Late Effects of Treatment for Childhood Cancer (PDQ®), part 2

In general, Leydig cell function is preserved, but germ cell failure is common in men treated with high cumulative doses of cyclophosphamide (7,500 mg/m2 or more) and more than 3 months of combination alkylating agent therapy.

Most studies suggest that prepubertal males are not at lower risk of chemotherapy-induced testicular damage than are postpubertal patients.[17-20]

Sources: 17 · 20

Cyclophosphamide:

Cyclophosphamide:

Male survivors of non-Hodgkin lymphoma who received a cumulative cyclophosphamide dose of greater than 9.5 g/m2 and underwent pelvic radiation therapy were at increased risk of failure to recover spermatogenesis.[21]

Sources: 21

In survivors of Ewing sarcoma and soft tissue sarcoma, treatment with a cumulative cyclophosphamide dose of greater than 7.5 g/m2 was correlated with persistent oligospermia or azoospermia.[22]

Sources: 22

Cyclophosphamide doses exceeding 7.5 g/m2 and ifosfamide doses exceeding 60 g/m2 produced oligospermia or azoospermia in most exposed individuals.[23-25]

Sources: 23 · 25

A small cohort study reported normal semen quality in adult long-term survivors of childhood ALL treated with 0 to 10 g/m2 of cyclophosphamide and cranial irradiation, whereas no spermatozoa were detected in semen samples from survivors treated with more than 20 g/m2 of cyclophosphamide.[26]

Sources: 26

Treatment with a cyclophosphamide equivalent dose of less than 4 g/m2 results in infrequent azoospermia or oligospermia. Approximately 89% of 31 men treated were normospermic.[27]

Sources: 27

Spermatogenesis was present in 67% of 15 men who received 200 mg/kg of cyclophosphamide before undergoing HSCT for aplastic anemia.[28]

Sources: 28

Dacarbazine:

Dacarbazine:

The combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) frequently produced oligospermia or azoospermia in adults during the course of treatment. However, recovery of spermatogenesis occurred after treatment was completed, which is in contrast to the experience reported after treatment with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP).[29]

Sources: 29

Alkylating agent plus procarbazine:

Alkylating agent plus procarbazine:

Most studies suggest that combination chemotherapy with an alkylating agent and procarbazine causes severe damage to the testicular germinal epithelium that is irreversible at high cumulative doses.[17,30-33]

Sources: 17 · 30 · 33

Azoospermia occurred less frequently in adults after treatment with two, rather than six, cycles of MOPP.[34]

Sources: 34

Elevation of the basal follicle-stimulating hormone (FSH) level, which may reflect impaired spermatogenesis, was less frequent among patients who received two courses of vincristine, procarbazine, prednisone, and doxorubicin (OPPA) than among those who received two courses of OPPA in combination with two or more courses of cyclophosphamide, vincristine, procarbazine and prednisone (COPP).[35]

Sources: 35

Alkylating agents plus low-dose cranial radiation:

Alkylating agents plus low-dose cranial radiation:

In a cross-sectional study that included male adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without cranial radiation, St. Jude Children's Research Hospital investigators demonstrated that cranial radiation at doses lower than 26 Gy has no demonstrable independent effect on spermatogenesis.[36]

Sources: 36

The potential for chronic pulmonary sequelae is related to the radiation dose administered, the volume of lung irradiated, and the fractional radiation therapy doses.[6]

Sources: 6

Combined-modality therapy, including radiation therapy and pulmonary toxic chemotherapy or thoracic/chest wall surgery, increases the risk of pulmonary function impairment.[7,8]

Sources: 7 · 8

Chronic pulmonary complications reported after treatment for pediatric malignancies include restrictive or obstructive chronic pulmonary disease, pulmonary fibrosis, and spontaneous pneumothorax.[9]

Sources: 9

After partial lung radiation, acute pulmonary toxicity was uncommon, with grade 2 to 3 incidence of radiation pneumonitis of less than 1%.

Late toxicities, including subclinical/asymptomatic impaired pulmonary function, were more common (<4%) and appeared to increase in incidence and severity over time.

The risk of pulmonary complications was low among children treated with a mean lung dose of lower than 14 Gy and total lung V20Gy less than 30%.

Within the spectrum of doses that could be analyzed, pulmonary toxicity was higher after whole-lung irradiation, but no dose-response relationship was identified.

Bleomycin and other chemotherapeutic agents at current dose regimens did not contribute substantially to adverse pulmonary outcomes after partial lung irradiation. However, this risk increased with whole-lung irradiation.

For survivors of pediatric Hodgkin lymphoma, the prevalence of pulmonary symptoms using contemporary involved-field techniques is reported to be low. However, some patients exhibit substantial subclinical dysfunction.[11]

Sources: 11

For survivors of pediatric Hodgkin lymphoma, the prevalence of pulmonary symptoms using contemporary involved-field techniques is reported to be low. However, some patients exhibit substantial subclinical dysfunction.[11]

A study of 54 children who were treated with induction chemotherapy (usually doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide–based chemotherapy) and 21 Gy of radiation therapy from 2008 through 2016 confirmed these findings.[12]

Sources: 12

For survivors of pediatric Hodgkin lymphoma, the prevalence of pulmonary symptoms using contemporary involved-field techniques is reported to be low. However, some patients exhibit substantial subclinical dysfunction.[11] › A study of 54 children who were treated with induction chemotherapy (usually doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide–based chemotherapy) and 21 Gy of radiation therapy from 2008 through 2016 confirmed these findings.[12]

At a median follow-up of 39.5 months, 3 of 54 patients (5.6%) or 3 of 108 lungs (2.8%) developed radiation pneumonitis (RP); two lungs had grade 1 RP and one lung had grade 2 RP.

RP was seen only in patients with a median lung dose of higher than 12.4 Gy or with an individual mean lung dose higher than 13.8 Gy.

For survivors of pediatric Hodgkin lymphoma, the prevalence of pulmonary symptoms using contemporary involved-field techniques is reported to be low. However, some patients exhibit substantial subclinical dysfunction.[11]

In a study of 109 patients (59% with Hodgkin lymphoma) who were irradiated at a median age of 13.8 years (range, 0.04–20.9 years; median follow-up, 3.4 years), patients were treated with a median prescribed radiation therapy dose of 21 Gy (range, 0.4–64.8 Gy); 58.7% of patients received bleomycin, and 83.5% of patients received cyclophosphamide.[13]

Sources: 13

For survivors of pediatric Hodgkin lymphoma, the prevalence of pulmonary symptoms using contemporary involved-field techniques is reported to be low. However, some patients exhibit substantial subclinical dysfunction.[11] › In a study of 109 patients (59% with Hodgkin lymphoma) who were irradiated at a median age of 13.8 years (range, 0.04–20.9 years; median follow-up, 3.4 years), patients were treated with a median prescribed radiation therapy dose of 21 Gy (range, 0.4–64.8 Gy); 58.7% of patients received bleomycin, and 83.5% of patients received cyclophosphamide.[13]

The 5-year cumulative incidence after irradiation was: pneumonitis, 6%; chronic cough, 10%; pneumonia, 35%; dyspnea, 11%; supplemental oxygen requirement, 2%; radiographic interstitial lung disease, 40%; and chest wall deformity, 12%.

One patient died of progressive respiratory failure.

Postirradiation pulmonary function tests available from 44 patients showed evidence of obstructive lung disease (25%), restrictive disease (11%), hyperinflation (32%), and abnormal diffusion capacity (12%).

Thoracic surgery, bleomycin, age, maximum lung irradiation dose V30 (volume of lung exposed to a radiation dose >30 Gy), and volume of lung exposed to a radiation dose of greater than 25 Gy were significant risk factors for the development of adverse pulmonary outcomes on univariate analysis.

Mean lung irradiation dose, maximum lung dose, and Vdose (percentage of volume of lung receiving the threshold dose or greater) were highly correlated. On multivariate analysis, mean lung irradiation dose was the sole significant predictor of adverse pulmonary outcome (P = .01).

Changes in lung function have been reported in children treated with whole-lung radiation therapy for metastatic Wilms tumor.[14,15]

Sources: 14 · 15

Changes in lung function have been reported in children treated with whole-lung radiation therapy for metastatic Wilms tumor.[14,15]

A dose of 12 Gy to 14 Gy reduced TLC and vital capacity to about 70% of predicted values, and even lower if the patient had undergone thoracotomy.

Administration of bleomycin alone can produce pulmonary toxicity and, when combined with radiation therapy, can heighten radiation reactions. Chemotherapeutic agents such as doxorubicin, dactinomycin, and busulfan are radiomimetic agents and can reactivate underlying radiation damage.[14,15]

Sources: 14 · 15

The development of bleomycin-associated pulmonary fibrosis with permanent restrictive disease is dose dependent, usually occurring at doses greater than 200 U/m2 to 400 U/m2, higher than those used in treatment protocols for pediatric malignancies.[16,17]

Sources: 16 · 17

Pediatric regimens for Hodgkin lymphoma using radiation therapy and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) have shown a significant incidence of asymptomatic pulmonary dysfunction after treatment, which appears to improve with time.[18] However, grades 3 and 4 pulmonary toxicity was reported in 9% of children receiving 12 cycles of ABVD followed by 21 Gy of extended-field radiation.[17]

Sources: 18 · 17

ABVD-related pulmonary toxic effects may result from fibrosis induced by bleomycin or radiation recall pneumonitis related to administration of doxorubicin.

One series included 207 children who were treated with bleomycin for Hodgkin lymphoma or germ cell tumors and had pulmonary function tests at least 1 year after the completion of therapy. At least one pulmonary function abnormality was present in 52.5% of patients. Obstructive lung disease was noted in 22.7% of patients, restrictive lung disease in 7.5%, hyperinflation in 28.8%, and nonuniform ventilation in 14%. Very few patients had pulmonary symptoms.[19]

Sources: 19

Pulmonary veno-occlusive disease has been observed rarely and has been attributed to bleomycin or alkylating agents.[20,21]

Sources: 20 · 21

Platinum-related sensorineural hearing loss develops as an acute toxicity that is generally irreversible and bilateral.[9]

Sources: 9

The prevalence of hearing loss has varied widely per series and is based on platinum treatment (e.g., platinum type, dose, infusion duration); host factors (e.g., age, genetic susceptibility, renal function); receipt of additional ototoxic therapy (cranial radiation therapy, aminoglycosides, loop diuretics), and the grading criteria used to report prevalence and severity of hearing loss.[8-10]

Sources: 8 · 10

Hearing loss manifests initially in the high frequencies and progresses to the speech frequencies with increasing cumulative exposure.[9]

Sources: 9

Cisplatin-induced hearing loss involving the speech frequencies (500–2,000 Hz) usually occurs with cumulative doses that exceed 400 mg/m2 in pediatric patients.[11,12]

Sources: 11 · 12

Prolonging the duration of infusion or splitting the dose has been reported to reduce the risk of significant hearing loss.[13]

Sources: 13

In two randomized trials (Children's Oncology Group ACCL0431 [NCT00716976] and International Childhood Liver Tumour Strategy Group SIOPEL-6 [NCT00652132]), sodium thiosulfate demonstrated efficacy in preventing cisplatin-induced hearing loss.[14,15] The SIOPEL-6 trial compared cisplatin alone with cisplatin plus delayed administration of sodium thiosulfate (sodium thiosulfate administered 6 hours after cisplatin) resulted in a 48% lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma. Sodium thiosulfate treatment did not jeopardize the overall survival or event-free survival.[15] These trials led to regulatory approval of sodium thiosulfate for prevention of cisplatin-induced hearing loss. However, each trial used a different hearing end point. In 2010, the SIOP-Boston ototoxicity scale was developed to overcome key limitations of the available scales, and it is central to harmonizing hearing end points. Using the SIOP scale, hearing outcomes from the ACCL0431 trial were re-evaluated. This analysis showed that children treated with sodium thiosulfate were approximately 90% less likely to develop higher than grade 2 cisplatin-induced hearing loss during the trial period or at the end of cisplatin therapy, compared with the observation group.[16]

Sources: ACCL0431 [NCT00716976] · SIOPEL-6 [NCT00652132] · 14 · 15 · 15 · 16

Otologic toxic effects after platinum chemotherapy have been reported to worsen years after completion of therapy.[17]

Sources: 17

Radiation therapy to the posterior fossa inclusive of the eighth cranial nerve (suggestive of damage to the cochlea at the end of therapy) increases the risk of late-onset hearing loss in survivors treated with cisplatin.[18]

Sources: 18

Carboplatin used in conventional (nonmyeloablative) dosing is typically not ototoxic.[19] However, delayed-onset hearing loss has been reported in the following populations:

Sources: 19

Carboplatin used in conventional (nonmyeloablative) dosing is typically not ototoxic.[19] However, delayed-onset hearing loss has been reported in the following populations:

In a cross-sectional, multicenter analysis that included 451 Dutch childhood cancer survivors who received platinum agents but not cranial radiation therapy, the incidence of ototoxicity (defined as Münster grade >2b [>20 dB at ≥4–8kHz]) associated with the use of carboplatin alone (n = 112) was 17%.[8]

Sources: 8

A single study of otologic toxic effects after non-HSCT dosing of carboplatin for retinoblastoma reported that 8 of 175 children developed hearing loss. For seven of the eight children, the onset of the otologic toxic effects was delayed a median of 3.7 years.[20]

Sources: 20

Another study that evaluated audiological outcomes among 60 retinoblastoma survivors treated with nonmyeloablative systemic carboplatin and vincristine estimated a cumulative incidence of hearing loss of 20.3% at 10 years.[21]

Sources: 21

Carboplatin used in conventional (nonmyeloablative) dosing is typically not ototoxic.[19] However, delayed-onset hearing loss has been reported in the following populations: › Another study that evaluated audiological outcomes among 60 retinoblastoma survivors treated with nonmyeloablative systemic carboplatin and vincristine estimated a cumulative incidence of hearing loss of 20.3% at 10 years.[21]

Among the ten patients (17%) who developed sustained grade 3 or grade 4 hearing loss, nine were younger than 6 months at the start of chemotherapy.

Younger age at the start of treatment was the only significant predictor of hearing loss. The cumulative incidence of hearing loss was 39% for patients younger than 6 months versus only 8.3% for patients aged 6 months and older.

The use of a carboplatin conditioning regimen for HSCT, particularly in combination with previous carboplatin or cisplatin therapy, may cause significant otologic toxic effects.[11,12]

Sources: 11 · 12

The use of a carboplatin conditioning regimen for HSCT, particularly in combination with previous carboplatin or cisplatin therapy, may cause significant otologic toxic effects.[11,12]

One series evaluated 115 patients with recurrent or refractory germ cell tumors (median age, 32 years) who had received first-line cisplatin-based chemotherapy. The study reported hearing outcomes for adolescents and young adults treated with three cycles of high-dose carboplatin therapy. Of the 106 patients with normal hearing or mild hearing loss before high-dose carboplatin therapy, 70 (66%) developed moderate-to-profound hearing loss in the speech frequencies after high-dose carboplatin therapy. Twenty-five patients (22%) were recommended for hearing aids after high-dose carboplatin therapy. Patients with moderate-to-profound hearing loss isolated to higher frequencies before high-dose carboplatin therapy were more likely to develop moderate-to-profound hearing loss in the speech frequencies after therapy and be recommended for hearing aids.[22]

Sources: 22

Cranial radiation therapy, when used as a single modality, may result in otologic toxic effects that may be gradual in onset, manifesting months to years after exposure. The threshold dose for auditory toxicity after radiation therapy alone is in the range of 35 Gy to 45 Gy for children.[23]

Sources: 23

High-frequency sensorineural hearing loss is uncommon at cumulative radiation doses below 35 Gy, and is rarely severe below doses of 45 Gy.[24] The exception is for patients with supratentorial tumors and ventriculoperitoneal shunts, in whom doses below 30 Gy may be associated with intermediate frequency (1,000–2,000 Hz) hearing loss.[23,25]

Sources: 24 · 23 · 25

To reduce the risk of hearing loss, the average cochlear dose should not exceed 30 Gy to 35 Gy, delivered over 6 weeks.

Sensorineural hearing loss after cranial radiation therapy can progress over time.

Sensorineural hearing loss after cranial radiation therapy can progress over time.

A study included 235 pediatric patients with brain tumors who were treated with conformal or intensity-modulated radiation therapy (without cisplatin or preexisting hearing loss) and monitored for a median of 9 years. Sensorineural hearing loss was prevalent in 14% of patients, with a median time to onset of 3.6 years from radiation therapy.[26]

Sources: 26

Sensorineural hearing loss after cranial radiation therapy can progress over time. › A study included 235 pediatric patients with brain tumors who were treated with conformal or intensity-modulated radiation therapy (without cisplatin or preexisting hearing loss) and monitored for a median of 9 years. Sensorineural hearing loss was prevalent in 14% of patients, with a median time to onset of 3.6 years from radiation therapy.[26]

Follow-up evaluations among 29 patients identified continued decline in hearing sensitivity.

Risk factors for cranial radiation–associated sensorineural hearing loss included younger age at initiation of radiation, higher cochlear radiation dose, and cerebrospinal fluid shunting.

When used concomitantly with cisplatin, radiation therapy can substantially exacerbate the hearing loss associated with platinum chemotherapy.[23,27-29]

Sources: 23 · 27 · 29

In two reports from the CCSS, the following clinical and genetic factors were reported in 5-year cancer survivors:

In two reports from the CCSS, the following clinical and genetic factors were reported in 5-year cancer survivors:

Increased risk of problems with hearing sounds (relative risk [RR], 2.3), tinnitus (RR, 1.7), hearing loss requiring an aid (RR, 4.4), and hearing loss in one or both ears not corrected by a hearing aid (RR, 5.2), compared with siblings. Temporal lobe irradiation (>30 Gy) and posterior fossa irradiation (>50 Gy but also 30–49.9 Gy) were associated with these adverse outcomes.[6]

Sources: 6

Exposure to platinum was associated with an increased risk of problems with hearing sounds (RR, 2.1), tinnitus (RR, 2.8), and hearing loss requiring an aid (RR, 4.1).[6]

Sources: 6

Males were more likely than females to report cranial radiation therapy–related tinnitus (9.4% vs. 5.4%) and hearing loss (14.0% vs. 10.7%).[30]

Sources: 30

Survivors with tinnitus or hearing loss were more likely than controls to experience persistent dizziness or vertigo, take antidepressants, and report poorer overall health.[30]

Sources: 30

A genome-wide association study identified a single-nucleotide polymorphism on chromosome 6 as nearly genome-wide significant for association with cranial radiation therapy–related hearing loss. A replication analysis in the St. Jude Life (SJLIFE) cohort study supported its significant association with cranial radiation therapy–related and de novo hearing loss.[30]

Sources: 30

The Pediatric Normal Tissue Effects in the Clinic (PENTEC) investigation included 457 cochleas at risk in patients treated with radiation therapy without chemotherapy, and 398 cochleas in patients treated with chemotherapy.[31]

Sources: 31

The Pediatric Normal Tissue Effects in the Clinic (PENTEC) investigation included 457 cochleas at risk in patients treated with radiation therapy without chemotherapy, and 398 cochleas in patients treated with chemotherapy.[31]

The incidence and severity of cochlear hearing loss from radiation therapy exposure alone is related to dose and age. Risk of hearing loss was less than 5% in cochlea receiving a mean dose 35 Gy or lower but increased to 30% at a dose of 50 Gy.

Hearing loss risk ranged from 25% to 40% in children younger than 5 years at diagnosis, declining to 10% in older children for any radiation dose.

Probability of similar severe hearing loss occurred at doses 18.3 Gy higher for children younger than 3 years than those older than 3 years.

High-frequency hearing loss was most common, with average onset occurring 3.6 years (range, 0.4–13.2 years) after radiation therapy.

Low-frequency hearing loss was also seen after radiation therapy (in contrast with chemotherapy that primarily affects high frequency).

Chronic comorbidities were assessed in a cohort of 6,778 2-year survivors of adolescent and young adult cancer (defined as diagnosed with cancer between the ages of 15–39 years), with a median follow-up of 5.1 years after cancer diagnosis. The risk of developing chronic comorbidities was compared with matched individuals without a history of cancer. The crude incidence rate ratio (IRR) was 3.0 for hearing loss associated with radiation exposure higher than 30 Gy to the head. In multivariate analyses, a combined exposure to platinum (>450 mg/m2) and radiation to the head (30 Gy) was associated with increased risk of hearing loss (IRR,14.9).[32]

Sources: 32

The CCSS reported the increased risk of developing vision late effects in survivors who were 5 or more years from diagnosis. These late effects included cataracts (RR, 10.8), glaucoma (RR, 2.5), legal blindness (RR, 2.6), double vision (RR, 4.1), and dry eye (RR, 1.9), compared with siblings.[56] In a separate report, the authors provided additional data on the interval from radiation therapy and the radiation dose associated with cataract development.[57] Among 13,902 study participants, 3.5% developed cataracts (41% within 5 years of radiation therapy), with a median time to onset of 9.6 years and a maximum time of 37 years. Lens radiation doses were associated with an increased prevalence: 1.3% if less than 0.5 Gy, 6.1% after 2.5 to 3.49 Gy, and 40.6% after 20 to 60 Gy.

Sources: 56 · 57

The CCSS reported the increased risk of developing vision late effects in survivors who were 5 or more years from diagnosis. These late effects included cataracts (RR, 10.8), glaucoma (RR, 2.5), legal blindness (RR, 2.6), double vision (RR, 4.1), and dry eye (RR, 1.9), compared with siblings.[56] In a separate report, the authors provided additional data on the interval from radiation therapy and the radiation dose associated with cataract development.[57] Among 13,902 study participants, 3.5% developed cataracts (41% within 5 years of radiation therapy), with a median time to onset of 9.6 years and a maximum time of 37 years. Lens radiation doses were associated with an increased prevalence: 1.3% if less than 0.5 Gy, 6.1% after 2.5 to 3.49 Gy, and 40.6% after 20 to 60 Gy.

Higher doses were associated with a shorter time interval to diagnosis. Of the group with cataracts, 31% reported having cataract surgery, supporting the clinical consequences.

Cytosine arabinoside (OR, 1.5) and doxorubicin (OR, 1.5) were independently associated with cataract development, methotrexate was inversely associated (OR, 0.6), and no positive interaction between the use of corticosteroids and radiation therapy was observed.

In a cohort of 517 survivors of childhood acute lymphoblastic leukemia (median time from diagnosis, 10.9 years) who were all evaluated by slit lamp examination, the 15-year cumulative incidence of cataract was 4.5%. CNS radiation therapy was the only treatment-related risk factor identified for cataract development, which occurred in 11.1% of irradiated survivors, compared with 2.8% of those who were not irradiated.[58]

Sources: 58

A retrospective study of 458 children (875 at-risk eyes) treated with proton therapy for intracranial malignancy assessed radiation therapy–related visual decline. Eyes were considered at risk if either the ipsilateral optic nerve or optic chiasm received 30 GyRBE or higher to 0.1 cm3.[59]

Sources: 59

A retrospective study of 458 children (875 at-risk eyes) treated with proton therapy for intracranial malignancy assessed radiation therapy–related visual decline. Eyes were considered at risk if either the ipsilateral optic nerve or optic chiasm received 30 GyRBE or higher to 0.1 cm3.[59]

No patients experienced complete vision loss.

The actuarial 5-year rate of visual acuity decline was 2.6%.

Tumor location significantly correlated with risk. Investigators found that children with tumors of the suprasellar or the optic pathway region are at greatest risk. The reported risk was about 5% decline in visual acuity with a dose of 56 GyRBE to the optic nerve or optic pathway.

For children with tumors arising elsewhere in the brain, no toxicity was observed.

A St. Jude Children's Research Hospital investigation evaluated ocular complications in school-aged children and adolescents who survived at least 1 year following allogeneic HSCT. Among 162 patients (mean age at transplant, 13.4 years; mean follow-up, 4 years), the following was reported:[60]

Sources: 60

A St. Jude Children's Research Hospital investigation evaluated ocular complications in school-aged children and adolescents who survived at least 1 year following allogeneic HSCT. Among 162 patients (mean age at transplant, 13.4 years; mean follow-up, 4 years), the following was reported:[60]

Cataract formation was noted in 57 patients (35%) and dry eye was noted in 51 patients (31%).

Multivariate analysis of significant variables showed that TBI was a risk factor for cataract formation, and chronic graft-versus-host disease (GVHD) was a significant risk factor for dry eye syndrome.

Compared with patients treated with busulfan or other chemotherapy, patients treated with single-dose or fractionated TBI are at increased risk of cataracts.[61-64]

Sources: 61 · 64

Compared with patients treated with busulfan or other chemotherapy, patients treated with single-dose or fractionated TBI are at increased risk of cataracts.[61-64]

The risk ranges from approximately 10% to 60% at 10 years posttreatment, depending on the total dose and fractionation, with a shorter latency period and more severe cataracts noted after single fraction and higher dose or dose-rate TBI.

One series evaluated 48 patients with high-risk neuroblastoma (median years since diagnosis, 14.1 years) who were all treated with multimodal therapy, including high-dose chemotherapy, HSCT (with or without TBI), radiation therapy, and immunotherapy.[10]

Sources: 10

One series evaluated 48 patients with high-risk neuroblastoma (median years since diagnosis, 14.1 years) who were all treated with multimodal therapy, including high-dose chemotherapy, HSCT (with or without TBI), radiation therapy, and immunotherapy.[10]

Twenty-five of the survivors (52%) developed cataracts.

All patients with cataracts had received TBI (P < .0001).

Patients receiving TBI doses of less than 40 Gy have a less than 10% chance of developing severe cataracts.[64]

Sources: 64

Corticosteroids and GVHD may further increase risk.[61,65]

Sources: 61 · 65

The prevalence of cataracts, evaluated by serial slit lamp testing, among 271 participants (mean follow-up, 10.3 years) in the Leucémie de l'Enfant et de l'Adolescent (LEA) program was 41.7%, with 8.1% requiring surgical intervention.[66]

Sources: 66

The prevalence of cataracts, evaluated by serial slit lamp testing, among 271 participants (mean follow-up, 10.3 years) in the Leucémie de l'Enfant et de l'Adolescent (LEA) program was 41.7%, with 8.1% requiring surgical intervention.[66]

The cumulative incidence of cataracts among those treated with TBI increased over time from 30% at 5 years to 70.8% at 15 years and 78% at 20 years.

The lack of a plateau in cataract incidence suggests that nearly all patients treated with TBI will develop cataracts as follow-up increases.

In contrast, the 15-year cumulative incidence of cataracts was 12.5% among those conditioned with busulfan.

Multivariable analysis identified high cumulative steroid dose as a potential cofactor with TBI for cataract risk.

Dry eye syndrome is the most common manifestation of chronic ocular GVHD, but it may occur as an isolated phenomenon in the absence of GVHD.

Dry eye syndrome is the most common manifestation of chronic ocular GVHD, but it may occur as an isolated phenomenon in the absence of GVHD.

A single-center study evaluated 484 consecutive children receiving HSCT who had ophthalmological examinations performed before HSCT and then annually until 5 years after HSCT.[67]

Sources: 67

Dry eye syndrome is the most common manifestation of chronic ocular GVHD, but it may occur as an isolated phenomenon in the absence of GVHD. › A single-center study evaluated 484 consecutive children receiving HSCT who had ophthalmological examinations performed before HSCT and then annually until 5 years after HSCT.[67]

The cumulate incidence of chronic ocular GVHD was 6.0%.

The cumulative incidence of new-onset dry eye disease was 8.7%.

Younger age (0–4 years vs. age 10–16 years) was associated with reduced risk of dry eye disease.

Survivors of childhood cancer who have undergone nephrectomy are at risk of hyperfiltration injury.

Compensatory hypertrophy of the remaining kidney typically occurs after nephrectomy, but over time, renal injury may manifest as reduced glomerular filtration, microalbuminuria and proteinuria, hypertension, and, rarely, focal glomerulosclerosis leading to chronic renal failure.[9,11]

Sources: 9 · 11

Patients with nonsyndromic unilateral Wilms tumor treated with unilateral radical nephrectomy have a 35-year cumulative incidence of late kidney failure of 2.4%, an approximately 10-fold increased rate relative to siblings. No single chemotherapy–related or radiation therapy–related exposure was associated with late kidney failure in a CCSS study of late health outcomes in Wilms tumor survivors (n = 2,008).[12]

Sources: 12

A meta-analysis examined data from 23 studies of patients with Wilms tumor (293 unilateral cases and 386 bilateral cases). The study demonstrated significantly increased odds of developing abnormal kidney function (OR, 4.29; 95% CI, 1.02–18.00) and having a lower estimated GFR (mean, -8.99) among patients treated with radical nephrectomy, compared with those treated with nephron-sparing surgery. Patients with bilateral Wilms tumor (mean follow-up, 7.7 years) treated with radical nephrectomy and contralateral nephron-sparing surgery had higher odds of developing abnormal kidney function (OR, 3.82; 95% CI, 1.76–8.33) and hypertension (OR, 5.81; 95% CI, 1.31–25.86), compared with those treated with bilateral nephron-sparing surgery.[13]

Sources: 13

Acute cisplatin-related nephrotoxicity has been reported in 30% to 100% of exposed children.[14] However, the prevalence of persistent renal dysfunction in long-term survivors appears to be considerably lower.

Sources: 14

The DCCSS-LATER 2 kidney analysis, a nationwide cross-sectional cohort study, evaluated 1,024 survivors (aged 18 years or older at the time of the study) for long-term tubular dysfunction. These patients were 5 or more years from diagnosis and treated between 1963 and 2001 with nephrectomy, abdominal radiation therapy, TBI, cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide, or HSCT. Survivors were compared with 500 age- and sex-matched controls.[6]

Sources: 6

The DCCSS-LATER 2 kidney analysis, a nationwide cross-sectional cohort study, evaluated 1,024 survivors (aged 18 years or older at the time of the study) for long-term tubular dysfunction. These patients were 5 or more years from diagnosis and treated between 1963 and 2001 with nephrectomy, abdominal radiation therapy, TBI, cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide, or HSCT. Survivors were compared with 500 age- and sex-matched controls.[6]

In general, prevalence and ORs for magnesium loss were significantly increased for childhood cancer survivors treated with cisplatin only (25.8%) or in combination with carboplatin (23.1%).

Magnesium loss was associated with all doses of cisplatin but highest for a cumulative dose greater than 500 mg/m2 (OR, 22.0). Childhood cancer survivors exposed only to cisplatin were at risk for potassium loss in comparison with controls (prevalence, 12%; OR, 3.2).

At cumulative doses of cisplatin of higher than 500 mg/m2, the odds for potassium (OR, 17.7) and phosphate loss (OR, 3.6) were increased.

Among 63 children treated with platinum agents, GFR was less than 60 mL/min per 1.73 m2 in 11% of children, and hypomagnesemia requiring oral supplements occurred in 7% of children at 10 years from completion of therapy.[15]

Sources: 15

In a prospective, longitudinal, single-center, cohort study of children monitored for more than 10 years after cisplatin or carboplatin therapy, older age at treatment was found to be the major risk factor for nephrotoxicity, especially for patients who received carboplatin, while cisplatin dose schedule and cumulative carboplatin dose were also important predictors of toxicity. Platinum nephrotoxicity did not change significantly over 10 years.[15]

Sources: 15

The DCCSS-LATER 2 kidney analysis, a nationwide cross-sectional cohort study, evaluated 1,024 survivors (aged 18 years or older at the time of the study) for long-term tubular dysfunction. In multivariable risk analysis, after a median follow-up of 25.5 years, carboplatin was associated with potassium loss at a cumulative dose higher than 2,800 mg/m2 (OR, 5.1).[6]

Sources: 6

The combination of carboplatin and ifosfamide may be associated with more renal damage than the combination of cisplatin and ifosfamide.[15-17]

Sources: 15 · 17

The DCCSS-LATER 2 kidney analysis, a nationwide cross-sectional cohort study, evaluated 1,024 survivors (aged 18 years or older at the time of the study) who had received potentially nephrotoxic therapy for long-term tubular dysfunction. In multivariable risk analysis, after a median follow-up of 25.5 years, ifosfamide was associated with potassium loss (OR, 2.4) and phosphate loss (OR, 2.3) (with cumulative dose >42 g/m2).[6]

Sources: 6

Ifosfamide doses greater than 60 g/m2, age younger than 5 years at treatment, and combination with cisplatin and carboplatin increase the risk of ifosfamide-associated renal tubular toxicity.[18-20]

Sources: 18 · 20

The kidney is relatively radiosensitive, with a tolerance dose of 20 Gy.[22]

Sources: 22

Doses of 18 Gy are considered unlikely to cause severe or chronic renal sequelae. In contrast, up to 50% of individuals treated with 20 Gy may develop glomerular dysfunction or hypertension within 20 years.[23]

Sources: 23

Specific quantitative data are sparse, but a study of 108 children treated for Wilms tumor who had undergone unilateral nephrectomy showed that 41% of children who received less than 12 Gy of radiation to the contralateral remaining kidney, 56% of children who received 12 Gy to 24 Gy, and 91% of children who received more than 24 Gy had a decreased creatinine clearance (GFR <63 mL/min/m2).[24]

Sources: 24

In a report from the German Registry for the Evaluation of Side Effects after Radiation in Childhood and Adolescence (RISK consortium), 126 patients who underwent radiation therapy to parts of the kidneys for various cancers were evaluated. All patients had also received potentially nephrotoxic chemotherapy. Whole-kidney volumes exposed to greater than 20 Gy (P = .031) or 30 Gy (P = .003) of radiation were associated with a greater risk of nephrotoxicity.[25]

Sources: 25

Risk factors for radiation injury include the following:

Risk factors for radiation injury include the following:

Age at time of radiation therapy.

Risk factors for radiation injury include the following: › Age at time of radiation therapy.

Neonates appear to have an increased sensitivity to radiation therapy; doses of 12 Gy to 24 Gy at 1.25 Gy to 1.5 Gy per fraction to the entire kidney were associated with a decreased GFR.[26]

Sources: 26

However, for older children, there is no convincing evidence that age at the time of radiation therapy is related to renal injury.[26]

Sources: 26

Risk factors for radiation injury include the following:

Unilateral versus bilateral radiation therapy.

Risk factors for radiation injury include the following: › Unilateral versus bilateral radiation therapy.

In the National Wilms Tumor Study experience, renal failure was more common in children with bilateral tumors than in children with unilateral tumors.[27]

Sources: 27

The effects of radiation also depend on whether partial or whole-kidney radiation therapy is administered. Renal failure is rare after the administration of partial-volume radiation doses between 12 Gy and 27 Gy.[28]

Sources: 28

When certain agents such as cyclosporine and teniposide are not used, TBI doses of up to 13 Gy are associated with a less than 8% incidence of kidney toxicity.[29]

Sources: 29

Risk factors for radiation injury include the following:

HSCT.

Risk factors for radiation injury include the following: › HSCT.

Chronic kidney disease is a long-term complication of HSCT that has been variably associated with acute kidney injury, lower pretransplant renal function, TBI, conditioning regimens such as fludarabine, graft-versus-host disease, and use of calcineurin inhibitors.[30-32]

Sources: 30 · 32

Most reports of renal outcomes among long-term survivors of childhood cancer treated with HSCT are limited to descriptive outcomes of very small cohorts.

For more information, see the Urinary System Late Effects section in Complications, Graft-Versus-Host Disease, and Late Effects After Pediatric Hematopoietic Stem Cell Transplant.

Sources: Urinary System Late Effects

The risk of toxicity from 10.5 Gy whole-abdomen irradiation was low among patients with Wilms tumor (risks of ≥grade 2 toxicity, 4% and risks of ≥grade 3 toxicity, 1%).

For fractionated 12-Gy TBI with various combinations of chemotherapy, the risk of severe toxicity was low, but low-grade toxicity was more common (risks of ≥grade 2 toxicity, 8% and risks of ≥grade 3 toxicity, 3%).

With a cisplatin dose of 480 mg/m2, a 3% risk of grade 3 or higher toxicity occurred without radiation, and a 5% risk when 26% of the kidney received 10 Gy or higher.

With an ifosfamide dose of 63 g/m2, a 5% risk of grade 3 or higher toxicity occurred without radiation, and a 10% toxicity risk occurred when 42% of the kidney received 10 Gy or higher.

The oxazaphosphorine alkylating agents (cyclophosphamide and ifosfamide) and radiation therapy exposing the bladder have been implicated in the development of hemorrhagic cystitis.

Chemotherapy-associated hemorrhagic cystitis presents as an acute toxicity and appears to be a rare persistent effect among clinically well characterized long-term survivor cohorts.[39,40]

Sources: 39 · 40

In a study of 6,119 children treated between 1986 and 2010 (mean age, 12.2 years ± 6.3 standard deviation), 1.6% of patients (n = 97) developed hemorrhagic cystitis (manifesting at mean 2.7 months after transplant induction therapy and mean 12.4 months after pelvic radiation), most of whom (75%) had severity scores of II or III (scale, I–IV).[41]

Sources: 41

In a study of 6,119 children treated between 1986 and 2010 (mean age, 12.2 years ± 6.3 standard deviation), 1.6% of patients (n = 97) developed hemorrhagic cystitis (manifesting at mean 2.7 months after transplant induction therapy and mean 12.4 months after pelvic radiation), most of whom (75%) had severity scores of II or III (scale, I–IV).[41]

Patients with radiological evidence of renal or bladder calculi or tumors that invaded the bladder wall were excluded from the study.

Older age, previous bone marrow or peripheral blood HSCT, and BK virus in the urine were risk factors for hemorrhagic cystitis and were associated with a higher severity score.

Previous exposure to cyclophosphamide has been linked to risk of bladder carcinoma. An excess prevalence of bladder tumors has also been observed in survivors of specific diagnostic types (e.g., heritable retinoblastoma), supporting the contribution of genetic factors in the development of subsequent neoplasms.[42,43]

Sources: 42 · 43

Pelvic radiation therapy is also associated with an increased risk of hemorrhagic cystitis that may be either acute or chronic in presentation.

The risk of radiation-induced hemorrhagic cystitis is greatest among survivors treated with radiation doses of more than 30 Gy to the whole bladder or more than 60 Gy to a portion of the bladder.[44]

Sources: 44

Long-term bladder fibrosis and contracture may result as sequelae from hemorrhagic cystitis or radiation therapy.[44]

Sources: 44

Surgical procedures involving the lower genitourinary tract have the potential to impair normal function of the bladder and normal voiding mechanisms.

Any cancer therapy or tumor infiltration that disrupts innervation of the bladder can have deleterious effects on bladder function that may manifest as impaired bladder storage, inability to void, and/or incontinence.

Children who have undergone ileal enterocystoplasty for bladder augmentation are at risk of developing a vitamin B12 deficiency. Serum B12 levels decrease over time after the procedure, with the greatest risk occurring 7 years postoperatively.[45]

Sources: 45

surgery

Sources: surgery

chemotherapy

Sources: chemotherapy

radiation therapy

Sources: radiation therapy

stem cell transplant

Sources: stem cell transplant

Skin exam is when a doctor or nurse checks the skin for bumps or spots that look abnormal in color, size, shape, or texture, especially in the area where radiation was given. It is suggested that a skin exam be done once a year to check for signs of skin cancer. The doctor will also provide information about sun protection behaviors to reduce the risk of skin cancer.

Breast self-exam is an exam of the breast by the patient. The patient carefully feels the breasts and under the arms for lumps or anything else that seems unusual. It is suggested that women treated with a higher dose of radiation therapy to the chest do a monthly breast self-exam beginning at puberty. Talk to the doctor about when breast self-exams should begin.

Sources: Breast self-exam · puberty

Clinical breast exam (CBE) is an exam of the breast by a doctor or other health professional. The doctor will carefully feel the breasts and under the arms for lumps or anything else that seems unusual. It is suggested that women treated with a higher dose of radiation therapy to the chest have a clinical breast exam every year beginning at puberty until age 25. After age 25 or 8 years after radiation treatments end (whichever is first), clinical breast exams are done every 6 months. Talk to the doctor about when clinical breast exams should begin.

Sources: Clinical breast exam

Mammogram is an x-ray of the breast. A mammogram may be done in women who had a higher dose of radiation to the chest and who do not have dense breasts. It is suggested that these women have a mammogram once a year starting 8 years after treatment or at age 25, whichever is later. Talk to the doctor about when mammograms to check for breast cancer should begin.

Sources: Mammogram · x-ray

Breast MRI (magnetic resonance imaging) uses a magnet, radio waves, and a computer to make a series of detailed pictures of the breast. This procedure is also called nuclear magnetic resonance imaging (NMRI). An MRI may be done in women who had a higher dose of radiation to the chest and who have dense breasts. It is suggested that these women have an MRI once a year starting 8 years after treatment or at age 25, whichever is later. Talk to the doctor about whether an MRI of the breast to check for breast cancer is needed.

Sources: MRI

Colonoscopy is a procedure to look inside the rectum and colon for polyps, abnormal areas, or cancer. A colonoscope is inserted through the rectum into the colon. A colonoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove polyps or tissue samples, which are checked under a microscope for signs of cancer. It is suggested that childhood cancer survivors who had a higher dose of radiation to the abdomen, pelvis, or spine have a colonoscopy every 5 years. This begins at age 30 or 5 years after treatment ended, whichever is later. Talk to your doctor about when colonoscopies to check for colorectal cancer should begin.

Sources: Colonoscopy · rectum · colon · spine

Multitarget stool DNA test is a test to collect stool to check for cancer cells. This test may be done every 3 years beginning at age 30 or 5 years after treatment ended.

Sources: stool · DNA

acute lymphoblastic leukemia (ALL)

Sources: acute lymphoblastic leukemia

acute myeloid leukemia (AML)

Sources: acute myeloid leukemia

brain and spinal cord tumors

Sources: brain · spinal cord

head and neck cancers

Sources: head and neck cancers

Hodgkin lymphoma

Sources: Hodgkin lymphoma

non-Hodgkin lymphoma

Sources: non-Hodgkin lymphoma

osteosarcoma

Sources: osteosarcoma

Wilms tumor

Sources: Wilms tumor

cancers treated with a stem cell transplant

Sources: stem cell transplant

Radiation to the chest, spine, brain, neck, kidneys, or total-body irradiation (TBI) as part of a stem cell transplant. The risk of problems depends on the area of the body that was exposed to radiation, the amount of radiation given, and whether the radiation was given in small or large doses.

Sources: Radiation · spine · kidneys · total-body irradiation · doses

Certain types of chemotherapy. Chemotherapy with anthracyclines such as doxorubicin, daunorubicin, idarubicin, and epirubicin, and with anthraquinones such as mitoxantrone increase the risk of heart and blood vessel problems. The risk of problems depends on the total dose of chemotherapy given and the type of drug used. It also depends on whether treatment with anthracyclines was given to a child younger than 13 years and whether a drug called dexrazoxane was given during treatment with anthracyclines. Dexrazoxane may lessen heart and blood vessel damage up to 5 years after treatment. Ifosfamide, cyclophosphamide, methotrexate, asparaginase, and chemotherapy with a platinum, such as carboplatin and cisplatin, may also cause heart and blood vessel late effects.

Sources: chemotherapy · anthracyclines · doxorubicin · daunorubicin · idarubicin · epirubicin · anthraquinones · mitoxantrone · drug · dexrazoxane · Ifosfamide · cyclophosphamide · methotrexate · asparaginase · platinum · carboplatin · cisplatin

Stem cell transplant.

Nephrectomy (surgery to remove all or part of a kidney).

Sources: Nephrectomy

Longer time since treatment.

Having high blood pressure or other risk factors for heart disease, such as a family history of heart disease, having excess body weight, smoking, high cholesterol, or diabetes. When these risk factors are combined, the risk of late effects is even higher.

Sources: high blood pressure · risk factors · family history · cholesterol · diabetes

Having lower than normal amounts of thyroid, growth, or sex hormones.

Sources: thyroid · growth · hormones

acute lymphoblastic leukemia (ALL)

Sources: acute lymphoblastic leukemia

acute myeloid leukemia (AML)

Sources: acute myeloid leukemia

brain and spinal cord tumors

head and neck cancers, including retinoblastoma

Sources: head and neck cancers · retinoblastoma

Hodgkin lymphoma

Sources: Hodgkin lymphoma

non-Hodgkin lymphoma

Sources: non-Hodgkin lymphoma

osteosarcoma

Sources: osteosarcoma

soft tissue sarcoma

Sources: soft tissue sarcoma

neuroblastoma

Sources: neuroblastoma

Wilms tumor

Sources: Wilms tumor

cancers treated with a stem cell transplant

Sources: stem cell transplant

head and neck cancers

Sources: head and neck cancers

Hodgkin lymphoma

Sources: Hodgkin lymphoma

neuroblastoma

Sources: neuroblastoma

leukemia that spreads to the brain and spinal cord

Sources: leukemia · spinal cord

nasopharyngeal cancer

Sources: nasopharyngeal cancer

brain tumors

Sources: brain tumors

cancers treated with total-body irradiation (TBI) as part of a stem cell transplant

Sources: total-body irradiation · stem cell transplant

radiation therapy to the head and neck

Sources: radiation therapy

TBI as part of a stem cell transplant

chemotherapy, especially with higher doses of alkylating agents such as cyclophosphamide

Sources: chemotherapy · doses · alkylating agents · cyclophosphamide

surgery in the head and neck area

germ cell tumors

Sources: germ cell tumors

Hodgkin lymphoma

non-Hodgkin lymphoma

Sources: non-Hodgkin lymphoma

neuroblastoma

rhabdomyosarcoma of the bladder or prostate, or near the testicles

Sources: rhabdomyosarcoma · bladder · prostate · testicles

Wilms tumor

Sources: Wilms tumor

Radiation therapy to the abdomen or areas near the abdomen, such as the esophagus, bladder, prostate, or testicles, may cause digestive tract problems that begin quickly and last for a short time. In some patients, however, digestive tract problems are delayed and long-lasting. These late effects are caused by radiation therapy that damages the blood vessels. Receiving higher doses of radiation therapy or receiving chemotherapy such as dactinomycin or anthracyclines together with radiation therapy may increase this risk.

Sources: abdomen · blood vessels · dactinomycin · anthracyclines

Abdominal surgery or pelvic surgery to remove the bladder.

Sources: Abdominal · pelvic

Chemotherapy with alkylating agents such as cyclophosphamide, procarbazine, and ifosfamide, or with anthracyclines such as doxorubicin, daunorubicin, idarubicin, and epirubicin.

Sources: procarbazine · ifosfamide · doxorubicin · daunorubicin · idarubicin · epirubicin

Stem cell transplant.

older age at diagnosis or when treatment begins

treatment with both radiation therapy and chemotherapy

a history of chronic graft-versus-host disease

Sources: chronic · graft-versus-host disease

acute lymphoblastic leukemia (ALL)

Sources: acute lymphoblastic leukemia

liver cancer

Sources: liver cancer

Wilms tumor

cancers treated with a stem cell transplant

surgery to remove part of the liver or a liver transplant

Sources: transplant

chemotherapy that includes high-dose cyclophosphamide as part of a stem cell transplant

chemotherapy such as 6-mercaptopurine, 6-thioguanine, methotrexate, and dactinomycin

Sources: 6-mercaptopurine · thioguanine · methotrexate

radiation therapy to the liver and bile ducts, with the risk depending on:

radiation therapy to the liver and bile ducts, with the risk depending on:

the dose of radiation and how much of the liver is treated

age when treated (the younger the age, the higher the risk)

whether there was surgery to remove part of the liver

whether chemotherapy, such as doxorubicin or dactinomycin, was given together with radiation therapy

stem cell transplant

hepatitis B or hepatitis C infection

Sources: hepatitis B · hepatitis C · infection

history of chronic graft-versus-host disease

liver damage caused by veno-occlusive disease/sinusoidal obstruction syndrome

Sources: veno-occlusive disease · sinusoidal obstruction syndrome

tissue and organ damage from the buildup of extra iron after having many blood transfusions

Sources: iron · blood transfusions

radiation therapy to the abdomen

total-body irradiation as part of a stem cell transplant

acute lymphoblastic leukemia (ALL)

Sources: acute lymphoblastic leukemia

brain tumors

Sources: brain tumors

head and neck cancers

Sources: head and neck cancers

Hodgkin lymphoma

Sources: Hodgkin lymphoma

neuroblastoma

Sources: neuroblastoma

cancers treated with a stem cell transplant

Sources: stem cell transplant

radiation therapy to the thyroid as part of radiation therapy to the head and neck or to the pituitary gland in the brain

Sources: radiation therapy · pituitary gland

total-body irradiation or chemotherapy as part of a stem cell transplant

Sources: total-body irradiation · chemotherapy

MIBG (radioactive iodine) therapy for neuroblastoma

Sources: radioactive iodine

chemotherapy such as alkylating agents, anthracyclines, or bleomycin

Sources: chemotherapy · alkylating agents · anthracyclines · bleomycin

surgery to remove part of the thyroid

acute lymphoblastic leukemia (ALL)

brain and spinal cord tumors

Sources: brain and spinal cord tumors

head and neck cancers

cancers treated with a stem cell transplant

high blood pressure

Sources: high blood pressure

high levels of triglycerides and low levels of high-density lipoprotein (HDL) cholesterol in the blood

high levels of glucose (sugar) in the blood

acute lymphoblastic leukemia (ALL)

cancers treated with a stem cell transplant

cancers treated with radiation to the abdomen, such as Wilms tumor or neuroblastoma

radiation therapy to the brain, abdomen, or pelvis

total-body irradiation (TBI) as part of a stem cell transplant

chemotherapy, such as alkylating agents

older age

acute lymphoblastic leukemia (ALL)

brain tumors, especially craniopharyngiomas

Sources: craniopharyngiomas

bone tumors

cancers treated with radiation to the brain, including TBI as part of a stem cell transplant

TBI for females

radiation therapy to the abdomen for males

certain types of chemotherapy (alkylating agents and anthracyclines)

being female

having a low household income

having a chronic illness

radiation therapy to the brain

surgery that damages the hypothalamus or pituitary gland, such as surgery to remove a craniopharyngioma brain tumor

having excess body weight at the time of a cancer diagnosis

being diagnosed with cancer between the ages of 5 and 9

being female

having growth hormone deficiency or low levels of the hormone leptin

Sources: leptin

lack of physical activity

taking an antidepressant called paroxetine

Sources: antidepressant · paroxetine

radiation therapy to the brain

TBI

surgery to remove the spleen

Sources: spleen

high-dose radiation therapy to the spleen that causes the spleen to stop working

Sources: high-dose radiation

stem cell transplant followed by graft-versus-host disease that causes the spleen to stop working

Sources: stem cell transplant · graft-versus-host disease

chemotherapy

Sources: chemotherapy

radiation therapy

Sources: radiation therapy

stem cell transplant with or without graft-versus-host disease

acute lymphoblastic leukemia (ALL)

Sources: acute lymphoblastic leukemia

bone cancer

Sources: bone cancer

brain and spinal cord tumors

Sources: brain · spinal cord

Ewing sarcoma

Sources: Ewing sarcoma

head and neck cancers

Sources: head and neck cancers

neuroblastoma

Sources: neuroblastoma

non-Hodgkin lymphoma

Sources: non-Hodgkin lymphoma

osteosarcoma

Sources: osteosarcoma

retinoblastoma

Sources: retinoblastoma

soft tissue sarcoma, such as rhabdomyosarcoma

Sources: soft tissue sarcoma · rhabdomyosarcoma

Wilms tumor

Sources: Wilms tumor

cancers treated with a stem cell transplant

Sources: stem cell transplant

changes in the way the face or skull form, especially when high-dose radiation with or without chemotherapy is given to children before age 5 years

Sources: skull · high-dose radiation · chemotherapy

short stature (being shorter than normal)

curving of the spine (scoliosis) or rounding of the spine (kyphosis)

Sources: spine · scoliosis · kyphosis

one arm or leg is shorter than the other arm or leg

weak or thin bones that can break easily (osteoporosis)

Sources: osteoporosis

parts of a bone to die from a lack of blood flow (osteoradionecrosis), especially the jaw

a benign tumor of the bone (osteochondroma)

Sources: benign tumor · osteochondroma

having problems with activities of daily living

Sources: activities of daily living

not being able to be as active as normal

chronic pain

Sources: chronic pain

problems with the way prosthetics fit or work

Sources: prosthetics

broken bone

additional surgeries later in life

the bone not healing well after surgery

one arm or leg is shorter than the other

weak or thin bones that can break easily (osteoporosis)

one or more parts of a bone to die from a lack of blood flow (osteonecrosis), especially in the hip or knee

Sources: osteonecrosis

Total-body irradiation given as part of a stem cell transplant may affect the body's ability to make growth hormone and cause short stature (being shorter than normal). It may also cause weak or thin bones that can break easily (osteoporosis) and the formation of a benign tumor called osteochondroma.

Sources: Total-body irradiation · growth hormone

Chronic graft-versus-host disease that may occur after a stem cell transplant can cause the muscles around joints to tighten, leading to stiff joints (joint contractures). Chronic graft-versus-host disease may also cause one or more parts of a bone to die from a lack of blood flow (osteonecrosis).

Sources: Chronic · graft-versus-host disease

acute lymphoblastic leukemia (ALL)

Sources: acute lymphoblastic leukemia

Ewing sarcoma

Sources: Ewing sarcoma

germ cell tumors

Sources: germ cell tumors

Hodgkin lymphoma

Sources: Hodgkin lymphoma

non-Hodgkin lymphoma

Sources: non-Hodgkin lymphoma

rhabdomyosarcoma

Sources: rhabdomyosarcoma

soft tissue sarcoma

Sources: soft tissue sarcoma

testicular cancer

Sources: testicular cancer

cancers treated with a stem cell transplant

Sources: stem cell transplant

acute lymphoblastic leukemia (ALL)

germ cell tumors

Hodgkin lymphoma

Wilms tumor

Sources: Wilms tumor

neuroblastoma

Sources: neuroblastoma

cancers treated with a stem cell transplant

surgery, such as the removal of a testicle, part of the prostate, lymph nodes in the abdomen, or one or both ovaries

Sources: prostate · lymph nodes · abdomen

chemotherapy with alkylating agents, such as cyclophosphamide, dacarbazine, procarbazine, ifosfamide, mechlorethamine, cisplatin, lomustine, and busulfan

Sources: chemotherapy · alkylating agents · cyclophosphamide · dacarbazine · procarbazine · ifosfamide

radiation therapy to the abdomen, pelvis, lower back, testicles, ovaries, uterus, or in the area of the hypothalamus in the brain

Sources: radiation therapy · pelvis · hypothalamus

total-body irradiation, high-dose chemotherapy, or both before a stem cell transplant

radiation therapy to the abdomen or pelvis with alkylating agents

germ cell tumors

Sources: germ cell tumors

head and neck cancers

Sources: head and neck cancers

Hodgkin lymphoma

Sources: Hodgkin lymphoma

leukemia

neuroblastoma

Sources: neuroblastoma

Wilms tumor

Sources: Wilms tumor

cancers treated with a stem cell transplant

Sources: stem cell transplant

surgery to remove all or part of the lung or chest wall

Sources: chest wall

chemotherapy, such as bleomycin, busulfan, carmustine, or lomustine

Sources: chemotherapy · bleomycin · busulfan · carmustine · lomustine

total-body irradiation or high-dose chemotherapy before a stem cell transplant

Sources: total-body irradiation

radiation therapy to the chest

Sources: radiation therapy

infections or graft-versus-host disease after a stem cell transplant

Sources: infections · graft-versus-host disease

lung or airway disease, such as asthma, before cancer treatment

Sources: asthma

an abnormal chest wall

Sources: abnormal

smoking cigarettes or other substances

bone cancer

Sources: bone cancer

brain tumors

Sources: brain tumors

germ cell tumors

Sources: germ cell tumors

head and neck cancers

Sources: head and neck cancers

liver cancer

Sources: liver cancer

neuroblastoma

Sources: neuroblastoma

retinoblastoma

Sources: retinoblastoma

soft tissue sarcoma

Sources: soft tissue sarcoma

cancers that are treated with a stem cell transplant

Sources: stem cell transplant

certain types of chemotherapy, such as cisplatin or high-dose carboplatin

Sources: chemotherapy · cisplatin · dose · carboplatin

radiation therapy to the brain

Sources: radiation therapy

acute lymphoblastic leukemia (ALL)

Sources: acute lymphoblastic leukemia

brain tumors

head and neck cancers

retinoblastoma, rhabdomyosarcoma, and other tumors of the eye

Sources: rhabdomyosarcoma

cancers treated with total-body irradiation (TBI) before a stem cell transplant

Sources: total-body irradiation

radiation therapy to the brain, eye, or eye socket

surgery to remove the eye or a tumor near the optic nerve

Sources: optic nerve

certain types of chemotherapy, such as cytarabine and doxorubicin

Sources: cytarabine · doxorubicin

TBI, busulfan, and corticosteroids as part of a stem cell transplant

Wilms tumor

Sources: Wilms tumor

cancers treated with a stem cell transplant

Sources: stem cell transplant

chemotherapy including cisplatin, carboplatin, ifosfamide, and methotrexate

Sources: chemotherapy · cisplatin · carboplatin · ifosfamide · methotrexate

radiation therapy to the abdomen or middle of the back

Sources: radiation therapy · abdomen

surgery to remove part or all of a kidney

stem cell transplant

Sources: stem cell transplant

having cancer in both kidneys

having a genetic syndrome that increases the risk of kidney problems, such as Denys-Drash syndrome or WAGR syndrome

Sources: Denys-Drash syndrome · WAGR syndrome

being treated with more than one type of treatment

retinoblastoma

Sources: retinoblastoma

cancers treated with a stem cell transplant

surgery to remove part or all of the bladder

surgery to the pelvis, spine, or brain

Sources: pelvis · spine

certain types of chemotherapy, such as cyclophosphamide or ifosfamide

Sources: cyclophosphamide

radiation therapy to areas near the bladder, pelvis, or urinary tract

Sources: urinary tract

stem cell transplant