Management of Overt Central Nervous System Metastases: Brain and Spinal Cord
Management of Overt Central Nervous System Metastases: Brain and Spinal Cord
Young Kwok
Roy A. Patchell
William F. Regine
Brain metastasis is very common in cancer, with an annual incidence in the United States of approximately 170,000 to 200,000. The rising incidence of brain metastasis is most likely from a combination of increasing survival from recent advances in systemic therapy, and a greater availability and use of magnetic resonance imaging (MRI). The most common primary site is the lung (50%) followed by breast (15%). The average age at presentation is approximately 60 years, and the median survival is usually less than 1 year. Metastatic brain tumors outnumber primary brain tumors by almost a factor of 10 to 1, with autopsy series demonstrating a 10% to 30% incidence rate for all patients with a diagnosis of cancer. 1,2
CLINICAL PRESENTATION, DIAGNOSIS, AND PROGNOSIS
Most patients present with significant neurologic signs and symptoms (Table 63.1).3 Although differential diagnoses such as an abscess or a stroke must be considered, new-onset neurologic symptoms in a known cancer patient should always be presumed to be from brain metastasis until proven otherwise.
MRI has become the gold standard for imaging of the central nervous system in cancer patients.4 Given its ability to image in multiple orientations and sequences, as well as having superior resolution and accuracy, it has replaced the older computed tomography (CT). MRI will frequently pick up smaller lesions not seen on CT scans, which can have a significant effect on the patient’s prognosis and treatment course. Full systemic workup (e.g., positron emission tomography [PET] and CT) should be promptly initiated if brain metastasis is the presenting event. The incidence of unknown primaries may subsequently decrease with the increasing popularity of integrated PET/CT scans.
Performance status and extracranial disease status have consistently been shown to impact prognosis. Gaspar et al.5 reported on the Radiation Oncology Therapy Group (RTOG) the experience of 1200 patients, which is summarized in Table 63.2. This analysis revealed three recursive partitioning analysis (RPA) classes, with the RPA class I (Karnofsky performance score [KPS] ≥70, controlled primary, age <65 years, brain metastasis only), II (not meeting requirements of classes I or III), and III (KPS <70) having median survivals of 7.1, 4.2, and 2.3 months, respectively.
CORTICOSTEROIDS
In symptomatic patients, the initial therapy should promptly start with corticosteroids (e.g., dexamethasone or methylprednisolone), which effectively improve edema and neurologic deficits in approximately two thirds of patients.6 The only randomized trial on the dosage question was reported by Vecht et al.7 This trial included two successive groups of patients. The first group (n = 47) evaluated 8 versus 16 mg/day initial dexamethasone doses, with tapering schedules over 4 weeks. The second group (n = 49) evaluated 4 versus 16 mg/day of initial dexamethasone, with continuation of these doses for 28 days before tapering. The patients were scheduled for whole-brain radiotherapy (WBRT) and concurrent ranitidine. All arms had similar KPS improvements at 7 days (54% to 70%) and 28 days (50% to 81%). The study concludes that 4 mg/day of dexamethasone (with a taper over 4 weeks) is the preferable regimen.
However, one should be cautious in interpreting the results of this study. Patients in the 4-mg/day arm had to have the medication reinstituted at a higher rate than the patients in the 8- or 16-mg/day arms. Furthermore, the arm with the greatest improvement in the KPS was the 16-mg/day arm when this was tapered over 4 weeks, compared with any of the other arms. It can be argued that higher KPS improvement arose from the maximal anti-inflammatory effects of the initial higher doses, with the 4-week taper minimizing the late toxicity associated with corticosteroids.
A reasonable corticosteroid regimen in patients with brain metastases is a 10-mg intravenous (IV) or oral bolus, followed by a 4 to 6 mg every 6 to 8 hours of dexamethasone equivalent dose (with a concurrent proton pump inhibitor), before this is tapered in a clinically cautious manner. In asymptomatic patients with little peritumoral edema or mass effect, initial corticosteroids may be reserved until the first sign of neurologic symptoms.
TABLE 63.1 Clinical Presentation of Brain Metastasis3
Symptom
Percent
Sign
Percent
Headache
49%
Hemiparesis
59%
Mental problems
32%
Cognitive deficits
58%
Focal weakness
30%
Sensory deficits
21%
Ataxia
21%
Papilledema
20%
Seizures
18%
Ataxia
19%
Speech problems
12%
Apraxia
18%
WHOLE-BRAIN RADIOTHERAPY
WBRT continues to be the standard of care in patients with brain metastasis. In general, WBRT should be given soon after the diagnosis of multiple brain metastases. There has never been any evidence to suggest that delaying systemic chemotherapy for WBRT compromises overall survival (OS), especially when one considers that progression in the brain frequently leads directly to the death of the patient.
Multiple randomized studies have been performed to determine the optimum dose and fractionation of WBRT. Table 63.3 summarizes selected randomized studies on WBRT fractionation.8,9,10,11 OS has not improved appreciably over the last 25 to 30 years. Typically, the radiographic and clinical response rates range from 50% to 75%. A total of 30 Gy in 10 fractions continues to be the standard for most patients. In chemotherapy refractory, RPA class III patients, a shorter fractionation scheme (e.g., 20 Gy in 5 fractions) should be considered. However, short fractionation schemes should be avoided in chemotherapy-naive patients with brain metastasis as the presenting event in the cancer diagnosis. The natural disease course of such patients can be frequently unpredictable, so they may live sufficiently long enough to experience late radiation toxicity posed by such short fractionation schedules. 12
SURGICAL RESECTION
Surgical resection can provide immediate relief of the tumor mass effect, whereas WBRT typically takes several days to work. Radiobiologically, 30 Gy in 10 fractions to a solid tumor (excluding radiosensitive tumors) is not adequate to achieve long-term tumor control. This issue is especially germane because historically, up to one half of all patients died from neurologic causes after being treated with WBRT alone.
There have now been three phase III trials testing the hypothesis that surgical resection to single brain metastasis is potentially beneficial. All three trials were on patients with a single lesion, which is defined as the presence of only one lesion in the brain regardless of the extracranial disease status, whereas a solitary lesion is defined as the presence of the CNS metastasis as the only site of the metastatic disease burden. Table 63.4 summarizes the three trials.13,14,15 The studies by Patchell et al.13 (KPS ≥70) and Noordijk et al.14 (World Health Organization grade ≤2) included patients with better performance status compared with the Mintz et al.’s15 study (KPS ≥50) that mainly contributed to the differences in the survival outcomes between the studies. The results of these studies suggest that surgical resection should be reserved for lesions causing life-threatening complications or those with good performance status (i.e., KPS ≥70).
RADIOSURGERY BOOST TRIALS
Radiosurgery provides an alternative to conventional surgery. The three randomized trials of surgical resection were performed before the widespread availability of stereotactic radiosurgery (SRS). Although no randomized trials have been performed comparing surgery with SRS, SRS appears to provide similar local control rates (in the order of 80% to 90% only when combined with WBRT). Unless the tumor causes significant edema and mass effect, with consequent hydrocephalus or herniation requiring urgent surgical intervention, SRS can serve as a noninvasive option. Frequently, a patient may not be a craniotomy candidate because of tumor location in eloquent areas or existing medical contraindications. Although two of the three conventional surgery trials have shown a survival benefit in single brain metastasis, there have been no randomized trials addressing multiple lesions and the retrospective data available are contradictory. For SRS, there have been three randomized trials assessing the efficacy of SRS in the treatment of multiple metastases.16,17,18 Key findings of the three trials are summarized in Table 63.5.
TABLE 63.4 Randomized Trials of Surgical Resection in Single Brain Metastasis
The first randomized trial was reported by Kondziolka et al.,16 but this study was stopped early at a planned interim analysis of 60% patient accrual because the authors reported to have found a large difference in the primary end point of local control in favor of SRS (92% vs. 0%; p = 0.0016). Unfortunately, the study used nonstandard end points to measure recurrence, defining it as any increase in the lesion size on MRI rather than the more usual 25% increase in product of the diameter. Furthermore, no attempt was made to control for corticosteroid use, radiation changes, or other factors that might produce small fluctuations in the lesion size on MRI. Therefore, this study is difficult to interpret.
The second trial was reported by Chougule et al.,17 and the results are only available in abstract form.17 This three arms trial randomized patients to treatment with SRS alone with Gamma Knife, SRS plus WBRT, or WBRT alone. This trial suffers from several serious methodological problems. Although the authors conclude that the survival times among the treatment arms were similar and that patients treated with SRS experienced superior local control and fewer brain metastases, no p values are reported. Furthermore, 51 of the patients had surgical resection for at least one symptomatic brain metastasis prior to entry into the study, and no attempt was made to stratify for previous surgery. The inclusion of the surgically resected patients effectively made this a six-arm trial and, therefore, the size of this trial was not large enough to support a meaningful analysis. Finally, the radiation doses used in the SRS arms cannot be considered conventional because the peripheral dose was not individualized based on the tumor size or volume. Thus, this study has not been interpretable.
The third study, RTOG 95-08, was reported by Andrews et al.18 The primary end point was OS, which was not statistically different between the WBRT plus SRS and WBRT-alone arms (6.5 and 5.7 months, respectively; p = 0.1356), although SRS boost favored the survival in the subgroup (planned analysis) of patients with single metastasis. For secondary end points, the local control and performance measures were higher in the SRS boost arm, but this did not translate into a lower death rate from neurologic progression. Multiple, unplanned subgroup analyses were made, and an OS benefit with the SRS boost was found in several subgroups that included patients with RPA class 1, tumor size ≥2 cm, and non-small cell lung cancer (NSCLC) or metastatic squamous histology from any site. Unfortunately, these subset analyses were not planned or prespecified, and the p values needed for significance should have been adjusted for inflation of the type I error. When this was done, none of these subgroup analyses showed a positive benefit for SRS.19 On the other hand, this trial did demonstrate that SRS is associated with lower edema and corticosteroid use, countering a commonly held notion that SRS actually increases the edema risk. However, with regard to the major end points for multiple metastases, this study should be considered a negative trial.
Although SRS boost is indicated (from RTOG 95-08 and from the extrapolation of surgical resection data) in patients with a single metastasis, it is difficult to justify its routine use in patients with multiple metastases in the light of the equivocal phase III SRS boost trials.
POSTOPERATIVE WHOLE-BRAIN RADIOTHERAPY
A controversy in the treatment of brain metastasis is the routine use of postoperative or post-SRS WBRT. In a multi-institutional retrospective SRS study, Sneed et al.20 argue for the omission of upfront WBRT because this does not compromise OS. Unfortunately, only an OS analysis was performed, and no local control or retreatment data were given. In an earlier study by the same group of investigators, patients who were initially treated with SRS alone without WBRT experienced worse freedom from new brain metastasis and overall brain freedom from progression despite the imbalance of the prognostic factors that favored the SRS-alone group, although the OS was not different. 21 Because of the equivalency of OS, many have advocated withholding upfront WBRT. They often use repeat SRS for the failures, which can be very expensive. Furthermore, brain failure can lead to unacceptable consequences. For example, Regine et al.22 reported on 36 patients with planned observation after initial SRS alone. Even with close follow-up with exams and high-resolution MRIs, 47% of patients experienced brain failure, with 71% and 59% experiencing symptomatic relapse and neurologic deficits, respectively.
The omission of upfront WBRT may have even more serious consequences for patients with more radioresistant tumors such as renal cell carcinoma (RCC). The SRS dose given is typically limited by tumor size and volume, and not by whether the patient received additional dose with WBRT. Therefore, a patient treated with WBRT plus SRS receives much higher tumor dose than SRS alone. It is then not a surprise that an Eastern Cooperative Oncology Group phase II study, which evaluated SRS alone in radioresistant tumors (RCC, melanoma, sarcoma), demonstrated very disappointing results,23 reporting a 6-month total brain failure rate of 48.3%. The authors correctly conclude that routine avoidance of WBRT should be approached judiciously.
Fortunately, there have been two phase III trials that have assessed the use of postoperative WBRT (Table 63.6). Patchell et al.24 demonstrated that surgical resection without WBRT led to a failure rate at the original site and the entire brain of 46% and 70%, respectively. More importantly, 44% of the patients in the surgery-alone arm died as a result of neurological sequalae from the brain failure. The results of this study have been frequently misinterpreted in the literature. Some have justified the withholding of upfront WBRT based on the fact that this study demonstrated equivalent survival. In fact, this study was designed with brain tumor recurrence rate as the primary end point and not OS. To show an OS difference, this trial needed to enroll over 2000 patients. The study met its primary end point and confirmed the importance of postoperative WBRT in preventing brain failure and death from neurologic causes.
Results of the JROSG 99-1 trial by Aoyoma et al.25 demonstrated similar benefits of WBRT. In this phase III trial of 1 to 4 lesions, the SRS-only arm experienced worse 6-month freedom from new brain metastasis (p = 0.003) and 1-year local control (p = 0.019). Most importantly, the average duration until deterioration of mini-mental state examination (MMSE) was 16.5 months in the WBRT+SRS arm versus 7.6 months in the SRS-alone group (p = 0.05). 26 The main drawback of this study was the designation of OS as the primary end point. 26a,26b There is very little evidence that adjuvant WBRT after surgery is likely to improve OS. However, this study did demonstrate the importance of WBRT in decreasing brain failure, corroborating the findings of the study by Patchell et al.24
TABLE 63.6 Randomized Trials of Postoperative Whole-Brain R adiotherapy
