Research Article | Open Access
Maria Pia Fuggetta, Maria Rita Migliorino, Serena Ricciardi, Giorgia Osman, Daniela Iacono, Alvaro Leone, Alessandra Lombardi, Giampietro Ravagnan, Stefania Greco, Daniele Remotti, Maria Concetta Pucci Romano, "Prophylactic Dermatologic Treatment of Afatinib-Induced Skin Toxicities in Patients with Metastatic Lung Cancer: A Pilot Study", Scientifica, vol. 2019, Article ID 9136249, 6 pages, 2019. https://doi.org/10.1155/2019/9136249
Prophylactic Dermatologic Treatment of Afatinib-Induced Skin Toxicities in Patients with Metastatic Lung Cancer: A Pilot Study
Background. Severe skin rash is listed among important side effects of EGFR tyrosine kinase inhibitors. Polydatin (PD), a glycosylated polyphenol, is endowed with anti-inflammatory activity in human epidermal keratinocytes. Objective. This study evaluated the effect of topical application of a moisturizer containing PD to prevent skin rash in patients with mutated non-small cell lung cancer (NSCLC) treated with afatinib. Materials and Methods. Eligible NSCLC patients with metastatic disease were treated with first-line afatinib 40 mg/die. One day before starting systemic therapy, all patients received topical administration of a 1.5% PD-based cream b.i.d. every day until the end of afatinib treatment. Results. Out of 34 treated patients, the incidence of skin rash (all grades) was 41.2% and grade 2 rash was 20.6%, and grade 3 rash was not observed in any of the patients. None of the patients discontinued therapy for toxicity. The mean duration of treatment was 6.4 months, calculated from the time treatment was started to the date treatment was stopped. Conclusion. The results showed that a PD-based cream can reduce the incidence of grade ≥2 skin toxicities in patients treated with afatinib. Clinical study registration number: Prot. No. 130/CE Lazio 1 Italy.
In recent years a substantial progress has been achieved in the treatment of non-small cell lung cancer (NSCLC) through molecular analysis capable of driving the development of more efficient and selective targeted therapy .
The epidermal growth factor receptor (EGFR or ErbB1 or HER1), a tyrosine kinase receptor, can activate a wide range of signalling pathways leading to cell growth, proliferation, and survival . Overexpression of EGFR is strongly associated with the development and progression of several malignant tumours, including advanced NSCLC . EGFR is overexpressed and frequently mutated in up to 40–80% of NSCLC and has been considered a good candidate as therapeutic target. The two most common mutations are exon 19 deletions (60%) and L858R missense substitutions at position 858 (35%), where leucine is replaced by arginine, leading to constitutive activation of the receptor [4, 5]. Mutant EGFR can be inhibited either by low-molecular-weight tyrosine kinase inhibitors (TKIs such as gefitinib, afatinib, and erlotinib) or monoclonal antibodies (e.g. cetuximab) [4–7]. Afatinib is a potent second-generation irreversible ErbB family blocker that inhibits tyrosine kinase activity of EGFR and all relevant ErbB family dimmers . In recent clinical trials, afatinib alone was found to be superior to platinum-based doublet chemotherapy in terms of either progression-free survival or overall survival of non-pretreated NSCLC patients with activating EGFR mutations [9–12].
In general, the cutaneous toxicities associated with these targeted agents can potentially affect patient quality of life and treatment compliance and predispose the skin to bacterial, fungal, or viral infections. It is urgently needed to adopt therapeutic and preventive strategies for the management of such toxicities to continue the treatment, maintaining maximal patient tolerability and avoiding treatment delays and interruptions . Strategies to reduce EGFR-TKIs-related adverse events are expected to obtain superior clinical outcomes, a better compliance, and an improved quality of life for patients with advanced NSCLC . Considering the severe local skin toxicity, the treatment is based on drugs capable of reducing mainly the inflammatory cell recruitment. Polydatin (PD, 3,4′,5-trihydroxystilbene-3-β-mono-D-glucoside, also known as piceid) is a polyphenol extracted from the root stem of a traditional Chinese herb named Polygonum cuspidatum . Among a number of different pharmacodynamic properties, PD has shown potent anti-inflammatory [16–19], antioxidant [20, 21], antiallergy , and anticancer activities . Furthermore, polyphenols as PD can interfere in the EGFR system in human keratinocytes, and this effect may be implicated in the regulation of inflammatory and repair-related processes in the skin [24, 25]. In addition, PD induces β-defensin production reducing inflammatory response , and preliminary human in vivo studies showed that daily dietary administration of PD significantly reduced lipid peroxidation levels .
All these data prompted us to consider cutaneous application of PD as protective treatment in afatinib-induced skin rash. The present retrospective pilot study evaluated the protective effect of topical application of a cream preparation containing PD against afatinib-induced skin rash in patients with EGFR-mutated stage IV NSCLC.
2. Materials and Methods
2.1. Patient Selection
Adult patients (age ≥ 18 years) with a histologic or cytologic documented diagnosis of metastatic stage IV NSCLC harbouring activating EGFR common mutations were considered. However, only patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, capable of receiving first-line afatinib 40 mg/die treatment, were eligible for the study. Main exclusion criteria were poor patient compliance, allergic/sensitive to PD, ongoing or previous treatment with other antioxidant topic or oral drugs, and concomitant skin diseases.
2.2. Study Design and Treatments
The trial was specifically designed to evaluate a topical protective treatment of EGFR-mediated skin toxicity in order to minimize dose reduction or treatment discontinuation. Patients, after a primary dermatologic visit, received a daily skin treatment, staring from 24 hours before their first dose of afatinib for the duration of antitumor therapy, for at least 3 months. Skin proactive treatment included SPF 30 UVA/UVB nonocclusive sunscreen and a 1.5% PD-based cream (GHIMAS) applied twice a day on the face and the whole body (including the periungual zone). The skin was cleansed with water-emulsified vegetable oils to ensure “affinity cleaning” which would avoid the depletion of the hydrolipid film, according to EPO recommendation . The patients were monitored every 7 days for the first month and after every 20 days or as needed.
The scale used for grading skin toxicities induced by EGFR-targeted therapies was the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) grading scale, version 3.0 (see Table 1).
BSA: body surface area; ADL: activities of daily living.
The study was approved by the ethics committee at the participating centre and was conducted in accordance with the Declaration of Helsinki (version 2000) and Good Clinical Practice guidelines.
Data on the severity, duration, and management of TKI-induced skin toxicity were analysed in all the treated patients by means of a descriptive statistics.
3. Results and Discussion
Thirty-four patients treated in the Oncologic Pneumology Unit of the Azienda Ospedaliera San Camillo-Forlanini, Rome, were suitable for the analysis. Table 2 shows the main characteristics of the patients. In particular, 75% of patients were aged over 65 years and 91% were nonsmokers. The median follow-up period was 6 months. The mean duration of treatment was 6.4 months, calculated from the time treatment was started to the date treatment was stopped.
The results are illustrated in Table 3. The incidence of skin rash (all grades) was 41.2% and grade 2 rash was 20.6%, and grade 3 rash was not observed in any of the patients. None of the patients discontinued therapy for toxicity. The rash includes tenderness, papulo-pustules, and periungual inflammation. The rash is characterized by interfollicular- and follicular-based erythematous papules and pustules, without microcomedones and comedones characteristic of acne, and is usually observed during the first 2 weeks of therapy.
The management of TKI-induced skin toxicities should be considered as a prerequisite for maintaining patient quality of life in the course of EGFR-targeted therapy .
A review on the incidence and severity of rash and other dermatologic adverse effects in selected phase II and III trials reported by the literature show that 45%–100% of patients develop rash . The cutaneous eruptions appear primarily on the face, neck, and upper trunk; the face is often the first area affected by the rash. The rash tends to wax and wane during therapy, with “flare ups” occasionally noted following infusions. Skin lesions resolve without scarring after the withdrawn of the treatment .
The pathophysiology of EGFRI-associated skin rash is not completely understood. It is reasonable to assume that anti-EGFR therapy could interfere with the proliferation, differentiation, migration, and attachment of keratinocytes. Moreover, as already mentioned, treatment with TKI could be able to recruit inflammatory cells adversely affecting cutaneous tissues. Since EGFR is highly expressed on epidermal keratinocytes, sebaceous glands, and epithelium of the hair follicle, the inhibition of these receptors can produce characteristic negative dermatologic effects .
A National Comprehensive Cancer Network (NCCN) consensus panel, based on expert opinion, reported treatment recommendations for the skin rash. The patients should use emollients for the dry skin, or xerosis, that accompanies anti-EGFR therapies. Moreover, a sunscreen cream application is mandatory, and indeed, the inhibition of EGF receptors produces the loss of the protective function against detrimental effects of sun exposure resulting in worse rash symptoms. Moreover, sunscreen products should have a high sun protection factor. On the other hand, moderate rash symptoms may not require intervention, and, if needed, clindamycin gel and/or topical hydrocortisone may be adequate. It should be pointed out that limited rash symptoms can also be managed with the combination of pimecrolimus 1% plus a tetracycline analogue agent, such as oral doxycycline or minocycline (100 mg twice daily). In contrast, severe rash requires dose interruption of anti-EGFR agents, tetracycline analogue treatment and application of hydrocortisone cream, clindamycin gel, or pimecrolimus, plus oral administration of anti-inflammatory corticosteroids .
In addition, PD can interfere in the EGFR system in human keratinocytes, and this effect may be involved in the regulation of inflammation and repair-related processes in the skin [25–27, 33–35]. Anti-EGFR treatment typically gives a rash with histological features of a typical dermatoses induced by keratinocyte-interleukin-8 production. Since PD is able to modulate interleukin-8 gene expression, it is possible to hypothesize that PD could act, at least in part, through an interleukin-8 inhibition mechanism [17, 20, 27].
In our study, the incidence of rash (all grades) was 41.2% (20.6% of grade 2), without any event of grade 3 and no withdrawal of treatment for skin adverse events. This incidence of rash is lower compared to that reported in literature; actually, in clinical trials with first-line afatinib, the overall incidence of rash was between 60% and 80%. Two of the largest trials are LUX-Lung 3 and LUX-Lung 6 [36, 37]. These trials have a comparable design with the exception of the platinum-based chemotherapy regimen: pemetrexed/cisplatin in LUX-Lung 3 and gemcitabine/cisplatin in LUX-Lung 6. In these studies, the patients, whose tumours have common EGFR mutations, receiving first-line afatinib showed a progression-free survival. In these patients, the most common adverse events (grade 3 and 4) related to afatinib in comparison with chemotherapy were rash/acne, diarrhoea, paronychia, and stomatitis/mucositis [36, 37]. In the LUX-Lung 3 trial, the treatment was discontinued because of treatment-related adverse events in 8% of patients. The incidence of rash (all grades) was 89.1%, grade 1-2 rash was 72.9%, and grade 3 rash was 16.2%. In the LUX-Lung 6, the adverse events-related drug withdrawal rate was lower than in LUX-Lung 3 trial (2.1%), as well as the incidences of rash (all grades: 80.8%: grade 1-2: 66.1%; grade 3: 14.2%). This could be explained by the fact that the treating physicians became more confident in the management of the side effects of afatinib and what was earlier perceived as higher grade toxicity was now thought to be of lower severity. In addition, Kudo et al.  retrospectively evaluated 49 consecutive patients with EGFR-mutant NSCLC treated with afatinib between 2009 and 2015. The results showed that grade ≥2 skin rash occurred in 17 patients (35%), 5 of them (10%) during the first week after the initiation of afatinib therapy. Compared to this report, our results look better because our global incidence of skin rash, including grade 1 events, is 40.2% versus 35% of grade ≥2 events. Another open-label, randomized, controlled trial evaluated the prophylactic effect of tetracycline versus no treatment in reducing afatinib skin rash in 90 NSCLC patients receiving afatinib 40 mg/day. Rash incidence of any grade and grade ≥2 was lower in the tetracycline arm with respect to the control arm (44.5 vs. 75.6%, , and 15.6 vs. 35.6%, , respectively). Compared to this report  we can observe that in our results the protective effect of PD is equivalent to that of a prophylaxis with tetracyclines, a well-recognized therapeutical strategy for the prevention of anti-EGFR skin rashes.
The present study, limited in the number of patients and very preliminary, suggests that a PD-based cream can reduce the incidence of grade 2-3 or greater skin toxicities without additional side effects in patients treated with afatinib. The results are compared with the toxicity data of LUX-Lung 3 and 6 trials. Topical treatments in alternative to oral antibiotics deserve to be considered, as topical treatment approaches are used extensively in this setting. Additional well-controlled prospective clinical trials are needed to further examine the potential benefits of prophylactic skin-treatment of EGFR-mediated toxicities and to establish a framework for consistent evidence-based treatment approaches based on biological mechanisms.
In this preliminary study, the activity of polydatin (PD), a well-tolerated natural extract, has been evaluated for the prophylaxis of skin toxicity during an afatinib-based treatment, avoiding the use of antibiotics.
These results suggest that a proactive prophylactic management of skin rash with a PD-based cream can reduce the incidence of grade ≥2 skin toxicities without additional side effects in patients treated with afatinib.
|ADL:||Activities of daily living|
|BSA:||Body surface area|
|CTCAE:||Common Terminology Criteria for Adverse Events|
|ECOG:||Eastern Cooperative Oncology Group|
|EGFR:||Epidermal growth factor receptor|
|HER2:||Human epidermal growth factor 2|
|NCCN:||National Comprehensive Cancer Network|
|NSCLC:||Non-small cell lung cancer|
|TKIs:||Tyrosine kinase inhibitors.|
The data used to support the findings of this study are available from the corresponding author upon request.
The study was approved by the ethics committee (Prot. No. 130/CE Lazio 1 Italy) at the participating centre and was conducted in accordance with the Declaration of Helsinki (version 2000) and Good Clinical Practice guidelines. This clinical study adheres to all ethical guidelines that are required by the jurisdiction in which the study was conducted.
Each patient signed a written informed consent before starting the study.
Each author participated sufficiently in the work to take public responsibility for appropriate portions of the content and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Conflicts of Interest
The authors declare that there are no conflicts of interest regarding the publication of this paper. Polydatin-based cream is produced by GHIMAS srl. GHIMAS exploits the patent (PCT/IB01/00983) owned by the Academic Spinoff GLURES srl.
All the authors contributed equally by working together for acquisition of data and analysis and interpretation of data. All the authors read and approved the final manuscript.
- E. Thunnissen, K. van der Oord, and M. den Bakker, “Prognostic and predictive biomarkers in lung cancer. A review,” Virchows Archiv, vol. 464, no. 3, pp. 347–358, 2014.
- B. A. Chan and B. G. Hughes, “Targeted therapy for non-small cell lung cancer: current standards and the promise of the future,” Translational Lung Cancer Research, vol. 4, no. 1, pp. 36–54, 2015.
- D. S. Salomon, R. Brandt, F. Ciardiello, and N. Normanno, “Epidermal growth factor-related peptides and their receptors in human malignancies,” Critical Reviews in Oncology/Hematology, vol. 19, no. 3, pp. 183–232, 1995.
- K. M. Kerr, L. Bubendorf, M. J. Edelman et al., “Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer,” Annals of Oncology, vol. 25, no. 9, pp. 1681–1690, 2014.
- M. Reck, S. Popat, N. Reinmuth et al., “ESMO Guidelines Working Group. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up,” Annals of Oncology, vol. 25, no. 3, pp. 27–39, 2014.
- T. S. Mok, Y.-L. Wu, S. Thongprasert et al., “Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma,” New England Journal of Medicine, vol. 361, no. 10, pp. 947–957, 2009.
- R. Rosell, E. Carcereny, R. Gervais 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,” The Lancet Oncology, vol. 13, no. 3, pp. 239–246, 2012.
- F. Solca, G. Dahl, A. Zoephel et al., “Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker,” Journal of Pharmacology and Experimental Therapeutics, vol. 343, no. 2, pp. 342–350, 2012.
- J. C.-H. Yang, Y.-L. Wu, M. Schuler et al., “Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials,” The Lancet Oncology, vol. 16, no. 2, pp. 141–151, 2015.
- M. Schuler, J. C.-H. Yang, K. Park et al., “Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial,” Annals of Oncology, vol. 27, no. 3, pp. 417–423, 2015.
- M. E. Lacouture, “Mechanisms of cutaneous toxicities to EGFR inhibitors,” Nature Reviews Cancer, vol. 6, no. 10, pp. 803–812, 2006.
- F. A. Shepherd, J. Rodrigues Pereira, T. Ciuleanu et al., “Erlotinib in previously treated non-small-cell lung cancer,” New England Journal of Medicine, vol. 353, no. 2, pp. 123–132, 2005.
- B. Wacker, T. Nagrani, J. Weinberg, K. Witt, G. Clark, and P. J. Cagnoni, “Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies,” Clinical Cancer Research, vol. 13, no. 13, pp. 3913–3921, 2007.
- A. Harandi, A. S. Zaidi, A. M. Stocker et al., “Clinical efficacy and toxicity of anti-egfr therapy in common cancers,” Journal of Oncology, vol. 2009, Article ID 567486, 14 pages, 2009.
- J. Fu, S. Wu, M. Wang et al., “Intestinal metabolism of polygonum cuspidatum in vitro and in vivo,” Biomedical Chromatography, vol. 30, no. 6, p. e4190, 2018.
- J. Ye, H. Piao, J. Jiang et al., “Polydatin inhibits mast cell-mediated allergic inflammation by targeting PI3K/Akt, MAPK, NF-κB and Nrf2/HO-1 pathways,” Scientific Reports, vol. 7, no. 1, p. 11895, 2017.
- G. Lanzilli, A. Cottarelli, G. Nicotera et al., “Anti-inflammatory effect of resveratrol and polydatin by in vitro IL-17 modulation,” Inflammation, vol. 35, no. 1, pp. 240–248, 2012.
- M. P. Fuggetta, V. Bordignon, A. Cottarelli et al., “Downregulation of proinflammatory cytokines in HTLV-1-infected T cells by Resveratrol,” Journal of Experimental and Clinical Cancer Research, vol. 35, no. 1, pp. 118–121, 2016.
- J. Zou, Y. Yang, Y. Yang, and X. Liu, “Polydatin suppresses proliferation and metastasis of non-small cell lung cancer cells by inhibiting NLRP3 inflammasome activation via NF-κB pathway,” Biomedicine and Pharmacotherapy, vol. 108, pp. 130–136, 2018.
- K. Huang, C. Chen, J. Hao et al., “Polydatin promotes Nrf2-ARE anti-oxidative pathway through activating Sirt1 to resist AGEs-induced upregulation of fibronetin and transforming growth factor-beta1 in rat glomerular messangial cells,” Molecular and Cellular Endocrinology, vol. 399, pp. 178–189, 2015.
- N. Pang, T. Chen, X. Deng et al., “Polydatin prevents methylglyoxal-induced apoptosis through reducing oxidative stress and improving mitochondrial function in human umbilical vein endothelial cells,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 7180943, 2017.
- B. Yang, J. J. Li, J. J. Cao et al., “Polydatin attenuated food allergy via store-operated calcium channels in mast cell,” World Journal of Gastroenterology, vol. 19, no. 25, pp. 3980–3989, 2013.
- S. Chen, J. Tao, F. Zhong et al., “Polydatin down-regulates the phosphorylation level of Creb and induces apoptosis in human breast cancer cell,” PLoS One, vol. 12, no. 5, Article ID e0176501, 2017.
- S. Pastore, D. Lulli, P. Fidanza et al., “Plant polyphenols regulate chemokine expression and tissue repair in human keratinocytes through interaction with cytoplasmic and nuclear components of epidermal growth factor receptor system,” Antioxidants and Redox Signaling, vol. 16, no. 4, pp. 314–328, 2012.
- V. A. Kostyuk, A. I. Potapovich, D. Lulli et al., “Modulation of human keratinocyte responses to solar UV by plant polyphenols as a basis for chemoprevention of non-melanoma skin cancers,” Current Medicinal Chemistry, vol. 20, no. 7, pp. 869–879, 2013.
- G. Ravagnan, A. De Filippis, M. Cartenì et al., “Polydatin, a natural precursor of resveratrol, induces β-defensin production and reduces inflammatory response,” Inflammation, vol. 36, no. 1, pp. 26–34, 2013.
- M. C. Pace, M. B. Passavanti, C. Aurilio et al., “Polydatin administration improves serum biochemical parameters and oxidative stress markers during chronic alcoholism: a pilot study,” In Vivo, vol. 29, no. 3, pp. 405–408, 2015.
- J. Ocvirk, S. Heeger, P. McCloud, and R. D. Hofheinz, “A review of the treatment options for skin rash induced by EGFR-targeted therapies: evidence from randomized clinical trials and a metanalysis,” Radiology and Oncology, vol. 47, no. 2, pp. 166–175, 2013.
- A. L. Agero, S. W. Dusza, C. Benvenuto-Andrade et al., “Dermatologic side effects associated with the epidermal growth factor receptor inhibitors,” Journal of the American Academy of Dermatology, vol. 55, no. 4, pp. 657–670, 2006.
- B. Eaby-Sandy, C. Grande, and P. Hallquist Viale, “Dermatologic toxicities in epidermal growth factor receptor and multikinase inhibitors,” Journal of the Advanced Practitioner in Oncology, vol. 3, no. 3, pp. 138–150, 2012.
- B. Eaby, A. Culkin, and M. Lacouture, “An interdisciplinary consensus on managing skin reactions associated with human epidermal growth factor receptor inhibitors,” Clinical Journal of Oncology Nursing, vol. 12, no. 2, pp. 283–290, 2007.
- B. Burtness, M. Anadkat, S. Basti et al., “NCCN task force report: management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer,” Journal of the National Comprehensive Cancer Network, vol. 7, no. 1, pp. S5–S21, 2009.
- H. L. Wang, J. P. Gao, Y. L. Han et al., “Comparative studies of polydatin and resveratrol on mutual transformation and antioxidative effect in vivo,” Phytomedicine, vol. 22, no. 5, pp. 553–559, 2015.
- D. Su, Y. Cheng, M. Liu et al., “Comparision of piceid and resveratrol in antioxidation and antiproliferation activities in vitro,” PLoS One, vol. 8, no. 1, Article ID e54505, 2013.
- R. Falchetti, M. P. Fuggetta, G. Lanzilli et al., “Effects of resveratrol on human immune cell function,” Life Sciences, vol. 70, no. 1, pp. 81–96, 2001.
- L. V. Sequist, J. C. Yang, N. Yamamoto et al., “Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations,” Journal of Clinical Oncology, vol. 31, no. 27, pp. 3327–3334, 2013.
- Y. L. Wu, C. Zhou, C. P. Hu 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,” The Lancet Oncology, vol. 15, no. 2, pp. 213–222, 2014.
- K. Kudo, K. Hotta, A. Bessho et al., “Development of a skin rash within the first week and the therapeutic effect in afatinib monotherapy for EGFR-mutant non-small cell lung cancer (NSCLC): Okayama Lung Cancer Study Group experience,” Cancer Chemotherapy and Pharmacology, vol. 77, pp. 1005–1009, 2016.
- O. Arrieta, M. T. Vega-González, D. López-Macías et al., “Randomized, open-label trial evaluating the preventive effect of tetracycline on afatinib induced-skin toxicities in non-small cell lung cancer patients,” Lung Cancer, vol. 88, no. 3, pp. 282–288, 2015.
Copyright © 2019 Maria Pia Fuggetta et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.