Treatment of Cancer-Associated Retinopathy With Rituximab

NCCN: Continuing Education

Case Summary

A 61-year-old right-handed woman presented in October 2010 with rapidly progressive painless visual dysfunction. She described fluctuating visual changes in the right eye for 4 days and subsequently in the left eye 2 days before presenting to her ophthalmologist. She reported experiencing diminished night vision, flashes of light, and dimming of the visual fields. She denied photosensitivity or headaches. Examination confirmed generalized constriction in her visual fields bilaterally and normal fundi. Electroretinography was flat to scotopia and photopia, and fluorescein angiography revealed window-like defects. She was suspected to have cancer-related autoimmune retinopathy and was referred to an oncologist for further evaluation. She had no detectable antiretinal antibodies.

She was a nonsmoker with no significant past medical history. She denied weight loss, fever, abdominal pain, dysuria, vaginal bleeding, or rash. On further review, she reported a mass in her lower abdomen, which had been causing mild pelvic pressure for approximately 3 days. Physical examination confirmed a non-tender poorly defined suprapubic mass. A CT scan of the chest, abdomen, and pelvis showed paraortic lymphadenopathy at the mediastinal, renal, and retrocrural levels, and an enlarged uterus. She proceeded to diagnostic laparoscopy, which revealed a bleeding uterine mass with hemoperitoneum. She had an emergent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Pathologic specimens were consistent with a high-grade small cell neuroendocrine cancer of the uterus, with lymphovascular invasion.

Her vision continued to worsen postoperatively and she was started on methylprednisolone, 1 g/d for 3 days, and transitioned to oral prednisone at 1 mg/kg, and experienced subsequent stabilization of visual deterioration. Two weeks after surgery, intravenous carboplatin and etoposide once every 3 weeks was initiated for extensive-stage small cell cancer. After chemotherapy cycle 4, while on 10 mg of prednisone daily, her vision deteriorated acutely despite dramatic reduction of systemic tumor burden. A second course of high-dose methylprednisolone was less effective at stabilizing her vision, and intravenous immunoglobulin (IVIG) was initiated. She received monthly IVIG at 1000 mg/m² for 5 doses along with maintenance prednisone, and had stable vision during that time. She completed cycle 5 and 6 of carboplatin/etoposide.

Three months after completion of chemotherapy, her systemic disease progressed, with several new hypermetabolic nodules in the left lower abdomen and posterior mediastinum. At the same time, approximately 8 months after diagnosis and while on 10 mg/d of prednisone, she again experienced narrowing of the visual fields. Her vision stabilized with an increase in prednisone to 60 mg/d. Oral topotecan and rituximab at 375 mg/m² weekly for 4 weeks were initiated. Repeat imaging 11 months after diagnosis showed progression of disease and she was started on third-line cyclophosphamide, adriamycin, and vincristine (CAV). Her vision remained stable on tapering dose of prednisone for 4 months after rituximab. A second course of rituximab was initiated for worsening vision 13 months after diagnosis. She progressed through third-line chemotherapy and started paclitaxel 16 months after diagnosis. At that time she was able to drive during the daytime and ski. She died from disease progression 18 months after diagnosis. At the time of her death, she was taking 12 mg/d of prednisone. She had minimal visual deterioration from the initiation of rituximab 8 to 9 months after diagnosis until her death, approximately 9 months later.

Discussion

Paraneoplastic syndromes occur in 10% to 15% of malignancies and are most often associated with carcinomas of the lung, breast, and ovary. Cancer-associated retinopathy (CAR) is a heterogenous group of paraneoplastic autoimmune disorders resulting from immunologic cross-reactivity between the tumor tissue and retina.¹ CAR was first described by Sawyer et al² in 1976 in 3 patients with lung cancer. It is most commonly associated with small cell cancers of the lung and gynecologic cancers, but associations with lymphoma and breast, non-small cell lung, prostate, pancreatic, bladder, colon, and larynx cancers have been described.³ Circulating antibodies cause destruction of cross-reacting antigens expressed by rods, cones, or retinal ganglion cells, leading to visual impairment.³ Recoverin, a 23-kDA retinal protein, is the most common antigen associated with CAR. Mutations involving the p53 tumor suppressor gene on chromosome 17 lead to overexpression of recoverin, a highly immunogenic protein that stimulates production of anti-recoverin antibodies.¹ Recoverin-specific antibodies bind to the antigen in photoreceptor cells and lead to ion channel closure, depolarization of the cells, and, ultimately, photoreceptor cell degeneration.³

CAR typically presents with subacute bilateral vision abnormalities progressing over weeks to months, ultimately leading to bilateral vision loss. Patients often complain of flickering or shimmering of lights. CAR can affect cones and/or rods bilaterally. Cone dysfunction causes photosensitivity, decreased visual acuity, decreased color vision, and central scotomas, whereas rod dysfunction causes nyctalopia, prolonged dark adaptation, mid-peripheral scotomas, and peripheral field deficits.¹ Jacobson et al⁴ proposed the triad of photosensitivity, ring scotoma, and attenuated retinal arteriole caliber to be associated with CAR. Early in the disease, funduscopy may be normal and disease progression leads to attenuation of the arterioles and mottling of the retinal pigment epithelium. Electroretinography frequently identifies irregularity associated with CAR. Patients with primarily rod dysfunction are characterized by abnormal scotopic electroretinography, whereas those with cone dysfunction are characterized by abnormal photopic electroretinography.¹ Serum antiretinal antibodies can be detected by Western blot, enzyme-linked immunosorbent assay, or immunohistochemical methods.¹

Review of the literature revealed no specific correlation between the response of the underlying cancer to therapy and visual abnormalities. Eltabbakh et al⁵ reported on a 65-year-old woman with uterine sarcoma whose CAR resolved after surgical debulking and chemotherapy. Sekiguchi et al,⁶ however, reported on a 60-year-old woman with stage IB small cell carcinoma of the uterus who completed surgical debulking without any visual improvement, but experienced some improvement in vision with steroid therapy. Glucocorticoids may transiently halt visual deterioration in some patients.³ No specific guidelines are available for the management of this rare disease, but most authors used methylprednisolone up to 1 g/d, followed by taper to 60 to 100 mg of oral prednisone daily.³ Other forms of immune-modulator therapies, such as IVIG,⁷ plasmapharesis,⁵ Tolpa Torf Preparation,⁸ cyclosporine, and alemtuzumab,⁹ have been used with some success.

Rituximab is a monoclonal antibody against CD20 primarily used in the treatment of non-Hodgkin’s B-cell lymphoma. CD20 is a cell surface antigen specific to B cells, and is present on all B cells except plasma cells. Rituximab is used in the management of a wide variety of autoimmune diseases, such as rheumatoid arthritis, immune thrombocytopenia, lupus, autoimmune hemolytic anemia, thrombotic thrombocytopenic purpura, graft-versus-host disease, multiple sclerosis, and neuromyelitis optica.¹⁰ Putative mechanisms of action of rituximab include complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, apoptosis, and increased phagocytic activity of the reticuloendothelial system.^10,11 The “decoy hypothesis,” further proposes that rituximab-IgG molecules bind to circulating effector cells, such as neutrophils, monocytes, and macrophages, reducing the availability of effector cells at the site of immune complex deposition and slowing tissue damage.¹¹ The authors chose rituximab given its success in treating autoimmune disorders.

This report presents an uncommon case of a patient with small cell carcinoma of the uterus with CAR in whom visual deterioration was successfully halted by the use of rituximab. In this patient, visual symptoms did not correlate with the systemic disease activity or disease response to cytotoxic chemotherapy, but seemed to stabilize with rituximab therapy. She had no detectable antiretinal antibodies, and response to therapy was monitored clinically. To the authors’ knowledge, only one previous report of rituximab use in CAR has been published.¹² Visual symptoms of CAR preceding the diagnosis of uterine cancer are also rare, and only 5 similar cases have been reported (Table 1).^6,8,13-15 The cases were predominantly in postmenopausal women, with a median age of 63.4 years, who presented at an advanced stage. The median survival was less than 1 year, and patients experienced transient improvements in vision.

Conclusions

Paraneoplastic syndromes such as CAR can occasionally precede the diagnosis of an underlying malignancy. CAR should be considered in patients presenting with subacute bilateral visual dysfunction of unknown cause. Visual impairment causes severe functional morbidity that must be addressed separately from the management of the underlying malignancy. The patient in this report experienced 9 months of preserved vision after rituximab was initiated, until she died as a result of systemic disease. The success of rituximab in treating autoimmune disorders warrants further exploration of the drug, and a phase I study is underway to determine the effectiveness of rituximab in treating autoimmune retinopathy (ClinicalTrials.gov identifier: NCT01086631).

Table 1

Reported Cases of Paraneoplastic Retinopathy Associated With Small Cell Cancer of the Endometrium

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