Brain Metastases - NCCN Guidelines for Patients

Metastases to the brain are the most common intracranial tumors in adults and may occur up to 10 times more frequently than primary brain tumors.

Population-based data reported that about 8% to 10% of patients with cancer are affected by symptomatic metastatic tumors in the brain.^415,416 Based on autopsy studies, brain metastases have been shown to be present in 25% of patients with cancer.⁴¹⁷

As a result of advances in diagnosis and treatment, many patients improve with proper management and do not die of progression of these metastatic lesions. Primary lung cancers are the most common source,⁴¹⁸ although melanoma has a high predilection to spread to the brain.⁴¹⁹ Diagnosis of CNS involvement is increasing in patients with breast cancer as therapy for metastatic disease is improving.⁴²⁰

Nearly 80% of brain metastases occur in the cerebral hemispheres, an additional 15% occur in the cerebellum, and 5% occur in the brainstem.⁴²¹ These lesions typically follow a pattern of hematogenous spread to the gray-white junction where the relatively narrow caliber of the blood vessels tends to trap tumor emboli. The majority of cases have multiple brain metastases evident on MRI scans. The presenting signs and symptoms of metastatic brain lesions are similar to those of other mass lesions in the brain, such as headache, seizures, and neurologic impairment.

Version 5.2020 © 2021 National Comprehensive Cancer Network^© (NCCN^©), All rights reserved. NCCN Guidelines^® and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-35 Treatment Overview

Surgery

Despite advances in surgical technique, surgery alone for brain

metastases is not sufficient for achieving local control.^422,423 The objectives of surgery for brain metastasis include retrieval of tissue for diagnosis, reduction of mass effect, and improvement of edema.⁴²⁴ To promote local control following resection of a brain metastasis, adjuvant RT represents an acceptable treatment strategy, discussed further below. Randomized trials reported in the 1990s demonstrated an OS benefit with surgical resection for patients with single brain metastases. In a study of 48 patients, Patchell et al⁴²⁵ demonstrated that surgery followed by WBRT compared with WBRT alone improved OS (40 vs. 15 weeks in WBRT arm;

P < .01) and functional dependence (38 vs. 8 weeks; P < .005), as well as decreased recurrence (20% vs. 52%; P < .02). Similarly, combined

surgery and WBRT led to longer survival and functional independence compared to WBRT alone in another randomized study by Vecht and colleagues (n = 63).⁴²⁶ A third study of 84 patients found no difference in survival between the two strategies; however, patients with extensive systemic disease and lower performance level were included, which likely resulted in poorer outcomes in the surgical arm.⁴²⁷

Stereotactic Radiosurgery

SRS offers an excellent minimally invasive ablative treatment option for brain metastases. Patients undergoing SRS avoid the risk of surgery-related morbidity, and SRS is generally preferred over surgery for patients with small, asymptomatic lesions that do not require surgery and for patients with lesions that are not surgically accessible.⁴²⁴ Late side effects of SRS such as symptomatic edema and RT necrosis are relatively uncommon, but may be observed at higher rates when treating larger lesions.⁴²⁸

The role of stereotactic SRS alone for limited brain metastases has been established by multiple phase III randomized trials comparing SRS alone to SRS plus WBRT.^429-432 Collectively, these studies demonstrate

comparable OS and superior cognitive preservation and quality of life with SRS alone compared to SRS plus WBRT. The role of SRS for patients with multiple metastases has also continued to expand. A prospective trial of 1194 patients found no differences in OS or neurologic mortality with SRS for 2 to 4 versus 5 to 10 brain metastases.⁴³³ A number of analyses have suggested that total volume of brain metastases and the rate of developing new brain metastases may be more important prognostic factors for OS than the number of discrete brain metastases.^434-437 Taken together, patients with multiple lesions but a low total volume of disease, as well as those with relatively indolent rates of developing new CNS lesions, can represent suitable candidates for SRS. Additionally, patients with a favorable histology of the primary tumor (such as breast cancer) or controlled primary tumors can often benefit from SRS regardless of the number of brain metastases present.^438,439 While brain metastases arising from small cell lung cancer have historically been treated with WBRT, an international retrospective study suggested that SRS may be suitable in some cases.⁴⁴⁰ Some brain metastases of radio-resistant primary tumors such as melanoma and renal cell carcinoma have also been shown to achieve good local control with SRS.⁴⁴¹ Other predictors of longer survival with SRS include younger age, good PS, and primary tumor

control.434,438,439,442 However, there are a number of contemporary series supporting SRS in patients with a poor prognosis, with poor KPS, or who are older.^443-446

Maximal marginal doses for SRS use should be based on tumor volume and range from 15 to 24 Gy when treating lesions with a single fraction of SRS.429,433,447 Multi-fraction SRS may be considered for larger tumors, with the most common doses being 27 Gy in 3 fractions and 30 Gy in 5

fractions.^448-450 Contouring guidelines have been published elsewhere.⁴⁵¹

control rates greater than 70% with SRS for patients with good PS and stable disease who have received prior WBRT.^452-455

Postoperative SRS also represents an important strategy to improve local control after resection of brain metastases. After resection alone, the rates of local recurrence are relatively high, and have been reported in the range of 50% at 1 to 2 years in prospective trials. Postoperative SRS to the surgical cavity is supported by a randomized phase III trial including 132 patients with resected brain metastases (1–3 lesions). This trial demonstrated that postoperative SRS was associated with a higher 12-month local recurrence-free rate compared to no postoperative treatment (72% vs. 43%, respectively; HR, 0.46; 95% CI, 0.24–0.88; P = .015).⁴²² A separate randomized phase III trial comparing postoperative SRS with postoperative WBRT demonstrated similar OS and better cognitive preservation with a strategy of postoperative SRS, despite superior CNS control outcomes with WBRT.⁴⁵⁶

Whole-Brain Radiation Therapy

Historically, WBRT was the mainstay of treatment for metastatic lesions in the brain. Although the role of WBRT has diminished over the last several decades, WBRT continues to play a role in the modern era, primarily in clinical scenarios where SRS and surgery are not feasible or indicated (eg, diffuse brain metastases). The standard dosing for WBRT is 30 Gy in 10 fractions or 37.5 Gy in 15 fractions. For patients with poor prognosis, 20 Gy in 5 fractions may also be used.

The impact of WBRT in addition to SRS has been evaluated in multiple randomized controlled studies.429-432,457 A 2018 Cochrane meta-analysis of randomized controlled trials found that the addition of WBRT to SRS alone was associated with better brain control, no differences in OS, and worse neurocognitive outcomes or quality of life in several trials.⁴⁵⁸ The

randomized phase III EORTC 22952 trial failed to show an OS benefit

from WBRT following resection or SRS, compared to observation,⁴³² even in subgroup analyses including only patients with controlled extracranial disease and a favorable prognostic score.⁴⁵⁹ Overall, for patients treated with SRS for brain metastases, the routine addition of WBRT is not recommended due to increased cognitive and quality-of-life toxicity and the lack of an OS benefit.

The randomized phase III non-inferiority QUARTZ trial compared WBRT to optimal supportive care in patients with non-small cell lung cancer

(NSCLC) who were not candidates for SRS, due to various factors including age, PS, and extent of disease. No differences in OS or quality of life were observed with WBRT versus optimal supportive care, which suggests that this population may derive minimal benefit from WBRT.⁴⁶⁰ Moreover, as noted above, a number of studies support SRS for older patients and those with poor prognosis who have historically received WBRT.443-446,461 The optimal treatment strategy of brain metastases for patients with a poor prognosis is highly individualized and may call for best supportive care, WBRT, SRS, or trials of CNS-active systemic agents depending on the clinical scenarios.

In light of the well-characterized deleterious cognitive effects of

WBRT,430,431,456 a number of trials have evaluated strategies to promote cognitive preservation in patients with brain metastases including

investigation of neuroprotective agents, anatomical avoidance strategies, and deferral of WBRT in favor of alternate strategies such as SRS or trials of CNS-active systemic agents. In patients undergoing WBRT for brain metastases, the RTOG 0614 (N = 554) compared concurrent and adjuvant memantine, an N-methyl-D-aspartate receptor antagonist, to placebo.

Memantine was well-tolerated in patients receiving WBRT for brain metastases, and the rates of toxicity were similar to patients receiving placebo.⁴⁶² There was possibly less decline in episodic memory (HVLT-R Delayed Recall) in the memantine arm compared to placebo at 24 weeks

decline (HR, 0.78; 95% CI, 0.62–0.99; P = .01), and the probability of cognitive function failure at 24 weeks was 54% in the memantine arm and 65% in the placebo arm. However, for most cognitive endpoints, no significant differences were observed between memantine and placebo, despite numerical trends that generally favored the memantine arm. For patients with a good prognosis, memantine may be considered during WBRT, as well as after treatment for as long as 6 months.

To evaluate an anatomic-avoidance strategy to promote cognitive preservation, the nonrandomized phase II RTOG-0933 trial showed that reduced radiation dose to the hippocampal neural stem-cell compartment was associated with a smaller decline in recall (P < .001), compared to a historical control.⁴⁶³ Based on these results, the phase III NRG-CC001 trial evaluated WBRT with memantine with or without hippocampal

avoidance.⁴⁶⁴ There were no significant differences in survival outcomes.

However, risk of cognitive failure was significantly lower in the

hippocampal avoidance arm than in the control arm (HR, 0.76; 95% CI, 0.60–0.98; P = .03). For patients without tumor in or around the

hippocampus, hippocampal-sparing WBRT may be preferred in select patients (eg, those with good prognosis).

In the postoperative setting, phase 3 trials have evaluated the role of WBRT after surgical resection of brain metastases. Patchell conducted a study that randomized 95 patients with single intracranial metastases to surgery with or without adjuvant WBRT.⁴⁶⁵ Postoperative RT was

associated with a dramatic reduction in tumor recurrence (18% vs. 70%; P

< .001) and likelihood of neurologic deaths (14% vs. 44%; P = .003). OS, a secondary endpoint, showed no difference between the arms. The

aforementioned EORTC 22952 trial randomized patients treated with local therapy (surgery or SRS) to observation versus WBRT.⁴³² Patients

randomized to WBRT were found to have superior brain disease control

and less death form neurological causes, but inferior quality of life and no differences in OS.^432,466 The NCCTG N107C/CEC-3 randomized phase III trial included 194 patients with resected brain metastases randomized to either postoperative SRS or WBRT.⁴⁵⁶ Although there was no significant difference between the treatment arms for OS, cognitive deterioration at 6 months was less frequent in the SRS arm than in the WBRT arm (52% vs.

85%, respectively; P < .001), and cognitive deterioration-free survival was also greater for postoperative SRS compared to WBRT (median 3.7 months vs. median 3.0 months; HR, 0.47; 95% CI, 0.35–0.63; P < .001). In another phase III trial, 215 patients with 1 to 3 brain metastases from melanoma were randomized to either WBRT or observation following local treatment with surgery or SRS.⁴⁶⁷ Though local failure rate was

significantly lower in the WBRT arm (20.0% vs. 33.6%, respectively; P = .03), there were no significant differences between the study arms for intracranial failure, OS, and deterioration in performance status. Further, grade 1 to 2 toxicity during the first 2 to 4 months was more frequently reported in the WBRT arm.

Systemic Therapy

Many tumors that metastasize to the brain are not chemosensitive or have already been heavily pretreated with organ-specific effective agents. Poor penetration through the BBB is an additional concern.⁴¹⁹ However, there are increasing numbers of systemic treatment options with demonstrated activity in the brain, and it is now reasonable to treat some of these patients (ie, those with asymptomatic brain metastases) with systemic therapy upfront instead of upfront SRS or WBRT.

Specific recommended regimens for brain metastases are based on effective treatment of the primary tumor (see below). However, there is also an increasing number of “basket” studies that evaluate the efficacy of targeted therapy options for a specific mutation or biomarker, regardless of tumor type. For example, the TRK inhibitors larotrectinib and entrectinib

fusion-positive solid tumors.^468,469

As CNS-active systemic agents are changing paradigms for the management of brain metastases, it is important to acknowledge that there is a paucity of prospective data to characterize optimal strategies regarding radiation and systemic therapy combinations or sequencing.

When considering a trial of upfront systemic therapy alone for brain metastases, a multidisciplinary discussion between medical and radiation oncology is recommended. Ongoing CNS surveillance with brain MRIs is essential to allow early interventions in cases of progression or inadequate response.

Melanoma

Rapid advancements in melanoma have produced effective systemic options for metastatic disease.^470,471 These include multiple

immunotherapy options. Two phase II trials support the use of a

combination of the immunotherapy agents ipilimumab and nivolumab for patients with asymptomatic untreated brain metastases from

melanoma.^472,473 In one of these trials, which was conducted in Australia, intracranial responses were observed in 46% of patients who received this combination, with a complete response observed in 17% (n = 79), and median duration of response was not reached at the time of publication (median 14 months of follow-up).⁴⁷² In the second trial, CheckMate 204, the intracranial response was 57%, with a complete response of 26% (N = 94), with median duration of intracranial response also not having been reached at time of publication (median 14 months of follow-up).⁴⁷³ In both of these trials, grade 3 or 4 treatment-related adverse events occurred in just over half of the patients evaluated.^472,473 Results from the Australian trial also suggest there may be a role for nivolumab monotherapy for patients with asymptomatic untreated brain metastases (n = 27), with an intracranial response rate of 20%.⁴⁷² For patients with asymptomatic

untreated lesions, the response rate for patients who received

ipilimumab/nivolumab was better than for nivolumab monotherapy. This trial also evaluated nivolumab monotherapy for a small number of patients for whom local therapy failed (n = 16), but the intracranial response rate was low (6%). A nonrandomized phase II study supports ipilimumab monotherapy for patients with small asymptomatic brain metastases from melanoma (n = 51), with a CNS disease control rate of 24% (no complete responses).⁴⁷⁴ Most of the patients in this study had received previous systemic or local treatment. Nivolumab monotherapy is a reasonable treatment option for a carefully monitored patient whose goal is to avoid radiation.

The anti-PD-1 antibody pembrolizumab is also supported for treatment of both untreated and progressive brain metastases from melanoma, based on early results of a phase II trial showing a CNS ORR of 22% (n = 18).⁴⁷⁵ Long-term follow-up from this trial showed a CNS response in 26% of the sample (N = 23), with four complete responses.⁴⁷⁶ In patients who had a CNS response, these responses were ongoing at 24 months in all of the patients. Median PFS and OS were 2 months and 17 months,

respectively. Grade 3–4 treatment-related adverse events were minimal.

Despite data showing that brain metastases can respond to immune checkpoint inhibitors, the data do not yet provide any robust comparison of these agents from treatment of brain metastases from melanoma.

There is also evidence that brain metastases from melanoma can respond to BRAF/MEK inhibitor combination therapy. The nonrandomized phase II COMBI-MB trial demonstrated clinical benefit and acceptable toxicity for the combination of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib in 125 patients with brain metastases from BRAF V600-mut melanoma.⁴⁷⁷ Among the patients with asymptomatic brain metastases, an intracranial response was observed in 58% of those with untreated

metastases and in 56% of those with previously treated metastases. In

observed in 59%. Use of the BRAF inhibitor vemurafenib for patients with both newly diagnosed and previously treated brain metastases from BRAF V600-mut melanoma is supported by nonrandomized studies.^478,479

Although there are no published prospective studies on the combination of vemurafenib and cobimetinib for patients with brain metastases from melanoma, there is high-quality evidence that, for distantly metastatic melanoma, combination therapy with vemurafenib and cobimetinib is associated with improved outcomes, compared with vemurafenib monotherapy.^480,481 A case series showed that the BRAF/MEK inhibitor combination encorafenib/binimetinib showed good CNS penetration.⁴⁸² Prospective randomized trials are needed to determine which BRAF-directed therapy options provide the best results in patients with brain metastases from melanoma.

Lung Cancer

Systemic treatment options for patients with brain metastases from NSCLC include immunotherapy agents and targeted therapies for cancer that is anaplastic lymphoma kinase (ALK) rearrangement-positive and EGFR mutation-positive.

PD-1/PD-L1 Inhibitors

A phase II trial showed a 33% response rate for pembrolizumab in 18 patients with brain metastases from PD-L1-positive NSCLC.⁴⁷⁵ Pooled analyses from a phase II trial⁴⁸³ and two phase III trials^484,485 showed that nivolumab for patients with previously treated brain metastases from NSCLC is well-tolerated, though results from these analyses are currently only reported in abstract form.⁴⁸⁶ Nivolumab for patients with brain

metastases from NSCLC is also supported by results from a retrospective multi-institutional study.⁴⁸⁷

ALK Inhibitors

At time of diagnosis, brain metastases are present in 24% of patients with ALK rearrangement-positive NSCLC.⁴⁸⁸ Crizotinib inhibits ALK

rearrangements, ROS1 rearrangements, and some MET TKIs. Crizotinib does demonstrate some CNS activity,⁴⁸⁹ but the response and control rates appear to be clearly lower than newer generation ALK inhibitors.

In a randomized phase III trial, the ALK inhibitor alectinib was compared to crizotinib in 303 patients with advanced ALK rearrangement-positive NSCLC and no previous systemic therapy treatment.⁴⁹⁰ Brain metastases were reported in 40.3% of the sample. Among these patients, a CNS response was observed in 81% of patients in the alectinib arm (8 complete responses) and 50% of patients in the crizotinib arm (1 complete

response). The median duration of intracranial response in these 122 patients was 17.3 months in the alectinib arm and 5.5 months in the crizotinib arm. Pooled analyses from two phase II studies^491,492 including patients with ALK rearrangement-positive NSCLC that progressed on crizotinib showed that alectinib was associated with a good objective response rate and excellent disease control in patients with brain

metastases.⁴⁹³ Patients who did not receive previous brain RT seemed to have a better response to alectinib than patients with previous RT, but the sample size for these analyses was small.

In a similar randomized phase III trial, brigatinib, another ALK inhibitor, was compared to crizotinib in 275 patients with locally advanced or metastatic ALK rearrangement-positive NSCLC and no previous systemic therapy treatment.⁴⁹⁴ Among patients with brain metastases (n = 90), an intracranial response was more likely in the brigatinib arm than in the crizotinib arm (67% vs. 17%, respectively; OR, 13.00; 95% CI, 4.38–

38.61). Complete intracranial responses were observed in 16 patients who received brigatinib and 2 patients who received crizotinib. Twelve-month survival without intracranial disease progression was greater in the brigatinib arm than in the crizotinib arm (67% vs. 21%, respectively; HR,

metastases from ALK rearrangement-positive NSCLC and disease progression on crizotinib is supported by the phase II ALTA trial, which showed an intracranial response rate of 67%.⁴⁹⁵ Median intracranial PFS was 12.8 months in these patients. A dosing schedule of 180 mg once daily with a 7-day lead-in at 90 mg was used to reduce the chance of early-onset moderate to severe pulmonary adverse events.

In a third similarly designed randomized phase III trial, the third-generation ALK/ROS1 TKI lorlatinib was compared to crizotinib in 296 patients with advanced ALK rearrangement-positive NSCLC and no previous systemic therapy treatment.⁴⁹⁶ Based on interim analysis of results including patients with brain metastases (n = 78), confirmed CNS response rates were higher in patients who received lorlatinib, compared to patients who received crizotinib (66% vs 20%, respectively; OR, 8.41; 95% CI, 2.59—

27.23), with a complete CNS response reported in 61% of patients with brain metastases who received lorlatinib (compared to 15% of patients who received crizotinib). Duration of intracranial response reaching 12 months was 72% for the lorlatinib arm vs 0% for the crizotinib arm.

The ALK inhibitor ceritinib was evaluated in a phase I trial including 246 patients with ALK rearrangement-positive NSCLC.⁴⁹⁷ About half the sample had brain metastases (n = 124). Retrospective analyses were used to evaluate intracranial response in these patients. Disease control rate was 78.9% in patients not previously treated with an ALK inhibitor and 65.3% in patients with previous ALK inhibitor treatment. However, most of these patients had received RT to the brain. Therefore, it is difficult to draw conclusions regarding the contribution of RT versus ceritinib to disease control rates in these patients.

In general, the panel prefers second- and third-generation ALK inhibitors for patients with brain metastases from ALK rearrangement-positive NSCLC, based on better activity profiles.

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Some treatment options for patients with advanced NSCLC that harbor EGFR-TKI–sensitizing mutations have been evaluated and are now available.

Older-generation EGFR-TKIs have demonstrated some CNS activity.

Gefitinib for treatment of patients with CNS metastases from NSCLC is supported by phase II studies.^498,499 Pulsatile erlotinib is supported by a phase I study including patients with untreated CNS metastases from EGFR-sensitizing mutation-positive NSCLC.⁵⁰⁰ Afatinib treatment was evaluated in patients with CNS metastasis from NSCLC and with disease progression following platinum-based chemotherapy and either erlotinib or gefitinib (n = 100).⁵⁰¹ Cerebral response was observed in 35% of these patients, and disease control was observed in 66%.

In a randomized phase III FLAURA trial, the EGFR-TKI osimertinib was compared to a different EGFR-TKI (gefitinib or erlotinib) in 556 patients with previously untreated EGFR-sensitizing mutation-positive NSCLC.⁵⁰² CNS metastases were reported in 20.9% of the sample. Median PFS was greater for these patients in the osimertinib arm than in the standard EGFR-TKI arm (15.2 months vs. 9.6 months, respectively; HR, 0.47; 95%

CI, 0.30–0.74; P < .001). Preplanned exploratory analyses including 41 patients with at least one measureable CNS lesion showed a CNS ORR of 91% in the osimertinib arm, compared to 68% in the EGFR-TKI arm, but this difference did not reach statistical significance (OR, 4.6; 95% CI, 0.9–

34.9; P = .066).⁵⁰³ Twenty-three percent of patients in the osimertinib arm had a complete CNS response, compared to none of the patients in the EGFR-TKI arm. CNS disease control rate did not significantly differ between the study arms in patients with at least one measureable CNS lesion.

Osimertinib has also been evaluated in the randomized phase III AURA3 trial, in which it was compared to pemetrexed with platinum-based therapy

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