Erlotinib Accumulation in Brain Metastases from Non-small Cell Lung Cancer: Visualization by Positron Emission Tomography in a Patient Harboring a Mutation in the Epidermal Growth Factor Receptor

Weber, Britta; Winterdahl, Michael; Memon, Ashfaque A.; Sørensen, Boe Sandahl; Keiding, Susanne; Sørensen, Leif Hovgaard; Nexø, Ebba; Meldgaard, Peter

doi:10.1097/jto.0b013e318219ab87

Cited by 117 publications

(79 citation statements)

References 14 publications

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“…However, when brain parenchymal metastases grow to >1-2 mm in diameter, the structure and function of the blood-brain barrier is disrupted, allowing drugs to enter the brain parenchyma (14). Weber et al (15) used the 11 C-marked erlotinib as a tracer with PET/CT to monitor a patient with brain metastasis from non-small-cell lung cancer. The results revealed that a high concentration of 11 C-marked erlotinib was detected in the patient's cerebellar metastasis, whereas no 11 C-marked erlotinib was detected in normal brain tissue.…”

Section: Discussionmentioning

confidence: 99%

The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer

Deng

Feng

et al. 2013

Molecular and Clinical Oncology

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Abstract. It has been demonstrated that erlotinib is effective in treating patients with brain metastasis from non-small-cell lung cancer. However, the number of studies determining the erlotinib concentration in these patients is limited. The purpose of this study was to measure the concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung carcinoma. Six patients were treated with the standard recommended daily dose of erlotinib (150 mg) for 4 weeks. All the patients had previously received chemotherapy, but no brain radiotherapy. At the end of the treatment period, blood plasma and cerebrospinal fluid samples were collected and the erlotinib concentration was determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS̸MS). The average erlotinib concentration in the blood plasma and the cerebrospinal fluid was 717.7±459.7 and 23.7±13.4 ng/ml, respectively. The blood-brain barrier permeation rate of erlotinib was found to be 4.4±3.2%. In patients with partial response (PR), stable disease (SD) and progressive disease (PD), the average concentrations of erlotinib in the cerebrospinal fluid were 35.5±19.0, 19.1±8.7 and 16.4±5.9 ng/ml, respectively. In addition, the efficacy rate of erlotinib for metastatic brain lesions was 33.3%, increasing to 50% in patients with EGFR mutations. However, erlotinib appeared to be ineffective in cases with wild-type EGFR. In conclusion, a relatively high concentration of erlotinib was detected in the cerebrospinal fluid of patients with brain metastases from non-small-cell lung cancer. Thus, erlotinib may be considered as a treatment option for this patient population.

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Section: Discussionmentioning

confidence: 99%

The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer

Deng

Feng

et al. 2013

Molecular and Clinical Oncology

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“…11 C]-erlotinib has shown effective erlotinib distribution to CNS metastases but not normal brain (31). The failure of some patients to benefit from erlotinib may be explained by the expression of efflux proteins both in the BBB and in the tumor cell membrane.…”

Section: Systemic Therapy Including Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

“…The gefitinib CSF exposure was 2.4% that of plasma, similar to previous reports (35). The CSF levels in such studies are likely to underestimate drug exposure within the tumor in the context of a disrupted BBB (31).…”

Section: Systemic Therapy Including Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Epidermal Growth Factor Receptor–Mutant Non–Small Cell Lung Cancer Metastatic to the Brain

Jamal‐Hanjani

Spicer

2012

Clinical Cancer Research

135

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Brain metastases are a common and devastating consequence of disease progression in patients with nonsmall cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib have shown efficacy in patients with NSCLC and brain metastases. The cerebrospinal fluid (CSF) exposure to these drugs is a small fraction of the plasma levels achieved with standard doses, but disruption of the blood-brain barrier in the presence of central nervous system metastases is likely to lead to locally increased drug concentration, and dose escalation to boost CSF exposure has documented clinical efficacy. The use of gefitinib and erlotinib in this setting is reviewed here, including evidence from case reports, case series, and single-arm phase II trials. High response rates in the brain are seen in patients with EGFR mutation, or in populations in which this genotype is expected. By contrast, activity in the context of documented wild-type EGFR in disease metastatic to the brain is not common. These drugs may potentiate the effectiveness of radiotherapy to the brain, and their use may also delay development of disease within the brain. Clin Cancer Res; 18(4); 938-44. Ó2011 AACR.

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“…12 The clinical use of EGFR inhibitors with concurrent radiation therapy is currently being investigated in several trials, including the Radiation Therapy Oncology Group 0617 (RTOG 0617) trial. Because the small-molecule EGFR inhibitor erlotinib has shown some evidence of blood-brain barrier penetration, 15,16 we hypothesized that EGFR inhibition could be combined with WBRT to enhance the therapeutic ratio by selectively targeting the cancer cells within the brain, thereby extending survival without increasing the neurotoxicity associated with WBRT. We tested this hypothesis in NCT00871923 [Tarceva With Whole Brain Radiation Therapy-Brain Mets From Non-Small Cell Lung Cancer], a phase II clinical trial of erlotinib and concurrent WBRT for patients with brain metastases from NSCLC.…”

Section: Journal Of Clinical Oncology O R I G I N a L R E P O R T V Omentioning

confidence: 99%

Phase II Trial of Erlotinib Plus Concurrent Whole-Brain Radiation Therapy for Patients With Brain Metastases From Non–Small-Cell Lung Cancer

Welsh

Komaki

Amini

et al. 2013

JCO

357

246

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A B S T R A C T PurposeBrain metastasis (BM) is a leading cause of death from non-small-cell lung cancer (NSCLC). Reasoning that activation of the epidermal growth factor receptor (EGFR) contributes to radiation resistance, we undertook a phase II trial of the EGFR inhibitor erlotinib with whole-brain radiation therapy (WBRT) in an attempt to extend survival time for patients with BM from NSCLC. Additional end points were radiologic response and safety. Patients and MethodsEligible patients had BM from NSCLC, regardless of EGFR status. Erlotinib was given at 150 mg orally once per day for 1 week, then concurrently with WBRT (2.5 Gy per day 5 days per week, to 35 Gy), followed by maintenance. EGFR mutation status was tested by DNA sequencing at an accredited core facility. ResultsForty patients were enrolled and completed erlotinib plus WBRT (median age, 59 years; median diagnosis-specific graded prognostic assessment score, 1.5). The overall response rate was 86% (n ϭ 36). No increase in neurotoxicity was detected, and no patient experienced grade Ն 4 toxicity, but three patients required dose reduction for grade 3 rash. At a median follow-up of 28.5 months (for living patients), median survival time was 11.8 months (95% CI, 7.4 to 19.1 months). Of 17 patients with known EGFR status, median survival time was 9.3 months for those with wild-type EGFR and 19.1 months for those with EGFR mutations. ConclusionErlotinib was well tolerated in combination with WBRT, with a favorable objective response rate. The higher-than-expected rate of EGFR mutations in these unselected patients raises the possibility that EGFR-mutated tumors are prone to brain dissemination. J Clin

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Erlotinib Accumulation in Brain Metastases from Non-small Cell Lung Cancer: Visualization by Positron Emission Tomography in a Patient Harboring a Mutation in the Epidermal Growth Factor Receptor

Abstract: Our data demonstrated that erlotinib accumulated in brain metastases in a NSCLC patient who responded to the treatment.

Cited by 117 publications

References 14 publications

The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer

The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Epidermal Growth Factor Receptor–Mutant Non–Small Cell Lung Cancer Metastatic to the Brain

Phase II Trial of Erlotinib Plus Concurrent Whole-Brain Radiation Therapy for Patients With Brain Metastases From Non–Small-Cell Lung Cancer

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