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Stereotactic Radiotherapy for Solitary Brain Metastases
Clinical Oncology (2001)13:228–234 # The Royal College of Radiologists
Clinical Oncology
Original Article Stereotactic Radiotherapy for Solitary Brain Metastases R. Jyothirmayi, F. H. Saran, R. Jalali, J. Perks, A. P. Warrington, D. Traish, S. Ashley, F. Hines and M. Brada The Royal Marsden NHS Trust and The Institute of Cancer Research, Sutton and London, UK Abstract. Purpose: Surgery is considered to be the treatment of choice for patients with solitary brain metastases. We report a single-centre experience of stereotactic radiotherapy (SRT)/radiosurgery as an alternative to surgery and define prognostic parameters that provide for a more rational selection of patients for appropriate treatment. Patients and Methods: Between 1990 and 1997, 96 patients with 106 brain metastases received SRT to a dose of 20 Gy in two fractions (range 20–30 Gy in 2–4 fractions) either alone or in combination with whole brain radiotherapy. Results: After SRT, 51% of patients had improvement in neurological function. The median survival of the 96 patients was 9 months. The Radiation Therapy Oncology Group prognostic grouping for patients with multiple brain metastases (prognostic factors: age, performance status, systemic metastases, status of primary tumour) was applicable to this cohort, with median survivals of 15, 8 and 2 months for favourable, intermediate and poor prognostic groups respectively. Conclusion: SRT is a non-invasive method of treatment of solitary brain metastases and the outcome is comparable with the results obtained after surgical excision. Prognosis is determined by factors defined for patients with multiple brain metastases, with performance status being the most important. SRT/radiosurgery should be reserved for patients with favourable prognostic factors, with a Karnofsky performance status >70, who have a reasonable chance of good quality prolonged survival. In future trials, radiosurgery should be compared in terms of survival, quality of life and health economics to whole brain radiotherapy and surgery. Keywords: Brain metastases; Radiosurgery; Stereotactic radiotherapy
Introduction Patients with solitary brain metastases (SBM) are considered to have better prognosis than those with multiple lesions. Aggressive local treatment in the form of surgery or local irradiation has been advocated [1]. Nevertheless, treatment for patients with metastatic disease is largely palliative and the most appropriate form of therapy should be effective not only in terms of tumour control and survival but it should also be easily administered and without morbidity. The efficacy of surgery in patients with SBM has been tested in three randomized trials. In two studies, the addition of surgical excision to whole brain radiotherapy (WBRT) was associated with better survival and tumour control than WBRT alone [2,3]; it was Correspondence and offprint requests to: Dr M. Brada, NeuroOncology Unit, Institute of Cancer Research and The Royal Marsden NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. E-mail: [email protected]
without benefit in the latest study, with the largest number of patients [4]. The advantage was seen only in patients with controlled or absent disease outside the brain. Currently, surgical excision is advocated in patients with accessible solitary lesions who have absent or stable systemic disease. However, surgery is an invasive treatment and should be evaluated further. Stereotactic radiotherapy (SRT)/radiosurgery is a technique of high-precision localized irradiation. It allows the administration of high-dose irradiation to the target volume with little radiation to surrounding normal tissue. The results of single-fraction radiosurgery for SBMs are comparable with those of surgical excision, although these techniques have not been formally compared in a randomized setting [5]. We reviewed the Royal Marsden Hospital experience of SRT for patients with SBM treated either at the time of the initial diagnosis or at recurrence after previous treatment. The response to treatment, survival and prognostic factors in this patient group were studied.
primary site and nine had extracranial metastases in addition to SBM. Eighty-four of the 96 patients had a pre-radiotherapy Karnofsky performance status (KPS) 570.
Materials and Methods Patient Details Between March 1990 and January 1997, 96 patients with 106 brain metastases were treated with SRT. The patient and tumour characteristics are summarized in Table 1. The solitary nature of a brain metastasis was confirmed by magnetic resonance imaging in all patients. The median age was 57 years (range 20–80). Primary disease was in remission in 51 patients, present but stable in 23 and progressive in nine. The disease status of the primary was not known in four patients. Nine had brain metastases from an unknown Table 1. Characteristics of 96 patients with solitary brain metastases Characteristic
No.
%
Age (years) 20–29 30–39 40–49 50–59 60–69 570
96 2 9 19 25 31 10
2 9 20 26 32 10
Sex Male Female
41 55
43 57
Primary site Lung Breast Melanoma Colon Ovary Testis Kidney Others Unknown Primary
30 22 16 5 3 3 5 3 9
31 23 17 5 3 3 5 3 9
Primary disease Not known Absent Present and stable Progressive disease
13 51 23 9
14 53 24 9
Site of metastases Cerebral hemispheres Thalamus Posterior fossa Other
71 4 16 5
74 4 17 5
Presenting featuresa Seizures Raised intracranial pressure Motor deficit Sensory deficit Higher mental deficit Cranial nerve deficit Visual disturbance Cerebral deficit
30 43 44 2 25 6 11 16
31 45 46 2 26 6 11 17
a
.Multiple features possible.
Treatment SRT was given at first diagnosis of brain metastasis in 67 patients and at recurrence after previous treatment in 29 patients. The prior treatment included WBRT in 18, of whom nine had also undergone prior surgical excision. Seven patients had had previous surgical excision without WBRT, and four had received chemotherapy alone. In previously treated patients the median interval from initial treatment of the SBM to SRT was 8 months (range 2–48). SRT was delivered using a 5 MV or 6 MV linear accelerator adapted for this procedure. The patients were immobilized in a Gill–Thomas–Cosman (GTC) relocatable frame and the Brown–Roberts–Wells (BRW) fiducial system was used for stereotactic space definition [6,7]. Details of the radiotherapy planning and treatment delivery have already been described [8]. SRT was delivered by multiple noncoplanar arcs in 90 lesions and by fixed non-coplanar conformal fields in 16 non-spherical lesions. The planning target volume (PTV) included the gross tumour volume and a margin of 1–2 mm. The PTV ranged from 1 cm3 to 53 cm3 (median 8). Of the 67 patients treated at first diagnosis, 45 received SRT alone and 22 received SRT after WBRT. Of 29 patients treated with SRT for recurrent intracranial disease, 26 received SRT alone and three received WBRT followed by SRT. In the initial doseescalation part of the study, patients received 20 Gy in four fractions (n = 3), followed by 26 Gy in two fractions (n = 15), 30 Gy in three fractions (n = 4), and 20 Gy in two fractions (n = 73). One patient with a sphenoid bone-based metastasis, which was in close proximity to the optic nerve, received a dose of 30 Gy in six fractions. The prescription of 20 Gy in two fractions was used in 73 patients (76% of the study population).
Assessment and Follow-up Patients were seen at 3-monthly intervals. The first 53 underwent routine follow-up scans at 4–8 weeks after radiotherapy (59 lesions). Routine scanning was not undertaken in patients in the latter part of the study because it did not affect further management decisions. A clinical response was defined as an improvement in neurological deficit, and clinical progression as progressive neurological deterioration that did not improve with corticosteroids and could not be attributed to treatment toxicity. A complete response was defined on imaging as disappearance of enhanStereotactic Radiotherapy for Solitary Brain Metastases
229
cing tumour and a partial response as >50% reduction in the product of two perpendicular maximum tumour dimensions. Progressive disease was defined as >25% increase in size. The remainder were classified as stable disease. Progression at the SRT sites was defined either on imaging or on clinical criteria alone. As the progression endpoint was not based on imaging in all patients, the local progression-free survival data are not fully reliable.
Statistical Methods Survival and local control were measured from the start of SRT and were analysed by the life table method of Kaplan and Meier [9]. Differences between groups were assessed by the log-rank statistic [10]. The validity of the Radiation Therapy Oncology Group (RTOG) prognostic index [11] was assessed for these patients by classifying them into good, intermediate and poor prognostic groups. Individual patient and disease characteristics were also investigated for their prognostic influence in a univariate survival analysis.
Results Survival The median survival of the 96 patients with SBM was 9 months (95% confidence interval (CI) 6–13) (Fig. 1). Patients treated at first diagnosis had a median survival of 9 months (95% CI 5–14); those receiving SRT after previous treatment had a median survival of 7 months (95% CI 6–8; P = 0.9). Patients treated at first diagnosis with SRT alone had a median survival of 10 months (95% CI 7–14) compared with 8 months (95% CI 2–15) for those receiving WBRT in addition to SRT (P40.9). Of 45 patients treated with SRT alone, seven relapsed in the brain and required further treatment. Four patients had WBRT, one surgery, one chemotherapy and one further SRT.
Fig. 1. Actuarial survival of 96 patients with SBM treated with SRT.
230
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Radiological Response A total of 59 lesions were assessed radiologically 4–8 weeks after SRT. Seven (12%) showed a complete response, 15 (25%) a partial response, 33 (56%) stable disease, and four (7%) progressive disease. Of the 31 patients with complete resolution of neurological symptoms, only five had a complete radiological response and nine a partial response. Eleven patients had stable disease and one progressive disease on imaging. Five patients with a complete clinical response were not assessed radiologically.
Neurological Status Two to 3 months after the completion of radiotherapy, neurological deficit had improved in 49 of the 96 patients (51%). Thirty-one (32%) recovered completely without residual deficit, and 18 (19%) had a partial recovery. Thirteen patients (14%) remained stable, and 13 (14%) deteriorated. Neurological status could not be assessed in 21 patients (22%). The relationship of corticosteroids to neurological recovery could not be assessed, although the majority of patients were either on a reduced dose or off corticosteroids at 2–3 months after treatment. Fiftyone patients (53%) deteriorated during follow-up. The median clinical neurological deterioration-free survival was 10 months (range 8–12).
Prognostic Factors Patients were divided into three prognostic groups according to the RTOG recursive partitioning analysis [11]. The favourable prognostic group included patients aged <65 years, with a KPS 570, with a controlled primary tumour, and without metastatic disease outside the brain. The poor prognosis group consisted of patients with a KPS <70. All other patients were included in the intermediate prognosis group. The median survival of favourable prognosis patients was 15 months (range 5–24), intermediate prognosis patients 8 months (range 5–12), and poor
Fig. 2. Survival of patients with SBM treated with SRT by RTOG prognostic grouping (P = 0.001).
prognosis patients 2 months (range 1–3) (P = 0.001) (Fig. 2). The median survival of patients with a preradiotherapy KPS <70 was 2 months compared with 10 months (range 8–12) for patients with KPS 570 (P = 0.007). Two-year local control was 64% (95% CI 34–83) for patients with small lesions (PTV <8 cm3) and 18% (95% CI 6–35) for patients with larger lesions (PTV >8 cm3), where 8 cm3 equates to an approximate diameter of 2.5 cm. Median survival was comparable in both groups (10 versus 8 months; P = 0.3) (Fig. 3). Age, sex, site of the intracranial lesion, histology and size of PTV were not significant predictors for survival (Table 2).
Fig. 3. Actuarial survival of patients with SBM treated with SRT: stratification by the size of the PTV (<8 cm3 versus >8 cm3) (P=0.3).
Table 2. Prognostic factors in patients treated with SRT for solitary brain metastases Prognostic factor
No. patients
Median survival (months)
P-value
All patients
96
Age (years) <65 565
69 27
10 6
>0.13
14 Not yet reached
>0.1
Sex Male Female
41 55
10 8
>0.6
19 14
>0.5
Disease extent None Primary Disseminated
44 15 37
12 6 5
>0.04
20 12 19
>0.6
KPS <70 570
12 84
2 10
>0.007
15 14
>0.7
Timing of SRT At first diagnosis Recurrence of SBM
67 29
9 7
>0.9
19 16
>0.02
Treatment SRT alone SRT and WBRT SRT for recurrence
45 22 29
10 8 7
>0.9
14 36 10
>0.02
Primary Lung Breast Melanoma Other
30 22 16 28
10 6 4 12
>0.06
14 10 19 19
>0.4
Prognostic group (RTOG) Good Medium Poor
27 57 12
15 8 2
>0.001
13 19 15
>0.8
Site Supratentorial Infratentorial
80 16
9 6
>0.04
15 12
>0.6
PTV (cm3) <8 58
38 44
10 8
>0.03
Not yet reached 12
<0.001
9a
Median local control (months)
P-value
15b
a
.95% CI 6–13. .95% CI 6–23.
b
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Treatment-Related Toxicity Eleven of the 96 patients (11%) experienced transient deterioration of neurological function requiring highdose steroids 1–5 months (median 4) after SRT. This was considered to be acute treatment-related toxicity as it was not associated with obvious disease progression on imaging. Three patients received an SRT boost after WBRT to total tumour doses of 40 Gy, 50 Gy and 54 Gy. Seven patients were treated with SRT alone. Toxicity was seen in seven of 83 patients (8%) who received 20 Gy in two fractions, and in four of 18 (22%) who received >20 Gy. Four patients had a complete and six a partial recovery of neurological function.
Discussion Ninety-six patients with SBM were treated with radiosurgery/SRT. The median survival from SRT was 9 months; 51% had improvement and 14% stabilization of neurological deficit. The RTOG prognostic index [11] separated patients into three groups, with a median survival of 15 months in the favourable prognostic group and a median survival of 2 months in the poor prognostic group defined by KPS <70. This single-centre experience of two-fraction SRT is comparable with the reported results of singlefraction radiosurgery [12–16]. Surgery is considered to be the treatment of choice in patients with resectable SBM who have controlled systemic disease [2,3]. Survival and tumour control results after radiosurgery are similar to those after surgical excision. The widely held belief is that SRT represents a non-invasive alternative to surgery. There are, however, no randomized studies comparing the two treatment modalities and there is, therefore, no formal comparison of all the important endpoints, including functional status and quality of life. Patients with brain metastases have limited prognosis [11,16] and the difference in outcome between the two treatment approaches is likely to be small, if any. Although it is possible to organize large randomized trials comparing surgery and radiosurgery, these are likely to be costly and in the palliative setting, where functional endpoints are important, difficult to perform. At present, we therefore have to rely on the results of single-arm Phase II studies. Based on the assumption that survival and tumour control for surgery and radiosurgery are equivalent, the choice of treatment will depend on the availability and easy access to radiosurgery facilities and patient preference. The conventional treatment of patients with multiple brain metastases is WBRT, which is also traditionally administered as adjuvant treatment after the resection of SBM [2,3,4]. A randomized trial comparing postoperative WBRT with no further treatment after complete resection of SBM showed 232
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improved progression-free survival in the brain without significant prolongation in survival [17]. However, the role of WBRT after SRT remains undefined. The reported study, in keeping with others [16,18], suggests that the addition of WBRT does not influence survival. While we await the results of randomized trials that are currently under way to assess the additional value of WBRT, it is reasonable to withhold it and to offer it only at the time of symptomatic disease progression. This avoids the additional morbidity of alopecia for at least a proportion of patients. However, this issue remains contentious and patient preference is an important and perhaps decisive factor. The optimum SRT dose and fractionation schedule has not been fully defined. Most centres use singlefraction radiosurgery with doses ranging from 16 Gy to 24 Gy. Effective local control has been reported with high single-fraction doses, although the treatment of large target volumes of >20 cm3 has been associated with a high risk of radiation damage, expressed as clinical toxicity [13]. The chosen dose of 20 Gy in two fractions was based on initial dose escalation studies [8] prior to the universal acceptance of a single-dose schedule. The low toxicity associated with this approach is similar to that reported after single-fraction radiosurgery. Although the use of noninvasive immobilization with a GTC frame allows for fractionated treatment, we have not demonstrated a clear benefit for biologically equivalent treatment using two compared with one fraction of irradiation. The prognostic factors defining the outcome in patients with SBM treated with single-fraction radiosurgery [12,13] are similar to the prognostic determinants in patients with multiple brain metastases [11]. We have therefore applied the RTOG prognostic index to patients treated with radiosurgery. This index offers a method of separating patients into prognostic groups with an option to offer treatment to those with a good prognosis and to withhold it from those with a poor prognosis (largely defined by performance status) who are likely to obtain little or no benefit. The metastasis size reflected in the SRT target volume inversely correlated with the probability of local control, with better results in patients with small metastases (PTV <8 cm3), although size did not correlate with survival. This is in keeping with other studies that reported no correlation between tumour size and survival [12,19]. The primary aim of therapy in patients with solitary or multiple brain metastases is palliation. An important endpoint is improvement in quality of life, but this has not been formally reported. When assessing the effect of the treatment of SBM on quality of life, it is difficult to distinguish between the influence of intracranial and extracranial disease and the effect of treatment. It is therefore reasonable, when assessing the effectiveness of localized treatment to the brain, to focus attention on the direct
expression of the intracranial disease in terms of neurological function. We have noted an improvement after SRT in neurological deficit in over half of our patients. In the absence of an objective measurement of disability and quality of life, this provides only partial information and a more comprehensive assessment should be a component of future studies of the treatment of brain metastases. SRT is generally advocated as equivalent to surgery with an assumed advantage over WBRT, based on analogy with published randomized trials of surgery. There has been no randomized comparison of surgery and WBRT in patients with multiple brain metastases and therefore no analogy that could demonstrate benefit of SRT over WBRT for the treatment of multiple lesions. Although the results of radiosurgery for SBM are encouraging and suggest an additional value for localized compared with whole brain treatment, the apparently improved survival may, at least in part, be due to the selection of favourable prognosis patients. Formal evaluation of the cost-effectiveness of SRT has suggested that it is more cost-effective than surgery for SBM in terms of cost per year of median survival [20,21]. However, the benefit for radiosurgery/SRT, which requires considerable capital investment and is time and labour intensive, should be assessed in randomized trials comparing SRT and WBRT. This is particularly important for patients with more than one lesion. Although some authors suggest that SRT should be offered to patients with multiple brain metastases (43) [22], the evidence of benefit is inadequate and questionable, and was not demonstrated in a recently completed randomized study [23]. Currently, SRT should be considered only for patients with SBM. Exceptionally, it can be considered within defined protocols for patients with two or three lesions who otherwise have the favourable prognostic factors of KPS >70, absent systemic metastases, and controlled disease at the primary site, particularly after the failure of WBRT.
Conclusions SRT/radiosurgery is an effective and well-tolerated localized treatment for SBM. The survival and tumour control results are comparable with the outcome after neurosurgical excision and the treatment provides a non-invasive palliative treatment alternative. The prognosis of patients with SBM is determined by factors defined in patients with multiple brain metastases, which include performance status, systemic tumour burden and activity, and age, with poor performance status being the most important adverse prognostic factor. Complex and costly treatment with radiosurgery should be reserved for patients with favourable prognostic factors: a KPS >70, with good neurological function, and a reasonable chance of
prolonged survival with functional recovery. The benefit of radiosurgery compared with WBRT in terms of quality of life as well as cost-effectiveness should be assessed in future randomized trials. Acknowledgements. This work was supported in part by the Neuro-Oncology Research Fund, the Royal Marsden NHS Trust and the Cancer Research Campaign. It was undertaken by the Royal Marsden NHS Trust, which received a proportion of its funding from the NHS Executive. The views expressed are those of the authors and not necessarily those of the NHS Executive.
References 1. Joseph J, Adler JR, Cox RS. Linear accelerator based stereotaxic radiosurgery for brain metastases: the influence of number of lesions on survival. J Clin Oncol 1996;14:1085–92. 2. 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. 3. Vecht CJ, Haaxma Reiche H, Noordijk EM, et al. Treatment of a single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol 1993;33:583–90. 4. Mintz AH, Kestle J, Rathbone MP, et al. A randomised trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 1996;78:1470–6. 5. Flickinger JC, Kondziolka D, Lunsford LD, et al. A multiinstitutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 1994;28:797–802. 6. Gill SS, Thomas DG, Warrington AP, et al. Relocatable frame for stereotactic external beam radiotherapy. Int J Radiat Oncol Biol Phys 1991;20:599–603. 7. Graham JD, Nahum AE, Brada M. A comparison of techniques for stereotactic radiotherapy by linear accelerator based on 3-dimensional dose distributions. Radiother Oncol 1991;22:29–35. 8. Laing RW, Warrington AP, Hines F, et al. Fractionated stereotactic external beam radiotherapy in the management of brain metastases. Eur J Cancer 1993;29A:1387– 91. 9. Kaplan EL, Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–8. 10. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomised clinical trials requiring prolonged observation of each patient. Part 2: Analysis and examples. Br J Cancer 1997;35:1–39. 11. 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. 12. Auchter RM, Lamond JP, Alexander E, et al. A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable and single brain metastasis. Int J Radiat Oncol Biol Phys 1996;35:27–35. 13. Engenhart R, Kimmig BN, Hover KH, et al. Long term follow up for brain metastases treated by percutaneous stereotactic single high dose irradiation. Cancer 1993;71:1353–61. 14. Shirato H, Takamura A, Tomita M. Stereotactic irradiation without whole brain irradiation for single brain metastasis. Int J Radiat Oncol Biol Phys 1997;37:385–91. 15. Alexander E, Moriarty TM, Davis RB, et al. Stereotactic radiosurgery for the definitive, noninvasive treatment of brain metastases. J Natl Cancer Inst 1995;87:34–40. 16. Pirzkall A, Debus J, Lohr F, et al. Radiosurgery alone or in
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combination with whole-brain radiotherapy for brain metastases. J Clin Oncol 1998;16:3563–9. Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 1998;280:1485–9. Fuller BG, Kaplan ID, Adler J, et al. Stereotaxic radiosurgery for brain metastases: the importance of adjuvant whole brain irradiation. Int J Radiat Oncol Biol Phys 1992;23:413–8. Sause WT, Crowley JJ, Morantz R, et al. Solitary brain metastasis: results of an RTOG/SWOG protocol evaluation surgery + RT versus RT alone. Am J Clin Oncol 1990;13:427–32. Rutgliano MJ, Lunsford LD, Kondziolka D. The cost effectiveness of stereotactic radiosurgery versus surgical resection in the treatment of solitary metastatic brain tumours. Neurosurgery 1995;37:445–53. Mehta M, Noyes W, Craig B, et al. A cost-effectiveness
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and cost–utility analysis of radiosurgery vs. resection for single brain metastases. Int J Radiat Oncol Biol Phys 1997;39:445–54. 22. 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. 23. Sperduto P, 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 unresected brain metastases. Int J Radiat Oncol Biol Phys 2000;48:113.
Received for publication September 2000 Accepted February 2001
Clinical Oncology
Original Article Stereotactic Radiotherapy for Solitary Brain Metastases R. Jyothirmayi, F. H. Saran, R. Jalali, J. Perks, A. P. Warrington, D. Traish, S. Ashley, F. Hines and M. Brada The Royal Marsden NHS Trust and The Institute of Cancer Research, Sutton and London, UK Abstract. Purpose: Surgery is considered to be the treatment of choice for patients with solitary brain metastases. We report a single-centre experience of stereotactic radiotherapy (SRT)/radiosurgery as an alternative to surgery and define prognostic parameters that provide for a more rational selection of patients for appropriate treatment. Patients and Methods: Between 1990 and 1997, 96 patients with 106 brain metastases received SRT to a dose of 20 Gy in two fractions (range 20–30 Gy in 2–4 fractions) either alone or in combination with whole brain radiotherapy. Results: After SRT, 51% of patients had improvement in neurological function. The median survival of the 96 patients was 9 months. The Radiation Therapy Oncology Group prognostic grouping for patients with multiple brain metastases (prognostic factors: age, performance status, systemic metastases, status of primary tumour) was applicable to this cohort, with median survivals of 15, 8 and 2 months for favourable, intermediate and poor prognostic groups respectively. Conclusion: SRT is a non-invasive method of treatment of solitary brain metastases and the outcome is comparable with the results obtained after surgical excision. Prognosis is determined by factors defined for patients with multiple brain metastases, with performance status being the most important. SRT/radiosurgery should be reserved for patients with favourable prognostic factors, with a Karnofsky performance status >70, who have a reasonable chance of good quality prolonged survival. In future trials, radiosurgery should be compared in terms of survival, quality of life and health economics to whole brain radiotherapy and surgery. Keywords: Brain metastases; Radiosurgery; Stereotactic radiotherapy
Introduction Patients with solitary brain metastases (SBM) are considered to have better prognosis than those with multiple lesions. Aggressive local treatment in the form of surgery or local irradiation has been advocated [1]. Nevertheless, treatment for patients with metastatic disease is largely palliative and the most appropriate form of therapy should be effective not only in terms of tumour control and survival but it should also be easily administered and without morbidity. The efficacy of surgery in patients with SBM has been tested in three randomized trials. In two studies, the addition of surgical excision to whole brain radiotherapy (WBRT) was associated with better survival and tumour control than WBRT alone [2,3]; it was Correspondence and offprint requests to: Dr M. Brada, NeuroOncology Unit, Institute of Cancer Research and The Royal Marsden NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. E-mail: [email protected]
without benefit in the latest study, with the largest number of patients [4]. The advantage was seen only in patients with controlled or absent disease outside the brain. Currently, surgical excision is advocated in patients with accessible solitary lesions who have absent or stable systemic disease. However, surgery is an invasive treatment and should be evaluated further. Stereotactic radiotherapy (SRT)/radiosurgery is a technique of high-precision localized irradiation. It allows the administration of high-dose irradiation to the target volume with little radiation to surrounding normal tissue. The results of single-fraction radiosurgery for SBMs are comparable with those of surgical excision, although these techniques have not been formally compared in a randomized setting [5]. We reviewed the Royal Marsden Hospital experience of SRT for patients with SBM treated either at the time of the initial diagnosis or at recurrence after previous treatment. The response to treatment, survival and prognostic factors in this patient group were studied.
primary site and nine had extracranial metastases in addition to SBM. Eighty-four of the 96 patients had a pre-radiotherapy Karnofsky performance status (KPS) 570.
Materials and Methods Patient Details Between March 1990 and January 1997, 96 patients with 106 brain metastases were treated with SRT. The patient and tumour characteristics are summarized in Table 1. The solitary nature of a brain metastasis was confirmed by magnetic resonance imaging in all patients. The median age was 57 years (range 20–80). Primary disease was in remission in 51 patients, present but stable in 23 and progressive in nine. The disease status of the primary was not known in four patients. Nine had brain metastases from an unknown Table 1. Characteristics of 96 patients with solitary brain metastases Characteristic
No.
%
Age (years) 20–29 30–39 40–49 50–59 60–69 570
96 2 9 19 25 31 10
2 9 20 26 32 10
Sex Male Female
41 55
43 57
Primary site Lung Breast Melanoma Colon Ovary Testis Kidney Others Unknown Primary
30 22 16 5 3 3 5 3 9
31 23 17 5 3 3 5 3 9
Primary disease Not known Absent Present and stable Progressive disease
13 51 23 9
14 53 24 9
Site of metastases Cerebral hemispheres Thalamus Posterior fossa Other
71 4 16 5
74 4 17 5
Presenting featuresa Seizures Raised intracranial pressure Motor deficit Sensory deficit Higher mental deficit Cranial nerve deficit Visual disturbance Cerebral deficit
30 43 44 2 25 6 11 16
31 45 46 2 26 6 11 17
a
.Multiple features possible.
Treatment SRT was given at first diagnosis of brain metastasis in 67 patients and at recurrence after previous treatment in 29 patients. The prior treatment included WBRT in 18, of whom nine had also undergone prior surgical excision. Seven patients had had previous surgical excision without WBRT, and four had received chemotherapy alone. In previously treated patients the median interval from initial treatment of the SBM to SRT was 8 months (range 2–48). SRT was delivered using a 5 MV or 6 MV linear accelerator adapted for this procedure. The patients were immobilized in a Gill–Thomas–Cosman (GTC) relocatable frame and the Brown–Roberts–Wells (BRW) fiducial system was used for stereotactic space definition [6,7]. Details of the radiotherapy planning and treatment delivery have already been described [8]. SRT was delivered by multiple noncoplanar arcs in 90 lesions and by fixed non-coplanar conformal fields in 16 non-spherical lesions. The planning target volume (PTV) included the gross tumour volume and a margin of 1–2 mm. The PTV ranged from 1 cm3 to 53 cm3 (median 8). Of the 67 patients treated at first diagnosis, 45 received SRT alone and 22 received SRT after WBRT. Of 29 patients treated with SRT for recurrent intracranial disease, 26 received SRT alone and three received WBRT followed by SRT. In the initial doseescalation part of the study, patients received 20 Gy in four fractions (n = 3), followed by 26 Gy in two fractions (n = 15), 30 Gy in three fractions (n = 4), and 20 Gy in two fractions (n = 73). One patient with a sphenoid bone-based metastasis, which was in close proximity to the optic nerve, received a dose of 30 Gy in six fractions. The prescription of 20 Gy in two fractions was used in 73 patients (76% of the study population).
Assessment and Follow-up Patients were seen at 3-monthly intervals. The first 53 underwent routine follow-up scans at 4–8 weeks after radiotherapy (59 lesions). Routine scanning was not undertaken in patients in the latter part of the study because it did not affect further management decisions. A clinical response was defined as an improvement in neurological deficit, and clinical progression as progressive neurological deterioration that did not improve with corticosteroids and could not be attributed to treatment toxicity. A complete response was defined on imaging as disappearance of enhanStereotactic Radiotherapy for Solitary Brain Metastases
229
cing tumour and a partial response as >50% reduction in the product of two perpendicular maximum tumour dimensions. Progressive disease was defined as >25% increase in size. The remainder were classified as stable disease. Progression at the SRT sites was defined either on imaging or on clinical criteria alone. As the progression endpoint was not based on imaging in all patients, the local progression-free survival data are not fully reliable.
Statistical Methods Survival and local control were measured from the start of SRT and were analysed by the life table method of Kaplan and Meier [9]. Differences between groups were assessed by the log-rank statistic [10]. The validity of the Radiation Therapy Oncology Group (RTOG) prognostic index [11] was assessed for these patients by classifying them into good, intermediate and poor prognostic groups. Individual patient and disease characteristics were also investigated for their prognostic influence in a univariate survival analysis.
Results Survival The median survival of the 96 patients with SBM was 9 months (95% confidence interval (CI) 6–13) (Fig. 1). Patients treated at first diagnosis had a median survival of 9 months (95% CI 5–14); those receiving SRT after previous treatment had a median survival of 7 months (95% CI 6–8; P = 0.9). Patients treated at first diagnosis with SRT alone had a median survival of 10 months (95% CI 7–14) compared with 8 months (95% CI 2–15) for those receiving WBRT in addition to SRT (P40.9). Of 45 patients treated with SRT alone, seven relapsed in the brain and required further treatment. Four patients had WBRT, one surgery, one chemotherapy and one further SRT.
Fig. 1. Actuarial survival of 96 patients with SBM treated with SRT.
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Radiological Response A total of 59 lesions were assessed radiologically 4–8 weeks after SRT. Seven (12%) showed a complete response, 15 (25%) a partial response, 33 (56%) stable disease, and four (7%) progressive disease. Of the 31 patients with complete resolution of neurological symptoms, only five had a complete radiological response and nine a partial response. Eleven patients had stable disease and one progressive disease on imaging. Five patients with a complete clinical response were not assessed radiologically.
Neurological Status Two to 3 months after the completion of radiotherapy, neurological deficit had improved in 49 of the 96 patients (51%). Thirty-one (32%) recovered completely without residual deficit, and 18 (19%) had a partial recovery. Thirteen patients (14%) remained stable, and 13 (14%) deteriorated. Neurological status could not be assessed in 21 patients (22%). The relationship of corticosteroids to neurological recovery could not be assessed, although the majority of patients were either on a reduced dose or off corticosteroids at 2–3 months after treatment. Fiftyone patients (53%) deteriorated during follow-up. The median clinical neurological deterioration-free survival was 10 months (range 8–12).
Prognostic Factors Patients were divided into three prognostic groups according to the RTOG recursive partitioning analysis [11]. The favourable prognostic group included patients aged <65 years, with a KPS 570, with a controlled primary tumour, and without metastatic disease outside the brain. The poor prognosis group consisted of patients with a KPS <70. All other patients were included in the intermediate prognosis group. The median survival of favourable prognosis patients was 15 months (range 5–24), intermediate prognosis patients 8 months (range 5–12), and poor
Fig. 2. Survival of patients with SBM treated with SRT by RTOG prognostic grouping (P = 0.001).
prognosis patients 2 months (range 1–3) (P = 0.001) (Fig. 2). The median survival of patients with a preradiotherapy KPS <70 was 2 months compared with 10 months (range 8–12) for patients with KPS 570 (P = 0.007). Two-year local control was 64% (95% CI 34–83) for patients with small lesions (PTV <8 cm3) and 18% (95% CI 6–35) for patients with larger lesions (PTV >8 cm3), where 8 cm3 equates to an approximate diameter of 2.5 cm. Median survival was comparable in both groups (10 versus 8 months; P = 0.3) (Fig. 3). Age, sex, site of the intracranial lesion, histology and size of PTV were not significant predictors for survival (Table 2).
Fig. 3. Actuarial survival of patients with SBM treated with SRT: stratification by the size of the PTV (<8 cm3 versus >8 cm3) (P=0.3).
Table 2. Prognostic factors in patients treated with SRT for solitary brain metastases Prognostic factor
No. patients
Median survival (months)
P-value
All patients
96
Age (years) <65 565
69 27
10 6
>0.13
14 Not yet reached
>0.1
Sex Male Female
41 55
10 8
>0.6
19 14
>0.5
Disease extent None Primary Disseminated
44 15 37
12 6 5
>0.04
20 12 19
>0.6
KPS <70 570
12 84
2 10
>0.007
15 14
>0.7
Timing of SRT At first diagnosis Recurrence of SBM
67 29
9 7
>0.9
19 16
>0.02
Treatment SRT alone SRT and WBRT SRT for recurrence
45 22 29
10 8 7
>0.9
14 36 10
>0.02
Primary Lung Breast Melanoma Other
30 22 16 28
10 6 4 12
>0.06
14 10 19 19
>0.4
Prognostic group (RTOG) Good Medium Poor
27 57 12
15 8 2
>0.001
13 19 15
>0.8
Site Supratentorial Infratentorial
80 16
9 6
>0.04
15 12
>0.6
PTV (cm3) <8 58
38 44
10 8
>0.03
Not yet reached 12
<0.001
9a
Median local control (months)
P-value
15b
a
.95% CI 6–13. .95% CI 6–23.
b
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Treatment-Related Toxicity Eleven of the 96 patients (11%) experienced transient deterioration of neurological function requiring highdose steroids 1–5 months (median 4) after SRT. This was considered to be acute treatment-related toxicity as it was not associated with obvious disease progression on imaging. Three patients received an SRT boost after WBRT to total tumour doses of 40 Gy, 50 Gy and 54 Gy. Seven patients were treated with SRT alone. Toxicity was seen in seven of 83 patients (8%) who received 20 Gy in two fractions, and in four of 18 (22%) who received >20 Gy. Four patients had a complete and six a partial recovery of neurological function.
Discussion Ninety-six patients with SBM were treated with radiosurgery/SRT. The median survival from SRT was 9 months; 51% had improvement and 14% stabilization of neurological deficit. The RTOG prognostic index [11] separated patients into three groups, with a median survival of 15 months in the favourable prognostic group and a median survival of 2 months in the poor prognostic group defined by KPS <70. This single-centre experience of two-fraction SRT is comparable with the reported results of singlefraction radiosurgery [12–16]. Surgery is considered to be the treatment of choice in patients with resectable SBM who have controlled systemic disease [2,3]. Survival and tumour control results after radiosurgery are similar to those after surgical excision. The widely held belief is that SRT represents a non-invasive alternative to surgery. There are, however, no randomized studies comparing the two treatment modalities and there is, therefore, no formal comparison of all the important endpoints, including functional status and quality of life. Patients with brain metastases have limited prognosis [11,16] and the difference in outcome between the two treatment approaches is likely to be small, if any. Although it is possible to organize large randomized trials comparing surgery and radiosurgery, these are likely to be costly and in the palliative setting, where functional endpoints are important, difficult to perform. At present, we therefore have to rely on the results of single-arm Phase II studies. Based on the assumption that survival and tumour control for surgery and radiosurgery are equivalent, the choice of treatment will depend on the availability and easy access to radiosurgery facilities and patient preference. The conventional treatment of patients with multiple brain metastases is WBRT, which is also traditionally administered as adjuvant treatment after the resection of SBM [2,3,4]. A randomized trial comparing postoperative WBRT with no further treatment after complete resection of SBM showed 232
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improved progression-free survival in the brain without significant prolongation in survival [17]. However, the role of WBRT after SRT remains undefined. The reported study, in keeping with others [16,18], suggests that the addition of WBRT does not influence survival. While we await the results of randomized trials that are currently under way to assess the additional value of WBRT, it is reasonable to withhold it and to offer it only at the time of symptomatic disease progression. This avoids the additional morbidity of alopecia for at least a proportion of patients. However, this issue remains contentious and patient preference is an important and perhaps decisive factor. The optimum SRT dose and fractionation schedule has not been fully defined. Most centres use singlefraction radiosurgery with doses ranging from 16 Gy to 24 Gy. Effective local control has been reported with high single-fraction doses, although the treatment of large target volumes of >20 cm3 has been associated with a high risk of radiation damage, expressed as clinical toxicity [13]. The chosen dose of 20 Gy in two fractions was based on initial dose escalation studies [8] prior to the universal acceptance of a single-dose schedule. The low toxicity associated with this approach is similar to that reported after single-fraction radiosurgery. Although the use of noninvasive immobilization with a GTC frame allows for fractionated treatment, we have not demonstrated a clear benefit for biologically equivalent treatment using two compared with one fraction of irradiation. The prognostic factors defining the outcome in patients with SBM treated with single-fraction radiosurgery [12,13] are similar to the prognostic determinants in patients with multiple brain metastases [11]. We have therefore applied the RTOG prognostic index to patients treated with radiosurgery. This index offers a method of separating patients into prognostic groups with an option to offer treatment to those with a good prognosis and to withhold it from those with a poor prognosis (largely defined by performance status) who are likely to obtain little or no benefit. The metastasis size reflected in the SRT target volume inversely correlated with the probability of local control, with better results in patients with small metastases (PTV <8 cm3), although size did not correlate with survival. This is in keeping with other studies that reported no correlation between tumour size and survival [12,19]. The primary aim of therapy in patients with solitary or multiple brain metastases is palliation. An important endpoint is improvement in quality of life, but this has not been formally reported. When assessing the effect of the treatment of SBM on quality of life, it is difficult to distinguish between the influence of intracranial and extracranial disease and the effect of treatment. It is therefore reasonable, when assessing the effectiveness of localized treatment to the brain, to focus attention on the direct
expression of the intracranial disease in terms of neurological function. We have noted an improvement after SRT in neurological deficit in over half of our patients. In the absence of an objective measurement of disability and quality of life, this provides only partial information and a more comprehensive assessment should be a component of future studies of the treatment of brain metastases. SRT is generally advocated as equivalent to surgery with an assumed advantage over WBRT, based on analogy with published randomized trials of surgery. There has been no randomized comparison of surgery and WBRT in patients with multiple brain metastases and therefore no analogy that could demonstrate benefit of SRT over WBRT for the treatment of multiple lesions. Although the results of radiosurgery for SBM are encouraging and suggest an additional value for localized compared with whole brain treatment, the apparently improved survival may, at least in part, be due to the selection of favourable prognosis patients. Formal evaluation of the cost-effectiveness of SRT has suggested that it is more cost-effective than surgery for SBM in terms of cost per year of median survival [20,21]. However, the benefit for radiosurgery/SRT, which requires considerable capital investment and is time and labour intensive, should be assessed in randomized trials comparing SRT and WBRT. This is particularly important for patients with more than one lesion. Although some authors suggest that SRT should be offered to patients with multiple brain metastases (43) [22], the evidence of benefit is inadequate and questionable, and was not demonstrated in a recently completed randomized study [23]. Currently, SRT should be considered only for patients with SBM. Exceptionally, it can be considered within defined protocols for patients with two or three lesions who otherwise have the favourable prognostic factors of KPS >70, absent systemic metastases, and controlled disease at the primary site, particularly after the failure of WBRT.
Conclusions SRT/radiosurgery is an effective and well-tolerated localized treatment for SBM. The survival and tumour control results are comparable with the outcome after neurosurgical excision and the treatment provides a non-invasive palliative treatment alternative. The prognosis of patients with SBM is determined by factors defined in patients with multiple brain metastases, which include performance status, systemic tumour burden and activity, and age, with poor performance status being the most important adverse prognostic factor. Complex and costly treatment with radiosurgery should be reserved for patients with favourable prognostic factors: a KPS >70, with good neurological function, and a reasonable chance of
prolonged survival with functional recovery. The benefit of radiosurgery compared with WBRT in terms of quality of life as well as cost-effectiveness should be assessed in future randomized trials. Acknowledgements. This work was supported in part by the Neuro-Oncology Research Fund, the Royal Marsden NHS Trust and the Cancer Research Campaign. It was undertaken by the Royal Marsden NHS Trust, which received a proportion of its funding from the NHS Executive. The views expressed are those of the authors and not necessarily those of the NHS Executive.
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Received for publication September 2000 Accepted February 2001