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Continuous or repeated prolonged cisplatin infusions in children: A prospective study on ototoxicity, platinum concentrations, and standard serum parameters
Abstract
To overcome the ototoxicity of cisplatin, single bolus infusions were replaced by repeated prolonged infusions of lower doses or by continuous infusions at still lower infusion rates. However, considering ototoxicity little is, in fact, known about the tolerance of repeated prolonged or continuous infusion in children.
Auditory function was monitored along with plasma concentrations of free and total platinum (Pt), and with standard serum parameters (sodium, potassium, calcium, magnesium, phosphate, chloride, and creatinine) in 24 children receiving cisplatin by continuous infusion for the treatment of neuroblastoma and osteosarcoma or by repeated 1 or 6 hr infusions for the treatment of germ cell tumors.
Hearing deteriorated in 10/15 osteosarcoma patients, 2/3 neuroblastoma patients, and 1/6 patients with germ cell tumors. Ototoxicity occurred after cumulative doses between 120 and 360 mg/m(2) cisplatin. In osteosarcoma patients, ototoxicity was associated with a comparatively higher mean plasma concentration of free Pt. However, Pt plasma concentrations did not discriminate between patients with or without ototoxicity. In patients experiencing ototoxicity serum creatinine increased by 45% compared to pre-treatment levels (mean). Serum creatinine increased by 26% in patients without ototoxicity (P < 0.05, Mann-Whitney Rank sum test). Despite standardized hydration, discrete but significant changes of potassium, sodium, magnesium, and phosphate were observed during and/or after cisplatin infusion, which, however, did not discriminate between patients with and without ototoxicity.
While continuous cisplatin infusions are less nephrotoxic than repeated prolonged infusions, we observed considerable ototoxicity in patients treated with continuous cisplatin infusions, which necessitates further evaluations on the tolerance of continuous cisplatin infusions in children.
... dosagens individuais já são capazes de comprometer o sistema auditivo 12 . ...
... Uma vez que a faixa etária avaliada era ampla, incluindo às vezes crianças muito pequenas, o método para avaliação auditiva precisava adequar-se às possibilidades de resposta da criança; por isso, para alguns dos estudos, foi necessário utilizar procedimentos objetivos e/ou subjetivos 8,12,20,28,30,33,39 . ...
... A imitanciometria, embora utilizada em boa parte dos estudos 12,20,24,27,28,31,35 , foi realizada principalmente com a finalidade de descartar possíveis alterações de orelha média que pudessem comprometer os resultados dos outros procedimentos, principalmente das Emissões Otoacústicas (EOA). ...
Purpose:
to identify and analyze the effects of chemotherapy on the auditory system of children and/or adolescents with cancer treated with cisplatin and carboplatin, assessed through standardized audiological procedures.
Methods:
studies in Brazilian Portuguese and in English were searched for, as available in the databases Science Direct, PubMed, LILACS, BIREME, Embase, SciELO, Web of Science and Cochrane. The descriptors were: Hearing Loss, Audiology, Child Cancer, Chemotherapy, and Child. Articles with levels 1 and 2 of scientific evidence, published in the last 20 years (1997 to 2017), were considered, of which the audiological results were analyzed, as well as the prevalence of hearing loss in children with cancer undergoing chemotherapy.
Results:
3,625 articles were found, of which only 23 were selected for analysis in the present review. Studies have shown a high incidence of sensorineural hearing loss and decrease or even loss of otoacoustic emissions in children and adolescents with cancer, even after the first dose of chemotherapy drugs, with high frequencies being the most affected.
Conclusion:
there is evidence that both carboplatin and especially cisplatin from the first doses may impair the hearing of children and adolescents, mainly affecting the cochlear function, thus, the importance of long-term audiological monitoring.
... Both bone and air conduction tests were performed to exclude hearing loss due to diseases of external auditory canals and middle ears. Each audiogram was classified according to the Mü nster classification (Supplementary Table 1) [9,26] that has the best sensitivity, specificity and positive and negative predictive value compared to other criteria [26,27]. All audiograms were examined by a well-trained investigator, and for quality control a random sample of 10% of the audiograms were examined by a second, independent, experienced audiologist (AaZ-D). ...
... For the purpose of the study, we have defined two groups with different degrees of ototoxicity: Münster0-2a versus Mü nster ! 2b [27]. ...
... In addition, the Brock criteria were applied as a secondary, independent validation [9]. The Brock classification has been considered a useful system in classifying high frequency ototoxicity [26,27]. We preferred the Mü nster classification [26,27] over the Brock classification [28] because of the better sensitivity and specificity. ...
... Although clinical risk factors are important predictors, they do not fully explain the large interindividual differences in the susceptibility to cisplatin ototoxicity [10,28]. For example, cumulative cisplatin doses of 360-480 mg/m 2 were tolerated without hearing loss in some children with osteosarcoma, whereas other children developed ototoxicity with cumulative doses of only 120 mg/m 2 [29]. Neither total nor free concentrations of platinum in the blood were significant predictors of cisplatin ototoxicity [29], and thus classical therapeutic drug monitoring (TDM) based on blood concentration measurements is not applicable to predict or limit ototoxic side effects of cisplatin. ...
... For example, cumulative cisplatin doses of 360-480 mg/m 2 were tolerated without hearing loss in some children with osteosarcoma, whereas other children developed ototoxicity with cumulative doses of only 120 mg/m 2 [29]. Neither total nor free concentrations of platinum in the blood were significant predictors of cisplatin ototoxicity [29], and thus classical therapeutic drug monitoring (TDM) based on blood concentration measurements is not applicable to predict or limit ototoxic side effects of cisplatin. Alternatively, TDM based on a priori pharmacogenetic information may be a valid approach and, accordingly, in recent years much effort has been focused on the identification of genetic factors predisposing to platinum ototoxicity. ...
Childhood cancer survival rates are now nearly 80% in more developed European countries because of improved therapies and better supportive care. Platinum chemotherapy drugs, such as cisplatin and carboplatin, are the cornerstone of many effective therapeutic protocols for childhood cancer. However, the antitumor efficacy of cisplatin and carboplatin comes at the cost of ototoxicity, which affects at least 60% of pediatric patients. Although ototoxicity is not life threatening, it can have debilitating effects on patients' quality of life. Recently, many initiatives have been launched with the ultimate goal of reducing cisplatin and high-dose carboplatin ototoxicity without compromising antitumor efficacy. This review addresses the incidence of platinum ototoxicity and its clinical presentation, time course, and early diagnostic evaluation. Genetic and non-genetic risk factors for platinum-associated ototoxicity, and their predictive value, are discussed. Recent developments in the prevention of platinum ototoxicity are also summarized.
... Several risk factors such as cumulative dosage, 8,9 age <5 years, 8 renal insufficiency, prior cranial irradiation, 10 the combination with other drugs, and high rate of cisplatin administration have been identified as risk factors for cisplatin-induced ototoxicity. 4,8,[11][12][13] Although the influences of nutrition 14 and noise stress 15 are also discussed, no dependent risk factors have been identified to date. Recently published studies showed interindividual susceptibility to cisplatin-induced ototoxicity in both clinical studies and animal tests. ...
... A total of 68 patients were eligible for the present study and the patients' characteristics are summarized in Table 2 Table 3 summarizes the association of patients' characteristics identified as risk factors in the relevant literatures 4,8,[11][12][13] and hearing impairment thought to be due to cisplatin-induced ototoxicity classified by Brock classification after treatment. Patients were classified into 2 groups, grade 0 and 1 to 4 by Brock classification, according to clinical implication of hearing impairment. ...
Cisplatin-induced ototoxicity, an important dose-limiting side effect, has proven high interindividual variability. Glutathione S-transferases (GSTs) are isoenzymes involved in cellular detoxification processes. Megalin has been demonstrated to bind aminoglycosides, known to be similar to cisplatin for their ototoxicity. The GSTs and megalin expression is genetically polymorphic, which might be responsible for the variability in cisplatin-induced ototoxicity. The genotyping of GSTM1, GSTT1 polymorphisms, and 2 nonsynonymous single nucleotide polymorphisms (SNPs) at megalin genes, rs2075252 and rs2228171, were performed in 68 children diagnosed with solid tumors who received cisplatin-based chemotherapy. After the end of treatment, audiometry demonstrated hearing loss in 79.4% of patients according to Brock classification. The cumulative cisplatin dose >400 mg/m is associated with increased risk of cisplatin-induced ototoxicity [odds ratio (OR), 17.5; 95% confidence interval (CI), 3.09-98.62]. GSTT1 wild genotype and C-allele of rs2228171 SNPs of megalin gene occurred with higher frequency in patients with ototoxicity (P=0.023; OR, 10; 95% CI, 1.80-56.00 and P=0.034; OR, 2.67; 95% CI, 1.22-5.82, respectively). In conclusion, our results suggested that GSTT1 wild genotype and C-allele of rs2228171 SNPs might be risk factors for ototoxicity. The cumulative cisplatin dose <400 mg/m should be beneficial in order to ameliorate ototoxicity.
... Furthermore, the dosing of cisplatinum has been increased in recent treatment protocols to increase cure rates, leading to increased ototoxicity. 2,3 Cisplatinum-induced cochlear damage is usually permanent and has a higher incidence in the pediatric population, with quoted rates of 50 to 75 percent. [4][5][6] Cisplatinum-induced ototoxicity is thought to be caused by the overproduction of oxygen-free radicals or reactive oxygen species. ...
... Sodium lactate is the main chemical component and is believed to have a potent antioxidant effect. Sodium lactate provides sodium (Na ϩ ) and lactate (C 3 ...
Ototoxicity is currently the most frequent dose-limiting side effect of cisplatinum chemotherapy. To date, there is no protocol to prevent dose-related ototoxicity, despite its prevalence and predictability. Previous animal studies have found lactate to be effective in the prevention of cisplatinum-induced ototoxicity. The objective of this study was to test the protective benefits of transtympanic Ringer's lactate in the prevention of cisplatinum-induced ototoxicity.
A randomized prospective controlled trial was conducted in an animal model.
Animal care research facilities of The Montreal Children's Hospital Research Institute.
A total of 44 chinchillas were exposed to systemic cisplatinum injected intraperitoneally in divided cycles to reach the targeted cumulative dosage of 16 mg/kg. Ototopical application of Ringer's lactate solution 0.2 mL twice per day during the chemotherapy cycles was performed. Each animal had one experimental (Ringer's) and one control ear. Distortion product otoacoustic emissions (DPOAEs) were collected for a wide range of frequencies (between 1 and 16 kHz), and scanning electron microscopy was performed to evaluate the protective effects of Ringer's lactate.
Ototopical application of Ringer's lactate solution in our established chinchilla animal model did not provide an otoprotective effect as measured by the DPOAE response and electron microscopy.
In our study, the intratympanic application of Ringer's lactate solution through a tympanostomy ventilation tube did not provide an otoprotective effect. Further studies are needed to better assess the otoprotective or ototoxic effects of Ringer's lactate and other antioxidants on animal and human hearing.
... As before, HeLa cells were also cotransfected with a constitutively active Renilla luciferase vector to calculate relative luciferase activity for controlling transfection efficiency. In these experiments, little to no luciferase activity was detectable at 25 mM cisplatin due to cell toxicity, so we elected to treat the cotransfected HeLa cells with cisplatin concentrations flanking 10 mM that are in line with serum concentrations of cisplatin following clinical treatment (Himmelstein et al, 1981;Lanvers-Kaminsky et al, 2006;Rajkumar et al, 2016). Introducing rs10759932 into the TLR4 promoter led to a significant reduction in TLR4 promoter activity when treated with 6.25 mM or 12.5 mM of cisplatin for 24 hours relative to the WT TLR4 promoter control as analyzed by two-way ANOVA with multiple testing comparisons (Fig. 3A). ...
... Tubular damage can lead to a Fanconi-like syndrome, characterized by a loss of reabsorption capabilities and resulting in losses of sodium, potassium, magnesium, calcium, glucose, bicarbonate (renal tubular acidosis) and protein [206][207][208]. Cisplatin-associated nephrotoxicity can be reduced by adequate pre-hydration and by prolonged cisplatin infusion rates [209,210]. As cisplatin-induced hypomagnesaemia can increase nephrotoxic effects, magnesium supplementation during and immediately following cisplatin administration is recommended [211][212][213][214][215]. Ototoxicity is another major concern related to cisplatin-based chemotherapy. ...
Osteosarcoma is a challenging disease requiring multidisciplinary management in expert centers for optimal
outcome. There are no current international protocols or guidelines specific for pediatric and adolescent osteosarcoma.
The European Standard Clinical Practice (ESCP) project is a collaboration between ERN PaedCan and
SIOP Europe’s Clinical Trial Groups to develop approved clinical recommendations reflecting current best
practice. This manuscript is a summary of the full ESCP guideline for patients with osteosarcoma. The manuscript
provides evidence graded recommendations for diagnosis, staging, management, response evaluation and followup.
The methodology as defined in the standard operating procedures of the European Society for Medical
Oncology (ESMO) was applied. Experts of the Fight OsteoSarcoma Through European Research (FOSTER)
consortium contributed. In summary, the ESCP provides guidance on low-grade, but has a focus on high-grade
osteosarcoma. In high-grade osteosarcoma the outcomes of most recent trials for clinical subgroups (e.g., metastatic
vs. non-metastatic, resectable vs. non-resectable) are discussed, for treatment-naïve as well as for
recurrent/refractory disease. An overview of current evidence also highlights the need for further therapeutic
development as patients with primary metastatic or recurrent/refractory high-grade osteosarcoma still have a
poor prognosis. Intensified collaborative research is identified as a prerequisite to increase survival and to limit
long-term toxicities.
... C o n c o m i t a n t a d m i n i s t r a t i o n o f aminoglycosides, bleomycin and loop-inhibitor diuretics may increase the risk of cisplatin-related ototoxicity [63]. ...
Platinum’ derivates are antineoplastic agents widely adopted for their efficacy for the treatment of many pediatric cancers. The use of cisplatin has positively influenced the results of the cure of different childhood malignancies. However, cisplatin-based treatments are limited by the risk of severe and progressive toxicities, such as oto- or nephrotoxicity, that can be more serious in very young children expecially when high cumulative doses and/or radiotherapy is administered. A correct knowledge of the cisplatin’ pharmacological features might be of interest for clinicians in order to manage its potential toxicities. Based on the positive trend in the cure of children with cancer, it is crucial that all children receiving cisplatin-based chemotherapy have and appropriate and long-term follow-up to improve their quality of life.
... The audiogram assessors were blinded to patient characteristics including their treatment, such as platinum compound, platinum dose, or cranial irradiation. The assessors graded the severity of hearing loss using the Muenster criteria [23,24]. The Muenster criteria considers minimal hearing loss (Muenster grade 1: >10 to ≤20 dB) and allows the detection of early post-cisplatin hearing loss. ...
Background
Survival rates after childhood cancer now reach nearly 80% in developed countries. However, treatments that lead to survival and cure can cause serious adverse effects with lifelong negative impacts on survivor quality of life. Hearing impairment is a common adverse effect in children treated with cisplatin-based chemotherapy or cranial radiotherapy. Ototoxicity can extend from high-tone hearing impairment to involvement of speech frequencies. Hearing impairment can impede speech and language and neurocognitive development. Although treatment-related risk factors for hearing loss following childhood cancer treatment have been identified, the individual variability in toxicity of adverse effects after similar treatment between childhood cancer patients suggests a role for genetic susceptibility. Currently, 12 candidate gene approach studies have been performed to identify polymorphisms predisposing to platinum-induced ototoxicity in children being treated for cancer. However, results were inconsistent and most studies were underpowered and/or lacked replication.
Objective
We describe the design of the PanCareLIFE consortium’s work packages that address the genetic susceptibility of platinum-induced ototoxicity.
Methods
As a part of the PanCareLIFE study within the framework of the PanCare consortium, we addressed genetic susceptibility of treatment-induced ototoxicity during and after childhood cancer treatment in a large European cohort by a candidate gene approach and a genome-wide association screening.
Results
This study included 1124 survivors treated with cisplatin, carboplatin, or cranial radiotherapy for childhood cancer, resulting in the largest clinical European cohort assembled for this late effect to date. Within this large cohort we defined a group of 598 cisplatin-treated childhood cancer patients not confounded by cranial radiotherapy. The PanCareLIFE initiative provided, for the first time, a unique opportunity to confirm already identified determinants for hearing impairment during childhood cancer using a candidate gene approach and set up the first international genome-wide association study of cisplatin-induced direct ototoxicity in childhood cancer patients to identify novel allelic variants. Results will be validated in an independent replication cohort. Patient recruitment started in January 2015 and final inclusion was October 2017. We are currently performing the analyses and the first results are expected by the end of 2019 or the beginning of 2020.
Conclusions
Genetic factors identified as part of this pan-European project, PanCareLIFE, may contribute to future risk prediction models that can be incorporated in future clinical trials of platinum-based therapies for cancer and may help with the development of prevention strategies.
International Registered Report Identifier (IRRID)
DERR1-10.2196/11868
... Hearing impairment was evaluated using Münster grading system (Table 2) [11]. The Münster's grading system was used as it is considered as providing the highest sensitivity, specificity, and positive and negative predictive value compared to other ototoxicity classification systems [12,13]. In addition, the International Society of Pediatric Oncology (SIOP) Boston grading system was used as a secondary, independent validation [11,14]. ...
Cisplatin and carboplatin are effective antineoplastic agents. They are also considered to be potentially highly ototoxic. To date, no long-term follow-up data from well-documented cohorts with substantial numbers of childhood cancer survivors (CCS) with platinum-related hearing loss are available. Therefore, in this study, we studied the reversibility of ototoxicity from discontinuation of treatment onwards in a national cohort of platinum-treated survivors with hearing loss at the end of cancer treatment. Of the 168 CCS with follow-up audiograms, we longitudinally evaluated the course of hearing function in 61 CCS who showed hearing impairment at discontinuation of treatment according to the Münster criteria (>20 dB at ≥4–8 kHz). Survivors were treated with platinum (median total cumulative dose cisplatin: 480 mg/m² and median total cumulative dose carboplatin: 2520 mg/m²). Median follow-up time was 5.5 years (range: 1.0–28.8 years). The results showed that none of these survivors revealed improvement of hearing function even till 28.8 years after discontinuation of treatment (grade <2b during long-term follow-up). An increase in hearing loss with two or three Münster degrees was observed in five of 61 survivors after 1.6–19.6 years. Overall, this indicates that ototoxicity after platinum treatment may be irreversible and that longitudinal clinical audiological monitoring and care is required in long-term survivors of childhood cancer on a large scale.
... Hearing impairment was evaluated using Münster grading system (Table 2) [11]. The Münster's grading system was used as it is considered as providing the highest sensitivity, specificity, and positive and negative predictive value compared to other ototoxicity classification systems [12,13]. In addition, the International Society of Pediatric Oncology (SIOP) Boston grading system was used as a secondary, independent validation [11,14]. ...
... Young age at diagnosis and treatment has been identified as a patient related risk factor [6,7,8,12] . However cisplatin ototoxicity has also been reported in higher median age groups as it happened in our patients [6,7,13] . In this study, median age at the initial platinum treatment was 9 and 14 years for grade 1 and grades 2 -4 HFHL, respectively. ...
Objective: To evaluate hearing impairment in children with cancer who received platinum compounds. Materials and Methods: There were 149 children who had received platinum-containing chemotherapy (cisplatin, carboplatin or both), and 62 of them were eligible in temis of medical and audiologic data. These patients were divided Into three groups; cisplatin-only group (30 children), carboplatin-only group (15 children) and cisplatin + carboplatin group (17 children). Results: Sixty-two patients were analyzed. Audiological assessments included pure tone audiometry, transient oto-acoustic emissions and auditory brainstem response testing. Medical records were analyzed for patient characteristics, details of platinum containing treatment, co-administration of other ototoxic drugs as well as head/neck radiotherapy. The median age at treatment was 9.4 years, and M:F ratio was 0.8. Ototoxicity incidence was 56% in cisplatin-only group (n=30), and 47% in cisplatin+carboplatin group (n=1 7). No patients had ototoxicity in carboplatin-only group (n=1 5). Majority (84%) of patients having ototoxicity was older than 5 years of age at the initial cancer diagnosis. Of the patients with moderate-severe ototoxicity, 90% was female, and 56% was pubertaLfpostpubertal girls. Conclusion: The results of this study is in agreement with previous reports showing that ototoxicity is a potential side effect of cisplatin, but the standard dose of carboplatin-only usually does not cause ototoxicity. In this study, children older than 5 years of age and adolescents were also susceptible to develop platinum-induced ototoxicity. Primary tumor site was a risk factor for ototoxicity in this group of patients. Children with germ cell tumors, particularly the intracranial germ cell tumors tended to develop ototoxicity more frequently. Collaboration of pediatric oncology and audiology departments is mandatory in order to monitor platinum induced ototoxicity to avoid further insult and also to rehabilitate when mutilating toxicity occurs.
... Young age at diagnosis and treatment has been identified as a patient related risk factor [6,7,8,12] . However cisplatin ototoxicity has also been reported in higher median age groups as it happened in our patients [6,7,13] . In this study, median age at the initial platinum treatment was 9 and 14 years for grade 1 and grades 2 -4 HFHL, respectively. ...
Objective: To evaluate hearing impairment in children with cancer who received platinum compounds. Materials and Methods: There were 149 children who had received platinum-containing chemotherapy (cisplatin, carboplatin or both), and 62 of them were eligible in terms of medical and audiologic data. These patients were divided into three groups; cisplatin-only group (30 children), carboplatin-only group (15 children) and cisplatin + carboplatin group (17 children). Results: Sixty-two patients were analyzed. Audiological assessments included pure tone audiometry, transient oto-acoustic emissions and auditory brainstem response testing. Medical records were analyzed for patient characteristics, details of platinum containing treatment, co-administration of other ototoxic drugs as well as head/neck radiotherapy. The median age at treatment was 9.4 years, and M:F ratio was 0.8. Ototoxicity incidence was 56% in cisplatin-only group (n=30), and 47% in cisplatin+carboplatin group (n=17). No patients had ototoxicity in carboplatin-only group (n=15). Majority (84%) of patients having ototoxicity was older than 5 years of age at the initial cancer diagnosis. Of the patients with moderate-severe ototoxicity, 90% was female, and 56% was pubertal/postpubertal girls. Conclusion: The results of this study is in agreement with previous reports showing that ototoxicity is a potential side effect of cisplatin, but the standard dose of carboplatin-only usually does not cause ototoxicity. In this study, children older than 5 years of age and adolescents were also susceptible to develop platinum-induced ototoxicity. Primary tumor site was a risk factor for ototoxicity in this group of patients. Children with germ cell tumors, particularly the intracranial germ cell tumors tended to develop ototoxicity more frequently. Collaboration of pediatric oncology and audiology departments is mandatory in order to monitor platinum induced ototoxicity to avoid further insult and also to rehabilitate when mutilating toxicity occurs.
... In addition our data are in line with previous observations that T allele carriers of rs316019 were less prone to cisplatin-induced nephrotoxicity [31,32]. However, in our study nephrotoxicity was not ascertained along with ototoxicity, because the vigorous hydration regimens prescribed in the pediatric treatment protocols virtually eliminated cisplatin nephrotoxicity [39]. ...
Assuming that genetic variants of the SLC22A2 and SLC31A1 transporter affect patients' susceptibility to cisplatin-induced ototoxicity, we compared the distribution of 11 SLC22A2 variants and the SLC31A1 variant rs10981694 between patients with and without cisplatin-induced ototoxicity.
Genotyping was performed in 64 pediatric patients and significant findings were re-evaluated in 66 adults.
The SLC22A2 polymorphism rs316019 (c.808G>T; Ser270Ala) was significantly associated with protection from cisplatin-induced ototoxicity in the pediatric (p = 0.022) and the adult cohort (p = 0.048; both: Fisher's exact test). This result was confirmed by multiple logistic regression analysis accounting for age which was identified as a relevant factor for ototoxicity as well (rs316019: OR [G/T vs G/G] = 0.12, p = 0.009; age: OR [per year]: 0.84, p = 0.02).
These results identified rs316019 as potential pharmacogenomic marker for cisplatin-induced ototoxicity and point to a critical role of SLC22A2 for cisplatin transport in humans and its contribution to the organ specific side effects of this drug. Original submitted 17 September 2014; Revision submitted 19 December 2014.
... All 10 patients were diagnosed with cancer by pathological evaluation, including two with lung cancer, two with gastric cancer, four with gynecological malignancies, one with gall bladder cancer, and one with common bile duct cancer. Each patient received several (2)(3)(4)(5)(6) cycles of cisplatin and i.v. dose calculated from the body surface area of each patient. ...
Background and Objectives
To compare the effectiveness of monitoring cisplatin-induced ototoxicity in adult patients using extended high-frequency pure-tone audiometry (EHF-PTA) or distortion-product otoacoustic emission (DP-OAE) and to evaluate the concurrence of ototoxicity and nephrotoxicity in cisplatin-treated patients.
Subjects and Methods
EHF-PTA was measured at frequencies of 0.25, 0.5, 1, 2, 3, 4, 6, 8, 9, 11.2, 12.5, 14, 16, 18, and 20 kHz and DP-OAE at frequencies of 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8 kHz in cisplatin-treated patients (n=10). Baseline evaluations were made immediately before chemotherapy and additional tests were performed before each of six cycles of cisplatin treatment. Laboratory tests to monitor nephrotoxicity were included before every cycle of chemotherapy.
Results
Four of 10 patients showed threshold changes on EHF-PTA. Five of 10 patients showed reductions in DP-OAE, but one was a false-positive result. The results of EHF-PTA and DP-OAE were consistent in two patients. Only one patient displayed nephrotoxicity on laboratory tests after the third cycle.
Conclusions
In our study, the incidence rate of cisplatin-induced ototoxicity was 40% with EHF-PTA or DP-OAE. Although both EHF-PTA and DP-OAE showed the same sensitivity in detecting ototoxicity, they did not produce the same results in all patients. These two hearing tests could be used to complement one another. Clinicians should use both tests simultaneously in every cycle of chemotherapy to ensure the detection of ototoxicity.
... Two patients with cerebellar pontine angle tumors were deaf on one ear (cases 4 and 5) at the time of diagnosis. Five patients developed grade 3 hearing loss (<4 kHz >20 dB) according to the Muenster classification [28] requiring hearing aids, and one patient (case 4) a grade 4 hearing loss (<4 kHz of at least 80 dB) requiring a cochlea implant. ...
Atypical teratoid rhabdoid tumors (ATRTs) are recently defined highly aggressive embryonal central nervous system tumors with a poor prognosis and no definitive guidelines for treatment. We report on the importance of an initial correct diagnosis and disease-specific therapy on outcome in 22 consecutive patients and propose a new treatment strategy. From 1992 to 2012, nine patients initially diagnosed correctly as ATRT (cohort A, median age 24 months) were treated according to an intensive multimodal regimen (MUV-ATRT) consisting of three 9-week courses of a dose-dense regimen including doxorubicin, cyclophosphamide, vincristine, ifosfamide, cisplatin, etoposide, and methotrexate augmented with intrathecal therapy, followed by high-dose chemotherapy (HDCT) and completed with local radiotherapy. Thirteen patients were treated differently (cohort B, median age 30 months) most of whom according to protocols in use for their respective diagnoses. As of July 2013, 5-year overall survival (OS) and event-free survival (EFS) for all 22 consecutive patients was 56.3 ± 11.3% and 52.9 ± 11.0%, respectively. For MUV-ATRT regimen-treated patients (cohort A) 5-year OS was 100% and EFS was 88.9 ± 10.5%. For patients treated differently (cohort B) 5-year OS and EFS were 28.8 ± 13.1%. All nine MUV-ATRT regimen-treated patients are alive for a median of 76 months (range: 16–197), eight in first complete remission. Our results compare favorably to previously published data. The drug combination and sequence used in the proposed MUV-ATRT regimen appear to be efficacious in preventing early relapses also in young children with M1–M3 stage disease allowing postponement of radiotherapy until after HDCT.
... Maintaining high plasma levels of platinum drugs is an important factor in avoiding resistance and can be achieved by administering the drug in continuous infusions for up to 5 days [32]. However, side effects like oto-and nephro-toxicities are strongly correlated to plasma peak concentrations [33,34]. Because of the slow elimination of platinum complexes, residual amounts can be observed for weeks. ...
The history of inorganic pharmacology can be traced to antiquity with the medicinal use of inorganic salts, coordination and organometallic compounds. The clinical applications of metal-based drugs today are limited, but extremely significant. The most common metallo-therapeutic drugs are platinum, gold and bismuth compounds used in anticancer protocols and in the treatment of rheumatoid arthritis and gastric and duodenal ulcers, respectively. Platinum(II)-derivatives are the most widely prescribed anticancer agents, especially for polychemotherapy. Years of clinical experience have yielded detailed information about the quantitative structure-activity relationship (QSAR), pharmacokinetics and mechanisms of action of Pt-drugs. The accuracy of this information depends on precise measurement of Pt levels in body fluids, tissues, cells and DNA. Inductively Coupled Plasma - Mass Spectrometry (ICP-MS) offers higher sensitivity and accuracy than conventional analytical techniques, making it possible to detect trace concentrations of Pt-drugs at truly pharmacological concentrations. Increased knowledge about the action and fate of Pt-drugs may lead to important insights for the development of new metallo-pharmaceuticals with even wider applications.
... Cisplatin (Cis-diamminedichloroplatinum II) is a potent and efficient chemotherapy agent used in the treatment of several adult and childhood cancers [1][2][3]. Main toxicities include severe nausea and vomiting, myelossupression, nephrotoxicity, and ototoxicity; neurotoxicity is also observed, to a minor extent [4,5]. The use of cisplatin can permanently damage the hearing system, causing irreversible hearing loss [6,7]. ...
Background:
Cisplatin may cause permanent cochlear damage by changing cochlear frequency selectivity and can lead to irreversible sensorineural hearing loss. High-frequency audiometry (HFA) is able to assess hearing frequencies above 8,000 Hz; hence, it has been considered a high-quality method to monitor and diagnose early and asymptomatic signs of ototoxicity in patients receiving cisplatin.
Procedure:
Forty-two pediatric patients were evaluated for hearing loss induced by cisplatin utilizing HFA, and its diagnostic efficacy was compared to that of standard pure-tone audiometry and distortion-product otoacoustic emissions (DPOAEs). The patient population consisted of those who signed an informed consent form and had received cisplatin chemotherapy between 1991 and 2008 at the Hospital de Clínicas de Porto Alegre Pediatric Unit, Brazil.
Results:
Forty-two patients were evaluated. The median age at study assessment was 14.5 years (range 4-37 years). Hearing loss was detected in 24 patients (57%) at conventional frequencies. Alterations of DPOAEs were found in 64% of evaluated patients and hearing loss was observed in 36 patients (86%) when high-frequency test was added. The mean cisplatin dose was significantly higher (P = 0.046) for patients with hearing impairment at conventional frequencies.
Conclusion:
The results suggest that HFA is more effective than pure-tone audiometry and DPOAEs in detecting hearing loss, particularly at higher frequencies. It may be a useful tool for testing new otoprotective agents, beside serving as an early diagnostic method for detecting hearing impairment.
... Each agent has a unique toxicity profile and can only be administered intravenously (IV). Cisplatin is associated with mild myelosuppression, and produces significant and potentially irreversible and cumulative nephrotoxicity, ototoxicity, and neurotoxicity [6][7][8][9]. The dose-limiting toxicity of carboplatin is myelosuppression, primarily thrombocytopenia. ...
Satraplatin is an orally bioavailable platinum analog with preclinical activity in cisplatin resistant models and clinical activity in adults with refractory cancers. The cerebrospinal fluid (CSF) penetration of cisplatin and carboplatin in non-human primates (NHP) is limited (3.7 and 2.6%, respectively). We evaluated the plasma and CSF pharmacokinetics (PK) of satraplatin after an intravenous (IV) dose in NHP.
Satraplatin (120 mg/m(2)) was administered as 1 h IV infusion in DMSO (5%) and normal saline to 5 NHP. Serial blood and CSF samples were obtained over 48 h. Plasma ultrafiltrate (UF) was immediately prepared by centrifugation. Platinum was quantified in plasma UF and CSF using a validated atomic absorption spectroscopy assay with lower limit of quantification (LLQ) of 0.025 μM in UF and 0.006 μM after concentration in CSF. Pharmacokinetic parameters were estimated using non-compartmental analyses. CSF penetration was calculated from the CSF AUC(0-48h) : plasma UF AUC(0-48h).
Satraplatin was well tolerated. Median (range) PK parameters in plasma UF were: maximum concentration (C (max)) 8.3 μM (5.7-10.6), area under the curve (AUC(0-48h)) 29.2 μM h (22.6-33.2), clearance 0.36 l/h/kg (0.31-0.37), and t (1/2) 18.8 h (13.4-25). Satraplatin was detected in the CSF of all NHP. Median (range) PK parameters in CSF were: C (max) 0.07 μM (0.02-0.12), AUC(0-48h) 1.2 μM h (0.49-2.43). The median (range) CSF penetration of satraplatin was 4.3% (2.2-7.4).
Satraplatin penetration into CSF is similar to that of carboplatin and cisplatin, despite its greater lipophilicity. The development of a phase I trial of satraplatin for refractory childhood solid tumors including brain tumors is in progress.
Pediatric cancers are relatively rare diseases when considering all types of cancer. Platinum-based chemotherapeutic agents are potent agents against a variety of pediatric malignancies. An important adverse effect of platinum-based agents is the occurrence of hearing loss. This hearing loss can pose a challenge to detect especially if the child is in his early of life. It will also significantly affect the child development of social, pedagogical, and personal dimensions. It is integral to identify incidence of platinum-based ototoxicity and risk factors that increase the likelihood of developing hearing loss in cancer children. We performed a retrospective chart review of 123 pediatric patients who had completed cisplatin and carboplatin therapy for a variety of malignancies. Patients were diagnosed at Princess Nourah Oncology Centre between January 2011 and December 2016, were less than 14 years old at diagnosis. Audiograms were scored using the International Society of Pediatric Oncology (SIOP) Boston Scale (0–4), a validated grading system for cisplatin-related hearing loss. Ototoxicity was reported in 16 patients out of 123 with a rate of 13%. The incidence of ototoxicity was highest in CNS tumors such as medulloblastoma (37.5%) and optic glioma (25%). Males were at greater risk for developing hearing loss than females. Cumulative cisplatin dose and addition radiation therapy were also identified as risk factors for development of ototoxicity (P = 0.008). Nature and location of cancer, gender, cumulative dose, and addition of radiation therapy are important clinical biomarkers of cisplatin ototoxicity.
The zebrafish has emerged as a robust animal model for preclinical anticancer drug screening and as an important tool for personalized medicine. Zebrafish produce large clutches of offspring, have been genetically manipulated to be optically transparent, and undergo rapid development resulting in functional organogenesis by 48 h postfertilization. These characteristics, along with the relatively cost-effective housing and husbandry, and live in vivo cell tracking, make the zebrafish an ideal platform for human cell xenotransplantation. The larval zebrafish has proven to be an effective model organism to study cancer progression and migration, as well as stem cell colony expansion. Candidate drug and moderate throughput unbiased drug screens are feasible. More recently, an adult zebrafish xenotransplantation model has demonstrated advantages in recapitulating the route and timing of drug administration in patients, providing a complementary preclinical platform. This chapter will discuss zebrafish xenotransplantation approaches used in cancer and stem cell research.
Ototoxicity (i.e., toxic damage to the ear) is a side effect of many drugs that are used in cancer treatment, including anticancer drugs and co-medication such as aminoglycoside antibiotics, glycopeptide antibiotics, macrolides, nonsteroidal anti-inflammatory drugs, loop diuretics, ototopical medication, and cranial irradiation, among others. Aminoglycosides and platinum-based chemotherapy agents are of greatest concern as they often lead to permanent ototoxicity. Ototoxic drugs can have severe short- and long-term effects on patients’ hearing and balance systems, such as impaired speech perception, which impedes language development, psychosocial development, educational attainment, employment prospects, and quality of life. Oncology professionals must balance the benefits of any planned drug treatment against these potential effects. Susceptibility to ototoxic effects is defined by genetic and non-genetic risk factors, such as age or other concomitant ototoxic treatment. Various subjective and objective audiological tests can be used to identify ototoxicity in individual patients, such as pure-tone or play audiometry alongside otoacoustic emissions (OAEs) and auditory brainstem response (ABR) testing. The pros and cons of diagnostic audiological practice, treatment options, and current research into otoprotective medication are discussed in this chapter.
Sarcomas of bone are a heterogeneous group of rare malignancies with unclear pathogenesis in the majority of cases. Evaluation is optimally performed with plan radiographs and magnetic resonance imaging (MRI) of the primary tumor and chest computed tomography (CT) to evaluate the most common site of metastatic disease, the lungs. Whole-body imaging is used to evaluate for other sites of skeletal involvement or metastasis and both bone scan and positron emission tomography (PET) are utilized depending on tumor type. A well-planned biopsy provides tissue for pathologic review, particularly grading, and molecular genetics. Prognosis is most heavily affected by disease burden: presence of metastatic disease and tumor size. Prognosis is also dependent on grade, response to systemic therapy in the case of osteosarcoma and Ewing sarcoma, and the ability to resect the primary tumor with negative margins. Staging takes the most critical of these factors into account with the American Joint Committee on Cancer system stratifying by grade, size, and presence and type of metastatic lesions. The Musculoskeletal Tumor Society surgical grading system distinguishes tumors based on grade, intra- or extra-compartmental involvement, and metastatic disease. The primary recommended treatment for nearly all bone sarcomas is wide surgical resection, which can be accomplished with limb-sparing techniques in 70-90% of patients. Reconstruction now involves many tissue and endoprosthetic options which can be tailored to patients’ needs. Radiation therapy can be utilized for local control of Ewing sarcomas, but rarely for other types bone sarcomas. Systemic therapy is vitally important for osteosarcoma and Ewing sarcoma, but less effective for chondrosarcoma. Future research into the genomic alterations in sarcomas and the development of targeted therapy based on those results show early promise.
Introduction: Platinum-derived drugs are commonly used for the treatment of solid tumors. The differences in chemical structures of these molecules lead to different pharmacological properties, in terms of indication, efficacy, and toxicity. Their pharmacokinetics (PK) differ according to their respective renal elimination and have led to many studies investigating their dose optimization.
Area covered: This review attempts to summarize and compare PK and pharmacodynamics of cisplatin, carboplatin, and oxaliplatin, with an emphasis on differences of dose calculations and opportunities for therapeutic drug monitoring (TDM) in various patient populations.
Expert opinion: Although cisplatin and carboplatin can be considered as analogs since they share the same DNA interacting properties, the slower hydrolysis of the latter results in a better safety profile. Carboplatin is the only drug in oncology to be administrated according to a target area under the curve of concentration versus time, considering that its PK variability is almost fully explained by renal function, not by body size. This enables individual dosing based on predicted carboplatin clearance (along with patients renal characteristics) or on actual clearance with TDM, especially in a high-dose protocol.
Dose-limiting toxicities for cisplatin administration, including ototoxicity and nephrotoxicity, impact the clinical utility of this effective chemotherapy agent and lead to lifelong complications, particularly in pediatric cancer survivors. Using a two-pronged drug screen employing the zebrafish lateral line as an in vivo readout for ototoxicity and kidney cell-based nephrotoxicity assay, we screened 1280 compounds and identified 22 that were both oto- and nephroprotective. Of these, dopamine and L-mimosine, a plant-based amino acid active in the dopamine pathway, were further investigated. Dopamine and L-mimosine protected the hair cells in the zebrafish otic vesicle from cisplatin-induced damage and preserved zebrafish larval glomerular filtration. Importantly, these compounds did not abrogate the cytotoxic effects of cisplatin on human cancer cells. This study provides insights into the mechanisms underlying cisplatin-induced oto- and nephrotoxicity and compelling preclinical evidence for the potential utility of dopamine and L-mimosine in the safer administration of cisplatin.
Background:
Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. This review is the third update of a previously published Cochrane Review.
Objectives:
To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life.
Search methods:
We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library 14 November 2019), MEDLINE (PubMed) (1945 to 14 November 2019) and Embase (Ovid) (1980 to 14 November 2019). In addition, we handsearched reference lists of relevant articles and we assessed the conference proceedings of the International Society for Paediatric Oncology (2009 up to and including 2019) and the American Society of Pediatric Hematology/Oncology (2014 up to and including 2019). We scanned ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; apps.who.int/trialsearch) for ongoing trials (both searched on 4 November 2019).
Selection criteria:
Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups.
Data collection and analysis:
Two review authors independently performed the study selection, 'Risk of bias' assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.
Main results:
We identified one RCT and no CCTs; in this update no additional eligible studies were identified. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one-hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days one to five of the cycle, but it is unclear if the infusion duration was a total of five days. Risk of bias was present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (risk ratio (RR) 1.39, 95% confidence interval (CI) 0.47 to 4.13, low-quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity, we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12, 95% CI 0.07 to 17.31, low-quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues.
Authors' conclusions:
Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one-hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high-quality research is needed.
Background:
Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. This review is the second update of a previously published Cochrane review.
Objectives:
To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life.
Search methods:
We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library 15 March 2018), MEDLINE (PubMed) (1945 to 15 March 2018) and Embase (Ovid) (1980 to 15 March 2018). In addition, we handsearched reference lists of relevant articles and we assessed the conference proceedings of the International Society for Paediatric Oncology (2009 up to and including 2017) and the American Society of Pediatric Hematology/Oncology (2014 up to and including 2017). We scanned ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; apps.who.int/trialsearch) for ongoing trials (searched on 12 March 2018 and 13 March 2018 respectively).
Selection criteria:
Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups.
Data collection and analysis:
Two review authors independently performed the study selection, 'Risk of bias' assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.
Main results:
We identified one RCT and no CCTs; in this update no additional studies were identified. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one-hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days one to five of the cycle, but it is unclear if the infusion duration was a total of five days. Risk of bias was present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (risk ratio (RR) 1.39, 95% confidence interval (CI) 0.47 to 4.13, low-quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity, we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12, 95% CI 0.07 to 17.31, low-quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues.
Authors' conclusions:
Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one-hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high-quality research is needed.
A new calibration strategy for elemental bioimaging based on on-line isotope dilution analysis (IDA) and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was developed and applied for the quantification of platinum in rat kidney tissues. A dry 194Pt spike aerosol was added in a post-cell setup, and the natural 194Pt/195Pt isotope ratio of the sample aerosol from laser ablation was changed accordingly. Spike mass flow determination was carried out based on reversed IDA using a reference standard. Quantitative data obtained by the new approach correlated well with those obtained by external calibration when analyzing parallel tissue slices of rat kidney from Cisplatin perfusion studies. The novel quantification approach is traceable to SI units, as IDA is an definitive method. Signal drifts are compensated as the second isotope acts as an internal standard.
The aim was to assess the activity of cisplatin (CDDP) in Ewing sarcoma (ES). The study consisted of front-line window therapy with CDDP 120 mg/sqm every 3 weeks for two courses in children and young adults with primary disseminated ES. Response was assessed using the Response Evaluation Criteria in Solid Tumours criteria, and Simon's two-stage design was applied. Twelve consecutive patients were enrolled in stage 1. Only one objective response was observed. Since the target response rate was not achieved, accrual was stopped and CDDP as a single agent in ES was judged unworthy of further assessment.
Background:
Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. This review is an update of a previously published Cochrane review.
Objectives:
To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life.
Search methods:
We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2016, Issue 4), MEDLINE (PubMed) (1945 to 18 May 2016) and EMBASE (Ovid) (1980 to 18 May 2016). In addition, we handsearched reference lists of relevant articles and we assessed the conference proceedings of the International Society for Paediatric Oncology (2009 up to and including 2015) and the American Society of Pediatric Hematology/Oncology (2014 and 2015). We scanned ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; apps.who.int/trialsearch) for ongoing trials (searched on 20 May 2016 and 24 May 2016 respectively).
Selection criteria:
Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups.
Data collection and analysis:
Two review authors independently performed the study selection, risk of bias assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.
Main results:
We identified one RCT and no CCTs; in this update no additional studies were identified. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one-hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days 1 to 5 of the cycle but it is unclear if the infusion duration was a total of 5 days. Methodological limitations were present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (risk ratio (RR) 1.39, 95% confidence interval (CI) 0.47 to 4.13, low quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12, 95% CI 0.07 to 17.31, low quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues.
Authors' conclusions:
Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one-hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high quality research is needed.
The antineoplastic agent’s cisplatin and carboplatin are widely used as they are highly effective. Unfortunately, ototoxicity is a frequently encountered side effect of platinum-based chemotherapy. Clinically, patients generally develop a progressive, bilateral, and irreversible sensorineural hearing loss. With rising cancer survival rates, a greater proportion of patients are living with the side effects of their chemotherapy treatments. Consequently, the quality of life of cancer survivors has now become a major concern for clinicians. Various classification systems are currently available to grade side effects and provide a guideline for subsequent treatments. An extensive review of the literature revealed that a variety of criteria are used worldwide for grading platinum-induced hearing loss in children and adults, including the National Cancer Institute criteria, Brock’s grading system, the American Speech-Hearing-Language Association criteria, the World Health Organization criteria, the Pediatric Oncology Group criteria, and the Muenster classification. Less commonly used criteria include the Chang classification, the Functional Hearing Loss scale, the HIT system (German Hirntumor study grading system), and most recently, the International Society of Pediatric Oncology Boston ototoxicity grading scale. The objective of this review is to evaluate the commonly used ototoxicity criteria and discuss their benefits and limitations.
Though some heavy metals, such as Pt, are considered toxic to humans, their toxic effects can be positively leveraged to treat diseases such as cancer. The use of Pt-based chemotherapies is, unfortunately, linked to severe side effects some occurring many years after treatment (late effects). Through the lens of geochemistry, it is possible to assess these late effects and associated biochemical interactions with other metals. This approach also presents a potential intervention/detection strategy for early detection and possible prevention of late effects. © 2013 Springer Science+Business Media Dordrecht. All rights reserved.
Decreasing oxidative damage with the antioxidant agent N-acetylcysteine (NAC) can block the side effects of chemotherapy, but may diminish anti-tumor efficacy. We tested the potential for interactions of high dose NAC against a minimally effective cisplatin chemotherapy regimen in rat models of human pediatric cancers. Athymic rats received subcutaneous implantation of human SK-N-AS neuroblastoma cells or intra-cerebellar implantation of human D283-MED medulloblastoma cells. Rats were untreated or treated with cisplatin (3 or 4 mg/kg IV) with or without NAC (1,000 mg/kg IV) 30 min before or 4 h after cisplatin treatment. Blood urea nitrogen (BUN) and tumor volumes were measured. Cisplatin decreased the growth of SK-N-AS neuroblastoma subcutaneous tumors from 17.7 ± 4.9 to 6.4 ± 2.5 fold over baseline 2 weeks after treatment (P < 0.001). Pretreatment with NAC decreased cisplatin efficacy, while 4 h delayed NAC did not significantly affect cisplatin anti-tumor effects (relative tumor volume 6.8 ± 2.0 fold baseline, P < 0.001). In D283-MED medulloblastoma brain tumors, cisplatin decreased final tumor volume to 3.9 ± 2.3 mm(3) compared to untreated tumor volume of 45.9 ± 38.7 (P = 0.008). Delayed NAC did not significantly alter cisplatin efficacy (tumor volume 6.8 ± 8.1 mm(3), P = 0.014 versus control). Cisplatin was minimally nephrotoxic in these models. NAC decreased cisplatin-induced elevations in BUN (P < 0.02). NAC chemoprotection did not alter cisplatin therapy, if delayed until 4 h after chemotherapy. These data support a Phase I/II clinical trial of delayed NAC to reduce ototoxicity in children with localized pediatric cancers.
Background:
Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied.
Objectives:
To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life.
Search methods:
We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 12), MEDLINE (PubMed) (1945 to 4 December 2013) and EMBASE (Ovid) (1980 to 4 December 2013). In addition, we handsearched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (2009 to 2013). We scanned ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (http://www.who.int/ictrp/en/) for ongoing trials (both searched on 13 December 2013).
Selection criteria:
Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups.
Data collection and analysis:
Two review authors independently performed the study selection, risk of bias assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.
Main results:
We identified one RCT and no CCTs. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days 1 to 5 of the cycle but it is unclear if the infusion duration was a total of 5 days. Methodological limitations were present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (RR 1.39; 95% CI 0.47 to 4.13, low quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12; 95% CI 0.07 to 17.31, low quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues.
Authors' conclusions:
Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high quality research is needed.
This project was supported by a grant from the Centers for Disease Control and Prevention, U57/CCU220685‐01 (S. Sheinfeld Gorin, PI). The funder played no role in the design or conduct of the study, collection, management, analysis, and interpretation of the data, the preparation, review, nor approval of the manuscript. The authors thank Edythe Hanus, Dr.P.H. for her generous contributions to the genesis of the paper and to the text. They appreciate the contributions of Andrew Mallon, Samantha Parker, and Ankita Sharma to data collection for the paper. There are no conflicts of interest for either of the authors of the study.
Cimetidine has been studied as an additive in cancer chemotherapy. It is claimed to reduce the side effects of Cisplatin. This study focuses on possible interactions between Cisplatin and cimetidine on the molecular level. Due to the fact that cimetidine is metabolized in the liver, interactions between its metabolites and Cisplatin are also investigated. By means of LC/ESI-MS, Cisplatin-cimetidine adducts were detected. In a second step, the metabolism of cimetidine was simulated by electrochemical oxidation. These results were compared with microsomal incubations of cimetidine using rat and human liver cell microsomes. Because the two methods showed a correlation, the electrochemical approach was further used to investigate Cisplatin's interactions with metabolites of cimetidine. However, notable interactions that might take place in the human body could neither be observed for pure cimetidine nor for its metabolites. Finally, the impact of cimetidine on Cisplatin-protein interactions were studied using the model protein β-lactoglobulin A. In the presence of cimetidine, the affinity of Cisplatin towards the model protein appears to be increased.
Platinum-compound chemotherapy is known to have ototoxic side-effects. However, there is a paucity of literature examining hearing function prospectively and longitudinally in cohorts containing paediatric and adult patients treated within the same cisplatin- or carboplatin-containing treatment trial protocols. In Germany, Austria and Switzerland, late effects of treatment for osteosarcoma and soft tissue sarcoma have been prospectively and longitudinally registered by the Late Effects Surveillance System since 1998. The aim of this study was to analyse cisplatin- and carboplatin-induced ototoxity in a group of 129 osteosarcoma and soft tissue sarcoma patients treated within the COSS-96, CWS-96 and CWS-2002P treatment trials. The cohort consisted of 112 children and 17 adults. The median age at diagnosis was 13.56 (IQR, 10.26-16.27) years. Follow-up was 6.97 (IQR, 0.87-15.63) months. Hearing function was examined by audiometry before and after platinum treatment. A total of 108 patients were treated with cisplatin with a median cumulative dose of 360 mg/m(2). Thirteen patients received carboplatin with a median cumulative dose of 1500 mg/m(2) and 8 patients were treated with both platinum compounds (median cisplatin dose, 240 mg/m(2); IQR, 240-360 mg/m(2) and median carboplatin dose: 1200 mg/m(2); IQR, 600-3000 mg/m(2)). Following cessation of therapy, 47.3% of the patients demonstrated a hearing impairment, namely 55 children (49.1%) and 6 adults (42.1%). Out of thirteen children treated with carboplatin with a cumulative dose of 1500 mg/m(2), six revealed a significant hearing impairment. Although ototoxicity caused by platinum compounds is considered irreversible, we identified hearing improvements over time in 11 children (9.8%) and 3 adults (17.6%). None of these patients received irradiation to the head. We conclude that hearing loss is frequent in children treated with protocols containing platinum compounds and recommend prospective testing via audiometry.
Background. This study was conducted to investigate the clinical characteristics and treatment results of osteosarcoma in pediatric patients during the past 30 years. Trends in survival rates and long-term toxicity were analyzed. Procedure. 130 pediatric patients under the age of 20 years with primary localized or metastatic high-grade osteosarcoma were analyzed regarding demographic, treatment-related variables, long-term toxicity, and survival data. Results. Comparison of the different time periods of treatment showed that the 5-year OS improved from 58.6% for children diagnosed during 1979-1983 to 78.6% for those diagnosed during 2003-2008 (P = 0.13). Interestingly, the basic treatment agents including cisplatin, doxorubicin, and methotrexate remained the same. Treatment reduction due to acute toxicity was less frequent in patients treated in the last era (7.1% versus 24.1% in patients treated in 1979-1983; P = 0.04). Furthermore, late cardiac effects and secondary malignancies can become evident many years after treatment. Conclusion. We elucidate the prevalence of toxicity to therapy of patients with osteosarcoma over the past 30 years. The overall improvement in survival may in part be attributed to improved supportive care allowing regimens to be administered to best advantage with higher tolerance of chemotherapy and therefore less chemotherapy-related toxicity.
Background
Cisplatin is commonly used as a chemotherapeutic agent in the treatment of solid tumors. Ototoxicity is an important side-effect. Melanin in the inner ear either plays an otoprotective role or has a negative influence on hearing. The concentration of cochlear melanin correlates with its concentration in the iris.
Patients and methods
We retrospectively examined 65 children (37 males, 28 females, average age 7.5 years) treated with cisplatin at the University Clinic of Muenster, Germany. We checked whether their eye color could be inferred from the prevalence and extent of cisplatin-induced hearing loss.
Results
We found a hearing loss of >20 dB in 29 light-eyed and in 21 dark-eyed patients. Seven light-eyed and eight dark-eyed patients did not suffer from hearing impairment. Using the χ2-test on these four parameters, we found no significant connection between iris pigmentation and the prevalence or extent of hearing loss, although light-eyed children (80.6%) suffered more from hearing loss than dark-eyed children (72.4%). After the end of therapy with cisplatin, the prevalence of hearing loss was 83.3% in children up to 6 years and 71.4% in children older than 6 years. The average cumulative dose of cisplatin was 372 mg/m2 of body surface in children with hearing loss, compared to 390 mg/m2 in children without hearing loss.
Conclusion
We found no significant correlation between iris pigmentation (eye color) and hearing loss. Cisplatin-induced hearing loss occurs frequently and requires repeated monitoring.
Platinum compounds are very effective drugs for the treatment of childhood malignancies and their use has contributed to an
increase in the long-term survival of children with cancer. Unfortunately the risk of severe disabling effects such as nephro-
and ototoxicity is well known among children receiving platinum-based chemotherapy as part of their treatment. Data from literature
suggest that very young children are more prone to develop cochlear damage especially when cranial radiotherapy or high cumulative
doses are administered.
In view of the increasing number of children safely cured of their tumors it is fundamental that children treated with platinum
drugs receive careful, continued, long-term followup.
KeywordsCisplatin–Carboplatin–Oxaliplatin–BBR3464–Ototoxicity–Children
Nanocarriers potentially reduce or prevent chemotherapy-induced side effects, facilitating the translation of nanocarrier formulation into the clinic. To date, organ-specific toxicity by nanocarriers remains to be clarified. Here, we studied the potential of polymeric micelle nanocarriers to prevent the ototoxicity, which is a common side effect of high-dose cisplatin (CDDP) therapy. In this study, we evaluated the ototoxicity of CDDP-incorporating polymeric micelles (NC-6004) in guinea pigs in comparison with that of cisplatin. Their auditory brainstem responses (ABRs) to 2, 6, 12, 20, and 30kHz sound stimulation were measured before and 5 days after the drug administration. Groups treated with NC-6004 showed no apparent ABR threshold shifts, whereas groups treated with CDDP showed dose-dependent threshold shifts particularly at the higher frequencies. Consistent with the ABR results, groups treated with NC-6004 showed excellent hair-cell preservation, whereas groups treated with CDDP exhibited significant hair-cell loss (P<0.05). Synchrotron radiation-induced X-ray fluorescence spectrometry imaging demonstrated that the platinum distribution and concentration in the organ of Corti were significantly reduced (P<0.01) in guinea pigs treated with NC-6004 compared with guinea pigs treated with CDDP. These findings indicate that micellization of CDDP reduces its ototoxicity by circumventing the vulnerable cells in the inner ear.
HSP90 plays a central role in stabilizing client proteins involved in malignant processes. SNX-2112 is an orally administered potent HSP90 inhibitor that has demonstrated pre-clinical anti-tumor activity in adult malignancies. As many childhood tumors depend upon HSP90 client proteins, we sought to test the pre-clinical efficacy of SNX-2112 in a panel of pediatric cancer cell lines both as a single-agent and in combination with cisplatin (CP).
Eight cell lines (from osteosarcoma, neuroblastoma, hepatoblastoma, and lymphoma) were studied. Short- and long-term effects of SNX-2112 were assessed by MTT and clonogenic assays. Cell cycling was measured using flow cytometry. Status of HSC70, HSP72, AKT1, C-Raf, and PARP was assessed by immunoblotting. Efficacy of SNX-2112 in combination with CP was assessed using median-effect analysis.
Cell lines studied demonstrated sensitivity to SNX-2112 with IC(50) values ranging from 10-100 nM. Low dose treatments (12 nM) resulted in a cytostatic response with a minimal increase in sub-G1 content. A higher dose (70 nM) exhibited a more prolonged inhibition and larger sub-G1 accumulation. Observed levels of AKT1 and C-Raf were markedly reduced over time along with an increase in PARP cleavage. In concurrently administered combination treatments, SNX-2112 and CP synergistically inhibited cell growth.
SNX-2112 showed marked single-agent activity in pediatric cancer cell lines with downstream effects on HSP90 client proteins. The combination of SNX-2112 and CP showed synergistic activity in two cell lines tested. Further studies of HSP90 inhibitors such as SNX-2112 as a single agent or in combination with chemotherapy are warranted in pediatric cancer.
Despite high survival rates, many survivors of hepatoblastoma develop late effects including ototoxicity and cardiomyopathy. With the goal of minimizing long-term toxicities, our institution treated hepatoblastoma with continuous infusion of doxorubicin and cisplatinum (PLADO), rather than short infusion or bolus dosing as used in other treatment protocols. This retrospective cohort study includes consecutive patients diagnosed between 1985 and 2007. Patients were scheduled for treatment with 6 cycles of continuous infusion of PLADO with resection after the third or fourth cycle. Audiograms and echocardiograms were obtained at baseline, after every 2 chemotherapy cycles and yearly after the completion of therapy. Fifty-five patients were treated (34 localized; 21 metastatic). Fifty-one patients received at least 1 cycle of PLADO. Median follow-up was 7.0 years (range, 0.11 to 17.8 y). Event-free and overall survival for these 51 patients were 72.2% (standard error 6.3%) and 75.6% (standard error 6.2%) respectively. Of the 38 survivors treated with cisplatin who had an audiogram during follow-up, 4 (11%) demonstrated severe (Brock grade 3/4) and 13 (34%) mild (Brock grade 1/2) hearing loss. At a median of 10.0 years (range, 5.0 to 13.0 y) after therapy, 2 of 41 (5%) patients who were still alive had evidence of cardiac dysfunction. Overall, continuous infusion of PLADO therapy resulted in survival rates consistent with those observed in intergroup studies, but rates of chronic cardiac and ototoxicity did not differ sufficiently from those observed after shorter infusion of PLADO therapy to warrant the use of continuous infusions.
The objective is to describe progressive changes in hearing and cochlear function in children and adolescents treated with platinum-based chemotherapy and to begin preliminary evaluation of the feasibility of extended high-frequency audiometry and distortion product otoacoustic emissions for ototoxicity monitoring in children.
Baseline and serial measurement of conventional pure-tone audiometry (0.5 to 8 kHz) and evoked distortion product otoacoustic emissions (DPOAEs) were conducted for 32 patients age 8 months to 20 years who were treated with cisplatin and/or carboplatin chemotherapy. Seventeen children also had baseline and serial measurement of extended high-frequency (EHF) audiometry (9 to 16 kHz). Audiologic data were analyzed to determine the incidence of ototoxicity using the American Speech-Language-Hearing Association criteria, and the relationships between the different measures of ototoxicity.
Of the 32 children, 20 (62.5%) acquired bilateral ototoxicity in the conventional frequency range during chemotherapy treatment, and 26 (81.3%) had bilateral decreases in DPOAE amplitudes and dynamic range. Of the 17 children with EHF audiometry results, 16 (94.1%) had bilateral ototoxicity in the EHF range. Pilot data suggest that EHF thresholds and DPOAEs show ototoxic changes before hearing loss is detected by conventional audiometry.
EHF audiometry and DPOAEs have the potential to reveal earlier changes in auditory function than conventional frequency audiometry during platinum chemotherapy in children.
Neuroblastoma is the most common extracranial solid tumour in childhood. It accounts for 15% of all paediatric oncology deaths. In the last few decades, improvement in treatment outcome for high-risk patients has not occurred, with an overall survival rate <30-40%. Many reasons may account for such a low survival rate. The aim of this review is to evaluate whether pharmacogenetic factors can explain treatment failure in neuroblastoma.
A literature search based on PubMed's database Medical Subject Headings (MeSH) was performed to retrieve all pertinent publications on current treatment options and new classes of drugs under investigation. One hundred and fifty-eight articles wer reviewed, and relevant data were extracted and summarised.
Few of the large number of polymorphisms identified thus far showed an effect on pharmacokinetics that could be considered clinically relevant. Despite their clinical relevance, none of the single nucleotide polymorphisms (SNPs) investigated can explain treatment failure. These findings seem to reflect the clinical context in which anti-tumour drugs are used, i.e. in combination with multimodal therapy. In addition, many pharmacogenetic studies did not assess (differences in) drug exposure, which could contribute to explaining pharmacogenetic associations. Furthermore, it remains unclear whether the significant activity of new drugs on different neuroblastoma cell lines translates into clinical efficacy, irrespective of resistance or myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN) amplification. Elucidation of the clinical role of pharmacogenetic factors in the treatment of neuroblastoma demands an integrated pharmacokinetic-pharmacodynamic approach to the analysis of treatment response data.
Cisplatin, a platinum-based chemotherapeutic drug, has severe dose-limiting side effects which include ototoxicity. In this study, we investigate the ototoxic effects of cisplatin in relation to the concentration of platinum in whole blood, plasma and perilymph. Guinea pigs were equipped with a permanent round window electrode for electrocochleography and treated with cisplatin on a daily basis (1.5mg/kg/day ip) until a 40dB shift of the compound action potential (CAP) threshold (3 microV isoresponse criterion) at 8kHz stimulation occurred. When this criterion was reached blood and perilymph was sampled and the total platinum concentration was measured. The number of days necessary to reach criterion threshold shift varied from 6 to 22. At this time, platinum concentration was found to be slightly more than 10 times higher in whole blood and plasma than in perilymph. While a significant correlation became apparent between threshold shift and total platinum concentration in whole blood and plasma, this was not the case for threshold shift and platinum concentration in perilymph.
The study was designed to investigate possible relationships between tumour response and exposure to cisplatin (area under the curve of unbound cisplatin in plasma, AUC) and DNA-adduct formation in leucocytes (WBC) in patients with solid tumours. Patients were treated with six weekly courses of cisplatin at a dose of 70 or 80 mg m-2. The AUC was determined during the first course and DNA-adduct levels in WBC during all courses at baseline, 1 h (A(max)) and 15 h after a 3 h infusion of cisplatin. The area under the DNA-adduct-time curve (AUA) was calculated. The tumour response was determined after six courses. Forty-five evaluable patients received 237 courses of cisplatin. Sixteen patients with head and neck cancer received a dose of 80 mg m-2 and 29 with various other tumour types received 70 mg m-2 plus daily 50 mg oral etoposide. There were 20 responders (partial and complete) and 25 non-responders (stable and progressive disease). The AUC was highly variable (mean +/- s.d. = 2.48 +/- 0.51 micrograms h-1 ml-1; range 1.10-3.82) and was closely correlated with the AUA (r = 0.78, P < 0.0001) and A(max) (r = 0.73, P < 0.0001). The AUC, AUA and A(max) were significantly higher in responders than in non-responders in the total population (P < 0.0001) and in the two subgroups treated at 70 or 80 mg m-2. In logistic regression analysis AUC, AUA and A(max) were important predictors of response. The magnitude of exposure to cisplatin is, through DNA-adduct formation, the major determinant of the response rate in this population. Hence, individualised dosing of cisplatin using AUC or DNA-adducts should lead to increased response rates.
The purpose of the study was to evaluate the incidence, risk factors and changes in severity with time of cisplatin nephrotoxicity in children. A total of 35 children underwent measurement of glomerular filtration rate (GFR) and tubular function after completion of cisplatin chemotherapy. No child received ifosfamide. A clinically relevant 'nephrotoxicity score' was derived from GFR and serum magnesium. Follow-up studies were performed in 16 children at 1 year and in 15 at 2 years after cisplatin. Considerable interpatient variability in nephrotoxicity was observed. Treatment was modified in three patients because of nephrotoxicity. GFR was low in 18 out of 31 patients. Proximal nephron toxicity caused hypomagnesaemia in ten patients and hypocalcaemia in five patients. Elevated urinary N-acetylglucosaminidase excretion was seen in 22 out of 30 children, indicating subclinical tubular toxicity. Nephrotoxicity was less severe in children who received cisplatin courses at a dose rate of 40 mg m(-2) day(-1) than in those who received higher dose rates (P < 0.005), but there was no correlation with total dose received. Follow-up studies revealed partial recovery of GFR (P < 0.05). Glomerular and proximal nephron toxicity are common in children treated with cisplatin, and more severe at higher dose rates. Despite partial recovery of GFR, the long-term outcome of nephrotoxicity remains unknown and careful monitoring of chronic toxicity is necessary.
SIOPEL 2 was a pilot study designed to test the efficacy and toxicity of two chemotherapy (CT) regimens, one for patients with hepatoblastoma (HB) confined to the liver and involving no more than three hepatic sectors (‘standard-risk (SR) HB’), and one for those with HB extending into all four sectors and/or with lung metastases or intra-abdominal extra hepatic spread ‘high-risk (HR) HB’. SR-HB patients were treated with four courses of cisplatin (CDDP), at a dose of 80 mg/m2 every 14 days, delayed surgery, and then two more similar CDDP courses. HR-HB patients were given CDDP alternating every 14 days with carboplatin (CARBO), 500 mg/m2, and doxorubicin (DOXO), 60 mg/m2. Two courses of CARBO/DOXO and one of CDDP were given postoperatively. Between October 1995 and May 1998, 77 SR-HB (10 of whom were actually treated with the HR protocol) and 58 HR-HB patients were registered and all 135 could be evaluated. Response rates for the entire SR-HB and HR-HB groups were 90% (95% CI 80–96%) and 78% (95% CI 65–87%), and resection rates were 97% (95% CI 87–99%) and 67% (95% CI 54–79%) including several children undergoing liver transplantation. For SR-HB patients, 3-year overall and progression-free survivals were 91% (±7%) and 89% (±7%) and for the HR-HB group 53% (±13%) and 48% (±13%), respectively. The short-term toxicity of these regimens was acceptable, with no toxic deaths. A treatment strategy based on CDDP monotherapy and surgery thus appears effective in SR-HB but, despite CT intensification, only half of the HR-HB patients are long-term survivors. For SR-HB patients, the efficacy of CDDP monotherapy and the CDDP/DOXO (‘PLADO') combination are now being compared in a prospective randomised trial (SIOPEL 3).
Purpose: To evaluate the long-term sequelae of treatment for malignant germ cell tumors (GCT) during childhood and adolescence.
Patients and Methods: Of 128 patients treated for GCT at St. Jude Children's Research Hospital between 1962 and 1988. 73 are long-term survivors (continuously disease-free for >= 5 years after diagnosis), with a median follow-up of 11.3 years). Survivors' ages at diagnosis ranged from birth to 18.3 years (median. 9.2 years); 64% (47 patients) were female. Initial surgical resection was followed by observation for stage I germinomas (n = 2), testicular tumors (n =13). and selected cases of ovarian or sacrococcygeal tumors (n = 2). and by radiation therapy (RT) for patients with stage II to III germinoma (n = 8). The remaining 48 patients received postoperative chemotherapy (vincristine, dactinomyein, and cyclophosphamide [VAC] +/- doxorubicin, 1962 to 1978; VAC and/or cisplatin, vinblastine, and bleomyrin [PVB], 1979 to 1988). RT was added to the chemotherapy for 21 patients. Late complications involving various organ systems and their relationship to treatment were evaluated.
Results: More than two-thirds of long-term survivors (n = 50) had at least I complication, and half (n = 38) had > 1 organ system affected. The systems most often involved included the musculoskeletal (417c of survivors), endocrine (42%). cardiovascular (16% excluding those who had only abnormal chest radiograph), gastrointestinal (25%). genitourinary tract (23%), pulmonary (19%). and neurologic (16%) systems. High-frequency hearing loss occurred in 58% (11 of 19) of patients treated with cisplatin. Musculoskeletal, gastrointestinal, and urinary tract abnormalities were most frequent in patients whose treatment included RT.
Conclusions: A high frequency of late effects after treatment for pediatric GCT, particularly in patients who received RT, was demonstrated. Treatment sequelae could be anticipated from the intensity and type of therapeutic modalities. Treatment-directed screening evaluations may improve quality of life in long-term survivors of pediatric GCT through timely identification of sequelae that can be prevented or ameliorated.
(C) 1999 Lippincott Williams & Wilkins, Inc.
Cisplatin is one of the most potent antitumor agents known, displaying clinical activity against a wide variety of solid tumors. Its cytotoxic mode of action is mediated by its interaction with DNA to form DNA adducts, primarily intrastrand crosslink adducts, which activate several signal transduction pathways, including those involving ATR, p53, p73, and MAPK, and culminate in the activation of apoptosis. DNA damage-mediated apoptotic signals, however, can be attenuated, and the resistance that ensues is a major limitation of cisplatin-based chemotherapy. The mechanisms responsible for cisplatin resistance are several, and contribute to the multifactorial nature of the problem. Resistance mechanisms that limit the extent of DNA damage include reduced drug uptake, increased drug inactivation, and increased DNA adduct repair. Origins of these pharmacologic-based mechanisms, however, are at the molecular level. Mechanisms that inhibit propagation of the DNA damage signal to the apoptotic machinery include loss of damage recognition, overexpression of HER-2/neu, activation of the PI3-K/Akt (also known as PI3-K/PKB) pathway, loss of p53 function, overexpression of antiapoptotic bcl-2, and interference in caspase activation. The molecular signature defining the resistant phenotype varies between tumors, and the number of resistance mechanisms activated in response to selection pressures dictates the overall extent of cisplatin resistance.
Cis-dichlorodiammineplatinum (CDDP) and VM26, both of which have been proven efficient in treating neuroblastoma, were combined in a sequential schedule and administered to 22 children with disseminated neuroblastomas resistant to treatment with cyclophosphamide and doxorubicin (Adriamycin). During this same study, 14 children were prospectively evaluated for the effect of CDDP on magnesium metabolism and the effect of the induced hypomagnesemia on parathyroid function. Complete or partial tumor responses were achieved in six and nine cases, respectively and were of prolonged duration (longer than six months) in eight of the 15 responding. It was also shown that CDDP-induced hypomagnesemia is the result of excessive renal loss and is severe enough to interfere with the normal parathormone response to hypocalcemia.
Eighteen patients with advanced squamous cell cancer of the head and neck were treated with cis-diamminedichloroplatinum in a 24-hour infusion. The most frequent dose used was 80 mg/m2 repeated every three weeks. Six were treated preoperatively for Stage III or IV disease, and twelve were treated for recurrent disease. The overall response rate was 72% with one complete remission, >50% regression in six patients, and 25-50% regression in six patients. Toxicity was minimal: creatinine >2 in 6% of courses, leukopenia in 9%, anemia in 29%, vomiting in 76%, and documented minimal hearing loss in one patient. Plasma and urine platinum levels during infusion are presented. The dosage of 80 mg/m2 administered over 24 hours gives a response rate in head and neck cancers equivalent to that reported with higher doses given by rapid infusion, and toxicity is minimal. Cancer 42:2135–2140, 1978.
Treatment with continuous infusions of cisplatin results in increased filterable drug exposures as measured by the area under the curve (AUC) of nonprotein-bound plasma platinum levels. To determine the dose-limiting toxicity and optimal method of administration, 24 patients were treated with continuous infusions of cisplatin at a dose rate of 25 mg/M2/day in a limited Phase I trial. A total of 47 courses were given. Nine patients received 13 courses of 4 days duration, 19 received 29 courses of 5 days duration, and five received courses of 6 or 7 days duration. Dose-limiting toxicity was found to be leukopenia: 42% of patients receiving the 5-day treatment developed a nadir count of less than 3000 cells/mm3. Nausea and vomiting were easily controlled. Minimal nephrotoxicity occurred in five patients and was associated with daily volume expansion with 2 l of 0.9% NaCl solution in four patients. All other patients were given 3 l of daily volume expansion during treatment. Responses were seen in 6 of 22 evaluable patients (27%). It is concluded that continuous infusion cisplatin at a dose rate of 25 mg/M2/day can be given safely for 5 days as a single agent if concomitant volume expansion with at least 3 l of 0.9% NaCl solution is given daily. Phase III comparative trials with a conventional bolus and newer high-dose regimens for response and toxicity are indicated. Cancer 59:15–18, 1987.
Objective:
To describe hearing changes in a group of 28 children (age range, 8-180 mo) undergoing protocol-based cisplatin therapy.
Methods:
Conventional, play audiometry, visual reinforcement audiometry (VRA), immittance audiometry, transient click evoked otoacoustic emissions (OAEs), and auditory brainstem response (ABR) evoked potentials were used to assess peripheral sensitivity and for threshold determination.
Results:
Bilateral symmetrical high-frequency sensorineural hearing loss was noted in 9 of the 28 children (26%). Hearing loss was evident as early as 1 month after chemotherapy and as late as 50 months and was not dependent on individual or cumulative dosage of cisplatin.
Conclusions:
1) Presence of sensorineural hearing loss was independent of individual and/or cumulative dosage of cisplatin; 2) audiologic assessment should be incorporated into a child's periodic medical evaluations after chemotherapy treatment, as onset of sensorineural hearing loss cannot be predicted; 3) personal hearing aids may be indicated for those children with hearing loss affecting the low- to mid-frequencies; a personal assistive listening device (frequency modulated system) may be more appropriate for losses above 3000 Hz; and 4) evaluation and intervention by a speech-language pathologist may be indicated to address possible articulation or language development problems consequent to hearing loss.
Although the acute renal toxicity of cisplatin has been well documented, long-term follow-up studies in cisplatin-treated children are scanty. We have evaluated the incidence and characteristics of both acute and chronic nephrotoxicity in 22 children (median age 8 years) treated with cisplatin as part of different chemotherapeutic protocols. All patients exhibited a significant and progressive decrease in plasma magnesium (Mg) values soon after cisplatin administration. Magnesiuria also increased immediately after therapy. Hypomagnesemia (plasma Mg <1.4 mg/dl) occurred in 10 patients and it was dose-dependent. Minimal and mean cumulated doses inducing hypomagnesemia were 300 and 500 mg/m2, respectively. In 18 children we followed renal function prospectively for a mean time of 2.3 years after arrest of cisplatin therapy. Chronic hypomagnesemia and moderate elevation of plasma creatinine were observed in 6 children, hypocalciuria in 5 children, and hypokalemia in 1 child. Presence of hypomagnesemia was unrelated to the total dose received or the time elapsed since cisplatin therapy. Renal function studies, performed in the 6 children with chronic hypomagnesemia, revealed different degrees of impairment in Mg reabsorption. The functional characteristics of chronic cisplatin nephrotoxicity found in the present series—contrary to prior reports—are not comparable to those present in the inherited Gitelman's syndrome. © 1997 Wiley-Liss, Inc.
We studied renal function and serum electrolytes in 51 patients receiving cisplatin chemotherapy by retrospectively reviewing the charts of 44 patients and prospectively following seven patients. Hypomagnesemia developed in 23 of 44 evaluable patients who were receiving cisplatin. We documented inappropriate renal magnesium wasting in four patients. Two patients required hospitalization for symptomatic hypomagnesemia. We conclude that cisplatin can induce a renal tubular defect in magnesium conservation and serious clinical syndromes of magnesium deficiency.
Eighteen patients with advanced squamous cell cancer of the head and neck were treated with cis-diamminedichloroplatinum in a 24-hour infusion. The most frequent dose used was 80 mg/m2 repeated every three weeks. Six were treated preoperatively for Stage III or IV disease, and twelve were treated for recurrent disease. The overall response rate was 72% with one complete remission, greater than 50% regression in six patients, and 25--50% regression in six patients. Toxicity was minimal: creatinine greater than 2 in 6% of courses, leukopenia in 9%, anemia in 29%, vomiting in 76%, and documented minimal hearing loss in one patient. Plasma and urine platinum levels during infusion are presented. The dosage of 80 mg/m2 administered over 24 hours gives a response rate in head and neck cancers equivalent to that reported with higher doses given by rapid infusion, and toxicity is minimal.
To clarify the difference in nephrotoxicity between cisplatin and carboplatin, the pharmacokinetics of platinum, renal function and nuclear DNA synthesis in renal cortical and outer medullary cells were studied in rats which had received cisplatin or carboplatin. Male Sprague-Dawley rats were given either cisplatin or carboplatin intravenously at an equi-toxic dose (LD10 or LD50) and were killed at various times within 7 days after the injection. Cisplatin bound to plasma proteins more avidly than carboplatin. Much more platinum was detectable in the renal nuclei after cisplatin injection than after carboplatin injection. BUN and serum creatinine levels in the rats treated with 8.5 mg/kg of cisplatin were significantly higher than in those treated with 100 mg/kg of carboplatin. Cisplatin markedly suppressed the renal nuclear DNA synthesis both in vivo and in vitro, when compared with carboplatin. It is concluded that the differences in nephrotoxicity between cisplatin and carboplatin are related to their different inhibitory effects on nuclear DNA synthesis in the renal cells.
Experimental and clinical observations support the view that uncorrected magnesium (Mg) deficiency impairs repletion of cellular potassium (K). This is consistent with the observed close association between K and Mg depletion. Concomitant Mg deficiency in K-depleted patients ranges from 38% to 42%. Refractory K repletion due to unrecognized concurrent Mg deficiency can be clinically perplexing. Refractory K repletion as a consequence of Mg deficiency may be operative in patients with congestive failure, digitalis toxicity, cisplatin therapy, and in patients receiving potent loop diuretics. Therefore, we recommend that: (1) serum Mg be routinely assessed in any patients in whom serum electrolytes are necessary for clinical management and (2) until serum Mg is routinely performed consideration should be given to treating hypokalemic patients with both Mg as well as K to avoid the problem of refractory K repletion due to coexisting Mg deficiency.
(Arch Intern Med. 1992;152:40-45)
Cis-platinum is an ototoxic antineoplastic drug. Evaluation of auditory thresholds in 33 children receiving cis-platinum shows that a threshold shift at 6 and 8 kHz is first measurable after a cumulative dose of 201 to 300 mg/m2. A 35- to 40-dB high-frequency threshold shift is evident after a cumulative cis-platinum dose of 301 to 400 mg/m2. Increasing cumulative doses of cis-platinum are associated with a greater degree of hearing loss. Receiver-operator characteristic curves were used to find a criterion value that effectively identified threshold shifts that were due to cis-platinum ototoxicity. A 15-dB or greater shift in the 6- and 8-kHz threshold average identifies a high true-positive (50%) and low false-positive (0%) rate of cis-platinum-induced hearing loss. Using this criterion, cis-platinum ototoxicity affected 77% of children who received cis-platinum (median cumulative dose 360 mg/m2).
Despite the recognized ototoxicity of cis-platinum, a clinical outline for the audiologic evaluation of patients receiving this drug has not been clearly defined. In a practical approach to this problem, the audiograms of 48 pediatric patients referred for monitoring during planned cis-platinum therapy were reviewed. Eleven patients tested with auditory brain-stem response (ABR) audiometry demonstrated several limitations of this modality. Fourteen children underwent initial ABR testing followed by at least two pure-tone audiograms. The remaining 23 patients had their hearing evaluated by pure-tone audiometry only. Various factors such as patient age, cis-platinum dosage, and cranial radiation exposure were analyzed for apparent effect. Younger patients tended to be more susceptible to audiologic changes with the administration of cis-platinum. The proportion of patients who demonstrated a hearing loss increased with successive dosing as did the severity of the hearing loss. Prior exposure to cranial radiation was strongly linked to the development of hearing loss following cis-platinum therapy. Guidelines are presented regarding the use of clinical audiometry in the screening of these pediatric oncology patients.
Unlabelled:
Information on persisting renal sequelae after cisplatin in children and adolescents is limited. Twelve patients aged 4-20 years had been treated with cisplatin and were healthy 4-43 months after stopping chemotherapy. Plasma creatinine, calcium, albumin and hydrogen ion concentration, plasma and urinary sodium, chloride, phosphate and urate, and urinary magnesium and potassium were comparable in patients and controls. However, mean calciuria, magnesemia and potassemia were significantly reduced and bicarbonatemia increased in the patients. Calciuria, magnesemia, potassemia and bicarbonatemia were normal in 3 patients only, calciuria was below -2 SD control in 9 patients, renal magnesium deficiency was demonstrated in 5 patients (all with hypocalciuria as well), and 4 patients presented with hypokalemic metabolic alkalosis (all with magnesium deficiency and hypocalciuria).
Conclusions:
(1) Renotubular dysfunctions persist very often after cisplatin; (2) hypocalciuria is more frequent than hypomagnesemia; (3) the most severe tubulopathy after cisplatin includes hypocalciuria, renal magnesium deficiency and hypokalemic metabolic alkalosis.
To evaluate the long-term renal toxicity of cisplatin, 40 children who had been without treatment at least 18 months (range 18 months to 7 years) were observed. In all the children, glomerular filtration rate (GFR) was estimated from the plasma clearance of chromium 51-labeled ethylenediaminetetraacetic acid, both at the end of treatment and at a median follow-up of 2 years 6 months after treatment was stopped (range 18 months to 7 years). In 21 children, serum magnesium level was also measured at follow-up. Median age at diagnosis was 15 months (range 13 days to 13 years 8 months), and median cumulative doses of cisplatin was 500 mg/m2 (range 120 to 1860 mg/m2). In 22 of 24 children with an end-of-treatment GFR of less than 80 ml/min per 1.73 m2, the median improvement in GFR at follow-up was 22 ml/min per 1.73 m2 (range 2 to 56 ml/min per 1.73 m2). Hypomagnesemia was found in 6 of 21 children and was independent of GFR. No significant correlation was found between improvement in renal function and total cisplatin dose, age, gender, tumor type, or associated nephrotoxic medication. We conclude that most children have some recovery from cisplatin glomerular toxicity, especially if damage is not severe, but that hypomagnesemia may persist.
A long-term follow-up study was carried out to assess ototoxicity in children who had been treated for a malignant tumour with "standard dose" cisplatin (60-100 mg/m2 per course), and were at least 2 years from stopping treatment. The median age at diagnosis was 2 years 2 months (range 1 month to 13.5 years). On the basis of hearing assessment by pure-tone audiometry, a practical grading system of hearing loss from 0 to 4 is proposed. Moderate to severe high-frequency hearing loss (grade 2-4) was found in half the children and 10 require appropriate hearing aids. The risk of developing ototoxicity increased significantly with the cumulative cisplatin dose (P = 0.027), although there was considerable individual susceptibility. Serial follow-up testing, to a median of 4 years after completion of cisplatin treatment, showed no recovery of hearing in any of these children. We suggest careful monitoring of young children by a consultant audiological physician throughout treatment with cisplatin, particularly when doses of 400 mg/m2 and over have been reached. Alternative chemotherapy should be discussed if grade 2 ototoxicity develops.
Assessment of the toxicity caused by chemotherapy in children with cancer has become more important as the number of long-term survivors has continued to increase. It is vital to monitor both acute life-threatening adverse effects and long-term toxicity that may impair the child's development and cause permanent morbidity. Renal damage may follow treatment with cytotoxic drugs, especially cisplatin or ifosfamide, and lead to glomerular, proximal tubular or distal tubular impairment or to any combination of these. Greater understanding of nephrotoxicity and of its prevention may enable the use of more intensive schedules or of higher doses of potentially nephrotoxic chemotherapy. However, the evaluation of cytotoxic drug-induced nephrotoxicity has frequently depended mainly on measurement of the plasma creatinine concentration, which may remain normal despite substantial glomerular impairment or severe tubular dysfunction. Detailed assessment of nephrotoxicity depends on an understanding of normal renal physiology and requires evaluation of all aspects of function. A comprehensive but simple investigatory protocol that enables assessment of the nature and severity of nephrotoxicity in children is described, which can be performed without admission to hospital. Glomerular function is assessed by measurement of the glomerular filtration rate from the plasma clearance of [51Cr]-ethylenediaminetetraacetic acid ([51Cr]-EDTA). Proximal nephron function is evaluated in three ways: by measurement of the concentration of calcium, magnesium, phosphate, glucose and urate in blood and urine along with calculations of their fractional excretion and of the renal threshold for phosphate; by determination of the excretion in urine of low-molecular-weight proteins (e.g. retinol-binding protein); and by investigation of urinary bicarbonate excretion in patients who are acidotic. Distal nephron function is initially investigated by examination of the concentration (osmolality) and acidification (pH) of an early morning sample of urine. Finally, a group of general investigations is performed, including quantitation of urinary excretion of renal tubular enzymes (e.g. N-acetylglucosaminidase) and measurement of blood pressure.
Fifty-four patients with metastatic cancer were followed audiometrically during high-dose (100-120 mg/m2) cisplatin chemotherapy. Eighty-one percent of the patients showed significant changes in air-conduction hearing thresholds after completion of therapy. Thirteen percent sustained a significant hearing handicap. An interindividual variation was found, ranging from severe hearing loss after the first course to unaffected hearing after three courses. The ototoxic effect was not increased by pre-existing hearing loss, but was slightly increased by age. The risk was determined more by the amount of the single dose than by the cumulative dose. The further ototoxic effect could not be predicted on the basis of the audiogram after the first course. Peak plasma concentration of platinum was measured in eight patients, and no ototoxic changes were noted below a concentration of 1 microgram/L.
Renotubular handling of sodium, potassium (K) calcium (Ca), phosphate, hydrogen ions and glucose, and urinary concentrating ability were studied in three children (aged 8, 8.5, 11 years) with renal magnesium (Mg) loss, persisting for more than 2 years after discontinuation of cisplatin treatment for neuroblastoma. A group of healthy children served as controls. Besides renal Mg wasting, a clear-cut tendency towards reduced calciuria associated with normal or slightly elevated plasma Ca was observed. Plasma K tended to be low (3.4-3.7 mmol/l), and plasma chloride was normal. Plasma bicarbonate (HCO3) ranged from 24.9 to 27.8 mmol/l, and urinary pH was always less than 6.0, indicating a renal HCO3 threshold exceeding 24 mmol/l. Plasma creatinine levels, glucosuria and phosphaturia, and urinary concentrating capacity were adequate. Comparable features were found in three children (aged 4.5, 9, 13 years) with primary renotubular hypomagnesaemia-hypokalaemia and hypocalciuria. This study complements the picture of chronic cisplatin tubulopathy in childhood demonstrating that, apart from Mg wasting, a reduced Ca excretion, and a tendency to hypokalaemia and metabolic alkalosis exist. Thus cisplatin may induce renal functional damage identical to that found in primary renotubular hypomagnesaemia--hypokalaemia with hypocalciuria.
Serial auditory evaluations were performed in 54 pediatric patients (5 to 18 yr) treated with cis-diamminedichloroplatinum(II) for osteosarcoma. Each course of cis-diamminedichloroplatinum(II) comprised 150 mg/m2 and was administered initially at two weekly intervals for seven courses (3 mo) and subsequently at three monthly intervals for 15 to 21 mo. Overall, 604 courses were administered, and observations were conducted from diagnosis to 6 yr. Bilateral hearing loss was detected in all patients. The loss varied from mild (20 to 40 dB) to profound (greater than 90 dB). Initial losses occurred in the higher frequencies and were also greater at these frequencies. Significant loss was first observed after 300 mg/m2 for frequencies over 4000 Hz and gradually shifted to incorporate the lower frequencies. Hearing loss was permanent.
Although increased efficacy has been described with a five-day schedule of high-dose cisplatin (CDDP) in hypertonic saline, severe myelosuppression and cumulative neurotoxicity have limited the usefulness of this therapy. In order to evaluate a possible dose-response relationship in non-small-cell lung cancer (NSCLC), 17 patients with metastatic disease were treated with a modified dose schedule delivering the same total dose (200 mg/m2) in a divided day 1 and 8 schedule. During a pilot study, a total of 47 cycles of therapy were administered, with a median of three cycles per patient and a median total cumulative dose of 600 mg/m2. Nine of 17 patients received at least 600 mg/m2. While nephrotoxicity was similar to previous reports of the five-day schedule, the incidence and severity of myelosuppression and peripheral neuropathy were markedly reduced. Using this modified schedule, severe myelosuppression did not occur. Clinically severe peripheral neuropathy developed in only one patient (6%). The overall response rate was 47% (eight of 17 patients). Plasma platinum pharmacokinetics during five cycles of the modified day 1 and 8 schedule were compared with pharmacokinetics of the five-day schedule. Accumulation of plasma ultrafiltrate platinum occurred in the five-day schedule, but not in the day 1 and 8 schedule. This difference in pharmacokinetics is one possible explanation for the reduced toxicity of this modified schedule. Although the degree of activity seen in this pilot study is encouraging, the efficacy of high-dose CDDP in NSCLC remains to be defined. In view of reduced myelosuppression and neurotoxicity, further trials with this modified schedule are indicated.
Three children with malignant solid tumors developed hyponatremia with renal sodium wasting associated with other signs of tubular dysfunction, such as hypokalemia or hypomagnesemia, a few days after cisdiammine dichloroplatinum (CDDP) administration. The normalization of serum electrolyte disturbances was obtained with increased parenteral intakes in fluids and electrolytes, and renal sodium wasting stopped by itself a few days later © 1987 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.
Covalent binding of platinum from the anticancer drug cisplatin has been determined in subcellular organelles from kidney and liver of guinea pig strains sensitive and resistant to the systemic toxicity of cisplatin. Organ distribution of platinum was similar between the two strains, but the sensitive animals (pigmented) excreted only half as much platinum in 24 hr as did the resistent animals (albino). Subcellular distribution of platinum in mitochondria, microsomes, and cytosol was approximately equal for both strains, but the sensitive animals had twice as much platinum bound covalently to cytosolic acid-insoluble protein as did the resistant animals. In the albino guinea pigs, concentrations of total platinum and of covalently bound platinum were greater in kidney subcellular organelles than in either liver or lung organelles, which may help explain the sensitivity of the kidney to the toxic effects of cisplatin.
Cisplatin (cis-diamminedichloroplatinum II), a chemotherapeutic agent used against epithelial neoplasms, is known to cause hypomagnesemia and renal magnesium wasting. In order to further characterize the effect of multiple doses of this drug upon serum magnesium levels and renal magnesium handling, we prospectively studied 28 patients who received a total of 82 doses of cisplatin. All patients developed hypomagnesemia that was dose-related (r = .66, P less than .001, n = 101); the lowest serum magnesium level reached in individual patients ranged from 0.3 to 1.7 mg/dL. Renal magnesium wasting was documented in 19 patients, with urinary fractional excretion of magnesium ranging from 2.9% to 22.3% despite serum magnesium levels of greater than or equal to 1.5 mg/dL. Evidence of renal tubular injury (renal tubular epithelial cells or tubular cell casts) was detected in 47 of 47 urine sediment examinations performed two to four days after cisplatin administration. There was no clear evidence that cisplatin caused defects in renal handling of electrolytes other than magnesium; in fact, 16 of the 28 patients demonstrated avid renal reabsorption of one or more other electrolytes despite significant magnesium wasting. We conclude that cisplatin alters renal tubular handling of magnesium, resulting in significant prolonged dose-related hypomagnesemia.
Twenty-four patients with head and neck neoplasms were prospectively evaluated for cisplatin (DDP)-induced ototoxicity. Patients were selected from a larger population based on the uniformity of their chemotherapy regimen, renal status, lack of prior or concurrent exposure to ototoxic agents, and availability for repetitive audiometric testing in the same setting. Scanning electron microscopy of the inner ear was performed on four temporal bones. Hearing impairment was found to be dose-related, irreversible within the confines of the study period, and primarily in the higher frequencies. Vestibular toxicity was rare and well-documented by our testing methods in only one patient. Based on the results of this study, and a review of animal and human data on DDP ototoxicity, the authors concluded that ototoxic screening should be reserved for patients defined as "at risk" and those patients receiving more than 400 mg of DDP under the conditions stated in this report.
Bleomycin produced regression of tumours in 10 of 15 cases of human squamous cell carcinoma. Hearing and equilibrium were not affected. No ototoxic effects were found in guinea pigs when Bleomycin was administered subcutaneously and intraperi-toneally. Cochlear damage was seen when the drug was injected into the middle ear.
Thirty patients with metastatic malignancy of various types were treated with cis-diamminedichloroplatinum(II) (DDP) administered by continuous infusion for 120 hours. The starting dose was 20 mg/m2/day (100 mg/m2/course) and was escalated by stages to 40 mg/m2/day (200 mg/m2/course). Dose-limiting toxicity was observed at 30 mg/m2/day (150 mg/m2/course), manifested as marrow suppression and particularly thrombocytopenia in 13 of 14 patients evaluated at doses greater than or equal to 30 mg/m2/day. The gastrointestinal toxicity characteristic of bolus treatment schedules was less intense but was cumulative and dose-related. Renal toxic effects developed in five of 30 patients in spite of adequate hydration and daily diuretic therapy. Peripheral neuropathy developed in the only two patients who received four courses of continuous-infusion DDP. Antitumor effects were observed in six patients (oral cancer, two; lymphoma, one; prostatic cancer, one; hepatoma, one; and bronchogenic carcinoma, one). The recommended starting dose for continuous venous infusion therapy with DDP is 30 mg/m2/day for 5 days.
Ninety-six cancer patients received a total of 280 courses of cis-diamminedichloroplatinum (DDP), alone (20 patients), or in combination with other agents. DDP was given in 20 mg/m2 as a continuous 24-hour infusion daily for 5 consecutive days, repeated every 4 to 6 weeks. Patients were adequately hydrated for 12 hours prior to treatment but no diuretics or mannitol were used. Twenty percent of the patients developed no toxicity. Nausea and vomiting were lacking in 42% of 256 evaluable cycles and were mild in 36%. Nephrotoxicity was observed in four patients (5%) and was reversible on cessation of therapy in all except one. Hypomagnesemia occurred in 4% of 140 evaluable cycles. Mild ototoxicity was noted in two patients. The therapeutic efficacy of this dose schedule could not be adequately assessed, but one patient with thymoma and extensive pulmonary metastases achieved partial remission on DDP alone, and another with progressive mediastinal thymoma achieved stabilization of disease. In conclusion, this study suggests that the toxicity of the 5-day continuous infusion regimen is relatively mild. Randomized trials are indicated to evaluate the therapeutic efficacy of this new regimen, and the role of DDP in the treatment of malignant thymoma should be further explored.
Cis-dichlorodiammineplatinum (CDDP) and VM26, both of which have been proven efficient in treating neuroblastoma, were combined in a sequential schedule and administered to 22 children with disseminated neuroblastomas resistant to treatment with cyclophosphamide and doxorubicin (Adriamycin). During this same study, 14 children were prospectively evaluated for the effect of CDDP on magnesium metabolism and the effect of the induced hypomagnesemia on parathyroid function. Complete or partial tumor responses were achieved in six and nine cases. Respectively and were of prolonged duration (longer than six months) in eight of the 15 responding. It was also shown that CDDP-induced hypomagnesemia is the result of excessive renal loss and is severe enough to interfere with the normal parathormone response to hypocalcemia.
A total of 146 serial audiograms that were performed for 32 patients who had received cisplatin treatment were analyzed. Fifteen patients developed significant audiometric abnormality after a mean cumulative dose of 203 mg/m2. Ototoxicity was more severe with higher cumulative doses and higher individual doses, and was most marked in those patients receiving bolus injections. Loss of perception of higher frequencies was most common. Symptoms of ototoxicity occurred in 23 patients and included deafness, tinnitus, otalgia, and recruitment. In some patients the symptoms were transient, and not all patients with symptoms developed audiometric abnormalities. Audiometric abnormalities were invariably preceded by one or more symptoms of ototoxicity. Ototoxicity resulted in dose modification or cessation of treatment in only three patients, and in each case the decision to modify the dose was made on the basis of symptoms of ototoxicity rather than on the audiometric findings. We conclude that audiometry has a limited role in the routine management of patients receiving cisplatin treatment.
To determine whether abnormalities in routine blood tests were associated with increased susceptibility to hearing loss induced by cisplatin chemotherapy.
Cohort study of patients with head and neck cancer receiving cisplatin chemotherapy who underwent audiometric testing.
A large, university-based hospital; part of a larger study regarding rehabilitation of patients with cancer.
Forty-two patients with head and neck cancer who agreed to participate underwent at least three serial treatments with high-dose cisplatin therapy. Routine blood tests and audiometric testing were performed before each course of chemotherapy. One hundred eighty audiograms were performed.
A deterioration of auditory threshold of 15 dB or more at one frequency or of 10 dB or more at three or more frequencies was considered a significant loss. Only frequencies at and below 4000 Hz were considered.
Multiple analysis of variance results indicated that decreased serum albumin level, hemoglobin level, red blood cell count, and hematocrit were associated with an increased likelihood of significant hearing loss during chemotherapy.
Patients in poor general medical condition with low levels of red blood cells or serum proteins are at increased risk for development of hearing loss from cisplatin chemotherapy. We recommend that hearing be tested before chemotherapy begins and after the first course of cisplatin. If there is no significant hearing loss at or below 4000 Hz at that time, then subsequent audiometric testing is required only if symptoms of hearing loss develop.