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Object: This report has been prepared to ensure more uniform reporting of Gamma Knife radiosurgery treatment parameters by identifying areas of controversy, confusion, or imprecision in terminology and recommending standards., Methods: Several working group discussions supplemented by clarification via email allowed the elaboration of a series of provisional recommendations. These were also discussed in open session at the 16th International Leksell Gamma Knife Society Meeting in Sydney, Australia, in March 2012 and approved subject to certain revisions and the performance of an Internet vote for approval from the whole Society. This ballot was undertaken in September 2012., Results: The recommendations in relation to volumes are that Gross Target Volume (GTV) should replace Target Volume (TV); Prescription Isodose Volume (PIV) should generally be used; the term Treated Target Volume (TTV) should replace TVPIV, GTV in PIV, and so forth; and the Volume of Accepted Tolerance Dose (VATD) should be used in place of irradiated volume. For dose prescription and measurement, the prescription dose should be supplemented by the Absorbed Dose, or DV% (for example, D95%), the maximum and minimum dose should be related to a specific tissue volume (for example, D2% or preferably D1 mm3), and the median dose (D50%) should be recorded routinely. The Integral Dose becomes the Total Absorbed Energy (TAE). In the assessment of planning quality, the use of the Target Coverage Ratio (TTV/ GTV), Paddick Conformity Index (PCI = TTV2/[GTV · PIV]), New Conformity Index (NCI = [GTV · PIV]/TTV2), Selectivity Index (TTV/PIV), Homogeneity Index (HI = [D2% –D98%]/D50%), and Gradient Index (GI = PIV0.5/PIV) are reemphasized. In relation to the dose to Organs at Risk (OARs), the emphasis is on dose volume recording of the VATD or the dose/volume limit (for example, V10) in most cases, with the additional use of a Maximum Dose to a small volume (such as 1 mm3) and/or a Point Dose and Mean Point Dose in certain circumstances, particularly when referring to serial organs. The recommendations were accepted by the International Leksell Gamma Knife Society by a vote of 92% to 8%., Conclusions: An agreed-upon and uniform terminology and subsequent standardization of certain methods and procedures will advance the clinical science of stereotactic radiosurgery.

Objective: The current study retrospectively assessed delayed gamma knife radiosurgery (GKRS) in the management of high-grade glioma recurrences., Methods: A total of 55 consecutive patients with high-grade glioma comprising 68 World Health Organization (WHO) III and WHO IV were treated with GKRS for local recurrences between 2001 and 2007. All patients had undergone microsurgery and radiochemotherapy, considered as standard therapy for high-grade glioma. Complete follow-up was available in all patients; median follow-up was 17.2 months (2.5-114.2 months). Median tumor volume was 5.2 mL, prescription dose was 20 Gy (14-22 Gy), and median max dose was 45 Gy (30-77.3 Gy)., Results: The patients with WHO III tumors showed a median survival of 49.6 months with and a 2-year survival of 90%. After GKRS of the recurrences, these patients showed a median survival of 24.2 months and a 2-year survival of 50%. The patients with WHO IV tumors had a median survival of 24.5 months with a 2-year survival of 51.4%. After the recurrence was treated with GKRS, the median survival was 11.3 months and a 2-year survival: 22.9% for the WHO IV patients., Conclusion: The current study shows a survival benefit for high-grade glioma recurrences when GKRS was administered after standard therapy. This is a relevant improvement compared with earlier studies that had had not been able to provide a beneficial effect timing radiosurgery in close vicinity to EBRT., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Chemotherapy has made substantial progress in the therapy of systemic cancer, but the pharmacological efficacy is insufficient in the treatment of brain metastases. Fractionated whole brain radiotherapy (WBRT) has been a standard treatment of brain metastases, but provides limited local tumor control and often unsatisfactory clinical results. Stereotactic radiosurgery using Gamma Knife, Linac or Cyberknife has overcome several of these limitations, which has influenced recent treatment recommendations. This present review summarizes the current literature of single session radiosurgery concerning survival and quality of life, specific responses, tumor volumes and numbers, about potential treatment combinations and radioresistant metastases. Gamma Knife and Linac based radiosurgery provide consistent results with a reproducible local tumor control in both single and multiple brain metastases. Ideally minimum doses of ≥18Gy are applied. Reported local control rates were 90-94% for breast cancer metastases and 81-98% for brain metastases of lung cancer. Local tumor control rates after radiosurgery of otherwise radioresistant brain metastases were 73-90% for melanoma and 83-96% for renal cell cancer. Currently, there is a tendency to treat a larger number of brain metastases in a single radiosurgical session, since numerous studies document high local tumor control after radiosurgical treatment of >3 brain metastases. New remote brain metastases are reported in 33-42% after WBRT and in 39-52% after radiosurgery, but while WBRT is generally applied only once, radiosurgery can be used repeatedly for remote recurrences or new metastases after WBRT. Larger metastases (>8-10cc) should be removed surgically, but for smaller metastases Gamma Knife radiosurgery appears to be equally effective as surgical tumor resection (level I evidence). Radiosurgery avoids the impairments in cognition and quality of life that can be a consequence of WBRT (level I evidence). High local efficacy, preservation of cerebral functions, short hospitalization and the option to continue a systemic chemotherapy are factors in favor of a minimally invasive approach with stereotactic radiosurgery., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A dose gradient index (GI) is proposed that can be used to compare treatment plans of equal conformity. The steep dose gradient outside the radiosurgical target is one of the factors that makes radiosurgery possible. It therefore makes sense to measure this variable and to use it to compare rival plans, explore optimal prescription isodoses, or compare treatment modalities. The GI is defined as the ratio of the volume of half the prescription isodose to the volume of the prescription isodose. For a plan normalized to the 50% isodose line, it is the ratio of the 25% isodose volume to that of the 50% isodose volume. The GI will differentiate between plans of similar conformity, but with different dose gradients, for example, where isocenters have been inappropriately centered on the edge of the target volume. In a retrospective series of 50 dose plans for the treatment of vestibular schwannoma, the optimal prescription isodose was assessed. A mean value of 40% (median 38%, range 30-61%) was calculated, not 50% as might be anticipated. The GI can show which of these prescription isodoses will give the steepest dose falloff outside the target. When planning a multiisocenter treatment, there may be a temptation to place some isocenters on the edge of the target. This has the apparent advantage of producing a plan of good conformity and a predictable prescription isodose; however, it risks creating a plan that has a low dose gradient outside the target. The quality of this dose gradient is quantified by the GI.

Radiosurgery is considered one of the most revolutionary recent developments in the therapy of certain intracranial tumors. It is generally accepted that radiosurgery with the Gamma Knife or stereotactic Linac is the least invasive effective treatment for cerebral metastases. The Gamma Knife provides so far the highest possible and practically applicable precision of radiation. Radiosurgery of brain metastases with a size of less than 12 cm3 results in excellent local tumor control rates and very low associated morbidity. The Gamma Knife has been shown to be highly effective also against multiple metastases and is likewise effective even for tumors that are relatively resistant to traditional external beam radiation therapy. Radiosurgery replaces open tumor operation in some indications. As an additive therapy it allows the conventional surgeon to operate less radically resulting in a lower complication rate. The goal is short hospitalization time and increased quality of life.

Although efficacy of gamma knife radiosurgery has been demonstrated in numerous studies, the policies in patients with multiple metastases seem to be unequivocal. The maintained quality of life, the possibility of short hospitalization and the continuation of a systemic chemotherapy are increasingly important arguments in favor of a minimally invasive radiosurgical approach. These factors are particularly emphasized in patients with a dismal prognosis. The current retrospective analysis was undertaken to summarize the clinical results of radiosurgery in patients with multiple cerebral metastases of various primary cancer. Fractionated whole brain radiotherapy (WBRT) was omitted as prophylactic treatment and applied only in cases with general tumor spread. Clinical data of all consecutive patients (n = 215) who received gamma knife radiosurgery for cerebral metastases between January 2001 and January 2003 at the gamma knife Centers of the Karolinska Hospital and H.M. Queen Sophia Hospital (Sophiahemmet) Stockholm were analyzed retrospectively. 172 patients were treated for multiple metastases (198 treatments). The median prescription dose was 22 Gy (range 14-34 Gy). The Kaplan Meier plot shows a median survival (MST) of 7.8 months for patients with multiple cerebral metastases and 13.7 months for patients with single metastases. There was no relation between survival and number of metastases in patients with multiple metastases. Within this group 11.6% (20/172 patients) developed adverse radiation reactions. Tumor recurrences were documented by FDG-PET in 7 patients (out of 172 patients: 4.1%) after a median latency of 10 months after radiosurgery. In summary, gamma knife radiosurgery provides a highly effective and minimally invasive method to treat patients with multiple cerebral metastases even without prophylactic WBRT. Local control and patient survival in the present series of patients is in accordance with other retrospective series of patients with single and multiple metastases.

Chromosome analysis of brain tumours can provide important pathobiological data; however, cytogenetic tools are so far not routinely applied for diagnosis. In the present study 25 paraffin embedded stereotactic biopsies from 19 glioma patients were studied using in situ hybridization of chromosome #10 and #15 using biotinylated pericentromeric probes. Numerical changes of chromosome #10 are frequent alterations in glioblastoma. Quantification of chromosome #15 served as a control in order to exclude artificial monosomies or nonspecific changes. The number of chromosomes in at least 200 cells were counted for each specimen. 18 of 25 biopsies could be evaluated quantitatively. The small volume of probes was not a limiting factor for analysis. Quantification of "nonspecific" chromosome #15 revealed single spots in 22-41% of all cells in the 18 biopsies. Chromosome #10 showed single spots in a range between 34 and 44% of counted nuclei in 13/18 biopsies. In 5 out of 18 biopsies 51-60% monosomies were found: in this subgroup were 4 high grade gliomas. These cases were interpreted as monosomy of chromosome #10. The results demonstrate feasibility and quantitative evaluability of cytogenetic analysis in stereotactic biopsy material using in situ hybridization.

The current study analyses the long-term clinical course of 12 patients with pineal germinomas. The histological diagnosis was established by stereotactic biopsy in all cases. In 11 of the 12 cases the diagnosis was correct. There was no operative mortality or morbidity. All patients were treated by external radiotherapy. The median follow-up period for the surviving patients is 5.9 years (range 4.5-8.8 years). After radiotherapy, CT and MRI follow-up examinations showed complete tumor remissions with no local tumor recurrences in all cases. Two patients died of other, unrelated, illnesses 1.4 and 5.8 years after diagnosis of the pineal germinoma. Since long-term survival and morbidity do not document any superiority of operative resection of germinomas, the minimally invasive approach with stereotactic biopsy and radiotherapy is strongly advocated. There is no longer any justification for irradiating pineal tumors to check the diagnosis now that stereotactic biopsy is available.

Due to its constant glial morphology and small variability as to tumor location and growth characteristics, the intracerebral D-54MG tumor xenograft provides the predictability and reproducibility needed by models for the study of stereotactic interstitial radiotherapy. Development and results of experimental brachytherapy in an intracerebral human gliomas derived xenograft tumor model are reported. Tumor homogenate prepared from homogenized subcutaneous D-54MG xenografts was inoculated into the frontal lobe of athymic BALB/c mice (nu/nu genotype). The D-54MG glioma xenografts grew at the site of inoculation without intraventricular or subarachnoid spread. The increase of median survival (IMS) was 58.33% for the highest dose (9370 cGy) and 33.3% for the intermediate dose (5654 cGy). In both experiments the survival prolongation was statistically significant (p < 0.05) as calculated by the Log Rank Rest for Kaplan Meier Survival Distributions. In the low dose group (3159 cGy) only a small and not significant IMS was achieved (16.67%). The results of the present investigation demonstrate the accuracy of the stereotactic operative procedure and the efficacy of experimental intracerebral interstitial radiotherapy with I 125 seeds. Using a constant dose rate, experimental interstitial brachytherapy in brain-tumor bearing nude mice was shown to result in a dose dependant survival prolongation for the treated animals. The model may help to optimize the rational basis of clinical brain tumor therapy and is well suited to simulate dose and dose rate related therapeutic effects.

Melphalan (L-phenylalanine mustard, L-PAM, alkeran; molecular weight, 305,000) is transported across tumor cell membranes and the blood-brain barrier by the large neutral amino acid (LNAA) transport system. Normally, plasma LNAA levels are high enough and the affinity low enough that this system does not transport much melphalan into the brain. However, plasma amino acids can be reduced by fasting and protein-free diet. We used this method to reduce competition and to increase melphalan transport into brain tumors. In nude mice fasted for 12 h and then fed a protein-free diet for 2 and 6 h, mean plasma LNAA levels were 46% and 42% of control values. Nude mice with xenotransplanted D-54MG human gliomas were used to study tissue distribution and uptake kinetics of [3H]melphalan in a control group and a diet group (after a 12-h fast and 2 h of a 0% protein diet). The K1 (blood-to-tissue transfer constant) of melphalan, determined by graphical analysis and by nonlinear fitting to a 2-compartment model, was higher in the diet group in all tumor regions except the necrotic center of subcutaneous tumors; the increase was significant in the tumor periphery of brain and s.c. tumors. The ratio of K1s (diet to control) varied from 1.2 to 1.3 in brain tumors, 1.9 to 2.1 in subcutaneous tumors, and 1.8 to 3.1 in tumor-free brain. The apparent [3H]melphalan distribution space was significantly higher in the tumor periphery of both brain and subcutaneous tumors of the 15- and 30-min diet group. We also measured blood-brain barrier transport of [alpha-14C]aminoisobutyric acid and blood flow (with [131I]iodoantipyrine): the K1 of [alpha-14C]aminoisobutyric acid was 28.1 +/- 6.6 (SE) in brain tumors and 24.3 +/- 8.9 microliters/g/min in subcutaneous tumors. Blood flow was 58.2 --> 3.9 in brain tumors and 5.2 +/- 0.4 ml/100 g/min in subcutaneous tumors. Fasting, when combined with a protein-free diet, reduces plasma amino acid levels and thereby reduces competition between melphalan and LNAAs. This may increase the amount of melphalan that can enter a brain tumor without increasing the administered drug dose and suggests a therapeutic manipulation that can be used to increase the delivery of melphalan.

An intracranial (i.c.) interstitial radiotherapy model in athymic nude mice bearing i.c. D-54 MG human glioma xenografts was developed, allowing evaluation of the therapeutic benefits seen after L-buthionine-S,R-sulfoximine (L-BSO)-mediated depletion of tumor glutathione levels. Administration of L-BSO [2.5 mmol/kg intraperitoneal injections x 4 doses plus concomitant availability in acidified (pH 3.0) drinking water at a concentration of 20 mM] resulted in depletion of tumor glutathione levels to 0.15 mumol/g wet weight (7.9% of control). The therapeutic activity of i.c. interstitial radiotherapy with an 125I seed was enhanced after L-BSO-mediated glutathione depletion, with increases in median survival of 13.4 to 30.5% over that seen with 125I seeds alone. These studies demonstrate a potential role for BSO in enhancing the therapeutic activity of interstitial radiotherapy.

In previous studies we demonstrated that administration of buthionine sulfoximine (BSO) to athymic BALB/c mice bearing intracranial human glioma xenografts resulted in highly selective depletion of glutathione in neoplastic tissue with minimal effects on contralateral normal brain tissue. In the present study we treated athymic BALB/c mice bearing intracranial human glioma (D-54 MG) or medulloblastoma (TE-671) xenografts with melphalan alone or BSO followed by melphalan. Administration of BSO depleted intracellular glutathione to 7.5% of the control level. BSO plus melphalan resulted in a significant increase in median survival over that produced by melphalan alone: 45.3% versus 26.4% in TE-671 and 69% versus 27.6% in D-54 MG. These studies justify further efforts to modulate chemotherapeutic and radiotherapeutic interventions of primary malignant brain tumors by depletion of glutathione.