Discussion
Following the advancement of therapeutic options for retinoblastoma, the survival rate for retinoblastoma is >95% in the developed world.5,10 As the rate of mortality from retinoblastoma has decreased, SPMNs have become the leading cause of death for patients with hereditary retinoblastoma.6The cumulative actuarial incidence of SPMNs in hereditary disease has been reported to be 15.7% at 20 years and around 30% at 40 years.5,11-13{Marees, 2010, Risk of third malignancies and death after a second malignancy in retinoblastoma survivors}At 60 years, a Danish cohort had a cumulative incidence of SPMNs of 51% for hereditary disease versus 13% for nonhereditary disease.6 The variance in published rates is due to a multitude of factors, including different lengths of follow-up, different definitions of SPMNs (some include pineoblastomas and non-melanoma skin cancers), different treatments provided for retinoblastoma, non-equivalent hereditary versus nonhereditary disease ratios, and use of national population-based studies versus tertiary referral center studies.5
Prior to the introduction of primary intravenous chemotherapy, EBRT was the predominant strategy for globe-salvaging therapy. EBRT for retinoblastoma has been associated with high rates of soft tissue and bony sarcomas in the field of radiation. In our study, 13 of 15 patients were diagnosed and treated prior to an effective and low toxicity CEV regimen of systemic chemotherapy, and all 15 patients were diagnosed and treated prior to the availability of selective ophthalmic intra-arterial chemotherapy at our center. This is reflected in the high rate of soft tissue and bony sarcomas in the field of radiation in our study (11 of 15 patients; 13 of 17 tumors). Additionally, 14 patients developed a SPMN in the head/neck region, 13 of whom had a history of prior EBRT.
Following the advent of an effective CEV intravenous chemotherapy as a treatment for retinoblastoma, there has been a change in patterns of SPMNs encountered. While hematologic SPMNs were rare prior to the introduction of chemotherapy, there has been an increased risk of hematologic SPMNs (most commonly acute myelogenous leukemia), especially in patients who received higher doses of chemotherapy.14,15,16 When used in combination with EBRT, chemotherapy may lead to higher rates of bone cancers and leiomyosarcomas in patients with hereditary disease compared to either treatment alone.17 Two patients in our study received intravenous chemotherapy during their treatment course. Patient 7 received both EBRT and a cyclophosphamide-based intravenous chemotherapy regimen, while patient 12 (the only patient that did not undergo EBRT) was treated with vincristine, etoposide, and carboplatin. Neither patient treated with systemic chemotherapy developed a hematologic SPMN.
Despite the mortality rate associated with SPMN in survivors of hereditary retinoblastoma, imaging surveillance of asymptomatic patients has not been associated with decreased mortality and may lead to increased costs and false-positive results.18 An expert consensus panel met in 2017 to evaluate follow-up recommendations for SPMNs and endorsed annual skin examinations for cutaneous melanoma screening but recommended against radiographic screening of asymptomatic patients. The panel also recommended an annual history and physical examination and educating patients on the need for prompt evaluation of symptoms consistent with persistent sinusitis, skeletal tenderness, and pain.18 As retinoblastoma treatment continues to evolve and long-term data on SPMNs related to intravenous chemotherapy and selective ophthalmic intra-arterial chemotherapy becomes available, screening guidelines may need to be updated.
Limitations of this study include its retrospective nature, the lack of follow-up information on the patients in the total group of 550 patients who did not develop a SPMN during available follow-up, the lack of baseline classification data on patients diagnosed and treated elsewhere prior to referral to the practice, the lack of information regarding the precise field of radiation, radiation dose, and fractionation schedule in most of the cases, and the referral bias of a single practice ocular oncology tertiary referral practice. An association of SPMNs with mutational status was not available in most cases in this series because genetic testing was not performed routinely during retinoblastoma management during the era of treatment for most patients in this cohort.
In conclusion, we describe our experience with non-pineoblastoma SPMNs in a tertiary referral practice. The vast majority of SPMNs in this series occurred in patients who had been treated by EBRT, and most occurred in the field of prior radiation. SPMNs occurred on average nearly two decades following the original diagnosis of retinoblastoma.
Conflicts of Interest Statement :
Maura Di Nicola consults for EyePoint Pharmaceuticals. Basil Williams consults for Allergan/Abbvie, Castle Biosciences, EyePoint Pharmaceuticals, Genentech/Roche, and Regeneron. No other authors have any conflict of interests.
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