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What is the Optimal Therapy of Brain Metastases?
Clinical Oncology (2001)13:105–111 # The Royal College of Radiologists
Clinical Oncology
Original Article What is the Optimal Therapy of Brain Metastases? Y. Marcou1, C. Lindquist2, C. Adams3, S. Retsas4 and P. N. Plowman1 1
St Bartholomew’s Hospital, London, 2Cromwell Hospital, London, 3Radcliffe Hospital, Oxford and Charing Cross Hospital, London, UK
4
Abstract. The conclusions of a symposium held in London in October 1999 and devoted to the optimal management of brain metastatic disease were: 1. Prognostic factors are: size and number of metastases (and the presence of mass effect); the status of the systemic cancer outside the central nervous system; performance/neurological status; the age of the patient; and the type of cancer. 2. Surgical management of the single, superficially located brain metastasis with symptomatic mass effect is recommended in good performance status patients. Many would follow this routinely by whole brian radiotherapy. 3. Whole brain radiotherapy is often not followed by durable control of the disease and carries morbidity; better management plans are required. In poor prognosis patients the delivery of radiotherapy may not always be indicated. 4. The current literature demonstrates that stereotactic radiosurgery can enhance the likelihood of sterilizing individual brain metastases compared with whole brain radiotherapy alone. 5. The results of questionnaire showed that the histological diagnosis and latency to onset made little difference to the opinion of neuroscience clinicians, who generally favoured stereotactic radiation therapy over whole brain radiotherapy (with or without a conventionally delivered boost) for all patients with less than four metastases. The opinions of oncologists differed. For bronchial and breast cancer patients, whole brain radiotherapy, with or without a boost, was favoured by the majority, particularly in oat cell cancer. However, with a long latency to ‘isolated’ brain metastasis, oncologists favoured focal radiation therapy. There was a strong preference amongst oncology experts to reserve stereotactic radiation therapy for apparently isolated brain metastasis; this opinion applied to bronchus and breast cancer, and also to melanoma. 6. Whole brain radiotherapy followed by positron emission tomography scanning to determine what viable metastatic disease remained (and potentially treatable by stereotactic/focal technology) was favoured by most of delegates who answered this question. Keywords: Brain metastases; Radiotherapy; Stereotactic radiosurgery; Surgery
Introduction Brain metastases occur in 20%–30% of patients with systemic cancer [1,2], causing symptoms frightening to the patient; untreated, they are very often the cause of rapid death. In most reported series, whole brain courses of conventionally fractionated radiotherapy extend life by 15–18 weeks, the maximum benefit being in those with good neurological status (inextricably linked to less critical number/extent/ volume/critical site/mass effect of brain metastases present) [3]. Better prognosis/neurological status Correspondence and offprint requests to: Dr P. N. Plowman, Department of Radiotherapy, St Bartholomew’s Hospital, London EC1A 7BE, UK.
patients derive longer survival benefit than the just quoted mean figure, providing their systemic cancer is not imminently life threatening [4]. In this retrospective analysis of Radiation Therapy Oncology Group (RTOG) trials, patients aged under 65 years, with a Karnofsky performance status (KPS) of 70 or more, a controlled primary tumour, and no systemic metastases, had a median survival of over 7 months, whereas patients with a KPS of under 70 had a median survival of only 2.3 months [4]. The radiotherapy dose prescription has been in the range 40 Gy over 3 weeks to 20 Gy over 1 week (week-daily fractionation), within which there are no apparent differences in the outcome [5–7]. Most practitioners settled for 30 Gy in 2 weeks after publication of the data just cited around the year
1980; radiotherapeutic minds became set and the subject was little discussed in the literature for over a decade or longer. Noting that patients with a solitary and operable brain metastasis seemed to have a better prognosis if operated on to resect the lesion (perhaps as a diagnostic procedure), at least two trials in the 1980s and one in the 1990s demonstrated that surgical resection of an apparently single brain metastasis followed by whole brain radiotherapy was attended by longer survival than that that followed whole brain radiotherapy alone [8–10]. The Mayo Clinic analysis looked at the problem the other way around: can surgical resection of an apparently isolated metastasis alone be all that is needed? The risk of subsequent brain relapse was reduced from 85% to 21% if postoperative radiotherapy was delivered, demonstrating that surgical resection of an apparently isolated metastasis was not ‘enough’ treatment by itself [11]. Thus, an aggressive local (surgical) therapy, followed by a whole brain radiotherapy approach, became best standard practice for the operable single brain metastasis in a patient with good systemic control of cancer. However, it was questioned whether an obliterative radiosurgical dose could not substitute the surgical procedure. During the 1990s, the technique of obliterative, single-fraction, stereotactically delivered radiation therapy (radiosurgery) has been developed to a high degree of precision and safety, the advances in the last decade coming from great strides in the sophistication of planning and imaging programmes. It was natural that the clinicians who were practising radiosurgery would examine its effects in metastatic disease. A manuscript from the Gamma Knife radiosurgery unit at Pittsburgh described high efficacy and concluded that ‘stereotactic radiosurgery eliminated the surgical and anaesthetic risks of craniotomy and resection of solitary metastasis’ [12]. There followed an appraisal by others of the optimum criteria for selection. A multi-institutional study concluded that radiosurgery in conjunction with whole brain radiotherapy can produce substantial advantages over whole brain radiotherapy alone [13]. The patients selected for this study recapitulated the selection criteria that were used for Patchell et al.’s [9] surgery/radiotherapy study and, like other authors, Auchter et al. [13] concluded that the most powerful predictors of long survival in this patient group were a high performance status and the absence of other systemic metastases at the time of presentation with a brain metastasis. Recent studies on the role of radiotherapy in the treatment of brain metastases have been more interpretable because they have been cognizant of the established prognostic factors for this patient group: (a) age; (b) performance status; (c) number of brain metastases; (d) size and presence or absence of 106
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symptomatic mass effect; and (e) histology of the primary. In 1998, Pirzkall et al. [14] reported a large trial involving 236 patients with up to three brain metastases and a KPS of greater than 50, who received either whole brain radiotherapy with a radiosurgery boost or radiosurgery alone. The whole brain radiotherapy demonstrably delivered protection against further brain metastases and the median survival of patients receiving both treatments was almost double (15.4 versus 8.3 months) that in the radiosurgery arm alone. The response to radiosurgical treatment, in terms of local control of the treated lesions, seemed relatively independent of the histological diagnosis of the primary (relapses: 5/75 bronchial carcinoma; 4/47 melanoma; 4/53 renal carcinoma; 1/17 colorectal carcinoma; and 1/13 breast carcinoma), although the histology probably predicts for the risk of other metastases. In this trial, as in others, age, performance status and size of metastases were prognostically predictive. In 1999, Kondziolka et al. [15] reported a small trial of patients with two to four brain metastases, none being greater than 2.5 cm in diameter and with patients having an KPS of 70 or greater. These patients received either whole brain radiotherapy alone or whole brain radiotherapy with a radiosurgical boost. This boost could precede, occur concurrently with or follow, within a month, the whole brain radiotherapy course. The rate of local failure at 1 year was 100% after whole brain radiotherapy alone versus 8% in patients who had received a radiosurgical boost. There was also a significant survival gain (11 months versus 7.5 months). Two editorials in the leading radiotherapy journal of North America have debated the role of local therapy in the optimal management of brain metastases within the last 5 years. Loeffler and Shrieve [16] emphasized the fact that better prognosis patients could be identified, as discussed above, and argued that stereotactic radiosurgery could be a substitute for surgery when local therapy was needed. With regard to the recent editorial that accompanied the Pittsburgh article, Shaw [17] posed the question of whether all patients with two to four metastases should be routinely treated with surgery or radiosurgery. He rhetorically answered ‘no’, but reasoned that a subset of good prognosis patients (under 65 years; good KPS; controlled extracranial disease; and Pittsburgh criteria for acceptance of brain metastases) were candidates for a more aggressive approach than the heavily criticized ‘30 Gy in ten fractions’ dose prescription of conventional megavoltage photon radiotherapy, which is the most widely prescribed radiotherapy schedule for brain metastatic disease delivered in the UK at present [17]. On 16 October 1999, a symposium held in London for representatives of the disciplines of neurosurgery, neurology, radiotherapy and medical oncology de-
bated the optimal management of brain metastases at the end of the twentieth century. This article presents the views of the delegates, based on discussions and a questionnaire, collated by the main speakers at the symposium. Conference delegates who contributed to the optional questionnaire came from all parts of the UK, mainland Europe, Scandinavia and the USA. A bias in the results presented here could have been introduced by the self-selection process by which only clinicians interested in a more aggressive approach to brain metastatic disease would have registered for the conference.
Materials and Methods The composition of delegates filling in the questionnaire was: oncology graduates 25, neurosciences 11, others 1 (Fig. 1). The questionnaire consisted of the following: Delegates, please circle the answer number that you think is most appropriate. Name of delegate ................................................................. Specialization in medicine ................................................... A. What would you recommend for a young, good performance status patient who relapses with an inoperable, deep seated and apparently single brain metastasis less than 3 cm diameter and without mass effect, 2 years after resection of a colonic carcinoma, there being no other obvious site of metastatic disease on scanning? 1. Whole brain, conventionally fractionated radiotherapy? 2. Whole brain radiotherapy and a boost to the site of the lesion – either conventional techniques or stereotactic boost radiation?
3. Stereotactic radiation only? B. What would you recommend if the patient’s primary had been a melanoma? 1. Whole brain, conventionally fractionated radiotherapy? 2. Whole brain radiotherapy and a boost to the site of the lesion – either conventional techniques or stereotactic boost radiation? 3. Stereotactic radiation only? C. What would you recommend if the primary had been bronchial cancer (non-oat cell) and the interval to diagnosis of the ‘solitary’ metastasis had been 6 months? 1. Whole brain, conventionally fractionated radiotherapy? 2. Whole brain radiotherapy and a boost to the site of the lesion – either conventional techniques or stereotactic boost radiation? 3. Stereotactic radiation only? D. What would you recommend if the primary had been bronchial cancer (oat cell) – no cranial radiotherapy prophylaxis – and the interval to diagnosis of the ‘solitary’ metastasis had been 6 months? 1. Whole brain, conventionally fractionated radiotherapy? 2. Whole brain radiotherapy and a boost to the site of the lesion – either conventional techniques or stereotactic boost radiation? 3. Stereotactic radiation only? E. What would you recommend if the primary had been a breast carcinoma and the interval to diagnosis of the ‘solitary’ brain metastasis had been 6 months? 1. Whole brain, conventionally fractionated radiotherapy? 2. Whole brain radiotherapy and a boost to the site of the lesion – either conventional techniques or stereotactic boost radiation? 3. Stereotactic radiation only? F. What would you recommend if the primary had been a breast carcinoma and the interval to diagnosis of the ‘solitary’ metastasis had been 6 years? 1. Whole brain, conventionally fractionated radiotherapy? 2. Whole brain radiotherapy and a boost to the site of the lesion – either conventional techniques or stereotactic boost radiation? 3. Stereotactic radiation only? G. Do you believe that you can do better for good performance status patients with multiple brain metastases than 30 Gy in ten fractions of whole brain radiotherapy? 1. Yes 2. No H. Do you believe that we should be exploring stereotactic radiation therapy to individual brain metastases as defined by magnetic resonance imaging? 1. Yes 2. No
Fig. 1. Pie chart of the distribution of delegates by medical specialty.
I. Do you believe that stereotactic radiosurgical technology should be used only as boost therapy, after conventionally fractionated wide field brain radiotherapy? 1. Yes 2. No What is the Optimal Therapy of Brain Metastases?
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J. Do you think PET scanning has a role in defining the population of post-whole brain radiotherapy patients who would potentially benefit from such a stereotactic boost? 1. Yes 2. No K. Do you believe there is a selective role for primary/ definitive stereotactic radiosurgery alone? 1. Yes 2. No L. Do you believe that there should be a cap on the number of metastases that should be treated with a primary/ definitive stereotactic radiosurgery strategy? 1. Unrestricted? 2. Less than four metastases? 3. Less than three metastases? 4. Reserved for single metastases only?
a
M. Should this strategy be modified depending on the original primary tumour’s histology, for example: If the primary tumour was melanoma: 1. Unrestricted? 2. Less than four metastases? 3. Less than three metastases? 4. Reserved for single metastases?
b Fig. 2. On the questions of: (a) whether we can improve on conventional palliative whole brain radiotherapy; and (b) whether we should explore stereotactic technology further in this disease.
If the primary tumour was breast: 1. Unrestricted? 2. Less than four metastases? 3. Less than three metastases? 4. Reserved for single metastases? If the primary tumour was bronchus (non-oat cell): 1. Unrestricted? 2. Less than four metastases? 3. Less than three metastases? 4. Reserved for single metastases?
a
Results Most delegates thought that the delivery of whole brain radiotherapy (specifically whole brain radiotherapy to 30 Gy in ten fractions, already noted to be the most commonly used regimen delivered in the UK at present) could be bettered and that stereotactic radiation therapy should be explored further (Fig. 2). The majority of delegates thought that there was a selective role for the use of stereotactic radiotherapy alone in the treatment of brain metastases (Figs 3–5). In the treatment of single brain metastases from lung cancer (oat cell and non-oat cell) oncologists favoured the whole brain approach (e.g. 92% recommending this in oat cell cancer). For breast cancer, replies were slightly different. When there was the early appearance of an apparently isolated brain metastasis (at 6 months from diagnosis) oncologists favoured whole brain radiotherapy. However, when the metastasis occurred 6 years from diagnosis, they were much more in favour of 108
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b
c Fig. 3. On the approach to the use of stereotactic radiosurgery by histology of the primary and the medical disciplines. (a) Single brain metastasis, 2 years after resection of colonic carcinoma. (b) Bronchial cancer (non-oat cell), single metastasis 6 months after diagnosis. (c) Oat cell cancer, single metastasis 6 months after diagnosis.
a
a
b Fig. 4. On the approach to the use of stereotactic radiosurgery for isolated brain metastasis from carcinoma of breast, particularly with respect to the latency to onset of the disease from the initial presentation of the primary: (a) 6 months after diagnosis; (b) 6 years after diagnosis.
stereotactic radiation therapy, the majority recommending stereotactic radiosurgery alone (60%) or whole brain radiotherapy with a stereotactic boost (Fig. 4). The same response was given by oncologists when confronted with a late onset and apparently isolated brain metastasis from colonic carcinoma (Fig. 3). When asked concerning their approach to using stereotactic radiation therapy for more than one metastasis, an interesting analysis resulted. In bronchial cancer, there was a clear preference for using the technique, if at all, for an isolated metastasis. For breast cancer and, indeed, the perceived more radioresistant melanoma, there remained a preference for reserving stereotactic radiation therapy for a single metastasis, but the cumulative number of delegates voting for extending the number of metastases to two, three, or even an unlimited number, outnumbered those voting for restricting this technology to single metastasis (Fig. 5). Neuroscience graduates were more consistent in their views, irrespective of the histological type of primary tumour. They favoured greater use of stereotactic technology in both bronchial and breast cancer, the latter when the metastasis occurred 6 months or 6 years after the presenting primary; this was also their policy for colonic cancer and melanoma. Thus, histological subtype, site of the primary and latency to onset of the brain disease did not alter their approach to management. The neuroscience graduates favoured stereotactic radiosurgery for anything up to four metastases for all histologies (Figs 3–5). Only 78% of delegates ventured an opinion on whether positron emission tomographic (PET) scanning was useful. However, the majority of oncologists favoured the use of PET to define the subpopulation
b
c Fig. 5. On the approach to the use of stereotactic radiosurgery according to different numbers of cerebral metastases, histology and medical discipline: (a) breast; (b) bronchus; (c) melanoma.
of patients who would benefit from stereotactic radiation therapy administered as a boost after whole brain radiotherapy.
Discussion An overwhelming majority of delegates (89%) believed that the oncology community could do better than the whole brain/30/10 approach for brain metastases and that stereotactically directed focal radiotherapy should be further explored. By inference, we believe that this applies to the better prognosis patients. Whole brain radiotherapy by conventional fractionation is still the overall favoured treatment modality of the majority of oncologists for apparently single metastases from all histologies, with one exception: when there is a long latency period from diagnosis to the identification of an apparently single brain metastasis (we specifically instanced colon cancer at 2 years and breast cancer at 6 years in our questionnaire), then there was much more interest in the use of ‘up-front’ focal radiation therapy options. From our discussions at the symposium, rather than from the questionnaire, we found that oncologists would also consider focal radiation therapy for isolated relapses after whole brain radiotherapy in otherwise better than average prognosis patients. What is the Optimal Therapy of Brain Metastases?
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Neuroscience clinicians were much more interested in using radiosurgery ‘up-front’ in all histologies. Our perception of the advantage of these approaches is that whole brain radiotherapy forestalls other (nascent) metastases from developing (for breast and bronchus primaries this is a considerable hazard). The main disadvantages to the patient are: multiple trips to hospital, some languor and total scalp depilation. Loss of dignity from depilation in a patient population who will ultimately do badly was a discussion ponit made from the symposium floor as an argument against whole brain radiotherapy (M. Rice-Edwards). In general, neuroscience clinicians did not believe that histology (and by inference therefore the increased likelihood of oat cell cancer over perhaps colon cancer patients to develop other brain metastases), the latency period, or the number of metastases up to three (all higher risk factors for the development of other metastases) should alter the overall viewpoint. We infer a high level of dissatisfaction in the neuroscience community for the whole brain radiation approach. Oncology postgraduates were, overall, less ready to eschew whole brain radiotherapy and bring focal radiation therapy into primary therapy (with the exception of the late single metastasis) and were more against the use of radiosurgery for multiple metastases. We infer that oncologists would retain focal radiation therapy for the occasional problem metastasis in an otherwise better prognosis patient. PET scanning may be helpful in delineating such patients, whose cerebral metastases remain viable after whole brain radiotherapy. The debate now ensues on how these views, expressed as answers to a questionnaire and made after a series of lectures reviewing the literature on this subject, should be forwarded in UK practice. With increased access to stereotactic radiosurgical facilities (three gamma units and more than ten linear accelerator units currently practising in the UK) it would seem clear that further studies should be conducted utilizing this modality in better prognosis patients. We would suggest first selecting those tumours that are perceived to be more radioresistant and often having a longer natural history (e.g. kidney, colon and perhaps melanoma, when occurring as late and single or less than three brain metastases) and comparing whole brain radiotherapy with or without a conventional boost versus radiosurgery alone or as a boost to magnetic resonance (PET positive) imaged lesions. We conclude that more attention needs to be paid to the optimal therapy of brain metastatic disease, particularly in those patients with few adverse prognostic features. The indisputable capabilities of stereotactic radiosurgical facilities to ablate individual metastases successfully should be more fully studied in the future (Fig. 6). 110
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a
b Fig. 6. Coronal, T1 unenhanced magnetic resonance scans demonstrating an apparently isolated cerebellar peduncle metastasis from a melanoma. The patient was symptomatic from this metastasis and yet had no other systemic evidence of disease. This patient is perceived to do badly after conventionally fractionated wide field radiotherapy to the brain. (a) The lesion before radiosurgery and (b) the excellent regression 3 months after therapy.
Acknowledgements. We are grateful to the following for their contributions: C. Adams, S. Ahmed, A. Aldin, N. Ali, R. Amin, S. Awwad, T. Blackburn, M. Brada, C. Cotterill, M. Rice-Edwards, D. Eliopoupos, E. Eljamel, S. Ewan, J. Glees, N. Gupta, K. Hopkins, M. Howard,R. Joss, L. Kihlstrom, C. Lindquist, E. Laine, S. Mangar, Y. Marcou, T. Oliver, P. Pandey, R. Philips, P. Plowman, J. Pomeroy, J. Preston, S.
Retsas, V. Rothschild, N. Shackleton, M. Sharr, H. Taylor, A. Timothy and B. Walker
10.
References 1. Cairncross JG, Posner JB. The management of brain metastases. Cancer Treat Res 1983;12:341–77. 2. Pickren JW, Lopez G, Tzukada Y, et al. Brain metastases: an autopsy study. Cancer Treat Symptoms 1983;2:295– 313. 3. Borgelt B, Gelber R, Kramer S, et al. The palliaton of brain metastases: final results of the first two studies by the radiation therapy oncology group. Int J Radiat Oncol Biol Phys 1980;6:1–9. 4. Gaspar L, Scott C, Rotman M. et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997;37:745–51. 5. Hendrickson FR. The optimum schedule for palliative brain radiotherapy for metastatic brain cancer. Int J Radiat Oncol Biol Phys 1977;2:165–8. 6. Kurtz JM, Gelber R, Brady LW, et al. The palliation of brain metastases in a favourable patient population: a randomised clinical trial by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1981;7:891–5. 7. Gelber RD, Larson M, Borgelt BB, et al. Equivalence of radiation schedules for palliative treatment of brain metastases in patients with favorable prognosis. Cancer 1981;48:1749–53. 8. Madell L, Hilaris B, Sullivan M, et al. The treatment of single brain metastasis from non-oat cell lung cancer. Cancer 1986;58:641–9. 9. Patchell RA, Tibbs PA, Walsh JW, et al. A randomised
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14. 15.
16. 17.
trial of surgery in the treatment of single metastasis of the brain. N Engl J Med 1990;322:494–500. Noordijk EM, Vecht CJ, Reiche HH, et al. The choice of treatment of single brain metastasis should be based on extracranial tumour activity and age. Int J Radiat Oncol Biol Phys 1994;29:711–7. Smalley SR, Schray MF, Laws ER, et al. Adjuvant radiation therapy after surgical resection of solitary brain metastasis: association with pattern of failure and survival. Int J Radiat Oncol Biol Phys 1987;13:1611–6. Coffey RJ, Flickinger JC, Bissonette DJ, et al. Radiosurgery for solitary brain metastases using the cobalt-60 gamma unit: methods and results in 24 patients. Int J Radiat Oncol Biol Phys 1991;20:1287–95. Auchter RM, Lamond JP, Alexander E, et al. A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Int J Radiat Oncol Biol Phys 1996;35:27–35. Pirzkall A, Debus J, Lohr F, et al. Radiosurgery alone or in combination with whole brain radiotherapy for brain metastases. J Clin Oncol 1998;16:3563–9. Kondziolka D, Patel A, Lunsford LD, et al. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 1999;45:427–34. Loeffler JS, Shrieve DC. What is appropriate therapy for a patient with a single brain metastasis? Int J Radiat Oncol Biol Phys 1994;29:915–7. Shaw EG. Radiotherapeutic management of multiple brain metastases: ‘3000 in 10’ whole brain is no longer a ‘no brainer’. Int J Radiat Oncol Biol Phys 1999;45:253–4. Received for publication June 2000 Accepted October 2000
What is the Optimal Therapy of Brain Metastases?
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Clinical Oncology
Original Article What is the Optimal Therapy of Brain Metastases? Y. Marcou1, C. Lindquist2, C. Adams3, S. Retsas4 and P. N. Plowman1 1
St Bartholomew’s Hospital, London, 2Cromwell Hospital, London, 3Radcliffe Hospital, Oxford and Charing Cross Hospital, London, UK
4
Abstract. The conclusions of a symposium held in London in October 1999 and devoted to the optimal management of brain metastatic disease were: 1. Prognostic factors are: size and number of metastases (and the presence of mass effect); the status of the systemic cancer outside the central nervous system; performance/neurological status; the age of the patient; and the type of cancer. 2. Surgical management of the single, superficially located brain metastasis with symptomatic mass effect is recommended in good performance status patients. Many would follow this routinely by whole brian radiotherapy. 3. Whole brain radiotherapy is often not followed by durable control of the disease and carries morbidity; better management plans are required. In poor prognosis patients the delivery of radiotherapy may not always be indicated. 4. The current literature demonstrates that stereotactic radiosurgery can enhance the likelihood of sterilizing individual brain metastases compared with whole brain radiotherapy alone. 5. The results of questionnaire showed that the histological diagnosis and latency to onset made little difference to the opinion of neuroscience clinicians, who generally favoured stereotactic radiation therapy over whole brain radiotherapy (with or without a conventionally delivered boost) for all patients with less than four metastases. The opinions of oncologists differed. For bronchial and breast cancer patients, whole brain radiotherapy, with or without a boost, was favoured by the majority, particularly in oat cell cancer. However, with a long latency to ‘isolated’ brain metastasis, oncologists favoured focal radiation therapy. There was a strong preference amongst oncology experts to reserve stereotactic radiation therapy for apparently isolated brain metastasis; this opinion applied to bronchus and breast cancer, and also to melanoma. 6. Whole brain radiotherapy followed by positron emission tomography scanning to determine what viable metastatic disease remained (and potentially treatable by stereotactic/focal technology) was favoured by most of delegates who answered this question. Keywords: Brain metastases; Radiotherapy; Stereotactic radiosurgery; Surgery
Introduction Brain metastases occur in 20%–30% of patients with systemic cancer [1,2], causing symptoms frightening to the patient; untreated, they are very often the cause of rapid death. In most reported series, whole brain courses of conventionally fractionated radiotherapy extend life by 15–18 weeks, the maximum benefit being in those with good neurological status (inextricably linked to less critical number/extent/ volume/critical site/mass effect of brain metastases present) [3]. Better prognosis/neurological status Correspondence and offprint requests to: Dr P. N. Plowman, Department of Radiotherapy, St Bartholomew’s Hospital, London EC1A 7BE, UK.
patients derive longer survival benefit than the just quoted mean figure, providing their systemic cancer is not imminently life threatening [4]. In this retrospective analysis of Radiation Therapy Oncology Group (RTOG) trials, patients aged under 65 years, with a Karnofsky performance status (KPS) of 70 or more, a controlled primary tumour, and no systemic metastases, had a median survival of over 7 months, whereas patients with a KPS of under 70 had a median survival of only 2.3 months [4]. The radiotherapy dose prescription has been in the range 40 Gy over 3 weeks to 20 Gy over 1 week (week-daily fractionation), within which there are no apparent differences in the outcome [5–7]. Most practitioners settled for 30 Gy in 2 weeks after publication of the data just cited around the year
1980; radiotherapeutic minds became set and the subject was little discussed in the literature for over a decade or longer. Noting that patients with a solitary and operable brain metastasis seemed to have a better prognosis if operated on to resect the lesion (perhaps as a diagnostic procedure), at least two trials in the 1980s and one in the 1990s demonstrated that surgical resection of an apparently single brain metastasis followed by whole brain radiotherapy was attended by longer survival than that that followed whole brain radiotherapy alone [8–10]. The Mayo Clinic analysis looked at the problem the other way around: can surgical resection of an apparently isolated metastasis alone be all that is needed? The risk of subsequent brain relapse was reduced from 85% to 21% if postoperative radiotherapy was delivered, demonstrating that surgical resection of an apparently isolated metastasis was not ‘enough’ treatment by itself [11]. Thus, an aggressive local (surgical) therapy, followed by a whole brain radiotherapy approach, became best standard practice for the operable single brain metastasis in a patient with good systemic control of cancer. However, it was questioned whether an obliterative radiosurgical dose could not substitute the surgical procedure. During the 1990s, the technique of obliterative, single-fraction, stereotactically delivered radiation therapy (radiosurgery) has been developed to a high degree of precision and safety, the advances in the last decade coming from great strides in the sophistication of planning and imaging programmes. It was natural that the clinicians who were practising radiosurgery would examine its effects in metastatic disease. A manuscript from the Gamma Knife radiosurgery unit at Pittsburgh described high efficacy and concluded that ‘stereotactic radiosurgery eliminated the surgical and anaesthetic risks of craniotomy and resection of solitary metastasis’ [12]. There followed an appraisal by others of the optimum criteria for selection. A multi-institutional study concluded that radiosurgery in conjunction with whole brain radiotherapy can produce substantial advantages over whole brain radiotherapy alone [13]. The patients selected for this study recapitulated the selection criteria that were used for Patchell et al.’s [9] surgery/radiotherapy study and, like other authors, Auchter et al. [13] concluded that the most powerful predictors of long survival in this patient group were a high performance status and the absence of other systemic metastases at the time of presentation with a brain metastasis. Recent studies on the role of radiotherapy in the treatment of brain metastases have been more interpretable because they have been cognizant of the established prognostic factors for this patient group: (a) age; (b) performance status; (c) number of brain metastases; (d) size and presence or absence of 106
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symptomatic mass effect; and (e) histology of the primary. In 1998, Pirzkall et al. [14] reported a large trial involving 236 patients with up to three brain metastases and a KPS of greater than 50, who received either whole brain radiotherapy with a radiosurgery boost or radiosurgery alone. The whole brain radiotherapy demonstrably delivered protection against further brain metastases and the median survival of patients receiving both treatments was almost double (15.4 versus 8.3 months) that in the radiosurgery arm alone. The response to radiosurgical treatment, in terms of local control of the treated lesions, seemed relatively independent of the histological diagnosis of the primary (relapses: 5/75 bronchial carcinoma; 4/47 melanoma; 4/53 renal carcinoma; 1/17 colorectal carcinoma; and 1/13 breast carcinoma), although the histology probably predicts for the risk of other metastases. In this trial, as in others, age, performance status and size of metastases were prognostically predictive. In 1999, Kondziolka et al. [15] reported a small trial of patients with two to four brain metastases, none being greater than 2.5 cm in diameter and with patients having an KPS of 70 or greater. These patients received either whole brain radiotherapy alone or whole brain radiotherapy with a radiosurgical boost. This boost could precede, occur concurrently with or follow, within a month, the whole brain radiotherapy course. The rate of local failure at 1 year was 100% after whole brain radiotherapy alone versus 8% in patients who had received a radiosurgical boost. There was also a significant survival gain (11 months versus 7.5 months). Two editorials in the leading radiotherapy journal of North America have debated the role of local therapy in the optimal management of brain metastases within the last 5 years. Loeffler and Shrieve [16] emphasized the fact that better prognosis patients could be identified, as discussed above, and argued that stereotactic radiosurgery could be a substitute for surgery when local therapy was needed. With regard to the recent editorial that accompanied the Pittsburgh article, Shaw [17] posed the question of whether all patients with two to four metastases should be routinely treated with surgery or radiosurgery. He rhetorically answered ‘no’, but reasoned that a subset of good prognosis patients (under 65 years; good KPS; controlled extracranial disease; and Pittsburgh criteria for acceptance of brain metastases) were candidates for a more aggressive approach than the heavily criticized ‘30 Gy in ten fractions’ dose prescription of conventional megavoltage photon radiotherapy, which is the most widely prescribed radiotherapy schedule for brain metastatic disease delivered in the UK at present [17]. On 16 October 1999, a symposium held in London for representatives of the disciplines of neurosurgery, neurology, radiotherapy and medical oncology de-
bated the optimal management of brain metastases at the end of the twentieth century. This article presents the views of the delegates, based on discussions and a questionnaire, collated by the main speakers at the symposium. Conference delegates who contributed to the optional questionnaire came from all parts of the UK, mainland Europe, Scandinavia and the USA. A bias in the results presented here could have been introduced by the self-selection process by which only clinicians interested in a more aggressive approach to brain metastatic disease would have registered for the conference.
Materials and Methods The composition of delegates filling in the questionnaire was: oncology graduates 25, neurosciences 11, others 1 (Fig. 1). The questionnaire consisted of the following: Delegates, please circle the answer number that you think is most appropriate. Name of delegate ................................................................. Specialization in medicine ................................................... A. What would you recommend for a young, good performance status patient who relapses with an inoperable, deep seated and apparently single brain metastasis less than 3 cm diameter and without mass effect, 2 years after resection of a colonic carcinoma, there being no other obvious site of metastatic disease on scanning? 1. Whole brain, conventionally fractionated radiotherapy? 2. Whole brain radiotherapy and a boost to the site of the lesion – either conventional techniques or stereotactic boost radiation?
3. Stereotactic radiation only? B. What would you recommend if the patient’s primary had been a melanoma? 1. Whole brain, conventionally fractionated radiotherapy? 2. Whole brain radiotherapy and a boost to the site of the lesion – either conventional techniques or stereotactic boost radiation? 3. Stereotactic radiation only? C. What would you recommend if the primary had been bronchial cancer (non-oat cell) and the interval to diagnosis of the ‘solitary’ metastasis had been 6 months? 1. Whole brain, conventionally fractionated radiotherapy? 2. Whole brain radiotherapy and a boost to the site of the lesion – either conventional techniques or stereotactic boost radiation? 3. Stereotactic radiation only? D. What would you recommend if the primary had been bronchial cancer (oat cell) – no cranial radiotherapy prophylaxis – and the interval to diagnosis of the ‘solitary’ metastasis had been 6 months? 1. Whole brain, conventionally fractionated radiotherapy? 2. Whole brain radiotherapy and a boost to the site of the lesion – either conventional techniques or stereotactic boost radiation? 3. Stereotactic radiation only? E. What would you recommend if the primary had been a breast carcinoma and the interval to diagnosis of the ‘solitary’ brain metastasis had been 6 months? 1. Whole brain, conventionally fractionated radiotherapy? 2. Whole brain radiotherapy and a boost to the site of the lesion – either conventional techniques or stereotactic boost radiation? 3. Stereotactic radiation only? F. What would you recommend if the primary had been a breast carcinoma and the interval to diagnosis of the ‘solitary’ metastasis had been 6 years? 1. Whole brain, conventionally fractionated radiotherapy? 2. Whole brain radiotherapy and a boost to the site of the lesion – either conventional techniques or stereotactic boost radiation? 3. Stereotactic radiation only? G. Do you believe that you can do better for good performance status patients with multiple brain metastases than 30 Gy in ten fractions of whole brain radiotherapy? 1. Yes 2. No H. Do you believe that we should be exploring stereotactic radiation therapy to individual brain metastases as defined by magnetic resonance imaging? 1. Yes 2. No
Fig. 1. Pie chart of the distribution of delegates by medical specialty.
I. Do you believe that stereotactic radiosurgical technology should be used only as boost therapy, after conventionally fractionated wide field brain radiotherapy? 1. Yes 2. No What is the Optimal Therapy of Brain Metastases?
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J. Do you think PET scanning has a role in defining the population of post-whole brain radiotherapy patients who would potentially benefit from such a stereotactic boost? 1. Yes 2. No K. Do you believe there is a selective role for primary/ definitive stereotactic radiosurgery alone? 1. Yes 2. No L. Do you believe that there should be a cap on the number of metastases that should be treated with a primary/ definitive stereotactic radiosurgery strategy? 1. Unrestricted? 2. Less than four metastases? 3. Less than three metastases? 4. Reserved for single metastases only?
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M. Should this strategy be modified depending on the original primary tumour’s histology, for example: If the primary tumour was melanoma: 1. Unrestricted? 2. Less than four metastases? 3. Less than three metastases? 4. Reserved for single metastases?
b Fig. 2. On the questions of: (a) whether we can improve on conventional palliative whole brain radiotherapy; and (b) whether we should explore stereotactic technology further in this disease.
If the primary tumour was breast: 1. Unrestricted? 2. Less than four metastases? 3. Less than three metastases? 4. Reserved for single metastases? If the primary tumour was bronchus (non-oat cell): 1. Unrestricted? 2. Less than four metastases? 3. Less than three metastases? 4. Reserved for single metastases?
a
Results Most delegates thought that the delivery of whole brain radiotherapy (specifically whole brain radiotherapy to 30 Gy in ten fractions, already noted to be the most commonly used regimen delivered in the UK at present) could be bettered and that stereotactic radiation therapy should be explored further (Fig. 2). The majority of delegates thought that there was a selective role for the use of stereotactic radiotherapy alone in the treatment of brain metastases (Figs 3–5). In the treatment of single brain metastases from lung cancer (oat cell and non-oat cell) oncologists favoured the whole brain approach (e.g. 92% recommending this in oat cell cancer). For breast cancer, replies were slightly different. When there was the early appearance of an apparently isolated brain metastasis (at 6 months from diagnosis) oncologists favoured whole brain radiotherapy. However, when the metastasis occurred 6 years from diagnosis, they were much more in favour of 108
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c Fig. 3. On the approach to the use of stereotactic radiosurgery by histology of the primary and the medical disciplines. (a) Single brain metastasis, 2 years after resection of colonic carcinoma. (b) Bronchial cancer (non-oat cell), single metastasis 6 months after diagnosis. (c) Oat cell cancer, single metastasis 6 months after diagnosis.
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b Fig. 4. On the approach to the use of stereotactic radiosurgery for isolated brain metastasis from carcinoma of breast, particularly with respect to the latency to onset of the disease from the initial presentation of the primary: (a) 6 months after diagnosis; (b) 6 years after diagnosis.
stereotactic radiation therapy, the majority recommending stereotactic radiosurgery alone (60%) or whole brain radiotherapy with a stereotactic boost (Fig. 4). The same response was given by oncologists when confronted with a late onset and apparently isolated brain metastasis from colonic carcinoma (Fig. 3). When asked concerning their approach to using stereotactic radiation therapy for more than one metastasis, an interesting analysis resulted. In bronchial cancer, there was a clear preference for using the technique, if at all, for an isolated metastasis. For breast cancer and, indeed, the perceived more radioresistant melanoma, there remained a preference for reserving stereotactic radiation therapy for a single metastasis, but the cumulative number of delegates voting for extending the number of metastases to two, three, or even an unlimited number, outnumbered those voting for restricting this technology to single metastasis (Fig. 5). Neuroscience graduates were more consistent in their views, irrespective of the histological type of primary tumour. They favoured greater use of stereotactic technology in both bronchial and breast cancer, the latter when the metastasis occurred 6 months or 6 years after the presenting primary; this was also their policy for colonic cancer and melanoma. Thus, histological subtype, site of the primary and latency to onset of the brain disease did not alter their approach to management. The neuroscience graduates favoured stereotactic radiosurgery for anything up to four metastases for all histologies (Figs 3–5). Only 78% of delegates ventured an opinion on whether positron emission tomographic (PET) scanning was useful. However, the majority of oncologists favoured the use of PET to define the subpopulation
b
c Fig. 5. On the approach to the use of stereotactic radiosurgery according to different numbers of cerebral metastases, histology and medical discipline: (a) breast; (b) bronchus; (c) melanoma.
of patients who would benefit from stereotactic radiation therapy administered as a boost after whole brain radiotherapy.
Discussion An overwhelming majority of delegates (89%) believed that the oncology community could do better than the whole brain/30/10 approach for brain metastases and that stereotactically directed focal radiotherapy should be further explored. By inference, we believe that this applies to the better prognosis patients. Whole brain radiotherapy by conventional fractionation is still the overall favoured treatment modality of the majority of oncologists for apparently single metastases from all histologies, with one exception: when there is a long latency period from diagnosis to the identification of an apparently single brain metastasis (we specifically instanced colon cancer at 2 years and breast cancer at 6 years in our questionnaire), then there was much more interest in the use of ‘up-front’ focal radiation therapy options. From our discussions at the symposium, rather than from the questionnaire, we found that oncologists would also consider focal radiation therapy for isolated relapses after whole brain radiotherapy in otherwise better than average prognosis patients. What is the Optimal Therapy of Brain Metastases?
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Neuroscience clinicians were much more interested in using radiosurgery ‘up-front’ in all histologies. Our perception of the advantage of these approaches is that whole brain radiotherapy forestalls other (nascent) metastases from developing (for breast and bronchus primaries this is a considerable hazard). The main disadvantages to the patient are: multiple trips to hospital, some languor and total scalp depilation. Loss of dignity from depilation in a patient population who will ultimately do badly was a discussion ponit made from the symposium floor as an argument against whole brain radiotherapy (M. Rice-Edwards). In general, neuroscience clinicians did not believe that histology (and by inference therefore the increased likelihood of oat cell cancer over perhaps colon cancer patients to develop other brain metastases), the latency period, or the number of metastases up to three (all higher risk factors for the development of other metastases) should alter the overall viewpoint. We infer a high level of dissatisfaction in the neuroscience community for the whole brain radiation approach. Oncology postgraduates were, overall, less ready to eschew whole brain radiotherapy and bring focal radiation therapy into primary therapy (with the exception of the late single metastasis) and were more against the use of radiosurgery for multiple metastases. We infer that oncologists would retain focal radiation therapy for the occasional problem metastasis in an otherwise better prognosis patient. PET scanning may be helpful in delineating such patients, whose cerebral metastases remain viable after whole brain radiotherapy. The debate now ensues on how these views, expressed as answers to a questionnaire and made after a series of lectures reviewing the literature on this subject, should be forwarded in UK practice. With increased access to stereotactic radiosurgical facilities (three gamma units and more than ten linear accelerator units currently practising in the UK) it would seem clear that further studies should be conducted utilizing this modality in better prognosis patients. We would suggest first selecting those tumours that are perceived to be more radioresistant and often having a longer natural history (e.g. kidney, colon and perhaps melanoma, when occurring as late and single or less than three brain metastases) and comparing whole brain radiotherapy with or without a conventional boost versus radiosurgery alone or as a boost to magnetic resonance (PET positive) imaged lesions. We conclude that more attention needs to be paid to the optimal therapy of brain metastatic disease, particularly in those patients with few adverse prognostic features. The indisputable capabilities of stereotactic radiosurgical facilities to ablate individual metastases successfully should be more fully studied in the future (Fig. 6). 110
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b Fig. 6. Coronal, T1 unenhanced magnetic resonance scans demonstrating an apparently isolated cerebellar peduncle metastasis from a melanoma. The patient was symptomatic from this metastasis and yet had no other systemic evidence of disease. This patient is perceived to do badly after conventionally fractionated wide field radiotherapy to the brain. (a) The lesion before radiosurgery and (b) the excellent regression 3 months after therapy.
Acknowledgements. We are grateful to the following for their contributions: C. Adams, S. Ahmed, A. Aldin, N. Ali, R. Amin, S. Awwad, T. Blackburn, M. Brada, C. Cotterill, M. Rice-Edwards, D. Eliopoupos, E. Eljamel, S. Ewan, J. Glees, N. Gupta, K. Hopkins, M. Howard,R. Joss, L. Kihlstrom, C. Lindquist, E. Laine, S. Mangar, Y. Marcou, T. Oliver, P. Pandey, R. Philips, P. Plowman, J. Pomeroy, J. Preston, S.
Retsas, V. Rothschild, N. Shackleton, M. Sharr, H. Taylor, A. Timothy and B. Walker
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