Chapter 13

Core Messages

■Virtually any molecule can serve as a target for therapy. The ideal target, however, is present only on abnormal cells, allowing normal cells to be spared from the treatment e ect.

■Rituximab was the first monoclonal antibody approved by the United States Food and Drug Administration for the treatment of cancer. It is a chimeric human/murine monoclonal anti-CD20 immunoglobulin G1 (IgG1) antibody. CD20 is a cell surface protein expressed on most B cells but not on uncommitted hematopoietic precursor cells. Rituximab is approved for the treatment of B-cell lymphoma. Rituximab has also been used successfully in the treatment of other lymphoproliferative disorders in the orbit, including lymphoid hyperplasia

■Ibritumomab is a murine IgG1 anti-CD20 antibody. It can be coupled with tiuxetan, a chelator, and ibritumomab tiuxetan can bind yttrium-90 to form yttrium-90-labeled ibritumomab tiuxetan (hereafter referred to as ibritumomab; Zevalin) [32]. In a trial comparing rituximab to rituximab plus ibritumomab for refractory or relapsed follicular or low-grade non-Hodgkin lymphoma, response rates were 56% for rituximab alone and 80% for the combination. In a prospective trial, 12 patients underwent combined treatment with rituximab and ibritumomab as front-line treatment for stage I-E ocular adnexal lymphoma. Ten patients had a complete response, and two had a partial response. There

was one local recurrence during the follow-up period; there were no distant relapses[14].

■Imatinib mesylate (imatinib; Gleevec) is a selective tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. Edema is the most commonly seen adverse e ect associated with imatinib mesylate, and the periorbital region is the most common site for edema. In a phase I trial of imatinib for the treatment of gastrointestinal stromal tumor,edema of the periorbital region or eyelids was seen in 55.1% of the 174 patients treated. Rarely, the edema can be so severe that surgical treatment is required.

■Cetuximab is a monoclonal antibody directed against epidermal growth factor receptor (EGFR), a member of the ErbB family of tyrosine kinase receptors. Cetuximab is used in the treatment of colon cancer and head and neck squamous cell carcinoma (SCC).Although SCC in the head and neck can involve the orbit,we found no published reports of cetuximab used in the treatment of periorbital SCC at the time of preparation of this chapter. However, there have been reports of EGFR expression in conjunctival SCC as well as in both ocular and extraocular sebaceous gland carcinomas, suggesting a potential role for EGFR inhibitors in treatment of conjunctival SCC, and sebaceous gland carcinoma of the eyelid. A common ocular side e ect of cetuximab and other EGFR inhibitors is trichomegaly.

13.1Introduction

All cells have molecules on the cell surface and within the cell that are potential targets for targeted therapy.Targeted therapies take advantage of di erences in molecular char-

acteristics between di erent cell types to direct treatment to specific cells [2, 5]. Targeted therapies are currently being used in the treatment of a variety of disease processes, including inflammatory, infectious, and neoplastic processes. Table 13.1 lists many of the targeted

therapies currently available for the treatment of cancer. Virtually any molecule can serve as a target for therapy. The ideal target, however, is present only on abnormal cells, allowing normal cells to be spared from the treatment e ect. Molecules that have been exploited for this purpose include CD20, vascular endothelial growth factor, bcr-abl, EGFR, and others. Targeted therapy is an attractive modality for the treatment of cancer anywhere in the body as it may decrease the need for other treatments (e.g., surgery, external beam radiation therapy, and traditional systemic chemotherapies) with potentially harmful e ects. Targeted therapy is especially attractive for treating tumors in the orbit, where surgery can cause major morbidity and where radiation exposure can cause cataracts, ocular surface dysfunction, retinopathy, and optic neuropathy. Several targeted agents have been successfully used in the treatment of orbital and periorbital malignancies (Table 13.1), and we discuss these agents in this chapter.

13.2Rituximab

Lymphoid neoplasms are logical targets because of the number of well-identified specific cell surface antigens that can serve as selective targets for therapy. In addition, lymphoid neoplasms are frequently associated with systemic involvement, and targeted therapies would be expected to treat malignant cells anywhere in the body.

Rituximab was the first monoclonal antibody approved by the United States Food and Drug Administration for the treatment of cancer. It is a chimeric human/murine monoclonal anti-CD20 IgG1 antibody. CD20 is a cell surface protein expressed on most B cells but not on uncommitted hematopoietic precursor cells. CD20 appears to function as a calcium channel [3] and is involved in cell cycle regulation [29]. Because it is specifically expressed on mature B cells, CD20 is an excellent target for use in the treatment of B-cell malignancies. Rituximab binds to CD20 and initiates cell death via either

complement-dependent cell lysis or antibody-dependent cellular cytotoxicity [24]. Directed therapy with rituximab can destroy B cells without a ecting stem cells.

Rituximab is approved for the treatment of B-cell lymphoma. Standard therapy for non-Hodgkin lymphoma has often included multiagent chemotherapy and external beam radiation therapy [21]. In the past, the typical chemotherapeutic regimen for advanced disease was cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP); there are also multiple other chemotherapy variations with similar e cacy. These regimens have yielded 3-year survival rates of 50–54% for advanced disease [16]. Rituximab has been added to the CHOP regimen (R-CHOP). Several randomized controlled studies have been done comparing CHOP to R-CHOP and have shown improved response rates and increased survival in the R-CHOP groups [4, 15].

The use of rituximab for orbital B-cell lymphomas was first reported in 2002 in a series of four patients with lowgrade lesions. Three of these patients were treated with 375 mg/m2 of rituximab intravenously weekly for 4 weeks. The fourth patient received intravenous rituximab in addition to ibritumomab according to the schedule used in the prospective trial of ocular adnexal lymphoma described in the next section of this chapter. All four patients responded to treatment [11]. Sullivan et al. reported complete or partial response in seven of eight patients in their series of orbital lymphomas treated with rituximab [28]. Rituximab has also been used successfully in the treatment of other lymphoproliferative disorders in the orbit, including lymphoid hyperplasia, by our

group and others [18, 27, 33] (Fig. 13.1). On et al. reported the use of rituximab concurrently with radiosurgery in the treatment of orbital pseudotumor [23]. The use of rituximab has also been reported in the treatment of thyroid orbitopathy [25].

13.3Yttrium-90-Labeled Ibritumomab Tiuxetan

Ibritumomab is a murine IgG1 anti-CD20 antibody. It can be coupled with tiuxetan, a chelator, and ibritumomab tiuxetan can bind yttrium-90 to form yttrium-90-labeled ibritumomab tiuxetan (hereafter referred to as ibritumomab; Zevalin) [32]. Yttrium-90 emits beta particles and has a half-life of 64h (Fig. 13.2). Ninety percent of the emitted energy is absorbed within 5.3mm [20, 32]. Like rituximab, ibritumomab can bind B cells expressing CD20 and induce cell lysis and initiate cell death via either comple- ment-dependent cell lysis or antibody-dependent cellular cytotoxicity. In addition, because of the coupled radioisotope, ibritumomab can deliver targeted radiation therapy.

In a trial comparing rituximab to rituximab plus ibritumomab for refractory or relapsed follicular or lowgrade non-Hodgkin lymphoma, response rates were 56% for rituximab alone and 80% for the combination [32].

The first reported use of ibritumomab in the orbit was in 2002 for a case of refractory orbital lymphoma [11]. Later, in a prospective trial, Esmaeli and associates [14] evaluated combined treatment with rituximab and ibritumomab as front-line treatment in patients with stage I-E

Monoclonal

antibody

13

Chelator

90Y Beta radionuclide radiation

Fig. 13.2 Schematic depicting the molecular structure of yttrium-90-labeled ibritumomab tiuxetan

ocular adnexal lymphoma. Patients were treated with two doses of intravenous rituximab (250 mg/m2) on consecutive weeks. After the second dose, ibritumomab was administered at a dose of 0.3 mCi/kg in patients with platelet counts under 150,000/m3 and 0.4 mCi/kg in patients with platelet counts of 150,000/m3 or more. Twelve patients were enrolled and followed for a median of 20 months. Ten patients had a complete response (Fig. 13.3), and two had a partial response. There was one

local recurrence during the follow-up period; there were no distant relapses. Adverse events included transient pancytopenia in all patients, fatigue, increased bruising, muscle and joint pain, headache, nausea, fever, flushing, and dizziness. No adverse e ects typically seen with external beam radiation therapy, such as cataract formation, keratopathy, or retinopathy, were seen during the follow-up period. Single-photon emission computed tomography was performed to estimate the radiation dose to the orbital tissues. The dose was found to be less than 3 Gy, approximately one tenth the dose received with external beam therapy [10].

13.4Imatinib Mesylate

Imatinib mesylate (imatinib; Gleevec) is a selective tyrosine kinase inhibitor used in the treatment of CML [9] and gastrointestinal stromal tumors [6]. Most cases of CML result from a translocation of chromosomes 9 and 22, the so-called Philadelphia chromosome, in which the Bcr gene and the c-abl gene are spliced together. The resulting protein product, the Bcr-abl oncoprotein, is a tyrosine kinase with activity that is known to be responsible for CML. Because CML is caused by this specific protein, which is not present in normal cells, Bcr-abl serves as an excellent target to selectively treat cancerous cells in patients with CML. Imatinib was initially selected from a large library of molecules by screening for inhibitory activity specific for the Bcr-abl protein [8]. In addition to this activity,