Treatment of Cancer-Associated Retinopathy with Rituximab

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CE Case Report

Treatment of Cancer-Associated Retinopathy With Rituximab

Irene Dy, MDa,b; Rangaswamy Chintapatla, MDa,b; Isabel Preeshagul, MDc; and Daniel Becker, MDa,b

Abstract NCCN designates this journal-based CME activity for a maximum of Cancer-associated retinopathy (CAR) is a rare autoimmune condi- 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only tion associated with various cancers, causing significant visual im- the credit commensurate with the extent of their participation in pairment. Visual symptoms in CAR may or may not correlate with the activity. the extent of systemic disease or its response to chemotherapy, and NCCN is accredited as a provider of continuing nursing education must be addressed separately from the management of systemic by the American Nurses Credentialing Center`s Commission on malignancy. Steroids have been the mainstay of CAR therapy. Vari- Accreditation. ous immunomodulatory therapies have also been described with This activity is accredited for 1.0 contact hours. Accreditation as varying responses, but the overall visual prognosis remains poor. a provider refers to recognition of educational activities only; ac- Rituximab is a monoclonal antibody used in the treatment of non- credited status does not imply endorsement by NCCN or ANCC of Hodgkin’s B-cell lymphoma and many autoimmune disorders. This any commercial products discussed/displayed in conjunction with case report describes a patient with small cell uterine cancer who the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our initially presented with visual impairment associated with CAR. nurse planner for this educational activity. The patient’s deteriorating visual symptoms were successfully halt- All clinicians completing this activity will be issued a certificate of ed for an extended, clinically meaningful period with rituximab. participation. To participate in this journal CE activity: 1) review (JNCCN 2013;11:1320–1324) the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/ node/31860; and 4) view/print certificate. Release date: November 14, 2013; Expiration date: November 14, NCCN: Continuing Education 2014 Accreditation Statement Learning Objectives This activity has been designated to meet the educational needs of Upon completion of this activity, participants will be able to: physicians and nurses involved in the management of patients with • Describe the etiology, clinical presentation, diagnosis, and cancer. There is no fee for this article. No commercial support was management of CAR received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical • Discuss the rationale for use of rituximab in the treatment education for physicians. of CAR

From the aContinuum Cancer Centers of New York; bDepartment of EDITOR Medicine, St. Luke’s–Roosevelt Hospital Center; and cDepartment of Kerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the Medicine, Beth Israel Medical Center, New York, New York. National Comprehensive Cancer Network Submitted September 23, 2012; accepted for publication April 25, 2013. Ms. Green has disclosed that she has no relevant financial relationships. The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the CE AUTHORS manufacturers of any products discussed in this article or their Deborah J. Moonan, RN, BSN, Manager, CE Supporter Outreach competitors. Ms. Moonan has disclosed the following relationship with commercial Correspondence: Rangaswamy Chintapatla, MD, St. Luke’s–Roosevelt interests: AstraZeneca: Stockholder/Former Employee. Hospital Center, Suite 11G, 1000 10th Avenue, New York, NY 10019. E-mail: [email protected] Ann Gianola, MA, Manager, Medical Education Accreditation and Grant Development Ms. Gianola has disclosed the following relationship with commercial interests: Actelion: Grant/Research Support. Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations Ms. Gregory has disclosed that she has no relevant financial relationships.

Cancer-Associated Retinopathy

Case Summary Three months after completion of chemothera- A 61-year-old right-handed woman presented in Oc- py, her systemic disease progressed, with several new tober 2010 with rapidly progressive painless visual hypermetabolic nodules in the left lower abdomen dysfunction. She described fluctuating visual changes and posterior mediastinum. At the same time, ap- in the right eye for 4 days and subsequently in the left proximately 8 months after diagnosis and while on eye 2 days before presenting to her ophthalmologist. 10 mg/d of prednisone, she again experienced nar- She reported experiencing diminished night vision, rowing of the visual fields. Her vision stabilized with flashes of light, and dimming of the visual fields. She an increase in prednisone to 60 mg/d. Oral topote- 2 denied photosensitivity or headaches. Examination can and rituximab at 375 mg/m weekly for 4 weeks confirmed generalized constriction in her visual fields were initiated. Repeat imaging 11 months after di- bilaterally and normal fundi. Electroretinography was agnosis showed progression of disease and she was flat to scotopia and photopia, and fluorescein angiog- started on third-line cyclophosphamide, adriamycin, raphy revealed window-like defects. She was suspect- and vincristine (CAV). Her vision remained stable ed to have cancer-related autoimmune retinopathy on tapering dose of prednisone for 4 months after and was referred to an oncologist for further evalua- rituximab. A second course of rituximab was initi- tion. She had no detectable antiretinal antibodies. ated for worsening vision 13 months after diagno- She was a nonsmoker with no significant past sis. She progressed through third-line chemotherapy medical history. She denied weight loss, fever, abdomi- and started paclitaxel 16 months after diagnosis. At nal pain, dysuria, vaginal bleeding, or rash. On further that time she was able to drive during the daytime review, she reported a mass in her lower abdomen, and ski. She died from disease progression 18 months which had been causing mild pelvic pressure for ap- after diagnosis. At the time of her death, she was tak- proximately 3 days. Physical examination confirmed ing 12 mg/d of prednisone. She had minimal visual a non-tender poorly defined suprapubic mass. A CT deterioration from the initiation of rituximab 8 to 9 scan of the chest, abdomen, and pelvis showed paraor- months after diagnosis until her death, approximate- tic lymphadenopathy at the mediastinal, renal, and ly 9 months later. retrocrural levels, and an enlarged uterus. She proceed- ed to diagnostic laparoscopy, which revealed a bleeding uterine mass with hemoperitoneum. She had an Discussion emergent total abdominal hysterectomy and bilateral Paraneoplastic syndromes occur in 10% to 15% of salpingo-oophorectomy. Pathologic specimens were malignancies and are most often associated with car- consistent with a high-grade small cell neuroendocrine cinomas of the lung, breast, and ovary. Cancer-asso- cancer of the uterus, with lymphovascular invasion. ciated retinopathy (CAR) is a heterogenous group of Her vision continued to worsen postoperatively paraneoplastic autoimmune disorders resulting from and she was started on methylprednisolone, 1 g/d for immunologic cross-reactivity between the tumor tis- 3 days, and transitioned to oral prednisone at 1 mg/ sue and retina.1 CAR was first described by Sawyer et kg, and experienced subsequent stabilization of vi- al2 in 1976 in 3 patients with lung cancer. It is most sual deterioration. Two weeks after surgery, intrave- commonly associated with small cell cancers of the nous carboplatin and etoposide once every 3 weeks lung and gynecologic cancers, but associations with was initiated for extensive-stage small cell cancer. lymphoma and breast, non–small cell lung, pros- After chemotherapy cycle 4, while on 10 mg of tate, pancreatic, bladder, colon, and larynx cancers prednisone daily, her vision deteriorated acutely de- have been described.3 Circulating antibodies cause spite dramatic reduction of systemic tumor burden. destruction of cross-reacting antigens expressed by A second course of high-dose methylprednisolone rods, cones, or retinal ganglion cells, leading to vi- was less effective at stabilizing her vision, and intra- sual impairment.3 Recoverin, a 23-kDA retinal pro- venous immunoglobulin (IVIG) was initiated. She tein, is the most common antigen associated with received monthly IVIG at 1000 mg/m2 for 5 doses CAR. Mutations involving the p53 tumor suppres- along with maintenance prednisone, and had stable sor gene on chromosome 17 lead to overexpression vision during that time. She completed cycle 5 and of recoverin, a highly immunogenic protein that 6 of carboplatin/etoposide. stimulates production of anti-recoverin antibodies.1

Dy et al

Recoverin-specific antibodies bind to the antigen in specific to B cells, and is present on all B cells ex- photoreceptor cells and lead to ion channel closure, cept plasma cells. Rituximab is used in the manage- depolarization of the cells, and, ultimately, photore- ment of a wide variety of autoimmune diseases, such ceptor cell degeneration.3 as rheumatoid arthritis, immune thrombocytopenia, CAR typically presents with subacute bilat- lupus, autoimmune hemolytic anemia, thrombotic eral vision abnormalities progressing over weeks to thrombocytopenic purpura, graft-versus-host dis- months, ultimately leading to bilateral vision loss. ease, multiple sclerosis, and neuromyelitis optica.10 Patients often complain of flickering or shimmer- Putative mechanisms of action of rituximab include ing of lights. CAR can affect cones and/or rods bi- complement-dependent cytotoxicity, antibody- laterally. Cone dysfunction causes photosensitivity, dependent cellular cytotoxicity, apoptosis, and in- decreased visual acuity, decreased color vision, and creased phagocytic activity of the reticuloendothelial central scotomas, whereas rod dysfunction causes system.10,11 The “decoy hypothesis,” further proposes nyctalopia, prolonged dark adaptation, mid-periph- that rituximab-IgG molecules bind to circulating ef- eral scotomas, and peripheral field deficits.1 Jacob- fector cells, such as neutrophils, monocytes, and mac- son et al4 proposed the triad of photosensitivity, ring rophages, reducing the availability of effector cells at scotoma, and attenuated retinal arteriole caliber to the site of immune complex deposition and slowing be associated with CAR. Early in the disease, fun- tissue damage.11 The authors chose rituximab given duscopy may be normal and disease progression leads its success in treating autoimmune disorders. to attenuation of the arterioles and mottling of the This report presents an uncommon case of a pa- retinal pigment epithelium. Electroretinography fre- tient with small cell carcinoma of the uterus with quently identifies irregularity associated with CAR. CAR in whom visual deterioration was successfully Patients with primarily rod dysfunction are charac- halted by the use of rituximab. In this patient, visual terized by abnormal scotopic electroretinography, symptoms did not correlate with the systemic disease whereas those with cone dysfunction are character- activity or disease response to cytotoxic chemothera- ized by abnormal photopic electroretinography.1 Se- py, but seemed to stabilize with rituximab therapy. She rum antiretinal antibodies can be detected by West- had no detectable antiretinal antibodies, and response ern blot, enzyme-linked immunosorbent assay, or to therapy was monitored clinically. To the authors’ immunohistochemical methods.1 knowledge, only one previous report of rituximab Review of the literature revealed no specific cor- use in CAR has been published.12 Visual symptoms relation between the response of the underlying can- of CAR preceding the diagnosis of uterine cancer cer to therapy and visual abnormalities. Eltabbakh are also rare, and only 5 similar cases have been re- et al5 reported on a 65-year-old woman with uterine ported (Table 1).6,8,13–15 The cases were predominantly sarcoma whose CAR resolved after surgical debulking in postmenopausal women, with a median age of 63.4 and chemotherapy. Sekiguchi et al,6 however, reported years, who presented at an advanced stage. The me- on a 60-year-old woman with stage IB small cell car- dian survival was less than 1 year, and patients experi- cinoma of the uterus who completed surgical debulk- enced transient improvements in vision. ing without any visual improvement, but experienced some improvement in vision with steroid therapy. Glu- cocorticoids may transiently halt visual deterioration Conclusions in some patients.3 No specific guidelines are available Paraneoplastic syndromes such as CAR can oc- for the management of this rare disease, but most au- casionally precede the diagnosis of an underlying thors used methylprednisolone up to 1 g/d, followed by malignancy. CAR should be considered in patients taper to 60 to 100 mg of oral prednisone daily.3 Other presenting with subacute bilateral visual dysfunc- forms of immune-modulator therapies, such as IVIG,7 tion of unknown cause. Visual impairment causes plasmapharesis,5 Tolpa Torf Preparation,8 cyclosporine, severe functional morbidity that must be addressed and alemtuzumab,9 have been used with some success. separately from the management of the underlying Rituximab is a monoclonal antibody against malignancy. The patient in this report experienced 9 CD20 primarily used in the treatment of non-Hodg- months of preserved vision after rituximab was initi- kin’s B-cell lymphoma. CD20 is a cell surface antigen ated, until she died as a result of systemic disease.

Cancer-Associated Retinopathy Overall Prognosis Died 6 mo after diagnosis Died 4 mo after PR Died 2 y after diagnosis from metastases N/A Died 18 mo after diagnosis Visual Prognosis No improvement; later HM OU No improvement; later HM OU No improvement; later HM OU Transient improvements; stable at HM N/A Stable Treatment for Treatment PR Steroids (30 Gy) OU XRT Steroid eyedrops Steroids, plasmapheresis, Torf Tolpa Preparation N/A Steroids, IVIG, rituximab Treatment for Cancer Treatment to pelvis XRT TAHBSO, medroxyprogesterone later chemo TAHBSO, on POD and XRT TAHBSO, chemo, megestrol acetate, 714X (experimental drug) to spine XRT metastasis chemo TAHBSO, Antibody to Retinal Antigen N/A N/A (+) 34 kDa (+) Recoverin N/A Negative Interval Between PR and CA PR 2.0 mo before CA CA 1 y before PR PR 4.0 mo before CA CA 3.0 mo before PR PR 1.5 mo before CA PR 1.5 mo before CA Symptoms 20/80 OU; central scotomas OU; ERG suppressed 0.3 OU; VA retinal detachments OU 0.1 OU; VA suppressed ERG 20/70 OD; CF OS Decreased VA; suppressed ERG –19.86 dB OD and –25.13 dB OS VA

Stage Visual IV IV IB IV IV IV Age (y) 72 67 60 61 57 61

8 15 1998 6 1997 1992 13 14 Table 1 Reported Cases of Paraneoplastic Retinopathy Associated With Small Cell Cancer the Endometrium Table Study Campo et al, Brink et al, Sekiguchi et al, Adamus and MacKay, 1998 Ju et al, 2005 Present case Abbreviations: CA, cancer; CF, counting fingers; chemo, chemotherapy; ERG, electroretinography; HM, hand movement; IVIG, intravenous immunoglobulin; N/A, not applicable; OD, right eye; OS, left OU, both eyes; POD, counting fingers; chemo, chemotherapy; ERG, electroretinography; HM, hand movement; IVIG, intravenous immunoglobulin; N/A, not applicable; OD, right Abbreviations: CA, cancer; CF, chemoradiation. visual acuity; XRT, total abdominal hysterectomy bilateral salpingo-oophorectomy; VA, progression of disease; PR, paraneoplastic retinopathy; TAHBSO,

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The success of rituximab in treating autoimmune dis- intravenous immunoglobulin. Arch Ophthalmol 1999;127:612–614. orders warrants further exploration of the drug, and a 8. Adamus G, MacKay C. Long term persistence of anti-recoverin phase I study is underway to determine the effective- antibodies in endometrial cancer-associated retinopathy. Arch Ophthalmol 1998;116:251–253. ness of rituximab in treating autoimmune retinopa- 9. Espander L, O’Brien S, Thirkill C, et al. Successful treatment of thy (ClinicalTrials.gov identifier: NCT01086631). cancer-associated retinopathy with alemtuzumab. J Neurooncol 2007;83:295–302. 10. Gurcan HM, Keskin DB, Stern JN, et al. A review of the current References use of rituximab in autoimmune diseases. Int Immunopharmacol 1. Khan N, Huang JJ, Foster CS. Cancer associated retinopathy 2009;9:10–25. (CAR): an autoimmune mediated paraneoplastic syndrome. Semin 11. Taylor RP, Lindorfer MA. Drug insight: the mechanism of action Ophthalmol 2006;21:135–141. of rituximab in autoimmune disease—the immune complex decoy 2. Sawyer RA, Selhorst JB, Zimmerman LE, et al. Blindness caused hypothesis. Nat Clin Pract Rheumatol 2007;3:86–95. by photoreceptor degeneration as a remote effect of cancer. Am J 12. Adamus G, Ren G, Weleber RG. Autoantibodies against retinal Ophthalmol 1976;181:606–613. proteins in paraneoplastic and autoimmune retinopathy. BMC 3. Chan JW. Paraneoplastic retinopathies and optic neuropathies. Ophthalmol 2004;4:5. Surv Ophthalmol 2003;48:12–36. 13. Campo E, Brunier MN, Merino MJ. Small cell carcinoma of the 4. Jacobson DM, Thirkill CE, Tipping SJ. A clinical triad to diagnose endometrium with associated ocular paraneoplastic syndrome. paraneoplastic retinopathy. Ann Neurol 1990;28:162–167. Cancer 1992;69:2283–2288. 5. Eltabbakh GH, Hoogerland DL, Kay MC. Paraneoplastic 14. Brink H, Deutman A, Beex L. Unusual retinal pigment retinopathy associated with uterine sarcoma. Gynecol Oncol epitheliopathy and choroidopathy in carcinomatosis: a rare case of 1995;58:120–123. cancer-associated retinopathy. Graefe’s Arch Clin Exp Ophthalmol 6. Sekiguchi I, Suzuki M, Sato I, et al. Rare case of small cell carcinoma 1997;235:59–61. arising from the endometrium with paraneoplastic retinopathy. 15. Ju W, Park IA, Kim SH, et al. Small cell carcinoma of the uterine Gynecol Oncol 1998;71:454–457. corpus manifesting with visual dysfunction. Gynecol Oncol 7. Guy J, Aptsiarui N. Treatment of paraneoplastic visual loss with 2005;99:504–506.

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Posttest Questions c. Increased phagocytosis through reticulo-endothelial system 1. Recoverin, a 23-kDA retinal protein is the most common an- d. Induction of direct cell death tigen associated with cancer-associated retinopathy. (apoptosis) a. True e. All of the above b. False 3. Visual symptoms in cancer-associated 2. Rituximab is a monoclonal antibody directed against CD20, retinopathy always correlate with the and is used in the treatment of B-cell non-Hodgkin’s lym- systemic disease burden and response phoma and multiple autoimmune diseases. Possible mecha- of the systemic disease to chemotherapy or other therapies nisms of action for rituximab include: directed against the primary cancer. a. Complement-dependent cytotoxicity a. True b. Antibody-dependent cellular cytotoxicity b. False