| Japanese Journal of Clinical Oncology | Pages |
Editorial
How to manage metastatic brain tumors
Soichiro Shibui, Neurosurgery Division, National Cancer Center Hospital, Tokyo, Japan
The frequency of metastatic brain tumors is increasing. Non-invasive examination such as computed tomography and magnetic resonance imaging makes it possible to detect brain metastases even in seriously ill patients. Moreover, the number of long survivors are increasing by the development of effective anti-cancer treatments for primary cancers and 20-40% of cancer patients are reported to have brain metastases at autopsy. Prognosis of patients with brain metastases has been very poor and radiotherapy to the whole brain has been a main and unique treatment until recently. Since 1990 several randomized studies have revealed the importance of surgical removal of brain metastases. Patchel et al. compared the survival time after treatment and the recurrence rate between the solitary brain metastasis patients who had been treated with surgery plus postoperative radiotherapy and those who had been treated only with radiotherapy (1). The median survival was 40 weeks in the group receiving combined treatment while it was 15 weeks in the group receiving radiotherapy alone. Local recurrence rate was 20% in the surgical group and 52% in the radiotherapy group. Vecht et al. conducted a similar study. Overall survival time in the combined treatment group and radiotherapy group was 10 months and 6 months, respectively (2). Although removal of brain metastasis improves survival time of the patients, two thirds of the patients have multiple lesions and many patients cannot be rendered to surgery.
Radiotherapy is effective for most brain metastases, but response rates are different among the primary cancers. Besides brain metastases of malignant lymphoma which is curable by conventional radiotherapy at least temporarily, those from lung cancer and breast cancer are rather sensitive to radiotherapy. Metastases from gastrointestinal tract cancer, renal cell cancer and malignant melanoma do not respond well. The anticancer effect of radiotherapy also depends on the size of tumors. In our experience of brain metastases from non-small cell lung cancer the response rate of radiotherapy for brain metastases less than 2 cm in diameter was 70%, while that of 2-5 cm tumors was 55% and that of >5 cm tumors was 50%. Even in brain metastases from non-small cell lung cancer which are considerably radiosensitive, tumors less than 2 cm in diameter are good candidates for radiotherapy. Daily dose also influences the radiation effects and optimal daily dose has been considered to be 2 Gy in conventional radiotherapy. In phase III studies conducted by the Radiation Therapy Oncology Group proved 30 Gy in 10 fractions over 2 weeks was as effective as more prolonged treatment (3). Radiotherapy of 30 Gy in 10 fractions or 40 Gy in 20 fractions is usually performed for brain metastases.
Craniotomy is an invasive and stressful treatment for patients and moreover it might not be a curative choice of treatment. Existence of brain metastasis means that the cancer cells have already entered the blood stream and scattered around the whole body. Taking account of these facts the surgical indication should be decided carefully. Large tumors, especially those exceeding 2 cm in diameter do not respond to radiotherapy well and it takes a long time until its antitumor effect comes out. The patients have to endure headaches and other neurological symptoms for several weeks until the tumor shrinks in size. Although tumors in the motor and speech cortex and the brain stem cannot be removed safely, surgical intervention is the first choice of treatment for large solitary tumors in other sites of the brain. Surgery is carried out for multiple brain tumors if all tumors can be removed by a single craniotomy or by plural craniotomies without changing the patients' position during surgery. Surgery is also recommended for the largest one of multiple tumors which is threatening the patient's life. Most brain metastases exist subcortically and cannot be seen on the surface of the brain. Intraoperative ultrasonography is very useful. It provides information on the precise location of the tumor and optimal site of corticotomy. In order to avoid dissemination of cancer cells, the tumor and surrounding reactive tissues should be removed en bloc if it is possible.
Postoperative radiotherapy reduces local recurrence and improves the survival time of patients (4). However, whole brain irradiation often induces neurological deterioration, dementia or both. The patients develop progressive dementia, ataxia, and urinary incontinence several months after radiotherapy. In such patients neuroradiological imaging often reveals cortical atrophy and hypodense white matter. Recently, local irradiation has been applied to the patients to avoid these complication. A high intensity area on the T2-weighted image of MRI is the target field of local irradiation. The recurrence rate out of the field is not different from that of whole brain irradiation (5).
Stereotactic radiosurgery using gamma knife is another treatment method available. A conventional linear accelerator is also modified to produce a similar dose distribution. Using these sophisticated treatment modalities a daily dose as high as 15-30 Gy can be delivered to the target volume without irradiating the normal surrounding brain. The control rate for the smaller tumors <2 cm3 is approximately 80% while it is 50% for tumors >10 cm3 (6). A large daily dose sometimes makes radionecrosis of the surrounding brain as well as the tumor itself, when the target exceeds 3 cm in diameter (7). The tumors can be irradiated effectively and safely only when they are smaller than 3 cm in diameter.
At present the following way of treatment methods are recommended for brain metastases. Large solitary tumors exceeding 2 cm in diameter should be removed surgically followed by local irradiation. For tumors less than 2 cm in diameter, especially deeply seated ones, stereotactic radiosurgery or radiotherapy is the first choice of treatment. Whole brain irradiation consisting of 30 Gy in 10 fractions or 40 Gy in 20 fractions is indicated for multiple tumors. Stereotactic radiosurgery is also considered when the number of tumors is less than three and for local recurrence after whole brain irradiation. Thus, treatment for brain metastases is not simple. Multiplicity, location and size of brain metastasis, stage of primary malignancy and performance status of patients should be considered carefully.
References
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