COLUMBUS-AD: phase III study of adjuvant encorafenib + binimetinib in resected stage IIB/IIC BRAF V600-mutated melanoma.

Stage IIB/IIC melanoma has a high risk of recurrence after surgical resection. While, for decades, surgery was the only option for high-risk stage II disease in most countries, adjuvant therapies now exist. Anti-programmed cell death protein 1 (PD-1) antibodies significantly improve recurrence-free survival versus placebo in patients with fully resected stage IIB/IIC melanoma. Combined BRAF MEK inhibitor therapy showed benefits in high-risk stage III and advanced disease; however, its role in patients with fully resected stage BRAF-mutated IIB/IIC melanoma is still unknown. Here we describe the rationale and design of the ongoing randomized, placebo-controlled COLUMBUS-AD trial, the first study of a BRAF-MEK inhibitor combination therapy (encorafenib + binimetinib) in patients with BRAF V600-mutated stage IIB/IIC melanoma.

Melanoma is a type of skin cancer. Although most stage II melanomas (cancer affecting the first two layers of skin) can be cured with surgery, the risk of the cancer returning and spreading to other areas of the body is high in some patients with stage IIB/IIC melanoma. Furthermore, once the melanoma has spread, it is much more difficult to treat successfully and remove all the cancer cells from the body. Some melanomas have a DNA alteration (or mutation) in what is known as the BRAF gene. This mutation can be identified by testing a sample of the tumor tissue removed during a biopsy or surgery. Testing for BRAF mutations at diagnosis can help ensure that patients receive the most appropriate treatment for their cancer. In some countries, surgery is the only option for patients with stage II melanoma, while in other countries, patients may be offered additional (adjuvant) anticancer treatment with immunotherapy (agents that work with the immune system to kill cancer cells). While immunotherapy can reduce the risk of melanoma recurrence, persistent, long-term toxicities are common and the use of this treatment in all stage IIB/IIC melanoma patients is not always possible. Here, we describe the rationale and design of an ongoing clinical trial (COLUMBUS-AD), which will be the first study (to our knowledge) to investigate the efficacy and safety of a treatment that specifically targets cancers with BRAF mutations (i.e., the BRAF-MEK inhibitor combination of the drugs encorafenib and binimetinib) in patients with BRAF-mutated stage IIB/IIC melanoma. Clinical Trial Registration: NCT05270044 (ClinicalTrials.gov).

Nonsurgical giant cell tumour of the tendon sheath or of the diffuse type: are MRI or 18F-FDG PET/CT able to provide an accurate prediction of long-term outcome?

PURPOSE: To investigate whether MRI (RECIST 1.1, WHO criteria and the volumetric approach) or (18)F-FDG PET/CT (PERCIST 1.0) are able to predict long-term outcome in nonsurgical patients with giant cell tumour of the tendon sheath or of the diffuse type (GCT-TS/DT). METHODS: Fifteen "nonsurgical" patients with a histological diagnosis of GCT-TS/DT were divided into two groups: symptomatic patients receiving targeted therapy and asymptomatic untreated patients. All 15 patients were evaluated by MRI of whom 10 were treated, and a subgroup of 7 patients were evaluated by PET/CT of whom 4 were treated. Early evolution was assessed according to MRI and PET/CT scans at baseline and during follow-up. Cohen's kappa coefficient was used to evaluate the degree of agreement between PERCIST 1.0, RECIST 1.1, WHO criteria, volumetric approaches and the reference standard (long-term outcome, delay 505 ± 457 days). The response rate in symptomatic patients with GCT-TS/DT receiving targeted therapy was also assessed in a larger population that included additional patients obtained from a review of the literature. RESULTS: The kappa coefficients for agreement between RECIST/WHO/volumetric criteria and outcome (15 patients) were respectively: 0.35 (p = 0.06), 0.26 (p = 0.17) and 0.26 (p = 0.17). In the PET/CT subgroup (7 patients), PERCIST was in perfect agreement with the late symptomatic evolution (kappa = 1, p < 0.05). In the treated symptomatic group including the additional patients from the literature the response rates to targeted therapies according to late symptomatic assessment, and PERCIST and RECIST criteria were: 65 % (22/34), 77 % (10/13) and 26 % (10/39). CONCLUSION: (18)F-FDG PET/CT with PERCIST is a promising approach to the prediction of the long-term outcome in GCT-TS/DT and may avoid unnecessary treatments, toxicity and costs. On MRI, WHO and volumetric approaches are not more effective than RECIST using the current thresholds.

Gated blood pool SPECT: The estimation of right ventricular volume and function is algorithm dependent in a clinical setting.

BACKGROUND: Gated blood pool SPECT (GBPS) requires further validation for the assessment of the right ventricle (RV). This study evaluated three algorithms: BP-SPECT, QBS, and TOMPOOL (results are referred using this order). We compared (1) their "quantitative-accuracy": estimation of RV ejection fraction (EF), end-diastolic volume (EDV), and cardiac output (CO); (2) their "qualitative-accuracy": threshold values allowing diagnosing an impairment of the RV function; (3) their reproducibility: inter-observer relative variability (IOV). METHODS AND RESULTS: Forty-eight consecutive patients underwent GBPS. Recommended reference standards were used: cardiac magnetic resonance imaging (CMR) (EDV, EF, n = 48), catheter measurements from thermodilution (TD) (CO, n = 25). (1) "Quantitative-accuracy": r = 0.42, 0.30, 0.42 for RVEF (CMR); r = 0.69, 0.77, 0.53 for RVEDV (CMR); 0.32, 0.36, 0.52 for RCO (TD). (2) "Qualitative-accuracy": optimal thresholds were 54.7%, 38.5%, 45.2% (AUC: 0.83, 0.80, 0.79) for RVEF; 229, 180, 94 mL (AUC: 0.83, 0.81, 0.81) for RVEDV; 4.1, 4.4, 2.6 L·minute(-1) (AUC: 0.73, 0.77, 0.80) for RCO. (3) Reproducibility: IOV was 5% ± 6%, 8% ± 12%, 17% ± 18% for RVEF; 6% ± 8%, 4% ± 4%, 21% ± 18% for RVEDV; 8% ± 8%, 11% ± 15%, 24% ± 20% for RCO. CONCLUSION: Diagnostic accuracies are similar. A CMR-based calibration is required for a quantitative-analysis (cautious interpretation) or an accurate qualitative analysis (thresholds must be adjusted). Automatic procedures (BP-SPECT, QBS) offer the best compromise accuracy/reproducibility.

Is TOMPOOL (gated blood-pool SPECT processing software) accurate to diagnose right and left ventricular dysfunction in a clinical setting?

BACKGROUND: The assessment of right ventricular function is crucial for management of heart disease. TOMPOOL is a software that processes data acquired with Tomographic Equilibrium Radionuclide Ventriculography. In this report, TOMPOOL's diagnostic accuracy and inter-observer reproducibility were assessed in a cohort of patients with various etiologies of ventricular dysfunction. METHODS AND RESULTS: End-diastolic volume (EDV), ejection fraction (EF), and cardiac output (CO) were calculated for the right ventricle (RV) and the left ventricle (LV) using TOMPOOL in 99 consecutive patients. Thirty-five patients underwent cardiac magnetic resonance imaging (CMR) considered as the reference-standard to measure EDV and EF; the Spearman's rho correlation coefficients were r = 0.73/0.80 and 0.67/0.73 for right/left EF and EDV, respectively. Twenty-one patients had thermodilution measurements of right CO (reference-standard), the correlation was r = 0.57. The best cut-off points (sensitivity/specificity) in order to diagnose a ventricular dysfunction or enlargement were 46% for RVEF (67%/89%), 62% for LVEF (100%/90%), 94 mL for RVEDV (77%/73%), and 84 mL for LVEDV (100%/91%). The areas under the ROC curve were, respectively, 0.79, 0.91, 0.83, and 0.99. Inter-observer reproducibility was r = 0.81/0.94, 0.77/0.90, and 0.78/0.75 for Right/Left EF, EDV, and CO, respectively. CONCLUSION: TOMPOOL is accurate: measurements of EDV, EF, and CO are reproducible and correlate with CMR and thermodilution. However, thresholds must be adjusted.

Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy. METHODS: This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomisation system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688. FINDINGS: 372 patients were registered and 369 were randomly assigned to receive pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4·6 months (95% CI 3·7-4·8) for pazopanib compared with 1·6 months (0·9-1·8) for placebo (hazard ratio [HR] 0·31, 95% CI 0·24-0·40; p<0·0001). Overall survival was 12·5 months (10·6-14·8) with pazopanib versus 10·7 months (8·7-12·8) with placebo (HR 0·86, 0·67-1·11; p=0·25). The most common adverse events were fatigue (60 in the placebo group [49%] vs 155 in the pazopanib group [65%]), diarrhoea (20 [16%] vs 138 [58%]), nausea (34 [28%] vs 129 [54%]), weight loss (25 [20%] vs 115 [48%]), and hypertension (8 [7%] vs 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib. INTERPRETATION: Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy. FUNDING: GlaxoSmithKline.

Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial.

BACKGROUND: The effect of adjuvant chemotherapy on survival for resected soft-tissue sarcoma remains unknown. We investigated the effect of intensive adjuvant chemotherapy on survival in patients after resection of high-risk soft-tissue sarcomas. METHODS: In this multicentre randomised trial, patients with macroscopically resected, Trojani grade II-III soft-tissue sarcomas at any site, no metastases, performance status lower than 2 and aged between 16 and 70 years were eligible within 4 weeks of definitive surgery. Patients were randomly assigned to receive adjuvant chemotherapy or no chemotherapy (control group). Randomisation was done with a minimisation technique, stratified by hospital, site of primary tumour, tumour size, planned radiotherapy, and isolated limb perfusion therapy. Chemotherapy consisted of five cycles of doxorubicin 75 mg/m(2), ifosfamide 5 g/m(2), and lenograstim every 3 weeks. Patients in both groups received radiotherapy if the resection was marginal or the tumour recurrent. The primary endpoint was overall survival and analyses were done by intention to treat. The final results are presented. This trial is registered with ClinicalTrials.gov, NCT00002641. FINDINGS: Between February, 1995, and December, 2003, 351 patients were randomly assigned to the adjuvant chemotherapy group (175 patients) or to the control group (176). 258 (73%) of 351 patients received radiotherapy, 129 in each group. Overall survival did not differ significantly between groups (hazard ratio [HR] 0·94 [95% CI 0·68-1·31], p=0·72) nor did relapse-free survival (HR 0·91 [0·67-1·22], p=0·51). 5-year overall survival rate was 66·5% (58·8-73·0) in the chemotherapy group and 67·8% (60·3-74·2) in the control group. Chemotherapy was well tolerated, with 130 (80%) of 163 patients who started it completing all five cycles. 16 (10%) patients had grade 3 or 4 fever or infection, but no deaths due to toxic effects were recorded. INTERPRETATION: Adjuvant chemotherapy with doxorubicin and ifosfamide in resected soft-tissue sarcoma showed no benefit in relapse-free survival or overall survival. Future studies should focus on patients with larger, grade III, and extremity sarcomas.

Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes.

BACKGROUND: Eribulin inhibits microtubule dynamics via a mechanism distinct from that of other tubulin-targeting drugs, inducing cell-cycle arrest and tumour regression in preclinical models. We assessed the activity and safety of eribulin in four strata of patients with different types of soft-tissue sarcoma. METHODS: In this non-randomised multicentre phase 2 study, patients were included if they had progressive or high-grade soft-tissue sarcoma and had received no more than one previous combination chemotherapy or up to two single drugs for advanced disease. They were stratified by the type of soft-tissue sarcoma they had. Eribulin was given intravenously at a concentration of 1·4 mg/m(2) over 2-5 min at days 1 and 8 every 3 weeks to primarily assess progression-free survival at 12 weeks (RECIST 1.0), which we evaluated in all patients who started treatment. Safety analyses were done in all patients who started treatment. This trial is registered at ClinicalTrials.gov, number NCT00413192. FINDINGS: Of 128 patients included, 37 had adipocytic sarcoma, 40 had leiomyosarcoma, 19 had synovial sarcoma, and 32 had other sarcomas. 12 (31·6%) of 38 patients with leiomyosarcoma evaluable for the primary endpoint, 15 (46·9%) of 32 patients with adipocytic sarcoma, four (21·1%) of 19 with synovial sarcoma, and five (19·2%) of 26 in other sarcomas were progression-free at 12 weeks. The most common grade 3-4 adverse events were neutropenia (66 [52%] of 127 patients evaluable for safety), leucopenia (44 [35%]), anaemia (nine [7%]), fatigue (nine [7%]), febrile neutropenia (eight [6%]), abnormal alanine aminotransferase concentrations (six [5%]), mucositis (four [3%]), and sensory neuropathy (four [3%]). INTERPRETATION: Eribulin deserves further study in this setting, based on progression-free survival at 12 weeks in leiomyosarcoma and adipocytic sarcoma. FUNDING: Eisai Limited, Hatfield, UK.

Phase I dose-escalation study of F50067, a humanized anti-CXCR4 monoclonal antibody alone and in combination with lenalidomide and low-dose dexamethasone, in relapsed or refractory multiple myeloma.

PURPOSE: Multiple myeloma (MM) remains an incurable disease as tumor cells ultimately resist to all available drugs. Homing of tumor cells to the bone marrow microenvironment, involving especially the CXCR4/SDF-1 axis, allows them to survive, proliferate and resist to therapy. F50067, a humanized anti-CXCR4 IgG1 antibody, has promising preclinical activity in MM.We present a phase I multicenter escalation study in relapsed/refractory MM (RRMM) to determine the maximum tolerated dose (MTD) for F50067 alone and in combination with lenalidomide and low dose dexamethasone (Len-Dex). EXPERIMENTAL DESIGN: 14 end-stage RRMM patients received F50067 single agent (n = 10) or in combination with Len-Dex (n = 4). RESULTS: One dose-limiting toxicity was observed, a grade 4 neutropenia lasting more than 7 days in combination arm. MTD could not be established. Thrombocytopenia was observed in 100% and neutropenia in 92.9% of patients with no cases of febrile neutropenia and no severe bleeding or hematoma. Non-hematological adverse events were of mild to moderate severity.Nine patients (6 in single arm and 3 in combination arm) were evaluable for response, with 66.7% overall response rate (≥PR) in combination arm, and 33.3% of disease control (≥SD) in single agent arm. At the time of study termination, 55.6% had progressed. CONCLUSION: This study suggests that egression of tumor cells to the blood stream can represent a novel therapeutic strategy for MM. However, because of significant hematological toxicity, this study had to be discontinued. Further studies are needed to validate the feasibility of this approach in clinical practice.

External validation of a published nomogram for prediction of brain metastasis in patients with extra-cerebral metastatic breast cancer and risk regression analysis.

BACKGROUND: Survival of patients with metastatic breast cancer (MBC) suffering from brain metastasis (BM) is limited and this event is usually fatal. In 2010, the Graesslin's nomogram was published in order to predict subsequent BM in patients with breast cancer (BC) with extra-cerebral metastatic disease. This model aims to select a patient population at high risk for BM and thus will facilitate the design of prevention strategies and/or the impact of early treatment of BM in prospective clinical studies. PATIENTS AND METHODS: Nomogram external validation was retrospectively applied to patients with BC and later BM between January 2005 and December 2012, treated in our institution. Moreover, risk factors of BM appearance were studied by Fine and Gray's competing risk analysis. RESULTS: Among 492 patients with MBC, 116 developed subsequent BM. Seventy of them were included for the nomogram validation. The discrimination is good (area under curve = 0.695 [95% confidence interval, 0.61-0.77]). Risk factors of BM appearance are: human epidermal growth factor receptor 2 (HER2) overexpression/amplification, triple-negative BC and number of extra-cerebral metastatic sites (>1). With a competing risk model, we highlight the nomogram interest for HER2+ tumour subgroup exclusively. CONCLUSION: Graesslin's nomogram external validation demonstrates exportability and reproducibility. Importantly, the competing risk model analysis provides additional information for the design of prospective trials concerning the early diagnosis of BM and/or preventive treatment on high risk patients with extra-cerebral metastatic BC.

Dosimetric comparison of flattened and unflattened beams for stereotactic body radiation therapy: Impact of the size of the PTV on dynamic conformal arc and volumetric modulated arc therapy.

PURPOSE: Flattening filter free (FFF) beams are frequently used for stereotactic body radiation therapy with various treatment modalities: conventional static fields, dynamic conformal arc (DCA) or Rapid Arc (RA). The goal of this study was to obtain some criteria to enable a conscious choice of the employment of FFF beams and of the DCA or RA technique, depending on the PTV size. METHODS AND MATERIALS: 24 PTVs from 1.52cm3 to 445.24cm3 were studied in various sites: virtual phantom, lung and liver. For each PTV, DCA and RA plans were prepared using two flattened (FF) and two unflattened photon beams. Parameters such as conformity index, gradient index, healthy-tissue and organs at risk mean doses, number of monitor units (MU), beam on time (BOT) were used to quantify obtained dose distributions. Friedman tests and Spearman's rank correlation coefficients were also performed. RESULTS: No significant differences were found between FF and FFF beams for RA regarding conformity and gradient indices. For DCA, 10FFF is less suitable and forward planning becomes more challenging as PTV volume increases. FFF beams provided a better sparing of healthy-tissues except for 10FFF used with DCA. 6FFF was slightly better than 10FFF in terms of healthy-tissue mean doses. FFF beams generated significantly reduced BOTs and increased MUs. These effects were more pronounced for larger volumes and especially for RA plans. CONCLUSIONS: FFF showed better results than FF beams for the considered plans. 10FFF used with DCA should be used with caution for medium and large volumes.

Dosimetric comparison between helical tomotherapy and volumetric modulated arc-therapy for non-anaplastic thyroid cancer treatment.

BACKGROUND: To evaluate and compare dosimetric parameters of volumetric modulated arctherapy (VMAT) and helical tomotherapy (HT) for non-anaplastic thyroid cancer adjuvant radiotherapy. METHODS: Twelve patients with non-anaplastic thyroid cancer at high risk of local relapse received adjuvant external beam radiotherapy with curative intent in our institution, using a two-dose level prescription with a simultaneous integrated boost approach. Each patient was re-planned by the same physicist twice using both VMAT and HT. Several dosimetric quality indexes were used: target coverage index (proportion of the target volume covered by the reference isodose), healthy tissue conformity index (proportion of the reference isodose volume including the target volume), conformation number (combining both previous indexes), Dice Similarity Coefficient (DSC), and homogeneity index ((D2%-D98%)/prescribed dose). Dose-volume histogram statistics were also compared. RESULTS: HT provided statistically better target coverage index and homogeneity index for low risk PTV in comparison with VMAT (respectively 0.99 vs. 0.97 (p=0.008) and 0.22 vs. 0.25 (p=0.016)). However, HT provided poorer results for healthy tissue conformity index, conformation number and DSC with low risk and high risk PTV. As regards organs at risk sparing, by comparison with VMAT, HT statistically decreased the D2% to medullary canal (25.3 Gy vs. 32.6 Gy (p=0.003)). Besides, HT allowed a slight sparing dose for the controlateral parotid (Dmean: 4.3 Gy vs. 6.6 Gy (p=0.032)) and for the controlateral sub-maxillary gland (Dmean: 29.1 Gy vs. 33.1 Gy (p=0.041)). CONCLUSIONS: Both VMAT and HT techniques for adjuvant treatment of non-anaplastic thyroid cancer provide globally attractive treatment plans with slight dosimetric differences. However, helical tomotherapy clearly provides a benefit in term of medullary canal sparing.

Evaluation of the effects of hyaluronic acid-carboxymethyl cellulose barrier on ovarian tumor progression.

BACKGROUND: Hyaluronic acid is a prognostic factor in ovarian cancers. It is also a component of Hyaluronic Acid-Carboxymethyl Cellulose (HA-CMC) barrier, an anti-adhesion membrane widely used during abdominal surgeries in particular for ovarian carcinosis. 70% of patients who undergo ovarian surgery will relapse due to the persistence of cancer cells. This study's objective was to determine the oncological risk from use of this material, in the presence of residual disease, despite the benefit gained by it decreasing post-surgical adhesions in order to provide an unambiguous assessment of its appropriateness for use in ovarian surgical management. METHODS: We assessed the effects of HA-CMC barrier on the in vitro proliferation of human ovarian tumor cell lines (OVCAR-3, IGROV-1 and SKOV-3). We next evaluated, in vivo in nude mice, the capacity of this biomaterial to regulate the tumor progression of subcutaneous and intraperitoneal models of ovarian tumor xenografts. RESULTS: We showed that HA-CMC barrier does not increase in vitro proliferation of ovarian cancer cell lines compared to control. In vivo, HA-CMC barrier presence with subcutaneous xenografts induced neither an increase in tumor volume nor cell proliferation (Ki67 and mitotic index). With the exception of an increased murine carcinosis score in peritoneum, the presence of HA-CMC barrier with intraperitoneal xenografts modified neither macro nor microscopic tumor growth. Finally, protein analysis of survival (Akt), proliferation (ERK) and adhesion (FAK) pathways highlighted no activation on the xenografts imputable to HA-CMC barrier. CONCLUSIONS: For the most part, our results support the lack of tumor progression activation due to HA-CMC barrier. We conclude that the benefits gained from using HA-CMC barrier membrane during ovarian cancer surgeries seem to outweigh the potential oncological risks.

Are peripheral purely undifferentiated pleomorphic sarcomas with MDM2 amplification dedifferentiated liposarcomas?

Dedifferentiated liposarcoma (DDLPS) has been defined as a tumor composed of well-differentiated liposarcoma associated with a nonlipogenic undifferentiated sarcoma and is genetically characterized by a 12q13-15 amplicon with MDM2 amplification. Some peripheral (extremities, trunk wall, head/neck) undifferentiated pleomorphic sarcomas (UPS) without areas of well-differentiated liposarcoma present an MDM2 amplification. We addressed whether they are true DDLPS or not. We compared the clinical data, histologic data, MDM2 status (immunohistochemistry [IHC], fluorescence in situ hybridization [FISH]), genomic profile (array comparative genomic hybridization), and follow-up of 19 patients with peripheral UPS with MDM2 amplification and 62 with peripheral conventional DDLPS retrieved from the French sarcoma network (RRePS) and the Conticabase (Connective Tissue Cancer Network database). For a control cohort, we described 153 patients from the Conticabase, with peripheral UPS without expression of MDM2 by IHC. By IHC, tumor cells were positive for MDM2 in 59 conventional DDLPS and in all UPS with MDM2 amplification. FISH analysis and/or quantitative polymerase chain reaction showed amplification of MDM2 in 54 conventional DDLPS and in all UPS with MDM2 amplification. The 2-year overall survival rates of UPS with MDM2 amplification, conventional DDLPS, and UPS without expression of MDM2 were 93.3%, 90.7%, and 73.9%, respectively. Such similarities in the clinical characteristics, morphology, genomic profile, and follow-up of peripheral UPS with MDM2 amplification and peripheral conventional DDLPS strongly suggest that peripheral UPS with MDM2 amplification are in fact DDLPS. Faced with histologic diagnosis of UPS, a systematic IHC evaluation of MDM2 allows a selection of cases for FISH analysis permitting the diagnosis of DDLPS.

Prognostic factors in adolescents and young adults (AYA) with high risk soft tissue sarcoma (STS) treated by adjuvant chemotherapy: a study based on pooled European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62771 and 62931.

BACKGROUND: We conducted a retrospective study, pooling data from two clinical trials in high risk soft tissue sarcoma (STS) patients, with the objective of comparing two different age groups: 15-29 years (adolescents and young adults (AYA) population) and ≥ 30 years. The aim was to determine prognostic factors for the AYA population. METHODS: Patients selected for analysis were treated in two randomised trials of adjuvant chemotherapy in STS (European Organisation for Research and Treatment of Cancer (EORTC) 62771 and 62931). A total of 793 patients were included with a median follow-up (FU) of 8.74 years (AYA population: n=161, median FU 9.46 years; patients ≥ 30 years: n=632, median FU 8.62 years). Study endpoints were overall survival (OS) and relapse-free survival (RFS). The variables of the multivariate analysis were gender, subtype and grade, tumour size and localisation (limb versus other), absence or presence of local recurrence and treatment (control arm versus adjuvant chemotherapy). RESULTS: Patients' characteristics were globally similar with two exceptions, histological subtype (p=0.0043) and tumour size (p<.0001). The commonest sarcoma subtype in the AYA population was synovial sarcoma (29%), whereas leiomyosarcoma (18%), malignant fibrous histiocytoma (MFH, presently being termed undifferentiated pleomorphic sarcoma (UPS), 16%) and liposarcoma (15%) were more frequent in patients ≥ 30 years. For OS, independent favourable prognostic factors were low grade and small tumour size for both groups; radical resection and MFH or liposarcoma subtype were favourable factors for patients ≥ 30 years only. For RFS, favourable prognostic factors were small tumour size and low grade for both groups; tumour location in the extremities was a favourable factor for the AYA population only, whereas radical resection and adjuvant chemotherapy treatment were favourable factors for patients ≥ 30y ears only. CONCLUSIONS: Significant differences could be found concerning prognostic factors between the AYA population and older patients. Interestingly, adjuvant chemotherapy was associated with improved RFS only in patients ≥ 30 years. The results may have further implications for the treatment of STS patients in different age groups, as well as the design of future clinical trials.

Protocol of the Definition for the Assessment of Time-to-event Endpoints in CANcer trials (DATECAN) project: formal consensus method for the development of guidelines for standardised time-to-event endpoints' definitions in cancer clinical trials.

INTRODUCTION: In randomised phase III cancer clinical trials, the most objectively defined and only validated time-to-event endpoint is overall survival (OS). The appearance of new types of treatments and the multiplication of lines of treatment have resulted in the use of surrogate endpoints for overall survival such as progression-free survival (PFS), or time-to-treatment failure. Their development is strongly influenced by the necessity of reducing clinical trial duration, cost and number of patients. However, while these endpoints are frequently used, they are often poorly defined and definitions can differ between trials which may limit their use as primary endpoints. Moreover, this variability of definitions can impact on the trial's results by affecting estimation of treatments' effects. The aim of the Definition for the Assessment of Time-to-event Endpoints in CANcer trials (DATECAN) project is to provide recommendations for standardised definitions of time-to-event endpoints in randomised cancer clinical trials. METHODS: We will use a formal consensus methodology based on experts' opinions which will be obtained in a systematic manner. RESULTS: Definitions will be independently developed for several cancer sites, including pancreatic, breast, head and neck and colon cancer, as well as sarcomas and gastrointestinal stromal tumours (GISTs). DISCUSSION: The DATECAN project should lead to the elaboration of recommendations that can then be used as guidelines by researchers participating in clinical trials. This process should lead to a standardisation of the definitions of commonly used time-to-event endpoints, enabling appropriate comparisons of future trials' results.

Prognostic and predictive factors for outcome to first-line ifosfamide-containing chemotherapy for adult patients with advanced soft tissue sarcomas: an exploratory, retrospective analysis on large series from the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG).

BACKGROUND: Adult patients with advanced soft tissue sarcomas (STS) are generally treated similarly, regardless of great differences between STS subtypes, disease presentation and patients' characteristics. As ifosfamide is frequently applied in first line systemic therapy, we aimed to establish prognostic and predictive factors for outcome to ifosfamide-based therapy. METHODS: A retrospective, exploratory analysis was performed on data from 1337 advanced STS patients who received first-line ifosfamide-containing chemotherapy. For predictive factor analysis, 660 patients treated with doxorubicin monotherapy served as comparators. RESULTS: Independent favourable prognostic factors for overall survival (OS) were good performance status, female gender, low histological grade, extremity primary tumour site and locally advanced disease; for progression-free survival (PFS), the combination of doxorubicin and ifosfamide, locally advanced disease, and tumour entity with a lower risk to progress for synovial sarcoma patients compared to leiomyosarcoma. For response, independent favourable prognostic factors were doxorubicin combined with ifosfamide, higher histological grade, and histology with synovial sarcoma patients having the highest chance to respond. Predictive factor analysis showed that compared to doxorubicin monotherapy, patients who benefited less from ifosfamide-based therapies were leiomyosarcoma patients in terms of OS, and patients with liposarcoma for response. No predictive factors were found for PFS. CONCLUSION: In this study, we established an independent set of prognostic and predictive factors for outcome to ifosfamide-based chemotherapy in advanced STS patients. This study provides important information for the interpretation and design of clinical trials for specific STS entities and may contribute to further treatment individualisation of advanced STS patients.