High-dose Carboplatin Research Articles

Carboplatin-induced oxidative stress in rat cochlea

Carboplatin is currently being used in the clinic against a variety of human cancers. However, high dose carboplatin chemotherapy resulted in ototoxicity in cancer patients. This is the first study to show carboplatin-induced oxidative stress response in the cochlea of rat. Male Wistar rats were divided into two groups of six animals each and treated as follows: (1) control (normal saline, i.p.) and (2) carboplatin (256 mg/kg, i.p.). Animals in both groups were sedated with ketamine/xylazine and auditory brainstem-evoked responses were recorded before and 4 days after treatments. The animals were sacrificed on the fourth day and cochleae were harvested and analyzed. A significant elevation of the hearing threshold shifts was noted at clicks, 8, 16, and 32 kHz tone burst stimuli following carboplatin administration. Carboplatin significantly increased nitric oxide and malondialdehyde levels, xanthine oxidase and manganese-superoxide dismutase activities in the cochlea indicating enhanced flux of free radicals. Cochlear glutathione levels, antioxidant enzyme activities such as copper zinc-superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione S-transferase and enzyme protein levels were significantly depleted 4 days after carboplatin treatment. The data suggest that carboplatin induced free radical generation and antioxidant depletion, and caused oxidative injury in the cochleae of rats.

Assessment of amifostine as protection from chemotherapy-induced toxicities after conventional-dose and high-dose chemotherapy in patients with germ cell tumor

We assessed the efficacy of amifostine for protection from chemotherapy-induced toxicities in patients treated with conventional-dose paclitaxel, ifosfamide, cisplatin (TIP) and high-dose carboplatin, etoposide and thiotepa (CET) followed by peripheral blood progenitor cell (PBPC) rescue. In a prospective single-center study 40 patients with relapsed or refractory germ-cell tumors (GCT) were treated with 3 cycles of conventional-dose TIP followed by one cycle of high-dose CET. Patients were randomized either to receive one fixed dose of 500 mg amifostine per day of conventional-dose TIP and two fixed doses of 500 mg per day amifostine during high-dose CET (group A, n = 20) or no amifostine (group B, n = 20). Prior to the first cycle of TIP, one course of 175 mg/m2 paclitaxel and 5 g/m2 ifosfamide (TI) followed by granulocyte-colony stimulating factor (G-CSF) at 10 microg/kg/day were given for PBPC mobilization. Toxicities and response to conventional-dose TIP and high-dose CET could be evaluated in 40 patients (100%) and 32 of 40 patients (80%), respectively. Peripheral neurotoxicity (i.e. paresthesia or sensorymotor impairment), hearing impairment, hematologic toxicity, nephrotoxicity, nausea, myalgia, skin- and liver-toxicity did not differ siginificantly between the two patient groups. Likewise, the response rates to TIP and high-dose CET were comparable in patients with or without amifostine. After a median follow-up of 18 months, 8 of 20 (40%) patients of group A and 6 of 20 (30%) patients of group B are without relapse. Repeated low doses of 500 mg amifostine additional to conventional-dose TIP or high-dose CET showed no unequivocal advantage in protection from treatment-related toxicities. Furthermore, no significant differences in response rates or survival could be observed in this small number of patients.

Urinary excretion of thioTEPA and its metabolites in patients treated with high-dose cyclophosphamide, thioTEPA and carboplatin.

The urinary excretion of N,N',N"-triethylenethiophosphoramide (thioTEPA), and its metabolites N,N',N"-triethylenephosphoramide (TEPA), N,N'-diethylene,N"-2-chloroethylphosphoramide (monochloroTEPA) and thioTEPA--mercapturate was determined in patients receiving thioTEPA as part of a high-dose combination chemotherapy regimen with cyclophosphamide and carboplatin. The thioTEPA dose was 40 or 60 mg/m(2) in short infusions, twice daily, during 4 days. Urine samples were collected after each voiding on each day of drug administration until 24--48 h after the last thioTEPA infusion. ThioTEPA, TEPA and monochloroTEPA concentrations were determined with gas chromatography and thioTEPA--mercapturate with liquid chromatography--mass spectrometry with direct sample injection. ThioTEPA was present in urine 30 min after infusion and was still excreted 18 h after the last infusion. All metabolites were detected in urine 1 h after infusion. Patients with a creatinine clearance above 140 ml/minl showed higher excretion of TEPA than patients with a creatinine clearance below 140 ml/min (12.8 versus 4.9%, p=0.01). The excretion of monochloroTEPA relative to the excreted amount of TEPA increased at lower pH values of the urine. The excretion of thioTEPA--mercapturate relative to the dose was higher in patients treated with 60 mg/m(2). Excretion of thioTEPA and monochloroTEPA both accounted for only 0.5% of the dose, while TEPA and thioTEPA--mercapturate both accounted for 11.1%.

Results of a prospective study with high-dose etoposide, thiotepa and carboplatin and peripheral blood stem cell rescue for high-risk stage II-IIIA and selected stage IV breast cancer patients.

To investigate the safety and efficacy of a high-dose chemotherapy regimen with etoposide, carboplatin and thiotepa in high-risk stage II-IIIA breast cancer and in responsive metastatic patients. From April 1992 to December 1998, 24 patients with high-risk stage II-IIIA breast cancer (> or = 9 positive nodes) and 9 responsive metastatic patients were enrolled in the trial. After induction chemotherapy with an anthracycline-based regimen, peripheral blood stem cells were mobilized with cyclophosphamide (7 g/m2) and G-CSF (5-16 microg/kg/s.c./day). The high-dose chemotherapy regimen consisted of etoposide (1000 mg/m2), carboplatin (800 mg/m2) and thiotepa (500 mg/m2). At the end of the high-dose chemotherapy, all stage II-IIIA patients received radiotherapy to the breast or chest wall and draining nodes; stage IV patients were irradiated to sites of disease, if feasible. All ER+ and/or PgR+ patients were treated with hormone therapy. For stage II-IIIA high-risk patients, the median follow-up was 4.36 years (range, 1.93-6.94), and the Kaplan-Meier estimate at 5 years of disease-free survival and overall survival was 54.8 +/- 11% SE and 76.73 +/- 9.4% SE, respectively. For metastatic patients, the median follow-up was 4.93 years (range, 4.15-7.95), and the Kaplan-Meier estimate at 5 years of progression-free survival and overall survival was 22.2 +/- 13.9% SE and 76.2 +/- 14.8% SE, respectively. No treatment-related deaths were observed. Our results are comparable to those obtained in other high-dose chemotherapy trials but do not seem to be superior to conventional-dose therapy given to similar patients.

A mechanism-based pharmacokinetic model for the cytochrome P450 drug-drug interaction between cyclophosphamide and thioTEPA and the autoinduction of cyclophosphamide.

Cyclophosphamide (CP) is widely used in high-dose chemotherapy regimens in combination with thioTEPA. CP is a prodrug and is activated by cytochrome P450 to 4-hydroxycyclophosphamide (HCP) which yields the final cytotoxic metabolite phosphoramide mustard (PM). The metabolism of CP into HCP exhibits autoinduction but is inhibited by thioTEPA. The aim of this study was to develop a population pharmacokinetic model for the bioactivation route of CP incorporating the phenomena of both autoinduction and the drug-drug interaction between CP and thioTEPA. Plasma samples were collected from 34 patients who received high-dose CP, thioTEPA and carboplatin in short infusions during 4 consecutive days. Elimination of CP was described by a noninducible route and an inducible route leading to HCP. The latter route was mediated by a hypothetical amount of enzyme. Autoinduction leads to a zero-order increase in amount of this enzyme during treatment. Inhibition by thioTEPA was modeled as a reversible, competitive, concentration-dependent inhibition. PM pharmacokinetics were described by first-order formation from HCP and first-order elimination. The final models for CP, HCP, and PM provided an adequate fit of the experimental data. The volume of distribution, noninducible and initial inducible clearances of CP were 31.0 L, 1.58 L/hr and 4.76 L/hr, respectively. The enzyme amount increased with a zero-order rate constant of 0.041 amount * hr-1. After each thioTEPA infusion, however, approximately 80% of the enzyme was inhibited. This inhibition was reversible with a half-life of 6.5 hr. The formation and elimination rate constants of PM were 1.58 and 0.338 hr-1, respectively. The developed model enabled the assessment of the complex pharmacokinetics of CP in combination with thio TEPA. This model provided an adequate description of enzyme induction and inhibition and can be used for treatment optimization in this combination.

Dose response of carboplatin-induced hearing loss in rats: antioxidant defense system

Carboplatin, a platinum-containing anticancer drug, is currently being used against a variety of cancers. However, a single high dose of carboplatin is ototoxic in cancer patients. This is the first study to show carboplatin-induced hearing loss in a rat model. Male Wistar rats were divided into five groups and treated as follows: (1) control (saline, intraperitoneally (i.p.)); (2) carboplatin (64 mg/kg, i.p.); (3) carboplatin (128 mg/kg i.p.); (4) carboplatin (192 mg/kg, i.p.) and (5) carboplatin (256 mg/kg, i.p.). Animals in all groups were sedated with ketamine/xylazine and auditory brain-evoked responses (ABRs) were recorded before and 4 days after treatments. The animals were sacrificed on the fourth day and cochleae were harvested and analyzed. Carboplatin dose-dependently decreased body weight. However, at higher doses of carboplatin (192 and 256 mg/kg), there was a significant elevation of hearing threshold shifts at clicks, 4, 8, 16 and 32 kHz tone burst stimuli. The higher doses of carboplatin (192 and 256 mg/kg) significantly increased cochlear lipid peroxidation (132 and 146% of control) and depleted cochlear glutathione levels (66 and 63% of control), respectively. The antioxidant enzyme activities such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase (GST) depressed significantly at higher doses of carboplatin. The data suggest that higher doses of carboplatin (above 128 mg/kg) induce hearing loss as evidenced by significant changes in ABRs, lipid peroxidation and antioxidants in the cochlea of rats.

Induction of spontaneous otoacoustic emissions in chinchillas from carboplatin-induced inner hair cell loss

Fifteen chinchillas were evaluated for spontaneous otoacoustic emissions (SOAEs) before and after administering carboplatin (126–200 mg/kg), an anti-neoplastic drug that selectively destroys inner hair cells (IHCs) in this species. SOAEs were absent from all animals prior to carboplatin treatment, but at 1 week post-treatment, 47% of the animals and 30% of the ears had developed SOAEs. SOAE frequencies were clustered between 5 and 10 kHz and SOAE intensity ranged from 10 to 32 dB SPL. All of the ears with SOAEs had IHC lesions exceeding 60% throughout most of the cochlea and two ears had outer hair cell lesions of 25–60% at a cochlear place associated with the frequency of the SOAE. Thus, high doses of carboplatin that cause IHC loss can be used to create an animal model with SOAEs.

Induction chemotherapy by superselective intra-arterial high-dose carboplatin infusion for head and neck cancer.

To evaluate the feasibility, maximum dose of drug tolerated, technical problems, systemic and local toxicity, response rate, overall and disease-free survival, we studied superselective intra-arterial infusion of high-dose carboplatin as part of a multimodality treatment for head and neck cancer. Forty patients with untreated stage II-IV head and neck squamous cell carcinomas received induction chemotherapy with high-dose carboplatin (three cycles at 2-week intervals using 300-350 mg/m2 per cycle), delivered via superselective transfemoral angiography followed by radiotherapy or surgery plus radiotherapy. No technical complications occurred during or after the infusion. Systemic toxicity was minimal, and local toxicity was moderate. At the end of chemotherapy the overall complete and partial response rate was 90% (36/40) at the primary site and 64% (16/25) at the neck nodes. The median follow-up was 24.4 months (range 3-52). To date 21 patients are alive without disease, 2 are alive with disease, 13 have died of disease, and 4 have developed a metachronous lung tumor. There was a good correlation between the response to chemotherapy and disease-free survival. No statistically significant benefit in survival was observed with respect to other series of head and neck tumors treated with different protocols. However, discriminating between responding and nonresponding patients, this procedure can have a prognostic significance in planning integrated treatments for these types of tumors.

Results of treatment after relapse from high-dose chemotherapy in germ cell tumors.

To identify therapy-related or patient-related characteristics that predict response and long-term survival after failure of high-dose chemotherapy (HDCT) for germ cell tumors (GCT). Between 1986 and 1997, 101 GCT patients relapsed after high-dose carboplatin and etoposide (VP-16) at Indiana University (Indianapolis, IN). Median time to relapse was 10 months (range, 1 to 17 months). HDCT was the first salvage treatment in 29 patients and second or later salvage treatment in 72 patients. Fifty-four of 101 patients received post-HDCT treatment. Of these, 47 received chemotherapy, alone (n = 35) or in combination with surgery (n = 12). Seven patients underwent surgery alone. There were only 12 objective responses (three complete and nine partial responses) for 66 chemotherapy regimens given to 47 patients, for an overall response rate of 18.2%. Fifteen patients received platinum-based chemotherapy, with only one objective response. Chemotherapy was discontinued in 17% of cases because of toxicity. A longer interval between HDCT and post-HDCT treatment was the only variable that was associated with response. Five patients (4.9%) are disease-free at 30, 53, 57, 85, and 93 months after relapse. Of these, three responded to oral VP-16 and underwent resection of residual mediastinal, retroperitoneal, and inguinal cancer, respectively. One had resection of residual mediastinal yolk sac tumor, followed by oral VP-16. One relapsed with teratoma and received thoracoabdominal resection without chemotherapy. Patients who experience disease progression after HDCT often receive further chemotherapy and/or surgery. Chemotherapy resulted in a response rate of less than 20%, with only three complete responses. All of the long-term survivors (4.9%) had surgery as a component of their post-HDCT regimen.

Enhancing effect of electric stimulation on cytotoxicity of anticancer agents against rat and human glioma cells

Electropermeabilization, or electroporation, has been used to deliver genes or drugs into the cytoplasm through micropores in the cell membrane caused by electric stimulation. The cytotoxic effect of a combination of anticancer agents with electric stimulation on rat C6 and human T98G glioma cells was examined in vitro. Electric pulses of 100 μsec square waves (eight cycles at 1 Hz) at various electric fields were delivered to C6 or T98G glioma cell suspensions in combination with several anticancer agents. Cell growth was evaluated 48–72 h after treatment. Measurement of cell lysis by electric stimulation was used to assess the optimum field strength for electroporation. Electric stimulation enhanced significantly the cytotoxicity of bleomycin to both C6 and T98G cells by more than 1000-fold using an electric field of 1750 V/cm for C6 cells and 1000 V/cm for T98G cells. The enhancement disappeared when bleomycin concentration was reduced to 100 pg/ml. The cytotoxicity of carboplatin was weakly but significantly enhanced by electric stimulation when a high dose of carboplatin was used. However, there was no enhancement of the cytotoxicity of nimustine hydrochloride (ACNU), etoposide, and vincristine. These results indicate that the combination of bleomycin and electroporation is the most potent candidate for electrochemotherapy in vivo.

Surgery, tamoxifen, carboplatin, and radiotherapy in the treatment of newly diagnosed glioblastoma patients.

A historically controlled phase II study was undertaken to investigate the efficacy and toxicity of a postoperative treatment consisting of high-dose continuous tamoxifen, carboplatin and radiotherapy in patients with newly diagnosed glioblastoma. Between 1995 and 1998, 50 patients with newly diagnosed glioblastomas underwent surgery and were subsequently treated with 200 mg day(-1) tamoxifen continuously, 3 cycles of carboplatin (300 mg m(-2)), and radiotherapy. Survival data for a historical control group were calculated from respective prognostic indices and were obtained from studies with comparable patient populations treated with operation and radiotherapy only. In our study, the median time to tumor progression was 30 weeks and the median survival time (MST) 55 weeks (95% confidence interval: 46-63 weeks). The MST of the control group (48 weeks) showed to be within this interval. In addition to already known prognostic factors in malignant gliomas (age, Karnofsky performance score, extent of tumor resection), the gender (females lived longer than males, p = 0.0025) showed to influence survival. Serious side effects (thrombosis, pulmonary embolism) occurred in 6 patients. A high incidence of multifocal tumor recurrences (33%), which might be related to study-treatment, was observed. In conclusion, the combined therapy failed to demonstrate a higher efficacy than standard treatment for glioblastoma patients.

Phase II trial of induction high-dose chemotherapy followed by surgical resection and radiation therapy for patients with marginally resectable non-small cell carcinoma of the lung

The combination of carboplatin and paclitaxel is an active regimen in non-small cell lung cancer (NSCLC). Historically, patients with stage III disease have manifested higher response rates than patients with metastatic disease, and patients achieving a pathologic complete response to induction chemoradiation therapy prior to surgery have shown better long-term outcome. Based upon our pilot data using high-dose carboplatin and paclitaxel, we designed a phase II trial in patients with marginally resectable stage IIIA NSCLC. Ten patients, with bulky nodal stage IIIA disease, initially received etoposide (2 g/m 2) and granulocyte colony-stimulating factor (G-CSF) to mobilize peripheral blood stem cells (PBSC). Two cycles, 28 days apart, of carboplatin (AUC 12 in seven patients; AUC 16 in three patients) and paclitaxel (250 mg/m 2) were administered with filgrastim (5 μg/kg) and PBSC support. After re-evaluation, patients underwent a thoracotomy followed by radiotherapy (44–60 Gy) if deemed resectable, or radiotherapy alone (60 Gy) if not resectable. The median age was 58.5 years (48–66) with a median ECOG performance status of 0 (0–1). Histology was adenocarcinoma in seven patients; the remainder had either squamous cell, large cell or bronchoalveolar carcinoma. Based on CT radiography, the overall response rate was 40%. Eight of ten patients underwent resection with four right pneumonectomies, three right upper lobectomies and one wedge resection of the right upper lobe. Six patients had a complete resection. Of eight patients resected, four were downstaged by induction therapy, three remained unchanged and one was found to have more extensive disease. The remaining two patients developed metastatic disease while receiving chemotherapy. The median dose of postoperative radiotherapy was 54 Gy (35–66 Gy). Actual median follow-up for all patients was 89 weeks (25 to 136+). The actuarial median overall survival was 124 weeks (25 to 136+) and time to progression was 57 weeks (17 to 136+). The median dose of carboplatin delivered expressed as mg/m 2 was 779 (615–1540). Neutropenic fever occurred in two patients during the initial mobilization cycle only. The median number of units of RBC and/or platelets transfused was 0 (0–2 and 0–6, respectively). There were no significant non-hematologic toxicities. High-dose induction chemotherapy with stem cell rescue is feasible and safe with an acceptable response rate. Thoracotomy, including pneumonectomy and postoperative radiotherapy, were well tolerated by patients after undergoing high-dose induction chemotherapy with no apparent increase in peri-operative morbidity. The pathologic complete response rate was low — one out of ten patients. These results indicate that dose escalation of induction chemotherapy does not improve response rates even in this highly selected patient population. Accordingly, the complexity and potential toxicity of high-dose chemotherapy, as delivered in this trial as neoadjuvant treatment of non-small cell lung cancer, is not warranted.

High dose chemotherapy?results of American studies

The role of high dose chemotherapy in the treatment of solid tumors is a subject of robust debate. Opinions range from the adoption of high dose chemotherapy with hematopoietic progenitor support as standard therapy for a number of solid tumors to the view that the application of such expensive and potentially toxic therapy is always experimental and should be the subject of clinical trials to define the role, if any. In germ cell tumors, the role of high dose chemotherapy is somewhat less contentious. In the US, high dose carboplatin and etoposide-based chemotherapy is routinely accepted as standard therapy for those patients failing prior standard dose regimens. There is increasing acceptance of the role of similar high dose therapy as a component of aggressive second line therapy and some initial acceptance of a potential role in primary treatment of poor risk disease. Formal study of these questions has been hampered by the rarity of the illness, the success of standard therapy and the smaller number of patients presenting with far advanced disease. This review will highlight the scientific underpinning of the role of high dose chemotherapy in multiply relapsed patients, as a component of initial salvage therapy and, finally as an attempt to improve outcome in patients with poor risk presenting features. As well, an attempt will be made to highlight where new prognostic information has influenced the design of current studies.

High dose chemotherapy for refractory urothelial carcinoma supported by peripheral blood stem cell transplantation

Chemotherapy with methotrexate (MTX), vinblastine, doxorubicin, and cisplatin (M-VAC) is reported to be the most effective regimen for urothelial carcinoma. Complete response (CR) is observed in many cases. However, to the authors' knowledge there is no alternative therapy for nonresponders. Thus, the authors attempted high dose chemotherapy (HDC) supported with peripheral blood stem cells (PBSCs) collected after a modified method of mobilization to yield sufficient PBSCs for the HDC regimen employed.PBSCs were collected from ten patients, all of whom had recurrent and/or refractory transitional cell carcinoma. They were treated by modified M-VAC (with pirarubicin in place of doxorubicin) for PBSC harvest. Seven micrograms per kilogram of body weight of granulocyte-colony stimulating factor was injected subcutaneously daily from Day 10 of treatment to the end of the harvest. Harvest was initiated from the day when peripheral leukocyte counts exceeded 10,000/microL and usually continued for 3 consecutive days. Each patient received two courses of HDC. Therefore, 20 courses of HDC comprised of 300 mg/body of MTX, 1500 mg/m(2) of etoposide, and high dose carboplatin (CBDCA) were given to these 10 patients. The dose of CBDCA was determined by the formula of Calvert et al., in which the target area under the concentration versus time curve of CBDCA was adjusted to 21 mg. minute/mL.Sufficient PBSCs were collected for myeloablative chemotherapy in all patients. No patient responded to the treatment with modified M-VAC. Response to HDC was observed in nine of ten patients. CR was achieved in seven patients and a partial response was noted in two patients. A patient with multiple bone metastases showed no response. All patients rapidly recovered after PBSC transplantation. No patient died of treatment-related toxicity.HDC supported by PBSC transplantation was found to have a remarkable response against refractory urothelial carcinoma, for which there was no alternative therapy.

Abrogation of the Hematological and Biological Activities of the Interleukin-3/Granulocyte-Macrophage Colony-Stimulating Factor Fusion Protein PIXY321 by Neutralizing Anti-PIXY321 Antibodies in Cancer Patients Receiving High-Dose Carboplatin

This dose-escalation study was performed to evaluate the hematologic activity, biological effects, immunogenicity, and toxicity of PIXY321 (an interleukin-3/granulocyte-macrophage colony-stimulating factor fusion protein) administered after high-dose carboplatin (CBDCA) treatment. Patients with advanced cancers received CBDCA at 800 mg/m2 intravenously on day 0 of repeated 28-day cycles. In part A of the study, patients were treated with CBDCA alone during cycle 1 and then received PIXY321 on days 1 through 18 of cycle 2 and later cycles. In part B, patients received 18 days of PIXY321 beginning on day 1 of all CBDCA cycles, including cycle 1. PIXY321 was administered subcutaneously in 2 divided doses. Total doses of 135, 250, 500, 750, and 1,000 micrograms/m2/d were administered to successive cohorts of 3 to 6 patients in part A. In part B, patient groups received PIXY321 doses of 750, 1,000, and 1,250 micrograms/m2/d. The hematologic effects of PIXY321 were assessed in the first 2 cycles of therapy. Anti-PIXY321 antibody formation was assessed by enzyme-linked immunosorbent assay (ELISA) and neutralization assay. Of the 49 patients enrolled, 31 were fully evaluable for hematologic efficacy. When comparing the first B cycle (cycle B-1; with PIXY321) with the first A cycle (cycle A-1; without PIXY321), the fusion protein had no significant effect on platelet nadirs or duration of platelets less than 20,000/microL but was able to speed the time of recovery of platelet counts to 100,000/microL (15 v 20 days; P =.01). Significant improvements in neutrophil nadir and duration of ANC less than 500 were observed in cycles A-2 and B-1 (with PIXY321) as compared with cycle A-1 (without PIXY321). Initial PIXY321 prophylaxis (cycle A-2 and cycle B-1), enhanced the recovery of ANC to greater than 1,500/microL by an average of at least 8 days as compared with cycle A-1 (without PIXY321; P </=.004). However, positive PIXY321 hematologic effects were lost in the second course of PIXY321 among patients treated in part B. ELISA analysis showed that 92% of patients had developed neutralizing anti-PIXY321 antibodies by the completion of 2 PIXY321-containing cycles. The incidental action of PIXY321 to depress serum cholesterol levels was also abrogated during cycle B-2. We conclude that PIXY321 was active in speeding hematologic recovery but that neutralizing anti-PIXY321 antibody formation suppressed the hematologic and biochemical effects by the second cycle of PIXY321 administration. The immunogenicity of this fusion protein provides a cautionary warning that clinical development of bioengineered human molecules requires thorough testing for immune neutralization.

Adjuvant Dose-Intense Chemotherapy With Peripheral Blood Stem Cell Support in Stage II-III Breast Cancer With Five to Nine Involved Axillary Lymph Nodes

The purpose of this study is to determine outcomes for patients with high-risk nonmetastatic breast cancer undergoing high-dose chemotherapy with peripheral blood stem cell support. Forty-three patients with stage II-III disease, five to nine positive axillary lymph nodes, and a median age of 44 years (range, 27-60 years) were enrolled in a study that included: 1) standard dose doxorubicin, 5-fluorouracil, and methotrexate adjuvant therapy; 2) cyclophosphamide, etoposide, filgrastim, and peripheral blood stem cell harvest; and 3) high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) followed by peripheral blood stem cell infusion. All 43 patients received doxorubicin, 5-fluorouracil, and methotrexate, 42 (98%) received etoposide, and 41 (95%) received CTCb. Thirty-two patients (74%) are alive, 28 (65%) without relapse at a median of 55 months (range, 41-87 months). Two died (5%) of treatment-related causes, (subclavian catheter complication after etoposide and late radiation pneumonitis), and nine other deaths (21%) were associated with recurrent breast cancer. The probabilities of overall and event-free survival at 4 years were 0.77 and 0.67, respectively, compared with 0.82 and 0.69, respectively, for 72 similar patients with 10 or more positive axillary nodes receiving the same sequence of therapy. Thus, patients with five to nine positive axillary lymph nodes have a similar risk of failure after high-dose chemotherapy and peripheral blood stem cell support as patients with 10 or more positive axillary lymph nodes.

Hearing loss 'almost certain' to occur after high-dose carboplatin

Hearing loss 'almost certain' to occur after high-dose carboplatin

Hearing loss ???almost certain??? to occur after high-dose carboplatin

Hearing loss ???almost certain??? to occur after high-dose carboplatin

Severe ototoxicity following carboplatin-containing conditioning regimen for autologous marrow transplantation for neuroblastoma.

Children with neuroblastoma receiving high-dose carboplatin as part of their conditioning regimen for autologous marrow transplantation have a high incidence of speech frequency hearing loss. We evaluated hearing loss in 11 children with advanced stage neuroblastoma who underwent autologous marrow transplantation, following a conditioning regimen containing high-dose carboplatin (2g/m2, total dose). Audiometric evaluations were obtained at diagnosis, prior to and following transplant. Exposure to other known ototoxins also was assessed. All patients sustained worsening of hearing following high-dose carboplatin. Nine of the 11 children (82%) had evidence of speech frequency hearing loss post transplant for which hearing aids were recommended (grades 3-4). Three of the nine children had speech frequency loss prior to transplant which progressed following transplant. The entire group was heavily pre-treated with platinum-containing chemotherapy pre-BMT and had extensive exposure to other ototoxins, including aminoglycoside antibiotics, diuretics, and noise exposure - all of which could have exacerbated the effects of carboplatin. High-dose carboplatin is ototoxic, particularly in patients who have been primed with previous platinum therapy or other ototoxic agents. We conclude that further efforts are needed to monitor and minimize this complication. In cases where hearing loss is inevitable due to cumulative ototoxic exposures, families need to be adequately prepared for the tradeoffs of potentially curable therapy.

Hörverlust durch Hochdosis-Carboplatintherapie

Carboplatin is regarded as a non-ototoxic or low-grade ototoxic chemotherapeutic agent. We report on three patients with a recurrence of testicular cancer after cisplatin chemotherapy who suffered hearing loss after subsequent high-dose carboplatin therapy. Audiometry demonstrated carboplatin-induced hearing loss primarily in the mid-range and high frequencies up to 45 dB at 3 kHz and up to 55 dB at 8 kHz. In two of three patients, transitory-evoked otoacoustic emissions were absent after carboplatin therapy. Following first-line cisplatin chemotherapy, salvage treatment with high-dose carboplatin can generate hearing loss in the middle and high frequencies.