Brain metastases are a local problem that can often be addressed well with local therapy. Because of the risk of intraoperative tumor seeding, surgical resection must be supplemented with conventional postoperative irradiation. Unlike surgical resection, radiosurgery does not need to be supplemented by conventional radiotherapy. Choosing the right therapy in the right patient and at the right time has become challenging in patients with brain metastases given the various local and generalized therapies available. The treatment decision should not be made without the involvement of a neurosurgeon and, if possible, a neurosurgeon practicing radiosurgery.
Brain metastases are unfortunately not a rare medical problem: they occur in approximately 20-40% of all patients with solid malignancies, depending on the literature. Meningeosis carcinomatosa occurs in approximately 5% of all patients with solid malignancies. The incidence of brain metastases is approximately 10/100,000 population per year. The most common brain metastases are from the following cancers: breast carcinoma, bronchus carcinoma, gastrointestinal tract carcinomas, malignant melanoma, and renal cell carcinoma. Other groups of brain metastases include those with unknown primary tumor and those with more than one primary tumor. Because of improved oncologic therapies, oncologists, neurologists, and neurosurgeons are now seeing increased brain metastases as a result of cancers such as ovarian, testicular, prostate, thyroid, etc., in addition to these relatively common brain metastases.
The more colorful the picture of brain metastases becomes and the more therapeutic options are available, the more challenging therapeutic management becomes. In general, there are the local therapies such as microsurgical resection and radiosurgery and the non-local therapies such as partial or whole brain irradiation. In the following, some aspects are presented from a predominantly neurosurgical point of view, which should help to approach the clinical picture of brain metastases diagnostically and therapeutically in a rational way.
Diagnosis
The diagnosis of brain metastasis(s) is based on contrast-enhanced MRI. A CT scan will miss smaller metastases, specifically posterior fossa metastases and any meningeal seeding. If brain metastases are suspected, MRI should be performed according to a specific protocol regarding the amount and type of contrast agent, time interval after administration of the contrast agent, etc. This is important because adequate baseline assessment is critical given the various therapeutic options available. It is also important to assess whether there is localized disease, i.e., brain metastases in the narrow sense, or generalized involvement, i.e., meningeal seeding.
Primary tumor
The primary tumor is relevant in the choice of therapy for brain metastases:
- If the primary tumor is unknown, open surgery is indicated when possible to reach a histologic diagnosis.
- If the cancer is small cell lung cancer, whole brain radiation is most likely indicated rather than focused radiosurgery because of the large number of brain metastases.
- If the primary tumor is malignant melanoma or renal cell carcinoma, radiosurgery is most likely indicated because of radioresistance to conventional radiotherapy.
- If brain metastases are involved in more than two primary tumors, surgical intervention to obtain the histologic diagnosis is not mandatory because histology does not affect conventional radiotherapy or radiosurgery of brain metastases. However, if either of the two known primary tumors is considered radioresistant, this would be another argument for radiosurgical treatment.
Tumor size
Tumor size is an important parameter in determining the further procedure. If the tumor is small, radiosurgical treatment is the gentlest and at the same time most effective therapy. In this way, metastases in delicate localizations such as the central region can also be treated well (Fig. 1) .
If the tumor is large with mass effect, open microsurgical resection is indicated, followed by postoperative partial brain irradiation. The question of which tumor size is still suitable for radiosurgical therapy and which is not is often difficult to answer, so the assessment should be made by a specialist. Larger tumors can also be successfully treated purely by radiosurgery (Fig. 2).
Number and localization of brain metastases
The number of brain metastases has some influence on the choice of therapy. For a long time, the rule of thumb was that up to three brain metastases should be treated with radiosurgery, and that whole-brain radiation was indicated for more metastases. This rule was arbitrary and not based on scientific evidence. In the meantime, there are many publications that have overturned this dogma. Nowadays, the line between radiosurgery and whole-brain irradiation tends to be drawn at a dozen brain metastases [1,2].
The localization of brain metastases also influences the choice of therapy. Radiosurgery is particularly well suited for metastases in eloquent areas such as the central region (Fig. 1), the speech center, the brainstem (Fig . 3), or the vermis cerebelli, where open resection is associated with a high risk of permanent neurologic deficits.
Meningeal seeding
Meningeal tumor seeding is a dreaded manifestation of cerebral metastasis leading to progressive cranial nerve loss. If signs of meningeosis carcinomatosa are found on MRI, the disease is disseminated and local therapy (surgery or radiosurgery) is then no longer indicated. In these cases, conventional whole-brain irradiation is indicated. The risk of iatrogenic meningeal seeding depends on the proximity of the metastasis to the meninges, the surgical method, and the primary tumor. Of the local therapies, radiosurgery carries the least risk for leptomeningeal seeding.
Microsurgical resection
Microsurgical resection is part of the classic standard repertoire of therapy for brain metastases. By its very nature, it is a local therapy. However, without subsequent conventional partial or whole brain irradiation, the risk of local recurrence is unacceptably high, so microsurgical resection is virtually always combined with conventional postradiation. Surgical resection is indicated whenever the brain metastasis results in a threatening space-occupying lesion and the patient is not in a terminal stage.
In addition to the usual surgical risks such as bleeding complications, postoperative infection, and postoperative CSF cushion, there is the specific risk of meningeal tumor seeding. The risk for surgery-related meningeal tumor seeding is highest for superficially located brain metastases, for piecemeal resection of the metastasis, and for use of an ultrasound aspirator.
Radiosurgery
Another form of local therapy has now been established, stereotactic single-session radiosurgery. In a single session, a dose of radiation that is supralocal for brain metastases is deposited in the tumor with high precision, sparing the surrounding brain tissue as much as possible. The applied dose is independent of the primary tumor. The local success rate is 90% for primary radiosurgical treatment without additional conventional radiotherapy >, regardless of the primary tumor. Even so-called radioresistant tumors such as metastases of malignant melanoma or renal cell carcinoma show a local tumor control rate of >90% after radiosurgery as sole therapy.
If brain metastases recur in the further course of the disease, they can be treated again with radiosurgery. (Fig.4). For large brain metastases, hypofractionated application of radiation dose in 3-5 fractions may be indicated, but optimal dose and number of fractions have not yet been established, and superiority over optimally performed single-session radiosurgical treatment has not been demonstrated. Larger brain metastases should rather be approached surgically anyway.
The risks of radiosurgical treatment are essentially limited to the development of radionecrosis. This risk is very low in small and medium-sized tumors after primary radiosurgical treatment, at <5%. It depends on the size of the tumor and the experience, knowledge and technique of the radiosurgeon. Secondary radiosurgery for tumor recurrence after whole-brain irradiation significantly increases the risk. A simultaneous resp. additional whole-brain irradiation does not prolong life expectancy. A prospective study at the MD Anderson Cancer Institute in Houston on this question had to be stopped prematurely because patients in the radiosurgery plus whole-brain irradiation study arm already showed significant cognitive impairment during the study compared with patients in the radiosurgery only study arm [3].
Stereotactic single-session radiosurgery is now primarily applied with the Gamma-Knife, the CyberKnife, or the Micro-multileaf collimator linear accelerator. Gamma-Knife and CyberKnife are dedicated devices for radiosurgery, while linear accelerators are adapted devices. The individual technologies have device-specific advantages and disadvantages, but much more important than the respective technology is the experience and knowledge of the respective surgeon or operator. Radiosurgeons [4].
Radiosurgery is a purely outpatient therapy, which is performed in one session. This is by far the gentlest for already highly burdened carcinoma patients compared to all other forms of therapy.
Conventional partial or whole brain irradiation
Conventional whole brain irradiation is the classic non-local form of therapy for brain metastases. Despite dose reduction and optimization of fractionation, whole-brain irradiation is still associated with a relatively high rate of subsequent dementia-related development. Often this development starts already one year after irradiation. Primarily, therefore, the use of whole-brain irradiation should be limited to brain metastases from non-small cell lung cancer, cases of meningeosis carcinomatosa, patients with a life expectancy of less than one year, and patients with a high number of brain metastases. Combination with radiosurgery is not warranted because life expectancy is not prolonged and early dementia is likely to develop. Because of the relatively high risk of dementia development, partial brain irradiation is more commonly performed postoperatively.
More than one-third of patients develop brain metastases again after whole-brain irradiation. Thus, irradiation does not protect against recurrence of CNS involvement. In this non-local form of therapy, a CNS volume of approximately 1500 cc is irradiated to treat a metastatic volume of a few per mille of this volume.
Chemotherapy
Chemotherapy is most likely to be considered in the form of intrathecal application for meningeosis carcinomatosa. Treatment of brain metastases with chemotherapy is not nearly as successful as surgery, radiosurgery, or radiotherapy. Temozolomide, which also acts as a radiosensitizer during radiation, is occasionally used as adjuvant chemotherapy. In this regard, the good oncology review by Péus and Hofer is recommended [5].
Best time for therapy
Unnecessary loss of time should be avoided, as brain metastases will inevitably become larger, making the use of the gentlest form of therapy less likely.
Sequence of the different therapies
If radiosurgery is considered, it should be used first. The use of radiosurgery for tumor recurrence after whole-brain irradiation is less favorable because of the increased incidence of radionecrosis with chronic edema and associated steroid dependence. If tumor recurrences occur after radiosurgery, it must be weighed up whether renewed radiosurgery or whole-brain irradiation is indicated in a second step. In general, repeated radiosurgical treatments are readily feasible and are also explicitly desired by patients with good Karnofsky Performance Score (KPS) (Fig. 4).
Forecast
The prognostic factors for life expectancy after radiosurgery have been best studied [6]. A statistically confirmed favorable influence on prognosis is a KPS >70 at the time of radiosurgery, bronchus and breast carcinoma as primary tumor, a low number of brain metastases, a low tumor volume, and inactive extracranial disease.
Progress controls
Given the prolonged life expectancy and good quality of life with timely and aggressive therapy of brain metastases, the following aspects gain importance: adequate MRI follow-up and preservation of cognitive abilities. With close follow-up and, if necessary, timely intervention, patients with brain metastases usually no longer die from cerebral metastasis but from the progressive underlying disease, in contrast to the situation in the past. In individual cases, it is even possible to speak of curative therapy rather than palliative therapy (Fig. 5).
Literature:
- Salvetti DJ, et al: Gamma Knife surgery for the treatment of 5 to 15 metastases to the brain. J Neurosurg 2013; 118: 1250-1257.
- Yamamoto M, et al: A case-matched study of stereotactic radiosurgery for patients with multiple brain metastases: comparing treatment results for 1-4 vs ≥5 tumors. J Neurosurg 2013; 118: 1258-1268.
- Chang EL, et al: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomized controlled trial. Lancet Oncol 2009; 10(11): 1037-1044.
- Mindermann T: Gamma Knife, CyberKnife or micro-multileaf collimator LINAC for intracranial radiosurgery? Acta Neurochir 2015; 157: 557-558.
- Péus D, Hofer S: Brain metastases: Prognostic assessment and therapeutic strategies. Switzerland Med Forum 2013; 13: 593-597.
- Serizawa T, et al: Testing different brain metastasis grading systems in stereotactic radiosurgery: Radiation Therapy Oncology Group’s RPA, SIR, BSBM, GPA, and modified RPA. J Neurosurg 2012; 117(Suppl): 31-37.
InFo ONCOLOGY & HEMATOLOGY 2015; 3(7): 9-13.
