Rita De Sanctis

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.

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.

Phase I pharmacokinetic and pharmacodynamic study of lapatinib in combination with sorafenib in patients with advanced refractory solid tumors.

BACKGROUND The epidermal growth factor receptor (EGFR) and ERBB2 (HER2) pathways and vascular endothelial growth factor (VEGF)-dependent angiogenesis have a pivotal role in cancer pathogenesis and progression. Robust experimental evidence has shown that these pathways are functionally linked and implicated in acquired resistance to targeted therapies making them attractive candidates for joined targeting. We undertook this phase I trial to assess the safety, the recommended dose for phase II trials (RPTD), pharmacokinetics (PK), pharmacodynamics (PD), and the preliminary antitumour activity of the combination of lapatinib and sorafenib in patients with advanced refractory solid tumours. METHODS Four cohorts of at least three patients each received lapatinib once daily and sorafenib twice daily together on a continuous schedule. Doses of lapatinib and sorafenib were escalated based on dose-limiting toxicities (DLTs) in the first treatment cycle following a traditional 3+3 design until the RPTD was reached. Additional patients were treated at the RPTD to characterise PK profiles of this combination and to investigate the potential interaction between lapatinib and sorafenib. Serum samples were collected at baseline and then prospectively every two cycles to assess changes in PD parameters. This trial is registered with ClinicalTrials.gov, number NCT00984425. FINDINGS Thirty patients with advanced refractory solid tumours were enroled. DLTs were grade three fatigue and grade 3 atypical skin rash observed at dose levels 3 and 4, respectively. The higher dose level explored (lapatinib 1250mg/day and sorafenib 400mg twice daily) represented the RPTD of the combination. The most common drug-related adverse events were fatigue (68%), hypocalcemia (61%), diarrhoea (57%), lymphopaenia (54%), anorexia (50%), rash (50%), and hypophosphatemia (46%). PK analysis revealed no significant effect of sorafenib on the PK profile of lapatinib. Of the 27 assessable patients for clinical activity, one achieved a confirmed complete response, four (15%) had a partial response, and 12 (44%) achieved disease stabilisation. The disease control rate overall was 63%. INTERPRETATION Combination treatment with lapatinib and sorafenib was feasible with promising clinical activity and without significant PK interactions. Long term tolerability seems to be challenging.

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.

Trabectedin for the treatment of soft tissue sarcomas

ABSTRACT Introduction: Trabectedin, a marine-derived DNA-binding antineoplastic agent, has been registered by the EMA and recently also by the FDA for the treatment of patients with advanced soft-tissue sarcoma (STS), a rare and heterogeneous disease. Areas covered: The antitumor activity of trabectedin is related both to direct effects on cancer cells, such as growth inhibition, cell death and differentiation, and indirect effects related to its anti-inflammatory and anti-angiogenic properties. Furthermore, trabectedin is the first compound that targets an oncogenic transcription factor with high selectivity in mixoid liposarcomas. This peculiar mechanism of action is the basis of its clinical development. The clinical pharmacology of trabectedin, the subsequent phase I, II and III trials are summarized and put into perspectives in this review. Expert opinion: Trabectedin is a relevant pleiotropic antitumoral agent within the complex scenario of the management of STS. It can be used in advanced STS, either after failure of anthracyclines and ifosfamide or in patients unfit for these drugs, especially when reaching a high-tumor control and a long-term benefit is a priority. Toxicity profile is acceptable and manageable with no reported cumulative toxicities. Therefore, trabectedin has become one relevant therapeutic option in metastatic STS, especially in selected histologies.

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.

Capecitabine in elderly patients with metastatic breast cancer

AIMS AND BACKGROUND Capecitabine is the reference treatment for anthracycline- and/or taxane-pretreated metastatic breast cancer (MBC). This study examined its efficacy, tolerability and impact on the quality of life of elderly patients with MBC. MATERIALS AND METHODS Between January 2002 and December 2009, 75 consecutive elderly patients with MBC received first-line chemotherapy with capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks. Endpoints were efficacy, tolerability and clinical-benefit response measured every 3 cycles. RESULTS Median age was 76 years (range 65-88); median ECOG performance status was 1 (range 0-2); 51 patients (68%) had received adjuvant chemotherapy and all patients had received hormonal therapy. Median exposure was 6 cycles. After 3 cycles, 11 patients (14.7%) had a partial response, one patient experienced a complete response, and 49 patients (65.3%) had stable disease, amounting to a disease control rate of 81.3%. Stable disease was maintained in 45 patients (60%) after 6 cycles, in 21 patients (28%) after 9 cycles, and in 13 patients (17.3%) after 12 cycles. A clinical-benefit response was experienced by 42 patients (56%), indicating a positive impact on quality of life. Treatment was well tolerated, the most common grade 3 events being diarrhea (12%) hand-foot syndrome (8%), and mucositis (8%). Adverse events were managed with dose adjustments and supportive therapy when required. CONCLUSIONS Our results indicate that capecitabine is active and well tolerated in elderly patients with MBC. This dosing regimen warrants further study in the first-line setting for patients with less aggressive MBC who are not candidates for combination therapy.

Imatinib mesylate in desmoplastic small round cell tumors

AIM To investigate the possible role of imatinib, an inhibitor of the tyrosine kinase activity of PDGF-R, in desmoplastic small round cell tumor (DSRCT). PATIENTS & METHODS From August 2005 to June 2009, DSRCT patients refractory to conventional treatment were enrolled. Patients received imatinib 400 mg daily. Primary end point of this open label, prospective, Phase II trial was objective response rate. RESULTS Of the 13 enrolled patients, eight were evaluable for response. Median age was 20 years (range: 9-32). Objective responses at 3 months were: stable disease in one patient and progressive disease in seven patients. CONCLUSION Imatinib showed no efficacy in the treatment of DSRCT unresponsive to conventional therapy, despite molecular-based selection of patients.

Juxtaglomerular Cell Tumor: Multicentric Synchronous Disease Associated With Paraneoplastic Syndrome

Case Report A 50-year-old white man presented to the emergency department for a hypertensive crisis that was causing headache and nausea. Blood pressure was 200/120 mmHg, the physical examination was unremarkable, whereas blood tests showed sodium levels of 116 mmol/L and potassium levels of 3.2 mmol/L. Past medical history included a myocardial infarction 10 years before, ischemic heart disease, diabetes, and arterial hypertension, which was poorly controlled by a calcium-channel blocker and an angiotensin-converting enzyme inhibitor. In the previous months, the patient had begun to suffer from abdominal pain, dyspepsia, and vomiting that had resulted in weight loss of 16 kg in 7 months. Gastroscopy and colonoscopy were negative, whereas an abdominal ultrasound revealed the presence of a splenic cyst that measured 4.5 cm in maximum diameter. The patient was admitted to the nephrology department for diagnosis and determination of a therapeutic approach. Laboratory values confirmed hypotonic euvolemic hyponatremia; levels of thryroid-stimulating hormone, cortisol, and adrenocorticotropic hormone were in the normal ranges, whereas urinary sodium was strongly elevated (111 mmol/L). Water restriction and hypertonic administration failed to raise sodium levels, thus ruling out primary polydipsia. Coexistence of hypotonic hyponatremia, without signs of depletion or expansion of blood volume or of hormonal imbalances, was consistent with diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH; Table 1). Pharmacologic causes of SIADH were ruled out, and we turned our attention toward locating a neoplasm responsible for the syndrome, considering the history of weight loss and abdominal pain. The patient underwent a thoraco-abdominal computed tomography (CT) scan that revealed the presence of a splenic mass that measured 9.1 7.6 cm, a left renal lesion that measured 2.1 cm, and a hepatic lesion that measured 1.6 cm. Subsequently, the patient underwent a splenic CT-guided biopsy. Histology showed the presence of a mesenchymal neoplasm with smooth muscle/ myopericitic differentiation that was suggestive of hemangiopericytoma/malignant glomus tumor. On the basis of the histologic findings, the limited extent of the disease, and the patient’s good performance status (Eastern Cooperative Oncology Group [ECOG] performance status of 0), in March 2008, a splenectomy, partial nephrectomy, and hepatic segmentectomy were performed. Histopathology confirmed the presence of multiple localizations of a malignant mesenchymal neoplasm that was characterized by proliferation of epithelioid cells with focal areas of necrosis and a perivascular pattern of growth. The immunophenotype was as follows: positivity for CD34, smooth muscle actin (focal), CD 138, Vimentin, collagen IV (focal) and negativity for CD31, the melanosome-related antigens HMB45 and Melan-A, cytokeratin 5/6, cytokeratin MNF116, epithelial membrane antigen, calretinin, CD56, S100, C-kit, and desmin. Morphologic and immunophenotypic features were inconsistent with the diagnosis of hemangiopericytoma and raised the suspicion of a juxtaglomerular cell tumor that originated from the kidney (Fig 1, hematoxylin and eosin staining; Fig 2, immunohistochemistry for CD34; original magnification 200). Therefore, plasmatic renin levels were determined by chemiluminescence (Immulite System, Siemens Healthcare Diagnostics, Genova, Italy; reference range, 3.3-41 mU/L), thus confirming strongly elevated values (147 mU/L). A definitive diagnosis was reached by the evidence of immunohistochemical positivity for renin in tumor cells (Fig 3; note strong cytoplasmic immunoreactivity for antirenin antibody in tumor cells). There were no data found in the literature on systemic therapy in this rare histologic subtype of a mesenchymal tumor. However, the Table 1. Diagnostic Criteria for SIADH