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Brain metastases
Pulmonary: The Problem of CNS Disease in Lung Cancer
Brain Metastases Roy A. Patchell. Depts. of Surgery (Neurosurgery) and Neurology, University of Kentucky Medical Center, Lexington, Kentucky, USA Metastases to the brain are the most common intracranial tumors in adults, occurring up to ten times more frequently than primary tumors. Brain metastases are also the most frequent metastatic neurological complication of systemic cancer and are second only to metabolic encephalopathies as a cause of central nervous system dysfunction in cancer patients. Within the last few years, significant advances have occurred in the diagnosis and treatment of metastases to the brain; and so the therapeutic nihilism of the past is now no longer warranted for most patients. With currently available treatments, most patients with lung cancer do not die of their brain metastases; rather, they usually experience effective palliation of neurological symptoms and meaningful extension of life. Many previous estimates of the frequency of brain metastases, based on historical neurosurgical series, suggested that metastases made up only about 10% of the total number of intracranial tumors. However, because of the past reluctance of surgeons to operate on patients with known systemic cancer, these older neurosurgical series grossly underestimated the actual occurrence of brain metastases. Modern neuroimaging techniques and more careful autopsy studies of cancer patients have shown that metastases to the brain, as a group, are actually the most common intracranial tumors in the adult population. At present, brain metastases are estimated to occur in 20 to 40 percent of lung cancer patients. Brain metastases may be single or multiple. The phrase sing/e brain metastasis refers to an apparent single cerebral lesion; no implication is made regarding the extent of cancer elsewhere in the body. On the other hand, the more restrictive phrase solitary brain metastasis is properly used to describe the relatively rare occurrence of a single brain metastasis that is the only known site of metastatic cancer in the body. Recent studies using magnetic resonance imaging (MRI) have shown that the percentage of single metastases is lower than was previously believed, occurring in only one-third to one-fourth of patients with cerebral metastases. The best diagnostic test for brain metastases is contrastenhanced MRI. This tool is more sensitive than enhanced CT scanning (including double-dose delayed- contrast) or nonenhanced MRI in detecting lesions in patients suspected of having intracranial metastases. Several factors must be considered when determining the best treatment for each patient; these include the extent of systemic disease, the patient’s neurological status at the time of diagnosis, and the number and sites of the metastases. Glucocorticoids, radiotherapy, and surgical therapy all have an established place in treatment. In addition, radiosurgery is increasingly being used in the management of brain metastases. Chemotherapy is also useful for treating some patients with chemosensitive tumors. Untreated patients with brain matastases have a median survival of only about four weeks, and nearly all untreated patients die as a direct result of the brain tumor. The median survival of patients treated with glucocorticoids alone is about two months (Ruderman and Hall 1965, Markesbery et al 1978, Chang et al 1992) although much longer survivals have been observed.
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Conventional whole brain radiation therapy (WBRT) is the most common treatment for patients with brain metastases. WBRT increases the median survival to 3 to 6 months. Despite the relatively unimpressive increase in median survival, radiotherapy is effective at achieving local control of disease in a substantial percentage of patients. Data from large retrospective studies has shown that more than half of patients treated with WBRT die ultimately of progressive systemic cancer and not as a direct result of brain metastases. Surprisingly, there is still no consensus on the optimal dose and schedule of WBRT in the treatment of brain metastases. The best available data on the effect of dose and schedule for the treatment of brain metastases come from several large scale multi-institutional trials conducted by the Radiation Therapy Oncology Group (RTOG). These studies have shown that there is no significant difference in the frequency and duration of response for radiation doses ranging from 20 Gy over one week to 50 Gy over four weeks. Extremely large fraction regimens of 10 Gy in a single dose, or 12 Gy in two doses were inferior. Surgical resection plus postoperative WBRT is currently the treatment of choice for patients with surgically accessible single brain metastases. The data supporting surgery for single brain metastases come from many retrospective studies and two randomized prospective trials, the results of which show that surgical resection is of benefit in selected patients. In a randomized trial performed at the University of Kentucky, 48 patients with known systemic cancer were treated with either biopsy of the suspected brain metastasis plus WBRT or complete surgical resection of the metastasis plus WBRT. The radiation doses were the same in both groups, consisting of a total dose of 36 Gy given as 12 daily fractions of 3 Gy. A statistically significant increase in survival time was found in the surgical group (40 weeks vs. 15 weeks). In addition, the time to recurrence of brain metastases, freedom from death due to neurologic causes, and duration of functional independence after treatment were significantly longer in the group treated with surgical resection. The one-month mortality rates were 4% in each group, indicating that surgery did not cause excess mortality or morbidity. A second randomized study, conducted as a multi-institutional trial in the Netherlands, evaluated 63 patients randomized either to complete surgical resection plus WBRT or to WBRT alone. The WBRT schedules were the same for both treatment arms, consisting of 40 Gy given in a nonstandard fractionation scheme of 2 Gy twice per day for 2 weeks (10 treatment days). Survival was significantly longer in the surgical group (10 months vs. 6 months), and a nonsignificant trend toward longer duration of functional independence was seen in the surgically treated patients. No data concerning recurrence of brain metastases were given. The one-month mortality rates were 9% in the group treated with surgery and 0% in the group treated with WBRT alone, a nonsignificant difference. It is unclear whether surgical therapy is useful in the management of multiple metastases. Two retrospective studies have come to opposite conclusions regarding the safety and efficacy of surgical removal of more than one brain metastasis. Bindal et al (1993) analyzed patients with multiple metastases who had all the tumors resected and compared these with patients with multiple metastases who had some but not all
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Pulmonmy:
The Problem of CNS Disease in Lung Cancer
of their brain metastases resected. A further comparison was made with patients with single metastases who were treated with complete resection plus WBRT. The authors found that the group with completely resected multiple metastases did relatively well (median survival 14 months) and was similar to the group with single resected metastases (median survival 14 months). The patients who did not have all of their brain tumors removed did less well (median survival 6 months). The 30 day mortality rate for the multiple metastases group was only 4%. No comparison was made with patients treated with WBRT alone (the standard treatment for multiple metastases). Hazuka et al (1993) reported a retrospective surgical series that contained 18 patients with multiple metastases and 28 patients with single metastases. The group with multiple metastases had a median survival of 5 months; those with single metastases had a median survival of 12 months. Overall, only 50% of patients had complete resections, and the complete resection rate in the multiple metastases group was not reported. The 30 day mortality rates in both groups were 0%. The above studies suggest that the postoperative morbidity and mortality rates for patients with multiple metastases treated with surgery are relatively low and are comparable with those reported in patients with single surgically resected metastases. However, it is difficult to draw firm conclusions regarding the efficacy of surgery for multiple metastases from the studies published to date. Current practice is to treat multiple metastases with WBRT alone or with radiosurgery followed by WBRT. A controversy exists regarding whether postoperative radiotherapy should be given as WBRT (as opposed to focal radiation) or whether radiotherapy is even necessary at all after an apparently complete resection of a single metastasis, The usefulness of postoperative WBRT has not yet been tested in a randomized trial; however, six nonrandomized retrospective studies have been reported. These retrospective studies do not conclusively establish the efficacy of postoperative WBRT in the treatment of single metastases, although they suggest that WBRT probably decreases the overall neurological re-
currence rate. A prospective, randomized trial is under way to decide the value of postoperative WBRT. However, current practice is to use WBRT postoperatively in most patients. Stereotactic radiosurgery, a method of delivering intense focal irradiation using a linear accelerator (LINAC) or multiple Cobalt-60 sources (Gamma Knife), has also been used to treat single and multiple brain metastases. Radiosurgery delivers a highly focused single dose of radiation to a circumscribed area of the brain with rapid dose fall off at the target edges. Radiosurgery is limited to lesions less than 3 cm in diameter. The technique causes tissue destruction in the area targeted; therefore, radiosurgery does not replace whole brain radiotherapy but may offer a substitute for surgical therapy. To date, no randomized trial comparing radiosurgery with any of the conventional methods of therapy has been reported, although many uncontrolled series have been published. The combined results of many retrospective reports suggest that radiosurgery prevents (or controls) local recurrence of 80-90% of treated metastases with about a 5-10% risk of radiation necrosis or new neurologic deficits. Auchter et al (1996) reported a retrospective review of the radiosurgery data bases of four institutions. The authors found 122 patients who met the following the same selection criteria used by Patchell et al (1990) in their randomized study discussed previously in this chapter, e.g., single brain matastasis; no prior cranial surgery or whole brain radiotherapy; age 218 years; surgically resectable lesion; KPS > 70; non-radiosensitive histology (e.g. lymphoma, small cell carcinoma). The patients in the Auchter study received WBRT (median 37.5 Gy) followed by a radiosurgery boost (median 17 Gy). The overall local control rate was 86% with an actuarial median survival, and a neurologic median survival of KPS > 70% of 44 weeks. The patients included in this study had an overall median survival was 56 weeks, and the duration of functionally independent survival was 44 weeks. These endpoints were similar to the surgical arms of the randomized trials of Patchell et al (1990) and Vecht et al (1993).
Brain Metastases Roy A. Patchell. Depts. of Surgery (Neurosurgery) and Neurology, University of Kentucky Medical Center, Lexington, Kentucky, USA Metastases to the brain are the most common intracranial tumors in adults, occurring up to ten times more frequently than primary tumors. Brain metastases are also the most frequent metastatic neurological complication of systemic cancer and are second only to metabolic encephalopathies as a cause of central nervous system dysfunction in cancer patients. Within the last few years, significant advances have occurred in the diagnosis and treatment of metastases to the brain; and so the therapeutic nihilism of the past is now no longer warranted for most patients. With currently available treatments, most patients with lung cancer do not die of their brain metastases; rather, they usually experience effective palliation of neurological symptoms and meaningful extension of life. Many previous estimates of the frequency of brain metastases, based on historical neurosurgical series, suggested that metastases made up only about 10% of the total number of intracranial tumors. However, because of the past reluctance of surgeons to operate on patients with known systemic cancer, these older neurosurgical series grossly underestimated the actual occurrence of brain metastases. Modern neuroimaging techniques and more careful autopsy studies of cancer patients have shown that metastases to the brain, as a group, are actually the most common intracranial tumors in the adult population. At present, brain metastases are estimated to occur in 20 to 40 percent of lung cancer patients. Brain metastases may be single or multiple. The phrase sing/e brain metastasis refers to an apparent single cerebral lesion; no implication is made regarding the extent of cancer elsewhere in the body. On the other hand, the more restrictive phrase solitary brain metastasis is properly used to describe the relatively rare occurrence of a single brain metastasis that is the only known site of metastatic cancer in the body. Recent studies using magnetic resonance imaging (MRI) have shown that the percentage of single metastases is lower than was previously believed, occurring in only one-third to one-fourth of patients with cerebral metastases. The best diagnostic test for brain metastases is contrastenhanced MRI. This tool is more sensitive than enhanced CT scanning (including double-dose delayed- contrast) or nonenhanced MRI in detecting lesions in patients suspected of having intracranial metastases. Several factors must be considered when determining the best treatment for each patient; these include the extent of systemic disease, the patient’s neurological status at the time of diagnosis, and the number and sites of the metastases. Glucocorticoids, radiotherapy, and surgical therapy all have an established place in treatment. In addition, radiosurgery is increasingly being used in the management of brain metastases. Chemotherapy is also useful for treating some patients with chemosensitive tumors. Untreated patients with brain matastases have a median survival of only about four weeks, and nearly all untreated patients die as a direct result of the brain tumor. The median survival of patients treated with glucocorticoids alone is about two months (Ruderman and Hall 1965, Markesbery et al 1978, Chang et al 1992) although much longer survivals have been observed.
109
Conventional whole brain radiation therapy (WBRT) is the most common treatment for patients with brain metastases. WBRT increases the median survival to 3 to 6 months. Despite the relatively unimpressive increase in median survival, radiotherapy is effective at achieving local control of disease in a substantial percentage of patients. Data from large retrospective studies has shown that more than half of patients treated with WBRT die ultimately of progressive systemic cancer and not as a direct result of brain metastases. Surprisingly, there is still no consensus on the optimal dose and schedule of WBRT in the treatment of brain metastases. The best available data on the effect of dose and schedule for the treatment of brain metastases come from several large scale multi-institutional trials conducted by the Radiation Therapy Oncology Group (RTOG). These studies have shown that there is no significant difference in the frequency and duration of response for radiation doses ranging from 20 Gy over one week to 50 Gy over four weeks. Extremely large fraction regimens of 10 Gy in a single dose, or 12 Gy in two doses were inferior. Surgical resection plus postoperative WBRT is currently the treatment of choice for patients with surgically accessible single brain metastases. The data supporting surgery for single brain metastases come from many retrospective studies and two randomized prospective trials, the results of which show that surgical resection is of benefit in selected patients. In a randomized trial performed at the University of Kentucky, 48 patients with known systemic cancer were treated with either biopsy of the suspected brain metastasis plus WBRT or complete surgical resection of the metastasis plus WBRT. The radiation doses were the same in both groups, consisting of a total dose of 36 Gy given as 12 daily fractions of 3 Gy. A statistically significant increase in survival time was found in the surgical group (40 weeks vs. 15 weeks). In addition, the time to recurrence of brain metastases, freedom from death due to neurologic causes, and duration of functional independence after treatment were significantly longer in the group treated with surgical resection. The one-month mortality rates were 4% in each group, indicating that surgery did not cause excess mortality or morbidity. A second randomized study, conducted as a multi-institutional trial in the Netherlands, evaluated 63 patients randomized either to complete surgical resection plus WBRT or to WBRT alone. The WBRT schedules were the same for both treatment arms, consisting of 40 Gy given in a nonstandard fractionation scheme of 2 Gy twice per day for 2 weeks (10 treatment days). Survival was significantly longer in the surgical group (10 months vs. 6 months), and a nonsignificant trend toward longer duration of functional independence was seen in the surgically treated patients. No data concerning recurrence of brain metastases were given. The one-month mortality rates were 9% in the group treated with surgery and 0% in the group treated with WBRT alone, a nonsignificant difference. It is unclear whether surgical therapy is useful in the management of multiple metastases. Two retrospective studies have come to opposite conclusions regarding the safety and efficacy of surgical removal of more than one brain metastasis. Bindal et al (1993) analyzed patients with multiple metastases who had all the tumors resected and compared these with patients with multiple metastases who had some but not all
110
Pulmonmy:
The Problem of CNS Disease in Lung Cancer
of their brain metastases resected. A further comparison was made with patients with single metastases who were treated with complete resection plus WBRT. The authors found that the group with completely resected multiple metastases did relatively well (median survival 14 months) and was similar to the group with single resected metastases (median survival 14 months). The patients who did not have all of their brain tumors removed did less well (median survival 6 months). The 30 day mortality rate for the multiple metastases group was only 4%. No comparison was made with patients treated with WBRT alone (the standard treatment for multiple metastases). Hazuka et al (1993) reported a retrospective surgical series that contained 18 patients with multiple metastases and 28 patients with single metastases. The group with multiple metastases had a median survival of 5 months; those with single metastases had a median survival of 12 months. Overall, only 50% of patients had complete resections, and the complete resection rate in the multiple metastases group was not reported. The 30 day mortality rates in both groups were 0%. The above studies suggest that the postoperative morbidity and mortality rates for patients with multiple metastases treated with surgery are relatively low and are comparable with those reported in patients with single surgically resected metastases. However, it is difficult to draw firm conclusions regarding the efficacy of surgery for multiple metastases from the studies published to date. Current practice is to treat multiple metastases with WBRT alone or with radiosurgery followed by WBRT. A controversy exists regarding whether postoperative radiotherapy should be given as WBRT (as opposed to focal radiation) or whether radiotherapy is even necessary at all after an apparently complete resection of a single metastasis, The usefulness of postoperative WBRT has not yet been tested in a randomized trial; however, six nonrandomized retrospective studies have been reported. These retrospective studies do not conclusively establish the efficacy of postoperative WBRT in the treatment of single metastases, although they suggest that WBRT probably decreases the overall neurological re-
currence rate. A prospective, randomized trial is under way to decide the value of postoperative WBRT. However, current practice is to use WBRT postoperatively in most patients. Stereotactic radiosurgery, a method of delivering intense focal irradiation using a linear accelerator (LINAC) or multiple Cobalt-60 sources (Gamma Knife), has also been used to treat single and multiple brain metastases. Radiosurgery delivers a highly focused single dose of radiation to a circumscribed area of the brain with rapid dose fall off at the target edges. Radiosurgery is limited to lesions less than 3 cm in diameter. The technique causes tissue destruction in the area targeted; therefore, radiosurgery does not replace whole brain radiotherapy but may offer a substitute for surgical therapy. To date, no randomized trial comparing radiosurgery with any of the conventional methods of therapy has been reported, although many uncontrolled series have been published. The combined results of many retrospective reports suggest that radiosurgery prevents (or controls) local recurrence of 80-90% of treated metastases with about a 5-10% risk of radiation necrosis or new neurologic deficits. Auchter et al (1996) reported a retrospective review of the radiosurgery data bases of four institutions. The authors found 122 patients who met the following the same selection criteria used by Patchell et al (1990) in their randomized study discussed previously in this chapter, e.g., single brain matastasis; no prior cranial surgery or whole brain radiotherapy; age 218 years; surgically resectable lesion; KPS > 70; non-radiosensitive histology (e.g. lymphoma, small cell carcinoma). The patients in the Auchter study received WBRT (median 37.5 Gy) followed by a radiosurgery boost (median 17 Gy). The overall local control rate was 86% with an actuarial median survival, and a neurologic median survival of KPS > 70% of 44 weeks. The patients included in this study had an overall median survival was 56 weeks, and the duration of functionally independent survival was 44 weeks. These endpoints were similar to the surgical arms of the randomized trials of Patchell et al (1990) and Vecht et al (1993).