Susan London

SAN FRANCISCO – National trends in gastrointestinal stromal tumors suggest that diagnosis of this malignancy has become more accurate and survival has improved in recent years, thanks to some key advances in molecular medicine.

In a population-based study, the number of new cases of gastrointestinal stromal tumors (GIST) annually rose almost fivefold between 1998 and 2002, according to results reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. It leveled off thereafter.

Lead investigator Dr. Elan R. Witkowski attributed the sharp rise mainly to the advent of testing for c-kit mutations, which drive the disease in the vast majority of cases. "Since [we’ve had] the ability to test for c-kit mutations, the diagnosis became much more precise," he explained in an interview, so tumors that would have otherwise been misclassified are now correctly recognized to be GIST.

Researchers should take note, according to Dr. Witkowski, a surgical resident at the University of Massachusetts in Worcester. "Prior to 2002, we probably shouldn’t be using this code to do research, [but] from 2002 on, we think it’s safe to do research with that one specific code," he said.

The study also found that survival was significantly better for patients with GIST that was diagnosed in 2005-2007 than for their counterparts with GIST that was diagnosed in 2002-2004.

"Our hypothesis is that the availability of Gleevec [imatinib] and the broadening of its indications are what are primarily responsible for that survival benefit," he commented, noting that there were no major advances in surgery or radiation therapy for the disease during that same time period.

Imatinib, manufactured by Novartis, is an inhibitor of the c-KIT tyrosine kinase (as well as the BCR-ABL and platelet-derived growth factor receptor tyrosine kinases). It was initially approved for GIST by the Food and Drug Administration in 2002, for the treatment of KIT-positive, unresectable and/or metastatic malignant tumors. Its GIST indication was later expanded to include adjuvant treatment in adults after resection of KIT-positive tumors.

For the study, the investigators analyzed data from the SEER (Surveillance, Epidemiology, and End Results) database for the years 1998-2007. They identified cases of GIST using the GIST-specific diagnostic code 8936 from the International Classification of Diseases for Oncology, third revision (ICD-O-3).

Analyses were based on 3,568 adult patients with a new GIST diagnosis. They were 63 years old on average, and the majority was white (71%) and male (53%), according to results reported in a poster session. Their tumors predominantly were in the stomach (52%) or small bowel (30%), and had a SEER stage of localized (51%).

Results showed that the annual number of new GIST cases in the database rose sharply between 1998 and 2002 (from approximately 100 to nearly 500), but remained fairly steady thereafter. The same pattern was also evident across individual centers participating in SEER, according to Dr. Witkowski.

"One of the things you see in the literature – particularly in prior years – is that it approximated the incidence of GIST by using a number of different variables because the diagnosis was not certain. So you had 10, 12, 15 variables that were often being combined together to approximate GIST," he commented. "Coinciding with [the increase in GIST diagnoses] was a decrease of all those other diagnosis codes that used to be used to approximate it."

The proportion of the patients who had a recommendation for surgery in their records fell between 2002 and 2007, from 85% to 80% (P = .0008). And the proportion of patients who actually underwent surgery fell as well, although not significantly so.

"Before the availability of Gleevec, surgery was really the only chance for significant response," said Dr. Witkowski. "So I think people were generally more aggressive."

Median overall survival improved in a comparison of patients receiving a new diagnosis in 2002-2004 with their peers receiving a new diagnosis in 2005-2007, with the actuarial 3-year rate increasing from approximately 70% to 75% (P = .03). Improved survival was noted both for patients who underwent resection and for those who did not.

In adjusted analyses for the years 2002-2007, patients had a decreased risk of death with each increase in the year of diagnosis (hazard ratio, 0.9) and if they underwent surgery (HR, 0.5).

On the other hand, they had an increased risk of death if they had a distant or regional stage of disease vs. a localized stage (HR, 2.4 and 1.6) or were male (HR, 1.2). Also, the risk rose with age (HR, 1.1).

Dr. Witkowski reported having no conflicts of interest related to the study.

SAN FRANCISCO – National trends in gastrointestinal stromal tumors suggest that diagnosis of this malignancy has become more accurate and survival has improved in recent years, thanks to some key advances in molecular medicine.

In a population-based study, the number of new cases of gastrointestinal stromal tumors (GIST) annually rose almost fivefold between 1998 and 2002, according to results reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. It leveled off thereafter.

Lead investigator Dr. Elan R. Witkowski attributed the sharp rise mainly to the advent of testing for c-kit mutations, which drive the disease in the vast majority of cases. "Since [we’ve had] the ability to test for c-kit mutations, the diagnosis became much more precise," he explained in an interview, so tumors that would have otherwise been misclassified are now correctly recognized to be GIST.

Researchers should take note, according to Dr. Witkowski, a surgical resident at the University of Massachusetts in Worcester. "Prior to 2002, we probably shouldn’t be using this code to do research, [but] from 2002 on, we think it’s safe to do research with that one specific code," he said.

The study also found that survival was significantly better for patients with GIST that was diagnosed in 2005-2007 than for their counterparts with GIST that was diagnosed in 2002-2004.

"Our hypothesis is that the availability of Gleevec [imatinib] and the broadening of its indications are what are primarily responsible for that survival benefit," he commented, noting that there were no major advances in surgery or radiation therapy for the disease during that same time period.

Imatinib, manufactured by Novartis, is an inhibitor of the c-KIT tyrosine kinase (as well as the BCR-ABL and platelet-derived growth factor receptor tyrosine kinases). It was initially approved for GIST by the Food and Drug Administration in 2002, for the treatment of KIT-positive, unresectable and/or metastatic malignant tumors. Its GIST indication was later expanded to include adjuvant treatment in adults after resection of KIT-positive tumors.

For the study, the investigators analyzed data from the SEER (Surveillance, Epidemiology, and End Results) database for the years 1998-2007. They identified cases of GIST using the GIST-specific diagnostic code 8936 from the International Classification of Diseases for Oncology, third revision (ICD-O-3).

Analyses were based on 3,568 adult patients with a new GIST diagnosis. They were 63 years old on average, and the majority was white (71%) and male (53%), according to results reported in a poster session. Their tumors predominantly were in the stomach (52%) or small bowel (30%), and had a SEER stage of localized (51%).

Results showed that the annual number of new GIST cases in the database rose sharply between 1998 and 2002 (from approximately 100 to nearly 500), but remained fairly steady thereafter. The same pattern was also evident across individual centers participating in SEER, according to Dr. Witkowski.

"One of the things you see in the literature – particularly in prior years – is that it approximated the incidence of GIST by using a number of different variables because the diagnosis was not certain. So you had 10, 12, 15 variables that were often being combined together to approximate GIST," he commented. "Coinciding with [the increase in GIST diagnoses] was a decrease of all those other diagnosis codes that used to be used to approximate it."

The proportion of the patients who had a recommendation for surgery in their records fell between 2002 and 2007, from 85% to 80% (P = .0008). And the proportion of patients who actually underwent surgery fell as well, although not significantly so.

"Before the availability of Gleevec, surgery was really the only chance for significant response," said Dr. Witkowski. "So I think people were generally more aggressive."

Median overall survival improved in a comparison of patients receiving a new diagnosis in 2002-2004 with their peers receiving a new diagnosis in 2005-2007, with the actuarial 3-year rate increasing from approximately 70% to 75% (P = .03). Improved survival was noted both for patients who underwent resection and for those who did not.

In adjusted analyses for the years 2002-2007, patients had a decreased risk of death with each increase in the year of diagnosis (hazard ratio, 0.9) and if they underwent surgery (HR, 0.5).

On the other hand, they had an increased risk of death if they had a distant or regional stage of disease vs. a localized stage (HR, 2.4 and 1.6) or were male (HR, 1.2). Also, the risk rose with age (HR, 1.1).

Dr. Witkowski reported having no conflicts of interest related to the study.

SAN FRANCISCO – National trends in gastrointestinal stromal tumors suggest that diagnosis of this malignancy has become more accurate and survival has improved in recent years, thanks to some key advances in molecular medicine.

In a population-based study, the number of new cases of gastrointestinal stromal tumors (GIST) annually rose almost fivefold between 1998 and 2002, according to results reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. It leveled off thereafter.

Lead investigator Dr. Elan R. Witkowski attributed the sharp rise mainly to the advent of testing for c-kit mutations, which drive the disease in the vast majority of cases. "Since [we’ve had] the ability to test for c-kit mutations, the diagnosis became much more precise," he explained in an interview, so tumors that would have otherwise been misclassified are now correctly recognized to be GIST.

Researchers should take note, according to Dr. Witkowski, a surgical resident at the University of Massachusetts in Worcester. "Prior to 2002, we probably shouldn’t be using this code to do research, [but] from 2002 on, we think it’s safe to do research with that one specific code," he said.

The study also found that survival was significantly better for patients with GIST that was diagnosed in 2005-2007 than for their counterparts with GIST that was diagnosed in 2002-2004.

"Our hypothesis is that the availability of Gleevec [imatinib] and the broadening of its indications are what are primarily responsible for that survival benefit," he commented, noting that there were no major advances in surgery or radiation therapy for the disease during that same time period.

Imatinib, manufactured by Novartis, is an inhibitor of the c-KIT tyrosine kinase (as well as the BCR-ABL and platelet-derived growth factor receptor tyrosine kinases). It was initially approved for GIST by the Food and Drug Administration in 2002, for the treatment of KIT-positive, unresectable and/or metastatic malignant tumors. Its GIST indication was later expanded to include adjuvant treatment in adults after resection of KIT-positive tumors.

For the study, the investigators analyzed data from the SEER (Surveillance, Epidemiology, and End Results) database for the years 1998-2007. They identified cases of GIST using the GIST-specific diagnostic code 8936 from the International Classification of Diseases for Oncology, third revision (ICD-O-3).

Analyses were based on 3,568 adult patients with a new GIST diagnosis. They were 63 years old on average, and the majority was white (71%) and male (53%), according to results reported in a poster session. Their tumors predominantly were in the stomach (52%) or small bowel (30%), and had a SEER stage of localized (51%).

Results showed that the annual number of new GIST cases in the database rose sharply between 1998 and 2002 (from approximately 100 to nearly 500), but remained fairly steady thereafter. The same pattern was also evident across individual centers participating in SEER, according to Dr. Witkowski.

"One of the things you see in the literature – particularly in prior years – is that it approximated the incidence of GIST by using a number of different variables because the diagnosis was not certain. So you had 10, 12, 15 variables that were often being combined together to approximate GIST," he commented. "Coinciding with [the increase in GIST diagnoses] was a decrease of all those other diagnosis codes that used to be used to approximate it."

The proportion of the patients who had a recommendation for surgery in their records fell between 2002 and 2007, from 85% to 80% (P = .0008). And the proportion of patients who actually underwent surgery fell as well, although not significantly so.

"Before the availability of Gleevec, surgery was really the only chance for significant response," said Dr. Witkowski. "So I think people were generally more aggressive."

Median overall survival improved in a comparison of patients receiving a new diagnosis in 2002-2004 with their peers receiving a new diagnosis in 2005-2007, with the actuarial 3-year rate increasing from approximately 70% to 75% (P = .03). Improved survival was noted both for patients who underwent resection and for those who did not.

In adjusted analyses for the years 2002-2007, patients had a decreased risk of death with each increase in the year of diagnosis (hazard ratio, 0.9) and if they underwent surgery (HR, 0.5).

On the other hand, they had an increased risk of death if they had a distant or regional stage of disease vs. a localized stage (HR, 2.4 and 1.6) or were male (HR, 1.2). Also, the risk rose with age (HR, 1.1).

Dr. Witkowski reported having no conflicts of interest related to the study.

SAN FRANCISCO – Advances in molecular prognosis may soon make it possible to predict the risk of recurrence of early colorectal cancer after curative resection – and thus the need for adjuvant therapy in patients who might not otherwise receive further treatment.

Five-Gene Tumor Signature

A new five-gene tumor prognostic signature has performed well in external validation testing among patients with stage I or II disease, according to Dr. Peter F. Lenehan, chief medical officer of Everist Genomics Inc., in Ann Arbor, Mich.

Dr. Lenehan and his coinvestigators validated the gene signature among 115 patients who had undergone curative resection for stage I or II colon cancer or stage I rectal cancer and did not receive adjuvant therapy. Some 40% experienced a recurrence within 3 years.

For predicting recurrence, the signature had a sensitivity of 70%, a specificity of 55%, a positive predictive value of 51%, and a negative predictive value of 73%. The overall accuracy was 61%.

Other prognostic tests can differentiate patients who will not recur, Dr. Lenehan said, but "we alone are best able to predict who is going to recur. For this population, we believe this is more clinically significant because the default position is not to treat stage I and II.

"So if we are able to detect those that actually need more aggressive follow-up or high consideration for adjuvant chemotherapy, then our test is better suited for this patient population."

Patients with a signature-predicted high risk of recurrence were more than twice as likely to have a recurrence as were their counterparts with a signature-predicted low risk (hazard ratio, 2.06; P = .02).

In contrast, the combination of criteria suggested by the National Comprehensive Cancer Network (NCCN) (T4 stage, fewer than 12 lymph nodes examined, grade of 3 or 4, lymphovascular invasion, bowel obstruction, localized perforation, or close, indeterminate, or positive margins) did not significantly predict risk.

"We are the first prognostic test in colorectal cancer to target stage I. The others target stage II and III," Dr. Lenehan added.

"The importance for us is that 10%-15% of stage I colorectal cancer patients actually recur and succumb to their disease," he said. "The standard of care for this stage is no treatment. And therefore, you have 3,000 or 4,000 patients per year which are potentially missing treatment that could potentially help them."

The signature could also be used to select only high-risk stage I patients for a clinical trial of adjuvant therapy, which would dramatically reduce the number of patients needed to determine benefit, he added.

GCC Expression in Lymph Nodes

Expression in lymph nodes of mRNA of the enzyme guanylyl cyclase C (GCC) predicts recurrence in patients with stage II colon cancer, according to Daniel J. Sargent, Ph.D., a professor of biostatistics and of oncology at the Mayo Clinic in Rochester, Minn.

"GCC is a marker that is only present in the colon, and if you find the GCC marker in the lymph nodes, it indicates that the tumor has metastasized from the colon to the lymph nodes," he explained in an interview. "So the presence of GCC in the lymph nodes should be a negative prognostic marker, and that’s indeed what we found."

The investigators retrospectively studied 241 patients who underwent resection for stage II colon cancer, did not receive adjuvant therapy, and had a minimum follow-up of 36 months. With a median follow-up of 60 months, 12% had a recurrence or cancer-related death. Some 10-41 lymph nodes (median, 15) were evaluated per patient.

The GCC assay results were expressed as a lymph node ratio (number of positive nodes divided by total number of informative nodes). In all, 35% of patients had a lymph node ratio of greater than 0.1.

These patients had more than double the risk of recurrence, compared with their counterparts who had a lower ratio (HR, 2.38; P = .02). The estimated 5-year rate of recurrence was 27% for the former and 10% for the latter.

The findings were even stronger in the subgroup of 181 patients with highly favorable clinical and pathological factors – namely, a T3 tumor, at least 12 lymph nodes examined, and negative margins – a third of whom had a lymph node ratio of greater than 0.1 (HR, 5.06; P = .003). Here, the estimated 5-year rate of recurrence was 27% with a ratio greater than 0.1 and just 4% with a lower ratio.

In a multivariate analysis among all patients that included potential confounders (age, T stage, number of lymph nodes assessed, and mismatch repair status), a GCC lymph node ratio greater than 0.1 was associated with a 2.61-fold higher risk of recurrence (P = .02).

The findings, which are considered preliminary, are being validated among an additional 500 patients, according to Dr. Sargent. "We think this is a very promising marker to be able to give patients with stage II disease an accurate prediction of what’s their likelihood of recurrence," he commented.

"We were able to define two-thirds of the population that have such a low risk for recurrence that I think it would be quite questionable whether there would be any potential reason to treat such patients," Dr. Sargent said, "whereas in the one-third of patients with high risk, they really look like stage III patients, and you might consider them as appropriate for treatment."

Tumor CDK1 Activity

Tumor activity of cyclin-dependent kinase 1 (CDK1), a key regulator of cell cycle progression, is a very strong and independent predictor of recurrence in patients with stage II colon cancer, investigators also reported.

"We believe that cell cycle profiling, the speed of the cell cycle, could be really important to predict tumor recurrence," said Dr. Masaki Shibayama of the Sysmex Corp. in Kobe, Japan, in an interview. Rapid proliferation "is one of the central hallmarks of cancer," he noted.

The investigators used the Cell Cycle Profiling (C2P) system (manufactured by Sysmex) to assess CDK1 enzymatic activity in fresh-frozen tumor samples from 254 patients from Germany and the Netherlands who underwent resection for stage II colon cancer and did not receive adjuvant therapy. With a median follow-up of 86 months, 11% developed distant metastases.

Some 40% of patients had a specific activity level of CDK1 that exceeded the cutoff of 11 and were classified as high risk, whereas 60% had a level of 11 or less and were classified as low risk. Relative to their low-risk peers, the high-risk patients were markedly more likely to develop distant metastases (HR, 6.2; P = .005) and to die from their cancer (HR, 7.6; P = .001).

These very high hazard ratios set this assay apart from other prognostic assays in stage II colon cancer, according to lead investigator Dr. Matthias Maak, a surgeon at the Technical University of Munich.

The hazard ratio for distant metastases was essentially the same after adjustment for age, sex, grade, and pathological T stage. It was still high (although no longer significant) after adjustment for tumor stroma content, possibly as a result of missing data for this parameter in about a third of cases.

"We believe this is a very nice result," Dr. Shibayama commented, and the assay may also extend to other solid tumors. "For example, we have a similar study for breast cancer, and it is also successful."

"This looks very promising," Dr. Maak concurred. "But this is, let’s say, the first test [of this assay] in colorectal carcinoma. Now we need more validation to find out if this works with another cohort, for example, or for another hospital. But we are rather positive that it will be as promising as it was in this trial."

Dr. Lenehan is an employee of Everist Genomics Inc. Dr. Sargent reported that his institution received research funding from DiagnoCure Inc. Dr. Shibayama is an employee of Sysmex Corp.; Dr. Maak did not report any conflicts of interest.

SAN FRANCISCO – Advances in molecular prognosis may soon make it possible to predict the risk of recurrence of early colorectal cancer after curative resection – and thus the need for adjuvant therapy in patients who might not otherwise receive further treatment.

Five-Gene Tumor Signature

A new five-gene tumor prognostic signature has performed well in external validation testing among patients with stage I or II disease, according to Dr. Peter F. Lenehan, chief medical officer of Everist Genomics Inc., in Ann Arbor, Mich.

Dr. Lenehan and his coinvestigators validated the gene signature among 115 patients who had undergone curative resection for stage I or II colon cancer or stage I rectal cancer and did not receive adjuvant therapy. Some 40% experienced a recurrence within 3 years.

For predicting recurrence, the signature had a sensitivity of 70%, a specificity of 55%, a positive predictive value of 51%, and a negative predictive value of 73%. The overall accuracy was 61%.

Other prognostic tests can differentiate patients who will not recur, Dr. Lenehan said, but "we alone are best able to predict who is going to recur. For this population, we believe this is more clinically significant because the default position is not to treat stage I and II.

"So if we are able to detect those that actually need more aggressive follow-up or high consideration for adjuvant chemotherapy, then our test is better suited for this patient population."

Patients with a signature-predicted high risk of recurrence were more than twice as likely to have a recurrence as were their counterparts with a signature-predicted low risk (hazard ratio, 2.06; P = .02).

In contrast, the combination of criteria suggested by the National Comprehensive Cancer Network (NCCN) (T4 stage, fewer than 12 lymph nodes examined, grade of 3 or 4, lymphovascular invasion, bowel obstruction, localized perforation, or close, indeterminate, or positive margins) did not significantly predict risk.

"We are the first prognostic test in colorectal cancer to target stage I. The others target stage II and III," Dr. Lenehan added.

"The importance for us is that 10%-15% of stage I colorectal cancer patients actually recur and succumb to their disease," he said. "The standard of care for this stage is no treatment. And therefore, you have 3,000 or 4,000 patients per year which are potentially missing treatment that could potentially help them."

The signature could also be used to select only high-risk stage I patients for a clinical trial of adjuvant therapy, which would dramatically reduce the number of patients needed to determine benefit, he added.

GCC Expression in Lymph Nodes

Expression in lymph nodes of mRNA of the enzyme guanylyl cyclase C (GCC) predicts recurrence in patients with stage II colon cancer, according to Daniel J. Sargent, Ph.D., a professor of biostatistics and of oncology at the Mayo Clinic in Rochester, Minn.

"GCC is a marker that is only present in the colon, and if you find the GCC marker in the lymph nodes, it indicates that the tumor has metastasized from the colon to the lymph nodes," he explained in an interview. "So the presence of GCC in the lymph nodes should be a negative prognostic marker, and that’s indeed what we found."

The investigators retrospectively studied 241 patients who underwent resection for stage II colon cancer, did not receive adjuvant therapy, and had a minimum follow-up of 36 months. With a median follow-up of 60 months, 12% had a recurrence or cancer-related death. Some 10-41 lymph nodes (median, 15) were evaluated per patient.

The GCC assay results were expressed as a lymph node ratio (number of positive nodes divided by total number of informative nodes). In all, 35% of patients had a lymph node ratio of greater than 0.1.

These patients had more than double the risk of recurrence, compared with their counterparts who had a lower ratio (HR, 2.38; P = .02). The estimated 5-year rate of recurrence was 27% for the former and 10% for the latter.

The findings were even stronger in the subgroup of 181 patients with highly favorable clinical and pathological factors – namely, a T3 tumor, at least 12 lymph nodes examined, and negative margins – a third of whom had a lymph node ratio of greater than 0.1 (HR, 5.06; P = .003). Here, the estimated 5-year rate of recurrence was 27% with a ratio greater than 0.1 and just 4% with a lower ratio.

In a multivariate analysis among all patients that included potential confounders (age, T stage, number of lymph nodes assessed, and mismatch repair status), a GCC lymph node ratio greater than 0.1 was associated with a 2.61-fold higher risk of recurrence (P = .02).

The findings, which are considered preliminary, are being validated among an additional 500 patients, according to Dr. Sargent. "We think this is a very promising marker to be able to give patients with stage II disease an accurate prediction of what’s their likelihood of recurrence," he commented.

"We were able to define two-thirds of the population that have such a low risk for recurrence that I think it would be quite questionable whether there would be any potential reason to treat such patients," Dr. Sargent said, "whereas in the one-third of patients with high risk, they really look like stage III patients, and you might consider them as appropriate for treatment."

Tumor CDK1 Activity

Tumor activity of cyclin-dependent kinase 1 (CDK1), a key regulator of cell cycle progression, is a very strong and independent predictor of recurrence in patients with stage II colon cancer, investigators also reported.

"We believe that cell cycle profiling, the speed of the cell cycle, could be really important to predict tumor recurrence," said Dr. Masaki Shibayama of the Sysmex Corp. in Kobe, Japan, in an interview. Rapid proliferation "is one of the central hallmarks of cancer," he noted.

The investigators used the Cell Cycle Profiling (C2P) system (manufactured by Sysmex) to assess CDK1 enzymatic activity in fresh-frozen tumor samples from 254 patients from Germany and the Netherlands who underwent resection for stage II colon cancer and did not receive adjuvant therapy. With a median follow-up of 86 months, 11% developed distant metastases.

Some 40% of patients had a specific activity level of CDK1 that exceeded the cutoff of 11 and were classified as high risk, whereas 60% had a level of 11 or less and were classified as low risk. Relative to their low-risk peers, the high-risk patients were markedly more likely to develop distant metastases (HR, 6.2; P = .005) and to die from their cancer (HR, 7.6; P = .001).

These very high hazard ratios set this assay apart from other prognostic assays in stage II colon cancer, according to lead investigator Dr. Matthias Maak, a surgeon at the Technical University of Munich.

The hazard ratio for distant metastases was essentially the same after adjustment for age, sex, grade, and pathological T stage. It was still high (although no longer significant) after adjustment for tumor stroma content, possibly as a result of missing data for this parameter in about a third of cases.

"We believe this is a very nice result," Dr. Shibayama commented, and the assay may also extend to other solid tumors. "For example, we have a similar study for breast cancer, and it is also successful."

"This looks very promising," Dr. Maak concurred. "But this is, let’s say, the first test [of this assay] in colorectal carcinoma. Now we need more validation to find out if this works with another cohort, for example, or for another hospital. But we are rather positive that it will be as promising as it was in this trial."

Dr. Lenehan is an employee of Everist Genomics Inc. Dr. Sargent reported that his institution received research funding from DiagnoCure Inc. Dr. Shibayama is an employee of Sysmex Corp.; Dr. Maak did not report any conflicts of interest.

SAN FRANCISCO – Advances in molecular prognosis may soon make it possible to predict the risk of recurrence of early colorectal cancer after curative resection – and thus the need for adjuvant therapy in patients who might not otherwise receive further treatment.

Five-Gene Tumor Signature

A new five-gene tumor prognostic signature has performed well in external validation testing among patients with stage I or II disease, according to Dr. Peter F. Lenehan, chief medical officer of Everist Genomics Inc., in Ann Arbor, Mich.

Dr. Lenehan and his coinvestigators validated the gene signature among 115 patients who had undergone curative resection for stage I or II colon cancer or stage I rectal cancer and did not receive adjuvant therapy. Some 40% experienced a recurrence within 3 years.

For predicting recurrence, the signature had a sensitivity of 70%, a specificity of 55%, a positive predictive value of 51%, and a negative predictive value of 73%. The overall accuracy was 61%.

Other prognostic tests can differentiate patients who will not recur, Dr. Lenehan said, but "we alone are best able to predict who is going to recur. For this population, we believe this is more clinically significant because the default position is not to treat stage I and II.

"So if we are able to detect those that actually need more aggressive follow-up or high consideration for adjuvant chemotherapy, then our test is better suited for this patient population."

Patients with a signature-predicted high risk of recurrence were more than twice as likely to have a recurrence as were their counterparts with a signature-predicted low risk (hazard ratio, 2.06; P = .02).

In contrast, the combination of criteria suggested by the National Comprehensive Cancer Network (NCCN) (T4 stage, fewer than 12 lymph nodes examined, grade of 3 or 4, lymphovascular invasion, bowel obstruction, localized perforation, or close, indeterminate, or positive margins) did not significantly predict risk.

"We are the first prognostic test in colorectal cancer to target stage I. The others target stage II and III," Dr. Lenehan added.

"The importance for us is that 10%-15% of stage I colorectal cancer patients actually recur and succumb to their disease," he said. "The standard of care for this stage is no treatment. And therefore, you have 3,000 or 4,000 patients per year which are potentially missing treatment that could potentially help them."

The signature could also be used to select only high-risk stage I patients for a clinical trial of adjuvant therapy, which would dramatically reduce the number of patients needed to determine benefit, he added.

GCC Expression in Lymph Nodes

Expression in lymph nodes of mRNA of the enzyme guanylyl cyclase C (GCC) predicts recurrence in patients with stage II colon cancer, according to Daniel J. Sargent, Ph.D., a professor of biostatistics and of oncology at the Mayo Clinic in Rochester, Minn.

"GCC is a marker that is only present in the colon, and if you find the GCC marker in the lymph nodes, it indicates that the tumor has metastasized from the colon to the lymph nodes," he explained in an interview. "So the presence of GCC in the lymph nodes should be a negative prognostic marker, and that’s indeed what we found."

The investigators retrospectively studied 241 patients who underwent resection for stage II colon cancer, did not receive adjuvant therapy, and had a minimum follow-up of 36 months. With a median follow-up of 60 months, 12% had a recurrence or cancer-related death. Some 10-41 lymph nodes (median, 15) were evaluated per patient.

The GCC assay results were expressed as a lymph node ratio (number of positive nodes divided by total number of informative nodes). In all, 35% of patients had a lymph node ratio of greater than 0.1.

These patients had more than double the risk of recurrence, compared with their counterparts who had a lower ratio (HR, 2.38; P = .02). The estimated 5-year rate of recurrence was 27% for the former and 10% for the latter.

The findings were even stronger in the subgroup of 181 patients with highly favorable clinical and pathological factors – namely, a T3 tumor, at least 12 lymph nodes examined, and negative margins – a third of whom had a lymph node ratio of greater than 0.1 (HR, 5.06; P = .003). Here, the estimated 5-year rate of recurrence was 27% with a ratio greater than 0.1 and just 4% with a lower ratio.

In a multivariate analysis among all patients that included potential confounders (age, T stage, number of lymph nodes assessed, and mismatch repair status), a GCC lymph node ratio greater than 0.1 was associated with a 2.61-fold higher risk of recurrence (P = .02).

The findings, which are considered preliminary, are being validated among an additional 500 patients, according to Dr. Sargent. "We think this is a very promising marker to be able to give patients with stage II disease an accurate prediction of what’s their likelihood of recurrence," he commented.

"We were able to define two-thirds of the population that have such a low risk for recurrence that I think it would be quite questionable whether there would be any potential reason to treat such patients," Dr. Sargent said, "whereas in the one-third of patients with high risk, they really look like stage III patients, and you might consider them as appropriate for treatment."

Tumor CDK1 Activity

Tumor activity of cyclin-dependent kinase 1 (CDK1), a key regulator of cell cycle progression, is a very strong and independent predictor of recurrence in patients with stage II colon cancer, investigators also reported.

"We believe that cell cycle profiling, the speed of the cell cycle, could be really important to predict tumor recurrence," said Dr. Masaki Shibayama of the Sysmex Corp. in Kobe, Japan, in an interview. Rapid proliferation "is one of the central hallmarks of cancer," he noted.

The investigators used the Cell Cycle Profiling (C2P) system (manufactured by Sysmex) to assess CDK1 enzymatic activity in fresh-frozen tumor samples from 254 patients from Germany and the Netherlands who underwent resection for stage II colon cancer and did not receive adjuvant therapy. With a median follow-up of 86 months, 11% developed distant metastases.

Some 40% of patients had a specific activity level of CDK1 that exceeded the cutoff of 11 and were classified as high risk, whereas 60% had a level of 11 or less and were classified as low risk. Relative to their low-risk peers, the high-risk patients were markedly more likely to develop distant metastases (HR, 6.2; P = .005) and to die from their cancer (HR, 7.6; P = .001).

These very high hazard ratios set this assay apart from other prognostic assays in stage II colon cancer, according to lead investigator Dr. Matthias Maak, a surgeon at the Technical University of Munich.

The hazard ratio for distant metastases was essentially the same after adjustment for age, sex, grade, and pathological T stage. It was still high (although no longer significant) after adjustment for tumor stroma content, possibly as a result of missing data for this parameter in about a third of cases.

"We believe this is a very nice result," Dr. Shibayama commented, and the assay may also extend to other solid tumors. "For example, we have a similar study for breast cancer, and it is also successful."

"This looks very promising," Dr. Maak concurred. "But this is, let’s say, the first test [of this assay] in colorectal carcinoma. Now we need more validation to find out if this works with another cohort, for example, or for another hospital. But we are rather positive that it will be as promising as it was in this trial."

Dr. Lenehan is an employee of Everist Genomics Inc. Dr. Sargent reported that his institution received research funding from DiagnoCure Inc. Dr. Shibayama is an employee of Sysmex Corp.; Dr. Maak did not report any conflicts of interest.

SAN FRANCISCO – National trends in gastrointestinal stromal tumors suggest that diagnosis of this malignancy has become more accurate and survival has improved in recent years, thanks to some key advances in molecular medicine.

In a population-based study, the number of new cases of gastrointestinal stromal tumors (GIST) annually rose almost fivefold between 1998 and 2002, according to results reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. It leveled off thereafter.

Lead investigator Dr. Elan R. Witkowski attributed the sharp rise mainly to the advent of testing for c-kit mutations, which drive the disease in the vast majority of cases. "Since [we’ve had] the ability to test for c-kit mutations, the diagnosis became much more precise," he explained in an interview, so tumors that would have otherwise been misclassified are now correctly recognized to be GIST.

Researchers should take note, according to Dr. Witkowski, a surgical resident at the University of Massachusetts in Worcester. "Prior to 2002, we probably shouldn’t be using this code to do research, [but] from 2002 on, we think it’s safe to do research with that one specific code," he said.

The study also found that survival was significantly better for patients with GIST that was diagnosed in 2005-2007 than for their counterparts with GIST that was diagnosed in 2002-2004.

"Our hypothesis is that the availability of Gleevec [imatinib] and the broadening of its indications are what are primarily responsible for that survival benefit," he commented, noting that there were no major advances in surgery or radiation therapy for the disease during that same time period.

Imatinib, manufactured by Novartis, is an inhibitor of the c-KIT tyrosine kinase (as well as the BCR-ABL and platelet-derived growth factor receptor tyrosine kinases). It was initially approved for GIST by the Food and Drug Administration in 2002, for the treatment of KIT-positive, unresectable and/or metastatic malignant tumors. Its GIST indication was later expanded to include adjuvant treatment in adults after resection of KIT-positive tumors.

For the study, the investigators analyzed data from the SEER (Surveillance, Epidemiology, and End Results) database for the years 1998-2007. They identified cases of GIST using the GIST-specific diagnostic code 8936 from the International Classification of Diseases for Oncology, third revision (ICD-O-3).

Analyses were based on 3,568 adult patients with a new GIST diagnosis. They were 63 years old on average, and the majority was white (71%) and male (53%), according to results reported in a poster session. Their tumors predominantly were in the stomach (52%) or small bowel (30%), and had a SEER stage of localized (51%).

Results showed that the annual number of new GIST cases in the database rose sharply between 1998 and 2002 (from approximately 100 to nearly 500), but remained fairly steady thereafter. The same pattern was also evident across individual centers participating in SEER, according to Dr. Witkowski.

"One of the things you see in the literature – particularly in prior years – is that it approximated the incidence of GIST by using a number of different variables because the diagnosis was not certain. So you had 10, 12, 15 variables that were often being combined together to approximate GIST," he commented. "Coinciding with [the increase in GIST diagnoses] was a decrease of all those other diagnosis codes that used to be used to approximate it."

The proportion of the patients who had a recommendation for surgery in their records fell between 2002 and 2007, from 85% to 80% (P = .0008). And the proportion of patients who actually underwent surgery fell as well, although not significantly so.

"Before the availability of Gleevec, surgery was really the only chance for significant response," said Dr. Witkowski. "So I think people were generally more aggressive."

Median overall survival improved in a comparison of patients receiving a new diagnosis in 2002-2004 with their peers receiving a new diagnosis in 2005-2007, with the actuarial 3-year rate increasing from approximately 70% to 75% (P = .03). Improved survival was noted both for patients who underwent resection and for those who did not.

In adjusted analyses for the years 2002-2007, patients had a decreased risk of death with each increase in the year of diagnosis (hazard ratio, 0.9) and if they underwent surgery (HR, 0.5).

On the other hand, they had an increased risk of death if they had a distant or regional stage of disease vs. a localized stage (HR, 2.4 and 1.6) or were male (HR, 1.2). Also, the risk rose with age (HR, 1.1).

Dr. Witkowski reported having no conflicts of interest related to the study.

SAN FRANCISCO – National trends in gastrointestinal stromal tumors suggest that diagnosis of this malignancy has become more accurate and survival has improved in recent years, thanks to some key advances in molecular medicine.

In a population-based study, the number of new cases of gastrointestinal stromal tumors (GIST) annually rose almost fivefold between 1998 and 2002, according to results reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. It leveled off thereafter.

Lead investigator Dr. Elan R. Witkowski attributed the sharp rise mainly to the advent of testing for c-kit mutations, which drive the disease in the vast majority of cases. "Since [we’ve had] the ability to test for c-kit mutations, the diagnosis became much more precise," he explained in an interview, so tumors that would have otherwise been misclassified are now correctly recognized to be GIST.

Researchers should take note, according to Dr. Witkowski, a surgical resident at the University of Massachusetts in Worcester. "Prior to 2002, we probably shouldn’t be using this code to do research, [but] from 2002 on, we think it’s safe to do research with that one specific code," he said.

The study also found that survival was significantly better for patients with GIST that was diagnosed in 2005-2007 than for their counterparts with GIST that was diagnosed in 2002-2004.

"Our hypothesis is that the availability of Gleevec [imatinib] and the broadening of its indications are what are primarily responsible for that survival benefit," he commented, noting that there were no major advances in surgery or radiation therapy for the disease during that same time period.

Imatinib, manufactured by Novartis, is an inhibitor of the c-KIT tyrosine kinase (as well as the BCR-ABL and platelet-derived growth factor receptor tyrosine kinases). It was initially approved for GIST by the Food and Drug Administration in 2002, for the treatment of KIT-positive, unresectable and/or metastatic malignant tumors. Its GIST indication was later expanded to include adjuvant treatment in adults after resection of KIT-positive tumors.

For the study, the investigators analyzed data from the SEER (Surveillance, Epidemiology, and End Results) database for the years 1998-2007. They identified cases of GIST using the GIST-specific diagnostic code 8936 from the International Classification of Diseases for Oncology, third revision (ICD-O-3).

Analyses were based on 3,568 adult patients with a new GIST diagnosis. They were 63 years old on average, and the majority was white (71%) and male (53%), according to results reported in a poster session. Their tumors predominantly were in the stomach (52%) or small bowel (30%), and had a SEER stage of localized (51%).

Results showed that the annual number of new GIST cases in the database rose sharply between 1998 and 2002 (from approximately 100 to nearly 500), but remained fairly steady thereafter. The same pattern was also evident across individual centers participating in SEER, according to Dr. Witkowski.

"One of the things you see in the literature – particularly in prior years – is that it approximated the incidence of GIST by using a number of different variables because the diagnosis was not certain. So you had 10, 12, 15 variables that were often being combined together to approximate GIST," he commented. "Coinciding with [the increase in GIST diagnoses] was a decrease of all those other diagnosis codes that used to be used to approximate it."

The proportion of the patients who had a recommendation for surgery in their records fell between 2002 and 2007, from 85% to 80% (P = .0008). And the proportion of patients who actually underwent surgery fell as well, although not significantly so.

"Before the availability of Gleevec, surgery was really the only chance for significant response," said Dr. Witkowski. "So I think people were generally more aggressive."

Median overall survival improved in a comparison of patients receiving a new diagnosis in 2002-2004 with their peers receiving a new diagnosis in 2005-2007, with the actuarial 3-year rate increasing from approximately 70% to 75% (P = .03). Improved survival was noted both for patients who underwent resection and for those who did not.

In adjusted analyses for the years 2002-2007, patients had a decreased risk of death with each increase in the year of diagnosis (hazard ratio, 0.9) and if they underwent surgery (HR, 0.5).

On the other hand, they had an increased risk of death if they had a distant or regional stage of disease vs. a localized stage (HR, 2.4 and 1.6) or were male (HR, 1.2). Also, the risk rose with age (HR, 1.1).

Dr. Witkowski reported having no conflicts of interest related to the study.

SAN FRANCISCO – National trends in gastrointestinal stromal tumors suggest that diagnosis of this malignancy has become more accurate and survival has improved in recent years, thanks to some key advances in molecular medicine.

In a population-based study, the number of new cases of gastrointestinal stromal tumors (GIST) annually rose almost fivefold between 1998 and 2002, according to results reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. It leveled off thereafter.

Lead investigator Dr. Elan R. Witkowski attributed the sharp rise mainly to the advent of testing for c-kit mutations, which drive the disease in the vast majority of cases. "Since [we’ve had] the ability to test for c-kit mutations, the diagnosis became much more precise," he explained in an interview, so tumors that would have otherwise been misclassified are now correctly recognized to be GIST.

Researchers should take note, according to Dr. Witkowski, a surgical resident at the University of Massachusetts in Worcester. "Prior to 2002, we probably shouldn’t be using this code to do research, [but] from 2002 on, we think it’s safe to do research with that one specific code," he said.

The study also found that survival was significantly better for patients with GIST that was diagnosed in 2005-2007 than for their counterparts with GIST that was diagnosed in 2002-2004.

"Our hypothesis is that the availability of Gleevec [imatinib] and the broadening of its indications are what are primarily responsible for that survival benefit," he commented, noting that there were no major advances in surgery or radiation therapy for the disease during that same time period.

Imatinib, manufactured by Novartis, is an inhibitor of the c-KIT tyrosine kinase (as well as the BCR-ABL and platelet-derived growth factor receptor tyrosine kinases). It was initially approved for GIST by the Food and Drug Administration in 2002, for the treatment of KIT-positive, unresectable and/or metastatic malignant tumors. Its GIST indication was later expanded to include adjuvant treatment in adults after resection of KIT-positive tumors.

For the study, the investigators analyzed data from the SEER (Surveillance, Epidemiology, and End Results) database for the years 1998-2007. They identified cases of GIST using the GIST-specific diagnostic code 8936 from the International Classification of Diseases for Oncology, third revision (ICD-O-3).

Analyses were based on 3,568 adult patients with a new GIST diagnosis. They were 63 years old on average, and the majority was white (71%) and male (53%), according to results reported in a poster session. Their tumors predominantly were in the stomach (52%) or small bowel (30%), and had a SEER stage of localized (51%).

Results showed that the annual number of new GIST cases in the database rose sharply between 1998 and 2002 (from approximately 100 to nearly 500), but remained fairly steady thereafter. The same pattern was also evident across individual centers participating in SEER, according to Dr. Witkowski.

"One of the things you see in the literature – particularly in prior years – is that it approximated the incidence of GIST by using a number of different variables because the diagnosis was not certain. So you had 10, 12, 15 variables that were often being combined together to approximate GIST," he commented. "Coinciding with [the increase in GIST diagnoses] was a decrease of all those other diagnosis codes that used to be used to approximate it."

The proportion of the patients who had a recommendation for surgery in their records fell between 2002 and 2007, from 85% to 80% (P = .0008). And the proportion of patients who actually underwent surgery fell as well, although not significantly so.

"Before the availability of Gleevec, surgery was really the only chance for significant response," said Dr. Witkowski. "So I think people were generally more aggressive."

Median overall survival improved in a comparison of patients receiving a new diagnosis in 2002-2004 with their peers receiving a new diagnosis in 2005-2007, with the actuarial 3-year rate increasing from approximately 70% to 75% (P = .03). Improved survival was noted both for patients who underwent resection and for those who did not.

In adjusted analyses for the years 2002-2007, patients had a decreased risk of death with each increase in the year of diagnosis (hazard ratio, 0.9) and if they underwent surgery (HR, 0.5).

On the other hand, they had an increased risk of death if they had a distant or regional stage of disease vs. a localized stage (HR, 2.4 and 1.6) or were male (HR, 1.2). Also, the risk rose with age (HR, 1.1).

Dr. Witkowski reported having no conflicts of interest related to the study.

SAN FRANCISCO – Early amniotomy appears safe and efficacious for shortening labor at term in nulliparous women having an indication for labor induction, according to results of a randomized controlled trial.

Among the 585 women studied, the average time from induction to delivery was 2.3 hours, or 11% shorter with early amniotomy vs. standard care, investigators reported at the meeting This benefit was achieved without an increase in rates of maternal or neonatal infections.

“Based on this clinical trial, it would seem that early amniotomy may be a useful adjunct for nulliparous labor inductions,” said Dr. George A. Macones, the Mitchell and Elaine Yanow Professor and chair of the department of ob.gyn. at Washington University in St. Louis.

Many studies have evaluated different methods of labor induction, he noted. “However, surprisingly, there are very few data on the timing of amniotomy in labor induction and how this may improve or worsen outcomes.”

Amniotomy is easy and inexpensive and may shorten labor, according to Dr. Macones. But it also may be associated with rare complications such as umbilical cord prolapse, and possibly with an increased infection risk resulting from a longer duration of ruptured membranes.

Women were eligible for the trial if they were nulliparous, had a singleton pregnancy, were at term (37 weeks' gestation or later), and needed induction as determined by their treating physician. They were excluded if they were HIV positive or had cervical dilatation exceeding 4 cm at the time of admission to labor and delivery.

The women were randomly assigned in a 1:1 ratio to nonblinded management with either early amniotomy (defined as artificial rupture of membranes performed when cervical dilatation was equal to or less than 4 cm) or standard care (defined as artificial rupture of membranes performed when cervical dilatation was greater than 4 cm). The primary method of induction (misoprostol, cervical Foley catheter, oxytocin, and/or prostaglandin gel) was left to the treating physician's discretion. “Just to be clear, we did not study the timing of amniotomy as a primary method of induction, but rather as an adjunct to other methods,” Dr. Macones noted.

All other decisions about intrapartum and postpartum care were similarly left up to the treating physicians. The 585 women randomized were 23 years old on average, and the majority (70%) was black. Almost a third had gestational hypertension or preeclampsia, and another third were positive for group B streptococcus. The mean gestational age was about 39.5 weeks, and the mean cervical dilatation was 1.1 cm on admission. The leading indications for induction were a gestation past 40 weeks (39%) and gestational hypertension or preeclampsia (28%).

The primary methods of induction used were similar across groups. In nearly three-fourths of women, the treating physicians used multiple methods.

Most women received epidural analgesia, with no difference between groups, according to Dr. Macones.

Median cervical dilatation at the time of rupture of membranes was 4 cm less in the early amniotomy group, compared with the standard care group (3.0 vs. 7.0 cm; P = .001). In intent-to-treat analyses, the time from induction to delivery was 2.3 hours shorter with early amniotomy (19.0 vs. 21.3 hours; P = .004). “This difference in the length of labor occurred mainly and not surprisingly in the first stage of labor, but not in the second stage,” Dr. Macones noted. In addition, these women were more likely to deliver within 24 hours of labor induction (68% vs. 56%; P = .002).

The early amniotomy group did not differ significantly from the standard care group with respect to rates of cesarean delivery (41% vs. 40%), cord prolapse (0.7% vs. 0%), and abruption (0.4% vs. 0.6%).

Fetal heart rate data were not analyzed, but rates of amnioinfusion (a “reasonable proxy” for variable decelerations) were similar, according to Dr. Macones.

The two groups also had statistically indistinguishable rates of infectious outcomes, including chorioamnionitis (11.5% vs. 8.5%) postpartum fever (10.4% vs. 9.4%) in the mother, and NICU admission (13.6% vs. 15.0%) and suspected or confirmed sepsis (9.7% vs. 11.1%) in the neonate.

In questions posed after the presentation, one attendee asked how the 4-cm threshold was selected for early amniotomy, and whether the findings would be similar with, say, a 2-cm threshold instead. “We chose 4 cm based on some earlier work in spontaneous labor with rupturing membranes,” Dr. Macones explained. “I agree that we could dial that down a bit.” However, within the early amniotomy group, the efficacy and safety findings appeared similar regardless of the timing of the procedure, he said.

When asked if the study was mixing cervical ripening with labor induction, Dr. Macones said, “I think the lines between ripening and induction are actually quite gray.” He contended that the study's aim was to assess the impact of amniotomy when the intention was to perform it as early as possible.

An alternative approach would be to look at women once their cervix is ripened and then ask what the role of amniotomy is, he acknowledged. “But I think that's a little bit different question than we actually had.”

Dr. Macones did not report any relevant financial disclosures.

'This difference in length of labor occurred mainly and not surprisingly in the first stage of labor.'

Source DR. MACONES

SAN FRANCISCO – Early amniotomy appears safe and efficacious for shortening labor at term in nulliparous women having an indication for labor induction, according to results of a randomized controlled trial.

Among the 585 women studied, the average time from induction to delivery was 2.3 hours, or 11% shorter with early amniotomy vs. standard care, investigators reported at the meeting This benefit was achieved without an increase in rates of maternal or neonatal infections.

“Based on this clinical trial, it would seem that early amniotomy may be a useful adjunct for nulliparous labor inductions,” said Dr. George A. Macones, the Mitchell and Elaine Yanow Professor and chair of the department of ob.gyn. at Washington University in St. Louis.

Many studies have evaluated different methods of labor induction, he noted. “However, surprisingly, there are very few data on the timing of amniotomy in labor induction and how this may improve or worsen outcomes.”

Amniotomy is easy and inexpensive and may shorten labor, according to Dr. Macones. But it also may be associated with rare complications such as umbilical cord prolapse, and possibly with an increased infection risk resulting from a longer duration of ruptured membranes.

Women were eligible for the trial if they were nulliparous, had a singleton pregnancy, were at term (37 weeks' gestation or later), and needed induction as determined by their treating physician. They were excluded if they were HIV positive or had cervical dilatation exceeding 4 cm at the time of admission to labor and delivery.

The women were randomly assigned in a 1:1 ratio to nonblinded management with either early amniotomy (defined as artificial rupture of membranes performed when cervical dilatation was equal to or less than 4 cm) or standard care (defined as artificial rupture of membranes performed when cervical dilatation was greater than 4 cm). The primary method of induction (misoprostol, cervical Foley catheter, oxytocin, and/or prostaglandin gel) was left to the treating physician's discretion. “Just to be clear, we did not study the timing of amniotomy as a primary method of induction, but rather as an adjunct to other methods,” Dr. Macones noted.

All other decisions about intrapartum and postpartum care were similarly left up to the treating physicians. The 585 women randomized were 23 years old on average, and the majority (70%) was black. Almost a third had gestational hypertension or preeclampsia, and another third were positive for group B streptococcus. The mean gestational age was about 39.5 weeks, and the mean cervical dilatation was 1.1 cm on admission. The leading indications for induction were a gestation past 40 weeks (39%) and gestational hypertension or preeclampsia (28%).

The primary methods of induction used were similar across groups. In nearly three-fourths of women, the treating physicians used multiple methods.

Most women received epidural analgesia, with no difference between groups, according to Dr. Macones.

Median cervical dilatation at the time of rupture of membranes was 4 cm less in the early amniotomy group, compared with the standard care group (3.0 vs. 7.0 cm; P = .001). In intent-to-treat analyses, the time from induction to delivery was 2.3 hours shorter with early amniotomy (19.0 vs. 21.3 hours; P = .004). “This difference in the length of labor occurred mainly and not surprisingly in the first stage of labor, but not in the second stage,” Dr. Macones noted. In addition, these women were more likely to deliver within 24 hours of labor induction (68% vs. 56%; P = .002).

The early amniotomy group did not differ significantly from the standard care group with respect to rates of cesarean delivery (41% vs. 40%), cord prolapse (0.7% vs. 0%), and abruption (0.4% vs. 0.6%).

Fetal heart rate data were not analyzed, but rates of amnioinfusion (a “reasonable proxy” for variable decelerations) were similar, according to Dr. Macones.

The two groups also had statistically indistinguishable rates of infectious outcomes, including chorioamnionitis (11.5% vs. 8.5%) postpartum fever (10.4% vs. 9.4%) in the mother, and NICU admission (13.6% vs. 15.0%) and suspected or confirmed sepsis (9.7% vs. 11.1%) in the neonate.

In questions posed after the presentation, one attendee asked how the 4-cm threshold was selected for early amniotomy, and whether the findings would be similar with, say, a 2-cm threshold instead. “We chose 4 cm based on some earlier work in spontaneous labor with rupturing membranes,” Dr. Macones explained. “I agree that we could dial that down a bit.” However, within the early amniotomy group, the efficacy and safety findings appeared similar regardless of the timing of the procedure, he said.

When asked if the study was mixing cervical ripening with labor induction, Dr. Macones said, “I think the lines between ripening and induction are actually quite gray.” He contended that the study's aim was to assess the impact of amniotomy when the intention was to perform it as early as possible.

An alternative approach would be to look at women once their cervix is ripened and then ask what the role of amniotomy is, he acknowledged. “But I think that's a little bit different question than we actually had.”

Dr. Macones did not report any relevant financial disclosures.

'This difference in length of labor occurred mainly and not surprisingly in the first stage of labor.'

Source DR. MACONES

SAN FRANCISCO – Early amniotomy appears safe and efficacious for shortening labor at term in nulliparous women having an indication for labor induction, according to results of a randomized controlled trial.

Among the 585 women studied, the average time from induction to delivery was 2.3 hours, or 11% shorter with early amniotomy vs. standard care, investigators reported at the meeting This benefit was achieved without an increase in rates of maternal or neonatal infections.

“Based on this clinical trial, it would seem that early amniotomy may be a useful adjunct for nulliparous labor inductions,” said Dr. George A. Macones, the Mitchell and Elaine Yanow Professor and chair of the department of ob.gyn. at Washington University in St. Louis.

Many studies have evaluated different methods of labor induction, he noted. “However, surprisingly, there are very few data on the timing of amniotomy in labor induction and how this may improve or worsen outcomes.”

Amniotomy is easy and inexpensive and may shorten labor, according to Dr. Macones. But it also may be associated with rare complications such as umbilical cord prolapse, and possibly with an increased infection risk resulting from a longer duration of ruptured membranes.

Women were eligible for the trial if they were nulliparous, had a singleton pregnancy, were at term (37 weeks' gestation or later), and needed induction as determined by their treating physician. They were excluded if they were HIV positive or had cervical dilatation exceeding 4 cm at the time of admission to labor and delivery.

The women were randomly assigned in a 1:1 ratio to nonblinded management with either early amniotomy (defined as artificial rupture of membranes performed when cervical dilatation was equal to or less than 4 cm) or standard care (defined as artificial rupture of membranes performed when cervical dilatation was greater than 4 cm). The primary method of induction (misoprostol, cervical Foley catheter, oxytocin, and/or prostaglandin gel) was left to the treating physician's discretion. “Just to be clear, we did not study the timing of amniotomy as a primary method of induction, but rather as an adjunct to other methods,” Dr. Macones noted.

All other decisions about intrapartum and postpartum care were similarly left up to the treating physicians. The 585 women randomized were 23 years old on average, and the majority (70%) was black. Almost a third had gestational hypertension or preeclampsia, and another third were positive for group B streptococcus. The mean gestational age was about 39.5 weeks, and the mean cervical dilatation was 1.1 cm on admission. The leading indications for induction were a gestation past 40 weeks (39%) and gestational hypertension or preeclampsia (28%).

The primary methods of induction used were similar across groups. In nearly three-fourths of women, the treating physicians used multiple methods.

Most women received epidural analgesia, with no difference between groups, according to Dr. Macones.

Median cervical dilatation at the time of rupture of membranes was 4 cm less in the early amniotomy group, compared with the standard care group (3.0 vs. 7.0 cm; P = .001). In intent-to-treat analyses, the time from induction to delivery was 2.3 hours shorter with early amniotomy (19.0 vs. 21.3 hours; P = .004). “This difference in the length of labor occurred mainly and not surprisingly in the first stage of labor, but not in the second stage,” Dr. Macones noted. In addition, these women were more likely to deliver within 24 hours of labor induction (68% vs. 56%; P = .002).

The early amniotomy group did not differ significantly from the standard care group with respect to rates of cesarean delivery (41% vs. 40%), cord prolapse (0.7% vs. 0%), and abruption (0.4% vs. 0.6%).

Fetal heart rate data were not analyzed, but rates of amnioinfusion (a “reasonable proxy” for variable decelerations) were similar, according to Dr. Macones.

The two groups also had statistically indistinguishable rates of infectious outcomes, including chorioamnionitis (11.5% vs. 8.5%) postpartum fever (10.4% vs. 9.4%) in the mother, and NICU admission (13.6% vs. 15.0%) and suspected or confirmed sepsis (9.7% vs. 11.1%) in the neonate.

In questions posed after the presentation, one attendee asked how the 4-cm threshold was selected for early amniotomy, and whether the findings would be similar with, say, a 2-cm threshold instead. “We chose 4 cm based on some earlier work in spontaneous labor with rupturing membranes,” Dr. Macones explained. “I agree that we could dial that down a bit.” However, within the early amniotomy group, the efficacy and safety findings appeared similar regardless of the timing of the procedure, he said.

When asked if the study was mixing cervical ripening with labor induction, Dr. Macones said, “I think the lines between ripening and induction are actually quite gray.” He contended that the study's aim was to assess the impact of amniotomy when the intention was to perform it as early as possible.

An alternative approach would be to look at women once their cervix is ripened and then ask what the role of amniotomy is, he acknowledged. “But I think that's a little bit different question than we actually had.”

Dr. Macones did not report any relevant financial disclosures.

'This difference in length of labor occurred mainly and not surprisingly in the first stage of labor.'

Source DR. MACONES

Major Finding: The rapid intrapartum GBS test, compared with antepartum culture, had a significantly better sensitivity (91% vs. 69%) and negative predictive value (97% vs. 91%). The specificity and positive predictive value were similarly high.

Data Source: A prospective study of 559 women in labor who had documented antepartum culture results and had not received intrapartum antibiotics.

Disclosures: Dr. Gupta did not report any relevant financial disclosures. Cepheid loaned the investigators the system used for rapid testing.

SAN FRANCISCO – A rapid intrapartum test for group B streptococcus may improve identification of colonized pregnant women, according to study results reported at the meeting

When the rapid test – a nucleic acid amplification test (NAAT) that yields results within an hour – was compared with a conventional antepartum bacterial culture, the rapid test was superior in identifying which of the 559 laboring women in the study had group B streptococcus (GBS) colonization (sensitivity, 91% vs. 69%). The rapid test also had a significantly better negative predictive value, and its specificity and positive predictive value were similarly high.

“In our population, intrapartum NAAT appeared to have superior test characteristics to antepartum culture for predicting intrapartum GBS culture status,” said Dr. Munish Gupta, an associate director of the neonatal intensive care unit at the Beth Israel Deaconess Medical Center in Boston.

“NAAT may be able to help identify women who are positive for GBS by intrapartum culture but negative by antepartum culture, a group of women that would be at particularly high risk for GBS transmission to their newborns by current standard management,” he commented.

In fact, about 60% of cases of neonatal early-onset GBS disease occur in infants born to mothers who screened negative by conventional means during their pregnancy, according to Dr. Gupta. “In addition, it has been well documented that results of antepartum GBS screening cultures do not always accurately predict intrapartum GBS status.”

The investigators prospectively studied pregnant women who were admitted to the labor and delivery department, had documented results of an antepartum GBS culture performed at 35–37 weeks' gestation, and had not received intrapartum antibiotics.

Two intrapartum rectovaginal samples were obtained according to Centers for Disease Control and Prevention guidelines.

One sample was sent for GBS culture by the hospital laboratory, and the result of this intrapartum culture served as the reference standard for the study, Dr. Gupta explained.

The other sample was used for rapid testing with the Xpert GBS test, performed in the department 24/7 on a system loaned to the investigators by the manufacturer, Cepheid.

“Of note, the intrapartum culture and NAAT results were not used for clinical management,” he pointed out.

Study results were based on 559 women who were 32 years old, on average. About 61% were white, 14% were Asian or Pacific Islander, 13% were black, 10% were Hispanic, and the rest were of other races or ethnicities.

The women had a mean gestational age of 39.4 weeks, and 99% had singleton pregnancies. Nearly three-fourths delivered vaginally.

Overall, 24% of the women had a positive result on the intrapartum GBS culture, according to Dr. Gupta.

The rapid test, compared with antepartum culture, had a significantly better sensitivity (91% vs. 69%) and negative predictive value (97% vs. 91%), and a similarly high specificity (98% vs. 96%) and positive predictive value (92% vs. 84%).

The results of antepartum and intrapartum culture were discordant in 10% of women overall. But the rate of discordance varied by race/ethnicity (P = .006), ranging from 4% in Asian women to 18% and 19% in their black and Hispanic counterparts, respectively.

Among women with a negative antepartum culture, 9% had a positive intrapartum culture, Dr. Gupta reported. Most of this subset did not receive intrapartum antibiotics (98%) and had infants who did not receive a sepsis evaluation (78%). Fully 81% of the subset had a positive rapid test result.

Previous studies of NAAT testing have raised concerns about the frequency of indeterminate test results in clinical practice, he noted. The results of the rapid test were indeterminate on first testing in 13% of the women studied, but they were indeterminate on repeated testing in merely 2%. The sample preparation time for the rapid test was 5 minutes, and the median processing time was 48 minutes, with 99.6% of samples processed in 50 minutes or less.

“Future work is needed to continue to explore the role of intrapartum GBS NAAT in clinical practice,” Dr. Gupta asserted. “It may be that the NAAT will prove to be a useful adjunct in certain populations in which the antepartum culture may not be a sufficient determinant of intrapartum GBS risk, such as [women who] are GBS negative on antepartum culture, black and Hispanic women, and preterm deliveries.”

The study did not have adequate power to assess the potential impact of the rapid test on neonatal outcomes, but they should be a focus in future studies, he recommended.

When asked by an attendee if he would argue with new guidelines that recommend prophylaxis in women with risk factors even if they have a negative NAAT test result, Dr. Gupta emphatically said he would not argue with them.

“I don't think any of us … involved in this study would look at the NAAT as a replacement for antepartum screening. Antepartum screening clearly has been incredibly effective and very important for reducing the burden of GBS disease, so I think the idea would be that NAAT might be a supplement in certain populations who are currently being missed by the antepartum culture,” he commented. “So I agree with current treatment for either antepartum culture–positive moms or moms with other risk factors. This [test] doesn't really seem to replace that.”

Major Finding: The rapid intrapartum GBS test, compared with antepartum culture, had a significantly better sensitivity (91% vs. 69%) and negative predictive value (97% vs. 91%). The specificity and positive predictive value were similarly high.

Data Source: A prospective study of 559 women in labor who had documented antepartum culture results and had not received intrapartum antibiotics.

Disclosures: Dr. Gupta did not report any relevant financial disclosures. Cepheid loaned the investigators the system used for rapid testing.

SAN FRANCISCO – A rapid intrapartum test for group B streptococcus may improve identification of colonized pregnant women, according to study results reported at the meeting

When the rapid test – a nucleic acid amplification test (NAAT) that yields results within an hour – was compared with a conventional antepartum bacterial culture, the rapid test was superior in identifying which of the 559 laboring women in the study had group B streptococcus (GBS) colonization (sensitivity, 91% vs. 69%). The rapid test also had a significantly better negative predictive value, and its specificity and positive predictive value were similarly high.

“In our population, intrapartum NAAT appeared to have superior test characteristics to antepartum culture for predicting intrapartum GBS culture status,” said Dr. Munish Gupta, an associate director of the neonatal intensive care unit at the Beth Israel Deaconess Medical Center in Boston.

“NAAT may be able to help identify women who are positive for GBS by intrapartum culture but negative by antepartum culture, a group of women that would be at particularly high risk for GBS transmission to their newborns by current standard management,” he commented.

In fact, about 60% of cases of neonatal early-onset GBS disease occur in infants born to mothers who screened negative by conventional means during their pregnancy, according to Dr. Gupta. “In addition, it has been well documented that results of antepartum GBS screening cultures do not always accurately predict intrapartum GBS status.”

The investigators prospectively studied pregnant women who were admitted to the labor and delivery department, had documented results of an antepartum GBS culture performed at 35–37 weeks' gestation, and had not received intrapartum antibiotics.

Two intrapartum rectovaginal samples were obtained according to Centers for Disease Control and Prevention guidelines.

One sample was sent for GBS culture by the hospital laboratory, and the result of this intrapartum culture served as the reference standard for the study, Dr. Gupta explained.

The other sample was used for rapid testing with the Xpert GBS test, performed in the department 24/7 on a system loaned to the investigators by the manufacturer, Cepheid.

“Of note, the intrapartum culture and NAAT results were not used for clinical management,” he pointed out.

Study results were based on 559 women who were 32 years old, on average. About 61% were white, 14% were Asian or Pacific Islander, 13% were black, 10% were Hispanic, and the rest were of other races or ethnicities.

The women had a mean gestational age of 39.4 weeks, and 99% had singleton pregnancies. Nearly three-fourths delivered vaginally.

Overall, 24% of the women had a positive result on the intrapartum GBS culture, according to Dr. Gupta.

The rapid test, compared with antepartum culture, had a significantly better sensitivity (91% vs. 69%) and negative predictive value (97% vs. 91%), and a similarly high specificity (98% vs. 96%) and positive predictive value (92% vs. 84%).

The results of antepartum and intrapartum culture were discordant in 10% of women overall. But the rate of discordance varied by race/ethnicity (P = .006), ranging from 4% in Asian women to 18% and 19% in their black and Hispanic counterparts, respectively.

Among women with a negative antepartum culture, 9% had a positive intrapartum culture, Dr. Gupta reported. Most of this subset did not receive intrapartum antibiotics (98%) and had infants who did not receive a sepsis evaluation (78%). Fully 81% of the subset had a positive rapid test result.

Previous studies of NAAT testing have raised concerns about the frequency of indeterminate test results in clinical practice, he noted. The results of the rapid test were indeterminate on first testing in 13% of the women studied, but they were indeterminate on repeated testing in merely 2%. The sample preparation time for the rapid test was 5 minutes, and the median processing time was 48 minutes, with 99.6% of samples processed in 50 minutes or less.

“Future work is needed to continue to explore the role of intrapartum GBS NAAT in clinical practice,” Dr. Gupta asserted. “It may be that the NAAT will prove to be a useful adjunct in certain populations in which the antepartum culture may not be a sufficient determinant of intrapartum GBS risk, such as [women who] are GBS negative on antepartum culture, black and Hispanic women, and preterm deliveries.”

The study did not have adequate power to assess the potential impact of the rapid test on neonatal outcomes, but they should be a focus in future studies, he recommended.

When asked by an attendee if he would argue with new guidelines that recommend prophylaxis in women with risk factors even if they have a negative NAAT test result, Dr. Gupta emphatically said he would not argue with them.

“I don't think any of us … involved in this study would look at the NAAT as a replacement for antepartum screening. Antepartum screening clearly has been incredibly effective and very important for reducing the burden of GBS disease, so I think the idea would be that NAAT might be a supplement in certain populations who are currently being missed by the antepartum culture,” he commented. “So I agree with current treatment for either antepartum culture–positive moms or moms with other risk factors. This [test] doesn't really seem to replace that.”

Major Finding: The rapid intrapartum GBS test, compared with antepartum culture, had a significantly better sensitivity (91% vs. 69%) and negative predictive value (97% vs. 91%). The specificity and positive predictive value were similarly high.

Data Source: A prospective study of 559 women in labor who had documented antepartum culture results and had not received intrapartum antibiotics.

Disclosures: Dr. Gupta did not report any relevant financial disclosures. Cepheid loaned the investigators the system used for rapid testing.

SAN FRANCISCO – A rapid intrapartum test for group B streptococcus may improve identification of colonized pregnant women, according to study results reported at the meeting

When the rapid test – a nucleic acid amplification test (NAAT) that yields results within an hour – was compared with a conventional antepartum bacterial culture, the rapid test was superior in identifying which of the 559 laboring women in the study had group B streptococcus (GBS) colonization (sensitivity, 91% vs. 69%). The rapid test also had a significantly better negative predictive value, and its specificity and positive predictive value were similarly high.

“In our population, intrapartum NAAT appeared to have superior test characteristics to antepartum culture for predicting intrapartum GBS culture status,” said Dr. Munish Gupta, an associate director of the neonatal intensive care unit at the Beth Israel Deaconess Medical Center in Boston.

“NAAT may be able to help identify women who are positive for GBS by intrapartum culture but negative by antepartum culture, a group of women that would be at particularly high risk for GBS transmission to their newborns by current standard management,” he commented.

In fact, about 60% of cases of neonatal early-onset GBS disease occur in infants born to mothers who screened negative by conventional means during their pregnancy, according to Dr. Gupta. “In addition, it has been well documented that results of antepartum GBS screening cultures do not always accurately predict intrapartum GBS status.”

The investigators prospectively studied pregnant women who were admitted to the labor and delivery department, had documented results of an antepartum GBS culture performed at 35–37 weeks' gestation, and had not received intrapartum antibiotics.

Two intrapartum rectovaginal samples were obtained according to Centers for Disease Control and Prevention guidelines.

One sample was sent for GBS culture by the hospital laboratory, and the result of this intrapartum culture served as the reference standard for the study, Dr. Gupta explained.

The other sample was used for rapid testing with the Xpert GBS test, performed in the department 24/7 on a system loaned to the investigators by the manufacturer, Cepheid.

“Of note, the intrapartum culture and NAAT results were not used for clinical management,” he pointed out.

Study results were based on 559 women who were 32 years old, on average. About 61% were white, 14% were Asian or Pacific Islander, 13% were black, 10% were Hispanic, and the rest were of other races or ethnicities.

The women had a mean gestational age of 39.4 weeks, and 99% had singleton pregnancies. Nearly three-fourths delivered vaginally.

Overall, 24% of the women had a positive result on the intrapartum GBS culture, according to Dr. Gupta.

The rapid test, compared with antepartum culture, had a significantly better sensitivity (91% vs. 69%) and negative predictive value (97% vs. 91%), and a similarly high specificity (98% vs. 96%) and positive predictive value (92% vs. 84%).

The results of antepartum and intrapartum culture were discordant in 10% of women overall. But the rate of discordance varied by race/ethnicity (P = .006), ranging from 4% in Asian women to 18% and 19% in their black and Hispanic counterparts, respectively.

Among women with a negative antepartum culture, 9% had a positive intrapartum culture, Dr. Gupta reported. Most of this subset did not receive intrapartum antibiotics (98%) and had infants who did not receive a sepsis evaluation (78%). Fully 81% of the subset had a positive rapid test result.

Previous studies of NAAT testing have raised concerns about the frequency of indeterminate test results in clinical practice, he noted. The results of the rapid test were indeterminate on first testing in 13% of the women studied, but they were indeterminate on repeated testing in merely 2%. The sample preparation time for the rapid test was 5 minutes, and the median processing time was 48 minutes, with 99.6% of samples processed in 50 minutes or less.

“Future work is needed to continue to explore the role of intrapartum GBS NAAT in clinical practice,” Dr. Gupta asserted. “It may be that the NAAT will prove to be a useful adjunct in certain populations in which the antepartum culture may not be a sufficient determinant of intrapartum GBS risk, such as [women who] are GBS negative on antepartum culture, black and Hispanic women, and preterm deliveries.”

The study did not have adequate power to assess the potential impact of the rapid test on neonatal outcomes, but they should be a focus in future studies, he recommended.

When asked by an attendee if he would argue with new guidelines that recommend prophylaxis in women with risk factors even if they have a negative NAAT test result, Dr. Gupta emphatically said he would not argue with them.

“I don't think any of us … involved in this study would look at the NAAT as a replacement for antepartum screening. Antepartum screening clearly has been incredibly effective and very important for reducing the burden of GBS disease, so I think the idea would be that NAAT might be a supplement in certain populations who are currently being missed by the antepartum culture,” he commented. “So I agree with current treatment for either antepartum culture–positive moms or moms with other risk factors. This [test] doesn't really seem to replace that.”

VANCOUVER, B.C. – The Centers for Medicare and Medicaid Services is currently offering providers a bonus for e-prescribing (electronically transmitting prescriptions to pharmacies). But providers will be hit with a penalty if they don't get on board soon with this practice.

“They are really promoting this,” Michael K. McCormick, a practice administrator at the DuPage Medical Group in Winfield, Ill., said at the meeting. But by transitioning from a bonus to a penalty over several years, “they are giving you time to get going on it.”

The Medicare Electronic Prescribing (eRx) Incentive Program, which began in 2009 and runs through 2013, provides bonus payments for e-prescribing when eligibility criteria are met, with bonus percentages being reduced over the span of the program, said Mr. McCormick, a registered respiratory therapist.

But the CMS will start financially penalizing providers who do not begin e-prescribing in 2011. The penalty for failing to e-prescribe will be 1%, 1.5%, and 2% of all Medicare Part B charges in 2012, 2013, and 2014, respectively.

The bottom line is to “e-prescribe at least 10 times in the first 6 months of 2011 so you won't be penalized in 2012,” Mr. McCormick recommended. “You really need to start doing this in 2011.”

The 2010 criteria require that health care providers report e-prescribing for at least 25 eligible patient encounters (which can include multiple encounters for a single patient) and that Medicare account for at least 10% of the provider's payer mix.

The bonus returned to providers for 2010 was 2% of the total Medicare Part B Physician Fee Schedule allowed charges for services for the entire year; it is 1% in 2011 and 2012, but only 0.5% in 2013.

The e-prescribing system used must meet certain criteria – for example, it must generate complete lists of all medications a patient is taking; provide information related to any lower-cost, therapeutically appropriate drugs; and, most notably, transmit prescriptions to pharmacies electronically.

Faxing of the prescription does not count, even if a computer system autogenerates the fax, Mr. McCormick cautioned. The prescription “must basically go from your computer to the pharmacy's computer, not through a fax.”

To obtain the bonus, providers can report their use of e-prescribing in any of three ways. “Probably the easiest way to get started is the claims-based reporting,” he said, which entails simply adding the G8553 code to the other codes. Alternately, providers can use registry-based reporting or electronic health record–based reporting.

The list of patient encounters considered eligible for e-prescribing is “pretty comprehensive,” including all outpatient office visits (those having 992xx codes), home health visits, nursing home visits, and psychiatric care visits, he said. However, inpatient visits are not eligible.

A noteworthy caveat is that providers will not be able to earn both the e-prescribing bonus and another bonus for implementing the electronic health records that the CMS is offering, because e-prescribing is among the 15 core measures of electronic health record implementation.

Put another way, “there is no double-dipping” in 2011, Mr. McCormick said. “So if you are going to go for that [electronic health record] bonus, which is a lot more money – $44,000 per provider paid over 5 years – you can't put in for the eRx bonus as well.”

Providers who are exempt from the penalty are those who generate fewer than 100 claims with eligible e-prescribing patient codes, those for whom less than 10% of patient encounters are eligible (e.g., hospital-based physicians), and those in rural areas with limited Internet service or a limited number of pharmacies that can receive prescriptions electronically.

The rules of the eRx Incentive Program, which change annually, are online at www.cms.gov/erxIncentive

'E-prescribe at least 10 times in the first 6 months of 2011 so you won't be penalized in 2012.'

Source MR. McCORMICK

VANCOUVER, B.C. – The Centers for Medicare and Medicaid Services is currently offering providers a bonus for e-prescribing (electronically transmitting prescriptions to pharmacies). But providers will be hit with a penalty if they don't get on board soon with this practice.

“They are really promoting this,” Michael K. McCormick, a practice administrator at the DuPage Medical Group in Winfield, Ill., said at the meeting. But by transitioning from a bonus to a penalty over several years, “they are giving you time to get going on it.”

The Medicare Electronic Prescribing (eRx) Incentive Program, which began in 2009 and runs through 2013, provides bonus payments for e-prescribing when eligibility criteria are met, with bonus percentages being reduced over the span of the program, said Mr. McCormick, a registered respiratory therapist.

But the CMS will start financially penalizing providers who do not begin e-prescribing in 2011. The penalty for failing to e-prescribe will be 1%, 1.5%, and 2% of all Medicare Part B charges in 2012, 2013, and 2014, respectively.

The bottom line is to “e-prescribe at least 10 times in the first 6 months of 2011 so you won't be penalized in 2012,” Mr. McCormick recommended. “You really need to start doing this in 2011.”

The 2010 criteria require that health care providers report e-prescribing for at least 25 eligible patient encounters (which can include multiple encounters for a single patient) and that Medicare account for at least 10% of the provider's payer mix.

The bonus returned to providers for 2010 was 2% of the total Medicare Part B Physician Fee Schedule allowed charges for services for the entire year; it is 1% in 2011 and 2012, but only 0.5% in 2013.

The e-prescribing system used must meet certain criteria – for example, it must generate complete lists of all medications a patient is taking; provide information related to any lower-cost, therapeutically appropriate drugs; and, most notably, transmit prescriptions to pharmacies electronically.

Faxing of the prescription does not count, even if a computer system autogenerates the fax, Mr. McCormick cautioned. The prescription “must basically go from your computer to the pharmacy's computer, not through a fax.”

To obtain the bonus, providers can report their use of e-prescribing in any of three ways. “Probably the easiest way to get started is the claims-based reporting,” he said, which entails simply adding the G8553 code to the other codes. Alternately, providers can use registry-based reporting or electronic health record–based reporting.

The list of patient encounters considered eligible for e-prescribing is “pretty comprehensive,” including all outpatient office visits (those having 992xx codes), home health visits, nursing home visits, and psychiatric care visits, he said. However, inpatient visits are not eligible.

A noteworthy caveat is that providers will not be able to earn both the e-prescribing bonus and another bonus for implementing the electronic health records that the CMS is offering, because e-prescribing is among the 15 core measures of electronic health record implementation.

Put another way, “there is no double-dipping” in 2011, Mr. McCormick said. “So if you are going to go for that [electronic health record] bonus, which is a lot more money – $44,000 per provider paid over 5 years – you can't put in for the eRx bonus as well.”

Providers who are exempt from the penalty are those who generate fewer than 100 claims with eligible e-prescribing patient codes, those for whom less than 10% of patient encounters are eligible (e.g., hospital-based physicians), and those in rural areas with limited Internet service or a limited number of pharmacies that can receive prescriptions electronically.

The rules of the eRx Incentive Program, which change annually, are online at www.cms.gov/erxIncentive

'E-prescribe at least 10 times in the first 6 months of 2011 so you won't be penalized in 2012.'

Source MR. McCORMICK

VANCOUVER, B.C. – The Centers for Medicare and Medicaid Services is currently offering providers a bonus for e-prescribing (electronically transmitting prescriptions to pharmacies). But providers will be hit with a penalty if they don't get on board soon with this practice.

“They are really promoting this,” Michael K. McCormick, a practice administrator at the DuPage Medical Group in Winfield, Ill., said at the meeting. But by transitioning from a bonus to a penalty over several years, “they are giving you time to get going on it.”

The Medicare Electronic Prescribing (eRx) Incentive Program, which began in 2009 and runs through 2013, provides bonus payments for e-prescribing when eligibility criteria are met, with bonus percentages being reduced over the span of the program, said Mr. McCormick, a registered respiratory therapist.

But the CMS will start financially penalizing providers who do not begin e-prescribing in 2011. The penalty for failing to e-prescribe will be 1%, 1.5%, and 2% of all Medicare Part B charges in 2012, 2013, and 2014, respectively.

The bottom line is to “e-prescribe at least 10 times in the first 6 months of 2011 so you won't be penalized in 2012,” Mr. McCormick recommended. “You really need to start doing this in 2011.”

The 2010 criteria require that health care providers report e-prescribing for at least 25 eligible patient encounters (which can include multiple encounters for a single patient) and that Medicare account for at least 10% of the provider's payer mix.

The bonus returned to providers for 2010 was 2% of the total Medicare Part B Physician Fee Schedule allowed charges for services for the entire year; it is 1% in 2011 and 2012, but only 0.5% in 2013.

The e-prescribing system used must meet certain criteria – for example, it must generate complete lists of all medications a patient is taking; provide information related to any lower-cost, therapeutically appropriate drugs; and, most notably, transmit prescriptions to pharmacies electronically.

Faxing of the prescription does not count, even if a computer system autogenerates the fax, Mr. McCormick cautioned. The prescription “must basically go from your computer to the pharmacy's computer, not through a fax.”

To obtain the bonus, providers can report their use of e-prescribing in any of three ways. “Probably the easiest way to get started is the claims-based reporting,” he said, which entails simply adding the G8553 code to the other codes. Alternately, providers can use registry-based reporting or electronic health record–based reporting.

The list of patient encounters considered eligible for e-prescribing is “pretty comprehensive,” including all outpatient office visits (those having 992xx codes), home health visits, nursing home visits, and psychiatric care visits, he said. However, inpatient visits are not eligible.

A noteworthy caveat is that providers will not be able to earn both the e-prescribing bonus and another bonus for implementing the electronic health records that the CMS is offering, because e-prescribing is among the 15 core measures of electronic health record implementation.

Put another way, “there is no double-dipping” in 2011, Mr. McCormick said. “So if you are going to go for that [electronic health record] bonus, which is a lot more money – $44,000 per provider paid over 5 years – you can't put in for the eRx bonus as well.”

Providers who are exempt from the penalty are those who generate fewer than 100 claims with eligible e-prescribing patient codes, those for whom less than 10% of patient encounters are eligible (e.g., hospital-based physicians), and those in rural areas with limited Internet service or a limited number of pharmacies that can receive prescriptions electronically.

The rules of the eRx Incentive Program, which change annually, are online at www.cms.gov/erxIncentive

'E-prescribe at least 10 times in the first 6 months of 2011 so you won't be penalized in 2012.'

Source MR. McCORMICK

SAN FRANCISCO – A rapid intrapartum test for group B streptococcus may improve identification of colonized pregnant women, according to study results reported at the annual meeting of the Society for Maternal-Fetal Medicine.

When the rapid test – a nucleic acid amplification test (NAAT) that yields results within an hour – was compared with conventional antepartum bacterial culture, the rapid test was superior in identifying which of the 559 laboring women in the study had group B streptococcus (GBS) colonization (sensitivity, 91% vs. 69%).

The rapid test also had a significantly better negative predictive value, and its specificity and positive predictive value were similarly high.

"In our population, intrapartum NAAT appeared to have superior test characteristics to antepartum culture for predicting intrapartum GBS culture status," said Dr. Munish Gupta, an associate director of the neonatal intensive care unit at the Beth Israel Deaconess Medical Center in Boston.

"NAAT may be able to help identify women who are positive for GBS by intrapartum culture but negative by antepartum culture, a group of women that would be at particularly high risk for GBS transmission to their newborns by current standard management," he commented.

In fact, about 60% of cases of neonatal early-onset GBS disease occur in infants born to mothers who screened negative by conventional means during their pregnancy, according to Dr. Gupta. "In addition, it has been well documented that results of antepartum GBS screening cultures do not always accurately predict intrapartum GBS status."

The investigators prospectively studied pregnant women who were admitted to the labor and delivery department, had documented results of an antepartum GBS culture performed at 35 to 37 weeks’ gestation, and had not received intrapartum antibiotics.

Two intrapartum rectovaginal samples were obtained according to Centers for Disease Control and Prevention guidelines.

One sample was sent for GBS culture by the hospital laboratory, and the result of this intrapartum culture served as the reference standard for the study, Dr. Gupta explained.

The other sample was used for rapid testing with the Xpert GBS test, performed in the department 24/7 on a system loaned to the investigators by the manufacturer, Cepheid.

"Of note, the intrapartum culture and NAAT results were not used for clinical management," he pointed out.

Study results were based on 559 women who were 32 years old, on average. Some 61% were white, 14% were Asian or Pacific Islander, 13% were black, 10% were Hispanic, and the rest were of other races or ethnicities.

The women had a mean gestational age of 39.4 weeks, and 99% had singleton pregnancies. Nearly three-fourths delivered vaginally.

Overall, 24% of the women had a positive result on the intrapartum GBS culture, according to Dr. Gupta.

The rapid test, compared with antepartum culture, had a significantly better sensitivity (91% vs. 69%) and negative predictive value (97% vs. 91%), and similarly high specificity (98% vs. 96%) and positive predictive value (92% vs. 84%).

The results of antepartum and intrapartum culture were discordant in 10% of women overall. But the rate of discordance varied by race/ethnicity (P = .006), ranging from 4% in Asian women to 18% and 19% in their black and Hispanic counterparts, respectively.

Among women with a negative antepartum culture, 9% had a positive intrapartum culture, Dr. Gupta reported. Most of this subset did not receive intrapartum antibiotics (98%) and had infants who did not receive a sepsis evaluation (78%). Fully 81% of the subset had a positive rapid test result.

Previous studies of NAAT testing have raised concerns about the frequency of indeterminate test results in clinical practice, he noted. The results of the rapid test were indeterminate on first testing in 13% of the women studied, but they were indeterminate on repeated testing in merely 2%.

The sample preparation time for the rapid test was 5 minutes, and the median processing time was 48 minutes, with 99.6% of samples processed in 50 minutes or less.

"Future work is needed to continue to explore the role of intrapartum GBS NAAT in clinical practice," Dr. Gupta asserted. "It may be that the NAAT will prove to be a useful adjunct in certain populations in which the antepartum culture may not be a sufficient determinant of intrapartum GBS risk, such as [women who] are GBS negative on antepartum culture, black and Hispanic women, and preterm deliveries."

The study did not have adequate power to assess the potential impact of the rapid test on neonatal outcomes, but they should be a focus in future studies, he recommended.

When asked by an attendee if he would argue with new guidelines that recommend prophylaxis in women with risk factors even if they have a negative NAAT test result, Dr. Gupta emphatically said he would not argue with them.

"I don’t think any of us ... involved in this study would look at the NAAT as a replacement for antepartum screening. Antepartum screening clearly has been incredibly effective and very important for reducing the burden of GBS disease, so I think the idea would be that NAAT might be a supplement in certain populations who are currently being missed by the antepartum culture," he commented. "So I agree with current treatment for either antepartum culture–positive moms or moms with other risk factors. This [test] doesn’t really seem to replace that."

Dr. Gupta did not report any relevant financial disclosures.

SAN FRANCISCO – A rapid intrapartum test for group B streptococcus may improve identification of colonized pregnant women, according to study results reported at the annual meeting of the Society for Maternal-Fetal Medicine.

When the rapid test – a nucleic acid amplification test (NAAT) that yields results within an hour – was compared with conventional antepartum bacterial culture, the rapid test was superior in identifying which of the 559 laboring women in the study had group B streptococcus (GBS) colonization (sensitivity, 91% vs. 69%).

The rapid test also had a significantly better negative predictive value, and its specificity and positive predictive value were similarly high.

"In our population, intrapartum NAAT appeared to have superior test characteristics to antepartum culture for predicting intrapartum GBS culture status," said Dr. Munish Gupta, an associate director of the neonatal intensive care unit at the Beth Israel Deaconess Medical Center in Boston.

"NAAT may be able to help identify women who are positive for GBS by intrapartum culture but negative by antepartum culture, a group of women that would be at particularly high risk for GBS transmission to their newborns by current standard management," he commented.

In fact, about 60% of cases of neonatal early-onset GBS disease occur in infants born to mothers who screened negative by conventional means during their pregnancy, according to Dr. Gupta. "In addition, it has been well documented that results of antepartum GBS screening cultures do not always accurately predict intrapartum GBS status."

The investigators prospectively studied pregnant women who were admitted to the labor and delivery department, had documented results of an antepartum GBS culture performed at 35 to 37 weeks’ gestation, and had not received intrapartum antibiotics.

Two intrapartum rectovaginal samples were obtained according to Centers for Disease Control and Prevention guidelines.

One sample was sent for GBS culture by the hospital laboratory, and the result of this intrapartum culture served as the reference standard for the study, Dr. Gupta explained.

The other sample was used for rapid testing with the Xpert GBS test, performed in the department 24/7 on a system loaned to the investigators by the manufacturer, Cepheid.

"Of note, the intrapartum culture and NAAT results were not used for clinical management," he pointed out.

Study results were based on 559 women who were 32 years old, on average. Some 61% were white, 14% were Asian or Pacific Islander, 13% were black, 10% were Hispanic, and the rest were of other races or ethnicities.

The women had a mean gestational age of 39.4 weeks, and 99% had singleton pregnancies. Nearly three-fourths delivered vaginally.

Overall, 24% of the women had a positive result on the intrapartum GBS culture, according to Dr. Gupta.

The rapid test, compared with antepartum culture, had a significantly better sensitivity (91% vs. 69%) and negative predictive value (97% vs. 91%), and similarly high specificity (98% vs. 96%) and positive predictive value (92% vs. 84%).

The results of antepartum and intrapartum culture were discordant in 10% of women overall. But the rate of discordance varied by race/ethnicity (P = .006), ranging from 4% in Asian women to 18% and 19% in their black and Hispanic counterparts, respectively.

Among women with a negative antepartum culture, 9% had a positive intrapartum culture, Dr. Gupta reported. Most of this subset did not receive intrapartum antibiotics (98%) and had infants who did not receive a sepsis evaluation (78%). Fully 81% of the subset had a positive rapid test result.

Previous studies of NAAT testing have raised concerns about the frequency of indeterminate test results in clinical practice, he noted. The results of the rapid test were indeterminate on first testing in 13% of the women studied, but they were indeterminate on repeated testing in merely 2%.

The sample preparation time for the rapid test was 5 minutes, and the median processing time was 48 minutes, with 99.6% of samples processed in 50 minutes or less.

"Future work is needed to continue to explore the role of intrapartum GBS NAAT in clinical practice," Dr. Gupta asserted. "It may be that the NAAT will prove to be a useful adjunct in certain populations in which the antepartum culture may not be a sufficient determinant of intrapartum GBS risk, such as [women who] are GBS negative on antepartum culture, black and Hispanic women, and preterm deliveries."

The study did not have adequate power to assess the potential impact of the rapid test on neonatal outcomes, but they should be a focus in future studies, he recommended.

When asked by an attendee if he would argue with new guidelines that recommend prophylaxis in women with risk factors even if they have a negative NAAT test result, Dr. Gupta emphatically said he would not argue with them.

"I don’t think any of us ... involved in this study would look at the NAAT as a replacement for antepartum screening. Antepartum screening clearly has been incredibly effective and very important for reducing the burden of GBS disease, so I think the idea would be that NAAT might be a supplement in certain populations who are currently being missed by the antepartum culture," he commented. "So I agree with current treatment for either antepartum culture–positive moms or moms with other risk factors. This [test] doesn’t really seem to replace that."

Dr. Gupta did not report any relevant financial disclosures.

SAN FRANCISCO – A rapid intrapartum test for group B streptococcus may improve identification of colonized pregnant women, according to study results reported at the annual meeting of the Society for Maternal-Fetal Medicine.

When the rapid test – a nucleic acid amplification test (NAAT) that yields results within an hour – was compared with conventional antepartum bacterial culture, the rapid test was superior in identifying which of the 559 laboring women in the study had group B streptococcus (GBS) colonization (sensitivity, 91% vs. 69%).

The rapid test also had a significantly better negative predictive value, and its specificity and positive predictive value were similarly high.

"In our population, intrapartum NAAT appeared to have superior test characteristics to antepartum culture for predicting intrapartum GBS culture status," said Dr. Munish Gupta, an associate director of the neonatal intensive care unit at the Beth Israel Deaconess Medical Center in Boston.

"NAAT may be able to help identify women who are positive for GBS by intrapartum culture but negative by antepartum culture, a group of women that would be at particularly high risk for GBS transmission to their newborns by current standard management," he commented.

In fact, about 60% of cases of neonatal early-onset GBS disease occur in infants born to mothers who screened negative by conventional means during their pregnancy, according to Dr. Gupta. "In addition, it has been well documented that results of antepartum GBS screening cultures do not always accurately predict intrapartum GBS status."

The investigators prospectively studied pregnant women who were admitted to the labor and delivery department, had documented results of an antepartum GBS culture performed at 35 to 37 weeks’ gestation, and had not received intrapartum antibiotics.

Two intrapartum rectovaginal samples were obtained according to Centers for Disease Control and Prevention guidelines.

One sample was sent for GBS culture by the hospital laboratory, and the result of this intrapartum culture served as the reference standard for the study, Dr. Gupta explained.

The other sample was used for rapid testing with the Xpert GBS test, performed in the department 24/7 on a system loaned to the investigators by the manufacturer, Cepheid.

"Of note, the intrapartum culture and NAAT results were not used for clinical management," he pointed out.

Study results were based on 559 women who were 32 years old, on average. Some 61% were white, 14% were Asian or Pacific Islander, 13% were black, 10% were Hispanic, and the rest were of other races or ethnicities.

The women had a mean gestational age of 39.4 weeks, and 99% had singleton pregnancies. Nearly three-fourths delivered vaginally.

Overall, 24% of the women had a positive result on the intrapartum GBS culture, according to Dr. Gupta.

The rapid test, compared with antepartum culture, had a significantly better sensitivity (91% vs. 69%) and negative predictive value (97% vs. 91%), and similarly high specificity (98% vs. 96%) and positive predictive value (92% vs. 84%).

The results of antepartum and intrapartum culture were discordant in 10% of women overall. But the rate of discordance varied by race/ethnicity (P = .006), ranging from 4% in Asian women to 18% and 19% in their black and Hispanic counterparts, respectively.

Among women with a negative antepartum culture, 9% had a positive intrapartum culture, Dr. Gupta reported. Most of this subset did not receive intrapartum antibiotics (98%) and had infants who did not receive a sepsis evaluation (78%). Fully 81% of the subset had a positive rapid test result.

Previous studies of NAAT testing have raised concerns about the frequency of indeterminate test results in clinical practice, he noted. The results of the rapid test were indeterminate on first testing in 13% of the women studied, but they were indeterminate on repeated testing in merely 2%.

The sample preparation time for the rapid test was 5 minutes, and the median processing time was 48 minutes, with 99.6% of samples processed in 50 minutes or less.

"Future work is needed to continue to explore the role of intrapartum GBS NAAT in clinical practice," Dr. Gupta asserted. "It may be that the NAAT will prove to be a useful adjunct in certain populations in which the antepartum culture may not be a sufficient determinant of intrapartum GBS risk, such as [women who] are GBS negative on antepartum culture, black and Hispanic women, and preterm deliveries."

The study did not have adequate power to assess the potential impact of the rapid test on neonatal outcomes, but they should be a focus in future studies, he recommended.

When asked by an attendee if he would argue with new guidelines that recommend prophylaxis in women with risk factors even if they have a negative NAAT test result, Dr. Gupta emphatically said he would not argue with them.

"I don’t think any of us ... involved in this study would look at the NAAT as a replacement for antepartum screening. Antepartum screening clearly has been incredibly effective and very important for reducing the burden of GBS disease, so I think the idea would be that NAAT might be a supplement in certain populations who are currently being missed by the antepartum culture," he commented. "So I agree with current treatment for either antepartum culture–positive moms or moms with other risk factors. This [test] doesn’t really seem to replace that."

Dr. Gupta did not report any relevant financial disclosures.

SAN FRANCISCO – Early amniotomy appears safe and efficacious for shortening labor at term in nulliparous women having an indication for labor induction, according to results of a randomized controlled trial.

Among the 585 women studied, the average time from induction to delivery was 2.3 hours, or 11% shorter with early amniotomy vs. standard care, investigators reported at the annual meeting of the Society for Maternal-Fetal Medicine. This benefit was achieved without an increase in rates of maternal or neonatal infections.

"Based on this clinical trial, it would seem that early amniotomy may be a useful adjunct for nulliparous labor inductions," said principal investigator Dr. George A. Macones, the Mitchell and Elaine Yanow Professor and chair of the department of ob.gyn. at Washington University in St. Louis.

Many studies have evaluated different methods of labor induction, he noted. "However, surprisingly, there are very few data on the timing of amniotomy in labor induction and how this may improve or worsen outcomes."

Amniotomy is easy and inexpensive and may shorten labor, according to Dr. Macones. But it also may be associated with rare complications such as umbilical cord prolapse, and possibly with an increased infection risk resulting from a longer duration of ruptured membranes.

Women were eligible for the trial if they were nulliparous, had a singleton pregnancy, were at term (37 weeks’ gestation or later), and needed induction as determined by their treating physician. They were excluded if they were HIV positive or had cervical dilatation exceeding 4 cm at the time of admission to labor and delivery.

The women were randomly assigned in a 1:1 ratio to nonblinded management with either early amniotomy (defined as artificial rupture of membranes performed when cervical dilatation was equal to or less than 4 cm) or standard care (defined as artificial rupture of membranes performed when cervical dilatation was greater than 4 cm).

The primary method of induction (misoprostol, cervical Foley catheter, oxytocin, and/or prostaglandin gel) was left to the treating physician’s discretion. "Just to be clear, we did not study the timing of amniotomy as a primary method of induction, but rather as an adjunct to other methods," Dr. Macones noted.

All other decisions about intrapartum and postpartum care were similarly left up to the treating physicians.

The 585 women randomized were 23 years old on average, and the majority (70%) was black. Almost a third had gestational hypertension or preeclampsia, and another third were positive for group B streptococcus.

The mean gestational age was about 39.5 weeks, and the mean cervical dilatation was 1.1 cm on admission. The leading indications for induction were a gestation past 40 weeks (39%) and gestational hypertension or preeclampsia (28%).

The primary methods of induction used were similar across groups. In nearly three-fourths of women, the treating physicians used multiple methods.

Most women received epidural analgesia, with no difference between groups, according to Dr. Macones.

Median cervical dilatation at the time of rupture of membranes was 4 cm less in the early amniotomy group, compared with the standard care group (3.0 vs. 7.0 cm; P = .001).

In intent-to-treat analyses, the time from induction to delivery was 2.3 hours shorter with early amniotomy (19.0 vs. 21.3 hours; P = .004). "This difference in the length of labor occurred mainly and not surprisingly in the first stage of labor, but not in the second stage," Dr. Macones noted.

In addition, these women were more likely to deliver within 24 hours of labor induction (68% vs. 56%; P = .002).

The early amniotomy group did not differ significantly from the standard care group with respect to rates of cesarean delivery (41% vs. 40%), cord prolapse (0.7% vs. 0%), and abruption (0.4% vs. 0.6%).

Fetal heart rate data were not analyzed, but rates of amnioinfusion (a "reasonable proxy" for variable decelerations) were similar, according to Dr. Macones.

The two groups also had statistically indistinguishable rates of infectious outcomes, including chorioamnionitis (11.5% vs. 8.5%) postpartum fever (10.4% vs. 9.4%) in the mother, and NICU admission (13.6% vs. 15.0%) and suspected or confirmed sepsis (9.7% vs. 11.1%) in the neonate.

In questions posed after the presentation, one attendee asked how the 4-cm threshold was selected for early amniotomy, and whether the findings would be similar with, say, a 2-cm threshold instead.

"We chose 4 cm based on some earlier work in spontaneous labor with rupturing membranes," Dr. Macones explained. "I agree that we could dial that down a bit."

However, within the early amniotomy group, the efficacy and safety findings appeared similar regardless of the timing of the procedure, he said.

When asked if the study was mixing cervical ripening with labor induction, Dr. Macones said, "I think the lines between ripening and induction are actually quite gray." He contended that the study’s aim was to assess the impact of amniotomy when the intention was to perform it as early as possible.

An alternative approach would be to look at women once their cervix is ripened and then ask what the role of amniotomy is, he acknowledged. "But I think that’s a little bit different question than we actually had."

Finally, an attendee questioned the importance of what might seem to be fairly small labor benefits with early amniotomy, given the potential for harm.

"I would argue that it matters to women that time to delivery is shorter," Dr. Macones commented. And it also matters to obstetricians in terms of "being efficient health care providers."

Dr. Macones did not report any relevant financial disclosures.

SAN FRANCISCO – Early amniotomy appears safe and efficacious for shortening labor at term in nulliparous women having an indication for labor induction, according to results of a randomized controlled trial.

Among the 585 women studied, the average time from induction to delivery was 2.3 hours, or 11% shorter with early amniotomy vs. standard care, investigators reported at the annual meeting of the Society for Maternal-Fetal Medicine. This benefit was achieved without an increase in rates of maternal or neonatal infections.

"Based on this clinical trial, it would seem that early amniotomy may be a useful adjunct for nulliparous labor inductions," said principal investigator Dr. George A. Macones, the Mitchell and Elaine Yanow Professor and chair of the department of ob.gyn. at Washington University in St. Louis.

Many studies have evaluated different methods of labor induction, he noted. "However, surprisingly, there are very few data on the timing of amniotomy in labor induction and how this may improve or worsen outcomes."

Amniotomy is easy and inexpensive and may shorten labor, according to Dr. Macones. But it also may be associated with rare complications such as umbilical cord prolapse, and possibly with an increased infection risk resulting from a longer duration of ruptured membranes.

Women were eligible for the trial if they were nulliparous, had a singleton pregnancy, were at term (37 weeks’ gestation or later), and needed induction as determined by their treating physician. They were excluded if they were HIV positive or had cervical dilatation exceeding 4 cm at the time of admission to labor and delivery.

The women were randomly assigned in a 1:1 ratio to nonblinded management with either early amniotomy (defined as artificial rupture of membranes performed when cervical dilatation was equal to or less than 4 cm) or standard care (defined as artificial rupture of membranes performed when cervical dilatation was greater than 4 cm).

The primary method of induction (misoprostol, cervical Foley catheter, oxytocin, and/or prostaglandin gel) was left to the treating physician’s discretion. "Just to be clear, we did not study the timing of amniotomy as a primary method of induction, but rather as an adjunct to other methods," Dr. Macones noted.

All other decisions about intrapartum and postpartum care were similarly left up to the treating physicians.

The 585 women randomized were 23 years old on average, and the majority (70%) was black. Almost a third had gestational hypertension or preeclampsia, and another third were positive for group B streptococcus.

The mean gestational age was about 39.5 weeks, and the mean cervical dilatation was 1.1 cm on admission. The leading indications for induction were a gestation past 40 weeks (39%) and gestational hypertension or preeclampsia (28%).

The primary methods of induction used were similar across groups. In nearly three-fourths of women, the treating physicians used multiple methods.

Most women received epidural analgesia, with no difference between groups, according to Dr. Macones.

Median cervical dilatation at the time of rupture of membranes was 4 cm less in the early amniotomy group, compared with the standard care group (3.0 vs. 7.0 cm; P = .001).

In intent-to-treat analyses, the time from induction to delivery was 2.3 hours shorter with early amniotomy (19.0 vs. 21.3 hours; P = .004). "This difference in the length of labor occurred mainly and not surprisingly in the first stage of labor, but not in the second stage," Dr. Macones noted.

In addition, these women were more likely to deliver within 24 hours of labor induction (68% vs. 56%; P = .002).

The early amniotomy group did not differ significantly from the standard care group with respect to rates of cesarean delivery (41% vs. 40%), cord prolapse (0.7% vs. 0%), and abruption (0.4% vs. 0.6%).

Fetal heart rate data were not analyzed, but rates of amnioinfusion (a "reasonable proxy" for variable decelerations) were similar, according to Dr. Macones.

The two groups also had statistically indistinguishable rates of infectious outcomes, including chorioamnionitis (11.5% vs. 8.5%) postpartum fever (10.4% vs. 9.4%) in the mother, and NICU admission (13.6% vs. 15.0%) and suspected or confirmed sepsis (9.7% vs. 11.1%) in the neonate.

In questions posed after the presentation, one attendee asked how the 4-cm threshold was selected for early amniotomy, and whether the findings would be similar with, say, a 2-cm threshold instead.

"We chose 4 cm based on some earlier work in spontaneous labor with rupturing membranes," Dr. Macones explained. "I agree that we could dial that down a bit."

However, within the early amniotomy group, the efficacy and safety findings appeared similar regardless of the timing of the procedure, he said.

When asked if the study was mixing cervical ripening with labor induction, Dr. Macones said, "I think the lines between ripening and induction are actually quite gray." He contended that the study’s aim was to assess the impact of amniotomy when the intention was to perform it as early as possible.

An alternative approach would be to look at women once their cervix is ripened and then ask what the role of amniotomy is, he acknowledged. "But I think that’s a little bit different question than we actually had."

Finally, an attendee questioned the importance of what might seem to be fairly small labor benefits with early amniotomy, given the potential for harm.

"I would argue that it matters to women that time to delivery is shorter," Dr. Macones commented. And it also matters to obstetricians in terms of "being efficient health care providers."

Dr. Macones did not report any relevant financial disclosures.

SAN FRANCISCO – Early amniotomy appears safe and efficacious for shortening labor at term in nulliparous women having an indication for labor induction, according to results of a randomized controlled trial.

Among the 585 women studied, the average time from induction to delivery was 2.3 hours, or 11% shorter with early amniotomy vs. standard care, investigators reported at the annual meeting of the Society for Maternal-Fetal Medicine. This benefit was achieved without an increase in rates of maternal or neonatal infections.

"Based on this clinical trial, it would seem that early amniotomy may be a useful adjunct for nulliparous labor inductions," said principal investigator Dr. George A. Macones, the Mitchell and Elaine Yanow Professor and chair of the department of ob.gyn. at Washington University in St. Louis.

Many studies have evaluated different methods of labor induction, he noted. "However, surprisingly, there are very few data on the timing of amniotomy in labor induction and how this may improve or worsen outcomes."

Amniotomy is easy and inexpensive and may shorten labor, according to Dr. Macones. But it also may be associated with rare complications such as umbilical cord prolapse, and possibly with an increased infection risk resulting from a longer duration of ruptured membranes.

Women were eligible for the trial if they were nulliparous, had a singleton pregnancy, were at term (37 weeks’ gestation or later), and needed induction as determined by their treating physician. They were excluded if they were HIV positive or had cervical dilatation exceeding 4 cm at the time of admission to labor and delivery.

The women were randomly assigned in a 1:1 ratio to nonblinded management with either early amniotomy (defined as artificial rupture of membranes performed when cervical dilatation was equal to or less than 4 cm) or standard care (defined as artificial rupture of membranes performed when cervical dilatation was greater than 4 cm).

The primary method of induction (misoprostol, cervical Foley catheter, oxytocin, and/or prostaglandin gel) was left to the treating physician’s discretion. "Just to be clear, we did not study the timing of amniotomy as a primary method of induction, but rather as an adjunct to other methods," Dr. Macones noted.

All other decisions about intrapartum and postpartum care were similarly left up to the treating physicians.

The 585 women randomized were 23 years old on average, and the majority (70%) was black. Almost a third had gestational hypertension or preeclampsia, and another third were positive for group B streptococcus.

The mean gestational age was about 39.5 weeks, and the mean cervical dilatation was 1.1 cm on admission. The leading indications for induction were a gestation past 40 weeks (39%) and gestational hypertension or preeclampsia (28%).

The primary methods of induction used were similar across groups. In nearly three-fourths of women, the treating physicians used multiple methods.

Most women received epidural analgesia, with no difference between groups, according to Dr. Macones.

Median cervical dilatation at the time of rupture of membranes was 4 cm less in the early amniotomy group, compared with the standard care group (3.0 vs. 7.0 cm; P = .001).

In intent-to-treat analyses, the time from induction to delivery was 2.3 hours shorter with early amniotomy (19.0 vs. 21.3 hours; P = .004). "This difference in the length of labor occurred mainly and not surprisingly in the first stage of labor, but not in the second stage," Dr. Macones noted.

In addition, these women were more likely to deliver within 24 hours of labor induction (68% vs. 56%; P = .002).

The early amniotomy group did not differ significantly from the standard care group with respect to rates of cesarean delivery (41% vs. 40%), cord prolapse (0.7% vs. 0%), and abruption (0.4% vs. 0.6%).

Fetal heart rate data were not analyzed, but rates of amnioinfusion (a "reasonable proxy" for variable decelerations) were similar, according to Dr. Macones.

The two groups also had statistically indistinguishable rates of infectious outcomes, including chorioamnionitis (11.5% vs. 8.5%) postpartum fever (10.4% vs. 9.4%) in the mother, and NICU admission (13.6% vs. 15.0%) and suspected or confirmed sepsis (9.7% vs. 11.1%) in the neonate.

In questions posed after the presentation, one attendee asked how the 4-cm threshold was selected for early amniotomy, and whether the findings would be similar with, say, a 2-cm threshold instead.

"We chose 4 cm based on some earlier work in spontaneous labor with rupturing membranes," Dr. Macones explained. "I agree that we could dial that down a bit."

However, within the early amniotomy group, the efficacy and safety findings appeared similar regardless of the timing of the procedure, he said.

When asked if the study was mixing cervical ripening with labor induction, Dr. Macones said, "I think the lines between ripening and induction are actually quite gray." He contended that the study’s aim was to assess the impact of amniotomy when the intention was to perform it as early as possible.

An alternative approach would be to look at women once their cervix is ripened and then ask what the role of amniotomy is, he acknowledged. "But I think that’s a little bit different question than we actually had."

Finally, an attendee questioned the importance of what might seem to be fairly small labor benefits with early amniotomy, given the potential for harm.

"I would argue that it matters to women that time to delivery is shorter," Dr. Macones commented. And it also matters to obstetricians in terms of "being efficient health care providers."

Dr. Macones did not report any relevant financial disclosures.

VANCOUVER, B.C. – Although physicians might be reluctant to bring up smoking cessation with their patients for many reasons, it is one of the most important preventive activities they can undertake, according to Dr. Arunabh Talwar.

Smokers are ambivalent about smoking, he said at the annual meeting of the American College of Chest Physicians. On any given day, their smoking status hangs in balance between one set of factors favoring quitting and another set favoring continuing (BMJ 2007;335:37-41).

"All we need to do is just [tip the balance]," said Dr. Talwar, who is a pulmonologist at North Shore University Hospital in Manhasset, N.Y.

Indeed, if self-reports are reliable, about 70% of smokers want to stop and 30% try each year. But only 2%-3% succeed.

Referring to the multistage model of behavioral change, he noted that making smokers aware of the link between smoking and end-organ damage is critical in starting the process. "That is the most important thing that physicians do – they move patients from a precontemplation to a contemplation stage and set the stage for the smoking cessation process to occur."

There is compelling evidence of the benefits of smoking cessation, he said. It has been identified as the single most effective step for lengthening and improving patients’ lives (BMJ 2004;328:947-9).

"Make no mistake, smoking cessation activity is very cost effective," he added. "I think it is the most cost-effective primary prevention action that a physician can take."

Brief advice to quit costs $338 per year of life saved – or less than 5% of the cost per year of life saved from giving pravastatin for primary prevention of cardiovascular disease, aspirin for secondary prevention of coronary heart disease, or simvastatin for secondary prevention of myocardial infarction (BMJ 2004;328:397-9).

Still, physicians cite numerous barriers to promoting smoking cessation with their patients, according to Dr. Talwar (J. Smok. Cessat. 2008;3:92-100). A common one is being too busy.

"But studies show us, a minimal intervention – as [little] as 3 minutes of a physician’s time – can move patients from ‘precontemplation’ to contemplation, can help improve quit status," he said. Furthermore, "as you increase the intervention, the success rate will improve."

For example, just 0.3% of smokers succeed in quitting long term on their own, but the value rises to 1.6% when physicians simply ask their smoking status, 3.3% when they ask and provide advice on quitting, and 5.1% when they ask, advise, and give a pamphlet (BMJ 1979;2:231-5).

Busy physicians can streamline efforts by using a team approach. "Some of it can be shared by other health care providers, whether they are nurses, nurse practitioners, physician assistants," Dr. Talwar explained. "We use our respiratory therapists and [pulmonary function test] lab technicians as well; that way, the load gets divided. But also, repeated messages to the patient will help move them along."

Physicians should also consider using telephone "quitlines" (now freely available in all states) and patient support groups in the behavioral modification part of cessation, he advised.

Another barrier physicians cite, lack of expertise, has a stronger negative influence on their smoking cessation activities than lack of interest, time, or materials (Eur. J. Public Health 2005;15:140-5).

Indeed, in a survey of New York City–area health care providers, Dr. Talwar and his colleagues found that only 20% believed their training had adequately prepared them to treat tobacco dependence. And less than 10% were familiar with treatment guidelines. "We are a little bit behind in this, but medical schools have made a change, and most medical schools now make an effort to make sure that standard curricula [on smoking cessation] are there," he said. In addition, comprehensive information is readily available in the ACCP’s Tobacco Dependence Treatment ToolKit.

Reassuringly, physicians who receive training in this area are 1.5 to 2.5 times more likely to perform smoking cessation tasks (Cochrane Database Syst. Rev. 2000;CD000214).

Physicians also report a lack of financial incentives to be a barrier. Dr. Talwar noted that two CPT codes – 99406 and 99407 – specifically pertain to cessation activities during visits. Physicians can usually bill for this counseling, in addition to routine office visits, four times annually.

Half of physicians still believe that reimbursement is insufficient. "But the situation is much better than 7 or 8 years ago, when it was much more difficult to get reimbursement for these activities," he commented.

Physicians also mention patients’ low likelihood of quitting as a barrier to broaching smoking cessation, according to Dr. Talwar. But the irony is that quit rates are influenced in large part by physicians’ efforts and the intensity of those efforts.

Discussing the so-called 5 A’s of smoking cessation – ask, advise, assess, assist, and arrange – he noted that physicians do fairly well on the first two, but not so well on the others.

For example, a study of 246 community-based primary care physicians found that 67% asked their patients about smoking status and 74% gave advice, but just 35% assisted with smoking cessation efforts and merely 8% arranged for follow-up (Prev. Med. 1998;27:720-9).

It is important to understand that relapses are part of the cessation process, Dr. Talwar stressed; in fact, smokers who succeed in quitting make five to seven attempts, on average, before succeeding. Hence, "you have just to have to be patient with them."

It might also be possible to improve the odds of successful quitting by approaching patients at teachable moments, he further noted. For instance, "admission [to the hospital] is an opportunity to interact, to make the change. Maybe that’s the time when you need to approach them."

His own 800-bed hospital generates a list each day of inpatients who smoke. A smoking cessation therapist then visits these patients and invites them to the smoking cessation clinic.

A final barrier is that some physicians themselves are smokers. "It’s been shown that physicians who smoke have very little faith in their own ability to promote smoking cessation," Dr. Talwar commented (Prev. Med. 2005;40:595-601).

On the other hand, this group has greater insight into the difficulties of quitting and might be able to draw on their own experiences to assist patients in this endeavor, he added.

Dr. Talwar did not report any conflicts of interest.

VANCOUVER, B.C. – Although physicians might be reluctant to bring up smoking cessation with their patients for many reasons, it is one of the most important preventive activities they can undertake, according to Dr. Arunabh Talwar.

Smokers are ambivalent about smoking, he said at the annual meeting of the American College of Chest Physicians. On any given day, their smoking status hangs in balance between one set of factors favoring quitting and another set favoring continuing (BMJ 2007;335:37-41).

"All we need to do is just [tip the balance]," said Dr. Talwar, who is a pulmonologist at North Shore University Hospital in Manhasset, N.Y.

Indeed, if self-reports are reliable, about 70% of smokers want to stop and 30% try each year. But only 2%-3% succeed.

Referring to the multistage model of behavioral change, he noted that making smokers aware of the link between smoking and end-organ damage is critical in starting the process. "That is the most important thing that physicians do – they move patients from a precontemplation to a contemplation stage and set the stage for the smoking cessation process to occur."

There is compelling evidence of the benefits of smoking cessation, he said. It has been identified as the single most effective step for lengthening and improving patients’ lives (BMJ 2004;328:947-9).

"Make no mistake, smoking cessation activity is very cost effective," he added. "I think it is the most cost-effective primary prevention action that a physician can take."

Brief advice to quit costs $338 per year of life saved – or less than 5% of the cost per year of life saved from giving pravastatin for primary prevention of cardiovascular disease, aspirin for secondary prevention of coronary heart disease, or simvastatin for secondary prevention of myocardial infarction (BMJ 2004;328:397-9).

Still, physicians cite numerous barriers to promoting smoking cessation with their patients, according to Dr. Talwar (J. Smok. Cessat. 2008;3:92-100). A common one is being too busy.

"But studies show us, a minimal intervention – as [little] as 3 minutes of a physician’s time – can move patients from ‘precontemplation’ to contemplation, can help improve quit status," he said. Furthermore, "as you increase the intervention, the success rate will improve."

For example, just 0.3% of smokers succeed in quitting long term on their own, but the value rises to 1.6% when physicians simply ask their smoking status, 3.3% when they ask and provide advice on quitting, and 5.1% when they ask, advise, and give a pamphlet (BMJ 1979;2:231-5).

Busy physicians can streamline efforts by using a team approach. "Some of it can be shared by other health care providers, whether they are nurses, nurse practitioners, physician assistants," Dr. Talwar explained. "We use our respiratory therapists and [pulmonary function test] lab technicians as well; that way, the load gets divided. But also, repeated messages to the patient will help move them along."

Physicians should also consider using telephone "quitlines" (now freely available in all states) and patient support groups in the behavioral modification part of cessation, he advised.

Another barrier physicians cite, lack of expertise, has a stronger negative influence on their smoking cessation activities than lack of interest, time, or materials (Eur. J. Public Health 2005;15:140-5).

Indeed, in a survey of New York City–area health care providers, Dr. Talwar and his colleagues found that only 20% believed their training had adequately prepared them to treat tobacco dependence. And less than 10% were familiar with treatment guidelines. "We are a little bit behind in this, but medical schools have made a change, and most medical schools now make an effort to make sure that standard curricula [on smoking cessation] are there," he said. In addition, comprehensive information is readily available in the ACCP’s Tobacco Dependence Treatment ToolKit.

Reassuringly, physicians who receive training in this area are 1.5 to 2.5 times more likely to perform smoking cessation tasks (Cochrane Database Syst. Rev. 2000;CD000214).

Physicians also report a lack of financial incentives to be a barrier. Dr. Talwar noted that two CPT codes – 99406 and 99407 – specifically pertain to cessation activities during visits. Physicians can usually bill for this counseling, in addition to routine office visits, four times annually.

Half of physicians still believe that reimbursement is insufficient. "But the situation is much better than 7 or 8 years ago, when it was much more difficult to get reimbursement for these activities," he commented.

Physicians also mention patients’ low likelihood of quitting as a barrier to broaching smoking cessation, according to Dr. Talwar. But the irony is that quit rates are influenced in large part by physicians’ efforts and the intensity of those efforts.

Discussing the so-called 5 A’s of smoking cessation – ask, advise, assess, assist, and arrange – he noted that physicians do fairly well on the first two, but not so well on the others.

For example, a study of 246 community-based primary care physicians found that 67% asked their patients about smoking status and 74% gave advice, but just 35% assisted with smoking cessation efforts and merely 8% arranged for follow-up (Prev. Med. 1998;27:720-9).

It is important to understand that relapses are part of the cessation process, Dr. Talwar stressed; in fact, smokers who succeed in quitting make five to seven attempts, on average, before succeeding. Hence, "you have just to have to be patient with them."

It might also be possible to improve the odds of successful quitting by approaching patients at teachable moments, he further noted. For instance, "admission [to the hospital] is an opportunity to interact, to make the change. Maybe that’s the time when you need to approach them."

His own 800-bed hospital generates a list each day of inpatients who smoke. A smoking cessation therapist then visits these patients and invites them to the smoking cessation clinic.

A final barrier is that some physicians themselves are smokers. "It’s been shown that physicians who smoke have very little faith in their own ability to promote smoking cessation," Dr. Talwar commented (Prev. Med. 2005;40:595-601).

On the other hand, this group has greater insight into the difficulties of quitting and might be able to draw on their own experiences to assist patients in this endeavor, he added.

Dr. Talwar did not report any conflicts of interest.

VANCOUVER, B.C. – Although physicians might be reluctant to bring up smoking cessation with their patients for many reasons, it is one of the most important preventive activities they can undertake, according to Dr. Arunabh Talwar.

Smokers are ambivalent about smoking, he said at the annual meeting of the American College of Chest Physicians. On any given day, their smoking status hangs in balance between one set of factors favoring quitting and another set favoring continuing (BMJ 2007;335:37-41).

"All we need to do is just [tip the balance]," said Dr. Talwar, who is a pulmonologist at North Shore University Hospital in Manhasset, N.Y.

Indeed, if self-reports are reliable, about 70% of smokers want to stop and 30% try each year. But only 2%-3% succeed.

Referring to the multistage model of behavioral change, he noted that making smokers aware of the link between smoking and end-organ damage is critical in starting the process. "That is the most important thing that physicians do – they move patients from a precontemplation to a contemplation stage and set the stage for the smoking cessation process to occur."

There is compelling evidence of the benefits of smoking cessation, he said. It has been identified as the single most effective step for lengthening and improving patients’ lives (BMJ 2004;328:947-9).

"Make no mistake, smoking cessation activity is very cost effective," he added. "I think it is the most cost-effective primary prevention action that a physician can take."

Brief advice to quit costs $338 per year of life saved – or less than 5% of the cost per year of life saved from giving pravastatin for primary prevention of cardiovascular disease, aspirin for secondary prevention of coronary heart disease, or simvastatin for secondary prevention of myocardial infarction (BMJ 2004;328:397-9).

Still, physicians cite numerous barriers to promoting smoking cessation with their patients, according to Dr. Talwar (J. Smok. Cessat. 2008;3:92-100). A common one is being too busy.

"But studies show us, a minimal intervention – as [little] as 3 minutes of a physician’s time – can move patients from ‘precontemplation’ to contemplation, can help improve quit status," he said. Furthermore, "as you increase the intervention, the success rate will improve."

For example, just 0.3% of smokers succeed in quitting long term on their own, but the value rises to 1.6% when physicians simply ask their smoking status, 3.3% when they ask and provide advice on quitting, and 5.1% when they ask, advise, and give a pamphlet (BMJ 1979;2:231-5).

Busy physicians can streamline efforts by using a team approach. "Some of it can be shared by other health care providers, whether they are nurses, nurse practitioners, physician assistants," Dr. Talwar explained. "We use our respiratory therapists and [pulmonary function test] lab technicians as well; that way, the load gets divided. But also, repeated messages to the patient will help move them along."

Physicians should also consider using telephone "quitlines" (now freely available in all states) and patient support groups in the behavioral modification part of cessation, he advised.

Another barrier physicians cite, lack of expertise, has a stronger negative influence on their smoking cessation activities than lack of interest, time, or materials (Eur. J. Public Health 2005;15:140-5).

Indeed, in a survey of New York City–area health care providers, Dr. Talwar and his colleagues found that only 20% believed their training had adequately prepared them to treat tobacco dependence. And less than 10% were familiar with treatment guidelines. "We are a little bit behind in this, but medical schools have made a change, and most medical schools now make an effort to make sure that standard curricula [on smoking cessation] are there," he said. In addition, comprehensive information is readily available in the ACCP’s Tobacco Dependence Treatment ToolKit.

Reassuringly, physicians who receive training in this area are 1.5 to 2.5 times more likely to perform smoking cessation tasks (Cochrane Database Syst. Rev. 2000;CD000214).

Physicians also report a lack of financial incentives to be a barrier. Dr. Talwar noted that two CPT codes – 99406 and 99407 – specifically pertain to cessation activities during visits. Physicians can usually bill for this counseling, in addition to routine office visits, four times annually.

Half of physicians still believe that reimbursement is insufficient. "But the situation is much better than 7 or 8 years ago, when it was much more difficult to get reimbursement for these activities," he commented.

Physicians also mention patients’ low likelihood of quitting as a barrier to broaching smoking cessation, according to Dr. Talwar. But the irony is that quit rates are influenced in large part by physicians’ efforts and the intensity of those efforts.

Discussing the so-called 5 A’s of smoking cessation – ask, advise, assess, assist, and arrange – he noted that physicians do fairly well on the first two, but not so well on the others.

For example, a study of 246 community-based primary care physicians found that 67% asked their patients about smoking status and 74% gave advice, but just 35% assisted with smoking cessation efforts and merely 8% arranged for follow-up (Prev. Med. 1998;27:720-9).

It is important to understand that relapses are part of the cessation process, Dr. Talwar stressed; in fact, smokers who succeed in quitting make five to seven attempts, on average, before succeeding. Hence, "you have just to have to be patient with them."

It might also be possible to improve the odds of successful quitting by approaching patients at teachable moments, he further noted. For instance, "admission [to the hospital] is an opportunity to interact, to make the change. Maybe that’s the time when you need to approach them."

His own 800-bed hospital generates a list each day of inpatients who smoke. A smoking cessation therapist then visits these patients and invites them to the smoking cessation clinic.

A final barrier is that some physicians themselves are smokers. "It’s been shown that physicians who smoke have very little faith in their own ability to promote smoking cessation," Dr. Talwar commented (Prev. Med. 2005;40:595-601).

On the other hand, this group has greater insight into the difficulties of quitting and might be able to draw on their own experiences to assist patients in this endeavor, he added.

Dr. Talwar did not report any conflicts of interest.

SAN FRANCISCO – The antiangiogenic agent bevacizumab is not efficacious when added to standard adjuvant chemotherapy for stage III colon cancer, despite its proven efficacy in the metastatic setting, a second randomized trial has reported.

Among 2,867 patients, the addition of bevacizumab (Avastin) to the adjuvant FOLFOX4 regimen or XELOX regimen did not improve the rate of disease-free survival, compared with FOLFOX4 alone, in the AVANT trial. Indeed, outcomes were slightly worse with the added bevacizumab.

"This study is negative," lead investigator Dr. Aimery de Gramont told attendees of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. "It’s very disappointing to say that bevacizumab is the third agent, after irinotecan and cetuximab, to fail in the adjuvant setting" despite showing efficacy in the metastatic setting.

The AVANT findings echo results of the NSABP (National Surgical Adjuvant Breast and Bowel Project) C-08 trial, which reported that about three-fourths of early colon cancer patients were disease free at 3 years, whether they had adjuvant bevacizumab or not after FOLFOX6. Roche had announced in September 2010 that AVANT failed to meet its primary end point of improving disease-free survival.

The AVANT data suggest that the poorer outcomes with bevacizumab were not a result of decreased treatment duration, increased toxicity, or a rebound effect after discontinuing the agent. Instead, Dr. de Gramont hypothesized, bevacizumab may have pushed the cancer into a dormant state.

"Cetuximab, irinotecan, and bevacizumab inhibit VEGF [vascular endothelial growth factor] signaling via HIF [hypoxia-inducible factor–1] alpha, and this can induce tumor dormancy," he elaborated. "We know that arrested angiogenesis is a component of cell dormancy. ... And cell dormancy, it has been shown by preclinical work, can protect tumor cells from chemotherapy."

AVANT enrolled 3,451 patients from 34 countries who had undergone resection of their high-risk, stage II or stage III colon cancer. The patients were randomized in nearly equal numbers to receive FOLFOX4 alone for 24 weeks followed by observation for 24 weeks; FOLFOX4 plus bevacizumab (5 mg/kg every 2 weeks) followed by bevacizumab monotherapy (7.5 mg/kg every 3 weeks); or XELOX plus bevacizumab (7.5 mg/kg every 3 weeks) followed by bevacizumab monotherapy (7.5 mg/kg every 3 weeks).

Bevacizumab, a monoclonal antibody to VEGF, is approved by the U.S. Food and Drug Administration for use in combination therapy to treat metastatic colorectal cancer, as well as some other cancers. It is manufactured by Genentech and Roche.

The primary end point was disease-free survival among the 83% of patients who had stage III cancer, according to Dr. de Gramont, head of the department of internal medicine/oncology at the Saint-Antoine Hospital in Paris. These patients were predominantly men (54%) and white (84%). The median duration of follow-up was slightly more than 4 years.

In intention-to-treat analysis conducted after a minimum follow-up of 3 years, the rate of disease-free survival did not differ significantly among groups. If anything, patients tended to fare worse if they were given FOLFOX4-bevacizumab (hazard ratio, 1.17; P = .07) or XELOX-bevacizumab (HR, 1.07; P = .44), compared with FOLFOX4 alone.

More-detailed analysis showed that the effect of added bevacizumab varied over time; that is, there was a transient early benefit in the first year with the combinations (HRs, 0.63 and 0.61) that was lost in subsequent years, a pattern similar to that seen in the NSABP C-08 trial.

Dr. de Gramont hypothesized that this may relate to a benefit of bevacizumab among patients who already have vascularized but undetectable micrometastases. "So these patients could have a [disease-free survival] effect during the first year," he said. "But after the first year, the treatment is not favorable, and this is even worse than in the C08 trial."

The 3-year rate of disease-free survival was 76% with FOLFOX4 alone, 73% with FOLFOX4-bevacizumab, and 75% with XELOX-bevacizumab.

An interim analysis of overall survival yielded similar findings. The risk of death was somewhat higher with FOLFOX4-bevacizumab (HR, 1.31) and with XELOX-bevacizumab (HR, 1.27) than with FOLFOX4 alone.

"Immature overall survival data suggest a possible detriment, but continued follow-up is needed to confirm [this]," cautioned Dr. de Gramont.

In the entire study population, the leading grade 3-5 adverse events were venous thromboembolism (seen in 5% of patients) and hypertension (1%) with FOLFOX4 alone; hypertension (11%) and venous thromboembolism (8%) with FOLFOX4-bevacizumab; and hypertension (10%) and venous thromboembolism (5%) with XELOX-bevacizumab.

Among the patients with stage III disease, the patterns of recurrence – including involvement of multiple sites – and the time from recurrence to death were similar across treatment arms.

These findings argue against a rebound effect after stopping bevacizumab, according to Dr. de Gramont. A "more aggressive tumor could have more involved sites," he explained. And "if there was a rebound effect, survival after relapse would have been worse in these patients."

The types of drugs given after recurrence were generally similar, except that patients in the FOLFOX4-alone group were more likely to receive bevacizumab. The most commonly used agents were irinotecan and 5-fluorouracil.

"A big translational effort is [being] done in the AVANT trial to look at different biomarkers to [determine] if there is a subpopulation that could benefit from this approach, and also to try to have predictive markers," Dr. de Gramont concluded.

"Everybody has been waiting for the results from AVANT to be presented because it’s very eagerly anticipated, given the results that we have seen of NSABP C-08," commented session discussant Dr. Johanna C. Bendell, director of the GI cancer research program at the Sarah Cannon Research Institute in Nashville, Tenn.

Results for the new trial differ in that the hazard ratios for disease-free survival increased after year 1 and showed not only lack of benefit of bevacizumab thereafter, but also possibly harm.

The time from recurrence to death was somewhat longer with FOLFOX4 alone, she noted. "But in the FOLFOX4 arm, more of those patients received bevacizumab after recurrence than [did] the patients in the bevacizumab arms," which could be contributing to their longer survival.

"When you really start to see the difference [between arms] is after the patients had already recurred, suggesting that something happens in the metastatic setting and perhaps not in the adjuvant until-disease-recurrence setting," said Dr. Bendell.

Roche sponsored the trial. Dr. de Gramont reported that he is a consultant for and has received honoraria from Roche (manufacturer of bevacizumab) and Sanofi-Aventis (manufacturer of oxaliplatin). Dr. Bendell reported having no relevant conflicts of interest.

SAN FRANCISCO – The antiangiogenic agent bevacizumab is not efficacious when added to standard adjuvant chemotherapy for stage III colon cancer, despite its proven efficacy in the metastatic setting, a second randomized trial has reported.

Among 2,867 patients, the addition of bevacizumab (Avastin) to the adjuvant FOLFOX4 regimen or XELOX regimen did not improve the rate of disease-free survival, compared with FOLFOX4 alone, in the AVANT trial. Indeed, outcomes were slightly worse with the added bevacizumab.

"This study is negative," lead investigator Dr. Aimery de Gramont told attendees of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. "It’s very disappointing to say that bevacizumab is the third agent, after irinotecan and cetuximab, to fail in the adjuvant setting" despite showing efficacy in the metastatic setting.

The AVANT findings echo results of the NSABP (National Surgical Adjuvant Breast and Bowel Project) C-08 trial, which reported that about three-fourths of early colon cancer patients were disease free at 3 years, whether they had adjuvant bevacizumab or not after FOLFOX6. Roche had announced in September 2010 that AVANT failed to meet its primary end point of improving disease-free survival.

The AVANT data suggest that the poorer outcomes with bevacizumab were not a result of decreased treatment duration, increased toxicity, or a rebound effect after discontinuing the agent. Instead, Dr. de Gramont hypothesized, bevacizumab may have pushed the cancer into a dormant state.

"Cetuximab, irinotecan, and bevacizumab inhibit VEGF [vascular endothelial growth factor] signaling via HIF [hypoxia-inducible factor–1] alpha, and this can induce tumor dormancy," he elaborated. "We know that arrested angiogenesis is a component of cell dormancy. ... And cell dormancy, it has been shown by preclinical work, can protect tumor cells from chemotherapy."

AVANT enrolled 3,451 patients from 34 countries who had undergone resection of their high-risk, stage II or stage III colon cancer. The patients were randomized in nearly equal numbers to receive FOLFOX4 alone for 24 weeks followed by observation for 24 weeks; FOLFOX4 plus bevacizumab (5 mg/kg every 2 weeks) followed by bevacizumab monotherapy (7.5 mg/kg every 3 weeks); or XELOX plus bevacizumab (7.5 mg/kg every 3 weeks) followed by bevacizumab monotherapy (7.5 mg/kg every 3 weeks).

Bevacizumab, a monoclonal antibody to VEGF, is approved by the U.S. Food and Drug Administration for use in combination therapy to treat metastatic colorectal cancer, as well as some other cancers. It is manufactured by Genentech and Roche.

The primary end point was disease-free survival among the 83% of patients who had stage III cancer, according to Dr. de Gramont, head of the department of internal medicine/oncology at the Saint-Antoine Hospital in Paris. These patients were predominantly men (54%) and white (84%). The median duration of follow-up was slightly more than 4 years.

In intention-to-treat analysis conducted after a minimum follow-up of 3 years, the rate of disease-free survival did not differ significantly among groups. If anything, patients tended to fare worse if they were given FOLFOX4-bevacizumab (hazard ratio, 1.17; P = .07) or XELOX-bevacizumab (HR, 1.07; P = .44), compared with FOLFOX4 alone.

More-detailed analysis showed that the effect of added bevacizumab varied over time; that is, there was a transient early benefit in the first year with the combinations (HRs, 0.63 and 0.61) that was lost in subsequent years, a pattern similar to that seen in the NSABP C-08 trial.

Dr. de Gramont hypothesized that this may relate to a benefit of bevacizumab among patients who already have vascularized but undetectable micrometastases. "So these patients could have a [disease-free survival] effect during the first year," he said. "But after the first year, the treatment is not favorable, and this is even worse than in the C08 trial."

The 3-year rate of disease-free survival was 76% with FOLFOX4 alone, 73% with FOLFOX4-bevacizumab, and 75% with XELOX-bevacizumab.

An interim analysis of overall survival yielded similar findings. The risk of death was somewhat higher with FOLFOX4-bevacizumab (HR, 1.31) and with XELOX-bevacizumab (HR, 1.27) than with FOLFOX4 alone.

"Immature overall survival data suggest a possible detriment, but continued follow-up is needed to confirm [this]," cautioned Dr. de Gramont.

In the entire study population, the leading grade 3-5 adverse events were venous thromboembolism (seen in 5% of patients) and hypertension (1%) with FOLFOX4 alone; hypertension (11%) and venous thromboembolism (8%) with FOLFOX4-bevacizumab; and hypertension (10%) and venous thromboembolism (5%) with XELOX-bevacizumab.

Among the patients with stage III disease, the patterns of recurrence – including involvement of multiple sites – and the time from recurrence to death were similar across treatment arms.

These findings argue against a rebound effect after stopping bevacizumab, according to Dr. de Gramont. A "more aggressive tumor could have more involved sites," he explained. And "if there was a rebound effect, survival after relapse would have been worse in these patients."

The types of drugs given after recurrence were generally similar, except that patients in the FOLFOX4-alone group were more likely to receive bevacizumab. The most commonly used agents were irinotecan and 5-fluorouracil.

"A big translational effort is [being] done in the AVANT trial to look at different biomarkers to [determine] if there is a subpopulation that could benefit from this approach, and also to try to have predictive markers," Dr. de Gramont concluded.

"Everybody has been waiting for the results from AVANT to be presented because it’s very eagerly anticipated, given the results that we have seen of NSABP C-08," commented session discussant Dr. Johanna C. Bendell, director of the GI cancer research program at the Sarah Cannon Research Institute in Nashville, Tenn.

Results for the new trial differ in that the hazard ratios for disease-free survival increased after year 1 and showed not only lack of benefit of bevacizumab thereafter, but also possibly harm.

The time from recurrence to death was somewhat longer with FOLFOX4 alone, she noted. "But in the FOLFOX4 arm, more of those patients received bevacizumab after recurrence than [did] the patients in the bevacizumab arms," which could be contributing to their longer survival.

"When you really start to see the difference [between arms] is after the patients had already recurred, suggesting that something happens in the metastatic setting and perhaps not in the adjuvant until-disease-recurrence setting," said Dr. Bendell.

Roche sponsored the trial. Dr. de Gramont reported that he is a consultant for and has received honoraria from Roche (manufacturer of bevacizumab) and Sanofi-Aventis (manufacturer of oxaliplatin). Dr. Bendell reported having no relevant conflicts of interest.

SAN FRANCISCO – The antiangiogenic agent bevacizumab is not efficacious when added to standard adjuvant chemotherapy for stage III colon cancer, despite its proven efficacy in the metastatic setting, a second randomized trial has reported.

Among 2,867 patients, the addition of bevacizumab (Avastin) to the adjuvant FOLFOX4 regimen or XELOX regimen did not improve the rate of disease-free survival, compared with FOLFOX4 alone, in the AVANT trial. Indeed, outcomes were slightly worse with the added bevacizumab.

"This study is negative," lead investigator Dr. Aimery de Gramont told attendees of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. "It’s very disappointing to say that bevacizumab is the third agent, after irinotecan and cetuximab, to fail in the adjuvant setting" despite showing efficacy in the metastatic setting.

The AVANT findings echo results of the NSABP (National Surgical Adjuvant Breast and Bowel Project) C-08 trial, which reported that about three-fourths of early colon cancer patients were disease free at 3 years, whether they had adjuvant bevacizumab or not after FOLFOX6. Roche had announced in September 2010 that AVANT failed to meet its primary end point of improving disease-free survival.

The AVANT data suggest that the poorer outcomes with bevacizumab were not a result of decreased treatment duration, increased toxicity, or a rebound effect after discontinuing the agent. Instead, Dr. de Gramont hypothesized, bevacizumab may have pushed the cancer into a dormant state.

"Cetuximab, irinotecan, and bevacizumab inhibit VEGF [vascular endothelial growth factor] signaling via HIF [hypoxia-inducible factor–1] alpha, and this can induce tumor dormancy," he elaborated. "We know that arrested angiogenesis is a component of cell dormancy. ... And cell dormancy, it has been shown by preclinical work, can protect tumor cells from chemotherapy."

AVANT enrolled 3,451 patients from 34 countries who had undergone resection of their high-risk, stage II or stage III colon cancer. The patients were randomized in nearly equal numbers to receive FOLFOX4 alone for 24 weeks followed by observation for 24 weeks; FOLFOX4 plus bevacizumab (5 mg/kg every 2 weeks) followed by bevacizumab monotherapy (7.5 mg/kg every 3 weeks); or XELOX plus bevacizumab (7.5 mg/kg every 3 weeks) followed by bevacizumab monotherapy (7.5 mg/kg every 3 weeks).

Bevacizumab, a monoclonal antibody to VEGF, is approved by the U.S. Food and Drug Administration for use in combination therapy to treat metastatic colorectal cancer, as well as some other cancers. It is manufactured by Genentech and Roche.

The primary end point was disease-free survival among the 83% of patients who had stage III cancer, according to Dr. de Gramont, head of the department of internal medicine/oncology at the Saint-Antoine Hospital in Paris. These patients were predominantly men (54%) and white (84%). The median duration of follow-up was slightly more than 4 years.

In intention-to-treat analysis conducted after a minimum follow-up of 3 years, the rate of disease-free survival did not differ significantly among groups. If anything, patients tended to fare worse if they were given FOLFOX4-bevacizumab (hazard ratio, 1.17; P = .07) or XELOX-bevacizumab (HR, 1.07; P = .44), compared with FOLFOX4 alone.

More-detailed analysis showed that the effect of added bevacizumab varied over time; that is, there was a transient early benefit in the first year with the combinations (HRs, 0.63 and 0.61) that was lost in subsequent years, a pattern similar to that seen in the NSABP C-08 trial.

Dr. de Gramont hypothesized that this may relate to a benefit of bevacizumab among patients who already have vascularized but undetectable micrometastases. "So these patients could have a [disease-free survival] effect during the first year," he said. "But after the first year, the treatment is not favorable, and this is even worse than in the C08 trial."

The 3-year rate of disease-free survival was 76% with FOLFOX4 alone, 73% with FOLFOX4-bevacizumab, and 75% with XELOX-bevacizumab.

An interim analysis of overall survival yielded similar findings. The risk of death was somewhat higher with FOLFOX4-bevacizumab (HR, 1.31) and with XELOX-bevacizumab (HR, 1.27) than with FOLFOX4 alone.

"Immature overall survival data suggest a possible detriment, but continued follow-up is needed to confirm [this]," cautioned Dr. de Gramont.

In the entire study population, the leading grade 3-5 adverse events were venous thromboembolism (seen in 5% of patients) and hypertension (1%) with FOLFOX4 alone; hypertension (11%) and venous thromboembolism (8%) with FOLFOX4-bevacizumab; and hypertension (10%) and venous thromboembolism (5%) with XELOX-bevacizumab.

Among the patients with stage III disease, the patterns of recurrence – including involvement of multiple sites – and the time from recurrence to death were similar across treatment arms.

These findings argue against a rebound effect after stopping bevacizumab, according to Dr. de Gramont. A "more aggressive tumor could have more involved sites," he explained. And "if there was a rebound effect, survival after relapse would have been worse in these patients."

The types of drugs given after recurrence were generally similar, except that patients in the FOLFOX4-alone group were more likely to receive bevacizumab. The most commonly used agents were irinotecan and 5-fluorouracil.

"A big translational effort is [being] done in the AVANT trial to look at different biomarkers to [determine] if there is a subpopulation that could benefit from this approach, and also to try to have predictive markers," Dr. de Gramont concluded.

"Everybody has been waiting for the results from AVANT to be presented because it’s very eagerly anticipated, given the results that we have seen of NSABP C-08," commented session discussant Dr. Johanna C. Bendell, director of the GI cancer research program at the Sarah Cannon Research Institute in Nashville, Tenn.

Results for the new trial differ in that the hazard ratios for disease-free survival increased after year 1 and showed not only lack of benefit of bevacizumab thereafter, but also possibly harm.

The time from recurrence to death was somewhat longer with FOLFOX4 alone, she noted. "But in the FOLFOX4 arm, more of those patients received bevacizumab after recurrence than [did] the patients in the bevacizumab arms," which could be contributing to their longer survival.

"When you really start to see the difference [between arms] is after the patients had already recurred, suggesting that something happens in the metastatic setting and perhaps not in the adjuvant until-disease-recurrence setting," said Dr. Bendell.

Roche sponsored the trial. Dr. de Gramont reported that he is a consultant for and has received honoraria from Roche (manufacturer of bevacizumab) and Sanofi-Aventis (manufacturer of oxaliplatin). Dr. Bendell reported having no relevant conflicts of interest.