Hearing loss in pediatric oncology patients receiving carboplatin-containing regimens

Carboplatin is a well-established chemotherapeutic agent used to treat a variety of pediatric malignancies. Platinum analogues such as cisplatin are known to be ototoxic, but little is known regarding the ototoxicity of carboplatin. We performed a single institution retrospective chart review of pediatric oncology patients who received platinum-containing regimens from 1993 to 2002. Ninety-nine patients with sufficient medical and audiologic data were identified. Significant hearing loss was defined as a Brock grade 1 or higher. The incidence was compared among 3 treatment groups (carboplatin only, carboplatin and cisplatin, and cisplatin only). Significant hearing loss in patients receiving carboplatin only was rare, observed in only 1/25 (4%) of patients. In contrast, 19/27 (70%) of patients receiving carboplatin and cisplatin possessed significant hearing loss, as did 27/47 (57%) of those patients receiving cisplatin only P<0.001. The difference in hearing loss could not be explained by different cumulative exposures of the platinum agents. Carboplatin, when used without cisplatin, is rarely associated with severe hearing loss, even at high cumulative doses.     

Cisplatin ototoxicity in children: a practical grading system

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.     

Hearing loss after platinum treatment is irreversible in noncranial irradiated childhood cancer survivors

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 loss in children with brain tumors treated with cisplatin and carboplatin-based high-dose chemotherapy with autologous bone marrow rescue

Carboplatin is less ototoxic than cisplatin, but ototoxicity may occur with carboplatin at higher doses. We evaluated hearing in children with brain tumors treated with conventional dose cisplatin followed by high-dose carboplatin. Children under 6 years of age, newly diagnosed with brain tumors, were treated after surgery with cisplatin, Etoposide, cyclophosphamide, and vincristine, followed by consolidation with carboplatin, ThioTEPA, Etoposide, and autologous bone marrow rescue. Hearing was assessed before and after consolidation, utilizing standard audiometric techniques. Seven of the 11 evaluable patients developed high-frequency sensorineural hearing loss after induction therapy. Hearing deteriorated after consolidation in five patients, with pure tone threshold shifts of up to 65 dB between 2,000 and 8,000 Hz. Of these five patients, audiological abnormalities were documented in four prior to consolidation, one received cranial irradiation after consolidation, and all five received aminoglycoside antibiotics for at least 2 weeks, with toxic drug levels in four. Three patients have subsequently required hearing aids. Significant ototoxicity is common in these patients. Ototoxicity related to consolidation therapy is likely due to the high dose of carboplatin used, prior cisplatin therapy, aminoglycosides, and, in one patient, cranial irradiation. Audiological assessment is essential in children treated with dose-intensive chemotherapy regimens containing cisplatin and carboplatin for identification and rehabilitation of ototoxicity. © 1996 Wiley-Liss, Inc.     

The incidence of hearing impairment after successful treatment of neuroblastoma

BACKGROUND: Platinum compound based chemotherapy has contributed to improved survival rates in neuroblastoma patients. We studied the association of hearing loss with the use of platinum based drugs. METHODS: Data of children from the two German neuroblastoma study cohorts, NB90 and NB97, were analyzed for the incidence of hearing impairments greater than WHO grade 2. Data from patients surviving more than 1 year after diagnosis without progression or recurrence were used. RESULTS: Of these 1,170 patients, 146 (12.5 %) had persisting hearing impairments. The incidence was low after localized neuroblastoma INSS stage 1 - 3 with 35/650 (5 %) and stage 4S with 2/113 (2 %), but high in stage 4 disease with 109/405 (27 %). Ototoxicity depended on the cumulative cisplatin dose. For doses of 1 - 200 mg/m (2), 201 - 400 mg/m (2), 401 - 600 mg/m (2) and 601 - 800 mg/m (2) we found hearing impairments in 5/39 (12 %), 28/221 (13 %), 61/230 (26 %) and 50/225 (22 %) patients, respectively. The incidence of hearing impairment was not age dependent. In stage 4 patients, there was an additional effect of high dosed carboplatin. 65/188 (40 %) patients developed hearing impairments after carboplatin containing (1,500 mg/m (2)) high dose chemotherapy with autologous stem cell reinfusion compared to only 33/217 (15 %) in patients receiving platinum free maintenance chemotherapy. Substitution of cisplatin (40 mg/m (2) x d, d 1 - 4, 96 h infusion) with carboplatin (100 mg/m (2) x d, d 1 - 4, 1 - 2 h infusion) due to otoxicity during induction chemotherapy did not reduce event free survival. CONCLUSION: One fourth of high risk neuroblastoma survivors suffer from treatment induced hearing impairments. The substitution of cisplatin with carboplatin was not associated with an increased rate of tumor recurrences.     

Prospective study of carboplatin-based chemotherapy for pediatric germ cell tumors

BACKGROUND: Survival of pediatric patients with malignant germ cell tumors has improved dramatically with the use of cisplatin-based chemotherapy, though patients are at high risk of significant long-term complications. In a prospective study, carboplatin was substituted for cisplatin in an attempt to minimize nephro- and oto-toxicities, while achieving excellent disease-free survival. PROCEDURE: All consecutive patients with malignant germ cell tumors at The Children's Hospital of Philadelphia were treated between 1989 and 1998. After pathologic confirmation of disease and pretreatment evaluation of pulmonary, renal, and otologic function, patients received etoposide 150 mg/m(2) days 1, 2, 3; carboplatin 600 mg/m(2) day 2; and bleomycin 10 mg/m(2) day 3 for at least four courses. RESULTS: Twenty-three patients were entered for study, and were available for evaluation. All patients achieved either a complete or partial remission following therapy with surgery and chemotherapy. With a median of 58 months of follow-up, overall survival is 91% and event-free survival is 87%. Therapy was given as an outpatient, and well tolerated, with 20 admissions for fever and neutropenia. Ototoxicity and nephrotoxicity, when evaluated, have been extremely limited. Three patients, all with stage III disease, have relapsed; one of these remains alive and disease free. CONCLUSIONS: Carboplatin can successfully substitute for cisplatin during the treatment of pediatric germ cell tumors without sacrificing response or survival. Long-term effects, especially nephrotoxicity and ototoxicity, were rare or mild among the small number of patients evaluated. Carboplatin appears to be a safe and efficacious alternative in the treatment of germ cell tumors, and should be considered as primary therapy for pediatric patients.     

A Pilot Study of High-Dose Carboplatin and Pulsed Etoposide in the Treatment of Childhood Solid Tumors

Carboplatin was administered at 1,000 mg/m²/course in combination with etoposide at 300 mg/m²/course to 23 patients aged 5 months to 16 years. Five patients were affected by neuroblastoma, four by CNS tumors, three by Ewing's sarcoma, two by rhabdomyosarcoma, two by malignant teratoma, two by Wilms' tumor, two by head and neck carcinoma, one by hepatoblastoma, one by synovial sarcoma, and one by Langerhans-cell histiocytosis. Eleven patients were pretreated, seven of them with high-dose cisplatin. The overall response rate was 7/11 (64%) for pretreated and 10/12 (83%) for previously untreated patients. Myelosuppression was the main side effect, with anemia and thrombocytopenia more pronounced than leukopenia. Gastrointestinal toxicity and ototoxicity were very mild; nephrotoxicity and neurotoxicity other than hearing loss were not observed. In children with malignant tumors, the therapeutic activity of carboplatin at high doses, even in combination chemotherapy, deserves further studies.     

Low incidence of ototoxicity with continuous infusion of cisplatin in the treatment of pediatric germ cell tumors

Cisplatin is an important chemotherapeutic agent in the treatment of many pediatric malignancies, but its use is limited in part by ototoxicity. The authors' institution has been administering standard-dose cisplatin by continuous infusion rather than bolus administration in germ cell tumors. The authors retrospectively reviewed 39 patients with germ cell tumors requiring chemotherapy over the past 20 years and recorded data including demographics, cumulative cisplatin dose, degree of ototoxicity (by the Brock grading system), and disease outcome. The median age was 9.4 years and the majority of children (48.7%) had endodermal sinus tumor. Twenty-one children received 400 mg/m of cisplatin or more. One child had evidence of significant ototoxicity at last follow-up (6.64 years after diagnosis). This patient received a total cumulative dose of 500 mg/m of cisplatin. Eighty-two percent of children achieved clinical remission of their disease. The authors conclude that continuous administration of cisplatin is associated with minimal ototoxicity while maintaining good tumoricidal efficacy, and further studies using this regimen are warranted.     

Survival and long-term outcomes in children with hepatoblastoma treated with continuous infusion of cisplatin and doxorubicin

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.     

Ototoxicity from cisplatin therapy in childhood cancer

Cisplatin has been associated with hearing damage. It is usually irreversible, bilateral, and characterized by high-frequency sensorineural hearing loss. This study was carried out to identify impairment of hearing function in children and adolescents with cancer after cisplatin therapy. Twenty-three survivors of childhood cancer treated with cisplatin at our Unit from 1991 to 2004 performed tympanometry, pure tone audiometry, transient otoacoustic emissions, and distortion product otoacoustic emissions (DPOAE). The median age at diagnosis was 12.3 years and the median total dose of cisplatin received was 406 mg/m2. Fifty-two percent of patients had bilateral and in the high frequencies range hearing loss on audiometry. Transient otoacoustic emission and DPOAE abnormalities were detected in 22% and in 71% of the patients, respectively. We found a high concordance between the findings of audiometry and DPOAE (P=0.01). There was no influence of sex and number of ototoxic drugs other than cisplatin on hearing loss. There was a trend for younger age and higher cumulative dose of cisplatin to be associated with greater severity of hearing damage. Our data provide further evidence on hearing damage due to cisplatin therapy in children. The high incidence of patients with hearing function abnormalities found in this study and in previous reports highlights the importance of monitoring hearing function in children and adolescents undergoing cisplatin therapy, or as early as possible at follow-up. This study also demonstrates that DPOAE should be used for screening of hearing abnormalities and, once hearing damage is identified, patients require expert audiologic pediatric evaluation and (where indicated) use of hearing aids and/or speech therapy.     

Nephrotoxicity of cisplatin and carboplatin in sarcoma patients: a report from the late effects surveillance system

BACKGROUND: Cisplatin and carboplatin are both nephrotoxic and can induce, to a different degree, impairment in glomerular function and hypomagnesemia. Prospective longitudinal studies on these renal impairments are rare in children and adolescents. PROCEDURE: Six hundred and fifty one sarcoma patients were investigated prospectively for nephrotoxicity in the Late Effects Surveillance System (LESS) network (median follow-up 2 years). Median cumulative dose was 360 mg/m(2) for cisplatin, and 1,500 mg/m(2) for carboplatin. Patients not treated with any platinum derivative were used as controls. Most patients (including controls) also received ifosfamide. Renal function was tested by serum magnesium, serum creatinine, and the GFR as estimated by the Schwartz formula. We evaluated incidence, dependencies, and the course of impairments. RESULTS: There was no observed platinum-induced reduction of glomerular function over time. After cessation of antineoplastic therapy, hypomagnesemia (<0.7 mmol/L) occurred in 12.1% (95% CI: 6.8%-19.4%) of patients after cisplatin therapy, and in 15.6% (95% CI: 5.3%-32.8%) after carboplatin therapy, in comparison with 4.5% (95% CI: 2.0%-8.7%) in patients without any treatment with platinum derivatives (P = 0.008). In all groups, the frequency of hypomagnesemia decreased with ongoing follow-up, but serum magnesium remained lower in platinum treated patients throughout the study period. CONCLUSION: Nephrotoxicity after treatment with cisplatin and carboplatin was mild in our study. Further studies have to show if serum magnesium is permanently decreased in platinum treated patients and if this will result in any clinically relevant impairment.     

Long-term renal and hearing toxicity of carboplatin in infants treated for localized and unresectable neuroblastoma: results of the SFOP NBL90 study

BACKGROUND: A secondary end point of the NBL90 protocol (Rubie H et al. Pediatr Oncol 2001;36:247-250) was the concern in this infant population for possible carboplatin-(CBDCA) induced late side effects including impaired renal and hearing functions. PROCEDURE: Glomerular filtration rate (GFR), tubular function (TF), pure tone audiometry (PTA), high-frequency, and transient evoked-otoacoustic emission were prospectively assessed in 30 children alive and disease-free 6 years after the end of the treatment. RESULTS: Median age at diagnosis and at assessment was 4.7 months and 7 years, respectively. Blood pressure was < or =97.5 centile in all children. The mean estimated GFR was 114 +/- 13 ml/min/1.73 m(2) by Schwartz formula [range 87-145]. TF assessment failed to demonstrate any impairment. 29/30 children had grade 0 ototoxicity and all transient evoked otoacoustic emission were normal. CONCLUSIONS: With a 6-year follow-up the combination of VP16 and carboplatin given at conventional doses is safe on renal and hearing functions in infants with unresectable neuroblastomas treated according to SFOP NB90.     

Use of amifostine in the therapy of osteosarcoma in children and adolescents

Amifostine protects normal tissue from the cytotoxic damage induced by radiation and chemotherapy. In this study, 39 consecutive newly diagnosed children with osteosarcoma were assessed; 20 received amifostine and 19 did not. The chemotherapy regimen included an induction phase of three cycles of cisplatin (100 mg/m2), carboplatin (500 mg/m2), and doxorubicin (60 mg/m2), followed by surgery. Alternating cycles of cisplatin/ifosfamide (9 mg/m2), ifosfamide/doxorubicin, carboplatin/doxorubicin, and ifosfamide/carboplatin were administered every 3 weeks to complete 26 weeks of treatment. Amifostine was administered 15 minutes before the infusions of cisplatin and carboplatin in a total of 193 infusions. Side effects during infusions and renal, hearing, and bone marrow toxicities were evaluated and compared between the two groups. Hypotension was observed in 28 (14.5%) infusions. No patient required discontinuation of therapy. Fewer than two episodes of vomiting occurred in 130 (71%) infusions and two to five episodes occurred in 51 (28%) infusions, and no patient had grade 4 toxicity. There was no difference between the two groups regarding renal toxicity (creatinine clearance). Neutropenia and leukopenia were significantly less frequent in the amifostine group. No difference was observed in platelet and hearing toxicities. Amifostine was well tolerated in doses of 740 mg/m2 in children and adolescents, and myelotoxicity was less severe in the amifostine group. This was a pilot study for further evaluation in a larger randomized trial.     

Auditory and visual toxicity during deferoxamine therapy in transfusion-dependent patients

Deferoxamine is a chelating agent that has extended the life expectancy of patients with thalassemia. In the 1980s, many investigators reported otologic and visual toxicity caused by deferoxamine. In July 1999 and 2 years later, the authors performed audiologic and ophthalmologic assessments in 30 transfusion-dependent patients receiving deferoxamine therapy (40-50 mg/kg per dose, subcutaneously for 8-10 hours, 4-7 days per week). In 1999, six patients (20%) had deferoxamine-related hearing impairment (>25 dB), all at high frequencies. Because the authors believed the benefits of chelation therapy outweighed the risk of ototoxicity, the dose of deferoxamine was not reduced. Two years later, the hearing impairment had not progressed in any of the patients. There was no association between ototoxicity and ferritin level. No patients had abnormalities of visual acuity or funduscopy in either 1999 or 2001. Based on this experience, deferoxamine at doses lower than 50 mg/kg/d was safe for the eyes and slightly toxic to the ears. The ototoxicity probably relates to individual susceptibility. Regular monitoring of auditory function and close follow-up of abnormal findings are recommended. According to this limited experience, reducing the dose or withdrawing deferoxamine might not be necessary if the hearing loss is stable in the face of ferritin levels above 2,000 ng/mL. Because of the relatively small patient numbers, more data are needed to confirm these conclusions.     

High-dose carboplatin in combination with etoposide (JET regimen) for childhood brain tumors

Fourteen patients aged 1 to 15 years with medulloblastoma (six patients), low-grade astrocytoma (four patients), and high-grade astrocytoma (four patients) were treated with carboplatin and etoposide (JET regimen). Six patients had been treated previously, two of them with cisplatin at conventional doses. Carboplatin was administered at 500 mg/m2/day over 5 h on days 1 and 2, in association with pulsed etoposide at 100 mg/m2/day on days 1, 2, and 3. Courses were repeated at 3-week intervals. The disease-specific response rates were as follows: five of six with three complete responses and two partial responses for medulloblastoma; zero of four for low-grade astrocytoma; and two of four with two partial responses for high-grade astrocytoma. Myelosuppression was the main side effect: anemia (hemoglobin less than 8.0 g/dl), thrombocytopenia (less than 25,000/microliter) and leukopenia (less than 1,000 white blood cells/microliters) were noted in 19 of 54, 10 of 54, and 7 of 54 courses, respectively. Gastrointestinal toxicity was very mild, and nephro- and neurotoxicity were not observed. No audiometric abnormalities were demonstrated in seven of seven patients who had not previously received cisplatin, and preexisting audiometric abnormalities were not worsened by the administration of carboplatin in one cisplatin-pretreated patient. The combination of carboplatin and etoposide administered in this study appears to be effective and well tolerated in children with brain tumors. Further studies on a larger number of patients are needed to ascertain its real activity in childhood brain tumors.     

Experiences with the combination carboplatin/VP 16 in the treatment of recurrent tumors in children

The efficiency and toxicity of Carboplatin, a derivate of cisplatin in clinical use since 1981, was investigated in combination with VP16 in 11 children with recurrent or refractory tumors. 10 patients received therapy as outpatients without hydration. 160 mg/m2/day of Carboplatin were administered days 1 to 3, or days 1 to 5 as one hour infusion, combined with VP16 100 mg/m2/day, days 1 to 3, or days 1 to 5 as one hour infusion. One patient received Carboplatin, 600 mg/m2, as 24 hrs. continuous infusion in combination with VM26, 150 mg/m2/day as one hour infusion, 8 hours after Carboplatin. 9 of the treated children had measurable disease. 3 of 9 patients achieved a tumor response of more than 50% (partial remission). 5 of 9 children showed tumor response of less than 50% (stable disease). 1 out of 9 patients had progressive disease. 8 of 9 patients reported improvement or disappearance of clinical symptoms after the first course. All patients had severe myelosuppression with different times to recover. The WBC nadir was 14 days after Carboplatin/VP16. The nadir platelet counts occurred 21 days after therapy with fast recovery. Non-hematological side effects were minimal.     

Continuous or repeated prolonged cisplatin infusions in children: a prospective study on ototoxicity, platinum concentrations, and standard serum parameters

BACKGROUND: 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. PROCEDURE: 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. RESULTS: 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. CONCLUSIONS: 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.     

Carboplatin and VP 16 in medulloblastoma: A phase II study of the French Society of Pediatric Oncology (sfop)

The purpose of this study is to evaluate the antitumor activity of combination carboplatin and etoposide in measurable medulloblastoma. From January '89 to January '92, 26 patients with medulloblastoma were included in a multicentric phase II study of 2 courses of carboplatin 160 mg/m²/d day 1 to day 5 and VP16 100 mg/m²/d day 1 to day 5. Median age was 10 years (19 months-14.5 years). First treatment was surgery alone in 1 patient, surgery + radiotherapy in 4 patients, surgery + chemotherapy in 2 patients less than 3 years old, surgery + radiotherapy + chemotherapy in 19 patients (“8 drugs in 1 day” based:17, SIOP I:1, SIOP II:1). Previous treatment included cisplatin (20 cases), carboplatin (1 case), and VP16 (7 cases). Measurable disease was evaluated by CT scan, MRI or myelogram and CSF. Response rate (RR) was 72 ± 10%:8 complete responses (CR), 10 partial responses (PR), 1 objective effect (OE), 6 progressive disease (PD), 1 non-evaluable. Thirty-six courses were evaluated for toxicity. Median duration of WHO grade 4 neutropenia was 8 days (0–23). One patient died at day 18 after the first course because of diffuse haemorrhage during septic aplasia. Five other non-life-threatening septicemias were recorded. Median number of platelet transfusions was 1 (0–4). One child who had achieved a PR after two courses died from CNS bleeding after the third course. This drug combination achieves a high response rate in childhood medulloblastoma. Severe toxicity has been mainly encountered in previously heavily treated patients. Tolerance may be acceptable in newly diagnosed children, but careful hematological follow-up and platelet transfusional support are definitely mandatory. © 1994 Wiley-Liss, Inc.     

Monitoring hearing during ototoxic cisplatin therapy

In the 1983-1988 period, the audition of 17 children was studied prior to and during antineoplastic chemotherapy with cumulative total cisplatin doses from 270 to 1530 mg/m2. The hearing tests were conducted by means of an objective method which doses not depend on patients' cooperation: the recording of fast auditory evoked potentials. Tone threshold audiograms were additionally obtained from cooperative children. Of the 17 patients, 14 showed a dose-dependent symmetric hearing loss which in part was severe and related in particular to the high-frequency domain. Three patients exhibited no hearing impairment even though the total cisplatin dose applied ranged from 630 to 810 mg/m2. To conclude, while allowing for reports in the literature, recommendations are given on how hearing impairment can be minimised in view of the priority of the antineoplastic action of cisplatin.     

5-HT3 antagonist ondansetron--an effective outpatient antiemetic in cancer treatment.

Thirty children aged 2-16 years with malignant tumours who were receiving chemotherapy were treated with the 5-HT3 antagonist ondansetron. Each received a single intravenous dose (5 mg/m2) followed by oral doses (2-4 mg depending on surface area) every eight hours for five days. Chemotherapy regimens comprised: carboplatin alone, carboplatin plus etoposide, cisplatin plus etoposide; adriamycin (doxorubicin) plus cyclophosphamide, or ifosfamide. Twelve patients received ondansetron with their first course of chemotherapy and the other patients were poor responders to previous antiemetic treatment. Efficacy was assessed by a questionnaire documenting the incidence of vomiting and severity of nausea. In a 24 hour period after starting chemotherapy a complete or major response (less than two vomiting episodes) was achieved in 87% of children. Although ondansetron was effective for early antiemesis after cisplatin or ifosfamide, delayed vomiting, retching, or nausea reduced responses to 50% and 20%, respectively. We conclude that in children ondansetron is an effective, well tolerated, oral antiemetic enabling simple administration in the outpatient setting. In the present schedule it was of limited efficacy against cisplatin or ifosfamide induced emesis.