Radiation Therapy Oncology Group has in addition ... received either prior whole brain radiation therapy in ... prophylactic cranial irradiation (PCI) and did not.
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CHAPTER
10
Stereotactic Radiosurgery of Brain Metastases from Non-Small Cell Lung Cancer: Comparison of Gamma Knife & CyberKnife
Marianne M. Young
Charles Engles
Clinton A. Medbery
W. Emery Reynolds
Astrid E. Morrison
Maximian F. D’Souza
Mary K. Gumerlock
Cindy Parry
Benjamin White
Vikki Harriet
Abstract
prescribed to the 50% isodose line (target/tumor periphery) with dose-volume histograms showing nearly 00% target volume coverage. CyberKnife doses were 4–30 Gy in –3 fractions, generally prescribed to the isodose line encompassing 95% of the lesion volume. Follow-up typically consisted of MRI at one month post-treatment, then every three months for the remainder of follow-up. Of our patients, 4/25 received either prior whole brain radiation therapy in the range of -25 months follow-up, or a prior surgical resection. They then received stereotactic radiosurgery either as a boost or for a recurrence. A total of 40/42 sites were controlled using the Gamma Knife with a range of –25 months follow-up, (median follow-up of five months), whereas 6/6 of sites were controlled using the CyberKnife with a range of –0 months follow-up, (median follow-up of six months). One of our Gamma Knife patients died a neurologic death; no CyberKnife patients died a neurologic death. Acute toxicity was similar in both
It has become common practice to offer patients with small numbers of brain lesions stereotactic radiosurgery, either alone or in combination with whole brain radiation therapy. Several groups have published data showing dramatic improvement in the control of brain disease with the use of radiosurgery and the Radiation Therapy Oncology Group has in addition shown survival benefit. Recent information from the University of Southern California reported that only 23% of their non-melanoma brain metastases population treated with radiosurgery died as a result of their brain metastases (neurologic death). We treated 25 patients with non-small cell lung cancer for brain metastases using stereotactic radiosurgery from December , 2003 through September 30, 2004. A total of 3 patients with 42 lesions were treated using the Gamma Knife and 2 patients with 6 lesions were treated using the CyberKnife®. Gamma Knife single-fraction doses were 4–20 Gy, generally
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groups and consisted primarily of symptomatic brain edema, which was treated with oral corticosteroids. CyberKnife stereotactic radiosurgery of intracranial metastases from non-small cell lung cancer offers results comparable to those of Gamma Knife stereotactic radiosurgery, but without the need for invasive frame placement.
Introduction Lung cancer continues to be the leading cause of cancer death, and the incidence of brain metastases in lung cancer is in the range 25–40%. The annual estimated incidence of brain metastases in the United State alone is in excess of 250,000 cases, with lung cancer responsible for half of this number. The majority of these patients die within several months of the discovery of their brain disease.1 Ongoing improvement in systemic therapies has led to longer disease-free survivals, resulting in a growing population of cancer survivors. Unfortunately, these effective systemic agents have poor, if any, penetration through the blood-brain barrier, increasing the likelihood of developing metastases in the brain. Thus, controlling brain disease in the surviving patients is all the more crucial.
Conventional Whole Brain Radiation Therapy Whole brain radiation therapy (WBRT) has been used to treat brain metastases for nearly half a century. The therapy is simple to deliver, inexpensive, and has little short-term morbidity. The Radiation Therapy Oncology Group (RTOG) has studied whole brain palliative therapy in several investigational protocols. Their assessment of fractionation schemes was published in 98 2 and reviewed ,830 patients. Five schemes were evaluated: 20 Gy in five fractions, 30 Gy in 0 fractions, 30 Gy in 5 fractions, 40 Gy in 5 fractions and 40 Gy in 20 fractions.
No difference in survival was noted among the five fractionation schemes. Performance status (ambulatory versus non-ambulatory) predicted the greatest survival difference: 28 weeks versus weeks, respectively. Other prognostic factors of significance were age less than 60, primary tumor control, and brain as a sole site of metastases.3, 4 Re-analysis in 993 demonstrated three or fewer lesions to be an additional favorable prognostic factor. 5 Given the RTOG results, most patients receive 30 Gy in 0 fractions or 40 Gy in 20 fractions. The Patterns of Care Survey confirmed that these are standard regimens in the United States radiotherapy community. In the early 990s, the RTOG published results of a phase I dose escalation trial using accelerated hyperfractionation to treat brain metastases. This trial resulted in survival and neurologic improvement advantages with higher doses in patients with better prognostic factors.6 A later phase III randomized evaluation of hyperfractionation (54.4 Gy at .6 Gy twice per day) did not show survival advantage over 30 Gy in 0 fractions.7 The fact remains that ‘standard’ doses often may not control brain disease and the magnitude of the problem of brain metastases regrowth is likely to be underestimated. In 990, Patchell et al 8 noted a recurrence rate of greater than 80% after WBRT for solitary lesions—far poorer than results with surgery. Consequently, WBRT is likely not to be adequate in patients with otherwise good expectations for at least intermediate-term survival. In the last decade, several investigators have reported significant neurological toxicity in long-term survivors of WBRT. 9 These patients generally received prophylactic cranial irradiation (PCI) and did not have neurologic effects of the apparent brain lesions. Altered fractionation and lower doses currently in use for PCI may prevent such sequelae, but there is still
C H A P T E R 10 : Stereotactic Radiosurgery of Brain Metastases from Non-Small Cell Lung Cancer:
Comparison of Gamma Knife & CyberKnife
reason for concern regarding late effects of WBRT in patients who survive their disease.
Surgery The role for surgical extirpation of brain metastases remains controversial. Patients with large, symptomatic lesions in easily operated areas and those in need of a tissue diagnosis are likely the best surgical candidates. Selection bias can certainly show results in favor of surgery, but even in these patients, recurrence is higher without the addition of WBRT. To study the benefit of improvement in intracranial control, three randomized trials have compared surgery plus whole brain radiotherapy to radiotherapy alone in patients with solitary lesions.8–10 Two of the trials showed a significant median survival benefit with the addition of surgery. Survival was in excess of 40 weeks and was most improved in patients with good Karnofsky performance status (KPS). 8, 9 The most recent of these trials, however, failed to identify a statistical improvement in survival with the addition of surgery. 10 Nonetheless, these results generally support the premise that aggressive management aimed at local control of brain metastases results in survival benefit for selected patients.
Radiosurgery Literature Survey The first published report on radiosurgery for brain metastases was by Sturm et al in 986,12 showing 00% clinical improvement and 7% radiographic response with a mean dose of 8 Gy. Since that initial report, scores of publications have reported on thousands of treated patients and lesions. In general, survival and morbidity reports show superior results to those
99
reported for surgery and WBRT. Table shows results of recent radiosurgery series. The multitude of data makes interpretation of these myriad results difficult to assess objectively. Using recursive partitioning analysis, the RTOG 51 trials have identified three major prognostic categories that significantly impact outcome. The most favorable patients, class , included KPS > 70, age < 65, controlled primary and no extracranial metastases. These patients had a median survival of greater than seven months and benefited significantly from radiosurgery over WBRT. Class 3 patients had KPS < 70 and median survival of 2.3 months; some reports showed no survival benefit from radiosurgery in this group. The class 2 patients (all others) generally showed a small but significant benefit from radiosurgery. A review of the series in Table shows local control rates of 25–99%, which suggest a benefit in local control for radiosurgery versus WBRT alone. These rates compare favorably to rates of control achieved with surgery. Although only a few of these reports provide actual data on local control, they support the observations of improved local control with radiosurgery.
Survival Benefit The results of RTOG 95-08 were reported recently by Andrews et al. 15 This trial randomized patients with –3 newly diagnosed brain metastases to WBRT or WBRT followed by a radiosurgery boost. Analysis showed survival advantage to WBRT and radiosurgery in patients with a single lesion. Louisiana State University published a retrospective analysis of their Gamma Knife experience in patients with lung cancer metastases and reported that only 22.7 % of patients died of their brain disease (failure of local control or new brain lesions). They concluded that Gamma Knife radiosurgery
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Institution/Literature reference
Number of patients/ metastases
SRS mode
dMedian value of Dmin (Gy)
Local control (%)
Median survival (months) 7
University of Pittsburgh/Sheehan 13
1088/NK
GK
12–20
84
University of Florida/Ulm 14
383/NK
Linac
15
75 (1 yr)
9
RTOG/Andrews 15
333/NK
GK, Linac
15–24
82
6.5
61/103
GK
15
81.6
8
160/468
GK
20
97
8.2
Tokyo Metropolitan Komagone Hospital/Niibe 19
77/90
Linac
25
90
NK
University of Maryland/Flannery
Louisiana State University, Shreveport/Jawahar 16, 17 University of Kentucky/Shehata 18
72/NK
GK
18
NK
15.7
Hokkaido University, Japan/Aoyama 21
87/159
Linac
35 (4 fx)
81 (1 yr)
8.7
University of Pittsburgh/Hasegawa 22
121/NK
GK
18.5
87
8
University of Pittsburgh NSCLC/Sheehan 23
273/627
GK
18.5
84
15
Verona/Gerosa 24
804/1307
GK
20.6
94
13.5
54/174
GK
25
85
8.4
University of Southern California/Petrovich 26
458/1305
GK
18
77
9
Ichiharo, Japan/Serizawa 27
245/NK
GK
21–22
98
9
University of California San Francisco/Hoffman 28
95/NK
GK
18
81
12
20
Philippines/Vesagas 25
41/66
CyberKnife
9–30
80
7.2
421/248
Linac
15
85
9.4
University of California San Francisco/Shiau 31
261/119
GK
18.5
77
12
Karolinska, Stockholm/Kihlstrom 32
235/160
GK
30
94
NK
Gamma Knife User's Group/Flickinger 33
116/116
GK
16
85
11
52/33
GK
25
94
NK
University of Osaka, Japan/Shimanoto 29 Harvard University/Alexander 30
Stanford University/Fuller 34 University of Wisconsin, Madison/Mehta 35
58/40
GK
18
82
6.5
Hospital Israelita,Sao Paulo,Brazil/Weltman 36
34/69
Linac
18
NK
6.4
Hokkaido University, Japan/Shirato 37
39/39
Linac
25
84
8.7
University of Cincinnati/Breneman 38
84/145
Linac
16
25
11
Emory University/Alleyne 39
40/41
Linac
14.9
71
9
University of California San Diego/Chamberlain 40
50/>50
Linac
20
NK
6.5
Stanford University/Joseph 41
120/184
Linac
26.6
96
8
Nakamura Memorial Hospital Sapporo, Japan/Fukuoka 42
130/215
GK
14–30
93
8
MD Anderson Cancer Center/Bindal 43
31/>31
Linac
18.7
60
8
University of Ulsan, Korea/Whang 44
28/60
GK
30
NK
15
Komaki City Hospital, Japan/Kida 45
20/55
GK
18.9
97
6.4
Clinica Flaminia, Rome/Valentino 46
139/139
Linac
50 (Dmax)
NK
13.4
Jiro Suzuki Memorial Clinic, Japan/Jokura 47
25/77
GK
26.1
99
8.5
University of Cologne, Germany/Voges 48
46/66
Linac
20
85
6
University of Heidelberg, Germany/Engenhart 49
69/102
Linac
21.5
95
6
University of Cologne, Germany/Sturm 50
39/54
Linac
18
93
6.5
Table . Reports of radiosurgery (SRS) published between 992 and 2004.13–50 GK: Gamma Knife. Linac: Linear
accelerator. For a given series of patients, the Dmin was not always the same and therefore the median value of Dmin is
quoted in this table. dWhen the median is not available, a dose range is quoted. NK: Not known. fx: fraction.
C H A P T E R 10 : Stereotactic Radiosurgery of Brain Metastases from Non-Small Cell Lung Cancer:
Comparison of Gamma Knife & CyberKnife
Patient Characteristics Number of patients
Gamma Knife
CyberKnife
3
2
44–76 (median 60)
4–8 (median 60)
8:5
7:5
Prior or subsequent WBRT
8
7
Prior or subsequent resection
2
4
Number of sites treated
42
6
4–20
4–30
Age range Male:Female ratio
Dose (Gy)
–3
50% to the target periphery
The % isodose line that encompasses about 95% of the lesion volume
40/42
6/6
–25 (median = 5)
–0 (median = 6)
Patients with a neurologic death
0
Sites with symptomatic necrosis
0
Number of fractions Prescription isodose line & its location Sites controlled Follow-up range (months)
0
significantly reduced mortality from brain metastases by improving local control in the brain.16 Finally, Shuto et al, 52 who reported retrospective Japanese data on the use of repeat Gamma Knife radiosurgery for multiple brain metastases, found that 6 patients who were treated four or more times achieved a median survival (measured from the diagnosis of their brain disease) of 22.4 months. Death due to progression of brain disease occurred in only 30% of patients. These data have established radiosurgery as the standard of care for patients with limited numbers of brain metastases, particularly in those with good prognostic status.
Dose & Toxicity The RTOG published results of a radiosurgery dose escalation trial RTOG 90-05.53 Escalations of the minimum tumor dose Dmin were stratified by tumor diameter. Based on grade 3 toxicity, the maximum
Table 2. Comparison between Gamma Knife and CyberKnife radiosurgery for
NSCLC patients treated in Oklahoma
City.
tolerable dose for a 30–40 mm diameter lesion was considered to be 8 Gy. The recommended dose prescriptions were 24 Gy for ≤ 20 mm, 8 Gy for 2–30 mm and 5 Gy for 3–40 mm 53. The UCSF data confirmed better local control for lesions treated to ≥ 8 Gy. 31 A review of the studies quoted in Table shows symptomatic necrosis to be only a minor problem, but it does represent the most common chronic complication of radiosurgery. The reported incidence is in the range 2–4%. The true risk appears to be a function of tumor volume and prior or current WBRT.54, 55 Acute toxicity is primarily a result of edema, and the vast majority of cases respond to steroid therapy.
CyberKnife Radiosurgery Osaka Shimamoto et al reported 29 the Osaka CyberKnife experience in the treatment of metastatic brain disease for 66 lesions treated in 4 patients. The prescribed
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Figure . 7-year-old female with metastatic non-small cell lung cancer to the brain. The patient had received prior whole brain prophylactic irradiation. Four lesions (vertex,
left ventricular horn, right ventricular horn & right cerebellum) were treated using the CyberKnife, each lesion receiving 24 Gy prescribed to the 74% isodose line, delivered in a single fraction.
C H A P T E R 10 : Stereotactic Radiosurgery of Brain Metastases from Non-Small Cell Lung Cancer:
Comparison of Gamma Knife & CyberKnife
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Figure 2. 52-year-old
female with metastatic non-small cell lung cancer to the brain. Gamma Knife treatment to two cerebellar lesions. 8 Gy was prescribed to the 50% isodose line for each lesion.
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doses were 9–30 Gy. Local control was more likely with doses of greater than 24 Gy but less than 20 Gy. No severe complications were noted.
Oklahoma City The CyberKnife system at St. Anthony’s Hospital in Oklahoma City began treating patients in December 2003, whereas the Gamma Knife at the University of Oklahoma Health Sciences Center has been in use for nearly eight years. The same physicians have had the opportunity to treat patients using both systems. We performed a retrospective analysis of all patients treated for brain metastases from December , 2003 through September 30, 2004. The subset of our patients with primary non-small cell lung cancer (NSCLC) is summarized in Table 2. An extended analysis to include all patients treated for brain metastases (including primary histologies and sites other than NSCLC) gave a total of 89 lesions in 26 patients treated with the Gamma Knife and 30 lesions in 22 patients treated with the CyberKnife. The overall site control rate for the Gamma Knife was 97.8% (87/89) and for the CyberKnife was 96.7% (29/30). Figures -2 are examples for one of our CyberKnife patients and one of our Gamma Knife patients.
Conclusions Radiosurgery has become a standard weapon in the armamentarium for the treatment of brain metastases. Most neurosurgeons and radiation oncologists agree on the use of such aggressive therapy for the treatment of patients with good performance status and expectation of intermediate-term survival, particularly given the low morbidity and recent data regarding survival benefit. Radiosurgical results are comparable to or better than those achieved with resection and likely more cost-effective. The role of whole brain radiation
remains somewhat unclear, with some studies indicating benefit and others none. The best initial treatment for every different individual with brain metastases is still being defined. CyberKnife radiosurgery of intracranial metastases from NSCLC offers results comparable to Gamma Knife radiosurgery without the need for an invasive frame placement. Also, unlike Gamma Knife SRS, CyberKnife SRS can be fractionated—which would be beneficial in areas around radiosensitive tissues. As other studies have also recently concluded, other systemic sites of disease failure remain the primary cause of death in most patients after radiosurgery of brain metastases.
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C H A P T E R 10 : Stereotactic Radiosurgery of Brain Metastases from Non-Small Cell Lung Cancer:
Comparison of Gamma Knife & CyberKnife
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27. Serizawa T, Ono J, Iichi T et al. Gamma Knife radiosurgery for metastatic brain tumors from lung cancer: a comparison between SCLC and NSCLC. J Neurosurg 2002;97:484–488.
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Comparison of Gamma Knife & CyberKnife
50. Sturm V, Kober B, Hover KH et al. Stereotactic percutaneous single dose irradiation of brain metastases with a linear accelerator. Int J Radiat Oncol Biol Phys 987;3:279–282.
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53. Shaw E, Scott C, Souhami L et al. Radiosurgery for the treatment of previously irradiated recurrent primary brain tumors and brain metastases: initial report of RTOG protocol 90–05. Int J Radiat Oncol Biol Phys 996;34:647–654.
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