1.Introduction
Although earlier domestic reports stated that brain metastases accounted for only 3.5%-10% of intracranial tumors [1]; however, recent foreign reports have indicated that the incidence of brain metastases can be as high as 4-5 times that of primary brain tumors and has become an important disease threatening human health [2]. Therefore, it is important to optimize the treatment plan of brain metastases to prolong the survival and improve the quality of survival of patients. Recently, the American Federation of Neurological Surgeons (the
Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS) Joint Oncology Section have recently organized a meeting of experts in microsurgery, stereotactic surgery, radiation therapy, and pharmacotherapy for the treatment of brain metastases. The 2010 AANS/CNS Evidence-Based Guidelines for the Treatment of Brain Metastases (hereinafter referred to as “the Guidelines”) were developed based on a systematic review of the relevant literature from 1990-2008 and a few back to 1970 using Medline and other databases. The Guidelines are divided into eight sections covering the role of whole brain radiotherapy, surgical resection, stereotactic radiosurgery and chemotherapy in the management of newly diagnosed brain metastases, the treatment of recurrent and/or progressive brain metastases, the use of prophylactic antiepileptic drugs, hormonal therapy and the use of new therapies [2-3]. The Guidelines are of reference value for the standardized treatment of brain metastases and are interpreted as follows.
2. Evidence classification and strength of recommendation in the guideline
2.1 Evidence sources are divided into 3 categories ① Class I Evidence provided by one or more well-designed randomized controlled clinical trials or meta-analyses; ② Evidence provided by well-designed clinical observations and concurrent controls; ③ Expert opinion, case studies or historical controlled studies [3].
2.2 There are three types of recommendation strength ① positive recommendation (level 1) treatment principles with high clinical credibility and universal acceptance; ② recommended adoption (level 2) treatments and techniques with clinical credibility; ③ cautious consideration (level 3) treatment strategies with uncertain clinical outcomes [3].
3.Guideline details
3.1 Role of whole-brain radiotherapy in the treatment of newly diagnosed brain metastases
3.1.1 Indications Primarily for newly diagnosed adult solitary brain metastases suitable for surgical resection, but the recommendations in this Guideline do not apply to small cell lung cancer, leukemia, lymphoma, germ cell tumors, and multiple myeloma, which are relatively sensitive to radiotherapy [4].
3.1.2 Surgical resection + whole brain radiation (WBRT) is superior to WBRT alone and is also superior to surgical resection alone in terms of improved control of initial metastases and overall control of the tumor (Class I evidence) [4]. The Guidelines positively recommend surgical resection + postoperative WBRT for those with good general functional status (self-care, less than 50% bed rest) and limited extracranial lesions, but there is insufficient evidence for surgical resection + WBRT for those with poor functional status scores, in advanced stages of cancer or with multiple brain metastases (level 1) [4].
3.1.3 There is no significant difference in median survival, local tumor control, or changes in neurocognitive function between a “standard” WBRT dose/split (30 Gy/10 doses) compared to a bioequivalent dose (e.g., 39 Gy/10 doses) (Class I evidence) [4].
3.1.4 There is insufficient evidence for the need to select the dose/segmentation regimen of WBRT based on the pathological type of the tumor [4].
3.2.Role of surgical resection in the treatment of newly diagnosed brain metastases
3.2.1 Indications Newly diagnosed, adult solitary brain metastases suitable for surgical resection [5].
3.2.2 Surgical resection + WBRT is superior to surgical resection alone in terms of both initial site of metastases and lesion control in the whole brain [5] (Grade 1).
3.2.3 Both surgical resection + WBRT and stereotactic radiosurgery (SRS) ± WBRT are effective treatment strategies with essentially the same patient survival rates. However, the efficacy of SRS in the treatment of tumors >3 cm in diameter with significant occupying effects (midline shift >1 cm) has not been proven (grade 2) [5]. The Guidelines suggest that in patients with solitary brain metastases, SRS alone is comparable to surgical resection + WBRT in terms of improving patient function and survival if promptly treated with remedial SRS once new metastases in distant septal sites are identified (Grade 3) [5].
3.2.4 Domestic experience Some authors have suggested that for brain metastases with lesions larger than 2 cm, surgery should be preferred whenever there is an indication for surgery [6]. This is because: (1) brain metastases are mostly located at the junction of gray matter and white matter, with shallow location, simple surgical operation, few complications, and fast postoperative recovery; (2) for multiple lesions, craniotomy can also be considered for resection via one craniotomy if the responsible lesions are adjacent to each other; (3) surgical treatment can not only prolong the patient’s life and improve the quality of life, but also clarify the pathological diagnosis for those with metastases as the first manifestation, so as to deduce the primary lesion and guide systemic comprehensive treatment [6]. Other authors, based on a retrospective analysis of 102 patients with surgically resected solitary brain metastases, suggested that factors associated with improved prognosis included age <65 years, absence of extracranial metastases, control of the primary site, patient KPS score ≥70, tumor pathology of non-small cell lung cancer, and stereotactic radiosurgery [7].
3.3 Role of SRS in the treatment of newly diagnosed brain metastases
3.3.1 Indications Newly diagnosed adult solid brain metastases with a maximum diameter of less than 3 cm and a mild occupying effect (midline shift of less than 1 cm) [8].
3.3.2 Comparison of SRS+WBRT with WBRT alone showed that (i) in patients with a single brain metastasis and a KPS ≥ 70 score, single SRS+WBRT was able to significantly prolong patient survival (grade 1) compared with WBRT alone; (ii) in patients with one to four brain metastases and a KPS ≥ 70 score, single SRS+WBRT was superior to WBRT alone in terms of local control of the tumor and the patient’s functional status maintenance than WBRT alone (grade 1); (iii) for patients with 2-3 brain metastases, single SRS+WBRT was able to significantly prolong patient survival compared with WBRT alone (grade 2); (iv) for patients with single or multiple brain metastases and KPS<70 scores, single SRS+WBRT was superior to WBRT alone in improving patient survival (grade 3) [8 -9].
3.3.3 SRS + WBRT is comparable to SRS alone in improving patient survival (Grade 2), but there is Class I evidence that SRS + WBRT reduces distant recurrence; therefore, the Guidelines recommend regular monitoring of patients treated with SRS only to enable early detection of local and distant lesion recurrence and prompt remedial treatment [8].
3.3.4 Both surgical resection + WBRT and SRS ± WBRT are effective treatment strategies, and patients treated with both regimens have similar survival; however, there is no evidence-based medical evidence for the efficacy of SRS for lesions that are large in size (>3 cm) or have significant occupancy effects (midline shift >1 cm) (level 2) [8].
3.3.5 Both SRS alone and WBRT alone are effective strategies for the treatment of brain metastases, but SRS alone is superior to WBRT (grade 3) in terms of prolonged survival in patients with less than 3 metastases [8].
3.3.6 Domestic experience Qian Wei et al [10] proposed on the basis of summarizing 780 cases of brain metastases treated with gamma knife: ① the average tumor diameter <3 cm and the maximum diameter ≤4 cm is appropriate; ② the vast majority of patients can be treated at one time, and it is appropriate to treat up to 4 lesions at one time; ③ for metastases less than 2 cm in diameter, 6-8 lesions can be treated at one time; ④ for patients with more metastases and larger tumor (4) for patients with more metastatic lesions and larger tumor volume, treatment can be divided; (5) those with intracranial hypertension before treatment cannot be completely considered as contraindications and can be treated while using mannitol and hormones. Shen Guangjian et al [11] concluded that radiosurgery is more effective for brain metastases that respond well to combined dexamethasone and mannitol, and suggested it as a rough but practical criterion for selecting cases and judging prognosis, especially for those for whom pathological diagnosis is not available.
3.4 The role of chemotherapy in the treatment of newly diagnosed brain metastases
3.4.1 Indications For newly diagnosed adult brain metastases, but the recommendations of this guideline do not apply to brain metastases from germ cell tumors that are highly sensitive to chemotherapy [12].
3.4.2 WBRT versus chemotherapy The Guide suggests that four Class I clinical studies performed with carboplatin, chloroethylnitrosoureas, tegafur and temozolomide have shown that the routine application of chemotherapy after WBRT is not helpful in prolonging patient survival and is not recommended [12]. However, the Guidelines also emphasize that two points need to be noted when developing individualized treatment regimens: first, the vast majority of data collected so far are limited to non-small cell lung cancer and breast cancer, so other pathological types of tumors are not excluded from benefiting from a WBRT+chemotherapy regimen; second, some clinical trials have shown that concurrent chemotherapy at the time of WBRT improves treatment response rates, especially in patients with non-small cell lung cancer Therefore, clinical trials in this regard are encouraged [12].
3.5. Retreatment of recurrent/progressive brain metastases
3.5.1 Indications Recurrent/progressive brain metastases in adults who have undergone WBRT, surgical resection, and/or radiosurgery, i.e., metastases that have recurred or increased in size at the initial site and/or other sites in the brain after initial treatment [12].
3.5.2 Choice of treatment The Guidelines recommend that individualized treatment plans should be developed based on the patient’s systemic functional status, extent of disease, type of primary cancer, size and number of metastases, site of disease, and the effectiveness of the initial treatment regimen, such as the choice of supportive therapy, surgical resection, relatively milder chemotherapy regimens, or re-radiation therapy (WBRT and/or SRS) (Level 3) [13].
3.6 Role of prophylactic antiepileptic therapy in the management of brain metastases
3.6.1 Indications Adult patients with solid brain metastases who have not had epilepsy [14].
3.6.2 The Guidelines do not recommend the routine use of antiepileptic drugs in such patients (Grade 3) [14].
3.7 The role of hormones in the treatment of brain metastases
3.7.1 Indications Adults with a diagnosis of brain metastases [15].
3.7.2 Selection of hormone therapy according to the situation ① Patients with asymptomatic brain metastases without occupying effect do not need hormone therapy. (ii) Corticosteroids can be carefully considered for temporary relief of symptoms in those with occupying effects but mild symptoms, and the recommended starting dose of dexamethasone is 4 to 8 mg/d (grade 3). (iii) Dexamethasone at a dose of 16 mg/d or higher (grade 3) is recommended for brain metastases secondary to increased intracranial pressure and cerebral edema and severe symptoms [15].
3.7.3 Choice of hormone type The Guidelines consider dexamethasone to be the best choice (grade 3).
3.7.4 Duration of hormone administration Individualized treatment regimens should be developed based on a full understanding of the side effects of long-term hormone application, which should generally be tapered over about 2 weeks and can be slightly longer for symptomatic individuals (level 3) [15].
3.8. The role of new therapies in brain metastases
3.8.1 Novel radiotherapy sensitizers Although the results of a subgroup analysis of a large sample of prospective randomized controlled studies showed that early application of motexafin-gadolinium (MGd) delayed the progression of neurological symptoms in patients by increasing sensitivity to radiotherapy, the Guidelines concluded that the evidence for the routine use of MGd was not sufficient (level 2) [16].
3.8.2 Intrastromal therapy Due to the lack of sufficient evidence-based medical evidence, novel or existing intrastromal radiotherapy, chemotherapy, and/or other intrastromal therapies have yet to be further investigated [16].
3.8.3 Novel chemotherapeutic agents Temozolomide combined with whole-brain radiotherapy is effective in the treatment of melanoma brain metastases (level 2) [16, 17]; temozolomide or fotemustine also benefit some patients with brain metastases (level 3) [16].
3.8.4 Molecularly targeted agents The Guidelines suggest that the epidermal growth factor receptor inhibitor gefitinib (gefitinib) can be used in the treatment of brain metastases from non-small cell lung cancer (grade 3) [16].
4. concluding remarks
In recent years, the incidence of brain metastases has been increasing. The reasons for this may be related to the following factors: (1) the influence of environmental factors and the advent of an aging society have increased the overall incidence of tumors in the population; (2) it may be related to the improvement of medical care, which has prolonged the life span of tumor patients, thus allowing enough time for the formation of symptomatic brain metastases; (3) the improvement of imaging technology has increased the detection rate of asymptomatic brain metastases, etc. Although the combination of whole brain radiotherapy, surgical resection, stereotactic radiosurgery, chemotherapy and emerging therapies have played an active role in the remission of symptoms and prolongation of survival of patients [4-12, 16, 20,
This guideline, based on a systematic review of the literature by the Joint Oncology Section of AANS and CNS, is an important reference for individualized protocols for the treatment of brain metastases in clinical practice, but of course it needs to be validated and improved in clinical practice.