Surgical Oncology

Over the past 3 decades, screening mammography may have overdiagnosed more than a million clinically insignificant breast tumors, while having virtually no impact on the incidence of metastatic disease.

Compared with the premammography era, routine screening now picks up 122 additional cases of early cancer per 100,000 women – just eight of which would likely have progressed to distant disease, Dr. Archie Bleyer and Dr. Gilbert Welch wrote in the Nov. 22 issue of the New England Journal of Medicine.

Courtesy Rhoda Baer/National Cancer Institute (NCI)

Looking at the results in light of a corresponding 28% decrease in breast cancer mortality puts screening mammography in perspective, the authors said: "Our data show that the true contribution of mammography to decreasing mortality must be at the low end of this range. They suggest that mammography has largely not met the first prerequisite for screening to reduce cancer-specific mortality – a reduction in the number of women who present with late-stage cancer.

Population cancer screening is a doubled-edged sword, wrote Dr. Bleyer of Oregon Health and Science University in Portland, and Dr. Welch of Geisel School of Medicine at Dartmouth in Hanover, N.H. While it’s impossible to say which screen-detected cancers would have caused serious disease or death, "there is certainty about what happens to [these women]. They undergo surgery, radiation therapy, hormonal therapy for 5 years or more, chemotherapy, or (usually) a combination of these treatments for abnormalities that otherwise would not have caused illness."

The authors used the Surveillance , Epidemiology, and End Results (SEER) database to examine screening mammography and breast cancer incidence data from 1976-2008. They considered the incidence baseline to be the number of cancers reported from 1976-1978, and compared it with incidence in 2006-2008. All of the models in the study controlled for an upswing of breast cancer from 1990 to 2005, which was associated with hormone-replacement therapy.

Screening mammography increased from about 30% of women aged 40 or older in the mid-80s to almost 70% by 2008. This was mirrored by an increase in the diagnosis of early-stage breast cancers diagnosed, from 112/100,000 to 234/100,000 per year – representing an absolute increase of 122/100,000 (N. Engl. J. Med. 2012;367:1998-2005 [doi:10.1056/NEJMoa1206809]).

"[This] reflects both the detection of more cases of localized disease and the advent of the detection of [ductal carcinoma in situ] (which was virtually not detected before mammography was available)," the authors said.

There was a much smaller concomitant decrease in late-stage cancers, which fell from 102/100,000 to 94 /100,000 women. This was almost entirely driven by a drop in regional disease, from about 85/100,000 in 1976 to 78/100,000 in 2008. The incidence of distant disease was almost entirely unchanged, hovering around 17/100,000 for the entire study period.

"If a constant underlying disease burden is assumed, only 8 of the 122 additional early diagnoses were destined to progress to advanced disease, implying a detection of 114 excess cases per 100,000 women" – a total of more than 1.5 million over the study period.

The incidence of overdiagnosis held when the authors used other models designed to favor mammography’s impact.

In a "best-guess estimate," they assumed that breast cancer incidence increased by 0.25% over the study period. "This approach suggests that the excess detection attributable to mammography ... involved more than 1.3 million women in the past 30 years."

The "extreme" model assumed that incidence increased by 0.5% each year, an estimate that minimized surplus diagnoses of early-stage disease and maximized the deficit of late-stage cancer. This model found that screening mammography detected an excess of 1.2 million cancers over the study period.

The "very extreme assumption" model assumed that incidence increased by 0.5% each year, and that the baseline incidence of late-stage disease was the highest ever observed (113 cases per 100,000 women, in 1985). Even with this model – the most favorable toward mammography – the authors estimated overdiagnosis of slightly more than 1 million women.

"Our analysis suggests that whatever the mortality benefit, breast-cancer screening involved substantial harm of excess detection of additional early-stage cancers that was not matched by a reduction in late-stage cancers. This imbalance indicates a considerable amount of overdiagnosis involving more than 1 million women in the past 3 decades – and, according to our best-guess estimate, more than 70,000 women in 2008."

SEER breast cancer mortality data help put the findings into perspective, the authors said. There has been a substantial reduction in mortality, which fell from 71/100,000 to 51/100,000 over the study period. "This reduction in mortality is probably due to some combination of the effects of screening mammography and better treatment," they said. But because the absolute reduction in deaths (20/100,000) was larger than the absolute reduction in late-stage cancer (8/100,000), screening mammography can’t be the main driver of change.

"Furthermore ... the small reduction in cases of late-stage cancer that has occurred has been confined to regional (largely node-positive) disease – a stage that can now often be treated successfully, with an expected 5-year survival rate of 85% among women 40 years of age or older. Unfortunately, however, the number of women in the United States who present with distant disease, only 25% of whom survive for 5 years, appears not to have been affected by screening."

Better therapy may even have altered the impact of screening, they added.

"Ironically, improvements in treatment tend to deteriorate the benefit of screening. As treatment of [disease detected by methods other than screening] improves, the benefit of screening diminishes. For example, since pneumonia can be treated successfully, no one would suggest that we screen for pneumonia."

The findings show that there are not absolutes for women considering whether or not to get a mammogram.

"Proponents of screening should provide women with data from a randomized screening trial that reflects improvements in current therapy and includes strategies to mitigate overdiagnosis in the intervention group. Women should recognize that our study does not answer the question, ‘Should I be screened for breast cancer?’ However, they can rest assured that the question has more than one right answer."

Dr. Bleyer disclosed that he is a consultant and speaker for Sigma-Tau Pharmaceuticals. Dr. Welch disclosed that he speaks on the topic of overdiagnosis with universities and medical schools, as well as to the Pharmacy Benefit Management Institute; all honoraria were donated to charitable organizations.

Over the past 3 decades, screening mammography may have overdiagnosed more than a million clinically insignificant breast tumors, while having virtually no impact on the incidence of metastatic disease.

Compared with the premammography era, routine screening now picks up 122 additional cases of early cancer per 100,000 women – just eight of which would likely have progressed to distant disease, Dr. Archie Bleyer and Dr. Gilbert Welch wrote in the Nov. 22 issue of the New England Journal of Medicine.

Courtesy Rhoda Baer/National Cancer Institute (NCI)

Looking at the results in light of a corresponding 28% decrease in breast cancer mortality puts screening mammography in perspective, the authors said: "Our data show that the true contribution of mammography to decreasing mortality must be at the low end of this range. They suggest that mammography has largely not met the first prerequisite for screening to reduce cancer-specific mortality – a reduction in the number of women who present with late-stage cancer.

Population cancer screening is a doubled-edged sword, wrote Dr. Bleyer of Oregon Health and Science University in Portland, and Dr. Welch of Geisel School of Medicine at Dartmouth in Hanover, N.H. While it’s impossible to say which screen-detected cancers would have caused serious disease or death, "there is certainty about what happens to [these women]. They undergo surgery, radiation therapy, hormonal therapy for 5 years or more, chemotherapy, or (usually) a combination of these treatments for abnormalities that otherwise would not have caused illness."

The authors used the Surveillance , Epidemiology, and End Results (SEER) database to examine screening mammography and breast cancer incidence data from 1976-2008. They considered the incidence baseline to be the number of cancers reported from 1976-1978, and compared it with incidence in 2006-2008. All of the models in the study controlled for an upswing of breast cancer from 1990 to 2005, which was associated with hormone-replacement therapy.

Screening mammography increased from about 30% of women aged 40 or older in the mid-80s to almost 70% by 2008. This was mirrored by an increase in the diagnosis of early-stage breast cancers diagnosed, from 112/100,000 to 234/100,000 per year – representing an absolute increase of 122/100,000 (N. Engl. J. Med. 2012;367:1998-2005 [doi:10.1056/NEJMoa1206809]).

"[This] reflects both the detection of more cases of localized disease and the advent of the detection of [ductal carcinoma in situ] (which was virtually not detected before mammography was available)," the authors said.

There was a much smaller concomitant decrease in late-stage cancers, which fell from 102/100,000 to 94 /100,000 women. This was almost entirely driven by a drop in regional disease, from about 85/100,000 in 1976 to 78/100,000 in 2008. The incidence of distant disease was almost entirely unchanged, hovering around 17/100,000 for the entire study period.

"If a constant underlying disease burden is assumed, only 8 of the 122 additional early diagnoses were destined to progress to advanced disease, implying a detection of 114 excess cases per 100,000 women" – a total of more than 1.5 million over the study period.

The incidence of overdiagnosis held when the authors used other models designed to favor mammography’s impact.

In a "best-guess estimate," they assumed that breast cancer incidence increased by 0.25% over the study period. "This approach suggests that the excess detection attributable to mammography ... involved more than 1.3 million women in the past 30 years."

The "extreme" model assumed that incidence increased by 0.5% each year, an estimate that minimized surplus diagnoses of early-stage disease and maximized the deficit of late-stage cancer. This model found that screening mammography detected an excess of 1.2 million cancers over the study period.

The "very extreme assumption" model assumed that incidence increased by 0.5% each year, and that the baseline incidence of late-stage disease was the highest ever observed (113 cases per 100,000 women, in 1985). Even with this model – the most favorable toward mammography – the authors estimated overdiagnosis of slightly more than 1 million women.

"Our analysis suggests that whatever the mortality benefit, breast-cancer screening involved substantial harm of excess detection of additional early-stage cancers that was not matched by a reduction in late-stage cancers. This imbalance indicates a considerable amount of overdiagnosis involving more than 1 million women in the past 3 decades – and, according to our best-guess estimate, more than 70,000 women in 2008."

SEER breast cancer mortality data help put the findings into perspective, the authors said. There has been a substantial reduction in mortality, which fell from 71/100,000 to 51/100,000 over the study period. "This reduction in mortality is probably due to some combination of the effects of screening mammography and better treatment," they said. But because the absolute reduction in deaths (20/100,000) was larger than the absolute reduction in late-stage cancer (8/100,000), screening mammography can’t be the main driver of change.

"Furthermore ... the small reduction in cases of late-stage cancer that has occurred has been confined to regional (largely node-positive) disease – a stage that can now often be treated successfully, with an expected 5-year survival rate of 85% among women 40 years of age or older. Unfortunately, however, the number of women in the United States who present with distant disease, only 25% of whom survive for 5 years, appears not to have been affected by screening."

Better therapy may even have altered the impact of screening, they added.

"Ironically, improvements in treatment tend to deteriorate the benefit of screening. As treatment of [disease detected by methods other than screening] improves, the benefit of screening diminishes. For example, since pneumonia can be treated successfully, no one would suggest that we screen for pneumonia."

The findings show that there are not absolutes for women considering whether or not to get a mammogram.

"Proponents of screening should provide women with data from a randomized screening trial that reflects improvements in current therapy and includes strategies to mitigate overdiagnosis in the intervention group. Women should recognize that our study does not answer the question, ‘Should I be screened for breast cancer?’ However, they can rest assured that the question has more than one right answer."

Dr. Bleyer disclosed that he is a consultant and speaker for Sigma-Tau Pharmaceuticals. Dr. Welch disclosed that he speaks on the topic of overdiagnosis with universities and medical schools, as well as to the Pharmacy Benefit Management Institute; all honoraria were donated to charitable organizations.

Over the past 3 decades, screening mammography may have overdiagnosed more than a million clinically insignificant breast tumors, while having virtually no impact on the incidence of metastatic disease.

Compared with the premammography era, routine screening now picks up 122 additional cases of early cancer per 100,000 women – just eight of which would likely have progressed to distant disease, Dr. Archie Bleyer and Dr. Gilbert Welch wrote in the Nov. 22 issue of the New England Journal of Medicine.

Courtesy Rhoda Baer/National Cancer Institute (NCI)

Looking at the results in light of a corresponding 28% decrease in breast cancer mortality puts screening mammography in perspective, the authors said: "Our data show that the true contribution of mammography to decreasing mortality must be at the low end of this range. They suggest that mammography has largely not met the first prerequisite for screening to reduce cancer-specific mortality – a reduction in the number of women who present with late-stage cancer.

Population cancer screening is a doubled-edged sword, wrote Dr. Bleyer of Oregon Health and Science University in Portland, and Dr. Welch of Geisel School of Medicine at Dartmouth in Hanover, N.H. While it’s impossible to say which screen-detected cancers would have caused serious disease or death, "there is certainty about what happens to [these women]. They undergo surgery, radiation therapy, hormonal therapy for 5 years or more, chemotherapy, or (usually) a combination of these treatments for abnormalities that otherwise would not have caused illness."

The authors used the Surveillance , Epidemiology, and End Results (SEER) database to examine screening mammography and breast cancer incidence data from 1976-2008. They considered the incidence baseline to be the number of cancers reported from 1976-1978, and compared it with incidence in 2006-2008. All of the models in the study controlled for an upswing of breast cancer from 1990 to 2005, which was associated with hormone-replacement therapy.

Screening mammography increased from about 30% of women aged 40 or older in the mid-80s to almost 70% by 2008. This was mirrored by an increase in the diagnosis of early-stage breast cancers diagnosed, from 112/100,000 to 234/100,000 per year – representing an absolute increase of 122/100,000 (N. Engl. J. Med. 2012;367:1998-2005 [doi:10.1056/NEJMoa1206809]).

"[This] reflects both the detection of more cases of localized disease and the advent of the detection of [ductal carcinoma in situ] (which was virtually not detected before mammography was available)," the authors said.

There was a much smaller concomitant decrease in late-stage cancers, which fell from 102/100,000 to 94 /100,000 women. This was almost entirely driven by a drop in regional disease, from about 85/100,000 in 1976 to 78/100,000 in 2008. The incidence of distant disease was almost entirely unchanged, hovering around 17/100,000 for the entire study period.

"If a constant underlying disease burden is assumed, only 8 of the 122 additional early diagnoses were destined to progress to advanced disease, implying a detection of 114 excess cases per 100,000 women" – a total of more than 1.5 million over the study period.

The incidence of overdiagnosis held when the authors used other models designed to favor mammography’s impact.

In a "best-guess estimate," they assumed that breast cancer incidence increased by 0.25% over the study period. "This approach suggests that the excess detection attributable to mammography ... involved more than 1.3 million women in the past 30 years."

The "extreme" model assumed that incidence increased by 0.5% each year, an estimate that minimized surplus diagnoses of early-stage disease and maximized the deficit of late-stage cancer. This model found that screening mammography detected an excess of 1.2 million cancers over the study period.

The "very extreme assumption" model assumed that incidence increased by 0.5% each year, and that the baseline incidence of late-stage disease was the highest ever observed (113 cases per 100,000 women, in 1985). Even with this model – the most favorable toward mammography – the authors estimated overdiagnosis of slightly more than 1 million women.

"Our analysis suggests that whatever the mortality benefit, breast-cancer screening involved substantial harm of excess detection of additional early-stage cancers that was not matched by a reduction in late-stage cancers. This imbalance indicates a considerable amount of overdiagnosis involving more than 1 million women in the past 3 decades – and, according to our best-guess estimate, more than 70,000 women in 2008."

SEER breast cancer mortality data help put the findings into perspective, the authors said. There has been a substantial reduction in mortality, which fell from 71/100,000 to 51/100,000 over the study period. "This reduction in mortality is probably due to some combination of the effects of screening mammography and better treatment," they said. But because the absolute reduction in deaths (20/100,000) was larger than the absolute reduction in late-stage cancer (8/100,000), screening mammography can’t be the main driver of change.

"Furthermore ... the small reduction in cases of late-stage cancer that has occurred has been confined to regional (largely node-positive) disease – a stage that can now often be treated successfully, with an expected 5-year survival rate of 85% among women 40 years of age or older. Unfortunately, however, the number of women in the United States who present with distant disease, only 25% of whom survive for 5 years, appears not to have been affected by screening."

Better therapy may even have altered the impact of screening, they added.

"Ironically, improvements in treatment tend to deteriorate the benefit of screening. As treatment of [disease detected by methods other than screening] improves, the benefit of screening diminishes. For example, since pneumonia can be treated successfully, no one would suggest that we screen for pneumonia."

The findings show that there are not absolutes for women considering whether or not to get a mammogram.

"Proponents of screening should provide women with data from a randomized screening trial that reflects improvements in current therapy and includes strategies to mitigate overdiagnosis in the intervention group. Women should recognize that our study does not answer the question, ‘Should I be screened for breast cancer?’ However, they can rest assured that the question has more than one right answer."

Dr. Bleyer disclosed that he is a consultant and speaker for Sigma-Tau Pharmaceuticals. Dr. Welch disclosed that he speaks on the topic of overdiagnosis with universities and medical schools, as well as to the Pharmacy Benefit Management Institute; all honoraria were donated to charitable organizations.

BOSTON – Here’s heartening news that physicians can convey to breast cancer survivors: Modern breast irradiation did not appear to cause late-term cardiac toxicity in a study that examined women a quarter of a century after they were treated.

Investigators found no significant differences in Framingham Heart Study risk scores, hemodynamic parameters, pericardial thickening, or heart failure among 50 women who had been randomized in the 1970s and 1980s to either mastectomy or breast-conserving surgery (BCS) and radiation, Dr. Charles B. Simone II reported at the annual meeting of the American Society for Radiation Oncology.

Neil Osterweil/IMNG Medical Media

Although the survival rate was slightly lower among patients treated with breast-conserving therapy, the difference does not appear to be related to radiation dose to the heart, said Dr. Simone of the Hospital of the University of Pennsylvania in Philadelphia. There were no differences in survival among women treated with BCS and radiation to left- or right-sided tumors.

"Based on this study, in the era of 3D planning, patients with early-stage breast cancer treated with radiotherapy do not have a higher risk of long-term cardiac morbidity compared with patients having mastectomy," he said.

The patients studied included 50 of 102 survivors from an original cohort of 237 women who had participated in the National Cancer Institute’s Breast Conservation Trial (79-C-0111), with randomization from 1979 to 1986. In that trial, women with stage I or II breast cancer received modified radical mastectomy with axillary node dissection or they underwent lumpectomy plus node dissection and a radiation dose of 45-50.4 Gy to the whole breast; the latter came with or without treatment of regional nodes, followed by a boost of 15-20 Gy with either iridium 192 brachytherapy or electrons.

All node-positive patients underwent 6-11 cycles of chemotherapy with doxorubicin and cyclophosphamide, and beginning in 1985 postmenopausal women with positive nodes were given tamoxifen.

The trial was unique at the time in that it used CT simulations for treatment planning and dose inhomogeneity corrections, Dr. Simone noted.

Diverging Survival Curves

At a median of 25.7 years after randomization, 43.8% of mastectomy patients were still alive, compared with 37.9% of BCS patients. Although the difference was not significant, it appeared to represent a divergence of survival curves that had been virtually identical for the first 25 years.

The trend could not be accounted for by secondary malignancies, changes in distant metastasis, or any other breast cancer–related causes, leading the investigators to question whether it might be due to radiation toxicity to the heart, as some studies have suggested.

In all, 26 patients who had had BCS and 24 who underwent mastectomy agreed to come back for the cardiac toxicity study.

The investigators took a detailed cardiac history, and subjected the women to exams, cardiac labs, cardiac MRI with a 3 Tesla magnet to look for anatomic and functional abnormalities, and CT angiogram to look for stenotic coronary disease and determine coronary arterial calcium score (CAC) of atherosclerotic burden.

They also looked at radiation technique parameters such as central lung distance, field size, dose, and boost dose.

On cardiac MRI, they only saw two significant between-group differences. Time to peak filling rate was shorter for BCS patients (487 milliseconds vs. 647 ms for mastectomy patients; P = .02), but there was no difference in the peak filling rate itself. Left ventricular mass was smaller for BCS patients (mean 90.5 gm vs. 111 gm for mastectomy patients), but this difference was no longer significant after adjustment for systolic blood pressure, Dr. Simone noted.

"Interestingly, we didn’t see any evidence of myocardial fibrosis in any patient assessed, and only one patient in each arm had any degree of pericardial thickening," he said.

Reassuring Data

Additionally, investigators saw no significant differences on CT angiography in the presence of visible plaque or significant or severe vascular stenosis. There were also no differences in plaque or stenosis in the left anterior descending arteries of women treated with radiation for tumors on the left or the right side of the body.

"For each and every vessel we looked at, there was no difference in the degree of stenosis," Dr. Simone said.

Median CAC scores were low and in the normal range, but patients who had received chemotherapy had a trend toward increased atherosclerosis and plaque formation, Dr. Simone noted.

The study "gives some reassurance to our patients that, after 25 years of follow-up, using modern radiation techniques the delivery of radiation to the left does not cause cardiac toxicity," Dr. Bruce Haffty, chair of radiation oncology at the Cancer Institute of New Jersey, New Brunswick, said at a briefing.

The study was supported by the National Cancer Institute. Dr. Simone and Dr. Haffty reported no relevant disclosures.

BOSTON – Here’s heartening news that physicians can convey to breast cancer survivors: Modern breast irradiation did not appear to cause late-term cardiac toxicity in a study that examined women a quarter of a century after they were treated.

Investigators found no significant differences in Framingham Heart Study risk scores, hemodynamic parameters, pericardial thickening, or heart failure among 50 women who had been randomized in the 1970s and 1980s to either mastectomy or breast-conserving surgery (BCS) and radiation, Dr. Charles B. Simone II reported at the annual meeting of the American Society for Radiation Oncology.

Neil Osterweil/IMNG Medical Media

Although the survival rate was slightly lower among patients treated with breast-conserving therapy, the difference does not appear to be related to radiation dose to the heart, said Dr. Simone of the Hospital of the University of Pennsylvania in Philadelphia. There were no differences in survival among women treated with BCS and radiation to left- or right-sided tumors.

"Based on this study, in the era of 3D planning, patients with early-stage breast cancer treated with radiotherapy do not have a higher risk of long-term cardiac morbidity compared with patients having mastectomy," he said.

The patients studied included 50 of 102 survivors from an original cohort of 237 women who had participated in the National Cancer Institute’s Breast Conservation Trial (79-C-0111), with randomization from 1979 to 1986. In that trial, women with stage I or II breast cancer received modified radical mastectomy with axillary node dissection or they underwent lumpectomy plus node dissection and a radiation dose of 45-50.4 Gy to the whole breast; the latter came with or without treatment of regional nodes, followed by a boost of 15-20 Gy with either iridium 192 brachytherapy or electrons.

All node-positive patients underwent 6-11 cycles of chemotherapy with doxorubicin and cyclophosphamide, and beginning in 1985 postmenopausal women with positive nodes were given tamoxifen.

The trial was unique at the time in that it used CT simulations for treatment planning and dose inhomogeneity corrections, Dr. Simone noted.

Diverging Survival Curves

At a median of 25.7 years after randomization, 43.8% of mastectomy patients were still alive, compared with 37.9% of BCS patients. Although the difference was not significant, it appeared to represent a divergence of survival curves that had been virtually identical for the first 25 years.

The trend could not be accounted for by secondary malignancies, changes in distant metastasis, or any other breast cancer–related causes, leading the investigators to question whether it might be due to radiation toxicity to the heart, as some studies have suggested.

In all, 26 patients who had had BCS and 24 who underwent mastectomy agreed to come back for the cardiac toxicity study.

The investigators took a detailed cardiac history, and subjected the women to exams, cardiac labs, cardiac MRI with a 3 Tesla magnet to look for anatomic and functional abnormalities, and CT angiogram to look for stenotic coronary disease and determine coronary arterial calcium score (CAC) of atherosclerotic burden.

They also looked at radiation technique parameters such as central lung distance, field size, dose, and boost dose.

On cardiac MRI, they only saw two significant between-group differences. Time to peak filling rate was shorter for BCS patients (487 milliseconds vs. 647 ms for mastectomy patients; P = .02), but there was no difference in the peak filling rate itself. Left ventricular mass was smaller for BCS patients (mean 90.5 gm vs. 111 gm for mastectomy patients), but this difference was no longer significant after adjustment for systolic blood pressure, Dr. Simone noted.

"Interestingly, we didn’t see any evidence of myocardial fibrosis in any patient assessed, and only one patient in each arm had any degree of pericardial thickening," he said.

Reassuring Data

Additionally, investigators saw no significant differences on CT angiography in the presence of visible plaque or significant or severe vascular stenosis. There were also no differences in plaque or stenosis in the left anterior descending arteries of women treated with radiation for tumors on the left or the right side of the body.

"For each and every vessel we looked at, there was no difference in the degree of stenosis," Dr. Simone said.

Median CAC scores were low and in the normal range, but patients who had received chemotherapy had a trend toward increased atherosclerosis and plaque formation, Dr. Simone noted.

The study "gives some reassurance to our patients that, after 25 years of follow-up, using modern radiation techniques the delivery of radiation to the left does not cause cardiac toxicity," Dr. Bruce Haffty, chair of radiation oncology at the Cancer Institute of New Jersey, New Brunswick, said at a briefing.

The study was supported by the National Cancer Institute. Dr. Simone and Dr. Haffty reported no relevant disclosures.

BOSTON – Here’s heartening news that physicians can convey to breast cancer survivors: Modern breast irradiation did not appear to cause late-term cardiac toxicity in a study that examined women a quarter of a century after they were treated.

Investigators found no significant differences in Framingham Heart Study risk scores, hemodynamic parameters, pericardial thickening, or heart failure among 50 women who had been randomized in the 1970s and 1980s to either mastectomy or breast-conserving surgery (BCS) and radiation, Dr. Charles B. Simone II reported at the annual meeting of the American Society for Radiation Oncology.

Neil Osterweil/IMNG Medical Media

Although the survival rate was slightly lower among patients treated with breast-conserving therapy, the difference does not appear to be related to radiation dose to the heart, said Dr. Simone of the Hospital of the University of Pennsylvania in Philadelphia. There were no differences in survival among women treated with BCS and radiation to left- or right-sided tumors.

"Based on this study, in the era of 3D planning, patients with early-stage breast cancer treated with radiotherapy do not have a higher risk of long-term cardiac morbidity compared with patients having mastectomy," he said.

The patients studied included 50 of 102 survivors from an original cohort of 237 women who had participated in the National Cancer Institute’s Breast Conservation Trial (79-C-0111), with randomization from 1979 to 1986. In that trial, women with stage I or II breast cancer received modified radical mastectomy with axillary node dissection or they underwent lumpectomy plus node dissection and a radiation dose of 45-50.4 Gy to the whole breast; the latter came with or without treatment of regional nodes, followed by a boost of 15-20 Gy with either iridium 192 brachytherapy or electrons.

All node-positive patients underwent 6-11 cycles of chemotherapy with doxorubicin and cyclophosphamide, and beginning in 1985 postmenopausal women with positive nodes were given tamoxifen.

The trial was unique at the time in that it used CT simulations for treatment planning and dose inhomogeneity corrections, Dr. Simone noted.

Diverging Survival Curves

At a median of 25.7 years after randomization, 43.8% of mastectomy patients were still alive, compared with 37.9% of BCS patients. Although the difference was not significant, it appeared to represent a divergence of survival curves that had been virtually identical for the first 25 years.

The trend could not be accounted for by secondary malignancies, changes in distant metastasis, or any other breast cancer–related causes, leading the investigators to question whether it might be due to radiation toxicity to the heart, as some studies have suggested.

In all, 26 patients who had had BCS and 24 who underwent mastectomy agreed to come back for the cardiac toxicity study.

The investigators took a detailed cardiac history, and subjected the women to exams, cardiac labs, cardiac MRI with a 3 Tesla magnet to look for anatomic and functional abnormalities, and CT angiogram to look for stenotic coronary disease and determine coronary arterial calcium score (CAC) of atherosclerotic burden.

They also looked at radiation technique parameters such as central lung distance, field size, dose, and boost dose.

On cardiac MRI, they only saw two significant between-group differences. Time to peak filling rate was shorter for BCS patients (487 milliseconds vs. 647 ms for mastectomy patients; P = .02), but there was no difference in the peak filling rate itself. Left ventricular mass was smaller for BCS patients (mean 90.5 gm vs. 111 gm for mastectomy patients), but this difference was no longer significant after adjustment for systolic blood pressure, Dr. Simone noted.

"Interestingly, we didn’t see any evidence of myocardial fibrosis in any patient assessed, and only one patient in each arm had any degree of pericardial thickening," he said.

Reassuring Data

Additionally, investigators saw no significant differences on CT angiography in the presence of visible plaque or significant or severe vascular stenosis. There were also no differences in plaque or stenosis in the left anterior descending arteries of women treated with radiation for tumors on the left or the right side of the body.

"For each and every vessel we looked at, there was no difference in the degree of stenosis," Dr. Simone said.

Median CAC scores were low and in the normal range, but patients who had received chemotherapy had a trend toward increased atherosclerosis and plaque formation, Dr. Simone noted.

The study "gives some reassurance to our patients that, after 25 years of follow-up, using modern radiation techniques the delivery of radiation to the left does not cause cardiac toxicity," Dr. Bruce Haffty, chair of radiation oncology at the Cancer Institute of New Jersey, New Brunswick, said at a briefing.

The study was supported by the National Cancer Institute. Dr. Simone and Dr. Haffty reported no relevant disclosures.

Patients with Zollinger-Ellison syndrome who also have multiple endocrine neoplasia type 1 usually follow an indolent clinical course that rarely results in disease-related death, unlike those who have the sporadic form of the syndrome, Dr. Maneesh H. Singh and his colleagues reported in the November issue of Clinical Gastroenterology and Hepatology.

This finding, from a retrospective study of 49 patients treated at a single tertiary care center since 1994, argues against surgery for the estimated 25%-50% of Zollinger-Ellison syndrome (ZES) patients who have multiple endocrine neoplasia type 1 (MEN-1). "Given these results, we support a conservative approach to disease management ... focusing on symptom control with pharmacologic agents," the investigators wrote (Clin. Gastroenterol. Hepatol. 2012 Aug. 20 [doi:10.1016/j.cgh.2012.08.014]).

Early and aggressive surgery is recommended for sporadic ZES because it improves survival and can be curative. But surgery’s role in those with MEN-1 has been contentious because it doesn’t appear to improve survival in these patients. Only the most radical surgery, which carries a 40% complication rate, appears to be curative in those with MEN-1,reported Dr. Singh and his colleagues at the Hospital of the University of Pennsylvania, Philadelphia.

Because ZES is such a rare disorder, this follow-up study of 34 ZES patients who underwent surgery and 15 who did not "represents one of the largest long-term studies of surgical outcomes from a tertiary care hospital" conducted to date, they wrote.

The study subjects’ mean age at diagnosis was 47 years. The mean duration of follow-up from the time of diagnosis was 7 years, ranging from 0 to 5 years for 19 patients, from 5 to 10 years for 10, from 10 to 20 years for 15, and for more than 20 years for 5.

Of the 15 patients who did not undergo surgery, 5 declined after a discussion of the risks and benefits of the procedure, 2 because they had no lesions greater than 2 cm in diameter in imaging studies, 3 because of extensive liver involvement that was deemed unresectable, and 5 because they had unrelated comorbidities that made them poor surgical candidates.

A total of 33 subjects had sporadic ZES, while the other 16 had associated MEN-1. In the latter group, there was no significant difference between the median survival for the nine who underwent surgery (22.4 years) and for the seven who did not (25.5 years).

Standard gastrinoma resection with duodenotomy did not achieve a cure in any of the ZES patients with accompanying MEN-1.

In contrast, surgery improved both disease-related and all-cause mortality in the sporadic form of the disorder, and surgery was deemed curative in 6 (32%) of the patients with sporadic ZES.

None of the patients with MEN-1died of progressive ZES, compared with 28 (85%) of the patients with sporadic ZES. Thus, the form of the disease associated with MEN-1 appears to have a much more benign course than the sporadic form, Dr. Singh and his associates reported.

ZES associated with MEN-1 also tends to have an earlier symptom onset than does sporadic ZES, but because it is more indolent, the mean age at death was nearly identical between the two groups.

In this study, ZES patients with MEN-1had rates of liver involvement at diagnosis and rates of later liver metastases that were similar to those of patients with sporadic ZES. But again, this did not reduce their survival as it did with sporadic ZES.

This finding suggests that there may be a fundamental difference in the basic tumor biology between the two forms of the disease. It supports the theory that sporadic ZES is "a rapidly progressive, malignant form of gastrinoma that defies prediction and advocates for swift surgical intervention," the researchers wrote.

They reported no industry support for this study and no other financial conflicts.

Patients with Zollinger-Ellison syndrome who also have multiple endocrine neoplasia type 1 usually follow an indolent clinical course that rarely results in disease-related death, unlike those who have the sporadic form of the syndrome, Dr. Maneesh H. Singh and his colleagues reported in the November issue of Clinical Gastroenterology and Hepatology.

This finding, from a retrospective study of 49 patients treated at a single tertiary care center since 1994, argues against surgery for the estimated 25%-50% of Zollinger-Ellison syndrome (ZES) patients who have multiple endocrine neoplasia type 1 (MEN-1). "Given these results, we support a conservative approach to disease management ... focusing on symptom control with pharmacologic agents," the investigators wrote (Clin. Gastroenterol. Hepatol. 2012 Aug. 20 [doi:10.1016/j.cgh.2012.08.014]).

Early and aggressive surgery is recommended for sporadic ZES because it improves survival and can be curative. But surgery’s role in those with MEN-1 has been contentious because it doesn’t appear to improve survival in these patients. Only the most radical surgery, which carries a 40% complication rate, appears to be curative in those with MEN-1,reported Dr. Singh and his colleagues at the Hospital of the University of Pennsylvania, Philadelphia.

Because ZES is such a rare disorder, this follow-up study of 34 ZES patients who underwent surgery and 15 who did not "represents one of the largest long-term studies of surgical outcomes from a tertiary care hospital" conducted to date, they wrote.

The study subjects’ mean age at diagnosis was 47 years. The mean duration of follow-up from the time of diagnosis was 7 years, ranging from 0 to 5 years for 19 patients, from 5 to 10 years for 10, from 10 to 20 years for 15, and for more than 20 years for 5.

Of the 15 patients who did not undergo surgery, 5 declined after a discussion of the risks and benefits of the procedure, 2 because they had no lesions greater than 2 cm in diameter in imaging studies, 3 because of extensive liver involvement that was deemed unresectable, and 5 because they had unrelated comorbidities that made them poor surgical candidates.

A total of 33 subjects had sporadic ZES, while the other 16 had associated MEN-1. In the latter group, there was no significant difference between the median survival for the nine who underwent surgery (22.4 years) and for the seven who did not (25.5 years).

Standard gastrinoma resection with duodenotomy did not achieve a cure in any of the ZES patients with accompanying MEN-1.

In contrast, surgery improved both disease-related and all-cause mortality in the sporadic form of the disorder, and surgery was deemed curative in 6 (32%) of the patients with sporadic ZES.

None of the patients with MEN-1died of progressive ZES, compared with 28 (85%) of the patients with sporadic ZES. Thus, the form of the disease associated with MEN-1 appears to have a much more benign course than the sporadic form, Dr. Singh and his associates reported.

ZES associated with MEN-1 also tends to have an earlier symptom onset than does sporadic ZES, but because it is more indolent, the mean age at death was nearly identical between the two groups.

In this study, ZES patients with MEN-1had rates of liver involvement at diagnosis and rates of later liver metastases that were similar to those of patients with sporadic ZES. But again, this did not reduce their survival as it did with sporadic ZES.

This finding suggests that there may be a fundamental difference in the basic tumor biology between the two forms of the disease. It supports the theory that sporadic ZES is "a rapidly progressive, malignant form of gastrinoma that defies prediction and advocates for swift surgical intervention," the researchers wrote.

They reported no industry support for this study and no other financial conflicts.

Patients with Zollinger-Ellison syndrome who also have multiple endocrine neoplasia type 1 usually follow an indolent clinical course that rarely results in disease-related death, unlike those who have the sporadic form of the syndrome, Dr. Maneesh H. Singh and his colleagues reported in the November issue of Clinical Gastroenterology and Hepatology.

This finding, from a retrospective study of 49 patients treated at a single tertiary care center since 1994, argues against surgery for the estimated 25%-50% of Zollinger-Ellison syndrome (ZES) patients who have multiple endocrine neoplasia type 1 (MEN-1). "Given these results, we support a conservative approach to disease management ... focusing on symptom control with pharmacologic agents," the investigators wrote (Clin. Gastroenterol. Hepatol. 2012 Aug. 20 [doi:10.1016/j.cgh.2012.08.014]).

Early and aggressive surgery is recommended for sporadic ZES because it improves survival and can be curative. But surgery’s role in those with MEN-1 has been contentious because it doesn’t appear to improve survival in these patients. Only the most radical surgery, which carries a 40% complication rate, appears to be curative in those with MEN-1,reported Dr. Singh and his colleagues at the Hospital of the University of Pennsylvania, Philadelphia.

Because ZES is such a rare disorder, this follow-up study of 34 ZES patients who underwent surgery and 15 who did not "represents one of the largest long-term studies of surgical outcomes from a tertiary care hospital" conducted to date, they wrote.

The study subjects’ mean age at diagnosis was 47 years. The mean duration of follow-up from the time of diagnosis was 7 years, ranging from 0 to 5 years for 19 patients, from 5 to 10 years for 10, from 10 to 20 years for 15, and for more than 20 years for 5.

Of the 15 patients who did not undergo surgery, 5 declined after a discussion of the risks and benefits of the procedure, 2 because they had no lesions greater than 2 cm in diameter in imaging studies, 3 because of extensive liver involvement that was deemed unresectable, and 5 because they had unrelated comorbidities that made them poor surgical candidates.

A total of 33 subjects had sporadic ZES, while the other 16 had associated MEN-1. In the latter group, there was no significant difference between the median survival for the nine who underwent surgery (22.4 years) and for the seven who did not (25.5 years).

Standard gastrinoma resection with duodenotomy did not achieve a cure in any of the ZES patients with accompanying MEN-1.

In contrast, surgery improved both disease-related and all-cause mortality in the sporadic form of the disorder, and surgery was deemed curative in 6 (32%) of the patients with sporadic ZES.

None of the patients with MEN-1died of progressive ZES, compared with 28 (85%) of the patients with sporadic ZES. Thus, the form of the disease associated with MEN-1 appears to have a much more benign course than the sporadic form, Dr. Singh and his associates reported.

ZES associated with MEN-1 also tends to have an earlier symptom onset than does sporadic ZES, but because it is more indolent, the mean age at death was nearly identical between the two groups.

In this study, ZES patients with MEN-1had rates of liver involvement at diagnosis and rates of later liver metastases that were similar to those of patients with sporadic ZES. But again, this did not reduce their survival as it did with sporadic ZES.

This finding suggests that there may be a fundamental difference in the basic tumor biology between the two forms of the disease. It supports the theory that sporadic ZES is "a rapidly progressive, malignant form of gastrinoma that defies prediction and advocates for swift surgical intervention," the researchers wrote.

They reported no industry support for this study and no other financial conflicts.

Radiofrequency ablation for high-grade dysplasia in the setting of Barrett’s esophagus is more cost effective than endoscopic surveillance until progression to cancer, reported Dr. Chin Hur and his colleagues in the September issue of Gastroenterology.

Moreover, the use of radiofrequency ablation (RFA) for stable, confirmed low-grade dysplasia can also be cost effective, said the investigators.

Dr. Hur of Harvard University and Massachusetts General Hospital, both in Boston, and his colleagues conducted several analyses comparing three treatment strategies for each of three disease states: Barrett’s esophagus with high-grade dysplasia, Barrett’s esophagus with low-grade dysplasia, and Barrett’s esophagus with no dysplasia.

The treatment strategies consisted of surveillance followed by esophagectomy upon disease progression to cancer, RFA upon disease progression to a higher-grade dysplasia or cancer, or initial RFA before disease progression (Gastroenterology 2012 [doi: 10.1053/j.gastro.2012.05.010]).

Cost calculations were based on Medicare reimbursement rates for 2011. The cost estimate for RFA, for example, was $6,400, and the cost of esophagectomy was $25,882. Based on these values, the authors then conducted a base-case analysis.

They found that in high-grade dysplasia, the strategy of initial RFA resulted in 0.704 more quality-adjusted life-years (QALYs) and cost $25,609 less than the strategy of surveillance without RFA followed by esophagectomy upon disease progression to cancer, assuming a 1% disease progression rate.

Similarly, in low-grade dysplasia, RFA upon disease progression to high-grade dysplasia also bested the strategy of surveillance until cancer and esophagectomy, resulting in 0.17 more QALYs and costing $7,446 less, assuming a 0.5% progression rate.

However, in low-grade dysplasia, when comparing initial RFA versus surveillance until progression to high-grade dysplasia and then RFA, the authors found that the latter approach cost only $1,969 less than the former, and that the former was associated with a 0.108 gain in QALYs.

That amounted to an incremental cost-effectiveness ratio of $18,231 per QALY – "below our willingness-to-pay threshold of $100,000/QALY, making it the most plausible strategy in terms of cost-effectiveness."

Finally, in scenarios involving Barrett’s esophagus but no dysplasia, RFA upon progression of disease to high-grade dysplasia was still the most cost-effective strategy: It was associated with a savings of $7,709 as well as 0.194 additional QALYs, compared with esophagectomy upon disease progression to cancer, assuming a 0.33% progression rate.

The authors noted that their model relies on a stringent definition of low-grade dysplasia that assumes "review and agreement between more than one expert pathologist" as well as a consistent level of dysplasia found on more than one endoscopy spaced at least 6 months apart. In addition, the progression rates used in this analysis were based on the current literature, but were still estimates involving some uncertainty.

"We believe that a multicenter, randomized, controlled trial for initial RF ablation versus surveillance in patients with BE without dysplasia is needed to confirm our model results and to inform clinical decision making," they added.

Long-term follow-up data from such a study could "provide much needed data regarding cancer progression and the need for surveillance, which significantly impacts the cost-effectiveness and patients’ preferences for RFA."

The authors stated that they had no disclosures relevant to this study. The study was supported by grants from the National Institutes of Health.

Radiofrequency ablation for high-grade dysplasia in the setting of Barrett’s esophagus is more cost effective than endoscopic surveillance until progression to cancer, reported Dr. Chin Hur and his colleagues in the September issue of Gastroenterology.

Moreover, the use of radiofrequency ablation (RFA) for stable, confirmed low-grade dysplasia can also be cost effective, said the investigators.

Dr. Hur of Harvard University and Massachusetts General Hospital, both in Boston, and his colleagues conducted several analyses comparing three treatment strategies for each of three disease states: Barrett’s esophagus with high-grade dysplasia, Barrett’s esophagus with low-grade dysplasia, and Barrett’s esophagus with no dysplasia.

The treatment strategies consisted of surveillance followed by esophagectomy upon disease progression to cancer, RFA upon disease progression to a higher-grade dysplasia or cancer, or initial RFA before disease progression (Gastroenterology 2012 [doi: 10.1053/j.gastro.2012.05.010]).

Cost calculations were based on Medicare reimbursement rates for 2011. The cost estimate for RFA, for example, was $6,400, and the cost of esophagectomy was $25,882. Based on these values, the authors then conducted a base-case analysis.

They found that in high-grade dysplasia, the strategy of initial RFA resulted in 0.704 more quality-adjusted life-years (QALYs) and cost $25,609 less than the strategy of surveillance without RFA followed by esophagectomy upon disease progression to cancer, assuming a 1% disease progression rate.

Similarly, in low-grade dysplasia, RFA upon disease progression to high-grade dysplasia also bested the strategy of surveillance until cancer and esophagectomy, resulting in 0.17 more QALYs and costing $7,446 less, assuming a 0.5% progression rate.

However, in low-grade dysplasia, when comparing initial RFA versus surveillance until progression to high-grade dysplasia and then RFA, the authors found that the latter approach cost only $1,969 less than the former, and that the former was associated with a 0.108 gain in QALYs.

That amounted to an incremental cost-effectiveness ratio of $18,231 per QALY – "below our willingness-to-pay threshold of $100,000/QALY, making it the most plausible strategy in terms of cost-effectiveness."

Finally, in scenarios involving Barrett’s esophagus but no dysplasia, RFA upon progression of disease to high-grade dysplasia was still the most cost-effective strategy: It was associated with a savings of $7,709 as well as 0.194 additional QALYs, compared with esophagectomy upon disease progression to cancer, assuming a 0.33% progression rate.

The authors noted that their model relies on a stringent definition of low-grade dysplasia that assumes "review and agreement between more than one expert pathologist" as well as a consistent level of dysplasia found on more than one endoscopy spaced at least 6 months apart. In addition, the progression rates used in this analysis were based on the current literature, but were still estimates involving some uncertainty.

"We believe that a multicenter, randomized, controlled trial for initial RF ablation versus surveillance in patients with BE without dysplasia is needed to confirm our model results and to inform clinical decision making," they added.

Long-term follow-up data from such a study could "provide much needed data regarding cancer progression and the need for surveillance, which significantly impacts the cost-effectiveness and patients’ preferences for RFA."

The authors stated that they had no disclosures relevant to this study. The study was supported by grants from the National Institutes of Health.

Radiofrequency ablation for high-grade dysplasia in the setting of Barrett’s esophagus is more cost effective than endoscopic surveillance until progression to cancer, reported Dr. Chin Hur and his colleagues in the September issue of Gastroenterology.

Moreover, the use of radiofrequency ablation (RFA) for stable, confirmed low-grade dysplasia can also be cost effective, said the investigators.

Dr. Hur of Harvard University and Massachusetts General Hospital, both in Boston, and his colleagues conducted several analyses comparing three treatment strategies for each of three disease states: Barrett’s esophagus with high-grade dysplasia, Barrett’s esophagus with low-grade dysplasia, and Barrett’s esophagus with no dysplasia.

The treatment strategies consisted of surveillance followed by esophagectomy upon disease progression to cancer, RFA upon disease progression to a higher-grade dysplasia or cancer, or initial RFA before disease progression (Gastroenterology 2012 [doi: 10.1053/j.gastro.2012.05.010]).

Cost calculations were based on Medicare reimbursement rates for 2011. The cost estimate for RFA, for example, was $6,400, and the cost of esophagectomy was $25,882. Based on these values, the authors then conducted a base-case analysis.

They found that in high-grade dysplasia, the strategy of initial RFA resulted in 0.704 more quality-adjusted life-years (QALYs) and cost $25,609 less than the strategy of surveillance without RFA followed by esophagectomy upon disease progression to cancer, assuming a 1% disease progression rate.

Similarly, in low-grade dysplasia, RFA upon disease progression to high-grade dysplasia also bested the strategy of surveillance until cancer and esophagectomy, resulting in 0.17 more QALYs and costing $7,446 less, assuming a 0.5% progression rate.

However, in low-grade dysplasia, when comparing initial RFA versus surveillance until progression to high-grade dysplasia and then RFA, the authors found that the latter approach cost only $1,969 less than the former, and that the former was associated with a 0.108 gain in QALYs.

That amounted to an incremental cost-effectiveness ratio of $18,231 per QALY – "below our willingness-to-pay threshold of $100,000/QALY, making it the most plausible strategy in terms of cost-effectiveness."

Finally, in scenarios involving Barrett’s esophagus but no dysplasia, RFA upon progression of disease to high-grade dysplasia was still the most cost-effective strategy: It was associated with a savings of $7,709 as well as 0.194 additional QALYs, compared with esophagectomy upon disease progression to cancer, assuming a 0.33% progression rate.

The authors noted that their model relies on a stringent definition of low-grade dysplasia that assumes "review and agreement between more than one expert pathologist" as well as a consistent level of dysplasia found on more than one endoscopy spaced at least 6 months apart. In addition, the progression rates used in this analysis were based on the current literature, but were still estimates involving some uncertainty.

"We believe that a multicenter, randomized, controlled trial for initial RF ablation versus surveillance in patients with BE without dysplasia is needed to confirm our model results and to inform clinical decision making," they added.

Long-term follow-up data from such a study could "provide much needed data regarding cancer progression and the need for surveillance, which significantly impacts the cost-effectiveness and patients’ preferences for RFA."

The authors stated that they had no disclosures relevant to this study. The study was supported by grants from the National Institutes of Health.

A novel robotic system designed to perform endoscopic submucosal dissection of early gastric neoplasia was safe and effective in a five-patient trial, reported Soo Jay Phee, Ph.D., and colleagues in Clinical Gastroenterology and Hepatology.

Indeed, the first human study of the robotic device showed that it achieved clear margins, no cases of major bleeding or perforation, and discharge within hours for several of the patients.

Dr. Phee of the School of Mechanical and Aerospace Engineering at Nanyang Technological University in Singapore and first author Dr. D. Nageshwar Reddy of the Asian Institute of Gastroenterology in Somajiguda, India, enrolled five patients from two centers in India and one in Hong Kong.

Only patients with gastric neoplasia limited to the mucosa, confirmed by biopsy and histopathology, were included.

All patients underwent endoscopic submucosal dissection with the assistance of a novel device called the Master and Slave Transluminal Endoscopic Robot (MASTER). The MASTER device has been described previously (Gastrointest. Endoscopy 2010;72:593-9).

According to the authors, the device is controlled by two operators, "one responsible for the steering of the endoscope while the other would be performing the submucosal dissection with the two robotic arms."

The investigators added, "The open edge of the mucosa with the tumor was grasped by one of the robotic arms to retract the mucosa and enhance exposure of the submucosa, while submucosal dissection was completed with the other L hook arm" (Clin. Gastroenterol. Hepatol. 2012 October [doi:10.1016/j.cgh.2012.05.019]).

All procedures were performed under general anesthesia and with ventilation by naso- or orotracheal intubation. All operators trained on porcine models prior to the study.

In the case of the first patient, a 41-year-old man with a 2-cm adenocarcinoma in the body of the stomach, "the submucosal dissection with the robotic system was successfully done in 19 minutes," reported the authors.

There was no bleeding for perforation, and histopathology of the specimen after retrieval showed intramucosal well-differentiated adenocarcinoma with clear resection margins. The patient was discharged after 12 hours.

The second case, a 60-year-old man, was found to have a 1.5-cm mucosal adenocarcinoma in the gastric antrum. "The submucosal dissection was completed in only 5 minutes," wrote the authors, with no complications, and clear margins on histopathology. The patient was discharged in 6 hours.

Similarly, the third patient (a 39-year-old man) had a 2-cm sessile lesion in the gastric antrum. Submucosal dissection with the MASTER was completed in 3 minutes, with no complications, clear margins, and discharge from the hospital 4 hours later.

The longest procedure was done in a 51-year-old woman with a 3-cm early gastric cancer; this procedure took 50 minutes. She had no major bleeding or perforation, had clear margins on histopathology, and had a 3-day hospital stay.

Finally, a 50-year-old man with a 2.5-cm sessile polypoid in the inferior wall of the prepyloric canal underwent a 16-minute dissection. "Severe bleeding was encountered during the procedure and required exchange of the MASTER-mounted endoscope for a waterjet endoscope to stop the bleeding with coagulation grapser," wrote the authors.

"The pathology showed hyperplastic polyp with clear margins. He was discharged from hospital on day 3 after the procedure."

At 30 days’ follow-up, no complications were reported by any of the patients, and the follow-up endoscopy showed "complete healing" of the resection site. At 6 months, the three patients with data available were "doing well," according to the authors.

The study was supported by a MedTech Seeding Fund from the National University of Singapore. The authors reported having no other relevant financial disclosures.

A novel robotic system designed to perform endoscopic submucosal dissection of early gastric neoplasia was safe and effective in a five-patient trial, reported Soo Jay Phee, Ph.D., and colleagues in Clinical Gastroenterology and Hepatology.

Indeed, the first human study of the robotic device showed that it achieved clear margins, no cases of major bleeding or perforation, and discharge within hours for several of the patients.

Dr. Phee of the School of Mechanical and Aerospace Engineering at Nanyang Technological University in Singapore and first author Dr. D. Nageshwar Reddy of the Asian Institute of Gastroenterology in Somajiguda, India, enrolled five patients from two centers in India and one in Hong Kong.

Only patients with gastric neoplasia limited to the mucosa, confirmed by biopsy and histopathology, were included.

All patients underwent endoscopic submucosal dissection with the assistance of a novel device called the Master and Slave Transluminal Endoscopic Robot (MASTER). The MASTER device has been described previously (Gastrointest. Endoscopy 2010;72:593-9).

According to the authors, the device is controlled by two operators, "one responsible for the steering of the endoscope while the other would be performing the submucosal dissection with the two robotic arms."

The investigators added, "The open edge of the mucosa with the tumor was grasped by one of the robotic arms to retract the mucosa and enhance exposure of the submucosa, while submucosal dissection was completed with the other L hook arm" (Clin. Gastroenterol. Hepatol. 2012 October [doi:10.1016/j.cgh.2012.05.019]).

All procedures were performed under general anesthesia and with ventilation by naso- or orotracheal intubation. All operators trained on porcine models prior to the study.

In the case of the first patient, a 41-year-old man with a 2-cm adenocarcinoma in the body of the stomach, "the submucosal dissection with the robotic system was successfully done in 19 minutes," reported the authors.

There was no bleeding for perforation, and histopathology of the specimen after retrieval showed intramucosal well-differentiated adenocarcinoma with clear resection margins. The patient was discharged after 12 hours.

The second case, a 60-year-old man, was found to have a 1.5-cm mucosal adenocarcinoma in the gastric antrum. "The submucosal dissection was completed in only 5 minutes," wrote the authors, with no complications, and clear margins on histopathology. The patient was discharged in 6 hours.

Similarly, the third patient (a 39-year-old man) had a 2-cm sessile lesion in the gastric antrum. Submucosal dissection with the MASTER was completed in 3 minutes, with no complications, clear margins, and discharge from the hospital 4 hours later.

The longest procedure was done in a 51-year-old woman with a 3-cm early gastric cancer; this procedure took 50 minutes. She had no major bleeding or perforation, had clear margins on histopathology, and had a 3-day hospital stay.

Finally, a 50-year-old man with a 2.5-cm sessile polypoid in the inferior wall of the prepyloric canal underwent a 16-minute dissection. "Severe bleeding was encountered during the procedure and required exchange of the MASTER-mounted endoscope for a waterjet endoscope to stop the bleeding with coagulation grapser," wrote the authors.

"The pathology showed hyperplastic polyp with clear margins. He was discharged from hospital on day 3 after the procedure."

At 30 days’ follow-up, no complications were reported by any of the patients, and the follow-up endoscopy showed "complete healing" of the resection site. At 6 months, the three patients with data available were "doing well," according to the authors.

The study was supported by a MedTech Seeding Fund from the National University of Singapore. The authors reported having no other relevant financial disclosures.

A novel robotic system designed to perform endoscopic submucosal dissection of early gastric neoplasia was safe and effective in a five-patient trial, reported Soo Jay Phee, Ph.D., and colleagues in Clinical Gastroenterology and Hepatology.

Indeed, the first human study of the robotic device showed that it achieved clear margins, no cases of major bleeding or perforation, and discharge within hours for several of the patients.

Dr. Phee of the School of Mechanical and Aerospace Engineering at Nanyang Technological University in Singapore and first author Dr. D. Nageshwar Reddy of the Asian Institute of Gastroenterology in Somajiguda, India, enrolled five patients from two centers in India and one in Hong Kong.

Only patients with gastric neoplasia limited to the mucosa, confirmed by biopsy and histopathology, were included.

All patients underwent endoscopic submucosal dissection with the assistance of a novel device called the Master and Slave Transluminal Endoscopic Robot (MASTER). The MASTER device has been described previously (Gastrointest. Endoscopy 2010;72:593-9).

According to the authors, the device is controlled by two operators, "one responsible for the steering of the endoscope while the other would be performing the submucosal dissection with the two robotic arms."

The investigators added, "The open edge of the mucosa with the tumor was grasped by one of the robotic arms to retract the mucosa and enhance exposure of the submucosa, while submucosal dissection was completed with the other L hook arm" (Clin. Gastroenterol. Hepatol. 2012 October [doi:10.1016/j.cgh.2012.05.019]).

All procedures were performed under general anesthesia and with ventilation by naso- or orotracheal intubation. All operators trained on porcine models prior to the study.

In the case of the first patient, a 41-year-old man with a 2-cm adenocarcinoma in the body of the stomach, "the submucosal dissection with the robotic system was successfully done in 19 minutes," reported the authors.

There was no bleeding for perforation, and histopathology of the specimen after retrieval showed intramucosal well-differentiated adenocarcinoma with clear resection margins. The patient was discharged after 12 hours.

The second case, a 60-year-old man, was found to have a 1.5-cm mucosal adenocarcinoma in the gastric antrum. "The submucosal dissection was completed in only 5 minutes," wrote the authors, with no complications, and clear margins on histopathology. The patient was discharged in 6 hours.

Similarly, the third patient (a 39-year-old man) had a 2-cm sessile lesion in the gastric antrum. Submucosal dissection with the MASTER was completed in 3 minutes, with no complications, clear margins, and discharge from the hospital 4 hours later.

The longest procedure was done in a 51-year-old woman with a 3-cm early gastric cancer; this procedure took 50 minutes. She had no major bleeding or perforation, had clear margins on histopathology, and had a 3-day hospital stay.

Finally, a 50-year-old man with a 2.5-cm sessile polypoid in the inferior wall of the prepyloric canal underwent a 16-minute dissection. "Severe bleeding was encountered during the procedure and required exchange of the MASTER-mounted endoscope for a waterjet endoscope to stop the bleeding with coagulation grapser," wrote the authors.

"The pathology showed hyperplastic polyp with clear margins. He was discharged from hospital on day 3 after the procedure."

At 30 days’ follow-up, no complications were reported by any of the patients, and the follow-up endoscopy showed "complete healing" of the resection site. At 6 months, the three patients with data available were "doing well," according to the authors.

The study was supported by a MedTech Seeding Fund from the National University of Singapore. The authors reported having no other relevant financial disclosures.

The risks of death, postoperative infection, and other adverse clinical outcomes were significantly increased among patients undergoing colorectal cancer surgery who received perioperative allogeneic blood transfusions, according to a meta-analysis of 55 studies published in the August issue of Annals of Surgery.

Dr. Austin G. Acheson of the Nottingham (England) Digestive Disease Center at Queen’s Medical Centre and his associates reviewed 12 prospective studies and 43 retrospective cohort studies published between December 2004 and October 2010. The studies included 20,795 patients who were followed for a mean of about 5 years after undergoing surgery for colorectal cancer. Almost 60% (12,242) of these patients received a mean of three units of allogeneic red blood cells (Ann. Surg. 2012;256:235-44).

©Andrei Malov/iStockphoto.com

Patients who were transfused tended to be older, and the transfusion rate was significantly higher in women, those undergoing rectal surgery (compared with those undergoing right or left colon surgery), those with greater surgical blood loss, and those with worsening Duke's stage.

All associations between ABT and the adverse clinical outcomes described below were statistically significant.

The rates of all-cause mortality in the 29 studies that looked at this outcome were 45% among the patients who received blood transfusions vs. 35% of those who did not, a significant difference that represented a 72% increased risk. After adjusting for the duration of the observation period, the investigators found that the annual incidence of all-cause mortality was almost 9% among the transfused patients vs. 6.5% among those who were not transfused.

The rate of cancer-related mortality was 31% vs. 24% in the 17 studies that measured this outcome, a 71% increased risk. After adjusting for the length of observation, the investigators said the annual incidence of cancer-related mortality was 5.4% of those transfused and 4% of those who were not.

The rate of the combined end point of death resulting from recurrence/metastasis was 43% of those who were transfused vs. 33% of those who were not transfused – a 66% increase in risk – in the 19 studies that measured this outcome.

The risk of postoperative infections in the 12 studies that measured this outcome was 29% among those who were transfused vs. 11% of those who were not transfused, which was more than a threefold increased risk. In the two studies that measured the need for surgical reintervention, the risk was increased fourfold among those who were transfused.

In the four studies that measured the length of hospitalization, the hospital stay was a mean of almost 18 days among those who received transfusions, compared with 14 days among those who did not.

Based on evidence in this meta-analysis and other studies showing that preoperative anemia is an independent risk factor for a worse prognosis after colon surgery, and based on the association between ABTs and poorer clinical outcomes in this meta-analysis, the authors wrote that "appropriate blood management measures should, therefore, be given an important place in the care of patients with CRC [colorectal cancer] undergoing elective surgery."

The use of ABT has dropped over the past 25 years because of improvements in patient care, and the authors stated that they believe efforts should be made to further minimize ABT use. Well-designed studies are needed "to determine whether and in which patients preoperative corrective measures of anemia, other than ABTs, will contribute not only in the field of colorectal surgery but also to improve clinical outcomes," they added.

The study was supported by an unrestricted research grant from Vifor Pharma AG, a specialty pharmaceuticals company focused on the treatment of iron deficiency, according to its website. The authors disclosed receiving honoraria and/or travel support for consulting or lecturing for companies that include Vifor, Ethicon Endosurgery, Johnson & Johnson, and AstraZeneca AG; their research departments received grant support from companies that included Vifor.

The risks of death, postoperative infection, and other adverse clinical outcomes were significantly increased among patients undergoing colorectal cancer surgery who received perioperative allogeneic blood transfusions, according to a meta-analysis of 55 studies published in the August issue of Annals of Surgery.

Dr. Austin G. Acheson of the Nottingham (England) Digestive Disease Center at Queen’s Medical Centre and his associates reviewed 12 prospective studies and 43 retrospective cohort studies published between December 2004 and October 2010. The studies included 20,795 patients who were followed for a mean of about 5 years after undergoing surgery for colorectal cancer. Almost 60% (12,242) of these patients received a mean of three units of allogeneic red blood cells (Ann. Surg. 2012;256:235-44).

©Andrei Malov/iStockphoto.com

Patients who were transfused tended to be older, and the transfusion rate was significantly higher in women, those undergoing rectal surgery (compared with those undergoing right or left colon surgery), those with greater surgical blood loss, and those with worsening Duke's stage.

All associations between ABT and the adverse clinical outcomes described below were statistically significant.

The rates of all-cause mortality in the 29 studies that looked at this outcome were 45% among the patients who received blood transfusions vs. 35% of those who did not, a significant difference that represented a 72% increased risk. After adjusting for the duration of the observation period, the investigators found that the annual incidence of all-cause mortality was almost 9% among the transfused patients vs. 6.5% among those who were not transfused.

The rate of cancer-related mortality was 31% vs. 24% in the 17 studies that measured this outcome, a 71% increased risk. After adjusting for the length of observation, the investigators said the annual incidence of cancer-related mortality was 5.4% of those transfused and 4% of those who were not.

The rate of the combined end point of death resulting from recurrence/metastasis was 43% of those who were transfused vs. 33% of those who were not transfused – a 66% increase in risk – in the 19 studies that measured this outcome.

The risk of postoperative infections in the 12 studies that measured this outcome was 29% among those who were transfused vs. 11% of those who were not transfused, which was more than a threefold increased risk. In the two studies that measured the need for surgical reintervention, the risk was increased fourfold among those who were transfused.

In the four studies that measured the length of hospitalization, the hospital stay was a mean of almost 18 days among those who received transfusions, compared with 14 days among those who did not.

Based on evidence in this meta-analysis and other studies showing that preoperative anemia is an independent risk factor for a worse prognosis after colon surgery, and based on the association between ABTs and poorer clinical outcomes in this meta-analysis, the authors wrote that "appropriate blood management measures should, therefore, be given an important place in the care of patients with CRC [colorectal cancer] undergoing elective surgery."

The use of ABT has dropped over the past 25 years because of improvements in patient care, and the authors stated that they believe efforts should be made to further minimize ABT use. Well-designed studies are needed "to determine whether and in which patients preoperative corrective measures of anemia, other than ABTs, will contribute not only in the field of colorectal surgery but also to improve clinical outcomes," they added.

The study was supported by an unrestricted research grant from Vifor Pharma AG, a specialty pharmaceuticals company focused on the treatment of iron deficiency, according to its website. The authors disclosed receiving honoraria and/or travel support for consulting or lecturing for companies that include Vifor, Ethicon Endosurgery, Johnson & Johnson, and AstraZeneca AG; their research departments received grant support from companies that included Vifor.

The risks of death, postoperative infection, and other adverse clinical outcomes were significantly increased among patients undergoing colorectal cancer surgery who received perioperative allogeneic blood transfusions, according to a meta-analysis of 55 studies published in the August issue of Annals of Surgery.

Dr. Austin G. Acheson of the Nottingham (England) Digestive Disease Center at Queen’s Medical Centre and his associates reviewed 12 prospective studies and 43 retrospective cohort studies published between December 2004 and October 2010. The studies included 20,795 patients who were followed for a mean of about 5 years after undergoing surgery for colorectal cancer. Almost 60% (12,242) of these patients received a mean of three units of allogeneic red blood cells (Ann. Surg. 2012;256:235-44).

©Andrei Malov/iStockphoto.com

Patients who were transfused tended to be older, and the transfusion rate was significantly higher in women, those undergoing rectal surgery (compared with those undergoing right or left colon surgery), those with greater surgical blood loss, and those with worsening Duke's stage.

All associations between ABT and the adverse clinical outcomes described below were statistically significant.

The rates of all-cause mortality in the 29 studies that looked at this outcome were 45% among the patients who received blood transfusions vs. 35% of those who did not, a significant difference that represented a 72% increased risk. After adjusting for the duration of the observation period, the investigators found that the annual incidence of all-cause mortality was almost 9% among the transfused patients vs. 6.5% among those who were not transfused.

The rate of cancer-related mortality was 31% vs. 24% in the 17 studies that measured this outcome, a 71% increased risk. After adjusting for the length of observation, the investigators said the annual incidence of cancer-related mortality was 5.4% of those transfused and 4% of those who were not.

The rate of the combined end point of death resulting from recurrence/metastasis was 43% of those who were transfused vs. 33% of those who were not transfused – a 66% increase in risk – in the 19 studies that measured this outcome.

The risk of postoperative infections in the 12 studies that measured this outcome was 29% among those who were transfused vs. 11% of those who were not transfused, which was more than a threefold increased risk. In the two studies that measured the need for surgical reintervention, the risk was increased fourfold among those who were transfused.

In the four studies that measured the length of hospitalization, the hospital stay was a mean of almost 18 days among those who received transfusions, compared with 14 days among those who did not.

Based on evidence in this meta-analysis and other studies showing that preoperative anemia is an independent risk factor for a worse prognosis after colon surgery, and based on the association between ABTs and poorer clinical outcomes in this meta-analysis, the authors wrote that "appropriate blood management measures should, therefore, be given an important place in the care of patients with CRC [colorectal cancer] undergoing elective surgery."

The use of ABT has dropped over the past 25 years because of improvements in patient care, and the authors stated that they believe efforts should be made to further minimize ABT use. Well-designed studies are needed "to determine whether and in which patients preoperative corrective measures of anemia, other than ABTs, will contribute not only in the field of colorectal surgery but also to improve clinical outcomes," they added.

The study was supported by an unrestricted research grant from Vifor Pharma AG, a specialty pharmaceuticals company focused on the treatment of iron deficiency, according to its website. The authors disclosed receiving honoraria and/or travel support for consulting or lecturing for companies that include Vifor, Ethicon Endosurgery, Johnson & Johnson, and AstraZeneca AG; their research departments received grant support from companies that included Vifor.

Many renal cancers can now be managed in a minimally invasive fashion with either laparoscopic or robotic-assisted surgery. Potentially of greatest importance is the elucidation of the biological basis of sporadic as well as hereditary forms of renal carcinomas.

Most renal tumors arise from loss of function of the von Hippel-Lindau (VHL) gene and activation of the hypoxic response, including upregulation of hypoxia inducible factor leading to vascular endothelial growth factor induction and ultimately angiogenesis. In addition to the VHL syndrome, other hereditary forms include hereditary papillary renal carcinoma, Birt-Hogg-Dubé, and hereditary leiomyomatosis-renal cell cancer.

Surgical resection of localized renal cell carcinoma can be curative for lower-stage disease, but patients with advanced or metastatic disease are rarely cured by surgery alone. Traditional chemotherapy has had poor response rates and systemic options have been focused on immunotherapy with cytokines, such as interleukin-2 and interferon alfa. Hence, new targeted agents being tested in the neoadjuvant and adjuvant settings have created some excitement.

Seven novel targeted agents approved by the Food and Drug Administration are available for patients with metastatic disease: the tyrosine kinase inhibitors sorafenib, sunitinib, pazopanib, and axitinib; mTOR inhibitors temsirolimus and everolimus; and VEGF-inhibiting monoclonal antibody bevacizumab. The role of these therapies in either the neoadjuvant or adjuvant setting is being investigated.

The Adjuvant Sorafenib or Sunitinib in Unfavorable Renal Cell Carcinoma (ASSURE; ECOG 2805) trial has enrolled 1,865 patients randomized to one year of sunitinib, sorafenib, or placebo therapy after surgical excision of the primary tumor. The current standard of care, even for patients with high-risk pathologic features, is surveillance after surgical procedures when no evidence of residual disease can be found. Thus, the study is designed to determine whether adjuvant targeted therapy improves cancer-specific survival and to demonstrate a 25 percent reduction in the hazard rate of disease-free survival events.

The EVErolimus for Renal Cancer Ensuing Surgical Therapy (EVEREST) study (SWOG 0931), similar in design to ASSURE, examines the benefit of adjuvant systemic therapy after surgical procedures in patients with intermediate high-risk or very high-risk disease. Although sorafenib, sunitinib, and everolimus are all used clinically, sorafenib and sunitinib are tyrosine kinase inhibitors, whereas everolimus is an mTOR inhibitor. An estimated 1,218 patients will be randomized to either everolimus or placebo, stratified by pathologic stage, histologic subtype, and performance status.

Similar ongoing adjuvant trials include the Pfizer-sponsored S-TRAC trial (n=720) comparing sunitinib with placebo and the Medical Research Council SORCE trial (n=1,656) comparing sorafenib with placebo. Other agents are also being tested in the adjuvant setting, including pazopanib (PROTECT), as well as those that exploit the purported immunogenicity of renal cell carcinoma.

An accrued phase III trial has tested the antibody girentuximab, which binds specifically to carbonic anhydrase IX (G250 antigen) that is expressed on the cell surface of clear renal cell carcinomas. Future trials may extend the potential role of cell-based immunotherapy from patients with metastatic disease to the adjuvant setting.

Dr. Meng is associate professor of urology, department of urology, University of California, San Francisco, and director of the fellowship in urologic oncology.

Dr. Nelson is Fred C. Andersen Professor of Surgery and chair, division of surgery research, Mayo Clinic College of Medicine, Rochester, MN, and Program Director of the Alliance/American College of Surgeons Clinical Research Program.

Many renal cancers can now be managed in a minimally invasive fashion with either laparoscopic or robotic-assisted surgery. Potentially of greatest importance is the elucidation of the biological basis of sporadic as well as hereditary forms of renal carcinomas.

Most renal tumors arise from loss of function of the von Hippel-Lindau (VHL) gene and activation of the hypoxic response, including upregulation of hypoxia inducible factor leading to vascular endothelial growth factor induction and ultimately angiogenesis. In addition to the VHL syndrome, other hereditary forms include hereditary papillary renal carcinoma, Birt-Hogg-Dubé, and hereditary leiomyomatosis-renal cell cancer.

Surgical resection of localized renal cell carcinoma can be curative for lower-stage disease, but patients with advanced or metastatic disease are rarely cured by surgery alone. Traditional chemotherapy has had poor response rates and systemic options have been focused on immunotherapy with cytokines, such as interleukin-2 and interferon alfa. Hence, new targeted agents being tested in the neoadjuvant and adjuvant settings have created some excitement.

Seven novel targeted agents approved by the Food and Drug Administration are available for patients with metastatic disease: the tyrosine kinase inhibitors sorafenib, sunitinib, pazopanib, and axitinib; mTOR inhibitors temsirolimus and everolimus; and VEGF-inhibiting monoclonal antibody bevacizumab. The role of these therapies in either the neoadjuvant or adjuvant setting is being investigated.

The Adjuvant Sorafenib or Sunitinib in Unfavorable Renal Cell Carcinoma (ASSURE; ECOG 2805) trial has enrolled 1,865 patients randomized to one year of sunitinib, sorafenib, or placebo therapy after surgical excision of the primary tumor. The current standard of care, even for patients with high-risk pathologic features, is surveillance after surgical procedures when no evidence of residual disease can be found. Thus, the study is designed to determine whether adjuvant targeted therapy improves cancer-specific survival and to demonstrate a 25 percent reduction in the hazard rate of disease-free survival events.

The EVErolimus for Renal Cancer Ensuing Surgical Therapy (EVEREST) study (SWOG 0931), similar in design to ASSURE, examines the benefit of adjuvant systemic therapy after surgical procedures in patients with intermediate high-risk or very high-risk disease. Although sorafenib, sunitinib, and everolimus are all used clinically, sorafenib and sunitinib are tyrosine kinase inhibitors, whereas everolimus is an mTOR inhibitor. An estimated 1,218 patients will be randomized to either everolimus or placebo, stratified by pathologic stage, histologic subtype, and performance status.

Similar ongoing adjuvant trials include the Pfizer-sponsored S-TRAC trial (n=720) comparing sunitinib with placebo and the Medical Research Council SORCE trial (n=1,656) comparing sorafenib with placebo. Other agents are also being tested in the adjuvant setting, including pazopanib (PROTECT), as well as those that exploit the purported immunogenicity of renal cell carcinoma.

An accrued phase III trial has tested the antibody girentuximab, which binds specifically to carbonic anhydrase IX (G250 antigen) that is expressed on the cell surface of clear renal cell carcinomas. Future trials may extend the potential role of cell-based immunotherapy from patients with metastatic disease to the adjuvant setting.

Dr. Meng is associate professor of urology, department of urology, University of California, San Francisco, and director of the fellowship in urologic oncology.

Dr. Nelson is Fred C. Andersen Professor of Surgery and chair, division of surgery research, Mayo Clinic College of Medicine, Rochester, MN, and Program Director of the Alliance/American College of Surgeons Clinical Research Program.

Many renal cancers can now be managed in a minimally invasive fashion with either laparoscopic or robotic-assisted surgery. Potentially of greatest importance is the elucidation of the biological basis of sporadic as well as hereditary forms of renal carcinomas.

Most renal tumors arise from loss of function of the von Hippel-Lindau (VHL) gene and activation of the hypoxic response, including upregulation of hypoxia inducible factor leading to vascular endothelial growth factor induction and ultimately angiogenesis. In addition to the VHL syndrome, other hereditary forms include hereditary papillary renal carcinoma, Birt-Hogg-Dubé, and hereditary leiomyomatosis-renal cell cancer.

Surgical resection of localized renal cell carcinoma can be curative for lower-stage disease, but patients with advanced or metastatic disease are rarely cured by surgery alone. Traditional chemotherapy has had poor response rates and systemic options have been focused on immunotherapy with cytokines, such as interleukin-2 and interferon alfa. Hence, new targeted agents being tested in the neoadjuvant and adjuvant settings have created some excitement.

Seven novel targeted agents approved by the Food and Drug Administration are available for patients with metastatic disease: the tyrosine kinase inhibitors sorafenib, sunitinib, pazopanib, and axitinib; mTOR inhibitors temsirolimus and everolimus; and VEGF-inhibiting monoclonal antibody bevacizumab. The role of these therapies in either the neoadjuvant or adjuvant setting is being investigated.

The Adjuvant Sorafenib or Sunitinib in Unfavorable Renal Cell Carcinoma (ASSURE; ECOG 2805) trial has enrolled 1,865 patients randomized to one year of sunitinib, sorafenib, or placebo therapy after surgical excision of the primary tumor. The current standard of care, even for patients with high-risk pathologic features, is surveillance after surgical procedures when no evidence of residual disease can be found. Thus, the study is designed to determine whether adjuvant targeted therapy improves cancer-specific survival and to demonstrate a 25 percent reduction in the hazard rate of disease-free survival events.

The EVErolimus for Renal Cancer Ensuing Surgical Therapy (EVEREST) study (SWOG 0931), similar in design to ASSURE, examines the benefit of adjuvant systemic therapy after surgical procedures in patients with intermediate high-risk or very high-risk disease. Although sorafenib, sunitinib, and everolimus are all used clinically, sorafenib and sunitinib are tyrosine kinase inhibitors, whereas everolimus is an mTOR inhibitor. An estimated 1,218 patients will be randomized to either everolimus or placebo, stratified by pathologic stage, histologic subtype, and performance status.

Similar ongoing adjuvant trials include the Pfizer-sponsored S-TRAC trial (n=720) comparing sunitinib with placebo and the Medical Research Council SORCE trial (n=1,656) comparing sorafenib with placebo. Other agents are also being tested in the adjuvant setting, including pazopanib (PROTECT), as well as those that exploit the purported immunogenicity of renal cell carcinoma.

An accrued phase III trial has tested the antibody girentuximab, which binds specifically to carbonic anhydrase IX (G250 antigen) that is expressed on the cell surface of clear renal cell carcinomas. Future trials may extend the potential role of cell-based immunotherapy from patients with metastatic disease to the adjuvant setting.

Dr. Meng is associate professor of urology, department of urology, University of California, San Francisco, and director of the fellowship in urologic oncology.

Dr. Nelson is Fred C. Andersen Professor of Surgery and chair, division of surgery research, Mayo Clinic College of Medicine, Rochester, MN, and Program Director of the Alliance/American College of Surgeons Clinical Research Program.