- Email: [email protected]
Successful empirical erlotinib treatment of a mechanically ventilated patient newly diagnosed with metastatic lung adenocarcinoma
Lung Cancer 86 (2014) 102–104
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Case report
Successful empirical erlotinib treatment of a mechanically ventilated patient newly diagnosed with metastatic lung adenocarcinoma Joaquim Bosch-Barrera a,b,c,∗,1 , Elia Sais a,1 , Carol Lorencio d , Rut Porta a,b,c , Angel Izquierdo a,b , Javier A. Menéndez b,e , Joan Brunet a,b,c , Josep Maria Sirvent d , Rafael Rosell f,∗∗ a
Department of Medical Oncology, Catalan Institute of Oncology, Doctor Josep Trueta University Hospital, Girona, Spain Girona Biomedical Research Institute (IDIBGi), Girona, Catalonia, Spain c Department of Medical Sciences, Medical School, University of Girona, Girona, Spain d Intensive Care Unit, Doctor Josep Trueta University Hospital, Girona, Spain e Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia, Spain f Department of Medical Oncology, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain b
a r t i c l e
i n f o
Article history: Received 8 July 2014 Accepted 13 July 2014 Keywords: Non-small-cell lung cancer Erlotinib Nasogastric tube EGFR mutation Critically ill patient Intensive care unit Mechanical ventilation
a b s t r a c t Background: Lung cancer is the most common solid tumor in critically ill cancer patients who are admitted to intensive care units (ICUs). An ICU trial consists of unlimited ICU support for a limited time period. Case report: We present the case of a 60-year-old woman with newly diagnosed metastatic lung adenocarcinoma who required mechanical ventilation due to respiratory failure. Empirical erlotinib treatment was administered through a nasogastric feeding tube as part of an ICU trial, which led to a dramatic and durable response. Conclusion: Empirical erlotinib should be considered when epidermal growth factor receptor (EGFR) mutations are suspected in ICU newly diagnosed patients with lung adenocarcinoma. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is the leading cause of cancer-related deaths worldwide and is the second most common cancer in both men and women [1]. Non-small-cell lung cancer (NSCLC) comprises up to 90% of all lung cancers, and the majority present with advanced or metastatic (stage IV) disease. Although smoking is the leading risk factor for lung cancer, 15–20% of lung cancers occur in patients who have never smoked [2]. Nearly half (49%) of patients who have never smoked and up to 42% of former light smokers (1–10 pack-years smoking history) with metastatic lung adenocarcinoma present epidermal growth factor receptor (EGFR) activating muta-
∗ Corresponding author at: Department of Medical Oncology, Catalan Institute of Oncology, Doctor Josep Trueta University Hospital, Avda Franc¸a s/n, 17007 Girona, Spain. Tel.: +34 972225834; fax: +34 972217344. ∗∗ Senior corresponding author at: Department of Medical Oncology, Catalan Institute of Oncology, Hospital Universitari Germans Trias i Pujol, Ctra Canyet s/n, 08916 Badalona, Spain. Tel.: +34 934978925; fax: +34 934978950. E-mail addresses: [email protected] (J. Bosch-Barrera), [email protected] (R. Rosell). 1 Both authors contributed equally to this work. http://dx.doi.org/10.1016/j.lungcan.2014.07.010 0169-5002/© 2014 Elsevier Ireland Ltd. All rights reserved.
tions [3]. Tumors that harbor EGFR mutations can present dramatic responses to first-line treatment with an EGFR tyrosine-kinase inhibitor (TKI), such as erlotinib [4,5], gefitinib [6] or afatinib [7]. Lung cancer is the most common solid tumor in critically ill cancer patients with cancer- or treatment-related complications who are admitted to ICUs [8]. The most common reason for ICU admission in these patients is respiratory failure, which necessitates mechanical ventilation. Despite recent improvements in the intensive care of critically ill cancer patients, the outcome of patients with lung cancer who are admitted to the ICU is poor, especially in those requiring mechanical ventilation as a result of respiratory failure [9]. Although several studies over the last decade have reported a progressive improvement in the outcome of lung cancer patients who are admitted to ICUs, it is clear that not all lung cancer patients will benefit from this aggressive care [10,11]. In some patients with cancer, the usual ICU admission triage criteria may be unreliable [7]. More recently, the criteria has expanded for qualification to an ICU trial and includes those patients who are newly diagnosed with cancer but with a life expectancy of less than 1 year [10]. The ICU trial consists of unlimited ICU support for a limited time period, and the parameters needed for the study are collected for at least 3–5 days [12].
J. Bosch-Barrera et al. / Lung Cancer 86 (2014) 102–104
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Fig. 1. A complete regression of right malignant pleural effusion (arrows) and the bilateral interstitial nodular pattern (arrowheads) was observed at CT scan after 3 months of erlotinib treatment (February 2014) compared with CT scan performed few days before ICU admission (November 2013). Circles indicate the primary tumor which presented a partial response.
Here, we present the case report of a newly diagnosed patient with metastatic lung adenocarcinoma who required mechanical ventilation due to respiratory failure caused by the disease. Based on clinical data, a high probability of EGFR mutation was suspected, and thus, empirical treatment with erlotinib was administered as a part of the ICU trial. This represents the first case report of successful empirical treatment with erlotinib in an ICU setting. 2. Case report A 60-year-old Caucasian female former light smoker (<10 packyears consumption) presented with a history of toxic syndrome and progressive dyspnea in November 2013. A contrast-enhanced computed tomography (CT) scan revealed a bilateral interstitial nodular pattern, right pleural effusion, and a lower right lobe mass (Fig. 1). A bronchoscopy was performed with transbronchial biopsy. Patient’s condition worsened with progressive respiratory failure and she was transferred to the ICU, where invasive mechanical ventilation with sedation was started. A nasogastric tube was placed for enteral nutrition. Three days later, the transbronchial biopsy was consistent with papillary lung adenocarcinoma. Empirical erlotinib treatment was discussed with her relatives who accepted this treatment. Erlotinib 150 mg/day was then administered by nasogastric tube; enteral nutrition ceased for 2 h before and after its administration. The patient progressively improved so that sedation was reduced, and after 5 days, the patient was extubated. Two days later the patient went to the hospital ward with low-flow nasal oxygen therapy support. After 10 days of treatment, the molecular laboratory confirmed the presence of an EGFR mutation in exon 19 (E746-T751). A bone scan showed metastatic bone involvement with metastases in the skull, spine, ribs, pelvic bones and both proximal femurs. The patient was given zoledronic acid in the hospital
to prevent skeletal-related events [13]. The patient was discharged from the hospital without oxygen therapy support two weeks later. A CT scan performed after 3 months of treatment revealed a dramatic radiological response with a residual spiculated nodular lesion in the lower right lobe of 18 mm × 18 mm × 17 mm (Fig. 1). The patient is currently receiving erlotinib with a performance status (PS) of 0, which allows her to live a normal life, and a CT scan performed after 6 months of treatment showed a maintenance of the radiological partial response. 3. Discussion Although the primary reasons for admission to the ICU are related to treatment and to other complications associated with cancer, some patients are admitted to the ICU before a cancer diagnosis is well-established or immediately after a recent diagnosis. The decision to initiate chemotherapy in critically ill cancer patients is extremely complex, especially in patients who are admitted to the ICU. The benefit of chemotherapy treatment in the ICU has primarily been explored in patients with hematological malignancies (acute leukemia and lymphoma), where fast and durable responses might be obtained with oncologic treatment [12]. The benefits of first-line treatment of metastatic NSCLC are limited, with a response rate of approximately 25% for chemotherapy treatment and a time to progression of up to 6 months in most of the pivotal randomized clinical trials [14]. In the last several years, molecular, targeted agents against EGFR have changed the first-line treatment standards of NSCLC. In 2004, EGFR mutations were defined as predictors of the response of patients treated with the tyrosine kinase inhibitor gefitinib, which imparted a rapid and often dramatic clinical response [15,16]. These favorable preliminary results have been confirmed by randomized phase III trials, which have demonstrated that first-generation
104
J. Bosch-Barrera et al. / Lung Cancer 86 (2014) 102–104
EGFR TKIs significantly improve the outcome by doubling the response rate (RR) and progression free survival (PFS) compared to chemotherapy [17]. Additionally, a meta-analysis showed that patients who received upfront EGFR TKI achieved a longer overall survival (OS) compared to upfront chemotherapy; however, differences did not reach statistical significance (30.5 months vs. 23.6 months; HR 0.94; 95% CI: 0.77–1.15; p = 0.57), mainly to the subsequent drugs cross-over [18]. It is widely accepted that patients with poor PS (ECOG PS ≥ 3) do not benefit from chemotherapy and instead suffer from its toxicity. This affirmation may not be appropriate for NSCLC patients with EGFR-activating mutations. Gefitinib treatment has been successfully used in 22 patients with poor performance status (PS 3–4) who harbor EGFR mutations. Nearly 70% of patients improve their PS from 3–4 at baseline to 0–1 after treatment [19]. Therefore, EGFR TKI agents can be considered for use in EGFR-mutant NSCLC patients with poor PS. Screening for EGFR mutations has become a current standard routine for most patients with advanced NSCLC. Unfortunately, the determination of EGFR mutation status by the molecular lab is not automatic, and requires at least 5 working days. In our case, the patient could not wait for this result due to her critical status. For this reason, we suggested an empirical treatment with an oral EGFR TKI as part of an ICU trial. Some studies have explored the role of first-line treatment with erlotinib in unselected patients (EGFR wild-type) who are unsuitable for chemotherapy treatment (including PS > 2). The TOPICAL study observed that patients who developed a first-cycle rash had better overall survival than patients in the placebo group (HR 0.76, 95% CI 0.63–0.92, p = 0.0058) [15]. Thus they suggested, as a conclusion, an empirical erlotinib front-line strategy that recommends the cessation of treatment if after 1 month the patients do not present with a skin rash. Despite this new approach, the TOPICAL study showed that the response to initial erlotinib treatment in EGFR wild-type tumors is far from the response observed in patients with mutant EGFR, where “Lazarus responses” have been described. Currently, most of the infectious diseases are treated with empirical antibiotics before cultures and antibiograms are available in patients that cannot wait for these results. Therefore, we suggests that in critically ill patients with a priori high probability of having an EGFR mutation, a strategy of “shoot first, ask later” might be reasonable. The probability of obtaining a response rate from empirical erlotinib in a never smoker or a former light smoker with a lung adenocarcinoma is around 17–35%, assuming 29–49% of EGFR mutation from epidemiologic studies [3] and 58–83% response rate to erlotinib from pivotal studies [17], which means a number needed to treat of 3–6 with this empirical approach. We want to state that this strategy should be employed only for patients who cannot wait for EGFR mutation status results due to their critical clinical situation because as the IPASS study has shown in EGFR wild-type tumors, frontline chemotherapy treatment is better than the EGFR TKI gefitinib [6]. 4. Conclusion This report provides insight into a successful empirical treatment with erlotinib in an ICU patient with newly diagnosed metastatic lung adenocarcinoma. Although the patient required critical support, a dramatic and durable response was obtained with the treatment. This case report represents a proof-ofconcept of the necessity of a multidisciplinary approach to treating
cancer patients in an ICU with the appearance of new, targeted agents against this disease in clinical practice. Conflict of interest statement All authors have no conflicts of interest. Acknowledgement Joaquim Bosch-Barrera is supported by an Emerging Research Grant 2013 from the Spanish Society of Medical Oncology (Sociedad ˜ de Oncología Médica, Madrid, Spain). Espanola References [1] Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics. CA Cancer J Clin 2014;64(1):9–29. [2] Ferketich AK, Niland JC, Mamet R, Zornosa C, D’Amico TA, Ettinger DS, et al. Smoking status and survival in the national comprehensive cancer network non-small cell lung cancer cohort. Cancer 2013;119(4):847–53. [3] D’Angelo SP, Pietanza MC, Johnson ML, Riely GJ, Miller VA, Sima CS, et al. Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas. J Clin Oncol 2011;29(15):2066–70. [4] Zhou C, Wu Y-L, Chen G, Feng J, Liu X-Q, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12(8):735–42. [5] Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13(3):239–46. [6] Fukuoka M, Wu Y-L, Thongprasert S, Sunpaweravong P, Leong S-S, Sriuranpong V, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011;29(21):2866–74. [7] Sequist LV, Yang JC-H, Yamamoto N, O’Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31(27):3327–34. [8] Adam AK, Soubani AO. Outcome and prognostic factors of lung cancer patients admitted to the medical intensive care unit. Eur Respir J 2008;31(1):47–53. [9] Soubani AO, Ruckdeschel JC. The outcome of medical intensive care for lung cancer patients: the case for optimism. J Thorac Oncol 2011;6(3):633–8. [10] Azoulay E, Soares M, Darmon M, Benoit D, Pastores S, Afessa B. Intensive care of the cancer patient: recent achievements and remaining challenges. Ann Intensive Care 2011;1(1):5. [11] Aygencel G, Turkoglu M, Turkoz Sucak G, Benekli M. Prognostic factors in critically ill cancer patients admitted to the intensive care unit. J Crit Care 2014;29(4):618–26. [12] Azoulay E, Afessa B. The intensive care support of patients with malignancy: do everything that can be done. Intensive Care Med 2006;32(1):3–5. [13] Isla D, Afonso R, Bosch-Barrera J, Martínez N. Zoledronic acid in lung cancer with bone metastases: a review. Expert Rev Anticancer Ther 2013;13(4): 421–6. [14] Bosch-Barrera J, Quer N, Brunet J. Costs and ethical issues related to first-line treatment of metastatic non-small-cell lung cancer: considerations from a public healthcare system perspective. Clin Lung Cancer 2011;12(6):335–40. [15] Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350(21):2129–39. [16] Taron M, Ichinose Y, Rosell R, Mok T, Massuti B, Zamora L, et al. Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res 2005;11(16):5878–85. [17] Remon J, Morán T, Reguart N, Majem M, Carcereny E, Lianes P. Beyond EGFR TKI in EGFR-mutant non-small cell lung cancer patients: main challenges still to be overcome. Cancer Treat Rev 2014;40(6):723–9. [18] Gao G, Ren S, Li A, Xu J, Xu Q, Su C, et al. Epidermal growth factor receptortyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: a meta-analysis from six phase III randomized controlled trials. Int J Cancer 2012;131(5):E822–9. [19] Inoue A, Kobayashi K, Usui K, Maemondo M, Okinaga S, Mikami I, et al. First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. J Clin Oncol 2009;27(9):1394–400.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Case report
Successful empirical erlotinib treatment of a mechanically ventilated patient newly diagnosed with metastatic lung adenocarcinoma Joaquim Bosch-Barrera a,b,c,∗,1 , Elia Sais a,1 , Carol Lorencio d , Rut Porta a,b,c , Angel Izquierdo a,b , Javier A. Menéndez b,e , Joan Brunet a,b,c , Josep Maria Sirvent d , Rafael Rosell f,∗∗ a
Department of Medical Oncology, Catalan Institute of Oncology, Doctor Josep Trueta University Hospital, Girona, Spain Girona Biomedical Research Institute (IDIBGi), Girona, Catalonia, Spain c Department of Medical Sciences, Medical School, University of Girona, Girona, Spain d Intensive Care Unit, Doctor Josep Trueta University Hospital, Girona, Spain e Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia, Spain f Department of Medical Oncology, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain b
a r t i c l e
i n f o
Article history: Received 8 July 2014 Accepted 13 July 2014 Keywords: Non-small-cell lung cancer Erlotinib Nasogastric tube EGFR mutation Critically ill patient Intensive care unit Mechanical ventilation
a b s t r a c t Background: Lung cancer is the most common solid tumor in critically ill cancer patients who are admitted to intensive care units (ICUs). An ICU trial consists of unlimited ICU support for a limited time period. Case report: We present the case of a 60-year-old woman with newly diagnosed metastatic lung adenocarcinoma who required mechanical ventilation due to respiratory failure. Empirical erlotinib treatment was administered through a nasogastric feeding tube as part of an ICU trial, which led to a dramatic and durable response. Conclusion: Empirical erlotinib should be considered when epidermal growth factor receptor (EGFR) mutations are suspected in ICU newly diagnosed patients with lung adenocarcinoma. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is the leading cause of cancer-related deaths worldwide and is the second most common cancer in both men and women [1]. Non-small-cell lung cancer (NSCLC) comprises up to 90% of all lung cancers, and the majority present with advanced or metastatic (stage IV) disease. Although smoking is the leading risk factor for lung cancer, 15–20% of lung cancers occur in patients who have never smoked [2]. Nearly half (49%) of patients who have never smoked and up to 42% of former light smokers (1–10 pack-years smoking history) with metastatic lung adenocarcinoma present epidermal growth factor receptor (EGFR) activating muta-
∗ Corresponding author at: Department of Medical Oncology, Catalan Institute of Oncology, Doctor Josep Trueta University Hospital, Avda Franc¸a s/n, 17007 Girona, Spain. Tel.: +34 972225834; fax: +34 972217344. ∗∗ Senior corresponding author at: Department of Medical Oncology, Catalan Institute of Oncology, Hospital Universitari Germans Trias i Pujol, Ctra Canyet s/n, 08916 Badalona, Spain. Tel.: +34 934978925; fax: +34 934978950. E-mail addresses: [email protected] (J. Bosch-Barrera), [email protected] (R. Rosell). 1 Both authors contributed equally to this work. http://dx.doi.org/10.1016/j.lungcan.2014.07.010 0169-5002/© 2014 Elsevier Ireland Ltd. All rights reserved.
tions [3]. Tumors that harbor EGFR mutations can present dramatic responses to first-line treatment with an EGFR tyrosine-kinase inhibitor (TKI), such as erlotinib [4,5], gefitinib [6] or afatinib [7]. Lung cancer is the most common solid tumor in critically ill cancer patients with cancer- or treatment-related complications who are admitted to ICUs [8]. The most common reason for ICU admission in these patients is respiratory failure, which necessitates mechanical ventilation. Despite recent improvements in the intensive care of critically ill cancer patients, the outcome of patients with lung cancer who are admitted to the ICU is poor, especially in those requiring mechanical ventilation as a result of respiratory failure [9]. Although several studies over the last decade have reported a progressive improvement in the outcome of lung cancer patients who are admitted to ICUs, it is clear that not all lung cancer patients will benefit from this aggressive care [10,11]. In some patients with cancer, the usual ICU admission triage criteria may be unreliable [7]. More recently, the criteria has expanded for qualification to an ICU trial and includes those patients who are newly diagnosed with cancer but with a life expectancy of less than 1 year [10]. The ICU trial consists of unlimited ICU support for a limited time period, and the parameters needed for the study are collected for at least 3–5 days [12].
J. Bosch-Barrera et al. / Lung Cancer 86 (2014) 102–104
103
Fig. 1. A complete regression of right malignant pleural effusion (arrows) and the bilateral interstitial nodular pattern (arrowheads) was observed at CT scan after 3 months of erlotinib treatment (February 2014) compared with CT scan performed few days before ICU admission (November 2013). Circles indicate the primary tumor which presented a partial response.
Here, we present the case report of a newly diagnosed patient with metastatic lung adenocarcinoma who required mechanical ventilation due to respiratory failure caused by the disease. Based on clinical data, a high probability of EGFR mutation was suspected, and thus, empirical treatment with erlotinib was administered as a part of the ICU trial. This represents the first case report of successful empirical treatment with erlotinib in an ICU setting. 2. Case report A 60-year-old Caucasian female former light smoker (<10 packyears consumption) presented with a history of toxic syndrome and progressive dyspnea in November 2013. A contrast-enhanced computed tomography (CT) scan revealed a bilateral interstitial nodular pattern, right pleural effusion, and a lower right lobe mass (Fig. 1). A bronchoscopy was performed with transbronchial biopsy. Patient’s condition worsened with progressive respiratory failure and she was transferred to the ICU, where invasive mechanical ventilation with sedation was started. A nasogastric tube was placed for enteral nutrition. Three days later, the transbronchial biopsy was consistent with papillary lung adenocarcinoma. Empirical erlotinib treatment was discussed with her relatives who accepted this treatment. Erlotinib 150 mg/day was then administered by nasogastric tube; enteral nutrition ceased for 2 h before and after its administration. The patient progressively improved so that sedation was reduced, and after 5 days, the patient was extubated. Two days later the patient went to the hospital ward with low-flow nasal oxygen therapy support. After 10 days of treatment, the molecular laboratory confirmed the presence of an EGFR mutation in exon 19 (E746-T751). A bone scan showed metastatic bone involvement with metastases in the skull, spine, ribs, pelvic bones and both proximal femurs. The patient was given zoledronic acid in the hospital
to prevent skeletal-related events [13]. The patient was discharged from the hospital without oxygen therapy support two weeks later. A CT scan performed after 3 months of treatment revealed a dramatic radiological response with a residual spiculated nodular lesion in the lower right lobe of 18 mm × 18 mm × 17 mm (Fig. 1). The patient is currently receiving erlotinib with a performance status (PS) of 0, which allows her to live a normal life, and a CT scan performed after 6 months of treatment showed a maintenance of the radiological partial response. 3. Discussion Although the primary reasons for admission to the ICU are related to treatment and to other complications associated with cancer, some patients are admitted to the ICU before a cancer diagnosis is well-established or immediately after a recent diagnosis. The decision to initiate chemotherapy in critically ill cancer patients is extremely complex, especially in patients who are admitted to the ICU. The benefit of chemotherapy treatment in the ICU has primarily been explored in patients with hematological malignancies (acute leukemia and lymphoma), where fast and durable responses might be obtained with oncologic treatment [12]. The benefits of first-line treatment of metastatic NSCLC are limited, with a response rate of approximately 25% for chemotherapy treatment and a time to progression of up to 6 months in most of the pivotal randomized clinical trials [14]. In the last several years, molecular, targeted agents against EGFR have changed the first-line treatment standards of NSCLC. In 2004, EGFR mutations were defined as predictors of the response of patients treated with the tyrosine kinase inhibitor gefitinib, which imparted a rapid and often dramatic clinical response [15,16]. These favorable preliminary results have been confirmed by randomized phase III trials, which have demonstrated that first-generation
104
J. Bosch-Barrera et al. / Lung Cancer 86 (2014) 102–104
EGFR TKIs significantly improve the outcome by doubling the response rate (RR) and progression free survival (PFS) compared to chemotherapy [17]. Additionally, a meta-analysis showed that patients who received upfront EGFR TKI achieved a longer overall survival (OS) compared to upfront chemotherapy; however, differences did not reach statistical significance (30.5 months vs. 23.6 months; HR 0.94; 95% CI: 0.77–1.15; p = 0.57), mainly to the subsequent drugs cross-over [18]. It is widely accepted that patients with poor PS (ECOG PS ≥ 3) do not benefit from chemotherapy and instead suffer from its toxicity. This affirmation may not be appropriate for NSCLC patients with EGFR-activating mutations. Gefitinib treatment has been successfully used in 22 patients with poor performance status (PS 3–4) who harbor EGFR mutations. Nearly 70% of patients improve their PS from 3–4 at baseline to 0–1 after treatment [19]. Therefore, EGFR TKI agents can be considered for use in EGFR-mutant NSCLC patients with poor PS. Screening for EGFR mutations has become a current standard routine for most patients with advanced NSCLC. Unfortunately, the determination of EGFR mutation status by the molecular lab is not automatic, and requires at least 5 working days. In our case, the patient could not wait for this result due to her critical status. For this reason, we suggested an empirical treatment with an oral EGFR TKI as part of an ICU trial. Some studies have explored the role of first-line treatment with erlotinib in unselected patients (EGFR wild-type) who are unsuitable for chemotherapy treatment (including PS > 2). The TOPICAL study observed that patients who developed a first-cycle rash had better overall survival than patients in the placebo group (HR 0.76, 95% CI 0.63–0.92, p = 0.0058) [15]. Thus they suggested, as a conclusion, an empirical erlotinib front-line strategy that recommends the cessation of treatment if after 1 month the patients do not present with a skin rash. Despite this new approach, the TOPICAL study showed that the response to initial erlotinib treatment in EGFR wild-type tumors is far from the response observed in patients with mutant EGFR, where “Lazarus responses” have been described. Currently, most of the infectious diseases are treated with empirical antibiotics before cultures and antibiograms are available in patients that cannot wait for these results. Therefore, we suggests that in critically ill patients with a priori high probability of having an EGFR mutation, a strategy of “shoot first, ask later” might be reasonable. The probability of obtaining a response rate from empirical erlotinib in a never smoker or a former light smoker with a lung adenocarcinoma is around 17–35%, assuming 29–49% of EGFR mutation from epidemiologic studies [3] and 58–83% response rate to erlotinib from pivotal studies [17], which means a number needed to treat of 3–6 with this empirical approach. We want to state that this strategy should be employed only for patients who cannot wait for EGFR mutation status results due to their critical clinical situation because as the IPASS study has shown in EGFR wild-type tumors, frontline chemotherapy treatment is better than the EGFR TKI gefitinib [6]. 4. Conclusion This report provides insight into a successful empirical treatment with erlotinib in an ICU patient with newly diagnosed metastatic lung adenocarcinoma. Although the patient required critical support, a dramatic and durable response was obtained with the treatment. This case report represents a proof-ofconcept of the necessity of a multidisciplinary approach to treating
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