The role of the gamma knife in the treatment of malignant primary and metastatic brain tumors

In the 1950s, Lars Leksell, a Swedish neurosurgeon coined the term radiosurgery to describe the delivery of a high dose of radiation to a small target within the brain on a single exposure.1 Leksell developed radiosurgery in an attempt to find a safer, less invasive alternative to direct cranial surgery. After exploring heavy particle systems and the linear accelerator, Leksell settled on gamma rays from cobalt 60 sources, carefully collimated and delivered in conjunction with his stereotactic system, as his preferred method for performing radiosurgery. The gamma unit or so-called “gamma knife” was used at first to treat benign brain tumors and arteriovenous malformations and to perform “functional” neurosurgery to treat entities such as chronic pain, trigeminal neuralgia, and movement disorders. More recently, attention has been directed toward the use of the gamma knife to treat both malignant primary and metastatic brain tumors. This article considers the role of the gamma knife in the treatment of both malignant primary and metastatic brain tumors, including patient selection, results of gamma knife treatment, and the place of the gamma knife in the overall management of patients with malignant intracranial tumors. It begins with a brief review of the technical details of the gamma knife. Figure 1 shows the external appearance of the gamma knife. The central body houses the 201 60Co sources, which emit gamma rays, and the primary collimator system (Fig 2). The primary and secondary collimator systems result in an array of 201 cylindrical gamma-ray beams. The basic principle of the gamma knife is that the radiation dose along any single beam is very low, but the dose at the intersection point of all of the beams is very high (approximately 200 times the dose along any single beam.) The secondary collimator helmets are designed so that all gamma-ray beams intersect at the same point. Collimators are available in four sizes, measuring 4, 8, 14, and 18 mm in diameter. The general principle of gamma knife radiosurgery is to place the lesion being treated at the focal point of the gamma ray beams. The lesion is placed with the use of stereotactic principles and a dedicated computer planning system, the GammaPlan. This UNIX-based computer allows multiple imaging sources—such as magnetic resonance (MR) imaging, computed tomography (CT), and angiography—to be used for dose planning. The system is rapid, accurate, and easy to use. The Leksell gamma unit, or gamma knife. Application of the stereotactic frame with the patient under local anesthesia An imaging study (usually MR imaging) performed with the stereotactic frame in place Computerized dose planning Delivery of the treatment The stereotactic frame is removed immediately when the procedure is completed. The entire procedure requires about 3 to 4 hours and is performed while the patient is under local anesthesia with mild supplementary intravenous sedation. Many centers in the United States have hospitalized patients overnight after treatment, but the trend is toward performing these procedures on an outpatient basis. The total actual treatment time is dependent primarily on the age of the 60Co sources, which decay with a half-life of about 5 years. Other factors that affect treatment time include the radiation dose to be delivered, the size of the patient's head, and the location of the tumor to be treated. Typically, treatment times vary from about 10 to 60 minutes. Irregularly shaped or large tumors may require more than a single gamma knife exposure or “multiple isocenter” treatment. Such complex treatments are easily and rapidly planned with the Gamma-Plan computer system, and the multiple isocenters are delivered sequentially during a single sitting. Two other devices are currently in use to deliver radiosurgical treatment. These are linear accelerator (LINAC)-based systems and systems that use accelerated protons. Except in rare instances, LINAC-based radiosurgical systems represent the conversion of standard linear accelerators, normally used to deliver radiotherapy, into units for radiosurgery.2 Several commercially available LINAC conversion systems are in use, and many other one-of-a-kind systems have been developed at individual institutions. A few institutions use dedicated LINAC-based radiosurgical units. Overall, the reported results of LINAC-based and gamma knife radiosurgical systems for treatment of malignant brain tumors are approximately equivalent. Diagrammatic view of gamma unit. Only one or two clinically active heavy particle units are currently in clinical use in the United States. Little information is available about the safety or efficacy of such systems in the treatment of malignant brain tumors,3 although these units have considerable experience in the radiosurgical treatment of other lesions, such as pituitary tumors and arteriovenous malformations. Because radiosurgery delivers the entire radiation dose during a single sitting, the radiobiologic effects are different from those of conventional fractionated radiotherapy.4 For instance, a particular dose of radiation delivered with the gamma knife has a biologic effectiveness equivalent to about three times the same dose in fractionated radiation. Gamma knife radiosurgery also involves radiation dose inhomogeneity, in which the dose to the central portion of the treated tumor is about twice as high as that to the periphery of the tumor. A typical gamma knife treatment might deliver 20 Gy to the periphery of a tumor at the 50% isodose line so that the center of the tumor would receive 40 Gy. These doses would be equivalent to about 60 Gy and 120 Gy, respectively, if delivered by conventional radiotherapy methods. In the latter case, however, the maximum safe dose to the brain is about 50 to 60 Gy, which limits the amount of radiation that can be delivered safely. Gamma knife treatment is primarily limited by size, because the treatment of lesions larger than 3.5 to 4.0 cm in average diameter results in the surrounding normal brain tissue receiving an excessive dose of radiation. The excessive radiation can result in complications caused by radiation necrosis or perilesional changes in white matter. The latter are often classified as “edema” because of their appearance on MR imaging scans. Laboratory studies, however, suggest that much of this response is a glial inflammatory response, which usually subsequently subsides, rather than increased water in the tissue.5 The treatment size limit of the gamma knife may be a consideration for large primary malignant brain tumors (e.g., glioblastomas) but is usually not a limitation in the treatment of metastatic brain tumors. CA) Patient with malignant glioma shown before gamma knife treatment. CB) The same patient is shown 6 months after gamma knife treatment. The lesion is no longer visible. The patient remains alive with normal neurologic function and no evidence of recurrent tumor 24 months after treatment. Gamma knife treatment is usually an adjunctive therapy for primary malignant brain tumors. The most common primary malignant brain tumors are glioblastomas and anaplastic astrocytomas.6 Low-grade gliomas, although usually thought of as benign, progress to more malignant forms in nearly 75% of patients. A few types of low-grade glial tumors (e.g., pilocytic astrocytomas) may at times be cured by surgical resection alone. Both glioblastomas and anaplastic astrocytomas are usually fatal lesions, with median survivals of about 1 year and 2 to 3 years, respectively, with conventional treatment. We favor maximal safe surgical resection of most glial tumors. Recent advances in imaging, computerized stereotactic surgery, microsurgery, and intraoperative monitoring have increased the safety of craniotomy for brain tumor resection and have made more lesions amenable to surgical resection.7 For nearly all malignant primary brain tumors we recommend fractionated external beam radiotherapy after maximal surgical resection and favor regional radiotherapy, rather than whole-brain radiotherapy, because it keeps complications at a minimum.8 Recent studies suggest that regional radiotherapy is as effective as and safer than whole-brain radiotherapy for the treatment of malignant primary brain tumors. We recommend gamma knife radiosurgery as a planned “boost” after surgery and radiotherapy (Fig. 3). We do not usually recommend gamma knife radiosurgery instead of radiotherapy because primary malignant brain tumors infiltrate well beyond the tumor margins that are apparent on imaging studies.9 (A) This patient had a large metastatic brain tumor in the left anterior temporal fossa from carcinoma of the prostate. Mass effect with compression and displacement of the ventricular system can be seen. (B) The same patient is shown 1 year after gamma knife treatment. The lesion has shrunk markedly and the mass effect has resolved. The patient remains alive with normal neurologic function 15 months after treatment. No new cerebral or other distant metastases have been identified. Because large tumor volumes cannot be treated safely with the gamma knife alone, we rely on fractionated radiotherapy to treat a wider field. The additional radiosurgical boost is delivered accurately to the smaller region of the tumor that shows contrast enhancement on T1-weighted contrast-enhanced MR imaging scans. The gamma knife also can be used to treat recurrent primary malignant brain tumors that have been treated previously with surgery, radiotherapy, and chemotherapy. Gamma knife treatment of such recurrent tumors also may be limited or impossible if the tumor is too large. Repeat surgical resection with or without implantation of carmustine-impregnated (Gliadel) wafers may be indicated in such situations to reduce the tumor volume before the patient can be treated with the gamma knife.10 Several studies have shown a survival advantage when radiosurgery is added to other forms of treatment of primary malignant brain tumors. The most recent comprehensive report, by Kondziolka and colleagues11 from the University of Pittsburgh, evaluated 64 patients with glioblastoma multiforme and 43 with anaplastic astrocytomas after gamma knife radiosurgery, which was used either as a planned boost to fractionated radiotherapy or at the time of later tumor progression. The median survival time after initial diagnosis for patients with glioblastoma multiforme was 26 months, approximately twice the median survival time of patients given conventional treatment without radiosurgery. For patients with anaplastic astrocytomas, the median survival after diagnosis was 32 months. The 2-year survival rate was 51% for glioblastoma multiforme patients and 67% for anaplastic astrocytoma patients. These results were compared with those of historical controls provided by the Radiation Therapy Oncology Group (RTOG) and stratified according to several prognostic variables. Survival benefit was improved for both glioblastoma multiforme and anaplastic astrocytoma patients who were treated with gamma knife radiosurgery. Larson et al12 also recently reported a retrospective multicenter study (in which our center participated) of gamma knife radiosurgery for the treatment of gliomas. That study also described an increased survival benefit for patients treated with the gamma knife. Factors favorably affecting outcome in both reports included younger age, smaller tumor volume, and better neurologic performance status. The Larson study also suggested that the degree of malignancy as indicated by the pathological tumor grade was an important prognostic factor, but the Kondziolka study did not. Several other reports exist concerning radiosurgical treatment of glial tumors.13-18 Although they generally support the results of the Kondziolka and Larson studies, some of these reports have shown that little benefit is gained by adding radiosurgery to conventional treatment. Alexander19, 20 has recently reviewed the approach of the Harvard group to the use of LINAC-based radiosurgery to treat malignant glial tumors and has commented on the Kondziolka report previously described. We agree with his assessment that “radiosurgery for gliomas is often a complex endeavor, with appropriate use of aggressive surgery blended in with radiosurgery for the optimal management of the difficult cases.”20 Radiosurgery has also been compared with brachytherapy because these two treatment techniques represent possible adjuncts to surgical resection, fractionated radiotherapy, and chemotherapy.21-28 These comparisons suggest that radiosurgery is as effective as brachytherapy but much safer and less expensive. Reoperations after brachytherapy occur in about 40% to 45% of patients, whereas after radiosurgery they occur in about 20% to 25% of patients.21-28 Radiosurgery is certainly not a cure for malignant primary brain tumors, but it does offer an adjunctive form of treatment that is clinically effective, safe, and cost-effective. The role of radiosurgery in the treatment of “less malignant” primary brain tumors (e.g., low-grade gliomas, oligodendrogliomas) is less clearly defined, but because fractionated radiotherapy combined with surgical excision is the mainstay of the treatment of these lesions, it seems logical that radiosurgery will improve survival in these tumors also. Few truly “benign” intrinsic brain tumors exist because nearly all such lesions tend to recur and eventually prove fatal. Extrinsic brain tumors (e.g., meningiomas, vestibular schwannomas) are more often benign in the sense that complete surgical removal or successful gamma knife treatment may permanently remove the threat that such lesions pose to the patient's life or neurologic function. Even with these benign lesions, however, recurrences, impaired neurologic function, and even death may occur. Radiosurgery is certainly not a cure for malignant primary brain tumors, but it does offer an adjunctive form of treatment that is clinically effective, safe, and cost-effective. The simplicity of the treatment, the fact that it interferes very little with normal life activities, and the virtual lack of perioperative complications make gamma knife radiosurgery attractive to both patients and referring physicians. Metastatic brain tumors are probably the most common form of malignant brain tumors or “brain cancers.” Up to 50% of patients with cancers develop neurologic symptoms resulting from brain metastases, and as many as 150,000 new cases of brain metastases may occur each year.29 The most common sources of brain metastases are cancers of the lung and breast, which in our experience make up about 60% of our total cases.29 Metastases from melanomas and cancers of the colon and kidney added to metastases from the lung and breast account for more than 80% of our total cases.29 Cerebral metastases present excellent targets for gamma knife radiosurgery because, unlike primary malignant brain tumors, metastatic tumors are usually spherical, small, and well demarcated from surrounding normal brain tissue. Median survival for patients with cerebral metastases that are untreated or treated with corticosteroids alone (to reduce cerebral edema) is only about 1 month. Fractionated whole-brain radiotherapy improves the median survival to about 3 to 4 months, but death from recurrent or persistent metastatic brain tumors occurs in about 50% of patients treated with whole-brain radiotherapy. Patchell et al30 showed in a randomized prospective study that the combination of surgical resection plus whole-brain radiation therapy increased the survival rate to a median of 10 months. Several recent reports suggest that radiosurgery with or without the addition of whole-brain radiotherapy is as effective as surgery and whole-brain radiotherapy and at considerably less morbidity and at substantially lower cost; however, not everyone is in agreement.31-46 Gamma knife radiosurgery alone controls more than 90% of metastatic tumors with a median survival of about 8 to 10 months. As with primary malignant brain tumors, lesion size may be a limiting factor in the use of gamma knife radiosurgery for treatment of metastatic brain tumors. The same size limitations (a maximum average diameter of 3.5 cm) generally apply. Large metastatic tumors that are in favorable locations in to brain function and are be treated by surgical neurologic performance (a of less than on the is an prognostic factor for both gamma knife radiosurgery and surgical resection, but this factor requires Metastatic brain tumors, even small lesions to cm in may be with The latter may neurologic symptoms such as or that result in neurologic with corticosteroids often and in with of symptoms and in neurologic a patient is for treatment of a metastatic brain tumor because of neurologic the of both the tumor and be in neurologic function resulting from successful treatment of often a patient who would be for treatment to a patient very for gamma knife treatment. Gamma knife radiosurgery alone controls more than 90% of metastatic tumors, with a median survival of about 8 to 10 to of the lesion without occurs in about 40% of treated a in lesion size occurs in about of treated or virtual of the treated lesion occurs in about 20% of treated Although not effective gamma knife radiosurgery often tumor within 2 to 3 months of treatment (Fig. may be to treat cerebral which is often in metastatic tumors during the after gamma knife treatment and before response of the tumor. local of brain metastases with radiosurgery the death rate from these lesions from about 50% with whole-brain radiotherapy to about The of death in the patients is fatal metastases in other than the brain as and Gamma knife radiosurgery in our experience also of with patients of about the few of The two primary types of complications with radiosurgery are radiation and radiation brain metastases were to be a of and a to radiosurgical treatment. We have however, that the median survival after treatment of multiple brain metastases is no different from the survival after treatment of a single on the is and if the primary and any metastases are multiple cerebral metastases are not a to radiosurgery. experience with multiple metastases has been in a retrospective of a large of patients by the Harvard We have treated as many as 15 metastatic tumors in a single patient without radiation and we have shown that the of cerebral metastases is not a of the of most patients with multiple metastases usually one or two lesions to cm in and several smaller lesions than cm in with multiple large metastases usually present with neurologic performance (e.g., less than and are not for radiosurgery, although whole-brain radiotherapy may some We have the role of whole-brain radiotherapy in the treatment of brain whole-brain radiotherapy when with surgical resection was the treatment of As radiosurgery has to surgical resection of brain metastases, the role of whole-brain radiotherapy also has been In our the median survival is not different whole-brain radiotherapy is combined with radiosurgery or radiosurgery alone is used to treat brain The Harvard group has also this A recent of our does that whole-brain radiotherapy the of new brain metastases, but this does not affect the or of Because whole-brain radiotherapy to the and of of life with the treatment of brain metastases, we no longer use or recommend it when radiosurgical treatment of brain metastases is whole-brain radiotherapy from the treatment of metastatic brain tumors also the complications of whole-brain radiotherapy, cerebral and new brain metastases after initial radiosurgical treatment occurs in about 25% of radiosurgical to treat the new lesions is as effective as an initial treatment and also this we have treated more than 20 brain metastases in a single patient in three different radiosurgical a to Two primary types of complications are with radiosurgery, radiation and radiation These complications may occur after the treatment of either primary or metastatic brain tumors. Radiation on MR imaging as surrounding the treated This has the MR imaging of increased water and is usually as although studies suggest that much of this is a of glial inflammatory response rather than Because perilesional is often with both primary and metastatic brain tumors, may occur in radiation from cerebral Such radiation also may be as tumor on MR imaging scans. radiation may or may not be with clinical the of the and in of the brain (e.g., may be with clinical whereas larger in (e.g., may not be with any clinical (e.g., may be used to treat perilesional radiation although in our experience the response to such treatment approach is to a of 4 four times a for about 1 symptoms improve the treatment is usually at a lower no occurs within a or the is Radiation time as as the changes are but neurologic may radiation even when the to Radiation are generally and of the treatment doses for radiosurgery according to the is to result in a neurologic rate of about A recent of from more than patients treated with the gamma knife at the University of that the actual rate may be to Radiation necrosis is a more to radiosurgery. It may result from the death of tumor and in surrounding normal or it may result from the necrosis of normal brain tissue surrounding the previously treated metastatic brain tumor. Such tend to occur more in larger lesions primary brain tumors or metastatic symptoms are more often with radiation necrosis than with a radiation Radiation necrosis has been to occur in 20% to 25% of patients treated for primary malignant brain tumors. This rate of radiation necrosis is lower than the 40% usually with brachytherapy of primary brain tumors, a form of adjunctive treatment often compared with radiosurgery. radiation necrosis and tumor is often and brain with or may in the of such In some a stereotactic may be to the but our experience in the radiosurgical treatment of primary malignant brain tumors that most of on to be radiation necrosis is a combination of tissue and tumor a radiation or radiation necrosis is with clinical symptoms that to to surgical resection of the mass may be the only to improve the of the patient's A single radiosurgical treatment at our center results in about in This is less than the of a craniotomy but more than whole-brain radiotherapy. For the treatment of primary brain tumors, radiosurgery an additional because it generally does not conventional treatment. radiosurgery to survival and in some may a craniotomy if tumor can be or Radiosurgery is also less than which requires surgical of the 5 to of and a much rate of surgery to treat radiation Recent comparisons for the treatment of metastatic brain tumors suggest that radiosurgery is the most form of treatment for these lesions on gained from each of the Because of recent in for radiosurgery, the for this to Radiosurgery is the primary form of treatment for brain the of these lesions has been to the benefit In the treatment of primary malignant brain tumors radiosurgery is a to surgical resection, radiotherapy, and chemotherapy. The addition of radiosurgery to these primary the of patients with malignant primary brain tumors. Radiosurgery has our approach to metastatic brain tumors. resection and whole-brain radiotherapy, previously the of the treatment of brain metastases, are generally used only when patients are not for radiosurgery, on tumor size and neurologic function. For most brain metastases, in our radiosurgery is the treatment of and will result in effective tumor in more than 90% of treated tumors.