Continuous Infusion Of Cisplatin Research Articles

Rh-endostatin plus camrelizumab and chemotherapy in first-line treatment of advanced non-small cell lung cancer: A multicenter retrospective study.

Clinical evidence of immune checkpoint inhibitors combined with antiangiogenic drugs in patients with advanced non-small cell lung cancer (NSCLC) was limited. Recombinant human endostatin (rh-endostatin), an antiangiogenic drug, and camrelizumab, an anti-PD-1 antibody, have been approved for the treatment of advanced NSCLC in China. This study aimed to investigate the efficacy and safety of rh-endostatin plus camrelizumab and chemotherapy in the treatment of advanced NSCLC. Eligible patients were enrolled and received camrelizumab (200 mg, day 1) every 3 weeks and continuous intravenous infusion of rh-endostatin (70 mg/day, days 1-3) and cisplatin combined with pemetrexed (for adenocarcinoma) or paclitaxel (for NSCLC other than adenocarcinoma) every 3 weeks. Primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profiles. Overall, 27 patients were included, and 25 patients were eligible for efficacy evaluation. For these 25 patients, ORR was 48.15% (13/27) and DCR was 85.19% (23/27). With a median follow-up of 10.37 months, the median PFS was 8.9 (95% CI: 4.23-13.57) months. Median OS was not reached. Overall, 96.3% of patients experienced at least one treatment-related adverse event, and grade 3 TRAEs occurred in 9 (33.3%) patients. No unexpected AEs were observed. Rh-endostatin plus camrelizumab and chemotherapy showed favorable efficacy and safety profile in patients with advanced NSCLC, representing a promising treatment regimen for these patients.

RRM1 and ERCC1 as biomarkers in patients with locally advanced and metastatic malignant pleural mesothelioma treated with continuous infusion of low-dose gemcitabine plus cisplatin

BackgroundMalignant Pleural Mesothelioma (MPM) is a rare but aggressive neoplasia that usually presents at advanced stages. Even though some advances have been achieved in the management of patients with MPM, this malignancy continuous to impose a deleterious prognosis for affected patients (12–18 months as median survival, and 5–10% 5-year survival rate), accordingly, the recognition of biomarkers that allow us to select the most appropriate therapy are necessary.MethodsImmunohistochemistry semi-quantitative analysis was performed to evaluate four different biomarkers (ERCC1, RRM1, RRM2, and hENT-1) with the intent to explore if any of them was useful to predict response to treatment with continuous infusion gemcitabine plus cisplatin. Tissue biopsies from patients with locally advanced or metastatic MPM were analyzed to quantitatively asses the aforementioned biomarkers. Every included patient received treatment with low-dose gemcitabine (250 mg/m2) in a 6-h continuous infusion plus cisplatin 35 mg/m2 on days 1 and 8 every 3 weeks as first-line therapy.ResultsFrom the 70 eligible patients, the mean and standard deviation (SD) for ERCC1, RRM1, RRM2 and hENT-1 were 286,178.3 (± 219, 019.8); 104,647.1 (± 65, 773.4); 4536.5 (± 5, 521.3); and 2458.7 (± 4, 983.4), respectively. Patients with high expression of RRM1 had an increased median PFS compared with those with lower expression (9.5 vs 4.8 months, p = < 0.001). Furthermore, high expression of RRM1 and ERCC1 were associated with an increased median OS compared with their lower expression counterparts; [(23.1 vs 7.2 months for RRM1 p = < 0.001) and (17.4 vs 9.8 months for ERCC1 p = 0.018)].ConclusionsERCC1 and RRM1 are useful biomarkers that predict better survival outcomes in patients with advanced MPM treated with continuous infusion of gemcitabine plus cisplatin.

R-DHA-Oxaliplatin before Autologous Stem Cell Transplantation Prolongs PFS and OS As Compared to R-DHA-Carboplatin and R-DHA-Cisplatin in Patients with Mantle Cell Lymphoma, a Subgroup Analysis of the LyMa Trial

BACKGROUND. The LyMA (ClinicalTrials.gov, NCT00921414) trial is a prospective international randomized phase III trial that investigated Rituximab maintenance (RM) after autologous-stem cell transplantation (ASCT) in young previously untreated mantle cell lymphoma (MCL) patients (Le Gouill et al., in press, 2017). Patients were included at diagnosis (<66y; stage >I) and induction immuno-chemotherapy consisted of 4 courses of R-DHAP-21 (Rituximab, Dexamethasone, High-dose cytarabine, Platinum salt) followed by ASCT consolidation. The conditioning regimen for ASCT was R-BEAM. Patients in response after ASCT were randomized (1:1) between RM or observation. 299 patients (<66y) were included of whom 240 were randomly assigned to RM or observation after ASCT. Median follow-up from randomization after ASCT was 50.2 (46.4-54.2) months. The final analysis demonstrates that RM is superior to observation with respect of EFS, PFS and OS. For induction with R-DHAP, local investigators were free to choose between cisplatin (continuous infusion cisplatin 100 mg/m2 over 24 h on day 1; DHA-Cis), carboplatin (with AUC = 5 mg/ml.min ; target Area Under the concentration vs. time Curve using the Calvert formula ; DHA-Ca) or oxaliplatin (130 mg/m² on day 1 ; DHA-Ox).METHODS. In the present analysis, we investigated the prognostic impact on PFS and OS of the nature of platinum salt used in the R-DHAP regimen. The intention-to-treat (ITT) analysis includes all patients who have received at least one course of R-DHAP (n=298; data missing in one patient) and per protocol analysis (PP) includes all patients who have received the same platinum salt during induction phase (n=227).RESULTS. Cisplatin, Carboplatin and oxaliplatin were used at course 1 in 184, 76 and 38 patients, respectively. Patients' characteristics at diagnosis (including MIPI) and randomization arm (RM or observation) were well balanced between the 3 groups. Twenty-seven (15%) and 38 (21%) out of 184 patients who received cisplatin from course 1 switched to carboplatin and oxaliplatin because of toxicity, respectively. In contrast, only one patient with DHA-Ca switched to DHACis and one patient with R-DHAOx switched to R-DHACa. All cases of renal failure during induction (n=8) occurred in the R-DHACis group. PFS and OS in both ITT and PP were identical in the R-DHACis and R-DHACa groups while there was a trend in favor of R-DHAOx in both PFS (p=0.092 in ITT and 0.0675 in PP) and OS (p= 0.013 in ITT and p= 0.0859 in PP). Because patients' outcome was identical with R-DHACa and R-DHACis, both groups were combined in one group (R-DHACa/DHACis) and then compared to R-DHAOx. In ITT, the 4y PFS and OS in the R-DHAOx vs R-DHACis/Ca were 86.5% (95%CI; 70.5 to 94.1) vs 65% (95%CI; 58.8 to 70.6) and 92% (95%CI; 77.1 to 97.3) vs 75.9% (95%CI; 70.1 to 80.7), respectively. In ITT, patients with R-DHAOx have a better PFS (HR=0.438; 95%CI, 0.204-0.944; p=0.035) and OS (HR=0.373; 95%CI, 0.136-1.023; p=0.0554) as compared to patients with R-DHACa/DHACis . Similar results were reached in the PP analysis: PFS (HR=0.414; 95%CI, 0.191-0.899; p=0.0257) and OS (HR=0.347; 95%CI, 0.126-0.959; p=0.0412). In multivariate analysis (with MIPI), R-DHAOx was independent prognostic marker for PFS and OS.Conclusion. The present analysis shows for the first time that R-DHAOx is a better induction regimen than R-DHACa and R-DHACis in MCL patients and strongly suggests that platinium salt are critical (and not only high dose AraC) in the R-DHAP regimen. Our finding may also have a major impact in other forms of lymphoma where R-DHAP is frequently used as a standard salvage therapy. DisclosuresLe Gouill:Roche: Consultancy, Honoraria, Research Funding; janssen: Consultancy, Honoraria; servier: Consultancy, Honoraria, Research Funding; bayer: Membership on an entity's Board of Directors or advisory committees; celgene: Honoraria, Research Funding. Thieblemont:Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Ribrag:BMS: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Nanostring: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Pharmamar: Consultancy; Esai: Honoraria, Research Funding; Servier: Consultancy, Honoraria; Roche: Honoraria, Other: travel, accommodation, expenses; ArgenX: Research Funding. Jourdan:NOVARTIS: Consultancy, Honoraria. Delarue:Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Salles:morphosys: Consultancy, Honoraria; BMS: Consultancy; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding. Tilly:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria. Lamy:Roche: Consultancy, Honoraria.

Efficacy, Safety, and Cost-Minimization Analysis of Continuous Infusion of Low-Dose Gemcitabine Plus Cisplatin in Patients With Unresectable Malignant Pleural Mesothelioma.

BackgroundMalignant pleural mesothelioma (MPM) is rare and aggressive neoplasia, with a poor prognosis; furthermore, the monetary cost of its treatment represents a major challenge for many patients. The economic burden this malignancy imposes is underscored by the fact that asbestos exposure, which is the most frequent risk factor, is much more prevalent in the lower socioeconomic population of developing countries. The aims of the present study were to evaluate the efficacy, safety, and cost of continuous infusion of low-dose Gemcitabine plus Cisplatin (CIGC) as a treatment strategy for patients with unresectable MPM.MethodsWe performed a prospective cohort study to determine efficacy and safety of continuous infusion gemcitabine at a dose of 250 mg/m2 in a 6-h continuous infusion plus cisplatin 35 mg/m2 on days 1 and 8 of a 21-day cycle in patients with unresectable MPM. We also performed a cost-minimization analysis to determine if this chemotherapy regimen is less expensive than other currently used regimens.ResultsThe median number of chemotherapy cycles was six (range 1–11 cycles); objective response rate was documented in 46.2%, and disease control rate was seen in 81.2%. Median PFS was 8.05 months (CI 95% 6.97–9.13); median OS was 16.16 months (CI 95% 12.5–19.9). The cost minimization analysis revealed savings of 66.4, 61.9, and 97.7% comparing CIGC with short-infusion gemcitabine plus cisplatin (SIGC), cisplatin plus pemetrexed (CP), and cisplatin plus pemetrexed and bevacizumab (CPB), respectively. Furthermore, this chemotherapy regimen proved to be safe at the administered dosage.ConclusionCIGC is an effective and safe treatment option for patients with unresectable MPM; besides, this combination is a cost-saving option when compared with other frequently used chemotherapy schemes. Therefore, this treatment scheme should be strongly considered for patients with unresectable MPM and limited economic resources.

Efficacy of ondansetron against emesis induced by a multiple-day cisplatin-based chemotherapy regimen for malignant lymphoma

ABSTRACT Objectives This study aimed to evaluate the antiemetic efficacy of a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA), ondansetron, in patients with malignant lymphoma receiving multi-day cisplatin-based combination chemotherapy. Methods We conducted a single-institution retrospective analysis of patients receiving the first course of an ESHAP (etoposide, cisplatin, methylprednisolone, cytarabine) regimen including 4-day continuous infusion of cisplatin (25 mg/m2/day). All patients received ondansetron 4 mg intravenously during 5-day administration of ESHAP. The primary endpoint was complete response (CR) for emesis, which was defined as absence of both emesis and rescue medications. Total control (TC) was defined as an absence of emetic episodes, including nausea and emesis, and complete protection (CP) was defined as an absence of emesis with addition of rescue antiemetics. Nausea and vomiting were assessed and graded daily by medical staff. Results Eighty-two patients were analyzed. Nausea and vomiting were generally well controlled, with the CR rates of emesis being 79% in the overall phase, 82% in the early phase (days 1–6), and 89% in the delayed phase (days 7–10). TC and CP were achieved in 51 patients (62%) and 77 patients (94%) in the overall phase. Discussion Most of the chemotherapy regimens for lymphoid malignancies include high-dose corticosteroid which may be also effective as antiemetics. Although NK1 receptor antagonist (NK1RA) is generally recommended for cisplatin-containing chemotherapy, it can interact with variety drugs. Conclusion Although NK1RA is generally recommended for cisplatin-containing regimen, our results suggest that ondansetron effectively controlled emesis in patients receiving ESHAP therapy which includes high-dose corticosteroid.

Proton beam therapy combined with retrograde intra-arterial infusion chemotherapy for an extremely rapid growing recurrent ameloblastic carcinoma: A case report.

Ameloblastic carcinoma (AC) is a very rare malignant odontogenic tumor. Although surgical resection is generally performed, treatment approaches have not been established for recurrent cases. Chemotherapy and radiotherapy are positioned as adjunctive therapies, and few studies investigated definitive non-operative therapy. We present the case of a 71-year-old male with recurrent secondary-type AC arising from the right maxilla, who was treated with proton beam therapy (PBT; 71.4 Gy relative biological effectiveness in 32 fractions) combined with continuous intra-arterial infusion of cisplatin (40 mg/m2) and docetaxel (8 mg/m2). The patient experienced acute grade 3 mucositis, dermatitis and neutropenia, which were resolved within 3 months of treatment. Late adverse events were grade 1 skin atrophy, and grade 2 right optic nerve disorder and retinopathy. After ~8 years of treatment, the patient died from another cause but did not experience any relapse or metastasis during the follow-up period of 94 months. To the best of our knowledge, this is the first report of recurrent AC treated with PBT and intra-arterial infusion chemotherapy without any severe late adverse events. This combination therapy approach may be considered as an effective therapeutic option for inoperable AC.

Different infusion durations for preventing platinum-induced hearing loss in children with cancer.

Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. This review is the third update of a previously published Cochrane Review. To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life. We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library 14 November 2019), MEDLINE (PubMed) (1945 to 14 November 2019) and Embase (Ovid) (1980 to 14 November 2019). In addition, we handsearched reference lists of relevant articles and we assessed the conference proceedings of the International Society for Paediatric Oncology (2009 up to and including 2019) and the American Society of Pediatric Hematology/Oncology (2014 up to and including 2019). We scanned ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; apps.who.int/trialsearch) for ongoing trials (both searched on 4 November 2019). Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups. Two review authors independently performed the study selection, 'Risk of bias' assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We identified one RCT and no CCTs; in this update no additional eligible studies were identified. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one-hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days one to five of the cycle, but it is unclear if the infusion duration was a total of five days. Risk of bias was present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (risk ratio (RR) 1.39, 95% confidence interval (CI) 0.47 to 4.13, low-quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity, we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12, 95% CI 0.07 to 17.31, low-quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one-hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high-quality research is needed.

Successfully overcoming carboplatin hypersensitivity by continuous 48-h infusion of cisplatin plus poly (ADP-ribose) polymerase inhibitor for heavily pretreated recurrent ovarian cancer

The success of ovarian cancer treatment is hampered by the recurrent nature and the resistance or hypersensitivity to a platinum regimen. The addition of poly (ADP-ribose) polymerase (PARP) inhibitors can increase the sensitivity to platinum-resistant tumors, although while increasing risk of hematologic toxicity. Substituting cisplatin for carboplatin could result in satisfactory outcomes in the case of carboplatin hypersensitivity. However, there are no efficacy and safety data regarding continuous low-dose cisplatin infusion combined with an oral PARP inhibitor for ovarian cancer patients with hypersensitivity to carboplatin. Herein, we report the case of a heavily pretreated ovarian cancer patient with carboplatin hypersensitivity who safely received low-dose cisplatin (30 mg/m2 every 3 weeks) over a 48-h infusion combined with a PARP inhibitor for a total of 10 days (D− 2–D7) and successfully achieved partial response after four cycles of treatment, the efficacy of which was further enhanced by the addition of deep regional hyperthermia.

Modified 3-weekly cisplatin or cisplatin-5-fluorouracil 5-day infusion as the concurrent chemoradiotherapy regimen in locally advanced squamous cell carcinoma of the head and neck: Comparison of efficacy and toxicity

Background: Concurrent chemoradiotherapy (CCRT) is an important therapeutic strategy in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). We evaluated the efficacy and toxicity of two CCRT regimens in treating LA-SCCHN. Materials and Methods: LA-SCCHN patients receiving CCRT with either a modified 3-weekly cisplatin 75 mg/m2 (Group A, n = 86) or 5-day continuous infusion of cisplatin 12 mg/m2 plus 5-fluorouracil (5-FU) 600 mg/m2 (Group B, n = 87) were enrolled. The Kaplan−Meier method was used to estimate overall survival (OS), progression-free survival (PFS), and locoregional recurrence-free survival (LRFS). Univariate and multivariate analyses were performed using Cox proportional hazard models to assess correlations between clinical parameters and survival. Results: With a median of 35.8 months' follow-up, the median OS and PFS in Group A and Group B were 65.9 versus 55.0 months (P = 0.546) and 34.6 versus 33.3 months (P = 0.948), respectively. LRFS was not reached in either group. Group B patients had more Grade 3−4 mucositis (53.7% vs. 32.28%, P= 0.001) and dermatitis (49.8% vs. 21.5%, P= 0.0001). Trends of higher incidence rates of Grade 3−4 hematologic and renal toxicity were observed in Group A. After statistical adjustment, higher disease stage (Stage IVb) (hazard ratio [HR] = 6.657, 95% confidence interval [CI] 1.786−24.81, P= 0.005) and pretreatment anemia (hemoglobin

EARLY Results of TOTAL Therapy 7 (TT7): High Response Rates of NEWLY Diagnosed High Risk Myeloma to Daratumumab

Background. The TT approach has significantly improved the outcome of multiple myeloma (MM) by combining new drugs with a regimen that comprises induction, tandem autologous stem cell transplantation (ASCT), consolidation and maintenance. However, a group of 15% of patients with high risk multiple myeloma (HRMM) have derived little benefit despite similar response rates to induction chemotherapy and ASCT when compared to low risk MM. The poor outcome of HRMM is explained by early relapse post ASCT resulting in a short progression free survival (PFS) with only 15-20% of patients surviving long-term. Daratumumab (Dara) is a human IgG1k anti-CD38 monoclonal antibody that has shown favorable results in early single-arm studies and more recently in phase III studies for relapsed/refractory and newly diagnosed MM. In TT7, we introduced Dara during all phases of therapy, including immune consolidation early post ASCT, to improve responses rate and PFS in HRMM. Methods. Patients had newly diagnosed HRMM as defined by high risk cytogenetic abnormalities, presence of extramedullary disease, &gt;3 focal lesions on CT-PET, elevated LDH due to MM, or ISS II/III with cytogenetic abnormality. Dara (16mg/kgx1) was added to induction with KTD-PACE (carfilzomib, thalidomide, dexamethasone; and four-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide). Conditioning for tandem autologous stem cell transplantation (ASCT) was with fractionated melphalan (50mg/m2x4) (fMEL) based on prior observations that patients with adverse cytogenetics fare better with fMEL rather than single high dose MEL200mg/m2.In the inter tandem ASCT period immunological consolidation with Dara (16mg/kg) alone for 2 doses was followed by Dara (16mg/kg) on day 1 combined with K (36mg/m2) and D (20mg) weekly for 2 cycles. DaraKD was administered to avoid treatment free periods allowing for myeloma regrowth. The 2nd ASCT was followed by further immunological consolidation with Dara (16mg/k) for 2 doses, and maintenance therapy for 3 yrs with 3-months block of alternating Dara-KD (dara 16mg/kg day 1; K 36mg/m2 and dex 20mg weekly) and Dara-lenalidomide (R)D (dara 16mg/kg day 1; R 15mg day 1-21 q28 and D 20mg weekly). Results. TT7 enrolled 43 patients thus far. The median follow-up was 11 months (range: 1-22). The median age was 61 yrs (range 44-73). Sixteen patients were ≥65 yrs (37.2%). A mean of 29.4x106 CD34+ cells/kg (range: 4.6-86.4) were collected. 36 patients completed ASCT #1 (83.7%) and 18 (41.9%) ASCT #2, whilst 14 patients have proceeded to the maintenance phase. R-ISS II/III or metaphase cytogenetic abnormalities were present in 85.1 and 58.1% of patients, respectively. Elevated LDH or &gt;3FL on CT-PET were noted in 30 and 41.8%. The 1-yr cumulative incidence estimates for reaching VGPR and PR were 87 and 83%, respectively. A CR or sCR was achieved in 68 and 46%. The 1-yr estimates of PFS and OS were 91.6 and 87.2%. 40 subjects are alive, whilst 5 progressed on study therapy and 3 subsequently died. 38 patients are progression free at the time of reporting. Dara was well-tolerated and no subjects discontinued therapy due to dara-related side effects. The CR and sCR rates compared favorably to the predecessor HRMM TT5 protocol where CR and sCR rates were 59 and 27%. Conclusion. The early results of TT7 point to increased response rates of HRMM to a dara-based TT regimen with especially higher rates of CR and sCR. Longer follow-up is required to determine if these early results translate into superior PFS and OS. Figure Disclosures van Rhee: Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy. Walker:Celgene: Research Funding. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding.

PF606 ADVERSE IMPACT OF PRIOR THERAPY ON TRANSPLANT OUTCOME IN MULTIPLE MYELOMA

Background:We have previously reported that multiple myeloma (MM) patients referred with &gt;1 month of prior therapy have worse outcomes compared to newly diagnosed patients on Total Therapy (TT) trials. We hypothesized that inferior results in previously drug‐exposed patients relate to more resistant disease. This prompted us to explore a less dose intense regimen avoiding high dose melphalan (M) autologous stem cell transplant (ASCT) and allowing for more frequent dosing thus minimizing between‐treatment periods. The aim is to prevent relapse during treatment free periods as a result of M 200 mg/m2‐ASCT as in a standard TT approach.Aims:To assess OS and PFS with a dose dense approach in previously treated patients.Methods:Patients who had undergone prior therapy for MM but were not transplanted were enrolled in TT6. Induction comprised eight‐drug combinations (M‐VTD‐PACE; melphalan, bortezomib, thalidomide, dexamethasone and four‐day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide). Conditioning prior to tandem ASCT was fractionated melphalan (20 mg/m2x4) supplemented by VRD‐PACE (R = lenalidomide). There were two inter‐ASCT cycles with M (5 mg/m2x4)‐VTD‐PACE. Maintenance therapy was 3 yrs VRD.Results:TT6 enrolled 116 patients with prior therapy. The median age was 61 yrs (range: 36–75); 30% of patients were &gt;65 yrs. The median follow‐up was 80 mths (range: 17–114). Three‐year estimate of OS and PFS for the whole cohort was 76% (range: 69–84) and 60% (range:51–69%). Ninety‐seven of the 116 patients had gene array analyses and these were divided into HR and low risk (LR) based on the GEP70 score. Consistent with previous findings LR patients fared consistently better than their HR counterparts: 3 yr‐OS 88% for LR patients (range 80–95%) vs 32% for HR patients, (p &lt; 0.001) and 3 yr‐PFS 68% for LR patients (range: 57–78%) vs. 18% for HR patients, p &lt; 0.0001) with superior 3 yr CR duration (62 vs 43%, p = 0.02). Next, we examined the impact of the duration of prior therapy. Using log‐rank analysis an optimal cutpoint was identified and patients were classified as having received ≤6 mths of prior therapy (n = 75) versus &gt;6 mths of prior therapy (n = 41). Comparison of baseline characteristics showed that patients with &gt;6 mths therapy had more adverse features including a platelet count &lt;150,000/ml (24 vs 8%, p = 0.017), metaphase cytogenetic abnormalities (54 vs 32%, p = 0.023) and &gt;3 FL on CT‐PET (40 vs 22%, p = .044). Both groups had similar (s)CR rates (55% vs 50%, p = 0.31). However, patients with &gt;6 mths therapy had significantly worse outcome in terms of 3 yr‐OS (65vs 83%, p = 0.001) and ‐PFS (38 vs 72%, p = 0.0002). Fifty percent of patients of HR patients with &lt;6 mths of prior therapy remained in (s)CR at 3 years, as compared to none of those with HR MM &gt;6 mths of pretreatment. In multivariate analysis GEP70 and &gt;6 mths prior therapy imparted worse outcome. The hazard ratios for OS were 4.6 (range: 1.9–11.2), p = 0.0007 and 3.4 (range: 1.6–7.3, p = 0.0015), respectively. Similarly, the ratios for PFS were 7.3 (range: 3.8–14.1–11.2), p &lt; 0.0001 and 3.2 (range: 1.6–6.2, p = 0.006).Summary/Conclusion:Dominant determinants of outcome were presence of HR MM and duration of prior therapy. This results suggest that patients should be referred early for M‐based ASCT to obtain the best results. Some caution is required since this study did not employ high M‐based ASCT (M‐200 mg/m2) nor was it designed to answer whether these results pertain to patients treated to progression with a standard regimen such as VRD followed by delayed transplant.image

Different infusion durations for preventing platinum-induced hearing loss in children with cancer.

Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. This review is the second update of a previously published Cochrane review. To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life. We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library 15 March 2018), MEDLINE (PubMed) (1945 to 15 March 2018) and Embase (Ovid) (1980 to 15 March 2018). In addition, we handsearched reference lists of relevant articles and we assessed the conference proceedings of the International Society for Paediatric Oncology (2009 up to and including 2017) and the American Society of Pediatric Hematology/Oncology (2014 up to and including 2017). We scanned ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; apps.who.int/trialsearch) for ongoing trials (searched on 12 March 2018 and 13 March 2018 respectively). Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups. Two review authors independently performed the study selection, 'Risk of bias' assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We identified one RCT and no CCTs; in this update no additional studies were identified. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one-hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days one to five of the cycle, but it is unclear if the infusion duration was a total of five days. Risk of bias was present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (risk ratio (RR) 1.39, 95% confidence interval (CI) 0.47 to 4.13, low-quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity, we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12, 95% CI 0.07 to 17.31, low-quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one-hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high-quality research is needed.

Preliminary Treatment Results of Radiation Therapy With Intra-Arterial Infusion Chemotherapy for Oral Cancer

We retrospectively evaluated the efficacy and safety of radiotherapy with intra-arterial infusion chemotherapy for oral cancer. Between June 2013 and February 2016, 19 patients with previously untreated oral cancer were treated with weekly retrograde intra-arterial chemotherapy by continuous infusion of cisplatin with sodium thiosulphate. Sixteen of the 19 cases were treated with systemic chemotherapy. There were 10 males and 9 females. The median age was 61 years (range, 31-77). The primary sites were the oral tongue (n=15, 79%), gingival (n=2, 11%), buccal mucosa (n=1, 5.3%), and floor of mouth (n=1, 5.3%). The clinical stages were II (n=2, 11%), III (n=1, 5.3%), IVA (n=15, 79%), and IVB (n=1, 5,3%). Most patients (n=17, 89%) were treated with more than 5 cycles of intra-arterial infusion chemotherapy with cisplatin (20-50 mg/m2, median total dose: 50 mg/m2). The median irradiation dose was 70 Gy/35 fractions. The median follow-up period was 23 months (range: 8-44 months). The 2-year overall survival, progression-free survival, and local control rate were 87%, 72%, and 94%respectively. One patients experienced local failure, three experienced regional failure, and two developed distant metastasis. Major acute toxicities of more than grade 3 were oral mucositis in 10 (53%) patients. There were no neurological complications. Radiotherapy with intra-arterial infusion chemotherapy for oral cancer is effective and safe.

Different infusion durations for preventing platinum-induced hearing loss in children with cancer.

Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. This review is an update of a previously published Cochrane review. To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life. We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2016, Issue 4), MEDLINE (PubMed) (1945 to 18 May 2016) and EMBASE (Ovid) (1980 to 18 May 2016). In addition, we handsearched reference lists of relevant articles and we assessed the conference proceedings of the International Society for Paediatric Oncology (2009 up to and including 2015) and the American Society of Pediatric Hematology/Oncology (2014 and 2015). We scanned ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; apps.who.int/trialsearch) for ongoing trials (searched on 20 May 2016 and 24 May 2016 respectively). Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups. Two review authors independently performed the study selection, risk of bias assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We identified one RCT and no CCTs; in this update no additional studies were identified. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one-hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days 1 to 5 of the cycle but it is unclear if the infusion duration was a total of 5 days. Methodological limitations were present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (risk ratio (RR) 1.39, 95% confidence interval (CI) 0.47 to 4.13, low quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12, 95% CI 0.07 to 17.31, low quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one-hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high quality research is needed.

PACE as salvage therapy for relapsed or refractory multiple myeloma

PACE as salvage therapy for relapsed or refractory multiple myeloma

Curing Multiple Myeloma (MM) with Total Therapy (TT)

Intra-tumoral heterogeneity is a hindrance to curing malignant disease. By employing all MM-active drugs upfront, TT was designed to overcome such obstacle by targeting all potential MM sub-clones broadly. We are reporting on long-term results of phase-2 TT1, phase-3 TT2 and phase-2 TT3a trials, with median follow-up times of 21yr, 12yr and 9yr, respectively. Five year estimates of OS, PFS and CR duration (CRD) increased from 58%, 28% and 40% with TT1 to 65%, 42% and 50% with TT2’s control arm (TT2-), to 68%, 56% and 58% with TT2’s thalidomide arm (TT2+), and to 74%, 65% and 74% with TT3a (all p<0.0001). The 5-yr estimates of time to progression (TTP)/time to relapse (TTR) from CR decreased from 59%/58% in TT1 to 43%/42% in TT2-, to 28%/34% in TT2+, and to 22%/18% in TT3a (all p<0.0001). When examined in the era of gene expression profiling (GEP) of purified plasma cells, 5-yr estimates of TTP/TTR in GEP70 low-risk MM were 47%/46% with TT2-, 26%%/36% with TT2+, and 18%/16% with TT3a (all p<0.0001); the corresponding data for the 15% with high-risk MM were 60%/50% with TT2-, 62%/64% in TT2+, and 48%/35% in TT3a (NS). Relative survival (RS) was computed per year in relationship to age- and sex-matched controls. RS ratios approached 1 at 10–15 years for TT1 and TT2-, but earlier, at 5-10 years, for TT2+ and TT3a. A parametric mixture cure model was used to estimate PFS and CR duration for each protocol, from baseline and from a 5-year landmark. The cure model fits the data well and provides cure-fraction estimates that increase with later protocols (Figure 1). Importantly, when comparing data from GEP-defined low-risk and high-risk MM, plateaus for both PFS- and CRD-based cure fractions emerged at 10 years in the former and earlier, at 5 years, in the latter (data not shown). PFS-based cure-fraction estimates increasedsignificantly with successive TT trials: 9% in TT1, 16% in TT2-, 25% in TT2+, and 33% in TT3a (p=0.04). CRD-based cure-fraction estimates were 18%, 28%, 36%, and 49%, respectively (p=0.17) (Table 1). When a 5-year landmark was applied to exclude early myeloma-related events, PFS-based cure fraction estimates were 28% in TT1, 39% in TT2-, 51% in TT2+, and 70% in TT3a (p<0.001); in this setting, CRD-based cure fraction estimates were 32%, 47%, 56%, and 75%, respectively (p=0.007). MRD flow cytometry was available in 83 of 175 TT2 PFS patients, of whom 78% were MRD-. Our TT results are consistent with curability of MM. Solely novel agent-based trials without transplant lack the long-term follow-up to determine their cure potential.As MM usurps the bone marrow micro-environment (ME) for its growth and survival, we reasoned that ME alterations reflecting an angiogenic switch may persist beyond the state of clinical CR and even MRD. We therefore performed GEP analyses of bone marrow biopsies in CR and compared findings with age- and sex-matched controls. Indeed, biopsy “normalization” was linked to superior CR duration and is being developed as an early “cure surrogate” marker to help define the length of maintenance therapy in future trials. Although about 50% of CR patients treated with TT3a can be considered cured, the median PFS in high-risk MM of 2yr has not improved with successive TT trials. Reasoning that cytokine storms emanating after myelosuppressive therapies to restore normal hematopoiesis may be growth-stimulatory to MM cells, we applied non-myelotoxic metronomic therapy (Papanikolaou, Haematologica, 2014). Six newly diagnosed transplant-ineligible high-risk patients were offered an extended 28-day course of low-dose metronomic therapy with bortezomib, thalidomide, dexamethasone and continuous infusions of doxorubicin and cisplatin, to which were added arsenic trioxide and vincristine infusions. Remarkably, 5 of 6 achieved CR status after a single course and remain disease-free without further therapy 6-8 months later. Our results attest to the curability of MM with TT and, given the short PFS of 2yr in high-risk MM, such patients should be the focus of future novel interventions that yield information in a timely manner.Table 1Cure fraction estimatesProtocolPFSCR durationNCure FractionNCure FractionFrom start of therapyTT12318.8%7917.9%TT2 -Thal34515.5%14628.2%TT2 +Thal32325.1%20035.6%TT3a30332.9%18948.8%From 5-yr landmarkTT16528.4%3332.3%TT2 -Thal14539.2%8447.4%TT2 +Thal15051.1%13455.9%TT3a19769.8%14874.7%PFSCR duration [Display omitted] Disclosuresvan Rhee:Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Millenium: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Heuck:Celgene: Honoraria; Foundation Medicine: Honoraria; Millennium: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees.

Low-Dose 28-Day Metronomically Scheduled Therapy (METRO) for Newly Diagnosed High-Risk Multiple Myeloma: A Pilot Study

Introduction: Gene expression profiling (GEP)-defined high-risk de novo multiple myeloma (HI-MM) has a dismal prognosis with median PFS and OS stagnating at 2 and 3 years, respectively, despite the incorporation of novel agents into our Total Therapy (TT) trials. Having seen encouraging results in relapsed-refractory MM with an extended 16-day metronomic therapy (Papanikolaou, Haematologica 2014), we tested this approach in a small cohort of untreated patients with HI-MM. METRO emphasizes targeting neo-angiogenesis and other components of the bone marrow micro-environment while avoiding cytokine surges with recovering hematopoiesis following myelotoxic therapy.Patients and Methods: 10 previously untreated patients with HI-MM, who were either ineligible or unwilling for our Total Therapy protocols received a single cycle of METRO. Therapy comprised of SC bortezomib 1.0mg/m2 (0.8mg/m2 in case of grade >2 peripheral neuropathy) on days 1, 4, 7, 10, 13, 16, 19, 22, 25 and 28 schedule, PO dexamethasone 12mg (8mg in case of prior intolerance of higher dose or diabetes mellitus) on days 1 to 4, 7 to 10, 13 to 16, 19 to 22 and 25 to 28, PO Thalidomide 100mg (50mg in case of peripheral neuropathy grade >2) and continuous IV infusions of doxorubicin and cisplatin at 1.0mg/m2 daily for 28 days. Cisplatin was dose-reduced for Cr >2mg/dL and omitted for Cr >3mg/dL. Arsenic tri-oxide was given at a fixed dose of 0.01mg/kg on the days after bortezomib. Laboratory monitoring for response and toxicities were done on a Monday-Wednesday-Friday schedule. Maximal responses, based on current IMWG definitions, were measured within 30 days of completion of cycle 1, and at least monthly thereafter. KM curves were current as of 07/31/14. The Institutional Review Board granted permission for our retrospective data review, the results of which are presented here.Results: Patient characteristics included age >=65 in 8, 5 male, 5 female with ISS III in 5 patients. Metaphase cytogenetic abnormalities (CA) were detected in 7 patients. GEP70 based high risk MM was present in all 10 patients, and GEP proliferation (PR) subgroup was dominant in 8 out of 10 patients. All 10 patients achieved at least PR, including 3 qualifying for VGPR and 4 for CR. Bone Marrow responses were equally encouraging in that 8 of 10 patients qualified for complete morphologic negativity including 4 with no minimal residual disease (MRD) by 8-color flow cytometry. Of 8 patients with FDG-avid PET-CT focal lesions, 6 achieved PET-CT CR; all patients showed decreases in SUV-max and SUV-diff (background SUV). Number and/or apparent diffusion coefficient (ADC) mapping of focal lesions and background marrow on diffusion-weighted MRI improved in all 7 evaluable patients. GEP70 risk morphed from high risk to low risk in 3/4 evaluable patients. Pre and post serologic, urinary and radiologic responses are shown in Figure 1. The median follow-up time for the population was 3.2 months (98 days). All 10 patients are alive from 1 to 7 months, and 1 suffered progression (Figure 2). Overall tolerance was good. Non-hematologic grade 3/4 SEs included fatigue, electrolyte abnormalities (20%), dyspnea, hypotension, LE edema and transaminitis (10%).Conclusion: Primary 28-day metronomic therapy is highly effective and well-tolerated in patients with previously untreated HI-MM. Further prospective studies with longer follow-up are currently being devised in an attempt to improve outcomes in this population. [Display omitted] [Display omitted] [Display omitted] Disclosuresvan Rhee:Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Millenium: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Zangari:Norvartis: Membership on an entity’s Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding.

Higher Expressions of PTH Receptor Type 1 and/or 2 in Bone Marrow Is Associated to Longer Survival in Newly Diagnosed Myeloma Patients Enrolled in Total Therapy 3

Higher Expressions of PTH Receptor Type 1 and/or 2 in Bone Marrow is Associated to Longer Survival in Newly Diagnosed Myeloma Patients Enrolled in Total Therapy 3 INTRODUCTIONThe Total Therapy 3 enrolled 303 newly diagnosed multiple myeloma patients at Myeloma Institute for Research and Therapy. Protocol included 2 cycles of VTD-PACE (bortezomib, thalidomide, and dexamethasone and 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, and etoposide) as induction and consolidation therapy after melphalan-based tandem transplantation, which is followed by 3 years of intended maintenance with VTD in year 1 and thalidomide/dexamethasone in years 2 and 3. As part of the protocol, gene expression profiling was performed from baseline bone marrow biopsy samples in 178 individuals.We have previously reported the clinical correlation between response to bortezomib and serum parathyroid hormone variations in myeloma patients as well as the interaction between receptor 1 and proteasome inhibitors function in cell line and myeloma mouse model.In this study we examine the PTH receptor 1 and 2 expression levels and their correlation to survival in total therapy 3 enrolled patients. METHODGene expression profiling was performed using Affymetrix U133 plus 2.0 Microarrays (Santa Clara, CA) in baseline bone marrow biopsy samples from 178 patients enrolled on total therapy 3. Of these 178 patients, 108 were male. The overall median age of these patients was 59 years old at enrollment; 10 % of patients were considered to have high risk disease by 70 GEP model. Cox proportional hazards analysis was performed on the MAS5 normalized log 2 expression values of PTH1R and PTH2R using overall survival as the end point. Optimal dichotomous break points were found for PTH1R and PTH2R that corresponded to the maximum log rank test statistic from all cox proportional hazard models examined. To confirm PTH receptor expression in bone marrow, we performed real-time PCR using Taqman probes (PTH1R: Assay ID Hs00174895_m1 and PTH2R: Assay ID Hs00175044_m1) on subset of samples. RESULTSBased on cox proportional hazards regression of PTH1R and PTH2R expression values, patients with higher PTH1R and PTH2R expression demonstrated better survival compared to lower expressing patients. PTH1R expression above optimal break point of 8.92 had a hazard ratio of 0.583 with a 95% confidence interval of (0.351, 0.969) and logrank test p-value of 0.035. PTH2R expression above optimal break point of 6.85 had a hazard ratio of 0.541 with a 95% confidence interval of (0.323, 0.905) and logrank test p-value of 0.018. Furthermore, the patients that were lower expressed in both PTH1R and PTH2R performed significantly poorer in outcome (n= 24 and median survival of 4.52 years logrank p-value+5.71e-05).Real-time PCR using Taqman probes was able to demonstrate relatively high levels of PTH1R and PTHR2 transcripts at bone marrow level. [Display omitted] CONCLUSIONSThis is the first report indicating that PTH receptors type 1 and 2 gene expression levels are positively associated to overall survival in symptomatic multiple myeloma patients. Also we describe the presence of PTH2R at bone marrow level which function appear associated to myeloma control. These data confirm the correlation and close interaction between the survival of multiple myeloma patients and the parathyroid hormone axis. DisclosuresZangari:Norvartis: Membership on an entity’s Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. Heuck:Celgene: Honoraria; Foundation Medicine: Honoraria; Millennium: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees. van Rhee:Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Millenium: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Morgan:Celgene Corp: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees; Myeloma UK: Membership on an entity’s Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity’s Board of Directors or advisory committees; The Binding Site: Membership on an entity’s Board of Directors or advisory committees; MMRF: Membership on an entity’s Board of Directors or advisory committees.

Different infusion durations for preventing platinum-induced hearing loss in children with cancer.

Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life. We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 12), MEDLINE (PubMed) (1945 to 4 December 2013) and EMBASE (Ovid) (1980 to 4 December 2013). In addition, we handsearched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (2009 to 2013). We scanned ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (http://www.who.int/ictrp/en/) for ongoing trials (both searched on 13 December 2013). Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups. Two review authors independently performed the study selection, risk of bias assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We identified one RCT and no CCTs. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days 1 to 5 of the cycle but it is unclear if the infusion duration was a total of 5 days. Methodological limitations were present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (RR 1.39; 95% CI 0.47 to 4.13, low quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12; 95% CI 0.07 to 17.31, low quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high quality research is needed.

A phase II trial of prolonged, continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma.

7579 Background: Low-dose, prolonged infusion of gemcitabine has effects similar to standard doses in several cancers. We evaluated the toxicity and efficacy of low-dose gemcitabine in prolonged in...