Gamma knife radiosurgery for trigeminal neuralgia secondary to benign lesions.

BACKGROUND: Investigate the clinical outcomes of gamma knife radiosurgery (GKS) in patients with benign intracranial lesions and accompanying trigeminal neuralgia (TN). METHODS: From February 2002 to November 2011, 50 patients (11 males, 39 females) underwent GKS for intracranial lesions accompanied by TN. Pathological diagnoses included meningioma in 30 patients, vestibular schwannoma in 11, trigeminal schwannoma in 7, epidermoid cyst in 1, and arteriovenous malformation in 1. Twenty-two (44%) had a lesion dominantly located in the middle fossa and 26 patients (52%) in the posterior fossa. Twenty-five (50%) patients complained of type I pain, and 18 patients (36%) suffered from type II pain. The other 7 patients (14%) presented with facial pain that could not be determined. Pain was assessed retrospectively by subjective descriptions and with the Barrow Neurological Institute pain intensity score before and after GKS. RESULTS: Tumor control was evaluated with magnetic resonance imaging in 44 (95.7%) of 46 patients over a median follow-up period of 54.8 months (range, 13-142 months). Initial improvement in pain after GKS was observed in 46 (92%) patients. The percentage of patients with improved Barrow Neurological Institute score was 73.5% at 1 year, 70.7% at 2 years, and 76.5% at 3 years. Complete pain relief at the final follow-up was achieved in 18 patients (36%). Pain recurred in 13 patients (28.3%) after initial improvement. Pathological diagnosis, location of the lesion, and type of facial pain did not influence the initial pain response after GKS. Pain recurred more frequently in patients with meningioma than in those with schwannoma (P = .045). Type II pain showed better response to the treatment (P = .006). CONCLUSION: The majority of patients with facial pain secondary to a benign intracranial lesion showed improvement after GKS. However, a substantial proportion of the patients experienced incomplete pain relief and recurrence. GKS needs to be combined with an additional modality or the technique must be modified to achieve complete and durable pain control.

Antiallergic effect of gami-hyunggyeyeongyotang on ovalbumin-induced allergic rhinitis in mouse and human mast cells.

BACKGROUND: Gami-hyunggyeyeongyotang (GMHGYGT) is a polyherbal medicine derived from an oriental prescription traditionally used in the treatment of allergic diseases such as allergic rhinitis (AR). This study aimed to evaluate the effects of GMHGYGT on ovalbumin (OVA) sensitization/challenge-induced AR in BALB/C mice, through examination of allergic inflammatory response regulation, as well as examination of human mast cells (HMC-1). METHODS: Nasal symptoms were evaluated in the OVA-induced allergic rhinitis mouse model, and total immunoglobulin (Ig)E and OVA-specific IgE levels in serum were investigated. Eosinophil infiltration and thickness of the nasal mucosa, and levels of interleukin (IL)-1ß and caspase-1 were also measured by immunohistochemistry. Additionally, the effect of GMHGYGT on the phorbol-12-myristate-13-acetate plus calcium ionophore A23187-induced phosphorylation of extracellular signal-regulated kinase, C-Jun N-terminal kinase and p38 in HMC-1 cells was investigated. RESULTS: GMHGYGT was demonstrated to have antiallergic effects on the nasal symptoms of the OVA-induced mouse model, decreasing serum levels of OVA-specific IgE and levels of the cytokines IL-5, IL-6, IL-1ß, monocyte chemotactic protein-1, and macrophage inflammatory protein-2. GMHGYGT reduced the number of eosinophils in the nasal mucosa and thickness of the nasal septum, and inhibited the expression of IL-1ß and caspase-1. Moreover, it inhibited the phosphorylation of extracellular signal-regulated kinase and C-Jun N-terminal kinase, as well as the activation of nuclear factor-κB on protein level in HMC-1 cells. CONCLUSION: These results suggest that GMHGYGT has therapeutic potential for the treatment of allergic rhinitis.

Xanthii Fructus inhibits allergic response in the ovalbumin-sensitized mouse allergic rhinitis model.

BACKGROUND: Xanthii Fructus (XF) is widely used in traditional anti-bacterial and anti-inflammatory Asian medicine. Allergic rhinitis is a common inflammatory disease characterized by markedly increased levels of anti-inflammatory factors and the recruitment of inflammatory cells into the nasal mucosa. We investigated the effects of XF in the allergen-induced rhinitis model. MATERIALS AND METHODS: Following ovalbumin (OVA)/alum intraperitoneal injection on days 0, 7 and 14, the BALB/c mice (albino, laboratory-bred strain of the house mice) were challenged intranasally with OVA for 10 days a week after the last sensitization. The number of sneezes was recorded for 10 days; additionally, the levels of cytokines, histamine, immunoglobulin E (IgE) and OVA-specific serum IgE were estimated. Eosinophil infiltration, thickness of nasal mucosa and expression of caspase-1 were determined by immunohistochemistry. We also evaluated the effect of XF on the phosphorylation of nuclear factor kappa-B (NF-κB) and inhibitor of nuclear factor kappa B-alpha (IκB-α) in human mast cell-1 (HMC-1), by Western blotting. RESULTS: The administration of XF significantly decreased sneezing and the serum levels of histamine, IgE, OVA-specific IgE, and cytokines such as tumor necrosis factor-alpha (TNF-α), interleukine-1 beta (IL-1ß), IL-5, IL-6, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2). XF inhibited the changes in thickness of the nasal septum, influx of eosinophils and expression of capase-1. In addition, XF inhibited the phosphorylation of IκB-α and NF-κB in phorbol-myristate-acetate plus calcium ionophore A23187 (A23187) stimulated HMC-1. CONCLUSION: This study suggests that XF acts a potent anti-allergic drug which alleviates the allergic responses in ovalbumin-sensitized mouse allergic rhinitis model.

Effectiveness of Postoperative Gamma Knife Radiosurgery to the Tumor Bed After Resection of Brain Metastases.

OBJECTIVE: The role of Gamma knife radiosurgery (GKS) after the resection of brain metastases remains undefined. We evaluated the outcomes of postoperative GKS to the tumor bed after the resection of brain metastasis compared with GKS alone without resection in the same patients. METHODS: We performed a retrospective review of 24 patients who underwent GKS to the tumor bed after the resection of brain metastases. In this cohort, 25 metastatic lesions were treated with postoperative GKS, and 37 brain metastatic lesions were simultaneously managed with GKS alone without resection. RESULTS: The median target volume and marginal dose of GKS to the surgical bed were 10.5 cm(3) and 15.0 Gy, respectively. The median target volume and marginal dose of GKS alone for the metastatic lesions were 0.5 cm(3) and 21.0 Gy, respectively. The actuarial 1-year and 2-year overall survival of the patients were 43.1% and 28.7%, respectively. The median overall survival of all patients was 11 months. The actuarial 6-month and 12-month local progression-free survival of GKS alone for metastatic lesions without resection were 92.6% and 84.9%; however, the actuarial 6-month and 12-month local progression-free survival of GKS to the surgical bed were 82% and 71%, respectively. CONCLUSIONS: For patients with brain metastases treated with surgical resection, postoperative GKS to the resection area is an effective and safe treatment option. Particularly, concurrent postoperative GKS to the surgical cavity with GKS alone for multiple small metastatic lesions is a feasible treatment strategy for multiple brain metastases.

Multisession Gamma Knife Radiosurgery for Orbital Apex Tumors.

OBJECTIVE: This study was performed to analyze the outcome of multisession gamma knife radiosurgery (GKS) in benign tumors located at the orbital apex. METHODS: Medical records of 23 patients who underwent multisession GKS for benign orbital apex tumors were reviewed retrospectively. Three patients were diagnosed by histology, and the other 20 patients were given the diagnoses on the basis of clinical and radiological findings. Diagnoses included cavernous hemangioma (8 cases), meningioma (8 cases), and schwannoma (7 cases). All patients were treated with 4 sessions of GKS with 12 hours of interval. Median marginal dose in each session was 5 Gy (range, 4.5-5.5 Gy) at the 50% isodose line (range, 50%-55%). RESULTS: Mean clinical and imaging follow-up duration after treatment were 52.1 and 34.2 months, respectively. Tumor control was achieved in 22 patients (95.7%). Significant tumor shrinkage was observed in 17 patients (73.9%), and mean tumor volume reduction rate was 53.9%. Visual function was improved in 16 patients (69.6%) and stable in 4 patients (17.4%). Deterioration of visual acuity was reported by 3 patients (13.0%). Clinical and radiological response to multisession GKS was most excellent in cavernous hemangiomas with tumor control in all patients, and the mean tumor volume reduction rate was 68.3%. CONCLUSIONS: Multisession GKS proved to be an effective and safe management strategy for benign orbital apex tumors. Response to treatment was different according to the pathology, and multisession GKS may be considered as the initial treatment of choice for specific pathology such as cavernous hemangioma.

Outcome of gamma knife thalamotomy in patients with an intractable tremor.

OBJECTIVE: Tremor is a common movement disorder that interferes with daily living. Since the medication for tremor has some limitations, surgical intervention is needed in many patients. In certain patients who cannot undergo aggressive surgical intervention, Gamma Knife thalamotomy (GKT) is a safe and effective alternative. METHODS: From June 2012 to August 2013, 7 patients with an intractable tremor underwent GKT. Four of these 7 patients had medical comorbidities, and 3 patients refused to undergo traditional surgery. Each patient was evaluated with the modified Fahn-Tolosa-Marin tremor rating scale (TRS) along with analysis of handwriting samples. All of the patients underwent GKT with a maximal dose of 130 Gy to the left ventralis intermedius (VIM) nucleus of the thalamus. Follow-up brain MRI was performed after 3 to 8 months of GKT, and evaluation with the TRS was also performed. RESULTS: Six patients showed objective improvement in the TRS score. Excluding one patient who demonstrated tremor progression, there was 28.9% improvement in the TRS score. However, five patients showed subjective improvement in their symptoms. On comparing the TRS scores between follow-up periods of more and less than 4 months, the follow-up TRS score at more than 4 months of GKT was significantly improved compared to that at less than 4 months of GKT. Follow-up MRI showed radiosurgical changes in 5 patients. CONCLUSION: GKT with a maximal dose of 130 Gy to the VIM is a safe procedure that can replace other surgical procedures.

Fractionated gamma knife radiosurgery for benign perioptic tumors: outcomes of 38 patients in a single institute.

BACKGROUND: This study was performed to evaluate the efficacy and safety of fractionated Gamma Knife radiosurgery (GKRS) for perioptic lesions. METHODS: Thirty-eight patients with perioptic tumors were treated at our institute from May 2004 to December 2008. All patients had a lesion in close contact with the optic apparatus. Twenty-four of these patients had undergone surgical resection before fractionated GKRS. Radiation was delivered in four sessions with 12 hours intervals between sessions. The mean target volume was 3,851 mm(3) and the median cumulative marginal dose was 20 Gy. The median follow-up was 38.2 months. Visual acuity and visual fields were analyzed according to visual impairment score using the German Ophthalmological Society guidelines. RESULTS: Tumor control was achieved in 35 (94.6%) of the 37 patients with available follow-up images. Progressive tumor growth was observed in two craniopharyngioma patients (5.4%). Favorable visual outcomes in the postoperative period were achieved in 94.7% of cases (36/38). Sixteen patients showed visual function after fractionated GKRS, twenty cases were stationary, and two patients showed visual function deterioration after GKRS. CONCLUSION: GKRS is a safe and effective alternative to either surgery or fractionated radiotherapy for selected benign lesions that are adjacent to the optic apparatus.

Multisession Gamma Knife surgery for benign orbital tumors.

OBJECT: The goal of this study was to investigate the safety and efficacy of multisession Gamma Knife surgery (GKS) in the treatment of benign orbital tumors. METHODS: Twenty-three patients who retained their vision despite having tumors touching their optic nerve were treated with multisession (4-fraction) GKS. The median tumor volume was 2800 mm(3) (range 211-10,800 mm(3)), and the median cumulative margin dose was 20 Gy (range 18-22 Gy). RESULTS: The median clinical follow-up duration in these patients was 38 months (range 9-74 months). No patient experienced tumor progression in this study. In particular, a higher degree of tumor shrinkage was found in the 7 patients with cavernous hemangiomas than in patients with other types of lesions (p < 0.05). Of the 23 patients whose preoperative vision was preserved, 11 showed improvement in visual acuity and/or visual field and 12 showed stable visual acuity. No GKS-related adverse events were noted during or after treatment. CONCLUSIONS: Multisession radiosurgery using the Gamma Knife may be a good strategy for tumors in direct contact with the optic nerve. A cumulative margin dose of up to 22 Gy delivered in 4 sessions is safe for preservation of visual function with a high probability of tumor control.

Leptomeningeal seeding in patients with brain metastases treated by gamma knife radiosurgery.

To characterize the development of leptomeningeal seeding (LMS) in patients with brain metastases after gamma knife radiosurgery (GKRS). Eight hundred and twenty-seven patients that underwent GKRS as a part of an initial treatment plan for brain metastases between January 2002 and December 2010 were included in the study. Six hundred and fifty patients were treated with GKRS alone and 177 patients received GKRS combined with upfront whole brain radiation therapy (WBRT). Actuarial curves for overall survival (OS) and the development of LMS were plotted using the Kaplan-Meier method. Median overall survival for all patients was 55 weeks (95 % CI, 47.8-62.2), and the overall incidence of LMS was 5.3 %. The actuarial rates for LMS at 6 and 12 months were 3.1 and 5.8, respectively. Uni- and multivariate analysis suggested that breast cancer and a large number of metastases (n ≥ 4) are significant risk factors of LMS (P < 0.05). Regarding treatment modalities, the addition of WBRT was found to have a significant impact on lowering the risk of LMS by multivariate analysis (P = 0.045). LMS is an important pattern of CNS failure. The risk of LMS following GKRS may be associated with multiple lesions, breast cancer, and the omission of WBRT. Additional data from large-scale, randomized controlled trials are required to identify risk factors associated with the LMS more accurately.

Antiallergic effects of Scutellaria baicalensis on inflammation in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria baicalensis (SB) is one of the most widely used medicinal herbs for the treatment of inflammation. In this study, we investigated the antiallergic effect of SB in vivo and in vitro. MATERIALS AND METHODS: Sprague-Dawley (SD) rats received intradermal injections of anti-DNP IgE at each of three dorsal skin sites. Forty-eight hours later, each rat received an injection of DNP-HSA in saline containing 4% Evans blue through the dorsal vein of the penis. One hour before injection, SB extract was administered orally. The dorsal skin of the rats was removed and the pigment area measured. In addition, rat peritoneal mast cells (RPMCs) were cultured and purified to investigate histamine release. In vitro, human mast cells (HMC-1) were pretreated with SB extract for 30min before stimulation with phorbol 12-myristate 13-acetate (PMA) plus A23187. The effects on pro-inflammatory cytokine expression and mitogen activated protein (MAP) kinase expression were investigated using TNF-α and IL-8 assays, and Western blotting analysis of HMC-1 cells. RESULTS AND CONCLUSIONS: SB treatment inhibited the passive cutaneous anaphylaxis reaction compared to the control group, and histamine release decreased significantly following treatment of RPMCs with SB. In HMC-1 cells, SB restored IL-8 and TNF-α expression and inhibited MAP kinase expression in compound 48/80-induced HMC-1 cells. These data suggest that SB may prove to be a useful anti-inflammatory agent through its downregulation of the expression of various inflammatory mediators.

Trans-differentiation of neural stem cells: a therapeutic mechanism against the radiation induced brain damage.

Radiation therapy is an indispensable therapeutic modality for various brain diseases. Though endogenous neural stem cells (NSCs) would provide regenerative potential, many patients nevertheless suffer from radiation-induced brain damage. Accordingly, we tested beneficial effects of exogenous NSC supplementation using in vivo mouse models that received whole brain irradiation. Systemic supplementation of primarily cultured mouse fetal NSCs inhibited radiation-induced brain atrophy and thereby preserved brain functions such as short-term memory. Transplanted NSCs migrated to the irradiated brain and differentiated into neurons, astrocytes, or oligodendrocytes. In addition, neurotrophic factors such as NGF were significantly increased in the brain by NSCs, indicating that both paracrine and replacement effects could be the therapeutic mechanisms of NSCs. Interestingly, NSCs also differentiated into brain endothelial cells, which was accompanied by the restoration the cerebral blood flow that was reduced from the irradiation. Inhibition of the VEGF signaling reduced the migration and trans-differentiation of NSCs. Therefore, trans-differentiation of NSCs into brain endothelial cells by the VEGF signaling and the consequential restoration of the cerebral blood flow would also be one of the therapeutic mechanisms of NSCs. In summary, our data demonstrate that exogenous NSC supplementation could prevent radiation-induced functional loss of the brain. Therefore, successful combination of brain radiation therapy and NSC supplementation would provide a highly promising therapeutic option for patients with various brain diseases.

Differential impact of whole-brain radiotherapy added to radiosurgery for brain metastases.

PURPOSE: The authors investigated whether the addition of whole-brain radiotherapy (WBRT) to stereotactic radiosurgery (SRS) provided any therapeutic benefit according to recursive partitioning analysis (RPA) class. METHODS AND MATERIALS: Two hundred forty-five patients with 1 to 10 metastases who underwent SRS between January 2002 and December 2007 were included in the study. Of those, 168 patients were treated with SRS alone and 77 patients received SRS followed by WBRT. Actuarial curves were estimated using the Kaplan-Meier method regarding overall survival (OS), distant brain control (DC), and local brain control (LC) stratified by RPA class. Analyses for known prognostic variables were performed using the Cox proportional hazards model. RESULTS: Univariate and multivariate analysis revealed that control of the primary tumor, small number of brain metastases, Karnofsky performance scale (KPS) > 70, and initial treatment modalities were significant predictors for survival. For RPA class 1, SRS plus WBRT was associated with a longer survival time compared with SRS alone (854 days vs. 426 days, p = 0.042). The SRS plus WBRT group also showed better LC rate than did the SRS-alone group (p = 0.021), although they did not show a better DC rate (p = 0.079). By contrast, for RPA class 2 or 3, no significant difference in OS, LC, or DC was found between the two groups. CONCLUSIONS: These results suggest that RPA classification should determine whether or not WBRT is added to SRS. WBRT may be recommended to be added to SRS for patients in whom long-term survival is expected on the basis of RPA classification.

Retrospective analysis on 76 cases of cerebral arteriovenous malformations treated by gamma knife radiosurgery.

OBJECTIVE: Outcome of gamma knife radiosurgery (GKS) in the consecutive 100 cases with cerebral arteriovenous malformations (AVMs) was analyzed. METHODS: Data from initial 100 patients treated with GKS in the authors' institute were reviewed retrospectively. Spetzler-Martin grade at diagnosis were I in 18 patients, II in 27, III in 36, IV in 11, and V in 8. Thirty-five patients had experienced previous bleeding, 27 patients presented with seizure, and 31 patients presented with headache. The mean volume of the lesion was 4.3 cm(3) (0.1-29.3 cm(3)). The median radiation dose delivered to the margin was 20.0 Gy (13-32 Gy). Mean follow-up period was 37.5 months (5-63 months). RESULTS: Angiographic follow-up was performed in 48 patients at least 2 years after GKS. Sixteen patients were lost in follow up following 2 years from GKS. Twenty-eight of 48 patients (58%) showed complete obliteration and 20 patients (42%) showed partial obliteration. Seven patients presented with post-GKS hemorrhage. Adverse radiation effect (ARE) was observed at follow-up MRI in 25 of 76 patients, and it was symptomatic in 5 patients. Complete obliteration was confirmed in 24 of 31 (77%) patients with volume less than 4 cm(3), meanwhile only 4 of 17 (24%) patients with volume of 4 cm(3) or more showed complete obliteration. Complete obliteration rate was 67% with 20 Gy or higher marginal dose, 63% with 15-20 Gy, and 17% with less than 15 Gy. CONCLUSION: GKS can provide high rates of obliteration with acceptable risk of morbidity in a subgroup of small AVMs. However, overall outcome in whole spectrum of AVMs, in which large proportion of cases have unfavorable characteristics for radiosurgery, is much worse. More effective therapeutic strategy needs to be developed for large AVMs that are difficult to be managed with current available treatment modalities.

Preliminary report of multisession gamma knife radiosurgery for benign perioptic lesions: visual outcome in 22 patients.

OBJECTIVE: Radiosurgery may be contraindicated for lesions adjacent to the optic pathways because of the substantial risk of visual complication. Multisession radiosurgery has been tried as a compromise between single session radiosurgery and fractionated radiotherapy. The purpose of this study is to evaluate the outcomes of multisession gamma knife radiosurgery (GKRS) in 22 patients with perioptic lesions of benign pathology. METHODS: In all 22 cases, the lesions were within 1 mm of the optic apparatus and were therefore not considered suitable for single session radiosurgery. Radiation was delivered in 3 to 4 fractions with a median cumulated marginal dose of 20 Gy (range, 15-20 Gy). RESULTS: During a mean follow-up of 29 months (range, 14-44 months), tumor control was achieved in 21 patients. Visual function improved in 7 patients, remained unchanged in 14 patients, and deteriorated in 1 patient with tumor progression. No other complication was observed. CONCLUSION: This preliminary result supports the idea that multisession GKRS may be an effective and safe alternative for treatment in perioptic lesions that are unsuitable for single session radiosurgery.

Gamma knife radiosurgery for ten or more brain metastases.

OBJECTIVE: This study was performed to assess the efficacy of GKS in patients with ten or more brain metastases. METHODS: From Aug 2002 to Dec 2007, twenty-six patients (13 men and 13 women) with ten or more cerebral metastatic lesions underwent GKS. The mean age was 55 years (32-80). All patients had Karnofsky performance status (KPS) score of 70 or better. According to recursive partitioning analysis (RPA) classification, 3 patients belonged to class I and 23 to class II. The location of primary tumor was lung (21), breast (3) and unknown (2). The mean number of the lesions per patient was 16.6 (10-37). The mean cumulated volume was 10.9 cc (1.0-42.2). The median marginal dose was 15 Gy (9-23). Overall survival and the prognostic factors for the survival were retrospectively analyzed by using Kaplan Meier method and univariate analysis. RESULTS: Overall median survival from GKS was 34 weeks (8-199). Local control was possible for 79.5% of the lesions and control of all the lesions was possible in at least 14 patients (53.8%) until 6 months after GKS. New lesions appeared in 7 (26.9%) patients during the same period. At the last follow-up, 18 patients died; 6 (33.3%) from systemic causes, 10 (55.6%) from neurological causes, and 2 (11.1%) from unknown causes. Synchronous onset in non-small cell lung cancer (p=0.007), high KPS score (>/=80, p=0.029), and controlled primary disease (p=0.020) were favorable prognostic factors in univariate analysis. CONCLUSION: In carefully selected patients, GKS may be a treatment option for ten or more brain metastases.

Stereotactic device for Gamma Knife radiosurgery in experimental animals: technical note.

OBJECTIVE: Radiosurgery has become a well-established treatment modality for many intracranial lesions and the information obtained from animal experiments is crucial in devising new strategies with improved efficacy and less risk. We constructed a stereotactic device for rats which can be used for both usual laboratory work and radiosurgery using a Gamma Knife. MATERIALS AND METHODS: The stereotactic device was made by modifying the basic design of the ordinary stereotactic frames used for usual laboratory work. It was developed for both Gamma Knife model B and C. An auxiliary tool was also devised which facilitates the placement of the target point at the radiation isocenter. RESULTS: The reliability of the device was verified by checking the radiation profile and absorbed dose. The results of the experimental irradiation in normal and tumor-cell-inoculated rats demonstrated the usefulness of the device. CONCLUSIONS: The modified animal stereotactic frame described herein can be used for both the production of experimental animal models and for performing radiosurgery with a common apparatus.

Gamma knife surgery for brain metastases in patients harboring four or more lesions: survival and prognostic factors.

OBJECT: This study was performed to evaluate the role of gamma knife surgery (GKS) in patients with a large number (four or more) of metastatic brain lesions. METHODS: The authors retrospectively reviewed the outcome in 130 patients who underwent GKS for metastatic lesions. Eighty-four patients presented with one to three lesions (Group A) and 46 presented with four or more lesions (Group B). The overall median survival time after GKS was 35 weeks. The median survival time in Group A (48 weeks) was significantly longer (p = 0.005) than the survival time in Group B (26 weeks). The recursive partitioning analysis (RPA) class was the only significant prognostic factor identified in multivariate analysis. The median survival for patients in RPA Classes I, II, and III was 72, 48, and 19 weeks, respectively, in Group A and 36 and 13 weeks for Classes II and III in Group B. The number of lesions, tumor volume, whole brain radiotherapy, primary tumor site, age, and sex did not affect survival significantly. CONCLUSIONS: It is suggested that GKS provides an increase in survival time even in patients with a large number (four or more) of metastatic lesions. Concerning the selection of patients for GKS, RPA class should be considered as the most important factor and multiplicity of the lesions alone should not be a reason for withholding GKS.