<?xml version="1.0" encoding="utf-8"?>
<recommendedContent xmlns="http://api.mspoke.com">
    <recommendedItem id="20100101_19_398"
                     title="ASCO GI: Gene Test, Nodes Predict Colon CA Recurrence Risk (CME/CE)"
                     score="0.01"
                     href="http://www.medpagetoday.com/MeetingCoverage/ASCOGI/tb/18301?impressionId=1265785612708"
                     
      &lt;p&gt;ORLANDO  --  An extended nodal examination and gene array test show promise for identifying patients at high risk of colorectal cancer recurrence in stage II disease, researchers reported at the Gastrointestinal Cancers Symposium.&lt;/p&gt;
&lt;p&gt;Across the range of recurrence scores, examination of at least 12 nodes was associated with about a 5% absolute decrease in the three-year risk of recurrence in resected stage II colon cancers, compared with the same recurrence score and examination of fewer nodes.&lt;/p&gt;
&lt;p&gt;Noting limitations of other tests and biomarkers developed to evaluate recurrence risk, the gene expression-derived recurrence score &quot;has a real chance to make its way into the clinical decision algorithm,&quot; said David Kerr, MD, of the University of Oxford in England.&lt;/p&gt;
&lt;p&gt;Both recurrence score and number of nodes examined were independent predictors of recurrence risk, but investigators found no association or interaction between the two parameters of risk assessment.&lt;/p&gt;
&lt;p&gt;&quot;The test gives us more information about individual patients about the likelihood of the cancer returning,&quot; said Kerr, who was an investigator in the study. &quot;I think the quality of the science underpinning it, the size of the sample, and the compelling statistics all combine to make this a potential winner.&quot;&lt;/p&gt;
&lt;p&gt;Another study reported at the meeting showed few tumor-related genetic characteristics to distinguish stage II colon cancer from stage III.&lt;/p&gt;
&lt;p&gt;Both studies involved use a 12-gene assay (Oncotype DX) validated for predicting recurrence risk in stage II colon cancer. Investigators in the QUASAR validation study used data from the trial to evaluate the prognostic value of nodal assessment combined with other parameters, including the 12-gene assay.&lt;/p&gt;
&lt;p&gt;The National Comprehensive Cancer Network (NCCN) clinical guidelines for stage II colon cancer include number of nodes examined as a prognostic factor, Richard Gray, PhD, of the University of Birmingham in England, and colleagues noted in a poster presentation.&lt;/p&gt;
&lt;p&gt;Records for 657 stage II patients randomized to surgery alone showed that the median number of nodes examined was 10, including fewer than six nodes in 19% of patients and &amp;#8805;12 nodes in 37%. Risk of recurrence was more closely associated with examination of fewer than eight nodes versus more (HR 1.77, &lt;em&gt;P&lt;/em&gt;&amp;lt;0.001) than with a cutoff point of 12 nodes (HR 1.38, &lt;em&gt;P&lt;/em&gt;=0.065). &lt;/p&gt;
&lt;p&gt;More nodes were examined in later than earlier years, the investigators found.&lt;/p&gt;
&lt;p&gt;In a model that included recurrence score derived from the gene assay and the 12-node threshold recommended by NCCN, both factors proved to be independent predictors of recurrence risk (&lt;em&gt;P&lt;/em&gt;=0.01, &lt;em&gt;P&lt;/em&gt;=0.05). Similar results emerged from models that incorporated mismatch repair (or microsatellite instability) and T stage.&lt;/p&gt;
&lt;p&gt;Across the range of recurrence scores, examination of &amp;#8805;12 nodes was associated with a 3% to 7% lower risk of recurrence compared with examination of fewer nodes (about 5% overall). The investigators concluded that both parameters should be included in assessment of recurrence risk after surgery for stage II colon cancer.&lt;/p&gt;
&lt;p&gt;The second study examined the 12-gene assay&apos;s ability to distinguish stage II from stage III colon cancer. Investigators evaluated the assay, pathologic markers, and expression of 375 different genes in 634 patients with stage II disease and 844 with stage III colon cancer.&lt;/p&gt;
&lt;p&gt;The data showed minimal differences in gene expression between the two stages of colon cancer.&lt;/p&gt;
&lt;p&gt;Five of the 375 genes differed significantly in their expression in stage II versus stage III cancer (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.05). Two tumor characteristics differed by stage, as stage II colon cancer was more likely to be mismatch repair-deficient (&lt;em&gt;P&lt;/em&gt;=0.04) and have mucinous histology (&lt;em&gt;P&lt;/em&gt;=0.007).&lt;/p&gt;
&lt;p&gt;The data also showed significant interaction of grade and stage (&lt;em&gt;P&lt;/em&gt;=0.005), and borderline significance for interactions of stage with T-stage, mismatch repair, and mucinous histology, reflecting prognostic value in stage II but not stage III disease.&lt;/p&gt;
&lt;p&gt;Overall, investigators in this second study found a &quot;striking similarity between stages for the recurrence score and the vast majority of genes analyzed.&quot;&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The studies were supported by Genomic Health.&lt;/p&gt;&lt;p&gt;Investigators in the studies included employees of Genomic Health.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_335"
                     title="Ultrasound Helps Predict Liver Damage in NAFLD (CME/CE)"
                     score="0.005"
                     href="http://www.medpagetoday.com/Gastroenterology/GeneralHepatology/tb/18211?impressionId=1265785612708"
                     
      &lt;p&gt;An ultrasound technique called transient elastography can accurately detect liver damage in most patients with non-alcoholic fatty liver disease (NAFLD), a condition that often accompanies obesity and type 2 diabetes, a new study found.&lt;/p&gt;
&lt;p&gt;Transient elastography (TE) accurately measured levels of liver stiffness, an indication of the amount of fibrosis, in more than 97% of patients with a body mass index below 30 kg/m&lt;sup&gt;2&lt;/sup&gt; and in 75% of obese patients, according to a report in the February issue of &lt;em&gt;Hepatology&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;&quot;The adoption of transient elastography could potentially spare two-thirds of NAFLD patients from liver biopsies,&quot; Victor de L&amp;#233;dinghen, MD, PhD, of H&amp;#244;pital Haut-L&amp;#233;v&amp;#234;que, in Pessac Cedex, France, and colleagues wrote. &quot;Since the prevalence of NAFLD is high in many affluent countries, this approach would be cost saving.&quot;&lt;/p&gt;
&lt;p&gt;Non-alcoholic fatty liver disease has become more common as the incidence of metabolic syndrome and obesity has grown. The condition can progress to cirrhosis and hepatocellular carcinoma, particularly among patients with non-alcoholic steatohepatitis (NASH), in which fat in the liver causes inflammation and tissue damage.&lt;/p&gt;
&lt;p&gt;Liver biopsy is typically used to determine levels of inflammation and fibrosis associated with NASH, but the procedure carries a small risk of hemorrhage, puncture of other internal organs, infection, and spread of cancer cells. Transvenous liver biopsy carries an additional risk of adverse reaction to the contrast material.&lt;/p&gt;
&lt;p&gt;These problems, in addition to the mixed results due to sampling variance&lt;strong&gt; &lt;/strong&gt;biopsies sometimes deliver, have researchers searching for alternative methods of determining the extent of liver fibrosis.&lt;/p&gt;
&lt;p&gt;L&amp;#233;dinghen and colleagues compared the accuracy of TE to biochemical tests for the diagnosis of fibrosis and cirrhosis in 246 NAFLD patients who underwent liver biopsies between May 2003 and April 2009 at University Hospital of Pessac and Prince of Wales Hospital in Hong Kong. The accuracy of the TE measurements was validated by biopsy results.&lt;/p&gt;
&lt;p&gt;Of the patients, 31 (12.6%) had advanced fibrosis and 25 (10.2%) had cirrhosis.&lt;/p&gt;
&lt;p&gt;The liver stiffness measurements of patients with F0, F1, F2, F3, and F4 stages of fibrosis were 5.7, 6.8, 7.8, 11.8, and 25.1 kPa, respectively (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.0001, by analysis of variance).&lt;/p&gt;
&lt;p&gt;TE was accurate for predicting fibrosis in patients with liver stiffness of at least 7.9 kPa; measurement and accuracy were not affected by hepatic steatosis, necroinflammation, and obesity.&lt;/p&gt;
&lt;p&gt;The most disagreement between the results of the TE and biopsy methods occurred in patients with short liver biopsy lengths and mild or no fibrosis.&lt;/p&gt;
&lt;p&gt;In patients with complete biochemical data, the accuracy of TE was compared with that of other means of predicting liver stiffness, and was found to be more reliable than aspartate aminotransferase&amp;#8211;to&amp;#8211;alanine aminotransferase ratio, aspartate aminotransferase&amp;#8211;to&amp;#8211;platelet ratio index, FIB-4, BARD, and NAFLD fibrosis scores.&lt;/p&gt;
&lt;p&gt;The authors cautioned that the results of the liver biopsies potentially could have been influenced by sampling bias and that referral&lt;strong&gt; &lt;/strong&gt;patients enrolled in the study may have had more advanced liver disease than the general population. They also noted that a significant proportion of obese patients were not analyzed because a liver stiffness measurement could not be obtained.&lt;/p&gt;
&lt;p&gt;In an accompanying editorial, Leon Adams, PhD, of the University of Western Australia, noted that the majority of individuals with NAFLD will not develop liver-related morbidity or die from liver disease.&lt;/p&gt;
&lt;p&gt;&quot;Thus, he wrote, &quot;the difficulty facing the managing physician is predicting which patients are at greatest risk of developing cirrhosis, thus identifying those who will benefit most from specific treatments, more intensive therapy, and monitoring.&quot;&lt;/p&gt;
&lt;p&gt;The new study, he wrote, suggests that TE is effective at excluding advanced fibrosis and cirrhosis in patients with NAFLD. However, he argues that the technique requires further validation in obese and morbidly obese populations and that sensitivity of the test is likely to vary between differing patient populations, different medical personnel administering the test, and underlying prior probability of fibrosis.&lt;/p&gt;
&lt;p&gt;&quot;Lastly,&quot; he concluded, &quot;if noninvasive markers are going to form part of the routine assessment of the millions of individuals with NAFLD, the expense and availability of each modality may play a decisive role in which the noninvasive method is most appropriately taken up by community physicians and specialty hepatologists.&quot;&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The study was supported by the Chinese University of Hong Kong.&lt;/p&gt;&lt;p&gt;Co-investigator Henry Lik-Yuen Chan reported receiving advising and speaking fees from Novartis, Bristol-Myers Squibb, Pharmasset, and Schering-Plough.&lt;/p&gt;&lt;p&gt;Co-investigator Sung reported receiving advising and speaking fees from AstraZeneca, GlaxoSmithKline, and Roche.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_276"
                     title="ASCO GI: Antibody Slows Metastatic Colon Cancer"
                     score="0.001"
                     href="http://www.medpagetoday.com/MeetingCoverage/ASCOGI/tb/18134?impressionId=1265785612708"
                     
      ORLANDO  --  Patients with nonmutated colorectal tumors had significant improvement in progression-free survival (PFS) when the monoclonal antibody panitumumab (Vectibix) was added to conventional chemotherapy, data from two randomized clinical trials showed.&lt;br&gt;
&lt;br&gt;When used in first-line therapy for metastatic cancer, the antibody-chemotherapy combination was associated with a 20% improvement in the hazard ratio for progression compared with chemotherapy alone. In the second-line metastatic setting, the combination improved the hazard ratio by 27%.&lt;br&gt;
&lt;br&gt;Separate analyses of the trials showed that the addition of panitumumab to chemotherapy did not improve PFS in patients whose tumors had K-ras mutations.&lt;br&gt;
&lt;br&gt;Overall survival was similar between treatment arms in both trials, according to presentations here at the Gastrointestinal Cancers Symposium.&lt;p&gt;&lt;/p&gt;
&lt;p&gt;&quot;The results of these two studies are consistent in that they demonstrate a benefit from the addition of panitumumab among patients with wild-type K-ras tumors,&quot; Salvatore Siena, MD, of Ospedale Niguarda Ca&apos;Granda in Milan, Italy, said in an interview. &quot;The results also are consistent with what we know about the role of K-ras in colorectal cancer.&quot;&lt;/p&gt;
&lt;p&gt;&quot;The addition of panitumumab to the chemotherapy regimens used in the studies was well tolerated, as no unexpected toxicity was observed,&quot; he added.&lt;/p&gt;
&lt;p&gt;Panitumumab is a fully human monoclonal antibody against epidermal growth factor receptor (EGFR). The agent is approved for treatment of chemotherapy-refractory metastatic colorectal cancer.&lt;/p&gt;
&lt;p&gt;The two clinical trials initially were designed to evaluate panitumumab in all patients, irrespective of K-ras status. Following reports about the adverse effect of K-ras mutations on therapeutic outcomes in colorectal cancer, the trials&apos; protocols were amended to test the hypothesis that adding panitumumab to chemotherapy would improve PFS in patients with wild-type K-ras status.&lt;/p&gt;
&lt;p&gt;The trial of first-line metastatic therapy compared panitumumab plus 5-FU/leucovorin/oxaliplatin (Eloxatin) chemotherapy versus chemotherapy (FOLFOX) alone. The open-label, randomized trial involved 1,183 patients enrolled at centers in Canada, South America, Europe, South Africa, and Australia.&lt;/p&gt;
&lt;p&gt;The primary endpoint was PFS, and secondary endpoints included overall survival, overall response rate, time to response, duration of response, and safety. The protocol excluded patients with prior chemotherapy for metastatic colorectal cancer or prior EGFR inhibitor therapy.&lt;/p&gt;
&lt;p&gt;Tissue samples were collected for biomarker assessment, but EGFR and K-ras status assessment were not required at entry. Siena said K-ras status was ascertained in 93% of the patients and showed that 60% of both treatment arms had wild-type K-ras tumors.&lt;/p&gt;
&lt;p&gt;In the primary analysis involving patients with wild-type K-ras tumors, the addition of panitumumab to FOLFOX was associated with a PFS of 9.6 months compared with 8.0 months for patients treated with chemotherapy alone (HR 0.80, 95% CI 0.66 to 0.97, &lt;em&gt;P&lt;/em&gt;=0.02). Addition of the antibody was associated with a trend toward improved overall survival (23.9 months versus 19.7 months, &lt;em&gt;P&lt;/em&gt;=0.07) and overall response rate (55% versus 48%, &lt;em&gt;P&lt;/em&gt;=0.07).&lt;/p&gt;
&lt;p&gt;Patients with mutant-type K-ras tumors fared better with chemotherapy alone, which led to a median PFS of 8.8 months versus 7.3 months for chemotherapy plus panitumumab (&lt;em&gt;P&lt;/em&gt;=0.02).&lt;/p&gt;
&lt;p&gt;Similar results emerged from the study of second-line therapy for metastatic cancer, reported by Marc Peeters, MD, of University Hospital Ghent in Belgium.&lt;/p&gt;
&lt;p&gt;The trial involved 1,186 patients who had previously received chemotherapy for metastatic colorectal cancer enrolled at centers in the U.S., Europe, Asia, and Australia. As in the study of first-line therapy, about 60% of the patients had wild-type K-ras tumors.&lt;/p&gt;
&lt;p&gt;The trial compared FOLFIRI chemotherapy (5-FU/leucovorin/irinotecan [Camptosar]) alone versus FOLFIRI plus panitumumab.&lt;/p&gt;
&lt;p&gt;Among patients with wild-type K-ras tumors, the addition of panitumumab was associated with a median PFS of 5.9 months versus 3.9 months for chemotherapy alone (HR 0.73, 95% CI 0.59 to 0.90, &lt;em&gt;P&lt;/em&gt;=0.004).&lt;/p&gt;
&lt;p&gt;Median overall survival was 14.5 months with the monoclonal antibody and 12.5 months without, a difference that did not reach statistical significance. The overall response rate was significantly higher in the panitumumab arm (35% versus 10%, &lt;em&gt;P&lt;/em&gt;=0.001).&lt;/p&gt;
&lt;p&gt;As in the first-line study, patients with mutant K-ras tumors did not benefit from the addition of panitumumab, which was associated with a median PFS of 5.0 months versus 4.9 months with chemotherapy alone. Overall survival was 11.8 months with panitumumab and 11.1 months without it, a nonsignificant difference.&lt;/p&gt;
&lt;p&gt;The panitumumab regimen was generally well tolerated in both studies. The principal difference in adverse events was an excess of skin toxicity with panitumumab, a recognized side effect of the monoclonal antibody.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;Both studies were supported by Amgen.&lt;/p&gt;&lt;p&gt;One or more investigators in the studies disclosed relatinships with Amgen, Merck Serono, Roche, Baxter International, Merck &amp;amp; Co., Roche, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, ImClone Slystems, sanofi-aventis, and Pfizer.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_271"
                     title="ASCO GI: Diet May Play Role in Colon Cancer Prevention"
                     score="0.001"
                     href="http://www.medpagetoday.com/MeetingCoverage/ASCOGI/tb/18128?impressionId=1265785612708"
                     
      &lt;p&gt;ORLANDO  --  Dietary polyamines may represent a modifiable risk factor for colon cancer, according to a new analysis of data from a prevention trial presented here.&lt;/p&gt;
&lt;p&gt;High intake of polyamine-rich foods increased the risk of large, high-grade, and advanced colonic adenomas by 40% to 65% compared with low intake. High dietary polyamine levels correlated with high polyamine levels in rectal tissue.&lt;/p&gt;
&lt;p&gt;&quot;Our results are consistent with several animal-model studies,&quot; Kavitha P. Raj, MD, of the University of California Irvine, said during a poster presentation at the Gastrointestinal Cancers Symposium.&lt;/p&gt;
&lt;p&gt;&quot;Dietary polyamines may be an important factor in adenoma prevention. Controlling exogenous polyamines may be an adjunctive strategy to chemoprevention with polyamine-inhibitory agents.&quot;&lt;/p&gt;
&lt;p&gt;Increased polyamine synthesis has been linked to colon carcinogenesis in preclinical models and in humans. Ornithine decarboxylase, a key regulatory enzyme involved in polyamine synthesis, is upregulated by several pathways implicated in colon cancer carcinogenesis, including K-ras.&lt;/p&gt;
&lt;p&gt;In a recent prevention study involving patients with sporadic colorectal adenomas, Raj and colleagues found that inhibition of polyamines by DFMO and sulindac reduced adenoma recurrence by 70% compared with placebo. Investigators reviewed data from the study to evaluate dietary polyamines&apos; effect on prevention with DFMO-sulindac therapy and to examine associations between dietary and tissue polyamine concentrations.&lt;/p&gt;
&lt;p&gt;Polyamines occur in a variety of foods, including aged or sharp cheeses, canned or frozen non-green vegetables, citrus fruits such as oranges and tangerines, fermented soy sources containing wheat, packaged or frozen shrimp, and some meats and poultry.&lt;/p&gt;
&lt;p&gt;Study participants completed a dietary questionnaire at enrollment, and investigators used that data to calculate total dietary polyamine content, derived from putrescine, spermine, and spermidine values. Dietary polyamine data were available for 222 of 335 patients enrolled in the interventional trial and for 188 of 267 patients who completed the study.&lt;/p&gt;
&lt;p&gt;Investigators separated study participants into quartiles of dietary polyamine content. Advanced adenomas were defined by size &amp;gt;1 cm, villous histology, high-grade dysplasia, or presence of multiple adenomas.&lt;/p&gt;
&lt;p&gt;Comparing baseline polyamine and polyp characteristics, Raj found that 43% of participants in the highest dietary polyamine quartile had adenomas &amp;gt;1 cm compared with 26.4% of participants in the three lower quartiles (&lt;em&gt;P&lt;/em&gt;=0.01).&lt;/p&gt;
&lt;p&gt;Moreover, 52.7% of the high polyamine group had advanced adenomas, compared with 35.9% of the remaining study participants (&lt;em&gt;P&lt;/em&gt;=0.03). High dietary polyamine content also tended to be associated with more high-grade adenomas (32.7% versus 20.4%), but the difference did not achieve statistical significance (&lt;em&gt;P&lt;/em&gt;=0.06).&lt;/p&gt;
&lt;p&gt;Investigators determined tissue polyamine levels from rectal biopsies of study participants. The high dietary polyamine group had significantly higher tissue spermine  concentrations (&lt;em&gt;P&lt;/em&gt;=0.04) and spermidine (&lt;em&gt;P&lt;/em&gt;=0.02).&lt;/p&gt;
&lt;p&gt;In their analysis of the entire study population, Raj and colleagues found significant interaction among treatment, dietary polyamine, and metachronous adenomas (&lt;em&gt;P&lt;/em&gt;=0.01).&lt;/p&gt;
&lt;p&gt;In the low dietary polyamine group, DFMO-sulindac therapy reduced the risk of recurrence by 80% (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.0001) compared with the placebo group. In contrast, participants in the highest dietary polyamine quartile derived no benefit from treatment, as the risk of recurrence was virtually identical to that of the control group (RR 1.04, 95% CI 0.32 to 3.36).&lt;/p&gt;
&lt;p&gt;In the low dietary polyamine group, separate analyses showed that treatment with DFMO-sulindac reduced the risk of large, high-grade, and advanced adenomas by 90% or more (&lt;em&gt;P&lt;/em&gt;=0.03 to &lt;em&gt;P&lt;/em&gt;=0.005). Too few participants were in the high dietary polyamine group to determine risk estimates.&lt;/p&gt;
&lt;p&gt;&quot;We observed strong interaction between treatment and dietary polyamine intake, which was a key factor in modulating the risk reduction of metachronous adenoma formation by DFMO and sulindac,&quot; said Raj. &quot;There was a 70% risk reduction with DFMO-sulindac in the parent study but an 81% reduction with DFMO-sulindac in the lower dietary polyamine group in this study.&quot;&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;One or more investigators disclosed relationships with Cancer Prevention Pharmaceuticals.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_260"
                     title="ASCO GI: Agent Targets IGF Receptor in Pancreatic Cancer (CME/CE)"
                     score="-0"
                     href="http://www.medpagetoday.com/MeetingCoverage/ASCOGI/tb/18124?impressionId=1265785612708"
                     
      &lt;p&gt;ORLANDO  --  A majority of patients with advanced pancreatic cancer had objective responses or stable disease when treated with an inhibitor of the insulin-like growth factor (IGF) receptor, according to data from a small clinical trial reported here.&lt;/p&gt;
&lt;p&gt;A fourth of patients had partial responses that lasted beyond 11 months in some cases. Another third had disease stabilization during treatment with the monoclonal antibody MK-0646, plus chemotherapy and erlotinib (Tarceva).&lt;/p&gt;
&lt;p&gt;&quot;We observed sustained partial responses with two different regimens,&quot; Milind Javle, MD, of M.D. Anderson Cancer Center in Houston, told attendees at the Gastrointestinal Cancers Symposium.&lt;/p&gt;
&lt;p&gt;&quot;Evaluation of MK-0646 is continuing in a randomized phase II study that will include correlative studies to identify predictive markers.&quot;&lt;/p&gt;
&lt;p&gt;Activation of the IGF-1 receptor is associated with an aggressive disease course in pancreatic cancer and acquired resistance to agents that target epidermal growth factor receptor (EGFR) such as erlotinib.&lt;/p&gt;
&lt;p&gt;&lt;/p&gt;
&lt;p&gt; &lt;/p&gt;
&lt;p&gt;Preclinical studies showed that combining an IGF-1 receptor antagonist and cetuximab (Erbitux) had synergistic activity against pancreatic cell lines, Javle said.&lt;/p&gt;
&lt;p&gt;MK-0646 preferentially binds IGF-1 receptor and not the insulin receptor. The antibody inhibits stimulation of IGF-1 receptor by both IGF-1 and IGF-2, Javle continued. MK-0646 downregulates expression of IGF-1 receptor in tumor models and has demonstrated antitumor activity in xenograft models.&lt;/p&gt;
&lt;p&gt;Phase I evaluation of MK-0646 as a single agent showed the antibody was well tolerated and led to downregulation of IGF-1 receptor and other molecules associated with tumor growth. Patients occasionally developed hyperglycemia, which was controlled with oral hypoglycemic agents.&lt;/p&gt;
&lt;p&gt;Javle reported data from a phase I-II study of MK-0646 in combination with gemcitabine (Gemzar) or gemcitabine plus erlotinib. The primary objective of the first phase was to determine the maximum tolerated dose of MK-0646 in combination therapy. Investigators assessed progression-free survival (PFS) of the two combination arms in the second phase.&lt;/p&gt;
&lt;p&gt;The study included patients with stage IV pancreatic adenocarcinoma at least six months after completion of adjuvant chemotherapy.&lt;/p&gt;
&lt;p&gt;Patients were enrolled in a nonrandomized, sequential manner to two treatment arms. One arm had a regimen consisting of weekly gemcitabine plus weekly MK-0646 at either 5 mg/kg or 10 mg/kg. In the second arm, patients received gemcitabine plus daily erlotinib and one of the two doses of MK-0646.&lt;/p&gt;
&lt;p&gt;Dose-limiting hematologic toxicity was defined as grade 4 thrombocytopenia, grade 4 neutropenia lasting at least seven days, or grade 3 or higher neutropenia with fever.&lt;/p&gt;
&lt;p&gt;Dose-limiting nonhematologic toxicity was defined as any grade 3-4 adverse event except rash and controlled hyperglycemia. Delayed dosing was defined as a delay of more than 14 days necessitated by toxicity.&lt;/p&gt;
&lt;p&gt;Of 28 patients enrolled in the study, 23 (82%) required dose adjustment of gemcitabine, and seven had toxicity-associated dose adjustments of erlotinib. Five patients discontinued erlotinib because of toxicity, but no patient withdrew from the study because of toxicity.&lt;/p&gt;
&lt;p&gt;The most frequent grade 3-4 nonhematologic toxicities were hyperglycemia and fatigue (five patients each) and elevated liver enzymes and hypermagnesemia (four each). Half the patients developed grade 3-4 neutropenia and five had grade 3-4 thrombocytopenia. No cases of febrile neutropenia occurred.&lt;/p&gt;
&lt;p&gt;Maximum tolerated dose (MTD) in the first arm was not reached at the 10 mg/kg dose of MK-0646. In the erlotinib arm, MTD was reached at the 5 mg/kg dose of MK-0646.&lt;/p&gt;
&lt;p&gt;Of 24 patients evaluable for response, six (25%) had partial responses and eight (33%) had stable disease. The remaining 10 patients had progressive disease. Response duration ranged from 14 to beyond 44 weeks. Time to progression did not differ between the treatment arms.&lt;/p&gt;
&lt;p&gt;A randomized phase II study of MK-0646 has already begun, said Javle. Patients receive one of three treatment regimens: gemcitabine plus the monoclonal antibody, with or without erlotinib, or control therapy with gemcitabine and erlotinib.&lt;/p&gt;
&lt;p&gt;The activity demonstrated in the study does not constitute an antitumor signal for MK-0646, Philip A. Philip, MD, of the Karmanos Cancer Center in Detroit, said during a formal discussion of the study.&lt;/p&gt;
&lt;p&gt;&quot;Further preclinical and clinical validation of and IGF-1 receptor-based multitargeted strategy in pancreatic cancer must be undertaken,&quot; he said. &quot;Additionally, predictive biomarkers must be developed for patient selection and stratification. We need more data before we begin to design a phase III study.&quot;&lt;/p&gt;
&lt;p&gt;Hyperglycemia with MK-0646 should not come as a surprise, Philip said. The IGF-1 receptor occurring on normal cells has 84% homology with insulin receptor.&lt;/p&gt;
&lt;p&gt;&quot;There will be overlap between IGF-1 receptor and insulin receptor when targeting IGF-1 receptor,&quot; said Philip. &quot;Moreover, up to 40% of patients with pancreatic cancer have diabetes mellitus.&quot;&lt;/p&gt;
&lt;p&gt;In an ongoing intergroup trial involving a different IGF-1 receptor inhibitor, almost half the patients developed grade 1 or 2 hyperglycemia, and 14% developed grade 3 or 4, he added. However, hyperglycemia does not appear to be a dose-limiting toxicity.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The study was supported by Merck.&lt;/p&gt;&lt;p&gt;One or more investigators in the study disclosed relationships with Merck.&lt;/p&gt;&lt;p&gt;Philip disclosed relationships with Bristol-Myers Squibb, ImClone, OSIP, sanofi-aventis, Genentech, Pfizer, Lilly, and Roche.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
</recommendedContent>