Stereotactic radiotherapy and radiosurgery for non-functioning and secreting pituitary adenomas.

Radiotherapy (RT) is frequently employed in patients with residual or recurrent pituitary adenoma with excellent rates of tumor control and remission of hormonal hypersecretion. Advances in RT have improved with the use of stereotactic techniques either as fractionated stereotactic radiotherapy (FSRT) or stereotactic radiosurgery (SRS), all aiming to improve the dose distribution to the tumor while reducing the amount of normal brain receiving significant doses of radiation. We provide an overview of the recent published literature on the long-term efficacy and adverse effects of stereotactic irradiation in nonfunctioning and secreting pituitary adenomas. Both techniques are associated with excellent clinical outcomes; however, advantages and drawbacks of each of these techniques in terms of local control, hormonal excess normalization, and radiation-induced toxicity remain a matter of debate. In clinical practice, single-fraction SRS may represent a convenient approach to patients with small and medium-sized pituitary adenoma away at least 2 mm from the optic chiasm, whereas FSRT is preferred over SRS for lesions >2.5-3 cm in size and/or involving the anterior optic pathway.

Single-Fraction Versus Multifraction (3 × 9 Gy) Stereotactic Radiosurgery for Large (>2 cm) Brain Metastases: A Comparative Analysis of Local Control and Risk of Radiation-Induced Brain Necrosis.

PURPOSE: To investigate the local control and radiation-induced brain necrosis in patients with brain metastases >2 cm in size who received single-fraction or multifraction stereotactic radiosurgery (SRS); factors associated with clinical outcomes and the development of brain radionecrosis were assessed. METHODS AND MATERIALS: Two hundred eighty-nine consecutive patients with brain metastases >2.0 cm who received SRS as primary treatment at Sant'Andrea Hospital, University of Rome Sapienza, Rome, Italy, were analyzed. Cumulative incidence analysis was used to compare local control and radiation-induced brain necrosis between groups from the time of SRS. To achieve a balanced distribution of baseline covariates between treatment groups, a propensity score analysis was used. RESULTS: The 1-year cumulative local control rates were 77% in the single-fraction SRS (SF-SRS) group and 91% in the multifraction SRS (MF-SRS) group (P=.01). Recurrences occurred in 25 and 11 patients who received SF-SRS or MF-SRS (P=.03), respectively. Thirty-one patients (20%) undergoing SF-SRS and 11 (8%) subjected to MF-SRS experienced brain radionecrosis (P=.004); the 1-year cumulative incidence rate of radionecrosis was 18% and 9% (P=.01), respectively. Significant differences between the 2 groups in terms of local control and risk of radionecrosis were maintained after propensity score adjustment. CONCLUSIONS: Multifraction SRS at a dose of 27 Gy in 3 daily fractions seems to be an effective treatment modality for large brain metastases, associated with better local control and a reduced risk of radiation-induced radionecrosis as compared with SF-SRS.

Repeated stereotactic radiosurgery for patients with progressive brain metastases.

In the present study we have evaluated the efficacy and toxicity of repeated stereotactic radiosurgery (SRS) in patients with recurrent/progressive brain metastases. Between March 2006 and October 2014, 43 patients (21 men and 22 women) with 47 lesions received a second course of SRS given in three daily fractions of 7-8 Gy. With a follow-up study of 19 months, the 1- and 2-year survival rates from repeated SRS were 37 and 20%, respectively, and the 1- and 2-year local control rates were 70 and 60%, respectively. Actuarial local control was significantly better for breast and lung metastases as compared with melanoma metastases; specifically, 1-year local control rates were 38% for melanoma, 78% for breast carcinoma and 73% for non-small cell lung cancer (NSCLC) metastases (p = 0.01). The cause of death was progressive systemic disease in 25 patients and progressive brain disease in 11 patients. Stable extracranial disease (p = 0.01) and Karnofsky performance status (KPS; p = 0.03) were predictive of longer survival. Radiologic changes suggestive of brain radionecrosis were observed in 9 (19%) out of 47 lesions, with an actuarial risk of 34% at 12 months. Neurological deficits (RTOG Grade 2 or 3) associated with brain necrosis occurred in 14% of patients. In conclusion, a second course of SRS given in three daily fractions is a feasible treatment for selected patients with recurrent/progressive brain metastases. Further studies are needed to explore the efficacy and safety of different dose-fractionation schedules, especially in patients with melanoma or large metastases.

Stereotactic Ablative Body Radiotherapy (SABR) in Pulmonary Oligometastatic/Oligorecurrent Non-small Cell Lung Cancer Patients: A New Therapeutic Approach.

AIM: Stage IV non-small cell lung cancer (NSCLC) is characterized by poor prognosis. Palliative chemotherapy and/or best supportive care are considered standard treatment. Nevertheless, for patients with limited distant metastases (1-5 metastases), called oligometastatic disease, better prognosis has been observed. We evaluated response rate, survival, time to progression and toxicity in oligometastatic/oligorecurrent NSCLC patients treated with stereotactic body radiotherapy (SBRT) delivered to all active sites in the lung. PATIENTS AND METHODS: Twenty-nine lung metastases in 22 patients affected by oligometastatic/oligorecurrent NSCLC were treated with SBRT to all active sites of disease. Inclusion criteria were: controlled primary tumor with complete response or stable disease after surgery/radiotherapy/combined therapy; ≤4 synchronous or metachronous lung metastases at the time of treatment; no other active sites of distant metastases. RESULTS: Response to treatment was as follows: complete response in 21% of lesions, partial response in 69% of metastases, stable disease in 10%. Ninenty-one percent of patients had complete metabolic response, and 9% had a partial metabolic response. Median follow-up was 18 months. The 1-year and 2-year OS was 86% and 49%, respectively. The 1-year and 2-year PFS was 79% and 40%, respectively. Median time to progression and median OS were 18 months and 24 months, respectively. Local control was 93% at 1 year and 64% at 2 years. Overall, acute toxicity occurred in 18% (4/22) of patients; two patients experienced grade 2 pneumonitis. Grade ≤2 late toxicity occurred in 50% of patients. No grade ≥3 toxicities were recorded. CONCLUSION: Aggressive stereotactic radiotherapy is a feasible and well-tolerated treatment for oligometastatic/oligorrecurrent NSCLC patients with lung metastases offering longer survival. Ablative radio therapy has a potential role in the management of well-selected stage IV NSCLC patients while increasing their quality of life and survival.

Hypofractionated Image-guided Radiation Therapy (3Gy/fraction) in Patients Affected by Inoperable Advanced-stage Non-small Cell Lung Cancer After Long-term Follow-up.

BACKGROUND: We conducted long-term follow-up analysis of the outcomes for patients affected by advanced-stage non-small cell lung cancer (NSCLC) treated with hypofractionated radiotherapy (RT). MATERIALS AND METHODS: Sixty patients with advanced-stage NSCLC (IIIA-IV) treated with hypofractionated radiotherapy (60Gy/20 fractions) were analyzed. Radiation was delivered using an image-guided RT technique to verify the correct position. Toxicities were graded according to the Common Toxicity Criteria for Adverse Effects v4.0 scale. RESULTS: Overall, six patients achieved a complete response and 46 patients had a partial response (tumor response rate 86%). After a median follow-up of 30 months, locoregional progression occurred in 23 patients and distant progression occurred in 38. The 1-year and 2-years overall survival were 57% and 40%, respectively. The 1-year and 2-years progression-free survival (PFS) were 47.1% and 33.5%, respectively. The median duration of OS and PFS was 13 months and 12 months, respectively. The 2-year local PFS and metastases-free survival (MFS) were 53% and 40.3%, respectively. On univariate analysis, the T-size (≥5 cm), and type of response to RT (non-response/progressive disease) were significantly associated with worse OS. Type of response was identified as significant prognostic factors for PFS (p<0.01) local PFS (p=0.015) and MFS (p<0.01). Acute grade 3 esophagitis and pneumonitis occurred in three patients (5%) and four patients (6%), respectively. Late grade 3 esophagitis and pneumonitis occurred in 2% (one patient) and 3% (two patients), respectively. No patient experienced grade 4 acute or late RT-related toxicities. CONCLUSION: Hypofractionated RT offers good disease control for patients with advanced-stage NSCLC with acceptable toxicity rates. Phase III randomized trials are necessary to compare hypofractionated RT with conventional RT.

Stereotactic Body Radiation Therapy for Liver Lesions. A Single-institution Experience.

AIM: To evaluate survival and toxicity in a cohort of patients treated with stereotactic body radiation therapy (SBRT) for unresectable intrahepatic malignancies. PATIENTS AND METHODS: From 2007 to 2014, 23 patients with 34 lesions (three primary and 31 metastatic liver tumors) were treated with SBRT. RESULTS: The median follow-up was 9 months (range=1-76) for all patients. Local control was reached in 27 out of 34 (79%) treated lesions, with 1 and 2 years rates of 93% and 73%, respectively. The progression-free survival at 1-year and 2-year was 50% and 25%, respectively. Median overall survival was 16 months (95% confidence interval=8-24 months), with 1-year and 2-year rates of 58% and 41%, respectively. Toxicity was very low consisting mainly of grade 1 and 2 events. CONCLUSION: SBRT provides good local control for both primary and metastatic liver lesions, with minimal toxicity.

Multifraction radiotherapy for palliation of painful bone metastases: 20 Gy versus 30 Gy.

AIMS AND BACKGROUND: To compare 2 multifraction radiotherapy schedules in the palliation of painful bone metastases. METHODS AND STUDY DESIGN: We retrospectively analyzed clinical data of 105 patients with a total of 140 painful bone metastases who were treated with 20 Gy in 5 fractions or 30 Gy in 10 fractions. The primary tumors were breast (30%), lung (28%), and prostate (14%). The main sites of irradiation were spine (n = 79) and sacrum or pelvis (n = 39). Pain was graded by patients according to the pain numeric rating scale just before and 1 month after radiotherapy. Pain progression was defined as an increase ≥2 on pain scale after an initial response. RESULTS: The overall response rate at 1 month was 88.6%. Overall response rate was 89.6% in the 20-Gy arm and 87.3% in the 30-Gy arm (p = 0.669). The rate of complete response was statistically better in patients treated with 30 Gy (p = 0.019). The mean reduction in pain was 3.2 in the 20-Gy group and 3.6 in the 30-Gy group. Pain progression was 6.5% and 1.6%, respectively. The incidence of acute toxicity was statistically significantly higher in the 30-Gy arm (23.8%) than in the 20-Gy arm (2.6%) (p = 0.001). One pathologic fracture of the irradiated bone was observed in the 30-Gy arm. Two lesions, one in each group, were re-irradiated for pain recurrence. Pain progression was found in 6.5% of the irradiated lesions in the 20-Gy arm and in 1.6% in the 30-Gy arm. CONCLUSIONS: In our series, both regimens achieved high rate of pain relief, although the group treated with higher total dose reported better complete response rate. The 30-Gy arm had a significantly higher rate of acute toxicity.

Radiation-induced malignant meningioma following proton beam therapy for a choroidal melanoma.

We report a woman with malignant meningioma diagnosed 9 years after the treatment of a choroidal melanoma with proton beam therapy. The risk of secondary cancers is a well-known adverse late effect of radiation therapy, especially with the use of advanced techniques such as intensity-modulated radiation therapy. However, this risk may be less with the use of proton beam therapy. A 79-year-old woman presented with symptoms of enophthalmos, ptosis and paralysis of the left medial rectus muscle. She had previously been successfully treated for a choroidal melanoma of the left eye with proton beam therapy (total dose: 60 cobalt gray equivalents) following local resection. MRI showed a lesion in the left cavernous sinus with extension into the orbit and a subsequent biopsy revealed a papillary meningioma. The cavernous tumor was treated with photon radiotherapy (total dose: 54Gy) which achieved an initial partial response. However, 8 months later the tumor extensively metastasized to the skull and the spine and the patient died 1 year after the treatment. The incidence of secondary malignancies after proton beam therapy is low but not negligible, therefore, it must be taken into account when planning a treatment as secondary tumors may present with a highly aggressive behaviour.

Role of salvage stereotactic body radiation therapy in post-surgical loco-regional recurrence in a selected population of non-small cell lung cancer patients.

AIM: This is a retrospective analysis of a selected series of high-risk non-small cell lung cancer (NSCLC) patients with post-surgical loco-regional relapse treated with salvage stereotactic body radiotherapy (SBRT). Outcome and toxicity profiles were assessed. PATIENTS AND METHODS: Twenty-eight patients (unfit for surgery or systemic therapy) with 30 lesions underwent salvage SBRT as an alternative therapy because of advanced age, co-morbid conditions or no response obtained from other treatments. RESULTS: Complete and partial responses were 16% and 70%, respectively. Local progression was observed in 3 patients. Regional relapse occurred in 5 patients. Distant progression occurred in 10 patients. The 2-year overall survival (OS) and disease-free survival (DFS) were 57.5% and 36.6%, respectively. Radiation acute pneumonitis occurred as follows: three patients developed grade 1, two patients experienced grade 2 and one patient experienced grade 3 toxicity. CONCLUSION: Stereotactic body radiotherapy could have an alternative role in isolated loco-regional relapse in patients unfit or resistant to other therapies.

Hypofractionated stereotactic radiotherapy in combination with bevacizumab or fotemustine for patients with progressive malignant gliomas.

To evaluate the efficacy of hypofractionated stereotactic radiotherapy performed as reirradiation in combination with fotemustine or bevacizumab as salvage treatment in patients with recurrent malignant glioma. Between May 2006 and December 2013, 54 patients with recurrent malignant glioma received hypofractionated stereotactic radiotherapy (HSRT, 25 Gy in 5-Gy fractions) plus either fotemustine or bevacizumab at University of Rome Sapienza, Sant'Andrea Hospital. All patients had Karnofsky performance score (KPS) ≥ 60 and were previously treated with standard chemoradiotherapy. Forty-two patients had a GBM and 12 patients had an anaplastic astrocytoma (AA). The median overall survival (OS) time and 12-month OS rates after HSRT was 11 months and 30 % for patients treated with HSRT plus bevacizumab and 8.3 months and 5 % for those treated with HSRT plus fotemustine (p = 0.01). Median PFS times were 4 and 6 months for patients treated with HSRT plus fotemustine or bevacizumab, respectively (p = 0.01). KPS > 70 (p = 0.04), AA histology, and the treatment with bevacizumab were independent favourable prognostic factors for OS. In general, both treatments were well tolerated with relatively low treatment-related toxicity. HSRT combined with bevacizumab or fotemustine may represent a feasible treatment option for patients with progressive malignant gliomas, although most of the tumors recur in a few months. Efficacy of bevacizumab or alkylating agents in combination with different radiation schedules needs to be evaluated in prospective studies.

Fractionated stereotactic radiotherapy for large and invasive non-functioning pituitary adenomas: long-term clinical outcomes and volumetric MRI assessment of tumor response.

OBJECTIVE: We describe the use of fractionated stereotactic radiotherapy (FSRT) for the treatment of large, invasive, nonfunctioning pituitary adenomas (NFPAs). FSRT is frequently employed for the treatment of residual or recurrent pituitary adenomas. PATIENTS AND METHODS: Sixty-eight patients with a large residual or recurrent NFPAs were treated between April 2004 and December 2012, including 39 males and 29 females (median age 51 years). Visual defects were present in 34 patients, consisting of visual field defects (n=31) and/or reduced visual acuity (n=12). Forty-five patients had evidence of partial or total hypopituitarism before FSRT. For most of the patients, the treatment was delivered through 5-10 noncoplanar conformal fixed fields using a 6-MV linear accelerator to a dose of 45 Gy in 25 fractions. RESULTS: At a median follow-up of 75 months (range 12-120 months), the 5- and 10-year actuarial local control were 97 and 91%, respectively, and overall survival 97 and 93%, respectively. Forty-nine patients had a tumor reduction, 16 remained stable, and three progressed. The relative tumor volume reduction measured using three-dimensional (3D) magnetic resonance imaging (MRI) was 47%. The treatment was well tolerated with minimal acute toxicity. Eighteen patients developed partial or complete hypopituitarism. The actuarial incidence of new anterior pituitary deficits was 40% at 5 years and 72% at 10 years. No other radiation-induced complications occurred. CONCLUSIONS: Our results suggest that FSRT is an effective treatment for large or giant pituitary adenomas with low toxicity.

Standard (60 Gy) or short-course (40 Gy) irradiation plus concomitant and adjuvant temozolomide for elderly patients with glioblastoma: a propensity-matched analysis.

PURPOSE: To evaluate 2 specific radiation schedules, each combined with temozolomide (TMZ), assessing their efficacy and safety in patients aged ≥65 years with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS: Patients aged ≥65 years with Karnofsky performance status (KPS) ≥60 who received either standard (60 Gy) or short-course (40 Gy) radiation therapy (RT) with concomitant and adjuvant TMZ between June 2004 and October 2013 were retrospectively analyzed. A propensity score analysis was executed for a balanced comparison of treatment outcomes. RESULTS: A total of 127 patients received standard RT-TMZ, whereas 116 patients underwent short-course RT-TMZ. Median overall survival and progression-free survival times were similar: 12 months and 5.6 months for the standard RT-TMZ group and 12.5 months and 6.7 months for the short-course RT-TMZ group, respectively. Radiation schedule was associated with similar survival outcomes in either unadjusted or adjusted analysis. O(6)-methylguanine-DNA methyltransferase promoter methylation was the most favorable prognostic factor (P=.0001). Standard RT-TMZ therapy was associated with a significant rise in grade 2 and 3 neurologic toxicity (P=.01), lowering of KPS scores during the study (P=.01), and higher posttreatment dosing of corticosteroid (P=.02). CONCLUSIONS: In older adults with GBM, survival outcomes of standard and short-course RT-TMZ were similar. An abbreviated course of RT plus TMZ may represent a reasonable therapeutic approach for these patients, without loss of survival benefit and acceptable toxicity.

Radiation therapy for older adults with glioblastoma: radical treatment, palliative treatment, or no treatment at all?

The incidence of glioblastoma in older adults has increased over the last few decades. Current treatment includes surgery, radiotherapy, and chemotherapy, but optimal disease management remains a matter of debate. Both standard (60 Gy in 30 daily fractions) and hypofractionated radiotherapy (30-40 Gy in 10-15 daily fractions) have been employed with a similar survival benefit. Recent randomized studies indicate that chemotherapy with the alkylating agent temozolomide is a safe and effective therapeutic option for patients aged 60 years or older with newly diagnosed glioblastoma, suggesting that it should be a sufficient treatment for patients presenting with a methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter gene. The addition of concomitant temozolomide chemotherapy, adjuvant temozolomide chemotherapy, or both to postoperative radiotherapy, which is the standard treatment for adults with glioblastoma, has been associated with a survival benefit for older patients with a good performance status; however, aggressive treatment in this population may be associated with a high risk of neurological toxicity and deterioration of quality of life. Survival stratification according to age, MGMT promoter methylation status, and neurological status may be useful for clinical decision making and designing randomized trials for adequately evaluating the optimal combination of radiotherapy and chemotherapy for older patients with glioblastoma.

Fractionated stereotactic radiosurgery for patients with skull base metastases from systemic cancer involving the anterior visual pathway.

BACKGROUND: To analyze the tumor control, survival outcomes, and toxicity after stereotactic radiosurgery (SRS) for skull base metastases from systemic cancer involving the anterior visual pathway. PATIENTS AND METHODS: We have analyzed 34 patients (23 females and 11 males, median age 59 years) who underwent multi-fraction SRS for a skull base metastasis compressing or in close proximity of optic nerves and chiasm. All metastases were treated with frameless LINAC-based multi-fraction SRS in 5 daily fractions of 5 Gy each. Local control, distant failure, and overall survival were estimated using the Kaplan-Meier method calculated from the time of SRS. Prognostic variables were assessed using log-rank and Cox regression analyses. RESULTS: At a median follow-up of 13 months (range, 2-36.5 months), twenty-five patients had died and 9 were alive. The 1-year and 2-year local control rates were 89% and 72%, and respective actuarial survival rates were 63% and 30%. Four patients recurred with a median time to progression of 12 months (range, 6-27 months), and 17 patients had new brain metastases at distant brain sites. The 1-year and 2-year distant failure rates were 50% and 77%, respectively. On multivariate analysis, a Karnofsky performance status (KPS) >70 and the absence of extracranial metastases were prognostic factors associated with lower distant failure rates and longer survival. After multi-fraction SRS, 15 (51%) out of 29 patients had a clinical improvement of their preexisting cranial deficits. No patients developed radiation-induced optic neuropathy during the follow-up. CONCLUSIONS: Multi-fraction SRS (5 x 5 Gy) is a safe treatment option associated with good local control and improved cranial nerve symptoms for patients with a skull base metastasis involving the anterior visual pathway.

Cytokines, fatigue, and cutaneous erythema in early stage breast cancer patients receiving adjuvant radiation therapy.

We investigated the hypothesis that patients developing high-grade erythema of the breast skin during radiation treatment could be more likely to present increased levels of proinflammatory cytokines which may lead, in turn, to associated fatigue. Forty women with early stage breast cancer who received adjuvant radiotherapy were enrolled from 2007 to 2010. Fatigue symptoms, erythema, and cytokine levels (IL-1ß, IL-2, IL6, IL-8, TNF-α, and MCP-1) were registered at baseline, during treatment, and after radiotherapy completion. Seven (17.5%) patients presented fatigue without associated depression/anxiety. Grade ≥2 erythema was observed in 5 of these 7 patients. IL-1ß, IL-2, IL-6, and TNF-α were statistically increased 4 weeks after radiotherapy (P < 0.05). After the Heckman two-step analysis, a statistically significant influence of skin erythema on proinflammatory markers increase (P = 0.00001) was recorded; in the second step, these blood markers showed a significant impact on fatigue (P = 0.026). A seeming increase of fatigue, erythema, and proinflammatory markers was observed between the fourth and the fifth week of treatment followed by a decrease after RT. There were no significant effects of hormone therapy, breast volume, and anemia on fatigue. Our study seems to suggest that fatigue is related to high-grade breast skin erythema during radiotherapy through the increase of cytokines levels.

Whole brain reirradiation and concurrent temozolomide in patients with brain metastases.

A second course of whole brain radiation therapy (WBRT) has been employed in selected patients with progressive brain metastases providing favorable symptomatic palliation with acceptable toxicity, although its efficacy and safety remain matter of debate. In the present study we have evaluated the outcomes in patients with progressive intracranial disease treated with WBRT reirradiation and concurrent temozolomide between October 2010 and May 2013. Data were obtained from a prospectively maintained database including patients with brain tumors treated with radiotherapy at Sant'Andrea Hospital. We identified 27 patients (10 males and 17 females) with a median age of 54 years who received WBRT reirradiation at a dose of 25 Gy in ten fractions plus concomitant daily temozolomide administered orally at a dose of 75 mg/m(2). At the time of repeat WBRT all patients had a KPS ≥ 60. The primary disease sites were lung (n = 18) and breast (n = 9). The median overall survival after the second course of WBRT was 6.2 months and the median time to progression was 5.5 months. Eight patients experienced complete resolution of symptoms, 9 patients had a significant improvement, and 6 patients had no change in their neurologic function. Four patients had further deterioration after reirradiation. Overall, 85 % of patients improved or maintained their neurologic status. No severe acute toxicity during or after the second course of WBRT reirradiation was observed. On multivariate analysis with the Cox proportional hazards model, stable or absent extracranial metastases (p = 0.005) and response to treatment (p = 0.01) were independent favorable prognostic factors for survival. The median and 12-month survival rates were 12 months and 50 % in patients with stable or absent extracranial disease and 4.6 months and 7 % in those with progressive extracranial disease (p = 0.001). In conclusion, in the respect to the small number of treated patients, repeat WBRT plus concomitant temozolomide may be a treatment option in selected patients with multiple brain metastases to improve or maintain neurological conditions and quality of life with acceptable toxicity. The favorable effects of concomitant temozolomide on survival remain unclear.

IDH1 mutation and MGMT methylation status predict survival in patients with anaplastic astrocytoma treated with temozolomide-based chemoradiotherapy.

Several molecular markers have been proposed as predictors of outcome in patients with high grade gliomas. We report a retrospective multicenter study of 97 consecutive adult patients with anaplastic astrocytoma (AA) treated with radiation therapy (RT) plus concomitant and adjuvant temozolomide (TMZ) between October 2004 and March 2012. Correlations between the isocitrate dehydrogenase 1 (IDH1) mutation and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation with survival outcomes have been analyzed. At a median follow-up time of 46 months (range 12-89 months), median and 5-year overall survival rates were 50.5 months (95 % CI, 37.8-63.2) and 38% (95 % CI, 25.7-50.7%), and median and 5-year progression-free survival rates were 36 months (95% CI, 28.5-44.0) and 22 % (95 % CI, 10-34%), respectively. IDH1 mutation and MGMT promoter methylation were present in 54 and 60% of evaluable patients, respectively. Multivariate Cox proportional hazards regression analysis showed that IDH1 mutation (P = 0.001), MGMT methylation (P = 0.01), age < 50 years (P = 0.02), and extent of resection (P = 0.04) were significantly associated with longer survival. Our study confirms the favorable prognostic value of IDH1 mutation and MGMT methylation in patients with AA treated with RT plus concomitant and adjuvant TMZ. The superiority of combined radiochemotherapy over other treatment modalities remains to be demonstrated.

Fractionated stereotactic radiosurgery for patients with brain metastases.

Stereotactic radiosurgery (SRS) delivered in 2-5 fractions (multi-fraction SRS) has been employed in patients with brain metastases as an alternative to single-fraction SRS with the aim to reduce late radiation-induced toxicity while maintaining high local control rate. In the present study we have evaluated the efficacy and toxicity of multi-fraction SRS in patients with 1-3 brain metastases. Between March 2006 and October 2012, 135 patients (63 men and 72 women) with 171 brain metastases have been treated with multi-fraction SRS (3 × 9 Gy or 3 × 12 Gy). At a median follow-up of 11.4 months, 16 lesions recurred locally. The 1- and 2-year local control rates were 88 and 72 %, respectively. The 1- and 2-year survival rates were 57 and 25 %, and respective distant failure rates were 52 and 73 %. Seventy-eight percent of patients succumbed to their extracranial disease and 22 % died of progressive intracranial disease. Multivariate analysis showed that melanoma histology was predictive of local failure (p = 0.02; HR 6.1, 95 % CI 1.5-24). Specifically, the 1-year local control rates were 68 % for melanoma, 92 % for breast carcinoma, and 88 % for NSCLC, respectively. Stable extracranial disease (p = 0.004) and Karnofsky performance status (p = 0.01) were predictive of longer survival. Radiologic changes suggestive of radionecrosis occurred in 12 (7 %) out of 171 lesions, with an actuarial risk of 9 % at 1 year and 17 % at 2 years, respectively. In conclusion, multi-fraction SRS appears to be an effective and safe treatment modality for brain metastases. It may represent an alternative to single-dose SRS for patients with large lesions or lesions located near critical structures.

Chemoradiation for anaplastic oligodendrogliomas: clinical outcomes and prognostic value of molecular markers.

Combination of procarbazine, lomustine and vincristine (PCV) with radiation therapy (RT) has been associated with longer survival in patients with anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA), especially in those with chromosome 1p/19q codeletion. We report a multicenter retrospective study of 84 consecutive adult patients with AO and AOA treated with RT plus concomitant and adjuvant temozolomide (TMZ) between February 2004 and January 2011. Correlations between chromosome 1p/19q codeletion, isocitrate dehydrogenase1 (IDH1) mutation, and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation with survival outcomes have been analyzed. For all 84 patients the median overall survival (OS) and progression-free survival rates were 55.6 and 45.2 months, respectively. Grade 3 or 4 hematological toxicity occurred in 17 % of patients. Chromosome 1p/19q codeletion was detected in 57 %, IDH1 mutation in 63 %, and MGMT promoter methylation in 74 % of evaluable patients. In multivariate analysis the presence of chromosome 1p/19q codeletion was associated with significant survival benefit (median OS 34 months in noncodeleted tumors and not reached in codeleted tumors; HR 0.16, 95 % CI 0.03-0.45; P = 0.005). IDH1 mutation was also of prognostic significance for longer survival (P = 0.001; HR 0.20, 95 % 0.06-0.41), whereas MGMT promoter methylation was only of borderline significance. The study indicates that RT with concomitant and adjuvant TMZ is a relatively safe treatment associated with longer survival in patients with 1p/19q codeleted and IDH1 mutated tumors. Results from ongoing randomized studies will be essential to clarify if RT plus TMZ may provide survival as good as or better than RT combined with PCV for patients with AO and AOA.