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Abstract: Recent publications have suggested that imatinib (Glivec) may be cardiotoxic. We have therefore assessed the largest study on the agent performed in patients with gastrointestinal stromal tumours, randomising a daily dose of 400mg versus 800mg. 946 Patients were entered, 942 patients received at least one dose of imatinib. The median time on treatment was 24 months. A total of 24,574 exposure months could be analysed. We could not identify an excess of cardiac events in the study population. In 2 patients (0.2%) a possible cardiotoxic effect of imatinib could not fully be excluded. The current analysis of a large randomised prospective study could not confirm previous suggestions of imatinib induced cardiac toxicity. [Copyright &y& Elsevier]

Abstract: The aim of this study was to identify prognostic factors for toxicity to treatment with imatinib. The study was based on 942 patients with gastrointestinal stromal tumours (GIST) randomised to receive imatinib at different doses. The correlation between toxicities occurring with a Common Toxicity Criteria (CTC) grade 2 or more (non-haematological) or grade 3 or 4 (haematological) and imatinib dose, age, sex, performance status, original disease site, site and size of lesions at trial entry, baseline haematological and biological parameters was investigated. Anaemia was correlated with dose and baseline haemoglobin level, and neutropaenia with baseline neutrophil count and haemoglobin level. The risk of non-haematological toxicities was dose dependent and higher in females (oedema, nausea, diarrhoea), and in patients of advanced age (oedema, rash fatigue), poor performance status (fatigue and nausea), prior chemotherapy (fatigue), tumour of identified gastrointestinal origin (diarrhoea) and small lesions (rash). A multivariate risk calculator that can be used in the clinic for individual patients is proposed. [Copyright &y& Elsevier]

Abstract: In the EORTC-ISG-AGITG trial 946 patients with advanced gastro-intestinal stromal tumours (GIST) were randomised to receive 400 or 800mg of imatinib daily. An increase in progression free survival (PFS) was demonstrated for patients randomised to the high-dose arm. Patients randomised to low-dose could cross-over to high-dose upon progression. We evaluated the feasibility, safety and efficacy of this policy. Of the 241 patients available for follow-up, 133 patients (55%) crossed over to high-dose imatinib according to the protocol. Of these patients, 92% had not had a prior dose reduction. The cumulative incidence of subsequent dose reductions after cross-over was 17% after six months with 51% discontinuing therapy without requiring a dose reduction. The extent of anaemia and fatigue increased significantly after cross-over, whilst neutropenia was less severe than during low-dose treatment. Objective responses after cross-over included three patients (2%) with a partial response and 36 (27%) with stable disease. The median PFS after cross-over was 81 days, although 18.1% of patients were still alive and progression free one year after cross-over. We conclude that a cross-over to high-dose imatinib is feasible and safe in GIST patients who progress on low-dose therapy. [Copyright &y& Elsevier]

Background Imatinib is approved worldwide for use in gastrointestinal stromal tumors (GIST). We aimed to assess dose dependency of response and progression-free survival with imatinib for metastatic GIST. Methods 946 patients were randomly allocated imatinib 400 mg either once or twice a day. Those assigned the once a day regimen who had progression were offered the option of crossover. The primary endpoint was progression-free survival. Analysis was by intention to treat. Findings At median follow-up of 760 days (IQR 644-859), 263 (56%) of 473 patients allocated imatinib once a day had progressed compared with 235 (50%) of 473 who were assigned treatment twice a day (estimated hazard ratio 0.82 [95% CI 0.69-0.98]; p=0.026). Side-effects arose in 465/470 (99%) patients allocated the once daily regimen compared with 468/472 (99%) assigned treatment twice a day. By comparison with the group treated once a day, more dose reductions (77 [16%] vs 282 [60%]) and treatment interruptions (189 [40%] vs 302 [64%]) were recorded in patients allocated the twice daily regimen, but treatment in both arms was fairly well tolerated. 52 (5%) patients achieved a complete response, 442 (47%) a partial response, and 300 (32%) stable disease, with no difference between groups. Median time to best response was 107 days (IQR 58-172). Interpretation If response induction is the only aim of treatment, a daily dose of 400 mg of imatinib is sufficient; however, a dose of 400 mg twice a day achieves significantly longer progression-free survival. [ABSTRACT FROM AUTHOR]

Purpose Metastatic gastrointestinal stromal tumour (GIST) is generally an incurable disease with variable response to imatinib. We aimed to develop prognostic nomograms to predict overall survival (OS) and progression-free survival (PFS) for patients treated with imatinib. Methods Nomograms were developed in a training cohort ( n = 330) of patients treated in a randomised trial (EORTC-ISG-AGITG 62005 phase III study) using Cox regression models, and validated in patients ( n = 236) treated in routine clinical care from six referral centres. Nomogram performance was assessed by calculating the c statistic. A classification based on the nomograms’ scores was generated to group patients according to risk. Results Nomogram risk factors for OS and PFS were size of the largest metastasis, tumour genotype, primary tumour mitotic count, haemoglobin and blood neutrophil count at commencement of imatinib. The nomograms predicted survival with a c statistic of 0.75 (training) and 0.62 (validation) for OS, and 0.69 (training) and 0.62 (validation) for PFS. When tested in the validation cohort, the nomograms discriminated well the high and intermediate risk from low risk patients (hazard ratio [HR] for OS 3.83, 95% confidence interval [CI] 1.71–8.56; and 2.48, 95% CI 1.12–5.50; for PFS 2.84, 95% CI 1.66–4.87; and 1.45, 95% CI 0.87–2.41, respectively). Conclusion The nomograms predicted the risk of GIST progression and death with good discrimination of risk groups, and may be of value for patient counselling and risk stratification. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Tumour response assessment to therapy is crucial in oncology. We analysed the morphology of liver metastases (LM) in gastrointestinal stromal tumour (GIST) patients to determine whether uni-dimensional measurement of lesions by Response Evaluation Criteria in Solid Tumours (RECIST), accurately reflects lesion volume. Materials and methods: The volumes of LM (n =139) from a GIST patient cohort were measured using computed tomography (CT) at baseline, 3, 6 and 12months after commencement of imatinib therapy. Baseline measurements were obtained by two independent investigators and inter-observer agreement assessed using Bland–Altman plots. Actual lesion volumes (VACTUAL) were measured and compared with volumes based on the RECIST measure (VRECIST), and with volumes based on three orthogonal measures (VELLIPSOID) at several time-points. Results: At baseline, the inter-observer bias for VACTUAL was just 1.8%. VRECIST and VELLIPSOID overestimated VACTUAL by a mean of 35% and only 9% respectively (P <0.0001 for both). At baseline, 44% (61/139) of LM were classified as spheroidal and 56% (78/139) as ellipsoidal. During treatment, only 42% of LM retained their original morphology. The remainder demonstrated significant changes in morphology (from spheroidal to ellipsoidal and vice versa) over time, while the RECIST measure did not reflect such changes. Conclusions: The morphology of LM in GIST is rarely spherical (an underlying assumption for RECIST) and can change considerably during imatinib therapy. In this setting, measurements using RECIST do not reflect changes in size and morphology. Additionally, whilst VELLIPSOID is a more suitable surrogate for volume estimation, it is still somewhat limited by the morphology and orientation of such lesions. Studies are warranted to further explore the clinical impact of these findings. [Copyright &y& Elsevier]

The article presents a case study of a 77 year old white male patient who was treated with a total gastrectomy for a gastrointestinal stromal tumor in 2006. A discussion of plasma and bile pharmacokinetics data of imatinib and its main metabolite CGP74588 which were obtained from the patient is presented.

Summary Background No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib. Methods Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at ClinicalTrials.gov, number NCT00075218. Findings 312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27·3 weeks (95% CI 16·0-32·1) in patients receiving sunitinib and 6·4 weeks (4·4-10·0) in those on placebo (hazard ratio 0·33; p<0·0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea. Interpretation We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable. [ABSTRACT FROM AUTHOR]

Abstract: A recent randomized EORTC phase III trial, comparing two doses of imatinib in patients with advanced gastrointestinal stromal tumours (GISTs), reported dose dependency for progression-free survival. The current analysis of that study aimed to assess if tumour mutational status correlates with clinical response to imatinib. Pre-treatment samples of GISTs from 377 patients enrolled in phase III study were analyzed for mutations of KIT or PDGFRA by combination of D-HPLC and direct sequencing of tumour genomic DNA. Mutation types were correlated with patients’ survival data. The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% (P <0.0001) and the relative risk of death by 190% (P <0.0001) when compared with KIT exon 11 mutants. Similarly, the relative risk of progression was increased by 108% (P <0.0001) and the relative risk of death by 76% (P =0.028) in patients without detectable KIT or PDGFRA mutations. In patients whose tumours expressed an exon 9 KIT oncoprotein, treatment with the high-dose regimen resulted in a significantly superior progression-free survival (P =0.0013), with a reduction of the relative risk of 61%. We conclude that tumour genotype is of major prognostic significance for progression-free survival and overall survival in patients treated with imatinib for advanced GISTs. Our findings suggest the need for differential treatment of patients with GISTs, with KIT exon 9 mutant patients benefiting the most from the 800mg daily dose of the drug. [Copyright &y& Elsevier]

Imatinib pharmacokinetics (PK) may be affected by a number of factors that are related to the disease being treated and to the response of that disease to imatinib. Patients in the phase I and phase II trials conducted by the EORTC in patients with gastrointestinal stromal tumours (GISTs) and other sarcomas had detailed blood sampling for imatinib PK on day 1 and on day 29. Patients with GISTs also had repeat sampling, using a limited sampling strategy, after approximately 12 months on therapy. This population PK study was carried out to examine what covariates affected imatinib PK in GIST patients and what PK changes occurred over time. In the model producing the best fit, low clearance (CL) correlated with low body weight and high granulocyte count, whereas low haemoglobin correlated with low volume of distribution. For a patient with 77% of the median body weight or with 1.87 times the median granulocyte count, the apparent CL is 6.53 l/h, about 70% of the typical apparent CL of 9.33 l/h; for a patient of 84% of the typical haemoglobin level, the volume of distribution is about 70%. Total white blood cell count correlated closely with granulocyte count and there was a moderate correlation between haemoglobin and albumin (r = 0.454). There was a trend towards increased imatinib clearance after chronic exposure over 12 months. The typical apparent CL increased 33% from day 1. Nevertheless, the approximate 95% confidence interval of the increase of the typical apparent CL was 33 +/- 34.6%, which contains zero. It is not yet clear whether this is a significant factor in the amelioration of imatinib toxicity that occurs with time or is related to disease control, and further work is required to confirm this observation. [ABSTRACT FROM AUTHOR]