Efficacy of Prophylactic Traditional Chinese Medicine on Skin Toxicity of Afatinib in EGFR Mutation-Positive Advanced Lung Adenocarcinoma: A Single-Center, Prospective, Double-Blinded, Randomized-Controlled Pilot Trial

Chia-Ling Li, Te-Chun Hsia, Su-Tso Yang, Kun-San Clifford Chao, Chih-Yen Tu, Hung-Jen Chen, Chia-Hsiang Li, Chia-Ling Li, Te-Chun Hsia, Su-Tso Yang, Kun-San Clifford Chao, Chih-Yen Tu, Hung-Jen Chen, Chia-Hsiang Li

Abstract

Objectives: To evaluate the efficacy of prophylactic traditional Chinese medicine (TCM) on skin toxicities in patients with advanced lung adenocarcinoma treated with first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in a randomized-controlled trial (RCT).

Materials and methods: This pilot study was a prospective, single-center, double-blinded RCT. The study enrolled patients with a new diagnosis of locally advanced and metastatic lung adenocarcinoma harboring EGFR mutations who were treated with first-line afatinib from July 1, 2016 to December 31, 2017. Thirty patients who met the inclusion and exclusion criteria were assigned to the TCM and placebo groups with simple randomization. TCM and placebo were initiated at the same time as afatinib and were administered for 3 months. The survival of each subject was followed until 3 years.

Results: There were 36 patients with newly diagnosed lung adenocarcinoma during the study period. After the exclusion of 6 patients, the remaining 30 patients were assigned to the TCM (n = 14) and placebo (n = 16) groups comprising the intention-to-treat population. The time to first skin toxicity was 22.3 days in the TCM group and 17.6 days in the placebo group (P = .510) in the per-protocol population. The analysis of the present pilot study results determined that the difference in time to first skin toxicity between the 2 groups would reach statistical significance with a sample size of 237 based on a power of 0.8. There were significant differences in certain subscales of quality of life between the TCM and placebo groups; however, there was no significant difference in progression-free survival or overall survival between the 2 groups.

Conclusions: Integrative TCM may prolong the time to first skin toxicity in patients with advanced lung adenocarcinoma treated with first-line afatinib. Prophylactic TCM could delay skin toxicity of any grade and reduce the incidence of grade 3 skin toxicity. Future large-scale RCTs are warranted to validate these findings.

Trial registration: ClinicalTrials.gov, NCT05204758. Registered on 24 Jan 2022.

Keywords: EGFR-TKI; advanced lung adenocarcinoma; prophylaxis; quality of life; skin toxicity; traditional Chinese medicine.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
CONSORT flow diagram of the patient enrollment process in the TCM and placebo groups in the ITT population, modified ITT population, and PP populations.
Figure 2.
Figure 2.
Skin toxicity of any grade on day 14 in the TCM and placebo groups in the PP population.
Figure 3.
Figure 3.
Time to first skin toxicity of any grade in the TCM and placebo groups in the PP population.
Figure 4.
Figure 4.
(A–C) Kaplan–Meier curves of OS in patients with advanced lung adenocarcinoma in the ITT population who were treated with first-line afatinib in combination with TCM or placebo during the follow-up period. (A) All patients, (B) those with del19, and (C) those with the L858R mutation. (D–F) Kaplan–Meier curves of PFS in patients with advanced lung adenocarcinoma in the ITT population who were treated with first-line afatinib in combination with TCM or placebo during the follow-up period. (D) All patients, (E) those with del19, and (F) those with the L858R mutation. Abbreviations: ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival; TCM, traditional Chinese medicine.

References

    1. Lynch TJ, Bell DW, Sordella R, et al.. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New Engl J Med. 2004;350:2129-2139.
    1. Paez JG, Jänne PA, Lee JC, et al.. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497-1500.
    1. Soda M, Choi YL, Enomoto M, et al.. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-566.
    1. Maemondo M, Inoue A, Kobayashi K, et al.. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. New Engl J Med. 2010;362:2380-2388.
    1. Mitsudomi T, Morita S, Yatabe Y, et al.. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121-128.
    1. Zhou C, Wu YL, Chen G, 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, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735-742.
    1. Rosell R, Carcereny E, Gervais R, 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;13:239-246.
    1. 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.
    1. Wu YL, Zhou C, Hu CP, et al.. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:213-222.
    1. Urata Y, Katakami N, Morita S, et al.. Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma: WJOG 5108L. J Clin Oncol. 2016;34:3248-3257.
    1. Nelson V, Ziehr J, Agulnik M, Johnson M. Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC. Onco Targets Ther. 2013;6:135-143.
    1. Park K, Tan EH, O’Byrne K, et al.. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17:577-589.
    1. Paz-Ares L, Tan EH, O’Byrne K, et al.. Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial. Ann Oncol. 2017;28:270-277.
    1. Ohashi K, Maruvka YE, Michor F, Pao W. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol. 2013;31:1070-1080.
    1. Wu SG, Liu YN, Tsai MF, et al.. The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients. Oncotarget. 2016;7:12404-12413.
    1. Jänne PA, Yang JC, Kim DW, et al.. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. New Engl J Med. 2015;372:1689-1699.
    1. Mok TS, Wu YL, Ahn MJ, et al.. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. New Engl J Med. 2017;376:629-640.
    1. Soria JC, Ohe Y, Vansteenkiste J, et al.. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. New Engl J Med. 2018;378:113-125.
    1. Ramalingam SS, Vansteenkiste J, Planchard D, et al.. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. New Engl J Med. 2020;382:41-50.
    1. Passaro A, Di Maio M, Del Signore E, Gori B, de Marinis F. Management of nonhematologic toxicities associated with different EGFR-TKIs in advanced NSCLC: a comparison analysis. Clin Lung Cancer. 2014;15:307-312.
    1. Melosky B, Leighl NB, Rothenstein J, Sangha R, Stewart D, Papp K. Management of egfr tki-induced dermatologic adverse events. Curr Oncol. 2015;22:123-132.
    1. Chen HJ, Yan HH, Yang JJ, et al.. Disease flare after EGFR tyrosine kinase inhibitor cessation predicts poor survival in patients with non-small cell lung cancer. Pathol Oncol Res. 2013;19:833-838.
    1. Takeda M, Okamoto I, Nakagawa K. Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. Lung Cancer. 2015;88:74-79.
    1. Chu CY, Chen KY, Wen-Cheng Chang J, Wei YF, Lee CH, Wang WM. Taiwanese Dermatological Association consensus for the prevention and management of epidermal growth factor receptor tyrosine kinase inhibitor-related skin toxicities. J Formos Med Assoc. 2017;116:413-423.
    1. Melosky B, Anderson H, Burkes RL, et al.. Pan Canadian Rash Trial: a randomized phase III trial evaluating the impact of a prophylactic skin treatment regimen on epidermal growth factor receptor-tyrosine kinase inhibitor-induced skin toxicities in patients with metastatic lung cancer. J Clin Oncol. 2016;34:810-815.
    1. Yang XB, Wu WY, Long SQ, Deng H, Pan ZQ. Effect of gefitinib plus Chinese herbal medicine (CHM) in patients with advanced non-small-cell lung cancer: a retrospective case-control study. Complement Ther Med. 2014;22:1010-1018.
    1. Liu ZL, Zhu WR, Zhou WC, et al.. Traditional Chinese medicinal herbs combined with epidermal growth factor receptor tyrosine kinase inhibitor for advanced non-small cell lung cancer: a systematic review and meta-analysis. J Integr Med. 2014;12:346-358.
    1. Eldridge SM, Chan CL, Campbell MJ, et al.. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. Pilot Feasibility Stud. 2016;2:64.
    1. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). (accessed 14 June 2010).
    1. Yang JC, Sequist LV, Zhou C, et al.. Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials. Ann Oncol. 2016;27:2103-2110.
    1. Eser S, Göksel T, Erbaycu AE, et al.. Comparison of generic and lung cancer-specific quality of life instruments for predictive ability of survival in patients with advanced lung cancer. Springerplus. 2016;5:1833.
    1. Hsu KH, Ho CC, Hsia TC, et al.. Identification of five driver gene mutations in patients with treatment-naïve lung adenocarcinoma in Taiwan. PLoS One. 2015;10:e0120852.
    1. Tang M, Wang S, Zhao B, et al.. Traditional Chinese medicine prolongs progression-free survival and enhances therapeutic effects in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treated non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations. Med Sci Monit. 2019;25:8430-8437.
    1. Jiao L, Xu J, Sun J, et al.. Chinese herbal medicine combined with EGFR-TKI in EGFR mutation-positive advanced pulmonary adenocarcinoma (CATLA): a multicenter, randomized, double-blind, placebo-controlled trial. Front Pharmacol. 2019;10:732.
    1. Li CL, Hsia TC, Li CH, Chen KJ, Yang YH, Yang ST. Adjunctive traditional Chinese medicine improves survival in patients with advanced lung adenocarcinoma treated with first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): a nationwide, population-based cohort study. Integr Cancer Ther. 2019;18:1534735419827079.
    1. Hochmair MJ, Morabito A, Hao D, et al.. Sequential afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: final analysis of the GioTag study. Future Oncol. 2020;16:2799-2808.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel