Cerebral arteriovenous malformations: issues of the interplay between stereotactic radiosurgery and endovascular surgical therapy.

Intracranial arteriovenous malformations (AVMs) are congenital lesions frequently diagnosed as a result of hemorrhage or other neurological symptoms. Prevention of such devastating neurological injury has promoted a variety of treatment strategies. The rich history of multimodal therapy in the treatment of AVMs includes microsurgery, endovascular embolization, and stereotactic radiosurgery (SRS). This article reviews the biology and natural history of AVMs, as well as their treatment with both SRS and endovascular neurosurgery. It considers various paradigms and goals of endovascular treatment, along with relevant issues such as the features of an AVM to be targeted. Issues of the interplay between SRS and endovascular neurosurgery include the compartments of an embolized AVM to contain within the radiosurgery plan, the radioprotective and radiosensitizing effects of the embolic agent, the durability of embolization, and the sequencing of embolization with respect to the radiosurgical treatment. Published literature on these topics is sparse, and the flimsiness of the data offers limited guidance.

Early decreased tumor volume following fractionated Gamma Knife Radiosurgery for metastatic melanoma and the role of "adaptive radiosurgery": case report.

OBJECTIVE: We report a case in which fractionated gamma knife radiosurgery was used to treat a metastatic melanoma lesion. The tumor demonstrated a rapid response to radiosurgery with an observable reduction in tumor volume between the second and third treatments, requiring a favorable modification in the third fractionated treatment. CLINICAL PRESENTATION: A 61-year-old woman presented with a frontal floor metastatic melanoma lesion that was located adjacent to the optic apparatus. INTERVENTION: Gamma knife radiosurgery was administered in three fractionated treatments of 6.5 Gy to the 50% isodose line in each case. Repeat imaging for the purpose of planning demonstrated that tumor volume at the time of the third treatment, 9 days following the first treatment, had decreased by 31%, resulting in a 21% decrease in the dose administered to the optic chiasm. CONCLUSION: A case of metastatic melanoma treated with fractionated GKRS is presented, in which a significant reduction in tumor volume was noted 9 days following the initial treatment. This case provides insight into the rate with which malignant neoplasms may respond to intermediate-dose hypofractionated GKRS, and lends support to the concept of "adaptive radiosurgery" as a means of optimizing radiation to an evolving target while minimizing collateral radiation to surrounding structures.

Long-term outcomes and patterns of tumor progression after gamma knife radiosurgery for benign meningiomas.

OBJECT: To characterize the timing and patterns of long-term treatment failure after Gamma Knife radiosurgery (GKRS) for benign meningiomas. METHODS: Data were retrospectively reviewed in 116 patients who underwent 136 GKRS treatments for benign intracranial meningiomas from 1996 to 2004. Patients with atypical or malignant meningiomas were excluded. Surgical resection preceded GKRS in 72 patients (62%). The median tumor volume was 3.4 cm, and the median prescription dose to the 50% isodose line was 16 Gy. RESULTS: The median follow-up time was 75 months (range, 4-146 months). Overall tumor control was achieved in 128 of 136 lesions (94%), of which tumor size was stable in 68% and decreased in 26%. Seven patients experienced disease progression in 8 tumors, occurring at a mean time of 90 months. The overall 5-year and 10-year actuarial tumor control rate was 98.9% and 84%, respectively. Characteristics corresponding to tumor progression included insufficient tumor coverage (98% vs 93%, P = .007), cavernous sinus lesions, and meningiomatosis. Complications after GKRS developed in 8% of patients, in whom the mean tumor volume was nearly double that in patients with no adverse effects (11 vs 5.7 cm3, P = .003). CONCLUSIONS: GKRS demonstrates excellent long-term tumor control in the management of benign meningiomas. Tumor progression occurred at a mean time of 7.5 years after GKRS, reinforcing the need for long-term surveillance despite initial tumor control. Treatment failure was related to undercoverage of lesions in the majority of cases, with the remainder demonstrating evidence of abnormal tumor biology.

HIV- positive anal cancer: an update for the clinician.

Anal cancer used to be a rare cancer traditionally associated with elderly women. There are approximately 5260 cases per year in the U.S. (1). The onslaught of the Human Immunodeficiency Virus (HIV) virus has led to a change in anal cancer demographics. Anal cancer is on the rise in the U.S and the number of anal cases documented has quadrupled in the past 20 yrs correlating with the rise of the HIV epidemic. The incidence of anal cancer is 40 to 80 fold higher in the HIV positive (HIV+) population when compared to the general population (2). With the advent of highly active antiretroviral therapy (HAART), HIV+ patients are living longer as less are progressing to AIDS. As a consequence non AIDS defining cancers such as anal cancer are on the rise. Factors implicated in the etiology of anal cancer in HIV+ patients include (Human papillomavirus) HPV virus status, sexual habits, and a history of smoking. HPV 16 and receptive anal intercourse (RAI) increase the risk of anal cancer by 33% over the general population. In the general population, the rate of anal cancer is approximately 0.9 cases per 100,000. In patients with a history of RAI, the rate approaches 35 cases per 100,000 which is equivalent to the prevalence of cervical cancer (3). Smokers are eight times more likely to develop anal cancer. There has been much discussion about tailoring treatment decisions in HIV+ patients with anal cancer. This review focuses on squamous cell carcinomas of the anal canal which comprise 80 to 90% of all anal cancers diagnosed and highlight key issues in the management of HIV+ anal cancer patients including recent clinical trials.

Delayed toxicity from gamma knife radiosurgery to lesions in and adjacent to the brainstem.

The aims of this study were to assess the incidence of, and risk factors for, delayed toxicity following gamma knife stereotactic radiosurgery (GKRS) to lesions in and adjacent to the brainstem. We retrospectively evaluated the delayed toxicity of GKRS following the treatment of 114 lesions in and adjacent to the brainstem in 107 patients. The median tumor volume was 6.2 cm(3) and the median dose to the tumor margin was 16Gy. The mean follow-up was 40 months. Thirteen patients (12%) demonstrated clinical evidence of delayed toxicity, with a median latency to the development of toxicity of 6 months. The actuarial incidence of toxicity at 1 year and 5 years was 10.2% and 13.8%. Larger tumor volume (p=0.02) and larger treatment volume (p=0.04) were associated with an increased incidence of delayed toxicity. Large lesions adjacent to the brainstem have a higher than previously suspected rate of delayed toxicity.

Chained lightning: part III--Emerging technology, novel therapeutic strategies, and new energy modalities for radiosurgery.

Radiosurgery is fundamentally the harnessing of energy and delivering it to a focal target for a therapeutic effect. The evolution of radiosurgical technology and practice has served toward refining methodologies for better conformal energy delivery. In the past, this has resulted in developing strategies for improved beam generation and delivery. Ultimately, however, our current instrumentation and treatment modalities may be approaching a practical limit with regard to further optimizing energy containment. In looking forward, several strategies are emerging to circumvent these limitations and improve conformal radiosurgery. Refinement of imaging techniques through functional imaging and nanoprobes for cancer detection may benefit lesion localization and targeting. Methods for enhancing the biological effect while reducing radiation-induced changes are being examined through dose fractionation schedules. Radiosensitizers and photosensitizers are being investigated as agents for modulating the biological response of tissues to radiation and alternative energy forms. Discovery of new energy modalities is being pursued through development of microplanar beams, free electron lasers, and high-intensity focused ultrasound. The exploration of these future possibilities will provide the tools for radiosurgical treatment of a broader spectrum of diseases for the next generation.

Postoperative Gamma Knife surgery for benign meningiomas of the cranial base.

OBJECT: The standard treatment for meningiomas is complete resection, but the proximity of skull base meningiomas to important neurovascular structures makes complete excision of the lesion difficult or impossible. The authors analyzed the mid- and long-term results obtained in patients treated with postresection Gamma Knife surgery (GKS) for residual or recurrent benign meningiomas of the cranial base. METHODS: Thirty-six patients with residual or recurrent benign meningiomas of the skull base following one or more surgical procedures underwent GKS. There were 31 women and five men, ranging in age from 22 to 73 years. The median tumor volume was 4.1 ml (range 0.8-20 ml) and the median radiation dose to the tumor margin was 16 Gy (range 15-16 Gy). RESULTS: Patients were followed for a median of 81 months (range 30-141 months) after GKS. At the end of the follow-up period, overall neurological improvement was observed in 16 patients (44.4%), whereas the condition in 20 patients (55.6%) was unchanged. One patient suffered transient cerebral edema 6 months after GKS. Based on imaging documentation, a partial response was seen in five patients (13.9%), the disease remained stable in 30 patients (83.3%), and in one patient (2.8%) there was an increase in tumor size. The actuarial progression-free survival rate was 100% at 5 years and 94.7% at 10 years. CONCLUSIONS: Gamma Knife surgery was shown to be an excellent adjunct to resection because of its durable rate of tumor control and low toxicity. It should be initially considered along with surgery for the treatment of complex skull base meningiomas.

Chained lightning, part II: neurosurgical principles, radiosurgical technology, and the manipulation of energy beam delivery.

The fundamental principle in the radiosurgical treatment of neurological conditions is the delivery of energy to a lesion with minimal injury to surrounding structures. The development of radiosurgical techniques from Leksell's original design has focused on the refinement of various methodologies to achieve energy containment within a target. This article is the second in a series reviewing the evolution of radiosurgical instruments with respect to issues of energy beam generation and delivery for improved conformal therapy. Continuing with concepts introduced in an earlier article, this article examines specific aspects of beam delivery and the emergence of stereotactic radiosurgery as a measure for focusing energy beams within a target volume. The application of stereotactic principles and devices to gamma ray and linear accelerator-based energy sources provides the methodology by which energy beams are generated and targeted precisely in a focal lesion. Advanced technological systems are reviewed, including fixed beams, dynamic radiosurgery, multileaf collimation, beam shaping, and robotics as various approaches for manipulating beam delivery. Radiosurgical instruments are also compared with regard to mechanics, geometry, and dosimetry. Finally, new radiosurgical designs currently on the horizon are introduced. In exploring the complex history of radiosurgery, it is evident that the discovery and rediscovery of ideas invariably leads to the development of innovative technology for the next generation.

Chained lightning, part I: Exploitation of energy and radiobiological principles for therapeutic purposes.

The fundamental principle of radiosurgery is the focusing of energy within a restricted target volume. In examining the history of radiosurgery, various strategies for addressing this issue of energy containment become apparent. This is the first in a series of articles that reviews the evolution of radiosurgery through the development of instruments for beam generation and delivery for improved conformal therapy. In this first part of the series, we focus specifically on beam generation and the development of particle beams as the initial approach in radiosurgery for focused radiation treatment. We examine the physical characteristics and biological effects of particles and the unique advantage they confer for radiosurgery. We consider clinical studies and treatment of neurological diseases with particles and also assess boron neutron capture therapy as a strategy for selectively targeting neutron beams. Later in this series, we explore methods of beam delivery with the development of stereotactic radiosurgery. Finally, we introduce new concepts and applications in radiosurgery such as nanotechnology, radiation enhancement, ultrasound, near infrared, and free electron lasers. The elaboration of these efforts sets the stage for neurosurgeons to further explore new ideas, develop innovative technology, and advance the practice of radiosurgery.

Stereotactic radiosurgery: adjacent tissue injury and response after high-dose single fraction radiation. Part II: Strategies for therapeutic enhancement, brain injury mitigation, and brain injury repair.

In the first part of this series, we reviewed the histological, radiographic, and molecular data gathered regarding the brain parenchymal response to radiosurgery and suggested future studies that could enhance our understanding of the topic. With this article, we begin by addressing methods of potentiating the effect of radiosurgery on target lesions of the central nervous system. Much of the work on potentiating the effects of cranial radiation has been performed in the field of whole-brain radiotherapy. Data from Phase III trials evaluating the efficacy of various agents as radiosensitizers or radioenhancers in whole-brain radiotherapy are reviewed, and trials for investigating certain agents as enhancers of radiosurgery are suggested. The roles of gene therapy and nanotechnology in enhancing the therapeutic efficacy of radiosurgery are then addressed. Focus is then shifted to a discussion of strategies of protecting healthy tissue from the potentially deleterious aspects of the brain's response to radiosurgery that were presented in the first article of this series. Finally, comments are made regarding the role of neural progenitor or stem cells in the repair of radiation-induced brain injury after radiosurgery. The importance of both the role of the extracellular matrix and properly directed axonal regrowth leading to appropriate target reinnervation is highlighted.

Stereotactic radiosurgery: adjacent tissue injury and response after high-dose single fraction radiation: Part I--Histology, imaging, and molecular events.

Radiosurgery is now the preferred treatment modality for many intracranial disease processes. Although almost 50 years have passed since it was introduced as a tool to treat neurological disease, investigations into its effects on normal tissues of the central nervous system are still ongoing. The need for these continuing studies must be underscored. A fundamental understanding of the brain parenchymal response to radiosurgery would permit development of strategies that would enhance and potentiate the radiosurgical treatment effects on diseased tissue while mitigating injury to normal structures. To date, most studies on the response of the central nervous system to radiosurgery have been performed on brain tissue in the absence of pathological lesions, such as benign tumors or metastases. Although instructive, these investigations fail to emulate the majority of clinical scenarios that involve radiosurgical treatment of specific lesions surrounded by normal brain parenchyma. This article is the first in a two-part series that addresses the brain parenchyma's response to radiosurgery. This first article analyzes the histological, radiographic, and molecular data gathered regarding the brain parenchymal response to radiosurgery and aims to suggest future studies that could enhance our understanding of the topic. The second article in the series begins by discussing strategies for radiosurgical therapeutic enhancement. It concludes by focusing on strategies for mitigation and repair of radiation-induced brain injury.