MAP plus maintenance pegylated interferon α-2b (MAPIfn) versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: First results of the EURAMOS-1 “good response” randomization.

2013 ◽  
Vol 31 (18_suppl) ◽  
pp. LBA10504-LBA10504 ◽  
Author(s):  
Stefan S. Bielack ◽  
Sigbjorn Smeland ◽  
Jeremy Whelan ◽  
Neyssa Marina ◽  
Jane Hook ◽  
...  
Keyword(s):  
Cox Model ◽  
Controlled Trial ◽  
Final Analysis ◽  
Pegylated Interferon ◽  
Interferon Α ◽  
High Grade ◽  
Treatment Optimization ◽  
Histologic Response ◽  
High Grade Osteosarcoma

LBA10504 Background: EURAMOS-1 (NCT00134030) is an international randomized controlled trial investigating treatment optimization in osteosarcoma on the basis of histologic response to preoperative chemotherapy (CT). In patients (pts) with “good response” (GR; <10% viable tumor at surgery) to induction CT, efficacy of maintenance therapy with pegylated interferon α-2b (Ifn) was investigated. Methods: Pts ≤40yrs with resectable localized or primary metastatic high-grade extremity or axial osteosarcoma were eligible for registration at diagnosis. Eligibility for randomization included: [a] receipt of two cycles pre-op methotrexate, doxorubicin, cisplatin (MAP); [b] complete macroscopic resection of primary tumor; and [c] no disease progression. GR pts were randomized (1:1) after surgery to four cycles MAP +/-Ifn. Ifn (0.5-1.0 μg/kg/wk) was given after CT until 2yr post registration. Primary endpoint: event free survival (EFS); secondary: overall survival, toxicity. The trial design sought improved 3yr EFS from 70% to 80% (80% power, 2-sided alpha 5%). The final analysis was planned after 147 EFS events. Results: 2,260 pts were registered (Apr 05 to Jun 11) from 17 countries (326 sites) making it the largest trial in this rare cancer. GR was reported in 1,034 pts and 715 consented to randomization (358 MAP, 357 MAPIfn) with baseline characteristics balanced by arm: median age 14yr, 59% male, 79% localized disease. 271/357 (76%) pts started Ifn; main reason for not starting was treatment refusal, 66/86. By Feb 13 234/271 had stopped Ifn. Median duration of Ifn if started was 455 days; grade 3+ toxicity during Ifn reported by 81pts (30%). Median follow-up is 3.1yr with 174 EFS events reported: 93 MAP, 81 MAPIfn. Hazard ratio for EFS from adjusted Cox model was 0.82 (95% CI 0.61-1.11; p=0.201) in favor of MAPIfn. Conclusions: With current follow-up, EFS for MAPIfn is not statistically superior to MAP alone in pts with high-grade osteosarcoma and good response to pre-op MAP. One-quarter of pts did not start Ifn, which may have influenced this finding. Further follow-up for events and survival continues. Clinical trial information: NCT00134030.

scholarly journals Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial

2015 ◽  
Vol 33 (20) ◽  
pp. 2279-2287 ◽  
Author(s):  
Stefan S. Bielack ◽  
Sigbjørn Smeland ◽  
Jeremy S. Whelan ◽  
Neyssa Marina ◽  
Gordana Jovic ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Pegylated Interferon ◽  
Interferon Alfa ◽  
High Grade ◽  
Random Assignment ◽  
Histologic Response ◽  
Randomized Controlled ◽  
Pegylated Interferon Alfa ◽  
High Grade Osteosarcoma

Purpose EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. Patients and Methods At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 μg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). Results Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. Conclusion At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues.

MAP plus maintenance pegylated interferon α-2b (MAP-IFN) versus MAP alone in patients (pts) with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: First results of the EURAMOS-1 good response randomization.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. LBA10504-LBA10504
Author(s):  
Stefan S. Bielack ◽  
Sigbjorn Smeland ◽  
Jeremy Whelan ◽  
Neyssa Marina ◽  
Jane Hook ◽  
...  
Keyword(s):  
Annual Meeting ◽  
Pegylated Interferon ◽  
Interferon Α ◽  
High Grade ◽  
Histologic Response ◽  
Daily News ◽  
Online Supplement ◽  
First Results ◽  
High Grade Osteosarcoma ◽  
Final Text

LBA10504 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

ABCB1/P-glycoprotein (Pgp) expression as stratification factor for treatment of patients with non-metastaticextremity high-grade osteosarcoma: A merged analysis of an Italian (ISG) and a Spanish (GEIS) sarcoma groups' multicentric prospective trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11527-11527
Author(s):  
Emanuela Palmerini ◽  
Catalina Marquez ◽  
Cristina Meazza ◽  
Angela Tamburini ◽  
Gianni Bisogno ◽  
...  
Keyword(s):  
Poor Response ◽  
High Dose ◽  
High Grade ◽  
Histologic Response ◽  
P Glycoprotein ◽  
Metastatic Osteosarcoma ◽  
Diagnostic Biopsy ◽  
Prospective Trials ◽  
High Grade Osteosarcoma

11527 Background: Overexpression of ABCB1/P-glycoprotein (Pgp) predicts poor outcome in retrospective osteosarcoma series.Two prospective trials with Pgp expression and post-induction histologic response as stratification factors were activated in Italy (ISG/OS-2) and Spain (GEIS-33). Methods: Patients ≤ 40 years with extremity non-metastatic high-grade osteosarcoma were eligible. Analysisi of Pgp expression from diagnostic biopsy was centralized. Preoperatively, all patients received methotrexate, adriamycin, cisplatinum (MAP). Surgery was performed at week 8. All patients received a dose of adriamycin following surgery. In case of Pgp overexpression (Pgp+), mifamurtide (2 mg/m2 twice/week for 3 months then weekly for 6 months) was added after surgery, with 4 consecutive cycles of ifosfamide 3 gr/m2/day, day 1-5 (HDIFO) in case of poor histologic response (necrosis < 90%) to MAP. Patients without overexpression of Pgp (Pgp-) received MAP postoperatively, regardless the pathological response. From March 2013, an amendment increased high dose methotrexate cumulative dose from 60 g/m2 (5 cycles) to 120 mg/m2 (10 cycles). The post-amendment regimen was adopted in the observational prospective study by GEIS. Here we present the merged analysis of ISG/OS-2 patients treated post-amendment and GEIS-33. Results: From March 2013 to April 2018, 274 patients were included. Median age was 14 years (range 4-38), male/female: 163/111; 90 were Pgp-, 164 were Pgp+, 20 not evaluable. With a median follow-up of 48 months (1.3-78.5 months), the 3-year EFS and OS were 71.9% (95%CI 66-76.9) and 88% (95%CI: 83.2-91.5) respectively, with no inferior survival for Pgp positive patients and improved survival for good responders (Table). Conclusions: In this prospective uncontrolled study with a risk-adapted strategy for non-metastatic osteosarcoma, survival is superior to that of all ISG/GEIS previous series. The 3-year EFS of 71.9% compares favorably with other reports. Pgp+ patients performed well in this study, in which mifamurtide and HDIFO were added after a poor response to MAP. Clinical trial information: NCT01459484; NCT04383288. [Table: see text]

EURAMOS-1 study: Recruitment, characteristics, and initial treatment of more than 2,000 patients (pts) with high-grade osteosarcoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10081-10081 ◽  
Author(s):  
Jeremy Whelan ◽  
Jane Hook ◽  
Stefan S. Bielack ◽  
Neyssa Marina ◽  
Sigbjorn Smeland ◽  
...  
Keyword(s):  
Primary Tumour ◽  
Neoadjuvant Treatment ◽  
Pegylated Interferon ◽  
Poor Responders ◽  
High Grade ◽  
Treatment Optimization ◽  
Viable Tumor ◽  
Treatment Data ◽  
Diagnostic Biopsy ◽  
High Grade Osteosarcoma

10081 Background: EURAMOS is a transAtlantic collaboration formed to improve survival in osteosarcoma by conducting RCTs in a clinically relevant timeframe. EURAMOS-1, the largest study conducted in this rare cancer, has completed accrual. It includes two randomized comparisons investigating treatment optimization on the basis of histological response to neoadjuvant chemotherapy. Methods: Pts ≤40yrs with resectable, high grade extremity or axial osteosarcoma were eligible for registration. All were planned for 2 cycles of neoadjuvant methotrexate, doxorubicin, cisplatin (MAP) then surgical resection of the primary tumour. Pts with complete macroscopic resection and no disease progression were eligible for randomization: [i] “good responders”, <10% viable tumor, MAP +/- 18m maintenance pegylated interferon; [ii] “poor responders”, ≥10% viable tumor, MAP vs MAPIE (MAP + ifosfamide, etoposide). Target sample size was ~1,260 pts randomized requiring ~2000 pts registered estimating a non-randomization rate of 30-35%. Results: From Apr 2005 to Dec 2011, 2,260 pts were registered and 1,332 randomized from 17 countries, 320 sites: median age 14yrs (IQR 11-17); 59% male; 50% femoral site; 23% definite/possible metastases; 92% conventional osteosarcoma (diagnostic biopsy). At Sep 2011 planned IDMC review, neoadjuvant treatment data were known for 2024 pts; 1926 (95%) completed 2 cycles pre-operative MAP with 3 treatment related deaths. 59% pts were randomized; non-consent was the most frequent reason for non-randomization. Relative to expected age-specific incidence (UK NCIN 1979-2007) there was apparent under recruiting of older pts: females ≥15yrs and all pts >19yrs, with greater under recruitment of females than males <35yrs. Pts 20-29yrs were less likely to be randomized than those aged 5-19 and ≥30 yrs, 52% vs 57-62%. Conclusions: EURAMOS-1 demonstrates that large RCTs are feasible in rare cancers with inter-continental collaboration and is a model for future trials. Neoadjuvant MAP was safe in a geographically diverse cohort. Improving clinical trial access and randomization rates for young people is still required. Multiple funders detailed at bit.ly/ymUR9w.

KAI-1 Expression in Pediatric High-Grade Osteosarcoma

2006 ◽  
Vol 9 (3) ◽  
pp. 219-224 ◽  
Author(s):  
Patrick J. Leavey ◽  
Charles Timmons ◽  
William Frawley ◽  
Donald Lombardi ◽  
Raheela Ashfaq
Keyword(s):  
Prognostic Markers ◽  
Clinical Phenotype ◽  
Tumor Resection ◽  
Progression Free Survival ◽  
Surface Proteins ◽  
High Grade ◽  
Free Survival ◽  
Treatment Groups ◽  
High Grade Osteosarcoma

Recent evidence implicates cell surface proteins of the tetraspanin superfamily in the process of metastasis whereas the downregulation of KAI-1, a member of the tetraspanin family, is associated with an aggressive clinical phenotype in several types of human cancers. To determine if expression of KAI-1-1 is associated with any known prognostic marker or clinical outcome in high-grade osteosarcoma, we examined 91 nondecalcified archival samples from 47 patients for the expression of KAI-1. Archival, paraffin-embedded, and decalcified pathologic samples were examined by immunohistochemistry and results were correlated to clinical outcomes and known prognostic markers. There were 46 samples from diagnostic biopsies (1 diagnostic sample was not available), 32 tumor resection samples, and 13 metastasis samples. Thirty-three percent (n = 30) of the samples expressed KAI-1 (16 biopsies, 9 resections, and 5 metastasis). KAI-1 expression was not significantly related to known prognostic markers or to either tumor necrosis after neoadjuvant therapy or the incidence of metastasis at diagnosis. KAI-1 expression was not significantly different between paired diagnostic tumor samples and either resection or metastasis tumor samples. Twenty-five patients remain alive at a median follow-up of 95 months. The overall and progression-free survival percentages at 5 years were 62% and 47% for KAI-1-positive patients and 49% and 38% for KAI-1-negative patients, respectively. This difference was not statistically significant. We conclude that KAI-1 is expressed in a proportion of high-grade osteosarcoma but is not of clinical significance and cannot be used to stratify treatment groups for these patients.

High Degree of Hematological Response After Pegylated Interferon Alpha-2a Therapy In Myeloproliferative Neoplasms

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5055-5055
Author(s):  
Jan Samuelsson ◽  
Gerd Larfars ◽  
Eva Ottosson ◽  
Mats Merup
Keyword(s):  
Side Effects ◽  
Median Time ◽  
Response Rate ◽  
Myeloproliferative Neoplasms ◽  
Pegylated Interferon ◽  
Interferon Α ◽  
Molecular Response ◽  
Hematological Response ◽  
Ifn Therapy

Abstract Abstract 5055 Objective: To retrospectively assess hematological response rates, and other clinical and molecular variables, in MPN patients treated with pegylated interferon α-2a (Pegasys®, Roche Ltd). Responses were graded according to criteria published by the European Leukemia Net for PV and ET (Barosi G et al Blood 2009;113:4829), with the exception that mesurement of spleen size using ultrasound was not routinely performed, and the European Myelofibrosis Network for PMF (Barosi G et al Blood 2005;106:2849), respectively. Patient characteristics: The 23 patient cohort consisted of 13 PV, 5 ET, 3 PMF and 2 post-ET/PV MF pts. Thirteen pts were JAK2V617F+, 6 were JAK2V617F wt, and in 4 pts JAK2 status is unknown. Median age was 50 years (range 26–69), 13 were female and 10 male. Median time from MPN diagnosis to start of pegylated interferon α-2a (Peg-IFN) therapy was 67 months (range 0–204). Six pts had a previous thrombotic event (TIA=2, portal vein thrombosis=2, DVT lower extremity=2), and 2 pts had a previous major hemorrhage (gynecological=1, gastrointestinal=1). Eleven pts had previously received therapy with anagrelide (n=8), hydroxyurea (n=4), interferon α-2b (n=1), busulfan (n=1) or P32 (n=1), while 12 pts had not received bone marrow suppressive therapy. All PV and ET pts were on aspirin. Phlebotomies were performed in PV with the aim of keeping the hematocrit < 0.45. Peg-IFN was given at a dose of 90 μg/week in 16 pts, 135μg/week in 6, and 180μg/week in 1. Results: The overall hematological response rate (CR+PR) was 18/21 (86 %), 14 pts achieving CR and 4 PR. Two pts are too early to evaluate at the time of astract submission. One PV and 1 PMF patient were non-responders. Resonse rates were similar in PV vs ET, female vs male pts, and previously treated vs previously untreated pts. Median time of follow-up on Peg-IFN therapy is 16 months (3+ - 49+). Thirteen pts are still on therapy, 9 in CR, 2 in PR, and 2 too early to evaluate. These 13 pts have very limited or no side effects. Therapy has also been stopped according to plan after long hematological CR with molecular response in 2 pts. Therapy has been discontinued in 8 pts, in five (22 %) due to side effects (depression n=3, joint pain n=3, hair loss n=2, pruritus n=1), non-response in 2 pts, and PMF progression in 1. Serial JAK2V617F measurements are available at time of abstract submission in 4 pts, 1 achieved molecular CR, 2 PR whereas 1 patient treated for 5 months had no molecular response. Three of 4 mildly anemic MF pts normalized their hemoglobin (HgB 113 → 137, 106 → 123, and 110 → 125 respectively). In one PMF patent a clear reduction of marrow fibrosis was noted, whereas it progressed in another. No thromboembolic or bleeding complications were observed during PEG-IFN therapy. Longer follow-up, as well as additional molecular and morphological studies will be presented. Conclusions: Pegylated interferon α-2a induced a higher hematological response rate with improved tolerability, compared to our previous experience with Peg-IFN α-2b (Samuelsson et al Cancer 2006;106:2397), although the current number of patients is limited. However, the two previous publications that describes Peg-IFN α-2a therapy in larger MPN patients cohorts have observed results similar to ours (Kiladjian JJ et al Blood. 2008;112:3065, Quintás-Cardama A et al J Clin Oncol. 2009;27:5418). Molecular responses noted in a subset of patients further highlights the effect of Peg-IFN α-2a on the malignant clone in MPN:s. Peg-IFN α-2a is a valuable therapeutic alternative in patients who tolerate initial side effects, and will soon be compared to hydroxyurea in a randomized trial in high-risk PV and ET pts performed by the MPD research consortium. Disclosures: Samuelsson: Roche Sweden: Advisory board on use of recombinant erytropoetin. Off Label Use: Alpha-interferon does not have a label for use in myeloproliferative neoplasms. Merup:Roche Sweden: Received honoraria for lectures on rituximab use in lymphoma.

A placebo-controlled trial of Sertraline's effects on symptoms, well-being and survival in advanced cancer: The ZEST Trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9002-9002 ◽  
Author(s):  
N. R. Wilcken ◽  
D. Goldstein ◽  
A. K. Nowak ◽  
P. J. Beale ◽  
M. Jefford ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Advanced Cancer ◽  
Cox Model ◽  
Controlled Trial ◽  
Depression Scale ◽  
Final Analysis ◽  
Well Being ◽  
Hazard Ratio ◽  
Sensitivity Analyses

9002 Background: Depression, anxiety, fatigue and impaired well-being are common, important and closely related in advanced cancer. We sought to determine the effects of sertraline (a well-tolerated, SSRI antidepressant) on these symptoms and survival in a broad cross-section of people with advanced cancer but without major depression. Methods: 189 participants (pts) were randomly allocated to sertraline 50 mg daily or placebo. Assessments were at baseline; months 1, 2, 4, 6, 9, 12; and, then 3-monthly. Outcome measures rated by pts included the: Centre for Epidemiologic Studies Depression scale (CES-D); Hospital Anxiety and Depression Scale (HADS-A, HADS-D); and the Functional Assessment of Cancer Therapy General and Fatigue scales (FACT-G and FACT-F). Clinicians completed Spitzer's Quality of Life Index (SQLI). Outcomes on all scales are expressed from 0 (worst) to 100 (best). The primary analyses of sertraline's effects on quality of life were based on scores at 4 and 8 weeks adjusted for baseline scores using generalised estimating equations. Efficacy analyses are by intention to treat; toxicity analyses by treatment received. P-values and 95% confidence intervals (CI) are 2-sided. Results: Recruitment was stopped after the first planned interim analysis of 150 pts showed a trend in overall survival favouring placebo (univariable logrank p=0.04; multivariable Cox model hazard ratio 1.61, CI 1.1 to 2.5, p=0.02). This trend was weaker at the final analysis including all 189 patients and longer follow-up (univariable logrank p=0.09); and, after accounting for baseline factors (multivariable Cox model hazard ratio 1.27, CI 0.87 to 1.8, p=0.2). Sertraline had no significant effects (scale: benefit over placebo, 95% CI) on depression (CES-D: 0.4, −2.6 to 3.4), anxiety (HADS-A: 2.0, −1.5 to 5.5), fatigue (FACT-F: 0.3, −4.3 to 4.9), overall quality of life (FACT-G: 1.7, −1.3 to 4.7) or clinicians’ ratings (SQLI: 2.0, −2.5 to 6.5). Subgroup and sensitivity analyses also excluded significant benefits. Sertraline was discontinued more often and earlier than placebo (logrank p = 0.03). The trial was closed for lack of benefit. Conclusions: Sertraline did not improve symptoms, well-being or survival and should be reserved for those with a proven indication. No significant financial relationships to disclose.

Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3065-3072 ◽  
Author(s):  
Jean-Jacques Kiladjian ◽  
Bruno Cassinat ◽  
Sylvie Chevret ◽  
Pascal Turlure ◽  
Nathalie Cambier ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Residual Disease ◽  
Pegylated Interferon ◽  
Interferon Α ◽  
First Year ◽  
Molecular Response ◽  
Sequential Samples ◽  
Low Toxicity ◽  
Pegylated Interferon Alfa

Abstract Interferon-α (IFN-α) is a nonleukemogenic treatment of polycythemia vera (PV) able to induce cytogenetic remissions. Its use is limited by toxicity, leading to treatment discontinuation in approximately 20% of patients. We completed a phase 2 multicenter study of pegylated IFN-α-2a in 40 PV patients. Objectives included evaluation of efficacy, safety, and monitoring of residual disease using JAK2V617F quantification (%V617F). Median follow-up was 31.4 months. At 12 months, all 37 evaluable patients had hematologic response, including 94.6% complete responses (CRs). Only 3 patients (8%) had stopped treatment. After the first year, 35 patients remained in hematologic CR, including 5 who had stopped pegylated IFN-α-2a. Sequential samples for %V617F monitoring, available in 29 patients, showed %V617F decrease in 26 (89.6%). Median %V617F decreased from 45% before pegylated IFN-α-2a to 22.5%, 17.5%, 5%, and 3% after 12, 18, 24, and 36 months, respectively. Molecular CR (JAK2V617F undetectable) was achieved in 7 patients, lasting from 6+ to 18+ months, and persisted after pegylated IFN-α-2a discontinuation in 5. No vascular event was recorded. These results show that pegylated IFN-α-2a yields high rates of hematologic and molecular response in PV with limited toxicity, and could even eliminate the JAK2 mutated clone in selected cases. Available at www.clinicaltrials.gov as #NCT00241241.

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