Randomised phase 2 study comparing the efficacy and safety of the oral tyrosine kinase inhibitor nintedanib with single agent ifosfamide in patients with advanced, inoperable, metastatic soft tissue sarcoma after failure of first-line chemotherapy: EORTC-1506-STBSG "ANITA".

PURPOSE: EORTC-1506-STBSG was a prospective, multicentric, randomised, open-label phase 2 trial to assess the efficacy and safety of second-line nintedanib versus ifosfamide in patients with advanced, inoperable metastatic soft tissue sarcoma (STS). The primary end-point was progression-free survival. PATIENTS/METHODS: Patients with a variety of STS subtypes were randomised 1:1 to nintedanib (200 mg b.i.d. p.o. until disease progression) or ifosfamide (3 g/m2 i.v. days 1-3, every 21 days for ≤6 cycles). A Korn design was applied aiming to detect an improvement in median progression-free survival (mPFS) from 3 to 4.5 months (HR = 0.667). An interim look was incorporated to stop the trial for futility if <19 of the first 36 patients treated with nintedanib were progression-free at week 12. RESULTS: At the interim analysis, among the first 36 eligible and evaluable patients randomised for nintedanib, only 13 (36%) were progression-free at week 12. The trial was closed for further accrual as per protocol. In total, 80 patients were randomised (40 per treatment group). The mPFS was 2.5 months (95% CI: 1.5-3.4) for nintedanib and 4.4 months (95% CI: 2.9-6.7) on ifosfamide (adjusted HR = 1.56 [80% CI: 1.14-2.13], p = 0.070). The median overall survival was 13.7 months (95% CI: 9.4-23.4) on nintedanib and 24.1 months (95% CI: 10.9-NE) on ifosfamide (adjusted HR = 1.65 [95%CI:0.89-3.06], p = 0.111). The clinical benefit rate for nintedanib and ifosfamide was 50% versus 62.5% (p = 0.368), respectively. Common treatment-related adverse events (all grades) were diarrhoea (35.9% of patients), fatigue (25.6%) and nausea (20.5%) for nintedanib; and fatigue (52.6%), nausea (44.7%) and vomiting, anorexia and alopecia (28.9% each) for ifosfamide. CONCLUSION: The trial was stopped for futility. The activity of nintedanib did not warrant further exploration in non-selected, advanced STSs.

Quality of surgery and surgical reporting for patients with primary gastrointestinal stromal tumours participating in the EORTC STBSG 62024 adjuvant imatinib study.

BACKGROUND: EORTC (European Organisation of Research and Treatment of Cancer) 62024 is a phase III randomised trial evaluating adjuvant imatinib in patients with gastrointestinal stromal tumours (GISTs) and no evidence of residual disease after surgery in 908 patients from 11 countries participated. As surgical treatment aspects (tumour rupture and incomplete resection) contribute to the risk of recurrence, the data of primary surgery were reviewed. METHODS: The surgical record, local pathology report and a surgical questionnaire on details of the operation had to be completed when patients entered the study. Surgeons from 5 countries, covering 8 languages, reviewed the full set of data being available from 793 patients (87.3%). RESULTS: A known GIST was the reason for surgery in only 58% of the cases, and 12% of the patients were treated as an emergency. The R0-resection rate was 87%. The extent of resection was local excision in 17%, segmental resection in 59%, full-organ resection in 11% and multivisceral resection in 11%, with lymphadenectomy performed in 24% of the patients. Shelling out of the tumour was performed in 9.7%, and the proportion of tumours removed in parts was higher in the endoscopy/laparoscopy group. The incidence of tumour rupture (representing M1) was 9%. The consistency between preoperative and intraoperative findings was 82%. The postoperative complication rate was 7.3%. CONCLUSION: The standardisation of surgery in this study was inferior. Given the review data, 18% of the patients should not have participated in the trial. Quality of surgery and improperly reported intraoperative details might influence the trial results. A detailed surgical questionnaire filled out by the surgeon is mandatory before entering the patient in an adjuvant trial in GIST.

Acetohydroxyacid synthase mutations conferring resistance to imidazolinone or sulfonylurea herbicides in sunflower.

Wild biotypes of cultivated sunflower ( Helianthus annuus L.) are weeds in corn ( Zea mays L.), soybean ( Glycine max L.), and other crops in North America, and are commonly controlled by applying acetohydroxyacid synthase (AHAS)-inhibiting herbicides. Biotypes resistant to two classes of AHAS-inhibiting herbicides-imidazolinones (IMIs) or sulfonylureas (SUs)-have been discovered in wild sunflower populations (ANN-PUR and ANN-KAN) treated with imazethapyr or chlorsulfuron, respectively. The goals of the present study were to isolate AHAS genes from sunflower, identify mutations in AHAS genes conferring herbicide resistance in ANN-PUR and ANN-KAN, and develop tools for marker-assisted selection (MAS) of herbicide resistance genes in sunflower. Three AHAS genes ( AHAS1, AHAS2, and AHAS3) were identified, cloned, and sequenced from herbicide-resistant (mutant) and -susceptible (wild type) genotypes. We identified 48 single-nucleotide polymorphisms (SNPs) in AHAS1, a single six-base pair insertion-deletion in AHAS2, and a single SNP in AHAS3. No DNA polymorphisms were found in AHAS2 among elite inbred lines. AHAS1 from imazethapyr-resistant inbreds harbored a C-to-T mutation in codon 205 ( Arabidopsis thaliana codon nomenclature), conferring resistance to IMI herbicides, whereas AHAS1 from chlorsulfuron-resistant inbreds harbored a C-to-T mutation in codon 197, conferring resistance to SU herbicides. SNP and single-strand conformational polymorphism markers for AHAS1, AHAS2, and AHAS3 were developed and genetically mapped. AHAS1, AHAS2, and AHAS3 mapped to linkage groups 2 ( AHAS3), 6 ( AHAS2), and 9 ( AHAS1). The C/T SNP in codon 205 of AHAS1 cosegregated with a partially dominant gene for resistance to IMI herbicides in two mutant x wild-type populations. The molecular breeding tools described herein create the basis for rapidly identifying new mutations in AHAS and performing MAS for herbicide resistance genes in sunflower.