Gefitinib-induced hemorrhagic cystitis and inflammatory contracted bladder in a patient with advanced lung adenocarcinoma harboring compound epidermal growth factor receptor G719S and S768I missense mutations: a case report

Introduction

Lung adenocarcinoma harboring sensitizing mutations in epidermal growth factor receptor (EGFR), including small in-frame deletions in exon 19, and missense mutation L858R, responds to gefitinib, a first-generation EGFR tyrosine kinase inhibitor (TKI) (1). Before its accelerated approval by the US Food and Drug Administration (FDA), the therapeutic efficacy and safety profile of gefitinib had been demonstrated in numerous clinical trials (2,3). At the standard recommended dose, gefitinib has a tolerable safety profile (4-6), with reported adverse reactions primarily involving the gastrointestinal system (i.e., diarrhea, nausea, vomiting), skin (i.e., rash, acne, dry skin), and liver [i.e., elevated alanine aminotransferase (ALT) and aspartate transaminase (AST)] (2,5,7). However, uncommon adverse reactions have been reported, including hematuria and hemorrhagic cystitis (8-14). Clinicians should pay more attention on monitoring for urinary symptoms and hematuria. Discontinuation of gefitinib is usually the main management approach of severe drug-related toxicities (2,9). This case report describes a patient with advanced lung adenocarcinoma who experienced gefitinib-induced hemorrhagic cystitis and inflammatory contracted bladder. With early detection and gefitinib discontinuation, the patient’s symptom relived quickly. We present the following article in accordance with the CARE reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-22-3233/rc).

Case presentation

In July 2019, a 56-year-old male with a 60-pack year smoking history sought medical attention due to chronic cough, sputum expectoration, and shortness of breath for 6 months that had worsened over the last 2 weeks. He had no known comorbidity and reported no family history of cancer. A computed tomography (CT) scan showed a high-density shadow in the upper left lung, a 3.63 cm × 2.68 cm soft tissue mass in the lower lobe of the right lung, and the presence of pleural effusion in the right lung (Figure 1A). Multiple nodules were observed in both lung lobes and pleura. Right hilar lymph nodes were also enlarged. He was diagnosed with stage IV adenocarcinoma of the right lower lung with bilateral lung metastases. Molecular testing using the next-generation sequencing-based assay of pleural effusion samples identified a compound EGFR G719S and S768I with the allelic abundance of 42.64% and 41.59%, respectively. The patient was administered with gefitinib (250 mg/day) as a first-line regimen. His initial clinical symptoms improved within 4 weeks from starting gefitinib therapy; however, he subsequently experienced grade 3 diarrhea (7–8 times/day). After 40 days of gefitinib therapy, he also experienced dysuria, decreased urine output, and gross hematuria. No fever, urinary stones, or other symptoms were noted. Despite the adverse events, the primary lesion in the right lower lobe shrunk to 2.81 cm × 2.58 cm and was evaluated as a partial response (PR) based on the criteria of the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST; Figure 1B). Grade 2 elevation of liver enzymes, including AST and ALT, were detected (Figure 1). Routine urinalysis indicated full high-power field (HPF) view of red blood cell (RBC) and 40–50/HPF white blood cell (WBC) counts at 1.5 months of gefitinib therapy as compared with 0/HPF RBC and WBC before gefitinib therapy (normal range: 0–1 RBC/HPF and 0–3 WBC/HPF). Cystoscopy showed narrowing of the bladder neck, distension of the posterior bladder wall, hypertrophied trigone, and a sunken bladder base. No trauma or inflammation of the bladder was observed (Figure 1C). These findings suggested a contracted bladder with hemorrhagic cystitis. Gefitinib therapy was immediately discontinued, which resolved the urinary symptoms and hematuria as indicated by the marked reduction of RBC (5–10 RBC/HPF and 0 WBC/HPF). In November 2019, his treatment was switched to icotinib (125 mg orally thrice daily); however, the primary lesion was not responsive to icotinib therapy, as shown by the enlargement of lymph nodes, multiple lung and pleural metastases, and increased pleural effusion (Figure 1D). Afatinib (40 mg/day) was then initiated in January 2020 as a third-line therapy, and the patient achieved PR within 2 months of treatment (Figure 1E). Grade 2 rashes were observed. On 10 April 2020, his cough and shortness of breath worsened, which were suspected to be symptoms of disease progression. He received his first chemotherapy regimen comprised of pemetrexed and cisplatin on 4 May 2020, and achieved PR after three cycles of the regimen. At follow-up on 4 September 2020, enhanced cranial magnetic resonance imaging (MRI) revealed brain metastasis (Figure 1F). The patient refused to undergo craniocerebral radiotherapy and was lost to follow-up. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was provided by the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 1 Clinical summary of the patient. (A,B,D,E) Thoracic CT scans of primary lung lesions at various time points, including at (A) baseline (3.63 cm × 2.68 cm); (B) 2 months of gefitinib therapy evaluated as PR; (D) evaluation of PD at 2 months of icotinib therapy; (E) PR after 2 months of afatinib therapy. (F) Contrast-enhanced cranial magnetic resonance imaging of brain metastatic lesions at PD after three cycles of pemetrexed plus cisplatin regimen. Red arrows indicate the primary or metastatic lesions. An illustrated summary of the treatment received by the patient, including the best OR and PFS in each line of treatment. Compound EGFR mutations and their corresponding allelic fractions detected at baseline using targeted NGS of pleural effusion. (C) Cystoscopy images showing the contracted bladder. PR, partial response; PD, progressive disease; PP, pemetrexed and cisplatin combination chemotherapy; OR, objective response; PFS, progression-free survival; AE, adverse events; qd, once a day; NGS, next generation sequencing; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CEA, carcinoembryonic antigen; RBC, red blood cell; WBC, white blood cell; HPF, high power field; CT, computed tomography.

Discussion

Gefitinib is effective in patients with advanced NSCLC harboring EGFR-activating mutations, and our patient achieved PR within 6 weeks of gefitinib therapy. Unfortunately, gefitinib was discontinued because of hemorrhagic cystitis and inflammatory contracted bladder. Gefitinib is primarily metabolized by the hepatic cytochrome P450 enzymes (15). Pharmacokinetic studies of gefitinib have demonstrated a urinary recovery of only <0.5%, indicating that the urinary system is only a minor route of excretion (4). Despite being generally well-tolerated, a small subset of patients have reported uncommon gefitinib-induced adverse reactions affecting the urinary system, including acute renal failure (10), hematuria (12), hemorrhagic cystitis (11,13), and inflammatory contracted bladder (11). In vitro studies have demonstrated that EGFR signaling is involved in the proliferation of urothelial cells, and gefitinib can inhibit the growth of normal urothelial cells and urothelial carcinoma cell lines (16). Hence, it is likely that gefitinib therapy might induce inflammatory changes in the urinary system in a subset of patients (11,13). Additional studies are required to elucidate how gefitinib can induce urinary system-related adverse events.

To relieve the symptoms of severe drug-related toxicities, discontinuation of the medication is the standard management (2,9). In our patient, the termination of gefitinib treatment alleviated the symptoms of toxicity. Drug-related toxicity was not observed even after switching to another first-generation EGFR-TKI icotinib or the second-generation EGFR-TKI afatinib, which indicates that different EGFR-TKIs involve different drug metabolic pathways. This observation was also consistent with another gefitinib-induced hemorrhagic cystitis in an EGFR exon 19-mutant lung adenocarcinoma patient (13) and a cohort from a previous study demonstrating that the administration of a second EGFR-TKI after severe adverse reaction from the first EGFR-TKI is safe and affords substantial benefit to patients with EGFR-mutant non-small-cell lung cancer (17).

Some case reports of gefitinib-induced renal/urinary system-related adverse reactions have not specified the EGFR status of the patients (10-12); hence, we might not know the correlation between the specific EGFR mutation and the occurrence of gefitinib-related toxicities. Our patient harbored compound EGFR G719S and S768I mutations. Patients harboring compound EGFR G719X and S768I mutations have been reported to respond to erlotinib and afatinib therapy (18-21). Consistently, our patient benefited from afatinib therapy; however, the response was also not durable. Furthermore, our patient also achieved PR to chemotherapy until he developed brain metastasis.

Our case shows that gefitinib can induce hemorrhagic cystitis and contracted bladder and contributes to the awareness that these uncommon adverse reactions affecting the urinary system could occur in patients with EGFR-mutant lung adenocarcinoma.

Acknowledgments

The authors thank the patient and his family. We also thank the investigators, study coordinators, operation staff, and the whole project team who worked on this case.

Funding: This work received financial grants from the Natural Science Foundation of Shanxi Province (No. 201901D111414), Research Project Supported by Shanxi Scholarship Council of China (No. 2020-178), and Fund Program for the Scientific Activities of Selected Returned Overseas Professionals in Shanxi Province (No. 20200029).

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-22-3233/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-3233/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are 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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was provided by the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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. N Engl J Med 2004;350:2129-39. [Crossref] [PubMed]
2. Cohen MH, Williams GA, Sridhara R, et al. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 2003;8:303-6. [Crossref] [PubMed]
3. Greenhalgh J, Boland A, Bates V, et al. First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer. Cochrane Database Syst Rev 2021;3:CD010383. [PubMed]
4. Swaisland H, Laight A, Stafford L, et al. Pharmacokinetics and tolerability of the orally active selective epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in healthy volunteers. Clin Pharmacokinet 2001;40:297-306. [Crossref] [PubMed]
5. Baselga J, Rischin D, Ranson M, et al. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 2002;20:4292-302. [Crossref] [PubMed]
6. Zhao Y, Cheng B, Chen Z, et al. Toxicity profile of epidermal growth factor receptor tyrosine kinase inhibitors for patients with lung cancer: A systematic review and network meta-analysis. Crit Rev Oncol Hematol 2021;160:103305. [Crossref] [PubMed]
7. Sim EH, Yang IA, Wood-Baker R, et al. Gefitinib for advanced non-small cell lung cancer. Cochrane Database Syst Rev 2018;1:CD006847. [Crossref] [PubMed]
8. Giaccone G. The role of gefitinib in lung cancer treatment. Clin Cancer Res 2004;10:4233s-7s. [Crossref] [PubMed]
9. Argiris A, Mittal N. Gefitinib as first-line, compassionate use therapy in patients with advanced non-small-cell lung cancer. Lung Cancer 2004;43:317-22. [Crossref] [PubMed]
10. Wan HL, Yao NS. Acute renal failure associated with gefitinib therapy. Lung 2006;184:249-50. [Crossref] [PubMed]
11. Arakawa M, Nakamura K, Yamada Y, et al. Association between gefitinib and hemorrhagic cystitis and severely contracted bladder: a case report. BMC Urol 2010;10:6. [Crossref] [PubMed]
12. Mori H, Ohno Y, Ito F, et al. Massive hematuria from the bilateral upper urinary tract in a patient treated for advanced lung cancer with gefitinib. Jpn J Clin Oncol 2010;40:263-6. [Crossref] [PubMed]
13. Zhang P, Tu J, Chen T, et al. Hemorrhagic Cystitis Associated With Gefitinib Treatment A Case Report. Urology 2018;120:6-8. [PubMed]
14. Waliany S, Zhu H, Wakelee H, et al. Pharmacovigilance Analysis of Cardiac Toxicities Associated With Targeted Therapies for Metastatic NSCLC. J Thorac Oncol 2021;16:2029-39. [Crossref] [PubMed]
15. Li J, Zhao M, He P, et al. Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin Cancer Res 2007;13:3731-7. [Crossref] [PubMed]
16. 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;12:2937-43. [Crossref] [PubMed]
17. Takeda M, Okamoto I, Tsurutani J, et al. Clinical impact of switching to a second EGFR-TKI after a severe AE related to a first EGFR-TKI in EGFR-mutated NSCLC. Jpn J Clin Oncol 2012;42:528-33. [Crossref] [PubMed]
18. Chen Z, Feng J, Saldivar JS, et al. EGFR somatic doublets in lung cancer are frequent and generally arise from a pair of driver mutations uncommonly seen as singlet mutations: one-third of doublets occur at five pairs of amino acids. Oncogene 2008;27:4336-43. [Crossref] [PubMed]
19. Kobayashi S, Canepa HM, Bailey AS, et al. Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors. J Thorac Oncol 2013;8:45-51. [Crossref] [PubMed]
20. Yang JC, Schuler M, Popat S, et al. Afatinib for the Treatment of NSCLC Harboring Uncommon EGFR Mutations: A Database of 693 Cases. J Thorac Oncol 2020;15:803-15. [Crossref] [PubMed]
21. Guo G, Li G, Liu Y, et al. Next-Generation Sequencing Reveals High Uncommon EGFR Mutations and Tumour Mutation Burden in a Subgroup of Lung Cancer Patients. Front Oncol 2021;11:621422. [Crossref] [PubMed]

(English Language Editor: J. Jones)