Novel Insights from Clinical Practice Oncol Res Treat 2014;37:262–265 DOI: 10.1159/000362488
Received: January 16, 2014 Accepted: March 21, 2014 Published online: April 14, 2014
Afatinib with Concurrent Radiotherapy in a Patient with Metastatic Non-Small Cell Lung Cancer Akin Atmacaa Salah-Eddin Al-Batranb Michael Allgäuerc Elke Jägera a Department of Oncology and Hematology; bInstitute of Clinical Cancer Research (IKF), Krankenhaus Nordwest, UCT University Cancer Center, Frankfurt/M.; cDepartment of Radiation Oncology, Krankenhaus Barmherzige Brüder, Regensburg, Germany
Established Facts • In general, first generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) seem to be a feasible treatment in combination with concurrent thoracic radiation. • There are also reports from patients who experienced severe toxicity, such as acute severe skin reactions or delayed-type events such as pneumonitis.
Novel Insights • The second generation, pan-Erb EGFR TKI afatinib could safely be administered in a dose of 30 mg/day with concurrent thoracic radiotherapy.
Summary Background: The combination of radiotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib in patients with advanced or metastatic non-small cell lung cancer (NSCLC) has not been widely investigated. For afatinib, a new second generation irreversible pan-EGFR TKI, no clinical trials in this setting have as yet been performed. Case Report: We report a patient with a pretreated metastatic NSCLC receiving afatinib in combination with concomitant palliative radiotherapy to the mediastinum and primary lung tumor. The treatment was feasible and well tolerated. The patient achieved a partial response in the irradiated tumor region and the metastatic sites. Conclusion: The combination of afatinib and radiotherapy is promising and should be investigated further. However, because of the limited experience and potential side effects known for other EGFR TKIs, a decision for treatment outside a clinical trial has to be made very carefully, balancing the risk and benefit on an individual patient basis.
© 2014 S. Karger GmbH, Freiburg 2296-5270/14/0375-0262$39.50/0 Fax +49 761 4 52 07 14 [email protected] www.karger.com
Accessible online at: www.karger.com/ort
Introduction Radiotherapy (RT) plays an important role in the management of lung cancer. It is established in patients with earlystage non-small cell lung cancer (NSCLC) who are not candidates for curative resection, or in locally advanced stages in combination with chemotherapy and/or operation. In the metastatic setting, RT is used in patients with directly tumorrelated, local symptomatic disease or to prevent imminent complications through direct tumor invasion. Common examples are brain metastases, painful or instable bone metastases or mediastinal tumors causing a vena cava superior compression. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are very effective drugs in the treatment of metastatic NSCLC, in tumors harboring activating EGFR mutations [1, 2]. The use of first generation EGFR TKIs, such as erlotinib and gefitinib, in combination with RT has not been widely investigated in clinical trials. In phase I and II trials with limited numbers of lung cancer patients, erlotinib or gefitinib seemed feasible in combination with concurrent thoracic radiation, and the toxicity was acceptable [3– 11]. However, there have also been reports of patients who experienced severe toxicity, such as acute severe skin reactions [12] or delayed-type events such as pneumonitis [13, 14].
Akin Atmaca, MD Department of Oncology and Hematology Krankenhaus Nordwest Steinbacher Hohl 2–26, 60488 Frankfurt/M., Germany [email protected]
Downloaded by: 198.143.55.65 - 8/13/2015 11:29:23 AM
Keywords Lung cancer · EGFR · Afatinib · Radiotherapy · Toxicity
Fig. 1. Target volume and dose distribution.
Therefore, the decision for the use of EGFR TKIs in combination with RT has to be discussed very carefully for each patient. Afatinib is a second generation TKI that binds irreversibly to all members of the ErbB family (i.e. EGFR, HER2 and ERBB4, thereby also inhibiting transphosphorylation of ERBB3). Like the first generation EGFR TKIs, afatinib is superior to standard chemotherapy in the first-line setting in patients with activating EGFR mutations [15]. It is also supposed to be active in patients who become refractory to previously effective first-generation TKI treatment [16]. Here we describe a patient with metastatic NSCLC who was treated with afatinib and received concurrent palliative thoracic RT.
A 77-year-old woman was referred to the hospital with acute rightsided thoracic pain and a history of shortness of breath and coughing for 4 months. A computed tomography (CT)/pulmonary angiography revealed a pulmonary embolism in the right lower and upper lobe pulmonary artery. Additionally, a mass in the right upper lobe and multiple pulmonary nodules were detected, suggesting a metastatic lung neoplasm. She had no smoking history and medically controlled hypertension. A bronchoscopy and endobronchial ultrasound was performed, showing a submucosal tumor infiltration in the right upper bronchus. The biopsy revealed a moderately differentiated adenocarcinoma, highly positive for thyroid transcription factor-1 (TTF1). Since positron emission tomography (PET)-CT showed uptake in the right iliac bone, the patient was diagnosed with NSCLC with diffuse pulmonary metastases and suspected bone metastasis, stage IVb. No EGFR mutation analysis was performed, as this was not broadly established at that time (time of fist diagnosis: August 2009). She received 6 cycles of cisplatin/pemetrexed for 4 months, initially resulting in disease control. After completion of the palliative chemotherapy, a slight progression was observed, so the patient continued treatment with a switch maintenance (or early second-line) to erlotinib 150 mg/day. With this treatment the patient reached disease stabilization. Due to skin toxicity, the daily dose of erlotinib was reduced to 100 mg/day. After 10 months on erlotinib, she switched to gefitinib due to unmanageable toxicity, especially paronychia. This decision was made due to the favorable course of disease under erlotinib; however, it has to be stated that this was an off-label use. After 6 months without disease progression on gefitinib, she relapsed with a significant increase of the tumor in the right upper lobe and progressive mediastinal lymph nodes with imminent upper vena cava compression. We decided to proceed to palliative RT for local control and to prevent vena cava superior syndrome. With respect to the simultaneously progressive systemic disease (diffuse pulmonary metastases), we enrolled the patient in a compassionate use program with afatinib. Because of relevant toxicity during previous erlotinib treatment and the potential interaction with RT, we decided to start with the reduced dose of 30 mg/day. The patient received a conventionally fractionated RT of the primary tumor region and the mediastinum with a total dose of 50 Gy (fractionated 25 × 2 Gy/day). The planning target volume and the dose distribution are depicted on figure 1. The volume of the right lung receiving 20 Gy was 25% (V20), of the left lung 0%. The dose exposure to 20% of the right lung (D20) was 24 Gy, to the left lung 8 Gy. The mean lung dose was 12.6 Gy right-sided, 3.9 Gy left-sided. The dose exposure to the lung was, therefore, comparatively low. There was no acute skin toxicity and only mild signs of esophagitis, easily manageable with local antacid/local anesthetic combination treatment (oxetacain/magnesium hydroxide/aluminum hydroxide) in the 3rd week of radiotherapy. In general, the patient developed no toxicity other than mild rash on her face (grade 1). After completion of RT we increased the afatinib dose to 40 mg/day. CT imaging after 2 cycles (2 months, fig. 2) of treatment showed a remarkable partial response in the irradiated tumor region, as well as in the diffuse pulmonary metastases. She continued with afatinib
Afatinib and Radiotherapy in Lung Cancer
Oncol Res Treat 2014;37:262–265
Fig. 2. Computed tomography imaging study exemplarily showing disease status prior to the initation of afatinib treatment (A) and 2 months after afatinib therapy (B). Post-treatment imaging (B) shows a shrinkage of the primary tumor in the right upper lobe and the mediastinal mass, and a reduction in number and size of bilateral pulmonary nodules.
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Case Report
for 4 additional months with an acceptable toxicity profile consisting of mild skin rash and conservatively manageable paronychia in her toes. In a subsequent imaging study 6 months after start of afatinib, we observed 1 new or increasing (retrospectively detectable on an imaging study 2 months previously) hepatic lesion. We continued treatment with afatinib due to acceptable systemic disease control and performed a locoregional treatment of the liver lesion with radio-frequency ablation. Unfortunately, the next imaging study 2 months later showed significant systemic disease progression with the occurrence of new metastatic lesions. Therefore, the afatinib treatment was terminated and the patient was treated with chemotherapy again (pemetrexed re-induction), and palliative radiation for symptomatic bone metastases was initiated. Since brain metastases were also newly diagnosed, she further received whole-brain radiation, but finally died due to massive and rapid disease progression 4 months later.
Discussion As yet, no case reports have been published on the combination of the second-generation EGFR TKI afatinib and RT; therefore, to our knowledge, this is the first report on a patient receiving palliative RT concurrently with daily afatinib. For this case, we have shown that afatinib treatment was feasible at a daily dose of 30 mg with concurrent thoracic RT. The dose-volume parameters of the lung were carefully considered. The patient had no major side effects from the systemic treatment or from the local radiation treatment. The rationale of combining afatinib with RT was based on observations of synergistic effects of EGFR TKI in vitro and in vivo [17]. Similar to first-generation EGFR TKI, a synergistic and radio-sensitizing effect has been observed with afatinib and radiation in animal models [18]. Afatinib was recently approved by the American Food and Drug Administration for first-line treatment of patients with metastatic NSCLC who harbored EGFR exon 19 deletions or
exon 21 (L858R) substitution mutations, and by the European Medicines Agency for the treatment of EGFR TKI-naïve adult patients with locally advanced or metastatic (NSCLC) with activating EGFR mutation(s). Many of these patients have symptomatic metastases (e.g. bone metastases), which need additional local treatment. Although systemic therapy with TKI can reduce symptoms within a short period after initiation, in selected cases additional loco-regional therapy such as RT is needed. Another scenario requiring concurrent RT with EGFR TKI is resistance to TKI treatment. When patients become ‘TKI resistant’, but the systemic disease control is still sufficient, EGFR TKI therapy will often be continued in parallel to additional local treatment, e.g. RT. There is thus a substantial need for clarifying the feasibility of EGFR TKI in general, and in particular of afatinib in combination with concurrent RT. Our case can serve as a basis for further investigations. No EGFR mutation analysis was performed in our patient. It should be noted, however, that EGFR TKI (gefitinib and afatinib) are only approved and effective in patients with activating EGFR mutations. Therefore, especially in patients with unknown EGFR status or patients becoming resistant to EGFR TKI, a re-biopsy needs to be considered. In conclusion, the combination of afatinib and RT is promising and should be further investigated in clinical trials. However, with respect to limited experience and the potential side effects known from other EGFR TKI, the decision for treatment outside a clinical trial has to be made very carefully, balancing the risk and benefit on an individual patient basis.
Disclosure Statement Akin Atmaca received honoraria from Boehringer Ingelheim Pharma for membership of advisory boards.
References
264
inoperable stage III NSCLC. J Thorac Oncol 2008;3:1003–1011. 6 Chang CC, Chi KH, Kao SJ, et al.: Upfront gefitinib/erlotinib treatment followed by concomitant radiotherapy for advanced lung cancer: a monoinstitutional experience. Lung Cancer 2011;73:189– 194. 7 Niho S, Ohe Y, Ishikura S, et al.: Induction chemotherapy followed by gefitinib and concurrent thoracic radiotherapy for unresectable locally advanced adenocarcinoma of the lung: A multicenter feasibility study (JCOG 0402). Ann Oncol 2012;23:2253–2258. 8 Okamoto I, Takahashi T, Okamoto H, et al.: Singleagent gefitinib with concurrent radiotherapy for locally advanced NSCLC harboring mutations of the epidermal growth factor receptor. Lung Cancer 2011;72:199–204. 9 Rothschild S, Bucher SE, Bernier J, et al.: Gefitinib in combination with irradiation with or without cisplatin in patients with inoperable stage III NSCLC: A phase I trial. Int J Radiat Oncol Biol Phys 2011;80:126–132.
Oncol Res Treat 2014;37:262–265
10 Stinchcombe TE, Morris DE, Lee CB, et al.: Induction chemotherapy with carboplatin, irinotecan, and paclitaxel followed by high dose three-dimension conformal thoracic radiotherapy (74 Gy) with concurrent carboplatin, paclitaxel, and gefitinib in unresectable stage IIIA and stage IIIB NSCLC. J Thorac Oncol 2008;3:250–257. 11 Ready N, Jänne PA, Bogart J, et al.: Chemoradiotherapy and gefitinib in stage III NSCLC with EGFR and KRAS mutation analysis: Cancer and leukemia group B (CALEB) 30106, a CALGB-stratified phase II trial. J Thorac Oncol 2010;5:1382–1390. 12 Huang YJ, Liu SF, Wang CJ, Huang MY: Exacerbated radiodermatitis and bilateral subdural hemorrhage after whole brain irradiation combined with EGFR TKI for brain metastases in lung cancer. Lung Cancer 2008;59:407–410. 13 Onal C, Abali H, Koc Z, Kara S: Radiation recall pneumonitis caused by erlotinib after palliative definitive radiotherapy. Onkologie 2012;35:191– 194.
Atmaca/Al-Batran/Allgäuer/Jäger
Downloaded by: 198.143.55.65 - 8/13/2015 11:29:23 AM
1 Mok TS, Wu YL, Thongprasert S, et al.: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947–957. 2 Rosell R, Carcereny E, Gervais R, et al.: Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive NSCLC (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239–246. 3 Wang J, Xia TY, Wang YJ, et al.: Prospective study of EGFR TKI concurrent with individualized radiotherapy for patients with locally advanced or metastatic non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81:e59–65. 4 Center B, Petty WJ, Ayala D, et al.: A phase I study of gefitinib with concurrent dose-escalated weekly docetaxel and conformal three-dimensional thoracic radiation followed by consolidative docetaxel and maintenance gefitinib for patients with stage III NSCLC. J Thorac Oncol 2010;5: 69–74. 5 Choong NW, Mauer AM, Haraf DJ, et al.: Phase I trial of erlotinib-based multimodality therapy for
Afatinib and Radiotherapy in Lung Cancer
16 Miller VA, Hirsh V, Cadranel J, et al.: Afatinib versus placebo for patients with advanced, metastatic NSCLC after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUXLung 1): A phase 2b/3 randomised trial. Lancet Oncol 2012;13:528–538. 17 Xu Y, Zhang Y, Ma S: EGFR inhibitors with concurrent thoracic radiation therapy for locally advanced NSCLC. Lung Cancer 2011;73:249–255.
18 Tsai YC, Yeh CH, Tzen KY, et al.: Targeting epidermal growth factor receptor/human epidermal growth factor receptor 2 signalling pathway by a dual receptor tyrosine kinase inhibitor afatinib for radiosensitisation in murine bladder carcinoma. Eur J Cancer 2013;49:1458–1466.
Oncol Res Treat 2014;37:262–265
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14 Nanda A, Dias-Santagata DC, Stubbs H, et al.: Unusual tumor response and toxicity from radiation and concurrent erlotinib for NSCLC. Clin Lung Cancer 2008;9:285–287. 15 Sequist LV, Yang JC, Yamamoto N, et al.: Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327– 3334.
Received: January 16, 2014 Accepted: March 21, 2014 Published online: April 14, 2014
Afatinib with Concurrent Radiotherapy in a Patient with Metastatic Non-Small Cell Lung Cancer Akin Atmacaa Salah-Eddin Al-Batranb Michael Allgäuerc Elke Jägera a Department of Oncology and Hematology; bInstitute of Clinical Cancer Research (IKF), Krankenhaus Nordwest, UCT University Cancer Center, Frankfurt/M.; cDepartment of Radiation Oncology, Krankenhaus Barmherzige Brüder, Regensburg, Germany
Established Facts • In general, first generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) seem to be a feasible treatment in combination with concurrent thoracic radiation. • There are also reports from patients who experienced severe toxicity, such as acute severe skin reactions or delayed-type events such as pneumonitis.
Novel Insights • The second generation, pan-Erb EGFR TKI afatinib could safely be administered in a dose of 30 mg/day with concurrent thoracic radiotherapy.
Summary Background: The combination of radiotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib in patients with advanced or metastatic non-small cell lung cancer (NSCLC) has not been widely investigated. For afatinib, a new second generation irreversible pan-EGFR TKI, no clinical trials in this setting have as yet been performed. Case Report: We report a patient with a pretreated metastatic NSCLC receiving afatinib in combination with concomitant palliative radiotherapy to the mediastinum and primary lung tumor. The treatment was feasible and well tolerated. The patient achieved a partial response in the irradiated tumor region and the metastatic sites. Conclusion: The combination of afatinib and radiotherapy is promising and should be investigated further. However, because of the limited experience and potential side effects known for other EGFR TKIs, a decision for treatment outside a clinical trial has to be made very carefully, balancing the risk and benefit on an individual patient basis.
© 2014 S. Karger GmbH, Freiburg 2296-5270/14/0375-0262$39.50/0 Fax +49 761 4 52 07 14 [email protected] www.karger.com
Accessible online at: www.karger.com/ort
Introduction Radiotherapy (RT) plays an important role in the management of lung cancer. It is established in patients with earlystage non-small cell lung cancer (NSCLC) who are not candidates for curative resection, or in locally advanced stages in combination with chemotherapy and/or operation. In the metastatic setting, RT is used in patients with directly tumorrelated, local symptomatic disease or to prevent imminent complications through direct tumor invasion. Common examples are brain metastases, painful or instable bone metastases or mediastinal tumors causing a vena cava superior compression. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are very effective drugs in the treatment of metastatic NSCLC, in tumors harboring activating EGFR mutations [1, 2]. The use of first generation EGFR TKIs, such as erlotinib and gefitinib, in combination with RT has not been widely investigated in clinical trials. In phase I and II trials with limited numbers of lung cancer patients, erlotinib or gefitinib seemed feasible in combination with concurrent thoracic radiation, and the toxicity was acceptable [3– 11]. However, there have also been reports of patients who experienced severe toxicity, such as acute severe skin reactions [12] or delayed-type events such as pneumonitis [13, 14].
Akin Atmaca, MD Department of Oncology and Hematology Krankenhaus Nordwest Steinbacher Hohl 2–26, 60488 Frankfurt/M., Germany [email protected]
Downloaded by: 198.143.55.65 - 8/13/2015 11:29:23 AM
Keywords Lung cancer · EGFR · Afatinib · Radiotherapy · Toxicity
Fig. 1. Target volume and dose distribution.
Therefore, the decision for the use of EGFR TKIs in combination with RT has to be discussed very carefully for each patient. Afatinib is a second generation TKI that binds irreversibly to all members of the ErbB family (i.e. EGFR, HER2 and ERBB4, thereby also inhibiting transphosphorylation of ERBB3). Like the first generation EGFR TKIs, afatinib is superior to standard chemotherapy in the first-line setting in patients with activating EGFR mutations [15]. It is also supposed to be active in patients who become refractory to previously effective first-generation TKI treatment [16]. Here we describe a patient with metastatic NSCLC who was treated with afatinib and received concurrent palliative thoracic RT.
A 77-year-old woman was referred to the hospital with acute rightsided thoracic pain and a history of shortness of breath and coughing for 4 months. A computed tomography (CT)/pulmonary angiography revealed a pulmonary embolism in the right lower and upper lobe pulmonary artery. Additionally, a mass in the right upper lobe and multiple pulmonary nodules were detected, suggesting a metastatic lung neoplasm. She had no smoking history and medically controlled hypertension. A bronchoscopy and endobronchial ultrasound was performed, showing a submucosal tumor infiltration in the right upper bronchus. The biopsy revealed a moderately differentiated adenocarcinoma, highly positive for thyroid transcription factor-1 (TTF1). Since positron emission tomography (PET)-CT showed uptake in the right iliac bone, the patient was diagnosed with NSCLC with diffuse pulmonary metastases and suspected bone metastasis, stage IVb. No EGFR mutation analysis was performed, as this was not broadly established at that time (time of fist diagnosis: August 2009). She received 6 cycles of cisplatin/pemetrexed for 4 months, initially resulting in disease control. After completion of the palliative chemotherapy, a slight progression was observed, so the patient continued treatment with a switch maintenance (or early second-line) to erlotinib 150 mg/day. With this treatment the patient reached disease stabilization. Due to skin toxicity, the daily dose of erlotinib was reduced to 100 mg/day. After 10 months on erlotinib, she switched to gefitinib due to unmanageable toxicity, especially paronychia. This decision was made due to the favorable course of disease under erlotinib; however, it has to be stated that this was an off-label use. After 6 months without disease progression on gefitinib, she relapsed with a significant increase of the tumor in the right upper lobe and progressive mediastinal lymph nodes with imminent upper vena cava compression. We decided to proceed to palliative RT for local control and to prevent vena cava superior syndrome. With respect to the simultaneously progressive systemic disease (diffuse pulmonary metastases), we enrolled the patient in a compassionate use program with afatinib. Because of relevant toxicity during previous erlotinib treatment and the potential interaction with RT, we decided to start with the reduced dose of 30 mg/day. The patient received a conventionally fractionated RT of the primary tumor region and the mediastinum with a total dose of 50 Gy (fractionated 25 × 2 Gy/day). The planning target volume and the dose distribution are depicted on figure 1. The volume of the right lung receiving 20 Gy was 25% (V20), of the left lung 0%. The dose exposure to 20% of the right lung (D20) was 24 Gy, to the left lung 8 Gy. The mean lung dose was 12.6 Gy right-sided, 3.9 Gy left-sided. The dose exposure to the lung was, therefore, comparatively low. There was no acute skin toxicity and only mild signs of esophagitis, easily manageable with local antacid/local anesthetic combination treatment (oxetacain/magnesium hydroxide/aluminum hydroxide) in the 3rd week of radiotherapy. In general, the patient developed no toxicity other than mild rash on her face (grade 1). After completion of RT we increased the afatinib dose to 40 mg/day. CT imaging after 2 cycles (2 months, fig. 2) of treatment showed a remarkable partial response in the irradiated tumor region, as well as in the diffuse pulmonary metastases. She continued with afatinib
Afatinib and Radiotherapy in Lung Cancer
Oncol Res Treat 2014;37:262–265
Fig. 2. Computed tomography imaging study exemplarily showing disease status prior to the initation of afatinib treatment (A) and 2 months after afatinib therapy (B). Post-treatment imaging (B) shows a shrinkage of the primary tumor in the right upper lobe and the mediastinal mass, and a reduction in number and size of bilateral pulmonary nodules.
263
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Case Report
for 4 additional months with an acceptable toxicity profile consisting of mild skin rash and conservatively manageable paronychia in her toes. In a subsequent imaging study 6 months after start of afatinib, we observed 1 new or increasing (retrospectively detectable on an imaging study 2 months previously) hepatic lesion. We continued treatment with afatinib due to acceptable systemic disease control and performed a locoregional treatment of the liver lesion with radio-frequency ablation. Unfortunately, the next imaging study 2 months later showed significant systemic disease progression with the occurrence of new metastatic lesions. Therefore, the afatinib treatment was terminated and the patient was treated with chemotherapy again (pemetrexed re-induction), and palliative radiation for symptomatic bone metastases was initiated. Since brain metastases were also newly diagnosed, she further received whole-brain radiation, but finally died due to massive and rapid disease progression 4 months later.
Discussion As yet, no case reports have been published on the combination of the second-generation EGFR TKI afatinib and RT; therefore, to our knowledge, this is the first report on a patient receiving palliative RT concurrently with daily afatinib. For this case, we have shown that afatinib treatment was feasible at a daily dose of 30 mg with concurrent thoracic RT. The dose-volume parameters of the lung were carefully considered. The patient had no major side effects from the systemic treatment or from the local radiation treatment. The rationale of combining afatinib with RT was based on observations of synergistic effects of EGFR TKI in vitro and in vivo [17]. Similar to first-generation EGFR TKI, a synergistic and radio-sensitizing effect has been observed with afatinib and radiation in animal models [18]. Afatinib was recently approved by the American Food and Drug Administration for first-line treatment of patients with metastatic NSCLC who harbored EGFR exon 19 deletions or
exon 21 (L858R) substitution mutations, and by the European Medicines Agency for the treatment of EGFR TKI-naïve adult patients with locally advanced or metastatic (NSCLC) with activating EGFR mutation(s). Many of these patients have symptomatic metastases (e.g. bone metastases), which need additional local treatment. Although systemic therapy with TKI can reduce symptoms within a short period after initiation, in selected cases additional loco-regional therapy such as RT is needed. Another scenario requiring concurrent RT with EGFR TKI is resistance to TKI treatment. When patients become ‘TKI resistant’, but the systemic disease control is still sufficient, EGFR TKI therapy will often be continued in parallel to additional local treatment, e.g. RT. There is thus a substantial need for clarifying the feasibility of EGFR TKI in general, and in particular of afatinib in combination with concurrent RT. Our case can serve as a basis for further investigations. No EGFR mutation analysis was performed in our patient. It should be noted, however, that EGFR TKI (gefitinib and afatinib) are only approved and effective in patients with activating EGFR mutations. Therefore, especially in patients with unknown EGFR status or patients becoming resistant to EGFR TKI, a re-biopsy needs to be considered. In conclusion, the combination of afatinib and RT is promising and should be further investigated in clinical trials. However, with respect to limited experience and the potential side effects known from other EGFR TKI, the decision for treatment outside a clinical trial has to be made very carefully, balancing the risk and benefit on an individual patient basis.
Disclosure Statement Akin Atmaca received honoraria from Boehringer Ingelheim Pharma for membership of advisory boards.
References
264
inoperable stage III NSCLC. J Thorac Oncol 2008;3:1003–1011. 6 Chang CC, Chi KH, Kao SJ, et al.: Upfront gefitinib/erlotinib treatment followed by concomitant radiotherapy for advanced lung cancer: a monoinstitutional experience. Lung Cancer 2011;73:189– 194. 7 Niho S, Ohe Y, Ishikura S, et al.: Induction chemotherapy followed by gefitinib and concurrent thoracic radiotherapy for unresectable locally advanced adenocarcinoma of the lung: A multicenter feasibility study (JCOG 0402). Ann Oncol 2012;23:2253–2258. 8 Okamoto I, Takahashi T, Okamoto H, et al.: Singleagent gefitinib with concurrent radiotherapy for locally advanced NSCLC harboring mutations of the epidermal growth factor receptor. Lung Cancer 2011;72:199–204. 9 Rothschild S, Bucher SE, Bernier J, et al.: Gefitinib in combination with irradiation with or without cisplatin in patients with inoperable stage III NSCLC: A phase I trial. Int J Radiat Oncol Biol Phys 2011;80:126–132.
Oncol Res Treat 2014;37:262–265
10 Stinchcombe TE, Morris DE, Lee CB, et al.: Induction chemotherapy with carboplatin, irinotecan, and paclitaxel followed by high dose three-dimension conformal thoracic radiotherapy (74 Gy) with concurrent carboplatin, paclitaxel, and gefitinib in unresectable stage IIIA and stage IIIB NSCLC. J Thorac Oncol 2008;3:250–257. 11 Ready N, Jänne PA, Bogart J, et al.: Chemoradiotherapy and gefitinib in stage III NSCLC with EGFR and KRAS mutation analysis: Cancer and leukemia group B (CALEB) 30106, a CALGB-stratified phase II trial. J Thorac Oncol 2010;5:1382–1390. 12 Huang YJ, Liu SF, Wang CJ, Huang MY: Exacerbated radiodermatitis and bilateral subdural hemorrhage after whole brain irradiation combined with EGFR TKI for brain metastases in lung cancer. Lung Cancer 2008;59:407–410. 13 Onal C, Abali H, Koc Z, Kara S: Radiation recall pneumonitis caused by erlotinib after palliative definitive radiotherapy. Onkologie 2012;35:191– 194.
Atmaca/Al-Batran/Allgäuer/Jäger
Downloaded by: 198.143.55.65 - 8/13/2015 11:29:23 AM
1 Mok TS, Wu YL, Thongprasert S, et al.: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947–957. 2 Rosell R, Carcereny E, Gervais R, et al.: Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive NSCLC (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239–246. 3 Wang J, Xia TY, Wang YJ, et al.: Prospective study of EGFR TKI concurrent with individualized radiotherapy for patients with locally advanced or metastatic non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81:e59–65. 4 Center B, Petty WJ, Ayala D, et al.: A phase I study of gefitinib with concurrent dose-escalated weekly docetaxel and conformal three-dimensional thoracic radiation followed by consolidative docetaxel and maintenance gefitinib for patients with stage III NSCLC. J Thorac Oncol 2010;5: 69–74. 5 Choong NW, Mauer AM, Haraf DJ, et al.: Phase I trial of erlotinib-based multimodality therapy for
Afatinib and Radiotherapy in Lung Cancer
16 Miller VA, Hirsh V, Cadranel J, et al.: Afatinib versus placebo for patients with advanced, metastatic NSCLC after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUXLung 1): A phase 2b/3 randomised trial. Lancet Oncol 2012;13:528–538. 17 Xu Y, Zhang Y, Ma S: EGFR inhibitors with concurrent thoracic radiation therapy for locally advanced NSCLC. Lung Cancer 2011;73:249–255.
18 Tsai YC, Yeh CH, Tzen KY, et al.: Targeting epidermal growth factor receptor/human epidermal growth factor receptor 2 signalling pathway by a dual receptor tyrosine kinase inhibitor afatinib for radiosensitisation in murine bladder carcinoma. Eur J Cancer 2013;49:1458–1466.
Oncol Res Treat 2014;37:262–265
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14 Nanda A, Dias-Santagata DC, Stubbs H, et al.: Unusual tumor response and toxicity from radiation and concurrent erlotinib for NSCLC. Clin Lung Cancer 2008;9:285–287. 15 Sequist LV, Yang JC, Yamamoto N, et al.: Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327– 3334.
