Gamma Knife = stereotactic radiosurgery for intracranial hemangiopericytomas

Clinical Study - Patient Study

Gamma Knife = stereotactic=20 radiosurgery for intracranial hemangiopericytomas

Jin Wook Kim¹,=20 Dong Gyu Kim^{1, 3}, Hyun-Tai Chung¹,=20 Sun Ha Paek^{1, 2}, = Yong Hwy Kim¹,=20 Jung Ho Han¹, Chul-Kee Park¹,=20 Chae-Yong Kim¹ and Hee-Won Jung¹

(1)

Department of Neurosurgery, Seoul = National=20 University College of Medicine, Seoul, = Korea

(2)

Cancer Research Institute, = Ischemic/Hypoxic=20 Disease Institute, Seoul National University College of Medicine, = Seoul,=20 Korea

(3)

Department of Neurosurgery, Seoul = National=20 University Hospital, 101 Daehangno, Jongno-gu, Seoul, 110-744,=20 Korea

Dong Gyu Kim
Email:=20 gknife@plaza.snu.ac.kr

Received:=20 4 September 2009 Accepted:=20 4 January 2010 Published online:=20 19 January 2010

Abstract

The purpose of this study is to determine the = efficacy of=20 Gamma Knife stereotactic radiosurgery (GK SRS) for intracranial=20 hemangiopericytomas, and to investigate the optimal dose for successful = tumor=20 control without adverse effects. We evaluated 17 hemangiopericytomas of = nine=20 patients treated with GK SRS between 1999 and 2008. The mean tumor = volume was=20 2.2 cm³ (range 0.2=969.9 cm³), and the = mean and=20 median marginal doses were 18.1 and 20 Gy (range 11=9622 Gy),=20 respectively, at the 50% isodose line. Mean clinical and radiological = follow-up=20 periods were 49 and 34 months, respectively. Successful tumor = control was=20 achieved in 14 of 17 lesions (82.4%) at time of last follow-up after GK = SRS.=20 Actuarial local tumor control rates at 1, 2, and 5 years after GK = SRS were=20 100%, 84.6%, and 67.7%, respectively. No adverse effects, such as = radiation=20 necrosis or marked peritumoral edema, were observed in any patient. = Marginal=20 dose (≥17 Gy) was the only statistically significant factor = for local tumor=20 control on univariate analysis. Extended analysis using lesion data = available=20 from previous studies revealed that higher marginal dose = (≥17 Gy) was also=20 significant (P =3D 0.028). GK SRS provides an effective = and safe=20 adjuvant management option for patients with recurrent or residual=20 hemangiopericytomas. Our results suggest that doses higher than = previously used=20 (around 15 Gy) are desirable to achieve better local tumor control = of=20 hemangiopericytomas. Close radiological follow-up is also necessary for = early=20 detection of small recurrent lesions.

Keywords Hemangiopericytoma = ;- Tumor=20 control - Radiosurgery - Gamma = Knife - Radiation=20 dose

Abbreviations HPC

Hemangiopericytoma

- GK = SRS

Gamma Knife stereotactic radiosurgery

- RT

Radiation therapy

- WHO

World Health Organization

- MRI

Magnetic resonance imaging

Introduction

Intracranial hemangiopericytomas (HPCs) are rare = malignant=20 tumors whose natural history, optimal treatment, and clinical outcome = are not=20 yet well understood. Over the past couple of decades, they have been = termed=20 =93angioblastic meningiomas=94 or =93soft tissue sarcomas.=94 They are = well known to=20 have biologically and clinically aggressive behavior, even after radical = resection followed by postoperative adjuvant radiation therapy (RT): = local=20 recurrences and extracranial metastases as well as intracranial = metastases are=20 common [1=964].=20

Surgical resection is the treatment of choice for = intracranial=20 HPCs. However, it has proven very difficult to cure the disease with = surgical=20 resection alone [4=967].=20 Because intracranial HPCs are known to be radiosensitive, some previous = studies=20 have suggested a role for adjuvant RT in the treatment of recurrent HPCs = [5,=20 7=969].=20

However, there are few treatment options for HPCs that = recur=20 even after surgical resection followed by adjuvant RT, particularly when = the=20 recurrent tumors are located in eloquent or deep-seated areas. Although = adjuvant=20 chemotherapy, repeated conformal RT, and radiosurgery have been tried, = the=20 efficacy of these adjuvant treatments for recurrent intracranial HPCs = remains=20 unclear due to the scarcity and insufficiency of clinical data [10,=20 11].=20

Gamma Knife stereotactic radiosurgery (GK SRS) was = introduced as=20 a treatment option for the management of intracranial HPCs recurring = after=20 surgical resection followed by RT, because GK SRS provides safe delivery = of a=20 relatively high dose of radiation to a well-defined target (like HPCs), = and it=20 is not difficult to reapply GK SRS for possible recurrences. However, = only a few=20 studies using GK SRS for recurrent HPCs have been reported to date = [1,=20 3,=20 4,=20 6,=20 11=9616].=20 Furthermore, the optimal dose for successful local control of HPCs = without=20 adverse effects remains unclear.

The aim of this retrospective study was to investigate = the=20 efficacy of GK SRS in the treatment of recurrent intracranial HPCs, and = to=20 verify the optimal dose for achieving successful local tumor control = without=20 adverse effects.

Methods and materials

Patient characteristics

Between August 1999 and February 2008, nine = consecutive patients=20 with HPCs underwent GK SRS for the treatment of 17 recurrent or residual = tumors.=20 Diagnoses of all patients were confirmed histopathologically after = surgical=20 resection before GK SRS. Six patients were female, and the mean age of = the=20 patients was 45 years (range 29=9661 years).

A single lesion was observed in four patients, and = multiple=20 lesions in five patients. On average, there were two intracranial = lesions per=20 patient. There were five HPCs of World Health Organization (WHO) = grade II=20 in four patients and 12 anaplastic HPCs of WHO grade III in five = patients.=20 GK SRS was performed for 15 recurrent lesions in seven patients who = previously=20 underwent surgical resection followed by RT (mean dose 56.9 Gy, = range=20 50.4=9661.2 Gy). The remaining two lesions in two patients were = treated with=20 GK SRS as an adjuvant therapy for new recurrent or residual lesions = after=20 resection without RT. Eight of 17 tumors were locally recurrent tumors = at the=20 resection margin of the primary operation; the other nine tumors were=20 intracranial metastatic lesions distant from the original tumor = location.=20 Patient characteristics are summarized in Table 1.

Table 1 Summary of=20 patient characteristics and radiosurgical parameters of nine patients = with 17=20 lesions

Age (years)	44.9 =B1 14.3 (29=9661)*
Male/female	3/6
WHO grade II/III	5/12
Mean/median clinical follow-up duration = (months)	48.8/45 (18=9682)
Mean/median radiological follow-up duration=20 (months)	34.2/32 (7=9682)
Number of previous craniotomies
1	5
2	4
Mean RT dose (Gy)^a	56.9 (50.4=9661.2)
Gamma Knife radiosurgery
After surgery^b	2
After surgery and RT	7
Mean/median tumor volume (cm³) =	2.2/1.0 (0.2=969.9)
Mean/median marginal dose (Gy)	18.1/20.0 (11.0=9622.0)
Mean isodose line (%)^c	50
Mean number of shots per lesion	6.5 (1=9613)

RT radiation therapy

* Values are mean =B1 standard = deviation=20 (range)

^aOne patient (patient no. 5) = underwent RT at=20 another hospital and the RT dose is unknown

^bTwo patients underwent GK SRS for = residual or=20 recurrent lesions after resection, without RT

^cAll isodose lines are 50%=20

GK SRS

GK SRS was performed using a Leksell Gamma Knife = (Elekta=20 Instrument, Stockholm, Sweden) model B or C. The planning system = was a=20 Leksell GammaPlan^TM system (Elekta Instrument), based on 1.0- = to=20 1.5-mm-thick magnetic resonance imaging (MRI) slices with gadolinium = contrast=20 enhancement. GK SRS planning was performed on axial images supplemented = with=20 reconstructed coronal and sagittal MRI images.

The prescription dose of 15=9622 Gy (mean = 19.0 Gy,=20 median 20 Gy) at the 50% isodose line was applied to the tumor = margin in=20 all patients except two. In these two patients, close proximity of = critical=20 neural structures such as the optic nerve reduced the marginal dose at = the 50%=20 isodose line to 11 and 12 Gy, respectively. In total, the overall = mean=20 marginal dose was 18.1 Gy. A summary of the treatment parameters is = given=20 in Table 1.=20

Follow-up

Follow-up brain MRIs were performed in all nine = patients=20 1 month after GK SRS, and then regularly at 3- to 6-month = intervals. At=20 each follow-up, tumor volumes were determined from brain MRI scans using = Osiris=20 software (version 4.8; Service of Medical Informatics, Geneva University = Hospital, Geneva, Switzerland). Tumor volume was computed by specifying = an=20 object in a series of regions of interest (ROIs) in a set of multiplanar = images,=20 and then summing ROI areas in each plane. The error associated with = repeat=20 measurements of tumor volume in each MRI scan was within =B110%.

Each tumor was categorized into one of four treatment = outcomes=20 after GK SRS: complete response (CR, tumor disappeared); partial = response (PR,=20 ≥50% decrease in tumor volume compared with measurements taken on = day of GK=20 SRS); stable disease (SD, <50% reduction or <25% increase in tumor = volume); or progressive disease (PD, ≥25% increase in volume). = Local tumor=20 control percentage was defined as the number of lesions in the CR, PR, = and SD=20 groups over the total number of lesions.

Both clinical and radiological data were collected up = to last=20 follow-up. The overall survival (OS) rate of patients was defined as the = time=20 interval between the date of GK SRS and the date of death or the date of = last=20 follow-up. The duration of local tumor control was defined as the time = interval=20 between the date of GK SRS and the date of local tumor recurrence. =

Statistical analysis

OS time and actuarial progression-free survival time = were=20 calculated by the Kaplan=96Meier method. A generalized Wilcoxon rank-sum = test was=20 used to compare the difference of local tumor control rates according to = the=20 optimal marginal dose, and to determine the correlation of OS with WHO = grade.=20 Statistical analysis was performed using SPSS version 12.0 (SPSS = Inc.,=20 Chicago, IL, USA). Results were regarded as significant for=20 P < 0.05.

Results

Detailed patient treatment information is given in=20 Table 2.=20 Mean clinical follow-up duration was 49 months (range = 18=9682 months),=20 and mean and median radiological follow-up duration were 34.2 and=20 32 months, respectively (range 7=9682 months). After GK SRS, = seven of=20 nine patients were alive at last follow-up, but two patients died during = the=20 follow-up period (patient nos. 1 and 2). One patient (patient = no. 1)=20 developed tumor recurrence and died 45 months after GK SRS. The = other=20 patient (patient no. 2) developed multiple intracranial tumors = after the=20 initial GK SRS and later underwent two further GK SRS treatments for = three new=20 lesions. This patient died 70 months after initial GK SRS, due to=20 dissemination of tumors throughout the whole neuraxis. Extracranial = metastasis=20 was observed in one patient (patient no. 5) during the follow-up = period.

Table 2 Summary of=20 detailed characteristics of patients and lesions, and tumor response =

Patient no.	Gender/age (years)	Lesion no.	Diagnosis	Tumor location	Recurrence type after previous = treatment	Pre-GK SRS treatment	Volume (cm³)	Marginal dose (Gy)/no. of shots	Radiological follow-up duration = (months)	Tumor response
1	M/35	1	HPC	Medial temporal	Op bed	OP(PR)-RT(5500 cGy)-OP(GTR)	1.5	12/11	38	PD
2	F/30	2	M-HPC	Falx	Distant	OP(NA)-OP(NA)-RT(5940 cGy)	0.5	18/7	44	CR
3	M-HPC	Medullar	Distant		0.6	15/9	33	CR
4	M-HPC	Medial temporal	Distant		0.4	15/5	33	PD
5	M-HPC	Medullar	Distant		0.2	20/4	18	CR
3	M/43	6	HPC	Falx	Distant	OP(GTR)-RT(5400)-OP(GTR)	0.6	20/6	82	PR
7	HPC	Tent	Op bed		1.0	20/3	13	CR
4	F/55	8	M-HPC	Torcular	Distant	OP(GTR)-RT(6120 cGy)	6.4	19/13	59	PR
9	M-HPC	Occipital	Distant		1.2	20/3	22	PR
10	M-HPC	Occipital	Distant		0.6	20/2	22	PR
5	F/61	11	M-HPC	Occipital	Op bed	Op(NA)-RT(NA)-OP(GTR)	9.9	16.5/12	56	PD
12	M-HPC	Pituitary stalk	Distant		1.8	11/5	7	PR
6	F/61	13	HPC	Falx	Op bed	OP(GTR)-RT(6120 cGy)	1.4	20/10	51	CR
7	M/60	14	M-HPC	Ventricle	Op bed	RT(5040)-OP(GTR)	0.4	22/3	27	CR
15	M-HPC	Ventricle	Op bed		0.3	22/1	27	CR
8	F/30	16	M-HPC	Medial temporal	Op bed	OP(GTR)	1.4	20/5	32	CR
9	F/29	17	M-HPC	Cerebellum	Op bed	OP(STR)	9.8	17/11	17	SD

HPC WHO grade II hemangiopericytoma, = M-HPC=20 WHO grade III anaplastic hemangiopericytoma, GK SRS Gamma = Knife=20 radiosurgery, OP operation, GTR gross total removal, = STR=20 subtotal removal, PR partial removal, RT radiation = therapy,=20 CR complete response, PR partial response, SD = stable=20 disease, PD progressive disease, NA not available=20

MRI volumetric evaluation after GK SRS demonstrated = that CR was=20 observed in eight tumors (47.1%), PR in five tumors (29.4%), SD in one = tumor=20 (5.9%), and PD in three tumors (17.6%). Local tumor control rate was = 82.4%.=20 Three lesions (lesion nos. 1, 4, and 11) were confirmed to be = progressive=20 on follow-up brain MRI scans taken 21, 22, and 38 months after GK = SRS,=20 respectively.

Of these three recurrent lesions, two lesions (lesion=20 nos. 4 and 11) were managed with repeated GK SRS. Lesion no. 4 = was=20 initially treated with a marginal dose of 15 Gy, but progressed=20 21 months after the initial GK SRS. A second GK SRS was performed = with a=20 marginal dose of 20 Gy, after which the tumor was well controlled = for=20 12 months. The other recurrent lesion (lesion no. 11) was = treated with=20 an initial marginal dose of 16.5 Gy. Twenty-two months after = initial GK=20 SRS, a second treatment was performed with a marginal dose of = 16 Gy. The=20 tumor remained unchanged for 22 months, but was finally confirmed = as=20 progressive 30 months after the second GK SRS.

OS rates were 100% and 83.3% at 2 and 5 years = after GK=20 SRS, respectively. Actuarial tumor control rates, as determined by the=20 Kaplan=96Meier method, were 100% at 1 year, 84.6% at 2 years, = and 67.7%=20 at 5 years (Fig. 1).=20 There were no significant differences in tumor control rate between WHO=20 grade II HPCs and WHO grade III HPCs = (P =3D 0.917). All=20 three failures of local tumor control occurred in the group treated with = low=20 marginal dose (<17 Gy). High marginal dose (≥17 Gy) = was=20 significantly associated with longer progression-free survival=20 (P =3D 0.003). Mean tumor volume did not significantly = differ=20 between the two groups, being 1.98 cm³ in the = low-marginal-dose=20 group, and 2.84 cm³ in the high-marginal-dose group=20 (P =3D 0.630). The 2-year progression-free survival was = 100% for=20 HPCs treated with high marginal dose, compared with 50% for HPCs treated = with=20 low marginal dose.=20

Fig. 1 Actuarial=20 tumor control rates were 100% at 1 year, 84.6% at 2 years, and = 67.7%=20 at 5 years. Control rates were analyzed by the Kaplan=96Meier = method

In no case were adverse effects from radiation, such = as=20 radiation necrosis or marked peritumoral edema, ever observed in any = patient who=20 received GK SRS, as of last follow-up.

Discussion

Surgical resection is generally accepted as the = standard=20 treatment of choice in the management of HPCs, although they are = hypervascular=20 tumors prone to cause intraoperative hemorrhage, and previous studies = have=20 reported surgical mortality rates as high as 9=9624% [4,=20 13,=20 14,=20 17].=20 Complete resection at first operation was strongly correlated with = prolongation=20 of time to recurrence and extension of survival duration [2,=20 6].=20 However, it is difficult to cure HPCs with surgical resection alone, = because of=20 their high rate of recurrence, and because intracranial and extracranial = metastases after resection are frequent. In order to achieve complete = resection=20 of HPCs, some authors have recommended supplementing surgical = intervention with=20 preoperative embolization of the feeding vessels, or even preoperative=20 radiotherapy [2,=20 17].=20 Because the hypervascular characteristics of HPCs imply = =93radiosensitivity,=94=20 postoperative adjuvant RT appears to significantly decrease the local = recurrence=20 rate and to lengthen recurrence-free duration [12,=20 16].=20 Guthrie et al. reported that the mean progression-free duration of=20 irradiated HPCs after surgical resection was 74 months, while that = of=20 nonirradiated HPCs was 29 months [5,=20 8,=20 18].=20 Full radiation doses of greater than 50 Gy were recommended for = best tumor=20 control outcome and to prevent early recurrence after surgical resection = [4,=20 8,=20 14].=20

However, it is very difficult to treat recurrent HPCs = after=20 surgical resection followed by RT. Treatment options in such cases may = include=20 repeat surgery, salvage chemotherapy, repeated fractionated stereotactic = radiotherapy, or radiosurgery. If there is low risk of significant = surgical=20 morbidity or mortality, repeat surgical resection for recurrent HPCs has = been=20 recommended as the first treatment option [4].=20 Salvage chemotherapy with various chemotherapeutic agents, including=20 α-interferon, provided limited efficacy with acceptable toxicity = for refractory=20 recurrent HPCs [10,=20 11].=20 Although results to date are disappointing, the hypervascular nature of = HPCs=20 suggest that antiangiogenic strategies might be another attractive new=20 therapeutic option for the treatment of recurrent HPCs [11].=20

GK SRS for HPCs

Since Coffey et al. reported their preliminary = study of=20 GK SRS for recurrent HPCs in 1993, only a few studies with limited = patient=20 numbers have been reported [1,=20 3,=20 4,=20 6,=20 11=9616].=20 Most studies reported immediate and dramatic shrinkage of tumors after=20 radiosurgery for HPCs, and local tumor control rates were 46=9693% = [1,=20 3,=20 4,=20 6,=20 11=9616].=20 Similarly, the local tumor control rate in the present study was 82.4%, = as=20 measured over a mean and median radiological follow-up period of 34 and=20 32 months, respectively. These results are summarized in = Table 3.

Table 3 Summary of=20 previous reports for hemangiopericytomas treated with Gamma Knife = radiosurgery=20

	No. of patients	No. of tumors	Tumor volume mean, range (cm³) =	Marginal dose, mean, range (Gy)	Tumor control rate (%)	Mean/median radiological follow-up duration, = range=20 (months)
Coffey et al.	5	11	8.5 (0.4=9624.3)	15.5 (12=9618)	82	12.7/15 (4=9617)
Galanis et al.	10	20	NA	NA (12=9618)	90	36/NA (NA)
Payne et al.	10	12	7.6 (0.3=9633.6)	14 (2.8=9625)	75	25/NA (3=9656)
Sheehan et al.	14	15	8.8 (0.3=9626.6)	15 (11=9620)	80	31.3/21 (5=9676)
Ecker et al.	15	45	7.8 (0.4=9658.3)	16 (12=9621)	93	45.6/NA (NA)
Chang et al.^a	8	8	NA	20.8 (16=9624)	87.5	44/NA (8=9677)
Sun et al.	22	58	5.4 (0.1=9637.2)	13.5 (10=9620)	89.7	26/NA (5=9662)
Kano et al.	20	29	4.5 (0.07=9634.3)	15.0 (10=9620)	72.4	37.9/23.3 (NA)
Olson et al.	21	28	4.6 (0.3=9618.7)	17.0 (2.8=9622)	46.4	69/68 (2=96138)
Current study	9	17	2.2 (0.2=969.9)	18.1 (11=9622)	82.4	33.8/32 (7=9682)

NA not available

^aTheir treatment modalities included = LINAC (four=20 patients) and Cyberknife (four patients)

During the follow-up period in our study, six lesions = in three=20 patients developed new distant metastases in sites different from that = initially=20 treated with GK SRS. This observation is consistent with previous = reports and=20 shows that GK SRS alone cannot prevent further distant metastases, even = when=20 local control is successful [1,=20 2,=20 4,=20 14].=20 However, RT as well as GK SRS after surgical resection did not seem to = prevent=20 further local or neuraxis recurrence [14].=20

Only two lesions were initially treated with GK SRS = without=20 previous RT in our study. These lesions were successfully controlled = throughout=20 the follow-up duration, but long-term follow-up data are required to = assess the=20 long-term outcome of GK SRS for these lesions. Recently, along with = progress in=20 microsurgical techniques, advanced imaging technology has provided an=20 opportunity to detect smaller residual and recurrent HPCs. These trends = might=20 make radiosurgical techniques such as GK SRS more attractive for the = treatment=20 of residual and recurrent HPCs. Payne et al. emphasized that, in = order to=20 minimize GK SRS-related complications for recurrent HPCs, GK SRS should = be=20 performed at the first sign of recurrence, when the tumors are small = [4].=20 The mean tumor volume (2.2 cm³) in the present study is=20 relatively small, and the mean marginal dose (18.1 Gy) is = relatively high=20 compared with in previous reports. We used aggressive imaging = surveillance=20 techniques to perform GK SRS for these tumors as early as possible, and = at as=20 high a marginal dose as possible. Most authors recommended close imaging = follow-up after GK SRS for HPCs, because of their high recurrence rates = and=20 their propensity to metastasize [4,=20 14].=20 Aggressive imaging follow-up at no more than 6-month intervals after GK = SRS=20 should be performed to detect early recurrence and new metastases. =

Optimal dose for the treatment of recurrent = HPCs

The mean marginal doses used in previous studies = ranged from=20 13.5 to 17 Gy [1,=20 3,=20 4,=20 6,=20 11=9616].=20 Only one study, reported by Chang et al., applied higher marginal = doses=20 (mean marginal dose of 20.5 Gy) than that of our study. However, = this study=20 employed different treatment modalities, namely LINAC and Cyberknife = [13].=20

The optimal dose for achieving successful tumor = control without=20 adverse radiation effects remains unclear. Shaw et al. reported on = the=20 maximum tolerated doses of single-fraction radiosurgery in patients with = recurrent, previously irradiated primary brain tumors and brain = metastases.=20 Their report gave the maximum tolerable doses as 24, 18, and 15 Gy = for=20 tumors ≤20, 21=9630, and 31=9640 mm in maximum diameter, = respectively [19].=20 Furthermore, relatively high prescription doses of 18 Gy were not=20 significantly related to adverse radiation effects in a report on = radiosurgery=20 for malignant meningioma by Ojemann et al. [20].=20 Considering the malignant characteristics of HPCs, a similar treatment = strategy=20 might apply to GK SRS for recurrent HPCs following RT. In the most = recent and=20 largest study, which included 22 patients with 51 HPCs, Sun et al.=20 suggested that treatment principles for GK SRS of HPCs should be similar = to=20 those used for intracranial metastases, and that an aggressive = prescription dose=20 could achieve a reduction in the rate of local recurrence [12].=20 This finding has been further supported by Sheehan et al., who = recommended=20 that a radiation dose of at least 15 Gy should be delivered to the = tumor=20 margin for successful local tumor control, and Kano et al., who = reported=20 significantly better progression-free survival in HPCs treated with high = marginal dose (≥14 Gy) [1,=20 14].=20

In this study, all three recurrent tumors that were = not=20 successfully treated by GK SRS occurred using a marginal dose that was=20 relatively low (12, 15, and 16.5 Gy, respectively). Higher marginal = dose=20 (≥17 Gy) also significantly correlated with longer = progression-free=20 survival. Our results demonstrate that recurrent HPCs should be treated = with a=20 relatively high marginal dose to achieve long-term tumor control, and = that close=20 radiological follow-up is necessary to detect early and small recurrent = lesions.=20

In order to overcome the small number of cases in = our study,=20 we added lesion data from the previous studies of Olson et al. and = Sheehan=20 et al. [3,=20 14].=20 These data were acceptable because the treatment parameters used in = those=20 studies were sufficiently well described to allow comparison with our = data. Four=20 lesions from these studies were excluded from this analysis: two lesions = from=20 Olson et al.=92s study, treated with marginal doses of 2.8 and = 3.3 Gy,=20 respectively; and two lesions from Sheehan=92s study with tumor volumes = of 23 and=20 26 cm³, respectively. A total of 52 HPCs were included = and=20 categorized into two groups according to the marginal dose used. Of the = 52=20 tumors, 31 (59.6%) tumors were treated with high marginal dose = (≥17 Gy) and=20 21 tumors (40.4%) were treated with low marginal dose (<17 Gy).=20 Progression-free survival rates after 2 and 5 years were 96.8% and = 91.9%,=20 respectively, in the high-dose group (≥17 Gy), in contrast to = 70.7% and=20 61.8%, respectively, in the other group (<17 Gy) (Fig. 2).=20 This difference was statistically significant = (P =3D 0.028). Mean=20 tumor volume was also smaller in the group with high marginal dose = (≥17 Gy)=20 than in the other group (3.29 and 5.75 cm³, = respectively);=20 however, this difference was not significant = (P =3D 0.088).=20 Adverse radiation effects related to a relatively high marginal dose = were not=20 reported. Although the possibility of different treatment scheme such as = target=20 delineation and target covered ratio among different institutes, we = could obtain=20 the same critical marginal dose (≥17 Gy), which was = significantly=20 associated with improved local tumor control on analysis of the expanded = data=20 set.=20

Fig. 2 Kaplan=96Meier=20 curves demonstrating the statistical difference between groups treated = with=20 different marginal doses (<17, ≥17 Gy). Data from Olson = et al. and=20 Sheehan et al. are also included [3,=20 14].=20 Marginal dose of ≥17 Gy was significantly associated with = longer=20 progression-free survival (P =3D 0.028)

To date, the efficacy of repeated GK SRS for failed = cases is=20 disappointing. Sheehan et al. reported that repeated GK SRS was=20 unsuccessful in achieving tumor control in two patients where the = initial GK SRS=20 was unsuccessful [14].=20 In our study, one of two lesions treated with repeated GK SRS progressed = 30 months after the second GK SRS; however, the lesion was treated = with a=20 low marginal dose (16 Gy) due to the relatively large tumor volume. = The=20 optimal treatment strategy for tumors that do not respond to initial GK = SRS=20 treatment should be considered in further studies.

Complications

As noted above, the possibility of additional adverse = radiation=20 effects is one of the most concerning aspects of GK SRS for recurrent = HPCs,=20 because most patients have had previous RT with more than 50 Gy. = Payne=20 et al. performed GK SRS with marginal dose decreased by = 2=964 Gy to=20 recurrent HPCs already treated with RT [4].=20 In our study, no additional adverse effects from radiation were = observed. In=20 particular, patients could receive multiple GK SRS treatments for = different=20 recurrences without adverse effects, such as pronounced edema or = radiation=20 necrosis, throughout their follow-up periods. This observation is = supported by=20 previous reports [4,=20 14].=20 However, long-term adverse effects cannot be excluded, and patients = should=20 therefore undergo close long-term follow-up.

Limitations of this study

This study is retrospective and limited to a small = number of=20 cases. Additionally, mean radiological follow-up duration was = 34 months.=20 Therefore, we cannot be certain that the treatment of choice for = recurrent=20 intracranial HPCs is GK SRS, or that the results presented herein = represent=20 final tumor control rates. Because of the scarcity of these tumors, a = further=20 well-designed, multi-institutional study with long-term follow-up is = mandatory=20 for determining optimal treatment strategy and dose for recurrent = intracranial=20 HPCs.

Conclusion

GK SRS provides an effective and safe adjuvant = management option=20 for patients with recurrent or residual HPCs. The results of our careful = study=20 demonstrate that doses higher than previously used (around 15 Gy) = are=20 desirable for better local tumor control of HPCs without severe adverse=20 radiation effects. Furthermore, the marginal dose is mainly determined = by tumor=20 volume, and it is important to identify tumor recurrence at an early = stage by=20 close follow-up imaging after treatment.

Acknowledgments This work was supported by the Nuclear Research and = Development=20 Program of the Korea Science and Engineering Foundation (KOSEF) grant = funded by=20 the Korean Government (MEST) (Grant: M800-20090068).

References

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