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Table of Contents
CASE REPORT
Year : 2019  |  Volume : 6  |  Issue : 2  |  Page : 92-95

Pembrolizumab-induced uveitis in a patient with metastatic urothelial carcinoma


1 Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
2 Department of Oncology; Graduate Institute of Clinical Medicine; National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan

Date of Submission24-Jul-2018
Date of Decision03-Oct-2018
Date of Acceptance05-Oct-2018
Date of Web Publication31-May-2019

Correspondence Address:
Dr. Jhe-Cyuan Guo
Department of Oncology, National Taiwan University Hospital, No. 7, Zhongshan South Road, Taipei 100-02
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCRP.JCRP_20_18

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  Abstract 


Immune checkpoint blockade, especially targeting the programmed cell death protein-1/programmed death-ligand 1 axis, has changed the paradigm of anticancer therapy in several cancer types. For urothelial carcinoma (UC), pembrolizumab is an immune checkpoint inhibitor approved by the US Food and Drug Administration for locally advanced or metastatic disease. The new anticancer modalities are complicated with immune-related adverse events (irAEs) which are significantly different from conventional treatment such as chemotherapy or targeted therapy. Herein, we present an 85-year-old man with metastatic UC who developed a rare kind of irAE, uveitis, under pembrolizumab therapy, who fortunately partially recovered with local and systemic steroids.

Keywords: Immune-related adverse event, pembrolizumab, programmed cell death protein-1, uveitis


How to cite this article:
Chen LH, Guo JC. Pembrolizumab-induced uveitis in a patient with metastatic urothelial carcinoma. J Cancer Res Pract 2019;6:92-5

How to cite this URL:
Chen LH, Guo JC. Pembrolizumab-induced uveitis in a patient with metastatic urothelial carcinoma. J Cancer Res Pract [serial online] 2019 [cited 2019 Aug 19];6:92-5. Available from: http://www.ejcrp.org/text.asp?2019/6/2/92/259490




  Introduction Top


In Taiwan, urinary bladder cancer accounted for 2.07% of all newly diagnosed cancers in 2015, mainly urothelial carcinoma (UC), and was the tenth leading cause of death in men.[1] The median age at diagnosis is 71 years in men and 72 years in women. Although cisplatin-based chemotherapy is the standard of care as first-line treatment for locally advanced and metastatic disease,[2] some patients are ineligible due to poor performance status and chronic kidney disease. Carboplatin-based therapy is often used for cisplatin-ineligible patients with advanced UC.[3] When platinum-based chemotherapy failed, no standard therapy had been approved before the era of immune checkpoint inhibitors except for vinflunine in Europe.[4] With the resurgence of immunotherapy with immune checkpoint inhibitors in treating melanoma, the US Food and Drug Administration (FDA) approved pembrolizumab for patients with locally advanced or metastatic UC who failed platinum-based chemotherapy in May 2017.[5] It was later approved by the Taiwan FDA. However, these new anticancer modalities are complicated with immune-related adverse events (irAEs) which are significantly different from conventional treatment such as chemotherapy or targeted therapy. These irAEs can involve every tissue or organ, especially the skin, colon, endocrine organs, liver, and lungs. Other sites are rarely seen, but irAEs can be severe and even lethal and include neurological disorders and myocarditis.[6],[7],[8] Thus, it is important to detect and deal with the diverse adverse events as early as possible.

Herein, we report a patient with metastatic UC who had uveitis, a rare kind of pembrolizumab-related irAE, who partially recovered after steroid treatment.


  Case Report Top


An 85-year-old man presented with urinary incontinence for 6 months. About 1 year before this presentation, he suffered from nocturia, at least three times per night. He visited a local clinic for help, and benign prostate hyperplasia was impressed. He then visited a local hospital, where transrectal ultrasound found a tumor at the neck of the urinary bladder. Transurethral resection of the prostate and the bladder tumor was done. The pathology disclosed high-grade infiltrating UC. A computed tomography (CT) scan of the abdomen and pelvis revealed a 2.2-cm tumor in the urinary bladder, with diffuse thickening of the anterior wall [Figure 1]a and perivesical fat strands, left hydroureter and hydronephrosis, and para-aortic lymphadenopathies (LAPs) [Figure 1]b. A bone scan found no definite metastatic lesions. He was diagnosed with Stage IV (T2aN3M1) UC, with metastatic para-aortic LAPs.
Figure 1: Serial computed tomography scans with contrast of the abdomen and pelvis. (a and b) Computed tomography scan for initial staging showed urinary bladder tumor and wall thickening nearby, with metastatic para-aortic lymphadenopathies (arrow). (c and d) Computed tomography scan after three cycles of pembrolizumab use showed partial response. (e and f) Computed tomography scan after palliative radiotherapy showed better local control and persistent absence of para-aortic lymphadenopathies

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Reviewing his medical history, he had taken antihypertensive drugs for many years but no herbs or health food. In his childhood, he drank groundwater. With the Eastern Cooperative Oncology Group performance status Grade 1 and chronic kidney disease, he received gemcitabine plus carboplatin as the first-line treatment. After the first administration of chemotherapy, he came to our clinic for a second opinion. We maintained gemcitabine 900 mg/m2 on days 1 and 15 and carboplatin area under the curve 2.25 on days 2 and 16 for six cycles, and a CT scan revealed a partial response with improved thickening of the urinary bladder and smaller LAPs. He then received a drug holiday in the following 3 months due to his old age.

However, his renal function deteriorated owing to local progression accompanied with bilateral hydroureters during the drug holiday. Urinary diversion was done using bilateral double-J tube insertions, and his renal function subsequently recovered. Thereafter, he received pembrolizumab 2.5 mg/kg (total 150 mg) every 3 weeks as second-line treatment. A CT scan after three cycles showed stable disease with improved thickening of the urinary bladder [Figure 1]c without the appearance of para-aortic LAPs [Figure 1]d.

After the fourth cycle of pembrolizumab, he complained of blurred vision, with an initial best-corrected visual acuity (BCVA) of 0.04/0.05 and normal intraocular pressure. After an ophthalmologic examination, slit lamp, and fluorescent dye test, bilateral panuveitis was diagnosed [Figure 2]. Serum interferon-γ release assays for tuberculosis, serologic test for syphilis, serum toxoplasma IgM and IgG, and blood cultures were all negative. Therefore, an irAE with Grade 3 panuveitis was favored. We held pembrolizumab and gave him oral prednisolone 20 mg/day, as well as topical corticosteroids. His vision gradually improved, with a subsequent BCVA of 0.63/0.5. He resumed pembrolizumab 7 weeks after being off the drug, with a reduced dose of 100 mg. For better local control, palliative radiotherapy to the urinary bladder tumor with 30 Gy separated into 10 fractions was given. A subsequent CT scan revealed good control of the primary tumor at the urinary bladder [Figure 1]e and a persistent absence of para-aortic LAPs [Figure 1]f. Prednisolone was gradually tapered to 5 mg daily, and his vision remained stable under subsequent pembrolizumab therapy.
Figure 2: Fundus photo of bilateral eyes showed uveitis

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  Discussion Top


Pembrolizumab is currently one of the standards of care for patients with locally advanced or metastatic UC who fail (second line) or are ineligible ( first line) for cisplatin-based chemotherapy. In the KEYNOTE-045 trial, 266 patients in the intention-to-treat arm received pembrolizumab at a dose of 200 mg every 3 weeks.[5] Adverse events of any grade occurred in 60.9% of these patients, of whom one quarter had Grade 3 or higher. In the pembrolizumab group, 7.5% had eye disorders, compared with 6.7% in the control group. Grade 3 or higher eye disorders were reported in two patients in the pembrolizumab group but none in the chemotherapy group. In two other large trials, eye disorders were not mentioned.[9],[10]

Reviewing the literature, five case reports described uveitis [Table 1], a rare irAE, in patients with metastatic melanoma treated with pembrolizumab.[11],[12],[13],[14],[15] The first case reported in 2016 was of an 82-year-old man with Stage IV melanoma with liver metastasis, in whom uveitis occurred after 2 months of pembrolizumab therapy.[11] Before pembrolizumab, chemotherapy with ipilimumab failed to control hepatic lesions. He presented with decreased vision without ocular pain or redness. Pembrolizumab held for 6 weeks until his vision improved with steroid eye drops. Although uveitis recurred later, it was well controlled by topical therapy. Three of the other four patients had also received ipilimumab, and the adverse events occurred 2 to 3 months after the initiation of pembrolizumab. Treatment options included topical, intraocular, or systemic steroids, depending on the severity. Interestingly, four patients reported a stable or partial response of melanoma, while one case report did not mention the tumor response.
Table 1: Characters of five cases with metastatic melanoma suffering from pembrolizumab-induced uveitis

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A subsequent pooled analysis including several prospective trials with immunotherapy reported an incidence rate of 1% for uveitis, the most common type of ocular toxicity except for dry eyes.[16] The incidence of uveitis for patients with advanced cancers other than melanoma receiving immune checkpoint inhibitor has not been reported. Our case involved pembrolizumab-induced uveitis in a patient with advanced UC, and fortunately, he had a good response to steroids and was well controlled after pembrolizumab resumed. As more indications are approved for immune checkpoint inhibitors, clinicians should be alert to the problems, which may be an early sign of severe irAEs.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Cancer Registry Annual Report. Taiwan; 2015.  Back to cited text no. 1
    
2.
von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005;23:4602-8.  Back to cited text no. 2
    
3.
De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol 2012;30:191-9.  Back to cited text no. 3
    
4.
Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol 2009;27:4454-61.  Back to cited text no. 4
    
5.
Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017;376:1015-26.  Back to cited text no. 5
    
6.
Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018;36:1714-68.  Back to cited text no. 6
    
7.
Haanen JB, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:iv119-42.  Back to cited text no. 7
    
8.
Haanen JB, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29:iv264-6.  Back to cited text no. 8
    
9.
Plimack ER, Bellmunt J, Gupta S, Berger R, Chow LQ, Juco J, et al. Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): A non-randomised, open-label, phase 1b study. Lancet Oncol 2017;18:212-20.  Back to cited text no. 9
    
10.
Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): A multicentre, single-arm, phase 2 study. Lancet Oncol 2017;18:1483-92.  Back to cited text no. 10
    
11.
Abu Samra K, Valdes-Navarro M, Lee S, Swan R, Foster CS, Anesi SD. Acase of bilateral uveitis and papillitis in a patient treated with pembrolizumab. Eur J Ophthalmol 2016;26:e46-8.  Back to cited text no. 11
    
12.
Basilious A, Lloyd JC. Posterior subcapsular cataracts and hypotony secondary to severe pembrolizumab induced uveitis: Case report. Can J Ophthalmol 2016;51:e4-6.  Back to cited text no. 12
    
13.
Diem S, Keller F, Rüesch R, Maillard SA, Speiser DE, Dummer R, et al. Pembrolizumab-triggered uveitis: An additional surrogate marker for responders in melanoma immunotherapy? J Immunother 2016;39:379-82.  Back to cited text no. 13
    
14.
Hanna KS. A rare case of pembrolizumab-induced uveitis in a patient with metastatic melanoma. Pharmacotherapy 2016;36:e183-8.  Back to cited text no. 14
    
15.
Aaberg MT, Aaberg TM Jr. Pembrolizumab administration associated with posterior uveitis. Retin Cases Brief Rep 2017;11:348-51.  Back to cited text no. 15
    
16.
Dalvin LA, Shields CL, Orloff M, Sato T, Shields JA. CHECKPOINT INHIBITOR IMMUNE THERAPY: Systemic indications and ophthalmic side effects. Retina 2018;38:1063-78.  Back to cited text no. 16
    


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