Late Effects of the Special Senses
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.
- CNS tumors.
- Concomitant cranial radiation therapy.
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 irradiation, aminoglycosides, loop diuretics), and the grading criteria used to report prevalence and severity of hearing loss.
- Cisplatin-induced hearing loss involving the speech frequencies (500–2000 Hz) usually occurs with cumulative doses that exceed 400 mg/m2 in pediatric patients.[3,5] Prolonging the duration of infusion or splitting the dose has been reported to reduce the risk of significant hearing loss. Exposure to cisplatin combined with myeloablative carboplatin significantly increases the risk of severe hearing loss. Otologic toxic effects after platinum chemotherapy have been reported to worsen years after completion of therapy. Radiation 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.
- Carboplatin used in conventional (nonmyeloablative) dosing is typically not ototoxic. 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. 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.
- 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.[3,5]
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 alone is in the range of 35 to 45 Gy for children. High-frequency sensorineural hearing loss is uncommon at cumulative radiation doses below 35 Gy. 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. 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.
When used concomitantly with cisplatin, radiation therapy can substantially exacerbate the hearing loss associated with platinum chemotherapy.[11-14] 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).
|Predisposing Therapy||Potential Auditory Effects||Health Screening/Interventions|
|FM = frequency modulated.|
|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|
|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.
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.[16,17] 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.[16,18,19] 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.[20-23]
(Refer to the PDQ summary on Retinoblastoma Treatment for more information on the treatment of retinoblastoma.)
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. Cataracts are reported after lower doses of 10 Gy to 18 Gy.[25-27]
(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.
In a study of 25 patients diagnosed with craniopharyngioma, 67% had visual complications at a mean follow-up of 11 years. 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.
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 survivors who 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. 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 irradiation 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.
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.[33-36] Patients receiving TBI doses of less than 40 Gy have a less than 10% chance of developing severe cataracts. Corticosteroids and graft-versus-host disease may further increase risk.[33,37] Epithelial superficial keratopathy has been shown to be more common if the patient was exposed to repeated high trough levels of cyclosporine A.
|Predisposing Therapy||Ocular/Vision Effects||Health Screening/Interventions|
|GVHD = graft-versus-host disease.|
|Busulfan; corticosteroids; radiation impacting the eye||Cataracts||History: decreased acuity, halos, diplopia|
|Eye exam: visual acuity, funduscopy|
|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|
|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|
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.
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- 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]
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- Bertolini P, Lassalle M, Mercier G, et al.: Platinum compound-related ototoxicity in children: long-term follow-up reveals continuous worsening of hearing loss. J Pediatr Hematol Oncol 26 (10): 649-55, 2004. [PUBMED Abstract]
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- 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]
- 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]
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- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
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- 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]
- 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]
- 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]
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