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Use of erlotinib throughout pregnancy: A case-report of a patient with metastatic lung adenocarcinoma
Lung Cancer 77 (2012) 469–472
Contents lists available at SciVerse ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Case report
Use of erlotinib throughout pregnancy: A case-report of a patient with metastatic lung adenocarcinoma Giovanna Rivas a,b,∗ , Nestor Llinás a,b , Carlos Bonilla a,b , Juan Rubiano a,b , Javier Cuello a,b , Natalia Arango a,b a b
Clinical Oncology Group, Cancerology National Institute, E.S.E., Bogota, Colombia Universidad el Bosque, Bogota, Colombia
a r t i c l e
i n f o
Article history: Received 19 February 2012 Received in revised form 6 March 2012 Accepted 9 March 2012 Keywords: Lung cancer Treatment Metastasis Non-small cell lung carcinoma Lung adenocarcinoma Erlotinib Pregnancy EGFR tyrosine kinase inhibitor
a b s t r a c t The use of erlotinib throughout pregnancy has not been previously reported. We present the case of a 40 year-old female patient with stage IV lung adenocarcinoma, mediastinal, bone and cerebral metastasis, a EGFR mutation and no smoking history, who had begun first line treatment with erlotinib 150 mg once daily. After two and a half months of treatment a fourteen-week pregnancy was documented, and after informing on fetal risks secondary to erlotinib use and maternal risks secondary to treatment withholding, she decided to continue with treatment under clinical surveillance by both the oncology and obstetrics clinics. At thirty-three weeks gestation a live born 1600 g female was born by caesarean section without evidence of congenital malformations. Imaging assessment after eight months of treatment showed complete bone and central nervous system response and partial lung and mediastinal response. The patient is currently undergoing the 11th month of treatment and is asymptomatic, the baby is 4 months old and is in good health. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The diagnosis of cancer and pregnancy is an emotional challenge and entails an ethical dilemma for the patient, her family, physicians and society [1]. The incidence of cancer and pregnancy is approximately 1 in 1000 pregnancies [2]. To our knowledge only 44 cases of women with lung cancer during pregnancy have been published, more than 80% corresponding to stages III and IV, with a median survival of 4.5 months. Only 9 achieved survival larger than 1 year and 26% had documented metastasis to the products of conception [1,3]. There is only one report on the use of erlotinib during the first 8 weeks of gestation [4]. We report on the first case of a patient with stage IV lung adenocarcinoma in whom a fourteen-week pregnancy had been documented under erlotinib treatment. The patient has achieved partial response, and the baby is in good health. 2. Case description A forty year-old female with no smoking history presented with two months of dry cough and moderate exertion dyspnea
∗ Corresponding author at: Calle 1 # 9-85, Bogotá DC, Colombia. Tel.: +57 1 3341111. E-mail address: [email protected] (G. Rivas). 0169-5002/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2012.03.026
which was followed by chest pain. A chest X-ray revealed a left lower lobe infiltrate interpreted as pneumonia and treated with clarithromycin with no improvement. Given the persistence of symptoms a computed tomography was obtained and a transbronchial biopsy performed which confirmed the diagnosis of non-mucinous bronchioloalveolar carcinoma with multiple pulmonary and mediastinal metastasis. She was referred to our hospital on February 2011, she was found in pain, with mild exertion dyspnea and 84% oxygen saturation. Staging tests were performed, a chest computed tomography revealed a mass in the left lower lobe, mediastinal enlarged lymph nodes, bilateral pulmonary nodes and pericardial effusion; echocardiography showed a mild to moderate pericardial effusion without hemodynamic compromise; bone scan evidenced a single sternal metastasis and cerebral resonance imaging showed a metastatic lesion of 5 mm in the frontal left region without vasogenico edema. A mutational analysis was requested for the EGFR gene using sequence analysis, fragment analysis and 5 -nuclease assay for PCR in paraffin blocks, which documented a L858R mutation of the EGFR exon 21 (Fig. 1). The patient received stereotactic cerebral radiosurgery with a single dose of 16 Gy on March 7, 2011, without complications. On March 17, 2011, treatment with tyrosine kinase inhibitor of EGFR (erlotinib 150 mg once daily) was started, prior request of informed consent, verification of the date of last menses (February 25, 2011) and use of hormonal contraception. After the first month
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G. Rivas et al. / Lung Cancer 77 (2012) 469–472
Fig. 1. Mutational analysis for the EGFR gene using sequence analysis, fragment analysis and 5 -nuclease assay for PCR.
of treatment the patient referred improvement of dyspnea and oligomenorrhea which prompted a pregnancy test. The patient returned for medical follow-up on May 28, 2011, asymptomatic, and she brought a report of a pregnancy test 34,983 mUI/ml, an obstetric ultrasound was requested and an intrauterine pregnancy of 14 weeks was confirmed, with a single live fetus, and without sings of congenital malformations. A special meeting was
held where the institutional multidisciplinary committee on cancer and pregnancy analyzed the potential risks for malformations, intrauterine growth restriction and fetal death as a consequence of erlotinib use during pregnancy; the possibility of pregnancy interruption, possible consequences during pregnancy (uterine bleeding, threat of preterm labor) as well as the risk of disease progression if treatment was withheld; all of which was explained to
Fig. 2. Thorax computed tomography scan, initial assessment (A) and (B), axial and coronal slice show a tumor involving both apex and posterior segments of the left inferior lobe. Follow-up assessment (C) and (D), eight months after the start of treatment show a marked reduction in tumor volume.
G. Rivas et al. / Lung Cancer 77 (2012) 469–472
471
Fig. 3. Contrast magnetic resonance imaging of the skull (A) shows cortical–subcortical metastases in the left frontal lobe and (B) post treatment assessment shows complete resolution of lesions. (C) Thorax contrasted computed tomography with coronal reconstruction shows pericardial effusion. (D) Follow-up non-contrasted post treatment assessment shows resolution of pericardial effusion.
the patient who decided to continue with pregnancy without suspending treatment. She was referred for high risk obstetric control for pregnancy follow-up. The patient continued treatment with acceptable tolerance, attending monthly follow-up visits at both oncology and obstetrics clinics. In October, 2011, at thirty-three weeks gestation an oligohydramnios and intrauterine growth restriction were documented and a cesarean section was performed, a live born female was born weighing 1600 g, APGAR score of 8 at 1 min and 10 at 5 min. Pediatric assessments did not reveal any signs of congenital malformations and thyroid, liver, renal, hematology, auditory and visual assessments were all normal, and the placenta was free of metastasis. The baby remained stable and she was sent home after 15 days weighing 1900 g. In November 2011, after 8 months of treatment complementary assessments were performed. Bone scan and cerebral magnetic resonance imaging showed a complete response and chest tomography evidenced partial response on primary tumor and on mediastinal compromise (Figs. 2 and 3). The patient is currently on month 11 of treatment with erlotinib and she is asymptomatic.
The baby is currently 4 months old and is in good health weighs 5200 g which corresponds to the 25th percentile in accordance to growth charts for Colombia.
3. Discussion Lung cancer is the fourth most frequent cause of cancer and the second cause of cancer death in women worldwide [5]. Patients with stage IV lung adenocarcinoma have a poor prognosis with a median survival of 5 months and a global survival of 23.3% at 1 year and 9.9% at 2 years [6]. To our knowledge only 44 cases of women with lung cancer during pregnancy have been published, 90% corresponding to advanced illness and thus were not candidates for surgical treatment. Most patients had a bad postpartum progression, only 9 achieved survivals larger than 1 year and 26% had documentation of metastases to the products of conception. Eight patients were treated with systemic therapy during pregnancy with normal fetal development and without evidence of metastases to
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G. Rivas et al. / Lung Cancer 77 (2012) 469–472
the new born or placenta; one patient was treated with erlotinib and seven patients received chemotherapy, regimens included cisplatin–gemcitabine, cisplatin–vinorelbine, cisplatin–docetaxel, carboplatin–paclitaxel, carboplatin–gemcitabine and cisplatin– etoposide; four out of eight patients died within 10 months of childbirth [3]. Nowadays tyrosine kinase inhibitors such as erlotinib are available showing an improvement in progression-free survival, as first line treatment in patients with metastatic lung adenocarcinoma with EGFR mutations in exons 10 or 21 [7,8]. The EURTAC study reported a progression-free survival of patients treated with erlotinib of 9.4 months vs. 5.2 months for those treated with chemotherapy HR, 0.42; p < 0.0001 [7]. The OPTIMAL study reported that patients under erlotinib had a median progression-free survival of 12.1 months compared to 4.6 months for the group treated with chemotherapy HR 0.16, 95% CI 0.10–0.26; p = 0.0001 [8]. Knowledge about the use of erlotinib during pregnancy derives from two case reports. Zambelli et al. published a case of a patient with metastatic lung cancer who suspended treatment after confirmation of an eight-weeks pregnancy, the baby did not present any congenital malformations; however, the patient presented with disease progression [4]. Lee et al. reported on a case of a patient with metastatic lung adenocarcinoma with a mutation at exon 19 of EGFR, who received erlotinib during the first trimester of pregnancy (at week 26) and whose treatment was changed to gefitinib (at week 28) given that this drug was less expensive in her country (Malaysia); the baby was born at 36 weeks gestation via vaginal labor and a computed tomography performed three months after the start of treatment revealed considerable reductions in primary tumor and thorax metastases sizes; the patient continued treatment with gefitinib [9]. Studies on rats and rabbits have evidenced that tyrosine kinase inhibitors alter placental angiogenesis, which is associated with toxicity for embryonic development, placental hemorrhage, visceral, neurologic and skeletal malformations, intrauterine growth restriction and fetal death [10,11]. Erlotinib has been reported as the cause of embryonic and fetal death in rabbits when administered at a dose that achieved plasma concentrations approximately 3 times higher than those used in humans. When administered in rats during the first week of pregnancy at doses 0.3–0.7 times a 150 mg dose an increase in early resorptions with a decrease in the number of live fetuses occurred (unpublished data). In our case, the patient was treated with erlotinib given a diagnosis of stage IV lung adenocarcinoma and presence of a EGFR mutation on exon 21. When pregnancy was documented at fourteen weeks gestation, the patient was informed of possible risks for the fetus associated with the use of erlotinib, possible complications during pregnancy and the consequences of suspending treatment given the poor prognosis of her disease, after which she decided to continue with pregnancy without suspending treatment. The baby had no congenital malformations and after four months follow-up presents a normal psychomotor development.
The patient has completed 11 months with erlotinib reaching a partial response and remains asymptomatic. In conclusion, given the poor experience in humans with the use of erlotinib this drug should be avoided during pregnancy, medical personnel must confirm the use of an effective contraception method and must perform a pregnancy test prior to the start of treatment. If despite this pregnancy occurs during treatment, applying the principle of beneficence the patient must be informed of the risks for the fetus and the consequences of treatment suspension, respecting her autonomy over the decision to continue with or suspension of pregnancy and treatment. Conflict of interest statement The authors declare no conflicts of interest. Acknowledgements We would like to thank Dr. Oswaldo Sánchez member of the Clinical Oncology Group at Cancerology National Institute and Dr. Alfonso Lozano member of the Radiology Group at Cancerology National Institute, Bogota, Colombia. References [1] Pavlidis N. Lung cancer during pregnancy: an emerging issue. Lung Cancer 2008;59(March (3)):279–81. [2] Pavlidis NA. Coexistence of pregnancy and malignancy. Oncologist 2002;7(4):279–87. Review. Erratum in: Oncologist 2002;7(4):279–87. [3] Azim Jr HA, Peccatori FA, Pavlidis N. Lung cancer in the pregnant woman: to treat or not to treat, that is the question. Lung Cancer 2010;67(March (3)): 251–6. [4] Zambelli A, Prada GA, Fregoni V, Ponchio L, Sagrada P, Pavesi L. Erlotinib administration for advanced non-small cell lung cancer during the first 2 months of unrecognized pregnancy. Lung Cancer 2008;60(June (3)):455–7. [5] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61(March–April (2)):69–90. [6] Morgensztern D, Waqar S, Subramanian J, Gao F, Govindan R. Improving survival for stage IV non-small cell lung cancer: a surveillance, epidemiology, and end results survey from 1990 to 2005. J Thorac Oncol 2009;4(December (12)):1524–9. [7] 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, January. [8] Lee HL, Liam CK, Pang YK, Chua KT, Lim BK, Lai NL. Successful pregnancy with epidermal growth factor receptor tyrosine kinase inhibitor treatment of metastatic lung adenocarcinoma presenting with respiratory failure. Lung Cancer 2011;74(2):349–51. [9] Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, openlabel, randomised, phase 3 study. Lancet Oncol 2011;12(August (8)):735–42. [10] Patyna S, Haznedar J, Morris D, Freshwater K, Peng G, Sukbuntherng J, et al. Evaluation of the safety and pharmacokinetics of the multi-targeted receptor tyrosine kinase inhibitor sunitinib during embryo-fetal development in rats and rabbits. Birth Defects Res B Dev Reprod Toxicol 2009;86(June (3)):204–13. [11] Wada Y, Ozaki H, Abe N, Nagamitsu T, Ohta H, Nakahara T, et al. Effects of KRN633, an inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase, on vascular development of placenta and fetus of mid-pregnancy in mice. J Pharmacol Sci 2010;112(3):290–8.
Contents lists available at SciVerse ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Case report
Use of erlotinib throughout pregnancy: A case-report of a patient with metastatic lung adenocarcinoma Giovanna Rivas a,b,∗ , Nestor Llinás a,b , Carlos Bonilla a,b , Juan Rubiano a,b , Javier Cuello a,b , Natalia Arango a,b a b
Clinical Oncology Group, Cancerology National Institute, E.S.E., Bogota, Colombia Universidad el Bosque, Bogota, Colombia
a r t i c l e
i n f o
Article history: Received 19 February 2012 Received in revised form 6 March 2012 Accepted 9 March 2012 Keywords: Lung cancer Treatment Metastasis Non-small cell lung carcinoma Lung adenocarcinoma Erlotinib Pregnancy EGFR tyrosine kinase inhibitor
a b s t r a c t The use of erlotinib throughout pregnancy has not been previously reported. We present the case of a 40 year-old female patient with stage IV lung adenocarcinoma, mediastinal, bone and cerebral metastasis, a EGFR mutation and no smoking history, who had begun first line treatment with erlotinib 150 mg once daily. After two and a half months of treatment a fourteen-week pregnancy was documented, and after informing on fetal risks secondary to erlotinib use and maternal risks secondary to treatment withholding, she decided to continue with treatment under clinical surveillance by both the oncology and obstetrics clinics. At thirty-three weeks gestation a live born 1600 g female was born by caesarean section without evidence of congenital malformations. Imaging assessment after eight months of treatment showed complete bone and central nervous system response and partial lung and mediastinal response. The patient is currently undergoing the 11th month of treatment and is asymptomatic, the baby is 4 months old and is in good health. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The diagnosis of cancer and pregnancy is an emotional challenge and entails an ethical dilemma for the patient, her family, physicians and society [1]. The incidence of cancer and pregnancy is approximately 1 in 1000 pregnancies [2]. To our knowledge only 44 cases of women with lung cancer during pregnancy have been published, more than 80% corresponding to stages III and IV, with a median survival of 4.5 months. Only 9 achieved survival larger than 1 year and 26% had documented metastasis to the products of conception [1,3]. There is only one report on the use of erlotinib during the first 8 weeks of gestation [4]. We report on the first case of a patient with stage IV lung adenocarcinoma in whom a fourteen-week pregnancy had been documented under erlotinib treatment. The patient has achieved partial response, and the baby is in good health. 2. Case description A forty year-old female with no smoking history presented with two months of dry cough and moderate exertion dyspnea
∗ Corresponding author at: Calle 1 # 9-85, Bogotá DC, Colombia. Tel.: +57 1 3341111. E-mail address: [email protected] (G. Rivas). 0169-5002/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2012.03.026
which was followed by chest pain. A chest X-ray revealed a left lower lobe infiltrate interpreted as pneumonia and treated with clarithromycin with no improvement. Given the persistence of symptoms a computed tomography was obtained and a transbronchial biopsy performed which confirmed the diagnosis of non-mucinous bronchioloalveolar carcinoma with multiple pulmonary and mediastinal metastasis. She was referred to our hospital on February 2011, she was found in pain, with mild exertion dyspnea and 84% oxygen saturation. Staging tests were performed, a chest computed tomography revealed a mass in the left lower lobe, mediastinal enlarged lymph nodes, bilateral pulmonary nodes and pericardial effusion; echocardiography showed a mild to moderate pericardial effusion without hemodynamic compromise; bone scan evidenced a single sternal metastasis and cerebral resonance imaging showed a metastatic lesion of 5 mm in the frontal left region without vasogenico edema. A mutational analysis was requested for the EGFR gene using sequence analysis, fragment analysis and 5 -nuclease assay for PCR in paraffin blocks, which documented a L858R mutation of the EGFR exon 21 (Fig. 1). The patient received stereotactic cerebral radiosurgery with a single dose of 16 Gy on March 7, 2011, without complications. On March 17, 2011, treatment with tyrosine kinase inhibitor of EGFR (erlotinib 150 mg once daily) was started, prior request of informed consent, verification of the date of last menses (February 25, 2011) and use of hormonal contraception. After the first month
470
G. Rivas et al. / Lung Cancer 77 (2012) 469–472
Fig. 1. Mutational analysis for the EGFR gene using sequence analysis, fragment analysis and 5 -nuclease assay for PCR.
of treatment the patient referred improvement of dyspnea and oligomenorrhea which prompted a pregnancy test. The patient returned for medical follow-up on May 28, 2011, asymptomatic, and she brought a report of a pregnancy test 34,983 mUI/ml, an obstetric ultrasound was requested and an intrauterine pregnancy of 14 weeks was confirmed, with a single live fetus, and without sings of congenital malformations. A special meeting was
held where the institutional multidisciplinary committee on cancer and pregnancy analyzed the potential risks for malformations, intrauterine growth restriction and fetal death as a consequence of erlotinib use during pregnancy; the possibility of pregnancy interruption, possible consequences during pregnancy (uterine bleeding, threat of preterm labor) as well as the risk of disease progression if treatment was withheld; all of which was explained to
Fig. 2. Thorax computed tomography scan, initial assessment (A) and (B), axial and coronal slice show a tumor involving both apex and posterior segments of the left inferior lobe. Follow-up assessment (C) and (D), eight months after the start of treatment show a marked reduction in tumor volume.
G. Rivas et al. / Lung Cancer 77 (2012) 469–472
471
Fig. 3. Contrast magnetic resonance imaging of the skull (A) shows cortical–subcortical metastases in the left frontal lobe and (B) post treatment assessment shows complete resolution of lesions. (C) Thorax contrasted computed tomography with coronal reconstruction shows pericardial effusion. (D) Follow-up non-contrasted post treatment assessment shows resolution of pericardial effusion.
the patient who decided to continue with pregnancy without suspending treatment. She was referred for high risk obstetric control for pregnancy follow-up. The patient continued treatment with acceptable tolerance, attending monthly follow-up visits at both oncology and obstetrics clinics. In October, 2011, at thirty-three weeks gestation an oligohydramnios and intrauterine growth restriction were documented and a cesarean section was performed, a live born female was born weighing 1600 g, APGAR score of 8 at 1 min and 10 at 5 min. Pediatric assessments did not reveal any signs of congenital malformations and thyroid, liver, renal, hematology, auditory and visual assessments were all normal, and the placenta was free of metastasis. The baby remained stable and she was sent home after 15 days weighing 1900 g. In November 2011, after 8 months of treatment complementary assessments were performed. Bone scan and cerebral magnetic resonance imaging showed a complete response and chest tomography evidenced partial response on primary tumor and on mediastinal compromise (Figs. 2 and 3). The patient is currently on month 11 of treatment with erlotinib and she is asymptomatic.
The baby is currently 4 months old and is in good health weighs 5200 g which corresponds to the 25th percentile in accordance to growth charts for Colombia.
3. Discussion Lung cancer is the fourth most frequent cause of cancer and the second cause of cancer death in women worldwide [5]. Patients with stage IV lung adenocarcinoma have a poor prognosis with a median survival of 5 months and a global survival of 23.3% at 1 year and 9.9% at 2 years [6]. To our knowledge only 44 cases of women with lung cancer during pregnancy have been published, 90% corresponding to advanced illness and thus were not candidates for surgical treatment. Most patients had a bad postpartum progression, only 9 achieved survivals larger than 1 year and 26% had documentation of metastases to the products of conception. Eight patients were treated with systemic therapy during pregnancy with normal fetal development and without evidence of metastases to
472
G. Rivas et al. / Lung Cancer 77 (2012) 469–472
the new born or placenta; one patient was treated with erlotinib and seven patients received chemotherapy, regimens included cisplatin–gemcitabine, cisplatin–vinorelbine, cisplatin–docetaxel, carboplatin–paclitaxel, carboplatin–gemcitabine and cisplatin– etoposide; four out of eight patients died within 10 months of childbirth [3]. Nowadays tyrosine kinase inhibitors such as erlotinib are available showing an improvement in progression-free survival, as first line treatment in patients with metastatic lung adenocarcinoma with EGFR mutations in exons 10 or 21 [7,8]. The EURTAC study reported a progression-free survival of patients treated with erlotinib of 9.4 months vs. 5.2 months for those treated with chemotherapy HR, 0.42; p < 0.0001 [7]. The OPTIMAL study reported that patients under erlotinib had a median progression-free survival of 12.1 months compared to 4.6 months for the group treated with chemotherapy HR 0.16, 95% CI 0.10–0.26; p = 0.0001 [8]. Knowledge about the use of erlotinib during pregnancy derives from two case reports. Zambelli et al. published a case of a patient with metastatic lung cancer who suspended treatment after confirmation of an eight-weeks pregnancy, the baby did not present any congenital malformations; however, the patient presented with disease progression [4]. Lee et al. reported on a case of a patient with metastatic lung adenocarcinoma with a mutation at exon 19 of EGFR, who received erlotinib during the first trimester of pregnancy (at week 26) and whose treatment was changed to gefitinib (at week 28) given that this drug was less expensive in her country (Malaysia); the baby was born at 36 weeks gestation via vaginal labor and a computed tomography performed three months after the start of treatment revealed considerable reductions in primary tumor and thorax metastases sizes; the patient continued treatment with gefitinib [9]. Studies on rats and rabbits have evidenced that tyrosine kinase inhibitors alter placental angiogenesis, which is associated with toxicity for embryonic development, placental hemorrhage, visceral, neurologic and skeletal malformations, intrauterine growth restriction and fetal death [10,11]. Erlotinib has been reported as the cause of embryonic and fetal death in rabbits when administered at a dose that achieved plasma concentrations approximately 3 times higher than those used in humans. When administered in rats during the first week of pregnancy at doses 0.3–0.7 times a 150 mg dose an increase in early resorptions with a decrease in the number of live fetuses occurred (unpublished data). In our case, the patient was treated with erlotinib given a diagnosis of stage IV lung adenocarcinoma and presence of a EGFR mutation on exon 21. When pregnancy was documented at fourteen weeks gestation, the patient was informed of possible risks for the fetus associated with the use of erlotinib, possible complications during pregnancy and the consequences of suspending treatment given the poor prognosis of her disease, after which she decided to continue with pregnancy without suspending treatment. The baby had no congenital malformations and after four months follow-up presents a normal psychomotor development.
The patient has completed 11 months with erlotinib reaching a partial response and remains asymptomatic. In conclusion, given the poor experience in humans with the use of erlotinib this drug should be avoided during pregnancy, medical personnel must confirm the use of an effective contraception method and must perform a pregnancy test prior to the start of treatment. If despite this pregnancy occurs during treatment, applying the principle of beneficence the patient must be informed of the risks for the fetus and the consequences of treatment suspension, respecting her autonomy over the decision to continue with or suspension of pregnancy and treatment. Conflict of interest statement The authors declare no conflicts of interest. Acknowledgements We would like to thank Dr. Oswaldo Sánchez member of the Clinical Oncology Group at Cancerology National Institute and Dr. Alfonso Lozano member of the Radiology Group at Cancerology National Institute, Bogota, Colombia. References [1] Pavlidis N. Lung cancer during pregnancy: an emerging issue. Lung Cancer 2008;59(March (3)):279–81. [2] Pavlidis NA. Coexistence of pregnancy and malignancy. Oncologist 2002;7(4):279–87. Review. Erratum in: Oncologist 2002;7(4):279–87. [3] Azim Jr HA, Peccatori FA, Pavlidis N. Lung cancer in the pregnant woman: to treat or not to treat, that is the question. Lung Cancer 2010;67(March (3)): 251–6. [4] Zambelli A, Prada GA, Fregoni V, Ponchio L, Sagrada P, Pavesi L. Erlotinib administration for advanced non-small cell lung cancer during the first 2 months of unrecognized pregnancy. Lung Cancer 2008;60(June (3)):455–7. [5] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61(March–April (2)):69–90. [6] Morgensztern D, Waqar S, Subramanian J, Gao F, Govindan R. Improving survival for stage IV non-small cell lung cancer: a surveillance, epidemiology, and end results survey from 1990 to 2005. J Thorac Oncol 2009;4(December (12)):1524–9. [7] 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, January. [8] Lee HL, Liam CK, Pang YK, Chua KT, Lim BK, Lai NL. Successful pregnancy with epidermal growth factor receptor tyrosine kinase inhibitor treatment of metastatic lung adenocarcinoma presenting with respiratory failure. Lung Cancer 2011;74(2):349–51. [9] Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, openlabel, randomised, phase 3 study. Lancet Oncol 2011;12(August (8)):735–42. [10] Patyna S, Haznedar J, Morris D, Freshwater K, Peng G, Sukbuntherng J, et al. Evaluation of the safety and pharmacokinetics of the multi-targeted receptor tyrosine kinase inhibitor sunitinib during embryo-fetal development in rats and rabbits. Birth Defects Res B Dev Reprod Toxicol 2009;86(June (3)):204–13. [11] Wada Y, Ozaki H, Abe N, Nagamitsu T, Ohta H, Nakahara T, et al. Effects of KRN633, an inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase, on vascular development of placenta and fetus of mid-pregnancy in mice. J Pharmacol Sci 2010;112(3):290–8.