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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