Intravenous Etoposide Research Articles

Impact of an Etoposide Chemotherapy Shortage on Patients With Extensive-Stage Small-Cell Lung Cancer: Results of a Natural Experiment.

A shortage of essential intravenous (IV) etoposide lasted from 2018 until 2020 in Ontario, Canada, allowing for a natural experiment in which external factors (IV etoposide availability) dictated patients' treatment assignment. The purpose of this study was to evaluate the impact of this IV etoposide shortage (IVES) on patient care outcomes. Individuals with extensive-stage small-cell lung cancer (ES-SCLC) treated during a pre-IVES (November 2017-October 2018) and IVES (November 2018-October 2019) time intervals were retrospectively reviewed at the Verspeeten Family Cancer Centre. We investigated the association of the shortage on health care utilization and survival using a time-to-event analysis, Cox proportional hazards and logistic regression modeling. A total of 119 patients with ES-SCLC were assessed, 49 in the pre-IVES interval and 70 in the IVES interval. The median age was 68 (IQR, 62-74) years, 48% (n = 57) were male, 33% (n = 39) had CNS metastases, and 69% (n = 82) received first-line systemic therapy. Alternate regimens used for IVES cohort included IV platinum-oral (PO) etoposide, IV platinum-IV irinotecan, and PO etoposide monotherapy. An adjusted multivariable model demonstrated a significant increase in hospitalization (odds ratio, 2.30 [95% CI, 1.01 to 5.24]; P = .047) and shorter progression-free survival (PFS; hazard ratio, 1.79 [95% CI, 1.19 to 2.68]; P = .005) during the IVES. This study demonstrated increased hospitalization, and decreased PFS, among patients with ES-SCLC treated with alternate chemotherapy regimens during an IVES. The impact of cancer drug shortages can be harmful, and optimizing a more secure drug supply with mitigation strategies is warranted.

Serplulimab vs. placebo combined with chemotherapy as first-line treatment for extensive-stage small-cell lung cancer: Extended follow-up results and patient-reported outcomes from the international phase 3 ASTRUM-005 study.

8100 Background: ASTRUM-005 is a randomized, double-blind, phase 3 trial comparing efficacy and safety of serplulimab (a novel anti-PD-1 antibody) plus chemotherapy (chemo) vs. placebo plus chemo as first-line therapy for extensive-stage small-cell lung cancer (ES-SCLC). Interim analysis presented at 2022 ASCO Annual Meeting showed significantly prolonged overall survival (OS) in the serplulimab arm. Continuing improvements were seen in all efficacy endpoints in an updated analysis reported at ESMO Asia Congress 2022. Here we present the updated results with an extended follow-up duration of 31.6 months and the previously undisclosed patient-reported outcomes (PROs). Methods: 585 patients with ES-SCLC who had not received prior systemic therapy were randomized 2:1 (serplulimab arm, n = 389; placebo arm, n = 196) to receive serplulimab 4.5 mg/kg or placebo intravenously every 3 weeks. All patients received up to 4 cycles of intravenous carboplatin and etoposide every 3 weeks. Stratification factors were PD-L1 expression level, brain metastases, and age. The primary endpoint was OS. PROs were assessed using EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L questionnaires. Results: By the data cutoff of June 13, 2023, 267 (68.6%) patients in the serplulimab arm and 160 (81.6%) in the placebo arm had died. Median OS was markedly longer in the serplulimab arm than that in the placebo arm (15.8 vs.11.1 months; stratified HR 0.61, 95% CI 0.50–0.74). Subgroup analysis by race showed similar trends of a prolonged median OS in Asians (unstratified HR 0.61, 95% CI 0.48–0.77) and non-Asians (all were White; unstratified HR 0.57, 95% CI 0.39–0.83). Estimated OS rate at 3 years was 24.6% (95% CI 19.5–30.1) and 9.8% (95% CI 5.6–15.4) in the respective arms. By-visit longitudinal changes in all domains of the 3 questionnaires were comparable between arms. Least square mean (LSM) changes from baseline to week 18 in QLQ-C30 functional and symptom domains, QLQ-LC13 symptom domains, and EQ-5D-5L VAS were similar and generally improved in both arms, with more pronounced and persistent amelioration in “pain in other parts” symptom domain for the serplulimab arm (difference in LSM change, −6.37 [95% CI −11.59 to −1.15], p = 0.0170). Time to deterioration was similar between arms: median, not reached (NR) vs. NR for global health status/quality of life (HR 0.90, 95% CI 0.59–1.39), physical functioning (HR 1.01, 95% CI 0.61–1.65), and role functioning (HR 1.17, 95% CI 0.74–1.87). Conclusions: With extended follow-up, the survival benefits brought by the addition of serplulimab were maintained in the first-line therapy of ES-SCLC. PROs were not adversely impacted, and pain in other parts was significantly improved. All these results support serplulimab plus chemo as a promising first-line treatment option for ES-SCLC. Clinical trial information: NCT04063163 .

Intracellular Retention of Tcrαβ/CD3 to Generate Novel Allogeneic CAR-T Cells (ThisCART19A) with Enhanced Antitumor Potency for Treating B-ALL

Background: Autologous CAR-T therapy has been complicated by long production time, high-cost and risks of manufacturing failure. Allogeneic CAR-T cells can overcome these hurdles, but would subsequently require specific strategies to inhibit allogeneic TCR responses and GvHD. Gene-editing technologies can efficiently deplete endogenous TCR, but also leads to off-target edits and chromosomal abnormality. Furthermore, genetic depletion of TCR disrupts the intracellular T cell activation signal and may compromise CAR-T cytotoxicity. It is thus necessary to develop non-gene-editing allogeneic CAR-T platforms and enhance the potency of allogeneic CAR-T cells. Methods: We developed a novel non-gene-editing platform named ThisCART ( TCRαβ/CD3 and/or HLA-I intracellular sequestered) to manufacture allogeneic CAR-T cells. The platform was based on the intracellular retention of TCRαβ/CD3 complex, allowing for allogeneic CAR-T production with a single lentiviral vector without genetic depletion of TCR. Allogeneic CD19 CAR-T cells (ThisCART19A) was a prototypic product for the platform. The construct contains a CD19-targeted CAR and a KDEL-tagged anti-CD3 single chain antibody (scFv) which prevents TCRαβ/CD3 from being secreted from the endoplasmic reticulum (ER) (Figure A). The efficacy and safety of ThisCART19A were tested in xenograft models. Finally, a phase I study was conducted to assess the safety, efficacy and pharmacokinetics in patients with relapsed or refractory (R/R) B-ALL (NCT05350787). All patients received intravenous fludarabine (30mg/m 2/d), cyclophosphamide (300mg/m 2/d) and etoposide (100mg/d) for 5 days followed by a single infusion of thisCART19A. Results: The manufacturing platform of ThisCART19A was able to achieve over 150-folds of ex vivo CAR-T expansion in all batches, with the purity of products (CAR-positive/TCRαβ-negative) above 99%. In preclinical models, ThisCART19A did not induce GvHD, and exhibited superior antitumor function compared to conventional CD19 CAR-T cells. In the Phase I study (Figure B), 10 patients were enrolled and 8 received thisCART19A at doses of 3 (n =5) and 5 (n = 3)×10 6/kg. All patients were diagnosed as relapse/refractory acute B cell leukemia (R/R B-ALL). Three patients previously received CD19-or CD22-targeted therapies (autologous CAR-T, BiTE or ADC). Grade 3-4 treatment-related adverse events were reported in 8/8 (100%) patients, the most frequent being neutropenia (100%) and thrombocytopenia (87.5%), which most likely related to lymphodepletion. Grade 3-4 CRS was reported in 2/8(25%) patients, and ICANS was reported in 3/8 (37.5%) patients which were all reversible with steroid treatment. 7 patients were evaluable for efficacy analyses (one died from CRS and infection at 5 days post infusion), and MRD-negative CR/CRi was achieved in 100% of these patients. With a median follow-up of 146 days (range, 56 to 407), 4/7 patients remained MRD-negative. Two patients were bridged to allo-HSCT. The mean peak of CAR-T number by FCM was 5908.8(0.51-17457.9) cells/µL , which occurred on day 9 (7-9). Conclusions: We report for the first time that intracellular retention of TCRαβ/CD3 complex can successfully manufacture allogeneic CAR-T cells, with superior activation potential. In patients with R/R B-ALL, ThisCART19A demonstrated acceptable safety, robust expansion and encouraging clinical response profiles. With streamlined single-vector-based production and enhanced CAR signaling, ThisCART platform represents an attractive alternative to gene-editing-based allogeneic CAR-T platforms.

High Dose Hyperfractionated Thoracic Radiotherapy vs. Standard Dose for Limited Stage Small-Cell Lung Cancer: A Multicenter, Open-Label Randomized, Phase 3 Trial

Limited stage small-cell lung cancer (LS-SCLC) is associated with poor prognosis. We aimed to assess the efficacy and safety of high-dose, hyperfractionated thoracic radiotherapy of 54 Gy in 30 fractions compared with standard dose (45 Gy in 30 fractions) as a first-line treatment for LS-SCLC. The study was an open-label, randomized, phase 3 trial, done at 16 public hospitals in China. Key inclusion criteria were patients aged 18-70 years, with previously histologically or cytologically confirmed LS-SCLC, previously untreated or received 1-2 courses of intravenous cisplatin (75 mg/m²of body-surface area, on day 1 or divided into two days of each cycle) or carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle)and intravenous etoposide (100 mg/m²of body-surface area, on days 1-3 of each cycle), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.Eligible patients were randomly assigned (1:1) to receive volumetric-modulated arc radiotherapy (VMAT) of 45 Gy in 30 fractions or the simultaneous integrated boost VMAT (SIB-VMAT) of 54 Gy in 30 fractions to the primary lung tumor and lymph node metastases starting 0-42 days after the first chemotherapy course. Both groups of patients received thoracic radiotherapy twice per day and 10 fractions per week. Prophylactic cranial radiation (PCI, 25 Gy in 10 fractions) was implemented to patients with responsive disease. The primary endpoint was overall survival. Safety was analyzed in the as-treated population. Between June 30, 2017, and April 6, 2021, 224 eligible patients were enrolled and randomly assigned to 54 Gy (n = 108) or 45 Gy (n = 116). Median follow-up for the primary analysis was 45 months (IQR 41-48). Median overall survival was significantly improved in the 54 Gy group (62.4 months) compared with the 45 Gy group (43.1 months; p = 0.001). Median progression-free survival was significantly improved in the 54 Gy group (30.5 months) compared with the 45 Gy group (16.7 months; p = 0.044). The most common grade 3-4 adverse events were neutropenia (30 [28%] of 108 patients in the 54 Gy group vs 27 [23%] of 116 patients in the 45 Gy group), neutropenic infections (6 [6%] vs 2 [2%]), thrombocytopenia (13 [12%] vs 12 [10%]), anemia (6 [6%] vs 4 [3%]), and esophagitis (1 [1%] vs 3 [3%]). Treatment-related serious adverse events occurred in 9 [8%] patients in the 54 Gy group and 16 [14%] patients in the 45 Gy group. There were one treatment-related deaths in 54 Gy group (myocardial infarction). Compared with standard thoracic radiotherapy dose of 45 Gy, the high dose of 54 Gy improved overall survival and progression-free survival without increasing toxicities in patients with LS-SCLC, supporting twice-daily hyperfractionated thoracic radiotherapy of 54 Gy with concurrent chemotherapy is an alternative treatment option for LS-SCLC. This study is complete and registered with ClinicalTrials.gov, NCT03214003.

Treatment outcomes of pediatric acute myeloid leukemia in Western Kenya before and after the implementation of the SIOP PODC treatment guideline.

The Pediatric Oncology in Developing Countries (PODC) committee of the International Society of Pediatric Oncology (SIOP) published a pediatric acute myeloid leukemia (AML)-specific adapted treatment guideline for low- and middle-income countries. We evaluated the outcomes of children with AML at a large Kenyan academic hospital before (period 1) and after (period 2) implementing this guideline. Records of children (≤17 years) newly diagnosed with AML between 2010 and 2021 were retrospectively studied. In period 1, induction therapy comprised two courses with doxorubicin and cytarabine, and consolidation comprised two courses with etoposide and cytarabine. In period 2, a prephase with intravenous low-dose etoposide was administered prior to induction therapy, induction course I was intensified, and consolidation was adapted to two high-dose cytarabine courses. Probabilities of event-free survival (pEFS) and overall survival (pOS) were estimated using the Kaplan-Meier method. One-hundred twenty-two children with AML were included - 83 in period 1 and 39 in period 2. Overall, 95 patients received chemotherapy. The abandonment rate was 19% (16/83) in period 1 and 3% (1/39) in period 2. The early death, treatment-related mortality, complete remission, and relapse rates in periods 1 and 2 were 46% (29/63) versus 44% (14/32), 36% (12/33) versus 47% (8/17), 33% (21/63) versus 38% (12/32), and 57% (12/21) versus 17% (2/12), respectively. The 2-year pEFS and pOS in periods 1 and 2 were 5% versus 15% (p = .53), and 8% versus 16% (p = .93), respectively. The implementation of the SIOP PODC guideline did not result in improved outcomes of Kenyan children with AML. Survival of these children remains dismal, mainly attributable to early mortality.

Efficacy and safety of high dose twice-daily thoracic radiotherapy versus standard dose for limited stage small-cell lung cancer: A multicentre, open-label randomised, phase 3 trial.

8587 Background: We aimed to assess the efficacy and safety of high-dose, hyperfractionated thoracic radiotherapy of 54 Gy in 30 fractions compared with standard dose(45 Gy in 30 fractions) as a first-line treatment for LS-SCLC. Methods: The study was an open-label, randomised, phase 3 trial, done at 16 public hospitals in China.Key inclusion criteria were patients aged 18-70 years, with previously histologically or cytologically confirmed LS-SCLC, previously untreated or received 1-2 courses of intravenous cisplatin (75 mg/m²of body-surface area, on day 1 or divided into two days of each cycle) or carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle)and intravenous etoposide (100 mg/m²of body-surface area, on days 1-3 of each cycle), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.Eligible patients were randomly assigned (1:1) to receive receive volumetric-modulated arc radiotherapy (VMAT) of 45 Gy in 30 fractions or the simultaneous integrated boost VMAT (SIB-VMAT) of 54 Gy in 30 fractions to the primary lung tumour and lymph node metastases starting 0-42 days after the first chemotherapy course. Both groups of patients received thoracic radiotherapy twice per day and 10 fractions per week.Prophylactic cranial radiation (PCI, 25Gy in 10 fractions) was implemented to patients with responsive disease. The primary endpoint was overall survival. Safety was analysed in the as-treated population. This study is complete and registered with ClinicalTrials.gov,NCT03214003. Results: Between June 30, 2017, and April 6, 2021, 224 eligible patients were enrolled and randomly assigned to 54 Gy (n = 108) or 45 Gy (n = 116).Median follow-up for the primary analysis was 45 months (IQR 41-48). Median overall survival was significantly improved in the 54 Gy group (62.4 months ) compared with the 45 Gy group (43.1 months; p = 0.001). Median progression-free survival was significantly improved in the 54 Gy group (30.5 months) compared with the 45 Gy group (16.7 months; p = 0.044). The most common grade 3-4 adverse events were neutropenia (30 [28%] of 108 patients in the 54 Gy group vs 27 [23%] of 116 patients in the 45 Gy group), neutropenic infections (6 [6%] vs 2 [2%]), thrombocytopenia (13 [12%] vs 12 [10%]), anaemia (6 [6%] vs 4 [3%]), and oesophagitis (1 [1%] vs 3 [3%]). There were one treatment-related deaths in 54 Gy group (myocardial infarction). Conclusions: Compared with standard thoracic radiotherapy dose of 45 Gy, the high dose dose of 54 Gy improved overall survival and progression-free survival without increasing toxicities in patients with LS-SCLC, supporting twice-daily hyperfractionated thoracic radiotherapy of 54 Gy with concurrent chemotherapy is an alternative treatment option for LS-SCLC. Clinical trial information: NCT03214003 .

Etoposide hypersensitivity reactions associated with in-line filter use: A retrospective cohort study at CHU de Québec-Université Laval.

A case series of hypersensitivity reactions (HSRs) during intravenous administration of etoposide was observed following the introduction of in-line filters (ILFs) at a specialized university-affiliated center. This raised questions about the possible involvement of filters in these reactions. Despite there being very little published evidence to inform clinical decision making in this potentially clinically significant situation, the use of ILFs was discontinued at this center pending further investigation. The aims of this study were to evaluate the cumulative incidence of etoposide-related HSR with and without the use of ILF and to describe the reactions in adult and pediatric patients with cancer. A retrospective cohort study was performed among all pediatric and adult patients treated with intravenous etoposide at a maximal concentration of 0.4 mg/mL at our center between 30 September 2015 and 16 August 2018. This covered periods of time during which ILFs were used, as well as 6 months before their implementation and after their withdrawal. Data were extracted from medical records and cumulative incidence was calculated for each of the time periods (pre-ILF, ILF, and post-ILF) as the proportion of patients who recorded an HSR (one or more). Confidence intervals were calculated for each proportion using Fisher's Exact 95%. Comparisons of proportions between time periods were performed using Exact Pearson Chi-squared tests. Data were stratified by a number of perfusion cycles (single cycle or multiple cycles) and by patient population (adult and pediatric). A total of 284 patients were included in the study. The overall cumulative incidence of etoposide HSR was 9.9%. The cumulative incidence of HSR tended to be higher during ILF use when compared with combined pre- and post-ILF periods (12.2% [95% CI: 7.9-17.8] vs. 5.2% [95% CI: 1.7-11.7], p = 0.09). In patients who received multiple cycles of etoposide, the cumulative incidence of HSRs was higher during ILF use when compared with combined pre- and post-ILF periods (15.0% [95% CI: 9.6-21.8] vs. 3.9% [95% CI: 0.8-11.0], p = 0.01). The majority of HSRs' maximal severity were grade 1 or 2 (85.7%) according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. This study suggests a link between the use of ILFs and increased incidence of HSR during etoposide perfusion.

A Novel Universal CD7-Targeted CAR-T Cell Therapy for Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia and T-Cell Lymphoblastic Lymphoma

Background Universal CAR-T (UCAR-T) using gene-editing techniques has attracted significant attention due to its prompt availability for patients. To date, there are only a few clinical case reports of universal CAR-T therapy for T-cell malignancies. Here, we explored the efficacy and safety of CD7-targeted UCAR-T (RD13-01) cells for relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) in a phase I clinical trial (NCT04620655). Methods RD13-01 is an allogeneic, healthy donor-derived, and CRISPR/Cas9-edited anti-CD7 CAR-T cell product. RD13-01 consists of a CAR with a CD7-binding single-chain variable fragment (scFv), a 4-1BB costimulatory domain, CD3ζ signaling domain, a γc intracellular domain, in addition to an NK inhibitory (NKi) ligand containing an EC1-EC2 extracellular domain of E-cadherin fused to a CD28 co-stimulatory domain. The CAR and the NKi ligand are linked by an F2A self-cleaving peptide. Intravenous fludarabine (25-30 mg/m2/d), cyclophosphamide (300mg/m2/d) and etoposide (100 mg/m2/d) were given to all patients on Day -6 to Day -3 prior to CD7 UCAR-T cell infusion. Results Between December 2020 and May 2022, 10 patients (7 males, 3 females), 7 with T-ALL and 3 with T-LBL were enrolled. Median patient age was 16.5 years (range: 2-27 years). Patients had a median of 4.5 (2-6) prior lines of therapies. Two patients relapsed from a previous allogeneic hematopoietic stem cell transplant (allo-HSCT) within 6 months. In addition, 3 patients who showed no response (NR) to prior autologous CD7 CAR-T therapy were also included. Patient characteristics are shown in Table 1. Four patients harbored high-risk genotypes including STIL-TAL1, TP53, BCR-ABL, and others. By morphology, the median bone marrow (BM) blasts at enrollment were 60% (4%-96.5%). Of the eight patients with peripheral blood (PB) blasts, the median blasts were 27% (9%-85%). At enrollment, 8 patients had extramedullary disease (EMD) including 3 with central nervous system (CNS) involvement (1 CNS-1, 2 CNS-3), 3 with diffuse involvement, and 3 had localized EMD. The median transfection efficiency of the RD13-01 product was 64.6% (range: 59.0%-91.2%). A single dose of CD7 UCAR-T cells were infused to the first 3 enrolled patients at 0.5-1×107 cells/kg. Subsequently, 6 patients received a medium dose of 2×107cells/kg, and 1 received a high dose of 4×107cells/kg. By the cut-off date of July 11, 2021, the median observation time was 153 days (range: 28-315 days). On day 28 post infusion, 8/10 (80%) patients achieved complete remission (CR) in BM/PB, and 7 of the 8 patients were minimal residual disease (MRD) negative. Notably, the 3 patients who had failed prior autologous CD7 CAR-T therapy achieved CR. The first enrolled 2 patients who received the low dose showed NR and withdrew on day 28. Among the 7 patients with EMD, 4 achieved EMD CR at the median day 30, 1 had progression disease (PD) and 2, with NR in BM, withdrew prior to EMD evaluation. With a median time of 47 days (40-67 days) following infusion, 6 patients in CR (including 1 MRD +CR) underwent consolidation allo-HSCT, and 4/6 remained progression-free longest up to 315 days. However, 2/6 relapsed without CD7 lost on day 186 and day 200, respectively, and subsequently died. In addition, 1 CR patient died from bacterial infection on day 35. One PD patient received salvage transplantation and died from relapse on day 150. Post infusion, 9/10 patients experienced grade I cytokine release syndrome (CRS) and 1/10 had grade 3 CRS. Only 1 patient with CNS-3 experienced grade 3 neurotoxicity. By qPCR, CD7 UCAR-T cells reached a median peak level of 1.43×106 copies /μg genomic DNA (1.11×105~4.33×106)copies /μg genomic DNA, which occurred on day 12 (7-24 days). The median peak of circulating CD7 UCAR-T was 47.6% (0.01%~83.9%) occurring on day 7 (6-19 days), as measured by flow cytometry (Figure.1). Conclusions Our phase I trial showed that the allogeneic "off-the-shelf” RD13-01 product was safe and dose-dependently effective in treating patients with heavily pretreated T-ALL/LBL, including those with EMD and prior allo-HSCT, those who already failed autologous CD7 CAR-T therapy, and who could not manufacture autologous CAR-T from the patient's own PB due to high blasts in PB and those with rapid disease progression. Long-term observation and more patients are needed to further evaluate the safety and efficacy of CD7 UCAR-T cells. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Simultaneous Integrated Boost vs. Routine IMRT in Limited-Stage Small-Cell Lung Cancer: An Open-Label, Non-Inferiority, Randomized, Phase 3 Trial—Interim Analysis

<h3>Purpose/Objective(s)</h3> Simultaneous integrated boost radiation technique in limited-stage small cell lung cancer is lack of evidence. This prospective study aims to evaluate whether the simultaneous integrated boost is as efficacious and safe as conventional fractionated radiotherapy. <h3>Materials/Methods</h3> This randomized, non-inferiority, open-label, phase 3 study was done in a single institution in China. Patients aged 18–70 years who was diagnosed with treatment-naïve and confirmed limited-stage SCLC were eligible. All participants received 4-6 courses of intravenous cisplatin 75 mg/m² or carboplatin (area under the curve 5–6 mg/mL × min, Calvert's formula) on day 1 and intravenous etoposide 100 mg/m² on days 1–3 every 3 weeks. Participants were randomly assigned (1:1) stratifying for the timing of thoracic radiation therapy to receive simultaneous integrated boost radiotherapy (PGTV 60.2Gy/2.15Gy/28F, PTV 50.4Gy/1.8Gy/28F) or conventional fractionated radiotherapy (PTV 60Gy/2Gy/30F) to the primary lung tumor and CT positive lymph node metastases. Responders were offered prophylactic cranial irradiation of 25Gy/2.5Gy/10F.The primary endpoint was 2-year progression-free survival, the secondary endpoints were 2-year overall survival, 2-year local-regional recurrence-free survival and toxicity. <h3>Results</h3> Between February 2017, and July 2019, 231 patients were enrolled. We analyzed 216 patients whose follow-up time was more than 2 years or who had died, among which 106 patients in the conventional fractionated radiotherapy group,110 patients in the SIB group. The 2-year progression-free survival rates were 45.2% vs 38.3% and the median progression-free survival was 18 months (95%CI:9.06-26.39) in the conventional fractionated radiotherapy group versus 17 months(95%CI:11.47-22.53) in the SIB group (P=0.2, HR 1.22,95%CI:0.87-1.72). The 2-year overall survival rates were 73.5% VS 60.9% (P=0.14, HR 1.35,95%CI:0.90-2.04). The 2-year local-regional recurrence-free survival rates were 68.7% VS 69.9% (P = 1.0, HR = 0.98, 95% CI = 0.62-1.56). The most common grade 3–4 adverse events were myelosuppression (21.7% vs 15.4%, P = 0.83), radiation pneumonitis (4.7% vs 2.7%, P = 0.44), radiation esophagitis (3.8% vs 1.8%, P = 0.51). <h3>Conclusion</h3> Simultaneous integrated boost radiotherapy was non-inferior to and had similar toxicities to conventional fractionated radiotherapy in patients with limited-stage small cell lung cancer. Further enrollment and follow-up are warranted to confirm these findings in this ongoing trial. This trial is registered at ClinicalTrials.gov, NCT04500145.

Oral Chemotherapy Application in Elderly Patients With Diffuse Large B-Cell Lymphoma: An Alternative Regimen in Retrospective Analysis.

A combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard treatment for diffuse large B-cell lymphoma (DLBCL). However, no standard treatment has been established for older patients (age ≥ 75 years). This study retrospectively analyzed different treatment strategies in older patients with DLBCL with different chemotherapy regimens and compared the survival rate of patients using oral or intravenous form cyclophosphamide and etoposide in a single center. We reviewed the records of older patients with DLBCL, aged ≥ 75 years, from January 2010 to August 2019. The different treatment combinations, clinical characteristics, response rates, and toxicity profiles were analyzed. The median overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier (KM) method. Cox regression model was used to identify the risk factors. Eighty-four patients were included. One-quarter of the patients received cytoreduction treatment because of their poor medical condition at the time of diagnosis. Twenty-six percent of the patients were aged ≥ 85 at the time of diagnosis and 46.7% completed the treatment course. Patients receiving non-anthracycline-containing (non-ACR) treatment had worse Charlson comorbidity index, worse PFS, lower body mass index, or were older. The mean anthracycline accumulative dose in the anthracycline-containing (ACR) group was 134 mg/m2. The median OS was 17.2 months and median PFS was 7.7 months. The PFS of R-CHOP is better than R-mini-CHOP and R-CVOP without statistical significance, but OS of R-CHOP is not better than the other regimens. The toxicity, efficacy, and KM curve for OS and PFS in the non-ACR group were lower compared to ACR group, without statistical significance. R-CVOP had similar OS with R-mini-CHOP in our study. The result does not mean etoposide could totally substitute for anthracycline, but etoposide did have lower early progression rate (12.5%), and it may be an option for frail patients with comorbidity. Oral form cyclophosphamide and etoposide could be considered as a substitute for intravenous administration because of the similar effect and toxic profile.

Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients With Extensive-Stage Small Cell Lung Cancer

Programmed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC. To evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC. This international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021. Patients were randomized 2:1 to receive either 4.5 mg/kg of serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks. The primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P < .012). There were 13 secondary outcomes, including progression-free survival and adverse events. Among the 585 patients who were randomized (mean age, 61.1 [SD, 8.67] years; 104 [17.8%] women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months [95% CI, 13.3 months-not evaluable]) than in the placebo group (10.9 months [95% CI, 10.0-14.3 months]) (hazard ratio, 0.63 [95% CI, 0.49-0.82]; P < .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months [95% CI, 5.5-6.9 months]) than in the placebo group (4.3 months [95% CI, 4.2-4.5 months]) (hazard ratio, 0.48 [95% CI, 0.38-0.59]). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group. Among patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population. ClinicalTrials.gov Identifier: NCT04063163.

Favourable Response to Chemotherapy in Ora-Located Intraocular Retinoblastoma Grade B, C, and D: A Case Series

Background: We aim to analyze which tumor location gives more favorable chemotherapy response in intraocular retinoblastoma grade B, C, and D as well as to report the first case series in Indonesia. Methods: Six boys with age ranging from 10 weeks to 47 months old were recruited into the study from April 2019 to January 2020 at National Eye Centre, Cicendo Eye Hospital, and Hasan Sadikin General Hospital, Bandung, West Java, Indonesia. Retinoblastoma (RB) patients underwent examination under anesthesia (EUA). Tumor size and location were evaluated by using RetCam pre and post 2 cycles of chemotherapy. The tumors were classified according to the International Intraocular Retinoblastoma Classification. Results: There were two patients with unilateral RB and four patients with bilateral RB. All patients had leukocoria and sought medical advice within 12 months of onset. There were one tumor in the macular zone, six tumors in the equatorial zone, and two tumors in the ora zone. Two cycles of intravenous vincristine, etoposide, and carboplatin (VEC) were administered and the tumor diameter was re-evaluated afterwards. The tumor size was decreased following 2 cycles of chemotherapy. Conclusions: Ora zone showed a more favorable chemotherapy response.

Serplulimab, a novel anti-PD-1 antibody, plus chemotherapy versus chemotherapy alone as first-line treatment for extensive-stage small-cell lung cancer: An international randomized phase 3 study.

8505 Background: Monoclonal antibodies against programmed death-ligand 1 (PD-L1) have been approved for the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC) in combination with chemotherapy. However, whether a programmed death 1 (PD-1) inhibitor provides similar survival benefit in this patient population remains unclear. In this study, the efficacy and safety of serplulimab, a novel humanized monoclonal anti-PD-1 antibody, were assessed in combination with chemotherapy in previously untreated ES-SCLC patients. Methods: In this international, randomized, double-blind, multicenter, phase 3 trial (NCT04063163), patients with ES-SCLC who had not received prior systemic therapy were randomized (2:1) to receive serplulimab 4.5 mg/kg or placebo intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 4 cycles. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. Results: Between September 12, 2019 and April 27, 2021, 585 patients were randomized (serplulimab group, n = 389; placebo group, n = 196). At interim analysis, the median follow-up duration was 12.3 months. Median OS was significantly prolonged in the serplulimab group than the placebo group (15.4 vs.10.9 months; hazard ratio [HR] 0.63, 95% CI 0.49–0.82; P &lt; 0.001). Median PFS assessed by the independent radiology review committee (IRRC) per RECIST v1.1 was significantly longer in the serplulimab group than the placebo group (5.8 vs. 4.3 months; HR 0.47, 95% CI 0.38–0.59; P &lt; 0.001). Efficacy improvements were also observed in ORR (80.2% vs. 70.4%) and DoR (5.6 vs. 3.2 months) as assessed by IRRC per RECIST v1.1. Grade ≥3 treatment-emergent adverse events (TEAEs) related to serplulimab or placebo were reported in 129 (33.2%) and 54 (27.6%) patients in the respective groups. Incidence of immune-related TEAEs was higher in the serplulimab group compared to the placebo group (37% vs. 18.4%), with the largest difference in endocrine disorders (18.3% vs. 4.6%), which are commonly reported with anti-PD-1/PD-L1 therapies. Four deaths (1 acute coronary syndrome, 1 pyrexia, and 1 platelet count decreased in the serplulimab group; 1 thrombocytopenia in the placebo group) that might be related to study drugs were reported. Conclusions: Serplulimab plus chemotherapy as first-line treatment provided significant benefits and a manageable safety profile compared with chemotherapy alone in ES-SCLC patients. For the first time, OS benefits was demonstrated with a PD-1 inhibitor in a global phase 3 study among previously untreated ES-SCLC patients. Clinical trial information: NCT04063163.

Higher efficacy of oral etoposide for mobilization of peripheral blood stem cells in patients with multiple myeloma

Abstract This study compares the efficacy, toxicity, hematopoietic recovery, and cost of stem-cell mobilization using intermediate-dose cyclophosphamide (IDCy) plus granulocyte colony-stimulating factor (G-CSF) compared with etoposide (VP-16) plus pegylated granulocyte colony-stimulating factor (PEG-rhG-CSF) in multiple myeloma (MM) patients. Two hundred forty-four consecutive patients undergoing mobilization with IDCy (3-3.5 g/m 2 ) plus G-CSF (n = 155) were compared with patients receiving VP-16 plus PEG-rhG-CSF (n = 89), including oral etoposide (n = 65) and intravenous etoposide (n = 24). Compared with IDCy, VP-16 use was associated with significantly higher median peak peripheral blood CD34 + cell count (8.20 [range: 1.84-84] × 106/kg vs 4.58 [range: 0.1-27.9] × 106/kg, P = .000), and ideal CD34 + cell yield of more than 6 × 106/kg (56.8% vs 35.1%, P = .001), notably with a higher efficacy in oral VP-16 use compared with IDCy use (CD 34 + cell counts: median peak peripheral blood 5.87 vs 4.58 × 106/kg and ≥6 × 106/kg [48.4% vs 35.1%]). The median number of apheresis courses was reduced from two in the IDCy group to one in the VP-16 group (P = .000). IDCy use was associated with significantly more frequent episodes of neutropenia (70.2% vs 35.2%; P = .000), intravenous antibiotic use (13.2% vs 11.4%; P = .672), and hospitalization (P = .000). The recoveries of neutrophils and platelets after autologous stem-cell transplantation were significantly faster in the VP-16 group compared with the IDCy group (P = .000). Our data indicate robust stem-cell mobilization in MM patients with VP-16 delivered either orally or intravenously. When compared with intravenous VP-16, oral VP-16 mobilization was associated with significantly more convenient, lower average total costs, and especially decreased the risk of hospital visits and exposure.

Phase II study of intravenous etoposide in patients with relapsed ependymoma (CNS 2001 04).

BackgroundRelapsed ependymoma has a dismal prognosis, and the role of chemotherapy at relapse remains unclear. This study prospectively evaluated the efficacy of intensive intravenous (IV) etoposide in patients less than 21 years of age with relapsed intracranial ependymoma (NCT00278252).MethodsThis was a single-arm, open-label, phase II trial using Gehan’s two-stage design. Patients received IV etoposide 100 mg/m2 on days 1-3, 8-10, and 15-17 of each 28-day cycle, up to maximum of 6 cycles. Primary outcome was radiological response after 3 cycles. Pharmacokinetic analysis was performed in 10 patients.ResultsTwenty-five patients were enrolled and included in the intention-to-treat (ITT) analysis. Three patients were excluded in per-protocol (PP) analysis. After 3 cycles of etoposide, 5 patients (ITT 20%/PP 23%) had a complete response (CR), partial response (PR), or objective response (OR). Nine patients (ITT 36%/PP 41%,) had a best overall response of CR, PR, or OR. 1-year PFS was 24% in ITT and 23% in PP populations. 1-year OS was 56% and 59%, 5-year OS was 20% and 18%, respectively, in ITT and PP populations. Toxicity was predominantly hematological, with 20/25 patients experiencing a grade 3 or higher hematological adverse event.ConclusionsThis study confirms the activity of IV etoposide against relapsed ependymoma, however, this is modest, not sustained, and similar to that with oral etoposide, albeit with increased toxicity. These results confirm the dismal prognosis of this disease, provide a rationale to include etoposide within drug combinations, and highlight the need to develop novel treatments for recurrent ependymoma.

Venetoclax with dose-adjusted EPOCH-R as initial therapy for patients with aggressive B-cell lymphoma: a single-arm, multicentre, phase 1 study

Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) is a front-line treatment for patients with aggressive B-cell lymphomas. Bcl-2 is associated with chemoresistance due to BCL2 gene rearrangement or protein overexpression and is antagonised by venetoclax. We aimed to assess the safety of venetoclax with dose-adjusted EPOCH-R as initial therapy in aggressive B-cell lymphoma. We conducted a single-arm, phase 1 study across seven treatment centres in the USA. Eligible patients were aged 18-80 years with histologically confirmed, previously untreated diffuse large B-cell lymphoma, transformed indolent non-Hodgkin lymphoma, high-grade B-cell lymphoma with double-hit or not otherwise specified, or primary mediastinal B-cell lymphoma, with Ann Arbor stage II-IV and Eastern Cooperative Oncology Group performance status of 0-2. Participants received six cycles of oral venetoclax 400 mg, 600 mg, or 800 mg once daily for 10 days per cycle with dose-adjusted EPOCH-R (one cycle every 3 weeks; baseline doses were intravenous rituximab 375 mg/m2 on day 1, intravenous etoposide 50 mg/m2 on days 1-4, oral prednisone 60 mg/m2 twice daily on days 1-5, intravenous vincristine 0·4 mg/m2 on days 1-4, intravenous cyclophosphamide 750 mg/m2 on day 5, and intravenous doxorubicin 10 mg/m2 on days 1-4). A subsequent cohort received venetoclax 600 mg once daily for 5 days per cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities, and the recommended phase 2 dose of venetoclax. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov, NCT03036904, and enrolment is now closed. Between Feb 3, 2017, and June 4, 2019, 34 patients were assessed for eligibility, and 30 were enrolled and received venetoclax with dose-adjusted EPOCH-R. The median patient age was 64·0 years (IQR 51·6-69·4). The maximum tolerated dose was 800 mg for 10 days and the established recommended phase 2 dose was 600 mg for 5 days due to tolerability for treatment duration. One (3%) of 30 patients had a dose-limiting toxicity in cycle one (grade 4 thrombocytopenia with 800 mg dose). The most common grade 3-4 adverse events were cytopenias (28 [93%] of 30 patients); febrile neutropenia occurred in 19 (63%) patients. Grade 3-4 non-haematological adverse events included hypophosphataemia (n=10), hypokalaemia (n=7), and hyperglycaemia (n=5). Serious adverse events included infection (n=7) and gastrointestinal toxicities including abdominal pain (n=3), colonic perforation (n=1), and small intestinal obstruction (n=1). There was one treatment-related death (sepsis). Overall response rate was 96·7% (95% CI 82·8-99·9); 28 (93·3% [77·9-99·2]) of 30 patients had complete response and one (3·3% [0·1-17·2]) had a partial response. Venetoclax with dose-adjusted EPOCH-R showed an acceptable safety profile at the recommended phase 2 dose and had encouraging preliminary activity in this population at high risk of adverse outcomes, and is worthy of further study. The combination is being investigated in Alliance 051701 (NCT03984448). Genentech.

Efficacy and Safety of Intensive Etoposide Aracytine Consolidation Following Rituximab Methotrexate Temozolomide Induction in Newly Diagnosed Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma (PCNSL) is reported as having a dismal prognosis, due to the limited blood-brain barrier crossing capacity of lymphoma chemotherapies. Long-term remission and even cure could be achieved for a significant proportion of PCNSL patients using methotrexate-based chemotherapy regimens and intensive consolidation strategies. We report our single center experience of 27 consecutive patients with newly diagnosed PCNSL treated with Rituximab Methotrexate Temozolomide (RMT) regimen, and high-dose Etoposide Aracytine (EA) consolidation, with particular consideration for safety data.Methods: All patients consecutively diagnosed with PCNSL from November 2013 to December 2016 at Cochin hospital (Paris, France) were retrospectively included. Primary vitro-retinal lymphoma without cerebral involvement (n=1) and immunodeficient patients (n=1) were excluded. Contrast-enhanced magnetic resonance imaging (MRI) was performed at diagnosis for all patients. Slit lamp evaluation and cerebrospinal fluid examination were performed at the diagnosis or during therapy. Induction therapy consisted of four cycles of 375mg/m² Rituximab and 8g/m² Methotrexate (with folinic acid rescue) at day 1 and 14, and Temozolomide 150mg/m² days 7 through 11, repeated every four weeks (the RMT regimen). Patients under 75 year-old without significant comorbidities and achieving a complete response (CR) or a partial response (PR) were treated with intravenous Etoposide 40mg/kg on a continuous 96h infusion days 1 through 4 and Aracytine 2g/m² twice a day days 1 through 4 (the EA regimen). MRI was performed after the second and fourth cycle of RMT and after treatment completion. Response was evaluated according to international PCNSL cooperative group (IPCG) criteria.Results: Median age was 68 and 26% of the patients were under 60. Median Karnofsky performans status was 60 (range, 40-100). After induction, we observed 16 (59.3%) CR/CRu, 6 (22.2%) progressive disease (PD), 2 (7.4%) unrelated lymphoma death and 3 (11.1%) were not evaluated but were in PR after 2 cycles. Nineteen patients achieved CR/PR and were eligible for subsequent consolidation therapy. Four patients received whole brain radiotherapy (30.6 Gy n=1, 23.4 Gy n=3), and two patients had a watchful waiting strategy. Thirteen (48.1%) patients received EA. Median age of EA cohort was 60. After 29 months (range, 8-43 months) of follow-up, 19 (70.4%) patients were alive in CR. Eight patients deceased, 4 (14.8%) from progressive disease and 4 (14.8%) from lymphoma-unrelated cause. Median of progression free survival (PFS) and overall survival (OS) were not reached. The two-year PFS and OS were 57% (CI 95%, 36-74%) and 67% (CI 95%, 44-82%), respectively when considering the whole cohort; and 82% (CI 95%, 44-95%) and 92% (CI 95%, 54-99%), respectively when focusing on patients who received EA consolidation (Figures 1a and 1b). Main toxic side-effects of RMT regimen, evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events V4.0 were infections (30% of grade 3-4) and liver enzymes modifications (37% of grade 3-4). We observed a single-case of fully-resolved grade 3 renal dysfunction. Regarding EA consolidation, median hospital stay and neutrophil recovery (neutrophil count over 0.5x109/l) was 22 (range, 20-183 days) and 11 days (range, 9-14 days), respectively. All patients developed grade 4 neutropenia and thrombocytopenia. Sixty one percent of patients experienced grade 3 anemia. Neutropenic fever was observed in 92.3% of patients. Grade 3-4 mucositis developed in 22.2% of patients. Sixty one percent of EA-treated patients experienced grade 3-4 infections, including documented bacterial infection in 6 patients (central venous catheter infection, n=3; septicemia, n=2 and Clostridium difficile colitis, n=1) and fungal infection in two patients (probable aspergillosis, n=1 and documented mucormycosis, n=1). We observed one case of vancomycine-induced grade 4 renal failure during febrile aplasia that fully recovered.Conclusion : The RMT regimen allowed a near 60% complete response rate with limited toxicity. Intensive Etoposide Aracytine consolidation is feasible but more toxic than previously reported. The high survival rate observed in patients receiving RMT induction and then EA consolidation support further comparative evaluation of this strategy in prospective trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PET-guided eBEACOPP treatment of advanced-stage Hodgkin lymphoma (HD18): follow-up analysis of an international, open-label, randomised, phase 3 trial

The German Hodgkin Study Group's HD18 trial established the safety and efficacy of PET-guided eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) for the treatment of advanced-stage Hodgkin lymphoma. However, because of a protocol amendment during the enrolment period (June 1, 2011) that changed standard treatment from eight to six cycles, the results of the HD18 trial have been partially immature. We report a prespecified 5-year follow-up analysis of the completed HD18 trial. HD18 was an international, open-label, randomised, phase 3 trial done in 301 hospitals and private practices in five European countries. Patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited. After receiving an initial two cycles of eBEACOPP (1250 mg/m2 intravenous cyclophosphamide [day 1], 35 mg/m2 intravenous doxorubicin [day 1], 200 mg/m2 intravenous etoposide [day 1-3], 100 mg/m2 oral procarbazine [day 1-7], 40 mg/m2 oral prednisone [day 1-14], 1·4 mg/m2 intravenous vincristine [day 8], and 10 mg/m2 intravenous bleomycin [day 8]), patients underwent a contrast-enhanced CT and PET scan (PET-2). Patients with positive PET-2 were randomly assigned to receive standard therapy (an additional six cycles of eBEACOPP; ie, eight cycles in total) or experimental therapy (an additional six cycles of eBEACOPP plus 375 mg/m2 intravenous rituximab; ie, eight cycles in total) until June 1, 2011. After June 1, 2011, all patients with positive PET-2 were assigned to the updated standard therapy with an additional four cycles of eBEACOPP (ie, six cycles in total). Patients with negative PET-2 were randomly assigned (1:1) to receive standard therapy (an additional six cycles of eBEACOPP [ie, eight cycles in total] until June 1, 2011; an additional four cycles of eBEACOPP [ie, six cycles in total] after June 1, 2011) or experimental therapy (an additional two cycles of eBEACOPP; ie, four cycles in total). Randomisation was done centrally with the minimisation method, including a random component, stratified by centre, age, stage, international prognostic score, and sex. The primary endpoint was progression-free survival. HD18 aimed to improve 5-year progression-free survival by 15% in the PET-2-positive intention-to-treat cohort and to exclude inferiority of 6% or more in 5-year progression-free survival in the PET-2-negative per-protocol population. This study is registered with ClinicalTrials.gov, NCT00515554, and is completed. Between May 14, 2008, and July 18, 2014, 2101 patients were enrolled and 1945 were assigned to a treatment group according to their PET-2 result. In the PET-2-positive cohort, with a median follow-up of 73 months (IQR 59 to 94), 5-year progression-free survival was 89·9% (95% CI 85·7 to 94·1) in 217 patients assigned to eight cycles of eBEACOPP before the protocol amendment and 87·7% (83·1 to 92·4) in 217 patients assigned to eight cycles of rituximab plus eBEACOPP (p=0·40). Among 506 patients who received six cycles of eBEACOPP after the protocol amendment, 5-year progression-free survival was 90·1% (95% CI 87·2 to 92·9), with a median follow-up of 58 months (IQR 39 to 66). In the PET-2-negative cohort, with a median follow-up of 66 months (IQR 54 to 85) in the combined pre-amendment and post-amendment groups, 5-year progression-free survival was 91·2% (95% CI 88·4 to 93·9) in 446 patients who received eight or six cycles of eBEACOPP and 93·0% (90·6 to 95·4) in 474 patients who received four cycles of eBEACOPP (difference 1·9% [95% CI -1·8 to 5·5]). In the subgroup of PET-2-negative patients randomly assigned after protocol amendment, 5-year progression-free survival was 90·9% (95% CI 86·8 to 95·1) in 202 patients assigned to receive six cycles of eBEACOPP and 91·0% (86·6 to 95·5) in 200 patients assigned to receive four cycles of eBEACOPP (difference 0·1% [-5·9 to 6·2]). Long-term follow-up confirms the efficacy and safety of PET-2-guided eBEACOPP in patients with advanced-stage Hodgkin lymphoma. The reduction from eight to four cycles of eBEACOPP represents a benchmark in the treatment of early-responding patients, who can now be potentially cured with a short and safe treatment approach. Deutsche Krebshilfe, Swiss State Secretariat for Education, Research and Innovation SERI (Switzerland), and Roche Pharma. For the German translation of the abstract see Supplementary Materials section.

Association between in-line filtration and Type I hypersensitivity reactions in pediatric oncology patients receiving intravenous etoposide

The objective of this study was to describe hypersensitivity reactions with and without the use of in-line filters during intravenous etoposide therapy in pediatric oncology patients. This was a retrospective review of all patients treated in the Division of Oncology/Hematology/Bone Marrow Transplant at British Columbia Children’s Hospital with intravenous etoposide between December 1, 2013 and February 1, 2018. Hypersensitivity reactions and anaphylaxis associated with etoposide infusions were compared over time, including 12 months prior to, 27 months during the use of, and for 12 months after the discontinuation of in-line filtration. There were 192 patients (median age 6.0 (IQR 2.8-13.0) years treated with etoposide and 486 etoposide infusions including 137 (28%) before, 261 (54%) during and 88 (18%) after use of in-line filters at our center. Twenty-six of 486 (5%) and 13/486 (3%) of infusions resulted in a type I hypersensitivity reaction and anaphylaxis, respectively. There were 2/137 (1%), 36/261 (14%) and 1/88 (1%) infusion reactions prior to, during and after in-line filter use, respectively. Infusion reactions during the in-line filter period were higher than during the pre-filter (Z = 3.978; p < 0.001) and post-filter (Z = 3.335; p < 0.001) periods of the study. These data suggest that the use of in-line filtration may be associated with increased frequency of hypersensitivity reactions to etoposide in pediatric cancer patients.

Comparison of oral versus intravenous etoposide in the management of small-cell lung cancer; A real-world, population-based study.

We looked at the utility of PO versus IV etoposide for first-line treatment in combination with a platinum agent (cisplatin/carboplatin) for Small-Cell Lung Cancer (SCLC). Patients with SCLC in Alberta from 2008 to 2015 were identified through the registry. Patients were separated on the basis of stage; limited disease (LD) and extensive disease (ED). Chemotherapy naïve patients receiving one cycle of combination chemotherapy, route of etoposide administration, dose reductions and vital status was noted. Survival was assessed using log-rank method and Kaplan-Meyer model RESULTS: About 2066 patients were identified with SCLC. N=762 were diagnosed with LD and n=1264 with ED. Patient characteristics were well balanced between age and sex among the two treatment groups. No statistically significant difference in overall survival (OS) between IV versus PO Etoposide (17.5 months vs 17.9 months). More dose reductions were seen in the PO group as compared to the IV group (32.5% vs 21.9% P=0.095). There was a nonsignificant numerical difference in OS in IV versus PO Etoposide (8.7 months vs 9.7 months P=0.124). More dose reductions were noted in the PO group as compared to the IV group (35.3% vs 21.1%). The two dosing schemes (PO and IV) yield similar OS in ES and LS SCLC, however, patients in the PO arm did require more dose modifications. Suggesting that PO etoposide may be equivalent and lead to similar outcomes as IV, however, more toxic but saving the patients multiple visits to the chemotherapy suite. Further analyses on cost efficacy and quality of life are required.