Multidisciplinary management of colorectal brain metastases: a retrospective study

BACKGROUND: The incidence of brain metastases (BM) from colorectal cancer (CRC) is increasing, and the management of this previously rare complication at a single institution is reported. METHODS: The records of all patients with BM from 1994 to 2005 were reviewed, and 49 patients (33 men, 16 women) with 102 BM from CRC were identified. Associations between patient and tumor characteristics, treatment modality, and survival were assessed. RESULTS: The median age at diagnosis of BM from CRC was 66 years. Forty patients (82%) had other systemic disease. The median survival after a diagnosis of BM from CRC was 5.1 months. Fifteen patients (31%) underwent surgery at some point, 14 patients (29%) underwent stereotactic radiosurgery (SRS), and 42 patients (86%) received whole-brain radiotherapy during their management. Seven patients (14%) underwent upfront SRS. On multivariate analysis, a longer interval from diagnosis of CRC to diagnosis of BM was associated significantly with shorter survival (p = .01). Sex, Karnofsky performance status, tumor location, recursive partitioning analysis class, and initial treatment modality did not have an impact on survival. CONCLUSIONS: Because BM from CRC are a late-stage phenomenon, the majority of patients in the current study had other systemic involvement, and survival after CNS involvement was poor. The results indicated that a high prevalence of systemic disease limits the proportion of patients who are strong candidates for upfront SRS, thereby limiting the impact that this modality has on outcomes in this population as a whole. Late development (>1 year after the primary tumor diagnosis) of CNS involvement may predict for poorer survival after therapy for patients with BM from CRC.     

The management of brain metastases

Brain metastases are neoplasms that originate in tissues outside the brain and then spread secondarily to the brain. Metastases to the brain are the most common intracranial tumours in adults. Substantial progress has been made in the treatment of these tumours, and radiotherapy, surgery, and stereotactic radiosurgery are now established treatments. With aggressive treatment, most patients experience meaningful symptom reduction and extension of life.     

Surgical management of brain metastases

Metastatic brain tumors are the most common intracranial tumors in adults and the most common cause of neurologic morbidity and mortality in these patients. Recent advances in the management of the primary cancer have resulted in improved prognosis, longer survival, and thus, increased identification of the presence of brain metastases. Data suggest that aggressive treatment of the metastatic brain tumor with surgical resection increases the length of survival in these patients. New techniques, including preoperative functional imaging, stereotactic surgical resection, image-guided neurosurgery, intraoperative ultrasound, and cortical mapping, have aided neurosurgeons in surgical resection and have helped to lower the associated surgical morbidity and mortality. The respective roles of surgery, patient selection, prognostic factors, and radiotherapy are addressed in this review.     

Current neurosurgical management of brain metastases

Brain metastases occur in a third of patients diagnosed with cancer; without any intervention, the prognosis is quite poor with a median survival of 1 month. Because of the constraints of the blood-brain barrier, chemotherapy is not effective and treatment options include surgery, whole brain radiation, or stereotactic radiation. This chapter is devoted to a review of the current management options for treatment of brain metastases.     

Innovation in the management of brain metastases

Metastatic lesions to the brain occur commonly in oncology patients and portend a very poor outcome, as they often occur in the setting of progressive systemic metastatic disease and can result in neurologic deterioration that may preclude therapy. Therapy of patients with brain metastases requires a combination of measures to achieve local control at the site of metastasis (e.g., with surgical resection or radiosurgery) and to reduce the subsequent risk of recurrences elsewhere in the brain (e.g., with whole-brain radiation). Successful therapy of extracranial systemic metastases is required for optimal outcomes. Clinical trials are currently underway to define the optimal role of whole-brain radiation and radiosurgery in different subsets of patients. Novel therapies to enhance radiation responsiveness are also under investigation. In the current review, we discuss recent developments in the management of patients with brain metastases.     

Radiotherapy and radiosurgical management of brain metastases

Out of the various cancer treatment modalities available, radiotherapy is the most commonly used for managing metastatic disease in the brain. Until recent years, this was almost exclusively limited to whole-brain radiotherapy (WBRT). Radiosurgery has emerged as a powerful technique for controlling small to moderate-sized brain metastases (<4 cm in diameter). Tumor control rates with radiosurgery are superior to those with WBRT and appear to equal or surpass those with surgery plus WBRT in most studies. The choice among various radiation management strategies (radiosurgery alone, radiosurgery plus WBRT, or surgery followed by radiotherapy) should be based on the size and location of the brain metastases, the functional and neurologic status of the patient, the type of tumor, the tumor imaging characteristics, and the patient’s concerns about the risks and side effects of the proposed treatment.     

Symptomatic management and imaging of brain metastases

Summary Brain metastasis is the most common malignancy of the nervous system. Survival is short and the majority of patients die within 5 months after diagnosis. In this review, clinical and pathophysiological aspects of brain metastases are described, including novel radiological methods as triple-dose gadolinium-enhanced MRI. Recursive partitioning analysis is a powerful tool to analyse prognosis, and recent studies contribute to subgroup division. Subsequently, treatment choices can be made, based on prognostic characteristics of the individual patient. Commonly, symptomatic therapy starts with the administration of corticosteroids, often resulting in improvement of neurological deficit. Anticonvulsants are administered in patients with symptomatic epilepsy. The risk on vascular complications in patients with brain metastases is increased and needs special attention. Treatment of psychiatric complications e.g. delirium or depression may also improve quality of life.     

Diagnosis and management of brain metastases.

In the past 15 years, significant advancement has been made in the diagnosis and treatment of brain metastases. The distinction between the management of single and multiple brain metastases is an important one. Although radiotherapy remains a mainstay of treatment, especially in multiple brain metastases, surgical resection and stereotactic radiosurgery also have their place in the management of selected patients. Rarely, interstitial radiation or chemotherapy also may be used to treat brain metastases in the setting of relapse.     

Multidisciplinary approach of colorectal liver metastases

Colorectal cancer (CRC) is the second most common cause of cancer death in Spain. Fifty percent of patients will develop colorectal liver metastases (CLM) during the course of the disease. Less than 20% of patients with CLM are initially resectable and for them 5-year disease-free survival (DFS) is about 20-25%, with a high recurrence rate. CLM is a heterogeneous disease. From a clinical point of view, four main groups can be differentiated: initially resectable, not optimally resectable, unresectable that could be resectable and unresectable that never will be likely to be resected. Treatment of CLM must be established, always, in a multidisciplinary team discussion with an analysis of prognostic factors and resectability. For patients with resectable CLM, the EORTC trial 364 demonstrated that chemotherapy plus surgery is better than surgery alone. Consequently most patients should be treated with perioperative chemotherapy based on oxaliplatin, and if resection has been done without chemotherapy, they should receive adjuvant chemotherapy after R0 resection. Based on oncological factors, the 5-year survival rate after resection of CLM ranges from 60% to only 14% with a poor score. If a patient has more than one of the poor prognostic factors he should probably be referred for preoperative (induction) chemotherapy. Only a minority of patients with CLM are amenable to surgery; therefore, efforts have been made to increase the percentage of patients who could be candidates for resection. Studies, mostly retrospective, have confirmed the ability of neoadjuvant chemotherapy (conversion chemotherapy) to render some metastases resectable. The regimens we must use depend on the KRAS mutational status and the toxicity profiles of drugs in the context of each patient. In k-ras mutated tumours we can use bevacizumab combined with standard chemotherapy or concomitant administration of the three active agents (FOLFOXIRI) in suitable patients. In k-ras wild-type patients, the combination of cetuximab and FOLFIRI-FOLFOX improved response rates and resection rate in phase III-II trials. With a lower level of evidence, panitumumab is an alternative combined with FOLFOX. Bevacizumab is also an alternative as it does not depend on KRAS status. Radiotherapy is becoming an alternative in selected patients, where surgery is not an alternative. For the majority of patients, who will never be resectable, the continuum of care with chemotherapy will be the paradigm for their management.     

Clinical symptoms and symptomatic management of brain metastases

Cancer patients frequently develop brain metastases. Symptomatic treatments are important to stabilize these patients before an oncological procedure (usually radiotherapy, sometimes surgery or chemotherapy) can be started. These symptomatic treatments mainly rely on steroids to reduce the peritumoral edema; anti-epileptic drugs for patients who previously had seizures, and low-molecular-weight heparin for patients at risk of thrombo-embolic events.     

Radiotherapeutic management of brain metastases from breast cancer

We have reviewed the medical records of 28 breast cancer patients with brain metastases who were treated with radiotherapy at our clinic from 1980 through 1994 (4 patients, postoperatively; 24 patients, radiotherapy alone). Radiotherapy was delivered as whole brain irradiation using lateral opposed 10 MV X-rays. Ten patients received an additional boost to a reduced field. One patient was treated with localized stereotactic irradiation alone. The radiation dose for tumors ranged from 32 Gy to 60 Gy (mean, 49 Gy) in 2 or 3 Gy daily fractionated doses. The brain was the first site of metastatic involvement in only two patients. In the 26 evaluable patients, neurologic functional improvement was achieved in 24 patients (92%) with complete response (CR) in 1 2 patients (46%) and partial response (PR) in 1 2 patients (46%). The survival rates from the initial treatment were 39% at 5 years and 16% at 10 years (median survival time, 50 months), and those after treatment of brain metastases were 29% at one year and 18% at 2 years (median survival time, 6 months). Performance status tended to be associated with survival (p=0.10), and the presence of liver metastasis was the most important risk factor concerning survival (p=0.056). Two patients suffered severe chronic complications. One patient developed severe dementia after whole brain irradiation with a total dose of 45 Gy in 3 Gy daily fractionated dose, and another patient developed widespread brain necrosis after combined radiotherapy with intrathecal local infusion of methotrexate. Radiotherapeutic management is useful for breast cancer patients with brain metastasis, and long-term survival may also be possible even if patients have preexisting extracranial metastases, except for hepatic involvement. Radiation-related complications should therefore be avoided in these patients.     

Multidisciplinary treatment of brain metastases derived from clear cell renal cancer incorporating stereotactic radiosurgery

BACKGROUND

Brain metastases are a frequent complication in patients with metastatic clear cell renal cancer. Survival after whole‐brain radiotherapy (WBRT) is disappointing. A retrospective analysis of multimodality treatment was performed in patients who had received linear accelerator (LINAC)‐based stereotactic radiosurgery (SRS).

METHODS

Thirty‐two patients underwent SRS‐based treatment for 71 metastatic foci between 2000 and 2006. All patients had a Karnofsky performance status ≥70 and all 32 patients had extracranial metastatic disease (Radiation Therapy Oncology Group recursive partitioning analysis [RPA] Class 2). Survival was calculated from the time of diagnosis of brain metastases. The minimum potential follow‐up was 1 year after SRS. Univariate and multivariate analysis of potential prognostic factors affecting survival was performed.

RESULTS

Twenty‐six patients required only 1 SRS treatment (84%) to achieve central nervous system (CNS) control, whereas 5 patients received 2 to 3 treatments (16%). The median survival of renal cancer patients from the diagnosis of brain metastases was 10.1 months (95% confidence interval, 6.4‐14.8 months). One‐year and 3‐year survival rates were 43% and 16%, respectively. The addition of surgery or WBRT did not appear to prolong survival. Immunotherapy after control of brain metastases with SRS appeared to result in significantly improved survival. Survival was also found to be strongly influenced by prognostic stratification of metastatic disease using Motzer or modified risk criteria.

CONCLUSIONS

The results of the current study demonstrated that SRS‐based treatment of patients with up to 5 brain metastases from clear cell renal cancer is feasible and results in excellent CNS control. Survival beyond 3 years from the time of diagnosis of brain metastases was achievable in 16% of patients and was associated with the use of systemic immunotherapy with interleukin‐2 and interferon but not antiangiogenic agents. Cancer 2008. © 2008 American Cancer Society.     

Modern management of rare brain metastases in adults

Brain metastases (BM) represent the main cause of intracranial neoplasms in adults, while being relatively less common in children. Today, better treatment options of the primary malignancy lead to higher remission rates as well as prolonged stable clinical conditions. This may in part explain the increased incidence of BM. Morbidity and mortality rates in patients with malignancies deteriorate significantly in cases of metastatic involvement of the central nervous system. Nowadays, especially modern management using surgical, medical, and radiotherapeutic options for treatment of BM tends to improve survival rates and enhance quality of life. Nonetheless, almost all treatment options are considered as palliative. In this review, we outline current knowledge of the incidence, diagnostic facilities, and therapeutic management of rare BM, with consideration of the basic aspects of the primary malignancy.     

Multimodality management of brain metastases in metastatic melanoma patients

Brain metastases are a frequent complication of advanced melanoma. Neurosurgery (generally followed by radiotherapy) may be useful in managing solitary, superficial brain metastases in good performance status patients, as well as for diagnostic purposes. Since most patients are not felt to be resectable and concurrent extracranial metastases frequently are present, whole-brain radiotherapy (WBRT) has become the de facto treatment standard. WBRT has resulted in disappointing outcomes, resulting in a 3.6-4.1-month median survival. Recent studies have suggested that focal irradiation using linear accelerator-based stereotactic radiosurgery or gamma-knife technologies can result in excellent local control and prolonged survival in some patients. It is possible that more aggressive combined modality treatment strategies, such as addition of systemic therapy, may further improve outcome. Current data suggest that aggressive treatment of patients with up to five brain melanoma brain metastases is capable of producing prolonged survival in many patients, including some long-term complete responses.     

Considerations in the diagnosis and management of brain metastases

Brain metastases are a common complication of systemic cancer and a significant cause of morbidity. For patients whose brain metastases remain untreated, the prognosis is poor. The advent of contrast-enhanced magnetic resonance imaging has made accurate diagnosis of brain metastases among symptomatic patients a much more manageable task. However, approximately one-third of patients with intracranial metastases are asymptomatic, and therefore, greater awareness of the risk factors for developing brain metastases may permit better targeting of "at risk" patients for further evaluation. Advances in technology and surgical techniques have created more options for the management of brain metastases via the use of various combinations of surgery, irradiation, and stereotactic radiosurgery. However, successful application of these therapies has redefined the potential for long-term morbidity associated with radiation therapy. Thus, considerable effort is now being directed toward finding a balance between the use of whole-brain radiotherapy, surgery, and radiosurgery, and tailoring those treatment modalities to the unique needs of the patient. Although more prospective, randomized studies are needed before an informed consensus regarding the optimal means for managing brain metastases can be established, this article provides an overview of some of the advantages and disadvantages of therapeutic approaches recently under study.     

A review of stereotactic radiosurgery in the management of brain metastases

This review addresses the epidemiology, historical reports, current issues, data and controversies involved in the management of brain metastases. The literature regarding surgery, whole brain radiation therapy, stereotactic radiosurgery or some combination of those treatments is discussed as well as issues of cost-effectiveness. Ongoing prospective randomized trials will further elucidate the optimal management for patients with brain metastases. Until those data are available, clinicians are encouraged to apply the existing data reviewed here in conjunction with best clinical judgment. A brief clinical guide is as follows. Patients with a solitary metastasis in an operable location and symptomatic mass effect should undergo surgery. Patients with poor performance status (KPS < 70) or more than three brain metastases should receive WBRT alone. Patients with 1-3 brain metastases and KPS >or= 70, should receive WBRT + SRS. If the patient refuses WBRT or needs salvage after WBRT, then SRS alone is appropriate. Clinicians should not be too dogmatic and should always apply the best clinical judgment.