Subsequent Neoplasms (SNs)

Heritable retinoblastoma. Patients with heritable retinoblastoma have a markedly increased incidence of SNs, independent of treatment with radiation therapy.[2,3,5] In a German series of 643 patients with heritable retinoblastoma, chemotherapy with or without radiation therapy was the only significant risk factor for the onset of second cancers outside the periorbital region.[3] A possible association between the type of RB1 variant and incidence of SNs may exist, with complete loss of RB1 activity associated with a higher incidence of SNs.[6] Patients who are heterozygous for regular-penetrance RB1 variants may be at a higher risk of developing SNs than patients with incomplete-penetrance RB1 variants.[7] Regular penetrance refers to patients with heritable disease and classic multifocal bilateral tumors. Incomplete penetrance, while rare, is a clinical phenotype in which affected family members may not develop retinoblastoma or they present with unilateral disease. With the increase in survival of patients with heritable retinoblastoma, it has become apparent that they are also at risk of developing epithelial cancers late in adulthood. A marked increase in mortality from lung, bladder, and other epithelial cancers has been described.[8,9]In a large series from two institutions, 2,053 patients with retinoblastoma (diagnosed between 1914–2016) were identified, with a maximum of 70 years of follow-up. Most deaths occurred in patients with hereditary retinoblastoma (518 of 1,129), and 267 of these deaths were caused by SNs. Increased risk of death resulting from cancers of the pancreas, large intestines, and kidney were reported. Overall risk of SNs was greater for patients who were treated with radiation therapy and chemotherapy compared with patients who were treated with radiation therapy alone, although patterns varied by organ site. In a cohort of 143 retinoblastoma survivors diagnosed between 1997 and 2006, continued improvements in mortality were seen.[4][Level of evidence C1] For patients with nonhereditary retinoblastoma, only 27 deaths in 924 patients were attributed to SNs. Among retinoblastoma survivors with heritable retinoblastoma, those with an inherited germline pathogenic variant are at a slightly higher risk of developing an SN than are those with a de novo variant. Melanoma was the most common SN seen in patients with germline pathogenic variants.[10]

Past treatment for retinoblastoma with radiation therapy. The cumulative incidence of SNs was reported to be 26% (± 10%) in nonirradiated patients and 58% (± 10%) in irradiated patients by 50 years after diagnosis of retinoblastoma, resulting in a rate of about 1% per year.[11]A German series of 633 patients with heritable retinoblastoma demonstrated a 5-year survival rate of 93%. However, 40 years later, only 80% of patients survived, with most succumbing to radiation-induced SNs (hazard ratio, approximately 3).[12] Other studies analyzing cohorts of patients treated with more advanced radiation planning and delivery technology have reported the SN rates to be about 9.4% in nonirradiated patients and about 30.4% in irradiated patients.[13] In a nonrandomized study that compared two contemporary cohorts of patients with hereditary retinoblastoma who were treated with either photon (n = 31) or proton (n = 55) therapy, the 10-year cumulative incidence of radiation-induced SNs was significantly different between the two groups (0% for proton radiation vs. 14% for photon radiation; P = .015).[14] Longer follow-up is required to further define the risk of SNs associated with proton radiation.The most common SN is sarcoma, specifically osteosarcoma, followed by soft tissue sarcoma and melanoma. These malignancies may occur inside or outside of the radiation field, although most are radiation induced. The carcinogenic effect of radiation therapy is associated with the dose delivered, particularly for subsequent sarcomas. A step-wise increase is apparent at all dose categories. In irradiated patients, two-thirds of SNs occur within irradiated tissue, and one-third of SNs occur outside the radiation field.[5,11,13,15] In a cohort of 952 irradiated survivors of hereditary retinoblastoma who were originally diagnosed between 1914 and 2006, 105 bone sarcomas and 125 soft tissue sarcomas were identified. Approximately two-thirds of these cancers occurred in the head and neck. The incidence rates were 2,000-fold higher for bone sarcomas and 500-fold higher for soft tissue sarcomas than was expected in the general population. Head and neck bone and soft tissue sarcomas were diagnosed in early childhood and continued into adulthood, with a 60-year cumulative incidence of 6.8% for bone sarcomas and 9.3% for soft tissue sarcomas. Bone and soft tissue sarcomas diagnosed elsewhere in the body were increased 169-fold and 45.7-fold, respectively, compared with the general population. Bone sarcomas primarily occurred in the long bones during adolescence. The incidence of soft tissue sarcomas was rare until age 30 years, when it rose steeply (60-year cumulative incidence, 6.6%), particularly for females (9.4%). The soft tissue sarcomas that occurred in females were leiomyosarcomas and were mainly located in the abdomen and pelvis.[5,11]; [16][Level of evidence C1]

Age at time of radiation therapy. The risk of SNs also appears to depend on the patient's age at the time that external-beam radiation therapy (EBRT) is administered, especially in children younger than 12 months. The histopathological types of SNs may be influenced by age.[13,17,18]

Previous SN. Patients who survive SNs are at a sevenfold increased risk of developing another SN.[19] The risk increases an additional threefold for patients treated with radiation therapy.[20]