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To determine if amifostine is effective in reducing the toxicities associated with the administration of platinum-containing regimens in children with hepatoblastoma (HB).
Patients were enrolled on P9645 beginning in March of 1999. Stage I/II patients received treatment with 4 cycles of cisplatin/5-fluorouracil/vincristine (C5V) +/− amifostine. Patients with Stage III/IV disease were randomized to receive treatment with six cycles of either C5V +/− amifostine or carboplatin alternating with cisplatin (CC) +/− amifostine. Patients randomized to receive amifostine were given a dose of 740 mg/m2 intravenously over 15 minutes prior to each administration of a platinum agent.
Eighty-two patients were considered in a special interim analysis of the incidence of toxicity. The disease outcome for patients receiving amifostine was similar to outcome in patients who did not receive amifostine (p = 0.22). The incidence of significant hearing loss (> 40 dB) was similar for patients treated with or without amifostine: 38% (14/37) vs. 38% (17/45) (p=0.68), respectively. There were no differences in the incidence of renal or bone marrow toxicities evaluated. Patients who received amifostine had a higher incidence of hypocalcemia (5% vs. 0.5%, p=0.00006).
Amifostine in the doses and schedule used in this study failed to significantly reduce the incidence of platinum-induced toxicities in patients with HB.
Cisplatin (CDDP) is one of the most effective agents against hepatoblastoma (HB), and the addition of this agent to HB treatment protocols in the mid-1980s by both the Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG) resulted in dramatically improved survival rates for these children.1,2 CDDP, however, is associated with significant toxicity including hearing loss, myelosuppression, and nephrotoxicity.3 Carboplatin has also been used in an effort to provide anti-tumor efficacy with another platinum agent that has less potential toxicity.4,5
Amifostine is an agent developed to selectively protect normal tissues from the cytotoxic effects of radiation and chemotherapy. Adult studies have demonstrated the ability of amifostine to reduce toxicity without altering outcome or therapeutic efficacy.6,7 The Children’s Oncology Group (COG) study P9645 was designed to determine if the intensification of platinum administered therapy could improve survival in newly diagnosed patients with HB as well as to determine if amifostine could prevent platinum-associated toxicities including hearing loss, renal dysfunction, and myelosuppression. This report describes the results of amifostine use and its effects in reducing the ototoxicity associated with the administration of platinum-containing regimens in children with hepatoblastoma (HB).
The Pediatric Intergroup Hepatoblastoma Study P9645 opened in March 1999. The study was designed as a factorial randomization for patients with stage III or IV disease. The details of the study are described in Figure 1. Patients were eligible for study entry if they were less than 21 years of age at diagnosis and had biopsy proven, previously untreated HB, and had adequate organ function documented at the time of study enrollment. The protocol was approved by the National Cancer Institute and the individual institutional review board requirements of the participating COG affiliated institutions. Informed consent was obtained for all patients prior to study entry. Randomization to carboplatin/cisplatin (CC) was suspended in January 2002 because the projected improvement in long-term outcome associated with CC was statistically excluded as a possible outcome of this trial.8 Subsequently, all patients were assigned to receive cisplatin/5-fluorouracil/vincristine (C5V) with or without amifostine.
Patients were treated according to the schema in Figure 1. Patients with tumors of pure fetal histology were observed following surgical resection without further therapy. Stage I (non pure fetal histology) and stage II patients received four cycles of C5V with or without amifostine. Patients with stage III and stage IV disease were randomized to receive six cycles of either C5V or CC with or without amifostine. Each cycle of C5V consisted of intravenous (IV) CDDP (100 mg/m2 or 3 mg/kg for patients < 1 year of age) administered over 4 hours followed by IV hydration on day 1 and VCR (1.5 mg/m2, IV push) and 5-FU (600 mg/m2 IV push) on day 2. Each cycle of CC consisted of carboplatin at 700 mg/m2 given IV over one hour (23 mg/kg for patients less than 10 kg) on day 0 (560 mg/m2 or 18.5 mg/kg for patients less than 10 kg after 2 cycles) followed by cisplatin 100 mg/m2 or 3mg/kg for patients < 1 year of age on day 14 administered as described above. G-CSF was used after each CC cycle. Amifostine was given at a dose of 740 mg/m2 over 15 minutes immediately prior to cisplatin. Total intended platinum dose for stage I (non-pure fetal) and stage II patients was 400 mg/m2 (12 mg/kg for patients < 1 year of age) of cisplatin. Total intended platinum dose for stage III and IV patients was 600 mg/m2 (18 mg/kg for patients < 1 year of age) of cisplatin and 3640 mg/m2 (120 mg/kg for patients < 10 kg) of carboplatin. Patients with a GFR < 100 ml/min/1.73m2 were to have the carboplatin dose calculated using Calvert's formula to achieve an area under the curve of 6. Patients were reevaluated at the end of the initial chemotherapy phase of four cycles. Patients with unresectable disease at that time were considered as treatment failures while those who underwent tumor resection received two more cycles of the therapy to which she or he had been initially randomized.
Physical examination, blood counts, serum alpha-fetoprotein (AFP) levels, and appropriate imaging studies, including computed tomography (CT) of the chest and either CT or MRI of the abdomen, and assessment of audiologic function (audiogram or auditory brainstem responses) were performed prior to therapy. Subsequent exams and AFP assays were done prior to every additional cycle of chemotherapy. AFP was to be monitored monthly for six months, then every two months until two years off therapy, then every three months until four years off therapy, and then yearly. Imaging studies were repeated after cycles two, four and six, and then at 2, 4, 6, 12, 18, and 24 months off therapy. Audiologic examination was repeated following the 4th cycle of chemotherapy, at the end of therapy, and yearly following therapy.
The individual incidents of various toxicities were graded on a scale of 1 to 4, according to National Cancer Institute Common Toxicity Criteria Version 2.0 (CTC). Limits for toxicity grades were dependent on both patient age and the particular organ system involved. The specific toxicity scales employed in this study are available from the CTEP Web site. Patients on regimen C5V with delays in therapy of greater than one week or who experienced fever and neutropenia were allowed to receive G-CSF (5 mcg/kg/day) beginning 24 hours following the 5-FU dose. Patients who experienced Grade 4 neurotoxicity had their VCR held until symptoms resolved and then their therapy was re-instituted at ½ the initial dose. No specific modifications in therapy were made for any decrease in hearing.
Patients were randomized after the initial surgical procedure. Patients were stratified according to stage of disease (stage I or II v. stage III or IV). Patients with stage I/II were randomly assigned to receive or not receive amifostine. Patients with stage III/IV were randomly assigned to C5V or CC and to receive or not receive amifostine. The primary outcome measure for the effect of chemotherapy and amifostine randomization was event-free survival (EFS). The study was intended to enroll patients for 5.5 years and follow the last patient for 3 years after enrollment.
In November 2003, an analysis of toxicity was performed using toxicity data provided by the routine data collection done by institutional investigators according to the CTC criteria. At that time, grade 3 or 4 ototoxicity by institutional reporting was 4%. Data from other authors9,10 using information derived from expert review of serial audiograms demonstrated that quantifying ototoxicity from the CTC criteria substantially underestimated the true incidence of significant hearing loss. In response to these observations, we conducted a retrospective assessment of hearing loss in a subgroup of patients enrolled to the study. A blinded, detailed review of ototoxicity using results of audiograms obtained as part of toxicity evaluations as directed by the protocol was performed by one of the authors (KWC) and compared auditory brainstem responses (ABR) and/or audiogram data (‘hearing evaluation’) obtained prior to the start of treatment with data obtained after all therapy was completed. The evaluation cohort consisted of any eligible patient enrolled on P9645 up to March 2003 who received cisplatin and who: (1) had completed protocol therapy as of March 1, 2003; (2) were alive; and (3) who had not experienced disease progression or a second malignant neoplasm while on protocol therapy. All data current to March 31, 2003 were used to establish which patients fit the criteria for inclusion in the evaluation cohort.
If more than one post-therapy hearing evaluation was available, the one done closest to March 31, 2003 was used. Modified Brock criteria11 (Table 1) were used to assign a rating of hearing loss for each ear.
An analysis was conducted using the lowest grade of hearing loss observed in either ear (‘best ear’). The randomized assignment to receive amifostine was stratified by stage of disease and most patients in stratum 2 also were randomized to receive one of two chemotherapy regimens. In order to account for these stratification factors, a log-linear model was used to assess whether significant hearing loss, defined as the presence of grade 2A or greater hearing loss in the patient’s best ear, was associated with the randomized amifostine assignment after adjustment for stage (I,II v. III,IV) or treatment regimen (CC v. C5V).12
Each course of protocol therapy received by a randomized patient enrolled by the cutoff date was evaluated by the institutional investigator for the presence of all toxicities and reported using CTC version 2 criteria. The incidence of each type of toxicity was calculated as the number of courses during which the toxicity was noted divided by the number of courses administered. These rates were compared across randomized regimens using the exact conditional test of proportions.13
In order to assess the relationship between amifostine and outcome, patients who were randomized and who enrolled by the cutoff date were considered. EFS was defined as the period from the date chemotherapy was started until evidence of an event (progressive disease, death, diagnosis of a second malignant neoplasm) or date of last contact, whichever occurred first. Patients who did not experience an event were censored on the date of last contact.
Life table estimates were calculated by the method of Kaplan and Meier,14 and the standard deviation of the Kaplan-Meier estimate of the survivor function at selected points was calculated using Greenwood’s formula.14 For treatment comparisons, outcome was assigned to the randomized treatment, regardless of the therapy received.
Two hundred eight-nine (289) patients were enrolled on P9645. A detailed description of the results of this trial are published elsewhere.15 Of this total, 120 patients comprised the evaluation cohort as described previously in the statistical section (see Figure 2). Audiologic data were interpreted by a pediatric otologist (KWC) and categorized as evaluable if there was enough information to accurately determine whether or not ototoxicity had occurred. Eighty-two (82) patients had sufficient audiologic data that made them fully evaluable for an analysis of ototoxicity. The demographic and treatment data of the evaluation cohort are detailed in Table 2.
Amifostine did not prevent ototoxicity. Thirty-one of 82 evaluable patients (38%) had noticeable hearing loss (grade 2A or greater). Two of 21 stage I/II patients (10%) had grade 2A hearing loss while twenty-nine of 61 stage III/IV patients (48%) had grade 2A or greater hearing loss (Table 3a). Six patients (7%) had correctable hearing deficits with hearing aids while two patients (2%) had hearing deficits that could not be completely corrected even with hearing aids. There was no relationship between noticeable hearing loss and amifostine assignment after adjustment for stage of disease and chemotherapy treatment arm (p = 0.68; Table 3b). Specifically, amifostine did not prevent hearing loss of any grade. Chemotherapy assignment was not related to hearing loss (p = 0.75), but stage III/IV patients were more likely to have experienced hearing loss than stage I/II patients (p = 0.002). Stage III/IV patients were to receive two more cycles of chemotherapy than stage I/II patients.
Of the thirty-eight (38) patients who were excluded from the audiologic analysis, fifteen (15) did not have a post-treatment evaluation and eleven (11) did not have data of sufficient quality to evaluate. Twelve (12) patients had detectable hearing loss, but had conductive rather than sensorineural hearing loss that prevented attribution of the loss to protocol therapy and therefore made them inevaluable for therapy-related ototoxicity.
The vast majority of subjects had behavioral audiometric data. A total of 44 patients had hearing evaluated by ABR. However, only tone burst threshold ABRs were considered evaluable and were performed in 11 patients while 25 patients were not included in the analysis because they were evaluated using non-frequency specific click-evoked ABRs that do not specifically test for high frequency hearing loss from ototoxicity Eight patients with non-threshold ABRs typically used to test neural latencies were also excluded from analysis as invalid clinical assessments of ototoxicity
The frequencies of renal toxicities (proteinuria, hemoglobinuria, hypokalemia, hyponatremia, and hypomagnesiumia) and bone marrow toxicities (need for transfusion, thrombocytopenia, neutropenia, and anemia) were not different for patients who did or did not receive amifostine (Table 4). However, the use of amifostine was associated with a higher incidence of hypocalcemia (5% vs. 0.5%, p=0.00006).
Use of amifostine was not significantly related to risk for an adverse event (Figure 3).
Previous data had suggested that amifostine could provide protection against the treatment-related toxicities associated with the administration of CDDP and provided the background rationale for this trial.6,7,16,17 This prospective, randomized trial failed to yield any evidence that amifostine could protect any degree of hearing loss as 38% of patients experienced noticeable hearing loss and 57% of patients experienced any measurable decrement in hearing. This is important in that even mild hearing loss may have a significant impact in children with hepatoblastoma who are at a crucial age of cognitive development. These results are similar to those reported in several other pediatric series. A report by Marina and colleagues revealed significant hearing loss in eighteen of 24 patients with germ cell tumors treated with high dose cisplatin and amifostine.9 Fisher and others administered amifostine prior to cisplatin in 11 patients with medulloblastoma and ototoxicity developed in seven of 9 evaluable patients.18 Petrilli and coworkers randomized 39 patients with osteosarcoma to receive amifostine before cisplatin therapy. No difference was found in the incidence of hearing toxicity.19 However, a recent publication by Fouladi et al described children with average-risk medulloblastoma who had a reduced risk of hearing loss in the group of patients who received amifostine. Interestingly, these patients had all been previously irradiated and received amifostine both prior to and in the middle of the cisplatin infusion. The disparity in the results from these trials and others may be explained by differences in a number of factors including: patient age, individual and cumulative platinum dosage, timing and dosage of amifostine, tumor site, and potential interaction with other treatment modalities. Other agents such as sodium thiosuflate, and n-acetylcysteine have been and continue to be evaluated as potential otoprotective compounds.
Historical data demonstrates that anywhere from 5–75% of patients may experience hearing loss following treatment with CDDP.9,10 As demonstrated in this analysis, audiological toxicity collected using the usual clinical trials mechanism, by the submission of grading information by the institutional investigator using CTC criteria, underestimated the true incidence of noticeable significant hearing loss (4% v. 38%) in this population. In addition, while the analysis of audiologic data was only possible on 68% (82 of 120) of potentially evaluable patients due to incomplete data, the evaluated cohort is a representative group that justifies the conclusion that amifostine was not otoprotective for this collection of patients. Specific guidelines on how to administer audiograms or BAERs were not part of the protocol.
Therefore, future pediatric trials that attempt to evaluate ototoxicity must be written with more stringent criteria for exactly what tests should be utilized and exactly how they should be performed. As part of this endeavor, a separate manuscript is in preparation that will detail pitfalls in data collection from this and other cooperative group studies and will make recommendations for more specific criteria to be included in future protocols. From this experience we suggest that the inclusion of otolaryngologists, audiologists, or others with the appropriate training and expertise is crucial in both study design and analysis so that the resulting data are both valid and reliable.
In the current study, the cytoprotective agent amifostine was administered in an effort to decrease platinum-induced toxicity without adversely affecting event-free or overall survival. However, in the doses and schedule used, amifostine did not protect against the ototoxicity associated with platinum agents. In addition, renal and bone marrow toxicity were also not ameliorated by the use of amifostine. The use of amifostine concomitantly with platinum therapy did not have an impact on the outcomes of children with HB (Figure 3). Amifostine was associated with a much higher incidence of hypocalcemia, which is a well known side effect of this agent.
This work was supported in part by grant numbers U10 CA29139 and U10 CA98413 from the NIH / NCI. We are extremely grateful for the hard work and diigence of the clinical research associates of our member institutions for data collection, and to the COG Publications Office for editorial assistance. We are grateful to B. Greffe, L.C. Bowman, K. Newman, R. Womer, and R.P. Castleberry for their contributions.
Consultant or Advisory Role: Albert Pappo, Ziopharm