J Neurosurg (Suppl) 105:75–78, 2006

Gamma Knife surgery targeting the resection cavity of brain

metastasis that has progressed after whole-brain radiotherapy
PAUL K. KIM, M.D., THOMAS L. ELLIS, M.D., VOLKER W. STIEBER, M.D.,
KEVIN P. MCMULLEN, M.D., EDWARD G. SHAW, M.D., THOMAS P. MCCOY, PH.D.,
RALPH B. D’AGOSTINO JR., PH.D., J. DANIEL BOURLAND, PH.D.,
ALLAN F. DEGUZMAN, PH.D., KENNETH E. EKSTRAND, PH.D.,
MICHAEL R. RABER, B.B.A., AND STEPHEN B. TATTER, M.D., PH.D.
Departments of Neurosurgery, Radiation Oncology, and Public Health (Section of Biostatistics), Wake
Forest University Baptist Medical Center, Winston–Salem, North Carolina

Object. Salvage treatment of large, symptomatic brain metastases after failure of whole-brain radiotherapy (WBRT)
remains challenging. When these lesions require resection, there are few options to lower expected rates of local
recurrence at the resection cavity margin. The authors describe their experience in using Gamma Knife surgery (GKS)
to target the resection cavity in patients whose tumors had progressed after WBRT.
Methods. The authors retrospectively identified 143 patients in whom GKS had been used to target a brain metastasis
resection cavity between 2000 and 2005. Seventy-nine of these patients had undergone WBRT prior to resection and
GKS. The median patient age was 53 years, and the median prescribed dose was 18 Gy (range 8–24 Gy), with resection
cavities of relatively larger volume (! 15 cm3 ). The GKS dose was prescribed at the 40 to 95% isodose contour (mode
50%).
Local recurrence within 1 cm of the treatment volume occurred in four (5.1%) of 79 cases. The median duration of
time to local recurrence was 6.1 months (range 2–13 months). The median duration of time to occurrence of distant
metastases following GKS of the resection cavity was 10.8 months (range 2–86 months). Carcinomatous meningitis
developed in four (5.1%) of 79 cases. Symptomatic radionecrosis requiring surgical treatment occurred in three (3.8%)
of 79 cases. The median duration of survival following GKS of the resection cavity was 69.6 weeks. The median 2-
and 5-year survival rates were 20.2 and 6.3%, respectively.
Conclusions. When metastases progress after WBRT and require resection, GKS targeting the resection cavity is a
viable strategy. In 75 (94.9%) of 79 cases, GKS of the resection cavity in patients in whom WBRT had failed appears
to have achieved its goal of local disease control.

KEY WORDS ! Gamma Knife surgery ! stereotactic radiosurgery ! metastasis !

resection cavity ! whole-brain radiotherapy

R
ESECTION in combination with postoperative WBRT
provides superior local disease control compared
with WBRT alone11,16 or surgery alone10 in patients
with brain metastases. More recently, SRS has emerged
as an effective primary treatment in patients with brain
metastases in whom WBRT has failed. For patients who
harbor progressive or new lesions after WBRT that are
too large, too symptomatic, or cause too much surround-
ing brain edema for SRS to be an attractive primary treat-
ment option, resection often offers the best hope of symp-
tomatic palliation. However, by analogy with the high
rates of local failure associated with resection alone at the
time of initial brain metastasis treatment, additional adju-
Abbreviations used in this paper: CI = confidence interval;
GKS = Gamma Knife surgery; RPA = recursive partitioning
analysis; RTOG = Radiation Therapy Oncology Group; SRS =
stereotactic radiosurgery; WBRT = whole-brain radiotherapy.
vant therapy is warranted after resection in cases in which
brain metastases progress despite WBRT. Little evidence
exists to support the use of SRS to target the postopera-
tive resection cavity after failure of WBRT. We describe
our experience with GKS targeting the resection cavity in
patients with brain metastases that have progressed after
WBRT.
Clinical Material and Methods
Prior approval was obtained by the institutional review
board of Wake Forest University Baptist Medical Center.
A total of 143 patients underwent GKS targeting the re-
section cavity of brain metastases between 1999 and 2005.
This retrospective review was conducted 1 year after the
last resection in the series was performed, providing the
opportunity for a minimum of 12 months of follow-up
data for each patient. Seventy-nine of these patients were
identified as having received WBRT prior to resection and

J. Neurosurg. / Volume 105 / December, 2006 75


a GKS-treated resection cavity. The medical records, ra-
diographic studies, and radiosurgical treatment plans of
these patients were retrospectively reviewed. Local recur-
rence was defined as the appearance of a metastatic lesion
within 1 cm of the GKS prescription volume. Distant oc-
currence was defined as the appearance of a new brain
metastasis at a site more than 1 cm outside of the GKS
volume. Carcinomatous meningitis was also considered
to reflect a distant metastasis. The duration of survival
was calculated from the date of GKS. Survival analysis
also involved patient classification based on the RTOG
RPA classes for patients with brain metastases.4 Actuar-
ial curves were generated from the Kaplan–Meier method
using the LIFETEST procedure.
Results
Patient Characteristics
The median age of the patients whose brain metastases
progressed dispites WBRT and who underwent resection
and GKS was 53 years (range 29–79 years). There were 39
men and 40 women. The location of the resected metasta-
sis was supratentorial in 82% and infratentorial in 18%. In
41.8% of the patients (33 of 79), metastatic brain disease
occurred without third organ involvement at the time of
GKS. For 31.6% of the patients (25 of 79), neurological
manifestations led to the diagnosis of metastatic cancer.
The median interval between diagnosis of the primary tu-
mor and development of brain metastasis was 25 months
(range 0–120 months). The primary tumor diagnoses are
listed in Table 1. Of the 12 cases in the “other” group,
seven involved small cell carcinoma of the lung metastatic
to the brain.
The local recurrence rate was 5.1% (four of 79 cases).
The median duration of time to local recurrence was 6.1
months (range 2–13 months). The median duration of time
to occurrence of distant metastases following GKS target-
ing the resection cavity in these patients with failed prior
WBRT was 10.8 months (range 2–86 months). Carcino-
matous meningitis occurred in 5.1% (four of 79 cases).
Symptomatic radionecrosis requiring resection occurred
in 3.8% (three of 79 cases).
The overall median duration of survival following GKS
was 17 months (95% CI 12.7–20.7 months). One-year,
3-year, and 5-year survival rates are listed in Table 2.
Median durations of survival for these patients based on
their RTOG metastatic brain cancer RPA classification are
provided in Table 3. The actuarial overall survival analysis
and the survival analysis by RPA classification following
GKS is shown in Figs. 1 and 2.
TABLE 1
Primary tumor diagnosis in 79 patients
Tumor Type No. of Cases
non–small cell lung 28
melanoma 17
breast 16
renal 4 I
colorectal 2 II
other 12
76
P. K. Kim, et al.
TABLE 2
One-, 3-, and 5-year survival rates of patients who
underwent GKS after failed WBRT
Survival % of Cases 95% CI
1 yr 62.8 50.1–73.1
3 yrs 15.7 8.1–25.6
5 yrs 4.7 1.2–11.9
Discussion
Local Control
For decades, the standard treatment for brain metastases
has been WBRT with various fractionated regimens.1,8
Moreover, the literature has established a clear benefit of
postoperative radiotherapy in the treatment of brain metas-
tases, as improved local as well as distant recurrence rates
have been demonstrated in Phase III trials.10,16 In addi-
tion, authors of several retrospective studies have shown
an improvement in local tumor control with the combina-
tion of SRS and WBRT compared with SRS alone;2,3,12–14
however, little evidence exists regarding the outcome of
patients with metastatic brain disease in whom initial treat-
ment with WBRT has failed.
In our series of 79 patients whose brain metastases pro-
gressed following WBRT, subsequent local disease con-
trol was achieved in 94.9% of those who underwent resec-
tion followed by GKS of the surgical cavity. These results
compare favorably with those of Patchell, et al.,10 who
demonstrated a 10% recurrence rate following postresec-
tion WBRT. Furthermore, they approximate other pub-
lished results on the efficacy of local control when us-
ing WBRT plus SRS in the management of smaller (≤
2 cm) metastatic lesions.2,12,14 Although larger, symp-
tomatic metastatic lesions often necessitate resection and
thereby preclude treatment with radiosurgery alone, our
results suggest that resection followed by GKS targeting
the resection cavity in patients in whom prior WBRT has
failed can achieve a relatively high local control rate as
salvage therapy.
Carcinomatous Meningitis
Carcinomatous meningitis occurs in approximately 5%
of patients overall with any known malignancy and is
most commonly associated with lung and breast cancer
as well as malignant melanoma.5,6 The authors of a re-
cent retrospective study reported a higher probability of
occurrence of carcinomatous meningitis in patients with
adenocarcinoma, in particular those with primary lung
cancer.9 Similarly, our study involved four cases of carci-
nomatous meningitis, two of which involved adenocarci-
noma of the lung, whereas the other two cases involved
TABLE 3
Median durations of survival based on RTOG metastatic
brain cancer RPA classification
RPA Class Median Survival (mos) 95% CI
17.9 12.8–23.8
17.0 8.5–24.4
III 9.9 8.6–19.0
J. Neurosurg. / Volume 105 / December, 2006
Use of the GKS for metastasis after WBRT
FIG. 1. Graph demonstrating actuarial overall survival Kaplan–
Meier estimates in patients undergoing GKS targeting the resec-
tion cavity after failed WBRT.
primary breast cancer. Although Kitaoka, et al.,7 suggested
that cerebellar tumors may be at more risk than other in-
tracranial sites for cerebrospinal fluid dissemination be-
cause of the proximity of the cerebellar cisterns, only
one of the four cases of carcinomatous meningitis in our
study followed resection of a posterior fossa metastatic
lesion. Our overall rate of 5.1% suggests that surgery fol-
lowed by GKS targeting the resection cavity as salvage
therapy after failed WBRT does not increase the risk of
carcinomatous meningitis in patients with metastatic brain
disease.
Posttreatment Radionecrosis
Symptomatic radionecrosis following GKS of brain
metastases occurs in approximately 5 to 10% of cases.15,17
In our study, 3.8% of the patients required resection of
symptomatic radionecrosis following GKS. The average
prescription dose was 17.3 Gy at the 50% isodose line.
The mean duration of time to occurrence of symptomatic
radionecrosis requiring resection was 6.7 months, in com-
parison to an interval of 8.6 months published by Truong,
et al.,15 who described their experience with GKS only as
the initial treatment of brain metastases.
FIG. 2. Graph depicting actuarial survival Kaplan–Meier esti-
mates in patients undergoing GKS targeting the resection cavity
after failed WBRT.
J. Neurosurg. / Volume 105 / December, 2006
Survival Analysis
Although postoperative radiotherapy has been shown
to reduce recurrence rates and death due to neurological
causes in patients with metastatic brain disease, it did not
result in increased actuarial survival or improve the dura-
tion of time patients were able to function independently
in the findings reported by Patchell, et al.11 These authors
attributed this lack of survival benefit in part to the ab-
sence of satisfactory treatment for systemic cancers and
not to the failure of postoperative radiotherapy to control
metastatic brain disease.
In our series, salvage therapy with resection followed
by GKS yielded an overall median duration of survival of
17 months, with 1-, 2-, and 5-year survival rates of 62.8,
15.7, and 4.7%, respectively. When stratifying our patients
based on the RTOG metastatic brain cancer RPA classi-
fication, the median duration of survival of RPA Class I
patients was 17.9 months; median survival rates for RPA
Class II and Class III patients were 17 and 9.9 months,
respectively. These results did not reach statistical signif-
icance, however, which may be due in part to the lack
of statistical power, as there were only 13 RPA Class III
patients. Although the RTOG RPA classification, based
on initial treatment rather than salvage treatment, may not
be strictly applicable to this series of patients, we believe
that it serves as a meaningful, if not valid, measure of the
survival benefit of resection with GKS in the management
of larger, symptomatic metastatic brain lesions that have
progressed following WBRT.
Conclusions
Our results suggest that resection followed by GKS tar-
geting the resection cavity should be given consideration
in patients with metastatic brain disease, regardless of
whether their Karnofsky Performance Scale score is less
than 70. Although the median survival rate of these pa-
tients may be lower than the other patients in our series,
the duration of survival and potential for neurological im-
provement following resection of a large, symptomatic
brain lesion followed by GKS targeting the resection cav-
ity should not be overlooked.
References
1. Borgelt B, Gelber R, Kramer S, Brady LW, Chang CH, Davis
LW, et al: The palliation of brain metastases: final results of the
first two studies by the Radiation Therapy Oncology Group.
Int J Radiat Oncol Biol Phys 96:1–9, 1980
2. Chidel MA, Suh JH, Reddy CA, Chao ST, Lundbeck MF,
Barnett GH: Application of recursive partitioning analysis and
evaluation of the use of whole brain radiation among patients
treated with stereotactic radiosurgery for newly diagnosed
brain metastases. Int J Radiat Oncol Biol Phys 47:993–999,
2000
3. Flickinger JC, Kondziolka D, Lunsford LD, Coffey RJ, Good-
man ML, Shaw EG, et al: A multi-institutional experience with
stereotactic radiosurgery for solitary brain metastases. Int J
Radiat Oncol Biol Phys 28:797–802, 1994
4. Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman
T, 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 37:
745–751, 1997
5. Grossman SA, Krabak MJ: Leptomeningeal carcinomatosis.
Cancer Treat Rev 25:103–119, 1999
77

6. Jayson GC, Howell A: Carcinomatous meningitis in solid
tumors. Ann Oncol 7:773–786, 1996
7. Kitaoka K, Abe H, Aida T, Satoh M, Nakamura N, Na-
gashima K, et al: Follow-up study on metastatic cerebellar
tumor surgery—characteristic problems of surgical treatment.
Neurol Med Chir 30:591–598, 1990
8. Kurtz J, Gelber R, Brady L, Carella RJ, Cooper JS: The palli-
ation of brain metatstases in a favorable patient population: a
randomized clinical trial by the Radiation Therapy Oncology
Group. Int J Radiat Oncol Biol Phys 7:891–895, 1981
9. Mahajan A, Borden J, Tsai JS: Carcinomatous meningitis: are
surgery or gamma knife radiosurgery treatment risk factors?
J Neurosurg (Suppl 5) 97:441–444, 2002
10. Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin
M, Kryscio RJ, et al: Postoperative radiotherapy in the treat-
ment of single metastases to the brain: a randomized trial.
JAMA 280:1485–1489, 1998
11. Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama
Y, Kryscio RJ, et al: A randomized trial of surgery in the
treatment of single metastases to the brain. N Engl J Med
322:494–500, 1990
12. Shehata MK, Young B, Reid B, Patchell RA, St. Clair W,
Sims J, et al: Stereotactic radiosurgery of 468 brain metastases
!2 cm: implications for SRS dose and whole brain radiation
therapy. Int J Radiat Oncol Biol Phys 59:87–93, 2004
13. Sneed PK, Lamborn K, Forstner JM, McDermott MW, Chang
S, Park E, et al: Radiosurgery for brain metastases: is whole
78
P. K. Kim, et al.
brain radiotherapy necessary? Int J Radiat Oncol Biol Phys
43:549–558, 1999
14. Sneed PK, Suh JH, Goetsch SJ, Sanghavi SN, Chappell R,
Buatti JM, et al: A multi-institutional review of radiosurgery
alone vs. radiosurgery with whole brain radiotherapy as the
initial management of brain metastases. Int J Radiat Oncol
Biol Phys 53:519–526, 2002
15. Truong MT, St Clair EG, Donahue BR, Rush SC, Miller DC,
Formenti SC, et al: Results of surgical resection for progres-
sion of brain metastases previously treated by gamma knife
radiosurgery. Neurosurgery 59:86–97, 2006
16. Vecht CJ, Haaxma-Reiche H, Noordijk EM, Padberg GW,
Voormolen JH, Hoekstra FH, et al: Treatment of a single
brain metastasis: radiotherapy alone or combined with neuro-
surgery. Ann Neurol 33:583–590, 1993
17. Yu CP, Cheung JY, Chan JF, Leung SC, Ho RT: Prolonged
survival in a subgroup of patients with brain metastases treated
by gamma knife surgery. J Neurosurg (Suppl) 102:262–265,
2005
Address reprint requests to: Paul K. Kim, M.D., Department of
Neurosurgery, Fifth Floor, Watlington Hall, Wake Forest Univer-
sity Baptist Medical Center, Medical Center Boulevard, Winston–
Salem, North Carolina 27157. email: pkim@wfubmc.edu.
J. Neurosurg. / Volume 105 / December, 2006