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10014
Background: Despite promising phase II trial results, most of new drugs failed to improve the overall survival (OS) in ASTS pts. The choice of the endpoint in early trials remains ...crucial. We have evaluated the Growth Modulation Index (GMI) as potential endpoint. The GMI is defined as the Time To Progression with the second (or n+1) line of chemotherapy (TTP2) divided by the TTP with the first (or n) line (TTP1). Methods: We have carried out a retrospective multicenter study in pts receiving second-line chemotherapy after failure/intolerance to doxorubicin-based regimens. Data collected included best response(s), TTP1 & TTP2 and OS. Treatments have been classified as "active" treatment according to the EORTC- STBSG criteria (3-month Progression-free rate >40% or 6-month PFR>14%: including trabectedin, ifosfamide, gemcitabine+docetaxel for all subtypes and weekly paclitaxel for angiosarcoma) versus non-active drugs. Comparisons used chi-2 tests and Log-rank tests. We performed a logistic regression analysis for identifying factors associated with longer GMI. Results: The study population consisted in 106 men and 121 women, the median age was 57 years. 110 pts (48.4%) have received "active drugs". The median TTP1, TTP2 and GMI were 197 days, 134 days and 0.75, respectively. The median OS was 446 days. 70 pts experienced GMI>1.33 (30.6%). There was a strong relation between best objective response and GMI (p<0.0001). The treatment with "active drug" was not associated with an improvement of the OS: 490 days 407 versus days (p=0.524). The median OS of pts with GMI<1, GMI=1.00-1.33 and GMI>1.33 were 324, 302 and 710 days, respectively (p<0.0001). None of the following factors were associated with GMI>1.33 in logistic regression analysis: age, gender, histological subtypes, grade, metastasis locations, interval between diagnosis & metastasis, association with ifosfamide or dacarbazine in 1st-line regimen or treatment with "active drug" in second-line. Conclusions: GMI seems to be an interesting endpoint providing additional information compared to classical criteria. GMI>1.33 is associated with significant improvement of the OS.
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10020
Background: There is no standard of care for both rare sarcomas. Regarding, the important vascularization of EHE and SFT, we explored the activity/toxicity of So in pts with these ...sarcomas. Methods: We conducted a multicenter one-step phase II trial of So (800 mg/d). The primary endpoint was the 9-months progression-free rate (9-PFR). According to EORTC criteria, So is considered as promising drug if 6-PFR≥14%. All pts have had documented progressive disease at entry. Results: 20 pts (15 EHE & 5 SFT) were enrolled from June 2009 to February 2011 in the 8 participating institutions. 12 men and 8 women. Median age was 57. The most common primaries were superficial trunk (8 cases) and liver (4 cases). PS were 0 in 10 cases, 1 in 7 cases and 2 in 3 cases. 16 pts had metastasic disease , especially in lung (15), liver (6) and bone (4). Eight pts received prior chemotherapy (Doxorubicin : n= 8 cases and taxane : n =3). The median So treatment duration was 124 days. 9 pts experienced grade-3 toxicities; the most frequent grade-3 toxic events were hand foot syndrome (5 pts), myalgia (1), stomatitis (1), anorexia (1), diarrhea (1) and arterial hypertension (1).Because of this toxicity, treatment discontinuation was necessary in 6 cases and dose reduction was necessary in 5 pts. The 9-PFR was 6/18 (33.3% 11.5-55.1). The 2, 4 and 6 PFR were 15/18 (83.3%), 8/18 (44.4%) and 7/18 (38.8) respectively We observed 2 partial responses lasting 2 and 9 months in 2 pts with EHE. Analysis of the predictive value of circulating pre-angiogenetic biomarkers is ongoing. Conclusions: According to the STBSG-EORTC criteria (3-PFR≥40% & 6-PFR≥14%), So is a promising drug for EHE and SFT pts. Further trials is needed, especially a discontinuation randomized trial.
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10092
Background: Factors predicting progression free survival (PFS) and overall survival (OS) of patients (pts) with advanced GIST treated with 400 mg daily dose IM included in the ...BFR14 study with a median follow up of 54 months (CI95%:47-61) was investigated evaluating added prognostic factors. Methods: 434 pts were included in this prospective multicenter trial from June 2002 to July 2009. After 1, 3 and 5 yrs of IM 400mg/day, pts free from progression were randomly offered to continue or interrupt (I arm) IM. Prognostic factors for overall survival were investigated in the entire cohort (randomized and not randomized pts) included in the BFR14. Survival was defined from the date of inclusion to the date of death for OS or to the first occurrence of disease progression under imatinib or death for PFS. A multivariate cox model including statistical significant baseline characteristics tested in univariate were included in a backward procedure d to identify independent prognostic factors for PFS then OS. Results: As of January 2012, there were 285 progressions (65%) and 161 deaths (37%). The median PFS of the entire cohort was 29 months (CI95%: 24-33) and the 4 and 5-yrs PFS were 31% and 24% respectively. A low tumour volume at inclusion, PS (0), sex (female), CD34 positivity on tumor cells were the four independent prognostic factors of a higher PFS. The 5-yrs OS was 54% (CI95%: 48-60). A higher OS was independently predicted by gender (female), PS (0), platelets count (<400 giga/L) and CD34 expression on GIST cells. Median PFS and OS were slightly superior in this more recent series as compared to B2222 consistently with the improved outcome of patients with low tumor volume. Conclusions: OS and PFS are predicted by gender, PS and CD34 expression in this large series of pts treated with standard dose IM. The biological significance of CD34 expression on tumor cells has to be explored in GIST.
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e13600^
Background: RG7112 is a small molecule MDM2 antagonist, designed to non-genotoxically activate p53. A phase I dose escalation (DE) was performed, followed by a sarcoma biomarker ...extension (EXT) in pts with wild type TP53. Methods: 106 pts (58M, 48 F), median age 57.9 yrs (range 22-84) participated; 76 in 9 cohorts (DE) from 20 to 1800 mg/m
2
, orally QD x 10 q28 days. 30 pts with sarcoma were treated at MTD (2500 mg) (EXT) with pre-and on dose (d5+/-2) biopsies. Analyses included TP53 mutation (AmpliChip), MDM2 amplification (ISH), p53 and p21 IHC, MDM2 RT-PCR, Ki-67, TUNEL and
18
F-FLT-PET. Blood was obtained for PK and MIC-1, a PD marker of p53 activation. Results: DE: MTD was1440 mg/m
2
/d (2500 mg flat dose). PK was ~dose linear (t½ 1-1.5 d) with high variability (CV~70%) in AUC and Cmax . Adverse events included nausea/GI and exposure-related neutropenia/thrombocytopenia. 3 DLTs: diarrhea, pancytopenia, hyponatremia occurred (at ≥ 640 mg/m
2
). Evidence of activity included: 1) concentration dependent increase in plasma MIC-1 (% baseline), 2) decrease in
18
F-FLT PET and PR each in liposarcoma pts at 1800 mg/m
2
and 1440 mg/m
2
, respectively. EXT: Grade3/ 4 cytopenias at MTD precluded subsequent cycles in 6/8 pts (10 day schedule). Dosing was changed to 5 days, and only 3 patients had Gr3/4 cytopenias. 8/22 pts remained on study for >4 cycles, including 2 pts with SD for 7 and 9 cycles respectively. 3 of 4 EXT pts had decreased
18
F-FLT-PET activity. Biopsies (pre- and on treatment) demonstrated: 1) increase in p53 (median 1.5 fold change (X) by IHC, n=15); 2) increase in p21 (median 2.7X by IHC, n=14); 3) increase in MDM2 (median 2.5X by RT-PCR, n = 27); 4) decrease in % Ki-67(+) cells (median % change from baseline -65.4%, range -91% to +275%, n=17 ); 5) increase in TUNEL(+) cells of 9.0 (density of + cells/mm
2
, range -26.2 to +45.5, n=22). These results were seen both in tumors with and without MDM2 gene amplification, and in multiple sarcoma subtypes. Conclusions: RG7112 has manageable AEs (GI ) and cytopenias correlating with AUC. Single agent disease control, and biomarker activity was seen in both MDM2 amplified and non-amplified, heavily pretreated soft tissue sarcoma pts, with changes reflecting activation of p53-related pathways.
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10035
Background: The role of surgery in pts with ASTS remains controversial. We have conducted an exploratory retrospective analysis of the role of metastasis surgery in ASTS pts ...receiving 1st-line chemotherapy (CT). Methods: The database includes all pts enrolled in PALSAR-1 and PALSAR-2 trials Fayette 2009; Bui-Nguyen 2011, treated with dose-intensified MAID or high-dose CT with peripheral blood stem cells support as 1st-line treatment of ASTS. In our analysis, the primary endpoint is overall survival (OS). Log-ranks are used for univariate analysis and Cox model for multivariate analysis. Impact of treatments had been evaluated after adjustment to confounders (Cox Model). Confounders were defined as parameters with significantly different distribution in pts who underwent metastasis surgery and those who did not (p<0.05) and significantly associated with OS (p<0.05). Results: The database consists of 410 pts (160 in PALSAR-1 and 248 in PALSAR-2) with a median age of 43. Among them, 77 patients (18%) underwent metastasis surgery. At the end of the treatment, 61 pts experienced complete response (CR), 45 with CT alone and 16 with metastasis surgery and CT. The median follow-up was 29 months. The median OS was 35.7 months (29.9-41.5). The following parameters are associated with longer OS in univariate analysis: primary location (p=0.0001), performance status (p=0.010) and absence of liver metastasis (p=0.001). We identified 4 factors associated with metastasis surgery (n=76): limb/trunk primaries, young age, absence of liver metastasis and absence of progression of the target lesions after 4 cycles. The sole identified confounder was primary location. In multivariate analysis the 2 categories of patients experiencing significant longer OS are those with CR without surgery (HR=2.2, 1.7-5.8, p=0.0001) and those with CR following metastasis surgery (HR=3.8, 2.3-6.2, p=0.0001). Conclusions: Among the pts with ASTS receiving poly-CT as 1st-line treatment, the OS of pts experiencing CR with or without metastasis surgery appears similar. Metastatis surgery without CR does not offer significant OS advantage.
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TPS10102^
Background: Masitinib is an oral tyrosine kinase inhibitor (TKI) that has greater in vitro kinase activity and/or selectivity than imatinib against KIT and PDGFRA/B. A phase 2 ...study has previously reported that masitinib treatment produced clinically relevant activity in imatinib-naïve patients with advanced GIST. Considering the promising long term response observed in overall survival (OS) (see Table) there is compelling evidence to compare masitinib against imatinib (the current standard of care) in the first-line setting. Methods: A multicenter, randomized, open label, phase 3, 1:1 study to compare efficacy and safety of masitinib (7.5 mg/kg/day) to the active control of imatinib (400 or 600 mg/day) in first-line treatment of patients with advanced GIST. Primary endpoint is progression-free survival (PFS), with secondary endpoints including OS, time to progression (TTP), and clinical response rates (RECIST). Based on a planned sample size of 222 patients (111/arm) this 15% non-inferiority study was designed to have an 85% power using a 95% two-sided CI of the hazard ratio. Patient eligibility criteria include: histologically proven, metastatic or locally advanced nonresectable, or recurrent post-surgery GIST; TKI naïve patient or patient previously receiving imatinib only as a neoadjuvant or adjuvant therapy; and confirmed KIT-positive or PDGFRA-positive tumors. Recruitment is ongoing. On 09/2011, the DMC recommended continuation of this study. Clinicaltrial.gov: NCT00812240. Table: see text
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10027
Background: Treatment options are limited for pts with advanced pretreated STS. HDACi have shown activity in preclinical models of STS and SCT Methods: Pts with advanced ...pretreated STS and SCT were enrolled in this open label, single arm, multicenter phase II study. Panobinostat was given orally, 40 mg thrice per week. The primary end-point was 3-month progression-free rate according to RECIST 1.1 using central review. Fleming-A’Hern single-stage design for phase II trials was used, and assuming a type I error alpha of 5% with 90% power, 15/47 pts were needed to be progression free at 3 months to reject a rate of 20%. Results: Fifty three pts were enrolled between January 2010 and January 2011. Median age was 59 (range 21-79) years, and 22 (42%) pts were males, 13 had translocation-related sarcoma (TRS) and 4 had SCT. All but 5 pts had metastatic disease. The most common sites were the lung and the liver. All but one pt had documented disease progression prior to study entry. The median number of prior lines of therapy was 2 (range 1-7). Panobinostat dose was lowered to 20 mg thrice a week after 11 pts were enrolled based on the recommendation of an independent safety committee. Fifty-two pts were evaluable for toxicity (1 pt never received treatment), 48 pts (92%) reported at least one adverse event (AE) and 22 (42%) reported at least one treatment-related grade 3 or 4 AE. The most common grade 3/4 AEs were thrombocytopenia, fatigue and anemia. Fifty pts were evaluable for the primary end-point, of these, 12 pts (24%, 95%CI13-38%) were progression-free at 3 months, including 4/13 pts (31%, 95%CI9-61%) with TRS and 2/4 pts (50%, 95%CI7-93%) with SCT. No CR was seen, two patients (4%) with SCT had a PR and 19 pts (37%) had SD as their best response. Seven pts were progression-free at 6 months: 2 pts with SCT, 2 with TRS, 1 with liposarcoma, 1 with malignant solitary fibrous tumor and 1 with leiomyosarcoma. Conclusions: Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited although some patients had prolonged SD. Activity in pts with SCT warrants further investigation.
To analyze the management and clinical outcome of patients treated for a first isolated local recurrence of soft tissue sarcomas (trunk or extremities) and to identify prognosis factors.
Between 1980 ...and 1999, 83 adult patients were included in the study.
Mean age was 61 years. Mean tumor size was 6cm. Most sarcomas were located in extremities (n=74), were deep (n=60), and proximal (n=53); 30 involved nerves or vessels. Histologic subtypes were mainly grade 2 (42%) or 3 (36%) histiocytofibrosarcomas (49%) and liposarcomas (20%).
Surgical treatment of recurrences consisted in wide excision (29 cases), marginal resection (43 cases), 5 patients requiring amputation. Final results were R0 (n=33), R1 (n=47) or R2 (n=3) resection. Besides surgery, 6 patients received neo-adjuvant and 7 others adjuvant chemotherapy. Twenty three patients received post-operative external beam radiotherapy (EBRT) (mean dose 55Gy) and 26 interstitial 192Ir low dose rate brachytherapy (BCT) (mean dose 45Gy for BCT alone, 22Gy when associated with EBRT), 19 patients being re-irradiated.
Mean follow up was 13 years. Thirty-seven (45%) patients relapsed, 62% of whom presenting an isolated local recurrence. Nineteen patients developed distant metastases.
Multivariate analysis showed only tumor depth (P=0.05) and re-resection for primary R1 resection (P=0.018) being independent prognosis factors for tumor control, radiotherapy (EBRT and/or BCT) being significant in univariate analysis (P=0.05).
Overall survival rate was 73%, 54%, and 47% at, respectively, 3.5 and 10 years, and was 65%, 35% and 32% after a further local recurrence. Multivariate analysis showed trunk (P=0.0001) or inferior extremity locations (P=0.023), symptomatic (P=0.001), high grade (P=0.01), deep (P=0.01) tumors, and the occurrence of a further local failure (P=0.004) as unfavorable characteristics for overall survival.
A first isolated local recurrence of STS increases mainly the risk of a subsequent local relapse. Quality of local treatment is decisive. When a conservative treatment is feasible, it should combine surgical resection and radiotherapy, BCT being the best suited in previously irradiated patients. Efforts have to be pursued to increase quality of the treatment of primary tumors, at best performed in centers that have expertise in this field.
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