Carboplatin is ototoxic

Summary For assessment of the ototoxic potential of carboplatin [cis-diammine-1,1-cyclobutane dicarboxylate platinum(II); CBDCA], pure-tone audiograms were evaluated in 27 patients receiving a total of 119 doses of carboplatin in the range of 300–400 mg/m². Pure-tone audiometry (PTA) was done immediately prior to and 4 weeks after the administration of 80 doses (67%). Defining carboplatin ototoxicity as an increase of ⩾ 30 dB in auditory thresholds that was unexplainable by other causes, we identified 5 examples (19%). Hearing loss tended to be cumulative with increasing dose and was always maximal at 8,000 Hz. Two patients had an increase in auditory thresholds at 1,000 Hz, but this only amounted to 10 dB in each case. Patients developing ototoxicity tended to be older. Sex, the pre-treatment creatinine clearance, the pretreatment audiogram, the number of doses, and the cumulative dose did not emerge as being reliable predictors of subsequent ototoxicity. We conclude that although carboplatin is ototoxic, clinically significant deafness does not occur with conventional dosing and routine audiometric monitoring is therefore unnecessary. However, we suggest that caution should be exercised when carboplatin is given either at higher doses or for longer periods when there is concomitant use of other potentially ototoxic agents or when there is significant pre-existing auditory impairment.     

Recommendations for cancer prevention trials using potentially ototoxic test agents.

PURPOSE: Preventive oncology applies pharmacologic agents to reverse, retard, or halt progression of neoplastic cells to invasive malignancy, a process that may require administration of agents over long periods of time. Although ototoxicity may be a tolerable side effect of anticancer or antimicrobial therapy, even modest ototoxicity may not be acceptable in agents developed for preventive oncology that are routinely administered to subjects who neither are, nor necessarily will become, clinically ill. MATERIALS AND METHODS: Age-related shifts in hearing may occur over the course of longterm or open-ended therapy; consequently, age-adjusted norms enable researchers to better distinguish hearing loss caused by drugs from that caused by aging. Norms for hearing sensitivity are derived from the Baltimore Longitudinal Study of Aging and are the basis for the proposed audiologic monitoring recommendations. RESULTS: Audiologic monitoring recommendations are presented that standardize patient selection, adverse event reporting, posttreatment follow-up, and audiologic testing for potentially ototoxic investigational agents. CONCLUSION: These recommendations are applicable to trials of investigational agents as well as various classes of drugs used in routine clinical care.     

Auditory toxicity effects of long-term cis-dichlorodiammineplatinum II therapy in genitourinary cancer patients

To determine the auditory toxicity effects of long-term cis-dichlorodiammineplatinum II therapy, pure tone hearing thresholds were measured prior to therapy and repeated before each subsequent treatment. CDDP was given by a slow intravenous drip method at a low dose of 1 mg/kg body weight, with 37.5 gm mannitol, once a week for six treatments and every 3 weeks thereafter. From a group of 173 genitourinary cancer patients treated, 50 male patients were selected who received at least 12 months of CDDP with no active conductive ear pathology, and whose audiograms obtained at baseline, 6th weeks, 26th weeks, and 52nd weeks of treatment were all available for comparison. Pure tone threshold levels deteriorated across time particularly by the 52nd week and at the higher frequencies. Threshold differences across time were statistically significant and within a linear trend. Of the 50 cases, 30% showed suspect or no ototoxicity, 26% mild, 32% moderate, 2% marked, and 4% showed severe ototoxic changes. Of the two cases who developed severe ototoxicity, one showed complete recovery. There was partial recovery in 26% and no recovery in 54%. Individual variability in susceptibility to and recovery from ototoxicity necessitates systematic audiometric monitoring throughout the therapy.     

Analysis of risk factors for cisplatin-induced ototoxicity in patients with testicular cancer.

This study evaluates the degree and relevance of persisting ototoxicity after cisplatin-based standard-dose chemotherapy for testicular cancer, with emphasis on identification of potential factors for an increased risk of this late sequel. Hearing thresholds of 86 patients with a median age of 31 years (range 21-53 years) and a median follow-up time of 58 months (range 15-159 months) were assessed by conventional pure-tone audiometry. Interviews were conducted evaluating the patients'' history with special regard to audiological risk factors, as well as circumstances of ototoxic symptoms. Details concerning treatment and patient variables were extracted retrospectively from the patients'' charts. An additional screening programme assessed current body functions, blood parameters and other late toxicities. Symptomatic ototoxicity persisted in 20% of patients (59% tinnitus, 18% hearing loss, 23% both), while 10% had experienced completely reversible ototoxic symptoms for a duration of 1-18 months after treatment. Symptoms were bilateral in 81% of patients. Hearing thresholds were compatible with cisplatin-induced hearing loss in 42% of audiograms performed. Subjective (history) and objective (audiogram) findings were not always consistent. The following statistically significant risk factors for ototoxicity were established: high cumulative dose of cisplatin (P < 0.0001); history of noise exposure (P = 0.006). Additionally, high doses of vincristine (P = 0.001) seemed to result in reversible ototoxic symptoms. No other independent risk factors were identified. In conclusion, persisting ototoxicity represents a clinical sequel for approximately 20% of testicular cancer patients treated at standard dose but may affect more than 50% of patients receiving cumulative doses of cisplatin > 400 mg m(-2). Previous noise exposure may also result in a threefold increased risk for cisplatin ototoxicity. Future studies should use these risk factors as important stratification criteria for trials aiming at the evaluation and prevention of cisplatin-induced ototoxicity.     

Sudden hearing loss due to oxaliplatin use in a patient with colon cancer

Oxaliplatin is used to treat advanced colorectal cancer. Platinum-containing chemotherapeutic agents are known to be ototoxic. However, ototoxicity is rare with newer generation platinum-derived agents, such as oxaliplatin. This case report presents a rare case of sudden unilateral sensorineural hearing loss following intravenous (IV) infusion of oxaliplatin in a 64-year-old woman with advanced colon cancer. The hearing loss was severe and did not respond to treatment. To the best of our knowledge, this is the fifth reported case of oxaliplatin ototoxicity. Although oxaliplatin ototoxicity is rare, physicians must be aware of this important adverse effect, and an audiometric evaluation must be performed when necessary. Patients treated with oxaliplatin should be followed closely for early signs and symptoms of hearing loss, and if hearing loss is detected, treatment should be stopped immediately.     

COAST (Cisplatin ototoxicity attenuated by aspirin trial): A phase II double-blind,randomised controlled trial to establish if aspirin reduces cisplatin induced hearing-loss

BackgroundCisplatin is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Cisplatin and gentamicin are thought to damage hearing through a common mechanism, involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin-induced ototoxicity. We, therefore, tested the hypothesis that aspirin could also reduce ototoxicity from cisplatin-based chemotherapy.MethodsA total of 94 patients receiving cisplatin-based chemotherapy for multiple cancer types were recruited into a phase II, double-blind, placebo-controlled trial and randomised in a ratio of 1:1 to receive aspirin 975 mg tid and omeprazole 20 mg od, or matched placebos from the day before, to 2 days after, their cisplatin dose(s), for each treatment cycle. Patients underwent pure tone audiometry before and at 7 and 90 days after their final cisplatin dose. The primary end-point was combined hearing loss (cHL), the summed hearing loss at 6 kHz and 8 kHz, in both ears.ResultsAlthough aspirin was well tolerated, it did not protect hearing in patients receiving cisplatin (p-value = 0.233, 20% one-sided level of significance). In the aspirin arm, patients demonstrated mean cHL of 49 dB (standard deviation [SD] 61.41) following cisplatin compared with placebo patients who demonstrated mean cHL of 36 dB (SD 50.85). Women had greater average hearing loss than men, and patients treated for head and neck malignancy experienced the greatest cHL.ConclusionsAspirin did not protect from cisplatin-related ototoxicity. Cisplatin and gentamicin may therefore have distinct ototoxic mechanisms, or cisplatin-induced ototoxicity may be refractory to the aspirin regimen used here.     

Cis-platinum ototoxicity after radiation treatment: an animal model

The chemotherapeutic agent cis-platinum has been used effectively as a treatment for many tumors. One of the most common toxic effects caused by this treatment is ototoxicity. More severe hearing loss has been reported in patients who had received cranial radiation prior to chemotherapy with cis-platinum. The present laboratory study was undertaken with chinchillas to determine whether ototoxicity is potentiated by cis-platinum administration after cochlear irradiation. Results support the clinical observation that cranial radiation prior to administration of an ototoxic chemotherapeutic agent can have a synergistic effect of increased susceptibility to the ototoxic potential of the agent.     

Study of the effects of chemotherapy on auditory function

Chemotherapeutic agents are known to cause multiple toxicities such as myelotoxicity, nephrotoxicity and ototoxicity. A prospective study was carried out on 60 patients receiving Cisplatin based chemotherapy in a tertiary care centre. The effects of Cisplatin on auditory function were studied using metabolic, biochemical and audiological parameters. The auditory effects were correlated with the dose and duration of chemotherapy. The study concluded that a significant percentage (15%) of patients who were subjected to chemotherapy based on Cisplatin developed high frequency sensorineural hearing loss which was permanent and irreversible in nature.     

Efficacy and Safety of Busulfan‐Based Conditioning Regimens for Multiple Myeloma

Multiple myeloma is a malignancy of B cells characterized by accumulation of abnormal plasma cells in the bone marrow. In the past 20 years, the use of high‐dose therapies and novel agents has resulted in significant and meaningful improvements in survival. Autologous stem cell transplantation (auto‐SCT) following a high‐dose melphalan‐conditioning regimen represents the standard of care for younger patients as well as older patients with a good performance status. A number of strategies have been proposed to improve the outcome of auto‐SCTs, including the incorporation of new agents such as thalidomide, lenalidomide, and bortezomib into the induction regimen administered before auto‐SCT; the administration of maintenance therapy after auto‐SCT; the incorporation of novel agents into chemotherapeutic regimens after transplantation as consolidation therapy; and the use of reduced‐intensity allogeneic transplantation after an initial autograft. Although these approaches have demonstrated some success in improving responses after auto‐SCT, none of these strategies are curative. An additional strategy to improve outcomes after auto‐SCT is to enhance the immediate pretransplant conditioning regimens by either increasing the dose of melphalan or by incorporating novel agents, such as busulfan. This literature review focuses on the efficacy and safety of busulfan‐based conditioning regimens for auto‐SCT in patients with multiple myeloma.     

Acute leukemia as a secondary malignancy in children and adolescents: Current findings and issues

Secondary acute leukemia is a devastating complication in children and adolescents who have been treated for cancer. Secondary acute lymphoblastic leukemia (s‐ALL) was rarely reported previously but can be distinguished today from recurrent primary ALL by comparison of immunoglobulin and T‐cell receptor rearrangement. Secondary acute myeloid leukemia (s‐AML) is much more common, and some cases actually may be second primary cancers. Treatment‐related and host‐related characteristics and their interactions have been identified as risk factors for s‐AML. The most widely recognized treatment‐related risk factors are alkylating agents and topoisomerase II inhibitors (epipodophyllotoxins and anthracyclines). The magnitude of the risk associated with these factors depends on several variables, including the administration schedule, concomitant medications, and host factors. A high cumulative dose of alkylating agents is well known to predispose to s‐AML. The prevalence of alkylator‐associated s‐AML has diminished among pediatric oncology patients with the reduction of cumulative alkylator dose and limited use of the more leukemogenic alkylators. The best‐documented topoisomerase II inhibitor‐associated s‐AML is s‐AML associated with epipodophyllotoxins. The risk of s‐AML in these cases is influenced by the schedule of drug administration and by interaction with other antineoplastic agents but is not consistently found to be related to cumulative dose. The unpredictable risk of s‐AML after epipodophyllotoxin therapy may discourage the use of these agents, even in patients at a high risk of disease recurrence, although the benefit of recurrence prevention may outweigh the risk of s‐AML. Studies in survivors of adult cancers suggest that, contrary to previous beliefs, the outcome of s‐AML is not necessarily worse than that of de novo AML when adjusted for cytogenetic features. More studies are needed to confirm this finding in the pediatric patient population. Cancer 2009. © 2008 American Cancer Society.     

Caring for caregivers and patients: Research and clinical priorities for informal cancer caregiving

Informal/family caregivers are a fundamental source of care for cancer patients in the United States, yet the population of caregivers and their tasks, psychosocial needs, and health outcomes are not well understood. Changes in the nature of cancer care and its delivery, along with the growing population of survivors and their caregivers, warrant increased attention to the roles and demands of caregiving. This article reviews current evidence presented at a 2‐day meeting examining the state of the science of informal cancer caregiving that was convened by the National Cancer Institute and the National Institute of Nursing Research. The meeting sought to define who is an informal cancer caregiver, summarize the state of the science in informal cancer caregiving, and describe both the kinds of interventions developed to address caregiving challenges and the various outcomes used to evaluate their impact. This article offers recommendations for moving science forward in 4 areas: 1) improving the estimation of the prevalence and burden of informal cancer caregiving; 2) advancing the development of interventions designed to improve outcomes for cancer patients, caregivers, and patient‐caregiver dyads; 3) generating and testing strategies for integrating caregivers into formal health care settings; and 4) promoting the use of technology to support informal cancer caregivers. Cancer 2016;122:1987–95 . © 2016 American Cancer Society.     

Cardiotoxicity of anticancer treatments: Epidemiology,detection, and management

Answer questions and earn CME/CNE Cancer and heart disease are the leading causes of morbidity and mortality in the industrialized world. Modern treatment strategies have led to an improvement in the chances of surviving a diagnosis of cancer; however, these gains can come at a cost. Patients may experience adverse cardiovascular events related to their cancer treatment or as a result of an exacerbation of underlying cardiovascular disease. With longer periods of survival, late effects of cancer treatment may become clinically evident years or decades after completion of therapy. Current cancer therapy incorporates multiple agents whose deleterious cardiac effects may be additive or synergistic. Cardiac dysfunction may result from agents that can result in myocyte destruction, such as with anthracycline use, or from agents that appear to transiently affect left ventricular contractility. In addition, cancer treatment may be associated with other cardiac events, such as severe treatment‐induced hypertension and vasospastic and thromboembolic ischemia, as well as rhythm disturbances, including QTc prolongation, that may be rarely life‐threatening. Early and late effects of chest radiation can lead to radiation‐induced heart disease, including pericardial disease, myocardial fibrosis, cardiomyopathy, coronary artery disease, valvular disease, and arrhythmias, in the setting of myocardial fibrosis. The discipline of cardio‐oncology has developed in response to the combined decision making necessary to optimize the care of cancer patients, whether they are receiving active treatment or are long‐term survivors. Strategies to prevent or mitigate cardiovascular damage from cancer treatment are needed to provide the best cancer care. This review will focus on the common cardiovascular issues that may arise during or after cancer therapy, the detection and monitoring of cardiovascular injury, and the best management principles to protect against or minimize cardiotoxicity during the spectrum of cancer treatment strategies. CA Cancer J Clin 2016;66:309‐325. © 2016 American Cancer Society .     

Dose optimization of tyrosine kinase inhibitors to improve outcomes in GIST

Tyrosine kinase inhibitors such as imatinib and sunitinib have greatly improved clinical outcomes for patients with gastrointestinal stromal tumors (GIST). Dose optimization of these agents is critical and involves multiple considerations, including ensuring a durable response, monitoring drug blood levels to confirm adequate dosing, deciding whether to use high‐dose imatinib or switch to second‐line sunitinib in the event of disease progression and appropriately managing treatment‐associated side effects. Imatinib is the standard first‐line therapy for unresectable or metastatic GIST and is also an option for the adjuvant treatment of resected disease. Despite the efficacy and safety of imatinib in patients with advanced GIST, some individuals develop primary or secondary resistance or intolerance to the drug. For patients with advanced disease, imatinib dose escalation to 800 mg/day is warranted in cases of disease progression on imatinib 400 mg/day. In addition, patients with documented KIT exon 9 mutations are likely to derive benefit from initial treatment with high‐dose imatinib to improve clinical outcomes. For patients who fail imatinib, sunitinib is an effective treatment option. However, the decision to use either high‐dose imatinib or sunitinib should be based on the underlying cause of failure on imatinib, KIT mutational status and on whether the patient is intolerant of or has developed a resistance to imatinib. In this article we review the existing literature supporting the use of imatinib and sunitinib in GIST to provide a current clinical perspective on how best to use these agents in the management of GIST to optimize patient outcomes.     

The Role of the Taxanes in the Treatment of Older Patients with Advanced Stage Non‐Small Cell Lung Cancer

The treatment of older patients with advanced non‐small cell lung cancer (NSCLC) represents a considerable challenge for physicians. A patient 's suitability for chemotherapy is frequently based solely on chronologic age; as a consequence, older patients with NSCLC are less likely to receive standard chemotherapy than younger patients. Although age‐related factors, such as comorbid illness, should be taken into consideration when assessing a patient 's suitability for treatment, fit and functionally independent older patients should be considered candidates for standard chemotherapy. The taxanes are widely used in the treatment of advanced‐stage NSCLC and are well tolerated in older patients. The efficacy of both paclitaxel and docetaxel has been studied in older patients and appears to be comparable with that seen in younger patients either as monotherapy or in combination with a platinum compound as first‐line therapy. In addition to the available evidence, prospective evaluation of novel agents in elderly‐specific or ‐enriched studies is necessary to guide the treatment of older patients with NSCLC.     

Management of patients with HER2‐positive metastatic breast cancer: Is there an optimal sequence of HER2‐directed approaches?

The successful development of therapies targeting the human epidermal growth factor receptor 2 (HER2) has altered the natural progression of disease among patients with HER2‐positive metastatic breast cancer. The monoclonal antibody trastuzumab was the first HER2‐directed agent and it was associated with significantly improved outcomes for patients. Subsequently, other HER2‐directed agents such as the monoclonal antibody pertuzumab, the tyrosine kinase receptor inhibitor lapatinib, and the immunoconjugate trastuzumab emtansine were developed to overcome resistance to trastuzumab and provide additional treatment options for patients. Recent data have demonstrated that the use of these HER2‐directed agents improves outcomes. However, with the emergence of new HER2‐targeted agents, the optimal sequencing of treatment remains unclear. Ongoing research is investigating new HER2 combinations, the role of sequencing, novel HER2‐directed agents, and combinations with other targeted agents to overcome resistance. Cancer 2015;121:17–24 . © 2014 American Cancer Society.     

The link between value motives,value success,and well‐being among people diagnosed with cancer

Objective: This study investigated the relationship between cancer patient's values and cancer related distress. Method: A total of 107 patients with cancer diagnoses completed an anonymous questionnaire. Results: Less self‐regulating motivation for health values was significantly related to poorer well‐being. Greater success at living one's values was significantly related to improved well‐being and distress‐related outcomes. Sex difference analysis suggested that success at friendship values was linked to less cancer‐related distress among women, but not men, whereas success at romantic relationship values was linked to less distress among men, but not women. Conclusion: The results have important implications for values focused interventions, highlighting the importance of facilitating success at valued living and attending to sex differences among cancer patients. Copyright © 2010 John Wiley & Sons, Ltd.     

The Evolving Role of Monoclonal Antibodies in Colorectal Cancer: Early Presumptions and Impact on Clinical Trial Development

Targeted biologic agents have an established role in treating metastatic colorectal cancer (mCRC). Bevacizumab, a recombinant monoclonal antibody against the vascular endothelial growth factor ligand is approved by the U.S. Food and Drug Administration (FDA) for bevacizumab‐naïve patients. Cetuximab, a chimeric monoclonal antibody (mAb) against the epidermal growth factor receptor (EGFR) is FDA approved as a single agent, or in combination with irinotecan, in both irinotecan‐naïve and refractory patients, and has additional efficacy in combination with oxaliplatin. Panitumumab, a fully human EGFR mAb, is FDA approved as a single agent in refractory patients but has additional efficacy in combination with chemotherapy. After reaching a temporary therapeutic plateau of FDA‐approved agents for the treatment of mCRC, pivotal results have developed that critically affect the care for these patients. Correlative data from randomized trials of EGFR inhibitors across disease settings have demonstrated higher response rates, specifically for patients with wild‐type K‐RAS tumors. The interpretation of the B‐RAF mutation and other molecular markers may further define the appropriateness of anti‐EGFR therapy. Recent literature revealed that the first‐line use of combined anti‐EGFR therapy plus bevacizumab resulted in inferior outcomes and additional toxicities. Furthermore, the role of biologic agents for locally advanced colon cancer cannot be advocated at this time. With impending changes in the health care system, the economic impact of mAbs will continue to be scrutinized. Hence, as the significance of molecular markers continues to develop, their role as it pertains to the appropriate use of biologic agents in the treatment of mCRC will continue to evolve.     

Ototoxicity of cisplatin plus standard radiation therapy vs. accelerated radiation therapy in glioblastoma patients

Summary Purpose: To assess the effect of cisplatin (CDDP) plus concurrent radiation therapy on hearing loss. Methods: 451 patients with glioblastoma multiforme (GBM) were randomly assigned after surgery to: Arm A: Carmustine (BCNU) + standard radiation therapy (SRT); Arm B: BCNU + accelerated radiation therapy (ART: 160 cGy twice daily for 15 days); Arm C: CDDP + BCNU + SRT; or Arm D: CDDP + BCNU + ART. Patients on arms C and D received audiograms at baseline, and prior to the start of RT, and prior to cycles 3 and 6. Otologic toxicities were recorded at each visit. Results: 56% of patients had hearing loss at baseline. 13% and 50% of patients experienced worsening ototoxicity after 1 year of treatment in arms A and B vs. C and D, respectively, with 13% of those on arms C and D experiencing significant ototoxicity (≥ grade 3) at 6 months. Increasing age was associated with an increased risk of ototoxicity. Conclusions: Increased exposure to CDDP increases the risk of ototoxicity over time. Older patients are more susceptible to hearing loss with CDDP. The low proportion of patients with clinically significant ototoxicity suggests that baseline screening is unnecessary in GBM patients.