Lung Cancer 86 (2014) 112–114
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Letters to the Editor
Lung cancer in the era of Greek economic crisis Dear Editor, Nikos, a 63-year-old gentleman presented to our clinic with a 12-month history of chest pain and a 9-month history of a progressively enlarged mass of the left hemi-thorax. The last three months the pain intensity score was reported to be 9–10, with 10 indicating the worst pain ever. Physical examination revealed an 18 cm mass fixed to the thorax. A specimen of the mass obtained through core biopsy revealed squamous cell lung cancer. The patient did not seek medical attention earlier because he did not want to loose any day from work. His four-member family was totally depended on his income after his wife and two children all lost their jobs to Greek economic crisis. This case illustrates how life in Greece has been turned on its head since the debt crisis commenced. But in few areas the change has been more striking than in health care. Until recently, Greece had a typical European health system, with employers and individuals contributing to a fund that with government assistance secured universal care. People who lost their jobs received health care and unemployment benefits for a year, but were still treated by hospitals if they could not afford to pay even after the benefits expired. Things changed in July 2011, when Greece signed a supplemental loan agreement with international lenders to avoid financial collapse. Now, as stipulated in the deal, Greeks must pay all costs out of pocket after their benefits expire. About half of Greece’s 1.2 million long-term unemployed lack health insurance, a number that is expected to explode in a country with 25 percent unemployment rate and a moribund economy, according to the Labor Institute of the General Confederation of Greek Workers. We were interested to study the crisis impact on lung cancer care, and we reviewed the medical records of 150 patients treated at the medical oncology department of our hospital for advanced nonsmall cell lung cancer, before the era of crisis (2008) and recently (2012). No difference was found regarding the performance status of patients at presentation, the proportion of patients who received costly medications (e.g. pemetrexed, bevacizumab), or in treatment outcome (progression-free and overall survival) in these two periods. Interestingly, no significant difference in the proportion of individuals with lack of insurance coverage was found among the patients treated for the same disease between years 2008 and 2009 (11 out of 354) and 2012–2013 (6 out of 340). These observations led us to the scary conclusion that uninsured patients have practically no access to the facilities of ESY (the national heath system) and are being forced to seek help outside the traditional health care system. However, for cancer care, with its lengthy and expensive treatment that might be a real challenge.
0169-5002/© 2014 Elsevier Ireland Ltd. All rights reserved.
The only hope for uninsured cancer patients and other ill people is the several surreptitious networks that have been set up during the last two years in every district of Athens and other big cities. These facilities operate off the official grid using only spare medicines donated by pharmacies, some pharmaceutical companies and the families of cancer patients who died. Sometimes, doctors found to help an uninsured person using hospital medicine and covering the cost from their own pockets. Volunteers from the Metropolitan Community Clinic of Helliniko, a makeshift medical center near an abandoned American Air Force base outside Athens, reported the reality for uninsured patients with cancer. All the patients who presented at the clinic with the diagnosis of cancer (62 males and 64 females, with 33 of them lung cancer) have not received any kind of anticancer treatment since diagnosis. Eighty percent of them knocked the door of the clinic four to eight months after the diagnosis. For a lung cancer patient this delay is approaching the median overall survival without treatment. All these needed chemotherapy and fifty percent radiation. Most of them received some kind of anticancer treatment thanks to spare medicines, at an off-hours infirmary at Sotiria hospital of Athens. Unfortunately, ten of them died within a month after presentation due to metastatic disease. Although the most powerful therapy might not be the medicines but the hope and the optimism these Robin Hood movements bring to those in need, there is no doubt that there is an expiration date. People at some point would not longer be able to volunteer or donate due to crisis, while the recently launched program funded by the National Strategic Reference Framework (NSRF), will meet needs of the uninsured hospital patients for a period of a few months. State authorities and the Troica (the International Monetary Fund and European Institutions), whose policy led Greece to the deepest and longest lasting economic recession in the history of the modern Western world must feel the pressure by the community and take responsibility and action.
Conflict of interest statement None to declare. Emmanouil Saloustros ∗ Medical Oncology Unit, General Hospital of Heraklion - ‘Venizelio’, Crete, Greece Georgios Vichas Metropolitan Community Cinic of Helliniko, Athens, Greece Anna Margiolaki Department of Medical Oncology, University Hospital of Heraklion, Crete, Greece
Letters to the Editor / Lung Cancer 86 (2014) 112–114
113
Sevasti Koumiotaki Department of Respiratory Medicine, General Hospital of Heraklion - ‘Venizelio’ Crete, Greece Nikolaos Androulakis Medical Oncology Unit, General Hospital of Heraklion - ‘Venizelio’, Crete, Greece Vassilis Georgoulias Department of Medical Oncology, University Hospital of Heraklion, Crete, Greece ∗ Corresponding
author at: Medical Oncology Unit, General Hospital of Heraklion - ‘Venizelio’, P.O. Box 44, 71409 Heraklion, Crete, Greece. Tel.: +30 2810 368158; fax: +30 2810 368053. E-mail address: [email protected] (E. Saloustros) 19 February 2014
http://dx.doi.org/10.1016/j.lungcan.2014.07.016
High exposure to erlotinib and severe druginduced interstitial lung disease in patients with non-small-cell lung cancer Keywords: Erlotinib Interstitial lung disease Pharmacokinetics High exposure ABCG2 Polymorphism
Erlotinib is a potent epidermal growth factor receptor tyrosine kinase inhibitor that is widely used to treat advanced nonsmall-cell lung cancer (NSCLC) [1]. Orally administered erlotinib shows large interindividual variability in its pharmacokinetics [2]. Although infrequent, severe and occasionally fatal interstitial lung disease (ILD) has been reported in patients who received erlotinib, and a relation between high plasma erlotinib concentrations and the development of ILD has been suggested [2]. Erlotinib is excreted into bile by ATP-binding cassette subfamily G member 2 (ABCG2). The natural allelic variant ABCG2 421C>A, which is associated with the decreased protein expression, has been linked to reduced clearance of erlotinib [2] and may thus be the underlying cause of severe erlotinib-induced pneumonia. We prospectively evaluated toxic effects and pharmacokinetics of erlotinib, and ABCG2 421C>A status in 25 patients with NSCLC (18 men and 7 women; median age 68 years, range 31–82) who received erlotinib in a dose of 150 mg once daily. Adverse events were classified according to the Common Terminology Criteria for Adverse Events, version. 4.0. Plasma erlotinib concentrations right before the erlotinib administration and 1, 2, 4, 8, and 24 h after the administration on day 1, and trough concentration (C0 ) on day 8 were analyzed by high-performance liquid chromatography as described by Faivre et al. [3], except that we used an Inertsil C8-3 analytical column (3.0 mm × 250 mm; 5 m; GL Sciences, Tokyo, Japan). The ABCG2 polymorphism was determined by direct sequencing. All patients gave written informed consent approved by the Institutional Review Board of Showa University. Among 25 patients evaluated, 3 patients suffered from severe ILD (≥ grade 4) within 8 days of erlotinib initiation. Especially, a 73-year-old man (patient A) had fatal erlotinib-related ILD with ground-glass opacity in the right lower lobe on day 7. Although erlotinib was immediately discontinued and corticosteroid pulse therapy administered, there was no improvement in respiratory
Fig. 1. Pharmacokinetics of erlotinib observed in 25 patients with NSCLC. Twentyfive patients with NSCLC received erlotinib in a dose of 150 mg once daily. Plasma erlotinib concentrations right before the erlotinib administration and 1, 2, 4, 8, and 24 h after the administration on day 1. Chain dashed line, patient A; chain double dashed line, patient B; dotted line, patient C.
failure, and the patient died of an acute exacerbation of ILD several days later. The other 78- and 80-year-old female patients (patients B and C) suffered from grade 4 ILD on day 7 and 8, respectively. The pharmacokinetic profiles of erlotinib on day 1 in 25 patients are shown in Fig. 1. The median area under the plasma concentration–time curve of erlotinib estimated from 0 to 24 h (AUC0–24 ) was 69.1 (range, 35.5–123) M h. The patients A and B showed the highest and the third highest erlotinib AUC0–24 (123 and 112 M h, respectively). Although patient C showed the lowest AUC0–24 (35.5 M h), the plasma concentration continuously increased after the erlotinib administration, and the maximum plasma concentration in patient C was observed at 24 h after the erlotinib administration (dotted line in Fig. 1). This atypical erlotinib pharmacokinetics in patient C resulted in the accumulation of erlotinib and the C0 on day 8 in this patient was the third highest (8.20 M) among patients examined (median 5.84 (range 3.51–8.33) M, n = 21). C0 values on day 8 were not available for patients A and B because of the onset of ILD on day 7. Our pharmacogenetic analysis revealed that the patient A was homozygous for ABCG2 C>A. Patients homozygous for ABCG2 C>A might have decreased elimination of erlotinib [2], resulting in very high exposure to the drug, potentially leading to fatal ILD. These results suggest that the high exposure to erlotinib, which is possibly related to functional ABCG2 polymorphism, makes patients prone to suffer from drug-induced severe ILD. The allele frequency of ABCG2 C>A in Japanese (∼30%) is higher than that in whites (∼10%) [4]. This difference might be related to higher incidence of ILD-like events in Japanese patients (∼5%) [5] than in patients in the United States (∼1%) [6]. However, the susceptibility to the adverse reaction must be determined not only by pharmacokinetics but also by toxicological properties of the drug. To date, unfortunately, underlying toxicological mechanism for the erlotinib-induced ILD was not fully elucidated. Further systematic studies are warranted to clarify these critical issues. Conflict of interest The authors have no conflict of interest to declare. Acknowledgements This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan [23-A-16 to YS]; and in part by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (JSPS) [23590648 to TH].
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Letters to the Editor
Lung cancer in the era of Greek economic crisis Dear Editor, Nikos, a 63-year-old gentleman presented to our clinic with a 12-month history of chest pain and a 9-month history of a progressively enlarged mass of the left hemi-thorax. The last three months the pain intensity score was reported to be 9–10, with 10 indicating the worst pain ever. Physical examination revealed an 18 cm mass fixed to the thorax. A specimen of the mass obtained through core biopsy revealed squamous cell lung cancer. The patient did not seek medical attention earlier because he did not want to loose any day from work. His four-member family was totally depended on his income after his wife and two children all lost their jobs to Greek economic crisis. This case illustrates how life in Greece has been turned on its head since the debt crisis commenced. But in few areas the change has been more striking than in health care. Until recently, Greece had a typical European health system, with employers and individuals contributing to a fund that with government assistance secured universal care. People who lost their jobs received health care and unemployment benefits for a year, but were still treated by hospitals if they could not afford to pay even after the benefits expired. Things changed in July 2011, when Greece signed a supplemental loan agreement with international lenders to avoid financial collapse. Now, as stipulated in the deal, Greeks must pay all costs out of pocket after their benefits expire. About half of Greece’s 1.2 million long-term unemployed lack health insurance, a number that is expected to explode in a country with 25 percent unemployment rate and a moribund economy, according to the Labor Institute of the General Confederation of Greek Workers. We were interested to study the crisis impact on lung cancer care, and we reviewed the medical records of 150 patients treated at the medical oncology department of our hospital for advanced nonsmall cell lung cancer, before the era of crisis (2008) and recently (2012). No difference was found regarding the performance status of patients at presentation, the proportion of patients who received costly medications (e.g. pemetrexed, bevacizumab), or in treatment outcome (progression-free and overall survival) in these two periods. Interestingly, no significant difference in the proportion of individuals with lack of insurance coverage was found among the patients treated for the same disease between years 2008 and 2009 (11 out of 354) and 2012–2013 (6 out of 340). These observations led us to the scary conclusion that uninsured patients have practically no access to the facilities of ESY (the national heath system) and are being forced to seek help outside the traditional health care system. However, for cancer care, with its lengthy and expensive treatment that might be a real challenge.
0169-5002/© 2014 Elsevier Ireland Ltd. All rights reserved.
The only hope for uninsured cancer patients and other ill people is the several surreptitious networks that have been set up during the last two years in every district of Athens and other big cities. These facilities operate off the official grid using only spare medicines donated by pharmacies, some pharmaceutical companies and the families of cancer patients who died. Sometimes, doctors found to help an uninsured person using hospital medicine and covering the cost from their own pockets. Volunteers from the Metropolitan Community Clinic of Helliniko, a makeshift medical center near an abandoned American Air Force base outside Athens, reported the reality for uninsured patients with cancer. All the patients who presented at the clinic with the diagnosis of cancer (62 males and 64 females, with 33 of them lung cancer) have not received any kind of anticancer treatment since diagnosis. Eighty percent of them knocked the door of the clinic four to eight months after the diagnosis. For a lung cancer patient this delay is approaching the median overall survival without treatment. All these needed chemotherapy and fifty percent radiation. Most of them received some kind of anticancer treatment thanks to spare medicines, at an off-hours infirmary at Sotiria hospital of Athens. Unfortunately, ten of them died within a month after presentation due to metastatic disease. Although the most powerful therapy might not be the medicines but the hope and the optimism these Robin Hood movements bring to those in need, there is no doubt that there is an expiration date. People at some point would not longer be able to volunteer or donate due to crisis, while the recently launched program funded by the National Strategic Reference Framework (NSRF), will meet needs of the uninsured hospital patients for a period of a few months. State authorities and the Troica (the International Monetary Fund and European Institutions), whose policy led Greece to the deepest and longest lasting economic recession in the history of the modern Western world must feel the pressure by the community and take responsibility and action.
Conflict of interest statement None to declare. Emmanouil Saloustros ∗ Medical Oncology Unit, General Hospital of Heraklion - ‘Venizelio’, Crete, Greece Georgios Vichas Metropolitan Community Cinic of Helliniko, Athens, Greece Anna Margiolaki Department of Medical Oncology, University Hospital of Heraklion, Crete, Greece
Letters to the Editor / Lung Cancer 86 (2014) 112–114
113
Sevasti Koumiotaki Department of Respiratory Medicine, General Hospital of Heraklion - ‘Venizelio’ Crete, Greece Nikolaos Androulakis Medical Oncology Unit, General Hospital of Heraklion - ‘Venizelio’, Crete, Greece Vassilis Georgoulias Department of Medical Oncology, University Hospital of Heraklion, Crete, Greece ∗ Corresponding
author at: Medical Oncology Unit, General Hospital of Heraklion - ‘Venizelio’, P.O. Box 44, 71409 Heraklion, Crete, Greece. Tel.: +30 2810 368158; fax: +30 2810 368053. E-mail address: [email protected] (E. Saloustros) 19 February 2014
http://dx.doi.org/10.1016/j.lungcan.2014.07.016
High exposure to erlotinib and severe druginduced interstitial lung disease in patients with non-small-cell lung cancer Keywords: Erlotinib Interstitial lung disease Pharmacokinetics High exposure ABCG2 Polymorphism
Erlotinib is a potent epidermal growth factor receptor tyrosine kinase inhibitor that is widely used to treat advanced nonsmall-cell lung cancer (NSCLC) [1]. Orally administered erlotinib shows large interindividual variability in its pharmacokinetics [2]. Although infrequent, severe and occasionally fatal interstitial lung disease (ILD) has been reported in patients who received erlotinib, and a relation between high plasma erlotinib concentrations and the development of ILD has been suggested [2]. Erlotinib is excreted into bile by ATP-binding cassette subfamily G member 2 (ABCG2). The natural allelic variant ABCG2 421C>A, which is associated with the decreased protein expression, has been linked to reduced clearance of erlotinib [2] and may thus be the underlying cause of severe erlotinib-induced pneumonia. We prospectively evaluated toxic effects and pharmacokinetics of erlotinib, and ABCG2 421C>A status in 25 patients with NSCLC (18 men and 7 women; median age 68 years, range 31–82) who received erlotinib in a dose of 150 mg once daily. Adverse events were classified according to the Common Terminology Criteria for Adverse Events, version. 4.0. Plasma erlotinib concentrations right before the erlotinib administration and 1, 2, 4, 8, and 24 h after the administration on day 1, and trough concentration (C0 ) on day 8 were analyzed by high-performance liquid chromatography as described by Faivre et al. [3], except that we used an Inertsil C8-3 analytical column (3.0 mm × 250 mm; 5 m; GL Sciences, Tokyo, Japan). The ABCG2 polymorphism was determined by direct sequencing. All patients gave written informed consent approved by the Institutional Review Board of Showa University. Among 25 patients evaluated, 3 patients suffered from severe ILD (≥ grade 4) within 8 days of erlotinib initiation. Especially, a 73-year-old man (patient A) had fatal erlotinib-related ILD with ground-glass opacity in the right lower lobe on day 7. Although erlotinib was immediately discontinued and corticosteroid pulse therapy administered, there was no improvement in respiratory
Fig. 1. Pharmacokinetics of erlotinib observed in 25 patients with NSCLC. Twentyfive patients with NSCLC received erlotinib in a dose of 150 mg once daily. Plasma erlotinib concentrations right before the erlotinib administration and 1, 2, 4, 8, and 24 h after the administration on day 1. Chain dashed line, patient A; chain double dashed line, patient B; dotted line, patient C.
failure, and the patient died of an acute exacerbation of ILD several days later. The other 78- and 80-year-old female patients (patients B and C) suffered from grade 4 ILD on day 7 and 8, respectively. The pharmacokinetic profiles of erlotinib on day 1 in 25 patients are shown in Fig. 1. The median area under the plasma concentration–time curve of erlotinib estimated from 0 to 24 h (AUC0–24 ) was 69.1 (range, 35.5–123) M h. The patients A and B showed the highest and the third highest erlotinib AUC0–24 (123 and 112 M h, respectively). Although patient C showed the lowest AUC0–24 (35.5 M h), the plasma concentration continuously increased after the erlotinib administration, and the maximum plasma concentration in patient C was observed at 24 h after the erlotinib administration (dotted line in Fig. 1). This atypical erlotinib pharmacokinetics in patient C resulted in the accumulation of erlotinib and the C0 on day 8 in this patient was the third highest (8.20 M) among patients examined (median 5.84 (range 3.51–8.33) M, n = 21). C0 values on day 8 were not available for patients A and B because of the onset of ILD on day 7. Our pharmacogenetic analysis revealed that the patient A was homozygous for ABCG2 C>A. Patients homozygous for ABCG2 C>A might have decreased elimination of erlotinib [2], resulting in very high exposure to the drug, potentially leading to fatal ILD. These results suggest that the high exposure to erlotinib, which is possibly related to functional ABCG2 polymorphism, makes patients prone to suffer from drug-induced severe ILD. The allele frequency of ABCG2 C>A in Japanese (∼30%) is higher than that in whites (∼10%) [4]. This difference might be related to higher incidence of ILD-like events in Japanese patients (∼5%) [5] than in patients in the United States (∼1%) [6]. However, the susceptibility to the adverse reaction must be determined not only by pharmacokinetics but also by toxicological properties of the drug. To date, unfortunately, underlying toxicological mechanism for the erlotinib-induced ILD was not fully elucidated. Further systematic studies are warranted to clarify these critical issues. Conflict of interest The authors have no conflict of interest to declare. Acknowledgements This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan [23-A-16 to YS]; and in part by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (JSPS) [23590648 to TH].
