Italian Sarcoma Group

BackgroundAmong sarcomas, which are rare cancers with an incidence of <6 per 100.000/year cases, ultra-rare sarcomas have an incidence of approximately ≤1/1,000,000/year cases and altogether account for ~20% of all soft tissue sarcomas (STS) and bone sarcomas. The Italian Sarcoma Group has recently performed a non-interventional, retrospective TrObs study with data from 512 anthracycline-pretreated patients with advanced multiple STS histologies and treated with trabectedin (Palmerini, Cancers 2021; ClinicalTrials.gov Identifier: NCT02793050).MethodsA post-hoc analysis of case series to evaluate the efficacy and safety of trabectedin on patients with ultra-rare and other rare translocation-related sarcomas included in TrObs study was performed. Main outcomes comprised investigator-assessed overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety.ResultsThirty-six patients (18 women) with ultra-rare and other rare sarcoma and a median age of 53.0 years (range: 22-81) were included. Most patients had solitary fibrous tumor (SFT; n=11) followed by epithelioid sarcoma (n=5), malignant peripheral nerve sheath tumor (MPNST; n=4), extraskeletal myxoid chondrosarcoma (EMC; n=3), desmoplastic small round cell tumor (DSRCT; n=3), and alveolar soft part sarcoma (ASPS), rhabdomyosarcoma and clear cell sarcoma (n=2 each). Thirty-five patients had metastatic disease and 23 patients received trabectedin as a second-line treatment. Among 35 patients evaluable for response, two patients with SFT and ASPS had a partial response and one patient with DSRCT obtained a complete response, reaching an ORR of 8.6% (95% CI: 2.8-23.4%). Among patients with an ORR, 6-months PFS was 100% in patients with ASPS, 45.7% in patients with SFT and 33.3% in those with DSRCT. Two patients with epithelioid sarcoma and myoepithelioma had disease stabilization lasting >24 months. Nine patients had at least one grade 3/4 adverse event, mostly being bone marrow toxicity (n=6).ConclusionsTrabectedin has some anti-tumor activity in some ultra-rare and other rare sarcomas, particularly translocation-related sarcomas, with the well-known manageable safety profile.

BackgroundAccording to retrospective osteosarcoma series, ABCB1/P‐glycoprotein (Pgp) overexpression predicts for poor outcomes. A prospective trial to assess a risk‐adapted treatment strategy using mifamurtide in Pgp+ patients was performed.MethodsThis was a phase 2, multicenter, uncontrolled trial including patients 40 years old or younger with nonmetastatic extremity high‐grade osteosarcoma stratified according to Pgp expression. All patients received high‐dose methotrexate, doxorubicin, and cisplatin (MAP) preoperatively. In Pgp+ patients, mifamurtide was added postoperatively and combined with MAP for a good histologic response (necrosis ≥ 90%; good responders [GRs]) or with high‐dose ifosfamide (HDIFO) at 3 g/m2/d on days 1 to 5 for a histologic response < 90% (poor responders [PRs]). Pgp– patients received MAP postoperatively. After an amendment, the cumulative dose of methotrexate was increased from 60 to 120 g/m2 (from 5 to 10 courses). The primary end point was event‐free survival (EFS). A postamendment analysis was performed.ResultsIn all, 279 patients were recruited, and 194 were included in the postamendment analysis: 70 (36%) were Pgp–, and 124 (64%) were Pgp+. The median follow‐up was 51 months. For Pgp+ patients, 5‐year EFS after definitive surgery (null hypothesis, 40%) was 69.8% (90% confidence interval [CI], 62.2%‐76.2%): 59.8% in PRs and 83.7% in GRs. For Pgp– patients, the 5‐year EFS rate was 66.4% (90% CI, 55.6%‐75.1%).ConclusionsThis study showed that adjuvant mifamurtide, combined with HDIFO for a poor response to induction chemotherapy, could improve EFS in Pgp+ patients. Overall, the outcomes compared favorably with previous series. Mifamurtide and HDIFO as salvage chemotherapy are worth further study.

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 &lt; 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]

10569 Background: TR is a DNA damaging agent as 2nd line-therapy in STS. We speculated that its antitumor activity could be potentiated by a “synthetic lethality” approach targeting key molecules i...

10572 Background: In STS third line treatment is poorly defined. However many patients (pts), after aggressive therapy as first and second line progress in their disease ask to be treated. Oral cyclophosphamide (CPM) was already used in breast cancer, prostate cancer and in elderly pts with STS with favourable results. Aim of our study was to define the feasibility, tolerability and activity of oral CPM as third line and further line chemotherapy Methods: 45 pts (19 M; 26 F) with advanced or metastatic STS heavily pretreated were included. Oral CPM was given daily at total dose of 50 mg/day without interruption excepted for toxicity or progressive disease Results: Median age was 60 (32-81), histological subtypes were: leiomyosarcoma 12, liposarcoma 10, condrosarcoma 5, sinovialsarcoma 4, sarcoma NOS 4, other 10. Primary sites were: extremities 21, retroperitoneum 19, trunk 5. 41 pts were metastatic, 4 locally advanced. 41 pts were pretreated with chemotheraphy (15 were in II line, 17 in III line, 7 in IV line, 2 in V line). Median PS (ECOG) was 2 . Median duration of theraphy was 4 months (1-38). Progression free survival (PFS) ranged from 0 to 42+ months (median 4 months). Treatment was well tolerated, we registred only one episode of leucopenia G2 and one of asthenia G2. No complete responses were seen. Only 3 minimal responses and 18 stable disease were seen. Conclusions: Oral CPM showed a mild activity and good tolerability in advanced soft tissue and metastatic STS. It could be an appropriate solution as second line and further therapy and in unfit or elderly pts.

10055 Background: STS are 1% of malignant tumors in adults. Rarity, heterogeneity in presentation, low expertise in primary care physicians (PCP) or in general hospitals, organisation problems in specialized centers may cause a delay in both diagnosis and treatment. Aim of this study is to acknowledge the barriers to optimal care and the consequences of the delay on prognosis. Methods: Patients with STS of the extremities, trunk, retroperitoneum treated and followed from 1999 to 2011 by the same multidisciplinary group were included. Time and pattern of symptoms onset, anatomic site, tumor volume, patients’ age, gender and home, interval between diagnosis and surgical treatment or neoadjuvant chemotherapy; time to start adjuvant RT or CT were considered in a univariate - multivariate analysis. Results: 449 adult patient (53% F, 47% M, median age 55 years) were followed for a median time of 116.38 months. 65.7% of STS were at the extremities, 17.6% retroperitoneal, 16.7% at the trunk wall. Median volume at diagnosis was 8 cm for trunk and extremities; 15 cm for retroperitoneum. Commonest histologies: liposarcoma. 18.2%; leiomyo 16.8%; mixofibro 13.6%. Increasing mass, pain, and abdominal disconfort were the main revealing signs of diseases. Median time of delay were: from onset of symptom to first medical visit 68 days for trunk and extremities, 82 for retroperitoneum; 104 days from symptoms to histological diagnosis; 129 days from symptoms to start of therapy. Time to surgery after definitive diagnosis was 12 days in extremities and 21 in abdomen. Adjuvant CT started 22 days after surgery for extremities, 25 in trunk, 35 in retroperitoneum. RT initiated after 78 days. Longer delay in treatment lead to worse prognosis: MS 89.95 months if delay was &gt; 3 months; 190.40 months if wait was &lt; 3 months (p 0.007). Conclusions: Low self consciousness of the patient; misdiagnosis or inadequate approach in general hospitals; late referral to specialized centres are 75% of the cause of wasted time. Organization problems at the referral Centre concur for 25% of delay. Guidelines implementation and educational programme among general population and PCP are necessary.

9002 Background: The ISG-SSG II study was undertaken to explore the effect of adding high-dose chemotherapy (HDCT) with peripheral blood stem cells support (PBSC) to conventional chemotherapy (CT) in patients with primary metastatic and/or axial localized OS. Methods: From May 1996 to Dec 2003, 57 patients, median age 17 years (range 2–38) entered the study. 46 patients had metastases at presentation, 39 with extremity localized tumors and 7 with axial tumors. All 46 had lung metastases (> 2 nodules in 31 cases), 3 additional lymph node involvement and 6 bone metastases. 11 patients had pelvic OS without metastases. Preoperative CT included two courses of Methotrexate 12 g/m2, Cisplatin 120 mg/m2 + Adriamycin 75 mg/m2 and Ifosfamide 15 g/m2. Stem cells were harvested after the first course of Ifosfamide (day 28). Post-operatively patients received 2 cycles of Adriamycin 90 mg/m2, Cyclophosphamide (CTX) 4000 mg/m2 + VP16 600 mg/m2, and 2 cycles of HDCT containing VP16 1800 mg/m2 + Carboplatin 1500 mg/m2 with PBSC rescue. Results: Surgery of primary tumour was performed in 46 (81%) patients. A median of 2 (range 1–7) aphaereses were performed, with a median collection of 6.9x106 CD34+/kg. 3 patients needed additional bone marrow harvest. 27 patients received 2 HDCTs and 9 patients 1 cycle. Conditioning regimen was well tolerated (median time to Neutrophils > 0.5x109/l and Platelets > 25x109/l: 10 days). One patient developed renal failure after Ifosfamide and 1 veno-occlusive disease after CTX + VP16. 38 (67%) patients (30 metastatic and 8 pelvic) achieved complete remission (C.R.). With a median follow-up of 26 months (range 4–101 months), 14 patients are alive in 1st C.R., 5 in 2nd or higher C.R., 3 patients are alive with disease and 35 have died of disease. The projected overall and event free survival (EFS) at 3-year are 39% and 21% respectively. For the group with metastatic disease (n=46) the 3-year overall and EFS rates are 34% and 16% respectively, and for the group of patients (n=38) who achieved C.R. 58% and 33%. Conclusions: The ISG-SSG II study demonstrates that HDCT in addition to conventional CT is feasible in high-risk OS patients. The reported survival rates do not support the use of HDCT in this subset of patients. No significant financial relationships to disclose.