Kay W. Chang

Platinum-Induced Ototoxicity in Children: A Consensus Review on Mechanisms, Predisposition, and Protection, Including a New International Society of Pediatric Oncology Boston Ototoxicity Scale

PURPOSE The platinum chemotherapy agents cisplatin and carboplatin are widely used in the treatment of adult and pediatric cancers. Cisplatin causes hearing loss in at least 60% of pediatric patients. Reducing cisplatin and high-dose carboplatin ototoxicity without reducing efficacy is important. PATIENTS AND METHODS This review summarizes recommendations made at the 42nd Congress of the International Society of Pediatric Oncology (SIOP) in Boston, October 21-24, 2010, reflecting input from international basic scientists, pediatric oncologists, otolaryngologists, oncology nurses, audiologists, and neurosurgeons to develop and advance research and clinical trials for otoprotection. RESULTS Platinum initially impairs hearing in the high frequencies and progresses to lower frequencies with increasing cumulative dose. Genes involved in drug transport, metabolism, and DNA repair regulate platinum toxicities. Otoprotection can be achieved by acting on several these pathways and generally involves antioxidant thiol agents. Otoprotection is a strategy being explored to decrease hearing loss while maintaining dose intensity or allowing dose escalation, but it has the potential to interfere with tumoricidal effects. Route of administration and optimal timing relative to platinum therapy are critical issues. In addition, international standards for grading and comparing ototoxicity are essential to the success of prospective pediatric trials aimed at reducing platinum-induced hearing loss. CONCLUSION Collaborative prospective basic and clinical trial research is needed to reduce the incidence of irreversible platinum-induced hearing loss, and optimize cancer control. Wide use of the new internationally agreed-on SIOP Boston ototoxicity scale in current and future otoprotection trials should help facilitate this goal.

Practical Grading System for Evaluating Cisplatin Ototoxicity in Children

PURPOSE We present a new ototoxicity grading system that has clearly defined and frequency-specific audiometric criteria. The purpose of this study was to validate this grading system by assessing its correspondence to audiology treatment recommendations and comparing it with the currently utilized Common Terminology Criteria for Adverse Events (CTCAE). PATIENTS AND METHODS A retrospective chart review was conducted using audiologic, demographic, and clinical data from 134 children receiving 149 courses of chemotherapy consisting of cisplatin and/or carboplatin. Pure-tone audiograms were evaluated using both our proposed grading criteria and the CTCAE criteria. The resulting grades were then compared with charted audiologic interventions and a number of clinical parameters to assess the clinical validity of the grading scale. RESULTS Chang grade 2a or higher predicted audiologic intervention. Although both the Chang and CTCAE ototoxicity grades were significantly related to audiologist recommendations for assistive devices such as hearing aids and/or frequency modulated systems (P < .0001), the Chang scale was more specific, with the CTCAE scale diverging from clinical recommendation at higher grades. As expected, patients receiving cisplatin had more severe hearing loss with concurrent carboplatin administration, radiation therapy exposure, younger age, smaller body-surface area, longer treatment exposure, and more severe disease. CONCLUSION This grading system provides robust and clinically useful criteria to represent clinical hearing loss induced by ototoxicity with regard to the impact on speech and language and the need for assistive hearing devices. It is both more specific and more sensitive than the traditional CTCAE criteria for identifying clinically significant ototoxicity.

Randomized controlled trial of Coblation versus electrocautery tonsillectomy

OBJECTIVE: To compare the postoperative recovery of patients receiving Coblation-assisted (Arthrocare, Sunnyvale, CA) intracapsular tonsillectomy with that of patients receiving traditional subcapsular electrocautery tonsillectomy. STUDY DESIGN AND SETTING: This was a prospective, randomized, double-blinded, controlled study. One hundred one children, aged 2 to 16 years, were randomized to Coblation or to conventional electrocautery tonsillectomy. Only patients with the operative indication of obstructive sleep apnea were entered into the study. Intracapsular tonsillectomy was performed on the Coblation group, and traditional subcapsular dissection was performed on the electrocautery group. Adenoidectomy was performed with the curette in both groups. Outcome measures were assessed on days 1, 3, and 5 after surgery. These included child and parental rating of pain by using the Wong Faces pain scale, analgesic use, oral intake, and activity level. Patients, parents, and the nurse practitioner obtaining the outcome data were blinded to treatment arm. RESULTS: Treatment groups were similar in age, gender, and weight. Surgical time and estimated blood loss were similar. There were no complications in either group. Coblation patients had less pain and greater oral intake at all 3 time points. Percentage of normal activity level returned to >70% earlier and more frequently in Coblation patients. There was slightly decreased analgesic use on postoperative day 5 in the Coblation group. CONCLUSIONS AND SIGNIFICANCE: Children with obstructive sleep apnea undergoing tonsillectomy and adenoidectomy demonstrate significantly better postoperative recovery after Coblation-assisted intracapsular tonsillectomy.

Propranolol for the treatment of a life-threatening subglottic and mediastinal infantile hemangioma.

An infant with a subglottic hemangioma remained in respiratory distress after multiple treatments failed and was found to have an enlarging mediastinal infantile hemangioma compressing the trachea. Treatment with oral propranolol resulted in resolution of symptoms within 2 days and a 50% reduction in lesion size within 1 week.

Prevention of Cisplatin Ototoxicity Using Transtympanic N-Acetylcysteine and Lactate

Hypothesis: Transtympanic administration of the antioxidant N-acetylcysteine or lactated Ringer’s solution onto the round window membrane will prevent cisplatin ototoxicity in the guinea pig model. Background: Cochlear ototoxicity is a well-known side effect of cisplatin administration, with the mechanism of injury thought to rest in oxidative damage to the outer hair cells. However, previous attempts at transtympanic antioxidant delivery have met with varied success. We present an effective method of counteracting cisplatin ototoxicity via the transtympanic application of lactated Ringer’s solution or N-acetylcysteine. Methods: Baseline distortion product otoacoustic emission measurements were obtained. Intraperitoneal cisplatin was administered to a cumulative dose of 20 mg/kg. The middle ears were either untreated (control) or filled with normal saline (negative control), 2%N-acetylcysteine diluted in normal saline (treatment), or lactated Ringer’s solution (treatment) via anterosuperior quadrant myringotomies. Posttreatment distortion product otoacoustic emissions were obtained. Results: Animals in the untreated control group and the negative control normal saline group demonstrated consistent obliteration of distortion product otoacoustic emissions. However, those receiving either lactated Ringer’s solution or 2%N-acetylcysteine diluted in normal saline demonstrated significant preservation of distortion product otoacoustic emissions. The treatment regimen was well tolerated, with minimal animal loss. Conclusion: We have demonstrated the efficacy of transtym-panic lactated Ringer’s solution and N-acetylcysteine in the prevention of cisplatin ototoxicity using a guinea pig model. The possible mechanisms for the high efficacy of lactated Ringer’s solution are discussed in detail.

GJB2‐associated hearing loss: Systematic review of worldwide prevalence, genotype, and auditory phenotype

To perform a systematic review of GJB2‐associated hearing loss to describe genotype distributions and auditory phenotype.

Amifostine does not prevent platinum-induced hearing loss associated with the treatment of children with hepatoblastoma. A report of the Intergroup Hepatoblastoma Study P9645 as a part of the Children's Oncology Group

The current study was conducted to determine whether amifostine is effective in reducing the toxicities associated with the administration of platinum‐containing regimens in children with hepatoblastoma (HB).

Propranolol for the treatment of airway hemangiomas: a case series and treatment algorithm.

OBJECTIVES (1) To present six patients with symptomatic airway hemangiomas treated with oral propranolol. (2) To review the diagnostic and treatment options for airway hemangiomas and propose a new management protocol. STUDY DESIGN Retrospective review. SETTING Tertiary care childrens hospital. SUBJECTS AND METHODS Pediatric patients diagnosed with obstructive airway hemangiomas treated with oral propranolol. Patients were followed for symptomatic improvement and relief of airway obstruction on imaging or laryngoscopy. RESULTS Seven patients presenting with airway obstruction were treated with propranolol. One patient had a focal hemangioma confined to the subglottis. Four patients had airway hemangiomas that extended beyond the confines of the larynx and trachea. A sixth patient had a bulky supraglottic hemangioma. A seventh patient with an extensive maxillofacial lesion failed propranolol therapy and was found to have a pyogenic granuloma on final pathology after excision. Six patients had failed standard medical therapy and/or surgical interventions and were treated successfully with oral propranolol with improvements in airway symptoms and oral intake, requiring no further surgical intervention. Treatment was initiated as early as 1.5 months of age, and as late as 22 months. No adverse side effects of propranolol were noted. CONCLUSIONS Oral propranolol was successfully used to treat airway hemangiomas, resulting in rapid airway stabilization, obviating the need for operative intervention, and reducing the duration of systemic corticosteroid therapy while causing no obvious adverse effects. These outstanding results enable the possibility of use of a standardized diagnostic and treatment algorithm for airway hemangiomas that incorporates systemic propranolol.

β -Adrenergic receptor expression in vascular tumors

Propranolol has recently emerged as an effective therapy for infantile hemangiomas causing regression. The β-adrenergic receptor (AR) antagonist is thought to cause vasoconstriction by its effect on nitric oxide, block angiogenesis by its effect on vascular endothelial growth factor (VEGF), and induce apoptosis. In a prior report, we identified expression of β2-AR (B2-AR) and its phosphorylated form (B2-ARP) in a case of infantile hemangioma that responded to propranolol treatment. We now explore the expression of βARs on a variety of vascular lesions utilizing a tissue microarray containing 141 lesions, including infantile hemangiomas, angiosarcomas, hemangiomas, hemangioendotheliomas, and various vascular malformations. The array was immunostained for B2-AR, B2-ARP, and β3-AR (B3-AR), and the results scored for the intensity of endothelial cell expression as negative, weak positive, or strong positive. All phases of infantile hemangiomas had strong expression of all three receptors, with the exception of only weak expression of B2-ARP in the proliferative phase infantile hemangioma. Strong expression of all three receptors was present in many hemangiomas, hemangioendotheliomas, and vascular malformations. Absent to weak expression of all three receptors was seen in glomus tumor, hobnail hemangioendothelioma, pyogenic granuloma, and reactive vascular proliferations. This is the first study to report β-AR expression in a variety of vascular lesions. Although immunohistochemical expression of the receptors does not necessarily indicate that similar pathways of responsiveness to β-blockade are present, it does raises the possibility that β-blockade could potentially affect apoptosis and decrease responsiveness to VEGF. Additional study is warranted, as therapeutic options are limited for some patients with these lesions.

Intracapsular versus subcapsular coblation tonsillectomy

OBJECTIVE: To compare the postoperative recovery of patients who undergo intracapsular to subcapsular Coblation tonsillectomy. STUDY DESIGN AND SETTING: This was a prospective, randomized, double-blinded study. A total of 69 children, aged 2 to 16 years, were randomized to intracapsular (n = 34) or subcapsular (n = 35) tonsillectomy. The Coblation technique was used with both groups. Outcomes measures were assessed on postoperative day 1 or 2 and 5 or 6. These included child and parental rating of pain with the Wong Faces pain scale, analgesic use, oral intake, and activity level. RESULTS: Intracapsular tonsillectomy patients had similar levels of pain to subcapsular tonsillectomy patients on day 1 or 2. However, at day 5 or 6, intracapsular tonsillectomy patients had significantly less pain than the subcapsular tonsillectomy patients. Intracapsular patients ate more and were more active at both time points. CONCLUSION AND SIGNIFICANCE: Children with obstructive sleep apnea who undergo tonsillectomy demonstrate better postoperative recovery after intracapsular tonsillectomy. The intracapsular versus subcapsular difference may be best appreciated at a delayed time point (day 5 or 6) rather than early (day 1 or 2).