<?xml version="1.0" encoding="utf-8"?>
<recommendedContent xmlns="http://api.mspoke.com">
    <recommendedItem id="20100101_19_452"
                     title="Study Backs Late Cardiotoxicity of Childhood Cancer Treatment (CME/CE)"
                     score="0.011"
                     href="http://www.medpagetoday.com/HematologyOncology/OtherCancers/tb/18384?impressionId=1265790753105"
                     
      A childhood cancer survivor&apos;s risk of dying from cardiovascular causes rises with the dose of radiation his heart received during treatment, researchers in France and the U.K. affirmed.&lt;br&gt;
&lt;br&gt;Those whose hearts were exposed had a 60% higher risk of cardiovascular death than the general population, even at a dose of 1 Gy (95% CI 20% to 250%), according to Florent de Vathaire, PhD, of L&apos;Institut National de la Sant&amp;#233; et de la Recherche M&amp;#233;dicale in Paris, and colleagues.&lt;br&gt;
&lt;br&gt;The risk jumped to 12.5-fold for a cumulative radiation dose to the heart of 5 to 14.9 Gy, and to 14.9-fold for a dose of more than 15 Gy (&lt;em&gt;P&lt;/em&gt;&amp;lt;0.01 for trend), the researchers reported online in the &lt;em&gt;Journal of Clinical Oncology&lt;/em&gt;.&lt;br&gt;
&lt;br&gt;The notion that exposing the heart to radiation increases the risk of cardiovascular disease and death is not surprising, according to an accompanying editorial.&lt;p&gt;&lt;/p&gt;
&lt;p&gt;However, this study examined cardiovascular mortality effects of both the dose of radiation and the dose of anthracyclines given to childhood cancer victims in the same cohort.&lt;/p&gt;
&lt;p&gt;That&apos;s something previous studies haven&apos;t done, according to editorialists Steven E. Lipshultz, MD, of the University of Miami and Holtz Children&apos;s Hospital in Miami, and M. Jacob Adams, MD, MPH, of the University of Rochester, N.Y.&lt;/p&gt;
&lt;p&gt;&quot;These are pretty profound findings,&quot; Lipshultz told &lt;em&gt;MedPage Today&lt;/em&gt;. &quot;These are the exact concerns we&apos;ve had based on careful subclinical assessments of how the heart in these survivors has been working.&quot;&lt;/p&gt;
&lt;p&gt;His group was one of the first to report that survivors of childhood cancer faced not only acute cardiotoxicity from treatment, but also late cardiac effects.&lt;/p&gt;
&lt;p&gt;As more effective treatment for childhood cancers came into play, the dramatic jump in survival rates  --  from less than 50% in the mid-1970s to 80% today  --  yielded a large enough population of survivors to make chronic issues from treatment apparent, Lipshultz noted.&lt;/p&gt;
&lt;p&gt;&quot;It appears that for some of these survivors we have substituted one fatal disease of childhood  --  cancer  --  for another fatal disease of early adult life,&quot; he said.&lt;/p&gt;
&lt;p&gt;de Vathaire&apos;s group studied a cohort of 4,122 French and British children diagnosed with childhood solid cancer between 1942 and 1986 and who survived at least five years.&lt;/p&gt;
&lt;p&gt;Over an average of 27 years of follow-up, they were at 8.3-fold higher risk of dying from any cause compared with the general populations in France and the U.K. (95% CI 7.6 to 9.0).&lt;/p&gt;
&lt;p&gt;The majority of these excess deaths occurred early after diagnosis, five to nine years afterward in this analysis  --  in which all patients survived to five years.&lt;/p&gt;
&lt;p&gt;Based on just 32 deaths from cardiovascular diseases in the cohort, the childhood cancer survivors experienced five times the cardiovascular mortality (95% CI 3.3 to 6.7) expected from the general population (1.7% cumulative at 35 years versus 0.3%).&lt;/p&gt;
&lt;p&gt;This elevation in risk was similar to that seen in large studies from the U.S. and Nordic countries, suggesting generalizability of the results, Lipshultz said.&lt;/p&gt;
&lt;p&gt;Radiation therapy also conferred a 5.0-fold elevation in risk of cardiovascular disease-related death (95% CI 1.2 to 21.4).&lt;/p&gt;
&lt;p&gt;Like radiation, a higher cumulative dose of anthracycline chemotherapy also increased risk of dying from cardiac diseases, compared with the general population (RR 4.4 for a dose over 360 mg/m&lt;sup&gt;2&lt;/sup&gt;, 95% CI 1.3 to 15.3).&lt;/p&gt;
&lt;p&gt;However, radiotherapy and chemotherapy did not appear to interact for cardiovascular mortality (&lt;em&gt;P&lt;/em&gt;=0.4).&lt;/p&gt;
&lt;p&gt;Notably, the vinca alkaloids were also significantly linked to cardiovascular disease-related death risk among childhood cancer survivors, even after adjustment for sex, treatment period, age at diagnosis, follow-up, and all other treatment modalities (RR 3.6, 95% CI 1.0 to 12.9).&lt;/p&gt;
&lt;p&gt;Currently, guidelines support regular long-term cardiovascular screening for childhood cancer survivors who received anthracycline-based chemotherapy but provide little to no direction for those treated with nonanthracycline chemotherapy or radiation, Lipshultz noted.&lt;/p&gt;
&lt;p&gt;These results suggested all three groups should be getting cardiac follow-up, he told &lt;em&gt;MedPage Today&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;However, because other research has suggested that these individual treatments affect the heart in different ways, such as diastolic rather than systolic dysfunction with radiotherapy, screening modalities may need to account for this as well, he said.&lt;/p&gt;
&lt;p&gt;The researchers cautioned that cardiovascular disease was probably under-reported as a cause of death in the cohort.&lt;/p&gt;
&lt;p&gt;&quot;Indeed, 15 of the deaths classified as results of cancer as the principal cause had cardiovascular diseases as the immediate cause,&quot; they wrote.&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 Ligue Nationale Contre le Cancer; the Programme Hospitalier de Recherche Clinique; the Agence Fran&amp;#231;aise de S&amp;#233;curit&amp;#233; Sanitaire et Produit de Sant&amp;#233;; Electricit&amp;#233; de France; the Wyeth Foundation for childhood and adolescent health; and a grant from the Foundation of France.&lt;/p&gt;&lt;p&gt;The researchers reported no conflicts of interest.&lt;/p&gt;&lt;p&gt;The editorialists reported no conflicts of interest.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_330"
                     title="Immune Cells Point to Skin Cancer Risk after Transplants (CME/CE)"
                     score="0.004"
                     href="http://www.medpagetoday.com/Nephrology/KidneyTransplantation/tb/18200?impressionId=1265790753105"
                     
      Monitoring two types of immune cells in kidney transplant recipients might identify patients with an increased risk of skin cancer, British investigators reported.&lt;br&gt;
&lt;br&gt;Increased levels of T-regulatory cells (Tregs) more than doubled the risk of squamous cell cancer of the skin. Decreased levels of natural killer (NK) cells were associated with more than a five-fold increased risk of skin cancer.&lt;br&gt;
&lt;br&gt;Both immune parameters had substantially greater predictive power than a history of squamous-cell skin cancer, according to an online report in the &lt;em&gt;Journal of the American Society of Nephrology&lt;/em&gt; by a team of Oxford University investigators.&lt;/p&gt;
&lt;p&gt;&quot;Squamous cell cancer of the skin affects about 30% of kidney transplant patients after 10 years of immunosuppression,&quot; Robert Carroll, MD, currently of Queen Elizabeth Hospital in Woodville, Australia, observed in a statement.&lt;/p&gt;
&lt;p&gt;&quot;A small number of patients develop multiple skin cancers per year, but there is no laboratory test to determine which transplant recipients will develop multiple skin cancers in the future.&quot;&lt;/p&gt;
&lt;p&gt;&quot;If a test can confirm high risk of skin cancer development, this may help clinicians to tailor immunosuppressive regimens for individual patients,&quot; he added.&lt;/p&gt;
&lt;p&gt;Long-term immunosuppression, such as that required for transplant recipients, confers an increased risk of squamous-cell skin cancer.&lt;/p&gt;
&lt;p&gt;Estimates of the magnitude have ranged as high as 200 times greater than the general population, the authors wrote. Additionally, 3% of organ transplant recipients require extensive plastic surgery each year as a result of skin cancer lesions.&lt;/p&gt;
&lt;p&gt;Age at transplantation and the immunosuppression dosage are the principal determinants of skin-cancer risk, and the dosage of immunosuppression also influences the risk of metastasis from squamous-cell cancer of the skin.&lt;/p&gt;
&lt;p&gt;In the general population, cancer has been associated with increased levels of Tregs, including CDR&lt;sup&gt;+&lt;/sup&gt;CD25&lt;sup&gt;high&lt;/sup&gt;FOXP3&lt;sup&gt;+&lt;/sup&gt; and CD8&lt;sup&gt;+&lt;/sup&gt;CD28&lt;sup&gt;-&lt;/sup&gt; cells. The same types of cells could play a role in the risk of skin cancer among organ transplant recipients, the authors wrote.&lt;/p&gt;
&lt;p&gt;Within the tumor microenvironment, Tregs may impair the antitumor activity of CD8&lt;sup&gt;+&lt;/sup&gt; and NK cell. However, in organ transplant recipients, Tregs help control or prevent rejections and may help improve long-term outcomes.&lt;/p&gt;
&lt;p&gt;Different immunosuppressive drugs affect Tregs differently, the authors continued. Sirolimus (Rapamune), for example, increases the number of FOXP3&lt;sup&gt;+&lt;/sup&gt; cells, whereas cyclosporine decreases Treg numbers.&lt;/p&gt;
&lt;p&gt;&quot;Tregs have not been assessed in relation to cancer after transplantation,&quot; the authors wrote. &quot;We therefore investigated the hypothesis that squamous-cell cancer in kidney transplant recipients would be associated with an increased number of Tregs.&quot;&lt;/p&gt;
&lt;p&gt;To examine the hypothesis, investigators phenotyped peripheral blood from 65 kidney transplant recipients with squamous skin cancer and 51 recipients without skin cancer, matched for age, sex, and duration of immunosuppression.&lt;/p&gt;
&lt;p&gt;They also quantified lymphocyte populations in skin cancer lesions from a subset of 25 patients and matched them with 25 other nontransplant patients with squamous cell cancer of the skin.&lt;/p&gt;
&lt;p&gt;The kidney transplant recipients had a median follow-up of 340 days. The investigators found that a concentration of &amp;gt;35 peripheral FOXP3&lt;sup&gt;+&lt;/sup&gt;CD4&lt;sup&gt;+&lt;/sup&gt;CD127&lt;sup&gt;low&lt;/sup&gt; regulatory T cells/&amp;#181;L was associated with a hazard ratio for squamous cell skin cancer of 2.48 (95% CI 1.04 to 5.98).&lt;/p&gt;
&lt;p&gt;An NK cell count &amp;lt;100 cells/&amp;#181;L was associated with a skin cancer hazard ratio of 5.6 (95% CI 1.31 to 24). A history of squamous cell cancer of the skin increased the risk of skin cancer recurrence by a third (HR 1.33, 95% CI 1.15 to 1.53).&lt;/p&gt;
&lt;p&gt;&quot;If similar immune phenotypes are predictive in other kidney transplant recipient populations, then immune phenotype method has the potential to inform immunosuppressive regimen manipulation in kidney transplant recipients at high risk for developing multiple squamous cell cancers,&quot; the authors concluded.&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 authors had no relevant disclosures.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_307"
                     title="Good Results in Poor-Risk Rectal Cancer (CME/CE)"
                     score="0.002"
                     href="http://www.medpagetoday.com/HematologyOncology/ColonCancer/tb/18169?impressionId=1265790753105"
                     
      &lt;p&gt;Patients with high-risk rectal cancer had high response and three-year survival rates on a regimen of preoperative chemotherapy, followed by standard chemoradiation and then surgical resection, according to results of a multicenter study.&lt;/p&gt;
&lt;p&gt;Three-fourths of patients had objective responses to neoadjuvant chemotherapy, increasing to 89% after chemoradiation, researchers reported online in &lt;em&gt;The Lancet Oncology&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;Additionally, 97% of patients who underwent surgery had microscopically clear surgical margins. At three years, 83% of patients remained alive, including almost 70% who were progression free.&lt;/p&gt;
&lt;p&gt;&quot;Intensification of systemic therapy with neoadjuvant combination chemotherapy before standard treatment is feasible in poor-risk, potentially operable rectal cancer, with acceptable safety and promising long-term outcomes,&quot; David Cunningham, MD, of the Royal Marsden Hospital in Sutton, England, and co-authors concluded.&lt;/p&gt;
&lt;p&gt;&quot;Future development of this multidisciplinary treatment strategy in randomized trials is warranted.&quot;&lt;/p&gt;
&lt;p&gt;Although surgery remains the primary and potentially curative therapy for localized rectal cancer, local recurrence rates as high as 40% have been reported with conventional resection.&lt;/p&gt;
&lt;p&gt;The introduction of standardized surgery and total mesorectal excision reduced local recurrence rates to less than 10%, which has been associated with improved survival, the authors noted.&lt;/p&gt;
&lt;p&gt;Preoperative radiotherapy and then chemoradiation further reduced the risk of local recurrence, but did not improve overall survival compared with surgery alone.&lt;/p&gt;
&lt;p&gt;Combination chemotherapy has led to higher response rates and progression-free survival compared with monotherapy for patients with advanced rectal cancer, the authors continued. Adjuvant chemotherapy containing oxaliplatin (Eloxatin) also has improved outcomes in resected colon cancer.&lt;/p&gt;
&lt;p&gt;Given that oxaliplatin-fluoropyrimidine combinations have become a preferred standard, investigators designed a clinical trial of high-risk rectal cancer to investigate preoperative treatment with oxaliplatin and capecitabine (Xeloda).&lt;/p&gt;
&lt;p&gt;A previous report involving the first 77 patients enrolled in the trial showed substantial tumor regression, rapid improvement in symptoms, and a high rate of clear surgical margins (&lt;em&gt;J Clin Oncol&lt;/em&gt; 2006; 24: 668-74).&lt;/p&gt;
&lt;p&gt;Nine treatment-related cardiac events occurred in eight of the 77 patients, prompting a protocol amendment to exclude patients with a recent history of clinically significant cardiac problems.&lt;/p&gt;
&lt;p&gt;The updated results comprised 105 patients, and only one cardiac event occurred after the change in eligibility criteria, the authors wrote.&lt;/p&gt;
&lt;p&gt;All of the patients had MRI-defined, poor-risk but nonmetastatic rectal cancer. Patients received four cycles of neoadjuvant chemotherapy over 12 weeks, followed by chemoradiotherapy consisting of a total radiation dose of 54 Gy administered over six weeks, plus daily capecitabine.&lt;/p&gt;
&lt;p&gt;After total mesorectal excision, patients received 12 weeks of adjuvant capecitabine.&lt;/p&gt;
&lt;p&gt;The primary endpoint was pathologic complete response, and median follow-up was 55 months.&lt;/p&gt;
&lt;p&gt;Radiologically confirmed response rates were 74% after neoadjuvant chemotherapy and 89% after chemoradiation. Of 97 patients who had surgery, 93 had microscopically clear margins, and 21 of 105 patients had pathologic complete responses.&lt;/p&gt;
&lt;p&gt;Three-year progression-free and overall survival were 68% and 83%, respectively. Among patients who had surgery, three-year, relapse-free survival was 74%.&lt;/p&gt;
&lt;p&gt;&quot;Our findings show the feasibility of neoadjuvant chemotherapy with capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision, which accord with the initial results of this study,&quot; the authors declared.&lt;/p&gt;
&lt;p&gt;&quot;High radiological response rates to preoperative treatment were recorded, and the number of pathological complete responses surpassed the prespecified number needed to meet the primary objective of this trial.&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 England&apos;s National Health Service and sanofi-aventis.&lt;/p&gt;&lt;p&gt;Cunningham and co-author Niall Tebbutt disclosed relationships with Roche and sanofi-aventis.&lt;/p&gt;&lt;p&gt;Co-author Ian Chau disclosed relationships with Roche and sanofi-aventis.&lt;/p&gt;&lt;p&gt;Co-author Yu Jo Chua disclosed relationships with Roche and sanofi-aventis.&lt;/p&gt;&lt;p&gt;Co-author Gina Brown disclosed a relationship with sanofi-aventis.&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="-0.001"
                     href="http://www.medpagetoday.com/MeetingCoverage/ASCOGI/tb/18124?impressionId=1265790753105"
                     
      &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>
    <recommendedItem id="20100101_19_259"
                     title="ASCO GI: Gene Therapy Shows Promise in Esophageal Cancer (CME/CE)"
                     score="-0.001"
                     href="http://www.medpagetoday.com/MeetingCoverage/ASCOGI/tb/18122?impressionId=1265790753105"
                     
      &lt;p&gt;ORLANDO  --  Injecting the gene encoding for tumor necrosis factor-alpha (TNF-alpha) directly into tumors led to pathologic complete responses in a third of patients and a median survival of four years in a small study of patients with locally advanced esophageal cancer.&lt;/p&gt;
&lt;p&gt;The gene-therapy strategy led to nodal conversion and downstaging in a majority of patients, most of whom underwent surgical resection following chemoradiation and the intratumoral injections of TNF.&lt;/p&gt;
&lt;p&gt;Patients who received the three lowest doses of TNF in the dose-finding study had a five-year median survival of 56%.&lt;/p&gt;
&lt;p&gt;&quot;This represents an encouraging increase in survival relative to historical controls,&quot; Kenneth J. Chang, MD, of the University of California Irvine, reported here at the Gastrointestinal Cancers Symposium. &quot;These results warrant further evaluation.&quot;&lt;/p&gt;
&lt;p&gt;However, another investigator in the multicenter study cautioned that the trial was stopped because of treatment-related deaths that have not been fully explained, and that the regimen is complicated and time-consuming.&lt;/p&gt;
&lt;p&gt;The primary objective of the study was to assess the safety, feasibility, and tolerability of weekly intratumoral injections of TNFerade, a second-generation replication-deficient adenovector, carrying the transgene encoding human TNF-alpha, regulated by the radiation-inducible promotor Egr-1.&lt;/p&gt;
&lt;p&gt;Upon its release inside a tumor, the gene therapy stimulates TNF production to help destroy the tumor. The therapy was developed for use with radiation and conventional chemotherapy.&lt;/p&gt;
&lt;p&gt;The gene therapy has received FDA fast-track status for evaluation as treatment for pancreatic cancer.&lt;/p&gt;
&lt;p&gt;Chang reported results from a dose-finding study involving 24 patients with locally advanced esophageal cancer. All were surgical candidates before enrollment. Each patient received five weekly injections of TNF concurrent with 5-FU, cisplatin, and external-beam radiation therapy. The TNF doses evaluated ranged from 4 x 10&lt;sup&gt;8&lt;/sup&gt; to 4 x 10&lt;sup&gt;11&lt;/sup&gt; PU.&lt;/p&gt;
&lt;p&gt;Staging results showed that all but one of the patients had T3 disease, and 18 had nodal involvement (N1).&lt;/p&gt;
&lt;p&gt;The preoperative therapy was administered over 5.5 weeks. Following a recovery period of five to 11 weeks, patients were to undergo surgical resection, which ultimately was performed in 19 of the 24 study participants.&lt;/p&gt;
&lt;p&gt;Of the 19 patients who underwent resection, six (32%) had pathologic complete responses. Chang reported that nine of 16 evaluable patients converted from N1 to N0 status following preoperative therapy, and 11 of 20 were downstaged from T3 to T2-T0.&lt;/p&gt;
&lt;p&gt;Median overall survival for the patients was 47.7 months. The 56% five-year survival applied to patients in the first three dosing levels. Patients who received the highest dose have not been followed long enough to determine five-year survival.&lt;/p&gt;
&lt;p&gt;During the discussion that followed the presentation, Jaffer Ajani, MD, of M.D. Anderson Cancer Center in Houston, cited concerns about the treatment-related deaths and complexity of the regimen.&lt;/p&gt;
&lt;p&gt;&quot;This is a very big production; it&apos;s not simple to do,&quot; said Ajani. &quot;You have to have a gastroenterologist available to inject every week.&quot;&lt;/p&gt;
&lt;p&gt;&quot;Your numbers are very small, and the pathological CR rate is no different than any other reported in even larger trials,&quot; he added. &quot;And then the subgroups with survival, I&apos;m not sure how meaningful that is because your numbers are so small.&quot;&lt;/p&gt;
&lt;p&gt;Responding to the concern about treatment-related deaths, Chang said none of the deaths was related to the TNF injections.&lt;/p&gt;
&lt;p&gt;With regard to the survival data, he acknowledged the small size of the study and said, &quot;It is what it is.&quot;&lt;/p&gt;
&lt;p&gt;&quot;It appears, as an adjunct, to be safe, and given the preliminary data, I think it is encouraging enough to go on to a larger trial,&quot; said Chang. &quot;That is basically what we are saying. We have something interesting that warrants further 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;The study was supported by GenVec.&lt;/p&gt;&lt;p&gt;One or more investigators disclosed relationships with GenVec.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
</recommendedContent>