other forms of chemotherapy and radiotherapy CCNU in continuation with irradiation following difficult. Chemotherapeutic trials which disregard these effects and particularly those in surgery as described by Walker (1973). which steroids are given in doses necessary to Our own work on intracavitary chemotherapy, maintain the patient in a reasonable neurological first using methotrexate (Garfield & Dayan 1973) state are of limited value. Provided the dosage and and later BCNU, assumed that reduction of use of dexamethasone is standardized its use may tumour mass would improve the effect of any be acceptable in other trials, although tumours chemotherapeutic agent. The studies were limited show a remarkable variation in response. to assessing the feasibility and duration of the REFERENCES method of drug administration, neurological Garfield J & Dayan A D complications, systemic toxicity, maximal dosage (1973) Journal of Neurosurgery 39, 315-322 and tumour pathology at operation and autopsy. Hitchcock E & Sato F (1964) Journal of Neurosurgery 21, 497 Neither radiotherapy nor steroids were given. Ramsey R G & Brand W N The simple catheter system was left in position (1973) Journal of Neurosurgery 39, 197 J M, Thompson H G & Pool J L for up to 44 days. Immediate neurological Taveras (1962) American Journal of Roentgenology 87, 473-479 complications were due to volume and position Walker M D of catheter tip and only to concentration with (1973) Cancer Chemotherapy Reports (Part 3) 4, No. 3, 21-26 BCNU above 10 mg/mi. System toxicity occurred Weir B (1973) Journal of Neurosurgery 38, 448-452 with methotrexate but not with BCNU despite maximum dosages of up to 1000 mg in 12 days. Methotrexate produced a zone of necrosis and cedema around the walls of the operation cavity and any residual tumour but this was impossible to quantify. BCNU produced a zone of acute necrosis in the wall of the cavity to a depth of The following paper was also read: 0.8-1.5 cm and a noticeable increase in the extent of pleomorphism in the tumours from long- Diagnostic Methods, in particular survival patients, but length of survival did not the EMI Scanner differ from that obtained with conventional Dr J A E Ambrose methods of treatment, there being one patient (Atkinson Morley's Hospital, alive and well 4j years after BCNU therapy. Wimbledon, London SW20)
