Systemic Therapy for Lung Cancer Brain Metastases: A Rationale for Clinical Trials

Despite the high prevalence of brain metastases in patients with metastatic lung cancer, these patients have been excluded from enrollment in clinical trials of new therapeutic drugs. The reasons for exclusion have centered on concerns that the blood-brain barrier may impede drug delivery into brain metastases, that brain metastases confer a dismal survival for metastatic lung cancer patients, and that brain metastases carry risk for cerebrovascular hemorrhage. A focused, updated review of these issues, however, clearly shows that these particular concerns are unwarranted. An extensive review of clinical trials on the efficacy of chemotheraputic agents against lung cancer brain metastases is also provided. This collective information describes an area in need of therapeutic development and supports an initiative to evaluate novel targeted therapies for lung cancer brain metastases.

The brain is a frequent site of metastases in patients with advanced lung cancer and can be associated with substantial morbidity. Historically, poor prognosis associated with brain metastases has led to therapeutic nihilism as a self-fulfilling prophecy. Over the past 10 years, however, with earlier detection of brain metastases and improved local treatment options, survival and prognosis have improved. These improvements are two of several factors that provide justification for including patients with brain metastases in clinical trials of new systemic therapies. We address several commonly cited beliefs that have hindered the development of therapeutic agents for central nervous system malignancies, and we advance reasons that we feel justify including patients with brain metastases in clinical trials of new therapeutic approaches for lung cancer.

The Blood-Brain Barrier May Not Substantially Impede Drug Delivery Into Brain Metastases

The microvasculature of the brain parenchyma is lined by a continuous, nonfenestrated endothelium with tight junctions and has little pinocytic vesicle activity.[1,2] This blood-brain barrier (BBB) limits the entrance of circulating macromolecules into the brain parenchyma. The BBB and the lack of a lymphatic system are responsible for maintaining the brain as an immunologically privileged site[3] and for protecting the brain against the entry of most drugs and invasion by microorganisms. This barrier has been hypothesized to be a reason why brain neoplasms and metastases are often resistant to chemotherapeutic drugs.[4,5]

The observation of brain metastases in 55% of patients who achieved a complete response (CR) with neoadjuvant chemotherapy (often developing very early after completion of therapy)[6] has been interpreted as evidence for the brain being a pharmacologic sanctuary. Very small metastases that have not yet developed neovascularizition may be protected from chemotherapy. However, there is little if any evidence that this has any relevance in the delivery of chemotherapy to established brain metastases with highly permeable angiogenic vasculature sufficiently abnormal to permit enhancement on magnetic resonance imaging (MRI) scans.[1-4]

Available Evidence

Abundant evidence exists that the BBB is not fully operational in brain tumors.[7-9] First, the barrier does not prevent the entry of circulating metastatic cancer cells into the brain parenchyma. In addition, many malignancies in the brain appear to degrade the integrity of the BBB, permitting tumor drug delivery.[10,11]

Second, animal studies demonstrate that molecular tracers as large as 1.5 kD can be extravasated from tumor vasculature of experimental brain metastases.[2,12] The progressive growth of brain metastases is associated with increased expression of vascular endothelial growth factor and leads to tumor vascular permeability, uncharacteristic of surrounding normal brain parenchymal vasculature.[13,14]

Third, the BBB can be permeable in ischemic regions of the brain where increased endothelial pinocytosis, opening of the interendothelial tight junctions, and damage to endothelial cells can occur.[15,16] Degeneration and central necrosis often occur in large (0.2-mm²) brain metastases, and the BBB in these lesions is not intact, possibly due in part to endothelial cell damage or a direct effect of vascular endothelial growth factor (VEGF).

Even more direct data exist on the accumulation to therapeutic levels of chemotherapeutic agents in brain tumors.[17-34] These data have been obtained from analyses conducted after surgical resection, biopsy, or autopsy removal of brain tumors from chemotherapy-treated patients. Direct tissue measurement of drug levels has demonstrated that chemotherapy agents accumulate heterogeneously but often to a much greater extent than in the surrounding normal brain[12,35-37] or cerebrospinal fluid.[26,29,38-40] Pharmacokinetic and anatomic studies of the BBB have suggested that lipophilic drugs penetrate the normal central nervous system (CNS) much more readily than do hydrophilic drugs. However, there is little evidence that this is true for brain tumors, and hydrophilic drugs have shown activity against brain tumors.

The hydrophilic agent cisplatin, like most other chemotherapeutic drugs that have been studied, accumulates in human brain tumors much more than penetration into the normal CNS would predict.[40,41] After therapeutic dosing, cisplatin could be measured in brain tumors from autopsied patients at potentially cytotoxic concentrations.[42] In patients undergoing biopsies after receiving small doses of cisplatin, the concentration of cisplatin in brain tumors, after correction for pharmacokinetics and tissue distribution, is equivalent to that in most normal tissues, except the liver and normal brain, where concentrations are higher and lower, respectively.[31,43]

Brain Metastases Do Not Necessarily Mandate a Dismal Survival for Metastatic NSCLC

Retrospective data from M. D. Anderson Cancer Center demonstrate that for patients with non–small-cell lung cancer (NSCLC) and metastases at one or two organ sites, survival is slightly worse if the brain is involved than if it is not (median survival of 7–8 vs 9–10 months, respectively; unpublished data). However, for patients with involvement of more than two organ sites, the presence of brain metastases does not appear to influence survival at all. Thus, it appears that the total burden of cancer is a more important prognostic factor than the presence of brain metastases per se.

More routine use of MRI screening for brain metastases can detect these lesions earlier, long before they are an imminent cause of death or disability. Earlier detection of oligometastatic brain lesions allows the opportunity to treat with effective stereotactic radiosurgery (SRS) techniques, which are much faster and less toxic than is traditional whole-brain radiotherapy (WBRT), so that systemic therapy is not delayed or compromised.[44] The detection and treatment of brain metastases at a low volume of disease is associated with better survival.[45]

Whole-Brain Radiotherapy

Historically, WBRT has been the mainstay of treating brain metastases, and the median survival time after WBRT has been 2.5 to 7 months.[46-48] The prognosis for brain metastasis patients before WBRT has been categorized according to a recursive partitioning analysis (RPA) schema from the Radiation Therapy Oncology Group (RPA class 1 = Karnofsky performance scale [KPS] score > 70%, age < 65 years, and no extracranial disease; RPA class 2 = KPS score > 70% and age ≥ 65 years or active extracranial disease; RPA class 3 = KPS score ≤ 70%). The median survival time has been 5 to 7 months for RPA class 1, 3 to 4 months for RPA class 2, and 2.5 to 3 months for RPA class 3.[45,47,49-51]

The prognosis and patterns of treatment failure for brain metastasis patients after WBRT have been categorized according to an RPA schema based on decision nodes that include KPS score ≤ 80%, age > 60 years, radiation dose < 66 Gy, weight loss > 5%, and malignant pleural effusion.[52] This RPA schema has demonstrated median survival differences ranging from 3.3 to 12.6 months.[52] Surgical resection of brain metastases has been generally reserved for patients in RPA class 1 or for patients with large symptomatic metastases refractory to radiotherapy.[53]

Stereotactic Radiosurgery

Since the late 1990s, SRS has been used with increasing frequency for the treatment of brain metastases.[54-61] For up to four tumors smaller than 3 cm and as small as 0.5 cm, SRS, using GammaKnife techniques (from a fixed cobalt source) or a linear accelerator, has demonstrated effective local control of brain metastases as a single-day outpatient procedure without the alopecia, fatigue, or potential neurocognitive toxicity encountered with WBRT.[58,59,61] WBRT is still essential in treating multiple or disseminated brain metastases, and neurosurgical resection is still the best option for management of large brain metastases that are resistant to radiotherapy or markedly symptomatic. However, SRS can now be used to treat most other cases of brain metastases effectively with fewer side effects, and systemic therapy can be resumed immediately.[54,58,59,61] In addition, SRS as consolidation therapy has been shown to improve survival after WBRT in patients with solitary brain metastases.[62]

Although the efficacy of SRS has not been directly compared with neurosurgical resection for NSCLC brain metastases, local control rates have invariably been high; the median survival time after SRS has been approximately 5 to 11 months and as high as 21 months for patients without extracranial disease, which is significantly better than the historical median survival time after WBRT.[54,57-60,63-65] This improvement is likely due to the practice of SRS being used selectively to treat lower-volume, early oligometastatic disease in the brain with a better prognosis, whereas WBRT is still the gold standard therapy for bulky and extensive metastatic disease in the brain with a poorer prognosis.[55,66,67]

SRS and WBRT appear to have equivalent efficacy, however, in patients with a similar disease burden. The overall survival for patients with up to four brain metastases treated with SRS alone or with concomitant WBRT has been the same in both retrospective and prospective randomized multi-institutional trials.[58,68,69] New sites of metastases are more likely to develop after SRS than after WBRT, but SRS can be repeated at new sites if the metastases develop gradually as oligometastatic disease[70,71] and can be used to effectively treat tumors that progress after WBRT.[56]

Other Factors Influencing Prognosis

In addition to the availability of SRS, which allows effective early intervention for NSCLC brain metastases with minimal morbidity, other factors have somewhat reduced the effect of brain metastases on prognosis. Specifically, routine MRI screening is now often detecting asymptomatic small brain metastases early, while patients have a relatively long life expectancy and a preserved performance status. Overall, the presence of brain metastases is no longer necessarily associated with the very poor prognosis that has historically been associated with them.

Because of this shift, it would be very reasonable to routinely include patients with brain metastases in clinical trials of new systemic therapies-particularly patients with small minimally symptomatic brain metastases (whether or not they have been treated with radiotherapy) and patients with oligometastatic brain disease that has been treated with SRS or surgical resection. If a new systemic therapy is effective against the small and minimally symptomatic brain metastases, the morbidity associated with WBRT might be deferred.

Existing Chemotherapeutic Regimens Have Demonstrated Activity Against Brain Tumors

The efficacy of multiple systemic therapies for lung cancer brain metastases has been documented.[72-74] Activity has been seen with regimens that are typically used to treat lung cancer at other sites as well as with agents and regimens that have demonstrated efficacy against primary brain tumors.

NSCLC Studies

TABLE 1

Reported Chemotherapy for Lung Cancer Brain Metastases: Non–Small-Cell Lung Cancer–Specific Chemotherapy

In NSCLC treated with standard chemotherapy, the response rates have been comparable in brain metastases and in extracranial disease (Table 1). The response rate of intracranial disease has been reported as 30% for cisplatin (100 mg/m²) on day 1 combined with etoposide (100 mg/m²) on days 1, 3, and 5 every 3 weeks,[75] 17% for carboplatin (300 mg/m²) on day 1 plus etoposide (120 mg/m² days 1-3 every 4 weeks,[76] 20% for carboplatin (area under the curve [AUC] 6) plus paclitaxel (225 mg/m²),[77] 38% for cisplatin (120 mg/m²) plus paclitaxel (135 mg/m²) plus either vinorelbine (30 mg/m²) or gemcitabine (800 mg/m²) on day 1,[78] 45% for vinorelbine (25 mg/m²), gemcitabine (1,000 mg/m²), and carboplatin (AUC 5) on day 1,[79] and up to 60% for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in Japanese patients.[80]

Although a response rate of only 10% was seen in an Italian study of gefitinib (Iressa) in brain metastases, most of the patients had previously received systemic chemotherapy and many had also previously received cranial irradiation.[81] Other publications have reported individual patients with intracranial metastases that responded to EGFR tyrosine kinase inhibitors.[80-84]

SCLC Studies

TABLE 2

Reported Chemotherapy for Lung Cancer Brain Metastases: Small-Cell Lung Cancer–Specific Chemotherapy

In small-cell lung cancer (SCLC) treated with standard chemotherapy, carboplatin (300 mg/m²) on day 1 plus etoposide (120 mg/m²) on days 1 to 3 every 3 weeks resulted in a 27% overall response rate and a concordant intracranial response rate (Table 2).[76] Cisplatin (35 mg/m²) on days 2 and 3, teniposide (Vumon, 50 mg/m²) on days 1 to 5, vincristine (1.3 mg/m², maximum 2.0 mg) on days 1, 8, and 15 every 3 weeks followed by three other repeating multidrug regimens resulted in a 50% overall response rate and 55% intracranial response rate.[85]

For an older regimen of cyclophosphamide (1,000 mg/m²) and doxorubicin (45 mg/m²) on day 1 and etoposide (100 mg/m²) on days 1, 3, and 5, for previously untreated patients, the intracranial response rate of 27% was considerably lower than the 73% response rate seen for extracranial disease.[86] However, a very similar regimen combined with vincristine (1.5 mg/m²) on days 1 and 5 gave intracranial and extracranial response rates of 82% and 75%, respectively.[87]

In previously treated patients with SCLC, cisplatin (60 mg/m²) on day 1 and topotecan (Hycamtin, 0.75 mg/m²) on days 1 to 5 resulted in response rates for brain metastases of 24% and 29% for patients with resistant and sensitive relapse, respectively.[88] In patients with relapsed SCLC (90% of whom were in sensitive relapse and 27% of whom had had prior prophylactic cranial radiation) and new brain metastases, single-agent topotecan (1.5–1.25 mg/m² for myelosuppression) on days 1 to 5 produced a 33% intracranial response rate.[89]

CNS-Targeted Therapy

TABLE 3

Reported Chemotherapy for Lung Cancer Brain Metastases: Central Nervous System–Targeted Chemotherapy

Some drugs have been evaluated for use in treating lung cancer brain metastases on the basis of their demonstrated activity against primary brain tumors, in the hopes that they would offer better penetration into the CNS (Table 3). Irinotecan (Camptosar) is an agent with established activity in SCLC, but because it has also shown activity against gliomas, there has been interest in evaluating it for patients with brain metastases. One study reported complete responses with irinotecan-based chemotherapy for brain metastases in three patients with SCLC, parotid cancer, and esophageal adenocarcinoma.[90] The combination of cisplatin, ifosfamide, and irinotecan in treatment-naive patients with NSCLC led to an intracranial response rate of 50% and an extracranial response rate of 62%.[91]

Other agents have been tested against brain metastases because of their activity in gliomas. In a trial of single-agent temozolomide (Temodar, 150 mg/m²) on days 1 to 5 for a variety of cancers metastatic to the brain, the only two patients to respond had NSCLC, and the intracranial response rate was 9%.[92] In NSCLC patients with brain metastases that developed after progression on front-line chemotherapy or recurred after WBRT, temozolomide (150 mg/m²) on days 1 to 5 every 4 weeks led to a 10% intracranial response rate.[93] Another study of temozolomide (200 mg/m²) on days 1 to 5 and irinotecan (200 mg/m²) on days 1 to 5 every 4 weeks in previously untreated patients with NSCLC brain metastases reported no responses.[94] Temozolomide (160 mg/m²) and cisplatin (75 mg/m²) on day 1 every 4 weeks resulted in a 17% intracranial response rate.[95]

Fotemustine and cisplatin on an alternating schedule (Table 1) in chemotherapy-naive patients produced 16% to 28% intracranial response rates but marked hematologic toxicity.[96,97] A regimen known as TPDC-FuHu (thioguanine [Tabloid], procarbazine [Matulane], dibromodulcitol, lomustine [CCNU, CeeNU], fluorouracil [5-FU], and hydroxyurea) on an alternating schedule (Table 1) led to 13% and 66% intracranial response rates in recurrent brain metastases in NSCLC and SCLC patients, respectively.[98]

The combination of cisplatin (100 mg/m²) on day 1 and teniposide (80 mg/m²) on days 1, 3, and 5 was administered to previously untreated NSCLC patients with brain metastases and resulted in intracranial and extracranial response rates of 35% and 26%, respectively.[99] Concurrent chemoradiotherapy for brain metastases appears to produce greater responses than radiotherapy alone but does not improve patient survival and is associated with potentially greater neurocognitive toxicity.[100-102]

These studies demonstrate that smaller molecular weight (MW) drugs expected to penetrate normal brain tissue, such as temozolomide (MW = 158) or fotemustine (MW = 316), are generally no better against lung cancer brain metastases than are larger drugs such as etoposide (MW = 589) or irinotecan (MW = 587), which theoretically would have poor brain penetration.[103]

Lung cancer brain metastases are sensitive to existing chemotherapies, particularly in treatment-naive patients. The frequently voiced impression that brain metastases are more resistant to chemotherapy than are metastases to other sites may be driven by observations in two clinical settings. First, if patients with newly diagnosed brain metastases receive both cranial irradiation and systemic chemotherapy, any response of the brain metastases is generally attributed to the radiotherapy. If brain metastases progress after the cranial irradiation or after prior systemic therapy, there is a high probability that they will be resistant to further therapy simply based on the fact that they have previously been exposed to therapy. However, the failure of further systemic therapy to be of benefit may erroneously be blamed instead on lack of drug penetration through the BBB.

Second, if patients are treated with chemotherapy combined with surgery or radiotherapy for localized disease or are treated with chemotherapy alone for advanced disease and they relapse or progress first in the brain, this is often attributed to protection of brain metastases by the BBB. Microscopic brain deposits could be protected from chemotherapy by the BBB before the induction of neoangiogenesis in the metastases, but any protection of such microscopic deposits would not necessarily apply to macrometastases that have formed abnormal blood vessels.

Overall, available data suggest that systemic therapies may be active against clinically apparent brain metastases, particularly in chemotherapy-naive patients. This idea suggests that such patients should be included in trials of new systemic therapies.

Brain Metastases Are Found in a Large Fraction of Metastatic Lung Cancer Patients

The prevalence of brain metastases in patients with lung cancer is at least 30%.[104-108] At our center, among metastatic NSCLC patients referred for second opinion or initial treatment, the prevalence of brain metastases is 36% (unpublished data). This prevalence applies to all the major histologic variants of lung cancer-adenocarcinoma, large-cell carcinoma, and small-cell carcinoma-except for squamous cell carcinoma.

About 10% of patients with newly diagnosed metastatic lung cancer present with brain metastases, and 14% to 19% of metastatic lung cancer patients later develop brain metastases during the course of their disease.[104-107] Yet, the likelihood of developing brain metastases for an individual patient may be even higher than this because the chance of developing brain metastases increases over time during the natural history of disease progression.[109] Autopsy studies have demonstrated that the prevalence of brain metastases in patients with adenocarcinoma, large-cell carcinoma, or small-cell carcinoma of the lung range from 40% to 50%.[104,105,108] At least a quarter of these metastases are not detected before death.[108]

To exclude patients with lung cancer brain metastases from clinical trials needlessly withholds new therapies from a large percentage of patients with metastatic lung cancer, and clinical trial results cannot be generalized to the large subpopulation of patients who have brain metastases. Clinical trials could be performed separately for patients with or without brain metastases, but this would waste additional time and resources unless the treatments were specifically targeting brain metastases based on the demonstration of unique molecular targets.

Brain Metastases From Lung Cancer Carry Minimal Risk for Cerebrovascular Hemorrhage

A lingering concern regarding the treatment of brain metastasis patients with new therapies is the theoretical risk of intracranial hemorrhage from tumor. The incidence of spontaneous hemorrhage in patients with brain metastases of various tumor types has been reported to be from 0.8% to 14%.[110,111] Across three trials using WBRT with or without SRS to treat more than 500 subjects, the rate of bleeding was ~1.2%; this value suggests an inherently low rate of bleeding after treatment using radiotherapy.[112-114]

An exception to this suggested incidence was a trial that evaluated 54 subjects with 131 brain metastases from various tumor types treated with SRS. Hemorrhage was present in 7.4% of the metastases before SRS and in 18.5% after SRS but was symptomatic in only three cases (5%).[115] It is not clear why a significantly higher rate of hemorrhage was observed both before and after radiosurgery in this trial, compared to similar trials. Excluding the outlying data from this one study, it appears that the rate of CNS metastasis–related hemorrhage is no higher than 1.2%, with the rate of symptomatic metastases at approximately 0.53%.[116]

For NSCLC, the incidence of brain metastasis–associated hemorrhage appears to be even lower. Our database of metastatic NSCLC patients at M.D. Anderson reports an intracranial hemorrhage incidence of 1.2% over 5 years and a rate of symptomatic or clinically significant hemorrhages of 0.5%, which is similar to the rate of hemorrhagic cerebrovascular accidents in the same patient population without brain metastases (unpublished data).[117]

Conclusions

REFERENCE GUIDE

Therapeutic Agents
Mentioned in This Article

Carboplatin
Cisplatin
Cyclophosphamide
Dibromodulcitol
Doxorubicin
Etoposide
Fluorouracil (5-FU)
Fotemustine
Gefitinib (Iressa)
Hycamtin
Hydroxyurea
Ifosfamide
Irinotecan (Camptosar)
Lomustine (CCNU, CeeNU)
Procarbazine (Matulane)
Temozolomide (Temodar)
Teniposide (Vumon)
Thioguanine (Tabloid)
Topotecan
Vincristine

Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

The current widespread practice of excluding lung cancer patients with brain metastases from clinical trials of new systemic agents cannot be justified, particularly for patients who have good performance status and do require corticosteroids or anticonvulsants. The perception that the BBB will limit uptake of drugs into established brain metastases is not borne out by the available data. Also, the frequently voiced concern that these patients (particularly those with asymptomatic brain metastases discovered on routine MRI screening) will deteriorate more rapidly than will other patients with NSCLC is not substantiated by published data, nor is it in keeping with the anecdotal clinical experience of the authors.

Because brain metastases are extremely common in lung cancer, excluding patients with brain metastases from clinical trials could seriously reduce the generalizability of the study results. Excluding patients with brain metastases might also be regarded as unnecessarily discriminatory because there are relatively few studies available for this very common patient population, and in an era when accrual on studies is often painfully slow, excluding this population further slows accrual rates. Another common cause for concern associated with brain metastases-intracranial hemorrhage-is actually a negligible risk for lung cancer patients.

Furthermore, by eliminating lung cancer patients with brain metastases from clinical trials, we may be eliminating a patient population that will respond unexpectedly well to a new agent. For example, a recent publication documented increased expression of EphA2 in the primary tumors of patients who develop brain metastases.[118] In addition, it has long been known that the molecular characteristics of a malignancy may substantially influence metastatic pattern. For example, estrogen-receptor expression in breast cancer is a predictor of bone and soft-tissue metastases as opposed to visceral metastases. Although it is not yet fully known what molecular characteristics predict the metastatic pattern in lung cancers, the molecular characteristics that govern it might also correlate with the efficacy of specific targeted agents. Hence, we feel it is wise to cast a broad net and include patients with brain metastases rather than exclude them.

In summary, we feel it is justified and very important to permit the inclusion of lung cancer patients with brain metastases in clinical trials of new agents, whether or not they have already had surgery or radiotherapy.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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