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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n\u003Cp id=\u0022p-1\u0022\u003EThis article discusses multiple clinical trials using imatinib for the treatment of\ngastrointestinal stromal tumor (GIST). Specific topics include the risk associated with the\ninterruption of imatinib therapy among advanced GIST patients, the link between higher doese of\nimatinib for GIST and longer progression-free survival, as well as the use of imatinib for\nrecurrence-free survival in completely resected GIST.\u003C\/p\u003E\n\u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EGastrointestinal Cancers\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EInterrupting imatinib therapy among advanced gastrointestinal stromal tumor (GIST) patients who\nhave had a long lasting response results in a high risk of rapid progression, according to results\nof a recent clinical trial (BFR14). That risk, said Axel Le Cesne, MD, speaking for the French\nSarcoma Group, persists regardless of the quality of prior response to therapy.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003E\u201cThe optimal duration of imatinib therapy in responding patients with advanced GIST is\nunknown,\u201d Dr. Le Cesne said, pointing out that in earlier results among 58 advanced GIST\npatients who had imatinib dose interruptions after 1-year of response, median progression-free\nsurvival (PFS) was 6.1 months among those whose imatinib dose was interrupted as compared with 28.3\nmonths for those who had continued imatinib therapy (p\u0026lt;0.0001). Overall survival (OS) was\nsimilar between the groups.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EThe current trial examined the effects of dose interruption in patients whose response (stable\ndisease, partial response, or complete response) to 400 mg of imatinib had been sustained for 3\nyears. Included individuals with advanced metastatic GIST were randomized to continued therapy\n(CONT) with imatinib 400 mg or to therapy interrupted (STOP) until progressive disease followed by\nresumed dosing at 400 mg. The main endpoint was PFS, with secondary endpoints of OS, and response to\nimatinib re-start in the STOP arm. BFR14 had initially included 338 patients, among whom 58 had been\nrandomized at 1 year. Another 50 were randomized to CONT or STOP at 3 years. The statistical\nhypothesis was that at 1-year PFS would be 90% in the CONT arm and \u0026gt;75% in the\nSTOP arm.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EMean age was \u223c61 years. Primary sites were most commonly gastric or in the small bowel. At\n1-year there were 12 events in the 25 STOP patients (PFS 20.2%) and 1 event among 24 CONT\npatients (PFS 91.7%, p=0.0013). Progressive disease rates in the STOP arm were\n47%, 64% and 85% at 6 months, 9 months and 1-year, respectively. There were no\ndeaths. Dr. Le Cesne pointed out that the 1-year PFS curves in the STOP arms of the 1- and 3-year\nanalyses were similar at 25.0% (1-year) and 20.2% (3-year).\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EWhen Dr. Le Cesne and colleagues asked also whether prolonged responding patients are different\nfrom the initial non-randomized population (n=276), they found female gender, small bowel\nprimary site, liver involvement only and smaller tumor size to be more commonly occurring features\n(only female gender significantly so). In addition, mutational analysis conducted in 49% of\npatients showed the exon 11 mutation to be present in 83% at randomization. Exon 9 and wild\ntype were each found in 8.5% of patients. In the exon 11 group, 90% of mutations were\nproximal (10% distal).\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EDr. Le Cesne concluded that imatinib interruption in responding patients after 3 years is\nassociated with reduced PFS and cannot be recommended outside of clinical trials. He noted further\nthat the impact of the re-introduction of imatinib at the same dose on tumor control is currently\nbeing investigated. The impact of imatinib interruption on OS after 3-years of treatment is yet\nunknown.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EDiscussant Peter Reichardt, MD, Bad Saarow, Germany, commenting on the similar PFS pattern in the\n1- and 3-year STOP arms, said, \u201cThis clearly leads to the question of whether we already need\nto think about a 3\u003Csup\u003Erd\u003C\/sup\u003E generation adjuvant trial with treatment duration beyond 3\nyears.\u201d Dr. Le Cesne, in fact, proposed a new randomization in non-progressing patients at\n5-years with the same statistical hypothesis.\u003C\/p\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n\u003Ch2 class=\u0022\u0022\u003ELonger Progression-Free Survival at Higher-Dose Imatinib in GIST\u003C\/h2\u003E\n\u003Cp id=\u0022p-9\u0022\u003EResults from the two largest clinical trials (combined n=1,640) ever conducted in\ngastrointestinal stromal tumors (GIST) show longer progression-free survival (PFS) with high-dose\nimatinib (800 mg daily) compared with standard dose (400 mg daily). They suggest also, stated\nMartine Van Glabbeke, PhD, speaking for the GIST Meta-analysis Group, that high-dose therapy\nbenefits depend on mutation type.\u003C\/p\u003E\n\u003Cp id=\u0022p-10\u0022\u003EThe two randomized, intergroup phase 3 trials were conducted among patients with unresectable or\nmetastatic GIST expressing the \u003Cem\u003EKIT\u003C\/em\u003E receptor tyrosine kinase (CD117). One, conducted\nin the US and Canada (US-CDN, n=694) had overall survival (OS) as its primary endpoint, and\nthe other, conducted in Europe, Australia and Asia (EU-AUS, n=946) had PFS as its primary\nendpoint. The trials, planned together, had wide entry criteria, including performance status up to\n3, with no upper age limit and prior therapy permitted. In both trials patients received either\nimatinib 400 mg daily or 800 mg daily until progression, with crossover to the higher dose allowed\nafter progression in the 400 mg group. Mutation data were gathered in a total of 772 cases.\u003C\/p\u003E\n\u003Cp id=\u0022p-11\u0022\u003EThe meta-analysis aims were to compare results between the two trials, to build prognostic models\nfor PFS and OS, and to characterize patients who may benefit from the high-dose therapy. Median\nfollow-up was 55\/42 months in the US-CDN\/EU-AUS trials.\u003C\/p\u003E\n\u003Cp id=\u0022p-12\u0022\u003EPFS and OS were consistent between the two trials, Dr. Van Glabbeke said. In the combined trials,\nmedian PFS was 19\/23 months in the 400 mg\/800 mg groups, respectively, a small but significant\nincrease for the higher dose (HR 0.89, p=0.04). Median OS was identical (49 months, HR\n1.00).\u003C\/p\u003E\n\u003Cp id=\u0022p-13\u0022\u003EMultivariate prognostic analysis revealed four factors adversely affecting both PFS and OS: poor\nperformance status, high neutrophil count at trial entry, absence of \u003Cem\u003EKIT\u003C\/em\u003E exon 11\nmutations and male gender. Small bowel origin and low hemoglobin at trial entry adversely affected\nPFS. OS was adversely affected significantly by advanced age, low albumin at trial entry and large\nlesions.\u003C\/p\u003E\n\u003Cp id=\u0022p-14\u0022\u003EMedian PFS and median OS (months) for \u003Cem\u003EKIT\u003C\/em\u003E exon 11 mutants\/\u003Cem\u003EKIT\u003C\/em\u003E\nexon 9 mutants\/wild types\/other were 26\/60, 13\/31, 16\/43 and 11\/34, respectively. Dr. Van Glabbeke\nnoted that cases with \u003Cem\u003EKIT\u003C\/em\u003E exon 11 mutants had doubled PFS and nearly doubled OS as\ncompared with those with \u003Cem\u003EKIT\u003C\/em\u003E exon 9 mutants.\u003C\/p\u003E\n\u003Cp id=\u0022p-15\u0022\u003EBecause of the modest 11% benefit in PFS, investigators looked for subpopulations with\nhigher potential benefit from high-dose therapy. They found that only the presence or absence of\n\u003Cem\u003EKIT\u003C\/em\u003E exon 9 mutations significantly affected the relative PFS (p=0.015)\nbenefit of high-dose therapy. The interaction was not significant for OS (p=0.071). PFS with\n\u003Cem\u003EKIT\u003C\/em\u003E exon 9 mutants was 6 months at 400 mg and 19 months at 800 mg (p=0.017);\nOS was 28\/35 months (p=0.15).\u003C\/p\u003E\n\u003Cp id=\u0022p-16\u0022\u003EDr. Van Glabbeke concluded, \u201cTreatment with high-dose imatinib compared with standard dose\nresults in a small but statistically significant PFS advantage, but this does not affect OS.\n\u2026There is statistically significant evidence that the relative benefit of high-dose therapy\ndepends on the mutation type.\u201d She added that starting imatinib therapy at a daily dose of\n800 mg in \u003Cem\u003EKIT\u003C\/em\u003E exon 9 mutants will improve PFS, but there is no evidence that it\nwill prolong survival.\u003C\/p\u003E\n\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n\u003Ch2 class=\u0022\u0022\u003EImatinib Increases Recurrence-Free Survival in Completely Resected GIST\u003C\/h2\u003E\n\u003Cp id=\u0022p-17\u0022\u003EAmong patients with resectable gastrointestinal stromal tumors (GIST), adjuvant imatinib mesylate\nat 400 mg\/day for a year increases recurrence-free survival (RFS) and is safe and well-tolerated.\nThe finding emerged from the North American Intergroup phase 3 trial ACOSOG Z9001, which included\npatients with completely resected, localized primary GIST.\u003C\/p\u003E\n\u003Cp id=\u0022p-18\u0022\u003ERonald DeMatteo, MD, Memorial Sloan-Kettering Cancer Center, New York, noted that GIST is the\nmost common sarcoma of the intestinal tract, and further that more than 90% of GIST tumors\nhave a \u003Cem\u003EKIT\u003C\/em\u003E or \u003Cem\u003EPDGFRa\u003C\/em\u003E mutation. Clinical trial experience has shown\nimatinib mesylate to provide benefit in more than 80% of patients with metastatic GIST. For\npatients with localized primary GIST, surgery has been the gold standard, Dr. DeMatteo said, and\ncurrently among patients with unresectable tumors, imatinib is the standard of care.\u003C\/p\u003E\n\u003Cp id=\u0022p-19\u0022\u003EThe question naturally arose whether imatinib would be beneficial given to patients with primary\nGIST just after surgery. Before the development of imatinib, when there were no therapies available,\n5-year survival was only 54%, according to Dr. DeMatteo\u0027s earlier research\n(\u003Cem\u003EAnn Surg\u003C\/em\u003E 2000). DeMatteo and colleagues hypothesized that adjuvant imatinib would\nprolong RFS following the complete resection of primary GIST.\u003C\/p\u003E\n\u003Cp id=\u0022p-20\u0022\u003EThe main entry criterion was primary GIST size of \u22653 cm. All patients had complete gross\nresection of KIT+ tumors and were randomized to a year of either placebo or of 400 mg daily\nof imatinib. The endpoints were recurrence-free survival (RFS, primary), overall survival (OS,\nsecondary) and safety. Progressing patients were unblinded and switched from placebo to imatinib 400\nmg or from 400 imatinib to 800 mg\/day.\u003C\/p\u003E\n\u003Cp id=\u0022p-21\u0022\u003EAfter the third scheduled 6-month analysis, with 644 of a planned 732 patients enrolled, the\ntrial was stopped prematurely. Similar percentages of the prescribed dose were delivered to both\ngroups (placebo 71%, imatinib 67%), with tumor recurrence (38% placebo,\n1% imatinib) and toxicity (7% placebo, 50% imatinib) the main causes,\nrespectively, of dose alterations. Grade 3\u20134 toxicities with imatinib were mainly\nneutropenia, liver function test elevations, skin rash and edema.\u003C\/p\u003E\n\u003Cp id=\u0022p-22\u0022\u003EOS was similar in both groups, with a surprisingly small number of events (4 deaths placebo, 3\ndeaths imatinib, p=0.72), Dr. DeMatteo said. Six (6) were attributed to disease recurrence.\nFor the primary PFS endpoint at 1-year, there were 62 events in the placebo arm and 21 in the\nimatinib arm (83% vs 97%, p=0.001). Dr. DeMatteo pointed out that at about 6\nmonths after the completion of treatment the RFS slope began to turn downward.\u003C\/p\u003E\n\u003Cp id=\u0022p-23\u0022\u003ESubgroup analysis showed stronger imatinib effects in patients with the largest tumors\n(\u226510 cm), with RFS of 67% in the placebo arm and 96% in the imatinib arm\n(p=0.001), and a descending PFS slope at about a year and one-half.\u003C\/p\u003E\n\u003Cp id=\u0022p-24\u0022\u003EDr. DeMatteo concluded, \u201cOne-year of 400 mg\/day imatinib mesylate is safe and\nwell-tolerated after the complete resection of a primary gastrointestinal stromal tumor.\nRecurrence-free survival is increased. Overall survival has not been altered at this time with these\npreliminary data.\u201d\u003C\/p\u003E\n\u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2007 MD Conference Express\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/7\/3\/30.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzmagq\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}