Brain metastases

Opinion statement Brain metastases are an increasingly common complication in patients with systemic cancer. The optimal treatment for each patient depends on careful evaluation of several factors: the location, size, and number of brain metastases; the patient's age, general condition, and neurologic status; and the extent of systemic cancer to name a few. For patients with a single brain metastasis and limited systemic disease, the standard treatment is surgical resection followed by whole brain radiation therapy. In patients with a small, single metastasis, stereotactic radiosurgery is probably comparable to surgery. Patients with several metastases (up to three) and controlled systemic disease can be treated with whole-brain radiation and stereotactic radiosurgery. Patients with multiple metastases (more than three) are generally treated with whole-brain radiation alone. Radiosurgery is effective in treating patients with a limited number of recurrent brain metastases and stable systemic diseases. Surgery may have a role in patients with a large symptomatic recurrent lesion producing mass effect. Reirradiation and chemotherapy may have a limited role in patients with multiple recurrent metastases.     

Management of brain metastases: the indispensable role of surgery

Brain metastases are the most common neurological complication of systemic cancer and carry a very poor prognosis. The management of patients with brain metastases has become more important recently because of the increased incidence of these tumors and the prolonged patient survival times that have accompanied increased control of systemic cancer. In this article, we review the current perspectives on surgical treatment of brain metastases in terms of patient selection criteria, intraoperative adjuncts, whole-brain radiation therapy (WBRT) as a postoperative adjuvant, reoperation for tumor recurrence, and resection of multiple and single metastases. Achieving the best outcome in treatment of brain metastasis requires the judicious and complementary use of surgical resection along with modalities such as whole-brain radiation therapy and stereotactic radiosurgery.     

Surgical treatment of brain metastasis

Treatment modalities for brain metastasis or metastatic brain tumor include surgery, conventional irradiation, stereotactic radiosurgery (SRS), chemotherapy, and supportive care with corticosteroid. In most cases, these treatments are used in combination. For a single metastasis, surgery followed by whole-brain radiation therapy (WBRT) has been the standard treatment. SRS has become increasingly popular and challenges the standard procedure, but there are still insufficient data for the outcomes of combinations including SRS. For the treatment of multiple metastases, WBRT is the standard procedure. For tumors larger than 3cm, and in life-threatening situations such as a large metastasis to the cerebellum, surgery is the only feasible approach. Histological examination is sometimes useful for characterizing metastatic tumors from unknown primary sites. Thus, although brain metastasis invariably indicates a stage 4 cancer, some patients can benefit from surgery.     

Surgical therapies in brain metastasis

Brain metastases are the most common intracranial tumors in adults and source of the most common neurological complications of systemic cancer. The treatment approach to brain metastases differs essentially from treatment of systemic metastases due to the unique anatomical and physiological characteristics of the brain. Surgery and radiosurgery are important components in the complex treatment of brain metastases and can prolong survival and improve the quality of life (QOL). Aggressive intervention may be indicated for selected patients with well-controlled systemic cancer and good performance status in whom central nervous system (CNS) disease poses the greatest threat to functionality and survival. In this review the respective roles of surgery and radiosurgery, patient selection, general prognostic factors and tailoring of optimal surgical management strategies for cerebral metastases are discussed.     

Chirurgische Therapie von Hirnmetastasen

Objective

Cerebral metastases are the most common tumors within the brain accounting for 30-40% of tumors. Surgery is one of the relevant treatment options. In this article the indications for surgery of isolated, multiple and recurrent brain metastases as well as the results achieved will be critically evaluated.

Material and methods

Prospective randomized and current retrospective trials (evidence level 1–3) were evaluated. Innovative surgical technical aspects are discussed.

Results

There are indications for surgery if metastases have a mass-occupying effect and are situated in the cortex or subcortex of the cerebrum or cerebellum. The median overall survival time of patients with an isolated brain lesion is about 1 year depending on the primary tumor (evidence level 2). Patients with multiple brain metastases profit from surgery if they are categorized as recursive partitioning analysis (RPA) class 1, the number of lesions does not extend to more than 3 and all lesions can be removed (evidence level 3). In cases of recurrent tumor growth surgery is indicated if the lesion is space-occupying, radiotherapy or radiosurgery have already been applied and there is an uncertainty about the histology of the lesion (e.g. necrosis or tumor regrowth). The patient should have a Karnofsky performance status scale (KPS) score >?70 (evidence level 3).

Conclusion

Surgery is a valuable treatment option for brain metastases. Patients with isolated lesions particularly profit from surgery. A KPS score >?70 is an essential parameter for the outcome and is also of importance for patients with multiple lesions and recurrent tumor growth. Adjuvant whole brain radiation therapy reduces local and distant recurrent growth but does not prolong the median overall survival time of patients. Innovative surgical techniques including the resection of a safety zone around the lesions can reduce local recurrence.     

The role of surgical resection in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline

Question

Should patients with newly-diagnosed metastatic brain tumors undergo open surgical resection versus whole brain radiation therapy (WBRT) and/or other treatment modalities such as radiosurgery, and in what clinical settings? Target population These recommendations apply to adults with a newly diagnosed single brain metastasis amenable to surgical resection. Recommendations Surgical resection plus WBRT versus surgical resection alone Level 1 Surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site of the metastasis and in the brain overall, when compared to surgical resection alone. Surgical resection plus WBRT versus SRS ± WBRT Level 2 Surgical resection plus WBRT, versus stereotactic radiosurgery (SRS) plus WBRT, both represent effective treatment strategies, resulting in relatively equal survival rates. SRS has not been assessed from an evidence-based standpoint for larger lesions (>3 cm) or for those causing significant mass effect (>1 cm midline shift). Level 3 Underpowered class I evidence along with the preponderance of conflicting class II evidence suggests that SRS alone may provide equivalent functional and survival outcomes compared with resection + WBRT for patients with single brain metastases, so long as ready detection of distant site failure and salvage SRS are possible. Note The following question is fully addressed in the WBRT guideline paper within this series by Gaspar et al. Given that the recommendation resulting from the systematic review of the literature on this topic is also highly relevant to the discussion of the role of surgical resection in the management of brain metastases, this recommendation has been included below. Question Does surgical resection in addition to WBRT improve outcomes when compared with WBRT alone? Target population This recommendation applies to adults with a newly diagnosed single brain metastasis amenable to surgical resection; however, the recommendation does not apply to relatively radiosensitive tumors histologies (i.e., small cell lung cancer, leukemia, lymphoma, germ cell tumors and multiple myeloma). Recommendation Surgical resection plus WBRT versus WBRT alone Level 1 Class I evidence supports the use of surgical resection plus post-operative WBRT, as compared to WBRT alone, in patients with good performance status (functionally independent and spending less than 50% of time in bed) and limited extra-cranial disease. There is insufficient evidence to make a recommendation for patients with poor performance scores, advanced systemic disease, or multiple brain metastases.     

The role of retreatment in the management of recurrent/progressive brain metastases: a systematic review and evidence-based clinical practice guideline

Question

What evidence is available regarding the use of whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), surgical resection or chemotherapy for the treatment of recurrent/progressive brain metastases? Target population This recommendation applies to adults with recurrent/progressive brain metastases who have previously been treated with WBRT, surgical resection and/or radiosurgery. Recurrent/progressive brain metastases are defined as metastases that recur/progress anywhere in the brain (original and/or non-original sites) after initial therapy. Recommendation Level 3 Since there is insufficient evidence to make definitive treatment recommendations in patients with recurrent/progressive brain metastases, treatment should be individualized based on a patient’s functional status, extent of disease, volume/number of metastases, recurrence or progression at original versus non-original site, previous treatment and type of primary cancer, and enrollment in clinical trials is encouraged. In this context, the following can be recommended depending on a patient’s specific condition: no further treatment (supportive care), re-irradiation (either WBRT and/or SRS), surgical excision or, to a lesser extent, chemotherapy. Question If WBRT is used in the setting of recurrent/progressive brain metastases, what impact does tumor histopathology have on treatment outcomes? No studies were identified that met the eligibility criteria for this question.     

Radiosurgery for solitary brain metastases using the cobalt-60 gamma unit: methods and results in 24 patients.

To define the role of stereotactic radiosurgery in the treatment of metastatic brain tumors we treated 24 consecutive patients (20 men, 4 women) with the 201-source 60Co gamma unit between May 1988 and March 1990. The primary tumors included malignant melanoma (n = 10), non-small cell lung carcinoma (n = 6), renal cell carcinoma (n = 3), colorectal carcinoma (n = 1), oropharyngeal carcinoma (n = 1), and adenocarcinoma of unknown origin (n = 3). All tumors were less than or equal to 3.0 cm in greatest diameter. Twenty patients received a planned combination of 30-40 Gy whole brain fractionated irradiation and a radiosurgical "boost" of 16-20 Gy to the tumor margins; one patient refused conventional fractionated irradiation. Three patients with recurrent, persistent, or new non-small cell lung carcinomas had radiosurgical treatment 12-20 months after receiving 30-42.5 Gy whole-brain external beam irradiation. Stereotactic computed tomographic imaging was used for target coordinate determination and imaging-integrated dose planning. All tumors were enclosed by the 50-90% isodose shell using one (n = 22), two (n = 1), or three (n = 1) irradiation isocenters. During this 23-month period (median follow-up of 7 months) no patient died from progression of a radiosurgically-treated brain metastasis. Ten patients died of systemic disease (n = 8) or remote central nervous system metastasis (n = 2) between 1 week and 10 months after radiosurgery. One patient had tumor progression and underwent craniotomy and tumor excision 5 months after radiosurgery. To date, median survival after radiosurgery has been 10 months; 1-year survival was 33.3%. Stereotactic radiosurgery eliminated the surgical and anesthetic risks associated with craniotomy and resection of solitary brain metastases. Radiosurgery also effectively controlled the growth of tumors considered "resistant" to conventional irradiation.     

Metastasis to nervous system: spinal epidural and intramedullary metastases

Summary Spinal cord epidural metastasis (SEM) is a common complication of systemic cancer with an increasing incidence. Prostate, breast and lung cancer are the most common offenders. Metastasis usually arises in the posterior aspect of vertebral body with later invasion of epidural space. Pathophysiologically, vascular insufficiency is more important than direct spinal cord compression. The most common complaint is pain, and two thirds of patients with SEM have motor signs at initial diagnosis. Currently magnetic resonance imaging is the most sensitive diagnostic tool. The optimal management of SEM is still arguable, but recent advances in surgical management of SEM and higher complication rate of surgery following radiotherapy should persuade clinicians to consider de novo surgery where possible. Radiotherapy has an important role, particularly in treatment of radiosensitive tumors and in patients who are not candidates for surgery. Novel approaches such as stereotactic radiosurgery are promising; however, response to chemotherapy depends on inherent properties of primary tumor. Recurrent SEM is a substantial problem for which surgery or repeat radiotherapy may be options. Intramedullary metastasis is rare but should be considered in patients with systemic malignancy and asymmetrical presentation of myelopathic symptoms. The prognosis is usually poor and preferred modality of treatment is radiotherapy.     

The Rationale for Targeted Therapies and Stereotactic Radiosurgery in the Treatment of Brain Metastases

Brain metastases are the most common intracranial malignancy. Many approaches, including radiation therapy, surgery, and cytotoxic chemotherapy, have been used to treat patients with brain metastases depending on the patient’s disease burden and symptoms. However, stereotactic surgery (SRS) has revolutionized local treatment of brain metastases. Likewise, targeted therapies, including small-molecule inhibitors and monoclonal antibodies that target cancer cell metabolism or angiogenesis, have transformed managing systemic disease. Prospective data on combining these treatments for synergistic effect are limited, but early data show favorable safety and efficacy profiles. The combination of SRS and targeted therapy will further individualize treatment, potentially obviating the need for cytotoxic chemotherapy or whole-brain radiation. There is a great need to pursue research into these exciting modalities and novel combinations to further improve the treatment of patients with brain metastases. This article discusses reported and ongoing clinical trials assessing the safety and efficacy of targeted therapy during SRS.

Implications for Practice:

Treatment of patients with brain metastases requires a multidisciplinary approach. Stereotactic radiosurgery is increasingly used in the upfront setting to treat new brain metastasis. Targeted therapies have revolutionized systemic treatment of many malignancies and may sometimes be used as initial treatment in metastatic patients. There is sparse literature regarding safety and efficacy of combining these two treatment modalities. This article summarizes the supporting literature and highlights ongoing clinical trials in combining radiosurgery with targeted therapy.     

Therapy and prophylaxis of brain metastases

Metastases of various tumors to the brain account for the majority of brain cancers, and are associated with a poor prognosis. The most common primary sites are lung, breast, skin, kidney and colon; 10–40% of cancer patients develop brain metastases during the course of the disease. The incidence of brain metastasis appears to be rising; reasons may include better therapies for the systemic disease with longer survival of cancer patients but lower efficiency against brain metastases. In this article, we will discuss the conventional treatment with surgery, radiosurgery, radiotherapy and chemotherapy, but also new directions in the management of solid brain metastases. While general therapeutic nihilism should be avoided, it is important to recognize that the number of brain metastases, the extent of the systemic disease and also the tumor type have to be taken into account when choosing individual treatment regimens. Finally, special emphasis will be put on established and future approaches to prevent the disease. We thus aim to provide a framework for treating patients with different presentations of brain metastases, and to highlight important avenues for research.     

Therapy and prophylaxis of brain metastases

Metastases of various tumors to the brain account for the majority of brain cancers, and are associated with a poor prognosis. The most common primary sites are lung, breast, skin, kidney and colon; 10-40% of cancer patients develop brain metastases during the course of the disease. The incidence of brain metastasis appears to be rising; reasons may include better therapies for the systemic disease with longer survival of cancer patients but lower efficiency against brain metastases. In this article, we will discuss the conventional treatment with surgery, radiosurgery, radiotherapy and chemotherapy, but also new directions in the management of solid brain metastases. While general therapeutic nihilism should be avoided, it is important to recognize that the number of brain metastases, the extent of the systemic disease and also the tumor type have to be taken into account when choosing individual treatment regimens. Finally, special emphasis will be put on established and future approaches to prevent the disease. We thus aim to provide a framework for treating patients with different presentations of brain metastases, and to highlight important avenues for research.     

Local Recurrence of Metastatic Brain Tumor after Stereotactic Radiosurgery or Surgery Plus Radiation

In this study, we compared the recurrence of metastatic brain tumors after radiosurgery versus after surgery plus radiation, and analyzed the factors associated with the recurrence of brain metastases. Twenty-eight and 35 patients with metastatic brain tumors underwent radiosurgery (52 lesions) and surgery plus radiation (46 lesions), respectively, between 1995 and 2001. The median tumor volume was 1.55ml (range: 0.02–10.4ml) in radiosurgery patients and 17.9ml (range: 0.26–195ml) in surgery plus radiation patients. The median radiosurgical tumor central and margin doses were 28.9 and 23.8Gy (range: 20–35 and 25–15Gy), respectively. The median total dose was 46.7Gy (range: 30–63Gy) in the surgery plus radiation group.The recurrence time from surgery plus radiation group (25 months) was significantly longer than that from the radiosurgery group (7.2 months) (p=0.0199). The factors affecting the recurrence of brain metastases after radiosurgery were size, central dose of radiation and histology (colon vs. others). No factors affected the recurrence of brain metastases after surgery plus radiation. To avoid early recurrences of metastatic brain tumors, surgery plus radiation is the preferable therapeutic modality. The size and histology of brain metastases, and the dose of radiation should be considered for the effective treatment of tumors by radiosurgery.     

Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options

Background

Lung cancer is the most common cause of cancer-related mortality in humans. There are several reasons for this high rate of mortality, including metastasis to several organs, especially the brain. In fact, lung cancer is responsible for approximately 50% of all brain metastases, which are very difficult to manage. Understanding the cellular and molecular mechanisms underlying lung cancer-associated brain metastasis brings up novel therapeutic promises with the hope to ameliorate the severity of the disease. Here, we provide an overview of the molecular mechanisms underlying the pathogenesis of lung cancer dissemination and metastasis to the brain, as well as promising horizons for impeding lung cancer brain metastasis, including the role of cancer stem cells, the blood-brain barrier, interactions of lung cancer cells with the brain microenvironment and lung cancer-driven systemic processes, as well as the role of growth factor/receptor tyrosine kinases, cell adhesion molecules and non-coding RNAs. In addition, we provide an overview of current and novel therapeutic approaches, including radiotherapy, surgery and stereotactic radiosurgery, chemotherapy, as also targeted cancer stem cell and epithelial-mesenchymal transition (EMT)-based therapies, micro-RNA-based therapies and other small molecule or antibody-based therapies. We will also discuss the daunting potential of some combined therapies.

Conclusions

The identification of molecular mechanisms underlying lung cancer metastasis has opened up new avenues towards their eradication and provides interesting opportunities for future research aimed at the development of novel targeted therapies.

     

Stereotactic radiosurgery and bevacizumab for recurrent glioblastoma multiforme

Despite contemporary surgery, image-guided radiotherapy, and chemotherapy, glioblastoma multiforme (GBM) persists or relapses in nearly all patients, and tumors almost always recur locally. Management of recurrent GBM is variable, but approaches include best supportive care, reoperation, reirradiation, and/or systemic therapy. Promising novel therapies include antiangiogenic agents and stereotactic radiosurgery, which have cytotoxic effects on tumor microvasculature. Emerging data suggest the safety and efficacy of bevacizumab and radiosurgery either alone or in combination. This report presents the case of a man with locally recurrent GBM treated with stereotactic radiosurgery and concurrent bevacizumab, and reviews the preclinical and clinical data supporting this approach.     

Local Control of Brain Metastasis: Treatment Outcome of Focal Brain Treatments in Relation to Subtypes

Purpose

To investigate treatment options for local control of metastasis in the brain, we compared focal brain treatment (FBT) with or without whole brain radiotherapy (WBRT) vs. WBRT alone, for breast cancer patients with tumor relapse in the brain. We also evaluated treatment outcomes according to the subtypes.

Methods

We conducted a retrospective review of breast cancer patients with brain metastasis after primary surgery. All patients received at least one local treatment for brain metastasis. Surgery or stereotactic radiosurgery was categorized as FBT. Patients were divided into two groups: the FBT group received FBT±WBRT, whereas the non-FBT group received WBRT alone. Subtypes were defined as follows: hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative, HR-positive/HER2-positive, HR-negative/HER2-positive, and triple-negative (TN). We examined the overall survival after brain metastasis (OSBM), brain metastasis-specific survival (BMSS), and brain metastasis-specific progression-free survival (BMPFS).

Results

A total of 116 patients were identified. After a median follow-up of 50.9 months, the median OSBM was 11.5 months (95% confidence interval, 9.0-14.1 months). The FBT group showed significantly superior OSBM and BMSS. However, FBT was not an independent prognostic factor for OSBM and BMSS on multivariate analyses. In contrast, multivariate analyses showed that patients who underwent surgery had improved BMPFS, indicating local control of metastasis in the brain. FBT resulted in better BMPFS in patients with HR-negative/HER2-positive cancer or the TN subtype.

Conclusion

We found that patients who underwent surgery experienced improved local control of brain metastasis, regardless of its extent. Furthermore, FBT showed positive results and could be considered for better local control of brain metastasis in patients with aggressive subtypes such as HER2-positive and TN.     

Multidisciplinary management of brain metastases

Metastatic brain tumors are the most common intracranial neoplasms in adults. The incidence of brain metastases appears to be rising as a result of superior imaging modalities, earlier detection, and more effective treatment of systemic disease. Therapeutic approaches to brain metastases include surgery, whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and chemotherapy. Treatment decisions must take into account clinical prognostic factors in order to maximize survival and neurologic function whilst avoiding unnecessary treatments. The goal of this article is to review important prognostic factors that may guide treatment selection, discuss the roles of surgery, radiation, and chemotherapy in the treatment of patients with brain metastases, and present new directions in brain metastasis therapy under active investigation. In the future, patients will benefit from a multidisciplinary approach focused on the integration of surgical, radiation, and chemotherapeutic options with the goal of prolonging survival, preserving neurologic and neurocognitive function, and maximizing quality of life.     

Gastrointestinal cancer and brain metastasis: a rare and ominous sign

Metastatic brain tumors represent 20% to 40% of all intracranial neoplasms and are found most frequently in association with lung cancer (50%) and breast cancer (12%). Although brain metastases occur in <4% of all tumors of the gastrointestinal (GI) tract, the incidence of GI brain metastasis is rising in part due to more effective systemic treatments and prolonged survival of patients with GI cancer. Data were collected from 25 studies (11 colorectal, 7 esophageal, 2 gastric, 1 pancreatic, 1 intestinal, 3 all-inclusive GI tract cancer) and 13 case reports (4 pancreatic, 4 gallbladder, and 5 small bowel cancer). Brain metastases are found in 1% of colorectal cancer, 1.2% of esophageal cancer, 0.62% of gastric cancer, and 0.33% of pancreatic cancer cases. Surgical resection with whole brain radiation therapy (WBRT) has been associated with the longest median survival (38.4-262 weeks) compared with surgery alone (16.4-70.8 weeks), stereotactic radiosurgery (20-38 weeks), WBRT alone (7.2-16 weeks), or steroids (4-7 weeks). Survival in patients with brain metastasis from GI cancer was found to be diminished compared with metastases arising from the breast, lung, or kidney. Prolonged survival and improvement in clinical symptoms has been found to be best achieved with surgical resection and WBRT. Although early treatment has been linked to prolonged survival and improved quality of life, brain metastases represent a late manifestation of GI cancers and remain an ominous sign.     

Stereotactic radiosurgery for benign meningiomas

Meningiomas are the second most common primary tumor of the brain. Surgical resection is the preferred treatment for easily accessible tumors that can be safely removed. However, many tumors arise deep within the skull base making complete surgical resection difficult or impossible. Stereotactic radiosurgery is a highly effective alternative to surgical resection that has been used as a primary therapy for benign meningiomas as well as an adjuvant treatment for residual or recurrent tumors. The 5-year tumor control rates for stereotactic radiosurgery are equivalent to gross-total resection with lower morbidity than surgery, especially for skull base lesions. Additionally, adjuvant treatment of subtotally resected tumors results in tumor control rates equivalent to gross-total resection. Stereotactic radiosurgery has been used extensively for the treatment of small and medium sized skull base meningiomas. This technique has also been applied to large meningiomas and superficial tumors such as convexity and parasagittal meningiomas. However, multiple studies demonstrate that tumor control is decreased for superficial lesions and with increasing tumor size. In addition, radiation toxicity increases with increasing tumor size and superficial location. Based on a thorough review of the literature, stereotactic radiosurgery should be considered the primary treatment for skull base meningiomas with high surgical risk and in cases of superficial meningiomas where surgery is contraindicated.     

Role of radiosurgery in the management of central nervous system metastases

Radiosurgery is being used more routinely to treat patients with inoperable, recurrent, or multiple brain metastases from systemic cancer. Results in >2000 treated patients have been published during the past 8 years. These results indicate that permanent local control can be obtained in >80% of treated lesions with complications in <10% of patients. Success is independent of the histology, ie, melanoma vs adenocarcinoma, of the treated lesion or number of lesions treated. The long-term results of radiosurgery compare favorably with those seen following surgical resection. The cost-effectiveness of radiosurgery compared to surgical resection favors an expanded role for this technology in the treatment of selected patients with brain metastases.