Introduction. Combinations of gefitinib and radiotherapy have been observed to have synergistic and anti-proliferative effects on lung cancer in vitro. In the clinical setting, patients who presented with respiratory difficulties such as superior vena cava syndrome (SVCS), radiotherapy should be given immediately to address the emergency while waiting for the results of epidermal growth factor receptor (EGFR) mutation test. However, there has been no study that described the role of radio-therapy in Indonesian patients with EGFR-mutant lung adenocarcinoma.
Methods. This preliminary study aimed to evaluate the efficacy and toxicities of gefitinib and radiotherapy combination in lung adenocarcinoma patients in Persahabatan National Respiratory Referral Hospital, Jakarta, Indonesia. Subjects were consecutively recruited between January 2013 and December 2016.
Results. Thirty-one lung adenocarcinoma with EGFR mutations were enrolled. Most of them were male (51.61%) with a median age of 54.5 years old (range 38-70 years old). EGFR mutation characteristics were on exon 21 L858R point mutation (61.30%), exon 21 L861Q point mutation (16.12%) and exon 19 deletion (22.58%). Radiotherapy was given at doses between 30-60 Gy. Among these subjects, median progression-free survival (PFS) was 185 days (95%CI; 123.69 – 246.30), 1-year survival rate (1-yr) was 45.2%, and median overall survival (OS) was 300 days (95%CI; 130.94 – 469.06). There were no grade 3/4 hematological and nonhematological toxicities recorded. The most frequent grade 1 and 2 non-hematological toxicities were skin rash, diarrhea, and paronychia that might be related to tyrosine kinase inhibitor (TKI).
Conclusion. The combination of TKI with radiation may be considered in EGFR-mutant lung adenocarcinoma subjects.
1. INDONESIAN NATIONAL COMMITTEE OF CANCER MANAGEMENT (Komite Nasional Penanggulangan Kanker [KPKN]). National Guideline of Lung Cancer Treatment (Panduan Nasional Penanganan Kanker Paru). Ministry of Health, the Republic of Indonesia (Kementrian Kesehatan Republik Indonesia); 2015.p.1-11.
2. JUSUF A., SYARIFUDDIN E., WIBAWANTO A., ICKSAN AG., JUNIARTI J., ENDARDJO S., et al. National Guideline for Diagnosis and Treatment of Non-Small Cell Lung Cancer in Indonesia (Pedoman diagnosis dan penatalaksanaan di Indonesia). The Indonesian Society of Respirology, Jakarta, 2016:1-31.
3. STOECKEL DA., MATUSCHAK GM., Lung Cancer. In: Human Organ System: Respiratory, an integrated approach to disease, McGraw-Hill, New York, 2003:307-318.
4. BRINK DS. Pathology of lung tumors, In: Human Organ System: Respiratory, an integrated approach to disease, McGraw-Hill, New York, 2003:295-305.
5. ISHII AS., KIM Y., SHIOZAWA T., IYAMA S., SATOMI K., KANO J., et al. Stratifin accelerates progression of lung adenocarcinoma at an early stage. Mol Cancer, 2015; 14:142.
6. CHANG SC., CHANG CY., SHIH JY., The role of epidermal growth factor receptor mutations and epidermal growth factor receptor-tyrosine kinase inhibitors in the treatment of lung cancer. Cancers. 2011; 3(2):2667-78.
7. RABEN D., Update of EGFR inhibitors and radiation in the management of non-small cell lung cancer, where do we go next? J Thorac Oncol., 2007; 2(8):153-4.
8. SATO Y., EBARA T., SUNAGA N., TAKAHASHI T., NAKANO T., Interaction of radiation and gefitinib on a human lung cancer cell line with mutant EGFR gene in vitro. Anticancer Res. 2012; 32(11):4877-4881.
9. IMAI H., SHUKUYA T., TAKAHASHI T, FUJIWARA S, MORI K, ONO A, AKAMATSU H, et al. Comparison of the time-to-response between radiotherapy and epidermal growth factor receptor – tyrosine kinase inhibitors for advanced non-small cell lung cancer with EGFR mutation. Anticancer Res. 2013; 33(8):3279-84.
10. YAHYA WS., ANDARINI SL., HUDOYO A., UTOMO AR., Efficacy and toxicities profile of the new epidermal growth factor receptor-tyrosine kinase (Profil efikasi dan toksisitas terapi target baru golongan epidermal growth factor receptor-Tyrosine kinase) [Thesis]. Jakarta: Universitas Indonesia; 2016.
11. CHEN J., FAN M., JIANG G., FU X., XIE L., XU X., et al., Phase I dose-escalation study of thoracic radiotherapy in combination with gefitinib in patients with IIIB/IV non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2010; 78(3):110-11.
12. XU Y., ZHANG Y., MA S., EGFR inhibitors with concurrent thoracic radiation therapy for locally advances non small cell lung cancer. Lung Cancer. 2011; 73(3):249-55.
13. SHI Y., AU JS., THONGPRASERT S., SRINIVASAN S., TSAI CM., KHOA MT., et al., A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol., 2014 Feb; 9(2):154-62.
15. MOSE S., STABIK C., EBERLEIN K, RAMM U., BOTTCHER HD., BUDISCHEWSKI K., Retrospective analysis of the superior vena cava syndrome in irradiated cancer patients. Anticancer Res., 2006; 26(6C):4933-6.
16. YU HA., SIMA CS., HUANG J., SOLOMON SB., RIMNER A., PAIK P., et al., Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol (2013) 8:346-51.
17. CONFORTI F., CATANIA C., TOFFALORIO F., DUCA M., SPITALERI G., BARBERIS M., et al., EGFR tyrosine kinase inhibitors beyond focal progression obtain a prolonged disease control in patients with advanced adenocarcinoma of the lung. Lung Cancer, 2013; 81:440-4.
18. LEVY A., BARDET E., LACAS B., PIGNON JP., ADAM J., LACOROIX L., et al., A phase II open label multicenter study of gefitinib in combination with irradiation followed by chemotherapy in patients with in operable stage III non-small cell lung cancer. Oncotarget. 2017; 8(9):15924-33.
19. FAN Y., XU Y., GONG L., FANG L., LU H., QIN J., et al., Effects of icotinib with and without radiation therapy on patients with EGFR mutant non-small cell lung cancer and brain metastases. Sci Rep., 2017; 23(7):45193.
20. WAN J., COHEN V., AGULNIK J., FARIA S., PORTELANCE L., OFIARA L., et al., Unexpected high lung toxicity from radiation pneumonitis in a Phase I/II trial of concurrent erlotinib with limited field radiation for intermediate prognosis patients with stage III or inoperable stage IIB non-small-cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys, 2009; 75(3): S110.
21. KRIS MG., NATALE RB., HERBST RS., LYNCH TJ., PRAGER D., BELANI CP., et al., Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase in symptomatic patients with non-small cell lung cancer. JAMA 2003; 290(16):2149-58.