Early reportHigh-dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases—One with a remarkable thoracic response as well
Introduction
EGFR-mutated NSCLC is associated with a favourable prognosis, high rate of response to EGFR-TKI's and consequently improved overall survival when compared to other subtypes of NSCLC. However, after an initial response to EGFR-TKI's, progression of disease is inevitable. A substantial number of patients develop CNS metastases, in some series up to 30%. CNS metastases are associated with disabling neurological symptoms, deterioration of performance status and poor survival. Traditionally, treatment of CNS metastases consists of radiotherapy and in selected cases, surgery. Systemic treatment is believed to have a limited role, due to the blood–brain barrier (BBB). Since EGFR TKI's are a substrate of P-glycoprotein, the BBB is preventing pharmacological dose of EGFR TKI's at standard dosing regimes to be reached in the CNS. Due to this lower drug concentration, selective pressure in the CNS is different and acquired resistance mechanisms that are often demonstrated in metastases outside the CNS are believed to be less common in CNS metastases. Hence, these metastases would still be sensitive to EGFR-TKI-treatment, if only sufficient penetration of these drugs into the CNS could be achieved. Theoretically, administering TKI's in a higher dose could achieve higher concentrations in the cerebrospinal fluid. This strategy has been applied before, with encouraging results [1], [2], [3], [4], [5], [6]. Here, we report two EGFR-mutated NSCLC-patients with leptomeningeal metastases successfully treated with high-dose, weekly erlotinib, one with a remarkable response of intrathoracic disease as well.
Section snippets
Case 1
A 49-year old, Creole female underwent a lobectomy of the left upper lobe in 2006 because of adenocarcinoma followed by adjuvant radiotherapy. In 2009 a local recurrence was diagnosed and mutational analysis showed an EGFR mutation exon 21 (L858R). She was treated with erlotinib on which she maintained stable disease for 12 months. In 2010 she developed single-site progression of a left supraclavicular lymph node. Biopsy revealed adenocarcinoma, with weak detection of the former L858R mutation,
Case 2
The second patient is a female patient of 51 years old diagnosed with stage IV NSCLC in 2008. An EGFR mutation was detected in exon 19 (del 747–752 (P753S)). She has been treated with erlotinib in combination with sorafenib, single agent erlotinib and afatinib in combination with cetuximab chronologically. After progression on the latter regimen in March 2012 she was treated with 2 cycles of cisplatin and pemetrexed at standard dose. A CT-scan showed stable disease of the intrathoracic lesions (
Discussion
Up to one third of EGFR-mutated NSCLC patients develop metastases in the CNS after initial successful treatment with an EGFR-TKI. Forty percent of these CNS metastases are leptomeningeal metastases [7]. Whereas leptomeningeal metastasis in EGFR-wild type NSCLC is associated with a dismal prognosis with a median survival of 3–4 months, median survival in EGFR-mutated NSCLC patients with leptomeningeal metastases is 7–14 months [8], [9]. Often, leptomeningeal metastases are diagnosed while other
Conflict of interest statement
The authors have declared they have no conflict of interest. Informed consent of both patients was acquired.
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Cited by (46)
Leptomeningeal metastasis
2018, Handbook of Clinical NeurologyCitation Excerpt :Long-duration responses have been reported with erlotinib after prior progression on gefitinib and vice versa in patients with LM (Choong et al., 2006; Katayama et al., 2009; Yi et al., 2009; Masuda et al., 2011; Hata et al., 2012; Park et al., 2012; Togashi et al., 2012b; Nakamichi et al., 2013; Xing et al., 2014; Kawamura et al., 2015). To achieve optimal intra-CSF concentrations, high-dose intermittent pulsatile schedule has been evaluated with gefitinib and erlotinib in LM patients (Omuro et al., 2005; Choong et al., 2006; Hashimoto et al., 2006; Kuiper and Smit, 2013; Xing et al., 2014; How et al., 2017). Both agents were safe and showed efficacy, including in patients who failed to respond to a previous EGFR TKI therapy at standard dose.
Emerging treatment paradigms for brain metastasis in non-small-cell lung cancer: An overview of the current landscape and challenges ahead
2017, Annals of OncologyCitation Excerpt :The possibility of ongoing TKI sensitivity in the CNS has engendered the strategy of dose escalation with pulsatile/high-dose treatment for progressive brain metastasis or leptomeningeal disease previously treated with standard-dose TKI. Although still largely experimental, several case reports have demonstrated activity and tolerability by using high-dose erlotinib and gefitinib (24,26–28). Despite the need for RCTs to define the optimal TKI drug and cranial radiation timing (both SRS and WBRT), based on the current evidence, we propose the use of erlotinib alongside SRS at initial presentation to treat symptomatic EGFR-mutant brain metastases given its increased CNS penetrability.
Management of brain metastasized non-small cell lung cancer (NSCLC) – From local treatment to new systemic therapies
2017, Cancer Treatment ReviewsCitation Excerpt :Gefitinib has also shown activity in NSCLC patients with brain metastases, with unknown EGFR mutational status, with CNS disease control rate ranging from 27% to 100% [52,53]. However, clinical evidence for efficacy of these agents in tumours affecting the CNS comes mainly from small prospective, retrospective observational studies and case-series [51,54–60] (Table 1). In general, EGFR-targeting agents have a low capacity to penetrate into the cerebrospinal fluid (CSF), although erlotinib achieved relatively higher level of CNS penetration, which might in part explain the improved control of brain metastasis that has been observed with erlotinib treatment, even in patients previously treated with gefitinib (Table 1) [61].
Systemic Treatment of Brain Metastases
2017, Hematology/Oncology Clinics of North AmericaCitation Excerpt :In contrast, high-dose pulsatile erlotinib, at doses of 1500 mg orally once a week, has been shown to achieve therapeutic concentrations in the CSF.59 Several case reports and small series have demonstrated the intracranial activity and tolerability of high-dose pulsatile erlotinib in patients with progressive CNS metastases.59–62 The largest of these studies, a case series of 9 patients, reported an RR of 67% and stable disease in 11%.60
Successful treatment with weekly high-dose erlotinib against meningeal metastases from epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma
2016, Respiratory InvestigationCitation Excerpt :On the other hand, since there is a possibility that the emergence of the T790M mutation in exon 20 was mediated by EGFR TKI exposure [6], we speculate that the limited concentration of EGFR TKIs in the CNS during previous treatments may account for the lack of the T790M mutation in exon 20 in CNS metastases in the present case. However, the primary lesion and pulmonary metastases did progress in the present case, consistent with the findings of a previous report demonstrating that weekly high-dose erlotinib was not effective in the resistant mutated lesions outside the CNS [4]. Weekly high-dose EGFR-TKIs may potentially be a therapeutic option in treatment for carcinomatous meningitis from EGFR-mutated lung adenocarcinoma.