Evaluation of local control strategies in patients with localized Ewing sarcoma of bone: A report from the Children’s Oncology Group.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9537-9537 ◽  
Author(s):  
Steven G. DuBois ◽  
Mark D. Krailo ◽  
Mark C. Gebhardt ◽  
Sarah S. Donaldson ◽  
Karen Chayt Marcus ◽  
...  
Keyword(s):  
Local Control ◽  
Ewing Sarcoma ◽  
Propensity Scores ◽  
Phase Iii ◽  
Tumor Site ◽  
Control Groups ◽  
Cox Models ◽  
Adjusted Risk ◽  
Risk Of Death ◽  
The Impact

9537 Background: Patients (pts) with Ewing sarcoma (EWS) require local control, either with surgery alone (S), radiation alone (R), or a combination of surgery + radiation (S+R). Optimal choice of local control for disease control remains unclear. Our primary aim was to determine the mode of local control associated with the highest event-free survival (EFS). Methods: Pts with localized EWS of bone treated on INT0091, INT0154, or AEWS0031 phase III trials were included if they had complete local control data, did not have cranial tumors, received local control starting 2-6 months after enrollment, and were randomized to receive standard dose 5-drug chemotherapy every 3 weeks. We used propensity scores to control for differences in age, tumor site, and year of diagnosis between local control groups. We constructed Cox models controlling for local control propensity scores to assess the impact of local control type on EFS and overall survival (OS) from the start of local control. Results: 465 pts were included. Pts selected for S were treated more recently (p < 0.001), more likely to have appendicular tumors (p < 0.001), and younger (p = 0.02). Pts treated with R, compared to S, had higher unadjusted risk of any event (HR 1.70; 95% CI 1.18 - 2.44; p = 0.004) or death (HR 1.84; 95% CI 1.18 – 2.85; p = 0.006). Pts treated with S+R, compared to S, had higher unadjusted risk of death (HR 1.75; 95% CI 1.10 – 2.76; p = 0.02). After adjusting for propensity scores, there was a trend of higher risk of any event for pts treated with R (HR 1.42; 95% CI 0.94 – 2.14; p = 0.10) compared to S, though this was not statistically significant. No other differences in adjusted risk of event or death between local control groups were statistically significant. We confirmed these results with standard Cox models using age, tumor site, and year of diagnosis as covariates. Conclusions: In this large group of uniformly treated pts, investigator choice of local control approach was not significantly related to EFS. These data support current practice of surgical resection when feasible, while validating radiotherapy as a reasonable alternative in selected pts.

scholarly journals The Effect of Anakinra in Hospitalized Patients with COVID-19: An Updated Systematic Review and Meta-Analysis

2021 ◽  
Vol 10 (19) ◽  
pp. 4462
Author(s):  
Konstantinos G. Kyriakoulis ◽  
Anastasios Kollias ◽  
Garyphallia Poulakou ◽  
Ioannis G. Kyriakoulis ◽  
Ioannis P. Trontzas ◽  
...  
Keyword(s):  
Systematic Review ◽  
Meta Analysis ◽  
Interleukin 1 ◽  
Severe Pneumonia ◽  
Hospitalized Patients ◽  
Current Evidence ◽  
Adjusted Risk ◽  
Risk Of Death ◽  
The Impact

The role of immunomodulatory agents in the treatment of hospitalized patients with COVID-19 has been of increasing interest. Anakinra, an interleukin-1 inhibitor, has been shown to offer significant clinical benefits in patients with COVID-19 and hyperinflammation. An updated systematic review and meta-analysis regarding the impact of anakinra on the outcomes of hospitalized patients with COVID-19 was conducted. Studies, randomized or non-randomized with adjustment for confounders, reporting on the adjusted risk of death in patients treated with anakinra versus those not treated with anakinra were deemed eligible. A search was performed in PubMed/EMBASE databases, as well as in relevant websites, until 1 August 2021. The meta-analysis of six studies that fulfilled the inclusion criteria (n = 1553 patients with moderate to severe pneumonia, weighted age 64 years, men 66%, treated with anakinra 50%, intubated 3%) showed a pooled hazard ratio for death in patients treated with anakinra at 0.47 (95% confidence intervals 0.34, 0.65). A meta-regression analysis did not reveal any significant associations between the mean age, percentage of males, mean baseline C-reactive protein levels, mean time of administration since symptoms onset among the included studies and the hazard ratios for death. All studies were considered as low risk of bias. The current evidence, although derived mainly from observational studies, supports a beneficial role of anakinra in the treatment of selected patients with COVID-19.

scholarly journals The high volume of patients admitted during the SARS-CoV-2 pandemic has an independent harmful impact on in-hospital mortality from COVID-19

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0246170
Author(s):  
Alessandro Soria ◽  
Stefania Galimberti ◽  
Giuseppe Lapadula ◽  
Francesca Visco ◽  
Agata Ardini ◽  
...  
Keyword(s):  
Hospital Mortality ◽  
High Volume ◽  
Hospitalized Patients ◽  
Urgent Care ◽  
Calendar Period ◽  
Cox Models ◽  
Hospital System ◽  
Risk Of Death ◽  
The Impact ◽  
Age And Sex

Background During the Coronavirus disease 2019 (COVID-19) pandemic, advanced health systems have come under pressure by the unprecedented high volume of patients needing urgent care. The impact on mortality of this “patients’ burden” has not been determined. Methods and findings Through retrieval of administrative data from a large referral hospital of Northern Italy, we determined Aalen-Johansen cumulative incidence curves to describe the in-hospital mortality, stratified by fixed covariates. Age- and sex-adjusted Cox models were used to quantify the effect on mortality of variables deemed to reflect the stress on the hospital system, namely the time-dependent number of daily admissions and of total hospitalized patients, and the calendar period. Of the 1225 subjects hospitalized for COVID-19 between February 20 and May 13, 283 died (30-day mortality rate 24%) after a median follow-up of 14 days (interquartile range 5–19). Hospitalizations increased progressively until a peak of 465 subjects on March 26, then declined. The risk of death, adjusted for age and sex, increased for a higher number of daily admissions (adjusted hazard ratio [AHR] per an incremental daily admission of 10 patients: 1.13, 95% Confidence Intervals [CI] 1.05–1.22, p = 0.0014), and for a higher total number of hospitalized patients (AHR per an increase of 50 patients in the total number of hospitalized subjects: 1.11, 95%CI 1.04–1.17, p = 0.0004), while was lower for the calendar period after the peak (AHR 0.56, 95%CI 0.43–0.72, p<0.0001). A validation was conducted on a dataset from another hospital where 500 subjects were hospitalized for COVID-19 in the same period. Figures were consistent in terms of impact of daily admissions, daily census, and calendar period on in-hospital mortality. Conclusions The pressure of a high volume of severely ill patients suffering from COVID-19 has a measurable independent impact on in-hospital mortality.

scholarly journals Risk of hospitalization and risk of death for healthcare workers with COVID-19 in nine European Union/European Economic Area countries, January 2020–January 2021

2021 ◽  
Author(s):  
Lisa Ferland ◽  
Joana Gomes Dias ◽  
Carlos Carvalho ◽  
Cornelia Adlhoch ◽  
Carl Suetens ◽  
...  
Keyword(s):  
European Union ◽  
Healthcare Workers ◽  
European Economic Area ◽  
European Economic ◽  
Adjusted Risk ◽  
Risk Of Death ◽  
Economic Area ◽  
The Impact ◽  
The Eu

AbstractWe assessed the impact of COVID-19 on healthcare workers (HCWs) from data on 2.9 million cases reported from nine countries in the EU/EEA. Compared to non-HCWs, HCWs had a higher adjusted risk of hospitalization (IRR 3.0 [95% CI 2.2-4.0]), but not death (IRR 0.9, 95% CI 0.4-2.0).Article Summary LineHealthcare workers are hospitalized more frequently than non-healthcare workers when adjusting for age, sex, and comorbidities.

Phase III Trial Adding Vincristine-Topotecan-Cyclophosphamide to the Initial Treatment of Patients With Nonmetastatic Ewing Sarcoma: A Children's Oncology Group Report

2021 ◽  
Author(s):  
Patrick J. Leavey ◽  
Nadia N. Laack ◽  
Mark D. Krailo ◽  
Allen Buxton ◽  
R. Lor Randall ◽  
...  
Keyword(s):  
Ewing Sarcoma ◽  
Tumor Volume ◽  
Phase Iii ◽  
Pelvic Bone ◽  
Experimental Therapy ◽  
Survival Outcomes ◽  
Primary Tumors ◽  
Risk Of Death ◽  
Increased Risk ◽  
To Receive

PURPOSE The primary aim of this phase III randomized trial was to test whether the addition of vincristine, topotecan, and cyclophosphamide (VTC) to interval compressed chemotherapy improved survival outcomes for patients with previously untreated nonmetastatic Ewing sarcoma. METHODS Patients were randomly assigned to receive standard five-drug interval compressed chemotherapy (regimen A) for 17 cycles or experimental therapy with five cycles of VTC within the 17 cycles (regimen B). Patients were stratified by age at diagnosis (< 18 years and ≥18 years) and tumor site (pelvic bone, nonpelvic bone, and extraosseous). Tumor volume at diagnosis was categorized as < 200 mL or ≥ 200 mL. Local control occurred following six cycles. Histologic response was categorized as no viable or any viable tumor. Event-free survival (EFS) and overall survival (OS) were compared between randomized groups with stratified log-rank tests. RESULTS Of 642 enrolled patients, 309 eligible patients received standard and 320 received experimental therapy. The 5-year EFS and OS were 78% and 87%, respectively. There was no difference in survival outcomes between randomized groups (5-year EFS regimen A v regimen B, 78% v 79%; P = .192; 5-year OS 86% v 88%; P = .159). Age and primary site did not affect the risk of an EFS event. However, age ≥ 18 years was associated with an increased risk of death at 5 years (hazard ratio 1.84; 95% CI, 1.15 to 2.96; P = .009). The 5-year EFS rates for patients with pelvic, nonpelvic bone, and extraosseous primary tumors were 75%, 78%, and 85%, respectively. Tumor volume ≥ 200 mL was significantly associated with lower EFS. CONCLUSION While VTC added to five-drug interval compressed chemotherapy did not improve survival, these outcomes represent the best survival estimates to date for patients with previously untreated nonmetastatic Ewing sarcoma.

Evaluation of soluble KIT (sKIT) as a potential surrogate marker for TTP in sunitinib malate (SU)-treated patients (pts) with advanced GIST

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10007-10007 ◽  
Author(s):  
M. Blackstein ◽  
X. Huang ◽  
G. D. Demetri ◽  
P. G. Casali ◽  
C. R. Garrett ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Surrogate Marker ◽  
Sampling Period ◽  
Clinical Results ◽  
Phase Iii ◽  
Plasma Samples ◽  
Double Blind ◽  
Cox Models ◽  
Time Changes ◽  
The Impact

10007 Background: SU is an oral, multitargeted tyrosine kinase inhibitor of KIT, PDGFRs, VEGFRs, RET and FLT3, approved multinationally for the treatment of imatinib (IM)-resistant/-intolerant GIST. Preliminary analysis in a SU phase I/II GIST study suggested that a decline in plasma sKIT levels may correlate with measures of clinical benefit. We evaluated the potential of sKIT as a surrogate marker for TTP using samples obtained in a randomized, double-blind, placebo-controlled phase III study of SU in pts with IM-resistant/-intolerant GIST, clinical results of which have been reported previously. Methods: 312 pts were randomized (2:1) to receive SU 50 mg (n=207) or placebo (n=105) daily in 6-wk cycles (4 wks on treatment, 2 wks off), respectively. The primary endpoint was TTP as per RECIST. Levels of sKIT in plasma samples were measured in cycle 1 on days 1, 14 and 28 and in cycles 2 and 3 on days 1 and 28 using a performance-validated ELISA. Prentice Criterion, Cox models and the Proportion of Treatment Effect (PTE) were used to analyze the results (PTE of 1 = ideal surrogate). Results: Numbers of pts with matched pairs of baseline and on-study plasma samples varied from 228 pts at cycle 1, day 14 to 106 pts at the end of cycle 3. After 4 wks of treatment (cycle 1, day 28), plasma sKIT levels began to exhibit a significant decrease (P<0.0001) in response to SU treatment; at the same time, changes in the level of sKIT (decreases vs. increases) also became indicators of TTP (HR=0.53; 95% CI, 0.37–0.75; P=0.0003), with decreases associated with longer TTP. This trend continued throughout the sampling period, with the effect persisting off treatment. Although the impact of SU on plasma sKIT levels continued to be seen after 2 cycles, sKIT changes became a better indicator of TTP than initial treatment group by cycle 2, day 28 (PTE = 0.62; HR=0.51; 95% CI, 0.38–0.69; P<0.0001), and at cycle 3, day 1 (PTE = 0.64; HR=0.42; 95% CI, 0.29–0.60; P<0.0001). Conclusion: These preliminary findings suggest that circulating sKIT may be a surrogate marker for TTP in GIST pts after 2 cycles of SU treatment. Further studies are warranted to confirm these findings and to establish whether sKIT can be used as a general surrogate marker of clinical outcomes in GIST pts with SU or other therapies. [Table: see text]

CD3+ tumor-infiltrating lymphocytes (TILs) as prognostic in patients (pts) with stage II colon cancer (CC) not treated with adjuvant chemotherapy (ADJ).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 167-167
Author(s):  
Edoardo Francini ◽  
Fang-Shu Ou ◽  
Stefano Lazzi ◽  
Roberto Petrioli ◽  
Andrea Giovanni Multari ◽  
...  
Keyword(s):  
Clinical Decision Making ◽  
Multivariable Analysis ◽  
Tumor Infiltrating Lymphocytes ◽  
Clinical Decision ◽  
Stage Ii ◽  
Prognostic Impact ◽  
Curative Surgery ◽  
Cox Models ◽  
Risk Of Death ◽  
The Impact

167 Background: Previous studies have reported high TILs are a favorable prognostic factor in stage II CC. However, whether the impact of TILs on overall survival (OS) differs among pts who did or did not receive ADJ is still to be determined. We assessed the prognostic value of CD3+ TILs in pts with stage II CC according to whether they received ADJ or not (no-ADJ). Methods: Pts treated with curative surgery for stage II CC (2002-2013) were identified through the Santa Maria alle Scotte Hospital database. CD3+ TILs at the invasive front, center of tumor, and stroma, were determined by immunohistochemistry and manually quantified as the rate of TILs/total tissue areas. High TILs (H-TILs) was defined as > 20%. Pts were classified as high or low TILs (L-TILs) and ADJ or no-ADJ. Cox models were used to assess OS with hazard ratio estimates (95% CI). Results: Of the 678 pts included (356 deaths), 137 (20%) received ADJ while 541 (80%) did not. ADJ comprised fluoropyrimidine +/- oxaliplatin. Median follow-up was 8.5 years. The distributions of the 4 groups were: 16% (L-TIL/ADJ), 64% (L-TIL/no-ADJ), 5% (H-TIL/ADJ), 15% (H-TIL/no-ADJ). Compared to H-TILs/no-ADJ, ADJ pts had a significantly longer OS (P < .0001) regardless of the TILS rate while L-TILs/no ADJ had significantly shorter OS and higher risk of death (HR = 1.41; 95% CI, 1.06-1.88; P < .0001) [See table]. On multivariable analysis, adjusting for perforation, obstruction, T-stage, grade, < 12 lymph nodes resected, lymphovascular and perineural invasion, the adverse prognostic impact of L-TILs (vs H-TILs) in no-ADJ pts was confirmed (HR = 1.36; 95% CI 1.02, 1.82; P = .0373). Conclusions: Low CD3+ TILs rate was independently associated with shorter OS in stage II CC pts who did not receive ADJ, but was not prognostic among pts who had ADJ. These data suggest a potentially different impact of TILs in chemo-treated vs -untreated stage II CC which could affect clinical decision making. [Table: see text]

Local Control in Pelvic Ewing Sarcoma: Analysis From INT-0091—A Report From the Children's Oncology Group

2006 ◽  
Vol 24 (24) ◽  
pp. 3838-3843 ◽  
Author(s):  
Torunn I. Yock ◽  
Mark Krailo ◽  
Christopher J. Fryer ◽  
Sarah S. Donaldson ◽  
James S. Miser ◽  
...  
Keyword(s):  
Local Control ◽  
Ewing Sarcoma ◽  
Local Failure ◽  
Distant Failure ◽  
Pelvic Tumors ◽  
Significant Difference ◽  
Study Population ◽  
The Impact ◽  
To Receive

Purpose The impact of the modality used for local control of Ewing sarcoma is uncertain. We investigated the relationship between the type of local control modality, surgery, radiation (RT) or both (S + RT), and subsequent risk for local failure (LF) in patients with nonmetastatic pelvic Ewing sarcoma treated on INT-0091. Patients and Methods Patients ≤ 30 years with Ewing sarcoma, primitive neuroectodermal tumor or primitive sarcoma of bone were randomly assigned to receive chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin, (VACA) or with these four drugs alternating with ifosfamide and etoposide (VACA-IE). The local control modality, surgery, RT or both was chosen by the treating physicians. The effect of local control modality was assessed after adjusting for the size of tumor (< 8 cm, ≥ 8 cm) and chemotherapy type. Results Seventy-five patients with pelvic tumors and a median follow-up of 4.4 years (0.6 to 11.4 years) comprised the study population. Twelve underwent surgery, 44 received RT, and 19 received both. The 5-year event-free survival (EFS) and cumulative incidence of LF was 49% and 21% (16%, LF only; 5%, LF and distant failure). There was no significant difference in EFS or LF by tumor size (< 8 cm, ≥ 8 cm), local control (LC) modality, or chemotherapy. However, VACA-IE seems to confer an LC benefit (11% v 30%; P = .06). Conclusion There was no significant effect of local control modality (surgery, RT or S + RT) selected by the treating physicians on rates of local failure or EFS. However, VACA-IE improves LC (11%) compared with previously published results for pelvic Ewing sarcoma.

Impact of older age on the efficacy of newer adjuvant therapies in >12,500 patients (pts) with stage II/III colon cancer: Findings from the ACCENT Database

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4010-4010 ◽  
Author(s):  
N. A. Jackson McCleary ◽  
J. Meyerhardt ◽  
E. Green ◽  
G. Yothers ◽  
A. de Gramont ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Recurrence ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Phase Iii ◽  
Cox Models ◽  
Time To Death ◽  
Time To Recurrence ◽  
Clinically Meaningful Outcomes ◽  
The Impact

4010 Background: Prior studies suggested that older and younger pts with colon cancer receive similar benefit from IV fluoropyrimidine (FU) adjuvant (adj) therapy (rx). Combination and/or oral FU rx are increasingly given as adj rx. We sought to determine the impact of pts age <70 v ≥70 yrs on colon cancer recurrence and mortality from adj rx with these newer options. Methods: We used data from 10,499 pts <70 yrs and 2,170 pts ≥70 yrs in 6 phase III adj rx trials comparing IV FU to combinations with irinotecan, oxaliplatin or oral FU (capecitabine and UFT/LV) in stage II/III colon cancer from the ACCENT database. Endpoints were overall survival (OS; time to death), disease-free survival (DFS; time to recurrence or death), and time to recurrence (TTR; censoring at last follow-up). Cox models were stratified by age and adjusted for gender and stage; interaction testing was used to explore the differential benefit by age. Results: Approximately 75% of pts had stage III disease (74% age<70, 77% age≥70). OS, DFS, and TTR were statistically significantly improved for those in the experimental v control arms among pts <70 but not those >70 ( table ); the interaction between age and rx was statistically significant for all endpoints (p=0.01 for OS, DFS, and TTR). These results were consistent whether experimental rx was oxaliplatin-based, irinotecan-based or oral FU. Deaths in first 6 month of adj rx were not statistically significantly different between experimental and control arm. Conclusions: Our results show conclusively that pts >70 do not receive the same benefit from combination and/or oral FU as those <70. Any benefit, if present, compared to IV FU/LV would not be clinically meaningful. Outcomes of experimental (combination or oral FU) vs control (IV 5-FU) by treatment and age [Table: see text] [Table: see text]

Pattern of progression in advanced HCC treated with ramucirumab/placebo: Results from two randomized phase III trials (REACH/REACH-2).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 544-544
Author(s):  
Maria Reig ◽  
Peter R. Galle ◽  
Masatoshi Kudo ◽  
Richard S. Finn ◽  
Josep M. Llovet ◽  
...  
Keyword(s):  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Cox Models ◽  
Poor Prognostic Factor ◽  
Advanced Hcc ◽  
Pooled Data ◽  
Phase Iii Trials ◽  
Ecog Ps ◽  
Post Hoc ◽  
The Impact

544 Background: REACH (NCT01140347) and REACH-2 (NCT02435433) studied ramucirumab (RAM) in pts with advanced hepatocellular carcinoma (HCC) following sorafenib; REACH-2 enrolled pts with baseline alpha-fetoprotein (AFP) ≥400 ng/mL, and met its primary endpoint of overall survival (OS) for RAM vs placebo. This post-hoc analysis examined radiological progression patterns (RPP) incidence every 6 weeks per RECIST v1.1, and if RPP were related to OS and post-progression survival (PPS). Methods: Pts with advanced HCC, Child-Pugh A, and ECOG PS 0-1 with prior sorafenib were randomized (REACH 1:1; REACH-2 2:1) to receive RAM 8 mg/kg or placebo Q2W. Among pts with ≥1 RPP (new extrahepatic lesion [NEH], new intrahepatic lesion [NIH], extrahepatic growth [EHG], or intrahepatic growth [IHG]), results were analyzed by trial and for pooled individual patient data of REACH-2 and REACH (AFP ≥400 ng/mL). Cox models evaluated treatment effect of RPP on OS, and prognostic implications of RPP on OS (adjusting baseline ECOG PS, AFP, macrovascular invasion, arm) and on PPS (adjusting ECOG PS, AFP at progression). Results: RPP incidence in the pooled population was: NEH 39%; NIH 24%; EHG 39%; IHG 37%. When examining NEH vs other RPP, PPS was worse among those with NEH in REACH (HR 2.33, 95% CI 1.51, 3.60), REACH-2 (HR 1.49, 95% CI 0.72, 3.08), and the pooled data (HR 1.75, 95% CI 1.12, 2.74). Use of post-discontinuation therapy may have influenced results. OS was also significantly reduced in those with NEH across studies (Table). RAM provided OS benefit in the pooled population, including pts with NEH (HR 0.56, 95% CI 0.39, 0.80). Conclusions: Acknowledging limitations of post-randomization RPP analysis, the emergence of NEH on RAM or placebo may be an independent poor prognostic factor for PPS. The impact of RAM on OS was consistent across all RPP subgroups. Clinical trial information: NCT01140347 and NCT02435433. [Table: see text]

Efficacy of dose intensification in induction therapy for localized Ewing sarcoma: Italian Sarcoma Group (ISG) and Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP) ISG/AIEOP EW-1 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11501-11501
Author(s):  
Roberto Luksch ◽  
Giuseppe Maria Milano ◽  
Francesco Barretta ◽  
Alessandra Longhi ◽  
Emanuela Palmerini ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Ewing Sarcoma ◽  
Phase Iii ◽  
Secondary Outcome ◽  
Poor Responders ◽  
High Dose ◽  
Type I ◽  
Tumour Site ◽  
Dose Intensification ◽  
The Impact

11501 Background: The role of dose intensification of chemotherapy in Ewing sarcoma (ES) is under evaluation in prospective trials. This is a controlled, randomized phase III study evaluating the impact on event-free survival (EFS) of two arms at different intensity of induction therapy in localized ES at onset. Methods: Newly diagnosed localized ES patients aged 2-40 were eligible. They were randomized to receive 4-courses induction therapy - 1 every 21 days - either with a standard arm (arm A) as per ISG/SSGIII protocol (Ferrari S, et at, Ann Oncol. 2011;22(5):1221) or with an intense arm B, consisting of vincristine 1,5mg/sqm+ doxorubicin 80mg/sqm+ifosfamide 9g/sqm for each course. After induction, patients underwent surgery and/or radiotherapy,followed by an adaptive treatment. Good responders received standard courses chemotherapy: arm A pts received 9 courses, while arm B pts received 5 courses. Poor responders in both arms received 4 courses followed by high-dose busulfan/melphalan+autologous stem cell rescue. The primary outcome measure was EFS for the 2 arms in the intention-to-treat population. Kaplan-Meier curves compared with log-rank test and Cox model were performed to assess differences between study arms. A secondary outcome was toxicity differences, assessed by means of the Fisher’s exact test. Initial sample size was 230 pts, type I error rate 5%, power 80%. Results: Between 2009 and 2019, 234 patients were randomized (arm A-115; arm B-119). M:F ratio was 1.8; median age 14 years (range 2-40); tumour site extremity in 55%, axial/pelvis in 45%; tumour volume < 200ml in 31% and ≥200ml in 69%. A good response was obtained in 56% in arm A and 60% in arm B. Median follow-up was 68 months. EFS was not significantly different between arms; HR: 0.85; 95% CI: 0,51-1,41, 5-year EFS (95% CI) was 73% (64-82%) in arm A and 75% (67-83%) in arm B ( p = 0.526). Good responders in arm A and in arm B and poor responders in arm B had comparable results: 5-year EFS (95% CI) was 80% (71-91%), 77% (67-88%), and 72% (59-86%), respectively, while poor responders in arm A showed a worse, not statistically significant (p = 0.164) performance (63%; 50-78%). Subgroup analyses showed similar outcome for age, tumour site and volume in both arms. Hematological, gastrointestinal, and cardiovascular grade ≥3 toxicities were more pronounced in arm B (p < 0.05). Conclusions: Intense induction therapy with arm B did not improve 5-year EFS when compared with the standard arm A. The higher toxicity observed in arm B than in arm A was counterbalanced, in good responders, by a similar outcome with a shorter treatment plan. For poor responders, with almost 30 patients per arm event-free and with < 48-month FUP, better 5-year EFS in arm B than in arm A was observed but needs further observation. Clinical trial information: NCT02063022.

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