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Activity of pemetrexed against brain metastases in a patient with adenocarcinoma of the lung
Lung Cancer 65 (2009) 383–384
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Short communication
Activity of pemetrexed against brain metastases in a patient with adenocarcinoma of the lung A. Omlin ∗ , G. D’Addario, S. Gillessen, T. Cerny, A. von Hessling, M. Früh Division of Oncology and Hematology, Cantonal Hospital St. Gallen, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland
a r t i c l e
i n f o
Article history: Received 12 March 2009 Accepted 16 March 2009 Keywords: Lung Cancer Pemetrexed Brain metastases
a b s t r a c t A 53-year-old woman was with adenocarcinoma of the lung metastatic to the brain was treated after several lines of chemotherapy with pemetrexed. After six cycles an impressive regression of the brain metastases was documented. A brief review of the literature on response of cerebral metastases to chemotherapy is added. © 2009 Elsevier Ireland Ltd. All rights reserved.
In January 2007, a 53-year-old otherwise healthy woman with a 40 pack year smoking history presented with dyspnea, chest pain and headache to our emergency department. She was diagnosed with stage IV adenocarcinoma of the lung with multiple small pumlonary lesions and several cerebral metastases of 0.5–1.7 cm in size. Because of compression of the right lateral ventricle, one metastasis was surgically removed followed by postoperative whole brain radiation therapy. In March 2007, she received four cycles of carboplatin and paclitaxel followed by six cycles of gemcitabine and vinorelbine and two months of erlotinib. Each of these therapies was stopped due to pulmonary progression. Twelve months after initial diagnosis, a routine brain MRI revealed multiple new asymptomatic bi-hemispheric lesions of up to 6 mm in size. A fourth-line chemotherapy with 3-weekly pemetrexed (Alimta@ ) in a dose of 500 mg/m2 with standard prophylactic co-medication including folic acid, vitamin B12 and dexamethason (for 3 days) was initiated. Reimaging after six cycles showed not only a partial remission of the lung lesions but also an impressive regression of all cerebral metastases including resolution of several lesions (Fig. 1). The patient currently shows no evidence of disease progression after twelve cycles. 1. Discussion Pemetrexed is a multitargeted antifolate that inhibits several enzymes in the folate pathway, resulting in decreased thymidine necessary for pyrimidine synthesis. Currently, pemetrexed
∗ Corresponding author. Tel.: +41 71 494 11 11; fax: +41 71 494 63 25. E-mail address: [email protected] (A. Omlin). 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.03.019
constitutes a commonly used standard second-line treatment and first-line treatment option in patients with metastatic nonsquamous cell non-small cell lung cancer (NSCLC) [1]. Brain metastases affect approximately 20–40% of all patients with NSCLC [2]. Irradiation and even surgery for selected patients with a limited number of brain lesions represent standard treatment options for these patients, whereas the role of systemic therapy remains unclear. Several smaller series described responses of brain metastases in patients with NSCLC treated with mono- or combination chemotherapy or new biological agents, namely gefitinib or erlotinibb [3]. These observations suggest that the protective role of the blood–brain barrier (BBB) may be limited to normal brain and micro-metastatic disease and may be disrupted in the presence of brain metastases and possibly also after previous radiotherapy. Molecular studies demonstrated that a P-glycoprotein (P-gp) is a major constituent of the blood–brain barrier acting as an effective efflux transporter protein [4]. In contrast to primary cerebral malignomas, brain metastases seem to express less P-gp leading to increased permeability of the BBB. To the best of our knowledge, this is the first report of a regression of brain metastases with pemetrexed. In preclinical studies, using simultaneous arterial blood and frontal cortex microdialysis sampling, pemetrexed showed a slightly higher brain penetration than methotrexate. However, based on pharmaco-kinetic studies, efficient efflux clearance processes were hypothesized [5]. In conclusion, pemetrexed is increasingly used in patients with metastatic NSCLC and therefore knowledge about its effect on brain metastases is clinically important. Based on our findings, pemetrexed may be a valuable treatment choice for selected patients with progressive brain metastases from adenocarcinoma of the lung in the absence of alternative treatment options.
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A. Omlin et al. / Lung Cancer 65 (2009) 383–384
Fig. 1. MRI images (axial T1 weighted sequences after iv Gadolinium) at the start of chemotherapy with pemetrexed (8.5.2008) and after six cycles of chemotherapy (23.9.2008). The metastasis frontal on the right side is markedly smaller and the metastases parieto-occipital on the left side almost completely disappeared.
Conflict of interest The enlisted authors do not have any conflict of interest. References [1] Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapynaive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008;26(21):3543–51.
[2] Adamo V, Franchina T, Adamo B, et al. Brain metastases in patients with non-small cell lung cancer: focus on the role of chemotherapy. Ann Oncol 2006;17:ii73–75. [3] Namba Y, Kijima T, Yokota S, et al. Gefitinib in patients with brain metastases from non-small-cell lung cancer: review of 15 clinical cases. Clin Lung Cancer 2004;6:123–8. [4] Gerstner ER, Fine RL. Increased permeability of the blood–brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol 2007;25:2306–12. [5] Dai H, Chen Y, Elmquist WF. Distribution of the novel antifolate pemetrexed to the brain. J Pharmacol Exp Ther 2005 October;315(1):222–9 [Epub 2005 June 29].
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Short communication
Activity of pemetrexed against brain metastases in a patient with adenocarcinoma of the lung A. Omlin ∗ , G. D’Addario, S. Gillessen, T. Cerny, A. von Hessling, M. Früh Division of Oncology and Hematology, Cantonal Hospital St. Gallen, Rorschacherstrasse 95, 9007 St. Gallen, Switzerland
a r t i c l e
i n f o
Article history: Received 12 March 2009 Accepted 16 March 2009 Keywords: Lung Cancer Pemetrexed Brain metastases
a b s t r a c t A 53-year-old woman was with adenocarcinoma of the lung metastatic to the brain was treated after several lines of chemotherapy with pemetrexed. After six cycles an impressive regression of the brain metastases was documented. A brief review of the literature on response of cerebral metastases to chemotherapy is added. © 2009 Elsevier Ireland Ltd. All rights reserved.
In January 2007, a 53-year-old otherwise healthy woman with a 40 pack year smoking history presented with dyspnea, chest pain and headache to our emergency department. She was diagnosed with stage IV adenocarcinoma of the lung with multiple small pumlonary lesions and several cerebral metastases of 0.5–1.7 cm in size. Because of compression of the right lateral ventricle, one metastasis was surgically removed followed by postoperative whole brain radiation therapy. In March 2007, she received four cycles of carboplatin and paclitaxel followed by six cycles of gemcitabine and vinorelbine and two months of erlotinib. Each of these therapies was stopped due to pulmonary progression. Twelve months after initial diagnosis, a routine brain MRI revealed multiple new asymptomatic bi-hemispheric lesions of up to 6 mm in size. A fourth-line chemotherapy with 3-weekly pemetrexed (Alimta@ ) in a dose of 500 mg/m2 with standard prophylactic co-medication including folic acid, vitamin B12 and dexamethason (for 3 days) was initiated. Reimaging after six cycles showed not only a partial remission of the lung lesions but also an impressive regression of all cerebral metastases including resolution of several lesions (Fig. 1). The patient currently shows no evidence of disease progression after twelve cycles. 1. Discussion Pemetrexed is a multitargeted antifolate that inhibits several enzymes in the folate pathway, resulting in decreased thymidine necessary for pyrimidine synthesis. Currently, pemetrexed
∗ Corresponding author. Tel.: +41 71 494 11 11; fax: +41 71 494 63 25. E-mail address: [email protected] (A. Omlin). 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.03.019
constitutes a commonly used standard second-line treatment and first-line treatment option in patients with metastatic nonsquamous cell non-small cell lung cancer (NSCLC) [1]. Brain metastases affect approximately 20–40% of all patients with NSCLC [2]. Irradiation and even surgery for selected patients with a limited number of brain lesions represent standard treatment options for these patients, whereas the role of systemic therapy remains unclear. Several smaller series described responses of brain metastases in patients with NSCLC treated with mono- or combination chemotherapy or new biological agents, namely gefitinib or erlotinibb [3]. These observations suggest that the protective role of the blood–brain barrier (BBB) may be limited to normal brain and micro-metastatic disease and may be disrupted in the presence of brain metastases and possibly also after previous radiotherapy. Molecular studies demonstrated that a P-glycoprotein (P-gp) is a major constituent of the blood–brain barrier acting as an effective efflux transporter protein [4]. In contrast to primary cerebral malignomas, brain metastases seem to express less P-gp leading to increased permeability of the BBB. To the best of our knowledge, this is the first report of a regression of brain metastases with pemetrexed. In preclinical studies, using simultaneous arterial blood and frontal cortex microdialysis sampling, pemetrexed showed a slightly higher brain penetration than methotrexate. However, based on pharmaco-kinetic studies, efficient efflux clearance processes were hypothesized [5]. In conclusion, pemetrexed is increasingly used in patients with metastatic NSCLC and therefore knowledge about its effect on brain metastases is clinically important. Based on our findings, pemetrexed may be a valuable treatment choice for selected patients with progressive brain metastases from adenocarcinoma of the lung in the absence of alternative treatment options.
384
A. Omlin et al. / Lung Cancer 65 (2009) 383–384
Fig. 1. MRI images (axial T1 weighted sequences after iv Gadolinium) at the start of chemotherapy with pemetrexed (8.5.2008) and after six cycles of chemotherapy (23.9.2008). The metastasis frontal on the right side is markedly smaller and the metastases parieto-occipital on the left side almost completely disappeared.
Conflict of interest The enlisted authors do not have any conflict of interest. References [1] Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapynaive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008;26(21):3543–51.
[2] Adamo V, Franchina T, Adamo B, et al. Brain metastases in patients with non-small cell lung cancer: focus on the role of chemotherapy. Ann Oncol 2006;17:ii73–75. [3] Namba Y, Kijima T, Yokota S, et al. Gefitinib in patients with brain metastases from non-small-cell lung cancer: review of 15 clinical cases. Clin Lung Cancer 2004;6:123–8. [4] Gerstner ER, Fine RL. Increased permeability of the blood–brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol 2007;25:2306–12. [5] Dai H, Chen Y, Elmquist WF. Distribution of the novel antifolate pemetrexed to the brain. J Pharmacol Exp Ther 2005 October;315(1):222–9 [Epub 2005 June 29].