J Neurooncol (2013) 113:459–465 DOI 10.1007/s11060-013-1138-y
CLINICAL STUDY
The efficacy and limitations of stereotactic radiosurgery as a salvage treatment after failed whole brain radiotherapy for brain metastases Shoji Yomo • Motohiro Hayashi
Received: 12 February 2013 / Accepted: 28 April 2013 / Published online: 10 May 2013 Ó Springer Science+Business Media New York 2013
Abstract The aim of the present study was to evaluate the efficacy and limitations of repeat stereotactic radiosurgery (SRS) salvage for patients with recurrence of brain metastases (BM) after whole brain radiotherapy (WBRT). This is a retrospective, observational, single-center trial analyzing 77 consecutive patients with recurrent BM who were treated primarily with WBRT. All patients underwent SRS as salvage treatment. Median age was 62 years, and median Karnofsky performance status (KPS) was 80. The median interval between the starting date of WBRT and radiosurgery was 10.6 months. One, two and more than two SRS sessions were required in 42, 13 and 22 patients, respectively. The median total planning target volume (PTV) was 8.1 mL and the median dose prescribed was 20 Gy. The median follow-up was 7.7 months. 1- and 2-year neurological death-free survival (NS) rates were 87 and 78 %, respectively. Competing risk analysis demonstrated active extra-central nervous system (CNS) disease [Hazard ratio (HR) 0.236, P = 0.041] and total PTV on initial SRS (C5 mL) (HR 4.22, P = 0.033) to be associated with the NS rate. 1- and 2-year overall survival (OS) rates were 41 and 11 %, respectively. The median OS time was 8.2 months. Active extra-CNS disease (HR 1.94, P = 0.034) and high KPS (C90) (HR 0.409, P = 0.006) were associated with the OS rate. In total, 798 tumors (75 %) in 66 patients (86 %) with sufficient radiological follow-up data were evaluated. 1- and 2-year metastasis S. Yomo (&) Division of Radiation Oncology, Aizawa Comprehensive Cancer Center, Aizawa Hospital, 2-5-1, Honjo, Matsumoto, Nagano Prefecture 390-0814, Japan e-mail:
[email protected] M. Hayashi Saitama Gamma Knife Center, San-ai Hospital, Saitama, Japan
local control rates were 76.6 and 57.9 %, respectively. Prescribed dose (C20 Gy) (HR 0.326, P \ 0.001), tumor volume (C2 mL) (HR 1.98, P = 0.007) and metastases from breast cancer (HR 0.435, P \ 0.001) were independent predictive factors for local tumor control. Repeat salvage SRS for recurrent BM after WBRT appeared to be a safe and effective treatment. In the majority of patients, even those with numerous BM, neurological death could be delayed or even prevented. Keywords Brain metastases Stereotactic radiosurgery Whole brain radiotherapy Re-irradiation Competing risk analysis
Introduction Brain metastases (BM) are a significant cause of morbidity and death for cancer patients. With major improvements in diagnostic and therapeutic options and a corresponding improvement in survival, BM are now diagnosed more frequently. Whole brain radiotherapy (WBRT) was long considered to be the standard treatment for most patients with extensive intracranial disease. Despite the use of WBRT with the addition of a local therapy such as surgical resection or stereotactic radiosurgery (SRS), recurrences continue to occur locally and elsewhere in the brain and require further therapeutic intervention. The role of re-irradiation using WBRT for patients who develop recurrent BM remains controversial because of its neurotoxicity [1–3] (Table 1). In this clinical setting, SRS appears to be a rational treatment option because most patients who have developed recurrent BM are followed closely with serial imaging studies. Therefore, recurrent or new metastases are
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460 Table 1 Outcomes of patients undergoing salvage treatment for recurrent/progressive brain metastases after WBRT
WBRT whole brain radiotherapy, NR not reported, MST median survival time, SRS stereotactic radiosurgery, GK gamma knife, LINAC linear accelerator a
Mean value
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First author and year
No. of patients
Median interval between WBRT and salvage treatment (months)
MST after salvage treatment (months)
Son et al. (2012) [2]
WBRT
17
15.3
5.2
Sadikov et al. (2007) [1]
WBRT
72
9.6
4.1
Abdel-Wahab et al. (1997) [17] Wong et al. (1996) [3]
WBRT WBRT
15 86
10 7.6
3.2 4.0
Cooper et al. (1990) [16]
WBRT
52
NR
5.2a
Hazuka and Kinzie (1988) [23]
WBRT
44
7.8
1.9
Kurup et al. (1980) [24]
WBRT
56
6.3a
3.3
Caballero et al. (2012) [6]
GK SRS
310
8.1
8.4
Maranzano et al. (2012) [4]
LINAC SRS
Chao et al. (2008) [7]
LINAC/GK SRS
Noel et al. (2001) [5]
LINAC SRS
Davey et al. (1994) [20]
LINAC SRS
more likely to be discovered when they are small and produce little or no mass effect. SRS has the advantages of being applicable to the management of surgically inaccessible tumors, multiple lesions, and even relapses after WBRT, in a single outpatient treatment session [4–7]. This retrospective study investigated the efficacy and limitations of salvage treatment using repeat SRS for patients with recurrent BM after failure of upfront WBRT.
Materials and methods Study design and patient population From January 2009 through September 2012, 77 patients with 1,059 recurrent BM after upfront WBRT were treated with Gamma Knife SRS in our institution. These interventions were conducted in a salvage, rather than a boost, setting. The treatment protocol for salvage treatment in the author’s institution has no set limitation on the number of BM provided patients’ systemic conditions are such that SRS intervention would be tolerable and consent for treatment was obtained. Selected patients with numerous recurrent BM were necessarily treated twice, and the second session was provided a month later at no charge. Surgical resection was recommended for tumors larger than 15 mL with a mass effect unresponsive to corticosteroid therapy. If surgery was not feasible due to poor prognosis and/ or advanced systemic disease, 2-session SRS was indicated for carefully selected large tumors [8]. Radiosurgical techniques SRS was performed using the Leksell G stereotactic frame (Elekta Instruments, Stockholm, Sweden). The frame was
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Salvage modality
69
11
10
111
7.8
9.9
54
9
7.8
12
6
6
placed on the patient’s head under local anesthesia supplemented with mild sedation. High-resolution 3-D volumetric gadolinium-enhanced T1-weighted magnetic resonance (MR) images, 2 mm in thickness T2-weighted MR images and contrast-enhanced computed tomography were routinely used for dose planning with Leksell Gamma Plan software (Elekta Instruments). The targets in salvage SRS sessions were principally limited to recurrent or newly-emerging lesions. Stable lesions continued to be monitored unless regrowth was documented. Prescribed doses were selected according to tumor size, location and proximity to critical structures. BM not exceeding 10 mL were treated with single-dose radiosurgery at prescribed doses ranging from 12 to 22 Gy (median, 20 Gy). The technical details of 2-session SRS for large tumors were described previously [8]. All treatments were performed with the Leksell Gamma Knife Model C or Perfexion. Post-SRS management and follow-up evaluation Clinical follow-up data as well as contrast-enhanced MR images were obtained every 1–3 months. If metachronous metastases were identified, they were principally managed with repeat SRS. Local control failure was defined as an at least 20 % increase in the diameter of the targeted lesions, taking as a reference the pre-SRS diameter, irrespective of true recurrence or delayed radiation injury. Delayed radiation injury was differentiated from tumor recurrence using the T1/T2 mismatch method [9] and, in selected cases, 11Cmethionine positron emission tomography [10]. Additional SRS was possible provided that the volume of the local tumor recurrence was small enough for single-dose SRS. Surgical removal was indicated when neurological signs became refractory to conservative management, with a
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radiological diagnosis of local tumor progression or radiation necrosis. Any adverse events attributable to SRS procedures were evaluated based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE; ver.3.0). Before closing the research database for analysis, the authors updated the follow-up data of patients who had not visited our outpatient department for more than 2 months. Inquiries about the date and mode of death were made by directly corresponding with the referring physician and/or the family of the deceased patient. Neurological death was defined as death attributable to central nervous system (CNS) metastases including tumor recurrence and carcinomatous meningitis. Events such as pneumonia due to a decline secondary to CNS disease progression were also scored as neurological deaths.
Table 2 Summary of clinical data from 77 consecutive patients
Time from WBRT to initial salvage SRS (months), median (range)
10.6 (1.6–127)
Statistical analysis
Leukoencephalopathya Grade 1/Grade 2/ Grade 3
7/17/6
Leptomeningeal dissemination Focal neurological deficit
12 (16 %) 39 (51 %)
No. of SRS interventions needed per patient, median (range)
1 (1–7)
No. of treated intracranial lesions per intervention, median (range)
5 (1–32)
No. of treated intracranial lesions per patient, median (range)
9 (1–91)
The neurological death-free survival (NS) rate was defined as the interval from the date of initial SRS until the date of neurological death. Death due to extra-CNS disease progression was regarded as a ‘‘competing event’’ in the estimation of the NS rate. The overall survival (OS) rate was similarly calculated by the period from the date of initial SRS treatment until the date of death. For estimation of the local tumor control rate, a starting point for each BM was separately set at the date of each SRS session. The NS rate was analyzed employing Gray’s test [11]. The OS and the local tumor control rates were similarly calculated by the Kaplan–Meier product limit method. The Fine-Gray proportional hazards model [12] and the Cox proportional hazards model were appropriately applied to investigate prognostic factors for NS, OS and local tumor control rates. Prognostic candidates were selected with reference to other salvage SRS series [4–7]. A statistical processing software package ‘‘R’’ version 2.14.2 (R Development Core Team, Vienna, Austria) was used for all statistical analyses. A P value of \0.05 was considered to indicate a statistically significant difference.
Results The characteristics of the 77 consecutive patients who had been treated with up-front WBRT are summarized in Table 2. Patient ages at the time of the first SRS intervention ranged from 33 to 82 years with a median age of 62 years. Forty-eight, 20, 3 and 6 patients had lung, breast, gastrointestinal and other cancers, respectively. The median interval between primary site diagnosis and WBRT was 10.1 months (range 0–96.4 months). The median interval between WBRT and the initial salvage SRS was
Characteristics
Values
Age (years), median (range)
62 (33–82)
Sex, male/female
38/39
KPS, median (range)
80 (40–100)
Active extra-CNS disease
52 (68 %)
RTOG-RPA Class 1/Class 2/Class 3
14/43/20
Time from primary diagnosis to BM detection (months), median (range)
10.1 (0–96.4)
Primary tumors Lung
47
Breast
20
Gastrointestinal tract
3
Others
7
KPS Karnofsky performance scale, CNS central nervous system, RTOG radiation therapy oncology group, RPA recursive partitioning analysis, BM brain metastasis, WBRT whole brain radiotherapy, SRS stereotactic radiosurgery a
According to National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0)
10.6 months (range 1.6–127 months). MR imaging at the time of the initial SRS revealed radiation-induced leukoencephalopathy in 30 patients (39 %), grade 1 in 7, grade 2 in 17 and grade 3 in 6 patients according to the NCICTCAE (v.3.0) classification. The total number of SRS sessions ranged from one to seven and 35 patients (45 %) underwent repeat SRS for distant metachronous metastases or local tumor recurrences. One, two and more than two SRS sessions were required in 42, 13 and 22 patients, respectively. The median total number of BM treated per patient was 9 (range 1–91). The median target volume was 0.5 mL (range 0.02–26.2) and the median total planning target volume (PTV) for each intervention was 8.1 mL (range 0.35–46.5). Five patients with large tumors were allocated to 2-session SRS. Patient survival Full clinical results were available for all 77 patients as none were lost to follow-up. The median follow-up time
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paradoxically, be associated with better NS rates [Hazard ratio (HR) 0.236, 95 % confidence interval (CI) 0.059–0.944, P = 0.041] (Table 3). Large total PTV, defined as no \5 mL, at the initial SRS session negatively influenced the NS rate (HR 4.22, 95 % CI 1.12–15.9, P = 0.033). The 1- and 2-year OS rates after SRS were 41 and 11 %, respectively (Fig. 1a). The median OS time was 8.2 months (95 % CI 6.7–12.5). The proportional hazards model for OS demonstrated active extra-CNS disease (HR 1.94, 95 % CI 1.05–3.60, P = 0.034) and high KPS (C90) (HR 0.409, 95 % CI 0.216–0.773, P = 0.006) to be factors independently predicting OS rates (Table 3). Local tumor control In total, 1,059 BM were treated with repeat salvage SRS. Of these, 477 (45 %) were treated at the first SRS and the other 582 tumors (55 %) which later recurred or newly emerged, were treated at the subsequent SRS sessions. Of these, only the 66 patients (86 %), with 798 tumors, (75 %) who had sufficient radiological follow-up data were analyzed herein because the other 11 died from extra-CNS progression without follow-up MR imaging. 1- and 2-year local tumor control rates were 76.6 % (95 % CI 71.2–81.1) and 57.9 % (95 % CI 48.4–66.4), respectively (Fig. 1b). One hundred and six metastases (13.2 %) were eventually considered to show failure of local tumor control at a median time of 6.6 months after SRS (range 2.5–26.4). The proportional hazards model demonstrated high prescribed dose (C20 Gy) (HR 0.326, 95 % CI 0.213–0.500, P \ 0.001), large tumor volume (C2 mL) (HR 1.98, 95 % CI 1.21–3.25, P = 0.007) and metastases from breast cancer (HR 0.435, 95 % CI 0.277–0.682, P \ 0.001) to be factors predicting local tumor control rates (Table 4). Fig. 1 Survival results for patients with recurrent BM treated with salvage SRS: a The dotted line represents the neurological death-free survival (NS) probability adjusted for competing events. The 1- and 2-year NS rates after SRS were 87 and 78 %, respectively. The solid line represents overall survival (OS) probability. The median survival time (MST) was 8.2 months (95 % CI 6.7–12.5). 1- and 2-year OS rates after SRS were 41 and 11 %, respectively. Note that the distance between these two lines, NS and OS, represents the cumulative incidence of non-neurological death. Kaplan–Meier curve for local control of recurrent BM after salvage SRS: b The 1- and 2-year local tumor control rates after SRS were 76.6 % (95 % CI 71.2–81.1) and 57.9 % (95 % CI 48.4–66.4), respectively
after SRS was 7.7 months. At the time of assessment, 16 patients (21 %) were alive and 61 (79 %) had died. The causes of death were intracranial local progression in 2 cases, meningeal carcinomatosis in 12 and progression of the primary lesion in 47. 1- and 2-year NS rates after SRS were 87 and 78 %, respectively (Fig. 1a). The proportional hazards model adjusted for competing events (extra-CNS death) demonstrated active extra-CNS disease to,
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Adverse effects and further management after radiosurgery As acute adverse effects, transient emesis occurred in one patient with multiple infratentorial metastases, necessitating a brief hospitalization for steroid administration (NCICTCAE Grade 3 toxicity). One patient having a metastasis in contact with the anterior visual pathway eventually lost vision in his left eye 3 months after SRS for local tumor control (NCI-CTCAE Grade 3 toxicity). Of 106 tumors showing local control failure after salvage SRS, 83 were retreated with stereotactic re-irradiation and surgical resection was necessary in three patients at 2.5, 7.3 and 9.8 months, respectively, after SRS. A mixture of viable tumor cell nests and radiation necrosis was demonstrated histologically in these cases. The remaining 20 tumors were closely observed with conservative management, as necessary. Of these, two patients required repeat
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Table 3 Analysis of factors predicting patient survival after salvage SRS (proportional hazards model) Covariate
NS P value
OS Hazard ratio (95 % CI)
P value
Hazard ratio (95 % CI)
Metastases from breast cancer
0.64
1.28 (0.443–3.74)
0.223
0.677 (0.361–1.27)
High KPS (C90)
0.53
0.691 (0.216–2.21)
0.006
0.409 (0.216–0.773)
Active extracranial disease
0.041
0.236 (0.059–0.944)
0.034
1.94 (1.05–3.60)
Short interval from WBRT to SRS (B1 years)
0.11
2.99 (0.766–11.7)
0.805
1.08 (0.602–1.92)
Leptomeningeal dissemination
0.83
0.878 (0.259–2.97)
0.224
0.584 (0.246–1.39)
Multiple BM (C10)
0.51
1.43 (0.494–4.15)
0.360
1.35 (0.710–2.58)
Large total PTV on the initial SRS (C5 mL)
0.033
4.22 (1.12–15.9)
0.280
1.35 (0.783–2.33)
SRS stereotactic radiosurgery, OS overall survival, NS neurological death-free survival, KPS Karnofsky performance scale, WBRT whole brain radiotherapy, BM brain metastases, PTV planning target volume
Table 4 Analysis of factors predicting local tumor control (Cox proportional hazards model) Parameter
P value
Hazard ratio (95 % CI)
Metastases from breast cancer
\.001
0.435 (0.277–0.682)
Metastases causing focal signs
0.681
1.13 (0.636–2.00)
Larger tumor volume (C2 mL) 0.007 Higher prescription dose (C20 Gy) \.001
1.98 (1.21–3.25) 0.326 (0.213–0.500)
bevacizumab therapy for delayed radiation injury refractory to steroids (NCI-CTCAE Grade 3 toxicity). Bevacizumab therapy was started 9.9 months in one case and 13.1 months in the other after the initial SRS salvage. Both received intravenous bevacizumab at a dose of 5 mg/kg every 2 weeks, at least 6 times, and showed clinical and radiological improvement over a prolonged period. All patients with CTCAE grade 3 adverse effects, with the exception of radiation-induced optic neuropathy, had necessarily undergone more than three SRS sessions, wherein the cumulative PTV had exceeded 30 mL.
Discussion Recent advances in systemic chemotherapy including molecular-targeting agents have substantially improved the survival of cancer patients, even those with BM [13, 14]. The long-term control of CNS disease has become increasingly important not only for overall disease control but also for maintaining the patient’s quality of life. Thus, the recurrence of BM after upfront WBRT remains a major issue. As there exists no class I or II evidence allowing definitive treatment recommendations in the setting of recurrent BM, treatment policies should be individualized based on a patient’s functional status, extent of systemic disease, volume/number of intracranial metastases, recurrence at the original versus non-original sites, previous
treatments and the type of primary cancer [15]. For salvage treatment, microsurgery, re-irradiation with WBRT or SRS and, to a lesser extent, chemotherapy may be reasonable options. Microsurgery should be considered in specific cases with neurological deficits secondary to a mass effect and showing immediate recovery, while this approach would be uncommon in patients with a relatively short anticipated survival and multiple recurrent BM. Re-irradiation to the whole brain may still have a place in BM management but reported median survival times (MSTs) appear to be consistently as short as 3–5 months [1–3, 16, 17] (Table 1). There is also a major concern about radiation-induced neurotoxicity [18, 19]. Since the first decade of the twenty first century, the efficacy of SRS for recurrent BM after failure of WBRT has been reported by several investigators [4–7] (Table 1). Patients with recurrent BM after WBRT generally have more advanced systemic disease. Their life expectancy is, unfortunately, assumed to be short. In fact, however, many of these patients actually die of extra-CNS disease progression, as demonstrated herein. Given this observation, OS, the primary outcome most articles have focused on, may not be an appropriate endpoint for evaluating the efficacy and limitations of salvage SRS for recurrent BM. The authors believe it to be critically important to measure how SRS might delay or even prevent neurological death, with adequate maintenance of the patient’s quality of life. From this viewpoint, clinical information about the mode of death and the local control of BM is indispensable. Understanding potential differences in the mode of death (CNS progression versus extra-CNS progression), is anticipated to facilitate answering the important question of whether treating recurrent BM delays neurological progression long enough to allow more aggressive therapy for the primary systemic disease. Noe¨l et al. [5] reported a crude neurological death rate of 11 %, which was similar to that in our present study, while Davey et al. [20] and Maranzano et al. [4] reported
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neurological death rates as high as 75 and 52 %, respectively. The number of lesions treated per patient was significantly higher in the present than in other salvage SRS series [4–7], mainly because a certain number of patients with numerous BM who were apparently unsuitable candidates for SRS had to be treated. Fourteen patients (18 %) had more than 10 recurrent BM at the first SRS intervention. Some of these patients maintained stable systemic disease, such that intracranial disease would be a major factor limiting their life expectancies. However, remaining treatment options for recurrent multiple BM after WBRT were fairly limited. This was the reason for the treatment protocol in the author’s institution having no set limitation on the number of BM, so long as treatment appeared to be feasible and the patient wanted further treatment. Neurological death could, however, be prevented in the majority of patients by repeat salvage treatment for recurrent BM. The MST reached 8.2 months, comparable to those of previous studies [4–7], apparently long enough for salvage SRS to be offered to cancer patients with recurrent BM. It should be noted that more than half of BM were treated in the subsequent SRS sessions. Given that BM might continue to recur or emerge metachronously even after the initial salvage SRS, continuous management would be warranted. Early detection and intervention for BM based on vigilant radiological follow-up, before they become large symptomatic tumors, can be regarded as the key to sustainable control of intracranial disease. Such an aggressive treatment policy has not yet, however, been validated and its safety is of major concern. The toxicities of adverse events observed in the present series were NCICTCAE grade 3 at a maximum, which we consider to be acceptable given the difficult clinical situations. Several investigators have already demonstrated the safety of such a treatment strategy [21, 22]. However, high-level evidence of its clinical efficacy remains insufficient and will have to be validated in future studies before this strategy becomes an established treatment option. The present study demonstrated active extra-CNS disease to be associated with a higher NS rate, which would apparently be paradoxical. Salvage SRS could provide most cases with palliative short- to mid-term local control, though CNS disease would ultimately become difficult to control in the long-term even with repeat SRS, provided that control of systemic disease were ensured. As shown in the present study, the 2-year local tumor control rate was significantly decreased (57.9 %) as compared to the favorable 1-year control rate (76.6 %). Furthermore, even with repeat SRS, it is of course difficult to overcome leptomeningeal carcinomatosis, which is responsible for most neurological deaths. Our results suggest that the rate of neurological death may increase with further prognostic improvement for cancer patients with advances in systemic
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chemotherapy. A combination approach with innovative modalities such as a radiosensitizer and molecular-targeting agents, including bevacizumab, would be warranted for achieving long-term durable control of recurrent BM. The results of the present study must be interpreted with caution. There is inherent selection bias because this study was conducted in a retrospective fashion with a heterogeneous group of patients and all treatments were given at a single institution. Small sample size and relatively short follow-up may have resulted in the dataset being underpowered to assess hypotheses and potential prognostic factors. The authors also recognize that the present series is unusual for several reasons. The patient inclusion criteria, in particular, are somewhat different from those employed in previous studies. Nonetheless, the novel analytical approach employed in the present study supported existing data regarding the role of salvage SRS and BM recurrence after WBRT was found to seldom be a survival-limiting factor.
Conclusion Salvage SRS appears to be a safe and effective treatment option for recurrent BM after failure of WBRT. The novel analytical approach employed in the present study demonstrated that neurological death could be delayed or prevented in the majority of patients by continuing active radiosurgical management. Acknowledgments We are grateful to Bierta Barfod, M.D., M.P.H. for her help with the preparation of this manuscript. Conflict of interest The authors have no personal, financial or institutional interests in any of the materials or devices described in this article.
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