Radiosurgery reirradiation for high-grade glioma recurrence: a retrospective analysis.

Despite various treatment strategies being available, recurrent high-grade gliomas (r-HGG) are difficult to manage. To obtain local control, radiosurgery (SRS) reirradiation has been considered as potential treatment. In the present study, a retrospective analysis was performed on r-HGG patients treated with salvage single- (s-SRS) or multi-fraction SRS (m-SRS). The aim of this study was to evaluate the effectiveness of salvage SRS in terms of overall survival (OS); toxicity was analyzed as well. Between 2004 May and 2011 December, 128 r-HGG patients (161 lesions) treated with CyberKnife(®) SRS reirradiation were retrospectively analyzed. Toxicity was graded according to Radiation Therapy Oncology Group and by Common Terminology Criteria for Adverse Events v.3 criteria. OS from the diagnosis date and OS from reirradiation were estimated using the Kaplan-Meier method. Median follow-up was 9 months (range 15 days-82 months). All patients completed SRS without high-grade toxicity. Radiation necrosis was observed in seven patients (6 %) with large volume lesions. The median survival from initial diagnosis was 32 months. The 1-, 2-, and 3-years survival rates from diagnosis were 95, 62, and 45 % respectively. Median survival following SRS was 11.5 months. The 1-, 2-, and 3-years survival rate following SRS was 48, 20, and 17 % respectively. On multivariate analysis, age <40 years, salvage surgery before SRS, and other post-SRS therapies (second-line chemotherapy and/or surgery) were found to significantly improve survival (p = 0.03). SRS represents a safe and feasible option to treat r-HGG patients with low complication rates and potential survival benefit.

Intradural extramedullary benign spinal lesions radiosurgery. Medium- to long-term results from a single institution experience.

BACKGROUND: Surgery represents the first-choice treatment for spinal intradural tumours. On the other hand, whether it is most appropriate in the setting of recurrences, residual or multiple lesions remains an open question. Moreover, some patients are less than ideal candidates for surgery. In this study we report about our own radiosurgery experience in the treatment of benign intradural extramedullary tumours of the spine. METHODS: In our study we analyzed the outcomes for 18 patients (21 lesions) treated for benign intradural extramedullary lesions, with a minimum follow-up period of 32 months. The lesions included 11 meningiomas, 9 schwannomas and 1 neurofibroma. RESULTS: The mean follow-up was 43 months (32-73 months). The median tumour volume was 2 cc (0.2-17.7 cc). Eleven lesions underwent single-fraction treatment (mean prescribed dose ranging from 10 to 13 Gy). The others received a multisession radiosurgery treatment (4-6 fractions) with a mean prescription dose ranging from 18.5 to 25 Gy. The maximum dose to the spinal cord ranged from 9.2 to 26 Gy. During the follow-up period, none of the lesions showed radiological evidence of progression. Neurological status was preserved or improved and no permanent sequelae were observed. Significant and durable pain relief was observed. CONCLUSIONS: Although surgical excision remains the primary treatment option for most intradural tumours, radiosurgery offers a real alternative therapeutic modality, especially in case of recurrent and residual lesions or when surgery is contraindicated.

Loco-regional treatments in first-diagnosis glioblastoma: literature review on association between Stupp protocol and Gliadel.

Loco-regional chemotherapy with carmustine wafers (Gliadel) positioned at surgery and followed by radiotherapy has been shown to prolong survival in first-diagnosis glioblastoma, as well as concomitant radiochemotherapy with temozolomide. The combination of Gliadel with the Stupp protocol has mostly been investigated in retrospective studies. objective of this study was to review the literature of efficacy and toxicities in patients with first-diagnosis glioblastoma treated with surgery, Gliadel, radiotherapy and temozolomide chemotherapy. The data in the literature regarding the combined use of Gliadel with chemotherapy, concomitant with radiotherapy and adjuvant temozolomide for glioblastoma was analyzed and compared. The results on survival and toxicity are summarized. The combination of Gliadel and radiotherapy with temozolomide is well tolerated and may increase survival without a substantial increase in major toxicity. However, only prospective comparative studies will be able to address the issue of true advantage in survival with this combination.

Hypofractionated stereotactic radiotherapy for oligometastases in the brain: a single-institution experience.

The treatment of brain metastases is changing. Many different radiotherapy options are now available and under clinical evaluation. As part of this effort, we retrospectively evaluated the efficacy and toxicity of hypofractionated stereotactic radiotherapy (HSRT) in patients with up to three brain metastases. Sixty-five patients with 81 lesions were treated with hypofractionated radiotherapy. Median dose was 24 Gy in three fractions. Median follow-up was 24.6 months. Actuarial tumour control was 75 and 45% at 9 months and 24 months after treatment, respectively. Median survival time was 7.5 months, and 32% of the patients died from brain tumour progression. Actuarial overall survival was 75% at 3 months and 25% at 12 months. Recursive partitioning analysis class was the only significant prognostic factor. Neoadjuvant whole-brain radiotherapy (in 29 patients) had no impact on survival or local control. Neurological status improved in 42 patients (65%). Adverse events were rare and usually mild. This experience suggests HSRT should be considered as an alternative approach in the treatment of one to three metastatic lesions in selected patients.

Deep brain stimulation and frameless stereotactic radiosurgery in the treatment of bilateral parkinsonian tremor: target selection and case report of two patients.

Considerable positive experience in functional radiosurgery has been reported since Leksell's first experience in 1951, but the development of frameless radiosurgery was been limited because of the difficulty of identifying invisible functional targets. In this paper we report on two cases of bilateral parkinsonian tremor successfully treated with DBS on one side and with frameless radiosurgery on the contralateral side. We focus on the methodology developed to define the three-dimensional target coordinates for frameless radiosurgery. Two patients suffering from a disabling upper-limb parkinsonian tremor underwent frameless radiosurgical thalamotomy. To accurately identify the treatment target the CT gantry was treated as a stereotactic frame; a rototranslation between the origin of the screen and the origin of the stereotactic atlas allowed us to obtain atlas-registered 3D coordinates of each point on the CT axial brain slices. Both patients achieved complete bilateral tremor control by unilateral radiosurgery and contralateral DBS. We developed a method for determining the 3D coordinates of a known functional target to treat with frameless radiosurgery. Based on the initial experiences, frameless radiosurgery appears to be an alternative treatment for Parkinsonian upper limb tremor in the presence of increased surgical risks for DBS placement.

Cisplatinum and BCNU chemotherapy in primary glioblastoma patients.

BACKGROUND: The prognosis of patients with glioblastoma is very poor with a mean survival of 10-12 months. Currently available treatment options are multimodal, which include surgery, radiotherapy, and chemotherapy. However, these have been shown to improve survival only marginally in glioblastoma multiforme (GBM) patients. Methylated methylguanine methyltransferase (MGMT) promoter is correlated with improved progression-free and overall survival in patients treated with alkylating agents. Strategies to overcome MGMT-mediated chemoresistance are being actively investigated. METHODS: A retrospective analysis on 160 adult patients (> or =16 years) treated for histologically confirmed GBM between 2003 and 2005 at our Institution was performed. All patients were treated with conventional fractionated radiotherapy and a combined chemotherapy treatment with Cisplatin (CDDP) (100 mg/sqm on day 1) and carmustine (BCNU) (160 mg/sqm on day 2); the treatment was repeated every 6 weeks for five cycles. Toxicity, progression free survival and overall survival were assessed. RESULTS: The median number of chemotherapy cycles delivered to each patient was 5 (range 3-6), with no patients discontinuing treatment because of refusal or toxicity. Dose reduction was required in 16 patients (10%), and all patients completed radiotherapy, whereas 5 patients discontinued chemotherapy before completing all planned cycles for disease progression. The primary toxicities were: neutropenia (grade 3-4: 23%), thrombocytopenia (grade 3-4: 18.5%), and nausea and vomiting (13%). Median progression-free survival times and 1-year progression free survival were 7.6 months (95% CI 6.6-8.5) and 17.3%, respectively. OS was 15.6 months (95% CI 14.1-17.1). CONCLUSIONS: Our results for PFS and overall survival are comparable with those obtained with temozolomide, but the toxicity occurring in our series was more frequent and persistent. The toxicity, and mainly the modalities of administration associated with cisplatin and BCNU combination, argues against future use in the treatment of patients with GBM.

Paragangliomas of head and neck: a treatment option with CyberKnife radiosurgery.

Paragangliomas are highly vascular and predominantly benign neoplasms that have traditionally been treated by surgery, embolization and/or external beam radiotherapy (EBRT). The aim of this study is to evaluate the short-term local tumor control and safety of CyberKnife radiosurgery for these lesions. Nine patients, eight with jugular glomus paragangliomas and one with a carotid body paraganglioma, were treated. The target contouring was performed on merged CT and MR images. Eight patients were treated with doses ranging from 11 to 13 Gy (mean 12.5 Gy) in a single fraction and one with 24 Gy in three fractions prescribed to 72-83% isodose line. The mean follow-up was 20 months. One patient died from unrelated causes. There were no local recurrences. All eight patients also demonstrated neurological stability or improvement. Neither cranial nerve palsies have arisen, nor has deterioration beyond baseline been observed. In conclusion, CyberKnife radiosurgery appears to be both safe and effective in the treatment of skull base paragangliomas. Determining whether long-term complications will arise will require further investigation.

Short course radiotherapy concomitant with temozolomide in GBM patients: a phase II study.

PURPOSE: Despite recent advances, the prognosis of glioblastoma (GBM) remains poor. The aim of this study was to assess the efficacy and tolerability of multiple daily fraction radiotherapy performed with multiple temozolomide (TMZ) administrations in newly diagnosed patients with GBM. METHODS: This trial was a prospective, open-label, monocentric, nonrandomized, single arm, phase II study. The primary endpoint was the proportion of progression-free patients at 12 months, and the secondary endpoints were overall survival (OS) and toxicity. Thirty-five patients underwent two radiotherapy courses concomitant with TMZ after surgery. At each course, radiation was delivered 3 times daily, 2 Gy/fraction, for 5 consecutive days, and the total dose was 60 Gy; concurrent TMZ was administered in a total dose of 150-200 mg/m2/day. RESULTS: The primary endpoint failed to be applied; Macdonald criteria could be used in 16 (46%) patients with local or intracerebral recurrence (group A). In 12 patients, due to suspicion of radiation necrosis vs recurrence, Macdonald criteria were not applied (group B). The OS was 22 months, and OS probabilities at 12, 18, and 24 months were 82%, 59%, and 44%, respectively. Hematologic toxicities generally did not exceed grade 2. The quality of life and cognitive functioning did not significantly change between baseline and the first follow-up. In the multivariate analysis, necrosis and pseudoprogression were significant prognostic factors of OS. CONCLUSIONS: To improve local control and OS, a more aggressive treatment schedule should be explored. The related higher necrosis risk and its implications regarding local control deserve further investigation.

Pattern of care and outcome in elderly patients with glioblastoma: Data in 151 patients from 3 Lombardia Hospitals.

The appropriate treatment approach for elderly patients with glioblastoma multiforme (GBM) is unclear, although different studies suggest survival benefit in fit patients treated with radiotherapy and chemiotherapy after surgery. We performed a retrospective analysis of 151 patients older than 65years with GBM treated in 3 Lombardia Hospitals. In univariate regression analysis higher KPS (p=0.02), macroscopical total resection (p<0.003), radiotherapy (p<0.0001), chemotherapy (p<0.0001) and second line chemotheraphy (p=0.02) were of positive prognostic value. On the contrary older age (>70years), presence of seizure at onset and additional resection after tumor recurrence did not influence OS. Multivariate analysis revealed radiotherapy (HR 0.2 p<0.0001) and extent of surgery (HR 0.3, p=0,0063) as positive independent prognostic factors. Patients receiving radio-chemiotherapy displayed more treatment-related toxicities with a slightly prolonged OS versus those receiving hypofractionated radiotherapy. With the limits of a retrospective study, our data suggest that in elderly fit patients extensive surgery should be considered, moreover adjuvant treatments led to an increase in OS. Randomized controlled study are needed to develop treatment guidelines for elderly GBM patients and to assess whether the combination of post-surgical radio and chemiotherapy may be superior to hypofractionated radiotherapy and chemiotherapy in fit patients.

Multisession Radiosurgery for Sellar and Parasellar Benign Meningiomas: Long-term Tumor Growth Control and Visual Outcome.

BACKGROUND: Concern about radiation-induced optic neuropathy (RION) has governed recent thinking about the role of radiation therapy in the treatment of meningiomas involving the anterior optic pathways. Despite this concern, during the last few years, the use of radiosurgery for such lesions has increased steadily. OBJECTIVE: To define both the tumor control rate and the risk of RION over a long-term follow-up period in a large cohort of patients treated with multisession radiosurgery. METHODS: The local control and visual outcome of 143 patients who underwent multisession radiosurgery (mRS) were evaluated. Neurological outcome was also analyzed. The data for the present study were obtained from a prospectively maintained database. RESULTS: The mean follow-up was 44 months (range, 12-113 months). All patients underwent mRS. The median prescription dose was 25 Gy delivered in 3 to 5 fractions. The prescription isodose, which typically encompassed at least 95% of the tumor, ranged from 65% to 86% (median, 80%). The mean tumor volume was 11.0 cm (range, 0.1-126.3 cm; median, 8 cm). The progression-free survival at 3, 5, and 8 years was 100%, 93%, and 90%, respectively. Compared with baseline, visual function improved in 36% of patients, whereas 7.4% experienced a worsening in visual function (5.1% excluding the patients with progressive disease). CONCLUSION: Good local control rate and a low risk of RION indicate that mRS is a safe and effective treatment option in cases of large meningiomas.

Quality of life and brain tumors: what beyond the clinical burden?

This study analyzed the subjective facets of quality of life (QoL) and their relation to the type of brain tumor (BT) and phase of disease. Two hundred and ninety-one patients with pinealoblastoma, medulloblastoma, low-grade glioma, anaplastic astrocytoma, or glioblastoma were evaluated. With respect to 110 healthy controls, patients in the phases of radiotherapy/chemotherapy, stable disease, or tumor recurrence were significantly more anxious and depressed compared with patients in the early postoperative period. All patients were impaired in mental flexibility and memory, with preservation of abstract reasoning. The Functional Living Index-Cancer (FLIC), previously validated in cancer and BT patients, yielded six subjective factors (disease perception, affective well-being, role and leisure, personal base, nausea, sharing). None of the FLIC factors were predicted by tumor type, which only related to the physical and cognitive performances and mood scores. Affective well-being, role and leisure, and sharing were predicted by the phase of disease. Personal base, including self-perception and confidence, was independent on tumor progression and treatment. To conclude, QoL encompasses different subjective aspects, which vary in relation to the phase of disease and clinical burden. However, some person-related facets appear independent on tumor progression and treatment, indicating individual resources. Knowing this may guide tailored interventions supporting QoL.

Prospective study of carmustine wafers in combination with 6-month metronomic temozolomide and radiation therapy in newly diagnosed glioblastoma: preliminary results.

OBJECT: Locoregional chemotherapy with carmustine wafers, positioned at surgery and followed by radiation therapy, has been shown to prolong survival in patients with newly diagnosed glioblastoma, as has concomitant radiochemotherapy with temozolomide. A combination of carmustine wafers with the Stupp treatment regimen has only been investigated in retrospective studies. METHODS: In a single-institution prospective study, the authors assessed 12-month progression-free survival (PFS), toxicity, and overall survival in patients with glioblastoma treated with surgery, carmustine wafers, radiotherapy, and 6-month metronomic temozolomide chemotherapy. Thirty-five patients with de novo glioblastoma, between the ages of 18 and 70 years, and with Karnofsky Performance Scale scores of at least 70, were included in the study. Patients were followed monthly and assessed using MRI every 2 months. RESULTS: After a median follow-up of 15 months, the median time to tumor progression was 12.5 months and median survival was 17.8 months. Due to toxicity (mostly hematological), 7 patients had to prematurely stop temozolomide treatment. Twenty-two patients developed Grade 3 CD4(+) lymphocytopenia. Three patients developed oral-esophageal candidiasis, 2 developed pneumonia, and 1 developed a dorsolumbar zoster. Early intracranial hypertension was observed in 1 patient, and 1 was treated empirically for suspected brain abscess. One patient died of Legionella pneumonia soon after repeat surgery. CONCLUSIONS: Overall, this treatment schedule produced promising results in terms of PFS without a marked increase in toxicities as compared with the Stupp regimen. However, the gain in median survival using this schedule was less clear. Only prospective comparative trials will determine whether these preliminary results will translate into a long-term survival advantage with an acceptable toxicity profile.

Multisession radiosurgery for optic nerve sheath meningiomas--an effective option: preliminary results of a single-center experience.

BACKGROUND: Traditional treatment options for optic nerve sheath meningiomas (ONSMs) include observation, surgery, and radiotherapy, but to date none of these has become the clear treatment of choice. OBJECTIVE: To evaluate the effectiveness and safety of multisession radiosurgery for ONSMs. METHODS: From May 2004 to June 2008, 21 patients with ONSMs were treated by radiosurgery using the frameless CyberKnife system. Patient age ranged from 36 to 73 years (mean, 54 years). All patients were treated using multisession radiosurgery, with 5 fractions of 5 Gy each to a total dose of 25 Gy prescribed to the 75% to 85% isodose line. Patients were evaluated for tumor growth control and visual function. RESULTS: The median pretreatment tumor volume was 2.8 mL (range, 0.3-23 mL). The mean follow-up was 30 months (range, 11-68 months). All patients tolerated treatment well, with only 1 patient in whom a mild optic neuropathy developed (which remitted after systemic steroid therapy). No other acute or late radiation-induced toxicities were observed. No patients showed ONSM progression on follow-up magnetic resonance imaging. Two patients (10%) had a partial response. No patients had worsening of visual function; visual function was stable in 65% and improved in 35% of patients. CONCLUSION: Multisession radiosurgery for ONSMs was found to be safe and effective. The preliminary results from this study, in terms of growth control, visual function improvement, and toxicity, are quite promising. Further investigations are warranted.

CyberKnife radiosurgery as a first treatment for idiopathic trigeminal neuralgia.

OBJECTIVE: To report the level of effectiveness and safety, in our experience, of CyberKnife (Accuray, Inc., Sunnyvale, CA) robotic radiosurgery as a first-line treatment against pharmacologically refractory trigeminal neuralgia. METHODS: We treated 33 patients with the frameless CyberKnife system as a monotherapy. The retrogasserian portion of the trigeminal nerve (a length of 4 mm, 2-3 mm anterior to the root entry zone) was targeted. Doses of 55 to 75 Gy were prescribed to the 100% isodose line, according to a dose escalation protocol. The patients were evaluated for the level of pain control, time to pain relief, hypesthesia, and time to pain recurrence. RESULTS: The median age was 74 years. All but 2 patients (94%) achieved a successful treatment outcome. The follow-up period was 9 to 37 months (mean, 23 months). The Barrow Neurological Institute Pain Intensity Scale (BPS) score before radiosurgery was III in 2 patients (6%), IV in 8 patients (24%), and V in 23 patients (70%). The time to pain relief was 1 to 180 days (median, 30 days). No facial numbness was observed. Only 1 patient developed a transitory dysesthesia of the tongue. After treatment, the BPS score was I, II, or III in 31 patients (97%). Pain recurred in 33% (11 patients) at a mean of 9 months (range, 1-43 months). Three patients with recurrences had low pain control by medication (BPS score, IV), and 1 patient (BPS score, V) needed a radiofrequency lesioning (BPS score, I at 12 months). CONCLUSION: CyberKnife radiosurgery for trigeminal neuralgia allows pain relief at safe doses and is suggested for pharmacologically refractory trigeminal neuralgia. Higher prescribed doses were not associated with improvement in pain relief or recurrence rate.

CXCL12, CXCR4 and CXCR7 expression in brain metastases.

Brain metastases occur in about 25% of patients who die of cancer. The most common sources of brain metastases in adults are lung, breast, kidney, colorectal cancer and melanoma. The chemokine/receptor system CXCL12/CXCR4 plays a key role in multiple biological functions; among these, homing of neoplastic cells from the primary site to the target and metastasis progression. Recently, an alternative CXCL12 receptor CXCR7 has been discovered. The aim of our study was to investigate the expression of CXCL12 and its receptors CXCR4 and CXCR7 by immunohistochemistry in 56 patients with metastatic brain disease from different non-CNS primary tumors and evaluate their prognostic relevance as well as that of other patient/treatment-related features on patient survival. CXCL12 showed an expression in tumor cells and in tumor vessels; CXCR7 was expressed by tumor and endothelial cells (both within the tumor and in the adjacent brain tissue), while CXCR4 showed a positivity in all samples with a nuclear pattern. Among the investigated immunohistochemical parameters, only CXCL12 expression in tumor endothelial cells showed a statistically significant correlation with shorter survival (p = 0.04 log-rank), perhaps identifying more aggressive tumors. Thus, this is the first study evaluating at the same time the expression of CXCL12 and its two receptors in a cohort of brain metastases.

Loss of heterozygosity studies in extracranial metastatic meningiomas.

Although most meningiomas are slow-growing tumours associated with favourable prognosis, they often present local recurrence after surgical treatment; by contrast, extracranial metastatic meningiomas are rare, occurring in less than 1% of the cases. Risk factors for distal spread remain largely unknown. We report three cases with lung or bone metastases from intracranial recurrent meningiomas. Loss of heterozygosity (LOH) analysis on 1p, 9p, 10q, 14q, and 22q was conducted in available primary, recurrent and metastatic lesions, showing the same LOH pattern in the distal metastases and in the intracranial meningioma. LOH at 1p, 14q and 9p, known to be associated with increased aggressiveness, were found. The results highlight the potential clinical relevance of integrating histopathological studies with molecular genetic analysis in the follow-up of patients with different types of meningiomas.

Combined chemotherapy and radiotherapy for intracranial germinomas in adult patients: a single-institution study.

We report on our experience in the treatment of intracranial germinomas (18 pure germinomas and two germinomas with syncytiotrophoblastic giant cells) according to a strategy of radiotherapy doses and fields reduction after a neoadjuvant chemotherapy (Cisplatin-vinblastine and bleomycin combination). Radiation therapy was delivered after the completion of the third and last course of chemotherapy. For the solitary germinoma the target volume was the gross tumour volume. In the five multifocal germinoma patients the whole ventricle volume was irradiated. For the single disseminated germinoma patient we treated the whole central nervous system. The cumulative doses were 30 Gy for the pure germinomas. For the STGCs, a cumulative dose of 35 Gy was used. The median follow-up was 55 months (range 12-120). 18 patients were alive without recurrence of disease. In the two patients with STGCs the death took place 16 and 35 months after diagnosis.

Intratumoral delivery of mitoxantrone in association with 90-Y radioimmunotherapy (RIT) in recurrent glioblastoma.

Twenty-six recurrent Glioblastoma (rGBM) patients sequentially treated at the National Neurological Institute 'C Besta' were enrolled for a second surgery in order to remove recurrent tumor and to place an Ommaya reservoire to allow local delivery of chemotherapy and local pre-targeted radio-immunotherapy (RIT). All patients had partial tumor resection and 75% of them had a residual tumor mass after exeresis larger than 2 cm. After surgery all patients were managed with a second line systemic chemotherapy (PCV). Moreover the protocol scheduled two cycles of local RIT (90 Yttrium 5- 25 mCi per cycle) with a 10 week interval. Locoregional mitoxantrone chemotherapy was locally delivered as a single dose of 4 mg every 20 days. Responses to treatment were assessed by monthly neurological examination and by MRI or contrast-enhanced CT scan performed every 2 months. For the whole group of patients the PFS after second surgery at 6 and 12 months was 61% and 22%, respectively and survival after recurrence at 6, 12 and 18 months was 80%, 53% and 42%, respectively. Neither major side effects occurred systemically nor related on the place of local injections. The percentage of long-term survivors was very high: 42% of patients were still alive at 18 months. We stress the concept that the combined treatments could be more effective if delivered into a smaller residual tumor mass and probably in an adjuvant setting, before tumour recurrence.