Patrice Wendling

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – After having reported striking phase II data that sent both clinicians and patients with triple-negative breast cancer clamoring for iniparib, researchers are puzzling over a puny survival advantage in the phase III trial, and are questioning how the novel drug actually works.

Iniparib (BSI-201) was thought to belong to the class of targeted therapeutics known as PARP (poly [ADP (adenosine diphosphate)–ribose] polymerase) inhibitors, which have shown promise as single agents in BRCA1- and BRCA2-associated breast and ovarian tumors.

Hopes for a targeted therapy in triple-negative breast cancer were raised when iniparib plus gemcitabine and carboplatin posted significant gains over chemotherapy alone in progression-free (hazard ratio, 0.59) and overall survival (HR, 0.57) without significant added toxicity in the metastatic setting in the 123-patient, phase II study (N. Engl. J. Med. 2011;364:205-14).

Adding iniparib to the same chemotherapy doublet in the much larger phase III trial provided an insignificant survival advantage, however, and failed to meet the coprimary end points of median progression-free survival (4.1 months vs. 5.1 months; HR, 0.79; P = .027) and overall survival (11.1 months vs. 11.8 months; HR, 0.88; P = 0.28).

Exploratory analyses suggested a potential efficacy benefit among second- and third-line patients, who accounted for 43% of the study population, lead author Dr. Joyce O’Shaughnessy said at the annual meeting of the American Society of Clinical Oncology.

Among these patients, iniparib plus chemotherapy increased progression-free survival from 2.9 months with chemotherapy alone to 4.2 months (HR, 0.67), and overall survival from 8.1 months to 10.8 months (HR, 0.65). There was no difference in first-line patients in either progression-free (4.6 months vs. 5.6 months; HR, 0.88) or overall survival (12.6 months vs. 12.4 months; HR, 1.1).

Multivariate analyses that adjusted for several prespecified baselines factors and replaced "time since diagnosis of metastatic disease" with "disease-free interval from primary breast cancer surgery to onset of metastatic disease" showed a significant improvement in overall survival (HR. 0.78; P = .05) in the overall population and in second-and third-line patients (HR, 0.71; P = .05), said Dr. O’Shaughnessy of the Baylor Charles A. Sammons Cancer Center at Dallas.

The difference between the two iniparib trials could not be explained by disease-free interval, although this was not assessed in the phase II trial, she said.

It’s possible that the phase III trial was enriched with patients who had BRCA1/2 genetic mutations, as the phase II results caused what was described by one attendee as "hysteria" among BRCA1/2 carriers to get on the trial. Testing for the genetic mutation was voluntary and was completed by only a minority of patients.

Part of the problem could lie in the heterogeneous nature of triple-negative breast cancer. TNBC is made up of a diverse group of molecular subtypes, which makes it hard to classify and thus target with biologic agents. Indeed, ongoing tumor subtyping identified several molecular subtypes in the phase III trial, including luminal A, luminal B, and basal-like subtypes, Dr. O’Shaughnessy said.

Invited discussant Dr. Lisa Carey of the cancer center at the University of North Carolina at Chapel Hill said that TNBC has been used as a surrogate for molecular subtypes of biological interest, and that the triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition.

"Whenever we use triple-negative eligibility to get at a subtype that’s defined biologically, we will always be misclassifying some of these tumors," she said.

TNBC is mostly made up of the basal-like subtype, which is also present in about 80% of BRCA1-associated breast cancer. The shared phenotypic pattern between sporadic basal-like breast cancer and BRCA1-associated cancer – sometimes referred to as "BRCAness" – has therapeutic implications because one of its hallmarks is sensitivity to DNA damage, Dr. Carey explained. PARP inhibitors work by inhibiting DNA-damage repair in BRCA-associated tumors.

Although iniparib has long been included in lists of PARP inhibitors, there is some question about its mechanism of action, she said. Iniparib has substantially lower (1,000-fold) PARP inhibitory activity than do other agents in this class; it does not have additive toxicity as observed in multiple PARP trials; and recent preclinical studies show that although it induces gamma-H2AX foci (a pharmacodynamic readout of DNA damage), it does not appear to do so via PARP 1 and 2 inhibition.

"The role (and frankly the mechanism) of iniparib is still a work in progress, but you can also say that clinical activity based on this study is certainly far less than was predicted," Dr. Carey said, adding that a better understanding of the mechanism is needed for rational determination of a target population.

The phase III, open-label trial randomly assigned 519 patients who had received at least two prior cytotoxic regimens for metastatic triple-negative breast cancer to 21-day cycles of gemcitabine (1,000 mg/m² IV) and carboplatin (area under the curve 2 IV), both on days 1 and 8, or the same chemotherapy doublet plus iniparib (5.6 mg/kg IV) on days 1, 4, 8 and 11.

The overall response rates by independent radiology review were 30% among the 258 chemotherapy patients and 34% among the 261 iniparib patients, Dr. O’Shaughnessy said. The clinical benefit rates were 36% and 41%.

The toxicity of iniparib plus gemcitabine and carboplatin was comparable with that of chemotherapy alone. One death from upper GI hemorrhage was attributed to iniparib therapy. Biomarker analyses are underway to evaluate patient populations that may benefit from iniparib, she said.

Sanofi-Aventis sponsored the trial in collaboration with BiPar Sciences. Dr. O’Shaughnessy disclosed honoraria from Sanofi-Aventis, which provided editorial support for the trial. A coauthor reported consulting/advising for Sanofi-Aventis. Dr. Carey disclosed consulting or advising for Sanofi-Aventis, Genentech, Novartis, GlaxoSmithKline, Pfizer, Schering-Plough and Wyeth.

CHICAGO – Data from the prospective, phase-III EURTAC trial cement the need for personalized treatment of lung cancer patients but also leave clinicians in uncharted waters in terms of treatment options.

First-line erlotinib (Tarceva) improved the primary end point of progression-free survival from 5.2 months with standard platinum-based chemotherapy to 9.4 months in white patients who had advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations in an interim analysis.

Study cochair Dr. Rafael Rosell, president of the Spanish Lung Cancer Group, reported a significant 63% reduction in the risk of progression (hazard ratio, 0.37; log-rank P less than .0001) in an updated analysis presented at the annual meeting of the American Society of Clinical Oncology.

Based on positive results in the earlier interim analysis, Genentech and partner OSI Pharmaceuticals announced in January that the trial had been halted and they were set to pursue a broader indication for erlotinib as first-line treatment in NSCLC with EGFR mutations.

Erlotinib, a tyrosine kinase inhibitor (TKI), is approved in the United States and Europe as a maintenance and second-line treatment for advanced or metastatic NSCLC with and without EGFR activating mutations. Genentech’s parent company, Roche, submitted a bid to the European Medicines Agency in June 2010 to expand the drug’s label.

Even though the proverbial cat had already been let out of the bag by the drug makers, EURTAC caused a stir at ASCO, where the full data were formally presented and the study was chosen as one of the Best of ASCO 2011.

Invited discussant Dr. Tony Mok of the Chinese University of Hong Kong called the data trustworthy and a true reflection of erlotinib’s efficacy in patients with EGFR mutations. He drew parallels between EURTAC and the OPTIMAL trial in which erlotinib proved potent among Asians with this genetically distinct form of lung cancer. EGFR mutations are present in about 10% of patients in the West and about 30% of Asians, and they are associated with an increased response to erlotinib and the TKI gefitinib (Iressa).

Dr. Mok said that there’s a good chance erlotinib will be approved as first-line therapy. The EURTAC data are on par with the IPASS trial that helped gain approval for gefitinib (Iressa) as first-line therapy for patients with EGFR mutations in more than 70 countries, except the United States, where gefitinib use is restricted and AstraZeneca has said it will not seek a new indication for the drug.

"Now we have two drugs," said Dr. Mok, principal investigator of IPASS. "What are we going to do when faced with an EGFR mutation? Is there a difference in terms of the effectiveness between the TKIs in patients with EGFR mutations? That is the million-dollar question or the billion-dollar question."

Dr. Mok pointed out that three other TKIs are in the pipeline for patients with EGFR mutations, including icotinib (Zhejang BetaPharma); afatinib (Boehringer Ingelheim), which binds EGFR and inhibits HER2; and the oral, once-daily PF-299804 (Pfizer). A poster presented at ASCO on the phase-III ICOGEN trial reported that icotinib provides similar overall efficacy and better tolerability than gefitinib in patients with NSCLC who progressed after one to two lines of chemotherapy; it also improved efficacy in a subset of EGFR-mutant patient.

The EURTAC trial randomly assigned 174 chemo-naive, stage IIIB/IV NSCLC patients with exon 19 deletions or L858R mutations to receive erlotinib 150 mg/day or platinum-based doublet chemotherapy every 3 weeks for four cycles. The doublet could include cisplatin 75 mg/m² on day 1 plus docetaxel 75 mg/m² on day 1; cisplatin 75 mg/m² on day 1 plus gemcitabine 1,250 mg/m² on days 1 and 8; carboplatin area under the curve (AUC) 6 on day 1 plus docetaxel 75 mg/m² on day 1 or carboplatin AUC 5 on day 1 plus gemcitabine 1,000 mg/m² on days 1 and 8.

The objective response rate was 58% for erlotinib vs. 15% for chemotherapy in the updated analysis, said Dr. Rosell, head of medical oncology at the Catalan Institute of Oncology in Barcelona. At the time of the interim analysis, two patients had a complete response to erlotinib and 40 had partial responses, with 8 additional partial responses reported in the updated analysis. No patient had a complete response with chemotherapy, eight patients had partial responses early on, and five more reported partial responses in the updated analysis.

The disease control rate in the interim analysis was 79% for erlotinib vs. 66% in the updated analysis.

Median overall survival was 18.8 months with chemotherapy and 22.9 months in the interim analysis (hazard ratio, 0.80; log rank P = 0.42). As of the Jan. 26, 2011 cutoff date for the updated analysis, 94 patients remain in overall survival follow-up, with a high level of known crossover, Dr. Rosell said. A subgroup analysis suggested that progression-free survival was better in patients with a performance status of 0, never-smokers, and those with an exon 19 deletion.

The majority of patients who relapsed on erlotinib were switched to chemotherapy. The tolerability of erlotinib was consistent with previous studies, he noted.

The Spanish Lung Cancer Group sponsored the trial. Dr. Rosell disclosed a consultant/advisory role with Roche. Two of his coauthors reported a similar role, with one also providing expert testimony for Roche. Dr. Mok disclosed relationships with several drug companies, including AstraZeneca, Roche, Boehringer Ingelheim, and Pfizer.

CHICAGO – Data from the prospective, phase-III EURTAC trial cement the need for personalized treatment of lung cancer patients but also leave clinicians in uncharted waters in terms of treatment options.

First-line erlotinib (Tarceva) improved the primary end point of progression-free survival from 5.2 months with standard platinum-based chemotherapy to 9.4 months in white patients who had advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations in an interim analysis.

Study cochair Dr. Rafael Rosell, president of the Spanish Lung Cancer Group, reported a significant 63% reduction in the risk of progression (hazard ratio, 0.37; log-rank P less than .0001) in an updated analysis presented at the annual meeting of the American Society of Clinical Oncology.

Based on positive results in the earlier interim analysis, Genentech and partner OSI Pharmaceuticals announced in January that the trial had been halted and they were set to pursue a broader indication for erlotinib as first-line treatment in NSCLC with EGFR mutations.

Erlotinib, a tyrosine kinase inhibitor (TKI), is approved in the United States and Europe as a maintenance and second-line treatment for advanced or metastatic NSCLC with and without EGFR activating mutations. Genentech’s parent company, Roche, submitted a bid to the European Medicines Agency in June 2010 to expand the drug’s label.

Even though the proverbial cat had already been let out of the bag by the drug makers, EURTAC caused a stir at ASCO, where the full data were formally presented and the study was chosen as one of the Best of ASCO 2011.

Invited discussant Dr. Tony Mok of the Chinese University of Hong Kong called the data trustworthy and a true reflection of erlotinib’s efficacy in patients with EGFR mutations. He drew parallels between EURTAC and the OPTIMAL trial in which erlotinib proved potent among Asians with this genetically distinct form of lung cancer. EGFR mutations are present in about 10% of patients in the West and about 30% of Asians, and they are associated with an increased response to erlotinib and the TKI gefitinib (Iressa).

Dr. Mok said that there’s a good chance erlotinib will be approved as first-line therapy. The EURTAC data are on par with the IPASS trial that helped gain approval for gefitinib (Iressa) as first-line therapy for patients with EGFR mutations in more than 70 countries, except the United States, where gefitinib use is restricted and AstraZeneca has said it will not seek a new indication for the drug.

"Now we have two drugs," said Dr. Mok, principal investigator of IPASS. "What are we going to do when faced with an EGFR mutation? Is there a difference in terms of the effectiveness between the TKIs in patients with EGFR mutations? That is the million-dollar question or the billion-dollar question."

Dr. Mok pointed out that three other TKIs are in the pipeline for patients with EGFR mutations, including icotinib (Zhejang BetaPharma); afatinib (Boehringer Ingelheim), which binds EGFR and inhibits HER2; and the oral, once-daily PF-299804 (Pfizer). A poster presented at ASCO on the phase-III ICOGEN trial reported that icotinib provides similar overall efficacy and better tolerability than gefitinib in patients with NSCLC who progressed after one to two lines of chemotherapy; it also improved efficacy in a subset of EGFR-mutant patient.

The EURTAC trial randomly assigned 174 chemo-naive, stage IIIB/IV NSCLC patients with exon 19 deletions or L858R mutations to receive erlotinib 150 mg/day or platinum-based doublet chemotherapy every 3 weeks for four cycles. The doublet could include cisplatin 75 mg/m² on day 1 plus docetaxel 75 mg/m² on day 1; cisplatin 75 mg/m² on day 1 plus gemcitabine 1,250 mg/m² on days 1 and 8; carboplatin area under the curve (AUC) 6 on day 1 plus docetaxel 75 mg/m² on day 1 or carboplatin AUC 5 on day 1 plus gemcitabine 1,000 mg/m² on days 1 and 8.

The objective response rate was 58% for erlotinib vs. 15% for chemotherapy in the updated analysis, said Dr. Rosell, head of medical oncology at the Catalan Institute of Oncology in Barcelona. At the time of the interim analysis, two patients had a complete response to erlotinib and 40 had partial responses, with 8 additional partial responses reported in the updated analysis. No patient had a complete response with chemotherapy, eight patients had partial responses early on, and five more reported partial responses in the updated analysis.

The disease control rate in the interim analysis was 79% for erlotinib vs. 66% in the updated analysis.

Median overall survival was 18.8 months with chemotherapy and 22.9 months in the interim analysis (hazard ratio, 0.80; log rank P = 0.42). As of the Jan. 26, 2011 cutoff date for the updated analysis, 94 patients remain in overall survival follow-up, with a high level of known crossover, Dr. Rosell said. A subgroup analysis suggested that progression-free survival was better in patients with a performance status of 0, never-smokers, and those with an exon 19 deletion.

The majority of patients who relapsed on erlotinib were switched to chemotherapy. The tolerability of erlotinib was consistent with previous studies, he noted.

The Spanish Lung Cancer Group sponsored the trial. Dr. Rosell disclosed a consultant/advisory role with Roche. Two of his coauthors reported a similar role, with one also providing expert testimony for Roche. Dr. Mok disclosed relationships with several drug companies, including AstraZeneca, Roche, Boehringer Ingelheim, and Pfizer.

CHICAGO – Data from the prospective, phase-III EURTAC trial cement the need for personalized treatment of lung cancer patients but also leave clinicians in uncharted waters in terms of treatment options.

First-line erlotinib (Tarceva) improved the primary end point of progression-free survival from 5.2 months with standard platinum-based chemotherapy to 9.4 months in white patients who had advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations in an interim analysis.

Study cochair Dr. Rafael Rosell, president of the Spanish Lung Cancer Group, reported a significant 63% reduction in the risk of progression (hazard ratio, 0.37; log-rank P less than .0001) in an updated analysis presented at the annual meeting of the American Society of Clinical Oncology.

Based on positive results in the earlier interim analysis, Genentech and partner OSI Pharmaceuticals announced in January that the trial had been halted and they were set to pursue a broader indication for erlotinib as first-line treatment in NSCLC with EGFR mutations.

Erlotinib, a tyrosine kinase inhibitor (TKI), is approved in the United States and Europe as a maintenance and second-line treatment for advanced or metastatic NSCLC with and without EGFR activating mutations. Genentech’s parent company, Roche, submitted a bid to the European Medicines Agency in June 2010 to expand the drug’s label.

Even though the proverbial cat had already been let out of the bag by the drug makers, EURTAC caused a stir at ASCO, where the full data were formally presented and the study was chosen as one of the Best of ASCO 2011.

Invited discussant Dr. Tony Mok of the Chinese University of Hong Kong called the data trustworthy and a true reflection of erlotinib’s efficacy in patients with EGFR mutations. He drew parallels between EURTAC and the OPTIMAL trial in which erlotinib proved potent among Asians with this genetically distinct form of lung cancer. EGFR mutations are present in about 10% of patients in the West and about 30% of Asians, and they are associated with an increased response to erlotinib and the TKI gefitinib (Iressa).

Dr. Mok said that there’s a good chance erlotinib will be approved as first-line therapy. The EURTAC data are on par with the IPASS trial that helped gain approval for gefitinib (Iressa) as first-line therapy for patients with EGFR mutations in more than 70 countries, except the United States, where gefitinib use is restricted and AstraZeneca has said it will not seek a new indication for the drug.

"Now we have two drugs," said Dr. Mok, principal investigator of IPASS. "What are we going to do when faced with an EGFR mutation? Is there a difference in terms of the effectiveness between the TKIs in patients with EGFR mutations? That is the million-dollar question or the billion-dollar question."

Dr. Mok pointed out that three other TKIs are in the pipeline for patients with EGFR mutations, including icotinib (Zhejang BetaPharma); afatinib (Boehringer Ingelheim), which binds EGFR and inhibits HER2; and the oral, once-daily PF-299804 (Pfizer). A poster presented at ASCO on the phase-III ICOGEN trial reported that icotinib provides similar overall efficacy and better tolerability than gefitinib in patients with NSCLC who progressed after one to two lines of chemotherapy; it also improved efficacy in a subset of EGFR-mutant patient.

The EURTAC trial randomly assigned 174 chemo-naive, stage IIIB/IV NSCLC patients with exon 19 deletions or L858R mutations to receive erlotinib 150 mg/day or platinum-based doublet chemotherapy every 3 weeks for four cycles. The doublet could include cisplatin 75 mg/m² on day 1 plus docetaxel 75 mg/m² on day 1; cisplatin 75 mg/m² on day 1 plus gemcitabine 1,250 mg/m² on days 1 and 8; carboplatin area under the curve (AUC) 6 on day 1 plus docetaxel 75 mg/m² on day 1 or carboplatin AUC 5 on day 1 plus gemcitabine 1,000 mg/m² on days 1 and 8.

The objective response rate was 58% for erlotinib vs. 15% for chemotherapy in the updated analysis, said Dr. Rosell, head of medical oncology at the Catalan Institute of Oncology in Barcelona. At the time of the interim analysis, two patients had a complete response to erlotinib and 40 had partial responses, with 8 additional partial responses reported in the updated analysis. No patient had a complete response with chemotherapy, eight patients had partial responses early on, and five more reported partial responses in the updated analysis.

The disease control rate in the interim analysis was 79% for erlotinib vs. 66% in the updated analysis.

Median overall survival was 18.8 months with chemotherapy and 22.9 months in the interim analysis (hazard ratio, 0.80; log rank P = 0.42). As of the Jan. 26, 2011 cutoff date for the updated analysis, 94 patients remain in overall survival follow-up, with a high level of known crossover, Dr. Rosell said. A subgroup analysis suggested that progression-free survival was better in patients with a performance status of 0, never-smokers, and those with an exon 19 deletion.

The majority of patients who relapsed on erlotinib were switched to chemotherapy. The tolerability of erlotinib was consistent with previous studies, he noted.

The Spanish Lung Cancer Group sponsored the trial. Dr. Rosell disclosed a consultant/advisory role with Roche. Two of his coauthors reported a similar role, with one also providing expert testimony for Roche. Dr. Mok disclosed relationships with several drug companies, including AstraZeneca, Roche, Boehringer Ingelheim, and Pfizer.

CHICAGO – Adalimumab induced and maintained clinical remission in children with moderate to severe Crohn’s disease and the treatment was not associated with any new safety signals in a double-blind, phase III, randomized trial.

The effect was most apparent in patients who were infliximab naive, Dr. Jeffrey S. Hyams said at the annual Digestive Disease Week.

Adalimumab (Humira), a human monoclonal antibody to tumor necrosis factor (TNF)–alfa, is indicated for the treatment of a variety of conditions including Crohn’s disease in adults and juvenile idiopathic arthritis, but it is not approved for juvenile Crohn’s disease.

The study involved 188 patients, aged 6-17 years, with moderate to severe Crohn’s disease that had lasted for at least 12 weeks, despite concurrent treatment with oral corticosteroids for at least 2 weeks and/or immunomodulators for at least 8 weeks. Roughly 45% of patients had used the chimeric monoclonal antibody to TNF, infliximab (Remicade).

All study patients received 4 weeks of open-label adalimumab induction therapy and were stratified based on response at week 4 and prior infliximab use to high- or low-dose maintenance adalimumab. High-dose adalimumab was 40 mg every other week for patients weighing 40 kg or more and 20 mg every other week if less than 40 kg. Low-dose adalimumab was 20 mg every other week for patients weighing 40 kg or more and 10 mg every other week if less than 40 kg. Dose escalation was allowed for flare or non-response beginning at week 12.

At week 26, 39% of the high-dose patients and 28% of low-dose patients met the study’s primary end point of clinical remission, defined as a Pediatric Crohn’s Disease Activity Index of 10 or less, said Dr. Hyams, director of the gastroenterology department at Connecticut Children’s Medical Center in Hartford. In addition, more high-dose patients than low-dose patients achieved clinical remission at week 52 (33% vs. 23%). The difference between groups was not statistically significant at week 26 or week 52.

A clinical response, defined as a decrease in Pediatric Crohn’s Disease Activity Index of at least 15 points from baseline, was observed in more high-dose than low-dose patients at week 26 (59% vs. 48%) and week 52, with the difference reaching statistical significance only at week 52 (42% vs. 28%; P = .03), he said.

When the data were broken down according to prior infliximab use, remission rates among infliximab-experienced patients were similar between the high- and low-dose adalimumab arms at week 26 (17% vs. 20%) and week 52 (19% vs. 17%).

Among infliximab-naive patients, however, clinical remission rates were significantly greater at week 26 in the high-dose vs. low-dose group (57% vs. 35%, P = .026), especially among week-4 responders (63% for high-dose group vs. 38% for low-dose group, P = .016). In all, 82% of the 188 patients responded to induction at week 4. Remission rates among infliximab-naive patients were statistically similar at week 52 (45% vs. 28%, P = .065).

Dr. Hyams said there were no "obvious safety signals" among patients who received at least one maintenance dose of adalimumab. Serious adverse events were reported in 19 (20%) of the 95 low-dose patients and 22 (24%) of the 93 high-dose patients. Notably, serious infections were reported in only 3 low-dose (3.2%) and 5 high-dose (5.4%) patients. No malignancies were observed.

Adalimumab carries a boxed warning for an increased risk of serious infections leading to hospitalization or death, particularly tuberculosis. In August 2009, the Food and Drug Administration also required that boxed warnings be added to the TNF-blocker class of drugs because of an increased risk of lymphoma and other malignancies in children and adolescents.

When asked during a discussion of the study about the effect of adalimumab on fistulas, Dr. Hyams said that 15%-20% of patients had active fistulas,and a beneficial response to therapy occurred in about 50% of the low-dose patients and about 80% of the high-dose patients.

Another attendee asked if prior treatment with immunomodulators affected response, and Dr. Hyams said it did not. If the patient experienced a clinical response, corticosteroid therapy was tapered after week 4 and could be increased to the baseline dose for flare or nonresponse. Immunomodulator therapy could be discontinued at or after week 26 and could not be reinstated.

The study was sponsored by Abbott Laboratories and an Abbott employee prepared the first draft and assisted in the production of the slides. Dr. Hyams disclosed consulting and advisory committee/review panel participation and grant/research support from Abbott. Five of the 13 coauthors are Abbott employees and five others have financial relationships with Abbott.

CHICAGO – Adalimumab induced and maintained clinical remission in children with moderate to severe Crohn’s disease and the treatment was not associated with any new safety signals in a double-blind, phase III, randomized trial.

The effect was most apparent in patients who were infliximab naive, Dr. Jeffrey S. Hyams said at the annual Digestive Disease Week.

Adalimumab (Humira), a human monoclonal antibody to tumor necrosis factor (TNF)–alfa, is indicated for the treatment of a variety of conditions including Crohn’s disease in adults and juvenile idiopathic arthritis, but it is not approved for juvenile Crohn’s disease.

The study involved 188 patients, aged 6-17 years, with moderate to severe Crohn’s disease that had lasted for at least 12 weeks, despite concurrent treatment with oral corticosteroids for at least 2 weeks and/or immunomodulators for at least 8 weeks. Roughly 45% of patients had used the chimeric monoclonal antibody to TNF, infliximab (Remicade).

All study patients received 4 weeks of open-label adalimumab induction therapy and were stratified based on response at week 4 and prior infliximab use to high- or low-dose maintenance adalimumab. High-dose adalimumab was 40 mg every other week for patients weighing 40 kg or more and 20 mg every other week if less than 40 kg. Low-dose adalimumab was 20 mg every other week for patients weighing 40 kg or more and 10 mg every other week if less than 40 kg. Dose escalation was allowed for flare or non-response beginning at week 12.

At week 26, 39% of the high-dose patients and 28% of low-dose patients met the study’s primary end point of clinical remission, defined as a Pediatric Crohn’s Disease Activity Index of 10 or less, said Dr. Hyams, director of the gastroenterology department at Connecticut Children’s Medical Center in Hartford. In addition, more high-dose patients than low-dose patients achieved clinical remission at week 52 (33% vs. 23%). The difference between groups was not statistically significant at week 26 or week 52.

A clinical response, defined as a decrease in Pediatric Crohn’s Disease Activity Index of at least 15 points from baseline, was observed in more high-dose than low-dose patients at week 26 (59% vs. 48%) and week 52, with the difference reaching statistical significance only at week 52 (42% vs. 28%; P = .03), he said.

When the data were broken down according to prior infliximab use, remission rates among infliximab-experienced patients were similar between the high- and low-dose adalimumab arms at week 26 (17% vs. 20%) and week 52 (19% vs. 17%).

Among infliximab-naive patients, however, clinical remission rates were significantly greater at week 26 in the high-dose vs. low-dose group (57% vs. 35%, P = .026), especially among week-4 responders (63% for high-dose group vs. 38% for low-dose group, P = .016). In all, 82% of the 188 patients responded to induction at week 4. Remission rates among infliximab-naive patients were statistically similar at week 52 (45% vs. 28%, P = .065).

Dr. Hyams said there were no "obvious safety signals" among patients who received at least one maintenance dose of adalimumab. Serious adverse events were reported in 19 (20%) of the 95 low-dose patients and 22 (24%) of the 93 high-dose patients. Notably, serious infections were reported in only 3 low-dose (3.2%) and 5 high-dose (5.4%) patients. No malignancies were observed.

Adalimumab carries a boxed warning for an increased risk of serious infections leading to hospitalization or death, particularly tuberculosis. In August 2009, the Food and Drug Administration also required that boxed warnings be added to the TNF-blocker class of drugs because of an increased risk of lymphoma and other malignancies in children and adolescents.

When asked during a discussion of the study about the effect of adalimumab on fistulas, Dr. Hyams said that 15%-20% of patients had active fistulas,and a beneficial response to therapy occurred in about 50% of the low-dose patients and about 80% of the high-dose patients.

Another attendee asked if prior treatment with immunomodulators affected response, and Dr. Hyams said it did not. If the patient experienced a clinical response, corticosteroid therapy was tapered after week 4 and could be increased to the baseline dose for flare or nonresponse. Immunomodulator therapy could be discontinued at or after week 26 and could not be reinstated.

The study was sponsored by Abbott Laboratories and an Abbott employee prepared the first draft and assisted in the production of the slides. Dr. Hyams disclosed consulting and advisory committee/review panel participation and grant/research support from Abbott. Five of the 13 coauthors are Abbott employees and five others have financial relationships with Abbott.

CHICAGO – Adalimumab induced and maintained clinical remission in children with moderate to severe Crohn’s disease and the treatment was not associated with any new safety signals in a double-blind, phase III, randomized trial.

The effect was most apparent in patients who were infliximab naive, Dr. Jeffrey S. Hyams said at the annual Digestive Disease Week.

Adalimumab (Humira), a human monoclonal antibody to tumor necrosis factor (TNF)–alfa, is indicated for the treatment of a variety of conditions including Crohn’s disease in adults and juvenile idiopathic arthritis, but it is not approved for juvenile Crohn’s disease.

The study involved 188 patients, aged 6-17 years, with moderate to severe Crohn’s disease that had lasted for at least 12 weeks, despite concurrent treatment with oral corticosteroids for at least 2 weeks and/or immunomodulators for at least 8 weeks. Roughly 45% of patients had used the chimeric monoclonal antibody to TNF, infliximab (Remicade).

All study patients received 4 weeks of open-label adalimumab induction therapy and were stratified based on response at week 4 and prior infliximab use to high- or low-dose maintenance adalimumab. High-dose adalimumab was 40 mg every other week for patients weighing 40 kg or more and 20 mg every other week if less than 40 kg. Low-dose adalimumab was 20 mg every other week for patients weighing 40 kg or more and 10 mg every other week if less than 40 kg. Dose escalation was allowed for flare or non-response beginning at week 12.

At week 26, 39% of the high-dose patients and 28% of low-dose patients met the study’s primary end point of clinical remission, defined as a Pediatric Crohn’s Disease Activity Index of 10 or less, said Dr. Hyams, director of the gastroenterology department at Connecticut Children’s Medical Center in Hartford. In addition, more high-dose patients than low-dose patients achieved clinical remission at week 52 (33% vs. 23%). The difference between groups was not statistically significant at week 26 or week 52.

A clinical response, defined as a decrease in Pediatric Crohn’s Disease Activity Index of at least 15 points from baseline, was observed in more high-dose than low-dose patients at week 26 (59% vs. 48%) and week 52, with the difference reaching statistical significance only at week 52 (42% vs. 28%; P = .03), he said.

When the data were broken down according to prior infliximab use, remission rates among infliximab-experienced patients were similar between the high- and low-dose adalimumab arms at week 26 (17% vs. 20%) and week 52 (19% vs. 17%).

Among infliximab-naive patients, however, clinical remission rates were significantly greater at week 26 in the high-dose vs. low-dose group (57% vs. 35%, P = .026), especially among week-4 responders (63% for high-dose group vs. 38% for low-dose group, P = .016). In all, 82% of the 188 patients responded to induction at week 4. Remission rates among infliximab-naive patients were statistically similar at week 52 (45% vs. 28%, P = .065).

Dr. Hyams said there were no "obvious safety signals" among patients who received at least one maintenance dose of adalimumab. Serious adverse events were reported in 19 (20%) of the 95 low-dose patients and 22 (24%) of the 93 high-dose patients. Notably, serious infections were reported in only 3 low-dose (3.2%) and 5 high-dose (5.4%) patients. No malignancies were observed.

Adalimumab carries a boxed warning for an increased risk of serious infections leading to hospitalization or death, particularly tuberculosis. In August 2009, the Food and Drug Administration also required that boxed warnings be added to the TNF-blocker class of drugs because of an increased risk of lymphoma and other malignancies in children and adolescents.

When asked during a discussion of the study about the effect of adalimumab on fistulas, Dr. Hyams said that 15%-20% of patients had active fistulas,and a beneficial response to therapy occurred in about 50% of the low-dose patients and about 80% of the high-dose patients.

Another attendee asked if prior treatment with immunomodulators affected response, and Dr. Hyams said it did not. If the patient experienced a clinical response, corticosteroid therapy was tapered after week 4 and could be increased to the baseline dose for flare or nonresponse. Immunomodulator therapy could be discontinued at or after week 26 and could not be reinstated.

The study was sponsored by Abbott Laboratories and an Abbott employee prepared the first draft and assisted in the production of the slides. Dr. Hyams disclosed consulting and advisory committee/review panel participation and grant/research support from Abbott. Five of the 13 coauthors are Abbott employees and five others have financial relationships with Abbott.

CHICAGO – Continued use of aspirin does not impair the healing of aspirin-related peptic ulcers under powerful proton pump inhibitor therapy, a randomized study in 160 patients suggests.

The ulcer healing rate, according to an intention-to-treat analysis, was 85.2% for patients receiving esomeprazole (Nexium) alone and 84.8% for those receiving esomeprazole plus aspirin. The per-protocol analysis showed nearly identical healing rates at 83.1% and 82.1%, Dr. Ping-I Hsu reported at the annual Digestive Disease Week.

The findings are noteworthy because patients are sometimes switched from aspirin to clopidogrel (Plavix) as an alternative treatment for aspirin-related peptic ulcers. There are no specific guidelines for the use of gastroprotective agents like proton pump inhibitors (PPIs) and clopidogrel. However, in a highly controversial move, the Food and Drug Administration discouraged concomitant use of clopidogrel and PPIs, especially omeprazole (Prilosec), because of a potential drug interaction.

Dr. Hsu pointed out that clopidogrel is far more expensive than aspirin, and that an earlier study showed that clopidogrel plus omeprazole had a similar ulcer healing rate as aspirin plus omeprazole (Aliment. Pharmacol. Ther. 2004;19:359-65). 

"We therefore suggest that continuing aspirin use plus a powerful PPI is the best initial treatment of aspirin-related peptic ulcers," said Dr. Hsu, with the division of gastroenterology, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan.

The trial randomized 160 patients who were on low-dose aspirin and had a 3 mm or more peptic ulcer to esomeprazole 40 mg/day alone or with aspirin 100 mg/day for 8 weeks. Patients with Helicobacter pylori infection were treated with 10-day, standard triple therapy.

Exclusion criteria included serious medical illness or acute gastrointestinal bleeding, cardiovascular events within 6 months, history of partial gastrectomy, concomitant use of clopidogrel or anticoagulant and long-term use of NSAIDs.

Ten patients in the esomeprazole group and 12 in the combination group were excluded because of poor compliance or refusal of follow-up endoscopy, leaving 71 esomeprazole and 67 combination patients in the per-protocol analysis.

At baseline, the 81 esomeprazole patients and 79 esomeprazole plus aspirin patients were similar with respect to NSAID use (17% vs. 11%), prior peptic ulcer bleeding (12% vs. 14%), H. pylori infection (47% vs. 37%), and rates of underlying diseases such as diabetes mellitus (27% vs. 33%), hypertension (67% vs. 58%), coronary artery disease (52% vs. 57%), and cerebrovascular accident (10% vs. 15%). Their mean age was 69 years.

At week 8, Lanza scores decreased from 4 at baseline to 1.27 in each group, Dr. Hsu said.

Dyspepsia symptom scores decreased in the esomeprazole group from 1.78 to 0.50 and from 1.59 to 0.5 in the combination group. No patient in either group experienced ulcer bleeding or perforation.

Cardiovascular outcomes also were similar with or without continuous aspirin use. Only one case of unstable angina occurred in the combination group, and no patients experienced an acute MI, ischemic stroke or died, he said.

Independent risk factors predicting ulcer healing failure were diabetes mellitus (odds ratio, 3.2), use of steroids (OR, 12.1) and persistent H. pylori infection (OR, 20.2), Dr. Hsu said. The healing rate of ulcers with H. pylori infection was 25% vs. 84% without infection.

"Eradicating H. pylori is important for the healing of aspirin-related peptic ulcers," he said.

Dr. Hsu disclosed no conflicts of interest.

CHICAGO – Continued use of aspirin does not impair the healing of aspirin-related peptic ulcers under powerful proton pump inhibitor therapy, a randomized study in 160 patients suggests.

The ulcer healing rate, according to an intention-to-treat analysis, was 85.2% for patients receiving esomeprazole (Nexium) alone and 84.8% for those receiving esomeprazole plus aspirin. The per-protocol analysis showed nearly identical healing rates at 83.1% and 82.1%, Dr. Ping-I Hsu reported at the annual Digestive Disease Week.

The findings are noteworthy because patients are sometimes switched from aspirin to clopidogrel (Plavix) as an alternative treatment for aspirin-related peptic ulcers. There are no specific guidelines for the use of gastroprotective agents like proton pump inhibitors (PPIs) and clopidogrel. However, in a highly controversial move, the Food and Drug Administration discouraged concomitant use of clopidogrel and PPIs, especially omeprazole (Prilosec), because of a potential drug interaction.

Dr. Hsu pointed out that clopidogrel is far more expensive than aspirin, and that an earlier study showed that clopidogrel plus omeprazole had a similar ulcer healing rate as aspirin plus omeprazole (Aliment. Pharmacol. Ther. 2004;19:359-65). 

"We therefore suggest that continuing aspirin use plus a powerful PPI is the best initial treatment of aspirin-related peptic ulcers," said Dr. Hsu, with the division of gastroenterology, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan.

The trial randomized 160 patients who were on low-dose aspirin and had a 3 mm or more peptic ulcer to esomeprazole 40 mg/day alone or with aspirin 100 mg/day for 8 weeks. Patients with Helicobacter pylori infection were treated with 10-day, standard triple therapy.

Exclusion criteria included serious medical illness or acute gastrointestinal bleeding, cardiovascular events within 6 months, history of partial gastrectomy, concomitant use of clopidogrel or anticoagulant and long-term use of NSAIDs.

Ten patients in the esomeprazole group and 12 in the combination group were excluded because of poor compliance or refusal of follow-up endoscopy, leaving 71 esomeprazole and 67 combination patients in the per-protocol analysis.

At baseline, the 81 esomeprazole patients and 79 esomeprazole plus aspirin patients were similar with respect to NSAID use (17% vs. 11%), prior peptic ulcer bleeding (12% vs. 14%), H. pylori infection (47% vs. 37%), and rates of underlying diseases such as diabetes mellitus (27% vs. 33%), hypertension (67% vs. 58%), coronary artery disease (52% vs. 57%), and cerebrovascular accident (10% vs. 15%). Their mean age was 69 years.

At week 8, Lanza scores decreased from 4 at baseline to 1.27 in each group, Dr. Hsu said.

Dyspepsia symptom scores decreased in the esomeprazole group from 1.78 to 0.50 and from 1.59 to 0.5 in the combination group. No patient in either group experienced ulcer bleeding or perforation.

Cardiovascular outcomes also were similar with or without continuous aspirin use. Only one case of unstable angina occurred in the combination group, and no patients experienced an acute MI, ischemic stroke or died, he said.

Independent risk factors predicting ulcer healing failure were diabetes mellitus (odds ratio, 3.2), use of steroids (OR, 12.1) and persistent H. pylori infection (OR, 20.2), Dr. Hsu said. The healing rate of ulcers with H. pylori infection was 25% vs. 84% without infection.

"Eradicating H. pylori is important for the healing of aspirin-related peptic ulcers," he said.

Dr. Hsu disclosed no conflicts of interest.

CHICAGO – Continued use of aspirin does not impair the healing of aspirin-related peptic ulcers under powerful proton pump inhibitor therapy, a randomized study in 160 patients suggests.

The ulcer healing rate, according to an intention-to-treat analysis, was 85.2% for patients receiving esomeprazole (Nexium) alone and 84.8% for those receiving esomeprazole plus aspirin. The per-protocol analysis showed nearly identical healing rates at 83.1% and 82.1%, Dr. Ping-I Hsu reported at the annual Digestive Disease Week.

The findings are noteworthy because patients are sometimes switched from aspirin to clopidogrel (Plavix) as an alternative treatment for aspirin-related peptic ulcers. There are no specific guidelines for the use of gastroprotective agents like proton pump inhibitors (PPIs) and clopidogrel. However, in a highly controversial move, the Food and Drug Administration discouraged concomitant use of clopidogrel and PPIs, especially omeprazole (Prilosec), because of a potential drug interaction.

Dr. Hsu pointed out that clopidogrel is far more expensive than aspirin, and that an earlier study showed that clopidogrel plus omeprazole had a similar ulcer healing rate as aspirin plus omeprazole (Aliment. Pharmacol. Ther. 2004;19:359-65). 

"We therefore suggest that continuing aspirin use plus a powerful PPI is the best initial treatment of aspirin-related peptic ulcers," said Dr. Hsu, with the division of gastroenterology, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan.

The trial randomized 160 patients who were on low-dose aspirin and had a 3 mm or more peptic ulcer to esomeprazole 40 mg/day alone or with aspirin 100 mg/day for 8 weeks. Patients with Helicobacter pylori infection were treated with 10-day, standard triple therapy.

Exclusion criteria included serious medical illness or acute gastrointestinal bleeding, cardiovascular events within 6 months, history of partial gastrectomy, concomitant use of clopidogrel or anticoagulant and long-term use of NSAIDs.

Ten patients in the esomeprazole group and 12 in the combination group were excluded because of poor compliance or refusal of follow-up endoscopy, leaving 71 esomeprazole and 67 combination patients in the per-protocol analysis.

At baseline, the 81 esomeprazole patients and 79 esomeprazole plus aspirin patients were similar with respect to NSAID use (17% vs. 11%), prior peptic ulcer bleeding (12% vs. 14%), H. pylori infection (47% vs. 37%), and rates of underlying diseases such as diabetes mellitus (27% vs. 33%), hypertension (67% vs. 58%), coronary artery disease (52% vs. 57%), and cerebrovascular accident (10% vs. 15%). Their mean age was 69 years.

At week 8, Lanza scores decreased from 4 at baseline to 1.27 in each group, Dr. Hsu said.

Dyspepsia symptom scores decreased in the esomeprazole group from 1.78 to 0.50 and from 1.59 to 0.5 in the combination group. No patient in either group experienced ulcer bleeding or perforation.

Cardiovascular outcomes also were similar with or without continuous aspirin use. Only one case of unstable angina occurred in the combination group, and no patients experienced an acute MI, ischemic stroke or died, he said.

Independent risk factors predicting ulcer healing failure were diabetes mellitus (odds ratio, 3.2), use of steroids (OR, 12.1) and persistent H. pylori infection (OR, 20.2), Dr. Hsu said. The healing rate of ulcers with H. pylori infection was 25% vs. 84% without infection.

"Eradicating H. pylori is important for the healing of aspirin-related peptic ulcers," he said.

Dr. Hsu disclosed no conflicts of interest.

CHICAGO – Continued use of aspirin does not impair the healing of aspirin-related peptic ulcers under powerful proton pump inhibitor therapy, a randomized study in 160 patients suggests.

The ulcer healing rate, according to an intention-to-treat analysis, was 85.2% for patients receiving esomeprazole (Nexium) alone and 84.8% for those receiving esomeprazole plus aspirin. The per-protocol analysis showed nearly identical healing rates at 83.1% and 82.1%, Dr. Ping-I Hsu reported at the annual Digestive Disease Week.

The findings are noteworthy because patients are sometimes switched from aspirin to clopidogrel (Plavix) as an alternative treatment for aspirin-related peptic ulcers. There are no specific guidelines for the use of gastroprotective agents like proton pump inhibitors (PPIs) and clopidogrel. However, in a highly controversial move, the Food and Drug Administration discouraged concomitant use of clopidogrel and PPIs, especially omeprazole (Prilosec), because of a potential drug interaction.

Dr. Hsu pointed out that clopidogrel is far more expensive than aspirin, and that an earlier study showed that clopidogrel plus omeprazole had a similar ulcer healing rate as aspirin plus omeprazole (Aliment. Pharmacol. Ther. 2004;19:359-65). 

"We therefore suggest that continuing aspirin use plus a powerful PPI is the best initial treatment of aspirin-related peptic ulcers," said Dr. Hsu, with the division of gastroenterology, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan.

The trial randomized 160 patients who were on low-dose aspirin and had a 3 mm or more peptic ulcer to esomeprazole 40 mg/day alone or with aspirin 100 mg/day for 8 weeks. Patients with Helicobacter pylori infection were treated with 10-day, standard triple therapy.

Exclusion criteria included serious medical illness or acute gastrointestinal bleeding, cardiovascular events within 6 months, history of partial gastrectomy, concomitant use of clopidogrel or anticoagulant and long-term use of NSAIDs.

Ten patients in the esomeprazole group and 12 in the combination group were excluded because of poor compliance or refusal of follow-up endoscopy, leaving 71 esomeprazole and 67 combination patients in the per-protocol analysis.

At baseline, the 81 esomeprazole patients and 79 esomeprazole plus aspirin patients were similar with respect to NSAID use (17% vs. 11%), prior peptic ulcer bleeding (12% vs. 14%), H. pylori infection (47% vs. 37%), and rates of underlying diseases such as diabetes mellitus (27% vs. 33%), hypertension (67% vs. 58%), coronary artery disease (52% vs. 57%), and cerebrovascular accident (10% vs. 15%). Their mean age was 69 years.

At week 8, Lanza scores decreased from 4 at baseline to 1.27 in each group, Dr. Hsu said.

Dyspepsia symptom scores decreased in the esomeprazole group from 1.78 to 0.50 and from 1.59 to 0.5 in the combination group. No patient in either group experienced ulcer bleeding or perforation.

Cardiovascular outcomes also were similar with or without continuous aspirin use. Only one case of unstable angina occurred in the combination group, and no patients experienced an acute MI, ischemic stroke or died, he said.

Independent risk factors predicting ulcer healing failure were diabetes mellitus (odds ratio, 3.2), use of steroids (OR, 12.1) and persistent H. pylori infection (OR, 20.2), Dr. Hsu said. The healing rate of ulcers with H. pylori infection was 25% vs. 84% without infection.

"Eradicating H. pylori is important for the healing of aspirin-related peptic ulcers," he said.

Dr. Hsu disclosed no conflicts of interest.

CHICAGO – Continued use of aspirin does not impair the healing of aspirin-related peptic ulcers under powerful proton pump inhibitor therapy, a randomized study in 160 patients suggests.

The ulcer healing rate, according to an intention-to-treat analysis, was 85.2% for patients receiving esomeprazole (Nexium) alone and 84.8% for those receiving esomeprazole plus aspirin. The per-protocol analysis showed nearly identical healing rates at 83.1% and 82.1%, Dr. Ping-I Hsu reported at the annual Digestive Disease Week.

The findings are noteworthy because patients are sometimes switched from aspirin to clopidogrel (Plavix) as an alternative treatment for aspirin-related peptic ulcers. There are no specific guidelines for the use of gastroprotective agents like proton pump inhibitors (PPIs) and clopidogrel. However, in a highly controversial move, the Food and Drug Administration discouraged concomitant use of clopidogrel and PPIs, especially omeprazole (Prilosec), because of a potential drug interaction.

Dr. Hsu pointed out that clopidogrel is far more expensive than aspirin, and that an earlier study showed that clopidogrel plus omeprazole had a similar ulcer healing rate as aspirin plus omeprazole (Aliment. Pharmacol. Ther. 2004;19:359-65). 

"We therefore suggest that continuing aspirin use plus a powerful PPI is the best initial treatment of aspirin-related peptic ulcers," said Dr. Hsu, with the division of gastroenterology, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan.

The trial randomized 160 patients who were on low-dose aspirin and had a 3 mm or more peptic ulcer to esomeprazole 40 mg/day alone or with aspirin 100 mg/day for 8 weeks. Patients with Helicobacter pylori infection were treated with 10-day, standard triple therapy.

Exclusion criteria included serious medical illness or acute gastrointestinal bleeding, cardiovascular events within 6 months, history of partial gastrectomy, concomitant use of clopidogrel or anticoagulant and long-term use of NSAIDs.

Ten patients in the esomeprazole group and 12 in the combination group were excluded because of poor compliance or refusal of follow-up endoscopy, leaving 71 esomeprazole and 67 combination patients in the per-protocol analysis.

At baseline, the 81 esomeprazole patients and 79 esomeprazole plus aspirin patients were similar with respect to NSAID use (17% vs. 11%), prior peptic ulcer bleeding (12% vs. 14%), H. pylori infection (47% vs. 37%), and rates of underlying diseases such as diabetes mellitus (27% vs. 33%), hypertension (67% vs. 58%), coronary artery disease (52% vs. 57%), and cerebrovascular accident (10% vs. 15%). Their mean age was 69 years.

At week 8, Lanza scores decreased from 4 at baseline to 1.27 in each group, Dr. Hsu said.

Dyspepsia symptom scores decreased in the esomeprazole group from 1.78 to 0.50 and from 1.59 to 0.5 in the combination group. No patient in either group experienced ulcer bleeding or perforation.

Cardiovascular outcomes also were similar with or without continuous aspirin use. Only one case of unstable angina occurred in the combination group, and no patients experienced an acute MI, ischemic stroke or died, he said.

Independent risk factors predicting ulcer healing failure were diabetes mellitus (odds ratio, 3.2), use of steroids (OR, 12.1) and persistent H. pylori infection (OR, 20.2), Dr. Hsu said. The healing rate of ulcers with H. pylori infection was 25% vs. 84% without infection.

"Eradicating H. pylori is important for the healing of aspirin-related peptic ulcers," he said.

Dr. Hsu disclosed no conflicts of interest.

CHICAGO – Continued use of aspirin does not impair the healing of aspirin-related peptic ulcers under powerful proton pump inhibitor therapy, a randomized study in 160 patients suggests.

The ulcer healing rate, according to an intention-to-treat analysis, was 85.2% for patients receiving esomeprazole (Nexium) alone and 84.8% for those receiving esomeprazole plus aspirin. The per-protocol analysis showed nearly identical healing rates at 83.1% and 82.1%, Dr. Ping-I Hsu reported at the annual Digestive Disease Week.

The findings are noteworthy because patients are sometimes switched from aspirin to clopidogrel (Plavix) as an alternative treatment for aspirin-related peptic ulcers. There are no specific guidelines for the use of gastroprotective agents like proton pump inhibitors (PPIs) and clopidogrel. However, in a highly controversial move, the Food and Drug Administration discouraged concomitant use of clopidogrel and PPIs, especially omeprazole (Prilosec), because of a potential drug interaction.

Dr. Hsu pointed out that clopidogrel is far more expensive than aspirin, and that an earlier study showed that clopidogrel plus omeprazole had a similar ulcer healing rate as aspirin plus omeprazole (Aliment. Pharmacol. Ther. 2004;19:359-65). 

"We therefore suggest that continuing aspirin use plus a powerful PPI is the best initial treatment of aspirin-related peptic ulcers," said Dr. Hsu, with the division of gastroenterology, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan.

The trial randomized 160 patients who were on low-dose aspirin and had a 3 mm or more peptic ulcer to esomeprazole 40 mg/day alone or with aspirin 100 mg/day for 8 weeks. Patients with Helicobacter pylori infection were treated with 10-day, standard triple therapy.

Exclusion criteria included serious medical illness or acute gastrointestinal bleeding, cardiovascular events within 6 months, history of partial gastrectomy, concomitant use of clopidogrel or anticoagulant and long-term use of NSAIDs.

Ten patients in the esomeprazole group and 12 in the combination group were excluded because of poor compliance or refusal of follow-up endoscopy, leaving 71 esomeprazole and 67 combination patients in the per-protocol analysis.

At baseline, the 81 esomeprazole patients and 79 esomeprazole plus aspirin patients were similar with respect to NSAID use (17% vs. 11%), prior peptic ulcer bleeding (12% vs. 14%), H. pylori infection (47% vs. 37%), and rates of underlying diseases such as diabetes mellitus (27% vs. 33%), hypertension (67% vs. 58%), coronary artery disease (52% vs. 57%), and cerebrovascular accident (10% vs. 15%). Their mean age was 69 years.

At week 8, Lanza scores decreased from 4 at baseline to 1.27 in each group, Dr. Hsu said.

Dyspepsia symptom scores decreased in the esomeprazole group from 1.78 to 0.50 and from 1.59 to 0.5 in the combination group. No patient in either group experienced ulcer bleeding or perforation.

Cardiovascular outcomes also were similar with or without continuous aspirin use. Only one case of unstable angina occurred in the combination group, and no patients experienced an acute MI, ischemic stroke or died, he said.

Independent risk factors predicting ulcer healing failure were diabetes mellitus (odds ratio, 3.2), use of steroids (OR, 12.1) and persistent H. pylori infection (OR, 20.2), Dr. Hsu said. The healing rate of ulcers with H. pylori infection was 25% vs. 84% without infection.

"Eradicating H. pylori is important for the healing of aspirin-related peptic ulcers," he said.

Dr. Hsu disclosed no conflicts of interest.

CHICAGO – Initial vancomycin monotherapy was associated with significantly higher rates of subsequent Clostridium difficile infection among 101 patients with inflammatory bowel disease in a retrospective observational study.

The rate of C. difficile infection (CDI) recurrence over the following year was 39.4% for patients initially treated with vancomycin (Vancocin), 14.5% for patients treated with metronidazole (Flagyl), and 13.3% for those given combination metronidazole and vancomycin. The difference was statistically significant between vancomycin and both metronidazole and combination therapy (P less than .05 for both), lead author Dr. Amar Naik said at the annual Digestive Disease Week.

No significant differences were found between groups in terms of disease duration or inflammatory bowel disease (IBD) maintenance therapy. There were 48 metronidazole patients, 38 vancomycin patients, and 15 combination patients, and each treatment group comprised almost equal numbers of men and women.

The cohort included 62 patients with Crohn’s disease and 39 patients with ulcerative colitis who were followed at a single IBD center. A total of 89% were on maintenance immunosuppression for their IBD. The overall CDI recurrence rate was 24% (24 patients), with a mean time to recurrence of 6 months.

Of the 24 patients with CDI recurrence, 7 (29%) were women and 17 (71%) were men.

Patients initially diagnosed as inpatients were also less likely to experience recurrence than were those diagnosed as outpatients, but this difference did not reach statistical significance (17% vs. 27%), he said.

Steroid use within 3 months of CDI was significantly associated with a higher recurrence rate, compared with no steroid use (32% vs. 15.7%, P less than .05), said Dr. Naik, a gastroenterologist with the Medical College of Wisconsin in Milwaukee.

In a multivariate analysis, the only two significant predictors of CDI recurrence were initial vancomycin monotherapy (odds ratio 7.45, P = .04) and female gender (OR 0.26, P = .02).

"Combination therapy with metronidazole and vancomycin in IBD immunosuppressed patients with C. difficile infection might be more efficacious at preventing CDI recurrence over the following year," Dr. Naik said.

During a discussion of the study, an attendee asked whether there is something about vancomycin that makes CDI recurrence more likely or whether severity may have played a role in the findings.

Dr. Naik replied that there may be an IBD disease severity issue, but also that vancomycin has a profound impact on the gut microbiome. He went on to say that after CDI treatment, there may also be increased rates of vancomycin-resistant enterococcus infection, which could potentially affect the microbiome.

The latest Ontario Ministry of Health report cites a sharp increase in the number of confirmed cases of vancomycin-resistant enterococcus, from 834 in 2006 to 1,154 in 2009, the latest year for which figures were available. At the same time, the rate of CDI dropped from 4,536 to 3,266, although CDI-related diarrhea caused 478 deaths in 2009. In a study cited by Dr. Naik, vancomycin was shown to be superior to metronidazole in treating patients with severe CDI-associated diarrhea (Clin. Infect. Dis. 2007;45:302-7).

Initial antibiotic treatment in the current study included a 14-day course of metronidazole 250 mg t.i.d., or vancomycin 250 mg q.i.d., or metronidazole 250 mg t.i.d. plus vancomycin 250 mg q.i.d..

Initial CDI was confirmed based on symptoms, positive ELISA toxin A/B testing, or a positive nucleic acid amplification test (NAAT). Subsequent CDI was identified according to symptom recurrence and a positive toxin A/B or NAAT test.

Finally, an attendee noted that there have been anecdotal recommendations from some of Dr. Naik’s colleagues to use vancomycin as first choice for CDI treatment, and asked whether the study findings have changed practice at the Medical College of Wisconsin. Dr. Naik said further prospective studies are needed before changing clinical practice, but added, "This actually shows [that] some caution is needed." When pressed as to what he prescribes for his patients, he said that for inpatients, combination therapy with vancomycin and metronidazole should be considered.

Dr. Naik and his coauthors reported no conflicts of interest.

CHICAGO – Initial vancomycin monotherapy was associated with significantly higher rates of subsequent Clostridium difficile infection among 101 patients with inflammatory bowel disease in a retrospective observational study.

The rate of C. difficile infection (CDI) recurrence over the following year was 39.4% for patients initially treated with vancomycin (Vancocin), 14.5% for patients treated with metronidazole (Flagyl), and 13.3% for those given combination metronidazole and vancomycin. The difference was statistically significant between vancomycin and both metronidazole and combination therapy (P less than .05 for both), lead author Dr. Amar Naik said at the annual Digestive Disease Week.

No significant differences were found between groups in terms of disease duration or inflammatory bowel disease (IBD) maintenance therapy. There were 48 metronidazole patients, 38 vancomycin patients, and 15 combination patients, and each treatment group comprised almost equal numbers of men and women.

The cohort included 62 patients with Crohn’s disease and 39 patients with ulcerative colitis who were followed at a single IBD center. A total of 89% were on maintenance immunosuppression for their IBD. The overall CDI recurrence rate was 24% (24 patients), with a mean time to recurrence of 6 months.

Of the 24 patients with CDI recurrence, 7 (29%) were women and 17 (71%) were men.

Patients initially diagnosed as inpatients were also less likely to experience recurrence than were those diagnosed as outpatients, but this difference did not reach statistical significance (17% vs. 27%), he said.

Steroid use within 3 months of CDI was significantly associated with a higher recurrence rate, compared with no steroid use (32% vs. 15.7%, P less than .05), said Dr. Naik, a gastroenterologist with the Medical College of Wisconsin in Milwaukee.

In a multivariate analysis, the only two significant predictors of CDI recurrence were initial vancomycin monotherapy (odds ratio 7.45, P = .04) and female gender (OR 0.26, P = .02).

"Combination therapy with metronidazole and vancomycin in IBD immunosuppressed patients with C. difficile infection might be more efficacious at preventing CDI recurrence over the following year," Dr. Naik said.

During a discussion of the study, an attendee asked whether there is something about vancomycin that makes CDI recurrence more likely or whether severity may have played a role in the findings.

Dr. Naik replied that there may be an IBD disease severity issue, but also that vancomycin has a profound impact on the gut microbiome. He went on to say that after CDI treatment, there may also be increased rates of vancomycin-resistant enterococcus infection, which could potentially affect the microbiome.

The latest Ontario Ministry of Health report cites a sharp increase in the number of confirmed cases of vancomycin-resistant enterococcus, from 834 in 2006 to 1,154 in 2009, the latest year for which figures were available. At the same time, the rate of CDI dropped from 4,536 to 3,266, although CDI-related diarrhea caused 478 deaths in 2009. In a study cited by Dr. Naik, vancomycin was shown to be superior to metronidazole in treating patients with severe CDI-associated diarrhea (Clin. Infect. Dis. 2007;45:302-7).

Initial antibiotic treatment in the current study included a 14-day course of metronidazole 250 mg t.i.d., or vancomycin 250 mg q.i.d., or metronidazole 250 mg t.i.d. plus vancomycin 250 mg q.i.d..

Initial CDI was confirmed based on symptoms, positive ELISA toxin A/B testing, or a positive nucleic acid amplification test (NAAT). Subsequent CDI was identified according to symptom recurrence and a positive toxin A/B or NAAT test.

Finally, an attendee noted that there have been anecdotal recommendations from some of Dr. Naik’s colleagues to use vancomycin as first choice for CDI treatment, and asked whether the study findings have changed practice at the Medical College of Wisconsin. Dr. Naik said further prospective studies are needed before changing clinical practice, but added, "This actually shows [that] some caution is needed." When pressed as to what he prescribes for his patients, he said that for inpatients, combination therapy with vancomycin and metronidazole should be considered.

Dr. Naik and his coauthors reported no conflicts of interest.

CHICAGO – Initial vancomycin monotherapy was associated with significantly higher rates of subsequent Clostridium difficile infection among 101 patients with inflammatory bowel disease in a retrospective observational study.

The rate of C. difficile infection (CDI) recurrence over the following year was 39.4% for patients initially treated with vancomycin (Vancocin), 14.5% for patients treated with metronidazole (Flagyl), and 13.3% for those given combination metronidazole and vancomycin. The difference was statistically significant between vancomycin and both metronidazole and combination therapy (P less than .05 for both), lead author Dr. Amar Naik said at the annual Digestive Disease Week.

No significant differences were found between groups in terms of disease duration or inflammatory bowel disease (IBD) maintenance therapy. There were 48 metronidazole patients, 38 vancomycin patients, and 15 combination patients, and each treatment group comprised almost equal numbers of men and women.

The cohort included 62 patients with Crohn’s disease and 39 patients with ulcerative colitis who were followed at a single IBD center. A total of 89% were on maintenance immunosuppression for their IBD. The overall CDI recurrence rate was 24% (24 patients), with a mean time to recurrence of 6 months.

Of the 24 patients with CDI recurrence, 7 (29%) were women and 17 (71%) were men.

Patients initially diagnosed as inpatients were also less likely to experience recurrence than were those diagnosed as outpatients, but this difference did not reach statistical significance (17% vs. 27%), he said.

Steroid use within 3 months of CDI was significantly associated with a higher recurrence rate, compared with no steroid use (32% vs. 15.7%, P less than .05), said Dr. Naik, a gastroenterologist with the Medical College of Wisconsin in Milwaukee.

In a multivariate analysis, the only two significant predictors of CDI recurrence were initial vancomycin monotherapy (odds ratio 7.45, P = .04) and female gender (OR 0.26, P = .02).

"Combination therapy with metronidazole and vancomycin in IBD immunosuppressed patients with C. difficile infection might be more efficacious at preventing CDI recurrence over the following year," Dr. Naik said.

During a discussion of the study, an attendee asked whether there is something about vancomycin that makes CDI recurrence more likely or whether severity may have played a role in the findings.

Dr. Naik replied that there may be an IBD disease severity issue, but also that vancomycin has a profound impact on the gut microbiome. He went on to say that after CDI treatment, there may also be increased rates of vancomycin-resistant enterococcus infection, which could potentially affect the microbiome.

The latest Ontario Ministry of Health report cites a sharp increase in the number of confirmed cases of vancomycin-resistant enterococcus, from 834 in 2006 to 1,154 in 2009, the latest year for which figures were available. At the same time, the rate of CDI dropped from 4,536 to 3,266, although CDI-related diarrhea caused 478 deaths in 2009. In a study cited by Dr. Naik, vancomycin was shown to be superior to metronidazole in treating patients with severe CDI-associated diarrhea (Clin. Infect. Dis. 2007;45:302-7).

Initial antibiotic treatment in the current study included a 14-day course of metronidazole 250 mg t.i.d., or vancomycin 250 mg q.i.d., or metronidazole 250 mg t.i.d. plus vancomycin 250 mg q.i.d..

Initial CDI was confirmed based on symptoms, positive ELISA toxin A/B testing, or a positive nucleic acid amplification test (NAAT). Subsequent CDI was identified according to symptom recurrence and a positive toxin A/B or NAAT test.

Finally, an attendee noted that there have been anecdotal recommendations from some of Dr. Naik’s colleagues to use vancomycin as first choice for CDI treatment, and asked whether the study findings have changed practice at the Medical College of Wisconsin. Dr. Naik said further prospective studies are needed before changing clinical practice, but added, "This actually shows [that] some caution is needed." When pressed as to what he prescribes for his patients, he said that for inpatients, combination therapy with vancomycin and metronidazole should be considered.

Dr. Naik and his coauthors reported no conflicts of interest.

CHICAGO – Initial vancomycin monotherapy was associated with significantly higher rates of subsequent Clostridium difficile infection among 101 patients with inflammatory bowel disease in a retrospective observational study.

The rate of C. difficile infection (CDI) recurrence over the following year was 39.4% for patients initially treated with vancomycin (Vancocin), 14.5% for patients treated with metronidazole (Flagyl), and 13.3% for those given combination metronidazole and vancomycin. The difference was statistically significant between vancomycin and both metronidazole and combination therapy (P less than .05 for both), lead author Dr. Amar Naik said at the annual Digestive Disease Week.

No significant differences were found between groups in terms of disease duration or inflammatory bowel disease (IBD) maintenance therapy. There were 48 metronidazole patients, 38 vancomycin patients, and 15 combination patients, and each treatment group comprised almost equal numbers of men and women.

The cohort included 62 patients with Crohn’s disease and 39 patients with ulcerative colitis who were followed at a single IBD center. A total of 89% were on maintenance immunosuppression for their IBD. The overall CDI recurrence rate was 24% (24 patients), with a mean time to recurrence of 6 months.

Of the 24 patients with CDI recurrence, 7 (29%) were women and 17 (71%) were men.

Patients initially diagnosed as inpatients were also less likely to experience recurrence than were those diagnosed as outpatients, but this difference did not reach statistical significance (17% vs. 27%), he said.

Steroid use within 3 months of CDI was significantly associated with a higher recurrence rate, compared with no steroid use (32% vs. 15.7%, P less than .05), said Dr. Naik, a gastroenterologist with the Medical College of Wisconsin in Milwaukee.

In a multivariate analysis, the only two significant predictors of CDI recurrence were initial vancomycin monotherapy (odds ratio 7.45, P = .04) and female gender (OR 0.26, P = .02).

"Combination therapy with metronidazole and vancomycin in IBD immunosuppressed patients with C. difficile infection might be more efficacious at preventing CDI recurrence over the following year," Dr. Naik said.

During a discussion of the study, an attendee asked whether there is something about vancomycin that makes CDI recurrence more likely or whether severity may have played a role in the findings.

Dr. Naik replied that there may be an IBD disease severity issue, but also that vancomycin has a profound impact on the gut microbiome. He went on to say that after CDI treatment, there may also be increased rates of vancomycin-resistant enterococcus infection, which could potentially affect the microbiome.

The latest Ontario Ministry of Health report cites a sharp increase in the number of confirmed cases of vancomycin-resistant enterococcus, from 834 in 2006 to 1,154 in 2009, the latest year for which figures were available. At the same time, the rate of CDI dropped from 4,536 to 3,266, although CDI-related diarrhea caused 478 deaths in 2009. In a study cited by Dr. Naik, vancomycin was shown to be superior to metronidazole in treating patients with severe CDI-associated diarrhea (Clin. Infect. Dis. 2007;45:302-7).

Initial antibiotic treatment in the current study included a 14-day course of metronidazole 250 mg t.i.d., or vancomycin 250 mg q.i.d., or metronidazole 250 mg t.i.d. plus vancomycin 250 mg q.i.d..

Initial CDI was confirmed based on symptoms, positive ELISA toxin A/B testing, or a positive nucleic acid amplification test (NAAT). Subsequent CDI was identified according to symptom recurrence and a positive toxin A/B or NAAT test.

Finally, an attendee noted that there have been anecdotal recommendations from some of Dr. Naik’s colleagues to use vancomycin as first choice for CDI treatment, and asked whether the study findings have changed practice at the Medical College of Wisconsin. Dr. Naik said further prospective studies are needed before changing clinical practice, but added, "This actually shows [that] some caution is needed." When pressed as to what he prescribes for his patients, he said that for inpatients, combination therapy with vancomycin and metronidazole should be considered.

Dr. Naik and his coauthors reported no conflicts of interest.

CHICAGO – Initial vancomycin monotherapy was associated with significantly higher rates of subsequent Clostridium difficile infection among 101 patients with inflammatory bowel disease in a retrospective observational study.

The rate of C. difficile infection (CDI) recurrence over the following year was 39.4% for patients initially treated with vancomycin (Vancocin), 14.5% for patients treated with metronidazole (Flagyl), and 13.3% for those given combination metronidazole and vancomycin. The difference was statistically significant between vancomycin and both metronidazole and combination therapy (P less than .05 for both), lead author Dr. Amar Naik said at the annual Digestive Disease Week.

No significant differences were found between groups in terms of disease duration or inflammatory bowel disease (IBD) maintenance therapy. There were 48 metronidazole patients, 38 vancomycin patients, and 15 combination patients, and each treatment group comprised almost equal numbers of men and women.

The cohort included 62 patients with Crohn’s disease and 39 patients with ulcerative colitis who were followed at a single IBD center. A total of 89% were on maintenance immunosuppression for their IBD. The overall CDI recurrence rate was 24% (24 patients), with a mean time to recurrence of 6 months.

Of the 24 patients with CDI recurrence, 7 (29%) were women and 17 (71%) were men.

Patients initially diagnosed as inpatients were also less likely to experience recurrence than were those diagnosed as outpatients, but this difference did not reach statistical significance (17% vs. 27%), he said.

Steroid use within 3 months of CDI was significantly associated with a higher recurrence rate, compared with no steroid use (32% vs. 15.7%, P less than .05), said Dr. Naik, a gastroenterologist with the Medical College of Wisconsin in Milwaukee.

In a multivariate analysis, the only two significant predictors of CDI recurrence were initial vancomycin monotherapy (odds ratio 7.45, P = .04) and female gender (OR 0.26, P = .02).

"Combination therapy with metronidazole and vancomycin in IBD immunosuppressed patients with C. difficile infection might be more efficacious at preventing CDI recurrence over the following year," Dr. Naik said.

During a discussion of the study, an attendee asked whether there is something about vancomycin that makes CDI recurrence more likely or whether severity may have played a role in the findings.

Dr. Naik replied that there may be an IBD disease severity issue, but also that vancomycin has a profound impact on the gut microbiome. He went on to say that after CDI treatment, there may also be increased rates of vancomycin-resistant enterococcus infection, which could potentially affect the microbiome.

The latest Ontario Ministry of Health report cites a sharp increase in the number of confirmed cases of vancomycin-resistant enterococcus, from 834 in 2006 to 1,154 in 2009, the latest year for which figures were available. At the same time, the rate of CDI dropped from 4,536 to 3,266, although CDI-related diarrhea caused 478 deaths in 2009. In a study cited by Dr. Naik, vancomycin was shown to be superior to metronidazole in treating patients with severe CDI-associated diarrhea (Clin. Infect. Dis. 2007;45:302-7).

Initial antibiotic treatment in the current study included a 14-day course of metronidazole 250 mg t.i.d., or vancomycin 250 mg q.i.d., or metronidazole 250 mg t.i.d. plus vancomycin 250 mg q.i.d..

Initial CDI was confirmed based on symptoms, positive ELISA toxin A/B testing, or a positive nucleic acid amplification test (NAAT). Subsequent CDI was identified according to symptom recurrence and a positive toxin A/B or NAAT test.

Finally, an attendee noted that there have been anecdotal recommendations from some of Dr. Naik’s colleagues to use vancomycin as first choice for CDI treatment, and asked whether the study findings have changed practice at the Medical College of Wisconsin. Dr. Naik said further prospective studies are needed before changing clinical practice, but added, "This actually shows [that] some caution is needed." When pressed as to what he prescribes for his patients, he said that for inpatients, combination therapy with vancomycin and metronidazole should be considered.

Dr. Naik and his coauthors reported no conflicts of interest.

CHICAGO – Initial vancomycin monotherapy was associated with significantly higher rates of subsequent Clostridium difficile infection among 101 patients with inflammatory bowel disease in a retrospective observational study.

The rate of C. difficile infection (CDI) recurrence over the following year was 39.4% for patients initially treated with vancomycin (Vancocin), 14.5% for patients treated with metronidazole (Flagyl), and 13.3% for those given combination metronidazole and vancomycin. The difference was statistically significant between vancomycin and both metronidazole and combination therapy (P less than .05 for both), lead author Dr. Amar Naik said at the annual Digestive Disease Week.

No significant differences were found between groups in terms of disease duration or inflammatory bowel disease (IBD) maintenance therapy. There were 48 metronidazole patients, 38 vancomycin patients, and 15 combination patients, and each treatment group comprised almost equal numbers of men and women.

The cohort included 62 patients with Crohn’s disease and 39 patients with ulcerative colitis who were followed at a single IBD center. A total of 89% were on maintenance immunosuppression for their IBD. The overall CDI recurrence rate was 24% (24 patients), with a mean time to recurrence of 6 months.

Of the 24 patients with CDI recurrence, 7 (29%) were women and 17 (71%) were men.

Patients initially diagnosed as inpatients were also less likely to experience recurrence than were those diagnosed as outpatients, but this difference did not reach statistical significance (17% vs. 27%), he said.

Steroid use within 3 months of CDI was significantly associated with a higher recurrence rate, compared with no steroid use (32% vs. 15.7%, P less than .05), said Dr. Naik, a gastroenterologist with the Medical College of Wisconsin in Milwaukee.

In a multivariate analysis, the only two significant predictors of CDI recurrence were initial vancomycin monotherapy (odds ratio 7.45, P = .04) and female gender (OR 0.26, P = .02).

"Combination therapy with metronidazole and vancomycin in IBD immunosuppressed patients with C. difficile infection might be more efficacious at preventing CDI recurrence over the following year," Dr. Naik said.

During a discussion of the study, an attendee asked whether there is something about vancomycin that makes CDI recurrence more likely or whether severity may have played a role in the findings.

Dr. Naik replied that there may be an IBD disease severity issue, but also that vancomycin has a profound impact on the gut microbiome. He went on to say that after CDI treatment, there may also be increased rates of vancomycin-resistant enterococcus infection, which could potentially affect the microbiome.

The latest Ontario Ministry of Health report cites a sharp increase in the number of confirmed cases of vancomycin-resistant enterococcus, from 834 in 2006 to 1,154 in 2009, the latest year for which figures were available. At the same time, the rate of CDI dropped from 4,536 to 3,266, although CDI-related diarrhea caused 478 deaths in 2009. In a study cited by Dr. Naik, vancomycin was shown to be superior to metronidazole in treating patients with severe CDI-associated diarrhea (Clin. Infect. Dis. 2007;45:302-7).

Initial antibiotic treatment in the current study included a 14-day course of metronidazole 250 mg t.i.d., or vancomycin 250 mg q.i.d., or metronidazole 250 mg t.i.d. plus vancomycin 250 mg q.i.d..

Initial CDI was confirmed based on symptoms, positive ELISA toxin A/B testing, or a positive nucleic acid amplification test (NAAT). Subsequent CDI was identified according to symptom recurrence and a positive toxin A/B or NAAT test.

Finally, an attendee noted that there have been anecdotal recommendations from some of Dr. Naik’s colleagues to use vancomycin as first choice for CDI treatment, and asked whether the study findings have changed practice at the Medical College of Wisconsin. Dr. Naik said further prospective studies are needed before changing clinical practice, but added, "This actually shows [that] some caution is needed." When pressed as to what he prescribes for his patients, he said that for inpatients, combination therapy with vancomycin and metronidazole should be considered.

Dr. Naik and his coauthors reported no conflicts of interest.