Accepted Manuscript. Hemorrhagic cystitis associated with gefitinib treatment: a case report. Peng Zhang, Jinjing Tu, Tieding Chen, Rubing Li

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1 Accepted Manuscript Hemorrhagic cystitis associated with gefitinib treatment: a case report Peng Zhang, Jinjing Tu, Tieding Chen, Rubing Li PII: S (18) DOI: /j.urology Reference: URL To appear in: Urology Received date: 29 March 2018 Revised date: 12 May 2018 Accepted date: 29 May 2018 Please cite this article as: Peng Zhang, Jinjing Tu, Tieding Chen, Rubing Li, Hemorrhagic cystitis associated with gefitinib treatment: a case report, Urology (2018), doi: /j.urology This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Hemorrhagic cystitis associated with gefitinib treatment: a case report Peng Zhang 1,2, Jinjing Tu 3,4, Tieding Chen 1,2, Rubing Li 1,2 1 Department of Urology, Ningbo Medical Center Lihuili Eastern Hospital, Ningbo, Zhejiang , China 2 Department of Urology, Taipei Medical University Ningbo Medical Center, Ningbo, Zhejiang , China 3 Department of Respiratory Medicine, Ningbo Medical Center Lihuili Eastern Hospital, Ningbo, Zhejiang , China 4 Department of Respiratory Medicine, Taipei Medical University Ningbo Medical Center, Ningbo, Zhejiang , China Send correspondence to: Peng Zhang, Department of Urology, Lihuili Eastern Hospital, No Jiangnan Road, Yinzhou District, Ningbo, Zhejiang , China. loversdrug@gmail.com. Key words: gefitinib; non-small-cell lung carcinoma; cystitis; cytochrome P-450 CYP3A the word count for the Abstract:0 the word count for the manuscript text:925 1

3 Acknowledgements: We thank Dr. Hui Xu and Dr. Yibing He for taking care of the patient. Written consent was obtained from the patient and his family prior to publication of this case report. Financial disclosures: Peng Zhang none; Jinjing Tu none; Tieding Chen none; Rubing Li none. Declaration of interest: none. 2

4 Background Gefitinib is an oral anticancer agent that inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors and then blocks cancer progression 1. Its efficacy for advanced non-small-cell lung cancer (NSCLC) has been proved in randomized, double-blind, phase III trials 2,3. Common side effects of gefitinib include diarrhea, rash, acne, dry skin, nausea, hepatic dysfunction, and vomiting 1. We describe the rare case of a patient treated with gefitinib, who later presented with hemorrhagic cystitis as a drug-related side effect. Case Presentation A 66-year-old Chinese man was hospitalized for further examinations because of an abnormal serum carcinoembryonic antigen level of μg/l (normal range, 0.00 to 5.00 μg/l). He never smoked, was in good general condition, and had no significant genitourinary history. The physical examination performed on admission revealed no abnormal signs. The levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were 10 U/L (normal range, 7 to 40 U/L) and 14 U/L (normal range, 13 to 35 U/L), respectively. The chest computed tomography (CT) scan showed a mm mass in the right lower lobe (Figure 1) and suspicious 3

5 metastasis in the eleventh thoracic vertebra. Subsequently, a CT-guided percutaneous lung biopsy was performed in this patient, and the pathology of the pulmonary mass was confirmed as adenocarcinoma. Additionally, gene detection indicated deletion mutation in exon 19 of the epidermal growth factor receptor (EGFR). According to these findings, oral gefitinib (250 mg once daily) was initiated in September In October 2017, the patient underwent chest CT, which showed that the size of the mass in the right lower lobe considerably decreased to mm. Since October 2017, the patient experienced urinary symptoms, including frequency, urgency, painful voiding, and gross hematuria. Urinalysis showed that the counts of red blood cells and white blood cells were /μl (normal range, 0.00 to 17.00/μl) and /μl (normal range, 0.00 to 28.00/μl), respectively. He reported that such urinary symptoms had never occurred before. Various examinations were performed to differentiate between infection, cancer, benign prostate hyperplasia, and tuberculosis. Results of the urine culture and tuberculous infection of T cells spot test were negative. The ultrasonogram indicated no suspicious lesion in the kidney, ureter, bladder, or prostate, and the volume of post-void residual urine was 4 ml. Additionally, the contrast-enhanced pelvic CT scan showed no suspicious lesion in the bladder. Empirical antibiotic agents and antimuscarinic agents were prescribed, but they did not relieve his urinary symptoms. Therefore, we admitted him to the Department of Urology in November

6 On admission, urinalysis showed that the red blood cell count was /μl, white blood cell count was normal, and serum prostate-specific antigen level was μg/l. The result of urinary cytology was negative for malignancy. The serum ALT and AST levels were 145 U/L and 82 U/L, respectively, suggesting hepatic dysfunction. Considering the side effects of gefitinib, surgeons and physicians had a serious conversation with the patient about treatment and obtained his consent to cease administration of this agent. Four days later, his urinary symptoms improved drastically. Cystourethroscopy revealed erythematous lesions and follicle-like lesions throughout the bladder (Figure 2), of which biopsies were obtained. The pathologic examination showed increased vascularity, infiltration with inflammatory cells, and the absence of urothelium (Figure 3), indicating hemorrhagic cystitis. Oral icotinib (125 mg thrice daily) was prescribed and initiated in November In January 2018, the patient s urinary symptoms disappeared completely, and urinalysis showed that the red blood cell and white blood cell counts were normal. Moreover, the serum ALT and AST levels decreased to 53 U/L and 40 U/L, respectively. Therefore, oral gefitinib (250 mg once daily) was prescribed again to substitute icotinib in January One month later, no urinary symptom recurred. The patient underwent chest CT in December 2017 and January 2018, and both scans demonstrated that the sizes of the mass in the right lower lobe and lesion in the eleventh thoracic vertebra were approximately similar to those in October

7 Discussion Rubing Li The predominant causes of hemorrhagic cystitis are chemical compounds, irradiation, infection, and systematic disease 4. In our case, hemorrhagic cystitis was associated with use of gefitinib. Considerable evidence has proven that EGFR signaling is associated with the proliferation of urothelial cells 5. In an organoid-like culture model, Daher et al. demonstrated that the regeneration of urothelium after trauma could be inhibited by anti-egfr antibodies and by AG1478, an EGFR tyrosine kinase-specific inhibitor 6. Nicolle et al. affirmed that gefitinib could block the expansion of normal urothelial cells and have growth-inhibitory and anti-invasive effects on urothelial cell carcinoma cell lines 7. According to the instruction provided by the Food and Drug Administration 8, gefitinib undergoes extensive hepatic metabolism in humans, mainly by cytochrome P450 3A4. Most of the drug and its metabolites are excreted through the intestinal tract and a minority through the kidneys, which seems insufficient to impair the urothelium of the bladder in most cases. Nevertheless, as previous case reports have mentioned 9-11, hemorrhagic cystitis is always accompanied with hepatic dysfunction in treatment with gefitinib, as in our case. Thus, we speculated that gefitinib and its 6

8 metabolites are excreted more through the kidneys as hepatic function worsens, and then the increased excretion in the bladder may affect the growth of normal urothelial cells, resulting in hemorrhagic cystitis. Conclusions Gefitinib is effective in patients with advanced NSCLC and EGFR-activating mutations, and it is considered a potential agent for urothelial cell carcinoma. However, surgeons and physicians should be aware of its unusual side effects that include hemorrhagic cystitis, especially in patients with hepatic dysfunction. The association between gefitinib and hemorrhagic cystitis requires clarification. References 1. Gridelli C, De Marinis F, Di Maio M, et al. Gefitinib as first-line treatment for patients with advanced non-small-cell lung cancer with activating epidermal growth factor receptor mutation: Review of the evidence. Lung Cancer. 2011;71(3): Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008;372(9652): Maruyama R, Nishiwaki Y, Tamura T, et al. Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell 7

9 lung cancer. J Clin Oncol. 2008;26(26): Traxer O, Desgrandchamps F, Sebe P, et al. Hemorrhagic cystitis: etiology and treatment. Prog Urol. 2001;11(4): Messing EM, Hanson P, Ulrich P, et al. Epidermal growth factor interactions with normal and malignant urothelium: in vivo and in situ studies. J Urol. 1987;138(5): Daher A, de Boer WI, El-Marjou A, et al. Epidermal growth factor receptor regulates normal urothelial regeneration. Lab Invest. 2003;83(9): Nicolle G, Daher A, Maillé P, et al. Gefitinib inhibits the growth and invasion of urothelial carcinoma cell lines in which Akt and MAPK activation is dependent on constitutive epidermal growth factor receptor activation. Clin Cancer Res. 2006;12(9): Drugs@FDA. IRESSA Accessed 26 February Argiris A, Mittal N. Gefitinib as first-line, compassionate use therapy in patients with advanced non-small-cell lung cancer. Lung Cancer. 2004;43(3): Song H, Chen L. Unusual side effect and dramatic response from gefitinib as first-line use in a male-patient with bronchioloalveolar carcinoma. The Chinese-German Journal of Clinical Oncology. 2007;6(6): Arakawa M, Nakamura K, Yamada Y, et al. Association between gefitinib and hemorrhagic cystitis and severely contracted bladder: a case report. BMC Urol. 8

10 2010;10(1):6. Figure Legends Figure 1 In August 2017, the chest computed tomography scan demonstrates a mm mass in the right lower lobe. Figure 2 Cystourethroscopy reveals erythematous lesions and follicle-like lesions throughout the bladder. Figure 3 Pathologic examination of the bladder lesions shows increased vascularity, infiltration with inflammatory cells, and the absence of urothelium. 9

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