Imatinib has tremendously changed the treatment of gastrointestinal stromal tumor (GIST). Research is currently focusing on its optimal use and the mechanisms of resistance that may emerge. A multidisciplinary approach including medical oncologists, surgeons, radiologists, and pathologists is crucial for the optimal management of these patients. Moreover, imatinib treatment in GIST represents an extraordinary model to expand our knowledge on the molecular mechanisms that are basic to the effects of molecularly targeted therapies. This review summarizes the existing knowledge of the imatinib treatment in GIST and describes directions for further development.

/pdf/imatinib-and-gastrointestinal-stromal-tumors-where-do-we-go-467vqhas89.pdf

Imatinib and gastrointestinal stromal tumors: Where do we go from here?

Anemia has myriad causes. In patients with cancer, the chief culprits are direct myelotoxicity from antineoplastic drugs and cytokine-mediated inhibition of erythropoiesis. A host of other malign influences may also be at work, including bleeding, renal injury, nutrient deficiency, and so on. A single patient may suffer from several causes of anemia simultaneously, and it is not always easy to distinguish these. However, it is important to try: although the physiological consequences of a low hemoglobin level are similar regardless of its origin, treatment differs considerably. In this issue of the Journal of Clinical Oncology, Smith et al report results from the Amgen 20010103 clinical trial (Amgen 103). These results suggest that whether or not an anemic patient is receiving myelosuppressive chemotherapy is a clinically relevant distinction, with therapeutic implications. Data from this trial were first presented by John Glaspy in April 2007 at the clinical plenary session of the annual meeting of the American Association for Cancer Research, an event that garnered considerable media attention. The Amgen 103 investigators randomly assigned 989 patients with cancer and hemoglobin 11 g/dL to receive either the erythropoiesis-stimulating agent (ESA) darbepoetin alfa or a placebo. Although 70% of enrolled patients had undergone prior chemotherapy, which finished a median of 9 months before trial participation, patients were not permitted to receive cytotoxic chemotherapy or myelosuppressive radiotherapy during the 16 weeks of study intervention. However, patients were allowed to receive nonmyelosuppressive radiotherapy or hormonal therapy, and many did. The results of the Amgen 103 trial are negative in two senses. Neither the primary end point—reduction in RBC transfusion needs with darbepoetin—nor a secondary quality of life end point was met. More disturbingly, patients who received darbepoetin did not live as long as those who received placebo (37 weeks v 47 weeks median survival; P .022). The trial’s sobering findings are included in the new ESA prescribing information approved by the United States Food and Drug Administration (FDA) in November 2007, and the study results have influenced the ongoing debate in the United States about Medicare beneficiaries’ access to ESAs. Several of the Amgen 103 study findings are difficult to interpret. Enrolled patients were diverse, with more than 15 different primary tumor sites and all stages of disease; anemia and ESA treatment may have distinct consequences in different cancer settings. Furthermore, survival was not the study’s primary end point, so the two study arms were not balanced for known prognostic markers. A retrospective analysis demonstrated that if the groups had been better balanced, the observed survival difference would no longer have been significant— similar to what happened with the Breast Cancer Erythropoietin Survival Trial (BEST) and ENHANCE studies, which also pointed to potential harm from off-label use of ESAs. In another echo of BEST, the Amgen 103 investigators were unable to adjudicate long-term causes of death in trial participants, so we don’t know what proportion of the patients died from progressive cancer, thromboembolism, or something else. The transfusion end point is also murky. The Amgen 103 study was multinational, and 75% of patients enrolled in Europe, including areas of Eastern Europe where blood bank shortages occur. Of the 75 study patients who did not undergo transfusion when their hemoglobin level decreased to less than 8 g/dL, 95% were from Eastern Europe. The trial’s primary end point of transfusion reduction with darbepoetin could have been met if these patients had undergone transfusion according to protocol guidelines. In retrospect, it was probably not a good idea to conduct a study with a transfusion primary end point at sites where access to blood is not assured. United States–based drug companies often pursue clinical trials overseas when they want to accrue patients rapidly, especially when the study question would be difficult to answer in North America because of entrenched clinical practice patterns. In the case of the Amgen 103 study, the study sponsor may have had little choice, because placebo-controlled studies of ESAs are notoriously difficult to conduct to in the United States. There are many reasons for this, but a major factor is the widespread use of drug purchasing contracts that limit physicians’ choice of ESA products in exchange for discounted pricing—an important but controversial revenue source for many oncology practices. If the results of the Amgen 103 study had appeared several years ago in the golden age of ESAs, they might have been chalked up to limitations of study design and execution. The possibility could still have been left open that in anemic cancer patients who aren’t getting chemotherapy, ESAs might modestly reduce transfusion needs and have no impact on survival. Instead, these results arrive at a tumultuous time, when ESAs and their manufacturer, Amgen, are subject to intense scrutiny, after the fallout from a February 2007 expose in The Cancer Letter about poorer survival in head and neck cancer patients treated with darbepoetin in the Danish Head and Neck Cancer study 10 trial. Now, ESA safety is on every oncologist’s mind, and the Amgen 103 study results only heighten those concerns. We need to take these results seriously, and unless new data emerge, I believe we can’t afford to risk testing ESAs in this population again. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 7 MARCH 1 2008

Is anemia of cancer different from chemotherapy-induced anemia?

Background Imatinib dose escalation is advocated for gastrointestinal stromal tumour (GIST) treatment, but its effectiveness compared with sunitinib and best supportive care (BSC) after failure at the 400 mg/day dose is unknown. Objectives To assess the effectiveness and cost-effectiveness of imatinib at escalated doses of 600 or 800 mg/day for patients with unresectable and/or metastatic GISTs whose disease had progressed on 400 mg/day. Data sources Electronic databases, including MEDLlNE, MEDLINE In-Process, EMBASE, BIOSIS, Science Citation Index, Health Management Information Consortium and the Cochrane Controlled Trials Register, were searched until September 2009. Review methods A systematic review of the literature was carried out according to standard methods. An economic model was constructed to assess the cost-effectiveness of seven alternative pathways for treating patients with unresectable and/or metastatic GISTs. Results Five primary studies involving 669 people were included for clinical effectiveness; four reported imatinib and one reported sunitinib. The data were essentially observational as none of the studies was designed to specifically assess treatment of patients whose disease had progressed on 400 mg/day imatinib. For 600 mg/day imatinib, between 26% and 42% of patients showed either a partial response (PR) or stable disease (SD). Median time to progression was 1.7 months (range 0.7–24.9 months). For 800 mg/day imatinib, between 29% and 33% of patients showed either a PR or SD. Median overall survival (OS) was 19 months [95% confidence interval (CI) 13 to 23 months]. Progression-free survival ranged from 81 days to 5 months (95% CI 2 to 10 months). Median duration of response was 153 days (range 37–574 days). Treatment progression led to 88% discontinuations but between 16% and 31% of patients required a dose reduction, and 23% required a dose delay. There was a statistically significant increase in the severity of fatigue (p   £45,000. Limitations The evidence base was sparse, data were non-randomised and potentially biased. The economic model results are surrounded by a considerable degree of uncertainty and open to biases of unknown magnitude and direction. Conclusions Around one-third of patients with unresectable and/or metastatic GIST, who fail on 400 mg/day of imatinib, may show response or SD with escalated doses. Between a threshold of £25,000 and £45,000, provision of an escalated dose of imatinib would be most likely to be cost-effective. However, these results should be interpreted with caution owing to the limited evidence available on outcomes following imatinib dose escalation or sunitinib for this group of patients. Funding The National Institute for Health Research Health Technology Assessment programme.

https://njl-admin.nihr.ac.uk/document/download/2033776

Clinical effectiveness and cost-effectiveness of imatinib dose escalation for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours that have progressed on treatment at a dose of 400 mg/day: a systematic review and economic evaluation

r Masson SAS. Tous droits réservés. Document téléchargé le 23/12/2019 Il est interdit et illégal L’efficacité de biothérapies ciblant l’epidermal growth actor receptor (EGFR) (cetuximab [3] et panitumumab [4] our les cancers colorectaux métastatiques non résécables CCRM] ; erlotinib [5] pour les cancers pancréatiques métatatiques), le KIT (imatinib [6] pour les tumeurs stromales astrointestinales [GIST] non résécables) et le mTOR (everoimus [7] pour les tumeurs endocrines bien différenciées) a alidé le concept d’inhibition ciblée en cancérologie digesive. Les biothérapies dites antiangiogéniques ciblent la oie du vascular endothelial growth factor (VEGF) proangioénique des cellules endothéliales (bevacizumab anticorps nti-VEGF) ou plusieurs voies pour les ITK dits multicibles sunitinib ITK de PDGFR , VEGFR-1 et -2, Flt3 et KIT ; soraenib ITK de VEGFR-2 et -3, RAF, PDGFR , Flt3 et KIT) [8]. Les ésultats de plusieurs essais ont validé le concept des biothéapies antiangiogéniques en cancérologie digestive pour le evacizumab [9,10], le sunitinib [11] et le sorafenib [12], qui nt obtenu une autorisation de mise sur le marché (AMM) resectivement dans le traitement des CCRM, des GIST, si échec ’imatinib, et des carcinomes hépatocellulaires avancés. Bien que leur action soit plus ciblée que celle des chiiothérapies, il ne faut pas méconnaître le fait que les

Biothérapies ciblées en cancérologie digestive : prise en charge de leurs effets secondaires

SUMMARY Till now ESA remains one of the basic options of treatment of anemia in oncology patients. However indications and, in a greater degree, contra-indications and restrictions to their use have recently undergone considerable changes. In the given review the basic changes in recommendations of the international ontological organizations (ASCO/ASH, EORTC) and foreign regulatory agencies (FDA, EMEA) are presented. Keywords: epoetin, darbepoetin, oncology, oncohaematology, safety.Federal Research Clinical Center for Pediatric Hematology, Oncology and Immunology, Ministry of Health Care and Social Security of the Russian Federation, MoscowКонтакты: zhukov.nikolay@rambler.ruПринято в печать: 22 апреля 2009 г. Кому не показано назначение эритропоэзстимулирующих препаратов Н. В. Жуков РЕФЕР А Т До настоящего времени эритропоэзстимулирующие препараты (ЭСП) остаются одним из основных вариантов лечения анемии у онкологических больных. Однако показания и, в большей степе-ни, противопоказания и ограничения к их использованию совсем недавно претерпели значительные изменения. В данном обзоре представлены основные изменения в рекомендациях международ-ных организаций (ASCO/ASH, EORTC) и зарубежных регуляторных органов (FDA, EMEA) по использованию ЭСП в онкологии.

Contraindications and restrictions of use for the erythropoiesis stimulating agents

9046 Background:Imatinib (Glivec®) is a c-kit tyrosine kinase inhibitor recently established as the standard treatment for advanced/metastatic GIST. Anemia is frequently observed in patients with advanced GIST, and is one of the most frequent side effects of imatinib (89% of patients) while this drug causes grade 3–4 anemia in 10% of patients. Whether EPO treatment is useful in the management of GIST patients receiving imatinib treatment is unknown. Methods:A retrospective study of EPO treatment in GIST patients receiving imatinib was undertaken in 4 centers. Thirty four patients received EPO treatment among the 319 GIST patients treated with imatinib in clinical trials or with compassionate use since 2001. The impact of EPO treatment on the anemia and the predictive factors of efficacy were investigated. Results:34 patients were included as follows: Male/Female=18/16; median age= 59 years; median WHO-PS= 1; metastatic/advanced GIST= 32/2. Original site of disease was mainly gastric (32%) and small bowel ...

Erythropoietin for anemia treatment of patients with GIST receiving imatinib

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Erythropoietin for anemia treatment of patients with GIST receiving imatinib