Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section F – Local Effects of Cancer and Its Metastasis

Chapter 56 – Brain Metastases and Neoplastic Meningitis

Penny K. Sneed,Norbert Kased,
Kim Huang,
James L. Rubenstein

SUMMARY OF KEY POINTS

Epidemiology

  

   

Central nervous system metastases are common, affecting up to 25% of cancer patients.

  

   

Most central nervous metastases involve the brain; less often, the dura, leptomeninges, skull base, or cranial nerves may be affected.

  

   

The terms neoplastic meningitis and carcinomatous meningitis refer to the dissemination of cancer cells within the leptomeningeal space.

  

   

The most frequent primary tumor types that give rise to brain metastases are lung cancer, melanoma, breast cancer, and renal cell carcinoma.

Diagnosis

  

   

Brain metastases are best detected with contrast-enhanced magnetic resonance imaging (MRI) and generally appear as enhancing, well-circumscribed lesions with surrounding vasogenic edema. Biopsy or resection might be indicated to confirm the diagnosis, particularly in a patient with a single lesion and no cancer diagnosis or no known metastatic disease.

  

   

Neoplastic meningitis often eludes early detection because meningeal enhancement is visible on MRI in only about 50% of cases and cerebrospinal fluid cytology may be negative initially in 40% to 50% of cases.

Prognosis

  

   

The most important factors predicting for longer survival of patients with brain metastases include age less than 65 years, good performance status, control of the primary tumor, and lack of extracranial metastases.

Treatment

  

   

The most standard treatment for brain metastases is whole-brain radiotherapy (WBRT), though patients with good prognosis who have a limited number of brain metastases might benefit from more aggressive therapy, such as surgery (especially for a single brain metastasis) or radiosurgery, with or without adjuvant WBRT. After WBRT alone, at least 60% of symptomatic patients improve significantly, and the median survival time is typically 3 to 6 months, with one third to one half of the patients dying of brain metastases and the rest dying of systemic disease. About 24% of brain metastases have a complete response to WBRT, and another 35% of lesions have a partial response, but the 1-year actuarial local control probability may be as low as 15%. Among patients with newly diagnosed brain metastases who are selected for surgery or radiosurgery with or without WBRT, the median survival time is approximately 9 to 11 months. One-year actuarial local control is about 35% for surgery alone, 85% for surgery and adjuvant WBRT, and 75% to 90% for radiosurgery with or without adjuvant WBRT. However, the increased local control that is achievable with surgery plus WBRT or with radiosurgery may only be meaningful in patients likely to live at least 6 or 12 months from the standpoint of their extracranial disease. Chemotherapy is not generally used as a primary treatment for brain metastases, but it has some efficacy on its own, and there is increasing interest in combining drugs with WBRT.

  

   

Intrathecal chemotherapy plays a major role in the management of neoplastic meningitis, alone or in combination with radiotherapy. Because craniospinal radiotherapy causes significant acute toxicity as well as long-lasting myelosuppression, neoplastic meningitis may be managed by using intrathecal chemotherapy combined with more limited radiotherapy, such as a lumbar field for gross disease in the cauda equina, skull base fields for cranial nerve involvement, or WBRT in patients with hydrocephalus stemming from diffuse brain leptomeningeal involvement.

INTRODUCTION

Central nervous system (CNS) metastases result from the intracranial spread of tumor cells that originate outside of the CNS. Most CNS metastases involve the brain parenchyma, dura, or leptomeninges; less commonly, metastases involve the base of skull, cranial nerves, or dural sinuses. This chapter deals with both parenchymal brain metastases and leptomeningeal metastases, also known as neoplastic or carcinomatous meningitis.

BRAIN METASTASES

Epidemiology

Brain metastases appear to be more common than primary malignant brain tumors, though the exact incidence is unknown. In a Memorial Sloan Kettering Cancer Center autopsy series, 24% of cancer patients had CNS metastases, and 15% had brain metastases,[1] and in a Roswell Park Memorial Institute autopsy study of 216 melanoma patients, 55% had brain metastases.[2] One population-based study in the Netherlands reported by Schouten and colleagues found that 8.5% of 2724 patients with melanoma or lung, breast, colorectal, or renal cell carcinoma developed brain metastases. The 5-year cumulative incidence of brain metastases was 7.4% in patients with melanoma and 16.3%, 9.8%, 5.0%, and 1.2% for patients with lung, renal cell, breast, or colorectal carcinoma, respectively.[3] Barnholtz-Sloan and colleagues calculated the population-based incidence of brain metastasis within the Metropolitan Detroit Cancer Surveillance System. In this cohort, 16,210 patients were found to have brain metastases, representing 9.6% of all lung, melanoma, breast, renal, and colorectal cancer patients diagnosed from 1973 to 2001. Lung and melanoma were the primary sites with the highest rates at 19.9% and 6.9%, respectively, and 5.1% of breast cancer patients, 6.5% of renal cancer patients, and 1.8% of colorectal cancer patients developed brain metastases.[4] It has been theorized that the incidence of brain metastases may be increasing as a result of improvements in cancer management leading to longer survival times and increased sensitivity of lesion detection made possible by contrast-enhanced, high-resolution magnetic resonance imaging (MRI), although Schouten and colleagues found no evidence of an increasing incidence of brain metastases over the period from 1986 through 1995.[3]

The most common primary tumors responsible for brain metastases are lung cancer (making up approximately 40% to 50% of cases), breast cancer (15%), melanoma (10%), and unknown primary (5% to 10%), followed by renal cell carcinoma, colorectal cancer, gynecologic cancers, and other miscellaneous tumors. [5] [6] Brain metastases may arise from any primary cancer, but certain tumors such as melanoma and carcinomas of the lung, kidney, and breast have a predilection for spread to the CNS. By contrast, some tumors rarely metastasize to the brain, such as prostate, oropharyngeal, and skin carcinomas. In children, the most common solid malignancies responsible for brain metastases are sarcomas, neuroblastoma, and germ cell tumor.[7]

Cancer can spread to the brain at various points in the course of disease. Synchronous brain metastases, found within 1 month of the primary cancer diagnosis, occur in up to one third of patients,[3]including cases in which brain metastases are responsible for a patient's presenting signs or symptoms. More commonly, however, brain metastases are discovered after the diagnosis of cancer, often after other systemic metastases have developed, at a median of less than 1 year after diagnosis of lung cancer and at a median of 2 to 3 years after diagnosis of melanoma, breast cancer, gynecologic cancer, or renal cell carcinoma.[6] Overall, the median time from primary diagnosis to diagnosis of brain metastases is 12 months.[6]

Pathophysiology

Brain metastases arise primarily from arterial hematogenous spread to the brain, with tumor cells tending to become trapped where blood vessels decrease in caliber at the gray/white matter junction and the distalmost vasculature (the border zones or “watershed” zones between arterial territories).[8] Metastatic cells then adhere to the endothelial cells, penetrate into the brain parenchyma, and proliferate. Larger aggregates of tumor cells that gain access to the venous circulation are filtered out in lung capillaries before entering the systemic arterial circulation, but individual tumor cells may pass through the lung to lodge in the brain. Tumor emboli may also break off from lung metastases or primary lung cancers to travel to the brain via the arterial circulation. It has also been theorized that cells from pelvic or abdominal cancers may gain access to the posterior fossa or leptomeninges through Batson's vertebral venous plexus without passing through the lungs.[5] Intracranial spread may also occur via direct extension from bone or dural metastases or perineural extension along cranial nerves. The distribution of metastases is roughly proportional to the relative blood flow to different regions; approximately 80% of brain metastases are located in the cerebral hemispheres, 10% to 15% in the cerebellum, and 1% to 5% in the brain stem. [5] [6] Posterior fossa metastases appear to arise disproportionately from pelvic or abdominal primary tumors.[5]

Most brain metastases are very well circumscribed. Although there may be extensive associated edema, the tumor cells do not tend to infiltrate into surrounding brain tissue, in contrast to primary malignant brain tumors. Most brain metastases are solid, but they can appear cystic because of necrosis, keratin deposits in squamous cell carcinoma, or mucin secretion from adenocarcinoma. Brain metastases may be hemorrhagic, particularly from melanoma, renal cell carcinoma, choriocarcinoma, and, less frequently, bronchogenic carcinoma.[9] The pathologist can easily identify well-differentiated metastases, but immunohistochemistry or electron microscopy might be needed to help make the diagnosis of metastatic versus primary brain neoplasm and to suggest the likely site of origin of poorly differentiated metastases.

Single brain metastases are more common than multiple metastases in patients with renal cell, gastrointestinal, or unknown primary cancers.[6] In the era of computed tomographic (CT) imaging, about 50% of brain metastasis patients had a single brain lesion.[5] By MRI criteria, the actual percentage of brain metastasis patients with a single lesion might be lower than this, because contrast-enhanced MRI is more sensitive than CT is[10] and because triple-dose gadolinium is more sensitive than is single-dose gadolinium-enhanced MRI.[11] Of note, the term solitary brain metastasis implies that a single brain metastasis is the only known site of metastatic disease, whereas the term single brain metastasis refers to a single cerebral lesion without implying whether or not there are extracranial metastases.

Clinical Presentation

The possibility of brain metastases should be suspected in any cancer patient who develops new neurologic signs or symptoms. Two thirds of cancer patients who are found to have brain metastases at autopsy had experienced neurologic symptoms from the metastases,[12] and only 10% of a series of 729 patients diagnosed by CT or MRI from 1973 through 1993 were asymptomatic.[6] The most common presenting symptoms are headache (24% to 53%), focal weakness (16% to 40%), altered mental status (24% to 31%), seizures (15% to 16%), and ataxia (9% to 20%). [6] [13] Symptoms may worsen gradually from a growing tumor and the associated edema. Less often, acute neurologic symptoms may occur from hemorrhage into a brain metastasis. Again, the histologic types with the greatest propensity to produce hemorrhagic brain metastases include melanoma, renal cell carcinoma, and choriocarcinoma.

Diagnosis

It is widely accepted that MRI is the best diagnostic test to detect brain metastases. Standard imaging includes T2-weighted and pre- and post-gadolinium-enhanced T1-weighted sequences; a postcontrast fluid-attenuated inversion-recovery sequence is also helpful in visualizing small metastases near cerebrospinal fluid (CSF) spaces ( Fig. 56-1 ). Gadolinium-enhanced MRI is much more sensitive than either nonenhanced MRI or contrast-enhanced CT imaging. [10] [14] In one study, 17 of 55 patients (31%) with a single metastasis based on contrast-enhanced CT imaging were found to have multiple metastases on contrast-enhanced MRI.[15] The sensitivity of MRI is improved by using triple-dose gadolinium (0.3 mmol/kg instead of 0.1 mmol/kg gadoteridol) to increase contrast enhancement[11] and by using contiguous axial 3-mm slices without skips and coronal three-dimensional spoiled gradient echo recovery volume imaging so that small lesions are not missed between slices. Functional imaging techniques such as positron emission tomography, magnetic resonance spectroscopy, and perfusion and diffusion MRI may aid in distinguishing metastatic lesions from necrosis, primary brain tumor, or nonmalignant processes. [16] [17] [18]

 
 

Figure 56-1  Typical appearance of a brain metastasis on magnetic resonance imaging. The lesion is well circumscribed and brightly enhancing on the postcontrast T1-weighted image (left). Both edema and cerebrospinal fluid show up as increased signal on the T2-weighted image (center). Both the metastasis and the surrounding edema appear bright on the postcontrast fluid-attenuated inversion-recovery image, while the cerebrospinal fluid signal is suppressed (right).

 

 

The differential diagnosis of an enhancing or hemorrhagic intracranial lesion includes brain metastasis, primary brain tumor, CNS lymphoma, abscess, encephalitis, cerebral infarct or hemorrhage, progressive multifocal leukoencephalopathy, tumefactive demyelinating disease, and radiation necrosis. Factors that aid in making a diagnosis based on imaging include characteristic appearance, a known cancer diagnosis, and multiplicity of lesions. However, a biopsy can be warranted if there is doubt about the diagnosis or if a single brain lesion is seen in a patient with a history of cancer but no other known metastatic disease, because management and prognosis may vary widely depending on the diagnosis. In a study reported by Patchell and colleagues that required biopsy or surgery before WBRT, 11% of 54 patients with a single brain lesion that was thought to be a metastasis turned out to have a glioblastoma, low-grade astrocytoma, abscess, or inflammatory process.[19] A stereotactic biopsy series in 100 patients with multifocal brain lesions and no known primary cancer diagnosed malignant gliomas in 37% of patients, primary CNS lymphoma in 15%, brain metastases in 15%, low-grade gliomas in 12%, infectious processes in 10%, and ischemic lesions in 6%.[20]

Prognostic Factors

In general, brain metastases are associated with a poor prognosis. In the pre-CT era, the median survival time of patients with symptomatic brain metastases was approximately 1 to 2 months without treatment, [21] [22] [23] 2 to 2.5 months with corticosteroid therapy,[24] and 3 to 6 months with WBRT. [25] [26] [27] Despite some major advances in cancer diagnosis, cancer treatment, and brain imaging, the overall survival time of unselected patients with brain metastases treated with WBRT has remained at 3 to 6 months since the 1950s. [6] [28] [29] [30] The majority of patients with brain metastases have or will soon develop disseminated systemic disease and overall survival is often determined by the extent and activity of the extracranial disease. In patients with a relatively short life expectancy, the treatment goal is to achieve rapid palliation and a neurologic symptom-free remission interval that is commensurate with the life expectancy. However, long-term survival or cure is possible in a small proportion of patients with brain metastases, and patients with a longer life expectancy from the standpoint of their extracranial disease might benefit from more aggressive therapies that will yield more durable control of their brain metastases.

Two large series of brain metastasis patients evaluated for prognostic factors are summarized here. Lagerwaard and colleagues studied 1292 patients with CT-diagnosed brain metastases who were treated at Daniel den Hoed Cancer Center in Rotterdam from 1981 through 1990.[31] The overall median survival time was 3.4 months, and the most important patient and tumor characteristics that were prognostic for longer survival time included better performance status, limited versus extensive systemic tumor activity, and normal serum lactate dehydrogenase level, followed by lesser factors, including breast cancer versus other primary sites, age less than 70 years, and 1 to 2 versus 3 or more brain metastases.[31] Gaspar and colleagues identified three prognostic groups using a recursive partitioning analysis (RPA) of over 1100 evaluable patients enrolled in three consecutive Radiation Therapy Oncology Group (RTOG) trials conducted from 1979 through 1993.[32] The median survival time was 7.1 months for the subgroup with the best prognosis, RPA class 1, consisting of patients less than 65 years old with a Karnofsky performance status (KPS) of at least 70, controlled primary tumor, and no extracranial metastases ( Table 56-1 ). The subgroup with the poorest prognosis, RPA class 3, including patients with KPS less than 70, had a median survival time of only 2.3 months; and the median survival time was 4.2 months for the remaining patients who made up RPA class 2 (see Table 56-1 ).[32] The prognostic value of these RPA classes has been validated in 569 patients with single or multiple brain metastases who were treated with radiosurgery with or without adjuvant WBRT, with median survival times of 14.0 to 15.2 months for RPA class 1, 7.0 to 8.2 months for RPA class 2, and 5.3 to 5.5 months for RPA class 3 (see Table 56-1 ).[33] Similarly, two groups reported median survival times of 13.4 to 25.4 months for RPA class 1, 5.9 to 9.3 months for RPA class 2, and 1.5 to 4.5 months for RPA class 3 patients treated with radiosurgery alone, [34] [35] and three surgical series found median survival times ranging from 10.9 to 21.4 months for RPA class 1, 9.0 to 9.9 months for RPA class 2, and 6.0 to 8.9 months for RPA class 3 patients who underwent surgical resection with or without adjuvant WBRT (see Table 56-1 ). [36] [37] [38]


Table 56-1   -- Median Survival Time by Radiation Therapy Oncology Group Recursive Partitioning Analysis Class

 

RPA CLASS 1

RPA CLASS 2

RPA CLASS 3

Treatment

No. of Patients

MST (Months)

No. of Patients

MST (Months)

No. of Patients

MST (Months)

WBRT alone[32]

236

7.1

765

4.2

175

2.3

RS alone initially[34]

23

25.4

74

5.9

20

4.2

RS alone initially[35]

15

13.4

65

9.3

21

1.5

RS alone initially[33]

39

14.0

197

8.2

29

5.3

RS + upfront WBRT[33]

64

15.2

222

7.0

9

5.5

Surgery + WBRT[36]

26

14.8

63

9.9

36

6.0

Surgery ± WBRT[37]

26

10.9

69

9.8

 

Surgery ± WBRT[38]

50

21.4

208

9.0

13

8.9

MST, median survival time; RPA, recursive partitioning analysis; RS, radiosurgery; WBRT, whole-brain radiotherapy.

 

 

 

Treatment

The symptoms resulting from brain metastases may be ameliorated with corticosteroids or osmotic therapy for the peritumoral edema or with anticonvulsants for seizure control. Direct antitumor therapies include surgery, radiotherapy (external beam radiotherapy, radiosurgery, and brachytherapy), chemotherapy, and molecular targeted drugs.

Corticosteroids

Corticosteroid therapy is generally instituted in symptomatic patients as soon as brain metastases are diagnosed, to help alleviate symptoms until the brain metastases and edema improve from specific antitumor treatment. Corticosteroids reduce the permeability of leaky tumor blood vessels and thereby reduce the mass effect and edema caused by brain metastases.[39] The most commonly used steroid is dexamethasone because of its relatively low mineralocorticoid activity, often using a loading dose of 10 mg followed by 4 mg every 6 hours. Lower doses (2 to 4 mg twice daily or 2 to 4 mg three times a day) may be adequate in many situations, and higher doses might rarely be needed. Patients commonly improve within hours after the first dose, attaining maximal benefit after approximately 3 to 7 days. After patients become asymptomatic or reach maximal benefit, the dose should be gradually tapered and either discontinued or maintained at the lowest dose level needed to manage symptoms. If headaches recur or neurologic symptoms worsen during the course of the taper, the dose should be increased as needed, and then the taper should proceed more gradually. Occasional patients develop steroid withdrawal symptoms of depression, fatigue, nausea, or poor appetite, necessitating reinstitution of low-dose dexamethasone and a gradual taper schedule in the low-dose range. Steroids have numerous adverse effects, particularly with long-term use. Common short term side effects include insomnia, increased appetite, fluid retention, mood changes, acne, and exacerbation of diabetes, and some of the serious long-term side effects include significant weight gain, steroid myopathy, immunosuppression, and aseptic necrosis of the femoral heads. Of note, steroid myopathy can cause fairly profound weakness in large proximal muscles, making it difficult for patients to get up and walk; this dysfunction may be mistaken as a sign of progression of CNS metastases and as an indication to continue or increase steroids when it is actually a complication of steroid therapy.

Anticonvulsants

Seizures are very unlikely to occur from infratentorial metastases but may be triggered by supratentorial metastases. About 15% of patients with brain metastases present with seizures and 30% to 40% experience seizures at some point in their disease course.[40] Any patient with brain metastases who experiences a seizure should be started on an anticonvulsant such as phenytoin, carbamazepine, or levetiracetam, but prophylactic anticonvulsants are not generally recommended because prospective and retrospective studies have failed to demonstrate a benefit for prophylactic anticonvulsants in patients with brain metastases. [39] [40] [41] Also, anticonvulsants can have adverse side effects or cause serious allergic reactions, such as Stevens-Johnson syndrome. It is important to note that certain anticonvulsants, such as phenytoin, can reduce the efficacy of corticosteroids and can activate the cytochrome P450 enzyme system.[42] This latter property can affect patients who are undergoing chemotherapy by altering the metabolism of some chemotherapeutic agents, thus requiring chemotherapy dose adjustment.

External Beam Radiation Therapy

The most standard treatment for brain metastases consists of WBRT covering the entire intracranial contents with shielding of the eyes ( Fig. 56-2 ). The benefits of WBRT were first described in the 1950s and 1960s. In these early studies, significant symptomatic improvement was noted in about 60% of patients, and the median survival time ranged from about 3 to 6 months with WBRT [25] [26] [27] compared with an expected median survival time of 1 to 2 months without treatment. [21] [22] [23]

 
 

Figure 56-2  Double-exposed portal image of a typical whole-brain radiotherapy field, showing radiation covering the entire brain with blocking of the eyes and other extracranial structures.

 

 

SELECTED RANDOMIZED TRIALS OF WHOLE-BRAIN RADIOTHERAPY ALONE.

The RTOG has conducted multiple large phase III randomized trials of WBRT since 1970 ( Table 56-2 ). The first two trials, which compared various WBRT fractionation schemes in over 1800 patients who were treated from 1971 through 1976, gathered a wealth of data. [28] [43] Complete or partial response of specific neurologic symptoms was observed in 60% to 90% of symptomatic patients; 47% to 52% of patients improved to a higher neurologic function class; the median duration of improvement was 10 to 12 weeks; and 75% to 80% of patients’ remaining survival time was spent in an improved or stable neurologic state. The overall median survival times were 18 weeks (4.1 months) in the first study and 15 weeks (3.4 months) in the second study, and brain metastases were reported to be the cause of death in 49% or 31% of the patients, respectively. There were no significant differences in symptomatic response rates, duration of response, or survival time according to the treatment regimen: 40 Gy in 20 fractions, 40 Gy in 15 fractions, 30 Gy in 15 fractions, 30 Gy in 10 fractions, or 20 Gy in 5 fractions. [28] [43] With the ultrarapid fractionation schemes that were tested by the RTOG (10 Gy in one fraction or 12 Gy in 2 fractions; see Table 56-1 ), there was some concern that irradiation might have led to herniation and death within 48 hours of treatment in a small number of cases, and time to neurologic progression was shorter than that with more protracted regimens. [44] [45] Both of these findings agreed with conclusions of a Memorial Sloan Kettering Cancer Center evaluation of 15 Gy in 2 fractions over 3 days compared with 30 Gy in 15 fractions.[46] Two later RTOG trials failed to show any advantage of 50 Gy in 20 fractions or 54.4 Gy at 1.6 Gy twice daily over 30 Gy in 10 fractions (see Table 56-1 ),[29] [30] further solidifying 30 Gy in 10 fractions over 2 weeks as the most frequently used WBRT treatment regimen. Other common treatment regimens include 35 to 37.5 Gy at 2.5 Gy per fraction, 40 to 50 Gy at 2.0 Gy per fraction, and 45 to 50.4 Gy at 1.8 Gy per fraction. Shorter regimens may be selected for patients with a shorter life expectancy or when WBRT is delaying chemotherapy that is needed to treat systemic disease, and smaller fraction size may be selected in patients with longer life expectancy on the basis of a suspicion that this might give less risk of late neurotoxicity.


Table 56-2   -- Selected Randomized Trials of Whole-Brain Radiotherapy Alone for Brain Metastases

Protocol

Years

No. of Patients

Fractionation Scheme

Median Survival Time (Months)

RTOG 6901 [28] [43]

1971–1973

233

30 Gy/10 fractions/2 weeks

4.8

First study

 

217

30 Gy/15 fractions/3 weeks

4.1

 

 

233

40 Gy/15 fractions/3 weeks

4.1

 

 

227

40 Gy/20 fractions/4 weeks

3.7

RTOG 7361 [28] [43]

1973–1976

447

20 Gy/5 fractions/1 week

3.4

Second study

 

228

30 Gy/10 fractions/2 weeks

3.4

 

 

227

40 Gy/15 fractions/3 weeks

4.1

RTOG 6901[44]

1971–1973

26

10 Gy/1 fractions/1 day

3.4

RTOG 7361[44]

1973–1976

33

12 Gy/2 fractions/2 days

3.0

Ultrarapid

 

 

 

 

RTOG 7606[29]

1976–1979

130

30 Gy/10 fractions/2 weeks

4.1

“Favorable patients”

 

125

50 Gy/20 fractions/4 weeks

3.9

RTOG 9104[30]

1991–1995

213

30 Gy/10 fractions/2 weeks

4.5

Accelerated hyperfractionation

 

216

54.4 Gy at 1.6 twice daily

4.5

RTOG, Radiation Therapy Oncology Group.

 

 

 

RESPONSE AND LOCAL CONTROL.

Neider and colleagues studied CT response of brain metastases to WBRT (30 Gy in 10 fractions).[47] By lesion, the complete response rate was 24%, and the partial response rate was 35%. The overall (complete plus partial) response rates were 81% for small cell carcinoma, 65% for breast cancer, 56% for squamous cell carcinoma, 50% for nonbreast adenocarcinoma, 46% for renal cell carcinoma, and 0% for melanoma. Absence of necrosis and smaller volume were associated with improved response rate; complete response rates were 39% for solid metastases, 15% for those with less than 50% necrosis, and 11% for those with at least 50% necrosis, and 52%, 39%, 17%, 20%, 5%, and 0% for lesion volumes up to 0.5 mL, 0.6 to 1.0 mL, 1.1 to 3.0 mL, 3.1 to 6.0 mL, 6.1 to 10.0 mL, and more than 10 mL, respectively.[47] In another study by the same group, there was a suggestion that a higher response rate was obtained with 40 at 2 Gy per fraction with or without a partial brain boost to 50 or 60 Gy compared with 30 Gy at 3 Gy per fraction.[48] For the WBRT-only arm of a recent RTOG trial of WBRT with or without radiosurgery, the complete response rate was 8%, the partial response rate was 54%, the stable disease rate was 22%, and the progression rate was 17% among 78 patients with imaging follow-up.[49] Data on long-term local control of brain metastases after WBRT alone are limited and highly variable. The 1-year actuarial local control probability by patient ranged from 0% to 14% in the WBRT-only arms of randomized trials reported by Kondziolka and colleagues[50] and Patchell and colleagues[19] but as high as 71% in the WBRT-only arm of the RTOG randomized trial of WBRT with or without radiosurgery.[49]

PARTIAL BRAIN RADIOTHERAPY.

Partial brain radiotherapy can be considered for a single metastasis in lieu of WBRT, but it is generally not advisable in that it would complicate or preclude later WBRT if needed (unlike radiosurgery, which delivers much more focal radiation dose). Caution is advised when postoperative radiotherapy to the posterior fossa alone is contemplated because cerebellar metastases appear to be associated with an increased risk of leptomeningeal dissemination after resection. [51] [52] On the other hand, partial brain radiotherapy might be useful for treating recurrent brain metastases that are not suitable for resection or radiosurgery.

TOXICITY OF WHOLE-BRAIN RADIOTHERAPY.

Acute toxicity of WBRT includes hair loss, fatigue, and modest skin reaction in essentially all patients and mild acute ototoxicity in some patients. The skin reaction resolves by several weeks, and fatigue improves gradually over one or several months. Hair generally regrows by 6 months following WBRT, but alopecia may be permanent in a central strip on the top and back of the head from the reduced skin sparing of tangential radiation beams. In the minority of patients who are long-term survivors after WBRT, there is a risk of late hearing loss, retinopathy if the retina was included in the radiation field, and permanent neurocognitive toxicity. DeAngelis and colleagues reported an 11% risk of severe radiation-induced dementia among 1-year survivors after resection of a single brain metastasis followed by postoperative WBRT to 20 to 40 Gy using high-dose daily fractions.[51] A separate report from the same group described 12 patients cured of brain metastases who developed severe radiation-induced dementia with associated ataxia and urinary incontinence.[53] Imaging with CT showed atrophy, ventricular dilatation, and hypodense white matter. The WBRT fractionation schemes included mostly mixtures of 3- or 4-Gy fractions with 5- or 6-Gy fractions, but two of the affected patients had received the standard regimen of 30 Gy in 10 fractions.[53] Nieder and colleagues reported a 42% 2-year actuarial probability of symptomatic mild, moderate, or severe late radiation toxicity in patients who were treated with resection of a single brain metastasis followed by WBRT to 30 Gy in 10 fractions or 40 Gy in 20 fractions, but no details were provided regarding the nature of the toxicity.[54] Among 112 patients on the WBRT-only arm of a recent RTOG randomized trial, Andrews and colleagues reported four grade 1, one grade 2, one grade 3, and one grade 4 late central neurologic toxicities; two grade 1, two grade 2, and one grade 3 late ototoxicities; and eleven grade 1 and four grade 2 chronic skin toxicities.[49] This RTOG trial did not include formal neurocognitive testing, but it is becoming more common to incorporate baseline and follow-up neurocognitive testing into prospective trials in patients with brain metastases.

Surgery

Surgery has important roles to play in certain subsets of patients: confirming the diagnosis when needed (as discussed in the section on Diagnosis); relieving mass effect from a large, symptomatic lesion (Fig. 56-3 ); improving the likelihood of durable local control for a single metastasis; and salvaging a failing metastasis after prior therapy. Surgical resection may also be useful for lesions with considerable peritumoral edema despite steroids or for lesions that are causing refractory seizures, even if the lesion is sufficiently small that radiosurgery would be a therapeutic option.[55] Resection of brain metastases has become safer with advances in neuroimaging and neurosurgery, such as image guidance, preoperative and intraoperative functional mapping, and intraoperative ultrasound and MRI.[56]

 
 

Figure 56-3  Preoperative (left), immediate postoperative (center), and 2-month postoperative (right) contrast-enhanced T1-weighted magnetic resonance images of a single metastasis treated with surgical resection.

 

 

RANDOMIZED TRIALS OF WHOLE-BRAIN RADIOTHERAPY WITH OR WITHOUT SURGERY.

Three prospective, randomized trials have been performed to evaluate the addition of surgery to WBRT ( Table 56-3 ). In the trial reported by Patchell and colleagues, 48 patients with a single brain metastasis were randomized to biopsy and WBRT versus resection and WBRT to 36 Gy in 12 fractions.[19] Patients who underwent resection had significantly improved local control (80% versus 48% for resection and WBRT versus biopsy and WBRT; P < 0.02), duration of functional independence (median: 38 weeks versus 8 weeks, P < 0.005), and survival (median: 40 weeks versus 15 weeks, P < 0.01). Factors that were associated with longer survival included younger age, no extracranial disease, surgical resection, and a longer interval from primary diagnosis to brain metastasis diagnosis.[19]


Table 56-3   -- Randomized Trials of Surgery or Radiosurgery and Whole-Brain Radiotherapy for Brain Metastases

First Author (Years)

Treatment

No. of Patients

Patients with Extracranial Disease (%)

Median Local FFP (Months)

Median Functionally Independent Survival (Months)

Median Survival (Months)

Patchell[19] (1985–1988)

Biopsy + WBRT

23

83

4.8

1.8

3.4

 

Surgery + WBRT

25

76

>13.6

8.7

9.2

 

(36 Gy/12 fx)

 

 

(P < 0.0001)

(P < 0.005)

(P < 0.01)

Noordijk[57] (1985–1990)

WBRT

31

68

3.5

6

 

Surgery + WBRT

32

69

7.5

10

 

(40 Gy at 2 Gy BID)

 

 

(P = 0.06)

(P = 0.04)

Mintz[58] (1989–1993)

WBRT

43

84

6.3

 

Surgery + WBRT

41

73

5.6

 

(30 Gy/10 fx)

 

 

(P = NS)

(P = 0.24)

Patchell[62] (1989–1997)

Surgery

46

65

6.2

8.0

9.9

 

Surgery + WBRT

49

63

>12.0

8.5

11.0

 

(50.4 Gy/28 fx)

 

 

(P < 0.001)

(P = 0.61)

(P = 0.39)

Kondziolka[50] (1985–1988)

WBRT

14

71

6

7.5

 

WBRT + RS

13

62

36

11.0

 

(36 Gy/12 fx)

 

 

(P = 0.0005)

(P = 0.22)

Andrews[49] (1996–2001)

WBRT

167

69

[71% 1-year LC]

5.7

 

WBRT + RS

164

68

[82% 1-year LC]

6.5

 

(37.5 Gy/15 fx)

 

 

(P = 0.013)

(P = 0.136)

Aoyama[90] (1999–2003)

RS

67

43

[73% at 1 year]

[27% at 1 year]

8.0

 

WBRT + RS

65

37

[89% 1-year LC]

[34% at 1 year]

7.5

 

(30 Gy/10 fx)

 

 

(P = 0.002)

(P = 0.53)

(P = 0.42)

FFP, freedom from progression; fx, fractions; LC, local control; NS, not significant; RS, radiosurgery; WBRT, whole-brain radiotherapy.

 

 

 

A trial that was performed in the Netherlands randomized 63 evaluable patients with a single brain metastasis to surgery plus WBRT versus WBRT alone (40 Gy at 2 Gy twice daily; see Table 56-3 ).[57]Patients on the surgery arm of the trial had longer functionally independent survival (median: 7.5 months for surgery and WBRT versus 3.5 months for WBRT alone, P = 0.06) and longer survival time (median: 10 months versus 6 months, P = 0.04). The survival benefit was seen only in patients without active extracranial disease, in whom the median survival time was 12 months for surgery and WBRT versus 7 months for WBRT alone (P = 0.02); the median survival time was 5 months for patients with active extracranial disease regardless of the treatment arm. Older age (over 60 versus 60 years or younger) was also confirmed as an important unfavorable prognostic factor (P = 0.003; hazard ratio = 2.74).[57]

A third trial failed to show a benefit for surgery in addition to WBRT (30 Gy in 10 fractions over 2 weeks; see Table 56-3 ).[58] The median survival times were 5.6 months among 41 patients randomized to surgery with WBRT versus 6.3 months among 43 patients randomized to WBRT alone (4 of whom had surgery before WBRT and 6 of whom had surgery after WBRT). There was no difference in duration of functional independence between the two treatment arms. The authors concluded that further trials and/or a meta-analysis was indicated,[58] but overall, these studies and previous nonrandomized experience [59] [60] [61] support the use of surgery in addition to WBRT in patients with good performance status, controlled extracranial disease, and a single brain metastasis.

RANDOMIZED TRIAL OF SURGERY WITH OR WITHOUT WHOLE-BRAIN RADIOTHERAPY.

Postoperative WBRT may help to prevent recurrence at the resection cavity and to prevent the appearance of new brain metastases by treating any microscopic metastases elsewhere in the brain and any dissemination of tumor cells as a result of the surgery. Following up on multiple retrospective studies that suggest a benefit for postoperative WBRT after resection of a brain metastasis, Patchell and colleagues performed a randomized trial (see Table 56-3 ).[62] Ninety-five adults were randomized to observation versus postoperative WBRT to 50.4 Gy in 28 fractions after complete resection of a single brain metastasis. The observation arm had a significantly increased risk of local failure (46% for observation versus 10% for WBRT), distant brain failure (37% versus 14%), and any brain failure (70% versus 18%); shorter time to local failure (median: 27 weeks versus more than 52 weeks [6.2 months versus more than 12 months]; P < 0.001; hazard ratio: 6.03); and shorter time to any brain failure (median: 26 weeks versus more than 70 weeks [6.0 months versus more than 16.1 months]; P < 0.001; hazard ratio: 4.94). Patients who were randomized to observation were more likely to die neurologic deaths (44% versus 14%; P = 0.003) but, interestingly, had similar duration of functional independence (median: 35 weeks [8.0 months] for observation versus 37 weeks [8.5 months] for WBRT; P = 0.61) and similar survival time (median: 43 weeks versus 48 weeks [9.9 months versus 11.0 months]; P = 0.39).[62] Topics that were not addressed in the report included the use or success of salvage therapy and acute and late toxicity of WBRT and salvage therapies.

SURGERY FOR MULTIPLE METASTASES.

Surgical resection may also be used successfully to manage selected patients with more than one brain metastasis. Bindal and colleagues reported a median survival time of 14 months among 26 patients with multiple brain metastases who underwent resection of all of their brain lesions in a single operation, identical to the survival time of matched patients who had had resection of a single metastasis.[63]The complication rate was 9% per craniotomy, the 30-day mortality rate was 4%, and only 6% of symptomatic patients worsened, while 83% improved and 11% remained stable.[63] A different group describing results of surgery and WBRT had noted significantly poorer survival among 18 patients with multiple brain metastases compared with 28 patients with a single metastasis, but apparently, only one patient with multiple metastases had undergone gross total resection of all (two) metastases, and this patient survived 46 months.[64] In a recent series, Paek and colleagues reported a median survival time of 8 months after surgery for approximately 103 patients with a newly diagnosed single metastasis versus 11 months after surgery for 46 patients with newly diagnosed multiple brain metastases (only 9 of whom had multiple brain metastases resected). Most patients received postoperative WBRT.[65]

TOXICITY OF SURGERY.

The morbidity and mortality associated with surgical resection of brain metastases have decreased over the years as techniques have improved. Lang and colleagues estimated the 30-day mortality rate to be about 4% to 5% after surgery for brain metastasis (essentially identical to the 30-day mortality rate in patients who were managed with WBRT alone).[56] The most common types of postoperative morbidity include wound infection, hemorrhage, meningitis, pneumonia, deep venous thrombosis, and pulmonary embolism, which occur in about 10% to 15% of patients on average. [56] [66] Most patients are symptomatic preoperatively; one surgical series reported that 0% to 13% of patients worsened neurologically, 65% to 84% improved, and 11% to 22% remained stable after resection of single or multiple brain metastasis.[63] Paek and colleagues recently reported outcomes in 208 patients who underwent resection of one (N = 191) or multiple (N = 17) newly diagnosed (N = 149) or recurrent (N = 59) brain metastases at a single institution using modern neurosurgical techniques.[65] The 30-day mortality rate was 1.9%, with two deaths from hemorrhage in the resection cavity, one from pulmonary embolism secondary to deep venous thrombosis, and one from bowel perforation with sepsis. The median hospital stay was 3 days after surgery, and KPS improved postoperatively in 33%, remained stable in 61%, and decreased in 6% of patients.[65]

Radiosurgery

Radiosurgery implies the delivery of carefully targeted, very focal radiation to one or more intracranial targets, usually using a specially adapted linear accelerator[67] or a gamma knife.[68] A stereotactic frame may be applied prior to the procedure under local anesthesia to help allow very precise targeting. Multiple beams or arcs provide for very steep falloff of dose outside of the target or targets, minimizing dose to surrounding normal brain tissue, but a thin shell of tissue around the target receives a potentially damaging dose of radiation ( Fig. 56-4 ). Because the risk of radiation injury increases with increasing volume, lower doses are generally prescribed for larger target volumes, and radiosurgery targets tend to be limited to about 2.5 to 3 cm in diameter.

 
 

Figure 56-4  Postcontrast T1-weighted magnetic resonance imaging of a brain metastasis shown on the day of radiosurgery with superimposed 50% and 25% isodose contours (left) and follow-up imaging 11 months later, showing near complete response (right). A dose of 17.5 Gy was prescribed at the 50% isodose contour.

 

 

RETROSPECTIVE RESULTS OF RADIOSURGERY.

Table 56-4 summarizes results of selected retrospective series of radiosurgery for single or multiple newly diagnosed or recurrent brain metastases treated with or without adjuvant WBRT. [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] For median target volumes ranging from 0.9 to 7.5 mL and median prescribed doses ranging from 15.0 to 27.0 Gy in a single fraction, the crude local control rates were 85% to 96% and the 1-year actuarial local control probabilities were 82% to 94% by lesion, with a 0% to 17% risk of symptomatic radiation necrosis (average risk, 4%). In most of the series, the median survival times ranged from 7 to 11 months.


Table 56-4   -- Results of Radiosurgery with or Without Whole-Brain Radiotherapy for Newly Diagnosed or Recurrent Brain Metastases

First Author

No. of Metastases/No. of Patients

Mean or Median Dose

Median Target Volume

Local Control by Lesion (%)

Median Survival Time (Months)

Necrosis (%)

Single metastases

Auchter[69]

122/122

17.0 Gy

2.7 mL

86[*]/85[†]

12.9

0

Flickinger[70]

116/116

17.5 Gy

85[*]

11

4

Simonova[71]

237/237

21.5 Gy

7.5 mL

95[*]

9

2.5

Single or multiple metastases

Deinsberger[72]

161/110

18.3 Gy

3.1 mL

89[*]

12.4

2

Flickinger[73]

229/157

16.0 Gy

3.0 mL

89[*]

10

1

Fukuoka[74]

>215/130

>25 Gy

5.5 mL

≥96[*]

8

5

Gerosa[75]

1307/804

20.6 Gy

4.8 mL

94[†]

13.5

Goodman[76]

682/258

18.5 Gy

1.7 mL

82[†]

9.1

Joseph[77]

189/120

26.6 Gy

5.3 mL

94[*]

7.4

17

Kihlstrom[78]

235/160

27.0 Gy

4.5 mL

94[*]

7

5

Moriarty[79]

643/353

15.0 Gy

2.5 mL

88[†]

10.5

3–6

Petrovich[80]

1305/458

18 Gy

0.9 mL

87[†]

9

4.7

Pirzkall[81]

311/236

20 Gy

92[*]

5.5

2

Sansur[82]

411/193

20 Gy

82 by patient

7.5

2

Young[83]

669/250

91[*]

7

<4

*

Crude.

1-year actuarial.

 

RADIOSURGERY DOSE-RESPONSE RELATIONSHIPS.

An RTOG dose escalation trial in patients with recurrent primary or metastatic brain tumors concluded that the maximum tolerated doses of single fraction radiosurgery (without WBRT) were 24 Gy for tumors 2 cm or less in maximum diameter, 18 Gy for tumors 2.1 to 3.0 cm, and 15 Gy for tumors 3.1 to 4.0 cm.[84] A dose-response analysis specifically in newly diagnosed or recurrent brain metastases 2 cm in diameter or smaller found crude local control rates of 91% using a radiosurgery dose less than 20 Gy (N = 46), 99% using a dose of 20 Gy (N = 158), and 96% using a dose higher than 20 Gy (N = 24) when radiosurgery was combined with planned WBRT. Because the risk of complications was 1.9% for radiosurgery doses of 20 Gy or less and 5.9% for doses above 20 Gy, the authors concluded that 20 Gy was the optimal radiosurgery dose for metastases 2 cm or less in diameter. Of note, the crude local control rates were 97% for radiosurgery with WBRT versus 87% for radiosurgery without planned WBRT (P = 0.0001).

On the basis of a data set of 518 newly diagnosed or recurrent brain metastases treated with radiosurgery with or without WBRT at the University of California, San Francisco,[76] the 1-year actuarial local freedom from progression probabilities were 88%, 75%, and 29% for doses of 18 Gy or more, 15.0 to 17.9 Gy, and less than 15.0 Gy, respectively, and 92%, 83%, 69%, and 37% for maximum target diameters 1.0 cm or less, 1.1 to 2.0 cm, 2.1 to 3.0 cm, and more than 3.0 cm, respectively. A study of 126 lesions in 80 patients who were treated with linac radiosurgery at the University of Chicago found 1-year local control probabilities of 50%, 97%, and 90% for prescribed doses of 10 to 13.99 Gy, 14 to 17.99 Gy, and 18 Gy or more, respectively, and 67%, 94%, and 93% for minimum tumor doses of 12 Gy or less, 12.1 to 18 Gy, and more than 18 Gy, respectively.[85]

RANDOMIZED TRIALS OF WHOLE-BRAIN RADIOTHERAPY WITH OR WITHOUT RADIOSURGERY.

The first reported randomized trial of WBRT (30 Gy in 12 fractions) with or without a radiosurgery boost (16 Gy) was performed in patients with a KPS of at least 70 and two to four brain metastases less than or equal to 2.5 cm in diameter, at least 5 mm from the optic chiasm.[50] The study accrued only 27 patients because of early stopping rules based on a significant difference in brain control between the two arms. Compared with WBRT alone, radiosurgery plus WBRT yielded significantly improved time to local failure (median: 36 months versus 6 months; P = 0.0005) and time to any brain failure (median: 34 months versus 5 months; P = 0.002). However, survival was not significantly different for the two arms (median: 7.5 months for WBRT versus 11 months for WBRT plus radiosurgery; P = 0.22; see Table 56-3 ). Multiple patients who failed WBRT alone underwent salvage radiosurgery.[50]

A recent RTOG trial randomized 331 patients with KPS of at least 70 and one to three newly diagnosed brain metastases to WBRT (37.5 Gy in 15 fractions) with or without a radiosurgery boost within 1 week after WBRT from 1996 through June 2001.[49] Treatment arms were fairly well balanced comparing WBRT alone to WBRT plus radiosurgery, with KPS of 90 to 100 in 63% versus 57%, age less than 65 years in 60% versus 66%, primary disease controlled or absent in 75% versus 77%, extracranial metastases in 69% versus 68%, and a single brain metastasis in 56% versus 56% of patients, respectively. The radiosurgery treatment arm had significantly improved KPS at 6 months (P = 0.033), decreased steroid use at 6 months (P = 0.016), and improved actuarial local control (with 1-year local control probabilities of 71% for WBRT alone versus 82% for WBRT + radiosurgery; P = 0.013). Although survival was not significantly different between the two groups overall (5.7 months for WBRT alone versus. 6.5 months for WBRT + radiosurgery; P = 0.136; see Table 56-3 ), there was a statistically significant difference in survival for patients who had a single metastasis (4.9 months for WBRT alone versus 6.5 months for WBRT + radiosurgery; P = 0.039).[49]

RADIOSURGERY WITHOUT WHOLE-BRAIN RADIOTHERAPY FOR NEWLY DIAGNOSED BRAIN METASTASES.

Because of concern about potential late toxicity of WBRT, multiple groups have tried managing patients using radiosurgery alone initially, followed by later salvage surgery, radiosurgery, WBRT, or chemotherapy as needed, [33] [35] [81] [86] [87] [88] [89] and one prospective, randomized trial of radiosurgery alone versus radiosurgery plus WBRT has been reported to date (see Table 56-3 and the following section).[90] Retrospective comparisons of radiosurgery alone initially to radiosurgery with upfront WBRT are summarized in Table 56-5 . Survival was similar for radiosurgery alone initially versus radiosurgery with upfront WBRT for three of five studies (∼5 months versus ∼6 months;[81] 11.3 months versus 11.1 months;[86] and 8.2 months versus 8.6 months[33]); in one study, median survival time was thought to be shorter in the WBRT group because of worse prognostic factors in this group,[87] and in the fifth study, there was a trend toward longer survival time in patients who were treated with RS + WBRT versus RS alone.[89] Multivariate analyses adjusting for known prognostic factors confirmed that the omission of upfront WBRT had no influence on survival time. [33] [81] [86] [87] Local control was slightly worse for radiosurgery alone initially, with 1-year actuarial local freedom from progression probabilities of 89% versus 92%,[81] 71% versus 79%,[86] and approximately 62% versus 75%.[87]Because of a much greater risk of developing new brain metastases when upfront WBRT was omitted, brain freedom from progression was significantly shorter for radiosurgery alone initially (median: 8.3 months versus 15.9 months[86] and 9.2 months versus 35.1 months).[87] In one series, the median brain freedom from progression allowing for salvage therapy was 19.8 months for radiosurgery alone initially versus 18.1 months for radiosurgery with upfront WBRT, and only 26% of radiosurgery-alone patients ultimately received WBRT.[86] Among 101 patients with one to three brain metastases who were treated with radiosurgery alone, Lutterbach and colleagues reported 1-year local brain, distant brain, and overall brain freedom from progression rates of 91%, 53%, and 51%, respectively; parameters that were associated with longer overall brain freedom from progression included single brain metastasis and an interval greater than 2 years from primary tumor diagnosis and diagnosis of brain metastases.[35]


Table 56-5   -- Nonrandomized Comparisons of Radiosurgery Alone Initially to Radiosurgery Plus Upfront Whole-Brain Radiotherapy for Single or Multiple Newly Diagnosed Brain Metastases

First Author (Years)

Treatment

No. of Patients

Single Brain Metastasis (%)

Extracranial Disease (%)

1-Year Local FFP

Median Brain FFP (Months)

Median Survival (Months)

Pirzkall[81] (1984–1997)

RS

158

76

68

89%

∼5

 

RS + WBRT

78

71

67

92%

∼6

 

 

 

 

 

(P = 0.13)

(P = NS)

Sneed[86] (1991–1997)

RS

62

58

74

71%

8.3 (19.8[*])

11.3

 

RS + WBRT

43

33

65

79%

15.9 (18.1[*])

11.1

 

 

 

 

 

(P = 0.30)

(P = 0.008; 0.31[*])

(P = 0.80)

Chidel[87] (1989–1998)

RS

78

74

∼62%

9.2

10.5

 

RS + WBRT

57

60

∼75%

35.1

6.4

 

 

 

 

 

(P = 0.034)

(P = 0.027)

Sneed[33] (1989–1998)

RS

268

63

70–71

8.2

 

RS + WBRT

301

58

64–68

8.6

 

 

 

 

 

 

 

(P = 0.93)

Wang[89] (1990–2000)

RS

130

59

15.4

 

RS + WBRT

83

40

20.9

 

 

 

 

 

 

 

(P = 0.12)

FFP, freedom from progression; NS, not significant; RS, radiosurgery; WBRT, whole-brain radiotherapy.

 

*

Median brain FFP and P value allowing for successful salvage therapy.

 

RANDOMIZED TRIAL OF RADIOSURGERY WITH OR WITHOUT WHOLE-BRAIN RADIOTHERAPY.

Aoyama and colleagues recently reported the first prospective, randomized trial comparing radiosurgery alone (N = 67) to WBRT plus radiosurgery (N = 65).[90] Patients with KPS of at least 70 and one to four brain metastases less than 3 cm in diameter were accrued at 11 institutions from 1999 through 2003. The WBRT dose was 30 Gy in 10 fractions, and the radiosurgery-alone doses were 22 to 25 Gy for lesions up to 2 cm and 18 to 20 Gy for lesions over 2 cm, with a 30% dose reduction when radiosurgery was combined with WBRT. Age, KPS, and extracranial disease activity were not significantly different between the two groups. Endpoints were measured from the date of randomization. The median survival times were similar for the two groups (8.0 months for radiosurgery alone versus 7.5 months for WBRT + radiosurgery; P = 0.42). Intracranial control was significantly lower in the radiosurgery-alone arm, with 1-year local control probabilities of 73% versus 89% (P = 0.002), 1-year freedom from new brain metastasis probabilities of 36% versus 58% (P = 0.003), and 1-year overall brain freedom from progression probabilities of 24% versus 53% (P < 0.001) for radiosurgery alone versus WBRT + radiosurgery, respectively. The majority of new brain metastases were asymptomatic. Salvage therapy for brain metastases was given in 29 patients on the radiosurgery-alone arm versus 10 patients on the WBRT + radiosurgery arm. There was no significant difference in functional independent survival (27% versus 34% at 1 year; P = 0.53) or neurologic preservation (70% versus 72% at 1 year; P = 0.99) for radiosurgery alone versus WBRT + radiosurgery, respectively. Deterioration of neurologic function occurred in 21 radiosurgery-alone patients and in 22 WBRT + radiosurgery patients; the deterioration was attributed to new or original brain metastases in 18 radiosurgery-alone patients versus 13 WBRT + radiosurgery patients. Leukoencephalopathy occurred in 2 radiosurgery-alone patients versus 7 WBRT + radiosurgery patients, and it was symptomatic in 3 of the 9 patients. The authors concluded that radiosurgery alone “could be a treatment option, provided that frequent monitoring of brain tumor status is conducted.”[90]

RADIOSURGERY COMPARED WITH SURGERY.

Radiosurgery has potential advantages over surgery in that it is less invasive and can more easily address inaccessible or multiple lesions. In addition, the border zone between the metastasis and normal brain tissue may receive sufficient radiation dose to decrease the risk of local recurrence. The two major disadvantages of radiosurgery are that it is generally applicable only to lesions less than about 2.5 to 3.0 cm in diameter and that it results in slow tumor shrinkage over weeks or months rather than relieving mass effect immediately.

In the absence of data to date from prospective, randomized trials, several authors have compared results cited in the literature for surgical patients with their own results for similar subsets of radiosurgery patients. Auchter and colleagues[69] reported a four-institution experience of radiosurgery and WBRT in 122 adults who met selection criteria similar to those used in randomized trials of WBRT with or without surgical resection: KPS of at least 70 and newly diagnosed, surgically resectable single brain metastases with “nonsensitive” histology (excluding lymphoma, leukemia, multiple myeloma, small cell lung cancer, and germ cell tumors) and no urgent indication for resection. Local control was achieved in 86% of lesions with a 1-year actuarial local control probability of 85%, a median duration of functional independence of 10.1 months, and median survival time of 12.9 months (see Table 56-4 ), comparable to the results of the surgery + WBRT arms of the randomized trials reported by Patchell and colleagues[19] and Noordijk and colleagues[57] (see Table 56-3 ).

Three other retrospective comparisons of radiosurgery and surgery are summarized in Table 56-6 , with somewhat differing results. [66] [91] [92] Bindal and colleagues reported 61% versus 87% crude local control rates for radiosurgery (with or without WBRT) versus surgery (with or without WBRT) and median survival times of 7.5 months versus 16.4 months, respectively.[91]


Table 56-6   -- Nonrandomized Comparisons of Radiosurgery with and Without Whole-Brain Radiotherapy to Surgery with and Without Whole-Brain Radiotherapy for Single Newly Diagnosed Brain Metastases

First Author (Years)

Treatment

No. of Patients

Single Brain Metastasis (%)

Extracranial Disease (%)

Local FFP (%)

Median Survival (Months)

Bindal[91] (1991–1994)

RS ± WBRT

31

77

42

61[*]

7.5

 

Surgery ± WBRT

62

74

52

87[*]

16.4

 

 

 

 

 

(P = 0.0001)

(P = 0.0018)

Muacevic[66] (1990–1997)

RS alone

56

100

83%[†]

8.0

 

Surgery + WBRT

52

100

75%[†]

15.6

 

 

 

 

 

(P = 0.49)

(P = 0.19)

O'Neill[92] (1991–1999)

RS ± WBRT

23

100

74

100%

56% 1-yr

 

Surgery ± WBRT

74

100

55

85%

62% 1-yr

 

 

 

 

 

(P = 0.020)

(P = 0.15)

FFP, freedom from progression; RS, radiosurgery; WBRT, whole-brain radiotherapy.

 

*

Crude.

1-year actuarial.

 

In another retrospective study, Muacevic and colleagues compared outcomes for patients with single metastases less than or equal to 3.5 cm in diameter who were treated with radiosurgery alone (56 patients) or surgery with WBRT (52 patients). One-year local freedom from progression probabilities were 83% for radiosurgery versus 75% for surgery with WBRT (P = 0.49); new brain metastases developed in 11 (20%) of the radiosurgery patients versus 6 (12%) of the surgery-plus-whole-brain-radiotherapy patients, but salvage radiosurgery was successful in all 6 radiosurgery patients who were offered salvage therapy. Median survival times were 8.0 months after radiosurgery versus 15.6 months after surgery with WBRT. Death rates from neurologic causes and complication rates were similar for the two treatment approaches, and steroid requirements tended to be less among the radiosurgery patients.[66]

A third retrospective study compared patients with single metastases who were candidates for either surgery or radiosurgery. Most patients received adjuvant WBRT in conjunction with radiosurgery (23 patients) or surgery (74 patients). Pretreatment performance status was worse in the radiosurgery group. Crude local control rates were 100% versus 85% (P = 0.02), and 1-year survival probabilities were 56% versus 62% for radiosurgery versus surgery, respectively (univariate P = 0.15; multivariate P = 0.62 with adjustment for age, performance status, and systemic disease status). Short-term and long-term complications occurred in 0% versus 13.5% and 17.4% versus 17.6% of radiosurgery and surgery patients, respectively.[92]

Because of the difficulties in overcoming selection bias and other confounding factors in retrospective studies, a prospective, randomized trial is underway to better compare radiosurgery versus surgery for single brain metastases.

TOXICITY OF RADIOSURGERY.

Acute complications of radiosurgery occur in about 10% of patients, including seizures, headaches, exacerbation of pre-existing neurologic deficits, nausea, and hemorrhage. [66] [86] [93] Early delayed and late complications may include transient perifocal edema responding to a short course of steroids in 7% to 18% of patients [66] [81] [93] or symptomatic radiation necrosis in an average of 4% of patients (seeTable 56-4 ), causing headaches, seizures, or neurologic deficits. Symptoms usually respond to steroids, but surgery might be needed if a patient requires a prolonged course of steroids, tolerates steroids poorly, or remains symptomatic on steroids or if there is uncertainty as to whether a lesion represents progressive tumor versus radiation necrosis.

Brachytherapy

Brachytherapy, the insertion of radioactive sources directly inside a tumor or tumor bed, allows delivery of a high dose of radiation to the target volume with a steep falloff of dose outside of the intendedregion owing to the fact that dose intensity decreases with the square of the distance from point sources and also decreases because of attenuation in tissue. Temporary brachytherapy has been applied to brain metastases by using high-activity sources, often within afterloading catheters inserted under stereotactic guidance into gross tumor or a resection cavity or using a balloon within a resection cavity inflated with radioactive liquid. Permanent brachytherapy is generally accomplished by lining a tumor bed with low-activity radiation sources intraoperatively after gross total resection of a metastasis. Results of brachytherapy for brain metastases are summarized in Table 56-7 . [94] [95] [96] [97] [98] [99] In patients who were treated for recurrent brain metastases, crude local freedom from progression rates ranged from 60% to 95%, and median survival times ranged from 6 to 13.9 months. Among patients who were treated for newly diagnosed brain metastases, local freedom from progression rates ranged from 80% to 95% and median survival times ranged from 9.2 to 17 months (except for an outlier median survival time of 68.2 months in 5 patients). The incidence of symptomatic radiation necrosis ranged from 0% to 30%, with an average of about 9%.


Table 56-7   -- Results of Brachytherapy for Newly Diagnosed or Recurrent Brain Metastases

First Author (Years)

Technique/Isotope

No. and Type of Patients

Adjuvant WBRT Given?

Crude Local FFP (%)

Median Survival (Months)

Necrosis (%)

Bernstein[94] (?–1994)

Temporary

10 recurrent

No

60

10.5

30

 

I-125

 

 

 

 

 

Bogart[95] (1991–1996)

Permanent

15 new

No

80

14

0

 

I-125

 

 

 

 

 

McDermott[96] (1979–1994)

Temporary

5 new

Yes (4/5)

68.2

10

 

I-125

25 recurrent

No

13.9

 

Ostertag[97] (1982–1992)

Temporary

38 new

Yes

89

17

0

 

I-125

34 new

No

91

15

 

 

 

21 recurrent

No

95

6

 

Rogers[98] (2001–2003)

GliaSite

54 new

No

82–87

9.2

17

Schulder[99] (1987–?)

Permanent

1 new

No

82

9

15

 

I-125

12 recurrent

No

 

 

 

Huang, K. (1997–2001)[*]

Permanent

19 new

No

95

12.0

16

 

I-125

21 recurrent

No

90

7.3

19

FFP, freedom from progression; I-125, iodine-125-labeled; WBRT, whole-brain radiotherapy.

 

*

Unpublished data from the University of California San Francisco.

 

Chemotherapy

Chemotherapy has generally been considered to be relatively ineffective for brain metastases, presumably because the blood-brain barrier prevents adequate access of chemotherapy to these tumors. However, some chemotherapeutic agents partially or even readily cross the blood-brain barrier, and the fact that brain metastases enhance with contrast on CT or MRI is proof that the blood-brain barrier is broken down within metastases. The chemosensitivity of the primary tumor is another critical factor in determining the potential efficacy of chemotherapy for brain metastases.[100] The responsiveness of brain metastases to chemotherapy is similar to that of the primary tumor and extracranial metastases. Primary small cell lung carcinoma (SCLC), lymphoma, germ cell tumors, and breast cancer are relatively chemosensitive[101] while nonsmall-cell lung carcinoma (NSCLC) and melanoma are less chemosensitive.

TRIALS ASSESSING CHEMOTHERAPY FOR BRAIN METASTASES FROM A VARIETY OF PRIMARY SITES.

Chemotherapy with cisplatin at 100 mg/m2 on day 1 and etoposide at 100 mg/m2 on days 4, 6, and 8 every 3 weeks was used as the primary treatment in a phase II study of 22 breast cancer patients with brain metastases, resulting in a 23% complete response rate and a 32% partial response rate.[102] This regimen was then used as first-line therapy in a prospective study conducted from 1986 to 1993 by a nine-institution group; 116 patients with recently diagnosed, previously untreated brain metastases from breast cancer, NSCLC, or melanoma were enrolled, and 107 were evaluable.[103] None of the melanoma patients achieved an objective response, but among the breast and lung cancer patients, the complete response rates were 13% and 7%, respectively, and the partial response rates 25% and 23%, respectively. The median duration of response was 7 to 8 months; the median overall time to progression was 3.9 months for breast and lung cancer patients; and the median survival times were 7.1 months for breast cancer patients, 7.4 months for lung cancer patients, and 3.9 months for melanoma patients.[103] Data were not collected on further therapy given after chemotherapy. Another group examined a similar two-drug regimen using intra-arterial carboplatin plus intravenous etoposide in 27 patients with brain metastases from a variety of primary tumors and were able to achieve a 54% response rate (25% partial response, 25% complete response, and 4% “minor” response).[104]

There has also been interest in temozolomide (TMZ), an oral alkalating agent that crosses the blood-brain barrier. Several studies have assessed the efficacy of TMZ in patients with brain metastases. At Memorial Sloan Kettering Cancer Center, 41 patients with recurrent or progressive brain metastases were treated with TMZ at 150 to 200 mg/m2 daily for 5 days, repeated monthly. The partial response rate was 5%, 37% of patients had stable disease, and the median survival time was 6.6 months.[105] Another group used a similar regimen in 27 heavily pretreated patients with brain metastases. Of the 24 evaluable patients, the authors reported only one partial response and four cases of disease stabilization, with an overall median survival time of 4.5 months.[106] TMZ has also been used concurrently with other agents. Christodoulou and colleagues administered TMZ at 150 to 200 mg/m2 daily for 5 days combined with cisplatin at 75 mg/m2 on day 1 every 28 days in 32 patients with brain metastases. The overall median survival time was 5.5 months. Although nine patients had a partial response (six with breast cancer, two with melanoma, and one with NSCLC), only one patient (with NSCLC) had a complete response, and five patients had disease stabilization.[107] Concurrent TMZ and liposomal doxorubicin has also been investigated; one group reported three complete responses and four partial responses in a cohort of 19 patients given this regimen.[108]

Various studies have examined the use of TMZ in conjunction with radiation therapy. In one phase II randomized trial, 48 evaluable patients were randomized to either WBRT alone or WBRT + TMZ. There were seven complete responses and seven partial responses for the WBRT alone group versus nine complete responses and 14 partial responses in the combined modality group, with median survival times of 7.0 months for WBRT versus 8.6 months for WBRT + TMZ.[109] A later phase II trial randomized 82 patients to receive either WBRT alone (N = 41) or WBRT with concurrent TMZ (N = 41) and found no significant differences in response rates or survival. The authors did, however, report a significant difference in progression-free survival at 90 days (54% for WBRT alone versus 72% for WBRT and TMZ). They noted that their patients had more aggressive disease and were more heavily pretreated than those in the aforementioned study by Antonadou and colleagues.[110] TMZ is also discussed in the following sections in the context of brain metastases from individual primary sites.

CHEMOTHERAPY FOR BRAIN METASTASES FROM PRIMARY NON-SMALL-CELL LUNG CARCINOMA.

Several trials have assessed the response of brain metastases from primary NSCLC after treatment with various systemic agents. Combined carboplatin and etoposide was used in a study of 30 patients with brain metastases from primary lung cancer (18 NSCLC, 12 SCLC); three patients had complete responses (all SCLC), while seven had partial responses (four SCLC, three NSCLC).[111] Concurrent cisplatin and teniposide yielded three complete responses and five partial responses among 23 patients with brain metastases from primary NSCLC.[112] Other regimens that have been studied in patients with brain metastases from NSCLC include vinorelbine, gemcitabine, and carboplatin (with 15% complete response and 30% partial response in 20 patients)[113] and paclitaxel and cisplatin combined with either vinorelbine or gemcitabine (resulting in a 38% objective response rate among 25 patients).[114] Fujita and colleagues used an alternative three-agent regimen of cisplatin, ifosfamide, and irinotecan with rhG-CSF support in 30 patients and were able to achieve a 50% partial response rate, although no patient had a complete response.[115] Two other groups have studied the efficacy of TMZ as a single agent in this context, one group reporting no objective treatment response in 12 patients[116] and another group achieving two complete responses and one partial response among 30 patients.[117]

The use of concomitant systemic chemotherapy and WBRT for brain metastases from NSCLC has also been studied by several groups. In a large phase III trial of 176 patients with brain metastases from NSCLC, Robinet and colleagues examined the use of cisplatin and vinorelbine in conjunction with either early or delayed WBRT. Neither cohort demonstrated significantly different response rates, survival, nor treatment-related toxicities.[118] One recent phase III trial examined outcomes in 42 patients with brain metastases from NSCLC treated either with WBRT alone or with concurrent carboplatin. Neither objective response rates (10% [WBRT alone] versus 29% [WBRT + carboplatin]) nor survival (4.4 months [WBRT alone] versus 3.7 months [WBRT + carboplatin]) were significantly different, and the trial closed early because of poor accrual.[119] The efficacy of TMZ and cisplatin followed by WBRT was studied in 50 patients with brain metastases from primary NSCLC in a recent phase II study; only 2% of patients achieved a complete response, while 10% had partial responses for their cerebral lesions.[120]

CHEMOTHERAPY FOR BRAIN METASTASES FROM SMALL CELL LUNG CARCINOMA.

Given the relative chemosensitivity of SCLC, brain metastases from this primary tumor type could theoretically be expected to respond to systemic chemotherapy. Twelves and colleagues examined this concept in an early study of 19 patients with symptomatic brain metastases from SCLC initially treated with cyclophosphamide, vincristine, and etoposide without upfront WBRT. On imaging follow-up, eight patients had a partial response, and one had a complete response.[121] Korfel and colleagues examined the efficacy of topotecan in a phase II study of 30 pretreated, relapsed patients with symptomatic brain metastases from SCLC. Of the 30 patients, 10 achieved an objective response (three complete responses and seven partial responses).[122] In another small study, carboplatin's efficacy as a second-line agent was investigated in 20 patients with recurrent or progressive brain metastases from primary SCLC. Nineteen of the 20 patients were evaluable, with two patients exhibiting a complete response and six showing a partial response.[123]

The use of teniposide, an agent that is known to be active against SCLC, was examined in a phase II study of 80 patients with brain metastases from primary SCLC; 33% of patients had an objective response to chemotherapy (6 had a complete response, and 20 had a partial response).[124] In a large phase III study also examining the use of teniposide, Postmus and colleagues randomized 120 patients with brain metastases from primary SCLC to receive either teniposide alone (N = 60) or concurrently with WBRT (N = 60). The teniposide + WBRT cohort had a significantly better response rate (18 complete responses, 16 partial responses) compared to the teniposide-alone arm (5 complete responses, 8 partial responses), although median survival times were not different (3.5 months [WBRT + teniposide] versus 3.2 months [teniposide alone]).[125]

CHEMOTHERAPY FOR BRAIN METASTASES FROM MELANOMA.

As was noted earlier, melanoma is relatively insensitive to systemic chemotherapy. The efficacy of various agents in treating patients with brain metastases from primary melanoma have been studied, largely without success. The study by Franciosi and colleagues, as discussed previously, reported no treatment response in melanoma brain metastases treated with cisplatin and etoposide.[103] One group reported only a 12% response rate (with two complete responses and two partial responses) and a median survival time of 4.5 months among 34 melanoma patients with brain metastases treated with sequential dacarbazine and fotemustine.[126] Another group examined fotemustine as a single agent in a subset of patients with brain metastases from primary melanoma within a larger study. Of the 36 patients who had cerebral metastases from primary melanoma, none had a complete response, while 9 patients had a partial response.[127] Mornex and colleagues studied two groups of patients with brain metastases from melanoma; one group was treated with fotemustine alone (N = 39), and the other was treated with fotemustine and WBRT (N = 37). The authors reported five partial responses—two in the fotemustine-alone group and three in the combined-therapy arm—with no significant differences in median survival time (2.7 months versus 3.4 months, respectively).[128]

TMZ has also been studied in patients with metastatic brain lesions from primary melanoma. One multicenter phase II study examined TMZ alone in 151 patients, none of whom had received any prior radiation therapy. Thirty-four patients, however, had received prior systemic chemotherapy. In the 117 chemotherapy-naive patients, one patient had a complete response and seven had a partial response. In the 34 previously treated patients, there were no complete responses, and only one patient had a partial response. For the entire patient cohort, median survival was only 3.2 months.[129] TMZ was used concurrently with carboplatin in 11 patients with brain metastases from melanoma in a small phase I study; none of these patients achieved an objective response.[130] Another study sought to assess TMZ with concurrent WBRT in 31 patients with no prior radiation therapy. Only one patient had a complete response, and two had partial responses. The median survival time was 6 months.[131]

CHEMOTHERAPY FOR BRAIN METASTASES FROM BREAST CANCER.

Aside from the small cohorts of breast cancer patients within the broader studies discussed previously, [102] [103] [104] [106] [107] other groups have focused specifically on patients with brain metastases from breast cancer. Rosner and colleagues examined the efficacy of several multiagent regimens in a group of 100 patients with brain metastases from primary breast cancer. The overall objective response rate was 50% (10 complete responses and 40 partial responses) with the authors reporting a median survival time of 39.5 months, 10.5 months, and 1.5 months for the complete responders, partial responders, and nonresponders, respectively.[132] Another group examined three-agent regimens of either cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (used in 20 patients) or cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) (used in two patients). Two patients (one using the CMF regimen and the other using the CAF regimen) had complete responses, while 10 patients had partial responses (nine using the CMF regimen and one using the CAF regimen).[133]

Follow-up and Salvage Therapy

In patients who are doing reasonably well from the standpoint of their systemic disease, we recommend follow-up MRI every 3 months after treatment for brain metastases to detect new, progressive, or recurrent brain metastases that might need to be addressed with salvage therapy. Of note, a contrast-enhancing lesion that is seen after high-dose external beam radiation, radiosurgery, or brachytherapy could represent radiation necrosis rather than recurrent tumor, and additional analyses might be needed before considering retreatment.[134] The same therapeutic options that are available for newly diagnosed brain metastases may be considered for new, progressive, or recurrent metastases, although the type of previous therapy that was given may influence therapeutic options at recurrence. In general, retreatment options include WBRT, radiosurgery (especially for lesions less than about 3 cm in diameter), surgery (especially for a single large or symptomatic progressive lesion), perhaps with permanent brachytherapy to help prevent local recurrence, and chemotherapy. If repeat WBRT is given, lower doses and smaller fraction sizes are generally used, such as 20 to 25 Gy in 10 fractions or 30 Gy at 1.0 Gy twice daily. Results are similar to those reported for a first course of WBRT, with symptomatic improvement in 42% to 75% of patients and median or mean survival time of 3.2 to 5 months after reirradiation. [135] [136] [137]

NEOPLASTIC MENINGITIS

Dissemination of cancer cells into the leptomeningeal space is an extremely serious complication that affects approximately 5% of patients with cancer. With incremental improvements in outcomes in systemic cancer, the incidence of metastatic disease to the leptomeninges appears to be on the rise. Neoplastic meningitis presents significant diagnostic and therapeutic challenges; early diagnosis can be elusive, and effective control for leptomeningeal carcinoma is usually difficult to achieve. With current therapies, the median survival time is 3 to 6 months.

Epidemiology

Virtually any type of cancer can disseminate into the leptomeningeal space. Acute leukemias and intermediate- or high-grade lymphomas are common causes of neoplastic meningitis. Among solid tumors, melanoma and small cell carcinoma exhibit the strongest propensity for leptomeningeal dissemination; up to 25% of patients with metastatic disease from these diagnoses develop this complication. Ultimately, between 2% and 5% of breast cancer patients develop carcinomatous meningitis. Leptomeningeal dissemination has also been documented in less common neoplasms, such as sarcomas, squamous cell carcinomas, and germ cell tumors. Primary tumors of the CNS such as medulloblastoma or ependymoma often seed the leptomeningeal space as well. [138] [139] [140] [141] [142]

Pathophysiology

The biologic basis for dissemination and multifocal seeding of the leptomeninges by malignant cells is not well understood. Several distinct pathways have been proposed: (1) most obviously as a consequence of drop metastases that may occur during resection of metastatic foci within the brain, especially after resection of posterior fossa tumors; (2) by direct extension from the cerebrum; (3) by infiltration through arachnoid vessels or the choroid plexus following hematogenous dissemination of the tumor; (4) by direct extension along peripheral nerves to the subarachnoid space or perivenous spread from the bone marrow within the skull; (5) by extension along perineural or perivascular lymphatics; and (6) from subependymal or choroid plexus metastases with subsequent escape into the CSF.[143] Spread of tumor cells along the meningeal surface is facilitated by bulk CSF flow. In turn, meningeal deposits may also invade parenchyma as well as cranial or spinal nerve roots. The most frequently affected regions of the CNS are the basilar cisterns, the posterior fossa, and the cauda equina, where gravity promotes deposition of circulating cells.

Clinical Presentation

Leptomeningeal dissemination of cancer elicits several distinct neurologic presentations. (1) Local tumor infiltration in the brain or spinal cord may cause headache; alterations in mental status; cranial nerve deficits causing diplopia, hearing loss, decreased taste, problems with swallowing, and hoarseness; and incontinence, lower motor neuron weakness, and back or radicular pain. (2) Metabolic dysfunction caused by disturbances in regional blood flow in the affected nervous tissue may cause seizures, isolated neurologic deficits, including strokelike symptoms, and even generalized encephalopathy. (3) Obstruction of normal CSF flow pathways by focal tumor deposits may cause increased intracranial pressure and hydrocephalus. [138] [139] [140] [141] [142] [144]

Diagnosis

CSF Evaluation

A high index of suspicion is required to make an early diagnosis of neoplastic meningitis; this ultimately requires a detailed examination of CSF. Routine measurements include opening pressure, cell count, differential, protein, glucose and direct cytologic evaluation of the CSF.[138] Patients with carcinomatous meningitis typically have elevated CSF opening pressure, increased CSF protein, and decreased CSF glucose.[145] While the CSF is abnormal in terms of protein or glucose concentration in most patients with neoplastic meningitis, cytologic evaluation of the CSF, the gold standard, is an insensitive test, especially initially; 40% to 50% of patients with neoplastic meningitis have negative CSF cytology on initial lumbar puncture.[138] While repeat CSF cytologic evaluations over time will increase diagnostic sensitivity, the eventual conversion to positive cytology usually occurs in pace with neurologic deterioration secondary to overt tumor progression. Because of the importance of early diagnosis and intervention, there has been significant effort to identify surrogate biomarkers for CNS and leptomeningeal metastases. For example, in the early 1980s, Posner's group demonstrated that the tumor antigen carcinoembryonic antigen as well as the enzymatic activity of β-glucuronidase could be detected in the CSF of patients with brain and leptomeningeal metastases.[146] The presence of these markers was shown to precede clinical detection of neoplastic meningitis and to rise and fall in parallel with the clinical course. Several other biomarkers have been examined in patients with carcinomatous meningitis from a variety of primary tumors, including lactate dehydrogenase, β-human chorionic gonadotropin, alkaline phosphatase, vascular endothelial growth factor, myelin basic protein, creatinine kinase, and others. The utility of these biomarkers is still under investigation.[145] The use of other diagnostic tools such as polymerase chain reactions, fluorescence in situ hybridization, immunohistochemical examinations of the CSF, and cytogenetic analysis may also enhance detection.[147]

Radiologic Features

The most frequent radiographic presentation is hydrocephalus without an identifiable mass lesion. Leptomeningeal contrast enhancement is suggestive of neoplastic meningitis ( Fig. 56-5 ) but may also be seen after lumbar puncture and with infection, inflammatory disease, trauma, subdural hematoma, or changes occurring post craniotomy.[138] The enhancement pattern may be focal (including tumor nodules) or diffuse.[147] While gadolinium-enhanced MRI is more sensitive than CT in identifying leptomeningeal enhancement, only approximately 50% of patients with neoplastic meningitis and spinal symptoms have abnormal imaging studies.[138]

 
 

Figure 56-5  Leptomeningeal enhancement on postcontrast T1-weighted magnetic resonance imaging from carcinomatous meningitis. Note the enhancement of the acoustic nerves (left) and cerebellar folia (right).

 

 

Treatment

Current therapeutic goals for most patients with neoplastic meningitis are to prevent further neurologic deterioration, to cytoreduce leptomeningeal tumor burden, and to prolong survival. Typically, untreated carcinomatous meningitis is associated with an advanced stage of systemic disease, often with concomitant parenchymal brain metastases and with anticipated survival time of 4 to 6 weeks. Because of the inefficient regenerative capacity of the CNS, early aggressive intervention is critical to preserve neurologic function. Therapeutic intervention relies on traditional approaches with radiation and/or chemotherapy with the goal of treating the entire neuroaxis.

Radiation Therapy

Radiation therapy is the most effective means of palliation with the focus on symptomatic sites and regions where imaging studies have demonstrated bulk disease. There is substantial acute toxicity of craniospinal axis irradiation, with nausea, vomiting, marked fatigue, and myelosuppression. There is also a long-duration negative impact on bone marrow function, compromising the safe administration of subsequent myelosuppressive chemotherapy. One strategy is to selectively apply external beam irradiation to symptomatic sites of disease and to rely on intrathecal chemotherapy to suppress the remainder of the disease in the neuroaxis. For example, in patients who present with cranial nerve deficits, one approach is to treat only the base of the skull with radiation. In patients who present with cauda equina syndrome, external beam irradiation may be directed to the lumbosacral spine. Patients who present with seizure or hydrocephalus caused by extensive cranial leptomeningeal disease may best be palliated with whole-brain irradiation. [139] [140] [141] [142]

Intrathecal Chemotherapy

The most reliable means of administering intrathecal chemotherapy is to use an implanted subcutaneous reservoir and ventricular catheter (Ommaya device). While subarachnoid injections of chemotherapy result in high local CSF concentrations, studies of administration by lumbar administration suggest that 10% to 15% of lumbar punctures fail to completely deliver all of the drug to the subarachnoid space.[142] In addition, retrospective analysis suggests that intraventricular administration may result in prolonged remission in patients with leptomeningeal leukemia compared with administration by lumbar puncture.[148] Chemotherapeutic agents administered into the ventricle are carried through the neuroaxis by bulk CSF flow. CSF flow abnormalities are common in patients with leptomeningeal metastases, who frequently present with hydrocephalus and increased intracranial pressure as a result of disease that impedes CSF flow. Radionuclide ventriculography in patients with neoplastic meningitis has demonstrated that as many as 70% have ventricular outlet obstruction, abnormal flow in the spinal canal, or impaired flow over the CSF convexities.[149] These CSF flow abnormalities may be reversed with local irradiation. Because of the potential risk of irreversible neurotoxicity from high sustained concentrations of intrathecal chemotherapy, a CSF flow study is recommended for every patient beginning intrathecal chemotherapy via a ventricular catheter. [139] [140]

Methotrexate and cytarabine are the most widely used agents for intrathecal chemotherapy. Intraventricular injection of methotrexate results in therapeutic concentrations (more than 1 mmol) that persist for up to 48 hours; serum levels peak at approximately 0.1 mmol and fall more slowly. Treatment of active neoplastic meningitis typically consists of twice weekly intrathecal therapy until CSF clears followed by weekly and then monthly maintenance therapy unless there is disease progression. The combination of twice weekly methotrexate plus radiation results in an approximate 50% rate of disease stability or clinical improvement. Response should be assessed both in the ventricle and in the lumbar sac, where cytology is more likely to be positive. Intrathecal methotrexate can cause myelosuppression as well as mucositis, toxicities that can be attenuated by leucovorin. Leucovorin does not efficiently cross the blood-brain barrier in amounts that are sufficient to interfere with intra-CNS effects of methotrexate.

Cytosine arabinoside is also commonly used but may have less efficacy in the treatment of neoplastic meningitis. Cytosine arabinoside is inactivated by deamination by the enzyme cytidine deaminase. Low CNS levels of this enzyme result in relatively slow deamination of cytosine arabinoside within the brain and CSF, resulting in an extended half-life in the CNS compartment.[142] Thiotepa, a cell cycle–nonspecific alkylating agent, is another commonly used intrathecal drug.[147] Other intrathecal agents that have been studied in this context include mafosphamide,[150] topotecan,[151] etoposide,[152]interferon-a,[153] and 5-fluoro-2′-deoxyuridine.[154] Further investigation of these agents is warranted.

Treatment-Related Toxicity

Placement of an intraventricular catheter is associated with less than a 1% risk of perioperative hemorrhage. Extended use of the device is associated with at least a 5% risk of infection, usually withStaphylococcus epidermidis or S. aureus. Impaired CSF flow of chemotherapy secondary to obstruction may result in seizures as well as acute arachnoiditis, characterized by nausea, vomiting, and mental status changes. For this reason, many practitioners will obtain a radionuclide CSF flow study before initiation of intra-Ommaya chemotherapy. Ultimately, the most significant toxicity associated with the treatment of leptomeningeal carcinomatosis is the development of a necrotizing leukoencephalopathy. This is most common in patients who have received intrathecal methotrexate following cranial irradiation. Initial findings are radiographic changes, usually symmetric abnormalities in white matter. Many of these patients subsequently develop progressive dementia that can progress to substantial debility and to death.[142]

Systemic Chemotherapy and New Approaches

A significant fraction of contrast-enhancing tumor that is visualized on neuroimaging studies is theoretically accessible by systemic chemotherapy, which is able to reach this fraction of tumor supplied by an abnormally permeable neovasculature. However, water-soluble chemotherapy drugs are limited by the intact blood-brain barrier, and systemic therapy fails to treat microscopic, nonenhancing disease both in brain parenchyma and in the subarachnoid space. One exception is in the use of high-dose systemic administration of methotrexate, which results in therapeutic levels in the CSF for a longer duration than the intrathecal route; this therapeutic strategy has been shown to be active in neoplastic meningitis both in lymphoma and in solid tumors. Moreover, systemic administration of methotrexate at high doses overcomes the problems associated with CSF flow obstruction, which can compromise subarachnoid administration. However, because high-dose methotrexate administration requires detailed inpatient monitoring of fluid status, urine alkalinization, and renal function, systemic administration of methotrexate at high doses is not appropriate or practical for all patients.[155]

Finally, in the current era of targeted therapeutics, there is increasing interest in the application of biologic therapies in the leptomeningeal compartment, particularly small molecule inhibitors of signal-transducing molecules such as protein kinases or monoclonal antibodies against tumor-associated cell surface molecules. There is increasing evidence that when these agents are administered systemically, they penetrate the leptomeningeal space inefficiently. For example, relatively low CSF levels of monoclonal antibodies that target CD20 in β-cell lymphomas or of small molecules that inhibit the bcr-abl tyrosine kinase have been documented after systemic administration. [156] [157] Direct intra-CSF administration of monoclonal antibodies and immunotoxins is an area of current early-phase investigation in the treatment and/or prophylaxis of neoplastic meningitis. [156] [158] A recent phase I dose escalation study formally evaluated the safety and efficacy of intrathecal administration of an anti-CD20 antibody in 10 patients with recurrent CNS and intraocular lymphoma.[159] Responses were identified in patients with meningeal, parenchymal, and intraocular disease, and a successor study of intraventricular rituximab plus methotrexate is under way. Another group reported promising results of targeted iodine-131-radiolabeled monoclonal antibodies administered to 52 patients with neoplastic meningitis.[160]Various case reports have also documented responses to trastuzumab, a humanized antibody directed to HER2, in patients with leptomeningeal carcinomatosis from HER2-overexpressing primary breast cancer. [161] [162]

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