Treatment of brain metastases
Untreated brain metastases have an average survival of 4 weeks and are the leading cause of death in cancer patients. Its treatment aims to improve symptoms, prolong patients’ survival time and improve the quality of survival. In the early years, the standard treatment included hormone and fractionated radiation therapy; in the past 30 years, surgical resection of tumor plus postoperative radiation therapy has become one of the standard treatments; since the 1990s, radiosurgery has been widely used in the treatment of brain metastases and has become an emerging means of modern standard treatment for brain metastases. The conditions of patients with brain metastases are diverse, and a variety of factors affect the prognosis of patients.
1. Assessment of prognostic factors for brain metastases
Gaspar et al. (2000) published a regression analysis (RPA) of prognostic factors in patients treated with radiation therapy for brain metastases, which classified patients with brain metastases into three levels according to long-term quality of life assessment (KPS), control of primary cancer, age and presence of extracranial metastases: I grade is KPS≥70, age<65 years, primary cancer regression and control, and no extracranial metastasis; grade II is KPS≥70, grade III is KPS<70, and 1~3 of the other 3 items do not meet grade I. The prognostic factors of surgical resection and radiosurgery for brain metastases must increase the pathological type of primary cancer, intracranial tumor status (number, size, location of lesions and concurrent cerebral edema, hydrocephalus, etc.).
2.The choice of treatment methods
(1) Whole brain radiation therapy (WBRT) WBRT has a long history of treating brain metastases.
A large number of studies have concluded that
①WBRT can make 50% of patients improve their symptoms and survive for 1~6 months after treatment, with an average survival of 3 months;
②Toxic side effects of radiation therapy include alopecia, fatigue, anorexia, nausea, vomiting, amenorrhea, fever, hearing loss, acute radiation encephalopathy, subacute demyelination syndrome, radiation brain necrosis, optic nerve atrophy, and secondary stroke. Long-term side effects include progressive dementia, gait disorders, and urinary and fecal incontinence;
(iii) The long course of WBRT delays the treatment of the primary cancer;
④According to Murray et al. 9104 RTOG studies, the standard treatment regimen for WBRT is a total dose of 3000 cGy in 10 fractions over two weeks. Increasing the total dose and fractionated dose does not improve the efficacy but increases the side effects;
⑤ The scope of WBRT treatment includes: diffuse intracranial metastases and cases of metastases that are not amenable to surgical and radiosurgical treatment. There are different claims regarding the addition of WBRT after surgical resection and after radiosurgery. Recent studies have shown that surgery combined with WBRT reduces recurrence of surgically resected tumors in situ and has no significance for recurrence of distant lesions and prolonged survival. WBRT can be used as an adjuvant treatment for multiple metastases that cannot be treated with radiosurgery alone [9].
(2) Surgical resection of tumors Surgical resection is indicated for patients with single metastases in superficial location, mean diameter >3.5 cm, primary cancer is stably controlled, no contraindication to surgery, age <65 years, and KPS >80 score. According to Buckner et al. (1992), who synthesized the results of several studies, 30% to 50% of brain metastases were solitary foci, and 1/2 of them were eligible for surgical resection.
Arbit et al. (1996) reported a mean survival of 9.4 months and a surgical mortality rate of 5.3% in 583 patients after surgical resection of brain metastases. There are different opinions on whether to attach WBRT after surgical resection. The earlier ones advocated that additional WBRT after surgery should be the standard of care. In a recent randomized comparative study represented by Patchell et al. (1998), there was no meaningful difference in survival and quality of survival between surgical resection alone and postoperative additional WBRT, suggesting that no additional WBRT is needed after surgery, while the side effects of WBRT are of concern and prevent retreatment of patients with postoperative recurrence.
The primary cancer is non-small cell lung cancer with single brain metastases suitable for surgical resection, Read et al. reported that the one-year survival rate of double resection of non-small cell lung cancer and brain metastases is 50%, Pieper et al. reported in 1996 that the average survival of surgical resection of brain metastases from breast cancer is 16 months and the 5-year survival rate is 17%, which is similar to the effect of radiosurgery; however, most of the brain metastases from melanoma are multiple and not suitable for surgical resection. However, most of the brain metastases from melanoma are multiple and not suitable for surgical resection; brain metastases from small cell lung cancer, kidney cancer and intestinal cancer have high recurrence rate and short survival time, which are not as effective as radiosurgery.
Radiosurgery is applicable to single and multiple tumors in any part of the brain, with an average tumor diameter <3.5cm, and patients with contraindications to surgical resection can also be treated, and patients whose tumors recur after treatment can be treated again. It has minimally invasive, short treatment time, few complications and no risk of death from direct treatment.
Radiosurgery for patients with untreated or uncontrolled primary cancer does not affect the treatment of the primary cancer. radiosurgery has been widely used in the treatment of brain metastases since the 1990s, and the rate of local control of tumors treated with radiosurgery depends on prognosis-related factors such as KPS score, tumor size, margin dose size, and control of the primary cancer. boyd and Mehta et al. (1997) reported the use of Gamma knife for 1700 cases of brain metastases, with a treatment control rate of 83-100% and a mean survival of 9.6 months.
Hasgawa et al. (2003) reported 172 cases of brain metastases treated with gamma knife, with a mean survival of 8 months. Patients aged <60 years with KPS ≥90 and primary cancer control had a mean survival of 28 months, with long-term survival cases of 96 months; Sheehan et al. (2003) reported a control rate of 96% in 69 brain metastases from renal cell carcinoma with a mean survival of 15 months (1-69 months). o'neill et al. (2003) A retrospective analysis found that 97 patients with a single metastasis and similar disease were treated with surgical resection or radiosurgery respectively at a mean follow-up of 20 months, and there was no significant difference in survival between the two, with one-year survival and local recurrence rates of 56% and 58% in the surgical group and 62% and 0% in the radiosurgery group, respectively. The quality of survival of surviving patients was better in the latter than in the former.
Complications of gamma knife brain metastases are rare, and the literature generally reports complications of transient perifocal cerebral edema, reversible neurological symptoms and intra-tumor hemorrhage, with an incidence of <5%, and no treatment mortality has been reported. The complications are classified as acute, subacute and chronic depending on the time of presentation.
Acute complications include headache, nausea, vomiting and seizures, which often occur hours to days after treatment and disappear quickly after symptomatic treatment; subacute complications are mainly radiation edema, worsening of neurological symptoms and seizures, which occur within 6 months after treatment; late complications are radiation brain necrosis, which has a high incidence in patients with large volume tumors and adjuvant whole brain radiotherapy. However, patients with brain metastases are already in the advanced stage of cancer and long-term survival is rare, therefore, clinical cases of radiation brain necrosis are rare.
Several issues in radiosurgery for brain metastases deserve in-depth discussion.
① About the marginal dose of radiosurgery for the treatment of brain metastases
The marginal dose used in the literature before 1995 was high, commonly 25-35 Gy, with a high complication rate. Since then, the marginal dose has been gradually reduced, and the same control rate at high doses has been achieved, and the complication rate has been reduced. Today the commonly used marginal dose is 16-20 Gy. In-depth studies have shown that there is a difference between the nature of the primary cancer case and the marginal dose of the tumor, for example, the marginal dose of metastases originating from kidney cancer, breast cancer and melanoma is higher than that of brain metastases from lung cancer.
Goodman et al. (2001) studied 682 brain metastases on enhanced MRI and classified them into three types: uniform enhancement in 59%, non-average enhancement in 32% and circumferential enhancement in 8%. The latter two types contain radioresistant hypoxic tumor cells and the dose used should be greater than that of the homogeneous type.
② Should WBRT be added after radiosurgery?
The results of recent studies consistently show that additional WBRT after radiosurgery does not have any meaningful improvement on survival, quality of life and tumor recurrence, and increases side effects and hinders retreatment of patients with recurrent tumors. Therefore, additional WBRT after radiosurgery is not advocated.
(3) Criteria for radiosurgery for the treatment of multiple metastases in the brain
There are different reports on the number of lesions limited to 3, 5, 10, or more than 10 for the treatment of multiple metastases in radiosurgery, and there is no uniform standard. From the perspective of treatment technology, the Leksell Gamma Knife can be designed for multiple matrices at the same time, and tumors in close proximity can be located in the same matrix, and more than 5 or even 10 lesions can be treated at one time.
According to recent research results, radiosurgery treatment of brain metastases should follow the following principles in order to achieve good results.
A. Patients with brain metastases should routinely undergo a strict RPA rating before treatment, and treatment plans should be formulated based on the patient’s RPA;
Chang et al. showed that the volume size of brain metastases was inversely correlated with the tumor control rate. According to most of the literature, radiosurgery tumor control rate is low and prone to complications when the tumor volume is greater than 35 cm3;
C. The permissible range of safe cumulative dose for multifocal multi-target therapy is 2.16~8.51 Gy. Nakaya et al. (2002) reported 105 patients with more than 10 metastases and a cumulative dose of 4.83 Gy for one treatment, which is less than the cumulative dose of 8.25 Gy for fractionated radiotherapy of 2.0 Gy each, and no serious complications were found in the follow-up, so it is considered that patients with more than 10 lesions can be Radiosurgery was used.
④ Adjuvant therapy
Hormones and hypertonic dehydration agents are mainly used for patients with cerebral edema and increased intracranial pressure; the combination of chemotherapy and radiotherapy for multiple small cell lung cancer and melanoma brain metastases has adjuvant treatment effect. Patients with combined epilepsy are treated with antiepileptic drugs before and after treatment.
VI. Conclusion
Brain metastases are the leading cause of death in cancer patients. Early diagnosis and treatment can effectively relieve symptoms, prolong survival and improve patients’ quality of life, and finally most patients with brain metastases die from the primary cancer. Modern treatment methods include WBRT, surgical resection and radiosurgery. Among them, radiosurgery is the most practical, safe, effective and simple, and is accepted by more and more patients.
The patient’s individual risk and prognostic factors are accurately evaluated, and the selection of treatment methods and protocols combined with the pathological type of the primary cancer, the location and size of metastases, the number of lesions and symptoms can achieve satisfactory results. The indications and technical parameters of radiosurgery for the treatment of brain metastases need to be further standardized.
Seven, the indications for gamma knife treatment of brain metastases
1.Applicable to single and multiple tumors in any part of the brain.
2, the average diameter of the tumor < 3.5 cm.
3.Patients with contraindications to surgical resection.
4.Tumors that recur after treatment.
5.Patients and family members request for gamma knife treatment.
6.No contraindication to gamma knife treatment.