POSTLAMINAR OPTIC NERVE INVASION

The greatest controversy exists for patients with postlaminar optic nerve invasion without involvement of the cut margin. Some experts report that, in the absence of choroidal or scleral invasion, patients with postlaminar optic nerve involvement and a negative margin have a very low rate of relapse (0 out of 21 patients53) and therefore they do not recommend adjuvant chemotherapy for this subgroup. Further, in the absence of choroidal invasion, optic nerve involvement alone is not a significant risk factor for metastatic disease.56 On the other hand, prior studies did not stratify postlaminar optic nerve invasion based on choroidal and scleral involvement, and many experts therefore recommend adjuvant chemotherapy for all patients with postlaminar optic nerve invasion.49,55

TUMOR AT CUT OPTIC NERVE MARGIN

Experts agree that patients with tumor at the cut optic nerve margin are at very high risk of relapse and require adjuvant chemotherapy.49,53–55 However, few studies effectively address adjuvant treatment for retinoblastoma extending beyond the cut margin of the optic nerve, precluding definitive recommendations.52,54 In a study of 51 patients, doxorubicin was added to cyclophosphamide, vincristine, and EBRT if the tumor extended beyond the cut margin of the optic nerve or through the sclera into the orbit.52 In patients with central nervous system (CNS) involvement, the authors added intrathecal chemotherapy (methotrexate, cytarabine, hydrocortisone) and cranial radiotherapy. The survival rate was 90.6% for patients with unilateral and 84.2% for patients with bilateral disease.

The decision to treat uveal metastases depends upon the individual case. Lesions that do not threaten vision or the status of the globe can be observed while the patient undergoes systemic treatment. Systemic treatment alone can induce tumor regression.64

CHEMOTHERAPY

Metastatic breast carcinoma is managed with cytotoxic chemotherapy with or without hormonal therapy. Anthracyclines, like doxorubin and epirubucin, represent a potent class of agents limited by their cardiotoxicity. Taxanes such as paclitaxel and docetaxel are often used in tandem or sequentially with other agents to improve effectiveness against breast cancer. Alkylating agents include cyclophosphamide and temozolomide, the latter boasting excellent CNS penetration. Antimetabolite fluorouracil and capecitabine (both pyrimidine analogues) and methotrexate (folic acid analogue) are also used. Hormonal therapies include aromatase inhibitors and antiestrogen agents (e.g., tamoxifen).62 The largest case series for metastatic breast carcinoma to the uvea (85 cases) reports a 65% rate of tumor regression with chemotherapy and/or hormonal therapy.65

Small-cell lung carcinoma is commonly treated with a combination of platinum-based agents (cisplatin, carboplatin), etoposide, cyclophosphamide, doxorubicin, methotrexate, and vincristine. By comparison, nonsmall-cell lung cancer is less sensitive to chemotherapy; treatment is usually palliative. Chemotherapeutic agents for nonsmall-cell lung cancer include cisplatin, carboplatin, gemcitabine, vinorelbine, paclitaxel, and docetaxel.62 Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, and erlotinib, a tyrosine kinase inhibitor, are novel targeted agents proven to increase survival in non- small-cell lung cancer66 (Figures 44.3 and 44.4).

METASTATIC RETINOBLASTOMA

Metastatic retinoblastoma carries a dismal prognosis, though the prognosis for distant metastases is better than that for CNS metastases. Rates of metastases are higher in developing countries. Retinoblastoma can metastasize to regional lymph nodes, CNS, and distant organs, usually bone and bone marrow.57,58 A study evaluating nine patients with CNS metastases and five with concomitant CNS and distant metastases reported 100% mortality in both groups. Four patients were treated with cyclophosphamide, doxorubicin, vincristine, carboplatin, and etoposide, along with intrathecal methotrexate, cytarabine, and hydro­ cortisone. Some studies have questioned the benefit of intrathecal chemotherapy.59,60 As such, ifosfamide, carboplatin, etoposide (ICE) was used in patients with CNS metastases because of its potential to penetrate possible metastatic retinoblastoma sites. Ifosfamide and carboplatin have high CNS penetration; carboplatin also penetrates bone marrow well. All patients underwent craniospinal EBRT. Unfortunately, all 10 patients with CNS metastases died from their disease. In comparison, four patients with only distant metastases were treated with ICE chemotherapy and survived.57

PROGNOSIS

Unfortunately, uveal metastases tend to occur later in the course of carcinoma, portending a poor prognosis. At the time of uveal metastasis diagnosis, up to 88% of patients will have metastases elsewhere. Life expectancy for patients with uveal metastases ranges between 0.2 and 48 months (median 6–9 months).62

UVEAL MELANOMA

Uveal melanoma is most commonly treated with enucleation, episcleral plaque brachytherapy, proton beam radiotherapy, transpupillary thermotherapy, or local resection. To date, no convincing evidence exists for chemotherapy to treat primary uveal melanoma. One patient with bilateral primary choroidal melanoma was unsuccessfully treated with systemic interferon-α, temozolomide, paclitaxel, and carboplatin.67 A trial of adjunctive subconjunctival interferon-α for uveal melanoma failed to find a protective effect for this experimental treatment.68

UVEAL METASTASIS

GENERAL CONSIDERATIONS

Metastatic carcinoma to the uveal tract remains the most common intraocular malignancy.61 Lung carcinoma is the most common primary source in men, while breast carcinoma is most common in women. Together lung and breast carcinoma account for 71–92% of cases.62 Treatment options include systemic chemotherapy, EBRT, proton beam radiotherapy, hormonal therapy, biological therapy, brachytherapy, laser photocoagulation, transpupillary thermotherapy, photodynamic therapy, anti-vascular endothelial growth factor treatment, enucleation, or a combination of these.62,63

METASTATIC UVEAL MELANOMA

Mortality rates for uveal melanoma have remained unchanged despite improvements in diagnosis. Though only 2% of patients have evidence of metastases at the time of uveal melanoma diagnosis, 35–50% will develop metastases within 5 years of enucleation. Most experts feel this is related to subclinical micrometastases at time of diagnosis.30 Unfortunately, median survival for metastatic uveal melanoma is only 2–15 months.69–71

No standard chemotherapy regimen exists for metastatic uveal melanoma. Moreover, treatment outcomes remain disappointing without compelling evidence of a survival advantage. Carboplatinor dacarbazine­-based regimens have low efficacy.72 A multicenter study evaluating the efficacy of BOLD (bleomycin, vincristine, lomustine, dacarbazine) therapy with subcutaneous interferon-α found no response.73 Chemoembolization of the hepatic artery with carmustine