Linear accelerator based stereotactic radiosurgery for melanoma brain metastases

Purpose: Melanoma is one of the most common malignancies to metastasize to the brain. Many patients with this disease will succumb to central nervous system (CNS) disease, highlighting the importance of effective local treatment of brain metastases for both palliation and survival of the disease. Our objective was to evaluate the outcomes associated with stereotactic radiosurgery (SRS) in the treatment of melanoma brain metastases. Materials and Methods: We retrospectively reviewed 54 patients with a total of 103 tumors treated with SRS. Twenty patients had prior surgical resection and nine patients underwent prior whole brain radiation therapy (WBRT). 71% of patients had active extracranial disease at the time of SRS. Median number of tumors treated with SRS was 1(range: 1-6) with median radiosurgery tumor volume 2.1 cm 3 (range: 0.05-59.7 cm 3 ). The median dose delivered to the 80% isodose line was 24 Gy in a single fraction. Results: The median follow-up from SRS was five months (range:1-30 months). Sixty-five percent of patients had a follow-up MRI available for review. Actuarial local control at six months and 12 months was 87 and 68%, respectively. Eighty-one percent of patients developed new distant brain metastases at a median time of two months. The six-month and 12-month actuarial overall survival rates were 50 and 25%, respectively. The only significant predictor of overall survival was surgical resection prior to SRS. Post-SRS bleeding occurred in 18% of patients and at a median interval of 1.5 months. There was only one episode of radiation necrosis with no other treatment-related toxicity. Conclusion: SRS for brain metastases from melanoma is safe and achieves acceptable local control.     

X线立体定向放射治疗脑转移瘤的疗效分析

目的观察立体定向放射手术治疗脑转移瘤的疗效。方法X线立体定向放射治疗脑转移瘤患者47例,采用10MV的直线加速器多个非共面弧旋转照射,肿瘤剂量为18～25Gy(平均22.1Gy)。40例患者在术后接受了肿瘤剂量30～40Gy的全脑放疗。结果中位生存期为11个月,1年生存率37.5%,疗后3个月的肿瘤控制率为90.7%,KPS≥70、原发肿瘤已控和无颅外转移患者的预后较好(P<0.05)。结论立体定向放射治疗脑转移瘤是安全和有效的。     

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.     

A phase I trial of concurrent sorafenib and stereotactic radiosurgery for patients with brain metastases

Journal of Neuro-Oncology - We hypothesized that sorafenib (BAY 43-9006), an oral multi-kinase inhibitor, used in combination with SRS will improve overall intracranial control. This Phase I study...     

Multimodality treatment of melanoma brain metastases incorporating stereotactic radiosurgery (SRS)

BACKGROUND: Brain metastases are a frequent complication in advanced melanoma. A 3.6 to 4.1-month median survival has been reported after treatment with whole brain radiotherapy. We performed a retrospective analysis of our institutional experience of multimodality treatment utilizing linear accelerator (Linac)-based stereotactic radiosurgery (SRS). METHODS: Forty-four melanoma patients with brain metastases underwent 66 SRS treatments for 156 metastatic foci between 1999 and 2004. Patients were treated with initial SRS if or=70, but 37 patients had active systemic metastases (Recursive Partition Analysis Class 2). Survival was calculated from the time of diagnosis of brain metastases. Minimum follow-up was 1 year after SRS. The potential role of prognostic factors on survival was evaluated including age, sex, interval from initial diagnosis to brain metastases, surgical resection, addition of whole brain radiotherapy (WBRT), number of initial metastases treated, and number of SRS treatments using Cox univariate analysis. RESULTS: The median survival of melanoma patients with brain metastases was 11.1 months (95% confidence interval [CI]: 8.2-14.9 months) from diagnosis. One-year and 2-year survivals were 47.7% and 17.7%, respectively. There was no apparent effect of age or sex. Surgery or multiple stereotactic radiotherapy treatments were associated with prolonged survival. Addition of WBRT to maintain control of brain metastases in a subset of patients did not improve survival. CONCLUSIONS: Our results suggest that aggressive treatment of patients with up to 5 melanoma brain metastases including SRS appears to prolong survival. Subsequent chemotherapy or immunotherapy after SRS may have contributed to the observed outcome.     

The treatment of recurrent brain metastases with stereotactic radiosurgery

Between May 1986 and August 1989, we treated 18 patients with 21 recurrent or persistent brain metastases with stereotactic radiosurgery using a modified linear accelerator. To be eligible for radiosurgery, patients had to have a performance status of greater than or equal to 70% and have no evidence of (or stable) systemic disease. All but one patient had received prior radiotherapy, and were treated with stereotactic radiosurgery at the time of recurrence. Polar lesions were treated only if the patient had undergone and failed previous complete surgical resection (10 patients). Single doses of radiation (900 to 2,500 cGy) were delivered to limited volumes (less than 27 cm3) using a modified 6MV linear accelerator. The most common histology of the metastatic lesion was carcinoma of the lung (seven patients), followed by carcinoma of the breast (four patients), and melanoma (four patients). With median follow-up of 9 months (range, 1 to 39), all tumors have been controlled in the radiosurgery field. Two patients failed in the immediate margin of the treated volume and were subsequently treated with surgery and implantation of 125I to control the disease. Radiographic response was dramatic and rapid in the patients with adenocarcinoma, while slight reduction and stabilization occurred in those patients with melanoma, renal cell carcinoma, and sarcoma. The majority of patients improved neurologically following treatment, and were able to be withdrawn from corticosteroid therapy. Complications were limited and transient in nature and no cases of symptomatic radiation necrosis occurred in any patient despite previous exposure to radiotherapy. Stereotactic radiosurgery is an effective and relatively safe treatment for recurrent solitary metastases and is an appealing technique for the initial management of deep-seated lesions as a boost to whole brain radiotherapy.     

First treatment for brain metastases by stereotactic radiosurgery]

Local control of brain metastases is better with first treatment by stereotactic radiosurgery than with radiosurgery for recurrence. We reported a retrospective analysis of the influence of clinical and technical factors on local control and survival after radiosurgery realised in first intention. From January 1994 to December 1997, 26 patients presenting with 43 metastases underwent radiosurgery. The median age was 61 years and the median Karnofsky index 70. Primary sites included: lung (12 patients), kidney (7 patients), breast (2 patients), colon (1 patient), melanoma (2 patients), osteosarcoma (1 patient), it was unknown for one patient. Seven patients had extracranial metastases. Twenty-one sessions of radiosurgery have been realized for one metastase, and 9 for two, three or four lesions. The median diameter was 21 mm and the median volume 1.8 cm3. The median peripheral dose to the lesion was 14 Gy, and the median dose at the isocenter 20 Gy. Forty-two metastases were evaluable for response analysis. The overall local control rate was 90.5% and the 1-year, 2- and 3-year actuarial rates were 85% and 75%. In univariate analysis, theorical radioresistance was significantly associated with better local control (100% versus 77%, p < 0.05). All patients were evaluable for survival. The median survival rate was 15 months. Four patients had a symptomatic oedema (RTOG grade II). Two lesions have required a surgical excision. In conclusion, low dose radiosurgery (14 Gy delivered at the periphery of metastasis) can be proposed in first intention for brain metastases, in particularly for theorical radioresistant lesions.     

Patient selection criteria for the treatment of brain metastases with stereotactic radiosurgery

In this study we evaluate prognostic factors that predict local-regional control and survival following stereotactic radiosurgery (SRS) in patients with brain metastasis and establish guidelines for patient selection. Our evaluation is based on 73 patients with brain metastasis treated with SRS at the University of Minnesota between March 1991 and November 1995. The ability of stereotactic radiosurgery to improve local control in patients with brain metastases is confirmed in our study in which only 6 of 62 patients failed locally after SRS, with an actuarial local progression-free survival of 80% at 2 years. Variables that predicted worse prognosis were larger tumor size (p=0.05) for local progression-free survival and multiplicity of metastasis (p=0.03) and infratentiorial location of metastases (p=0.006) for regional progression-free survival. Absence of extracranial disease, KPS 70, and single intracranial metastasis were significant predictors of longer survival. Patients who fulfill all three criteria will survive longer after SRS (MS=17.7 months) and will most likely benefit from the increase local control in the brain achieved by SRS. Survival in patients who do not meet any of these criteria is very poor (MS=1.5 months), and these patients are less likely to benefit from this treatment. Careful selection of patients for SRS is warranted.     

X射线立体定向放射治疗多发脑转移瘤的价值

目的　探讨X射线立体定向放射治疗多发脑转移瘤的疗效。方法　在 4种预后因素(年龄、治疗前卡氏评分、有无其他部位转移及转移灶数目 )相同或相似的条件下 ,配对选择两组病例。X射线立体定向放射治疗加常规放射治疗组 (研究组 )和常规放射治疗组 (对照组 )各 53例。在研究组中 ,X射线立体定向放射治疗采用单次照射 40例 ,分次照射 1 3例 ;单次靶区平均周边剂量为 2 0Gy,分次照射剂量为 4～ 1 2Gy/次 ,2次 /周 ,总剂量为 1 5～ 30Gy。X射线立体定向放射治疗结束后即开始全脑放射治疗。对照组采用全脑照射 30～ 40Gy,3～ 4周。结果　研究组和对照组中位生存期分别为1 1 .6、6 .7个月 (P <0 .0 5) ;1年生存率分别为 44 .3 %、1 7.1 % (P <0 .0 1 ) ;1年局部控制率分别为50 .9%、1 3 .2 % (P <0 .0 5) ;治疗后 1个月卡氏评分增加者分别占 69.8%、30 .2 % (P <0 .0 1 ) ;治疗后 3个月影像学上的有效率分别为 82 .0 %、55 .0 % (P <0 .0 1 )。在死因分析中 ,研究组死于脑转移的占2 3 .3 % ,比对照组的 51 .0 %低 (P <0 .0 5)。两组病例放射并发症的发生率相似。结论　对于多发脑转移瘤 ,X射线立体定向放射治疗加常规放射疗在提高局部控制率、延长生存期和提高生存质量方面均优于单纯放射治疗。     

Repeat stereotactic radiosurgery for the management of locally recurrent brain metastases

Purpose

Stereotactic radiosurgery (SRS) is a well-established treatment option for brain metastases (BM). Repeat SRS for progressive BM is an increasingly used paradigm, although little data is available to support this practice. The goal of this study was to assess the safety and efficacy of a second SRS procedure on a previously treated BM.

Methods

We performed a retrospective metastasis-level analysis of patients who underwent two SRS procedures on the same lesion and for whom at least 6 months of radiological follow-up was available. The data collected included patient characteristics, clinical symptoms at time of treatment, SRS parameters, radiological response per RANO-BM criteria, clinical evolution and survival.

Results

Seventy-five BM in 56 patients were included in the analysis. Most frequent primary histologies were non-small-cell lung cancer (59%) and breast cancer (19%). At the second SRS, median treatment volume was 1.19 cc (range 0.07–20.6) treated with a median margin dose of 18 Gy (range 12–20) at the 50% isodose line (range 30–80%). Median follow-up was 11 months. Progression per RANO-BM criteria occurred in 31%, yielding actuarial local control at 1, 2, and 5 years of 68%, 54% and 54% respectively. At last follow-up, 10 patients (18%) had improved relative to the initial presentation, while 21 (38%) were stable and 25 (44%) were deteriorated. Radiation-induced edema and radionecrosis occurred in 8.3% and 5% respectively. The median survival from the diagnosis of BM was 30 months.

Conclusion

Repeat SRS is a safe and effective novel therapeutic approach to consider in carefully selected patients.

     

Role of stereotactic radiosurgery in the treatment of brain metastases

Stereotactic radiosurgery (SRS) is a highly conformal form of radiation therapy designed to deliver a high dose in a single treatment to the target volume while sparing adjacent normal tissues. Its role in the treatment of brain metastases continues to be defined, but the recently reported RTOG 95-08 trial demonstrated a survival benefit with the addition of SRS to whole-brain radiation therapy in select patients with a single brain metastasis, as well as a local control and palliative benefit in select patients with 1 to 3 brain metastases. The authors review the role of SRS in the treatment of brain metastases and discuss the use of SRS with or without whole-brain radiation therapy, optimal dose of SRS, SRS delivery methods, and selection of appropriate patients for SRS.     

Lymphopenia predicts response to stereotactic radiosurgery in lung cancer patients with brain metastases

Journal of Neuro-Oncology - Intracranial glioblastomas with simultaneous spinal lesions prior to chemoradiation therapy or craniotomy, defined as initial spinal metastasis, are not well understood....     

Integration of immuno-oncology with stereotactic radiosurgery in the management of brain metastases

Journal of Neuro-Oncology - Brain metastases traditionally carried a poor prognosis with treatment being a combination of surgery, whole-brain radiation therapy, and glucocorticoids; however, this...     

Hypofractionated stereotactic radiotherapy as an alternative to radiosurgery for the treatment of patients with brain metastases

PURPOSE: Modeling studies have demonstrated a potential biologic advantage of fractionated stereotactic radiotherapy for malignant brain tumors as compared to radiosurgery (SRS), even when only a few fractions are utilized. We prospectively evaluated the feasibility, toxicity, efficacy and cost of hypofractionated stereotactic radiotherapy (HSRT) in the treatment of selected radiosurgery-eligible patients with brain metastases. METHODS AND MATERIALS: Patients with a limited number of brain metastases not involving the brainstem or optic chiasm underwent linac-based HSRT delivered in 3 fractions using a relocatable stereotactic frame. Depth-helmet and reference point measurements were recorded to address treatment accuracy. All patients underwent whole brain radiotherapy to a dose of 30 Gy. Toxicity, response, and survival duration were recorded for each patient. Prognostic factors were assessed by Cox regression analysis. Cost comparisons with a cohort of SRS treated patients were performed. RESULTS: Thirty-two patients with 57 brain metastases were treated with HSRT. Twenty-three and 9 patients underwent HSRT for upfront and salvage treatment, respectively. The median dose delivered was 27 Gy, given in 3 fractions of 9 Gy. From 3328 depth-helmet measurements, the absolute median setup deviation in AP, lateral, and vertical orientations was approximately 1.0 mm. No significant acute toxicity was seen. Late toxicities included seizures in four patients, and radionecrosis in two patients. The median survival duration from treatment was 12 months. KPS (p = 0.039) and RTOG-RPA class (p = 0.039) were identified as significant prognostic factors for survival. HSRT was $4119 less costly than SRS. CONCLUSION: HSRT, as delivered in this study, is more comfortable for patients and less costly than SRS in the treatment of selected patients with brain metastases. Proper dose selection and radiobiologic/toxicity trade-offs with SRS await further study.     

Hypofractionated stereotactic radiosurgery for pituitary metastases

Pituitary metastases (PMs) are uncommon, representing only 1% of pituitary lesions. The diagnosis of PMs can be challenging and an optimal management remains to be determined. Here, we present a pilot clinical study on the efficacy and safety of hypofractionated stereotactic radiosurgery (SRS) with an optimized dosimetric plan in treating PMs. Between June 2013 and December 2014, seven consecutive patients (4 men and 3 women; median age 62 years) had been diagnosed with PMs based on their characteristic clinical and radiological features and subsequently treated using hypofractionated SRS. Primary cancers originated from the lung (n?=?5) or the breast (n?=?2). All patients presented with diabetes insipidus (DI). Anterior pituitary and visual dysfunction were combined in 4 and 3 patients, respectively. On magnetic resonance imaging (MRI), PMs involved the pituitary stalk and/or the posterior lobe in all patients. SRS of a cumulative marginal dose 31 Gy with dose-volume constraints for the optic apparatus was delivered in 5 daily fractions. As results, tumor was locally controlled in all patients with substantial responses on MRI (including complete remission in 4 patients). The median survival time was 14 months (range, 6–24 months) after SRS. DI and visual dysfunction improved in all patients, although anterior pituitary dysfunction did not recover. No patients experienced any deterioration in visual, pituitary, or other cranial nerve functions. These results suggest a promising role of hypofractionated SRS in treating PMs in terms of both tumor control and functional outcomes.     

Incidence and characteristics of melanoma brain metastases developing during treatment with vemurafenib

Vemurafenib is indicated for the treatment of patients with BRAF ^V600 -mutant metastatic melanoma. We studied for the first time the characteristics of brain metastases developed during treatment with vemurafenib in real-life conditions. We included all patients treated over 3 years with vemurafenib in our department for metastatic melanoma without initial brain involvement. Our primary endpoint was to assess the incidence of brain metastases in these patients. Our secondary endpoints were to identify the risk factors for metastases occurrence and their characteristics and course. In our retrospective cohort of 86 patients, 20 % had developed brain metastases on average 5.3 months after vemurafenib initiation. The median follow-up was 9 months (1–26 months). Radiological examinations revealed multiple brain metastases in 41 % of patients. The only risk factor for metastasis occurrence identified was a high number of metastatic sites when initiating vemurafenib (p = 0.045). Metastasis development was associated with a trend toward a decrease in overall survival from 12.8 to 8.5 months (p = 0.07) and a significant decrease in progression-free survival from 7 to 5 months (p = 0.04). Among the patients who developed brain metastases, 82 % died, of whom 64 % within 3 months, versus 58 % of patients without brain metastases over the same period. The extra-cerebral disease was well controlled in 59 % of patients during brain progression. In vemurafenib-treated melanoma patients, brain metastases are frequent and associated with a particularly poor prognosis. Because of their high frequency in patients with controlled extra-cerebral disease, brain explorations should be systematically performed during treatment.     

Leptomeningeal disease following stereotactic radiosurgery for brain metastases from breast cancer

Leptomeningeal disease (LMD) is a highly aggressive and usually rapidly fatal condition. The purpose of this study is to identify clinical factors that can serve to predict for LMD at the time of stereotactic radiosurgery (SRS) for brain metastases from breast carcinoma. We conducted a retrospective review of patients with brain metastases from breast cancer treated with SRS from 1995 to 2014 at our institution. Clinical, radiographic, and dosimetric data were collected. LMD was diagnosed by cerebrospinal fluid (CSF) cytology or MRI demonstrating CSF seeding. Comparative statistical analyses were conducted using Cox proportional hazards regression, binary logistic regression, and/or log-rank test. 126 patients met inclusion criteria. Eighteen patients (14 %) developed LMD following SRS. From the time of SRS, the actuarial rate of LMD at 12 months from diagnosis of brain metastasis was 9 % (11 patients). Active disease in the chest at the time of SRS was associated with development of LMD (p = 0.038). Factors including receptor status, tumor size, number of intra-axial tumors, cystic tumor morphology, prior WBRT, active bone metastases, and active liver metastases were not significantly associated with the development of LMD. In patients with brain metastasis from breast cancer that undergo SRS, there is a relatively low rate of LMD. We found that while tumor hormonal status, bone metastases, and hepatic metastases were not associated with the development of LMD, active lung metastases at SRS was associated with LMD. Further research may help to delineate a causative relationship between metastatic lung disease and LMD.

     

Health-related quality of life of patients with brain metastases selected for stereotactic radiosurgery

Journal of Neuro-Oncology - Preclinical studies have suggested promising activity for the combination of disulfiram and copper (DSF/Cu) against glioblastoma (GBM) including re-sensitization to...