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The management of brain metastases
CANCER TREATMENT REVIEWS 2003; 29: 533–540 doi:10.1016/S0305-7372(03)00105-1
ANTI-TUMOUR TREATMENT
The management of brain metastases Roy A. Patchell Division of Neurosurgery, University of Kentucky Medical Center, Lexington, KY 40536, USA Brain metastases are neoplasms that originate in tissues outside the brain and then spread secondarily to the brain. Metastases to the brain are the most common intracranial tumours in adults. Substantial progress has been made in the treatment of these tumours, and radiotherapy, surgery, and stereotactic radiosurgery are now established treatments. With aggressive treatment, most patients experience meaningful symptom reduction and extension of life. C 2003 Elsevier Ltd. All rights reserved.
INTRODUCTION There are two types of brain tumours. Primary brain tumours arise from cells native to the central nervous system (CNS) and originate in the brain itself. Metastatic brain tumours begin growth in tissues outside the CNS and then spread secondarily to involve the brain. Of the two, brain metastases are the most common and outnumber primary brain tumours by at least 10 to 1. Metastases to the brain occur in over 170,000 patients per year in the USA (1) and are an extremely common complication of systemic cancer. During the past 15 years, significant advances have been made in the diagnosis and treatment of brain metastases. Although the development of brain metastases still usually indicates a poor overall prognosis for the patient, it is now possible to reverse most of the symptoms of brain metastases and significantly improve a patient’s quality and length of life.
FREQUENCY Brain metastases occur in 20 to 40% of cancer patients (1–3). This number may increase in the future
Correspondence to: Roy A. Patchell MD, Chief of NeuroOncology, Division of Neurosurgery, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536; E-mail: [email protected] 0305-7372/$ - see front matter
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as the ability to detect small tumours with magnetic resonance imaging (MRI) improves. The frequency of brain metastases may also be rising due to the longer survival of cancer patients in general. The histological type of primary tumour is strongly associated with the frequency and pattern of intracranial spread (Table 1).
METHOD OF SPREAD AND DISTRIBUTION Most tumour cells reach the brain by haematogenous spread, usually through the arterial circulation. Most commonly, the metastasis originates in the lung from either a primary lung cancer or from a metastasis to the lung. Within the brain, metastases are most commonly found in the area directly beneath the grey/white junction (4,5). This is due to a change in the size of blood vessels at that point; the narrowed vessels act as a trap for emboli. Brain metastases tend to be more common at the terminal ‘‘watershed areas’’ of arterial circulation (the zones on the border of or between the territories of the major cerebral vessels). The distribution of metastases among the large subdivisions of the central nervous system follows roughly the relative weight and blood flow to each area. As a result, about 80% of brain metastases are located in the cerebral hemispheres, 15% in the cerebellum, and 5% in the brain stem (1,4). Experience with MRI indicates that the proportion of multiple metastases is in the range of
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TA B L E 1 Frequency of brain metastases by primary tumour type Primary tumour
No. of patients
Percent
Lung Breast Melanoma Colon Other Known Primary Unknown Primary
270 82 50 26 72 61
48 15 9 5 13 11
Total
561
100
two-thirds to three-fourths of patients with brain metastases (6). Further evidence (7) (discussed below) suggests that the actual percentage of multiple metastases is 80 to 90%. It is probable that with the widespread use of MRI and new improvements in MRI contrast agents and resolution, the proportion of multiple metastases will be found to be even higher in the future. Terminology can sometimes be confusing. The phrase single brain metastasis refers to those patients with an apparent single cerebral lesion; no implication is made regarding the extent of cancer elsewhere in the body. On the other hand, the phrase solitary brain metastasis is properly used to describe the relatively rare subgroup of patients who have a single brain metastasis that is the only known site of metastatic cancer in the body.
CLINICAL PRESENTATION Brain metastases may be detected at the same time the primary is diagnosed (synchronous presentation) or in over 80% of cases, the brain metastases develop after the primary is diagnosed (metachronous presentation). Metastases to the brain are usually symptomatic, and more than two-thirds of patients with brain metastases have some neurological symptoms during the course of their illness (2,8). Headache is a common presenting symptom, is more common with multiple metastases or with posterior fossa lesions and may be mild. Focal weakness is second only to headache in frequency as a presenting symptom. Focal or generalized seizures occur in approximately 10% of patients at presentation, and are more common in patients with multiple metastases. Abnormalities of higher mental functions may take the form of a nonfocal encephalopathy (1 to 2% of patients with metastases) or may relate to localized dysfunction (e.g., aphasia). The signs and symptoms of cerebral lesions are often quite subtle, therefore, brain metastases should be suspected in all patients with known systemic cancer in whom new neurologic findings develop.
DIAGNOSIS The best diagnostic test for brain metastases is contrast enhanced MRI (6,9). If the clinical history is typical and lesions are multiple, usually there is little doubt surrounding the diagnosis. However, it is important that metastases be distinguished carefully from primary brain tumours (benign or malignant), abscesses, cerebral infarction, and haemorrhages. One study (10) has shown that the false positive rate, even when using contrast MRI for the diagnosis of single brain metastases, is approximately 11%. Other diagnostic tests, such as arteriography or biopsy, may be needed to establish the diagnosis firmly.
TREATMENT The optimum therapy of brain metastases is still evolving. Corticosteroids, radiotherapy, surgical therapy, and radiosurgery all have an established place in management. In addition, chemotherapy is useful in some patients. There are several things to be considered when determining the best treatment for each patient, including the extent of systemic disease, neurological status at diagnosis and the number and site of metastases. Regardless of treatment, brain metastases are associated with a poor prognosis. Untreated patients have a median survival time of only about four weeks (11). Nearly all untreated patients die as a direct result of the brain tumour, with increasing intracranial pressure leading to obtundation and terminal cerebral herniation.
Radiotherapy Radiotherapy is the treatment of choice for most patients with brain metastases. Most patients are treated with whole brain radiotherapy (WBRT). This is because over 70% have multiple metastases at the time of diagnosis and this usually makes surgical or other purely focal treatments ineffective. Unfortunately, there is still no consensus on the optimum radiation dose and schedule. Several large scale multi-institutional trials (12) conducted by the Radiation Therapy Oncology Group (RTOG) have shown that there appears to be no significant difference in the frequency and duration of response for total radiation doses ranging from 2000 cGy over one week to 5000 cGy over four weeks. Currently, typical radiation treatment schedules for brain metastases consist of short courses (7 to 15 days) of whole brain irradiation with relatively high doses
THE MANAGEMENT OF BRAIN METASTASES
per fraction (150 to 400 cGy per day) with total doses in the range of 3000 to 5000 cGy. These schedules minimize the duration of treatment while still delivering adequate amounts of radiation to the tumour. Giving a boost dose of conventional radiotherapy to the tumour site along with WBRT is no better than WBRT alone in preventing neurological recurrences or increasing length of survival (13). WBRT increases the median survival time to 3 to 6 months (1,2,12). Data from large retrospective studies (1,2,12) have shown that more than half of patients treated with whole brain radiotherapy die ultimately of progressive systemic cancer and not as a direct result of brain metastases. Retrospective studies on large numbers of patients treated in RTOG brain metastasis protocols have identified patient subgroups that were more likely to respond to whole brain radiotherapy (12,14). More favorable outcome is associated with (1) Karnofsky performance scores in the range of 70% or above, (2) absent or ‘‘controlled’’ primary tumour, (3) patient age less than 60 years, and (4) metastatic spread limited to the brain. Building on these results, a recursive partitioning analysis (RPA) (15) was applied to a combined group consisting of patients from several past RTOG radiotherapy studies. Three distinct prognostic groups were identified. The most favorable prognostic group was designated RPA class 1 and consisted of patients whose Karnofsky scores were 70% or higher, age was 65 years or less, primary tumours were ‘‘controlled,’’ and no extracranial metastases were present. RPA Class 3 patients had the worst prognoses; these patients had Karnofsky scores less than 70% (with or without other unfavorable factors). RPA Class 2 patients included patients who did not fit into Class 1 or 3 (i.e., patients who had Karnofsky scores 70% or higher but also had one or more of the other unfavorable factors). Obviously, performance status at the time of treatment for brain metastases is the most important prognostic factor. Radiotherapy has complications. Almost all patients experience a temporary loss of hair; hair usually returns 6 to 12 months after completing therapy. Also, in the short term, patients may have a transient worsening of neurological symptoms while receiving therapy. Many physicians believe that maintaining patients on steroids during radiotherapy, will minimize radiation complications, although conclusive proof of this has not been forthcoming. The long term side effects of radiotherapy are usually not a significant issue in the treatment of patients with brain metastases because of the relatively short survival time of these patients. The frequency of serious long term complications is unknown. One often quoted retrospective study by DeAngelis et al. (16) suggests that as many as 11% of
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long term survivors (>12 months) of brain metastases treated with WBRT develop dementia. However, virtually all of the patients in that sample who developed dementia had been treated with atypically large radiation fractionation schedules. The patients treated with fraction sizes less than 3.0 Gy per day did not develop clinically apparent dementia. So, the actual frequency of radiation related dementia when using convention fractionation schedules is not known, but is certainly less than 11%. In any event, the frequency of long-term neuropsychological side effects of WBRT in adult brain metastases patients appears to have been overestimated and seems to be within the acceptable range when modern fractionation schemes are employed.
Surgery There have been three prospective randomized trials (10,17,18) assessing the value of surgical removal of single brain metastases (Table 2). In a prospective randomized trial (10) performed at the University of Kentucky, 48 patients with known systemic cancer were treated with either biopsy of the suspected brain metastasis plus WBRT or complete surgical resection of the metastasis plus WBRT. The radiation doses were the same in both groups and consisted of a total dose of 3600 cGy given as 12 daily fractions of 300 cGy each. There was a statistically significant increase in survival in the surgical group (40 weeks vs. 15 weeks). In addition, the time to recurrence of brain metastases, freedom from death due to neurologic causes, and duration of functional independence were significantly longer in the surgical resection group. The one month mortality was 4% in each group, indicating that there was no extra mortality from surgery. An important finding was that
TA B L E 2 Surgery for single brain metastases: randomized trials N
Median survival (weeks)
Length of functional independence (weeks)
CNS death (%)
S + WBRT Patchell et al. (10) Vecht et al. (17) Mintz et al. (18)
25 32 41
40 43 24
38 33 8
29 35 46
WBRT only Patchell et al. (10) Vecht et al. (17) Mintz et al. (18)
23 31 43
15 26 27
8 15 9
50 33 63
S, surgery; WBRT, whole brain radiotherapy.
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despite screening with both contrast enhanced MRI and CT before entry into the study, 6 out of 54 (11%) patients with known diagnoses of systemic malignancies were found not to have metastatic brain tumours when tissue was obtained at biopsy or attempted resection. The nonmetastatic lesions consisted of 3 astrocytomas, two abscesses and one sterile inflammatory lesion. A second randomized study (17), conducted as a multi-institutional trial in the Netherlands, contained 63 evaluable patients. Patients were randomized to either complete surgical resection plus WBRT or WBRT alone. The WBRT schedules were the same for both treatment arms and consisted of 4000 cGy given in a nonstandard fractionation scheme of 200 cGy twice per day for 2 weeks (10 treatment days). Survival time was significantly longer in the surgical group (10 months vs. 6 months). There was also a nonsignificant trend toward longer duration of functional independence in the surgically treated patients. No data concerning recurrence of brain metastases were given. The one month mortality rates were 9% in the surgery group and 0% in the WBRT alone group; this was not a statistically significant difference. Although diagnostic biopsies were not obtained in the WBRT alone group, one patient (out of 31) in the WBRT alone arm was later found to have a malignant glioma after having surgery performed on the brain lesion after progression of the presumed metastatic lesion. All 32 patients in the surgery group had metastatic tumours verified by tissue at operation. It is of note that 2 other patients were randomized into the study but excluded from the final analysis because they were found not to have metastatic tumours before the start of treatment. In all, 5% (3/65) did not have metastatic tumours. A third randomized trial, conducted in Canada by Mintz et al. (18), failed to find a benefit from surgical treatment. In that study, 84 patients were randomized to receive radiotherapy alone (3000 cGy) or surgery plus radiotherapy. No difference was found in overall survival; the median survival time was 6.3 months in the radiotherapy alone group and 5.6 months for the surgical group. There was also no difference in causes of death or quality of life. Only one patient of the 40 who had surgery had a lesion that was not a metastatic brain tumour; that patient had a glioblastoma. It is unclear why the Canadian study was not in agreement with the other two trials. In all three studies (10,17,18), the control arms (the radiation alone arms) had median lengths of survival in the 3 to 6 months range – well within the expected range for patients treated with radiotherapy alone. The major difference in the studies was the poor results obtained in the surgical arm of the Canadian trial
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(18). That study contained a higher proportion of patients with extensive systemic disease and lower performance scores (Table 3). Differences in patient selection in the Canadian trial may well have contributed to its failure to detect a significant benefit from the addition of surgical therapy. Also, the Canadian health care system sometimes discourages aggressive and expensive systemic treatment for patients with disseminated cancer. It is possible that these factors (i.e., selection/philosophy) resulted in more patients dying of their systemic cancer before a long term benefit of surgery was seen. Although the data supporting surgery for single brain metastases were derived from relatively small randomized trials that were not uniformly positive, the results have generally been interpreted to show that the surgical resection is of benefit in selected patients. Surgical therapy plus post-operative WBRT is now an established treatment for patients with surgically accessible single brain metastases. The value of surgery in the management of multiple metastases remains to be demonstrated. It is difficult to draw firm conclusions regarding the efficacy of surgery for multiple metastases from the studies published to date (19,20). Current practice is to treat multiple metastases with WBRT alone. Surgery is sometimes performed on patients with multiple metastases who have one life threatening brain lesion (e.g., a large compressive cerebellar lesion). The intent of surgery in these cases is to remove the single life threatening lesion without taking out the other lesions. Although this approach is speculative, long survival times have been achieved occasionally. The best results from surgery are seen in those patients with a single surgically accessible lesion and either no remaining systemic disease (true solitary metastasis) or with controlled systemic cancer limited to the primary site only. Also, surgical treatment is indicated in those patients without known systemic cancer (to obtain a tissue diagnosis) and in patients with impending herniation due to pressure effects.
TA B L E 3 Comparison of randomized trials for surgery Vecht et al. (17) (%)
Mintz et al. (18) (%)
77 38
52 32
53 45
100 4
– –
90 25
Patchell et al. (10) (%) Lung cancer Disseminated systemic disease Complete resection Cross-over to WBRT –, not reported.
THE MANAGEMENT OF BRAIN METASTASES
Radiosurgery Stereotactic radiosurgery is a method of delivering intense focal irradiation using a linear accelerator (LINAC) or a multiple Cobalt-60 sources (Gamma Knife). Radiosurgery does not replace conventional radiotherapy to the brain but offers a substitute for surgical treatment in patients with lesions less than about 3 cm in diameter. The role of radiosurgery has been the subject of three randomized trials to date. Kondziolka et al. (21) reported the first trial on the subject. This study had only 27 patients in it and used nonstandard endpoints. As a result, this trial was uninterpretable. A second study reported in abstract form by Chougule et al. (22) contained methodological problems that made it impossible to draw firm conclusions from the data. The largest randomized study to date has been reported in abstract form by the RTOG (23,24). This study (RTOG 9508) included patients with single and multiple brain metastases. There was a primary stratification based on number of metastases (one vs. two or three). To date, separate abstracts describing the results of the multiple brain metastases portion of the study (23) and the combined study (24) have been published. With regard to multiple metastases (23), the trial contained 144 patients with 2 or 3 brain metastases. These patients were randomized to treatment with either WBRT (37.5 Gy) plus radiosurgery or WBRT (37.5 Gy) alone. There was no significant difference in local failure rates in the brain with 21% in the radiosurgery arm and 37% in the WBRT alone arm (P ¼ 0:107). There was also no significant difference in the length of survival of the two groups (median, 5.3 months for radiosurgery and 6.7 months for WBRT alone). Most noteworthy was the lack of significant difference between the fraction of patients in each group who died of neurological causes (33% radiosurgery vs. 35% WBRT alone). Lower posttreatment Karnofsky scores and steroid dependence were more common in the WBRT alone patients. Nevertheless, for multiple brain metastases, this was a completely negative trial with regard to the major endpoints of tumour control in the brain, overall survival, and prevention of death due to neurological causes. A second abstract (24), reporting the combined results of RTOG 9805 and including patients with single and two or three brain metastases has been published. Patients with single metastases treated with radiosurgery plus WBRT lived significantly longer than patients treated with WBRT alone (median survival time, 6.5 months vs. 4.9 months, P ¼ 0:04). There was no significant difference in
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cause of death. The report goes on to claim an advantage for radiosurgery in a wide variety of subgroups that include patients with single and multiple brain metastases. However, the primary stratification was for number of lesions and the subgroup analysis used to make these claims was not part of the original study design. These attempted extensions are beyond the capability of the study to support. Analyses of this type are not reliable for drawing firm conclusions but are useful for hypothesis generation and future study. It is hoped that the final paper reporting this trial will clarify this issue. The results of RTOG 9508 have caused a major reevaluation of the use of radiosurgery in the treatment of brain metastases. This was the largest and best trial done to date, and it failed to show a benefit of radiosurgery in the treatment of multiple brain metastases when radiosurgery was given in the initial management of newly diagnosed tumours. Treatment with WBRT alone would now appear to be the treatment of choice in these circumstances. For multiple brain metastases, radiosurgery may still have a place in the treatment as salvage therapy in patients who have recurrent brain tumours after treatment with WBRT, but this remains to be demonstrated. The study did show that radiosurgery is beneficial in patients with single metastases. The rates of local control and overall survival with radiosurgery and WBRT are comparable to that in patients treated with conventional surgery plus WBRT. Radiosurgery now offers a real alternative to surgery. Conventional surgery is probably best reserved for patients in whom tissue is needed for diagnosis, patients with lesions too large for radiosurgery (>3 cm), and in patients with life threatening mass effect that would benefit from immediate decompression.
Adjuvant WBRT with surgery or radiosurgery With the establishment of the efficacy of focal treatments (surgery and radiosurgery) a new controversy has arisen whether adjuvant WBRT is necessary after a ‘‘complete resection’’ of a single metastasis or ‘‘successful’’ treatment with radiosurgery. Adjuvant WBRT is felt to be of benefit because there may be residual disease in the tumour bed or at distant microscopic sites in the brain. However, brain metastases tend to be discrete masses that are theoretically capable of being removed totally or destroyed, and so WBRT may not be necessary after ‘‘successful’’ focal therapy. Only one randomized trial (7) has addressed the question of adjuvant radiotherapy. In that study,
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95 patients who had single brain metastases that were completely resected by conventional surgery were randomized to treatment with post-operative WBRT (50.4 Gy) or to observation with no further treatment of the brain metastasis (until recurrence). Recurrence of tumour anywhere in the brain was less frequent in the radiotherapy group than in the observation group (18% vs. 70%, P < 0:001). Postoperative radiotherapy prevented brain recurrence at the site of the original metastasis (10% vs. 46%, P < 0:001) and at other sites in the brain (14% vs. 37%, P < 0:01). As a result, patients in the radiotherapy group were less likely to die of neurologic causes than patients in the observation group (6 of 43 who died [14%] vs. 17 of 39 [44%]; P ¼ 0:003). There was no significant difference between the two groups in overall length of survival or the length of time that patients remained functionally independent. Despite the fact that the randomized trial (7) was overwhelmingly positive for preventing recurrences, this study has actually provoked controversy rather than settling the issue. Since adjuvant WBRT apparently had no effect on length of survival, it has been argued that radiation makes no difference and can be dispensed with. In pursuit of this argument, several retrospective studies (25–28) have been published comparing patients treated with SRS who received WBRT with those who did not receive WBRT. These studies have generally shown that the recurrence rate is reduced by adjuvant WBRT but that length of survival is not increased. However, a closer look at these studies shows that, paradoxically, they may actually provide an argument in favor of giving WBRT. Since these were retrospective studies, treatment assignment was not random, and patient selection bias very clearly entered into the decision for treatment. In all of these studies, the WBRT group contained many more poor prognosis patients including those with multiple metastases and other unfavorable factors. For example, in series reported by Sneed et al. (27), single brain metastases were present in 58% of the SRS alone group but only 33% of the SRS + WBRT group. In addition, the intracranial tumour burden (as measured by the median total target volume) was substantially higher in the WBRT treated patients than in the SRS alone group (5.6 ml vs. 4.3 ml). Additionally, this was almost certainly an underestimate for the patients in the WBRT group because the volume given referred only to the SRS treated volume; there were many more multiple metastases in the WBRT group that were not included in the SRS volume. Despite these disadvantages, the median survival times in both groups were almost identical (8.2 months for SRS alone vs. 8.6 months for SRS + WBRT).
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This was not the expected result given the difference in prognostic factors between the two treatment arms. It would have been expected that the WBRT arm should have done worse, but instead there was no difference. This suggests that WBRT may have improved survival time and actually made a difference overall, a conclusion opposite to that drawn by the study’s authors. The real lesson here is that nonrandomized, retrospective studies cannot be used to resolve the question because of the insurmountable problem of patient selection bias inherent in these types of studies. The most compelling argument in favor of adjuvant WBRT involves an examination of the effects of not giving WBRT. Patients who do not receive adjuvant WBRT suffer substantially more recurrent brain metastases than patients who are treated with WBRT. As was discussed above, the side effects of WBRT appear to have been overestimated in the past and are in the acceptable range. Unfortunately, the same cannot be said of the side effects of recurrence of brain metastases. Several recent studies (29,30) have demonstrated that the recurrence of brain metastases has a negative effect on the neurocognitive functioning of patients. A study by Regine et al. (30) found that in 36 patients with brain metastases treated with SRS alone, 47% had recurrence of brain metastases and 71% of the recurrences were symptomatic. Significantly, 59% of the patients with recurrent tumours had associated neurological deficits that did not improve even with successful treatment of the recurrence. Another study by Regine et al. (29) showed that, at three months post-treatment, patients treated for brain metastases with WBRT had greater negative changes in their minimental status examinations with uncontrolled brain tumours than they did with controlled brain tumours ()6.3 points vs. )0.5 points, P ¼ 0:02). Also relevant (but perhaps somewhat farther afield) was a study by Taylor et al. (31) that showed that, in patients with primary brain tumours at 12 months post-treatment, changes in minimental status examinations were worse in patients with uncontrolled tumours ()2.42 points) than in patients with controlled tumours (+0.076 points) (P ¼ 0:0046). All of the patients in this study had received large total doses of conventional radiation therapy. These studies all suggest strongly that uncontrolled brain tumours result in a substantial decrease in mental performance and that this reduction far outweighs any decrement seen with cranial radiation therapy. Therefore, the side effects of recurrent tumours are worse than the side effects of preventive treatment. This is an extremely strong argument for the use of adjuvant WBRT in association with focal therapy.
THE MANAGEMENT OF BRAIN METASTASES
Chemotherapy Although chemotherapy has not yet emerged as a standard of therapy for patients with brain metastases, evidence has accumulated to suggest that chemotherapy may have a role in the treatment of selected patients. Since more than half of the patients with brain metastases who are treated with surgery or radiotherapy will subsequently die of progression of the systemic disease, a chemotherapeutic agent that is effective against both systemic and brain disease is highly desirable. However, most systemically administered chemotherapeutic agents that have proven effective against the primary sites of cancer have been ineffective against cerebral metastases from the same cell population. Chemotherapy has been used in the treatment of brain metastases from a variety of primary tumours; however, the results have generally been unimpressive (32,33). However, good results in some small uncontrolled series of patients with certain highly chemosensitive tumours (e.g., breast, small cell lung cancer, germ cell tumours) have been reported. More recently temozolomide, a newer oral chemotherapeutic agent, has shown some promise in the treatment of brain metastases, especially those from lung cancer. However, chemotherapy is not usually the primary therapy for most patients and is seldom the only therapy. Based on current knowledge, a reasonable use for chemotherapy for brain metastases would be in those patients with small, asymptomatic tumours from primaries that are known to be chemosensitive. If progression occurs with the patient receiving chemotherapy alone, more definitive treatment with surgery, radiosurgery, or radiotherapy may be given.
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539 7. Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. J Am Med Assoc 1998; 280: 1485–1489. 8. Posner JB. Clinical manifestations of brain metastases. In: Weiss L, Gilbert HA, Posner JB (eds.), Brain Metastases. GK Hall: Boston, 1980; 189–207. 9. Davis PC, Hudgins PA, Peterman SB, et al. Diagnosis of cerebral metastases: double dose delayed CT vs contrast enhanced MR imaging. AJNR 1991; 12: 293–300. 10. Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990; 322: 494–500. 11. Markesbery WR, Brooks WH, Gupta GD, et al. Treatment for patients with cerebral metastases. Arch Neurol 1978; 35: 754–756. 12. Berk L. An overview of radiotherapy trials for the treatment of brain metastases. Oncology 1995; 9: 1205–1219. 13. Hoskins PJ, Crow J, Ford HT. The influence of extent and local management on the outcome of radiotherapy for brain metastases. Int J Radiat Oncol Biol Phys 1990; 19: 111–115. 14. Deiner-West M, Dobbins TW, Phillips TL, et al. Identification of an optimal subgroup for treatment evaluation of patients with brain metastases using RTOG study 7916. Int J Radiat Oncol Biol Phys 1989; 16: 669–673. 15. 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: 745–751. 16. DeAngelis LM, Delattre JY, Posner JB. Radiation-induced dementia in patients cured of brain metastases. Neurology 1989; 39: 789–796. 17. Vecht CJ, Haaxma-Reiche H, Noordijk EM, et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery. Ann Neurol 1993; 33: 583–590. 18. Mintz AH, Kestle J, Gaspar L, et al. A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with single cerebral metastasis. Cancer 1996; 78: 1470–1476. 19. Bindal RK, Sawaya R, Leavens ME, Lee JJ. Surgical treatment of multiple brain metastases. J Neurosurg 1993; 79: 210–216. 20. Hazurka MB, Burleson W, Stroud DN, et al. Multiple brain metastases are associated with poor survival in patients treated with surgery and radiotherapy. J Clin Oncol 1993; 11: 369–373. 21. Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 1999; 45: 427–434. 22. Chougule PB, Burton-Williams M, Saris S, et al. Randomized treatment of brain metastases with gamma knife radiosurgery, whole brain radiotherapy or both. Int J Radiat Oncol Biol Phys 2000; 48: 114. 23. Sperduto PW, Scott C, Andrews D, et al. Preliminary report of RTOG-9508: a phase III trial comparing whole brain irradiation alone versus whole brain irradiation plus stereotactic radiosurgery for patients with two or three brain metastases. Int J Radiat Oncol Biol Phys 2000; 48: 113. 24. Sperduto PW, Scott C, Andrews D, et al. A phase III trial comparing whole brain irradiation alone versus whole brain irradiation plus stereotactic radiosurgery for patients with one to three brain metastases. Int J Radiat Oncol Phys 2002; 51,2S: 3. 25. Flickinger JC, Kondziolka D, Lunsford LD, et al. Multiinstitutional experience with stereotactic radiosurgery for Solitary Brain Metastasis. Int J Radiat Oncol Biol Phys 1994; 28: 797–802.
540 26. 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: 3563–3569. 27. Sneed PK, Lamborn KR, Forstner JM, et al. Radiosurgery for brain metastases: Is whole brain radiotherapy necessary? Int J Radiat Oncol Biol Phys 1999; 43: 549–558. 28. Sneed PK, Suh JH, Goetsch SJ, et al. A multi-institutional review of radiosurgery alone vs radiosurgery with whole brain radiotherapy as the initial management of brain metastases. Int J Radiat Oncol Biol Phys 2002; 53: 519– 526. 29. Regine WF, Scott C, Murray K, Curran W. Neurocognitive outcome in brain metastases patients treated with acceleratedfraction vs. accelerated-hyperfractionated radiotherapy: an
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ANTI-TUMOUR TREATMENT
The management of brain metastases Roy A. Patchell Division of Neurosurgery, University of Kentucky Medical Center, Lexington, KY 40536, USA Brain metastases are neoplasms that originate in tissues outside the brain and then spread secondarily to the brain. Metastases to the brain are the most common intracranial tumours in adults. Substantial progress has been made in the treatment of these tumours, and radiotherapy, surgery, and stereotactic radiosurgery are now established treatments. With aggressive treatment, most patients experience meaningful symptom reduction and extension of life. C 2003 Elsevier Ltd. All rights reserved.
INTRODUCTION There are two types of brain tumours. Primary brain tumours arise from cells native to the central nervous system (CNS) and originate in the brain itself. Metastatic brain tumours begin growth in tissues outside the CNS and then spread secondarily to involve the brain. Of the two, brain metastases are the most common and outnumber primary brain tumours by at least 10 to 1. Metastases to the brain occur in over 170,000 patients per year in the USA (1) and are an extremely common complication of systemic cancer. During the past 15 years, significant advances have been made in the diagnosis and treatment of brain metastases. Although the development of brain metastases still usually indicates a poor overall prognosis for the patient, it is now possible to reverse most of the symptoms of brain metastases and significantly improve a patient’s quality and length of life.
FREQUENCY Brain metastases occur in 20 to 40% of cancer patients (1–3). This number may increase in the future
Correspondence to: Roy A. Patchell MD, Chief of NeuroOncology, Division of Neurosurgery, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY 40536; E-mail: [email protected] 0305-7372/$ - see front matter
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as the ability to detect small tumours with magnetic resonance imaging (MRI) improves. The frequency of brain metastases may also be rising due to the longer survival of cancer patients in general. The histological type of primary tumour is strongly associated with the frequency and pattern of intracranial spread (Table 1).
METHOD OF SPREAD AND DISTRIBUTION Most tumour cells reach the brain by haematogenous spread, usually through the arterial circulation. Most commonly, the metastasis originates in the lung from either a primary lung cancer or from a metastasis to the lung. Within the brain, metastases are most commonly found in the area directly beneath the grey/white junction (4,5). This is due to a change in the size of blood vessels at that point; the narrowed vessels act as a trap for emboli. Brain metastases tend to be more common at the terminal ‘‘watershed areas’’ of arterial circulation (the zones on the border of or between the territories of the major cerebral vessels). The distribution of metastases among the large subdivisions of the central nervous system follows roughly the relative weight and blood flow to each area. As a result, about 80% of brain metastases are located in the cerebral hemispheres, 15% in the cerebellum, and 5% in the brain stem (1,4). Experience with MRI indicates that the proportion of multiple metastases is in the range of
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TA B L E 1 Frequency of brain metastases by primary tumour type Primary tumour
No. of patients
Percent
Lung Breast Melanoma Colon Other Known Primary Unknown Primary
270 82 50 26 72 61
48 15 9 5 13 11
Total
561
100
two-thirds to three-fourths of patients with brain metastases (6). Further evidence (7) (discussed below) suggests that the actual percentage of multiple metastases is 80 to 90%. It is probable that with the widespread use of MRI and new improvements in MRI contrast agents and resolution, the proportion of multiple metastases will be found to be even higher in the future. Terminology can sometimes be confusing. The phrase single brain metastasis refers to those patients with an apparent single cerebral lesion; no implication is made regarding the extent of cancer elsewhere in the body. On the other hand, the phrase solitary brain metastasis is properly used to describe the relatively rare subgroup of patients who have a single brain metastasis that is the only known site of metastatic cancer in the body.
CLINICAL PRESENTATION Brain metastases may be detected at the same time the primary is diagnosed (synchronous presentation) or in over 80% of cases, the brain metastases develop after the primary is diagnosed (metachronous presentation). Metastases to the brain are usually symptomatic, and more than two-thirds of patients with brain metastases have some neurological symptoms during the course of their illness (2,8). Headache is a common presenting symptom, is more common with multiple metastases or with posterior fossa lesions and may be mild. Focal weakness is second only to headache in frequency as a presenting symptom. Focal or generalized seizures occur in approximately 10% of patients at presentation, and are more common in patients with multiple metastases. Abnormalities of higher mental functions may take the form of a nonfocal encephalopathy (1 to 2% of patients with metastases) or may relate to localized dysfunction (e.g., aphasia). The signs and symptoms of cerebral lesions are often quite subtle, therefore, brain metastases should be suspected in all patients with known systemic cancer in whom new neurologic findings develop.
DIAGNOSIS The best diagnostic test for brain metastases is contrast enhanced MRI (6,9). If the clinical history is typical and lesions are multiple, usually there is little doubt surrounding the diagnosis. However, it is important that metastases be distinguished carefully from primary brain tumours (benign or malignant), abscesses, cerebral infarction, and haemorrhages. One study (10) has shown that the false positive rate, even when using contrast MRI for the diagnosis of single brain metastases, is approximately 11%. Other diagnostic tests, such as arteriography or biopsy, may be needed to establish the diagnosis firmly.
TREATMENT The optimum therapy of brain metastases is still evolving. Corticosteroids, radiotherapy, surgical therapy, and radiosurgery all have an established place in management. In addition, chemotherapy is useful in some patients. There are several things to be considered when determining the best treatment for each patient, including the extent of systemic disease, neurological status at diagnosis and the number and site of metastases. Regardless of treatment, brain metastases are associated with a poor prognosis. Untreated patients have a median survival time of only about four weeks (11). Nearly all untreated patients die as a direct result of the brain tumour, with increasing intracranial pressure leading to obtundation and terminal cerebral herniation.
Radiotherapy Radiotherapy is the treatment of choice for most patients with brain metastases. Most patients are treated with whole brain radiotherapy (WBRT). This is because over 70% have multiple metastases at the time of diagnosis and this usually makes surgical or other purely focal treatments ineffective. Unfortunately, there is still no consensus on the optimum radiation dose and schedule. Several large scale multi-institutional trials (12) conducted by the Radiation Therapy Oncology Group (RTOG) have shown that there appears to be no significant difference in the frequency and duration of response for total radiation doses ranging from 2000 cGy over one week to 5000 cGy over four weeks. Currently, typical radiation treatment schedules for brain metastases consist of short courses (7 to 15 days) of whole brain irradiation with relatively high doses
THE MANAGEMENT OF BRAIN METASTASES
per fraction (150 to 400 cGy per day) with total doses in the range of 3000 to 5000 cGy. These schedules minimize the duration of treatment while still delivering adequate amounts of radiation to the tumour. Giving a boost dose of conventional radiotherapy to the tumour site along with WBRT is no better than WBRT alone in preventing neurological recurrences or increasing length of survival (13). WBRT increases the median survival time to 3 to 6 months (1,2,12). Data from large retrospective studies (1,2,12) have shown that more than half of patients treated with whole brain radiotherapy die ultimately of progressive systemic cancer and not as a direct result of brain metastases. Retrospective studies on large numbers of patients treated in RTOG brain metastasis protocols have identified patient subgroups that were more likely to respond to whole brain radiotherapy (12,14). More favorable outcome is associated with (1) Karnofsky performance scores in the range of 70% or above, (2) absent or ‘‘controlled’’ primary tumour, (3) patient age less than 60 years, and (4) metastatic spread limited to the brain. Building on these results, a recursive partitioning analysis (RPA) (15) was applied to a combined group consisting of patients from several past RTOG radiotherapy studies. Three distinct prognostic groups were identified. The most favorable prognostic group was designated RPA class 1 and consisted of patients whose Karnofsky scores were 70% or higher, age was 65 years or less, primary tumours were ‘‘controlled,’’ and no extracranial metastases were present. RPA Class 3 patients had the worst prognoses; these patients had Karnofsky scores less than 70% (with or without other unfavorable factors). RPA Class 2 patients included patients who did not fit into Class 1 or 3 (i.e., patients who had Karnofsky scores 70% or higher but also had one or more of the other unfavorable factors). Obviously, performance status at the time of treatment for brain metastases is the most important prognostic factor. Radiotherapy has complications. Almost all patients experience a temporary loss of hair; hair usually returns 6 to 12 months after completing therapy. Also, in the short term, patients may have a transient worsening of neurological symptoms while receiving therapy. Many physicians believe that maintaining patients on steroids during radiotherapy, will minimize radiation complications, although conclusive proof of this has not been forthcoming. The long term side effects of radiotherapy are usually not a significant issue in the treatment of patients with brain metastases because of the relatively short survival time of these patients. The frequency of serious long term complications is unknown. One often quoted retrospective study by DeAngelis et al. (16) suggests that as many as 11% of
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long term survivors (>12 months) of brain metastases treated with WBRT develop dementia. However, virtually all of the patients in that sample who developed dementia had been treated with atypically large radiation fractionation schedules. The patients treated with fraction sizes less than 3.0 Gy per day did not develop clinically apparent dementia. So, the actual frequency of radiation related dementia when using convention fractionation schedules is not known, but is certainly less than 11%. In any event, the frequency of long-term neuropsychological side effects of WBRT in adult brain metastases patients appears to have been overestimated and seems to be within the acceptable range when modern fractionation schemes are employed.
Surgery There have been three prospective randomized trials (10,17,18) assessing the value of surgical removal of single brain metastases (Table 2). In a prospective randomized trial (10) performed at the University of Kentucky, 48 patients with known systemic cancer were treated with either biopsy of the suspected brain metastasis plus WBRT or complete surgical resection of the metastasis plus WBRT. The radiation doses were the same in both groups and consisted of a total dose of 3600 cGy given as 12 daily fractions of 300 cGy each. There was a statistically significant increase in survival in the surgical group (40 weeks vs. 15 weeks). In addition, the time to recurrence of brain metastases, freedom from death due to neurologic causes, and duration of functional independence were significantly longer in the surgical resection group. The one month mortality was 4% in each group, indicating that there was no extra mortality from surgery. An important finding was that
TA B L E 2 Surgery for single brain metastases: randomized trials N
Median survival (weeks)
Length of functional independence (weeks)
CNS death (%)
S + WBRT Patchell et al. (10) Vecht et al. (17) Mintz et al. (18)
25 32 41
40 43 24
38 33 8
29 35 46
WBRT only Patchell et al. (10) Vecht et al. (17) Mintz et al. (18)
23 31 43
15 26 27
8 15 9
50 33 63
S, surgery; WBRT, whole brain radiotherapy.
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despite screening with both contrast enhanced MRI and CT before entry into the study, 6 out of 54 (11%) patients with known diagnoses of systemic malignancies were found not to have metastatic brain tumours when tissue was obtained at biopsy or attempted resection. The nonmetastatic lesions consisted of 3 astrocytomas, two abscesses and one sterile inflammatory lesion. A second randomized study (17), conducted as a multi-institutional trial in the Netherlands, contained 63 evaluable patients. Patients were randomized to either complete surgical resection plus WBRT or WBRT alone. The WBRT schedules were the same for both treatment arms and consisted of 4000 cGy given in a nonstandard fractionation scheme of 200 cGy twice per day for 2 weeks (10 treatment days). Survival time was significantly longer in the surgical group (10 months vs. 6 months). There was also a nonsignificant trend toward longer duration of functional independence in the surgically treated patients. No data concerning recurrence of brain metastases were given. The one month mortality rates were 9% in the surgery group and 0% in the WBRT alone group; this was not a statistically significant difference. Although diagnostic biopsies were not obtained in the WBRT alone group, one patient (out of 31) in the WBRT alone arm was later found to have a malignant glioma after having surgery performed on the brain lesion after progression of the presumed metastatic lesion. All 32 patients in the surgery group had metastatic tumours verified by tissue at operation. It is of note that 2 other patients were randomized into the study but excluded from the final analysis because they were found not to have metastatic tumours before the start of treatment. In all, 5% (3/65) did not have metastatic tumours. A third randomized trial, conducted in Canada by Mintz et al. (18), failed to find a benefit from surgical treatment. In that study, 84 patients were randomized to receive radiotherapy alone (3000 cGy) or surgery plus radiotherapy. No difference was found in overall survival; the median survival time was 6.3 months in the radiotherapy alone group and 5.6 months for the surgical group. There was also no difference in causes of death or quality of life. Only one patient of the 40 who had surgery had a lesion that was not a metastatic brain tumour; that patient had a glioblastoma. It is unclear why the Canadian study was not in agreement with the other two trials. In all three studies (10,17,18), the control arms (the radiation alone arms) had median lengths of survival in the 3 to 6 months range – well within the expected range for patients treated with radiotherapy alone. The major difference in the studies was the poor results obtained in the surgical arm of the Canadian trial
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(18). That study contained a higher proportion of patients with extensive systemic disease and lower performance scores (Table 3). Differences in patient selection in the Canadian trial may well have contributed to its failure to detect a significant benefit from the addition of surgical therapy. Also, the Canadian health care system sometimes discourages aggressive and expensive systemic treatment for patients with disseminated cancer. It is possible that these factors (i.e., selection/philosophy) resulted in more patients dying of their systemic cancer before a long term benefit of surgery was seen. Although the data supporting surgery for single brain metastases were derived from relatively small randomized trials that were not uniformly positive, the results have generally been interpreted to show that the surgical resection is of benefit in selected patients. Surgical therapy plus post-operative WBRT is now an established treatment for patients with surgically accessible single brain metastases. The value of surgery in the management of multiple metastases remains to be demonstrated. It is difficult to draw firm conclusions regarding the efficacy of surgery for multiple metastases from the studies published to date (19,20). Current practice is to treat multiple metastases with WBRT alone. Surgery is sometimes performed on patients with multiple metastases who have one life threatening brain lesion (e.g., a large compressive cerebellar lesion). The intent of surgery in these cases is to remove the single life threatening lesion without taking out the other lesions. Although this approach is speculative, long survival times have been achieved occasionally. The best results from surgery are seen in those patients with a single surgically accessible lesion and either no remaining systemic disease (true solitary metastasis) or with controlled systemic cancer limited to the primary site only. Also, surgical treatment is indicated in those patients without known systemic cancer (to obtain a tissue diagnosis) and in patients with impending herniation due to pressure effects.
TA B L E 3 Comparison of randomized trials for surgery Vecht et al. (17) (%)
Mintz et al. (18) (%)
77 38
52 32
53 45
100 4
– –
90 25
Patchell et al. (10) (%) Lung cancer Disseminated systemic disease Complete resection Cross-over to WBRT –, not reported.
THE MANAGEMENT OF BRAIN METASTASES
Radiosurgery Stereotactic radiosurgery is a method of delivering intense focal irradiation using a linear accelerator (LINAC) or a multiple Cobalt-60 sources (Gamma Knife). Radiosurgery does not replace conventional radiotherapy to the brain but offers a substitute for surgical treatment in patients with lesions less than about 3 cm in diameter. The role of radiosurgery has been the subject of three randomized trials to date. Kondziolka et al. (21) reported the first trial on the subject. This study had only 27 patients in it and used nonstandard endpoints. As a result, this trial was uninterpretable. A second study reported in abstract form by Chougule et al. (22) contained methodological problems that made it impossible to draw firm conclusions from the data. The largest randomized study to date has been reported in abstract form by the RTOG (23,24). This study (RTOG 9508) included patients with single and multiple brain metastases. There was a primary stratification based on number of metastases (one vs. two or three). To date, separate abstracts describing the results of the multiple brain metastases portion of the study (23) and the combined study (24) have been published. With regard to multiple metastases (23), the trial contained 144 patients with 2 or 3 brain metastases. These patients were randomized to treatment with either WBRT (37.5 Gy) plus radiosurgery or WBRT (37.5 Gy) alone. There was no significant difference in local failure rates in the brain with 21% in the radiosurgery arm and 37% in the WBRT alone arm (P ¼ 0:107). There was also no significant difference in the length of survival of the two groups (median, 5.3 months for radiosurgery and 6.7 months for WBRT alone). Most noteworthy was the lack of significant difference between the fraction of patients in each group who died of neurological causes (33% radiosurgery vs. 35% WBRT alone). Lower posttreatment Karnofsky scores and steroid dependence were more common in the WBRT alone patients. Nevertheless, for multiple brain metastases, this was a completely negative trial with regard to the major endpoints of tumour control in the brain, overall survival, and prevention of death due to neurological causes. A second abstract (24), reporting the combined results of RTOG 9805 and including patients with single and two or three brain metastases has been published. Patients with single metastases treated with radiosurgery plus WBRT lived significantly longer than patients treated with WBRT alone (median survival time, 6.5 months vs. 4.9 months, P ¼ 0:04). There was no significant difference in
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cause of death. The report goes on to claim an advantage for radiosurgery in a wide variety of subgroups that include patients with single and multiple brain metastases. However, the primary stratification was for number of lesions and the subgroup analysis used to make these claims was not part of the original study design. These attempted extensions are beyond the capability of the study to support. Analyses of this type are not reliable for drawing firm conclusions but are useful for hypothesis generation and future study. It is hoped that the final paper reporting this trial will clarify this issue. The results of RTOG 9508 have caused a major reevaluation of the use of radiosurgery in the treatment of brain metastases. This was the largest and best trial done to date, and it failed to show a benefit of radiosurgery in the treatment of multiple brain metastases when radiosurgery was given in the initial management of newly diagnosed tumours. Treatment with WBRT alone would now appear to be the treatment of choice in these circumstances. For multiple brain metastases, radiosurgery may still have a place in the treatment as salvage therapy in patients who have recurrent brain tumours after treatment with WBRT, but this remains to be demonstrated. The study did show that radiosurgery is beneficial in patients with single metastases. The rates of local control and overall survival with radiosurgery and WBRT are comparable to that in patients treated with conventional surgery plus WBRT. Radiosurgery now offers a real alternative to surgery. Conventional surgery is probably best reserved for patients in whom tissue is needed for diagnosis, patients with lesions too large for radiosurgery (>3 cm), and in patients with life threatening mass effect that would benefit from immediate decompression.
Adjuvant WBRT with surgery or radiosurgery With the establishment of the efficacy of focal treatments (surgery and radiosurgery) a new controversy has arisen whether adjuvant WBRT is necessary after a ‘‘complete resection’’ of a single metastasis or ‘‘successful’’ treatment with radiosurgery. Adjuvant WBRT is felt to be of benefit because there may be residual disease in the tumour bed or at distant microscopic sites in the brain. However, brain metastases tend to be discrete masses that are theoretically capable of being removed totally or destroyed, and so WBRT may not be necessary after ‘‘successful’’ focal therapy. Only one randomized trial (7) has addressed the question of adjuvant radiotherapy. In that study,
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95 patients who had single brain metastases that were completely resected by conventional surgery were randomized to treatment with post-operative WBRT (50.4 Gy) or to observation with no further treatment of the brain metastasis (until recurrence). Recurrence of tumour anywhere in the brain was less frequent in the radiotherapy group than in the observation group (18% vs. 70%, P < 0:001). Postoperative radiotherapy prevented brain recurrence at the site of the original metastasis (10% vs. 46%, P < 0:001) and at other sites in the brain (14% vs. 37%, P < 0:01). As a result, patients in the radiotherapy group were less likely to die of neurologic causes than patients in the observation group (6 of 43 who died [14%] vs. 17 of 39 [44%]; P ¼ 0:003). There was no significant difference between the two groups in overall length of survival or the length of time that patients remained functionally independent. Despite the fact that the randomized trial (7) was overwhelmingly positive for preventing recurrences, this study has actually provoked controversy rather than settling the issue. Since adjuvant WBRT apparently had no effect on length of survival, it has been argued that radiation makes no difference and can be dispensed with. In pursuit of this argument, several retrospective studies (25–28) have been published comparing patients treated with SRS who received WBRT with those who did not receive WBRT. These studies have generally shown that the recurrence rate is reduced by adjuvant WBRT but that length of survival is not increased. However, a closer look at these studies shows that, paradoxically, they may actually provide an argument in favor of giving WBRT. Since these were retrospective studies, treatment assignment was not random, and patient selection bias very clearly entered into the decision for treatment. In all of these studies, the WBRT group contained many more poor prognosis patients including those with multiple metastases and other unfavorable factors. For example, in series reported by Sneed et al. (27), single brain metastases were present in 58% of the SRS alone group but only 33% of the SRS + WBRT group. In addition, the intracranial tumour burden (as measured by the median total target volume) was substantially higher in the WBRT treated patients than in the SRS alone group (5.6 ml vs. 4.3 ml). Additionally, this was almost certainly an underestimate for the patients in the WBRT group because the volume given referred only to the SRS treated volume; there were many more multiple metastases in the WBRT group that were not included in the SRS volume. Despite these disadvantages, the median survival times in both groups were almost identical (8.2 months for SRS alone vs. 8.6 months for SRS + WBRT).
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This was not the expected result given the difference in prognostic factors between the two treatment arms. It would have been expected that the WBRT arm should have done worse, but instead there was no difference. This suggests that WBRT may have improved survival time and actually made a difference overall, a conclusion opposite to that drawn by the study’s authors. The real lesson here is that nonrandomized, retrospective studies cannot be used to resolve the question because of the insurmountable problem of patient selection bias inherent in these types of studies. The most compelling argument in favor of adjuvant WBRT involves an examination of the effects of not giving WBRT. Patients who do not receive adjuvant WBRT suffer substantially more recurrent brain metastases than patients who are treated with WBRT. As was discussed above, the side effects of WBRT appear to have been overestimated in the past and are in the acceptable range. Unfortunately, the same cannot be said of the side effects of recurrence of brain metastases. Several recent studies (29,30) have demonstrated that the recurrence of brain metastases has a negative effect on the neurocognitive functioning of patients. A study by Regine et al. (30) found that in 36 patients with brain metastases treated with SRS alone, 47% had recurrence of brain metastases and 71% of the recurrences were symptomatic. Significantly, 59% of the patients with recurrent tumours had associated neurological deficits that did not improve even with successful treatment of the recurrence. Another study by Regine et al. (29) showed that, at three months post-treatment, patients treated for brain metastases with WBRT had greater negative changes in their minimental status examinations with uncontrolled brain tumours than they did with controlled brain tumours ()6.3 points vs. )0.5 points, P ¼ 0:02). Also relevant (but perhaps somewhat farther afield) was a study by Taylor et al. (31) that showed that, in patients with primary brain tumours at 12 months post-treatment, changes in minimental status examinations were worse in patients with uncontrolled tumours ()2.42 points) than in patients with controlled tumours (+0.076 points) (P ¼ 0:0046). All of the patients in this study had received large total doses of conventional radiation therapy. These studies all suggest strongly that uncontrolled brain tumours result in a substantial decrease in mental performance and that this reduction far outweighs any decrement seen with cranial radiation therapy. Therefore, the side effects of recurrent tumours are worse than the side effects of preventive treatment. This is an extremely strong argument for the use of adjuvant WBRT in association with focal therapy.
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Chemotherapy Although chemotherapy has not yet emerged as a standard of therapy for patients with brain metastases, evidence has accumulated to suggest that chemotherapy may have a role in the treatment of selected patients. Since more than half of the patients with brain metastases who are treated with surgery or radiotherapy will subsequently die of progression of the systemic disease, a chemotherapeutic agent that is effective against both systemic and brain disease is highly desirable. However, most systemically administered chemotherapeutic agents that have proven effective against the primary sites of cancer have been ineffective against cerebral metastases from the same cell population. Chemotherapy has been used in the treatment of brain metastases from a variety of primary tumours; however, the results have generally been unimpressive (32,33). However, good results in some small uncontrolled series of patients with certain highly chemosensitive tumours (e.g., breast, small cell lung cancer, germ cell tumours) have been reported. More recently temozolomide, a newer oral chemotherapeutic agent, has shown some promise in the treatment of brain metastases, especially those from lung cancer. However, chemotherapy is not usually the primary therapy for most patients and is seldom the only therapy. Based on current knowledge, a reasonable use for chemotherapy for brain metastases would be in those patients with small, asymptomatic tumours from primaries that are known to be chemosensitive. If progression occurs with the patient receiving chemotherapy alone, more definitive treatment with surgery, radiosurgery, or radiotherapy may be given.
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