Vittorio Quagliuolo

Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial

BACKGROUND Previous trials from our group suggested an overall survival benefit with five cycles of adjuvant full-dose epirubicin plus ifosfamide in localised high-risk soft-tissue sarcoma of the extremities or trunk wall, and no difference in overall survival benefit between three cycles versus five cycles of the same neoadjuvant regimen. We aimed to show the superiority of the neoadjuvant administration of histotype-tailored regimen to standard chemotherapy. METHODS For this international, open-label, randomised, controlled, phase 3, multicentre trial, patients were enrolled from 32 hospitals in Italy, Spain, France, and Poland. Eligible patients were aged 18 years or older with localised, high-risk (high malignancy grade, 5 cm or longer in diameter, and deeply located according to the investing fascia), soft-tissue sarcoma of the extremities or trunk wall and belonging to one of five histological subtypes: high-grade myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumour, and undifferentiated pleomorphic sarcoma. Patients were randomly assigned (1:1) to receive three cycles of full-dose standard chemotherapy (epirubicin 60 mg/m2 per day [short infusion, days 1 and 2] plus ifosfamide 3 g/m2 per day [days 1, 2, and 3], repeated every 21 days) or histotype-tailored chemotherapy: for high-grade myxoid liposarcoma, trabectedin 1·3 mg/m2 via 24-h continuous infusion, repeated every 21 days; for leiomyosarcoma, gemcitabine 1800 mg/m2 on day 1 intravenously over 180 min plus dacarbazine 500 mg/m2 on day 1 intravenously over 20 min, repeated every 14 days; for synovial sarcoma, high-dose ifosfamide 14 g/m2, given over 14 days via an external infusion pump, every 28 days; for malignant peripheral nerve sheath tumour, intravenous etoposide 150 mg/m2 per day (days 1, 2, and 3) plus intravenous ifosfamide 3 g/m2 per day (days 1, 2, and 3), repeated every 21 days; and for undifferentiated pleomorphic sarcoma, gemcitabine 900 mg/m2 on days 1 and 8 intravenously over 90 min plus docetaxel 75 mg/m2 on day 8 intravenously over 1 h, repeated every 21 days. Randomisation was stratified by administration of preoperative radiotherapy and by country of enrolment. Computer-generated random lists were prepared by use of permuted balanced blocks of size 4 and 6 in random sequence. An internet-based randomisation system ensured concealment of the treatment assignment until the patient had been registered into the system. No masking of treatment assignments was done. The primary endpoint was disease-free survival. The primary and safety analyses were planned in the intention-to-treat population. We did yearly futility analyses on an intention-to-treat basis. The study was registered with ClinicalTrials.gov, number NCT01710176, and with the European Union Drug Regulating Authorities Clinical Trials, number EUDRACT 2010-023484-17, and is closed to patient entry. FINDINGS Between May 19, 2011, and May 13, 2016, 287 patients were randomly assigned to a group (145 to standard chemotherapy and 142 to histotype-tailored chemotherapy), all of whom, except one patient assigned to standard chemotherapy, were included in the efficacy analysis (97 [34%] with undifferentiated pleomorphic sarcoma; 64 [22%] with high-grade myxoid liposarcoma; 70 [24%] with synovial sarcoma; 27 [9%] with malignant peripheral nerve sheath tumour; and 28 [10%] with leiomyosarcoma). At the third futility analysis, with a median follow-up of 12·3 months (IQR 2·75-28·20), the projected disease-free survival at 46 months was 62% (95% CI 48-77) in the standard chemotherapy group and 38% (22-55) in the histotype-tailored chemotherapy group (stratified log-rank p=0·004; hazard ratio 2·00, 95% CI 1·22-3·26; p=0·006). The most common grade 3 or higher adverse events in the standard chemotherapy group (n=125) were neutropenia (107 [86%]), anaemia (24 [19%]), and thrombocytopenia (21 [17%]); the most common grade 3 or higher adverse event in the histotype-tailored chemotherapy group (n=114) was neutropenia (30 [26%]). No treatment-related deaths were reported in both groups. In agreement with the Independent Data Monitoring Committee, the study was closed to patient entry after the third futility analysis. INTERPRETATION In a population of patients with high-risk soft-tissue sarcoma, we did not show any benefit of a neoadjuvant histotype-tailored chemotherapy regimen over the standard chemotherapy regimen. The benefit seen with the standard chemotherapy regimen suggests that this benefit might be the added value of neoadjuvant chemotherapy itself in patients with high-risk soft-tissue sarcoma. FUNDING European Union grant (Eurosarc FP7 278472).

Preoperative chemo-radiation therapy for localised retroperitoneal sarcoma: A phase I-II study from the Italian Sarcoma Group

BACKGROUND To study feasibility, safety and activity of the combination of high-dose long-infusion ifosfamide (HLI) and radiotherapy (RT) as preoperative treatment for resectable localised retroperitoneal sarcoma (RPS). METHODS Patients received three cycles of HLI (14 g/m2). RT was started in combination with second cycle and administered up to a total dose of 50.4 Gy. Surgery was scheduled 4-6 weeks after the end of RT. Primary end-point was 3-year relapse free survival (RFS). The trial is registered with ITASARC_∗II_2004_003. FINDINGS Between December 2003 and 2010, 83 patients were recruited. Main histological subtypes were well differentiated liposarcoma (19/83, 23%), dedifferentiated liposarcoma (26/83, 31%), leiomyosarcoma (14/83, 17%). Median tumour size was 120 mm (interquartile (IQ) range=82-160). The overall preoperative treatment was completed in 60 patients. Chemotherapy (CT) was completed in 65, while RT in 73. Four patients progressed before surgery and were not operated. 79 patients underwent surgery. At a median follow-up of 4.8 years (IQ range = 3-6.1), 23 and 15 patients developed local recurrence (LR) and distant metastases (DM); 30 patients died of disease. 3 and 5-year RFS and overall survival were 0.56 (90% confidence interval (CI): 0.45, 0.65) and 0.44 (90% CI: 0.27, 0.48), and 0.74 (90% CI: 0.62, 0.81) and 0.59 (90% CI: 0.33, 0.58). Crude cumulative incidence of LR and DM at 5 years were 0.37 (standard error (SE): 0.06) and 0.26 (SE: 0.06). INTERPRETATION The combination of preoperative HLI and RT was feasible in two thirds of patients, while preoperative RT could be completed in most (73/83). Although a systemic coverage can be added to RT when this is felt to be appropriate, the ongoing international phase III trial is exploring the role of RT alone. FUNDING This is a pure academic trial. No funding sources contributed to it.

The Italian Research Group for Gastric Cancer (GIRCG) guidelines for gastric cancer staging and treatment: 2015

This article reports the guidelines for gastric cancer staging and treatment developed by the GIRCG, and contains comprehensive indications for clinical management, including radiological, endoscopic, surgical, pathological, and oncological paths.

Stereotactic body radiation therapy for lung metastases from soft tissue sarcoma

PURPOSE To appraise the role of stereotactic body radiation therapy (SBRT) in patients with lung metastasis from primary soft tissue sarcoma. METHODS Twenty-eight patients (51 lesions) were analysed. All patients were in good performance status (1-2 eastern cooperative oncology group (ECOG)), unsuitable for surgical resection, with controlled primary tumour and the number of lung metastases was ⩽4. In a risk adaptive scheme, the dose prescription was: 30Gy/1fr, 60Gy/3fr, 60Gy/8fr and 48Gy/4fr. Treatments were performed with Volumetric Modulated Arc Therapy. Clinical outcome was evaluated by thoracic and abdominal computed tomography (CT) scan before SBRT and than every 3months. Toxicity was evaluated with Common Terminology Criteria for Adverse Events (CTCAE) scale version 4.0. RESULTS Leiomyosarcoma (36%) and synovial sarcoma (25%) were the most common histologies. Five patients (18%) initially presented with pulmonary metastasis, whereas 23 (82%) developed them at a median time of 51months (range 11-311months) from the initial diagnosis. The median follow-up time from initial diagnosis was 65months (5-139months) and from SBRT was 21months (2-80months). No severe toxicity (grades III-IV) was recorded and no patients required hospitalisation. The actuarial 5-years local control rate (from SBRT treatment) was 96%. Overall survival at 2 and 5years was 96.2% and 60.5%, respectively. At last follow-up 15 patients (54%) were alive. All other died because of distant progression. CONCLUSIONS SBRT provides excellent local control of pulmonary metastasis from soft tissue sarcoma (STS) and may improve survival in selected patients. SBRT should be considered for all patients with pulmonary metastasis (PM) and evaluated in a multidisciplinary team.

Role of surgery in the multimodal treatment of primary and recurrent leiomyosarcoma of the inferior vena cava.

The optimal treatment of leiomyosarcoma (LMS) of the inferior vena cava (IVC) is still unclear, especially in the metastatic and/or recurrent setting. We herein evaluated the long‐term outcome after aggressive management.

Efficacy of trabectedin in advanced soft tissue sarcoma: beyond lipo- and leiomyosarcoma.

Objective Trabectedin is effective in leiomyosarcoma and liposarcoma, especially the myxoid variant, related to the presence of the FUS-CHOP transcript. We evaluated the efficacy of trabectedin in specific subgroups of patients with soft tissue sarcomas (STS). Methods Seventy-two patients with advanced anthracycline-pretreated STS, who received trabectedin at a dose of 1.5 mg/m2 every 3 weeks by continuous 24-hour infusion, were retrospectively analyzed. Best response rate according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria and severe adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.02) were evaluated. Secondary endpoints included progression-free survival and overall survival (OS). Results Median age was 48 (range, 20–75) years, with a median Eastern Cooperative Oncology Group performance status of 0. The median number of previous chemotherapy regimens was 1 (range, 0–5). Median number of trabectedin cycles was 3 (range, 1–17). About 69/72 patients (95.8%) were evaluable for response: 9 patients (13%) achieved partial response and 26 (37.7%) stable disease. According to histotype, clinical benefit (partial response + stable disease) was reported in synovial sarcoma (n=5), retroperitoneal liposarcoma (n=10), myxoid liposarcoma (n=5), leiomyosarcoma (n=8), high-grade undifferentiated pleomorphic sarcoma (n=5), Ewing/peripheral primitive neuroectodermal tumor (n=1), and malignant peripheral nerve sheath tumor (n=1). Any grade AEs were noncumulative, reversible, and manageable. G3/G4 AEs included anemia (n=1, 1.4%), neutropenia (n=7, 9.6%), liver toxicity (n=6, 8.3%), and fatigue (n=2, 2.8%). With a median follow-up time of 11 (range, 2–23) months, median progression-free survival and OS of the entire cohort were 2.97 months and 16.5 months, respectively. Conclusion Our experience confirms trabectedin as an effective therapeutic option for metastatic lipo- and leiomyosarcoma and suggests promise in synovial sarcomas and high-grade undifferentiated pleomorphic sarcoma.

Preoperative chemotherapy in gastric cancer: expanding the indications, limiting the overuse

The three main European Oncologic Societies (ESMO, ESSO, ESTRO) have recently published the joint Guidelines for the Management of Gastric Cancer (GC) [1] that should drive daily clinical practice in a region where GC is the sixth commonest cancer diagnosis and the fourth commonest cause of cancer-related death [2]. The Guidelines properly emphasize the role of multidisciplinary treatment. In particular, preoperative chemotherapy (PCHT) has been advocated as the preferred pathway for operable disease with stage[T1N0 [1]. This statement has been made on the basis of the results of the pivotal MAGIC and FFCD trials [3, 4]. Considering that early stages at the presentation are relatively uncommon in Western countries, the current Guidelines have theoretically expanded the application of PCHT to the majority of newly diagnosed GC. However, such an extended application of PCHT may give rise to some issues, in particular in patient selection. The efficacy of PCHT could depend on some tumour features affecting the grade of response. Tumour site, grading, and Lauren’s histotype have been proposed as pre-therapeutic factors associated with response in a retrospective study including 410 patients [5], and signet-ring cell carcinoma has been reported to be less responsive to PCHT [6]. A phase II/III trial comparing surgery versus chemotherapy plus surgery in patients with a signet-ring cell GC is currently ongoing (NCT01717924) and will be probably yield clarification on this question. These findings confirm the importance of identifying reliable criteria in order to properly select patients for PCHT. Another point as regards post-operative morbidity after PCHT is that several studies have proven that gastrectomy after PCHT is safe in terms of complications [3, 4], and a recent meta-analysis showed no differences in post-operative morbidity and mortality rates between patients who did receive and who did not receive PCHT [7]. On the other hand, a recent Korean study including 123 patients who underwent PCHT followed by D2-gastrectomy reported a higher than expected rate of post-operative complications of 29.3 % [8]. Similarly, the EORTC phase III trial, prematurely closed due to low patient accrual, reported a higher rate of post-operative complications in the PCHT arm than in the control arm (27.1 vs. 16.2 %), although the difference was not statistically significant [9]. Importantly, in both studies D2 resection rate was more than 90 %, with a median number of harvested lymph nodes higher than 31. Conversely, in the MAGIC trial, a D2 resection was performed in about 40 % of patients, and in the FFCD trial the median number of retrieved nodes was 19 [3, 4]. These data may suggest that PCHT may increase surgical morbidity in patients treated with an extended surgical approach such as a D2-lymphadenectomy. Adequate surgery still remains the cornerstone in the treatment of operable GC, and D2-gastrectomy has been recently accepted as the standard surgical treatment also in the Western countries, especially in specialised centres [1]. In the MAGIC and FFCD trials, patients were frequently treated with \D2-lymphadenectomy, whereas a D2F. C. M. Cananzi (&) L. Cozzaglio V. Quagliuolo Surgical Oncology Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, MI, Italy e-mail: fcm.cananzi@hotmail.it

NEUTROPENIC ENTEROCOLITIS: IS THERE A RIGHT TIMING FOR SURGERY? ASSESSMENT OF A CLINICAL CASE

Neutropenic enterocolitis is a severe and potentially life-threatening complication that may affect patients undergoing chemotherapy for acute leukemia or lymphoma. These patients may develop systemic sepsis through bacterial or fungal translocation across the intestinal wall. In many cases neutropenic enterocolitis is confined to the cecum, but the entire colon is sometimes involved. Most patients are treated conservatively because an improvement occurs when the absolute neutrophil count rises. However, a surgical approach consisting of resection of the colon may sometimes be necessary, even in patients with complete aplasia and a high risk of complications. The right time to perform surgery is hard to define. Intestinal wall thickness, evaluated by ultrasound, is an important prognostic factor which could act as a guide to surgical indication. We analyze a case of neutropenic enterocolitis which occurred in a patient with acute myeloid leukemia during chemotherapy and we suggest that, as well as intestinal wall thickness, hemodynamic worsening should be considered an indication for surgery.

Leiomyosarcoma arising from the inferior mesenteric vein draining in the splenomesenteric angle with a tumour thrombus at the splenomesenteric confluence: a case report and review of the literature

Leiomyosarcoma (LMS) is a very rare vascular tumour that arises from the media of the blood vessels. We present the case of a 64-year-old patients affected by LMS of the inferior mesenteric vein (IMV) with a tumour thrombus treated with surgery and adjuvant chemotherapy. In this case report, we want to point out the importance of a dedicated multidisciplinary soft tissue sarcoma team in planning the right surgical strategy.

Chemoradiotherapy in Gastric Cancer: A Door Ajar

TO THE EDITOR: The ARTIST (Adjuvant Chemoradiotherapy in Stomach Tumors) trial was designed to overcome one of the main limitations of the landmark Intergroup 0116 trial in which 90% of patients had suboptimal surgery (D0 or D1 lymphadenectomy) before receive adjuvant chemoradiation therapy (CRT). The real advantage of postoperative CRT in curatively D2 resected gastric cancer remained unknown, considering the hypothesis that D2 resection alone may be sufficient to locoregional disease control. Indeed, the first results of the Korean trial demonstrated that the addition of CRT did not significantly reduce recurrence after curative D2 gastrectomy. The final report of the ARTIST trial, published after a median follow-up of 7 years, has drawn the same conclusions as the first report, showing still no benefit in adding radiotherapy in the adjuvant setting. Nevertheless, some important issues have been raised from this updated report deserving further consideration. The early results of the trial showed that postoperative radiotherapy adds no benefit to D2 resection in term of locoregional recurrence or distant metastases between the two treatment arms. On the contrary, the updated results showed a significantly different pattern of recurrence, suggesting that adjuvant radiotherapy may reduce the rate of local recurrence even after D2 lymphadenectomy. This extremely important result seems to overturn the conclusion of the early report of the ARTIST trial, potentially providing a strong rationale for the administration of adjuvant CRT. In addition, this local effect might justify the overall result of the trial based on a population with a high rate of diffuse-type (with higher incidence of distant recurrence) and early-stage cancer (with lower overall recurrence rate). However, it remains unclear whether this result may depend on a real biological effect of CRT or not. After the subgroups analysis, Park et al stated that adjuvant radiotherapy may be of benefit in patients with node-positive disease and a high lymph node ratio (ie, the ratio between the number of metastatic and harvested lymph nodes). As properly highlighted by Park et al, this statement may be affected by the high number of N0/N1 patients (about 70%) included in the trial. Moreover, the depth of tumor infiltration (T stage) may strongly influence the survival of patients, but, unfortunately, the prognostic value of Tand its interactions with nodal status and administration of adjuvant CRT remain unknown, because no ad hoc analyses were performed in the study. Also, a high lymph node ratio value may depend on a high number of metastatic nodes or a low number of harvested nodes. Then, it would be of some interest to better define the patients with high lymph node ratio who received adjuvant RT, also considering the misleading categorization specified in the trial methods. Park and colleagues used a two-tier classification based on the mean value of the node ratio (, 0.083 v