TRAbectedin in adVanced rEtroperitoneal well differentiated/dedifferentiated Liposarcoma and Leiomyosarcoma (TRAVELL): results of a phase II study from the Italian Sarcoma Group.

BACKGROUND: This is a multicentre, single-arm, phase II study aimed at further exploring the activity of trabectedin as second-/further-line treatment in retroperitoneal leiomyosarcoma (LMS) and well-differentiated/dedifferentiated liposarcoma (LPS). MATERIALS AND METHODS: The primary endpoint was the growth modulation index (GMI) defined as the ratio between PFS under trabectedin (PFS) and during previous chemotherapy treatment: time to progression (TTP-1). Secondary endpoints were objective response rate (ORR) and PFS. As per protocol, patients were considered responders if the GMI was >1.33, non-responders if <0.75 and neither if 0.76-1.32. RESULTS: Overall 91 patients were assessable for the primary endpoint (32 patients with LMS and 59 patients with LPS): the median number of cycles received was 6.0 (Q1-Q3 3.0-12.0), and the main reason for treatment discontinuation was disease progression in 72% of patients. The median PFS was 6.0 months, while the median TTP1 was 7.5 months (8.1 and 6.4 months for LMS and LPS, respectively). Thirty-three patients [52%, 95% confidence interval (CI) 36% to 58%, P = 0.674, odds of response 1.1] had a GMI >1.33 (LMS 46%, 95% CI 26% to 67%, odds of response 0.85; LPS 56%, 95% CI 40% to 72%, odds of response 1.3). Overall, in LPS we observed 15/47 patients with a GMI <0.5 and 15/47 patients with a GMI >2. Among LMS patients, 9/26 had a GMI <0.5 and 10/26 had a GMI >2. Overall, ORR (complete response + partial response) was 16% (24% for LMS and 12% for LPS). CONCLUSIONS: While the primary endpoint of the study was not met, we noticed a subgroup of patients with a markedly discrepant TTP with trabectedin in comparison to previous therapy (GMI <0.5 or >2, the latter including some patients with a long TTP with trabectedin). A mismatch between PFS and overall survival was observed, possibly due to the natural history of the two different histologies and the availability of further lines in LMS.

The sacral chordoma margin.

OBJECTIVE: Aim of the manuscript is to discuss how to improve margins in sacral chordoma. BACKGROUND: Chordoma is a rare neoplasm, arising in half cases from the sacrum, with reported local failure in >50% after surgery. METHODS: A multidisciplinary meeting of the "Chordoma Global Consensus Group" was held in Milan in 2017, focusing on challenges in defining and achieving optimal margins in chordoma with respect to surgery, definitive particle radiation therapy (RT) and medical therapies. This review aims to report on the outcome of the consensus meeting and to provide a summary of the most recent evidence in this field. Possible new ways forward, including on-going international clinical studies, are discussed. RESULTS: En-bloc tumor-sacrum resection is the cornerstone of treatment of primary sacral chordoma, aiming to achieve negative microscopic margins. Radical definitive particle therapy seems to offer a similar outcome compared to surgery, although confirmation in comparative trials is lacking; besides there is still a certain degree of technical variability across institutions, corresponding to different fields of treatment and different tumor coverage. To address some of these questions, a prospective, randomized international study comparing surgery versus definitive high-dose RT is ongoing. Available data do not support the routine use of any medical therapy as (neo)adjuvant/cytoreductive treatment. CONCLUSION: Given the significant influence of margins status on local control in patients with primary localized sacral chordoma, the clear definition of adequate margins and a standard local approach across institutions for both surgery and particle RT is vital for improving the management of these patients.

Phase II prospective study with sorafenib in advanced soft tissue sarcomas after anthracycline-based therapy.

INTRODUCTION: We investigated the activity and safety of sorafenib, a multitargeted tyrosine-kinase inhibitor, in patients with advanced soft tissue sarcomas (STS). PATIENTS AND METHODS: An open-label nonrandomised multicentre phase II study was conducted in advanced STS patients pre-treated with anthracycline-based chemotherapy. Patients received sorafenib 400 mg twice daily for 28 days. The primary end point was the progression-free survival (PFS) rate at 6 months. Toxicity was assessed. Clinical outcomes were evaluated in all histologies and in leiomyosarcoma (L) and angiovascular sarcomas (A). RESULTS: Between November 2006 and January 2010, 101 patients (36 L, 19 A, and 46 others) were enrolled; 76 patients per-protocol (PP) and 100 per intention-to-treat (ITT) were assessable for the primary end point. In the PP analysis, 11 (14.5%) achieved partial response and 25 (32.9%) stable disease; 6-month PFS rates were all histologies, 34.5%; L, 38.4%; and A, 56.3%. In the ITT analysis, 6-month PFS results were 27.1, 35, and 35.5% in all histologies, L, and A, respectively. When stratified by histology, we observed a better PFS favouring leiomyosarcoma versus other histologies (P = 0.033). Treatment was well tolerated. CONCLUSIONS: Sorafenib appears to be a promising option in leiomyosarcoma patients. This finding warrants further evaluation in histology-driven trials.

New advances in biology and treatment of gastrointestinal stromal tumours (GISTs).

Gastrointestinal stromal tumours (GISTs) are a precise oncogenetic entity that has started the new era of targeted therapies in solid tumours. GISTs are now a model to understand the role of oncogenic kinase mutation in tumourigenesis, duplication, cell regulation, apoptosis and drug resistance. Ninety-five percent of GISTs have some activacting mutation of c-KIT or PDGFRA tyrosine kinase. The studies of the last two years have found concrete correlations between mutations and anatomical locations of GISTs, prognosis, response to therapy and resistance to therapy. Genotyping has increased of importance in the last years as a new field for translational researches. The important advances made in molecular studies are now a practical tool in diagnosis and therapy of GISTs.

Biology, diagnosis and therapeutic options in gastrointestinal stromal tumours.

Gastrointestinal stromal tumours (GIST) are the most common form of mesenchymal tumour of the intestinal tract. The incidence in Italy is approximately 800-1,400 new cases/year; the most common localization is the stomach (50-60%), small bowel (20-30%), rectum (10%) and esophagus (5%). Extra-abdominal localizations are very rare. GIST characteristically express the Kit protein, a transmembrane tyrosine kinase receptor for the specific ligand. Most GIST have a mutation in kit receptor which becomes constitutive for the neoplasm. Kit mutation is a early tumorogenesis event. The disease clinically can present as an occasionally finding or can be diagnosed after hemorrhage, perforation or obstruction of the gastrointestinal tract. Surgery is the mainstay of the therapy mainly in primary tumour. More debated is its role in metastatic disease. In this situation imatinib mesilate, a tyrosine kinase inhibitor, is the drug of choice which has changed the natural history of the disease. Metastatic GIST before imatinib mesilate discovery had 6 months survival, now in the 3 published studies after 3 years of follow-up, median survival has not already reached. New drugs are now under evaluation in order to prolong the pharmacological activity of tyrosine kinase inhibition after progression of the disease.

Echocolor Power Doppler with contrast medium to evaluate vascularization in lesions of the soft tissues of the limbs.

PURPOSE: Echocolor Power Doppler with contrast medium forms a non-invasive vascular image; the purpose of the study is to evaluate the effectiveness in differentiating benign and malignant tumors in the soft tissues of the limbs. MATERIAL AND METHOD: Echocolor Power Doppler with contrast medium was used to study 80 patients with swelling in the soft tissues of the limbs: there were 54 benign lesions, 22 sarcomas, and 4 aggressive desmoid fibromatoses. RESULTS: Were identified 4 patterns of wash-in and wash-out curves that could be correlated to the histological diagnosis: type I was present in 85% of benign lesions, type III in 91% of malignant lesions and in 3.7% of the benign ones, type II in aggressive fibromatoses, anomalous type in 4 benign lesions and 2 sarcomas; the curve was absent in 2 benign lesions. CONCLUSIONS: Power Doppler Echocolor with contrast medium can become a useful method to be associated with traditional imaging methods in the differential diagnosis of swelling of the soft tissues of the limbs.

Two episodes of ifosfamide-related neurotoxicity in the same patient following different schedules and doses of the drug. A case report.

We report the first case of recurrent ifosfamide-related neurotoxicity in the same patient following two distinct administrations of the drug at different doses and schedules and with a long interval between the two episodes. Remarkably, the first event was characterized by confusion and hallucinations, while the second, 29 months later, was characterized by partial and generalized seizures. Between the two episodes the patient had received high-dose cyclophosphamide, an oxazophoshorine agent closely related to ifosfamide, without any neurological side effects. We briefly discuss the diagnosis and management of ifosfamide-related encephalopathy.

Treatment of advanced colorectal cancer (CRC) in daily practice: results of a survey in two Italian regions, Piemonte and Valle d'Aosta.

AIMS AND BACKGROUND: Colorectal cancer (CRC) is one of the most important health problems in Western countries: it is the fourth cancer in terms of incidence and the second cause of cancer death. Surgery is the main therapeutic choice and there is broad consensus on the role of adjuvant chemotherapy (CT) after resection. Unfortunately, 50% of the patients will relapse and die of the disease. Palliative CT based on 5-fluorouracil (5FU) may induce a 9-48% response rate with a median survival of 11.5 months. At present there is no gold standard for CT In advanced CRC and the situation has become more complicated since the advent of new drugs (Raltitrexed, Irinotecan, Oxaliplatin). The aim of this study was the identification of the different approaches to treatment of advanced CRC among the clinicians (oncologists, radiologists, internal medicine specialists, surgeons) who practice CT. METHODS AND STUDY DESIGN: Forty-six clinicians from two Italian Regions (Piemonte and Valle d'Aosta) were interviewed by telephone. RESULTS: 5FU modulated with Lederfolin according to the classic Machover scheme is the main option in daily practice. More sophisticated therapies are reserved to patients with a good performance status (PS) and are prescribed only in the larger centers. The planned therapies usually consist of six courses. Restaging may be performed after three or six courses. A marked difference has been recorded in the evaluation of a situation of no change (NC): 25.5% of the clinicians evaluate stable disease as a positive result. In the event of disease progression or relapse, 35% of the clinicians do not prescribe second-line CT. In case of further treatment, the options are totally subjective. CONCLUSIONS: A national survey on this issue is necessary under the auspices of AIOM (Associazione Italiana Oncologia Medica) and involving oncologists, epidemiologists and statisticians, in order to define the reasons for variations in therapy in advanced CRC and determine the differences between clinicians of different age, specialization and location. This survey could lead to a definition of guidelines for the treatment of advanced CRC.

Pharmacokinetics of ifosfamide administered according to three different schedules in metastatic soft tissue and bone sarcomas.

Ifosfamide is a leading drug in soft tissue sarcoma therapy. Recently high dose therapy (>9 g/m2) has been introduced in different schemes to obtain a higher response rate. All these higher doses can be administered following two different schedules: continuous infusion 24 hours a day for 4-5 days or bolus administration for 5 consecutive days. In this study we compare the differences in the pharmacokinetic profile between the two schedules. In both schemes we saw a very important autoinduction phenomenon, with a corresponding half-life decrease and total body clearance increase during the days of therapy. The clearances were not directly correlated with the administered dose. We can conclude that ifosfamide continuous infusion therapy is equivalent to fractionated administration, at least from a pharmacokinetic point of view. Short-term infusion is subjectively better tolerated and is therefore preferred.