Brain metastases are the most common intracranial tumor in adults, occurring about 10 times more frequently than primary intracranial tumors. 8-10% of patients with malignant tumors develop intracranial metastases. Autopsies have reported results even higher than this probability. With advances in diagnostic and treatment techniques, many patients receive appropriate treatment and do not ultimately die from brain metastases.
Although the literature reports the highest probability of brain metastases from malignant melanoma, lung cancer remains the most common source of intracranial metastases, accounting for approximately 50% of intracranial metastases. Breast cancer patients have an increasing incidence of central nervous system invasion due to advances in treatment. 80% of brain metastases occur in the cerebral hemispheres, 15% in the cerebellum, and 5% in the brainstem. The cerebral corticomedullary junction has narrower branching vessels, which is why metastases tend to occur there.
The clinical symptoms and signs of brain metastases are similar to those of other intracranial occupying lesions, including increased intracranial pressure such as headache, nausea, vomiting, and neurological localization signs.
Treatment overview
1.Surgical treatment
With the advancement of surgical techniques, the mortality rate of surgery has decreased from 4.6% in 1988-1990 to 2.3% in 1997-2000, and surgical resection + whole brain radiotherapy (WBRT) is currently one of the standard treatments for intracranial solitary brain metastases. However, the outcome of surgery is related to the size of the hospital and the technical proficiency of the surgeon.
Patchel randomized 95 patients with solitary brain metastases to the surgery and surgery + WBRT groups. As a result, postoperative WBRT significantly reduced local recurrence (18% vs. 70%, p<0.001) and neurologically related mortality (14% vs. 44%, p=0.003), with no significant difference in overall survival between the two groups.
In multiple brain metastases, the role of surgery is limited to obtaining pathology or reducing the occupying effect and symptoms of cranial hypertension. However, there is evidence that surgical resection can prolong survival in some patients with 1-3 metastases who have a better prognosis.
2. Stereotactic radiosurgery (SRS)
Compared to surgery, SRS is minimally invasive, has no procedure-related deaths, and late complications such as edema and radionecrosis are rare. There is increasing evidence that total tumor volume is a better predictor of survival after SRS for patients with brain metastases than the number of metastases.
A multiple regression analysis of 205 patients with multiple brain metastases (4 or more) undergoing SRS showed that total volume was the most important prognostic factor, whereas the number of metastases had no significant effect on prognosis. Another analysis from the same study suggested that the subgroup of patients with less than 7cc total volume and less than 7 metastases had a better prognosis, and these patients had a significantly longer survival (13 months versus 6 months, p<0.0005). < p="">
Another randomized controlled study suggested that patients with a total treated volume of <5cc or 5-10cc of brain metastases had a significantly longer survival than those with >10cc, and there was no significant difference in survival between patients with single and multiple brain metastases.
Chang et al. grouped patients according to the number of metastases and found no significant differences in survival or local control rates between the groups. However, patients with more than 15 lesions were more likely to develop new metastases and distant tumor progression.
In general, patients with multiple brain metastases with small overall tumor volumes are suitable for SRS; in addition, patients with good prognostic pathological types (e.g., breast cancer) and patients with controlled primary tumors are more likely to benefit from SRS treatment regardless of the number of metastases. SRS has also achieved better local control in some radiation-resistant pathology types such as malignant melanoma and renal cancer. Other prognostic factors for SRS include age, PS score, and control of the primary tumor.
In Japan, 132 patients with brain metastases less than 3 cm in diameter and 1-4 lesions were randomized into two groups: the SRS group and the SRS+WBRT group.
Another randomized controlled study was terminated early due to severe cognitive decline in the SRS+WBRT group compared to the SRS group (52% vs. 24%), enrolling 58 patients. Data analysis suggested that the 1-year relapse-free survival rate was higher in the SRS+WBRT group than in the SRS group (73% versus 27%).
The EORTC 22952-26001 study enrolled 359 patients with 1-3 brain metastases who were treated with surgery or SRS first and then divided into two groups based on the presence or absence of WBRT, with reduced intracranial recurrence and neurologically related mortality in the WBRT group, but similar overall survival.
Another meta-analysis also showed that SRS followed by WBRT did not result in an overall survival benefit.
Retrospective analysis showed that overall survival was similar or better in the SRS+WBRT compared with surgery+WBRT, and local control rates were also higher in the SRS+WBRT group, especially in radiosensitive tumors or solid metastases.
A retrospective study enrolling 1194 patients with brain metastases treated with SRS found no significant difference in overall survival between patients with 2-4 brain metastases and those with 5-10 brain metastases. The SRS alone group was less invasive, had similar overall survival and local control rates, but had a somewhat higher rate of intracranial distant recurrence.
In addition, data from several studies have shown that patients with brain metastases with high PS scores and stable primary tumors can still achieve local control rates of more than 70% with SRS after WBRT.
3.Whole brain radiotherapy (WBRT)
WBRT has been the main treatment for patients with brain metastases for many years. Even now, WBRT plays a very important role in the treatment of brain metastases. For example, surgical resection or SRS is not feasible (e.g., multiple brain metastases), combined with SRS or surgery to prevent recurrence, and as salvage therapy for patients with recurrence.
Three randomized controlled studies compared the clinical outcomes of WBRT and surgery + WBRT. patchel reported 48 patients in whom WBRT after surgery prolonged overall survival (40 weeks versus 15 weeks, p<0.01) and time to self-care (38 weeks versus 8 weeks, p<0.05) and reduced the rate of local recurrence (20% versus 52%, p<0.02). < p="">
Vecht and colleagues reached similar conclusions (n = 61), with the greatest differences in median survival and time to self-care between the two groups in patients with stable primary tumors: median survival was 12 and 7 months, respectively, and time to self-care was 9 and 4 months, respectively. In another study, which enrolled 84 patients, there was no significant difference in survival between the two treatment regimens, probably because patients with extensive systemic metastases and poor physical status were not excluded from the enrollment criteria, and these patients had a poorer prognosis for surgical resection.
Two randomized controlled studies evaluated the effect of SRS push after WBRT. 333 patients with 1-3 brain metastases were randomized in the RTOG9508 study to the WBRT and WBRT+SRS groups. Although some patients with large metastases (3-4 cm) that were not suitable for SRS treatment were not excluded, the authors still found a significant survival benefit in the combination therapy group for patients with single brain metastases (6.5 and 4.9 months, p=0.04), but patients with 2-3 metastases did not have prolonged survival from the combination therapy.
Another clinical study with a small sample of 2-4 lesions showed no significant difference in survival between the two groups despite the prolonged time to local failure with SRS nudging after WBRT (36 months versus 4 months, p=0.005).
Meta-analysis showed no significant difference in survival between the WBRT and WBRT+SRS groups, but local control and patient physical status were significantly improved in the WBRT+SRS group. post-WBRT SRS boost prolonged survival in patients with solitary brain metastases (6.5 months versus 4.9 months, p=0.04).
Overall, patients with solid metastases in good physical condition who underwent surgical resection + WBRT or SRS had a better prognosis than those who underwent WBRT alone. However, many patients are not suitable for surgical resection, such as tumors located in functional areas, extensive systemic metastases, or other reasons. Whole brain radiotherapy is the primary treatment for these patients.
Treatment options for recurrent patients are not supported by RCT data. However, a retrospective case study suggests that 31-70% of patients can achieve symptomatic improvement after recurrent radiotherapy.
4. Systemic therapy
Systemic therapy is rarely used as the initial treatment for patients with brain metastases. Temozolomide (TMZ) has been reported to increase progression-free survival and response rate to radiotherapy, but randomized controlled studies have demonstrated that carboplatin or TMZ+WBRT do not improve overall survival. This may be due to the insensitivity of brain metastases to chemotherapy or to multiple prior chemotherapies, as well as the difficulty of crossing the blood-brain barrier with chemotherapy drugs.
Nevertheless, chemotherapy is the last treatment option that has to be considered when other treatments (surgery, SRS, radiotherapy) are not available for relapsed patients. The choice of drug depends on the pathological type of the primary tumor. Implantation of carmustine extended release at the time of surgery in patients with recurrence is a reasonable option.
Among chemotherapeutic agents, TMZ is effective in patients with brain metastases from primary malignant melanoma. a phase II clinical study of TMZ in combination with a long course of thalidomide for brain metastases was conducted, but the high treatment toxicity and low response rate made this regimen not very reasonable.
High-dose methotrexate regimens for brain metastases from breast cancer have achieved 56% disease control rates. Other agents such as platinum and etoposide, capecitabine ± lapatinib are also effective in brain metastases from breast cancer.
A phase Ι/II clinical study demonstrated a 72% response rate with topotecan + WBRT in 75 patients with brain metastases, but the phase III study was closed early due to slow enrollment.
Rapid advances in the treatment of malignant melanoma have provided effective systemic therapy options for the treatment of metastatic malignant melanoma. Immunotherapeutic agents (lipilimumab) and BRAF inhibitors (dabrafenib and vemurafenib) are both effective for brain metastases from malignant melanoma.
NCCN recommends
1. Screening
CT or MRI for single or multiple intracranial brain metastases, or if the primary tumor is unclear, a systemic workup, including chest x-ray or CT, abdominal or pelvic CT, or other tests.
FDG-PET may be considered in patients with multiple brain metastases or unclear primary tumors. If biopsy of other sites is difficult, stereotactic or cranial biopsy is recommended to confirm the diagnosis. Patients with definite primary tumors who are in doubt about the diagnosis of brain metastases are recommended to have stereotactic, cranial biopsy or SRT for definite diagnosis. The NCCN expert committee recommends multidisciplinary consultation before treatment to develop a reasonable treatment plan.
2.Treatment options for 1-3 metastases
Aggressive treatment is highly recommended for brain metastases with low systemic tumor load or with appropriate systemic treatment options. Surgery + WBRT is recommended for patients with operable brain metastases (Category 1) or SRS + WBRT for patients with single brain metastases (Category 1). Other treatment options include SRS alone or SRS after surgical resection (Class 2B recommendation).
The goal of surgery is total microscopic resection. The choice of craniotomy or SRS depends on the size and location of the tumor. SRS treatment of small, deeply located brain metastases with an experienced treatment team often results in the best outcome. If the tumor cannot be removed, WBRT or SRS may be considered.
Surgery may also be used for symptomatic relief. Patients with asymptomatic brain metastases with a primary tumor and a therapeutic target (e.g., EGFR mutation in NSCLC, BRAF mutation in malignant melanoma) may also be justified to try targeted therapy prior to radiotherapy.
Patients should have their MRI reviewed every 2-3 months and after 1 year depending on the clinical situation. In particular, patients with SRS alone should be followed up closely every 2 months. Sometimes recurrence on imaging can be misdiagnosed as a treatment effect of SRS. Biopsy should be performed when recurrence is highly suspected. If tumor recurrence is confirmed, the next treatment step should be selected based on the history of previous treatment and local and systemic tumor.
For patients with local recurrence after surgery, the following treatment options are available: surgery; single or divided SRS; WBRT; and chemotherapy. Patients with recurrence who previously received WBRT should not receive WBRT because of the risk of radiation brain necrosis.
The treatment of new intracranial metastases after SRS depends on the number of new metastases and may consider whole brain radiotherapy or local/systemic chemotherapy. Patients with 1-3 new metastases may also be considered for surgery or repeat SRS.
Patients without WBRT may be treated with WBRT (30-45 Gy, 1.8-3.0 Gy/f) depending on the patient’s PS score. Local/systemic chemotherapy may be used selectively in patients with multiple brain metastases and uncontrolled disease after SRS.
Palliative or best supportive care is preferred if the patient is progressive and in poor physical condition with no effective treatment options. Patients without prior radiotherapy may be treated with WBRT, and patients after WBRT may also be considered for recourse to radiotherapy, provided that the patient has a good initial outcome.
3. Treatment options for patients with >3 metastases
All patients with more than 3 brain metastases should be treated with either WBRT or SRS as initial treatment. 30 Gy/10f or 37.5 Gy/15f is the standard regimen for WBRT, and short courses of radiotherapy (20 Gy/5f) may be considered for patients with poor neurological status. Palliative surgery may be considered if the tumor has a strong occupying effect, hemorrhage, or life-threatening hydrocephalus.
Patients should undergo MRI enhancement scans every 3 months for 1 year after WBRT or SRS. If recurrence is detected, treatment options depend on the stability of the patient’s systemic tumor and the availability of effective systemic therapies. Patients with progressive tumors may be considered for palliative care, best supportive care, or radiation therapy. Patients with stable tumors may be considered for surgery, radiotherapy or chemotherapy.