Late Effects of Treatment for Childhood Cancer (PDQ®) 11/11 –Health Professional Version - National Cancer Institute

Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version - National Cancer Institute

Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version

Late Effects of the Special Senses

In This Section

• Hearing
  • Hearing loss and platinum-based therapy
  • Hearing loss and cranial radiation therapy
  • Hearing loss and quality of life
• Orbital and Optic
  • Retinoblastoma
  • Rhabdomyosarcoma
  • Low-grade optic pathway glioma and craniopharyngioma
  • Treatment-specific effects

Hearing

Hearing loss as a late effect of therapy can occur after exposure to platinum compounds (cisplatin and carboplatin), cranial radiation therapy, or both. These therapeutic exposures are most common in the treatment of central nervous system (CNS) and non-CNS solid tumors. Children are more susceptible to otologic toxic effects from platinum agents than are adults.[1,2] A report from the Swiss Childhood Cancer Survivor Study (CCSS) (N = 2,061) estimated the prevalence of hearing loss in survivors at 10%, compared with 3% in siblings. Hearing loss was most common in survivors of CNS tumors (25%), neuroblastoma (23%), hepatic tumor (21%), germ cell tumor (20%), bone tumor (16%), and soft tissue sarcoma (16%).[3] Data from the Swiss CCSS indicate that the relative rate of first occurrence of auditory complications (problems hearing sounds, tinnitus, hearing loss, deafness) is greatest in the time period from diagnosis to 5 years postdiagnosis; however, during the period of 5 or more years postdiagnosis, the risk of developing such conditions for survivors remained significantly higher than for siblings.[4]

Risk factors associated with hearing loss include the following:

• Younger age at treatment.
• Higher cumulative dose of platinum-based chemotherapy (≥300 mg/m2).[5]
• Exposure to cisplatin combined with carboplatin.[5]
• CNS tumors.
• Cranial radiation therapy.
• Neurosurgery.

Hearing loss and platinum-based therapy

Platinum-related sensorineural hearing loss develops as an acute toxicity that is generally irreversible and bilateral. Hearing loss manifests initially in the high frequencies and progresses to the speech frequencies with increasing cumulative exposure. 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.[5,6]

• 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.[7,8] Prolonging the duration of infusion or splitting the dose has been reported to reduce the risk of significant hearing loss.[9]
  In a randomized trial that compared cisplatin alone with cisplatin plus delayed administration of sodium thiosulfate, the administration of sodium thiosulfate 6 hours after cisplatin chemotherapy resulted in a 48% lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma and did not jeopardize overall survival or event-free survival.[10]
• Exposure to cisplatin combined with myeloablative carboplatin significantly increases the risk of severe hearing loss.[8] Otologic toxic effects after platinum chemotherapy have been reported to worsen years after completion of therapy.[11]
  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.[12]
• Carboplatin used in conventional (nonmyeloablative) dosing is typically not ototoxic.[13] 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 given alone (n = 112) was 17%.[5]
  • A single study of otologic toxic effects after non–stem cell transplant 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.[14]
  • 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. 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.[15]
• The use of a carboplatin conditioning regimen for hematopoietic stem cell transplantation, particularly in combination with previous carboplatin or cisplatin therapy, may cause significant otologic toxic effects.[7,8]

Hearing loss and cranial radiation therapy

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 to 45 Gy for children.[16] High-frequency sensorineural hearing loss is uncommon at cumulative radiation doses below 35 Gy, and is rarely severe below doses of 45 Gy.[17] 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.[16,18] To reduce the risk of hearing loss, the average cochlear dose should not exceed 30 to 35 Gy, delivered over 6 weeks. Young patient age and presence of a brain tumor and/or hydrocephalus can increase susceptibility to hearing loss.

Sensorineural hearing loss after cranial radiation therapy can progress over time. In a study of 235 pediatric brain tumor patients treated with conformal or intensity-modulated radiation therapy (without cisplatin or pre-existing 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. 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.[19]

When used concomitantly with cisplatin, radiation therapy can substantially exacerbate the hearing loss associated with platinum chemotherapy.[16,20-22] In a report from the CCSS, 5-year survivors were at 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. 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).[4]

Hearing loss and quality of life

Importantly, children treated for malignancies may be at risk of early- or delayed-onset hearing loss that can affect learning, communication, school performance, social interaction, and overall quality of life.

• Among 137 child survivors of neuroblastoma (aged 8–17 years), hearing loss was associated with problems with reading and math skills, as well as higher risk of learning disability and/or special education needs. In addition, hearing loss was associated with poorer school-related quality of life.[23]
• In a study of adult survivors of pediatric CNS tumors (n = 180) and non-CNS solid tumors (n = 226) who were treated with potentially ototoxic cancer therapy, serious hearing loss (requiring aid or resulting in deafness) was associated with a twofold increased risk of nonindependent living and unemployment or not graduating from high school.[24]

The Children’s Oncology Group has published recommendations for the evaluation and management of hearing loss in survivors of childhood and adolescent cancers to promote early identification of at-risk survivors and timely referral for remedial services.[25]

Table 17 summarizes auditory late effects and the related health screenings.

Table 17. Auditory Late Effectsa

Predisposing Therapy	Potential Auditory Effects	Health Screening/Interventions
FM = frequency modulated.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult CancersExit Disclaimer.
Platinum agents (cisplatin, carboplatin); radiation impacting the ear	Otologic toxic effects; sensorineural hearing loss; tinnitus; vertigo; dehydrated ceruminosis; conductive hearing loss	History: hearing difficulties, tinnitus, vertigo
		Otoscopic exam
		Audiology evaluation
		Amplification in patients with progressive hearing loss
		Speech and language therapy for children with hearing loss
		Otolaryngology consultation in patients with chronic infection, cerumen impaction, or other anatomical problems exacerbating or contributing to hearing loss
		Educational accommodations (e.g., preferential classroom seating, FM amplification system, etc.)

Orbital and Optic

Orbital complications are common after radiation therapy for retinoblastoma and after total-body irradiation (TBI) and in children with head and neck sarcomas and CNS tumors.

Retinoblastoma

For survivors of retinoblastoma, a small orbital volume may result from either enucleation or radiation therapy. Age younger than 1 year may increase risk, but this finding is not consistent across studies.[26,27] Progress has been made in the management of retinoblastoma, with better enucleation implants, intravenous chemoreduction, and intra-arterial chemotherapy in addition to thermotherapy, cryotherapy, and plaque radiation therapy. Longer follow-up is needed to assess the impact on vision in patients undergoing these more contemporary treatment modalities.[26,28,29] Previously, tumors located near the macula and fovea were associated with an increased risk of complications leading to vision loss, although treatment of these tumors with foveal laser ablation has shown promise in preserving vision.[30-33]

(Refer to the PDQ summary on Retinoblastoma Treatment for more information on the treatment of retinoblastoma.)

Rhabdomyosarcoma

Survivors of orbital rhabdomyosarcoma are at risk of dry eye, cataract, orbital hypoplasia, ptosis, retinopathy, keratoconjunctivitis, optic neuropathy, lid epithelioma, and impairment of vision after radiation therapy doses of 30 Gy to 65 Gy. The higher dose ranges (>50 Gy) are associated with lid epitheliomas, keratoconjunctivitis, lacrimal duct atrophy, and severe dry eye. Retinitis and optic neuropathy may also result from doses of 50 Gy to 65 Gy and even at lower total doses if the individual fraction size is higher than 2 Gy.[34] Cataracts are reported after lower doses of 10 Gy to 18 Gy.[35-37]

(Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information on the treatment of rhabdomyosarcoma in children.)

Low-grade optic pathway glioma and craniopharyngioma

Survivors of optic pathway glioma and craniopharyngioma are also at risk of visual complications, resulting in part from tumor proximity to the optic nerve.

In a retrospective cohort study of 59 pediatric patients with sporadic optic pathway gliomas diagnosed between 1990 and 2014 (median follow up, 5.2 years), there was a significant burden of long-term visual impairment. The findings showed that more than two-thirds of the patients had evidence of long-term vision loss, more than one-half had severe vision loss in at least one eye, and one-quarter of the patients had severe bilateral vision loss. Identified risk factors for poor visual outcome were postchiasmal involvement, younger age, and optic nerve pallor at presentation.[38]

Longitudinal follow-up (mean, 9 years) of 21 patients with optic pathway gliomas indicated that before treatment, 81% of patients had reduced visual acuity, 81% had optic nerve pallor, and all had reduced visual evoked potentials in one or both eyes. Treatment arrested acuity loss for 4 to 5 years. Visual acuity was stable or improved in 33% of patients at last follow-up; however, it declined on average. Visual acuity at follow-up was related to tumor volume at initial presentation.[39]

In a study of 51 children with low-grade gliomas and low-grade glioneural tumors diagnosed within the first year of life, visual acuity was decreased in 27 of 48 patients (56%), 13 (27%) of whom were legally blind. The tumor location (hypothalamic or optic pathway) was significantly associated with decreased visual acuity (P = .002).[40]

In a study of 25 patients diagnosed with craniopharyngioma, 67% had visual complications at a mean follow-up of 11 years.[41] A retrospective review of 30 children with craniopharyngioma revealed that 19 patients had vision loss before surgery; 21 patients had postsurgical vision loss. Preoperative vision loss was predicative of postoperative vision loss.[42]

CCSS investigators evaluated the impact of impaired vision on cognitive and psychosocial outcomes among 1,233 adult survivors of childhood low-grade gliomas. Some degree of visual impairment was prevalent in 22.5% of patients, and 3.8% of patients were blind in both eyes. Survivors who were blind in both eyes were more likely to be unmarried, live dependently, and be unemployed than were survivors with unimpaired vision. However, bilateral blindness did not impact self-reported cognitive or emotional outcomes. Impaired (with some remaining) vision was not associated with psychological or economic outcomes.[43]

Treatment-specific effects

Survivors of childhood cancer are at increased risk for ocular late effects related to both glucocorticoid and radiation exposure to the eye.

Evidence (ocular effects of radiation exposure):

1. The CCSS reported that survivors who were 5 or more years from diagnosis were at increased risk of developing 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.[44]
2. The 15-year cumulative incidence of cataract was 4.5% among 517 survivors of childhood acute lymphoblastic leukemia (median, 10.9 years from diagnosis), systematically evaluated by slit lamp examination. 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.[45]
3. A report from the CCSS provides additional data on the interval from radiation therapy and the radiation dose associated with the development of cataracts.[46]
   • 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 (odds ratio [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.

Ocular complications, such as cataracts and dry eye syndrome, are common after stem cell transplantation in childhood.

Evidence (ocular effects of stem cell transplantation):

1. Compared with patients treated with busulfan or other chemotherapy, patients treated with single-dose or fractionated TBI are at increased risk of cataracts. 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.[47-50]
2. Patients receiving TBI doses of less than 40 Gy have a less than 10% chance of developing severe cataracts.[50]
3. Corticosteroids and graft-versus-host disease may further increase risk.[47,51]
4. The prevalence of cataracts, evaluated by serial slit lamp testing, among 271 participants (mean follow-up, 10.3 years) in the Leucémie Enfants Adolescents (LEA) program was 41.7%, with 8.1% requiring surgical intervention.[52] In this cohort, 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.
5. Dry eye syndrome has been shown to be more common if the patient was exposed to repeated high trough levels of cyclosporine.[53]

Table 18 summarizes ocular late effects and the related health screenings.

Table 18. Ocular Late Effectsa

Predisposing Therapy	Ocular/Vision Effects	Health Screening/Interventions
GVHD = graft-versus-host disease; 131I = iodine I 131.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult CancersExit Disclaimer.
Busulfan; corticosteroids; radiation impacting the eye	Cataracts	History: decreased acuity, halos, diplopia
		Eye exam: visual acuity, funduscopy
		Ophthalmology consultation
Radiation impacting the eye, including radioiodine (131I)	Ocular toxicity (orbital hypoplasia, lacrimal duct atrophy, xerophthalmia [keratoconjunctivitis sicca], keratitis, telangiectasias, retinopathy, optic chiasm neuropathy, enophthalmos, chronic painful eye, maculopathy, papillopathy, glaucoma)	History: visual changes (decreased acuity, halos, diplopia), dry eye, persistent eye irritation, excessive tearing, light sensitivity, poor night vision, painful eye
		Eye exam: visual acuity, funduscopy
		Ophthalmology consultation
Hematopoietic cell transplantation with any history of chronic GVHD	Xerophthalmia (keratoconjunctivitis sicca)	History: dry eye (burning, itching, foreign body sensation, inflammation)
		Eye exam: visual acuity, funduscopy
Enucleation	Impaired cosmesis; poor prosthetic fit; orbital hypoplasia	Ocular prosthetic evaluation
		Ophthalmology

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult CancersExit Disclaimer for information on the late effects of special senses, including risk factors, evaluation, and health counseling.

References

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17. Bhandare N, Jackson A, Eisbruch A, et al.: Radiation therapy and hearing loss. Int J Radiat Oncol Biol Phys 76 (3 Suppl): S50-7, 2010. [PUBMED Abstract]
18. Merchant TE, Gould CJ, Xiong X, et al.: Early neuro-otologic effects of three-dimensional irradiation in children with primary brain tumors. Int J Radiat Oncol Biol Phys 58 (4): 1194-207, 2004. [PUBMED Abstract]
19. Bass JK, Hua CH, Huang J, et al.: Hearing Loss in Patients Who Received Cranial Radiation Therapy for Childhood Cancer. J Clin Oncol 34 (11): 1248-55, 2016. [PUBMED Abstract]
20. Cheuk DK, Billups CA, Martin MG, et al.: Prognostic factors and long-term outcomes of childhood nasopharyngeal carcinoma. Cancer 117 (1): 197-206, 2011. [PUBMED Abstract]
21. Merchant TE, Hua CH, Shukla H, et al.: Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to cognitive function. Pediatr Blood Cancer 51 (1): 110-7, 2008. [PUBMED Abstract]
22. Paulino AC, Lobo M, Teh BS, et al.: Ototoxicity after intensity-modulated radiation therapy and cisplatin-based chemotherapy in children with medulloblastoma. Int J Radiat Oncol Biol Phys 78 (5): 1445-50, 2010. [PUBMED Abstract]
23. Gurney JG, Tersak JM, Ness KK, et al.: Hearing loss, quality of life, and academic problems in long-term neuroblastoma survivors: a report from the Children's Oncology Group. Pediatrics 120 (5): e1229-36, 2007. [PUBMED Abstract]
24. Brinkman TM, Bass JK, Li Z, et al.: Treatment-induced hearing loss and adult social outcomes in survivors of childhood CNS and non-CNS solid tumors: Results from the St. Jude Lifetime Cohort Study. Cancer 121 (22): 4053-61, 2015. [PUBMED Abstract]
25. Bass JK, Knight KR, Yock TI, et al.: Evaluation and Management of Hearing Loss in Survivors of Childhood and Adolescent Cancers: A Report From the Children's Oncology Group. Pediatr Blood Cancer 63 (7): 1152-62, 2016. [PUBMED Abstract]
26. Kaste SC, Chen G, Fontanesi J, et al.: Orbital development in long-term survivors of retinoblastoma. J Clin Oncol 15 (3): 1183-9, 1997. [PUBMED Abstract]
27. Peylan-Ramu N, Bin-Nun A, Skleir-Levy M, et al.: Orbital growth retardation in retinoblastoma survivors: work in progress. Med Pediatr Oncol 37 (5): 465-70, 2001. [PUBMED Abstract]
28. Shields CL, Shields JA: Retinoblastoma management: advances in enucleation, intravenous chemoreduction, and intra-arterial chemotherapy. Curr Opin Ophthalmol 21 (3): 203-12, 2010. [PUBMED Abstract]
29. Abramson DH, Dunkel IJ, Brodie SE, et al.: Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery). Ophthalmology 117 (8): 1623-9, 2010. [PUBMED Abstract]
30. Shields CL, Shields JA: Recent developments in the management of retinoblastoma. J Pediatr Ophthalmol Strabismus 36 (1): 8-18; quiz 35-6, 1999 Jan-Feb. [PUBMED Abstract]
31. Shields CL, Shields JA, Cater J, et al.: Plaque radiotherapy for retinoblastoma: long-term tumor control and treatment complications in 208 tumors. Ophthalmology 108 (11): 2116-21, 2001. [PUBMED Abstract]
32. Shields JA, Shields CL: Pediatric ocular and periocular tumors. Pediatr Ann 30 (8): 491-501, 2001. [PUBMED Abstract]
33. Schefler AC, Cicciarelli N, Feuer W, et al.: Macular retinoblastoma: evaluation of tumor control, local complications, and visual outcomes for eyes treated with chemotherapy and repetitive foveal laser ablation. Ophthalmology 114 (1): 162-9, 2007. [PUBMED Abstract]
34. Kline LB, Kim JY, Ceballos R: Radiation optic neuropathy. Ophthalmology 92 (8): 1118-26, 1985. [PUBMED Abstract]
35. Paulino AC, Simon JH, Zhen W, et al.: Long-term effects in children treated with radiotherapy for head and neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 48 (5): 1489-95, 2000. [PUBMED Abstract]
36. Oberlin O, Rey A, Anderson J, et al.: Treatment of orbital rhabdomyosarcoma: survival and late effects of treatment--results of an international workshop. J Clin Oncol 19 (1): 197-204, 2001. [PUBMED Abstract]
37. Raney RB, Anderson JR, Kollath J, et al.: Late effects of therapy in 94 patients with localized rhabdomyosarcoma of the orbit: Report from the Intergroup Rhabdomyosarcoma Study (IRS)-III, 1984-1991. Med Pediatr Oncol 34 (6): 413-20, 2000. [PUBMED Abstract]
38. Wan MJ, Ullrich NJ, Manley PE, et al.: Long-term visual outcomes of optic pathway gliomas in pediatric patients without neurofibromatosis type 1. J Neurooncol 129 (1): 173-8, 2016. [PUBMED Abstract]
39. Kelly JP, Leary S, Khanna P, et al.: Longitudinal measures of visual function, tumor volume, and prediction of visual outcomes after treatment of optic pathway gliomas. Ophthalmology 119 (6): 1231-7, 2012. [PUBMED Abstract]
40. Liu APY, Hastings C, Wu S, et al.: Treatment burden and long-term health deficits of patients with low-grade gliomas or glioneuronal tumors diagnosed during the first year of life. Cancer : , 2019. [PUBMED Abstract]
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44. Whelan KF, Stratton K, Kawashima T, et al.: Ocular late effects in childhood and adolescent cancer survivors: a report from the childhood cancer survivor study. Pediatr Blood Cancer 54 (1): 103-9, 2010. [PUBMED Abstract]
45. Alloin AL, Barlogis V, Auquier P, et al.: Prevalence and risk factors of cataract after chemotherapy with or without central nervous system irradiation for childhood acute lymphoblastic leukaemia: an LEA study. Br J Haematol 164 (1): 94-100, 2014. [PUBMED Abstract]
46. Chodick G, Sigurdson AJ, Kleinerman RA, et al.: The Risk of Cataract among Survivors of Childhood and Adolescent Cancer: A Report from the Childhood Cancer Survivor Study. Radiat Res 185 (4): 366-74, 2016. [PUBMED Abstract]
47. Ferry C, Gemayel G, Rocha V, et al.: Long-term outcomes after allogeneic stem cell transplantation for children with hematological malignancies. Bone Marrow Transplant 40 (3): 219-24, 2007. [PUBMED Abstract]
48. Fahnehjelm KT, Törnquist AL, Olsson M, et al.: Visual outcome and cataract development after allogeneic stem-cell transplantation in children. Acta Ophthalmol Scand 85 (7): 724-33, 2007. [PUBMED Abstract]
49. Gurney JG, Ness KK, Rosenthal J, et al.: Visual, auditory, sensory, and motor impairments in long-term survivors of hematopoietic stem cell transplantation performed in childhood: results from the Bone Marrow Transplant Survivor study. Cancer 106 (6): 1402-8, 2006. [PUBMED Abstract]
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52. Horwitz M, Auquier P, Barlogis V, et al.: Incidence and risk factors for cataract after haematopoietic stem cell transplantation for childhood leukaemia: an LEA study. Br J Haematol 168 (4): 518-25, 2015. [PUBMED Abstract]
53. Fahnehjelm KT, Törnquist AL, Winiarski J: Dry-eye syndrome after allogeneic stem-cell transplantation in children. Acta Ophthalmol 86 (3): 253-8, 2008. [PUBMED Abstract]

Late Effects of the Urinary System

In This Section

• Therapy-related factors affecting the kidney
• Genetic factors predisposing to renal dysfunction
• Therapy-related bladder complications

Acute toxicity of the urinary system from cancer therapy is well known. Less is known about the genitourinary outcomes in long-term survivors.[1] The evidence for long-term renal injury in childhood cancer survivors is limited by studies characterized by small sample size, cohort selection and participation bias, cross-sectional assessment, heterogeneity in time since treatment, and method of ascertainment. In particular, the inaccuracies of diagnosing chronic kidney dysfunction by estimating equations of glomerular dysfunction should be considered.[2] Cancer treatments predisposing to renal injury and/or high blood pressure later in life include the following:

• Chemotherapeutic drugs (cisplatin, carboplatin, ifosfamide, methotrexate).
• Renal radiation therapy.
• Nephrectomy.

The risk and degree of renal dysfunction depend on type and intensity of therapy, and the interpretation of the studies is compromised by variability in testing.

Few large-scale studies have evaluated late renal-health outcomes and risk factors for renal dysfunction among survivors treated with potentially nephrotoxic modalities.

Evidence (renal dysfunction in childhood cancer survivors):

1. In a large, cross-sectional study of 1,442 childhood cancer survivors (median attained age, 19.3 years; median time from diagnosis, 12.1 years), Dutch investigators assessed the presence of albuminuria, hypomagnesemia, hypophosphatemia, and hypertension, and they estimated glomerular filtration rate (GFR) among survivors treated with ifosfamide, cisplatin, carboplatin, high-dose cyclophosphamide (>1 g/m2or more per course), or high-dose methotrexate (>1 g/m2 or more per course), radiation therapy to the kidney region, total-body irradiation (TBI), or nephrectomy.[3]
   • At least one abnormality of renal function or hypertension was detected in 28.1% of survivors.
   • History of nephrectomy (odds ratio [OR], 8.6; 95% confidence interval [CI], 3.4–21.4) had the strongest association with a GFR of less than 90 mL/min per 1.73 m2.
   • The prevalence of decreased GFR was highest among those treated with multimodality therapy including nephrectomy, nephrotoxic chemotherapy, and abdominal radiation therapy. Nearly 5% of these survivors had a GFR of less than 90 mL/min per 1.73 m2.
   • Abdominal irradiation was the only significant treatment-related risk factor for hypertension (OR, 2.5; 95% CI, 1.4–4.5).

Therapy-related factors affecting the kidney

Cancer treatments predisposing to late renal injury and hypertension include the following:[4-6]

• Nephrectomy. 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.
  In a cross-sectional study of 1,442 5-year childhood cancer survivors (median 12.1 years from diagnosis), 28.1% of all survivors had at least one renal adverse effect, with hypertension (14.8%) and albuminuria (14.5%) being the most prevalent. Survivors who had undergone nephrectomy had the highest risk of diminished renal function (OR, 8.6; 95% CI, 3.4–21.4).[3,5] However, patients with nonsyndromic unilateral Wilms tumor treated with unilateral radical nephrectomy without nephrotoxic chemotherapy or ionizing radiation therapy appear to be at low risk of developing significant long-term renal dysfunction.[7]
• Chemotherapy.
  • Cisplatin. Cisplatin can cause glomerular and tubular damage resulting in a diminished GFR and electrolyte wasting (particularly magnesium, calcium, and potassium).[8-10]
    Acute cisplatin-related nephrotoxicity has been reported in 30% to 100% of exposed children.[11] However, the prevalence of persistent renal dysfunction in long-term survivors appears to be considerably lower.
    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. Among 651 sarcoma patients evaluated after cessation of antineoplastic therapy (median follow-up, 2 years), hypomagnesemia occurred in 12.1% of patients after cisplatin therapy and in 15.6% after carboplatin therapy, compared with 4.5% who did not receive any platinum derivatives. In all groups, the frequency of hypomagnesemia decreased with ongoing follow-up, but serum magnesium remained lower in platinum-treated patients throughout the study period.[10,12]
  • Carboplatin. Carboplatin is a cisplatin analog and is less nephrotoxic than cisplatin. 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 receiving carboplatin, while cisplatin dose schedule and cumulative carboplatin dose were also important predictors of toxicity. Platinum nephrotoxicity did not change significantly over 10 years.[10]
    The combination of carboplatin and ifosfamide may be associated with more renal damage than the combination of cisplatin and ifosfamide.[8-10]
    Additional follow-up in larger numbers of survivors treated with carboplatin (without other nephrotoxic agents and modalities) must be evaluated before potential renal toxicity can be better defined.
  • Ifosfamide. Ifosfamide can also cause glomerular and tubular toxicity, with renal tubular acidosis and Fanconi syndrome, a proximal tubular defect characterized by impairment of resorption of glucose, amino acids, phosphate, and bicarbonate. 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.[13-15]
    A French study that evaluated the prevalence of late renal toxicity after ifosfamide reported normal tubular function in 90% of pediatric cancer survivors (median follow-up, 10 years); 79% of the cancer survivors had normal GFR, and all survivors had normal serum bicarbonate and calcium.[15] Hypomagnesemia and hypophosphatemia were seen in 1% of cancer survivors. Glycosuria was detected in 37% of cancer survivors but was mild in 95% of cases. Proteinuria was observed in 12% of cancer survivors. In multivariate analysis, ifosfamide dose and interval from therapy were predictors of tubulopathy, and older age at diagnosis and interval from therapy were predictors of abnormal GFR.
  • High-dose methotrexate. High-dose methotrexate (1,000–33,000 mg/m2) has been reported to cause acute renal dysfunction in up to 12.4% of patients. Long-term renal sequelae have not been described.[5,16]
• Radiation therapy. Radiation therapy to the kidney can result in radiation nephritis or nephropathy after a latent period of 3 to 12 months. The kidney is relatively radiosensitive, with a tolerance dose of 20 Gy.[17] 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.[18]
  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).[19]
  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.[20]
  Risk factors for radiation nephritis 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. However, for older children, there is no convincing evidence that age at the time of radiation therapy is related to renal injury.[21]
  • 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.[22] 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.[23] When certain agents such as cyclosporine and teniposide are not used, total-body irradiation doses of up to 13 Gy are associated with a less than 8% incidence of kidney toxicity.[24]
• Hematopoietic stem cell transplantation (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.[25-27]
  Most reports of renal outcomes among long-term survivors of childhood cancer treated with HSCT are limited to descriptive outcomes of very small cohorts.
  Refer to the Urinary System Late Effects section of the Childhood Hematopoietic Cell Transplantation summary for more information.

Genetic factors predisposing to renal dysfunction

Many childhood survivors of Wilms tumor who develop chronic renal failure have syndromes accompanying WT1 mutations or deletions that predispose to renal disease. Data from the National Wilms Tumor Study Group and the U.S. Renal Data System indicate that the 20-year cumulative incidence of end-stage renal disease in children with unilateral Wilms tumor and Denys-Drash syndrome is 74%, 36% for those with WAGR (Wilms tumor, aniridia, genitourinary abnormalities, mental retardation) syndrome, 7% for male patients with genitourinary anomalies, and 0.6% for patients with none of these conditions.[28] For patients with bilateral Wilms tumors, the incidence of end-stage renal disease is 50% for Denys-Drash syndrome, 90% for WAGR, 25% for genitourinary anomaly, and 12% for others.[28,29] End-stage renal disease in patients with WAGR and genitourinary anomalies tended to occur relatively late, and often during or after adolescence.[28]

Therapy-related bladder complications

Pelvic or central nervous system surgery, alkylator-containing chemotherapy such as cyclophosphamide or ifosfamide, pelvic radiation therapy, and certain spinal and genitourinary surgical procedures have been associated with urinary bladder late effects, as follows:[30]

• Chemotherapy. The oxazophorine 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.[31,32]
  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). Patients with radiological evidence of renal or bladder calculi or tumors invading the bladder wall were excluded from the study. Older age, previous bone marrow or peripheral stem cell transplantation, and BK virus in the urine were risk factors for hemorrhagic cystitis and were associated with a higher severity score.[33]
  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.[34,35]
• Radiation therapy. 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. Long-term bladder fibrosis and contracture may result as sequelae from hemorrhagic cystitis or radiation therapy.[30]
• Surgery. Surgical procedures involving the lower genitourinary tract have the potential to impair normal function of the bladder and normal voiding mechanisms. Likewise, 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.[36]

Table 19 summarizes kidney and bladder late effects and the related health screenings.

Table 19. Kidney and Bladder Late Effectsa

Predisposing Therapy	Renal/Genitourinary Effects	Health Screening
BUN = blood urea nitrogen; NSAIDs = nonsteroidal anti-inflammatory drugs; RBC/HFP = red blood cells per high-field power (microscopic exam).
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult CancersExit Disclaimer.
Cisplatin/carboplatin; ifosfamide; calcineurin inhibitors	Renal toxicity (glomerular injury, tubular injury [renal tubular acidosis], Fanconi syndrome, hypophosphatemic rickets)	Blood pressure
		BUN, Creatinine, Na, K, Cl, CO2, Ca, Mg, PO4 levels
		Urinalysis
		Electrolyte supplements for patients with persistent electrolyte wasting
		Nephrology consultation for patients with hypertension, proteinuria, or progressive renal insufficiency
Methotrexate; radiation impacting kidneys/urinary tract	Renal toxicity (renal insufficiency, hypertension)	Blood pressure
		BUN, Creatinine, Na, K, Cl, CO2, Ca, Mg, PO4 levels
		Urinalysis
		Nephrology consultation for patients with hypertension, proteinuria, or progressive renal insufficiency
Nephrectomy	Renal toxicity (proteinuria, hyperfiltration, renal insufficiency)	Blood pressure
		BUN, Creatinine, Na, K, Cl, CO2, Ca, Mg, PO4 levels
		Urinalysis
		Discuss contact sports, bicycle safety (e.g., avoiding handlebar injuries), and proper use of seatbelts (i.e., wearing lap belts around hips, not waist)
		Counsel to use NSAIDs with caution
		Nephrology consultation for patients with hypertension, proteinuria, or progressive renal insufficiency
Nephrectomy; pelvic surgery; cystectomy	Hydrocele	Testicular exam
Cystectomy	Cystectomy-related complications (chronic urinary tract infections, renal dysfunction, vesicoureteral reflux, hydronephrosis, reservoir calculi, spontaneous neobladder perforation, vitamin B12/folate/carotene deficiency [patients with ileal enterocystoplasty only])	Urology evaluation
		Vitamin B12 level
Pelvic surgery; cystectomy	Urinary incontinence; urinary tract obstruction	History: hematuria, urinary urgency/frequency, urinary incontinence/retention, dysuria, nocturia, abnormal urinary stream
		Counsel regarding adequate fluid intake, regular voiding, seeking medical attention for symptoms of voiding dysfunction or urinary tract infection, compliance with recommended bladder catheterization regimen
		Urologic consultation for patients with dysfunctional voiding or recurrent urinary tract infections
Cyclophosphamide/Ifosfamide; radiation impacting bladder/urinary tract	Bladder toxicity (hemorrhagic cystitis, bladder fibrosis, dysfunctional voiding, vesicoureteral reflux, hydronephrosis)	History: hematuria, urinary urgency/frequency, urinary incontinence/retention, dysuria, nocturia, abnormal urinary stream
		Urinalysis
		Urine culture, spot urine calcium/creatinine ratio, and ultrasound of kidneys and bladder for patients with microscopic hematuria (defined as ≥5 RBC/HFP on at least 2 occasions)
		Nephrology or urology referral for patients with culture-negative microscopic hematuria AND abnormal ultrasound and/or abnormal calcium/creatinine ratio
		Urology referral for patients with culture negative macroscopic hematuria

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult CancersExit Disclaimer for urinary late effects information including risk factors, evaluation, and health counseling.

References

1. Shnorhavorian M, Friedman DL, Koyle MA: Genitourinary long-term outcomes for childhood cancer survivors. Curr Urol Rep 10 (2): 134-7, 2009. [PUBMED Abstract]
2. Green DM: Evaluation of renal function after successful treatment for unilateral, non-syndromic Wilms tumor. Pediatr Blood Cancer 60 (12): 1929-35, 2013. [PUBMED Abstract]
3. Knijnenburg SL, Jaspers MW, van der Pal HJ, et al.: Renal dysfunction and elevated blood pressure in long-term childhood cancer survivors. Clin J Am Soc Nephrol 7 (9): 1416-27, 2012. [PUBMED Abstract]
4. Jones DP, Spunt SL, Green D, et al.: Renal late effects in patients treated for cancer in childhood: a report from the Children's Oncology Group. Pediatr Blood Cancer 51 (6): 724-31, 2008. [PUBMED Abstract]
5. Dekkers IA, Blijdorp K, Cransberg K, et al.: Long-term nephrotoxicity in adult survivors of childhood cancer. Clin J Am Soc Nephrol 8 (6): 922-9, 2013. [PUBMED Abstract]
6. Mulder RL, Knijnenburg SL, Geskus RB, et al.: Glomerular function time trends in long-term survivors of childhood cancer: a longitudinal study. Cancer Epidemiol Biomarkers Prev 22 (10): 1736-46, 2013. [PUBMED Abstract]
7. Interiano RB, Delos Santos N, Huang S, et al.: Renal function in survivors of nonsyndromic Wilms tumor treated with unilateral radical nephrectomy. Cancer 121 (14): 2449-56, 2015. [PUBMED Abstract]
8. Marina NM, Poquette CA, Cain AM, et al.: Comparative renal tubular toxicity of chemotherapy regimens including ifosfamide in patients with newly diagnosed sarcomas. J Pediatr Hematol Oncol 22 (2): 112-8, 2000 Mar-Apr. [PUBMED Abstract]
9. Hartmann JT, Fels LM, Franzke A, et al.: Comparative study of the acute nephrotoxicity from standard dose cisplatin +/- ifosfamide and high-dose chemotherapy with carboplatin and ifosfamide. Anticancer Res 20 (5C): 3767-73, 2000 Sep-Oct. [PUBMED Abstract]
10. Skinner R, Parry A, Price L, et al.: Persistent nephrotoxicity during 10-year follow-up after cisplatin or carboplatin treatment in childhood: relevance of age and dose as risk factors. Eur J Cancer 45 (18): 3213-9, 2009. [PUBMED Abstract]
11. Skinner R, Kaplan R, Nathan PC: Renal and pulmonary late effects of cancer therapy. Semin Oncol 40 (6): 757-73, 2013. [PUBMED Abstract]
12. Stöhr W, Paulides M, Bielack S, et al.: Nephrotoxicity of cisplatin and carboplatin in sarcoma patients: a report from the late effects surveillance system. Pediatr Blood Cancer 48 (2): 140-7, 2007. [PUBMED Abstract]
13. Skinner R, Cotterill SJ, Stevens MC: Risk factors for nephrotoxicity after ifosfamide treatment in children: a UKCCSG Late Effects Group study. United Kingdom Children's Cancer Study Group. Br J Cancer 82 (10): 1636-45, 2000. [PUBMED Abstract]
14. Stöhr W, Paulides M, Bielack S, et al.: Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: a report from the Late Effects Surveillance System. Pediatr Blood Cancer 48 (4): 447-52, 2007. [PUBMED Abstract]
15. Oberlin O, Fawaz O, Rey A, et al.: Long-term evaluation of Ifosfamide-related nephrotoxicity in children. J Clin Oncol 27 (32): 5350-5, 2009. [PUBMED Abstract]
16. Widemann BC, Balis FM, Kim A, et al.: Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome. J Clin Oncol 28 (25): 3979-86, 2010. [PUBMED Abstract]
17. Cohen EP, Robbins ME: Radiation nephropathy. Semin Nephrol 23 (5): 486-99, 2003. [PUBMED Abstract]
18. Dawson LA, Kavanagh BD, Paulino AC, et al.: Radiation-associated kidney injury. Int J Radiat Oncol Biol Phys 76 (3 Suppl): S108-15, 2010. [PUBMED Abstract]
19. Mitus A, Tefft M, Fellers FX: Long-term follow-up of renal functions of 108 children who underwent nephrectomy for malignant disease. Pediatrics 44 (6): 912-21, 1969. [PUBMED Abstract]
20. Bölling T, Ernst I, Pape H, et al.: Dose-volume analysis of radiation nephropathy in children: preliminary report of the risk consortium. Int J Radiat Oncol Biol Phys 80 (3): 840-4, 2011. [PUBMED Abstract]
21. Peschel RE, Chen M, Seashore J: The treatment of massive hepatomegaly in stage IV-S neuroblastoma. Int J Radiat Oncol Biol Phys 7 (4): 549-53, 1981. [PUBMED Abstract]
22. Ritchey ML, Green DM, Thomas PR, et al.: Renal failure in Wilms' tumor patients: a report from the National Wilms' Tumor Study Group. Med Pediatr Oncol 26 (2): 75-80, 1996. [PUBMED Abstract]
23. Paulino AC, Wilimas J, Marina N, et al.: Local control in synchronous bilateral Wilms tumor. Int J Radiat Oncol Biol Phys 36 (3): 541-8, 1996. [PUBMED Abstract]
24. Cheng JC, Schultheiss TE, Wong JY: Impact of drug therapy, radiation dose, and dose rate on renal toxicity following bone marrow transplantation. Int J Radiat Oncol Biol Phys 71 (5): 1436-43, 2008. [PUBMED Abstract]
25. Hoffmeister PA, Hingorani SR, Storer BE, et al.: Hypertension in long-term survivors of pediatric hematopoietic cell transplantation. Biol Blood Marrow Transplant 16 (4): 515-24, 2010. [PUBMED Abstract]
26. Abboud I, Porcher R, Robin M, et al.: Chronic kidney dysfunction in patients alive without relapse 2 years after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 15 (10): 1251-7, 2009. [PUBMED Abstract]
27. Ellis MJ, Parikh CR, Inrig JK, et al.: Chronic kidney disease after hematopoietic cell transplantation: a systematic review. Am J Transplant 8 (11): 2378-90, 2008. [PUBMED Abstract]
28. Breslow NE, Collins AJ, Ritchey ML, et al.: End stage renal disease in patients with Wilms tumor: results from the National Wilms Tumor Study Group and the United States Renal Data System. J Urol 174 (5): 1972-5, 2005. [PUBMED Abstract]
29. Hamilton TE, Ritchey ML, Haase GM, et al.: The management of synchronous bilateral Wilms tumor: a report from the National Wilms Tumor Study Group. Ann Surg 253 (5): 1004-10, 2011. [PUBMED Abstract]
30. Ritchey M, Ferrer F, Shearer P, et al.: Late effects on the urinary bladder in patients treated for cancer in childhood: a report from the Children's Oncology Group. Pediatr Blood Cancer 52 (4): 439-46, 2009. [PUBMED Abstract]
31. Hudson MM, Ness KK, Gurney JG, et al.: Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309 (22): 2371-81, 2013. [PUBMED Abstract]
32. Landier W, Armenian SH, Lee J, et al.: Yield of screening for long-term complications using the children's oncology group long-term follow-up guidelines. J Clin Oncol 30 (35): 4401-8, 2012. [PUBMED Abstract]
33. Riachy E, Krauel L, Rich BS, et al.: Risk factors and predictors of severity score and complications of pediatric hemorrhagic cystitis. J Urol 191 (1): 186-92, 2014. [PUBMED Abstract]
34. Kersun LS, Wimmer RS, Hoot AC, et al.: Secondary malignant neoplasms of the bladder after cyclophosphamide treatment for childhood acute lymphocytic leukemia. Pediatr Blood Cancer 42 (3): 289-91, 2004. [PUBMED Abstract]
35. Frobisher C, Gurung PM, Leiper A, et al.: Risk of bladder tumours after childhood cancer: the British Childhood Cancer Survivor Study. BJU Int 106 (7): 1060-9, 2010. [PUBMED Abstract]
36. Rosenbaum DH, Cain MP, Kaefer M, et al.: Ileal enterocystoplasty and B12 deficiency in pediatric patients. J Urol 179 (4): 1544-7; discussion 1547-8, 2008. [PUBMED Abstract]

Changes to This Summary (06/04/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information About Late Effects of Treatment for Childhood Cancer

Added Norsker et al. as reference 14.

Subsequent Neoplasms (SNs)

Added text about the results of a study of 4,905 1-year survivors of allogeneic hematopoietic cell transplantation who underwent transplant between 1969 and 2014 for malignant or nonmalignant diseases that demonstrated a strong effect of total-body irradiation dose and dose fractionation on risk of SNs (cited Baker et al. as reference 10).

Added Chaussade et al. as reference 63.

Added text about the results of a Dutch Childhood Oncology Group (DCOG)-LATER study of 5,843 childhood cancer survivors that found that survivors had a 30-fold increased risk of developing basal cell carcinomas (cited Teepen et al. as reference 73).

Added text about the results of a large series from two institutions that identified 2,053 patients with retinoblastoma (cited Kleinerman et al. as reference 83).

Late Effects of the Cardiovascular System

Added text about the results of a Childhood Cancer Survivor Study (CCSS) of 24,214 5-year survivors diagnosed between 1970 and 1999 that assessed the impacts of radiation therapy dose and exposed cardiac volume, select chemotherapeutic agents, and age at exposure on risk of late-onset cardiac disease (cited Bates et al. as reference 18).

Added text to state that low-to-moderate radiation therapy doses to large cardiac volumes are associated with an increased rate of cardiac disease compared with survivors who did not have any cardiac radiation therapy exposure. High doses of radiation to small cardiac volumes are associated with an elevated rate of cardiac disease.

Late Effects of the Central Nervous System (CNS)

Added text to state that CNS tumor survivors remain at higher risk of new-onset adverse neurologic events across their lifetimes than siblings. Also added text about the results of a longitudinal study from the CCSS that determined that no plateau had been reached for new adverse sequelae, even 30 years from diagnosis for 5-year survivors of CNS tumors (cited Wells et al. as reference 85).

Added text about the results of a CCSS study of 1,876 5-year survivors of CNS tumors that determined the incidence of late-onset seizures.

Added text to state that childhood CNS tumor survivors have a 43-fold elevated risk of stroke compared with siblings. Cranial radiation therapy, baseline atherosclerosis, hypertension, and African American ethnicity are identified risk factors (cited Gurney et al., Ullrich et al., Wang and et al. as references 92, 93, and 94, respectively).

Added Hypersomnia (daytime sleepiness) or narcolepsy as a neurologic complication that may occur in survivors of childhood cancer. Also added text about the results of a retrospective review of brain tumor patients treated at St. Jude Children's Research Hospital that identified 39 of 2,336 patients who were diagnosed with hypersomnia/narcolepsy (cited Khan et al. as reference 95).

Added text about the results of a CCSS study of 1,876 5-year survivors of CNS tumors that reported the cumulative incidence of headaches, coordination problems, motor impairment, hearing loss, tinnitus, and vertigo.

Late Effects of the Endocrine System

Added text to state that in 189 children and young adults with brain tumors who were treated with proton radiation therapy, the actuarial rate of hypothyroidism was 20.1%, with 90% central thyroid-stimulating hormone deficiency. This is concordant with previous studies. However, the cumulative incidence of primary hypothyroidism was 3% after craniospinal irradiation and 1.6% overall and is substantially lower than previous reports of 56% to 65% incidence after craniospinal irradiation with photons (cited Vatner et al. as reference 67).

Added Ketterl et al. as reference 126.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the late effects of treatment for childhood cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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The lead reviewers for Late Effects of Treatment for Childhood Cancer are:

• Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
• Melissa Maria Hudson, MD (St. Jude Children's Research Hospital)
• Nita Louise Seibel, MD (National Cancer Institute)

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PDQ® Pediatric Treatment Editorial Board. PDQ Late Effects of Treatment for Childhood Cancer. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/childhood-cancers/late-effects-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389273]

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• Updated: June 4, 2019