Questions About Cancer? 1-800-4-CANCER

Late Effects of Treatment for Childhood Cancer (PDQ®)

Health Professional Version
Last Modified: 10/27/2014

Late Effects of the Special Senses

Hearing
        Hearing loss and platinum-based therapy
        Hearing loss and cranial radiation therapy
Orbital and Optic
        Retinoblastoma
        Rhabdomyosarcoma
        Optic pathway glioma and craniopharyngioma
        Treatment-specific effects



Hearing

Children treated for malignancies may be at risk for early- or delayed-onset hearing loss that can affect learning, communication, school performance, social interaction, and overall quality of life. Hearing loss as a late effect of therapy can occur after exposure to platinum compounds (cisplatin and carboplatin), cranial radiation, 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]

Risk factors associated with hearing loss include the following:

  • Younger age at treatment.
  • Higher cumulative dose of platinum-based chemotherapy.
  • Exposure to cisplatin combined with myeloablative carboplatin.[3]
  • CNS tumors.
  • Concomitant cranial radiation therapy.
Hearing loss and platinum-based therapy

Cisplatin-induced hearing loss involving the speech frequencies (500–2000 Hz) usually occurs with cumulative doses that exceed 400 mg/m2 in pediatric patients.[3,4] Otologic toxic effects after platinum chemotherapy can present or worsen years after completion of therapy.

Studies of hearing loss after platinum-based therapy in childhood cancer survivors have reported the following:

  • In a study of 59 patients who received cisplatin, 51% of survivors developed late-onset hearing loss (occurring at least 6 months after the last dose of cisplatin). Radiation to the posterior fossa inclusive of the eighth cranial nerve and the use of hearing aids (suggestive of damage to the cochlea at the end of therapy) were associated with late-onset hearing loss.[5]

  • Carboplatin used in conventional (nonmyeloablative) dosing is typically not ototoxic.[6] However, delayed-onset hearing loss has been reported in specific populations. 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.[7] 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.[8]

Hearing loss and cranial radiation therapy

Cranial radiation therapy, when used as a single modality, may result in otologic toxic effects when cochlear dosage exceeds 32 Gy. Young patient age and presence of a brain tumor and/or hydrocephalus can increase susceptibility to hearing loss. The onset of radiation-associated hearing loss may be gradual, manifesting months to years after exposure.

When used concomitantly with cisplatin, radiation therapy can substantially exacerbate the hearing loss associated with platinum chemotherapy.[9-12] In a report from the Childhood Cancer Survivor Study (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 radiation (>30 Gy) and posterior fossa radiation (>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).[13]

Table 15. Auditory Late Effects
Predisposing Therapy Potential Auditory Effects Health Screening/Interventions 
FM = frequency modulated.
Platinum agents (cisplatin, carboplatin); radiation impacting the earOtologic toxic effects; sensorineural hearing loss; tinnitus; vertigo; dehydrated ceruminosis; conductive hearing lossHistory: 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.[14,15] 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. Longer follow-up is needed to assess the impact on vision in patients undergoing these more contemporary treatment modalities.[14,16,17] 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.[18-21]

(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.[22] Cataracts are reported after lower doses of 10 Gy to 18 Gy.[23-25]

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

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.

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.[26]

In a study of 25 patients diagnosed with craniopharyngioma, 67% had visual complications at a mean follow-up of 11 years.[27] 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.[28]

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. The CCSS reported that survivorswho were 5 or more years from diagnosis were at increased risk for 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. The dose of radiation to the eye is significantly associated with risk of cataracts, legal blindness, double vision, and dry eye, in a dose-dependent manner. Risk of cataracts was associated with a radiation dose of 30 Gy or more to the posterior fossa and temporal lobe and treatment with prednisone. The cumulative incidence of cataracts, double vision, dry eye, and legal blindness continued to increase up to 20 years after diagnosis for those who received more than 5 Gy to the eye.[29]

Ocular complications, such as cataracts and dry-eye syndrome, are common after stem cell transplantation in childhood. 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.[30-33] Patients receiving TBI doses of less than 40 Gy have a less than 10% chance of developing severe cataracts.[33] Corticosteroids and graft-versus-host disease (GVHD) may further increase risk.[30,34] Epithelial superficial keratopathy has been shown to be more common if the patient was exposed to repeated high trough levels of cyclosporine A.[35]

Table 16. Ocular Late Effects
Predisposing Therapy Ocular/Vision Effects Health Screening/Interventions 
GVHD = graft-versus-host disease.
Busulfan; corticosteroids; radiation impacting the eyeCataractsHistory: decreased acuity, halos, diplopia
Eye exam: visual acuity, funduscopy
Ophthalmology consultation
Radiation impacting the eye, including radioiodine (I-131)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 GVHDXerophthalmia (keratoconjunctivitis sicca)History: dry eye (burning, itching, foreign body sensation, inflammation)
Eye exam: visual acuity, funduscopy
EnucleationImpaired cosmesis; poor prosthetic fit; orbital hypoplasiaOcular prosthetic evaluation
Ophthalmology

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

References
  1. Grewal S, Merchant T, Reymond R, et al.: Auditory late effects of childhood cancer therapy: a report from the Children's Oncology Group. Pediatrics 125 (4): e938-50, 2010.  [PUBMED Abstract]

  2. Li Y, Womer RB, Silber JH: Predicting cisplatin ototoxicity in children: the influence of age and the cumulative dose. Eur J Cancer 40 (16): 2445-51, 2004.  [PUBMED Abstract]

  3. Landier W, Knight K, Wong FL, et al.: Ototoxicity in children with high-risk neuroblastoma: prevalence, risk factors, and concordance of grading scales--a report from the Children's Oncology Group. J Clin Oncol 32 (6): 527-34, 2014.  [PUBMED Abstract]

  4. Kushner BH, Budnick A, Kramer K, et al.: Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma. Cancer 107 (2): 417-22, 2006.  [PUBMED Abstract]

  5. Kolinsky DC, Hayashi SS, Karzon R, et al.: Late onset hearing loss: a significant complication of cancer survivors treated with Cisplatin containing chemotherapy regimens. J Pediatr Hematol Oncol 32 (2): 119-23, 2010.  [PUBMED Abstract]

  6. Fouladi M, Gururangan S, Moghrabi A, et al.: Carboplatin-based primary chemotherapy for infants and young children with CNS tumors. Cancer 115 (14): 3243-53, 2009.  [PUBMED Abstract]

  7. Jehanne M, Lumbroso-Le Rouic L, Savignoni A, et al.: Analysis of ototoxicity in young children receiving carboplatin in the context of conservative management of unilateral or bilateral retinoblastoma. Pediatr Blood Cancer 52 (5): 637-43, 2009.  [PUBMED Abstract]

  8. Qaddoumi I, Bass JK, Wu J, et al.: Carboplatin-associated ototoxicity in children with retinoblastoma. J Clin Oncol 30 (10): 1034-41, 2012.  [PUBMED Abstract]

  9. 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]

  10. Hua C, Bass JK, Khan R, et al.: Hearing loss after radiotherapy for pediatric brain tumors: effect of cochlear dose. Int J Radiat Oncol Biol Phys 72 (3): 892-9, 2008.  [PUBMED Abstract]

  11. 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]

  12. 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]

  13. Whelan K, Stratton K, Kawashima T, et al.: Auditory complications in childhood cancer survivors: a report from the childhood cancer survivor study. Pediatr Blood Cancer 57 (1): 126-34, 2011.  [PUBMED Abstract]

  14. 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]

  15. 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]

  16. 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]

  17. 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]

  18. 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]

  19. 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]

  20. Shields JA, Shields CL: Pediatric ocular and periocular tumors. Pediatr Ann 30 (8): 491-501, 2001.  [PUBMED Abstract]

  21. 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]

  22. Kline LB, Kim JY, Ceballos R: Radiation optic neuropathy. Ophthalmology 92 (8): 1118-26, 1985.  [PUBMED Abstract]

  23. 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]

  24. 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]

  25. 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]

  26. 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]

  27. Poretti A, Grotzer MA, Ribi K, et al.: Outcome of craniopharyngioma in children: long-term complications and quality of life. Dev Med Child Neurol 46 (4): 220-9, 2004.  [PUBMED Abstract]

  28. Fisher PG, Jenab J, Gopldthwaite PT, et al.: Outcomes and failure patterns in childhood craniopharyngiomas. Childs Nerv Syst 14 (10): 558-63, 1998.  [PUBMED Abstract]

  29. 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]

  30. 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]

  31. 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]

  32. 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]

  33. Kal HB, VAN Kempen-Harteveld ML: Induction of severe cataract and late renal dysfunction following total body irradiation: dose-effect relationships. Anticancer Res 29 (8): 3305-9, 2009.  [PUBMED Abstract]

  34. Holmström G, Borgström B, Calissendorff B: Cataract in children after bone marrow transplantation: relation to conditioning regimen. Acta Ophthalmol Scand 80 (2): 211-5, 2002.  [PUBMED Abstract]

  35. 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]