Prise en charge des patients atteints de métastases cérébrales de mélanome

Whereas immune checkpoint inhibitors of serine/threonine protein kinase B-raf therapy dramatically changed metastatic outcomes of patients with melanoma, they remain at high risk of brain extension. Additional local treatment can be offered in this situation such as surgery and or stereotactic radiotherapy. In this review article, we describe the different options with published data and their optimal timing.     

Prise en charge symptomatique des métastases cérébrales

Indications and choice of antiepileptic drugs (AED), treatments for cerebral edema and prophylactic and curative treatments of thromboembolic complications of brain metastasis are discussed.     

Place de la chirurgie dans les métastases cérébrales

Surgical excision in brain metastases has been well evaluated in unique metastases. Two randomized phase III trials have shown that combined with adjuvant whole brain radiotherapy, it significantly improves overall survival. However, even in the presence of multiple brain metastases, surgery may be useful in large, symptomatic or life-threatening lesions (posterior fossa tumor with mass effect). Also, even in lesions amenable to radiosurgery, surgical resection is preferred when tumors displayed cystic or necrotic aspect with important edema or when located in highly eloquent areas or cortico-subcortically. Furthermore, surgery may have a diagnostic role, in the absence of histological documentation of the primary disease, if the radiological aspect is atypical to rule out differential diagnosis (brain abscess, lymphoma, primary tumor of the central nervous system) or in case of suspicion of progression after irradiation to differentiate radionecrosis from a genuine progression of brain disease. Finally, the issue of biological documentation of brain disease may arise in situations where a specific targeted therapy can be proposed. If the surgical indications are relatively well defined, the selection of patients who will really benefit from surgery should take into account three factors, clinical and functional status of the patient, systemic disease status and characteristics of intracranial metastases. Given the improved survival of cancer patients due to the advent of effective targeted therapies on systemic disease, a renewed interest has been given to local therapy (surgery or radiosurgery) in brain metastases. Surgical resection currently represents a valuable tool in the armamentarium of brain metastases but has also become a diagnostic and decision tool that can affect therapeutic strategies in these patients.     

Aspects anatomocliniques des métastases cérébrales des carcinomes nasopharyngés

Metastasis to the central nervous system, either through a hematogenous route or through the cerebrospinal fluid, is extremely rare in nasopharynx cancer. We aim to expose clinical aspects, therapeutic features and prognosis of nasopharyngeal carcinoma with brain metastases. We retrospectively reviewed the medical history of about 420 patients with nasopharyngeal carcinoma treated during 17 years at the university hospital of Sfax (Tunisia). Among them, three patients had brain metastasis. We excluded patients with direct extension to the brain. Tumours of the nasopharynx were locally advanced. The first patient had brain metastases at the initial diagnosis. The two other patients had brain metastases at 10 and 16 months during the follow-up. Ocular signs were the symptoms. Lesions were unique in two patients. Synchronous bone metastases were recorded in the three cases. All patients had whole brain radiation therapy and palliative chemotherapy. All patients had a progression of the disease and died. Brain metastases in nasopharynx cancer represent a rare event. Prognosis is poor, depending on age, surgical excision and synchronous metastases. Survival does not exceed 6 months.     

Épidémiologie des métastases cérébrales et tropisme cérébral

Recent progresses in chemotherapies and targeted therapies have improved survival in cancer patients. In this context of better-controlled systemic disease, brain metastases (BM) are emerging as a new challenge for the oncologist. However, BM epidemiology and biology remain largely unclear. Incidence of BM is increasing. This trend could be explained by improvement in the quality of neuro-imaging (MRI) and increased survival. Primary cancers associated with BM patients are mainly: lung, breast, renal, colorectal cancers and melanoma. Prevalence of BM is estimated at 9% although this figure is probably underestimated. Time from initial to BM diagnoses is increasing and BM is occurring more frequently in individuals with advanced-stage disease. Biology of BM remains poorly known. Interactions between circulated tumoral cells (CTC) and blood-brain-barrier (BBB) cells are required. Some cytokines may act as CTC attractants and promote BM formation. BM development also involves several steps (extravasations through non-fenestrated capillaries, local proliferation, neoangiogenesis…), which represent potential therapeutic targets.     

Place de la chirurgie dans la prise en charge des métastases cérébrales

Surgical excision of brain metastases has been well evaluated in unique metastases. Two randomized phase III trial have shown that combined with adjuvant whole brain radiotherapy, it significantly improves overall survival. However, even in the presence of multiple brain metastases, surgery may be useful. Also, even in lesions amenable to radiosurgery, surgical resection is preferred when tumors displayed cystic or necrotic aspect with important edema or when located in highly eloquent areas or cortico-subcortically. Furthermore, surgery may have a diagnostic role, in the absence of histological documentation of the primary disease, to rule out a differential diagnosis (brain abscess, lymphoma, primary tumor of the central nervous system or radionecrosis). Finally, the biological documentation of brain metastatic disease might be useful in situations where a specific targeted therapy can be proposed. Selection of patients who will really benefit from surgery should take into account three factors, clinical and functional status of the patient, systemic disease status and characteristics of intracranial metastases. Given the improved overall survival of cancer patients partially due to the advent of effective targeted therapies on systemic disease, a renewed interest has been given to the local treatment of brain metastases. Surgical resection currently represents a valuable tool in the armamentarium of brain metastases but has also become a diagnostic and decision tool that can affect therapeutic strategies in these patients.     

Stratégies de prise en charge des métastases cérébrales des malades atteints de cancers bronchiques primitifs

Brain metastases from primary lung cancer represent 40% of all brain metastases. On the other hand, 10 to 80% of primary lung cancer patients will present with synchronous or metachronous brain metastases. Management of these patients is therefore a big challenge. The management will depend on the circumstances of diagnosis (symptomatic or not), the cancer history (synchronous or metachronous brain metastases), the histology and the number of lesions.     

Métastases cérébrales de cancer du sein : traitements systémiques

An increase in the incidence of breast cancer patients with brain metastases has been observed over the last years, mainly because the recent development of new drugs including therapies targeting HER2 (human epidermal growth factor receptor 2) resulted in an increased survival of these patients. With HER2+ patients living longer and the well-known neurotropism of HER2+ tumour cells, the resulting high incidence of brain metastases is not really surprising. Moreover, brain metastases more often occur within a context of existing extracranial metastases. These need to be treated at the same time in order to favourably impact patients’ survival. Consequently, the management of breast cancer patients with brain metastases clearly relies on a multidisciplinary approach, including systemic treatment. A working group including neuro-oncologists, neurosurgeons, radiation oncologists and oncologists was created in order to provide French national guidelines for the management of brain metastases within the “Association des neuro-oncologues d’expression française” (ANOCEF). The recommendations regarding the systemic treatment in breast cancer patients are reported here including key features of their management.     

Traitements médicamenteux des métastases cérébrales des cancers du sein HER2+

Breast cancer is the second leading cause of brain metastases. In patients with HER2-positive breast cancer, the incidence of brainmetastases is 40%. Although the arrival of anti-HER2 therapies has meant better control of other metastatic diseases, progress still needs to be made with regard to therapies for treating brain metastases. Currently, research is concentrating on chemoradiotherapy combinations, anti-HER2 and chemotherapy combinations, more specifically, combining lapatinib and capecitabine, or even intrathecal administration of herceptin.     

Traitements systémiques des métastases cérébrales (MC) des cancers bronchiques à petites cellules (CPC)

Patients with small cell lung cancer present initially with brain metastases in 10 to 24 % of the cases when detected respectively by CT scan or Gadolinium-enhanced MRI of the brain. The aim of this review is to evaluate the effectiveness of systemic chemotherapy for the treatment of brain metastases from small cell lung cancer in first and second line: in fact, there are only case reports, small phase II studies and one phase III study. In spite of the scarcity of these data, the efficacy of the systemic treatment is shown and the guidelines recommend the use of chemotherapy, particularly in asymptomatic patients.     

Place de l’irradiation stéréotaxique hypofractionnée dans le traitement des métastases cérébrales

PurposeA survey of the literature has been performed to find arguments in order to help the choice between radiosurgery and hypofractionnated stereotactic radiotherapy in the treatment of brain metastases.Patients and methodsA comparison of two groups of brain metastases treated with hypofractionnated stereotactic radiotherapy or radiosurgery, with or without WBRT was performed. Hypofractionnated stereotactic radiotherapy: there were eight series including 448 patients published from 2000 to 2009; treated with 5–6 MV X-Rays, non invasive head immobilization, a margin 2 to 10 mm; 24 to 40 Gy in three to five fractions; a 5 to 8 days duration in six series and 15–16 days in two other series. WBRT (30%) ; radiosurgery: there were 12 series (1994 to 2005) including 2157 patients; an invasive head immobilization, no margin; doses from 10 to 25 Gy; six series over 12 had Gamma Knife radiosurgery and six had Linacs X-Rays. WBRT (30 Gy/10 F/12 days) associated to radiosurgery in several series. The following parameters were compared: median GTV, median survival, 1-year survival rate, local control rate, necrosis and WBRT rates.ResultsHypofractionnated stereotactic radiotherapy series: the parameters were respectively: 0,52–4,47 cm³ (median 2,8 cm³); 5–16 months (median 8,7 months); 68,2–93% (median 82,5%); necrosis rate 3,1%; associated WBRT 30%. Radiosurgery series: the parameters were respectively: 1,3 to 5,5 cm³ (median 2 cm³); 5,5 to 22 months (median 11 months); 71 to 95% (median 85%); 0,5 to 6% (median 2,4%); associated WBRT 58%. Results seem similar in the two groups: Hypofractionnated stereotactic radiotherapy with non invasive immobilization could theoretically treat all brain metastases sizes except lesions < 10 mm (500 mm³). In large volumes, > 4200 mm³ GTV, the toxicity of hypofractionnated stereotactic radiotherapy was not reported, thus it was difficult to compare its results with the published reports of radiosurgery toxicity. WBRT was a confusing parameter. Obviously, this initial survey has important limitations, specifically its methodology.ConclusionRadiosurgery and hypofractionnated stereotactic radiotherapy could be used to treat brain metastases with GTV > 500 mm³ and ≤ 4200 mm³ (Ø 20 mm); for GTV < 500 mm³ (Ø 10 mm) an invasive procedure with radiosurgery is necessary. For GTV > 4200 mm³ (Ø 20 mm), hypofractionnated stereotactic radiotherapy could be proposed, provided further studies, using 4 to 6 Gy fractions, a duration less or equal to 10–12 days and a margin of 2 mm will be performed.     

Place de la radiothérapie panencéphalique dans les métastases cérébrales

Brain metastases are the leading cause of intracranial malignancy and a major cause of mortality and morbidity. From 20 to 40% of cancer patients develop brain metastases. The irradiation of the whole brain remains the most commonly undertaken treatment, but should be discussed in relation to other therapeutic alternatives such as stereotactic radiotherapy or the use of new chemotherapy drugs. Its use according to pathology should be discussed. It can lead to a long-term neurocognitive toxicity that should be evaluated more precisely. This literature review aims to highlight the role of whole-brain radiotherapy used alone or in combination with other treatments.     

La réirradiation des métastases cérébrales : revue des cinq dernières années

No recommandations have been established for reirradiation of brain metastases yet. The purpose of this review is to analyse the data of the five last years about the feasibility, efficacy and tolerance of reirradiation of brain metastases. Reirradiation can be 3D conformal or stereotactic. Whole brain irradiation seems appropriate for multiple brain metastases in order to obtain symptomatic relief, with or without supportive care. Stereotactic reirradiation has shown satisfying results in terms of overall survival, local control, without significant toxicity. Prospective trials are necessary in order to validate consensual recommandations.     

Traitements systémiques des métastases cérébrales des cancers du sein : chimiothérapies cytotoxiques et thérapies ciblées

Prevalence of brain metastases is increasing in breast cancer. Brain metastases represent a poor-prognosis disease for which local treatments continue to play a major role. In spite of the presence of a physiological blood-brain barrier limiting their activity, some systemic treatments may display a significant antitumor activity at the central nervous system level. In HER2-positive metastatic breast cancer with brain metastases not previously treated with whole brain radiotherapy, capecitabine and lapatinib combination obtains a volumetric reponse in two thirds of patients (LANDSCAPE study). If confirmed, these results could modify in selected patients the layout of therapeutic strategies. Promoting novel targeted approaches and innovative therapeutic combinations is a critical need to improve survival of breast cancer patients with brain metastases.     

La radiothérapie en conditions stéréotaxiques des métastases cérébrales en situation complexe

Stereotactic radiation therapy of brain metastases is a treatment recognized as effective, well tolerated, applicable for therapeutic indications codified and validated by national and international guidelines. However, the effectiveness of this irradiation, the evolution of patient care and the technical improvements enabling its implementation make it possible to consider it in more complex situations: proximity of brain metastases to organs at risk; large, cystic, haemorrhagic or multiple brain metastases, combination with targeted therapies and immunotherapy, stereotactic radiotherapy in patients with a pacemaker. This article aims to put forward the arguments available to date in the literature and those resulting from clinical practice to provide decision support for the radiation oncologists.     

Adaptation de la radiothérapie des métastases cérébrales selon la classification GPA (Graded Prognostic Assessment)

The management of patients with brain metastases remains a difficult and controversial subject. For years, the standard treatment has been whole-brain radiation therapy alone, but its validity is now under question because of improvements in surgery and the development of radiosurgery or novel targeted therapies and also because whole-brain radiation therapy is responsible for long term neurocognitive toxicity. Therefore it is important to assess diagnosis-specific prognostic factors and indexes when scheduling treatments. The GPA score (Graded Prognostic Assessment), established for various histologic tumor types, includes five prognostic factors: age, Karnofsky Performance Status, presence of extracranial metastases, number of brain metastases and also genetic subtype for breast cancer. We propose an adaptation of the management of brain metastases according to the GPA score.     

Place de la radiochirurgie et de la radiothérapie stéréotaxique hypofractionnée dans la prise en charge des métastases cérébrales

Brain metastases management is still controversial even though many trials are trying to define the respective roles of neurosurgery, whole-brain radiotherapy, single-dose stereotactic radiotherapy and fractionated stereotactic radiotherapy. In this article, we review data from trials that examine the role of radiosurgery and fractionated stereotactic radiotherapy in the management of brain metastases.