High-dose Carboplatin Research Articles

MDB-09. WNT AND GROUP 4 MEDULLOBLASTOMAS OF EARLY CHILDHOOD TREATED WITH HIGH DOSE CHEMOTHERAPY AND CRANIOSPINAL IRRADIATION SPARING APPROACH

Abstract BACKGROUND WNT and group 4 medulloblastoma (MB) are rare in young children and their outcome when treated with radiation avoidance infant strategies is unknown. METHOD This retrospective international cohort included children less than 7 years of age, with molecularly characterized group 4 or WNT MB, treated with high-dose chemotherapy(HDC) and CSI sparing approach. RESULTS The current cohort includes 29 patients (19M/10F). For the 26 patients with group 4 MB (median age at diagnosis 45.9 months), 16 (61.5%) were M0 and 17 (65.3%) underwent initial gross total resection (GTR). The most common consolidation regimen used was three cycles of high dose carboplatin and thiotepa (65.5%) or a single cycle of high dose of carboplatin, etoposide and thiotepa (31%).Two received adjuvant focal radiotherapy. Sixteen patients (61.5%) relapsed at a median time of 21.4 months from diagnosis (median age of 5.2 years). Relapse was local for 50% of the patients. One patient underwent palliative management and 15 received radiation-based salvage therapy (2 focal, 13 CSI+/- boost).The median dose of CSI was 36Gy (18-36). Five of the 15 died of disease. Overall, at a median follow-up of 37.9 months from diagnosis, 17/26 (65.3%) patients were alive, six had died of disease and two of toxicity. All 3 WNT patients (median age at diagnosis 57.8 months) underwent GTR and two were M0. Two received sequential high dose carboplatin and thiotepa. One patient with initial partial response, progressed 2 months after treatment completion and received salvaged CSI (18Gy). All of them were alive at a median follow up of 88 months from diagnosis. CONCLUSIONS HDC and CSI sparing approaches led to a high rate of relapse for young patient with group 4 (61.5%). However, 2/3 were salvaged with radiation-based therapy given at a median age 5.2 yrs. Additional WNT patients are needed to better describe their management.

High-dose carboplatin causes hearing loss in most patients

High-dose carboplatin causes hearing loss in most patients

Ototoxicity associated with high-dose carboplatin for patients with previously treated germ cell tumors.

High-dose carboplatin is an essential part of curative high-dose chemotherapy (HDCT) for patients with previously treated germ cell tumors (GCTs). Although hearing loss (HL) is a known side effect of HDCT, data on its severity and characteristics are limited. Eligible patients received HDCT for GCTs from 1993 to 2017 and had audiograms before and after HDCT. HL severity was classified by American Speech-Language-Hearing Association criteria, and mean change in hearing threshold at each frequency (0.25-8kHz) was estimated from pre- to post-HDCT and between HDCT cycles. Of 115 patients (median age, 32 years), 102 (89%) received three cycles of HDCT. Of 106 patients with normal hearing to mild HL in the speech frequencies (0.5-4kHz) before HDCT, 70 (66%) developed moderate to profound HL in the speech frequencies after HDCT. Twenty-five patients (22%) were recommended for hearing aids after HDCT. Patients with moderate to profound HL isolated to the higher frequencies (6-8kHz) before HDCT were more likely to develop moderate to profound HL in the speech frequencies after HDCT (94% vs. 61%; p=.01) and to be recommended for hearing aids (39% vs. 18%; p=.05). HL was frequent after HDCT for GCTs, with most patients developing at least moderate HL in the speech frequencies and approximately one in five recommended for hearing aids. Moderate to profound HL isolated to high frequencies at baseline was predictive of more clinically significant hearing impairment after HDCT. Some patients with germ cell tumors, the most common malignancy in adolescent and young adult men, are not cured with standard-dose chemotherapy and require high-dose chemotherapy (HDCT). Using detailed hearing assessments of patients receiving HDCT, we found that most patients developed significant hearing loss and that one in five needed hearing aids. Thus, strategies to reduce this side effect are urgently needed, and all patients receiving HDCT should have a hearing test after therapy.

Assessment of the change of antiemetic prophylaxis from double to triple combination in patients with high dose carboplatin chemotherapy.

Chemotherapy-induced nausea and vomiting (CINV) is one of the adverse events that most affects oncologic patients' quality of life. Carboplatin AUC ≥ 4 belongs to agents with high emetic risk (moderate risk in ASCO guidelines). We aimed to compare the effectiveness of netupitant/palonosetron and dexamethasone triple combination (TC) therapy versus ondansetron and dexamethasone double combination (DC) therapy as antiemetic prophylaxis in patients with carboplatin AUC ≥ 4. As a secondary endpoint, in TC group we evaluated the effectiveness of changing NEPA administration timing from 1 h to 15 min before chemotherapy. Open-label prospective study conducted in a tertiary-care hospital in patients receiving carboplatin AUC ≥ 4. CINV was evaluated using MASCC antiemetic tool, in acute (<24 h) and delayed phase (24-120 h). Results were analyzed using χ2 test. Two-hundred four completed questionnaires (CQ) were analyzed (76 in DC and 128 in TC). The proportion of patients who remained emesis-free was superior for TC-treated group compared to DC, either in acute (99.2% vs 92.1%, p = 0.0115) and delayed phase (97.6% vs 90.7%, p = 0.043). Likewise, a higher proportion of TC-treated patients compared to DC remained nausea-free for the first 24 h after treatment (90.6% vs 71%, p = 0.0004) and between 24 and 120 h (82.3% vs 62.7%, p = 0.0025). The change of NEPA administration time showed similar effectiveness in terms of CINV control (81.6% vs 74.5%, p = 0.70). TC showed superiority in early and delayed CINV control in carboplatin AUC ≥ 4 regimens, with no significant differences among cancer types. Change in NEPA administration timing has beneficial implications; it allows NEPA to be administered at hospitals before chemotherapy session.

TANDEM HIGH DOSE CHEMOTHERAPY WITH AUTOLOGOUS BONE MARROW TRANSPLANTATION IN GERM CELL TUMOR— EXPERIENCE FROM A TERTIARY CARE CENTER FROM SOUTH INDIA

Background: The use of high-dose chemotherapy with autologous hematopoietic cell transplantation is well established as a potentially curative approach in patients with relapsed or refractory disease in testicular Germ cell tumours after initial cisplatin-based chemotherapy. The use of tandem transplant with high-dose carboplatin and etoposide conditioning has been a tried and is a feasible option in relapse setting.Overall, HDCTand Autologous stem cell transplant can offer cure rates of up to 60% in the relapsed GCTsetting. Data on Tandem HDCTand ASCTis very limited in Indian subcontinent. Hence we report our experience with respect to safety, efcacy and tolerability, survival outcomes of HDCT/ ASCT in patients with relapsed GCT. Methods: Patients who were diagnosed with relapsed or refractory Germ cell tumours and underwent Tandem HDCT and ASCT were analysed from patient records from 2013 to 2020. Results: Both our patients received BEP (bleomycin, etoposide, and cisplatin) as rst-line therapy. HDCT was done after 2nd line salvage chemotherapies in both patients. Both patients were treated with 2 courses of High-dose carboplatin (700mg/m2) and etoposide(750mg/m2) as conditioning regimen followed by stem cell rescue(CD34+ stem cells yield – 5 to 6x106 cells/kg ) 3-4 weeks apart. Grade ¾ toxicities including myelosuppression, diarrhea, mucositis were observed in both patients. After ASCT both patients were followed up with imaging and serial monitoring of tumour markers. 1st patient died 3 months after ASCT due to disease relapse and our 2nd patient was disease free for 22 months, after which he developed progressive disease in brain and succumbed to disease. Conclusion: This is the rst report from India on tandem HDCT with ACST in relapsed GCTs. Tandem HDCT/ASCT seems to be safe and feasible option in relapsed/ refractory testicular GCT's.

Modifiable Risk Factors Are Associated with Reduced Bone Mineral Density and Fractures in a National Cohort of 2,003 Dutch Childhood Cancer Survivors

Introduction Childhood cancer survivors are at risk of developing skeletal late effects. However, evidence on risk factors for very low bone mineral density (BMD, Z-score ≤-2), as well as on risk and risk factors of (vertebral) fractures is limited. We investigated this in a national cohort of Dutch childhood cancer survivors treated from 1963-2002. Methods This cross-sectional study is part of the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort. Individuals who survived at least five years after cancer diagnosis and aged 18-45 years at invitation were included. BMD was assessed by dual-energy X-ray absorptiometry (DXA, n=1,548). We defined low BMD as a Z-score ≤-1 and very low BMD as a Z-score ≤-2. Fractures that occurred >5 years after cancer diagnosis were assessed by medical history (n=1,892). Fracture incidence was compared with Swedish normative data by calculating a standardized incidence ratio (SIR). Vertebral fractures were evaluated by DXA-assisted vertebral fracture assessment using the Genant semiquantitative method (n=249). Associations between demographic, treatment-related, endocrine, as well as lifestyle-related factors and reduced BMD and (vertebral) fractures were evaluated using univariable or multivariable logistic regression models. Results A total of 2,003 childhood cancer survivors participated in this study (32.3% lymphoid leukemia, 5.1% myeloid and other leukemia, 18.6% lymphoma, 28.0% solid tumors, and 16.0% CNS and brain tumors) with a mean age of 33.1 (standard deviation ±7.2) years. Low BMD at any site occurred in 35.3% (95%CI=32.1-38.5%) of survivors with hematologic malignancies, and very low BMD in 9.6% (95%CI=7.7-11.2%). Additionally, 32.3% (95%CI=29.5-35.2%), 16.8% (95%CI=14.6-19.2%), and 13.3% (95%CI=11.3-15.5%) of survivors with hematologic malignancies had experienced any fracture, a long bone fracture, or a fragility fracture, respectively. The SIR of any first fracture that occurred at least 5 years after cancer diagnosis was 3.53 (95%CI=3.06-4.06) for male survivors and 5.35 (95%CI=4.46-6.52) for female survivors. Vertebral fractures were prevalent in 13.3% of evaluable survivors. In the models for low or very low BMD, male sex, underweight, shorter follow-up time (continuous), total body irradiation, cranial irradiation, carboplatin (≥2,000 mg/m2), alkylating agents (≥8,000 g/m2), hypogonadism, growth hormone deficiency (GHD), hyperthyroidism, low physical activity, severe vitamin D deficiency, vitamin B12 deficiency, and folic acid deficiency were statistically significant. Male sex, obesity, previous/current smoking, and very low lumbar spine BMD were significantly associated with reported clinical fractures. Older attained age, platinum compounds, GHD, and low physical activity were significantly associated with vertebral fractures. Conclusions: Childhood cancer survivors are at increased risk of any fracture. Reduced BMD at follow-up (especially very low lumbar spine BMD) was significantly associated with fractures, which underscores the importance of active BMD surveillance for high-risk survivors (i.e. those treated with cranial/craniospinal or total body irradiation). We identified high-dose carboplatin as a new treatment-related risk factor for low BMD, whereas corticosteroid (dose) was not significantly associated with reduced BMD or fractures. In addition, several modifiable risk factors for reduced BMD (i.e. hypogonadism, GHD, low physical activity, severe vitamin D deficiency, vitamin B12 deficiency, and folic acid deficiency) and vertebral fractures (i.e. GHD and low physical activity) were identified.

GYNECOLOGICAL MALIGNANCIES

A large study of tumors of low malignant potential confirmed the favorable survival in this group of patients compared to invasive epithelial ovarian tumors. Only 8% of patients died with recurrent disease after surgery. Patients with stage IA borderline tumors with mucinous histology tended to recur later and carried a poorer prognosis than patients with serous histology and similar stage. The group at highest risk for relapse were age greater than 70, stage II or III tumors, and histology other than serous. Long-term survival in this group was less than 75%. This high-risk group of patients should be targeted for innovative adjuvant treatment strategies. This year several well-designed studies with large sample sizes showed DNA ploidy to be an important new independent prognostic factor in stage I ovarian carcinoma. In patients with well-differentiated early stage ovarian cancer, DNA flow cytometric analysis may indicate subgroups with less favorable prognostic characteristics. This method of analysis may be beneficial in determining the need for additional treatments after surgery for early stage ovarian carcinoma. Recommendations for the definitive management of early stage ovarian cancer awaits completion of current GOG and European randomized prospective studies. Paclitaxel given in combination with platinum-containing agents is an intense area of research for treatment of advanced stage disease. Early data from a prospective randomized trial of patients with advanced ovarian cancer showed a higher response rate and longer disease-free survival in patients treated with paclitaxel and cisplatin compared to a standard regimen of cyclophosphamide and cisplatin. The impact of this treatment on long-term survival awaits maturation of data. Preliminary results evaluating G-CSF in combination with paclitaxel and cisplatin for dose escalation was reported. Paclitaxel, 250 mg/m2, and cisplatin, 75 mg/m2, were the maximally tolerated doses, with peripheral neuropathy or myalgias the dose limiting toxicities. Further studies are now underway to test the effect of dose-response with escalation therapies and to determine the optimal dose and schedule for the management of patients with advanced ovarian cancer. IL-3 significantly ameliorated neutropenia but did not prevent cumulative platelet toxicity in a regimen utilizing high-dose carboplatin. This mild improvement in myelosuppression was obtained at the cost of significant toxicity. Nausea, vomiting, malaise, bone pain, headache, fever, chills and facial flushing were frequent. Intraperitoneal chemotherapy was tested as a means of consolidation treatment for patients after having a negative second-look laparotomy. These treatments were shown to be feasible; however, prospective randomized trials will be necessary to determine a benefit over operative therapy alone. Several studies addressed to problem of residual disease after primary surgery and adjuvant chemotherapy. A large phase II study conducted by the GOG confirmed the activity of salvage cisplatin-based intraperitoneal chemotherapy in patients with small-volume residual ovarian cancer with favorable pretreatment characteristics. Whether intraperitoneal platinum-based therapy represents an advantage over systemic platinum therapy is being addressed in a prospective SWOG study. The use of six additional cycles of CAP for treatment of residual disease after primary treatment of surgery and adjuvant chemotherapy did not significantly improve complete pathological response and survival. Prolonged duration of chemotherapy above six cycles is not likely to impact treatment for residual disease. A regimen of high dose carboplatin was compared to whole abdominal radiotherapy for treatment of residual disease after initial chemotherapy. There was no difference in survival or disease-free survival between treatments.(ABSTRACT TRUNCATED)

Cyclophosphamide, Etoposide, and Intermediate-Dose of Carboplatin; An Efficient Preparative Regimen for Autologous Transplantation for Patients with Lymphoma, a Good Alternative to Those Based on Carmustine. Experience with 108 Patients

Autologous Stem Cell Transplantation (ASCT); is a universal accepted therapy for rescuing relapsed Hodgkin (HL) and non-Hodgkin (NHL) lymphoma patients and for consolidation of mantle cell lymphoma (MCL). The most used preparative regimens in this setting are BEAM and CBV. both of them include carmustine, a medication with serious shortage and cost problems, therefore , is very important to find alternative regimens. During the nineties the combination of high dose of carboplatin plus cyclophosphamide and etoposide (CEC) was explored, however, it was abandoned due to high toxicity. We present our experience with 108 patients using this regimen but with intermediate dose of carboplatin (Inter CEC)Methods:We did a retrospective descriptive longitudinal observational study. All consecutive patients who met the inclusion criteria; age above 18 years, diagnosis of HL, NHL, M CL, and transplanted with Inter CEC were included. The preparative regimen consisted of carboplatin 900 mg/m2, etoposide 900 mg/m2, and cyclophosphamide 6.000 mg/m2, split in five days (fig 1). All patients received peripheral blood stem cells, and from d + 5 until neutrophil recovery, daily filgrastim. Every patient signed informed consent and the study was approved for institutional ethical committee.Results:From Oct 2013 to May 2020, 108 patients were included; median age was 45 years (18-70), 43.5% were female, 20% were older than 60 years and 79.6% had advanced disease at diagnosis. Thirty-five (32.4%) had HL, 35 (32.4 %) NHL (28 diffuse large B cell, 7 follicular), 29 (26,9%) had MCL, and 9 (8.3%) had other lymphomas. 34% of HL patients and 48% of cases were transplanted in CR1 after being refractory to first line therapy, while 44% and 14% of HL and NHL respectively had active disease at the time of transplantation. Regarding MCL cases; 21 (72,4%) had MIPI above 3 points and 96.5% were transplanted in first remission.All of the evaluable patients at day + 30 had hematopoietic recovery, median time to achieve 500 neutrophil /ul or more was 12.3 days (10-30) and for self-sustained platelet counts, 20.000/ul or more, was 15.3 (10-34).After a median follow up for surviving patients of 42,2 months the overall survival (OS) (Kaplan-Meier) at 48 months for the entire group was 74% (CI 63-82) and the event free survival (EFS) was 57% (CI 43-69). When the OS and EFS were discriminated for diseases, it was; for HL 76% (CI 56-88) and 43% (CI 17-66), for NHL 78% (CI: 57-90) and 68% (CI 42-83), and for MCL 69% (48-83) and 57% (CI 32-76) respectively (Fig 2). Eleven out of 18 patients (61%) transplanted with active disease achieved complete remission and 14 out of the entire group relapsed during the first years of transplantThe transplant related mortality (TRM) at 1 year was 2.8%, the relapse associated deaths were 13% and, in 5 patients, who died after one year of transplant, the cause was not found. The main toxicity was mucositis; 46%, (grade II-IV: 22%), 30 patients (28%) had confirmed infections; bacteremia 17 cases, pneumonia 5, and others infections 6. Renal toxicity occurred in 24 cases (22%), grade 1; 15.8%, grade 2; 4.6% and grade 3; 1.8%DiscussionComparing results among trials is always difficult; however, despite that, in our series 58% of the cases were transplanted with active disease, our outcomes compare favorably with the results informed after the use of BEAM or CBV presented by CIBMTR in the largest trial published so far (table 1). The use of intermediate dose of carboplatin plus etoposide and cyclophosphamide produces a very good control of the lymphoma activity with acceptable toxicity, and achieves good OS and EFS. Other advantage of this regimen is that is carmustine free. The next step in our study is to do a matched paired analysis with patients transplanted with BEAM or CBV [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Autologous Stem Cell Transplantation in Testicular Germ Cell Tumor-Preliminary Experience from a Single Center.

Background Germ cell tumor (GCT) of the testis is one of the highly curable solid organ malignancies. Those who experience relapse after platinum-based chemotherapy can be salvaged with systemic therapy followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). Complete remission can be obtained in approximately 50 to 60% of patients treated with HDCT. Our experience reports the efficacy and safety of HDCT followed by ASCT in relapsed GCT. Methods Analysis of patient records (2012–2019) showed that three patients had received HDCT and ASCT. Results All the three patients were treated with BEP (bleomycin, etoposide, and cisplatin) as first-line therapy. HDCT was done in Case 1 after third-line salvage and in other two patients after second-line salvage chemotherapies. High-dose carboplatin and etoposide were used as conditioning regimen. Granulocyte colony-stimulating factor was used for the mobilization of stem cells. After ASCT, complete remission was documented in all the patients. All were alive and disease-free till the last follow-up. Grade ¾ toxicities including myelosuppression, diarrhea, and mucositis were observed in all three patients. Conclusion This is the first report from India on HDCT with ASCT in GCT. HDCT/ASCT seems to be feasible, safe, and effective in relapsed testicular GCTs.

Abstract PS13-51: A phase II study of neoadjuvant weekly carboplatin/paclitaxel followed by dose-dense doxorubicin/cyclophosphamide (DD AC)in patients with triple negative breast cancer (TNBC): Wisconsin oncology network (WON) study

Abstract Background: The CALGB 40603 and BrighTNess studies found that adding high dose carboplatin every 3 weeks to the standard neoadjuvant DD AC - paclitaxel regimen in TNBC increased the pathologic complete response (pCR) rate to 54-58% but with the cost of increased treatment related toxicities resulting in decreased completion of the full course of treatment. Our hypothesis is by changing the high dose carboplatin every 3 weeks to low dose weekly carboplatin, it will retain the same benefit in pathologic response rate and minimize the treatment related toxicities, which in turn permits the full course of neoadjuvant treatment given to patients. Patients and Methods: This multi-center study was conducted through the WON (NCT03301350). Eligible TNBC patients for neoadjuvant chemotherapy received weekly carboplatin (AUC=2) and paclitaxel 80 mg/m2 for 12 doses, followed by dose dense doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 weeks with granulocyte growth factor support for 4 cycles. A one-week break was added before DD AC after the first 22 patients in order to minimize prolonged cytopenia. Primary end point was pCR. Secondary endpoints were frequency of dose modification and treatment related toxicities. Results: Accrual target was 50 with 80% power to detect a 20% difference using a one-sided binomial test at an alpha significance level of 0.025, but study was terminated earlier. Twenty-nine eligible patients consented for the study from November 2017 to February 2020. Median age was 52 year-old (range, 33-80). Twenty-eight patients received the study regimen. Three were removed due to early study termination and one (3.8%) died from grade 5 neutropenic sepsis after the last cycle of DD AC before surgery. Thus, 24 patients were evaluable for the primary outcome and 26 were evaluable for dose modification and toxicity outcomes. Eight patients (33%) achieved pCR and another 4 patients (17%) had minimal (ypT1aN0) residual disease. Of 26 patients, 24 (92%) were able to receive the full course of treatment +/- dose modification. One patient required the discontinuation of weekly carboplatin/paclitaxel completely due to severe infusion reaction and one did not finish the treatment before the study was terminated. Eight patients (31%) required dose delay with 5 of them during the weekly carboplatin/paclitaxel treatment. Seven patients (27%) also required dose reduction with 5 of them during the weekly carboplatin/paclitaxel treatment. Seventeen patients (65%) experienced severe adverse event (grade 3 or 4) with the majority of events (12/17) relating to grade 3-4 neutropenia or neutropenic fever. Conclusion: Although our study showed a lower pCR rate of 33% in compare to the previous CALGB 40603 (54%) and BrighTNess (58%) studies, we demonstrated that the majority of patients (92%) were able to receive the full course of study treatment. This weekly carboplatin with paclitaxel - AC regimen was used in the recent Keynote 522 study as the backbone chemotherapy to combine with check-point inhibitor immunotherapy in TNBC. However, any dosing schedules of carboplatin, weekly or every 3 weeks, add substantially to grade 3 or 4 toxicity of paclitaxel - AC. Aggressive supportive care management is needed when carboplatin is used. Citation Format: Yee Chung Cheng, Ruth O'Regan, Lubna N Chaudhary, Sailaja Kamaraju, Harvey Einhorn, Emmanuel Sampene, Marialane Pigsley, Mark E Burkard, Christopher R Chitambar, Kari B Wisinski. A phase II study of neoadjuvant weekly carboplatin/paclitaxel followed by dose-dense doxorubicin/cyclophosphamide (DD AC)in patients with triple negative breast cancer (TNBC): Wisconsin oncology network (WON) study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-51.

262 - High-Dose Carboplatin and Thiotepa with Autologous Hematopoietic Stem Cell Rescue (auHSCR) for Medulloblastoma (Mdl) and Atypical Teratoid Rhabdoid Tumors (ATRT) of Central Nervous System (CNS)

262 - High-Dose Carboplatin and Thiotepa with Autologous Hematopoietic Stem Cell Rescue (auHSCR) for Medulloblastoma (Mdl) and Atypical Teratoid Rhabdoid Tumors (ATRT) of Central Nervous System (CNS)

LGG-24. CARBOPLATIN-INDUCED HEMATURIA IN A PEDIATRIC PATIENT WITH LOW-GRADE GLIOMA AND REVIEW OF LITERATURE

OBJECTIVEIn this case report, we present a pediatric patient with gross hematuria and hydroureteronephrosis associated with high dose carboplatin. Given the paucity of literature on the subject, we also conduct and present a review of cases. CASE PRESENTATION: A 6-year-old Caucasian female with history of Type 1 neurofibromatosis was undergoing treatment for a low-grade glioma with monthly high dose carboplatin (560 mg/m2). After 8th dose out of 13, the patient developed severe nausea and vomiting and was admitted for dehydration. She was noted to have microscopic hematuria. After 9th dose, the patient again developed severe nausea, vomiting and gross hematuria with clots. She was admitted and treated with IV hydration. Renal ultrasound showed newly developed bilateral hydroureteronephrosis. Coagulation studies were normal. Multiple cultures and viral studies were negative. Hematuria cleared spontaneously after 4 days of aggressive hydration.RESULTSSubsequent carboplatin was given with aggressive hydration and minimized nausea/vomiting and no hematuria was observed. Literature review revealed only 4 reported cases of carboplatin-induced hematuria, including only one pediatric case that occurred in a patient with concurrent thrombocytopenia. Carboplatin may exhibit toxicity to the transitional epithelial cells of the urogenital tract causing hemorrhage from the renal pelvis and ureters. If untreated, this may lead to urinary outflow obstruction and subsequent obstructive nephropathy.CONCLUSIONWe present a rare toxicity, gross hematuria caused by high-dose carboplatin treatment. Providers should be aware of this rare toxicity and provide timely hydration and supportive care to prevent development of obstructive kidney injury and/or renal failure.

Response to guadecitabine (SGI-110) combined with cisplatin and gemcitabine (GCG) in platinum refractory germ cell tumors (GCTs).

e17057 Background: Treatment options for platinum refractory GCTs are limited. Platinum resistance derives, in part, from tumour suppressor gene promotor methylation. In vitro, this reverses on co-administration of a DNA hypomethylating agent. Guadecitabine is a next generation hypomethylating agent. SPIRE is a phase Ib/IIa clinical trial to establish a GCG dose/schedule. Methods: We report 2 platinum refractory GCT patients (pts) treated (txd) in SPIRE with GCG (guadecitabine 20 mg/m2, SC, day (D) 1-5; cisplatin 70 mg/m2, IV, D8; gemcitabine 1000 mg/m2, IV, D8 + 15; filgrastim 300 μg, SC, D15-21; q21). Results: Pt 1: 21 yo man, testicular mixed GCT (seminoma/malignant teratoma intermediate). Prior tx: 2001, orchidectomy; 2005, 3 x BEP (bleomycin, etoposide, cisplatin) + retroperitoneal lymph node dissection. 2015, 2 x TI (paclitaxel, ifosfamide), 3 x TIP (cisplatin, ifosfamide, paclitaxel); 2016, 3 x HDCE (high dose carboplatin/ etoposide + autologous stem cell transplantation); 2017, 6 x GOP (gemcitabine, oxaliplatin, paclitaxel). In 2017, received 6 x GCG in SPIRE for CT confirmed lung metastases (mets) and rising β-hCG (human chorionic gonadotropin). Response: RECIST stable disease with metabolic CR on PET in lungs and &gt; 90% β-hCG reduction. In Cycle 6, pt developed symptomatic brain mets, treated with WBRT (40Gy, 20#) + cyberknife to the six mets completed 2018. Since 2018, ongoing complete marker and radiologic (brain and systemic) remission (20 months). Pt 2: 44 yo man, primary mediastinal non-seminomatous GCT. Prior tx: 2008, 4 x BEP + mediastinal mass resection; 2015, 4 x TIP; 2016, 1 x HDCE. In 2017, received 5 x GCG in SPIRE for a PET avid mediastinal/pulmonary relapse and AFP (alpha-fetoprotein) rise. Response: RECIST stable and &gt; 50% AFP reduction for 6 months (subsequent progression with intracerebral metastasis). Treatment was well tolerated. Grade 4 neutropenia/ thrombocytopenia occurred in both and febrile neutropenia in pt 1. Both required a 25% dose reduction in Cis/Gem. Conclusions: GCG produced exceptional clinical responses in both platinum refractory GCT pts. Prospective evaluation is warranted. Clinical trial information: 16332228.

Detailed evaluation of hearing loss (HL) associated with high-dose (HD) carboplatin for salvage treatment of germ cell tumors (GCT).

401 Background: HD carboplatin is an essential part of curative salvage high-dose chemotherapy (HDCT) for GCT. Although ototoxicity is a known side effect of HD carboplatin, data on severity and characteristics of HL in this population are limited. Methods: Eligible patients (pts) received salvage HD carboplatin for GCT at our center from 1993-2017 and had audiograms pre- and post-HDCT. All pts were planned for 3 sequential cycles of HD carboplatin; some had audiograms after each cycle. HL severity was classified by ASHA criteria (slight: 15-24dB; mild: 25-40dB; moderate: 41-55dB; moderately severe: 56-70dB; severe: 71-90dB; profound: &gt;90dB). Change in hearing threshold at each frequency (0.25 – 8 kHz) was analyzed by clinical and treatment variables using the Wilcoxon rank-sum test. The proportion of pts recommended for hearing aids was also recorded. Results: Of 115 pts (median age 31, 77% nonseminoma), 96 received TI-CE and 19 received TI-TIC on a clinical trial (Feldman CGUC 2015). Pts varied by prior cisplatin exposure (77% with ≤4 vs 23% with 5-9 cycles) and number of HD carboplatin cycles (89% had 3, 10% had 2, and 2% had 1). Carboplatin AUC was 21 in 23%, 24 in 75%, and 28 in 3%. Moderate to profound HL was present in 23% pre-HD carboplatin vs 82% post, preferentially at high frequencies (Table). Of 89 pts with normal to mild HL at baseline, 78% developed moderate or worse HL post-HD carboplatin, including 61% with moderately severe or severe HL. Higher AUC (24 vs 21) and number of HD carboplatin cycles were associated with greater HL with HD carboplatin whereas prior cisplatin exposure was not. Due to moderate or severe HL in the vital speech frequency range (2 – 4kHz), 20 (17%) pts were recommended for hearing aids post-HD carboplatin. Conclusions: In the largest series to detail ototoxicity in pts receiving salvage HD carboplatin for GCT, we show HL, particularly at high frequencies, is a major dose-dependent toxicity. Most pts will have at least moderate high frequency HL after HD carboplatin with approximately 1 in 6 recommended for hearing aids. [Table: see text]

Changes in glomerular filtration rate and clinical course after sequential doses of carboplatin in children with embryonal brain tumors undergoing autologous stem cell transplantation

BackgroundTreatment for malignant embryonal brain tumors in young children usually employs cycles of standardly dosed cisplatinum followed by high-dose carboplatinum-containing conditioning with single or tandem autologous stem cell rescue (HDC-ASCR). High-dose carboplatin is potentially nephrotoxic, and additive platinum exposure may acutely impact renal function. Aiming to determine if decrease in renal function during conditioning assessed prior to each carboplatin dose was associated with acute increases in creatinine, requirement for dialysis or transplant-related mortality (TRM). This was a retrospective study of consecutive patients with medulloblastoma (n = 15) / atypical teratoid/rhabdoid tumor (AT/RT, n = 5) receiving HDC-ASCR. Fifteen patients underwent 1 HDC-ASCR (carboplatin × 3 doses/ etoposide/ thiotepa) and 5 patients underwent at least 1 of 3 planned tandem HDC-ASCR (carboplatin × 2 doses/ thiotepa). Renal function was assessed by daily creatinine and nuclear medicine glomerular filtration rate (GFR)/ creatinine clearance before each carboplatin dose.ResultsIn this cohort of 20 patients, 3 had doses of carboplatin omitted due to decreases in GFR: 1 did not develop nephrotoxicity, 1 experienced nephrotoxicity without need for dialysis, and 1 required dialysis temporarily but recovered renal function. Two patients did not have GFR changes but developed post-ASCR renal failure requiring dialysis and TRM.ConclusionDaily assessment of renal function by GFR, prior each dose of carboplatin during HDC-ASCR, will help in protecting the kidney in heavily treated population of oncology/HSCT patients. Although the study had a small number of patients which is a major limitation of the study, but it points to a serious transplant-related morbidity and mortality. So, larger scale studies are needed to clarify the best approach to carboplatin dosing to insure the optimal balance between efficacy and toxicity.

Pharmacokinetics of high-dose carboplatin in children undergoing high-dose chemotherapy and autologous stem cell transplantation with BSA-based dosing.

Body surface area (BSA)-based carboplatin dosing is used in various centers due to practical issues of renal function-based dosing with area under the curve (AUC) measurement. Pharmacokinetic (PK) analysis of high-dose carboplatin was performed in pediatric solid tumor patients undergoing high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) with BSA-based dosing to calculate the AUCs achieved with this dosing method and to find the correlation between the PK and the renal functions and the adverse events. Carboplatin was administered as once daily intravenous doses at 300, 400, or 500 mg/m2/day over 1 h for 3 or 4 days. On the first and the last day of carboplatin administration, PK samplings were done at 0, 1, 2, and 5 h and only at 0 h on any other days. Mean AUC on the first and the last day were 4.85 ± 0.95 min × mg/mL and 5.27 ± 1.04 min × mg/mL, respectively (n = 23). Overall, negative correlations between the renal functions and the AUCs were mild to moderate, but they were stronger in nephrectomized patients. 51Cr-EDTA clearance decreased with statistical significance with each additional dose of carboplatin (P = 0.020). Optimal high-dose carboplatin dosing method and optimal target AUCs for the different tumors need further analysis.

Effects of ultrasound combined with microbubbles on intracellular Ca2+ homeostasis in carboplatin-treated microenvironment of A549 cell line

Objective To investigate the effects of ultrasound combined with microbubbles on intracellular Ca2+ homeostasis in carboplatin(CBP)-treated A549 cell and its possible mechanisms of inhibiting A549 cell line activity. Methods According to whether SonoVue was used or not, and the different dose of CBP, the groups A-F were arranged as the ultrasound(US) group(group A), the ultrasound combined with microbubbles (USMB) group(group B), the low dose CBP (100 μg/ml)+ US group(group C), the low dose CBP+ USMB group(group D), the high dose CBP (200 μg/ml)+ US group (group E) and the high dose CBP+ USMB group(group F). A549 cells were bathed and washed by a calcium-free buffer, loaded with Ca2+ indicator fluo-4 AM. Real-time images were acquired using laser confocal microscopy. The fluorescence intensity of intracellular calcium ion concentration ([Ca2+ ]i) in individual living cell was observed and the calcium overload was analyzed. Results After ultrasound irradiation, the normalized fluorescence intensity of [Ca2+ ]i increased rapidly, then returned to a new homeostasis (selected cells in groups A, B, E, F) or experienced a second calcium oscillation (some cells in group C and D). All the selected cells in group B and some cells in group C and D exhibited superimposed oscillations. The calcium overloading time in group D was longer than those of any other groups. Four cells in group A experienced delayed calcium oscillations. Compared with group A, the selected cells in other groups exhibited a larger amplitude of calcium oscillation(all P<0.05) and the selected cells in group B and D exhibited calcium oscillation for a longer period of time(all P<0.05). Conclusions In the calcium-free buffer, US, USMB, CBP+ US, CBP+ USMB are direct stimuli of calcium overload in A549 cells. SonoVue, CBP, CBP+ SonoVue are all synergistic stimuli of calcium overload in A549 cells irradiated by ultrasound.US, USMB and CBP may synergistically induce calcium release from intracellular store sites in A549 cells. Calcium overload is a possible mechanism of ultrasound combined with microbubbles in assisting CBP chemotherapy. Key words: Sonication; Microbubbles; Carboplatin; A549 cell; Calcium overload; Cavitation effect

Population pharmacokinetics of carboplatin, etoposide and melphalan in children: a re-evaluation of paediatric dosing formulas for carboplatin in patients with normal or mild impairment of renal function.

Carboplatin dosage is calculated by using the estimated glomerular filtration rate (GFR) to achieve a target plasma area under the plasma concentration-time curve (AUC). The aims of the present study were to investigate factors that influence the pharmacokinetics of carboplatin in children with high-risk neuroblastoma, and whether target exposures for carboplatin were achieved using current treatment protocols. Data on children receiving high-dose carboplatin, etoposide and melphalan for neuroblastoma were obtained from two study sites [European International Society for Paediatric Oncology (SIOP) Neuroblastoma study, Children's Hospital at Westmead; n = 51]. A population pharmacokinetic model was built for carboplatin to evaluate various dosing formulas. The pharmacokinetics of etoposide and melphalan was also investigated. The final model was used to simulate whether target carboplatin AUC (16.4mg ml-1 ·min) would be achieved using the paediatric Newell formula, modified Calvert formula and weight-based dosing. Allometric weight was the only significant, independent covariate for the pharmacokinetic parameters of carboplatin, etoposide and melphalan. The paediatric Newell formula and modified Calvert formula were suitable for achieving the target AUC of carboplatin for children with a GFR <100ml min-1 1.73m-2 but not for those with a GFR ≥100ml min-1 1.73m-2 . A weight-based dosing regimen of 50mg kg-1 achieved the target AUC more consistently than the other formulas, regardless of renal function. GFR did not appear to influence the pharmacokinetics of carboplatin after adjusting pharmacokinetic parameters for weight. This model-based approach validates the use of weight-based dosing as an appropriate alternative for carboplatin in children with either mild renal impairment or normal renal function.

Autologous Stem-Cell Transplantation Outcomes for Relapsed Metastatic Germ-Cell Tumors in the Modern Era.

High-dose chemotherapy (HDCT) with autologous stem-cell transplantation (aSCT) has been a standard therapy for relapsed metastatic germ-cell tumors (GCTs) over the last 2 decades, but there have been many changes in practice over time with respect to stem-cell source, mobilization, and conditioning regimens. Mobilization is impaired with greater cisplatin exposure. Patients with relapsed GCT who received HDCT/aSCT at Dana-Farber Cancer Institute between 1997 and 2017 were identified. Diagnosis, first-line chemotherapy, stem-cell mobilization, HDCT, toxicity, and survival outcomes were annotated and descriptively summarized. Univariable associations of clinicopathologic features and relapse and survival were assessed. Time-to-event analyses were performed by HDCT type and duration. Thirty-five eligible patients were identified. The most common regimen before HDCT was paclitaxel, ifosfamide, and cisplatin, and it resulted in a high rate of successful initial mobilization (95%). Ten patients (29%) were mobilized with filgrastim and plerixafor (CXCR4 antagonist). All plerixafor-treated patients were mobilized with sufficient cells for 2 transplants. Oxazaphosphorine (cyclophosphamide or ifosfamide)-containing (O-C) HDCT was provided between 1997 and 2008, and subsequent patients were treated with high-dose carboplatin plus etoposide (CE). O-C HDCT was associated with excessive cardiac (33%), severe liver (93%), and renal dysfunction compared to CE. Two O-C-treated patients died of drug-related lung toxicity. Fifty-one percent of the cohort experienced relapse, and 46% died. Plerixafor has a role in stem-cell mobilization and aSCT for relapsed GCT when cisplatin in bridging before HDCT may be problematic. O-C and CE HDCT regimens have different toxicity patterns that are clinically meaningful.

Individualization of high dose carboplatin based on therapeutic drug monitoring (TDM) for the treatment of testicular germ cell tumors (TICE protocol): Results of a multicenter phase II study.

4554 Background: We conducted a national phase II multicenter trial that aimed at evaluating the efficacy and tolerance of Paclitaxel plus Ifosfamide followed by high-dose carboplatin plus etoposide treatment (TICE) in previously treated germ cell tumors. The particularity of our study (in comparison with the standard protocol [Motzer RJ, et al. J Clin Oncol 2000 Mar; 18(6): 1173-1180.]) is that the carboplatin dose was individualized for each patient according to therapeutic drug monitoring (TDM) in order to reach the target AUC of 24 mg.min/ml over 3 days. Methods: In total, 89 patients were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/ml over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC and the intra- and inter-cycle clearance variability. Secondly, a population pharmacokinetic analysis was also performed on 59 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future patients treated with the TICE protocol. The performance of this new equation was then prospectively evaluated on the other 30 patients along with different methods of carboplatin clearance prediction. Results: TDM allowed us to control the carboplatin exposure with a mean actual AUC of 24.5 mg.min/ml (22.2 and 28.0 for 5th and 95thpercentile respectively) per cycle. We observed a modest but significant decrease of carboplatin clearance over cycles (median value of change of -11.8% from cycle 1 to cycle 3, maximum value of -36%). The new covariate equation allows unbiased and more accurate prediction of carboplatin clearance in the prospective validation cohort compared to other equations. Conclusions: Carboplatin TDM allowed the target AUC to be accurately reached and thereby avoid over- or under-exposure. We propose a new equation to predict carboplatin clearance more adapted to these particular patients (young males) that could be used as an alternative if the TDM cannot be organized. Clinical trial information: 2008-005068-14.