Keywords
brain metastases, non-small cell lung cancer, EGFR mutation, epidermal growth factor receptor tyrosine kinase inhibitors, gefitinib, erlotinib
Outline
Introduction 142
Treatment Options for Brain Metastases 145
Whole Brain Radiotherapy (WBRT) 145
Surgery 145
Stereotactic Radiosurgery (SRS) 145
Systemic Therapy 145
Targeted Therapy 146
Obstacles to Drug Activity within the CNS and Ways to Overcome 148
Clinical Implications of EGFR Mutations 150
Prophylactic Role of the Drugs 151
Adverse Reactions of Gefitinib and Erlotinib, Pros and Cons 151
Future Directions/Additional Agents 152
References
Introduction
A 60-year old never-smoker woman presents with left-sided weakness and ataxia due to innumerable metastatic lesions within the brain originating from an advanced adenocarcinoma of the lung. She receives whole brain radiotherapy (WBRT) and systemic chemotherapy and her symptoms temporarily improve. A few months later her disease recurs both clinically and radiographically within the brain. Institution of erlotinib, a small molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, results in a complete radiographic resolution of brain lesions, improvement in clinical symptoms and performance status, and partial response of the primary lung tumor ( Figures 14.1 and 14.2 ) ( ).
Metastatic tumors are among the most common mass lesions in the brain. In the USA, up to 200 000 people per year, or approximately 40% of patients diagnosed with an invasive malignancy, will develop brain metastases during the course of their illness ( ). Such lesions adversely affect the quality of life as well as the overall survival duration. The incidence of metastatic neoplasms involving the brain is greater than primary central nervous system (CNS) neoplasms. The majority of patients are greater than 60 years old, which is consistent with the median age of most invasive neoplasms. While metastatic disease to the brain may arise from any primary site, the most common sites of origin are the lung, followed by the breast, skin (overwhelmingly, melanomas) and the gut.
Approximately 85% of metastases are supratentorial, while only 1–3% are to the brainstem ( ). Approximately 10% of patients will have an unknown primary site and, in 9% with a known source, the brain is the sole site of metastases. Primary lung cancers make up half of all metastatic brain tumors. Of those patients with lung cancer who survive for at least 2 years, 80% will have brain metastases. However, even within lung cancers, there is a differential propensity for the development of brain metastases based upon histology: small cell lung cancers comprise only 15–20% of all lung cancers, but lead to half of all brain metastases from lung cancers. Notably, about 30–40% of patients with non-small cell lung cancer (NSCLC) may develop clinically apparent metastatic disease to the brain; an early autopsy series noted that 55% of patients with NSCLC were found to have brain metastases ( ).
A considerable body of work has been dedicated to find effective and safe treatments to improve survival of patients with brain metastases. These include surgery or stereotactic radiosurgery for oligometastatic disease, whole brain radiotherapy, and chemotherapy, either alone or as combined-modality treatments. Most of the larger reports, series or trials of localized treatments of brain metastases include a variety of tumor histologies. More importantly, the natural history of the underlying systemic disease often impacts the overall survival and, in some cases, the clinical benefit of any aggressive treatment specifically directed to the brain metastases. One of the largest retrospective analyses of patients with NSCLC and brain metastases was reported from the Cleveland Clinic ( ). The goal was to evaluate the outcome of treatment in patients with newly diagnosed NSCLC who also had an isolated, single, synchronous brain metastasis, with the brain being the sole metastatic site. Over a 14-year period (1982–1996) a total of 219 patients with lung cancer and synchronous brain metastases were identified; of these, only 33 patients had a solitary metastasis, and were further studied. The majority of those patients (64%) were treated with surgical resection followed by whole brain radiotherapy, and the remaining patients were treated with surgery alone or some form of radiotherapy, either as whole brain or stereotactic radiotherapy. The disease in the CNS was controlled in 31 patients (94%). The median disease-free survival (DFS) was 3.3 months, with only nine patients suffering brain recurrence. The median overall survival (OS) was 6.9 months, though patients who received whole brain radiotherapy had a markedly prolonged OS compared to those who did not receive WBRT, 9.1 months versus 2.9 months ( p =0.002). Most of the patients died from systemic disease progression; control of extracranial disease was associated with a markedly prolonged median OS of 20.1 months. While these results are encouraging, there are several notable factors: this was a very small and highly selected patient population; 85% of the patients in the original cohort had multiple brain metastases, where a surgical resection or stereotactic radiosurgery may not be practical or of benefit. Furthermore, the main cause of death in the studied population was still systemic disease progression, though 27% also had intracranial relapse. The low radiotolerance of normal brain tissue limits the cumulative dose of whole brain radiotherapy. With these factors in mind, it is clear that alternative agents must be developed to treat intracranial metastases from NSCLC.
Treatment Options for Brain Metastases
Whole Brain Radiotherapy (WBRT)
Cranial radiotherapy (RT) is most frequently used to control neurologic symptoms caused by brain metastases. An important role for RT, that is a sensitizing effect for epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), has also been proposed ( ). However, the efficacy of RT is influenced by patient performance status, the number of metastatic lesions in the brain and extracranial tumor histology. Furthermore, RT has acute and chronic side effects which could impact overall quality of life. Overall, WBRT may extend survival by 4–6 months.
Surgery
Surgery is another option to treat brain metastases but is limited to single lesions (oligometastases) with accessible locations. When combined with subsequent RT, surgery improves survival compared to radiotherapy alone in lung cancer patients with oligometastatic disease ( ). However, as many patients with NSCLC and brain metastases have multiple brain lesions, this option is not widely used.
Stereotactic Radiosurgery (SRS)
SRS treats CNS metastatic lesions by directing high dose radiation precisely to the affected sites with minimal irradiation of the surrounding unaffected tissues. It has been shown that SRS may yield a median survival of 9.4 months with 3-year local control rate of 65% ( ). It is possible to target multiple lesions with multiple beams. However, the efficacy of SRS depends on tumor volume and the amount of radiation. Overall, it has been accepted that up to four lesions, each<4 cm in diameter, in properly selected patients may be treated by SRS. When combined with WBRT, SRS improves tumor control, performance status, and decreases post-treatment recurrence of brain metastases compared to WBRT alone but does not usually translate into improvements in overall survival. In a phase III trial, combined use of WBRT plus SRS vs WBRT alone significantly ( p =0.03) improved survival, though only in patients with a single lesion; the combination was of no benefit in patients with multiple lesions ( ).
Systemic Therapy
Multiple cytotoxic chemotherapeutic drugs have been used to treat intracranial metastases from NSCLC. Several factors have significantly limited the potential efficacy of such agents. Most chemotherapeutic agents do not cross the blood–brain barrier sufficiently to allow for cytocidal levels in the cerebrospinal fluid (CSF) or brain parenchyma. Those agents that provide adequate CSF levels, such as the high doses of methotrexate or cytarabine as utilized in hematologic malignancies, are minimally active against NSCLC, despite being structurally related to pemetrexed and gemcitabine, respectively, which have demonstrated activity in NSCLC. Additionally, adequate CSF levels do not insure adequate parenchymal penetration.
Several agents have been evaluated which do provide CNS responses in other solid tumor malignancies, including temozolomide, topotecan, and capecitabine ( ). However, the majority of reported clinical experience is in primary CNS tumors (temozolomide) or metastases from other sites, such as small cell lung cancer (topotecan) or breast cancer (capecitabine). With respect to temozolomide, the experience does appear to be modest in most, though not all, of the trials reported of patients with brain metastases from NSCLC. Topotecan does have some activity in NSCLC, but is only approved for SCLC. Capecitabine is approved for treatment of breast cancer and gastrointestinal malignancies, though it is often substituted for 5-fluorouracil in a variety of treatment regimens. However, there are very few data on the activity of capecitabine in NSCLC. Pemetrexed demonstrated benefit in 32 of 39 patients with intracranial metastases in a report by . This deserves confirmation in a larger trial, though it should be noted that pemetrexed is inactive in the squamous cell type of NSCLC.
Targeted Therapy
The discovery of molecular targets within subgroups of neoplasms, some of which are heavily dependent upon a specific aberrantly activated oncogene or pathway, has opened up new opportunities for clinically beneficial treatment. “Targeted therapy”, that is, the development of drugs designed to take advantage of specific molecular differences between malignant and normal cells, has existed since the development of agents to interrupt sex steroid signal transduction in subsets of breast and prostate cancer. Recently, a growing number of such targets have been identified in other solid tumors. Data obtained over the past several years have led to a better appreciation of the importance of histology in NSCLC, but even more so, the molecular subtype. For example, specific gene mutations or rearrangements have been identified in over half of all adenocarcinomas, many of which can be targeted with clinically available drugs. More recently, squamous cell carcinomas have likewise been divided into multiple subtypes by activated pathway; in fact, 96% of such NSCLC squamous cell subtypes contained potentially druggable activated tyrosine or serine/threonine kinases ( ). Many of these targeted drugs have been evaluated in a variety of neoplasms, and many have demonstrated an ability to provide some clinical benefit in the treatment of intracranial metastases. However, only two such pathways have been investigated in NSCLC to the point where specific agents are now commercially available: (1) the epidermal growth factor receptor (EGFR) pathway and, in particular, EGFR activating mutations in exons 19 and 21, which are potently inhibited by the small molecule tyrosine kinase inhibitors erlotinib (Tarceva) and gefitinib (Iressa); (2) activating anaplastic lymphoma kinase (ALK) gene rearrangements, which are blocked by crizotinib (Xalkori). Erlotinib and gefitinib exert their antitumor activity by binding to the ATP-binding site of the tyrosine kinase domain of the EGFR. This prevents auto/transphosphorylation of the receptors, which is needed for activation of the downstream signal cascade, thereby stopping tumor cell proliferation. In the following sections, we will review trials of the two best studied EGFR-TKIs, gefitinib and erlotinib.
Trials of Gefitinib
The efficacy of gefitinib in patients with NSCLC and brain metastases initially was suggested by several case reports. Thereafter, multiple retrospective or prospective trials evaluated the use of gefitinib in this patient population. In a prospective trial of 41 patients with NSCLC and brain metastases, patients who were treated with gefitinib achieved a median progression-free survival (PFS) and OS of 3 and 5 months, respectively. Four (10%) patients had partial response (PR) and seven (17%) had stable disease (SD) yielding a 27% disease control (DC) rate. Patients who had previously received WBRT attained a significantly higher DC rate than radio-naïve patients ( p =0.0006). Finally, adenocarcinoma histology was significantly ( p =0.04) associated with longer PFS ( ).
In another prospective study, 40 patients with brain metastases, all with adenocarcinoma histology and previously treated with chemotherapy, received gefitinib at 250 mg daily. The study showed a 32% objective response rate and 77% DC. The median PFS and OS were 9 and 15 months, respectively. Patients who had been treated previously with WBRT had significantly ( p =0.041) improved OS. Similarly, female gender was associated with a significantly improved overall survival, with a male to female hazard ratio of 3.29 (95% CI, 1.36–7.96 p =0.008) ( ).
in a retrospective analysis on 14 NSCLC with brain metastases found 100% DC rate after treatment with gefitinib. The median PFS and median OS for these patients were 8.8 and 9.1 months, respectively. Of these, seven patients simultaneously expressed objective responses to both intra- and extracranial lesions, suggesting the possible correlation between sensitivity of brain metastases to gefitinib and that of extracranial tumors.
None of the patients in these studies were selected for having clinical characteristics associated with increased sensitivity to gefitinib, such as East-Asian ethnicity, female gender and never-smokers, or were molecularly selected for having specific activating EGFR mutations. However, with the striking discovery of the role of EGFR mutations in the responsiveness of patients to EGFR-TKIs, clinical trials conducted thereafter focused on this issue.
In a retrospective study of eight patients with NSCLC and brain metastases harboring EGFR activating mutations in which mutation status was determined by sampling of the primary tumor before the treatment was initiated, patients were treated with gefitinib, five patients experienced objective tumor response in brain lesions. In contrast, in all the remaining three patients in whom no objective tumor response was detected, EGFR mutation was not found ( ). Another retrospective analysis identified 14 patients with NSCLC and brain metastases receiving standard dose gefitinib, to assess the importance of EGFR mutation to the CNS response to this drug. Nine out of 14 (65%) with brain metastases and 30 out of 96 (31%) without brain metastases had mutant EGFR genotypes suggesting that development of brain metastases may correlate with EGFR mutation status ( p <0.05). Eight out of nine (89%) patients with EGFR mutation and brain metastases objectively responded to gefitinib, highlighting the role of patient selection based on mutation status ( ). As we see in these trials, gefitinib has acceptable efficacy in brain metastases in NSCLC patients who harbor an EGFR mutation.
Trials of Erlotinib
To assess the efficacy of erlotinib in NSCLC patients with brain metastases, several trials have been conducted in East-Asian patients selected either as having a clinical determinant of sensitivity to EGFR-TKIs or having an activating EGFR mutation. In a retrospective study evaluating the efficacy of erlotinib or gefitinib in 23 chemo-naïve, never-smoking Korean patients with lung adenocarcinoma and asymptomatic synchronous brain metastases (EGFR mutation status was undefined), the use of erlotinib was associated with 6.5 and 10.4 months PFS and OS, respectively ( ).
In another retrospective analysis, 69 patients with NSCLC and brain metastases receiving erlotinib were studied to elucidate the role of EGFR mutation in sensitizing patients to the drug. Seventeen out of 69 patients were found to have an activating EGFR mutation. Most of the patients with EGFR mutations also had clinical determinants of EGFR-TKIs sensitivity [female gender (65%); never-smoker (65%); adenocarcinoma histology (80%)]. The objective response rate in these patients was 82%, of which 47% showed complete resolution of the brain tumors. Interestingly, no objective response was detected in the remaining unselected control group in which EGFR mutational status was either unknown or wild-type, resulting in a significant difference in favor of erlotinib use in patients harboring EGFR mutation ( p <0.001). With respect to extracranial disease, all patients with a mutant EGFR achieved an extracranial tumor response or stabilization of disease. The median time to progression in patients with EGFR mutations was significantly ( p <0.05) higher (11.7 months) than in those without activating mutations (5.8 months). Similarly, patients harboring EGFR mutations had a significantly higher OS of 12.9 months compared to 3.1 months in patients with a wild-type EGFR ( p <0.001) ( ).
In a phase II study on the efficacy of erlotinib or gefitinib in patients with EGFR mutations, 28 individuals with EGFR mutant NSCLC and measurable brain metastases were enrolled. The rates of objective response and DC in brain metastases were 83% and 93%, respectively. Furthermore, after a median follow-up time of 17.5 months, median PFS and OS were 6.6 and 15.9 months, respectively. There were no statistically significant differences between treatment outcomes with either agent ( ).
Finally, in a more recently phase II study in which erlotinib was used as second-line treatment after failure of first-line chemotherapy in 48 patients with NSCLC and brain metastases, the objective response rate in the brain metastases was 56%, and the median PFS was higher in patients with (23.2 months) than without (8.2 months) EGFR mutations ( p =0.06) ( ).
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