Susan London

VANCOUVER, B.C. — New-onset pulmonary abnormalities in patients with rheumatoid arthritis should keep rheumatologists and pulmonologists on the edge of their seats, clinically speaking. The lung is a frequent site of extra-articular arthritis, and its most common manifestation – interstitial lung disease – carries significant morbidity and mortality risks, according to Dr. Kevin R. Flaherty.

Pulmonary Manifestations of RA

The lifetime risk of interstitial lung disease is nearly 8% in patients with RA, compared with 1% in the general population (Arthritis Rheum. 2010;62:1583-91).

And this disease confers a poor prognosis, with a near tripling of the risk of death and with a median survival after diagnosis of 2.5 years, noted Dr. Flaherty, who is a pulmonologist and associate professor at the University of Michigan Health System in Ann Arbor.

High-resolution computed tomography (HRCT) and pulmonary functioning testing appear to be useful for identifying interstitial lung disease early in its course, according to Dr. Flaherty.

For example, among patients within 2 years of a RA diagnosis, 44% have been found to have HRCT, pulmonary function test, and other abnormalities consistent with interstitial lung disease in the absence of symptoms (Am. J. Respir. Crit. Care Med. 1997;156:528-35).

“The [HRCT] features were mild – reticular thickening, ground glass, and not much honeycombing – suggesting maybe that we might be able to impact the disease, because I think once you get to honeycomb lung and end-stage fibrosis, our ability to impact this disease is likely to be lower,” he said.

As for which patients to screen for interstitial lung disease, the predictors of abnormal pulmonary function testing in the RA population are respiratory symptoms, smoking, anti–cyclic citrullinated peptide positivity, and use of prednisone (Arthritis Res. Ther. 2010;12:R104).

When it comes to monitoring interstitial lung disease, HRCT appears to be more sensitive than pulmonary function testing for detecting disease progression (Arch. Intern. Med. 2008;168:159-66).

And carbon monoxide diffusing capacity at diagnosis is the best predictor of progression (Ann. Rheum. Dis. 2002;61:517-21).

“We are starting … to see data emerging that really mirrors what we see in idiopathic lung disease, that the histopathology and the CT appearance can help us in terms of stratifying patients for risk of subsequent mortality,” Dr. Flaherty said.

A study of patients with RA-associated interstitial lung disease found 50% mortality in those with a usual interstitial pneumonia (UIP) histology, compared with none in those with a nonspecific interstitial pneumonia (NSIP) histology after a similar median follow-up of about 4 years (Chest 2005;127:2019-27).

A honeycomb pattern on HRCT was found only in the UIP group, suggesting that this radiographic pattern is a good surrogate for this histology, Dr. Flaherty noted. And indeed, patients having a definite UIP radiographic appearance have poorer survival (Eur. Respir. J. 2010;35:1322-8).

Rigorous studies are lacking when it comes to treating interstitial lung disease in the RA population, according to Dr. Flaherty.

Pulmonary Adverse Effects of RA Therapy

Pneumonitis is often a concern in patients using methotrexate to treat RA. But with low-dose therapy, only 3% of patients develop this complication after a mean treatment duration of 23 months (Chest 1996;109:933-8), Dr. Flaherty pointed out.

Anti–tumor necrosis factor agents such as infliximab have been associated with pulmonary adverse effects and complications, including infection, atypical presentation of tuberculosis, and pulmonary fibrosis.

Some research reports have also raised concern that anti-TNF agents may hasten progression of interstitial lung disease in patients with RA and thus increase mortality.

“The data on that are still out,” Dr. Flaherty said. Evidence thus far suggests that mortality in patients treated with these agents is similar to that in their counterparts treated with traditional disease-modifying antirheumatic drugs (Ann. Rheum. Dis. 2010;69:1086-91).

Rituximab has been linked to severe infections in patients with RA, the largest share of which (40%) are pulmonary (Arthritis Rheum. 2010;62:2625-32). Only a single infection was opportunistic, and most were bacterial.

Pulmonary Cancers

Patients with RA have increased risk of lung cancer (standardized incidence ratio, 1.63) as well as for another malignancy that can involve the lung, lymphoma (Arthritis Res. Ther. 2008;10:R45), as a result of their underlying disease, long-term immunosuppression, or both.

Treatment with biologic agents has not been associated with a significantly elevated risk of lung cancer among patients with RA, according to Dr. Flaherty.

But treatment with methotrexate has, with the incidence of lung cancer among methotrexate users about triple that of the general population (Arthritis Rheum. 2008;59:794-9).

Users of this drug also have sharply increased rates of non-Hodgkin's lymphoma and melanoma.

Dr. Flaherty did not report any disclosures.

VANCOUVER, B.C. — New-onset pulmonary abnormalities in patients with rheumatoid arthritis should keep rheumatologists and pulmonologists on the edge of their seats, clinically speaking. The lung is a frequent site of extra-articular arthritis, and its most common manifestation – interstitial lung disease – carries significant morbidity and mortality risks, according to Dr. Kevin R. Flaherty.

Pulmonary Manifestations of RA

The lifetime risk of interstitial lung disease is nearly 8% in patients with RA, compared with 1% in the general population (Arthritis Rheum. 2010;62:1583-91).

And this disease confers a poor prognosis, with a near tripling of the risk of death and with a median survival after diagnosis of 2.5 years, noted Dr. Flaherty, who is a pulmonologist and associate professor at the University of Michigan Health System in Ann Arbor.

High-resolution computed tomography (HRCT) and pulmonary functioning testing appear to be useful for identifying interstitial lung disease early in its course, according to Dr. Flaherty.

For example, among patients within 2 years of a RA diagnosis, 44% have been found to have HRCT, pulmonary function test, and other abnormalities consistent with interstitial lung disease in the absence of symptoms (Am. J. Respir. Crit. Care Med. 1997;156:528-35).

“The [HRCT] features were mild – reticular thickening, ground glass, and not much honeycombing – suggesting maybe that we might be able to impact the disease, because I think once you get to honeycomb lung and end-stage fibrosis, our ability to impact this disease is likely to be lower,” he said.

As for which patients to screen for interstitial lung disease, the predictors of abnormal pulmonary function testing in the RA population are respiratory symptoms, smoking, anti–cyclic citrullinated peptide positivity, and use of prednisone (Arthritis Res. Ther. 2010;12:R104).

When it comes to monitoring interstitial lung disease, HRCT appears to be more sensitive than pulmonary function testing for detecting disease progression (Arch. Intern. Med. 2008;168:159-66).

And carbon monoxide diffusing capacity at diagnosis is the best predictor of progression (Ann. Rheum. Dis. 2002;61:517-21).

“We are starting … to see data emerging that really mirrors what we see in idiopathic lung disease, that the histopathology and the CT appearance can help us in terms of stratifying patients for risk of subsequent mortality,” Dr. Flaherty said.

A study of patients with RA-associated interstitial lung disease found 50% mortality in those with a usual interstitial pneumonia (UIP) histology, compared with none in those with a nonspecific interstitial pneumonia (NSIP) histology after a similar median follow-up of about 4 years (Chest 2005;127:2019-27).

A honeycomb pattern on HRCT was found only in the UIP group, suggesting that this radiographic pattern is a good surrogate for this histology, Dr. Flaherty noted. And indeed, patients having a definite UIP radiographic appearance have poorer survival (Eur. Respir. J. 2010;35:1322-8).

Rigorous studies are lacking when it comes to treating interstitial lung disease in the RA population, according to Dr. Flaherty.

Pulmonary Adverse Effects of RA Therapy

Pneumonitis is often a concern in patients using methotrexate to treat RA. But with low-dose therapy, only 3% of patients develop this complication after a mean treatment duration of 23 months (Chest 1996;109:933-8), Dr. Flaherty pointed out.

Anti–tumor necrosis factor agents such as infliximab have been associated with pulmonary adverse effects and complications, including infection, atypical presentation of tuberculosis, and pulmonary fibrosis.

Some research reports have also raised concern that anti-TNF agents may hasten progression of interstitial lung disease in patients with RA and thus increase mortality.

“The data on that are still out,” Dr. Flaherty said. Evidence thus far suggests that mortality in patients treated with these agents is similar to that in their counterparts treated with traditional disease-modifying antirheumatic drugs (Ann. Rheum. Dis. 2010;69:1086-91).

Rituximab has been linked to severe infections in patients with RA, the largest share of which (40%) are pulmonary (Arthritis Rheum. 2010;62:2625-32). Only a single infection was opportunistic, and most were bacterial.

Pulmonary Cancers

Patients with RA have increased risk of lung cancer (standardized incidence ratio, 1.63) as well as for another malignancy that can involve the lung, lymphoma (Arthritis Res. Ther. 2008;10:R45), as a result of their underlying disease, long-term immunosuppression, or both.

Treatment with biologic agents has not been associated with a significantly elevated risk of lung cancer among patients with RA, according to Dr. Flaherty.

But treatment with methotrexate has, with the incidence of lung cancer among methotrexate users about triple that of the general population (Arthritis Rheum. 2008;59:794-9).

Users of this drug also have sharply increased rates of non-Hodgkin's lymphoma and melanoma.

Dr. Flaherty did not report any disclosures.

VANCOUVER, B.C. — New-onset pulmonary abnormalities in patients with rheumatoid arthritis should keep rheumatologists and pulmonologists on the edge of their seats, clinically speaking. The lung is a frequent site of extra-articular arthritis, and its most common manifestation – interstitial lung disease – carries significant morbidity and mortality risks, according to Dr. Kevin R. Flaherty.

Pulmonary Manifestations of RA

The lifetime risk of interstitial lung disease is nearly 8% in patients with RA, compared with 1% in the general population (Arthritis Rheum. 2010;62:1583-91).

And this disease confers a poor prognosis, with a near tripling of the risk of death and with a median survival after diagnosis of 2.5 years, noted Dr. Flaherty, who is a pulmonologist and associate professor at the University of Michigan Health System in Ann Arbor.

High-resolution computed tomography (HRCT) and pulmonary functioning testing appear to be useful for identifying interstitial lung disease early in its course, according to Dr. Flaherty.

For example, among patients within 2 years of a RA diagnosis, 44% have been found to have HRCT, pulmonary function test, and other abnormalities consistent with interstitial lung disease in the absence of symptoms (Am. J. Respir. Crit. Care Med. 1997;156:528-35).

“The [HRCT] features were mild – reticular thickening, ground glass, and not much honeycombing – suggesting maybe that we might be able to impact the disease, because I think once you get to honeycomb lung and end-stage fibrosis, our ability to impact this disease is likely to be lower,” he said.

As for which patients to screen for interstitial lung disease, the predictors of abnormal pulmonary function testing in the RA population are respiratory symptoms, smoking, anti–cyclic citrullinated peptide positivity, and use of prednisone (Arthritis Res. Ther. 2010;12:R104).

When it comes to monitoring interstitial lung disease, HRCT appears to be more sensitive than pulmonary function testing for detecting disease progression (Arch. Intern. Med. 2008;168:159-66).

And carbon monoxide diffusing capacity at diagnosis is the best predictor of progression (Ann. Rheum. Dis. 2002;61:517-21).

“We are starting … to see data emerging that really mirrors what we see in idiopathic lung disease, that the histopathology and the CT appearance can help us in terms of stratifying patients for risk of subsequent mortality,” Dr. Flaherty said.

A study of patients with RA-associated interstitial lung disease found 50% mortality in those with a usual interstitial pneumonia (UIP) histology, compared with none in those with a nonspecific interstitial pneumonia (NSIP) histology after a similar median follow-up of about 4 years (Chest 2005;127:2019-27).

A honeycomb pattern on HRCT was found only in the UIP group, suggesting that this radiographic pattern is a good surrogate for this histology, Dr. Flaherty noted. And indeed, patients having a definite UIP radiographic appearance have poorer survival (Eur. Respir. J. 2010;35:1322-8).

Rigorous studies are lacking when it comes to treating interstitial lung disease in the RA population, according to Dr. Flaherty.

Pulmonary Adverse Effects of RA Therapy

Pneumonitis is often a concern in patients using methotrexate to treat RA. But with low-dose therapy, only 3% of patients develop this complication after a mean treatment duration of 23 months (Chest 1996;109:933-8), Dr. Flaherty pointed out.

Anti–tumor necrosis factor agents such as infliximab have been associated with pulmonary adverse effects and complications, including infection, atypical presentation of tuberculosis, and pulmonary fibrosis.

Some research reports have also raised concern that anti-TNF agents may hasten progression of interstitial lung disease in patients with RA and thus increase mortality.

“The data on that are still out,” Dr. Flaherty said. Evidence thus far suggests that mortality in patients treated with these agents is similar to that in their counterparts treated with traditional disease-modifying antirheumatic drugs (Ann. Rheum. Dis. 2010;69:1086-91).

Rituximab has been linked to severe infections in patients with RA, the largest share of which (40%) are pulmonary (Arthritis Rheum. 2010;62:2625-32). Only a single infection was opportunistic, and most were bacterial.

Pulmonary Cancers

Patients with RA have increased risk of lung cancer (standardized incidence ratio, 1.63) as well as for another malignancy that can involve the lung, lymphoma (Arthritis Res. Ther. 2008;10:R45), as a result of their underlying disease, long-term immunosuppression, or both.

Treatment with biologic agents has not been associated with a significantly elevated risk of lung cancer among patients with RA, according to Dr. Flaherty.

But treatment with methotrexate has, with the incidence of lung cancer among methotrexate users about triple that of the general population (Arthritis Rheum. 2008;59:794-9).

Users of this drug also have sharply increased rates of non-Hodgkin's lymphoma and melanoma.

Dr. Flaherty did not report any disclosures.

SAN FRANCISCO – Bisphosphonates may hold promise for chemoprevention of colorectal cancer, based on a case-control study conducted in Israel, but randomized trials will be needed to confirm the results.

Among the 1,866 postmenopausal women studied, the use of a bisphosphonate for more than 1 year was associated with a 59% reduction in the risk of colorectal cancer, according to data reported at the meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"It’s an association study. ... One needs to be careful," lead investigator Dr. Gad Rennert acknowledged in an interview. "It will call for randomized trials now to see that it really is true."

The vast majority of women were taking alendronate, an oral bisphosphonate sold under the brand name Fosamax but also available generically. The apparent anticancer benefit became significant after 1 year of use and did not increase by much with longer duration.

"If it is shown to be true, then we are talking about a simple, cheap drug for short use," commented Dr. Rennert, who is director of the National Israeli Cancer Control Center and a professor at Technion–Israel Institute of Technology in Haifa. "This is perfect ... if it is supported by other studies."

Last year, his research team found that bisphosphonate use was associated with a reduced risk of breast cancer, a finding that has since been verified by three other investigative groups. However, a concern with that association is the potential confounding by low estrogen levels, which would not only cause osteoporosis (and hence bisphosphonate use) but also reduce breast cancer risk.

The new study, therefore, looked at colorectal cancer, in which such confounding is unlikely. "This is a tumor that is not known to have strong hormonal influences, so estrogen deprivation is not necessarily known to be a protective situation for colorectal cancer," he explained.

The study was conducted within the MECC (Molecular Epidemiology of Colorectal Cancer) study, which ascertained all incident cases of the disease diagnosed in northern Israel in 1998-2004 and matched those patients with unaffected individuals from the general population. Study participants were interviewed to collect information on their social, demographic, and medical characteristics.

The bisphosphonate analysis focused only on postmenopausal women: 933 who had experienced colorectal cancer and 933 who had not. They had mean ages of 71 and 72 years, respectively, according to results reported in a poster session.

Pharmacy records indicated that the women who had experienced colorectal cancer were less likely to have filled at least three bisphosphonate prescriptions (10% vs. 15%; P = .004) and to have used these agents for more than 1 year (6% vs. 11%; P less than .0001).

The analyses showed that compared with no bisphosphonate use, any use was associated with a significantly lower risk of colorectal cancer (odds ratio, 0.67).

When duration was considered, there was no benefit with less than 1 year of use. But there was significant benefit with at least 1 year of use (OR, 0.50) that was roughly the same with more than 2 years of use (OR, 0.51) and with more than 3 years of use (OR, 0.39).

This protection with relatively short use and its fairly stable magnitude thereafter bode well for using bisphosphonates for chemoprevention, according to Dr. Rennert.

"It’s important because if we ever want to use this drug for prevention, it actually means that we will be able to give it for a very short period only," he explained. "So it’s not a drug that somebody will need to take for years or for a lifetime."

In a multivariate model that took into account confounders (family history, sports activity, body mass index, vegetable intake, and use of aspirin, statins, postmenopausal hormones, vitamin D, and calcium), the use of bisphosphonates for more than 1 year was associated with a greater-than-one-half reduction in the risk of colorectal cancer (relative risk, 0.41; 95% confidence interval, 0.25-0.67).

Moreover, a similar risk reduction was seen for cancers of the right colon and cancers of the left colon individually. The risk of rectal cancer was also reduced, but not significantly so.

The investigators speculate that the anticancer benefit of bisphosphonates is related to their effects on the mevalonate metabolic pathway and inhibition of isoprenoid biosynthesis, which cancer cells require for growth-related processes.

Fosamax is currently approved by the Food and Drug Administration for the prevention of osteoporosis in postmenopausal women, for the treatment of osteoporosis in men and postmenopausal women, and for some other conditions compromising skeletal health.

Dr. Rennert reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Bisphosphonates may hold promise for chemoprevention of colorectal cancer, based on a case-control study conducted in Israel, but randomized trials will be needed to confirm the results.

Among the 1,866 postmenopausal women studied, the use of a bisphosphonate for more than 1 year was associated with a 59% reduction in the risk of colorectal cancer, according to data reported at the meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"It’s an association study. ... One needs to be careful," lead investigator Dr. Gad Rennert acknowledged in an interview. "It will call for randomized trials now to see that it really is true."

The vast majority of women were taking alendronate, an oral bisphosphonate sold under the brand name Fosamax but also available generically. The apparent anticancer benefit became significant after 1 year of use and did not increase by much with longer duration.

"If it is shown to be true, then we are talking about a simple, cheap drug for short use," commented Dr. Rennert, who is director of the National Israeli Cancer Control Center and a professor at Technion–Israel Institute of Technology in Haifa. "This is perfect ... if it is supported by other studies."

Last year, his research team found that bisphosphonate use was associated with a reduced risk of breast cancer, a finding that has since been verified by three other investigative groups. However, a concern with that association is the potential confounding by low estrogen levels, which would not only cause osteoporosis (and hence bisphosphonate use) but also reduce breast cancer risk.

The new study, therefore, looked at colorectal cancer, in which such confounding is unlikely. "This is a tumor that is not known to have strong hormonal influences, so estrogen deprivation is not necessarily known to be a protective situation for colorectal cancer," he explained.

The study was conducted within the MECC (Molecular Epidemiology of Colorectal Cancer) study, which ascertained all incident cases of the disease diagnosed in northern Israel in 1998-2004 and matched those patients with unaffected individuals from the general population. Study participants were interviewed to collect information on their social, demographic, and medical characteristics.

The bisphosphonate analysis focused only on postmenopausal women: 933 who had experienced colorectal cancer and 933 who had not. They had mean ages of 71 and 72 years, respectively, according to results reported in a poster session.

Pharmacy records indicated that the women who had experienced colorectal cancer were less likely to have filled at least three bisphosphonate prescriptions (10% vs. 15%; P = .004) and to have used these agents for more than 1 year (6% vs. 11%; P less than .0001).

The analyses showed that compared with no bisphosphonate use, any use was associated with a significantly lower risk of colorectal cancer (odds ratio, 0.67).

When duration was considered, there was no benefit with less than 1 year of use. But there was significant benefit with at least 1 year of use (OR, 0.50) that was roughly the same with more than 2 years of use (OR, 0.51) and with more than 3 years of use (OR, 0.39).

This protection with relatively short use and its fairly stable magnitude thereafter bode well for using bisphosphonates for chemoprevention, according to Dr. Rennert.

"It’s important because if we ever want to use this drug for prevention, it actually means that we will be able to give it for a very short period only," he explained. "So it’s not a drug that somebody will need to take for years or for a lifetime."

In a multivariate model that took into account confounders (family history, sports activity, body mass index, vegetable intake, and use of aspirin, statins, postmenopausal hormones, vitamin D, and calcium), the use of bisphosphonates for more than 1 year was associated with a greater-than-one-half reduction in the risk of colorectal cancer (relative risk, 0.41; 95% confidence interval, 0.25-0.67).

Moreover, a similar risk reduction was seen for cancers of the right colon and cancers of the left colon individually. The risk of rectal cancer was also reduced, but not significantly so.

The investigators speculate that the anticancer benefit of bisphosphonates is related to their effects on the mevalonate metabolic pathway and inhibition of isoprenoid biosynthesis, which cancer cells require for growth-related processes.

Fosamax is currently approved by the Food and Drug Administration for the prevention of osteoporosis in postmenopausal women, for the treatment of osteoporosis in men and postmenopausal women, and for some other conditions compromising skeletal health.

Dr. Rennert reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Bisphosphonates may hold promise for chemoprevention of colorectal cancer, based on a case-control study conducted in Israel, but randomized trials will be needed to confirm the results.

Among the 1,866 postmenopausal women studied, the use of a bisphosphonate for more than 1 year was associated with a 59% reduction in the risk of colorectal cancer, according to data reported at the meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"It’s an association study. ... One needs to be careful," lead investigator Dr. Gad Rennert acknowledged in an interview. "It will call for randomized trials now to see that it really is true."

The vast majority of women were taking alendronate, an oral bisphosphonate sold under the brand name Fosamax but also available generically. The apparent anticancer benefit became significant after 1 year of use and did not increase by much with longer duration.

"If it is shown to be true, then we are talking about a simple, cheap drug for short use," commented Dr. Rennert, who is director of the National Israeli Cancer Control Center and a professor at Technion–Israel Institute of Technology in Haifa. "This is perfect ... if it is supported by other studies."

Last year, his research team found that bisphosphonate use was associated with a reduced risk of breast cancer, a finding that has since been verified by three other investigative groups. However, a concern with that association is the potential confounding by low estrogen levels, which would not only cause osteoporosis (and hence bisphosphonate use) but also reduce breast cancer risk.

The new study, therefore, looked at colorectal cancer, in which such confounding is unlikely. "This is a tumor that is not known to have strong hormonal influences, so estrogen deprivation is not necessarily known to be a protective situation for colorectal cancer," he explained.

The study was conducted within the MECC (Molecular Epidemiology of Colorectal Cancer) study, which ascertained all incident cases of the disease diagnosed in northern Israel in 1998-2004 and matched those patients with unaffected individuals from the general population. Study participants were interviewed to collect information on their social, demographic, and medical characteristics.

The bisphosphonate analysis focused only on postmenopausal women: 933 who had experienced colorectal cancer and 933 who had not. They had mean ages of 71 and 72 years, respectively, according to results reported in a poster session.

Pharmacy records indicated that the women who had experienced colorectal cancer were less likely to have filled at least three bisphosphonate prescriptions (10% vs. 15%; P = .004) and to have used these agents for more than 1 year (6% vs. 11%; P less than .0001).

The analyses showed that compared with no bisphosphonate use, any use was associated with a significantly lower risk of colorectal cancer (odds ratio, 0.67).

When duration was considered, there was no benefit with less than 1 year of use. But there was significant benefit with at least 1 year of use (OR, 0.50) that was roughly the same with more than 2 years of use (OR, 0.51) and with more than 3 years of use (OR, 0.39).

This protection with relatively short use and its fairly stable magnitude thereafter bode well for using bisphosphonates for chemoprevention, according to Dr. Rennert.

"It’s important because if we ever want to use this drug for prevention, it actually means that we will be able to give it for a very short period only," he explained. "So it’s not a drug that somebody will need to take for years or for a lifetime."

In a multivariate model that took into account confounders (family history, sports activity, body mass index, vegetable intake, and use of aspirin, statins, postmenopausal hormones, vitamin D, and calcium), the use of bisphosphonates for more than 1 year was associated with a greater-than-one-half reduction in the risk of colorectal cancer (relative risk, 0.41; 95% confidence interval, 0.25-0.67).

Moreover, a similar risk reduction was seen for cancers of the right colon and cancers of the left colon individually. The risk of rectal cancer was also reduced, but not significantly so.

The investigators speculate that the anticancer benefit of bisphosphonates is related to their effects on the mevalonate metabolic pathway and inhibition of isoprenoid biosynthesis, which cancer cells require for growth-related processes.

Fosamax is currently approved by the Food and Drug Administration for the prevention of osteoporosis in postmenopausal women, for the treatment of osteoporosis in men and postmenopausal women, and for some other conditions compromising skeletal health.

Dr. Rennert reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Bisphosphonates may hold promise for chemoprevention of colorectal cancer, based on a case-control study conducted in Israel, but randomized trials will be needed to confirm the results.

Among the 1,866 postmenopausal women studied, the use of a bisphosphonate for more than 1 year was associated with a 59% reduction in the risk of colorectal cancer, according to data reported at the meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"It’s an association study. ... One needs to be careful," lead investigator Dr. Gad Rennert acknowledged in an interview. "It will call for randomized trials now to see that it really is true."

The vast majority of women were taking alendronate, an oral bisphosphonate sold under the brand name Fosamax but also available generically. The apparent anticancer benefit became significant after 1 year of use and did not increase by much with longer duration.

"If it is shown to be true, then we are talking about a simple, cheap drug for short use," commented Dr. Rennert, who is director of the National Israeli Cancer Control Center and a professor at Technion–Israel Institute of Technology in Haifa. "This is perfect ... if it is supported by other studies."

Last year, his research team found that bisphosphonate use was associated with a reduced risk of breast cancer, a finding that has since been verified by three other investigative groups. However, a concern with that association is the potential confounding by low estrogen levels, which would not only cause osteoporosis (and hence bisphosphonate use) but also reduce breast cancer risk.

The new study, therefore, looked at colorectal cancer, in which such confounding is unlikely. "This is a tumor that is not known to have strong hormonal influences, so estrogen deprivation is not necessarily known to be a protective situation for colorectal cancer," he explained.

The study was conducted within the MECC (Molecular Epidemiology of Colorectal Cancer) study, which ascertained all incident cases of the disease diagnosed in northern Israel in 1998-2004 and matched those patients with unaffected individuals from the general population. Study participants were interviewed to collect information on their social, demographic, and medical characteristics.

The bisphosphonate analysis focused only on postmenopausal women: 933 who had experienced colorectal cancer and 933 who had not. They had mean ages of 71 and 72 years, respectively, according to results reported in a poster session.

Pharmacy records indicated that the women who had experienced colorectal cancer were less likely to have filled at least three bisphosphonate prescriptions (10% vs. 15%; P = .004) and to have used these agents for more than 1 year (6% vs. 11%; P less than .0001).

The analyses showed that compared with no bisphosphonate use, any use was associated with a significantly lower risk of colorectal cancer (odds ratio, 0.67).

When duration was considered, there was no benefit with less than 1 year of use. But there was significant benefit with at least 1 year of use (OR, 0.50) that was roughly the same with more than 2 years of use (OR, 0.51) and with more than 3 years of use (OR, 0.39).

This protection with relatively short use and its fairly stable magnitude thereafter bode well for using bisphosphonates for chemoprevention, according to Dr. Rennert.

"It’s important because if we ever want to use this drug for prevention, it actually means that we will be able to give it for a very short period only," he explained. "So it’s not a drug that somebody will need to take for years or for a lifetime."

In a multivariate model that took into account confounders (family history, sports activity, body mass index, vegetable intake, and use of aspirin, statins, postmenopausal hormones, vitamin D, and calcium), the use of bisphosphonates for more than 1 year was associated with a greater-than-one-half reduction in the risk of colorectal cancer (relative risk, 0.41; 95% confidence interval, 0.25-0.67).

Moreover, a similar risk reduction was seen for cancers of the right colon and cancers of the left colon individually. The risk of rectal cancer was also reduced, but not significantly so.

The investigators speculate that the anticancer benefit of bisphosphonates is related to their effects on the mevalonate metabolic pathway and inhibition of isoprenoid biosynthesis, which cancer cells require for growth-related processes.

Fosamax is currently approved by the Food and Drug Administration for the prevention of osteoporosis in postmenopausal women, for the treatment of osteoporosis in men and postmenopausal women, and for some other conditions compromising skeletal health.

Dr. Rennert reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Bisphosphonates may hold promise for chemoprevention of colorectal cancer, based on a case-control study conducted in Israel, but randomized trials will be needed to confirm the results.

Among the 1,866 postmenopausal women studied, the use of a bisphosphonate for more than 1 year was associated with a 59% reduction in the risk of colorectal cancer, according to data reported at the meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"It’s an association study. ... One needs to be careful," lead investigator Dr. Gad Rennert acknowledged in an interview. "It will call for randomized trials now to see that it really is true."

The vast majority of women were taking alendronate, an oral bisphosphonate sold under the brand name Fosamax but also available generically. The apparent anticancer benefit became significant after 1 year of use and did not increase by much with longer duration.

"If it is shown to be true, then we are talking about a simple, cheap drug for short use," commented Dr. Rennert, who is director of the National Israeli Cancer Control Center and a professor at Technion–Israel Institute of Technology in Haifa. "This is perfect ... if it is supported by other studies."

Last year, his research team found that bisphosphonate use was associated with a reduced risk of breast cancer, a finding that has since been verified by three other investigative groups. However, a concern with that association is the potential confounding by low estrogen levels, which would not only cause osteoporosis (and hence bisphosphonate use) but also reduce breast cancer risk.

The new study, therefore, looked at colorectal cancer, in which such confounding is unlikely. "This is a tumor that is not known to have strong hormonal influences, so estrogen deprivation is not necessarily known to be a protective situation for colorectal cancer," he explained.

The study was conducted within the MECC (Molecular Epidemiology of Colorectal Cancer) study, which ascertained all incident cases of the disease diagnosed in northern Israel in 1998-2004 and matched those patients with unaffected individuals from the general population. Study participants were interviewed to collect information on their social, demographic, and medical characteristics.

The bisphosphonate analysis focused only on postmenopausal women: 933 who had experienced colorectal cancer and 933 who had not. They had mean ages of 71 and 72 years, respectively, according to results reported in a poster session.

Pharmacy records indicated that the women who had experienced colorectal cancer were less likely to have filled at least three bisphosphonate prescriptions (10% vs. 15%; P = .004) and to have used these agents for more than 1 year (6% vs. 11%; P less than .0001).

The analyses showed that compared with no bisphosphonate use, any use was associated with a significantly lower risk of colorectal cancer (odds ratio, 0.67).

When duration was considered, there was no benefit with less than 1 year of use. But there was significant benefit with at least 1 year of use (OR, 0.50) that was roughly the same with more than 2 years of use (OR, 0.51) and with more than 3 years of use (OR, 0.39).

This protection with relatively short use and its fairly stable magnitude thereafter bode well for using bisphosphonates for chemoprevention, according to Dr. Rennert.

"It’s important because if we ever want to use this drug for prevention, it actually means that we will be able to give it for a very short period only," he explained. "So it’s not a drug that somebody will need to take for years or for a lifetime."

In a multivariate model that took into account confounders (family history, sports activity, body mass index, vegetable intake, and use of aspirin, statins, postmenopausal hormones, vitamin D, and calcium), the use of bisphosphonates for more than 1 year was associated with a greater-than-one-half reduction in the risk of colorectal cancer (relative risk, 0.41; 95% confidence interval, 0.25-0.67).

Moreover, a similar risk reduction was seen for cancers of the right colon and cancers of the left colon individually. The risk of rectal cancer was also reduced, but not significantly so.

The investigators speculate that the anticancer benefit of bisphosphonates is related to their effects on the mevalonate metabolic pathway and inhibition of isoprenoid biosynthesis, which cancer cells require for growth-related processes.

Fosamax is currently approved by the Food and Drug Administration for the prevention of osteoporosis in postmenopausal women, for the treatment of osteoporosis in men and postmenopausal women, and for some other conditions compromising skeletal health.

Dr. Rennert reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Bisphosphonates may hold promise for chemoprevention of colorectal cancer, based on a case-control study conducted in Israel, but randomized trials will be needed to confirm the results.

Among the 1,866 postmenopausal women studied, the use of a bisphosphonate for more than 1 year was associated with a 59% reduction in the risk of colorectal cancer, according to data reported at the meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"It’s an association study. ... One needs to be careful," lead investigator Dr. Gad Rennert acknowledged in an interview. "It will call for randomized trials now to see that it really is true."

The vast majority of women were taking alendronate, an oral bisphosphonate sold under the brand name Fosamax but also available generically. The apparent anticancer benefit became significant after 1 year of use and did not increase by much with longer duration.

"If it is shown to be true, then we are talking about a simple, cheap drug for short use," commented Dr. Rennert, who is director of the National Israeli Cancer Control Center and a professor at Technion–Israel Institute of Technology in Haifa. "This is perfect ... if it is supported by other studies."

Last year, his research team found that bisphosphonate use was associated with a reduced risk of breast cancer, a finding that has since been verified by three other investigative groups. However, a concern with that association is the potential confounding by low estrogen levels, which would not only cause osteoporosis (and hence bisphosphonate use) but also reduce breast cancer risk.

The new study, therefore, looked at colorectal cancer, in which such confounding is unlikely. "This is a tumor that is not known to have strong hormonal influences, so estrogen deprivation is not necessarily known to be a protective situation for colorectal cancer," he explained.

The study was conducted within the MECC (Molecular Epidemiology of Colorectal Cancer) study, which ascertained all incident cases of the disease diagnosed in northern Israel in 1998-2004 and matched those patients with unaffected individuals from the general population. Study participants were interviewed to collect information on their social, demographic, and medical characteristics.

The bisphosphonate analysis focused only on postmenopausal women: 933 who had experienced colorectal cancer and 933 who had not. They had mean ages of 71 and 72 years, respectively, according to results reported in a poster session.

Pharmacy records indicated that the women who had experienced colorectal cancer were less likely to have filled at least three bisphosphonate prescriptions (10% vs. 15%; P = .004) and to have used these agents for more than 1 year (6% vs. 11%; P less than .0001).

The analyses showed that compared with no bisphosphonate use, any use was associated with a significantly lower risk of colorectal cancer (odds ratio, 0.67).

When duration was considered, there was no benefit with less than 1 year of use. But there was significant benefit with at least 1 year of use (OR, 0.50) that was roughly the same with more than 2 years of use (OR, 0.51) and with more than 3 years of use (OR, 0.39).

This protection with relatively short use and its fairly stable magnitude thereafter bode well for using bisphosphonates for chemoprevention, according to Dr. Rennert.

"It’s important because if we ever want to use this drug for prevention, it actually means that we will be able to give it for a very short period only," he explained. "So it’s not a drug that somebody will need to take for years or for a lifetime."

In a multivariate model that took into account confounders (family history, sports activity, body mass index, vegetable intake, and use of aspirin, statins, postmenopausal hormones, vitamin D, and calcium), the use of bisphosphonates for more than 1 year was associated with a greater-than-one-half reduction in the risk of colorectal cancer (relative risk, 0.41; 95% confidence interval, 0.25-0.67).

Moreover, a similar risk reduction was seen for cancers of the right colon and cancers of the left colon individually. The risk of rectal cancer was also reduced, but not significantly so.

The investigators speculate that the anticancer benefit of bisphosphonates is related to their effects on the mevalonate metabolic pathway and inhibition of isoprenoid biosynthesis, which cancer cells require for growth-related processes.

Fosamax is currently approved by the Food and Drug Administration for the prevention of osteoporosis in postmenopausal women, for the treatment of osteoporosis in men and postmenopausal women, and for some other conditions compromising skeletal health.

Dr. Rennert reported that he had no relevant conflicts of interest.

VANCOUVER, B.C. – Contemporary management of pulmonary sarcoidosis is moving away from hard clinical targets and toward patients’ self-reported well-being and goals, according to Dr. Daniel A. Culver, a pulmonologist at the Cleveland Clinic.

Physicians may treat sarcoidosis for a variety of reasons, and research is helping to sort out which of them are valid, he said at the annual meeting of the American College of Chest Physicians.

One reason might be to improve radiographic or physiologic parameters. In particular, the Scadding stage of a patient’s chest x-ray at presentation has been used for about 50 years to estimate prognosis and the need for treatment.

"But in fact there are a number of pieces of data coming out now that suggest that the chest x-ray may not be the most ideal way to measure how things are going to go for patients," he commented.

In one study, for example, half of patients with pulmonary sarcoidosis were rated as having a better chest x-ray during an exacerbation as compared with before, despite their worsening symptoms and spirometry (Respirology 2008;13:97-102).

Another reason for undertaking treatment might be to improve patients’ symptoms, according to Dr. Culver.

In this regard, a recent review has described a so-called sarcoidosis penumbra, a collection of disease-related issues that affect patients’ well-being but are often not well captured by tests physicians rely on (Semin. Respir. Crit. Care Med. 2010;31:501-18). For instance, two in every three patients have depression, and one in six has sleep apnea.

"This took us a long time as sarcoidologists to recognize, that it’s not the x-ray and vital capacity that the patients care about," but rather their daily ability to function and enjoy life, he commented.

"To optimally treat sarcoidosis, one of the new things we are discovering is that we need to ask the patients the questions that get to these sorts of issues and target our treatment to these sorts of issues," Dr. Culver said. "Going forward ... for both immunosuppressive therapy and the treatment of sarcoidosis in general, we are going to see it more focused on patient-centered outcomes and quality of life rather than things that we’d all like to measure, like the vital capacity."

Another reason that physicians may treat sarcoidosis is to alter the natural history of the disease and prevent fibrosis.

But "most sarcoidosis will resolve within the first 5 years, at least radiologically," Dr. Culver noted, and current evidence suggests treatment does little to alter this trajectory.

In one study, 39% of patients with stage 2 or 3 disease on chest x-ray had neither progression nor improvement during a 6-month period. When these stable patients were assigned either to immediate treatment with a fairly aggressive regimen of prednisolone or to as-needed treatment only if spirometry showed deterioration, just 19% of the latter group required treatment during the next 5 years (Thorax 1996;51:238-47).

"If you can hold off on treating, you may be able to prevent side effects from medicines ... and still have a patient who has their disease spontaneously resolve," he commented.

That said, the as-needed treatment group had a smaller improvement in forced vital capacity (FVC), and there were some other potentially important differences in outcomes between groups.

"Suffice it to say that right now, we don’t think that steroid therapy given preemptively has a tremendous impact on the natural history of the disease," Dr. Culver commented. "This is probably the best study that addresses this question, but this doesn’t necessarily resolve the issue."

Finally, physicians may initiate treatment for sarcoidosis because they feel compelled to do something, according to Dr. Culver.

"It makes us feel better when we go home at night: We have done something for the patient who came to see us," he commented. "But the evidence for this [practice] really is not very strong, despite the fact that steroids have been used for about 60 years now."

A recently proposed algorithm for treating pulmonary sarcoidosis draws on all of these accumulated data and recommends symptom assessment as a first step (Semin. Respir. Crit. Care Med. 2010;31:501-18).

"If the symptoms are relatively mild or modest – and this requires a discussion with the patient – then I think observation is completely reasonable," Dr. Culver said.

In more severe cases, the algorithm proposes short-course, moderate-dose therapy with prednisone 20-30 mg daily for 3-4 weeks, as supported by several studies, including a recent one among patients with acute exacerbations (Am. J. Med. Sci. 2010;339:1-4).

In other words, "be less aggressive with your steroid dosing," he recommended. "You can really get away with shorter courses, with lower doses than we have been using in the past."

For patients who have a good response, the goal is to taper to 10 mg daily or less, a practice endorsed by a Delphi consensus study of sarcoidosis management (Respir. Med. 2010;104:717-23).

"That’s evolving as an important target for long-term management of sarcoidosis patients," he noted, and it also helps minimize steroid adverse effects.

When patients have an inadequate response to prednisone or are unable to reduce the dosage to 10 mg daily, the algorithm suggests adding an immune modulator (methotrexate, azathioprine, leflunomide, or mycophenolate) to therapy.

"The choice of immune modulators ... is really dealer’s choice," Dr. Culver commented. "Suffice it to say that it’s most important that you become comfortable with something and you are used to how to use it, more so than necessarily exactly which one to use."

There have been few head-to-head comparisons of these agents, although methotrexate is by far the agent preferred by U.S. physicians treating sarcoidosis, partly because it has been the best studied.

"That’s the drug that we use as our second-line agent," he noted. "The reason that we like methotrexate is it seems to work pretty well, it’s pretty inexpensive and pretty reliable, and it’s not hard to get through the insurance company."

Data from his institution show that leflunomide also works well. A review of 40 patients with pulmonary sarcoidosis found they had an improvement in FVC within 6 months of starting this drug (P = .01), as well as a reduction in the average prednisone dose to 5 mg daily. "So we have really moved leflunomide to the next agent in our algorithm after methotrexate," he said.

Infliximab is the only agent that has been shown to be efficacious in a double-blind, randomized controlled trial of patients with sarcoidosis, according to Dr. Culver.

In unselected patients, infliximab is associated with just a 2.5% improvement in percent predicted FVC (Clin. Chest Med. 2008;29:533-48, ix-x) – or about that seen with steroids. But among the subset having more severe lung disease, with an FVC of less than 69%, there is a roughly 3.25% improvement. The improvement was 6% in the randomized trial (Sarcoidosis Vasc. Diffuse Lung Dis. 2006;23:201-8).

"So, in fact, we think for patients failing cytotoxic agents that infliximab is a nice option," Dr. Culver commented.

And studies are helping to identify which patients are most likely to benefit from infliximab: those who have had disease for more than 2 years, have worse dyspnea (a Medical Research Council dyspnea score of at least 2), lower FVC, poorer quality of life (assessed with the St. George’s Respiratory Questionnaire), reticulonodular changes on their chest x-ray, or an elevated C-reactive protein level.

"In fact, these are some of the same entry criteria that are being used for the current trial of biologics in sarcoidosis, trying to target that more severe patient population," he noted.

In concluding, Dr. Culver advised physicians to establish and keep in mind the goals of treatment, and to remember the chronic nature of sarcoidosis.

"If I can leave you with one thing, the message is ... you have to sit and talk to your patient and find out what’s important to them, what do they want to accomplish," he said. "That’s the best thing that you can do as you think about treating your patient longitudinally, because remember, you are not treating this as if it’s an infection, you are treating this as if it’s hypertension that needs to be controlled in the long term."

Dr. Culver reported having affiliations with the biotechnology and pharmaceutical companies Centocor (manufacturer of infliximab), Takeda, and Actelion.

VANCOUVER, B.C. – Contemporary management of pulmonary sarcoidosis is moving away from hard clinical targets and toward patients’ self-reported well-being and goals, according to Dr. Daniel A. Culver, a pulmonologist at the Cleveland Clinic.

Physicians may treat sarcoidosis for a variety of reasons, and research is helping to sort out which of them are valid, he said at the annual meeting of the American College of Chest Physicians.

One reason might be to improve radiographic or physiologic parameters. In particular, the Scadding stage of a patient’s chest x-ray at presentation has been used for about 50 years to estimate prognosis and the need for treatment.

"But in fact there are a number of pieces of data coming out now that suggest that the chest x-ray may not be the most ideal way to measure how things are going to go for patients," he commented.

In one study, for example, half of patients with pulmonary sarcoidosis were rated as having a better chest x-ray during an exacerbation as compared with before, despite their worsening symptoms and spirometry (Respirology 2008;13:97-102).

Another reason for undertaking treatment might be to improve patients’ symptoms, according to Dr. Culver.

In this regard, a recent review has described a so-called sarcoidosis penumbra, a collection of disease-related issues that affect patients’ well-being but are often not well captured by tests physicians rely on (Semin. Respir. Crit. Care Med. 2010;31:501-18). For instance, two in every three patients have depression, and one in six has sleep apnea.

"This took us a long time as sarcoidologists to recognize, that it’s not the x-ray and vital capacity that the patients care about," but rather their daily ability to function and enjoy life, he commented.

"To optimally treat sarcoidosis, one of the new things we are discovering is that we need to ask the patients the questions that get to these sorts of issues and target our treatment to these sorts of issues," Dr. Culver said. "Going forward ... for both immunosuppressive therapy and the treatment of sarcoidosis in general, we are going to see it more focused on patient-centered outcomes and quality of life rather than things that we’d all like to measure, like the vital capacity."

Another reason that physicians may treat sarcoidosis is to alter the natural history of the disease and prevent fibrosis.

But "most sarcoidosis will resolve within the first 5 years, at least radiologically," Dr. Culver noted, and current evidence suggests treatment does little to alter this trajectory.

In one study, 39% of patients with stage 2 or 3 disease on chest x-ray had neither progression nor improvement during a 6-month period. When these stable patients were assigned either to immediate treatment with a fairly aggressive regimen of prednisolone or to as-needed treatment only if spirometry showed deterioration, just 19% of the latter group required treatment during the next 5 years (Thorax 1996;51:238-47).

"If you can hold off on treating, you may be able to prevent side effects from medicines ... and still have a patient who has their disease spontaneously resolve," he commented.

That said, the as-needed treatment group had a smaller improvement in forced vital capacity (FVC), and there were some other potentially important differences in outcomes between groups.

"Suffice it to say that right now, we don’t think that steroid therapy given preemptively has a tremendous impact on the natural history of the disease," Dr. Culver commented. "This is probably the best study that addresses this question, but this doesn’t necessarily resolve the issue."

Finally, physicians may initiate treatment for sarcoidosis because they feel compelled to do something, according to Dr. Culver.

"It makes us feel better when we go home at night: We have done something for the patient who came to see us," he commented. "But the evidence for this [practice] really is not very strong, despite the fact that steroids have been used for about 60 years now."

A recently proposed algorithm for treating pulmonary sarcoidosis draws on all of these accumulated data and recommends symptom assessment as a first step (Semin. Respir. Crit. Care Med. 2010;31:501-18).

"If the symptoms are relatively mild or modest – and this requires a discussion with the patient – then I think observation is completely reasonable," Dr. Culver said.

In more severe cases, the algorithm proposes short-course, moderate-dose therapy with prednisone 20-30 mg daily for 3-4 weeks, as supported by several studies, including a recent one among patients with acute exacerbations (Am. J. Med. Sci. 2010;339:1-4).

In other words, "be less aggressive with your steroid dosing," he recommended. "You can really get away with shorter courses, with lower doses than we have been using in the past."

For patients who have a good response, the goal is to taper to 10 mg daily or less, a practice endorsed by a Delphi consensus study of sarcoidosis management (Respir. Med. 2010;104:717-23).

"That’s evolving as an important target for long-term management of sarcoidosis patients," he noted, and it also helps minimize steroid adverse effects.

When patients have an inadequate response to prednisone or are unable to reduce the dosage to 10 mg daily, the algorithm suggests adding an immune modulator (methotrexate, azathioprine, leflunomide, or mycophenolate) to therapy.

"The choice of immune modulators ... is really dealer’s choice," Dr. Culver commented. "Suffice it to say that it’s most important that you become comfortable with something and you are used to how to use it, more so than necessarily exactly which one to use."

There have been few head-to-head comparisons of these agents, although methotrexate is by far the agent preferred by U.S. physicians treating sarcoidosis, partly because it has been the best studied.

"That’s the drug that we use as our second-line agent," he noted. "The reason that we like methotrexate is it seems to work pretty well, it’s pretty inexpensive and pretty reliable, and it’s not hard to get through the insurance company."

Data from his institution show that leflunomide also works well. A review of 40 patients with pulmonary sarcoidosis found they had an improvement in FVC within 6 months of starting this drug (P = .01), as well as a reduction in the average prednisone dose to 5 mg daily. "So we have really moved leflunomide to the next agent in our algorithm after methotrexate," he said.

Infliximab is the only agent that has been shown to be efficacious in a double-blind, randomized controlled trial of patients with sarcoidosis, according to Dr. Culver.

In unselected patients, infliximab is associated with just a 2.5% improvement in percent predicted FVC (Clin. Chest Med. 2008;29:533-48, ix-x) – or about that seen with steroids. But among the subset having more severe lung disease, with an FVC of less than 69%, there is a roughly 3.25% improvement. The improvement was 6% in the randomized trial (Sarcoidosis Vasc. Diffuse Lung Dis. 2006;23:201-8).

"So, in fact, we think for patients failing cytotoxic agents that infliximab is a nice option," Dr. Culver commented.

And studies are helping to identify which patients are most likely to benefit from infliximab: those who have had disease for more than 2 years, have worse dyspnea (a Medical Research Council dyspnea score of at least 2), lower FVC, poorer quality of life (assessed with the St. George’s Respiratory Questionnaire), reticulonodular changes on their chest x-ray, or an elevated C-reactive protein level.

"In fact, these are some of the same entry criteria that are being used for the current trial of biologics in sarcoidosis, trying to target that more severe patient population," he noted.

In concluding, Dr. Culver advised physicians to establish and keep in mind the goals of treatment, and to remember the chronic nature of sarcoidosis.

"If I can leave you with one thing, the message is ... you have to sit and talk to your patient and find out what’s important to them, what do they want to accomplish," he said. "That’s the best thing that you can do as you think about treating your patient longitudinally, because remember, you are not treating this as if it’s an infection, you are treating this as if it’s hypertension that needs to be controlled in the long term."

Dr. Culver reported having affiliations with the biotechnology and pharmaceutical companies Centocor (manufacturer of infliximab), Takeda, and Actelion.

VANCOUVER, B.C. – Contemporary management of pulmonary sarcoidosis is moving away from hard clinical targets and toward patients’ self-reported well-being and goals, according to Dr. Daniel A. Culver, a pulmonologist at the Cleveland Clinic.

Physicians may treat sarcoidosis for a variety of reasons, and research is helping to sort out which of them are valid, he said at the annual meeting of the American College of Chest Physicians.

One reason might be to improve radiographic or physiologic parameters. In particular, the Scadding stage of a patient’s chest x-ray at presentation has been used for about 50 years to estimate prognosis and the need for treatment.

"But in fact there are a number of pieces of data coming out now that suggest that the chest x-ray may not be the most ideal way to measure how things are going to go for patients," he commented.

In one study, for example, half of patients with pulmonary sarcoidosis were rated as having a better chest x-ray during an exacerbation as compared with before, despite their worsening symptoms and spirometry (Respirology 2008;13:97-102).

Another reason for undertaking treatment might be to improve patients’ symptoms, according to Dr. Culver.

In this regard, a recent review has described a so-called sarcoidosis penumbra, a collection of disease-related issues that affect patients’ well-being but are often not well captured by tests physicians rely on (Semin. Respir. Crit. Care Med. 2010;31:501-18). For instance, two in every three patients have depression, and one in six has sleep apnea.

"This took us a long time as sarcoidologists to recognize, that it’s not the x-ray and vital capacity that the patients care about," but rather their daily ability to function and enjoy life, he commented.

"To optimally treat sarcoidosis, one of the new things we are discovering is that we need to ask the patients the questions that get to these sorts of issues and target our treatment to these sorts of issues," Dr. Culver said. "Going forward ... for both immunosuppressive therapy and the treatment of sarcoidosis in general, we are going to see it more focused on patient-centered outcomes and quality of life rather than things that we’d all like to measure, like the vital capacity."

Another reason that physicians may treat sarcoidosis is to alter the natural history of the disease and prevent fibrosis.

But "most sarcoidosis will resolve within the first 5 years, at least radiologically," Dr. Culver noted, and current evidence suggests treatment does little to alter this trajectory.

In one study, 39% of patients with stage 2 or 3 disease on chest x-ray had neither progression nor improvement during a 6-month period. When these stable patients were assigned either to immediate treatment with a fairly aggressive regimen of prednisolone or to as-needed treatment only if spirometry showed deterioration, just 19% of the latter group required treatment during the next 5 years (Thorax 1996;51:238-47).

"If you can hold off on treating, you may be able to prevent side effects from medicines ... and still have a patient who has their disease spontaneously resolve," he commented.

That said, the as-needed treatment group had a smaller improvement in forced vital capacity (FVC), and there were some other potentially important differences in outcomes between groups.

"Suffice it to say that right now, we don’t think that steroid therapy given preemptively has a tremendous impact on the natural history of the disease," Dr. Culver commented. "This is probably the best study that addresses this question, but this doesn’t necessarily resolve the issue."

Finally, physicians may initiate treatment for sarcoidosis because they feel compelled to do something, according to Dr. Culver.

"It makes us feel better when we go home at night: We have done something for the patient who came to see us," he commented. "But the evidence for this [practice] really is not very strong, despite the fact that steroids have been used for about 60 years now."

A recently proposed algorithm for treating pulmonary sarcoidosis draws on all of these accumulated data and recommends symptom assessment as a first step (Semin. Respir. Crit. Care Med. 2010;31:501-18).

"If the symptoms are relatively mild or modest – and this requires a discussion with the patient – then I think observation is completely reasonable," Dr. Culver said.

In more severe cases, the algorithm proposes short-course, moderate-dose therapy with prednisone 20-30 mg daily for 3-4 weeks, as supported by several studies, including a recent one among patients with acute exacerbations (Am. J. Med. Sci. 2010;339:1-4).

In other words, "be less aggressive with your steroid dosing," he recommended. "You can really get away with shorter courses, with lower doses than we have been using in the past."

For patients who have a good response, the goal is to taper to 10 mg daily or less, a practice endorsed by a Delphi consensus study of sarcoidosis management (Respir. Med. 2010;104:717-23).

"That’s evolving as an important target for long-term management of sarcoidosis patients," he noted, and it also helps minimize steroid adverse effects.

When patients have an inadequate response to prednisone or are unable to reduce the dosage to 10 mg daily, the algorithm suggests adding an immune modulator (methotrexate, azathioprine, leflunomide, or mycophenolate) to therapy.

"The choice of immune modulators ... is really dealer’s choice," Dr. Culver commented. "Suffice it to say that it’s most important that you become comfortable with something and you are used to how to use it, more so than necessarily exactly which one to use."

There have been few head-to-head comparisons of these agents, although methotrexate is by far the agent preferred by U.S. physicians treating sarcoidosis, partly because it has been the best studied.

"That’s the drug that we use as our second-line agent," he noted. "The reason that we like methotrexate is it seems to work pretty well, it’s pretty inexpensive and pretty reliable, and it’s not hard to get through the insurance company."

Data from his institution show that leflunomide also works well. A review of 40 patients with pulmonary sarcoidosis found they had an improvement in FVC within 6 months of starting this drug (P = .01), as well as a reduction in the average prednisone dose to 5 mg daily. "So we have really moved leflunomide to the next agent in our algorithm after methotrexate," he said.

Infliximab is the only agent that has been shown to be efficacious in a double-blind, randomized controlled trial of patients with sarcoidosis, according to Dr. Culver.

In unselected patients, infliximab is associated with just a 2.5% improvement in percent predicted FVC (Clin. Chest Med. 2008;29:533-48, ix-x) – or about that seen with steroids. But among the subset having more severe lung disease, with an FVC of less than 69%, there is a roughly 3.25% improvement. The improvement was 6% in the randomized trial (Sarcoidosis Vasc. Diffuse Lung Dis. 2006;23:201-8).

"So, in fact, we think for patients failing cytotoxic agents that infliximab is a nice option," Dr. Culver commented.

And studies are helping to identify which patients are most likely to benefit from infliximab: those who have had disease for more than 2 years, have worse dyspnea (a Medical Research Council dyspnea score of at least 2), lower FVC, poorer quality of life (assessed with the St. George’s Respiratory Questionnaire), reticulonodular changes on their chest x-ray, or an elevated C-reactive protein level.

"In fact, these are some of the same entry criteria that are being used for the current trial of biologics in sarcoidosis, trying to target that more severe patient population," he noted.

In concluding, Dr. Culver advised physicians to establish and keep in mind the goals of treatment, and to remember the chronic nature of sarcoidosis.

"If I can leave you with one thing, the message is ... you have to sit and talk to your patient and find out what’s important to them, what do they want to accomplish," he said. "That’s the best thing that you can do as you think about treating your patient longitudinally, because remember, you are not treating this as if it’s an infection, you are treating this as if it’s hypertension that needs to be controlled in the long term."

Dr. Culver reported having affiliations with the biotechnology and pharmaceutical companies Centocor (manufacturer of infliximab), Takeda, and Actelion.

Patients with locally advanced adenocarcinoma of the esophagogastric junction have a better prognosis if their cancer shows an early metabolic response to preoperative chemotherapy, as detected by positron emission tomography, new data show.

In a prospective study known as MUNICON-2 that was conducted in Germany, 59% of patients had a PET-detected response after 2 weeks of chemotherapy, investigators said in a press briefing in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

Even though the nonresponders were then given intensified treatment with chemoradiation, the responders were still more likely to be able to undergo curative resection and had a 4-year rate of progression-free survival that was twice as high as that of the nonresponders.

"Early metabolic response assessment, after only 2 weeks of preoperative chemotherapy, performed with fluorodeoxyglucose (FDG)-PET, is a feasible approach and allows for a response-guided treatment," lead investigator Dr. Florian Lordick said in the press briefing.

"Unfortunately, we found that survival is still poorer in PET nonresponders, despite the addition of radiation," he continued. "Therefore, we can conclude that early metabolic response assessment by FDG-PET allows us to identify patients with a very poor tumor biology."

The investigators studied 56 patients with locally advanced, nonmetastatic adenocarcinoma of the esophagogastric junction of types I and II (cT3/4,Nx,M0). The patients underwent FDG-PET imaging before and after 2 weeks of platinum- and 5-fluorouracil-based chemotherapy.

They were defined as having a response if the tumor’s standardized uptake value decreased by at least 35%, according to Dr. Lordick, director of the department of hematology and oncology at Klinikum Braunschweig in Brunswick, Germany, and a senior lecturer at Hannover Medical School.

Responders received more of the same chemotherapy for a total duration of 3 months and then underwent surgery. Nonresponders were given salvage chemoradiation consisting of 32 Gy of external beam radiation therapy plus daily cisplatin, and then underwent surgery.

"The expectation was that by adding radiation therapy to those patients not responding to chemotherapy, we might improve their prognosis, we might improve local control, we might improve survival compared to historic controls," he commented.

The 56 patients studied had a median age of 62 years; 91% were male, and 77% had an ECOG Performance Status score of 0. In terms of disease characteristics, 70% of patients had type I tumors, 93% had an ultrasound T3 stage, and 100% had clinically node-positive disease.

A PET-detected response to chemotherapy was found in 59% (33 patients). Responders were more likely than were nonresponders (23 patients) to be able to be able to undergo curative resection (82% vs 70%, respectively), although the difference was not statistically significant.

The rate of major histologic remission, defined as having less than 10% residual tumor, was also higher for responders (36% vs 26%).

After a median follow-up of 38 months, the 4-year Kaplan-Meier estimate of progression-free survival was about 60% for PET responders, compared with 30% for PET nonresponders.

Responders fared much better in terms of median event-free survival (not reached, vs 15.4 months) and median duration of overall survival (not reached, vs 18.3 months).

"The addition of radiation therapy has some local effect, as we saw in the resection specimens" from the nonresponders, Dr. Lordick commented. "But it seems that it was not strong enough to change the tumor biology of these patients."

"The next step that we want to take now on a multicenter level within the EORTC (European Organisation for Research and Treatment of Cancer) is to ... study different alterations of treatment in PET nonresponders by adding an alternative chemotherapy regimen and new biologically targeted therapies," concluded Dr. Lordick.

The study’s findings exemplify the use of predictors to individualize therapy, according to Dr. Jennifer C. Obel, moderator of the press briefing and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill.

"This approach allows us to either stop therapies that have minimal benefit or continue those that are likely helping patients live longer," she commented.

"Really, this study is quite intriguing because it demonstrates that patients with no response on PET scan after limited chemotherapy have a poor outcome," said Dr. Obel. "Hopefully, in the future, we can use this technology to quickly move to other therapies and evaluate whether they are helping the patient or not."

Dr. Lordick and Dr. Obel both reported that they did not have any relevant conflicts of interest.

Patients with locally advanced adenocarcinoma of the esophagogastric junction have a better prognosis if their cancer shows an early metabolic response to preoperative chemotherapy, as detected by positron emission tomography, new data show.

In a prospective study known as MUNICON-2 that was conducted in Germany, 59% of patients had a PET-detected response after 2 weeks of chemotherapy, investigators said in a press briefing in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

Even though the nonresponders were then given intensified treatment with chemoradiation, the responders were still more likely to be able to undergo curative resection and had a 4-year rate of progression-free survival that was twice as high as that of the nonresponders.

"Early metabolic response assessment, after only 2 weeks of preoperative chemotherapy, performed with fluorodeoxyglucose (FDG)-PET, is a feasible approach and allows for a response-guided treatment," lead investigator Dr. Florian Lordick said in the press briefing.

"Unfortunately, we found that survival is still poorer in PET nonresponders, despite the addition of radiation," he continued. "Therefore, we can conclude that early metabolic response assessment by FDG-PET allows us to identify patients with a very poor tumor biology."

The investigators studied 56 patients with locally advanced, nonmetastatic adenocarcinoma of the esophagogastric junction of types I and II (cT3/4,Nx,M0). The patients underwent FDG-PET imaging before and after 2 weeks of platinum- and 5-fluorouracil-based chemotherapy.

They were defined as having a response if the tumor’s standardized uptake value decreased by at least 35%, according to Dr. Lordick, director of the department of hematology and oncology at Klinikum Braunschweig in Brunswick, Germany, and a senior lecturer at Hannover Medical School.

Responders received more of the same chemotherapy for a total duration of 3 months and then underwent surgery. Nonresponders were given salvage chemoradiation consisting of 32 Gy of external beam radiation therapy plus daily cisplatin, and then underwent surgery.

"The expectation was that by adding radiation therapy to those patients not responding to chemotherapy, we might improve their prognosis, we might improve local control, we might improve survival compared to historic controls," he commented.

The 56 patients studied had a median age of 62 years; 91% were male, and 77% had an ECOG Performance Status score of 0. In terms of disease characteristics, 70% of patients had type I tumors, 93% had an ultrasound T3 stage, and 100% had clinically node-positive disease.

A PET-detected response to chemotherapy was found in 59% (33 patients). Responders were more likely than were nonresponders (23 patients) to be able to be able to undergo curative resection (82% vs 70%, respectively), although the difference was not statistically significant.

The rate of major histologic remission, defined as having less than 10% residual tumor, was also higher for responders (36% vs 26%).

After a median follow-up of 38 months, the 4-year Kaplan-Meier estimate of progression-free survival was about 60% for PET responders, compared with 30% for PET nonresponders.

Responders fared much better in terms of median event-free survival (not reached, vs 15.4 months) and median duration of overall survival (not reached, vs 18.3 months).

"The addition of radiation therapy has some local effect, as we saw in the resection specimens" from the nonresponders, Dr. Lordick commented. "But it seems that it was not strong enough to change the tumor biology of these patients."

"The next step that we want to take now on a multicenter level within the EORTC (European Organisation for Research and Treatment of Cancer) is to ... study different alterations of treatment in PET nonresponders by adding an alternative chemotherapy regimen and new biologically targeted therapies," concluded Dr. Lordick.

The study’s findings exemplify the use of predictors to individualize therapy, according to Dr. Jennifer C. Obel, moderator of the press briefing and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill.

"This approach allows us to either stop therapies that have minimal benefit or continue those that are likely helping patients live longer," she commented.

"Really, this study is quite intriguing because it demonstrates that patients with no response on PET scan after limited chemotherapy have a poor outcome," said Dr. Obel. "Hopefully, in the future, we can use this technology to quickly move to other therapies and evaluate whether they are helping the patient or not."

Dr. Lordick and Dr. Obel both reported that they did not have any relevant conflicts of interest.

Patients with locally advanced adenocarcinoma of the esophagogastric junction have a better prognosis if their cancer shows an early metabolic response to preoperative chemotherapy, as detected by positron emission tomography, new data show.

In a prospective study known as MUNICON-2 that was conducted in Germany, 59% of patients had a PET-detected response after 2 weeks of chemotherapy, investigators said in a press briefing in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

Even though the nonresponders were then given intensified treatment with chemoradiation, the responders were still more likely to be able to undergo curative resection and had a 4-year rate of progression-free survival that was twice as high as that of the nonresponders.

"Early metabolic response assessment, after only 2 weeks of preoperative chemotherapy, performed with fluorodeoxyglucose (FDG)-PET, is a feasible approach and allows for a response-guided treatment," lead investigator Dr. Florian Lordick said in the press briefing.

"Unfortunately, we found that survival is still poorer in PET nonresponders, despite the addition of radiation," he continued. "Therefore, we can conclude that early metabolic response assessment by FDG-PET allows us to identify patients with a very poor tumor biology."

The investigators studied 56 patients with locally advanced, nonmetastatic adenocarcinoma of the esophagogastric junction of types I and II (cT3/4,Nx,M0). The patients underwent FDG-PET imaging before and after 2 weeks of platinum- and 5-fluorouracil-based chemotherapy.

They were defined as having a response if the tumor’s standardized uptake value decreased by at least 35%, according to Dr. Lordick, director of the department of hematology and oncology at Klinikum Braunschweig in Brunswick, Germany, and a senior lecturer at Hannover Medical School.

Responders received more of the same chemotherapy for a total duration of 3 months and then underwent surgery. Nonresponders were given salvage chemoradiation consisting of 32 Gy of external beam radiation therapy plus daily cisplatin, and then underwent surgery.

"The expectation was that by adding radiation therapy to those patients not responding to chemotherapy, we might improve their prognosis, we might improve local control, we might improve survival compared to historic controls," he commented.

The 56 patients studied had a median age of 62 years; 91% were male, and 77% had an ECOG Performance Status score of 0. In terms of disease characteristics, 70% of patients had type I tumors, 93% had an ultrasound T3 stage, and 100% had clinically node-positive disease.

A PET-detected response to chemotherapy was found in 59% (33 patients). Responders were more likely than were nonresponders (23 patients) to be able to be able to undergo curative resection (82% vs 70%, respectively), although the difference was not statistically significant.

The rate of major histologic remission, defined as having less than 10% residual tumor, was also higher for responders (36% vs 26%).

After a median follow-up of 38 months, the 4-year Kaplan-Meier estimate of progression-free survival was about 60% for PET responders, compared with 30% for PET nonresponders.

Responders fared much better in terms of median event-free survival (not reached, vs 15.4 months) and median duration of overall survival (not reached, vs 18.3 months).

"The addition of radiation therapy has some local effect, as we saw in the resection specimens" from the nonresponders, Dr. Lordick commented. "But it seems that it was not strong enough to change the tumor biology of these patients."

"The next step that we want to take now on a multicenter level within the EORTC (European Organisation for Research and Treatment of Cancer) is to ... study different alterations of treatment in PET nonresponders by adding an alternative chemotherapy regimen and new biologically targeted therapies," concluded Dr. Lordick.

The study’s findings exemplify the use of predictors to individualize therapy, according to Dr. Jennifer C. Obel, moderator of the press briefing and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill.

"This approach allows us to either stop therapies that have minimal benefit or continue those that are likely helping patients live longer," she commented.

"Really, this study is quite intriguing because it demonstrates that patients with no response on PET scan after limited chemotherapy have a poor outcome," said Dr. Obel. "Hopefully, in the future, we can use this technology to quickly move to other therapies and evaluate whether they are helping the patient or not."

Dr. Lordick and Dr. Obel both reported that they did not have any relevant conflicts of interest.

Patients with locally advanced adenocarcinoma of the esophagogastric junction have a better prognosis if their cancer shows an early metabolic response to preoperative chemotherapy, as detected by positron emission tomography, new data show.

In a prospective study known as MUNICON-2 that was conducted in Germany, 59% of patients had a PET-detected response after 2 weeks of chemotherapy, investigators said in a press briefing in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

Even though the nonresponders were then given intensified treatment with chemoradiation, the responders were still more likely to be able to undergo curative resection and had a 4-year rate of progression-free survival that was twice as high as that of the nonresponders.

"Early metabolic response assessment, after only 2 weeks of preoperative chemotherapy, performed with fluorodeoxyglucose (FDG)-PET, is a feasible approach and allows for a response-guided treatment," lead investigator Dr. Florian Lordick said in the press briefing.

"Unfortunately, we found that survival is still poorer in PET nonresponders, despite the addition of radiation," he continued. "Therefore, we can conclude that early metabolic response assessment by FDG-PET allows us to identify patients with a very poor tumor biology."

The investigators studied 56 patients with locally advanced, nonmetastatic adenocarcinoma of the esophagogastric junction of types I and II (cT3/4,Nx,M0). The patients underwent FDG-PET imaging before and after 2 weeks of platinum- and 5-fluorouracil-based chemotherapy.

They were defined as having a response if the tumor’s standardized uptake value decreased by at least 35%, according to Dr. Lordick, director of the department of hematology and oncology at Klinikum Braunschweig in Brunswick, Germany, and a senior lecturer at Hannover Medical School.

Responders received more of the same chemotherapy for a total duration of 3 months and then underwent surgery. Nonresponders were given salvage chemoradiation consisting of 32 Gy of external beam radiation therapy plus daily cisplatin, and then underwent surgery.

"The expectation was that by adding radiation therapy to those patients not responding to chemotherapy, we might improve their prognosis, we might improve local control, we might improve survival compared to historic controls," he commented.

The 56 patients studied had a median age of 62 years; 91% were male, and 77% had an ECOG Performance Status score of 0. In terms of disease characteristics, 70% of patients had type I tumors, 93% had an ultrasound T3 stage, and 100% had clinically node-positive disease.

A PET-detected response to chemotherapy was found in 59% (33 patients). Responders were more likely than were nonresponders (23 patients) to be able to be able to undergo curative resection (82% vs 70%, respectively), although the difference was not statistically significant.

The rate of major histologic remission, defined as having less than 10% residual tumor, was also higher for responders (36% vs 26%).

After a median follow-up of 38 months, the 4-year Kaplan-Meier estimate of progression-free survival was about 60% for PET responders, compared with 30% for PET nonresponders.

Responders fared much better in terms of median event-free survival (not reached, vs 15.4 months) and median duration of overall survival (not reached, vs 18.3 months).

"The addition of radiation therapy has some local effect, as we saw in the resection specimens" from the nonresponders, Dr. Lordick commented. "But it seems that it was not strong enough to change the tumor biology of these patients."

"The next step that we want to take now on a multicenter level within the EORTC (European Organisation for Research and Treatment of Cancer) is to ... study different alterations of treatment in PET nonresponders by adding an alternative chemotherapy regimen and new biologically targeted therapies," concluded Dr. Lordick.

The study’s findings exemplify the use of predictors to individualize therapy, according to Dr. Jennifer C. Obel, moderator of the press briefing and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill.

"This approach allows us to either stop therapies that have minimal benefit or continue those that are likely helping patients live longer," she commented.

"Really, this study is quite intriguing because it demonstrates that patients with no response on PET scan after limited chemotherapy have a poor outcome," said Dr. Obel. "Hopefully, in the future, we can use this technology to quickly move to other therapies and evaluate whether they are helping the patient or not."

Dr. Lordick and Dr. Obel both reported that they did not have any relevant conflicts of interest.

Patients with locally advanced adenocarcinoma of the esophagogastric junction have a better prognosis if their cancer shows an early metabolic response to preoperative chemotherapy, as detected by positron emission tomography, new data show.

In a prospective study known as MUNICON-2 that was conducted in Germany, 59% of patients had a PET-detected response after 2 weeks of chemotherapy, investigators said in a press briefing in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

Even though the nonresponders were then given intensified treatment with chemoradiation, the responders were still more likely to be able to undergo curative resection and had a 4-year rate of progression-free survival that was twice as high as that of the nonresponders.

"Early metabolic response assessment, after only 2 weeks of preoperative chemotherapy, performed with fluorodeoxyglucose (FDG)-PET, is a feasible approach and allows for a response-guided treatment," lead investigator Dr. Florian Lordick said in the press briefing.

"Unfortunately, we found that survival is still poorer in PET nonresponders, despite the addition of radiation," he continued. "Therefore, we can conclude that early metabolic response assessment by FDG-PET allows us to identify patients with a very poor tumor biology."

The investigators studied 56 patients with locally advanced, nonmetastatic adenocarcinoma of the esophagogastric junction of types I and II (cT3/4,Nx,M0). The patients underwent FDG-PET imaging before and after 2 weeks of platinum- and 5-fluorouracil-based chemotherapy.

They were defined as having a response if the tumor’s standardized uptake value decreased by at least 35%, according to Dr. Lordick, director of the department of hematology and oncology at Klinikum Braunschweig in Brunswick, Germany, and a senior lecturer at Hannover Medical School.

Responders received more of the same chemotherapy for a total duration of 3 months and then underwent surgery. Nonresponders were given salvage chemoradiation consisting of 32 Gy of external beam radiation therapy plus daily cisplatin, and then underwent surgery.

"The expectation was that by adding radiation therapy to those patients not responding to chemotherapy, we might improve their prognosis, we might improve local control, we might improve survival compared to historic controls," he commented.

The 56 patients studied had a median age of 62 years; 91% were male, and 77% had an ECOG Performance Status score of 0. In terms of disease characteristics, 70% of patients had type I tumors, 93% had an ultrasound T3 stage, and 100% had clinically node-positive disease.

A PET-detected response to chemotherapy was found in 59% (33 patients). Responders were more likely than were nonresponders (23 patients) to be able to be able to undergo curative resection (82% vs 70%, respectively), although the difference was not statistically significant.

The rate of major histologic remission, defined as having less than 10% residual tumor, was also higher for responders (36% vs 26%).

After a median follow-up of 38 months, the 4-year Kaplan-Meier estimate of progression-free survival was about 60% for PET responders, compared with 30% for PET nonresponders.

Responders fared much better in terms of median event-free survival (not reached, vs 15.4 months) and median duration of overall survival (not reached, vs 18.3 months).

"The addition of radiation therapy has some local effect, as we saw in the resection specimens" from the nonresponders, Dr. Lordick commented. "But it seems that it was not strong enough to change the tumor biology of these patients."

"The next step that we want to take now on a multicenter level within the EORTC (European Organisation for Research and Treatment of Cancer) is to ... study different alterations of treatment in PET nonresponders by adding an alternative chemotherapy regimen and new biologically targeted therapies," concluded Dr. Lordick.

The study’s findings exemplify the use of predictors to individualize therapy, according to Dr. Jennifer C. Obel, moderator of the press briefing and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill.

"This approach allows us to either stop therapies that have minimal benefit or continue those that are likely helping patients live longer," she commented.

"Really, this study is quite intriguing because it demonstrates that patients with no response on PET scan after limited chemotherapy have a poor outcome," said Dr. Obel. "Hopefully, in the future, we can use this technology to quickly move to other therapies and evaluate whether they are helping the patient or not."

Dr. Lordick and Dr. Obel both reported that they did not have any relevant conflicts of interest.

Patients with locally advanced adenocarcinoma of the esophagogastric junction have a better prognosis if their cancer shows an early metabolic response to preoperative chemotherapy, as detected by positron emission tomography, new data show.

In a prospective study known as MUNICON-2 that was conducted in Germany, 59% of patients had a PET-detected response after 2 weeks of chemotherapy, investigators said in a press briefing in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

Even though the nonresponders were then given intensified treatment with chemoradiation, the responders were still more likely to be able to undergo curative resection and had a 4-year rate of progression-free survival that was twice as high as that of the nonresponders.

"Early metabolic response assessment, after only 2 weeks of preoperative chemotherapy, performed with fluorodeoxyglucose (FDG)-PET, is a feasible approach and allows for a response-guided treatment," lead investigator Dr. Florian Lordick said in the press briefing.

"Unfortunately, we found that survival is still poorer in PET nonresponders, despite the addition of radiation," he continued. "Therefore, we can conclude that early metabolic response assessment by FDG-PET allows us to identify patients with a very poor tumor biology."

The investigators studied 56 patients with locally advanced, nonmetastatic adenocarcinoma of the esophagogastric junction of types I and II (cT3/4,Nx,M0). The patients underwent FDG-PET imaging before and after 2 weeks of platinum- and 5-fluorouracil-based chemotherapy.

They were defined as having a response if the tumor’s standardized uptake value decreased by at least 35%, according to Dr. Lordick, director of the department of hematology and oncology at Klinikum Braunschweig in Brunswick, Germany, and a senior lecturer at Hannover Medical School.

Responders received more of the same chemotherapy for a total duration of 3 months and then underwent surgery. Nonresponders were given salvage chemoradiation consisting of 32 Gy of external beam radiation therapy plus daily cisplatin, and then underwent surgery.

"The expectation was that by adding radiation therapy to those patients not responding to chemotherapy, we might improve their prognosis, we might improve local control, we might improve survival compared to historic controls," he commented.

The 56 patients studied had a median age of 62 years; 91% were male, and 77% had an ECOG Performance Status score of 0. In terms of disease characteristics, 70% of patients had type I tumors, 93% had an ultrasound T3 stage, and 100% had clinically node-positive disease.

A PET-detected response to chemotherapy was found in 59% (33 patients). Responders were more likely than were nonresponders (23 patients) to be able to be able to undergo curative resection (82% vs 70%, respectively), although the difference was not statistically significant.

The rate of major histologic remission, defined as having less than 10% residual tumor, was also higher for responders (36% vs 26%).

After a median follow-up of 38 months, the 4-year Kaplan-Meier estimate of progression-free survival was about 60% for PET responders, compared with 30% for PET nonresponders.

Responders fared much better in terms of median event-free survival (not reached, vs 15.4 months) and median duration of overall survival (not reached, vs 18.3 months).

"The addition of radiation therapy has some local effect, as we saw in the resection specimens" from the nonresponders, Dr. Lordick commented. "But it seems that it was not strong enough to change the tumor biology of these patients."

"The next step that we want to take now on a multicenter level within the EORTC (European Organisation for Research and Treatment of Cancer) is to ... study different alterations of treatment in PET nonresponders by adding an alternative chemotherapy regimen and new biologically targeted therapies," concluded Dr. Lordick.

The study’s findings exemplify the use of predictors to individualize therapy, according to Dr. Jennifer C. Obel, moderator of the press briefing and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill.

"This approach allows us to either stop therapies that have minimal benefit or continue those that are likely helping patients live longer," she commented.

"Really, this study is quite intriguing because it demonstrates that patients with no response on PET scan after limited chemotherapy have a poor outcome," said Dr. Obel. "Hopefully, in the future, we can use this technology to quickly move to other therapies and evaluate whether they are helping the patient or not."

Dr. Lordick and Dr. Obel both reported that they did not have any relevant conflicts of interest.

An investigational test based on an 18-gene profile predicts recurrence risk and may help inform decisions about the need for adjuvant chemotherapy in patients with localized colorectal cancer.

The test, called ColoPrint, was validated in a study using tumor samples from 135 patients who underwent curative surgery for stage II colorectal cancer.

Just 5% of patients with a low-risk test result had a distant metastatic recurrence within 5 years, compared with 20% of their counterparts with a high-risk result. The data were presented during a teleconference held Jan. 18 in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology (ASCO).

"Our results confirm previous validation studies of ColoPrint," lead investigator Dr. Robert Rosenberg said. "ColoPrint is able to predict the development of distant metastases of stage II patients and facilitates the identification of patients who might not need additional chemotherapy."

"This study constitutes the second independent validation of the profile ColoPrint, and that makes it unique in itself," he added. "No other prognostic genomic profile in colon cancer has been submitted yet to a second independent validation."

The investigators used the microarray-based test to analyze fresh frozen tumor tissue from 135 patients who underwent curative resection of stage II colorectal cancer at the University Hospital of the Technical University in Munich between 1987 and 2003.

The 18-gene profile includes some genes already known to be associated with carcinogenesis and metastasis, explained Dr. Rosenberg, an assistant professor and surgeon at the hospital, "but at least five genes have not been described yet."

Agendia, the test manufacturer, ran ColoPrint on samples while blinded to patient data. The investigators in Munich assessed the association of test results with clinical outcome.

Study results showed that the test classified the majority of patients (74%) as having a low risk of recurrence, and indeed, just 5% of these patients developed distant metastases within 5 years.

The remaining patients (26%) were classified as having a high recurrence risk, and 20% of this group developed distant metastases during this time period.

In univariate analyses, the ColoPrint result was the only factor significantly predicting the risk of distant metastases, with a 4.1-fold greater likelihood for patients with a high-risk, compared with a low-risk, result (P = .009).

In contrast, none of a variety of clinical and pathologic factors – age, sex, tumor location, grade, number of lymph nodes assessed, pathologic T stage, or the combination of factors in the ASCO risk score (T4 stage, perforation, fewer than 12 lymph nodes assessed, and high grade) – were significant predictors.

In multivariate analyses, a high-risk ColoPrint test result independently predicted a more than quadrupling of the likelihood of recurrence (hazard ratio, 4.3; P = .01). Again, the ASCO risk score was not significantly associated with this outcome.

When patients were stratified by both ColoPrint result and ASCO risk score, agreement was limited. "ASCO risk factors and ColoPrint identify different patients. There is overlap but also a clear discordance," Dr. Rosenberg said. "It will therefore be interesting to find out if and how clinical factors can add to the value of ColoPrint."

Those questions are being addressed in an ongoing international study, called PARSC (Prospective Analysis of Risk Stratification by ColoPrint), which is prospectively comparing the genomic profile with clinical risk factors in 600 patients with stage II colon cancer. "We expect first results from PARSC this year," he commented.

Other tests and markers are also being used to assess recurrence risk in patients with stage II colorectal cancer, acknowledged Dr. Rosenberg. One such marker is microsatellite instability (MSI), with previous research showing that an MSI-high status is associated with a good prognosis.

"We were able to see that the good prognosis of MSI-high patients was recognized by ColoPrint in most of the patients," he said: fully 86% of those having a low-risk test result had a high MSI status. "Only one of the MSI-high patients experienced a relapse, and this patient was correctly identified as ColoPrint high-risk, so the results are independent of the MSI status."

The Oncotype DX colon cancer assay (manufactured by Genomic Health) is also being used to estimate prognosis in these patients and, like ColoPrint, taps a tumor’s genetic information, "but the tests are completely different," Dr. Rosenberg asserted.

Key differences include the ways in which the genomic signatures were developed, the genes they assess, the technology used for the assay, and the nature of the test result, with ColoPrint giving a binary result and Oncotype Dx having an intermediate category, he said.

Offering a clinical perspective, Dr. Jennifer C. Obel, moderator of the teleconference and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill., noted that the two tests "are very similar in some regards in terms of the questions they answer to identify stage II patients at higher risk of recurrence." Hence, clinicians’ choice between them might be driven by logistic factors, such as the steps required for tissue preparation. At the same time, she cautioned that, thus far, both tests have been shown to provide only prognostic information.

"Those tests help to further identify patients at higher risk for recurrence, though neither test helps to ... predict benefit from chemotherapy," said Dr. Obel, who did not report any relevant conflicts of interest.

Dr. Rosenberg reported that he had no relevant conflicts of interest. Some of the other coinvestigators have employment or leadership positions with or own stock in Agendia.

An investigational test based on an 18-gene profile predicts recurrence risk and may help inform decisions about the need for adjuvant chemotherapy in patients with localized colorectal cancer.

The test, called ColoPrint, was validated in a study using tumor samples from 135 patients who underwent curative surgery for stage II colorectal cancer.

Just 5% of patients with a low-risk test result had a distant metastatic recurrence within 5 years, compared with 20% of their counterparts with a high-risk result. The data were presented during a teleconference held Jan. 18 in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology (ASCO).

"Our results confirm previous validation studies of ColoPrint," lead investigator Dr. Robert Rosenberg said. "ColoPrint is able to predict the development of distant metastases of stage II patients and facilitates the identification of patients who might not need additional chemotherapy."

"This study constitutes the second independent validation of the profile ColoPrint, and that makes it unique in itself," he added. "No other prognostic genomic profile in colon cancer has been submitted yet to a second independent validation."

The investigators used the microarray-based test to analyze fresh frozen tumor tissue from 135 patients who underwent curative resection of stage II colorectal cancer at the University Hospital of the Technical University in Munich between 1987 and 2003.

The 18-gene profile includes some genes already known to be associated with carcinogenesis and metastasis, explained Dr. Rosenberg, an assistant professor and surgeon at the hospital, "but at least five genes have not been described yet."

Agendia, the test manufacturer, ran ColoPrint on samples while blinded to patient data. The investigators in Munich assessed the association of test results with clinical outcome.

Study results showed that the test classified the majority of patients (74%) as having a low risk of recurrence, and indeed, just 5% of these patients developed distant metastases within 5 years.

The remaining patients (26%) were classified as having a high recurrence risk, and 20% of this group developed distant metastases during this time period.

In univariate analyses, the ColoPrint result was the only factor significantly predicting the risk of distant metastases, with a 4.1-fold greater likelihood for patients with a high-risk, compared with a low-risk, result (P = .009).

In contrast, none of a variety of clinical and pathologic factors – age, sex, tumor location, grade, number of lymph nodes assessed, pathologic T stage, or the combination of factors in the ASCO risk score (T4 stage, perforation, fewer than 12 lymph nodes assessed, and high grade) – were significant predictors.

In multivariate analyses, a high-risk ColoPrint test result independently predicted a more than quadrupling of the likelihood of recurrence (hazard ratio, 4.3; P = .01). Again, the ASCO risk score was not significantly associated with this outcome.

When patients were stratified by both ColoPrint result and ASCO risk score, agreement was limited. "ASCO risk factors and ColoPrint identify different patients. There is overlap but also a clear discordance," Dr. Rosenberg said. "It will therefore be interesting to find out if and how clinical factors can add to the value of ColoPrint."

Those questions are being addressed in an ongoing international study, called PARSC (Prospective Analysis of Risk Stratification by ColoPrint), which is prospectively comparing the genomic profile with clinical risk factors in 600 patients with stage II colon cancer. "We expect first results from PARSC this year," he commented.

Other tests and markers are also being used to assess recurrence risk in patients with stage II colorectal cancer, acknowledged Dr. Rosenberg. One such marker is microsatellite instability (MSI), with previous research showing that an MSI-high status is associated with a good prognosis.

"We were able to see that the good prognosis of MSI-high patients was recognized by ColoPrint in most of the patients," he said: fully 86% of those having a low-risk test result had a high MSI status. "Only one of the MSI-high patients experienced a relapse, and this patient was correctly identified as ColoPrint high-risk, so the results are independent of the MSI status."

The Oncotype DX colon cancer assay (manufactured by Genomic Health) is also being used to estimate prognosis in these patients and, like ColoPrint, taps a tumor’s genetic information, "but the tests are completely different," Dr. Rosenberg asserted.

Key differences include the ways in which the genomic signatures were developed, the genes they assess, the technology used for the assay, and the nature of the test result, with ColoPrint giving a binary result and Oncotype Dx having an intermediate category, he said.

Offering a clinical perspective, Dr. Jennifer C. Obel, moderator of the teleconference and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill., noted that the two tests "are very similar in some regards in terms of the questions they answer to identify stage II patients at higher risk of recurrence." Hence, clinicians’ choice between them might be driven by logistic factors, such as the steps required for tissue preparation. At the same time, she cautioned that, thus far, both tests have been shown to provide only prognostic information.

"Those tests help to further identify patients at higher risk for recurrence, though neither test helps to ... predict benefit from chemotherapy," said Dr. Obel, who did not report any relevant conflicts of interest.

Dr. Rosenberg reported that he had no relevant conflicts of interest. Some of the other coinvestigators have employment or leadership positions with or own stock in Agendia.

An investigational test based on an 18-gene profile predicts recurrence risk and may help inform decisions about the need for adjuvant chemotherapy in patients with localized colorectal cancer.

The test, called ColoPrint, was validated in a study using tumor samples from 135 patients who underwent curative surgery for stage II colorectal cancer.

Just 5% of patients with a low-risk test result had a distant metastatic recurrence within 5 years, compared with 20% of their counterparts with a high-risk result. The data were presented during a teleconference held Jan. 18 in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology (ASCO).

"Our results confirm previous validation studies of ColoPrint," lead investigator Dr. Robert Rosenberg said. "ColoPrint is able to predict the development of distant metastases of stage II patients and facilitates the identification of patients who might not need additional chemotherapy."

"This study constitutes the second independent validation of the profile ColoPrint, and that makes it unique in itself," he added. "No other prognostic genomic profile in colon cancer has been submitted yet to a second independent validation."

The investigators used the microarray-based test to analyze fresh frozen tumor tissue from 135 patients who underwent curative resection of stage II colorectal cancer at the University Hospital of the Technical University in Munich between 1987 and 2003.

The 18-gene profile includes some genes already known to be associated with carcinogenesis and metastasis, explained Dr. Rosenberg, an assistant professor and surgeon at the hospital, "but at least five genes have not been described yet."

Agendia, the test manufacturer, ran ColoPrint on samples while blinded to patient data. The investigators in Munich assessed the association of test results with clinical outcome.

Study results showed that the test classified the majority of patients (74%) as having a low risk of recurrence, and indeed, just 5% of these patients developed distant metastases within 5 years.

The remaining patients (26%) were classified as having a high recurrence risk, and 20% of this group developed distant metastases during this time period.

In univariate analyses, the ColoPrint result was the only factor significantly predicting the risk of distant metastases, with a 4.1-fold greater likelihood for patients with a high-risk, compared with a low-risk, result (P = .009).

In contrast, none of a variety of clinical and pathologic factors – age, sex, tumor location, grade, number of lymph nodes assessed, pathologic T stage, or the combination of factors in the ASCO risk score (T4 stage, perforation, fewer than 12 lymph nodes assessed, and high grade) – were significant predictors.

In multivariate analyses, a high-risk ColoPrint test result independently predicted a more than quadrupling of the likelihood of recurrence (hazard ratio, 4.3; P = .01). Again, the ASCO risk score was not significantly associated with this outcome.

When patients were stratified by both ColoPrint result and ASCO risk score, agreement was limited. "ASCO risk factors and ColoPrint identify different patients. There is overlap but also a clear discordance," Dr. Rosenberg said. "It will therefore be interesting to find out if and how clinical factors can add to the value of ColoPrint."

Those questions are being addressed in an ongoing international study, called PARSC (Prospective Analysis of Risk Stratification by ColoPrint), which is prospectively comparing the genomic profile with clinical risk factors in 600 patients with stage II colon cancer. "We expect first results from PARSC this year," he commented.

Other tests and markers are also being used to assess recurrence risk in patients with stage II colorectal cancer, acknowledged Dr. Rosenberg. One such marker is microsatellite instability (MSI), with previous research showing that an MSI-high status is associated with a good prognosis.

"We were able to see that the good prognosis of MSI-high patients was recognized by ColoPrint in most of the patients," he said: fully 86% of those having a low-risk test result had a high MSI status. "Only one of the MSI-high patients experienced a relapse, and this patient was correctly identified as ColoPrint high-risk, so the results are independent of the MSI status."

The Oncotype DX colon cancer assay (manufactured by Genomic Health) is also being used to estimate prognosis in these patients and, like ColoPrint, taps a tumor’s genetic information, "but the tests are completely different," Dr. Rosenberg asserted.

Key differences include the ways in which the genomic signatures were developed, the genes they assess, the technology used for the assay, and the nature of the test result, with ColoPrint giving a binary result and Oncotype Dx having an intermediate category, he said.

Offering a clinical perspective, Dr. Jennifer C. Obel, moderator of the teleconference and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill., noted that the two tests "are very similar in some regards in terms of the questions they answer to identify stage II patients at higher risk of recurrence." Hence, clinicians’ choice between them might be driven by logistic factors, such as the steps required for tissue preparation. At the same time, she cautioned that, thus far, both tests have been shown to provide only prognostic information.

"Those tests help to further identify patients at higher risk for recurrence, though neither test helps to ... predict benefit from chemotherapy," said Dr. Obel, who did not report any relevant conflicts of interest.

Dr. Rosenberg reported that he had no relevant conflicts of interest. Some of the other coinvestigators have employment or leadership positions with or own stock in Agendia.

An investigational test based on an 18-gene profile predicts recurrence risk and may help inform decisions about the need for adjuvant chemotherapy in patients with localized colorectal cancer.

The test, called ColoPrint, was validated in a study using tumor samples from 135 patients who underwent curative surgery for stage II colorectal cancer.

Just 5% of patients with a low-risk test result had a distant metastatic recurrence within 5 years, compared with 20% of their counterparts with a high-risk result. The data were presented during a teleconference held Jan. 18 in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology (ASCO).

"Our results confirm previous validation studies of ColoPrint," lead investigator Dr. Robert Rosenberg said. "ColoPrint is able to predict the development of distant metastases of stage II patients and facilitates the identification of patients who might not need additional chemotherapy."

"This study constitutes the second independent validation of the profile ColoPrint, and that makes it unique in itself," he added. "No other prognostic genomic profile in colon cancer has been submitted yet to a second independent validation."

The investigators used the microarray-based test to analyze fresh frozen tumor tissue from 135 patients who underwent curative resection of stage II colorectal cancer at the University Hospital of the Technical University in Munich between 1987 and 2003.

The 18-gene profile includes some genes already known to be associated with carcinogenesis and metastasis, explained Dr. Rosenberg, an assistant professor and surgeon at the hospital, "but at least five genes have not been described yet."

Agendia, the test manufacturer, ran ColoPrint on samples while blinded to patient data. The investigators in Munich assessed the association of test results with clinical outcome.

Study results showed that the test classified the majority of patients (74%) as having a low risk of recurrence, and indeed, just 5% of these patients developed distant metastases within 5 years.

The remaining patients (26%) were classified as having a high recurrence risk, and 20% of this group developed distant metastases during this time period.

In univariate analyses, the ColoPrint result was the only factor significantly predicting the risk of distant metastases, with a 4.1-fold greater likelihood for patients with a high-risk, compared with a low-risk, result (P = .009).

In contrast, none of a variety of clinical and pathologic factors – age, sex, tumor location, grade, number of lymph nodes assessed, pathologic T stage, or the combination of factors in the ASCO risk score (T4 stage, perforation, fewer than 12 lymph nodes assessed, and high grade) – were significant predictors.

In multivariate analyses, a high-risk ColoPrint test result independently predicted a more than quadrupling of the likelihood of recurrence (hazard ratio, 4.3; P = .01). Again, the ASCO risk score was not significantly associated with this outcome.

When patients were stratified by both ColoPrint result and ASCO risk score, agreement was limited. "ASCO risk factors and ColoPrint identify different patients. There is overlap but also a clear discordance," Dr. Rosenberg said. "It will therefore be interesting to find out if and how clinical factors can add to the value of ColoPrint."

Those questions are being addressed in an ongoing international study, called PARSC (Prospective Analysis of Risk Stratification by ColoPrint), which is prospectively comparing the genomic profile with clinical risk factors in 600 patients with stage II colon cancer. "We expect first results from PARSC this year," he commented.

Other tests and markers are also being used to assess recurrence risk in patients with stage II colorectal cancer, acknowledged Dr. Rosenberg. One such marker is microsatellite instability (MSI), with previous research showing that an MSI-high status is associated with a good prognosis.

"We were able to see that the good prognosis of MSI-high patients was recognized by ColoPrint in most of the patients," he said: fully 86% of those having a low-risk test result had a high MSI status. "Only one of the MSI-high patients experienced a relapse, and this patient was correctly identified as ColoPrint high-risk, so the results are independent of the MSI status."

The Oncotype DX colon cancer assay (manufactured by Genomic Health) is also being used to estimate prognosis in these patients and, like ColoPrint, taps a tumor’s genetic information, "but the tests are completely different," Dr. Rosenberg asserted.

Key differences include the ways in which the genomic signatures were developed, the genes they assess, the technology used for the assay, and the nature of the test result, with ColoPrint giving a binary result and Oncotype Dx having an intermediate category, he said.

Offering a clinical perspective, Dr. Jennifer C. Obel, moderator of the teleconference and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill., noted that the two tests "are very similar in some regards in terms of the questions they answer to identify stage II patients at higher risk of recurrence." Hence, clinicians’ choice between them might be driven by logistic factors, such as the steps required for tissue preparation. At the same time, she cautioned that, thus far, both tests have been shown to provide only prognostic information.

"Those tests help to further identify patients at higher risk for recurrence, though neither test helps to ... predict benefit from chemotherapy," said Dr. Obel, who did not report any relevant conflicts of interest.

Dr. Rosenberg reported that he had no relevant conflicts of interest. Some of the other coinvestigators have employment or leadership positions with or own stock in Agendia.

An investigational test based on an 18-gene profile predicts recurrence risk and may help inform decisions about the need for adjuvant chemotherapy in patients with localized colorectal cancer.

The test, called ColoPrint, was validated in a study using tumor samples from 135 patients who underwent curative surgery for stage II colorectal cancer.

Just 5% of patients with a low-risk test result had a distant metastatic recurrence within 5 years, compared with 20% of their counterparts with a high-risk result. The data were presented during a teleconference held Jan. 18 in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology (ASCO).

"Our results confirm previous validation studies of ColoPrint," lead investigator Dr. Robert Rosenberg said. "ColoPrint is able to predict the development of distant metastases of stage II patients and facilitates the identification of patients who might not need additional chemotherapy."

"This study constitutes the second independent validation of the profile ColoPrint, and that makes it unique in itself," he added. "No other prognostic genomic profile in colon cancer has been submitted yet to a second independent validation."

The investigators used the microarray-based test to analyze fresh frozen tumor tissue from 135 patients who underwent curative resection of stage II colorectal cancer at the University Hospital of the Technical University in Munich between 1987 and 2003.

The 18-gene profile includes some genes already known to be associated with carcinogenesis and metastasis, explained Dr. Rosenberg, an assistant professor and surgeon at the hospital, "but at least five genes have not been described yet."

Agendia, the test manufacturer, ran ColoPrint on samples while blinded to patient data. The investigators in Munich assessed the association of test results with clinical outcome.

Study results showed that the test classified the majority of patients (74%) as having a low risk of recurrence, and indeed, just 5% of these patients developed distant metastases within 5 years.

The remaining patients (26%) were classified as having a high recurrence risk, and 20% of this group developed distant metastases during this time period.

In univariate analyses, the ColoPrint result was the only factor significantly predicting the risk of distant metastases, with a 4.1-fold greater likelihood for patients with a high-risk, compared with a low-risk, result (P = .009).

In contrast, none of a variety of clinical and pathologic factors – age, sex, tumor location, grade, number of lymph nodes assessed, pathologic T stage, or the combination of factors in the ASCO risk score (T4 stage, perforation, fewer than 12 lymph nodes assessed, and high grade) – were significant predictors.

In multivariate analyses, a high-risk ColoPrint test result independently predicted a more than quadrupling of the likelihood of recurrence (hazard ratio, 4.3; P = .01). Again, the ASCO risk score was not significantly associated with this outcome.

When patients were stratified by both ColoPrint result and ASCO risk score, agreement was limited. "ASCO risk factors and ColoPrint identify different patients. There is overlap but also a clear discordance," Dr. Rosenberg said. "It will therefore be interesting to find out if and how clinical factors can add to the value of ColoPrint."

Those questions are being addressed in an ongoing international study, called PARSC (Prospective Analysis of Risk Stratification by ColoPrint), which is prospectively comparing the genomic profile with clinical risk factors in 600 patients with stage II colon cancer. "We expect first results from PARSC this year," he commented.

Other tests and markers are also being used to assess recurrence risk in patients with stage II colorectal cancer, acknowledged Dr. Rosenberg. One such marker is microsatellite instability (MSI), with previous research showing that an MSI-high status is associated with a good prognosis.

"We were able to see that the good prognosis of MSI-high patients was recognized by ColoPrint in most of the patients," he said: fully 86% of those having a low-risk test result had a high MSI status. "Only one of the MSI-high patients experienced a relapse, and this patient was correctly identified as ColoPrint high-risk, so the results are independent of the MSI status."

The Oncotype DX colon cancer assay (manufactured by Genomic Health) is also being used to estimate prognosis in these patients and, like ColoPrint, taps a tumor’s genetic information, "but the tests are completely different," Dr. Rosenberg asserted.

Key differences include the ways in which the genomic signatures were developed, the genes they assess, the technology used for the assay, and the nature of the test result, with ColoPrint giving a binary result and Oncotype Dx having an intermediate category, he said.

Offering a clinical perspective, Dr. Jennifer C. Obel, moderator of the teleconference and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill., noted that the two tests "are very similar in some regards in terms of the questions they answer to identify stage II patients at higher risk of recurrence." Hence, clinicians’ choice between them might be driven by logistic factors, such as the steps required for tissue preparation. At the same time, she cautioned that, thus far, both tests have been shown to provide only prognostic information.

"Those tests help to further identify patients at higher risk for recurrence, though neither test helps to ... predict benefit from chemotherapy," said Dr. Obel, who did not report any relevant conflicts of interest.

Dr. Rosenberg reported that he had no relevant conflicts of interest. Some of the other coinvestigators have employment or leadership positions with or own stock in Agendia.

An investigational test based on an 18-gene profile predicts recurrence risk and may help inform decisions about the need for adjuvant chemotherapy in patients with localized colorectal cancer.

The test, called ColoPrint, was validated in a study using tumor samples from 135 patients who underwent curative surgery for stage II colorectal cancer.

Just 5% of patients with a low-risk test result had a distant metastatic recurrence within 5 years, compared with 20% of their counterparts with a high-risk result. The data were presented during a teleconference held Jan. 18 in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology (ASCO).

"Our results confirm previous validation studies of ColoPrint," lead investigator Dr. Robert Rosenberg said. "ColoPrint is able to predict the development of distant metastases of stage II patients and facilitates the identification of patients who might not need additional chemotherapy."

"This study constitutes the second independent validation of the profile ColoPrint, and that makes it unique in itself," he added. "No other prognostic genomic profile in colon cancer has been submitted yet to a second independent validation."

The investigators used the microarray-based test to analyze fresh frozen tumor tissue from 135 patients who underwent curative resection of stage II colorectal cancer at the University Hospital of the Technical University in Munich between 1987 and 2003.

The 18-gene profile includes some genes already known to be associated with carcinogenesis and metastasis, explained Dr. Rosenberg, an assistant professor and surgeon at the hospital, "but at least five genes have not been described yet."

Agendia, the test manufacturer, ran ColoPrint on samples while blinded to patient data. The investigators in Munich assessed the association of test results with clinical outcome.

Study results showed that the test classified the majority of patients (74%) as having a low risk of recurrence, and indeed, just 5% of these patients developed distant metastases within 5 years.

The remaining patients (26%) were classified as having a high recurrence risk, and 20% of this group developed distant metastases during this time period.

In univariate analyses, the ColoPrint result was the only factor significantly predicting the risk of distant metastases, with a 4.1-fold greater likelihood for patients with a high-risk, compared with a low-risk, result (P = .009).

In contrast, none of a variety of clinical and pathologic factors – age, sex, tumor location, grade, number of lymph nodes assessed, pathologic T stage, or the combination of factors in the ASCO risk score (T4 stage, perforation, fewer than 12 lymph nodes assessed, and high grade) – were significant predictors.

In multivariate analyses, a high-risk ColoPrint test result independently predicted a more than quadrupling of the likelihood of recurrence (hazard ratio, 4.3; P = .01). Again, the ASCO risk score was not significantly associated with this outcome.

When patients were stratified by both ColoPrint result and ASCO risk score, agreement was limited. "ASCO risk factors and ColoPrint identify different patients. There is overlap but also a clear discordance," Dr. Rosenberg said. "It will therefore be interesting to find out if and how clinical factors can add to the value of ColoPrint."

Those questions are being addressed in an ongoing international study, called PARSC (Prospective Analysis of Risk Stratification by ColoPrint), which is prospectively comparing the genomic profile with clinical risk factors in 600 patients with stage II colon cancer. "We expect first results from PARSC this year," he commented.

Other tests and markers are also being used to assess recurrence risk in patients with stage II colorectal cancer, acknowledged Dr. Rosenberg. One such marker is microsatellite instability (MSI), with previous research showing that an MSI-high status is associated with a good prognosis.

"We were able to see that the good prognosis of MSI-high patients was recognized by ColoPrint in most of the patients," he said: fully 86% of those having a low-risk test result had a high MSI status. "Only one of the MSI-high patients experienced a relapse, and this patient was correctly identified as ColoPrint high-risk, so the results are independent of the MSI status."

The Oncotype DX colon cancer assay (manufactured by Genomic Health) is also being used to estimate prognosis in these patients and, like ColoPrint, taps a tumor’s genetic information, "but the tests are completely different," Dr. Rosenberg asserted.

Key differences include the ways in which the genomic signatures were developed, the genes they assess, the technology used for the assay, and the nature of the test result, with ColoPrint giving a binary result and Oncotype Dx having an intermediate category, he said.

Offering a clinical perspective, Dr. Jennifer C. Obel, moderator of the teleconference and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill., noted that the two tests "are very similar in some regards in terms of the questions they answer to identify stage II patients at higher risk of recurrence." Hence, clinicians’ choice between them might be driven by logistic factors, such as the steps required for tissue preparation. At the same time, she cautioned that, thus far, both tests have been shown to provide only prognostic information.

"Those tests help to further identify patients at higher risk for recurrence, though neither test helps to ... predict benefit from chemotherapy," said Dr. Obel, who did not report any relevant conflicts of interest.

Dr. Rosenberg reported that he had no relevant conflicts of interest. Some of the other coinvestigators have employment or leadership positions with or own stock in Agendia.

Intensity-modulated radiation therapy is as efficacious as conventional radiation therapy when used to treat anal cancer, and it has less acute toxicity, investigators have reported.

A total of 325 patients given conventional radiation therapy (RT) plus chemotherapy in a previous trial and 52 patients who underwent intensity-modulated radiation therapy (IMRT) plus chemotherapy in a new phase II trial had statistically indistinguishable 2-year rates of disease-free survival (75% and 77%) and overall survival (91% and 86%).

Of note, the IMRT group had significantly lower rates of grade 3 or higher acute skin toxicity and acute gastrointestinal toxicity, according to data presented Jan. 18 in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. The trial was conducted by the Radiation Therapy Oncology Group (RTOG).

"Dose-painted IMRT with 5-fluoruracil and mitomycin-C chemotherapy for anal canal cancer is associated with significant sparing of grade 3+ dermatologic and gastrointestinal acute toxicity without compromising 2-year outcomes," principal investigator Dr. Lisa Kachnic said. "It is feasible with very rigorous quality assurance [QA] and continued education."

"Dose-painted IMRT with real-time QA will be our platform in future RTOG anal canal studies incorporating novel agents and may allow for further radiation dose escalation for those with more advanced-stage disease," she added.

Given the cross-trial nature of the comparison, a formal phase III trial is a possibility, according to Dr. Kachnic, who is chair of radiation oncology at Boston University.

"The goal of this study was not to, in a randomized phase III fashion, compare the efficacy between the two types of radiation. It was really to test the feasibility [of IMRT] and see if we can reduce the acute toxicities," she explained. "So I’m not making a claim that it is becoming standard in the U.S. It’s just going to be the radiation platform for RTOG."

In the RTOG 0529 trial (pdf) investigators enrolled patients with stage II or III (T2-4,N0-3,M0) squamous cell or cloacogenic cancer of the anal canal, including those having HIV.

The patients were treated with dose-painted IMRT plus concurrent chemotherapy. The IMRT was tailored to tumor stage and delivered in 28 to 30 fractions over 5.5 to 6 weeks. The chemotherapy consisted of 5-fluorouracil (1,000 mg/m2 per day as a 96-hour infusion) and mitomycin-C (10 mg/m2 as a bolus) on days 1 and 29.

"Probably the most important note to make about this trial was that quality assurance of all the radiation plans were done by myself and several of the other coinvestigators prior to any patients being treated," Dr. Kachnic noted.

The trial’s primary end point was a 15% reduction in the combined rate of grade 2 or higher acute gastrointestinal and genitourinary toxicities from that seen in one arm of an earlier trial, RTOG 9811, in which 325 patients received the same chemotherapy but with conventional, nonconformal RT.

The 52 analyzable patients had a median age of 58 years, and 81% were female. Approximately 54% had stage II disease, 25% had stage IIIA disease, and 21% had stage IIIB disease. Their median duration of follow-up was 26.7 months.

The IMRT and conventional RT populations were well balanced with respect to most clinical and pathologic characteristics, according to Dr. Kachnic. The former were significantly more likely to have node-positive disease and to have advanced disease, however.

The quality assurance procedure led to a recontouring of the treatment plan in 81% of cases, in particular, to ensure coverage of the mesorectum, which is typically avoided in prostate cancer radiation therapy.

"I think that since it was sort of a shift from what [the radiation oncologists] were used to with prostate, they were having some difficulty with this," she commented. The investigators also published an atlas that helped improve contouring.

On final review of dosimetry for the treated patients, only three were found to have major violations in their IMRT. "We put very tight constraints on our normal tissues in hoping to see toxicity sparing," she explained. "In those three cases, the tumor and all the nodes were covered beautifully, but the constraints we put on the normal tissues were slightly over what we made as our ... recommendation for the study."

Overall, 98% of patients completed their IMRT as planned, and 84% completed both cycles of chemotherapy as planned.

The median duration of radiation therapy was shorter for the IMRT group than for the historical conventional radiation therapy group (43 vs. 49 days, P less than .0001). "That’s important because we have seen from other studies, the longer the duration, the more chance of having local recurrence," she noted.

"Our primary end point was not met," said Dr. Kachnic, who reported having no conflicts of interest related to the trial. That is, the rate of grade 2 or higher acute gastrointestinal and genitourinary toxicities combined was essentially the same with IMRT and conventional radiation, at about 77% in each group.

The IMRT group did have significantly lower rates of grade 3 or higher acute gastrointestinal and genitourinary toxicities combined (P = .005), gastrointestinal toxicity alone (P = .008), and skin toxicity (P less than .0001), as well as a lower rate of grade 2 or higher acute hematologic toxicity (P = .03).

The IMRT and conventional radiation therapy patients had similar 2-year rates of efficacy outcomes, with overlapping 95% confidence intervals for locoregional failure (19% and 19%), colostomy failure (8% and 11%), colostomy-free survival (84% and 83%), disease-free survival (77% and 75%), and overall survival (86% and 91%).

"After short-term follow-up, IMRT appears to be as effective as conventional radiation in the treatment of anal cancer but with decreased side effects," commented Dr. Jennifer C. Obel, moderator of the presscast and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill. "By limiting treatment of nearby tissues, a patient’s quality of life is improved during treatment."

"While larger studies will need to be performed and longer follow-up is required, IMRT may emerge as a key treatment modality for anal cancers," noted Dr. Obel, who did not report any conflicts of interest.

Intensity-modulated radiation therapy is as efficacious as conventional radiation therapy when used to treat anal cancer, and it has less acute toxicity, investigators have reported.

A total of 325 patients given conventional radiation therapy (RT) plus chemotherapy in a previous trial and 52 patients who underwent intensity-modulated radiation therapy (IMRT) plus chemotherapy in a new phase II trial had statistically indistinguishable 2-year rates of disease-free survival (75% and 77%) and overall survival (91% and 86%).

Of note, the IMRT group had significantly lower rates of grade 3 or higher acute skin toxicity and acute gastrointestinal toxicity, according to data presented Jan. 18 in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. The trial was conducted by the Radiation Therapy Oncology Group (RTOG).

"Dose-painted IMRT with 5-fluoruracil and mitomycin-C chemotherapy for anal canal cancer is associated with significant sparing of grade 3+ dermatologic and gastrointestinal acute toxicity without compromising 2-year outcomes," principal investigator Dr. Lisa Kachnic said. "It is feasible with very rigorous quality assurance [QA] and continued education."

"Dose-painted IMRT with real-time QA will be our platform in future RTOG anal canal studies incorporating novel agents and may allow for further radiation dose escalation for those with more advanced-stage disease," she added.

Given the cross-trial nature of the comparison, a formal phase III trial is a possibility, according to Dr. Kachnic, who is chair of radiation oncology at Boston University.

"The goal of this study was not to, in a randomized phase III fashion, compare the efficacy between the two types of radiation. It was really to test the feasibility [of IMRT] and see if we can reduce the acute toxicities," she explained. "So I’m not making a claim that it is becoming standard in the U.S. It’s just going to be the radiation platform for RTOG."

In the RTOG 0529 trial (pdf) investigators enrolled patients with stage II or III (T2-4,N0-3,M0) squamous cell or cloacogenic cancer of the anal canal, including those having HIV.

The patients were treated with dose-painted IMRT plus concurrent chemotherapy. The IMRT was tailored to tumor stage and delivered in 28 to 30 fractions over 5.5 to 6 weeks. The chemotherapy consisted of 5-fluorouracil (1,000 mg/m2 per day as a 96-hour infusion) and mitomycin-C (10 mg/m2 as a bolus) on days 1 and 29.

"Probably the most important note to make about this trial was that quality assurance of all the radiation plans were done by myself and several of the other coinvestigators prior to any patients being treated," Dr. Kachnic noted.

The trial’s primary end point was a 15% reduction in the combined rate of grade 2 or higher acute gastrointestinal and genitourinary toxicities from that seen in one arm of an earlier trial, RTOG 9811, in which 325 patients received the same chemotherapy but with conventional, nonconformal RT.

The 52 analyzable patients had a median age of 58 years, and 81% were female. Approximately 54% had stage II disease, 25% had stage IIIA disease, and 21% had stage IIIB disease. Their median duration of follow-up was 26.7 months.

The IMRT and conventional RT populations were well balanced with respect to most clinical and pathologic characteristics, according to Dr. Kachnic. The former were significantly more likely to have node-positive disease and to have advanced disease, however.

The quality assurance procedure led to a recontouring of the treatment plan in 81% of cases, in particular, to ensure coverage of the mesorectum, which is typically avoided in prostate cancer radiation therapy.

"I think that since it was sort of a shift from what [the radiation oncologists] were used to with prostate, they were having some difficulty with this," she commented. The investigators also published an atlas that helped improve contouring.

On final review of dosimetry for the treated patients, only three were found to have major violations in their IMRT. "We put very tight constraints on our normal tissues in hoping to see toxicity sparing," she explained. "In those three cases, the tumor and all the nodes were covered beautifully, but the constraints we put on the normal tissues were slightly over what we made as our ... recommendation for the study."

Overall, 98% of patients completed their IMRT as planned, and 84% completed both cycles of chemotherapy as planned.

The median duration of radiation therapy was shorter for the IMRT group than for the historical conventional radiation therapy group (43 vs. 49 days, P less than .0001). "That’s important because we have seen from other studies, the longer the duration, the more chance of having local recurrence," she noted.

"Our primary end point was not met," said Dr. Kachnic, who reported having no conflicts of interest related to the trial. That is, the rate of grade 2 or higher acute gastrointestinal and genitourinary toxicities combined was essentially the same with IMRT and conventional radiation, at about 77% in each group.

The IMRT group did have significantly lower rates of grade 3 or higher acute gastrointestinal and genitourinary toxicities combined (P = .005), gastrointestinal toxicity alone (P = .008), and skin toxicity (P less than .0001), as well as a lower rate of grade 2 or higher acute hematologic toxicity (P = .03).

The IMRT and conventional radiation therapy patients had similar 2-year rates of efficacy outcomes, with overlapping 95% confidence intervals for locoregional failure (19% and 19%), colostomy failure (8% and 11%), colostomy-free survival (84% and 83%), disease-free survival (77% and 75%), and overall survival (86% and 91%).

"After short-term follow-up, IMRT appears to be as effective as conventional radiation in the treatment of anal cancer but with decreased side effects," commented Dr. Jennifer C. Obel, moderator of the presscast and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill. "By limiting treatment of nearby tissues, a patient’s quality of life is improved during treatment."

"While larger studies will need to be performed and longer follow-up is required, IMRT may emerge as a key treatment modality for anal cancers," noted Dr. Obel, who did not report any conflicts of interest.

Intensity-modulated radiation therapy is as efficacious as conventional radiation therapy when used to treat anal cancer, and it has less acute toxicity, investigators have reported.

A total of 325 patients given conventional radiation therapy (RT) plus chemotherapy in a previous trial and 52 patients who underwent intensity-modulated radiation therapy (IMRT) plus chemotherapy in a new phase II trial had statistically indistinguishable 2-year rates of disease-free survival (75% and 77%) and overall survival (91% and 86%).

Of note, the IMRT group had significantly lower rates of grade 3 or higher acute skin toxicity and acute gastrointestinal toxicity, according to data presented Jan. 18 in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. The trial was conducted by the Radiation Therapy Oncology Group (RTOG).

"Dose-painted IMRT with 5-fluoruracil and mitomycin-C chemotherapy for anal canal cancer is associated with significant sparing of grade 3+ dermatologic and gastrointestinal acute toxicity without compromising 2-year outcomes," principal investigator Dr. Lisa Kachnic said. "It is feasible with very rigorous quality assurance [QA] and continued education."

"Dose-painted IMRT with real-time QA will be our platform in future RTOG anal canal studies incorporating novel agents and may allow for further radiation dose escalation for those with more advanced-stage disease," she added.

Given the cross-trial nature of the comparison, a formal phase III trial is a possibility, according to Dr. Kachnic, who is chair of radiation oncology at Boston University.

"The goal of this study was not to, in a randomized phase III fashion, compare the efficacy between the two types of radiation. It was really to test the feasibility [of IMRT] and see if we can reduce the acute toxicities," she explained. "So I’m not making a claim that it is becoming standard in the U.S. It’s just going to be the radiation platform for RTOG."

In the RTOG 0529 trial (pdf) investigators enrolled patients with stage II or III (T2-4,N0-3,M0) squamous cell or cloacogenic cancer of the anal canal, including those having HIV.

The patients were treated with dose-painted IMRT plus concurrent chemotherapy. The IMRT was tailored to tumor stage and delivered in 28 to 30 fractions over 5.5 to 6 weeks. The chemotherapy consisted of 5-fluorouracil (1,000 mg/m2 per day as a 96-hour infusion) and mitomycin-C (10 mg/m2 as a bolus) on days 1 and 29.

"Probably the most important note to make about this trial was that quality assurance of all the radiation plans were done by myself and several of the other coinvestigators prior to any patients being treated," Dr. Kachnic noted.

The trial’s primary end point was a 15% reduction in the combined rate of grade 2 or higher acute gastrointestinal and genitourinary toxicities from that seen in one arm of an earlier trial, RTOG 9811, in which 325 patients received the same chemotherapy but with conventional, nonconformal RT.

The 52 analyzable patients had a median age of 58 years, and 81% were female. Approximately 54% had stage II disease, 25% had stage IIIA disease, and 21% had stage IIIB disease. Their median duration of follow-up was 26.7 months.

The IMRT and conventional RT populations were well balanced with respect to most clinical and pathologic characteristics, according to Dr. Kachnic. The former were significantly more likely to have node-positive disease and to have advanced disease, however.

The quality assurance procedure led to a recontouring of the treatment plan in 81% of cases, in particular, to ensure coverage of the mesorectum, which is typically avoided in prostate cancer radiation therapy.

"I think that since it was sort of a shift from what [the radiation oncologists] were used to with prostate, they were having some difficulty with this," she commented. The investigators also published an atlas that helped improve contouring.

On final review of dosimetry for the treated patients, only three were found to have major violations in their IMRT. "We put very tight constraints on our normal tissues in hoping to see toxicity sparing," she explained. "In those three cases, the tumor and all the nodes were covered beautifully, but the constraints we put on the normal tissues were slightly over what we made as our ... recommendation for the study."

Overall, 98% of patients completed their IMRT as planned, and 84% completed both cycles of chemotherapy as planned.

The median duration of radiation therapy was shorter for the IMRT group than for the historical conventional radiation therapy group (43 vs. 49 days, P less than .0001). "That’s important because we have seen from other studies, the longer the duration, the more chance of having local recurrence," she noted.

"Our primary end point was not met," said Dr. Kachnic, who reported having no conflicts of interest related to the trial. That is, the rate of grade 2 or higher acute gastrointestinal and genitourinary toxicities combined was essentially the same with IMRT and conventional radiation, at about 77% in each group.

The IMRT group did have significantly lower rates of grade 3 or higher acute gastrointestinal and genitourinary toxicities combined (P = .005), gastrointestinal toxicity alone (P = .008), and skin toxicity (P less than .0001), as well as a lower rate of grade 2 or higher acute hematologic toxicity (P = .03).

The IMRT and conventional radiation therapy patients had similar 2-year rates of efficacy outcomes, with overlapping 95% confidence intervals for locoregional failure (19% and 19%), colostomy failure (8% and 11%), colostomy-free survival (84% and 83%), disease-free survival (77% and 75%), and overall survival (86% and 91%).

"After short-term follow-up, IMRT appears to be as effective as conventional radiation in the treatment of anal cancer but with decreased side effects," commented Dr. Jennifer C. Obel, moderator of the presscast and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill. "By limiting treatment of nearby tissues, a patient’s quality of life is improved during treatment."

"While larger studies will need to be performed and longer follow-up is required, IMRT may emerge as a key treatment modality for anal cancers," noted Dr. Obel, who did not report any conflicts of interest.

Intensity-modulated radiation therapy is as efficacious as conventional radiation therapy when used to treat anal cancer, and it has less acute toxicity, investigators have reported.

A total of 325 patients given conventional radiation therapy (RT) plus chemotherapy in a previous trial and 52 patients who underwent intensity-modulated radiation therapy (IMRT) plus chemotherapy in a new phase II trial had statistically indistinguishable 2-year rates of disease-free survival (75% and 77%) and overall survival (91% and 86%).

Of note, the IMRT group had significantly lower rates of grade 3 or higher acute skin toxicity and acute gastrointestinal toxicity, according to data presented Jan. 18 in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. The trial was conducted by the Radiation Therapy Oncology Group (RTOG).

"Dose-painted IMRT with 5-fluoruracil and mitomycin-C chemotherapy for anal canal cancer is associated with significant sparing of grade 3+ dermatologic and gastrointestinal acute toxicity without compromising 2-year outcomes," principal investigator Dr. Lisa Kachnic said. "It is feasible with very rigorous quality assurance [QA] and continued education."

"Dose-painted IMRT with real-time QA will be our platform in future RTOG anal canal studies incorporating novel agents and may allow for further radiation dose escalation for those with more advanced-stage disease," she added.

Given the cross-trial nature of the comparison, a formal phase III trial is a possibility, according to Dr. Kachnic, who is chair of radiation oncology at Boston University.

"The goal of this study was not to, in a randomized phase III fashion, compare the efficacy between the two types of radiation. It was really to test the feasibility [of IMRT] and see if we can reduce the acute toxicities," she explained. "So I’m not making a claim that it is becoming standard in the U.S. It’s just going to be the radiation platform for RTOG."

In the RTOG 0529 trial (pdf) investigators enrolled patients with stage II or III (T2-4,N0-3,M0) squamous cell or cloacogenic cancer of the anal canal, including those having HIV.

The patients were treated with dose-painted IMRT plus concurrent chemotherapy. The IMRT was tailored to tumor stage and delivered in 28 to 30 fractions over 5.5 to 6 weeks. The chemotherapy consisted of 5-fluorouracil (1,000 mg/m2 per day as a 96-hour infusion) and mitomycin-C (10 mg/m2 as a bolus) on days 1 and 29.

"Probably the most important note to make about this trial was that quality assurance of all the radiation plans were done by myself and several of the other coinvestigators prior to any patients being treated," Dr. Kachnic noted.

The trial’s primary end point was a 15% reduction in the combined rate of grade 2 or higher acute gastrointestinal and genitourinary toxicities from that seen in one arm of an earlier trial, RTOG 9811, in which 325 patients received the same chemotherapy but with conventional, nonconformal RT.

The 52 analyzable patients had a median age of 58 years, and 81% were female. Approximately 54% had stage II disease, 25% had stage IIIA disease, and 21% had stage IIIB disease. Their median duration of follow-up was 26.7 months.

The IMRT and conventional RT populations were well balanced with respect to most clinical and pathologic characteristics, according to Dr. Kachnic. The former were significantly more likely to have node-positive disease and to have advanced disease, however.

The quality assurance procedure led to a recontouring of the treatment plan in 81% of cases, in particular, to ensure coverage of the mesorectum, which is typically avoided in prostate cancer radiation therapy.

"I think that since it was sort of a shift from what [the radiation oncologists] were used to with prostate, they were having some difficulty with this," she commented. The investigators also published an atlas that helped improve contouring.

On final review of dosimetry for the treated patients, only three were found to have major violations in their IMRT. "We put very tight constraints on our normal tissues in hoping to see toxicity sparing," she explained. "In those three cases, the tumor and all the nodes were covered beautifully, but the constraints we put on the normal tissues were slightly over what we made as our ... recommendation for the study."

Overall, 98% of patients completed their IMRT as planned, and 84% completed both cycles of chemotherapy as planned.

The median duration of radiation therapy was shorter for the IMRT group than for the historical conventional radiation therapy group (43 vs. 49 days, P less than .0001). "That’s important because we have seen from other studies, the longer the duration, the more chance of having local recurrence," she noted.

"Our primary end point was not met," said Dr. Kachnic, who reported having no conflicts of interest related to the trial. That is, the rate of grade 2 or higher acute gastrointestinal and genitourinary toxicities combined was essentially the same with IMRT and conventional radiation, at about 77% in each group.

The IMRT group did have significantly lower rates of grade 3 or higher acute gastrointestinal and genitourinary toxicities combined (P = .005), gastrointestinal toxicity alone (P = .008), and skin toxicity (P less than .0001), as well as a lower rate of grade 2 or higher acute hematologic toxicity (P = .03).

The IMRT and conventional radiation therapy patients had similar 2-year rates of efficacy outcomes, with overlapping 95% confidence intervals for locoregional failure (19% and 19%), colostomy failure (8% and 11%), colostomy-free survival (84% and 83%), disease-free survival (77% and 75%), and overall survival (86% and 91%).

"After short-term follow-up, IMRT appears to be as effective as conventional radiation in the treatment of anal cancer but with decreased side effects," commented Dr. Jennifer C. Obel, moderator of the presscast and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill. "By limiting treatment of nearby tissues, a patient’s quality of life is improved during treatment."

"While larger studies will need to be performed and longer follow-up is required, IMRT may emerge as a key treatment modality for anal cancers," noted Dr. Obel, who did not report any conflicts of interest.

Intensity-modulated radiation therapy is as efficacious as conventional radiation therapy when used to treat anal cancer, and it has less acute toxicity, investigators have reported.

A total of 325 patients given conventional radiation therapy (RT) plus chemotherapy in a previous trial and 52 patients who underwent intensity-modulated radiation therapy (IMRT) plus chemotherapy in a new phase II trial had statistically indistinguishable 2-year rates of disease-free survival (75% and 77%) and overall survival (91% and 86%).

Of note, the IMRT group had significantly lower rates of grade 3 or higher acute skin toxicity and acute gastrointestinal toxicity, according to data presented Jan. 18 in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. The trial was conducted by the Radiation Therapy Oncology Group (RTOG).

"Dose-painted IMRT with 5-fluoruracil and mitomycin-C chemotherapy for anal canal cancer is associated with significant sparing of grade 3+ dermatologic and gastrointestinal acute toxicity without compromising 2-year outcomes," principal investigator Dr. Lisa Kachnic said. "It is feasible with very rigorous quality assurance [QA] and continued education."

"Dose-painted IMRT with real-time QA will be our platform in future RTOG anal canal studies incorporating novel agents and may allow for further radiation dose escalation for those with more advanced-stage disease," she added.

Given the cross-trial nature of the comparison, a formal phase III trial is a possibility, according to Dr. Kachnic, who is chair of radiation oncology at Boston University.

"The goal of this study was not to, in a randomized phase III fashion, compare the efficacy between the two types of radiation. It was really to test the feasibility [of IMRT] and see if we can reduce the acute toxicities," she explained. "So I’m not making a claim that it is becoming standard in the U.S. It’s just going to be the radiation platform for RTOG."

In the RTOG 0529 trial (pdf) investigators enrolled patients with stage II or III (T2-4,N0-3,M0) squamous cell or cloacogenic cancer of the anal canal, including those having HIV.

The patients were treated with dose-painted IMRT plus concurrent chemotherapy. The IMRT was tailored to tumor stage and delivered in 28 to 30 fractions over 5.5 to 6 weeks. The chemotherapy consisted of 5-fluorouracil (1,000 mg/m2 per day as a 96-hour infusion) and mitomycin-C (10 mg/m2 as a bolus) on days 1 and 29.

"Probably the most important note to make about this trial was that quality assurance of all the radiation plans were done by myself and several of the other coinvestigators prior to any patients being treated," Dr. Kachnic noted.

The trial’s primary end point was a 15% reduction in the combined rate of grade 2 or higher acute gastrointestinal and genitourinary toxicities from that seen in one arm of an earlier trial, RTOG 9811, in which 325 patients received the same chemotherapy but with conventional, nonconformal RT.

The 52 analyzable patients had a median age of 58 years, and 81% were female. Approximately 54% had stage II disease, 25% had stage IIIA disease, and 21% had stage IIIB disease. Their median duration of follow-up was 26.7 months.

The IMRT and conventional RT populations were well balanced with respect to most clinical and pathologic characteristics, according to Dr. Kachnic. The former were significantly more likely to have node-positive disease and to have advanced disease, however.

The quality assurance procedure led to a recontouring of the treatment plan in 81% of cases, in particular, to ensure coverage of the mesorectum, which is typically avoided in prostate cancer radiation therapy.

"I think that since it was sort of a shift from what [the radiation oncologists] were used to with prostate, they were having some difficulty with this," she commented. The investigators also published an atlas that helped improve contouring.

On final review of dosimetry for the treated patients, only three were found to have major violations in their IMRT. "We put very tight constraints on our normal tissues in hoping to see toxicity sparing," she explained. "In those three cases, the tumor and all the nodes were covered beautifully, but the constraints we put on the normal tissues were slightly over what we made as our ... recommendation for the study."

Overall, 98% of patients completed their IMRT as planned, and 84% completed both cycles of chemotherapy as planned.

The median duration of radiation therapy was shorter for the IMRT group than for the historical conventional radiation therapy group (43 vs. 49 days, P less than .0001). "That’s important because we have seen from other studies, the longer the duration, the more chance of having local recurrence," she noted.

"Our primary end point was not met," said Dr. Kachnic, who reported having no conflicts of interest related to the trial. That is, the rate of grade 2 or higher acute gastrointestinal and genitourinary toxicities combined was essentially the same with IMRT and conventional radiation, at about 77% in each group.

The IMRT group did have significantly lower rates of grade 3 or higher acute gastrointestinal and genitourinary toxicities combined (P = .005), gastrointestinal toxicity alone (P = .008), and skin toxicity (P less than .0001), as well as a lower rate of grade 2 or higher acute hematologic toxicity (P = .03).

The IMRT and conventional radiation therapy patients had similar 2-year rates of efficacy outcomes, with overlapping 95% confidence intervals for locoregional failure (19% and 19%), colostomy failure (8% and 11%), colostomy-free survival (84% and 83%), disease-free survival (77% and 75%), and overall survival (86% and 91%).

"After short-term follow-up, IMRT appears to be as effective as conventional radiation in the treatment of anal cancer but with decreased side effects," commented Dr. Jennifer C. Obel, moderator of the presscast and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill. "By limiting treatment of nearby tissues, a patient’s quality of life is improved during treatment."

"While larger studies will need to be performed and longer follow-up is required, IMRT may emerge as a key treatment modality for anal cancers," noted Dr. Obel, who did not report any conflicts of interest.

Intensity-modulated radiation therapy is as efficacious as conventional radiation therapy when used to treat anal cancer, and it has less acute toxicity, investigators have reported.

A total of 325 patients given conventional radiation therapy (RT) plus chemotherapy in a previous trial and 52 patients who underwent intensity-modulated radiation therapy (IMRT) plus chemotherapy in a new phase II trial had statistically indistinguishable 2-year rates of disease-free survival (75% and 77%) and overall survival (91% and 86%).

Of note, the IMRT group had significantly lower rates of grade 3 or higher acute skin toxicity and acute gastrointestinal toxicity, according to data presented Jan. 18 in advance of a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology. The trial was conducted by the Radiation Therapy Oncology Group (RTOG).

"Dose-painted IMRT with 5-fluoruracil and mitomycin-C chemotherapy for anal canal cancer is associated with significant sparing of grade 3+ dermatologic and gastrointestinal acute toxicity without compromising 2-year outcomes," principal investigator Dr. Lisa Kachnic said. "It is feasible with very rigorous quality assurance [QA] and continued education."

"Dose-painted IMRT with real-time QA will be our platform in future RTOG anal canal studies incorporating novel agents and may allow for further radiation dose escalation for those with more advanced-stage disease," she added.

Given the cross-trial nature of the comparison, a formal phase III trial is a possibility, according to Dr. Kachnic, who is chair of radiation oncology at Boston University.

"The goal of this study was not to, in a randomized phase III fashion, compare the efficacy between the two types of radiation. It was really to test the feasibility [of IMRT] and see if we can reduce the acute toxicities," she explained. "So I’m not making a claim that it is becoming standard in the U.S. It’s just going to be the radiation platform for RTOG."

In the RTOG 0529 trial (pdf) investigators enrolled patients with stage II or III (T2-4,N0-3,M0) squamous cell or cloacogenic cancer of the anal canal, including those having HIV.

The patients were treated with dose-painted IMRT plus concurrent chemotherapy. The IMRT was tailored to tumor stage and delivered in 28 to 30 fractions over 5.5 to 6 weeks. The chemotherapy consisted of 5-fluorouracil (1,000 mg/m2 per day as a 96-hour infusion) and mitomycin-C (10 mg/m2 as a bolus) on days 1 and 29.

"Probably the most important note to make about this trial was that quality assurance of all the radiation plans were done by myself and several of the other coinvestigators prior to any patients being treated," Dr. Kachnic noted.

The trial’s primary end point was a 15% reduction in the combined rate of grade 2 or higher acute gastrointestinal and genitourinary toxicities from that seen in one arm of an earlier trial, RTOG 9811, in which 325 patients received the same chemotherapy but with conventional, nonconformal RT.

The 52 analyzable patients had a median age of 58 years, and 81% were female. Approximately 54% had stage II disease, 25% had stage IIIA disease, and 21% had stage IIIB disease. Their median duration of follow-up was 26.7 months.

The IMRT and conventional RT populations were well balanced with respect to most clinical and pathologic characteristics, according to Dr. Kachnic. The former were significantly more likely to have node-positive disease and to have advanced disease, however.

The quality assurance procedure led to a recontouring of the treatment plan in 81% of cases, in particular, to ensure coverage of the mesorectum, which is typically avoided in prostate cancer radiation therapy.

"I think that since it was sort of a shift from what [the radiation oncologists] were used to with prostate, they were having some difficulty with this," she commented. The investigators also published an atlas that helped improve contouring.

On final review of dosimetry for the treated patients, only three were found to have major violations in their IMRT. "We put very tight constraints on our normal tissues in hoping to see toxicity sparing," she explained. "In those three cases, the tumor and all the nodes were covered beautifully, but the constraints we put on the normal tissues were slightly over what we made as our ... recommendation for the study."

Overall, 98% of patients completed their IMRT as planned, and 84% completed both cycles of chemotherapy as planned.

The median duration of radiation therapy was shorter for the IMRT group than for the historical conventional radiation therapy group (43 vs. 49 days, P less than .0001). "That’s important because we have seen from other studies, the longer the duration, the more chance of having local recurrence," she noted.

"Our primary end point was not met," said Dr. Kachnic, who reported having no conflicts of interest related to the trial. That is, the rate of grade 2 or higher acute gastrointestinal and genitourinary toxicities combined was essentially the same with IMRT and conventional radiation, at about 77% in each group.

The IMRT group did have significantly lower rates of grade 3 or higher acute gastrointestinal and genitourinary toxicities combined (P = .005), gastrointestinal toxicity alone (P = .008), and skin toxicity (P less than .0001), as well as a lower rate of grade 2 or higher acute hematologic toxicity (P = .03).

The IMRT and conventional radiation therapy patients had similar 2-year rates of efficacy outcomes, with overlapping 95% confidence intervals for locoregional failure (19% and 19%), colostomy failure (8% and 11%), colostomy-free survival (84% and 83%), disease-free survival (77% and 75%), and overall survival (86% and 91%).

"After short-term follow-up, IMRT appears to be as effective as conventional radiation in the treatment of anal cancer but with decreased side effects," commented Dr. Jennifer C. Obel, moderator of the presscast and a medical oncologist with the NorthShore University HealthSystem in Evanston, Ill. "By limiting treatment of nearby tissues, a patient’s quality of life is improved during treatment."

"While larger studies will need to be performed and longer follow-up is required, IMRT may emerge as a key treatment modality for anal cancers," noted Dr. Obel, who did not report any conflicts of interest.