Giovanni Grignani

Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial

BACKGROUNDnA non-randomised, phase 2 study showed activity and tolerability of eribulin in advanced or metastatic soft-tissue sarcoma. In this phase 3 study, we aimed to compare overall survival in patients with advanced or metastatic soft-tissue sarcoma who received eribulin with that in patients who received dacarbazine (an active control).nnnMETHODSnWe did this randomised, open-label, phase 3 study across 110 study sites in 22 countries. We enrolled patients aged 18 years or older with intermediate-grade or high-grade advanced liposarcoma or leiomyosarcoma who had received at least two previous systemic regimens for advanced disease (including an anthracycline). Using an interactive voice and web response system, an independent statistician randomly assigned (1:1) patients to receive eribulin mesilate (1·4 mg/m(2) intravenously on days 1 and 8) or dacarbazine (850 mg/m(2), 1000 mg/m(2), or 1200 mg/m(2) [dose dependent on centre and clinician] intravenously on day 1) every 21 days until disease progression. Randomisation was stratified by disease type, geographical region, and number of previous regimens for advanced soft-tissue sarcoma and in blocks of six. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT01327885, and is closed to recruitment, but treatment and follow-up continue.nnnFINDINGSnBetween March 10, 2011 and May 22, 2013, we randomly assigned patients to eribulin (n=228) or dacarbazine (n=224). Overall survival was significantly improved in patients assigned to eribulin compared with those assigned to dacarbazine (median 13·5 months [95% CI 10·9-15·6] vs 11·5 months [9·6-13·0]; hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·0169). Treatment-emergent adverse events occurred in 224 (99%) of 226 patients who received eribulin and 218 (97%) of 224 who received dacarbazine. Grade 3 or higher adverse events were more common in patients who received eribulin (152 [67%]) than in those who received dacarbazine (126 [56%]), as were deaths (10 [4%] vs 3 [1%]); one death (in the eribulin group) was considered treatment-related by the investigators.nnnINTERPRETATIONnOverall survival was improved in patients assigned to eribulin compared with those assigned to an active control, suggesting that eribulin could be a treatment option for advanced soft-tissue sarcoma.nnnFUNDINGnEisai.

A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study

PURPOSEnAfter standard multimodal therapy, the prognosis of relapsed and unresectable high-grade osteosarcoma is dismal and unchanged over the last decades. Recently, mitogen-activated protein kinases were shown to be activated in osteosarcoma specimens, suggesting, therefore, they are suitable targets for the multikinase inhibitor sorafenib. Thus, we explored sorafenib activity in patients with relapsed and unresectable osteosarcoma.nnnEXPERIMENTAL DESIGNnPatients > 14 years, progressing after standard treatment, were eligible to receive 400 mg of sorafenib twice daily until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) at 4 months. Secondary objectives were PFS, overall survival (OS), clinical benefit rate (CBR), defined as no progression at 6 months and safety. This nonrandomized phase II study used a Simon two-stage design. PFS and OS at 95% confidence intervals (95% CIs) were calculated by the Kaplan-Meier method. All tests were two sided.nnnRESULTSnThirty-five patients were enrolled. PFS at 4 months was 46% (95% CI 28% to 63%). Median PFS and OS were 4 (95% CI 2-5) and 7 (95% CI 7-8) months, respectively. The CBR was 29% (95% CI 13% to 44%). We observed 3 (8%) partial responses (PRs), 2 (6%) minor responses (< 30% tumor shrinkage) and 12 (34%) stable diseases (SDs). For six patients (17%), PR/SD lasted ≥ 6 months. Noteworthy, tumor density reduction and [(18)F]2-fluoro-2-deoxy-d-glucose-positron emission tomography responses were observed among SD patients. Sorafenib was reduced or briefly interrupted in 16 (46%) patients and permanently discontinued in one (3%) case due to toxicity.nnnCONCLUSIONSnSorafenib demonstrated activity as a second- or third-line treatment in terms of PFS at 4 months with some unprecedented long-lasting responses. Sorafenib, the first targeted therapy showing activity in osteosarcoma patients, deserves further investigations.

Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways

BackgroundOsteosarcoma (OS) is the most common primary bone tumour in children and young adults. Despite improved prognosis, metastatic or relapsed OS remains largely incurable and no significant improvement has been observed in the last 20 years. Therefore, the search for alternative agents in OS is mandatory.ResultsWe investigated phospho-ERK 1/2, MCL-1, and phospho-Ezrin/Radixin/Moesin (P-ERM) as potential therapeutic targets in OS. Activation of these pathways was shown by immunohistochemistry in about 70% of cases and in all OS cell lines analyzed. Mutational analysis revealed no activating mutations in KRAS whereas BRAF gene was found to be mutated in 4/30 OS samples from patients. Based on these results we tested the multi-kinase inhibitor sorafenib (BAY 43-9006) in preclinical models of OS. Sorafenib inhibited OS cell line proliferation, induced apoptosis and downregulated P-ERK1/2, MCL-1, and P-ERM in a dose-dependent manner. The dephosphorylation of ERM was not due to ERK inhibition. The downregulation of MCL-1 led to an increase in apoptosis in OS cell lines. In chick embryo chorioallantoic membranes, OS supernatants induced angiogenesis, which was blocked by sorafenib and it was also shown that sorafenib reduced VEGF and MMP2 production. In addition, sorafenib treatment dramatically reduced tumour volume of OS xenografts and lung metastasis in SCID mice.ConclusionIn conclusion, ERK1/2, MCL-1 and ERM pathways are shown to be active in OS. Sorafenib is able to inhibit their signal transduction, both in vitro and in vivo, displaying anti-tumoural activity, anti-angiogenic effects, and reducing metastatic colony formation in lungs. These data support the testing of sorafenib as a potential therapeutic option in metastatic or relapsed OS patients unresponsive to standard treatments.

Sporadic desmoid-type fibromatosis: a stepwise approach to a non-metastasising neoplasm—a position paper from the Italian and the French Sarcoma Group

Desmoid-type fibromatosis (DF) is a rare locally aggressive monoclonal proliferation of myofibroblasts lacking metastatic capacity. It may be observed in nearly every part of the body. Considering the variable clinical presentations, anatomic locations, and biologic behaviors, an individualized treatment approach is required. The pathogenesis of DF is not completely understood even if a high prevalence (∼85%) of CTNNB1 mutations discovered in sporadic DF underlies the importance of the Wnt/&bgr;-catenin pathway. No established and evidence-based approach for the treatment of this neoplasm is available as of today. Considering the unpredictable behavior and the heterogeneity of this disease, we propose a treatment algorithm approved by the French and the Italian Sarcoma Group, based on a front-line wait and see approach and subsequent therapy in the case of progression. A careful counseling at a referral center is mandatory and should be offered to all patients affected by sporadic DF from the time of their diagnosis.Desmoid-type fibromatosis (DF) is a rare locally aggressive monoclonal proliferation of myofibroblasts lacking metastatic capacity. It may be observed in nearly every part of the body. Considering the variable clinical presentations, anatomic locations, and biologic behaviors, an individualized treatment approach is required. The pathogenesis of DF is not completely understood even if a high prevalence (∼85%) of CTNNB1 mutations discovered in sporadic DF underlies the importance of the Wnt/β-catenin pathway. No established and evidence-based approach for the treatment of this neoplasm is available as of today. Considering the unpredictable behavior and the heterogeneity of this disease, we propose a treatment algorithm approved by the French and the Italian Sarcoma Group, based on a front-line wait and see approach and subsequent therapy in the case of progression. A careful counseling at a referral center is mandatory and should be offered to all patients affected by sporadic DF from the time of their diagnosis.

Management of Recurrent Retroperitoneal Sarcoma (RPS) in the Adult: A Consensus Approach from the Trans-Atlantic RPS Working Group

IntroductionRetroperitoneal soft tissue sarcomas (RPS) are rare tumors. Surgery is the mainstay of curative therapy, but local recurrence is common. No recommendations concerning the best management of recurring disease have been developed so far. Although every effort should be made to optimize the initial approach, recommendations to treat recurring RPS will be helpful to maximize disease control at recurrence.MethodsAn RPS transatlantic working group was established in 2013. The goals of the group were to share institutional experiences, build large multi-institutional case series, and develop consensus documents on the approach to this difficult disease. The outcome of this document applies to recurrent RPS that is nonvisceral in origin. Included are sarcomas of major veins, undifferentiated pleomorphic sarcoma of psoas, ureteric leiomyosarcoma (LMS). Excluded are desmoids-type fibromatosis, angiomyolipoma, gastrointestinal stromal tumors, sarcomas arising from the gut or its mesentery, uterine LMS, prostatic sarcoma, paratesticular/spermatic cord sarcoma, Ewing sarcoma, alveolar/embryonal rhabdomyosarcoma, sarcoma arising from teratoma, carcinosarcoma, sarcomatoid carcinoma, clear cell sarcoma, radiation-induced sarcoma, paraganglioma, and malignant pheochromocytoma.ResultsRecurrent RPS management was evaluated from diagnosis to follow-up. It is a rare and complex malignancy that is best managed by an experienced multidisciplinary team in a specialized referral center. The best chance of cure is at the time of primary presentation, but some patients may experience prolonged disease control also at recurrence, when the approach is optimized and follows the recommendations contained herein.ConclusionsInternational collaboration is critical for adding to the present knowledge. A transatlantic prospective registry has been established.

Treatment of Extraspinal Painful Bone Metastases with Percutaneous Cementoplasty: A Prospective Study of 50 Patients

The aim of this study was to assess the efficacy of percutaneous cementoplasty (PC) with polymethylmethacrylate (PMMA) in painful extravertebral lytic bone metastases not responding to conventional therapy. Fifty patients (25 females), mean age 64.7xa0±xa011.2xa0years, underwent PC after giving informed consent. Procedures were performed under fluoroscopy (1/50) or combined fluoroscopy-CT (49/50) guidance in local anesthesia or under deep sedation in 7 patients with large metastases who underwent radiofrequency thermoablation (RFA) in the same session. Seventy lesions were treated (1-6 per patient; average, 1.4xa0±xa00.9), arranging in size from 1 to 10xa0cm (average, 3.6xa0±xa02.1xa0cm). Mean volume of PMMA per lesion was 5.9xa0±xa03.2xa0ml (range, 1.5–15.0xa0ml). Pain was prospectively evaluated on an 11-point visual analog scale (VAS) before and after the procedure (follow-up, 15 to 36xa0months). Mean VAS score dropped from 9.1xa0±xa01.2 (range: 6–10) to 2.1xa0±xa02.5 (range: 0–9). Mean VAS difference was 7.0xa0±xa02.3 (range, 1–10; pxa0<xa00.0001, Wilcoxon signed rank test). Forty-seven of the 50 patients (94%) suspended narcotic drugs, in 22 (44%) pain was controlled with a nonsteroidal anti-inflammatory drug, in 25 (50%) analgesic therapy was suspended, and 13 of 50 (26%) had complete pain regression. In 3 of the 50 patients (6%) pain was not improved. No statistical difference between osteoplasty and osteoplasty plus RFA was found (pxa0=xa00.8338, Mann–Whitney test). No complications arose during the procedure. Two patients with metastases in the femoral diaphysis reported a fracture 1xa0month after treatment. PC is effective to obtain pain regression in painful bone metastases not responding to conventional analgesic therapy; bone consolidation cannot be obtained in the diaphysis of long weight-bearing bones.

Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall

BACKGROUNDnTo explore correlation between the quality of surgery and outcome in high-risk soft tissue sarcoma (STS) patients treated within a phase III randomized trial.nnnPATIENTS AND METHODSnIn the trial, all patients received three cycles of preoperative chemotherapy (CT) with epirubicin 120 mg/m(2) and ifosfamide 9 g/m(2) and were randomly assigned to receive two further postoperative cycles. Radiotherapy (RT) could be delivered in the preoperative or postoperative setting. The association between surgical margins and overall survival (OS) was studied in a univariate and multivariate fashion.nnnRESULTSnTwo hundred and fifty-two patients completed the whole treatment and were operated conservatively. At a median follow-up of 60 months (IQR, 45-74 months), the 5-year OS was 0.73, even in patients with positive and negative margins. The 5-year cumulative incidence (CI) of local recurrence (LR) in patients with positive and negative microscopic margins was 0.17 (standard error, SE, 0.08) and 0.03 (SE, 0.01), respectively. In the subgroup of patients receiving combined preoperative CT-RT and with positive surgical margins, the CI of LR was 0.nnnCONCLUSIONSnIn this setting of high-risk STS treated by preoperative CT or CT-RT, the negative impact of positive margins on the outcome was limited. When close margins can be anticipated preoperative CT-RT may be a reasonable option to maximize the chance of cure.

Primary metastatic Ewing's family tumors: results of the Italian Sarcoma Group and Scandinavian Sarcoma Group ISG/SSG IV Study including myeloablative chemotherapy and total-lung irradiation

BACKGROUNDnThe Italian Sarcoma Group and the Scandinavian Sarcoma Group designed a joint study to improve the prognosis for patients with Ewings family tumors and synchronous metastatic disease limited to the lungs, or the pleura, or a single bone.nnnPATIENTS AND METHODSnThe study was opened in 1999 and closed to the enrollment in 2008. The program consisted of intensive five-drug combination chemotherapy, surgery and/or radiotherapy as local treatment, and consolidation treatment with high-dose busulfan/melphalan plus autologous stem cell rescue and total-lung irradiation.nnnRESULTSnDuring the study period, 102 consecutive patients were enrolled. The median follow-up was 62 months (range 24-124). The 5-year event-free survival probability was 0.43 [standard deviation (SD) = 0.05] and the 5-year overall survival probability was 0.52 (SD = 0.052). Unfavorable prognostic factors emerging on multivariate analysis were a poor histological/radiological response at the site of the primary tumor [relative risk (RR) = 3.4], and incomplete radiological remission of lung metastases after primary chemotherapy (RR = 2.6). One toxic death and one secondary leukemia were recorded.nnnCONCLUSIONSnThis intensive approach is feasible and long-term survival is achievable in ∼50% of patients. New treatment approaches are warranted for patients responding poorly to primary chemotherapy.BACKGROUNDnThe Italian Sarcoma Group and the Scandinavian Sarcoma Group designed a joint study to improve the prognosis for patients with Ewings family tumors and synchronous metastatic disease limited to the lungs, or the pleura, or a single bone.nnnPATIENTS AND METHODSnThe study was opened in 1999 and closed to the enrollment in 2008. The program consisted of intensive five-drug combination chemotherapy, surgery and/or radiotherapy as local treatment, and consolidation treatment with high-dose busulfan/melphalan plus autologous stem cell rescue and total-lung irradiation.nnnRESULTSnDuring the study period, 102 consecutive patients were enrolled. The median follow-up was 62 months (range 24-124). The 5-year event-free survival probability was 0.43 [standard deviation (SD) = 0.05] and the 5-year overall survival probability was 0.52 (SD = 0.052). Unfavorable prognostic factors emerging on multivariate analysis were a poor histological/radiological response at the site of the primary tumor [relative risk (RR) = 3.4], and incomplete radiological remission of lung metastases after primary chemotherapy (RR = 2.6). One toxic death and one secondary leukemia were recorded.nnnCONCLUSIONSnThis intensive approach is feasible and long-term survival is achievable in ∼50% of patients. New treatment approaches are warranted for patients responding poorly to primary chemotherapy.

Short, full-dose adjuvant chemotherapy (CT) in high-risk adult soft tissue sarcomas (STS): long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group

BACKGROUNDnTo report on long-term results of a phase 3 trial comparing three versus five cycles of adjuvant chemotherapy (CT) with full-dose epirubicin+ifosfamide in high-risk soft tissue sarcomas (STS).nnnMETHODSnPatients (pts) were randomized to receive three preoperative cycles of epirubicin 120 mg/m2 and ifosfamide 9 g/m2 (Arm A) or to receive the same three preoperative cycles plus two postoperative cycles (Arm B). Radiotherapy could be either delivered in the preoperative or in the postoperative setting. Non-inferiority of the primary end point, OS, was assessed by the confidence interval of the hazard ratio (HR; Arm A/Arm B) derived from Cox model.nnnRESULTSnBetween January 2002 and April 2007, 164 pts were assigned to arm A and 164 to arm B. At a median follow-up (FU) of 117 months (IQ range 103-135 months), 123 deaths were recorded: 58 in Arm A and 65 in Arm B. Ten-year OS was 61% for the entire group of patients: 64% in Arm A and 59% in Arm B. The intention-to-treat analysis confirmed that three cycles were not inferior to five cycles (one-sided 95% upper confidence limit was 1.24). A per protocol analysis was consistent with these results. Pts with leiomyosarcoma and undifferentiated pleomorphic sarcoma (UPS) had the lowest, and the highest response rates, respectively. Consistently, Leiomyosarcoma and UPS had the worse and the best prognosis, respectively.nnnCONCLUSIONSnAt a longer FU, the non-inferiority of three cycles of a full-dose conventional CT in comparison to five is confirmed. Response to therapy is also confirmed to be associated with better survival. This regimen is currently tested within an ongoing international trial against three cycles of a neoadjuvant histology-tailored CT (ClinicalTrials.gov Identifier: NCT01710176).

Percutaneous vertebroplasty in multiple myeloma: Prospective long-term follow-up in 106 consecutive patients

PurposePercutaneous vertebroplasty (PV) is a minimally invasive procedure involving the injection of bone cement within a collapsed vertebral body. Although this procedure was demonstrated to be effective in osteoporosis and metastases, few studies have been reported in cases of multiple myeloma (MM). We prospectively evaluated the safety and efficacy of PV in the treatment of vertebral compression fractures (VCFs) resulting from MM.Materials and MethodsPV was performed in 106 consecutive MM patients who had back pain due to VCFs, the treatment of which had failed conservative therapies. Follow-up (28.2xa0±xa012.1xa0months) was evaluated at 7 and 15xa0days as well as at 1, 3, 6, 12, 18, and every 6xa0months after PV. Visual analog scale (VAS) pain score, opioid use, external brace support, and Oswestry Disability Index (ODI) score were recorded.ResultsThe median pretreatment VAS score of 9 (range 4–10) significantly (Pxa0<xa00.001) decreased to 1 (range 0–9) after PV. Median pre-ODI values of 82% (range 36–89%) significantly improved to 7% (range 0–82%) (Pxa0<xa00.001). Differences in pretreatment and posttreatment use of analgesic drug were statistically significant (Pxa0<xa00.001). The majority of patients (70 of 81; 86%) did not use an external brace after PV (Pxa0<xa00.001).ConclusionPV is a safe, effective, and long-lasting procedure for the treatment of vertebral compression pain resulting from MM.