The Sound of Silence: A Proxy for Platinum Toxicity
Authors: Jan Oldenburg, Jourik A. Gietema
Journal: Journal of Clinical Oncology (2016)

In the article that accompanies this editorial, Frisina et al report on ototoxicity after cisplatin-based chemotherapy in the Platinum Study. This study comprehensively assesses hearing impairment, both as audiometric and as patient-reported outcome, as well as tinnitus in 488 cisplatin-treated testicular cancer (TC) survivors. One out of five survivors was found to have such severe hearing loss that a hearing aid was recommended. However, only 1.2% of the participants reported actually using such a device. Cisplatin-based chemotherapy was introduced in the late 1970s by Larry Einhorn and cures most patients with metastatic TC. However, long-term complications and late effects after cancer treatment are increasingly recognized as a major contributor to morbidity of survivors, influencing quality of life (QoL) and representing a burden for the growing community of cancer survivors. Similar to the unique position of TC as a model for a curable neoplasm, TC survivors represent a prime cohort for long-term survivorship studies because of their good life expectancy as a result of high cure rates and young age at diagnosis. Although the report by Frisina et al is a valuable contribution to the literature, it would have benefitted from inclusion of additional information, such as pretreatment assessments, the impact of ototoxicity on health-related QoL, details about and adjustment for other ototoxic agents (eg, aminoglycosides), and occupational hearing loss after completion of cisplatin-based chemotherapy. The cohort represents TC survivors receiving standard cisplatin-based chemotherapy for metastatic disease for which we do have some long-term ototoxicity outcomes, whereas high-quality data on ototoxicity after adjuvant chemotherapy with either one or two cycles of bleomycin, etoposide, and cisplatin (BEP) or carboplatin as well as after high-dose chemotherapy are still lacking. In general, long observation periods—a prerequisite for survivorship research—make translation of the impact of former to contemporary treatment challenging. Testicular cancer is an exception. For the last four decades, no alternative regimen was superior to BEP. In accordance with current guidelines, roughly nine out of 10 participants received three or four cycles of BEP or four cycles of etoposide and cisplatin (EP). Normative data from healthy individuals comprising median quartile threshold values for different age groups were applied to categorize decibel thresholds of individual TC survivors in an ordinal fashion up to 8 kHz as adjustment for physiologic age-related hearing decline—an approach similar to the percentiles of pediatric growth curves. Retesting this survivor cohort in some years would yield longitudinal data allowing testing of whether this group is vulnerable to subsequent age-related declines. A hypothesized reduced functional reserve leading to accelerated hormonal ageing could recently be demonstrated in TC survivors with a similar percentile categorization. Except for patients with TC who depend strongly on unimpaired hearing capability (eg, musicians, composers, or ornithologists), the risk of high-frequency hearing impairment should generally play no role in treatment planning of advanced testicular cancer in view of the high curative potential of platinum-based chemotherapy in this setting. In this study, hearing loss according the American SpeechLanguage-Hearing Association criteria was found in 80% of TC survivors, including 18% with a severe (71 to 90 dB) or profound (. 90 dB) hearing loss. On the other hand, one cycle of cisplatin increased the hearing threshold only by 2.5 dB. Thus, cisplatinbased chemotherapy for metastases should not cause more than 10 dB of hearing loss. Age-related hearing decline probably represented much of the observed hearing loss as defined by the American Speech-Language-Hearing Association, which might not be optimal for cross-sectional studies without preceding measurements. Calculation of hearing decline over various frequencies is complex: “For each patient i, the geometric mean Yi was calculated using standard methods by taking the arithmetic mean of the natural log-transformed hearing threshold, di, from n frequencies and then using exponentiation to return the computation to the original decibel scale (ie, log-average).” Understanding this end point, which scores high on specificity and poor on patient relevance (Fig 1), is difficult formost readers who are not familiar with this field. High specificity is needed for disentangling the impact of a single component on a given end point. Chemotherapy-related development of cardiovascular disease (CVD), for example, is complex to assess both due to interaction of different chemotherapy components and further dilution of the cause-effect relationship by multiple genetic and environmental risk factors. Chemotherapyinduced ototoxicity, on the other hand, is almost exclusively linked to cisplatin. Hypertension and hearing loss might be associated independent of cisplatin treatment. However, both symptoms might represent different cisplatin-related long-term toxicities despite adjustment for the cumulative cisplatin dose. Residual serum platinum increases the risk of paresthesia and Raynaud phenomenon more strongly than the applied cumulative cisplatin dose. Residual platinum, however, was not associated with tinnitus or hearing impairment assessed by the Scale for