Susan London

SAN FRANCISCO – Combining monoclonal antibodies that target different cellular signaling pathways may improve antitumor activity in patients with metastatic colorectal cancer, according to the first results of an ongoing, randomized, phase II trial.

The combination of panitumumab (Vectibix, which targets the epidermal growth factor receptor [EGFR] and inhibits its downstream signaling) plus investigational rilotumumab (AMG-102, which targets hepatocyte growth factor [HGF] and inhibits downstream c-Met signaling) yielded a better objective response rate than did panitumumab alone (31% vs. 21%).

In contrast, the combination of panitumumab plus investigational ganitumab (AMG-479, which targets the insulinlike growth factor I receptor [IGF-IR] and inhibits downstream signaling through the PI3K/AKT and MAPK pathways) improved little on the rate that was seen with just panitumumab (22% vs. 21%).

"This is the first study to show promising evidence of the efficacy by an HGF inhibitor, rilotumumab, ... when combined with panitumumab in patients with pretreated metastatic colorectal cancer ... [of] KRAS wild type," lead investigator Dr. Eric Van Cutsem told attendees at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"Preclinical studies indeed have indicated that there is a complex interdependence between the HGF/c-Met and the IGF-IR and EGFR pathways," he noted, explaining the trial’s rationale. "Combinations of agents that block these receptors are being investigated for their potential to generate additive or synergistic anticancer effects."

To be eligible for the trial, patients had to have metastatic colorectal cancer with wild-type KRAS (because mutations in KRAS confer panitumumab resistance); progression during or after prior irinotecan- and/or oxaliplatin-based chemotherapy; a glycosylated hemoglobin level of 8% or less; a good performance status; and no previous EGFR, c-Met, or IGF-IR inhibitor therapy.

The patients were randomly assigned in nearly equal numbers to receive panitumumab (6 mg/kg every 2 weeks) in combination with placebo, with rilotumumab (10 mg/kg every 2 weeks), or with ganitumab (12 mg/kg every 2 weeks).

All three antibodies are manufactured by Amgen. Panitumumab is approved by the Food and Drug Administration for the treatment of EGFR-expressing metastatic colorectal cancer that has progressed during or after conventional chemotherapy. The other two antibodies are investigational.

The trial’s primary end point was the objective response rate as determined with modified RECIST (Response Evaluation Criteria in Solid Tumors). "It’s important to mention that all responses were required to be confirmed at least 4 weeks after response criteria were first met," noted Dr. Van Cutsem, head of digestive oncology at the University Hospital Gasthuisberg in Leuven, Belgium.

Median follow-up was 6.9 months, as of the data cutoff for the analyses reported. Some 58% of the 142 patients enrolled were men, and the average age was about 58 years. Nearly two-thirds had metastases in the liver plus other sites. About a third had received three or more prior lines of therapy.

All of the responses were partial ones. The median duration of response was 3.7 months with panitumumab alone, 5.1 months with panitumumab plus rilotumumab, and 3.7 months with panitumumab plus ganitumab. The corresponding values for the disease control rate (complete response, partial response, and stable disease) were 56%, 71%, and 61%.

The median duration of progression-free survival was 3.7 months with panitumumab. This compared with 5.2 months with panitumumab-rilotumumab and 5.3 months with panitumumab-ganitumab.

"In general, the safety and toxicity was acceptable in all three arms of this study," commented Dr. Van Cutsem. The overall rate of grade 3/4 adverse events was 52% with panitumumab alone and higher with panitumumab-rilotumumab (71%) and with panitumumab-ganitumab (63%).

Although the nature of these grade 3/4 events was generally similar across groups, the addition of rilotumumab to panitumumab increased the rate of rash (from 8% to 29%), and the addition of ganitumab to panitumumab increased the rate of hypomagnesemia (from 2% to 15%).

"We hope to report in future meetings and manuscripts further details and especially also analysis of biomarkers for response in serum and tissue samples that have been collected and that are underway," Dr. Van Cutsem concluded.

"I am very proud to say ... that we do have movement forward," said discussant Dr. Johanna C. Bendell, director of GI oncology research with the Sarah Cannon Research Institute in Nashville, Tenn. "Targeting the c-Met or HGF pathway in combination with anti-EGFR therapy looks promising for colorectal cancer in this small study."

Targeting both EGFR and Met signaling has been tapped with marked clinical benefit in patients with non–small cell lung cancer who have high Met expression (Ann. Oncol. 2010;21[suppl. 8]:viii7 [abstract LBA15]), she noted. But those whose tumors had low Met expression actually fared worse when they were given dual therapy than when they were given anti-EGFR therapy alone.

"We do await further progression-free survival data, but the early look looks quite interesting," concluded Dr. Bendell. "Also, we are very interested in the biomarker data that will be associated with this looking at whether or not – like we see in non–small cell lung cancer – if over–Met expression has some sort of effect on how patients do with colorectal cancer."

Amgen sponsored the trial. Dr. Van Cutsem reported receiving research funding from Amgen. Dr. Bendell reported having no relevant conflicts of interest.

SAN FRANCISCO – Combining monoclonal antibodies that target different cellular signaling pathways may improve antitumor activity in patients with metastatic colorectal cancer, according to the first results of an ongoing, randomized, phase II trial.

The combination of panitumumab (Vectibix, which targets the epidermal growth factor receptor [EGFR] and inhibits its downstream signaling) plus investigational rilotumumab (AMG-102, which targets hepatocyte growth factor [HGF] and inhibits downstream c-Met signaling) yielded a better objective response rate than did panitumumab alone (31% vs. 21%).

In contrast, the combination of panitumumab plus investigational ganitumab (AMG-479, which targets the insulinlike growth factor I receptor [IGF-IR] and inhibits downstream signaling through the PI3K/AKT and MAPK pathways) improved little on the rate that was seen with just panitumumab (22% vs. 21%).

"This is the first study to show promising evidence of the efficacy by an HGF inhibitor, rilotumumab, ... when combined with panitumumab in patients with pretreated metastatic colorectal cancer ... [of] KRAS wild type," lead investigator Dr. Eric Van Cutsem told attendees at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"Preclinical studies indeed have indicated that there is a complex interdependence between the HGF/c-Met and the IGF-IR and EGFR pathways," he noted, explaining the trial’s rationale. "Combinations of agents that block these receptors are being investigated for their potential to generate additive or synergistic anticancer effects."

To be eligible for the trial, patients had to have metastatic colorectal cancer with wild-type KRAS (because mutations in KRAS confer panitumumab resistance); progression during or after prior irinotecan- and/or oxaliplatin-based chemotherapy; a glycosylated hemoglobin level of 8% or less; a good performance status; and no previous EGFR, c-Met, or IGF-IR inhibitor therapy.

The patients were randomly assigned in nearly equal numbers to receive panitumumab (6 mg/kg every 2 weeks) in combination with placebo, with rilotumumab (10 mg/kg every 2 weeks), or with ganitumab (12 mg/kg every 2 weeks).

All three antibodies are manufactured by Amgen. Panitumumab is approved by the Food and Drug Administration for the treatment of EGFR-expressing metastatic colorectal cancer that has progressed during or after conventional chemotherapy. The other two antibodies are investigational.

The trial’s primary end point was the objective response rate as determined with modified RECIST (Response Evaluation Criteria in Solid Tumors). "It’s important to mention that all responses were required to be confirmed at least 4 weeks after response criteria were first met," noted Dr. Van Cutsem, head of digestive oncology at the University Hospital Gasthuisberg in Leuven, Belgium.

Median follow-up was 6.9 months, as of the data cutoff for the analyses reported. Some 58% of the 142 patients enrolled were men, and the average age was about 58 years. Nearly two-thirds had metastases in the liver plus other sites. About a third had received three or more prior lines of therapy.

All of the responses were partial ones. The median duration of response was 3.7 months with panitumumab alone, 5.1 months with panitumumab plus rilotumumab, and 3.7 months with panitumumab plus ganitumab. The corresponding values for the disease control rate (complete response, partial response, and stable disease) were 56%, 71%, and 61%.

The median duration of progression-free survival was 3.7 months with panitumumab. This compared with 5.2 months with panitumumab-rilotumumab and 5.3 months with panitumumab-ganitumab.

"In general, the safety and toxicity was acceptable in all three arms of this study," commented Dr. Van Cutsem. The overall rate of grade 3/4 adverse events was 52% with panitumumab alone and higher with panitumumab-rilotumumab (71%) and with panitumumab-ganitumab (63%).

Although the nature of these grade 3/4 events was generally similar across groups, the addition of rilotumumab to panitumumab increased the rate of rash (from 8% to 29%), and the addition of ganitumab to panitumumab increased the rate of hypomagnesemia (from 2% to 15%).

"We hope to report in future meetings and manuscripts further details and especially also analysis of biomarkers for response in serum and tissue samples that have been collected and that are underway," Dr. Van Cutsem concluded.

"I am very proud to say ... that we do have movement forward," said discussant Dr. Johanna C. Bendell, director of GI oncology research with the Sarah Cannon Research Institute in Nashville, Tenn. "Targeting the c-Met or HGF pathway in combination with anti-EGFR therapy looks promising for colorectal cancer in this small study."

Targeting both EGFR and Met signaling has been tapped with marked clinical benefit in patients with non–small cell lung cancer who have high Met expression (Ann. Oncol. 2010;21[suppl. 8]:viii7 [abstract LBA15]), she noted. But those whose tumors had low Met expression actually fared worse when they were given dual therapy than when they were given anti-EGFR therapy alone.

"We do await further progression-free survival data, but the early look looks quite interesting," concluded Dr. Bendell. "Also, we are very interested in the biomarker data that will be associated with this looking at whether or not – like we see in non–small cell lung cancer – if over–Met expression has some sort of effect on how patients do with colorectal cancer."

Amgen sponsored the trial. Dr. Van Cutsem reported receiving research funding from Amgen. Dr. Bendell reported having no relevant conflicts of interest.

SAN FRANCISCO – Combining monoclonal antibodies that target different cellular signaling pathways may improve antitumor activity in patients with metastatic colorectal cancer, according to the first results of an ongoing, randomized, phase II trial.

The combination of panitumumab (Vectibix, which targets the epidermal growth factor receptor [EGFR] and inhibits its downstream signaling) plus investigational rilotumumab (AMG-102, which targets hepatocyte growth factor [HGF] and inhibits downstream c-Met signaling) yielded a better objective response rate than did panitumumab alone (31% vs. 21%).

In contrast, the combination of panitumumab plus investigational ganitumab (AMG-479, which targets the insulinlike growth factor I receptor [IGF-IR] and inhibits downstream signaling through the PI3K/AKT and MAPK pathways) improved little on the rate that was seen with just panitumumab (22% vs. 21%).

"This is the first study to show promising evidence of the efficacy by an HGF inhibitor, rilotumumab, ... when combined with panitumumab in patients with pretreated metastatic colorectal cancer ... [of] KRAS wild type," lead investigator Dr. Eric Van Cutsem told attendees at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"Preclinical studies indeed have indicated that there is a complex interdependence between the HGF/c-Met and the IGF-IR and EGFR pathways," he noted, explaining the trial’s rationale. "Combinations of agents that block these receptors are being investigated for their potential to generate additive or synergistic anticancer effects."

To be eligible for the trial, patients had to have metastatic colorectal cancer with wild-type KRAS (because mutations in KRAS confer panitumumab resistance); progression during or after prior irinotecan- and/or oxaliplatin-based chemotherapy; a glycosylated hemoglobin level of 8% or less; a good performance status; and no previous EGFR, c-Met, or IGF-IR inhibitor therapy.

The patients were randomly assigned in nearly equal numbers to receive panitumumab (6 mg/kg every 2 weeks) in combination with placebo, with rilotumumab (10 mg/kg every 2 weeks), or with ganitumab (12 mg/kg every 2 weeks).

All three antibodies are manufactured by Amgen. Panitumumab is approved by the Food and Drug Administration for the treatment of EGFR-expressing metastatic colorectal cancer that has progressed during or after conventional chemotherapy. The other two antibodies are investigational.

The trial’s primary end point was the objective response rate as determined with modified RECIST (Response Evaluation Criteria in Solid Tumors). "It’s important to mention that all responses were required to be confirmed at least 4 weeks after response criteria were first met," noted Dr. Van Cutsem, head of digestive oncology at the University Hospital Gasthuisberg in Leuven, Belgium.

Median follow-up was 6.9 months, as of the data cutoff for the analyses reported. Some 58% of the 142 patients enrolled were men, and the average age was about 58 years. Nearly two-thirds had metastases in the liver plus other sites. About a third had received three or more prior lines of therapy.

All of the responses were partial ones. The median duration of response was 3.7 months with panitumumab alone, 5.1 months with panitumumab plus rilotumumab, and 3.7 months with panitumumab plus ganitumab. The corresponding values for the disease control rate (complete response, partial response, and stable disease) were 56%, 71%, and 61%.

The median duration of progression-free survival was 3.7 months with panitumumab. This compared with 5.2 months with panitumumab-rilotumumab and 5.3 months with panitumumab-ganitumab.

"In general, the safety and toxicity was acceptable in all three arms of this study," commented Dr. Van Cutsem. The overall rate of grade 3/4 adverse events was 52% with panitumumab alone and higher with panitumumab-rilotumumab (71%) and with panitumumab-ganitumab (63%).

Although the nature of these grade 3/4 events was generally similar across groups, the addition of rilotumumab to panitumumab increased the rate of rash (from 8% to 29%), and the addition of ganitumab to panitumumab increased the rate of hypomagnesemia (from 2% to 15%).

"We hope to report in future meetings and manuscripts further details and especially also analysis of biomarkers for response in serum and tissue samples that have been collected and that are underway," Dr. Van Cutsem concluded.

"I am very proud to say ... that we do have movement forward," said discussant Dr. Johanna C. Bendell, director of GI oncology research with the Sarah Cannon Research Institute in Nashville, Tenn. "Targeting the c-Met or HGF pathway in combination with anti-EGFR therapy looks promising for colorectal cancer in this small study."

Targeting both EGFR and Met signaling has been tapped with marked clinical benefit in patients with non–small cell lung cancer who have high Met expression (Ann. Oncol. 2010;21[suppl. 8]:viii7 [abstract LBA15]), she noted. But those whose tumors had low Met expression actually fared worse when they were given dual therapy than when they were given anti-EGFR therapy alone.

"We do await further progression-free survival data, but the early look looks quite interesting," concluded Dr. Bendell. "Also, we are very interested in the biomarker data that will be associated with this looking at whether or not – like we see in non–small cell lung cancer – if over–Met expression has some sort of effect on how patients do with colorectal cancer."

Amgen sponsored the trial. Dr. Van Cutsem reported receiving research funding from Amgen. Dr. Bendell reported having no relevant conflicts of interest.

SAN FRANCISCO – Endoscopic resection may help tailor management for clinically node–negative superficial squamous cell carcinoma of the esophagus, new data from Japan suggest.

A retrospective study of 83 patients who underwent endoscopic resection and had subsequent treatment because of the depth of invasion of their cancer found a 5-year survival rate of 76% when it was followed by chemoradiation and 100% when it was followed by surgery.

The most common complication of the endoscopic resection was stenosis, noted in 11% of cases overall, lead investigator Dr. Toshiro Iizuka, a gastroenterologist at Toranomon Hospital in Tokyo, reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"Endoscopic therapy plus additional treatment for M3 to SM2 superficial carcinoma of the esophagus did not entail the development of any serious complications. Thus, such combined treatment was safe and feasible," Dr. Iizuka commented. "The long-term follow-up results were fairly gratifying."

"Surgical resection has been considered as a standard treatment in cases of superficial esophageal cancer with potential lymph node metastasis," he noted, but up to two-thirds of patients experience serious complications.

"The frequency of lymph node metastases in superficial squamous cell carcinoma of the esophagus ... depends on the depth of invasion," said Dr. Iizuka. "Accordingly, a therapeutic strategy has become feasible whereby endoscopic submucosal dissection aimed at local control is undertaken first, followed by considering additional treatment based on the results of the histological examination."

The patients studied all had T1 tumors and clinically node–negative (cN0) status as determined by endoscopy, endoscopic ultrasound, computed tomography, and positron emission tomography.

They underwent endoscopic resection, either endoscopic mucosal resection (EMR) before March 2005 or endoscopic submucosal dissection (ESD) thereafter.

Histologic evaluation of the endoscopically resected lesions showed that 140 patients had pathologic M3, SM1, or SM2 tumors, and they therefore received additional treatment. Patients found to have pathologic M1 or M2 tumors were followed.

Dr. Iizuka focused on results for 27 patients who underwent subsequent surgical resection and 56 who underwent subsequent chemoradiation, with the choice between these two options left to patients after discussion of the pros and cons of each in their case.

Overall, these patients had a mean age of about 63 years, and 87% were men. Tumors were roughly equally located in the upper, middle, and lower esophagus; the mean size was 42 mm in the surgery group and 26 mm in the chemoradiation group. The majority of endoscopic resections were ESD.

In the surgery group, patients more often had a three-field lymph node dissection (59%) than a two-field one (41%). In the chemoradiation group, the majority of patients received 40-45 Gy of radiation (86%) and low-dose 5-fluorouracil and cisplatin chemotherapy (57%).

Results for all 140 patients who underwent endoscopic resection showed a resection rate of 81% and an R0 resection rate of 72%. Overall, 15% of patients had a complication from the procedure, with stenosis, at 11%, being the most common.

The main complications of surgery were anastomotic stenosis (seen in 15% of patients) and recurrent nerve palsy (7%). Also, 7% of patients were found to have residual cancer and 4% were found to have lymph node metastases. The main serious complication of chemoradiation was grade-3 leukopenia (14%). There were no treatment-related deaths or grade-4 adverse events.

The median duration of follow-up was 42.5 months in the surgery group and 33 months in the chemoradiation group.

None of the patients had a local recurrence. The actuarial 5-year rates of relapse-free survival were 100% and 88%, respectively; the actuarial 5-year rates of overall survival were 100% and 76%, respectively.

"Endoscopic therapy with subsequent additional treatment is considered to be valid and ... [achieved] good local control and selection of the treatment based on the precise diagnosis," asserted Dr. Iizuka.

"To overcome ... [the study’s] shortcomings, a prospective multicenter trial is ongoing in the Japan Clinical Oncology Group," he concluded. "We will have to await the results of this trial."

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

SAN FRANCISCO – Endoscopic resection may help tailor management for clinically node–negative superficial squamous cell carcinoma of the esophagus, new data from Japan suggest.

A retrospective study of 83 patients who underwent endoscopic resection and had subsequent treatment because of the depth of invasion of their cancer found a 5-year survival rate of 76% when it was followed by chemoradiation and 100% when it was followed by surgery.

The most common complication of the endoscopic resection was stenosis, noted in 11% of cases overall, lead investigator Dr. Toshiro Iizuka, a gastroenterologist at Toranomon Hospital in Tokyo, reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"Endoscopic therapy plus additional treatment for M3 to SM2 superficial carcinoma of the esophagus did not entail the development of any serious complications. Thus, such combined treatment was safe and feasible," Dr. Iizuka commented. "The long-term follow-up results were fairly gratifying."

"Surgical resection has been considered as a standard treatment in cases of superficial esophageal cancer with potential lymph node metastasis," he noted, but up to two-thirds of patients experience serious complications.

"The frequency of lymph node metastases in superficial squamous cell carcinoma of the esophagus ... depends on the depth of invasion," said Dr. Iizuka. "Accordingly, a therapeutic strategy has become feasible whereby endoscopic submucosal dissection aimed at local control is undertaken first, followed by considering additional treatment based on the results of the histological examination."

The patients studied all had T1 tumors and clinically node–negative (cN0) status as determined by endoscopy, endoscopic ultrasound, computed tomography, and positron emission tomography.

They underwent endoscopic resection, either endoscopic mucosal resection (EMR) before March 2005 or endoscopic submucosal dissection (ESD) thereafter.

Histologic evaluation of the endoscopically resected lesions showed that 140 patients had pathologic M3, SM1, or SM2 tumors, and they therefore received additional treatment. Patients found to have pathologic M1 or M2 tumors were followed.

Dr. Iizuka focused on results for 27 patients who underwent subsequent surgical resection and 56 who underwent subsequent chemoradiation, with the choice between these two options left to patients after discussion of the pros and cons of each in their case.

Overall, these patients had a mean age of about 63 years, and 87% were men. Tumors were roughly equally located in the upper, middle, and lower esophagus; the mean size was 42 mm in the surgery group and 26 mm in the chemoradiation group. The majority of endoscopic resections were ESD.

In the surgery group, patients more often had a three-field lymph node dissection (59%) than a two-field one (41%). In the chemoradiation group, the majority of patients received 40-45 Gy of radiation (86%) and low-dose 5-fluorouracil and cisplatin chemotherapy (57%).

Results for all 140 patients who underwent endoscopic resection showed a resection rate of 81% and an R0 resection rate of 72%. Overall, 15% of patients had a complication from the procedure, with stenosis, at 11%, being the most common.

The main complications of surgery were anastomotic stenosis (seen in 15% of patients) and recurrent nerve palsy (7%). Also, 7% of patients were found to have residual cancer and 4% were found to have lymph node metastases. The main serious complication of chemoradiation was grade-3 leukopenia (14%). There were no treatment-related deaths or grade-4 adverse events.

The median duration of follow-up was 42.5 months in the surgery group and 33 months in the chemoradiation group.

None of the patients had a local recurrence. The actuarial 5-year rates of relapse-free survival were 100% and 88%, respectively; the actuarial 5-year rates of overall survival were 100% and 76%, respectively.

"Endoscopic therapy with subsequent additional treatment is considered to be valid and ... [achieved] good local control and selection of the treatment based on the precise diagnosis," asserted Dr. Iizuka.

"To overcome ... [the study’s] shortcomings, a prospective multicenter trial is ongoing in the Japan Clinical Oncology Group," he concluded. "We will have to await the results of this trial."

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

SAN FRANCISCO – Endoscopic resection may help tailor management for clinically node–negative superficial squamous cell carcinoma of the esophagus, new data from Japan suggest.

A retrospective study of 83 patients who underwent endoscopic resection and had subsequent treatment because of the depth of invasion of their cancer found a 5-year survival rate of 76% when it was followed by chemoradiation and 100% when it was followed by surgery.

The most common complication of the endoscopic resection was stenosis, noted in 11% of cases overall, lead investigator Dr. Toshiro Iizuka, a gastroenterologist at Toranomon Hospital in Tokyo, reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"Endoscopic therapy plus additional treatment for M3 to SM2 superficial carcinoma of the esophagus did not entail the development of any serious complications. Thus, such combined treatment was safe and feasible," Dr. Iizuka commented. "The long-term follow-up results were fairly gratifying."

"Surgical resection has been considered as a standard treatment in cases of superficial esophageal cancer with potential lymph node metastasis," he noted, but up to two-thirds of patients experience serious complications.

"The frequency of lymph node metastases in superficial squamous cell carcinoma of the esophagus ... depends on the depth of invasion," said Dr. Iizuka. "Accordingly, a therapeutic strategy has become feasible whereby endoscopic submucosal dissection aimed at local control is undertaken first, followed by considering additional treatment based on the results of the histological examination."

The patients studied all had T1 tumors and clinically node–negative (cN0) status as determined by endoscopy, endoscopic ultrasound, computed tomography, and positron emission tomography.

They underwent endoscopic resection, either endoscopic mucosal resection (EMR) before March 2005 or endoscopic submucosal dissection (ESD) thereafter.

Histologic evaluation of the endoscopically resected lesions showed that 140 patients had pathologic M3, SM1, or SM2 tumors, and they therefore received additional treatment. Patients found to have pathologic M1 or M2 tumors were followed.

Dr. Iizuka focused on results for 27 patients who underwent subsequent surgical resection and 56 who underwent subsequent chemoradiation, with the choice between these two options left to patients after discussion of the pros and cons of each in their case.

Overall, these patients had a mean age of about 63 years, and 87% were men. Tumors were roughly equally located in the upper, middle, and lower esophagus; the mean size was 42 mm in the surgery group and 26 mm in the chemoradiation group. The majority of endoscopic resections were ESD.

In the surgery group, patients more often had a three-field lymph node dissection (59%) than a two-field one (41%). In the chemoradiation group, the majority of patients received 40-45 Gy of radiation (86%) and low-dose 5-fluorouracil and cisplatin chemotherapy (57%).

Results for all 140 patients who underwent endoscopic resection showed a resection rate of 81% and an R0 resection rate of 72%. Overall, 15% of patients had a complication from the procedure, with stenosis, at 11%, being the most common.

The main complications of surgery were anastomotic stenosis (seen in 15% of patients) and recurrent nerve palsy (7%). Also, 7% of patients were found to have residual cancer and 4% were found to have lymph node metastases. The main serious complication of chemoradiation was grade-3 leukopenia (14%). There were no treatment-related deaths or grade-4 adverse events.

The median duration of follow-up was 42.5 months in the surgery group and 33 months in the chemoradiation group.

None of the patients had a local recurrence. The actuarial 5-year rates of relapse-free survival were 100% and 88%, respectively; the actuarial 5-year rates of overall survival were 100% and 76%, respectively.

"Endoscopic therapy with subsequent additional treatment is considered to be valid and ... [achieved] good local control and selection of the treatment based on the precise diagnosis," asserted Dr. Iizuka.

"To overcome ... [the study’s] shortcomings, a prospective multicenter trial is ongoing in the Japan Clinical Oncology Group," he concluded. "We will have to await the results of this trial."

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

SAN FRANCISCO – Endoscopic resection may help tailor management for clinically node–negative superficial squamous cell carcinoma of the esophagus, new data from Japan suggest.

A retrospective study of 83 patients who underwent endoscopic resection and had subsequent treatment because of the depth of invasion of their cancer found a 5-year survival rate of 76% when it was followed by chemoradiation and 100% when it was followed by surgery.

The most common complication of the endoscopic resection was stenosis, noted in 11% of cases overall, lead investigator Dr. Toshiro Iizuka, a gastroenterologist at Toranomon Hospital in Tokyo, reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"Endoscopic therapy plus additional treatment for M3 to SM2 superficial carcinoma of the esophagus did not entail the development of any serious complications. Thus, such combined treatment was safe and feasible," Dr. Iizuka commented. "The long-term follow-up results were fairly gratifying."

"Surgical resection has been considered as a standard treatment in cases of superficial esophageal cancer with potential lymph node metastasis," he noted, but up to two-thirds of patients experience serious complications.

"The frequency of lymph node metastases in superficial squamous cell carcinoma of the esophagus ... depends on the depth of invasion," said Dr. Iizuka. "Accordingly, a therapeutic strategy has become feasible whereby endoscopic submucosal dissection aimed at local control is undertaken first, followed by considering additional treatment based on the results of the histological examination."

The patients studied all had T1 tumors and clinically node–negative (cN0) status as determined by endoscopy, endoscopic ultrasound, computed tomography, and positron emission tomography.

They underwent endoscopic resection, either endoscopic mucosal resection (EMR) before March 2005 or endoscopic submucosal dissection (ESD) thereafter.

Histologic evaluation of the endoscopically resected lesions showed that 140 patients had pathologic M3, SM1, or SM2 tumors, and they therefore received additional treatment. Patients found to have pathologic M1 or M2 tumors were followed.

Dr. Iizuka focused on results for 27 patients who underwent subsequent surgical resection and 56 who underwent subsequent chemoradiation, with the choice between these two options left to patients after discussion of the pros and cons of each in their case.

Overall, these patients had a mean age of about 63 years, and 87% were men. Tumors were roughly equally located in the upper, middle, and lower esophagus; the mean size was 42 mm in the surgery group and 26 mm in the chemoradiation group. The majority of endoscopic resections were ESD.

In the surgery group, patients more often had a three-field lymph node dissection (59%) than a two-field one (41%). In the chemoradiation group, the majority of patients received 40-45 Gy of radiation (86%) and low-dose 5-fluorouracil and cisplatin chemotherapy (57%).

Results for all 140 patients who underwent endoscopic resection showed a resection rate of 81% and an R0 resection rate of 72%. Overall, 15% of patients had a complication from the procedure, with stenosis, at 11%, being the most common.

The main complications of surgery were anastomotic stenosis (seen in 15% of patients) and recurrent nerve palsy (7%). Also, 7% of patients were found to have residual cancer and 4% were found to have lymph node metastases. The main serious complication of chemoradiation was grade-3 leukopenia (14%). There were no treatment-related deaths or grade-4 adverse events.

The median duration of follow-up was 42.5 months in the surgery group and 33 months in the chemoradiation group.

None of the patients had a local recurrence. The actuarial 5-year rates of relapse-free survival were 100% and 88%, respectively; the actuarial 5-year rates of overall survival were 100% and 76%, respectively.

"Endoscopic therapy with subsequent additional treatment is considered to be valid and ... [achieved] good local control and selection of the treatment based on the precise diagnosis," asserted Dr. Iizuka.

"To overcome ... [the study’s] shortcomings, a prospective multicenter trial is ongoing in the Japan Clinical Oncology Group," he concluded. "We will have to await the results of this trial."

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

SAN FRANCISCO – Endoscopic resection may help tailor management for clinically node–negative superficial squamous cell carcinoma of the esophagus, new data from Japan suggest.

A retrospective study of 83 patients who underwent endoscopic resection and had subsequent treatment because of the depth of invasion of their cancer found a 5-year survival rate of 76% when it was followed by chemoradiation and 100% when it was followed by surgery.

The most common complication of the endoscopic resection was stenosis, noted in 11% of cases overall, lead investigator Dr. Toshiro Iizuka, a gastroenterologist at Toranomon Hospital in Tokyo, reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"Endoscopic therapy plus additional treatment for M3 to SM2 superficial carcinoma of the esophagus did not entail the development of any serious complications. Thus, such combined treatment was safe and feasible," Dr. Iizuka commented. "The long-term follow-up results were fairly gratifying."

"Surgical resection has been considered as a standard treatment in cases of superficial esophageal cancer with potential lymph node metastasis," he noted, but up to two-thirds of patients experience serious complications.

"The frequency of lymph node metastases in superficial squamous cell carcinoma of the esophagus ... depends on the depth of invasion," said Dr. Iizuka. "Accordingly, a therapeutic strategy has become feasible whereby endoscopic submucosal dissection aimed at local control is undertaken first, followed by considering additional treatment based on the results of the histological examination."

The patients studied all had T1 tumors and clinically node–negative (cN0) status as determined by endoscopy, endoscopic ultrasound, computed tomography, and positron emission tomography.

They underwent endoscopic resection, either endoscopic mucosal resection (EMR) before March 2005 or endoscopic submucosal dissection (ESD) thereafter.

Histologic evaluation of the endoscopically resected lesions showed that 140 patients had pathologic M3, SM1, or SM2 tumors, and they therefore received additional treatment. Patients found to have pathologic M1 or M2 tumors were followed.

Dr. Iizuka focused on results for 27 patients who underwent subsequent surgical resection and 56 who underwent subsequent chemoradiation, with the choice between these two options left to patients after discussion of the pros and cons of each in their case.

Overall, these patients had a mean age of about 63 years, and 87% were men. Tumors were roughly equally located in the upper, middle, and lower esophagus; the mean size was 42 mm in the surgery group and 26 mm in the chemoradiation group. The majority of endoscopic resections were ESD.

In the surgery group, patients more often had a three-field lymph node dissection (59%) than a two-field one (41%). In the chemoradiation group, the majority of patients received 40-45 Gy of radiation (86%) and low-dose 5-fluorouracil and cisplatin chemotherapy (57%).

Results for all 140 patients who underwent endoscopic resection showed a resection rate of 81% and an R0 resection rate of 72%. Overall, 15% of patients had a complication from the procedure, with stenosis, at 11%, being the most common.

The main complications of surgery were anastomotic stenosis (seen in 15% of patients) and recurrent nerve palsy (7%). Also, 7% of patients were found to have residual cancer and 4% were found to have lymph node metastases. The main serious complication of chemoradiation was grade-3 leukopenia (14%). There were no treatment-related deaths or grade-4 adverse events.

The median duration of follow-up was 42.5 months in the surgery group and 33 months in the chemoradiation group.

None of the patients had a local recurrence. The actuarial 5-year rates of relapse-free survival were 100% and 88%, respectively; the actuarial 5-year rates of overall survival were 100% and 76%, respectively.

"Endoscopic therapy with subsequent additional treatment is considered to be valid and ... [achieved] good local control and selection of the treatment based on the precise diagnosis," asserted Dr. Iizuka.

"To overcome ... [the study’s] shortcomings, a prospective multicenter trial is ongoing in the Japan Clinical Oncology Group," he concluded. "We will have to await the results of this trial."

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

SAN FRANCISCO – Endoscopic resection may help tailor management for clinically node–negative superficial squamous cell carcinoma of the esophagus, new data from Japan suggest.

A retrospective study of 83 patients who underwent endoscopic resection and had subsequent treatment because of the depth of invasion of their cancer found a 5-year survival rate of 76% when it was followed by chemoradiation and 100% when it was followed by surgery.

The most common complication of the endoscopic resection was stenosis, noted in 11% of cases overall, lead investigator Dr. Toshiro Iizuka, a gastroenterologist at Toranomon Hospital in Tokyo, reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"Endoscopic therapy plus additional treatment for M3 to SM2 superficial carcinoma of the esophagus did not entail the development of any serious complications. Thus, such combined treatment was safe and feasible," Dr. Iizuka commented. "The long-term follow-up results were fairly gratifying."

"Surgical resection has been considered as a standard treatment in cases of superficial esophageal cancer with potential lymph node metastasis," he noted, but up to two-thirds of patients experience serious complications.

"The frequency of lymph node metastases in superficial squamous cell carcinoma of the esophagus ... depends on the depth of invasion," said Dr. Iizuka. "Accordingly, a therapeutic strategy has become feasible whereby endoscopic submucosal dissection aimed at local control is undertaken first, followed by considering additional treatment based on the results of the histological examination."

The patients studied all had T1 tumors and clinically node–negative (cN0) status as determined by endoscopy, endoscopic ultrasound, computed tomography, and positron emission tomography.

They underwent endoscopic resection, either endoscopic mucosal resection (EMR) before March 2005 or endoscopic submucosal dissection (ESD) thereafter.

Histologic evaluation of the endoscopically resected lesions showed that 140 patients had pathologic M3, SM1, or SM2 tumors, and they therefore received additional treatment. Patients found to have pathologic M1 or M2 tumors were followed.

Dr. Iizuka focused on results for 27 patients who underwent subsequent surgical resection and 56 who underwent subsequent chemoradiation, with the choice between these two options left to patients after discussion of the pros and cons of each in their case.

Overall, these patients had a mean age of about 63 years, and 87% were men. Tumors were roughly equally located in the upper, middle, and lower esophagus; the mean size was 42 mm in the surgery group and 26 mm in the chemoradiation group. The majority of endoscopic resections were ESD.

In the surgery group, patients more often had a three-field lymph node dissection (59%) than a two-field one (41%). In the chemoradiation group, the majority of patients received 40-45 Gy of radiation (86%) and low-dose 5-fluorouracil and cisplatin chemotherapy (57%).

Results for all 140 patients who underwent endoscopic resection showed a resection rate of 81% and an R0 resection rate of 72%. Overall, 15% of patients had a complication from the procedure, with stenosis, at 11%, being the most common.

The main complications of surgery were anastomotic stenosis (seen in 15% of patients) and recurrent nerve palsy (7%). Also, 7% of patients were found to have residual cancer and 4% were found to have lymph node metastases. The main serious complication of chemoradiation was grade-3 leukopenia (14%). There were no treatment-related deaths or grade-4 adverse events.

The median duration of follow-up was 42.5 months in the surgery group and 33 months in the chemoradiation group.

None of the patients had a local recurrence. The actuarial 5-year rates of relapse-free survival were 100% and 88%, respectively; the actuarial 5-year rates of overall survival were 100% and 76%, respectively.

"Endoscopic therapy with subsequent additional treatment is considered to be valid and ... [achieved] good local control and selection of the treatment based on the precise diagnosis," asserted Dr. Iizuka.

"To overcome ... [the study’s] shortcomings, a prospective multicenter trial is ongoing in the Japan Clinical Oncology Group," he concluded. "We will have to await the results of this trial."

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

SAN FRANCISCO – A pancreatic cancer’s molecular markers might make it possible to predict whether a patient will benefit from surgery, suggests a study from the New South Wales Pancreatic Cancer Network in Australia.

In the cohort of 372 patients who underwent surgical resection for pancreatic cancer, the markers S100A2 and S100A4, which are associated with more aggressive tumor behavior, predicted worse survival after surgery.

Median survival was almost three times longer when a tumor was immunohistochemically negative for both markers, compared with positive for S100A2 (34.3 vs. 11.9 months). A third group of patients having tumors positive only for S100A4 had intermediate survival (15.6 months).

"Perhaps we can use these two markers to stratify resectable pancreatic cancer into three different phenotypes of prognosis and response to therapy," lead investigator Dr. David K. Chang said at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"So we can make the argument that for those patients in the good prognostic group, we can subject them to a potentially more morbid operation and more aggressive locoregional control, such as synchronous arterial-venous resection," he elaborated. "And for the group of patients [that] we know are going to do very poorly after surgery, perhaps it’s best to place them on the neoadjuvant pathways."

Surgery remains the only potentially curative therapy for pancreatic cancer, a disease whose survival has improved little over 45 years, according to Dr. Chang, a doctoral student at the Garvan Institute of Medical Research in Sydney.

"We know that surgery works," he commented. "However ... we do not have the ability to predict who is going to benefit from surgery preoperatively. Currently, we select patients for surgery based on CT criteria. ... And we predict prognosis based on clincopathologic variables that are only available after surgery, and sometimes they are fairly inconsistent."

Dr. Chang and his coinvestigators assessed the two markers in a cohort of 372 patients who underwent resection of their pancreatic cancer. Immunohistochemistry was performed on the tumors to ascertain whether their epithelial cells expressed S100A2 in the cytoplasm and S100A4 in the cytoplasm and/or nucleus.

Both markers are calcium-binding proteins. S100A2 has been associated with metastasis, invasiveness, and larger tumor size. S100A4 (also known as MTS1, metastasin, FSP1, and p9ka) has been associated with metastasis, chemoresistance, and a mesenchymal phenotype.

Multivariate analysis showed that each marker independently predicted an increased risk of death, with a hazard ratio of 1.76 (P = .005) for patients having S100A2+ tumors and 1.69 (P = .002) for patients having S100A4+ tumors.

Combination of the two markers stratified patients into three distinct groups having different survival after surgery, according to Dr. Chang. Median survival was 34.3 months for patients with S100A2–/A4– tumors, 15.6 months for patients with S100A2–/A4+ tumors, and 11.9 months for patients with S100A2+ tumors (P less than .0001).

In the same cohort, the investigators compared a new nomogram integrating the two markers with preoperative factors such as tumor size against a previously validated prognostic nomogram for patients undergoing resection that relies on some variables available only after surgery (Ann. Surg. 2004;240:293-8).

The new nomogram "performed just as good if not slightly better than the postoperative nomogram using clinicopathologic variables that are only available postoperatively," Dr. Chang reported.

A subsequent pilot experiment has shown good correlation between quantitative RT-PCR levels of the markers in biopsy tissue obtained by endoscopic ultrasound with fine-needle aspiration and the immunohistochemical results on resected surgical specimens. The team is now assessing the use of the assays on tissue obtained by fine-needle core biopsy.

"Aberrant expression of S100A4 and S100A2 stratified pancreatic cancer into three distinct prognostic phenotypes," Dr. Chang said, summing up the study’s findings. "This may be used to improve the accuracy of prognostic nomograms and to help us better prognosticate and predict prognosis preoperatively."

And from the larger perspective, "It may help us to better select patients for more appropriate and personalized therapies so that we only operate on the right patients and, as a consequence, it may improve the overall outcomes," he concluded.

Dr. Chang reported having no conflicts of interest related to the research.

SAN FRANCISCO – A pancreatic cancer’s molecular markers might make it possible to predict whether a patient will benefit from surgery, suggests a study from the New South Wales Pancreatic Cancer Network in Australia.

In the cohort of 372 patients who underwent surgical resection for pancreatic cancer, the markers S100A2 and S100A4, which are associated with more aggressive tumor behavior, predicted worse survival after surgery.

Median survival was almost three times longer when a tumor was immunohistochemically negative for both markers, compared with positive for S100A2 (34.3 vs. 11.9 months). A third group of patients having tumors positive only for S100A4 had intermediate survival (15.6 months).

"Perhaps we can use these two markers to stratify resectable pancreatic cancer into three different phenotypes of prognosis and response to therapy," lead investigator Dr. David K. Chang said at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"So we can make the argument that for those patients in the good prognostic group, we can subject them to a potentially more morbid operation and more aggressive locoregional control, such as synchronous arterial-venous resection," he elaborated. "And for the group of patients [that] we know are going to do very poorly after surgery, perhaps it’s best to place them on the neoadjuvant pathways."

Surgery remains the only potentially curative therapy for pancreatic cancer, a disease whose survival has improved little over 45 years, according to Dr. Chang, a doctoral student at the Garvan Institute of Medical Research in Sydney.

"We know that surgery works," he commented. "However ... we do not have the ability to predict who is going to benefit from surgery preoperatively. Currently, we select patients for surgery based on CT criteria. ... And we predict prognosis based on clincopathologic variables that are only available after surgery, and sometimes they are fairly inconsistent."

Dr. Chang and his coinvestigators assessed the two markers in a cohort of 372 patients who underwent resection of their pancreatic cancer. Immunohistochemistry was performed on the tumors to ascertain whether their epithelial cells expressed S100A2 in the cytoplasm and S100A4 in the cytoplasm and/or nucleus.

Both markers are calcium-binding proteins. S100A2 has been associated with metastasis, invasiveness, and larger tumor size. S100A4 (also known as MTS1, metastasin, FSP1, and p9ka) has been associated with metastasis, chemoresistance, and a mesenchymal phenotype.

Multivariate analysis showed that each marker independently predicted an increased risk of death, with a hazard ratio of 1.76 (P = .005) for patients having S100A2+ tumors and 1.69 (P = .002) for patients having S100A4+ tumors.

Combination of the two markers stratified patients into three distinct groups having different survival after surgery, according to Dr. Chang. Median survival was 34.3 months for patients with S100A2–/A4– tumors, 15.6 months for patients with S100A2–/A4+ tumors, and 11.9 months for patients with S100A2+ tumors (P less than .0001).

In the same cohort, the investigators compared a new nomogram integrating the two markers with preoperative factors such as tumor size against a previously validated prognostic nomogram for patients undergoing resection that relies on some variables available only after surgery (Ann. Surg. 2004;240:293-8).

The new nomogram "performed just as good if not slightly better than the postoperative nomogram using clinicopathologic variables that are only available postoperatively," Dr. Chang reported.

A subsequent pilot experiment has shown good correlation between quantitative RT-PCR levels of the markers in biopsy tissue obtained by endoscopic ultrasound with fine-needle aspiration and the immunohistochemical results on resected surgical specimens. The team is now assessing the use of the assays on tissue obtained by fine-needle core biopsy.

"Aberrant expression of S100A4 and S100A2 stratified pancreatic cancer into three distinct prognostic phenotypes," Dr. Chang said, summing up the study’s findings. "This may be used to improve the accuracy of prognostic nomograms and to help us better prognosticate and predict prognosis preoperatively."

And from the larger perspective, "It may help us to better select patients for more appropriate and personalized therapies so that we only operate on the right patients and, as a consequence, it may improve the overall outcomes," he concluded.

Dr. Chang reported having no conflicts of interest related to the research.

SAN FRANCISCO – A pancreatic cancer’s molecular markers might make it possible to predict whether a patient will benefit from surgery, suggests a study from the New South Wales Pancreatic Cancer Network in Australia.

In the cohort of 372 patients who underwent surgical resection for pancreatic cancer, the markers S100A2 and S100A4, which are associated with more aggressive tumor behavior, predicted worse survival after surgery.

Median survival was almost three times longer when a tumor was immunohistochemically negative for both markers, compared with positive for S100A2 (34.3 vs. 11.9 months). A third group of patients having tumors positive only for S100A4 had intermediate survival (15.6 months).

"Perhaps we can use these two markers to stratify resectable pancreatic cancer into three different phenotypes of prognosis and response to therapy," lead investigator Dr. David K. Chang said at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"So we can make the argument that for those patients in the good prognostic group, we can subject them to a potentially more morbid operation and more aggressive locoregional control, such as synchronous arterial-venous resection," he elaborated. "And for the group of patients [that] we know are going to do very poorly after surgery, perhaps it’s best to place them on the neoadjuvant pathways."

Surgery remains the only potentially curative therapy for pancreatic cancer, a disease whose survival has improved little over 45 years, according to Dr. Chang, a doctoral student at the Garvan Institute of Medical Research in Sydney.

"We know that surgery works," he commented. "However ... we do not have the ability to predict who is going to benefit from surgery preoperatively. Currently, we select patients for surgery based on CT criteria. ... And we predict prognosis based on clincopathologic variables that are only available after surgery, and sometimes they are fairly inconsistent."

Dr. Chang and his coinvestigators assessed the two markers in a cohort of 372 patients who underwent resection of their pancreatic cancer. Immunohistochemistry was performed on the tumors to ascertain whether their epithelial cells expressed S100A2 in the cytoplasm and S100A4 in the cytoplasm and/or nucleus.

Both markers are calcium-binding proteins. S100A2 has been associated with metastasis, invasiveness, and larger tumor size. S100A4 (also known as MTS1, metastasin, FSP1, and p9ka) has been associated with metastasis, chemoresistance, and a mesenchymal phenotype.

Multivariate analysis showed that each marker independently predicted an increased risk of death, with a hazard ratio of 1.76 (P = .005) for patients having S100A2+ tumors and 1.69 (P = .002) for patients having S100A4+ tumors.

Combination of the two markers stratified patients into three distinct groups having different survival after surgery, according to Dr. Chang. Median survival was 34.3 months for patients with S100A2–/A4– tumors, 15.6 months for patients with S100A2–/A4+ tumors, and 11.9 months for patients with S100A2+ tumors (P less than .0001).

In the same cohort, the investigators compared a new nomogram integrating the two markers with preoperative factors such as tumor size against a previously validated prognostic nomogram for patients undergoing resection that relies on some variables available only after surgery (Ann. Surg. 2004;240:293-8).

The new nomogram "performed just as good if not slightly better than the postoperative nomogram using clinicopathologic variables that are only available postoperatively," Dr. Chang reported.

A subsequent pilot experiment has shown good correlation between quantitative RT-PCR levels of the markers in biopsy tissue obtained by endoscopic ultrasound with fine-needle aspiration and the immunohistochemical results on resected surgical specimens. The team is now assessing the use of the assays on tissue obtained by fine-needle core biopsy.

"Aberrant expression of S100A4 and S100A2 stratified pancreatic cancer into three distinct prognostic phenotypes," Dr. Chang said, summing up the study’s findings. "This may be used to improve the accuracy of prognostic nomograms and to help us better prognosticate and predict prognosis preoperatively."

And from the larger perspective, "It may help us to better select patients for more appropriate and personalized therapies so that we only operate on the right patients and, as a consequence, it may improve the overall outcomes," he concluded.

Dr. Chang reported having no conflicts of interest related to the research.

SAN FRANCISCO – A pancreatic cancer’s molecular markers might make it possible to predict whether a patient will benefit from surgery, suggests a study from the New South Wales Pancreatic Cancer Network in Australia.

In the cohort of 372 patients who underwent surgical resection for pancreatic cancer, the markers S100A2 and S100A4, which are associated with more aggressive tumor behavior, predicted worse survival after surgery.

Median survival was almost three times longer when a tumor was immunohistochemically negative for both markers, compared with positive for S100A2 (34.3 vs. 11.9 months). A third group of patients having tumors positive only for S100A4 had intermediate survival (15.6 months).

"Perhaps we can use these two markers to stratify resectable pancreatic cancer into three different phenotypes of prognosis and response to therapy," lead investigator Dr. David K. Chang said at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"So we can make the argument that for those patients in the good prognostic group, we can subject them to a potentially more morbid operation and more aggressive locoregional control, such as synchronous arterial-venous resection," he elaborated. "And for the group of patients [that] we know are going to do very poorly after surgery, perhaps it’s best to place them on the neoadjuvant pathways."

Surgery remains the only potentially curative therapy for pancreatic cancer, a disease whose survival has improved little over 45 years, according to Dr. Chang, a doctoral student at the Garvan Institute of Medical Research in Sydney.

"We know that surgery works," he commented. "However ... we do not have the ability to predict who is going to benefit from surgery preoperatively. Currently, we select patients for surgery based on CT criteria. ... And we predict prognosis based on clincopathologic variables that are only available after surgery, and sometimes they are fairly inconsistent."

Dr. Chang and his coinvestigators assessed the two markers in a cohort of 372 patients who underwent resection of their pancreatic cancer. Immunohistochemistry was performed on the tumors to ascertain whether their epithelial cells expressed S100A2 in the cytoplasm and S100A4 in the cytoplasm and/or nucleus.

Both markers are calcium-binding proteins. S100A2 has been associated with metastasis, invasiveness, and larger tumor size. S100A4 (also known as MTS1, metastasin, FSP1, and p9ka) has been associated with metastasis, chemoresistance, and a mesenchymal phenotype.

Multivariate analysis showed that each marker independently predicted an increased risk of death, with a hazard ratio of 1.76 (P = .005) for patients having S100A2+ tumors and 1.69 (P = .002) for patients having S100A4+ tumors.

Combination of the two markers stratified patients into three distinct groups having different survival after surgery, according to Dr. Chang. Median survival was 34.3 months for patients with S100A2–/A4– tumors, 15.6 months for patients with S100A2–/A4+ tumors, and 11.9 months for patients with S100A2+ tumors (P less than .0001).

In the same cohort, the investigators compared a new nomogram integrating the two markers with preoperative factors such as tumor size against a previously validated prognostic nomogram for patients undergoing resection that relies on some variables available only after surgery (Ann. Surg. 2004;240:293-8).

The new nomogram "performed just as good if not slightly better than the postoperative nomogram using clinicopathologic variables that are only available postoperatively," Dr. Chang reported.

A subsequent pilot experiment has shown good correlation between quantitative RT-PCR levels of the markers in biopsy tissue obtained by endoscopic ultrasound with fine-needle aspiration and the immunohistochemical results on resected surgical specimens. The team is now assessing the use of the assays on tissue obtained by fine-needle core biopsy.

"Aberrant expression of S100A4 and S100A2 stratified pancreatic cancer into three distinct prognostic phenotypes," Dr. Chang said, summing up the study’s findings. "This may be used to improve the accuracy of prognostic nomograms and to help us better prognosticate and predict prognosis preoperatively."

And from the larger perspective, "It may help us to better select patients for more appropriate and personalized therapies so that we only operate on the right patients and, as a consequence, it may improve the overall outcomes," he concluded.

Dr. Chang reported having no conflicts of interest related to the research.

SAN FRANCISCO – A pancreatic cancer’s molecular markers might make it possible to predict whether a patient will benefit from surgery, suggests a study from the New South Wales Pancreatic Cancer Network in Australia.

In the cohort of 372 patients who underwent surgical resection for pancreatic cancer, the markers S100A2 and S100A4, which are associated with more aggressive tumor behavior, predicted worse survival after surgery.

Median survival was almost three times longer when a tumor was immunohistochemically negative for both markers, compared with positive for S100A2 (34.3 vs. 11.9 months). A third group of patients having tumors positive only for S100A4 had intermediate survival (15.6 months).

"Perhaps we can use these two markers to stratify resectable pancreatic cancer into three different phenotypes of prognosis and response to therapy," lead investigator Dr. David K. Chang said at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"So we can make the argument that for those patients in the good prognostic group, we can subject them to a potentially more morbid operation and more aggressive locoregional control, such as synchronous arterial-venous resection," he elaborated. "And for the group of patients [that] we know are going to do very poorly after surgery, perhaps it’s best to place them on the neoadjuvant pathways."

Surgery remains the only potentially curative therapy for pancreatic cancer, a disease whose survival has improved little over 45 years, according to Dr. Chang, a doctoral student at the Garvan Institute of Medical Research in Sydney.

"We know that surgery works," he commented. "However ... we do not have the ability to predict who is going to benefit from surgery preoperatively. Currently, we select patients for surgery based on CT criteria. ... And we predict prognosis based on clincopathologic variables that are only available after surgery, and sometimes they are fairly inconsistent."

Dr. Chang and his coinvestigators assessed the two markers in a cohort of 372 patients who underwent resection of their pancreatic cancer. Immunohistochemistry was performed on the tumors to ascertain whether their epithelial cells expressed S100A2 in the cytoplasm and S100A4 in the cytoplasm and/or nucleus.

Both markers are calcium-binding proteins. S100A2 has been associated with metastasis, invasiveness, and larger tumor size. S100A4 (also known as MTS1, metastasin, FSP1, and p9ka) has been associated with metastasis, chemoresistance, and a mesenchymal phenotype.

Multivariate analysis showed that each marker independently predicted an increased risk of death, with a hazard ratio of 1.76 (P = .005) for patients having S100A2+ tumors and 1.69 (P = .002) for patients having S100A4+ tumors.

Combination of the two markers stratified patients into three distinct groups having different survival after surgery, according to Dr. Chang. Median survival was 34.3 months for patients with S100A2–/A4– tumors, 15.6 months for patients with S100A2–/A4+ tumors, and 11.9 months for patients with S100A2+ tumors (P less than .0001).

In the same cohort, the investigators compared a new nomogram integrating the two markers with preoperative factors such as tumor size against a previously validated prognostic nomogram for patients undergoing resection that relies on some variables available only after surgery (Ann. Surg. 2004;240:293-8).

The new nomogram "performed just as good if not slightly better than the postoperative nomogram using clinicopathologic variables that are only available postoperatively," Dr. Chang reported.

A subsequent pilot experiment has shown good correlation between quantitative RT-PCR levels of the markers in biopsy tissue obtained by endoscopic ultrasound with fine-needle aspiration and the immunohistochemical results on resected surgical specimens. The team is now assessing the use of the assays on tissue obtained by fine-needle core biopsy.

"Aberrant expression of S100A4 and S100A2 stratified pancreatic cancer into three distinct prognostic phenotypes," Dr. Chang said, summing up the study’s findings. "This may be used to improve the accuracy of prognostic nomograms and to help us better prognosticate and predict prognosis preoperatively."

And from the larger perspective, "It may help us to better select patients for more appropriate and personalized therapies so that we only operate on the right patients and, as a consequence, it may improve the overall outcomes," he concluded.

Dr. Chang reported having no conflicts of interest related to the research.

SAN FRANCISCO – A pancreatic cancer’s molecular markers might make it possible to predict whether a patient will benefit from surgery, suggests a study from the New South Wales Pancreatic Cancer Network in Australia.

In the cohort of 372 patients who underwent surgical resection for pancreatic cancer, the markers S100A2 and S100A4, which are associated with more aggressive tumor behavior, predicted worse survival after surgery.

Median survival was almost three times longer when a tumor was immunohistochemically negative for both markers, compared with positive for S100A2 (34.3 vs. 11.9 months). A third group of patients having tumors positive only for S100A4 had intermediate survival (15.6 months).

"Perhaps we can use these two markers to stratify resectable pancreatic cancer into three different phenotypes of prognosis and response to therapy," lead investigator Dr. David K. Chang said at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

"So we can make the argument that for those patients in the good prognostic group, we can subject them to a potentially more morbid operation and more aggressive locoregional control, such as synchronous arterial-venous resection," he elaborated. "And for the group of patients [that] we know are going to do very poorly after surgery, perhaps it’s best to place them on the neoadjuvant pathways."

Surgery remains the only potentially curative therapy for pancreatic cancer, a disease whose survival has improved little over 45 years, according to Dr. Chang, a doctoral student at the Garvan Institute of Medical Research in Sydney.

"We know that surgery works," he commented. "However ... we do not have the ability to predict who is going to benefit from surgery preoperatively. Currently, we select patients for surgery based on CT criteria. ... And we predict prognosis based on clincopathologic variables that are only available after surgery, and sometimes they are fairly inconsistent."

Dr. Chang and his coinvestigators assessed the two markers in a cohort of 372 patients who underwent resection of their pancreatic cancer. Immunohistochemistry was performed on the tumors to ascertain whether their epithelial cells expressed S100A2 in the cytoplasm and S100A4 in the cytoplasm and/or nucleus.

Both markers are calcium-binding proteins. S100A2 has been associated with metastasis, invasiveness, and larger tumor size. S100A4 (also known as MTS1, metastasin, FSP1, and p9ka) has been associated with metastasis, chemoresistance, and a mesenchymal phenotype.

Multivariate analysis showed that each marker independently predicted an increased risk of death, with a hazard ratio of 1.76 (P = .005) for patients having S100A2+ tumors and 1.69 (P = .002) for patients having S100A4+ tumors.

Combination of the two markers stratified patients into three distinct groups having different survival after surgery, according to Dr. Chang. Median survival was 34.3 months for patients with S100A2–/A4– tumors, 15.6 months for patients with S100A2–/A4+ tumors, and 11.9 months for patients with S100A2+ tumors (P less than .0001).

In the same cohort, the investigators compared a new nomogram integrating the two markers with preoperative factors such as tumor size against a previously validated prognostic nomogram for patients undergoing resection that relies on some variables available only after surgery (Ann. Surg. 2004;240:293-8).

The new nomogram "performed just as good if not slightly better than the postoperative nomogram using clinicopathologic variables that are only available postoperatively," Dr. Chang reported.

A subsequent pilot experiment has shown good correlation between quantitative RT-PCR levels of the markers in biopsy tissue obtained by endoscopic ultrasound with fine-needle aspiration and the immunohistochemical results on resected surgical specimens. The team is now assessing the use of the assays on tissue obtained by fine-needle core biopsy.

"Aberrant expression of S100A4 and S100A2 stratified pancreatic cancer into three distinct prognostic phenotypes," Dr. Chang said, summing up the study’s findings. "This may be used to improve the accuracy of prognostic nomograms and to help us better prognosticate and predict prognosis preoperatively."

And from the larger perspective, "It may help us to better select patients for more appropriate and personalized therapies so that we only operate on the right patients and, as a consequence, it may improve the overall outcomes," he concluded.

Dr. Chang reported having no conflicts of interest related to the research.

SEATTLE – Women at average risk are often screened for ovarian cancer, even though national guidelines recommend against this practice, based on a study reported at the annual meeting of the North American Primary Care Research Group.

In a cross-sectional survey of 1,088 primary care physicians presented with examples cases, 72% said they would almost never offer low-risk women transvaginal ultrasound or the cancer antigen (CA)-125 blood test, and 35% said they would almost never do so for medium-risk women.

Of concern, 30% of physicians overall said they would almost always offer or order the tests for such women.

"Screening is actually not recommended for either of these groups, suggesting that physicians are either not accurately assessing the risk or that they are choosing to offer or order the test despite recommendations to the contrary," commented lead investigator Dr. Laura-Mae Baldwin.

Besides risk assessment, a mistaken belief that the tests are effective for screening in average-risk women – endorsed by a third of the physicians – was the next strongest predictor of nonadherence to guidelines.

In fact, transvaginal ultrasound and the CA-125 test have high false-positive rates and low positive predictive values when used for ovarian cancer screening, according to Dr. Baldwin, who is a professor of family medicine and director of the Family Medicine Research Section at the University of Washington, Seattle.

"There is no professional organization or government agency that currently recommends routine ovarian cancer screening," she noted. "The U.S. Preventive Services Task Force (USPSTF) actually gives it a D grade, meaning that the harms exceed the benefits, and they recommend against the test."

"But as we know, physicians have demonstrated enthusiasm for some cancer screening tests that don’t have clear proven benefit, and we thought it might be possible that women may be exposed to the potential harms of ovarian cancer screening despite these recommendations," she said.

The investigators sent vignette-based surveys to a cross-sectional sample of U.S. primary care physicians selected from American Medical Association Physician Masterfiles.

The vignettes portrayed women at low, medium, and high risk for ovarian cancer. Respondents were asked, for the patient described, how often they would offer or order each of a list of tests for cancer screening, and were given response options of almost always, sometimes, and almost never.

"We excluded the physicians who had vignettes of women at high risk for ovarian cancer because there are some recommendations that suggest that it may be appropriate to screen in those women, so we wanted really to look at a group that had a more average risk of ovarian cancer," Dr. Baldwin explained.

Results were based on 1,088 respondents who represented a weighted sample of 106,001 physicians nationally. Some 42% were general internists, 41% were family physicians, and 17% were obstetrician-gynecologists.

Nearly three-fourths of the physicians worked in group practices. When asked about their sources of information on cancer screening, the most common were the American Cancer Society (66% listed it among their top three), the USPSTF (53%), the National Institutes of Health and National Cancer Institute (33%), and the American College of Obstetricians and Gynecologists (31%).

In a finding that Dr. Baldwin described as highly surprising, 33% of physicians believed that transvaginal ultrasound, the CA-125 test, or both were effective for ovarian cancer screening in average-risk women.

For low-risk patients, 72% of physicians were adherent to screening recommendations (defined as almost never offering or ordering either screening test); for medium-risk patients, 35% were adherent.

On the flip side, 6% of physicians said they would almost always offer or order a screening test for a low-risk patient, and 24% said they would almost always do so for a medium-risk patient.

In multivariate analyses, physicians were less likely to be adherent to recommendations against screening if the patient was at medium risk or requested testing, or they had been in practice for at least 10 years, Dr. Baldwin reported.

On the other hand, physicians were more likely to be adherent if they high-listed USPSTF as an information source, did not have any personal or family experience with cancer, were involved with clinical teaching, or were in a group practice.

However, when belief about the effectiveness of the screening tests was added to the other physician factors, physicians believing them to be effective were less likely to adhere to recommendations than their peers believing them to be ineffective.

Also, three of the other factors – years in practice, high-listing the USPSTF, and group practice – were no longer significantly related to adherence. "So basically, those associations were mediated by the degree to which those groups believed in the effectiveness of these tests," she explained.

"We don’t really understand why a third of physicians believe that these are effective ovarian cancer screening tests," Dr. Baldwin commented. "But use of the USPSTF recommendations, and practice in settings that promote interactions between physicians, like group practices, may help dispel misconceptions about the effectiveness of the ovarian cancer screening tests."

"Further research is definitely needed to try to understand what’s going on with these misconceptions and the contribution of potential risk assessment errors to this screening," she concluded.

Dr. Baldwin reported that she had no relevant financial conflicts of interest.

SEATTLE – Women at average risk are often screened for ovarian cancer, even though national guidelines recommend against this practice, based on a study reported at the annual meeting of the North American Primary Care Research Group.

In a cross-sectional survey of 1,088 primary care physicians presented with examples cases, 72% said they would almost never offer low-risk women transvaginal ultrasound or the cancer antigen (CA)-125 blood test, and 35% said they would almost never do so for medium-risk women.

Of concern, 30% of physicians overall said they would almost always offer or order the tests for such women.

"Screening is actually not recommended for either of these groups, suggesting that physicians are either not accurately assessing the risk or that they are choosing to offer or order the test despite recommendations to the contrary," commented lead investigator Dr. Laura-Mae Baldwin.

Besides risk assessment, a mistaken belief that the tests are effective for screening in average-risk women – endorsed by a third of the physicians – was the next strongest predictor of nonadherence to guidelines.

In fact, transvaginal ultrasound and the CA-125 test have high false-positive rates and low positive predictive values when used for ovarian cancer screening, according to Dr. Baldwin, who is a professor of family medicine and director of the Family Medicine Research Section at the University of Washington, Seattle.

"There is no professional organization or government agency that currently recommends routine ovarian cancer screening," she noted. "The U.S. Preventive Services Task Force (USPSTF) actually gives it a D grade, meaning that the harms exceed the benefits, and they recommend against the test."

"But as we know, physicians have demonstrated enthusiasm for some cancer screening tests that don’t have clear proven benefit, and we thought it might be possible that women may be exposed to the potential harms of ovarian cancer screening despite these recommendations," she said.

The investigators sent vignette-based surveys to a cross-sectional sample of U.S. primary care physicians selected from American Medical Association Physician Masterfiles.

The vignettes portrayed women at low, medium, and high risk for ovarian cancer. Respondents were asked, for the patient described, how often they would offer or order each of a list of tests for cancer screening, and were given response options of almost always, sometimes, and almost never.

"We excluded the physicians who had vignettes of women at high risk for ovarian cancer because there are some recommendations that suggest that it may be appropriate to screen in those women, so we wanted really to look at a group that had a more average risk of ovarian cancer," Dr. Baldwin explained.

Results were based on 1,088 respondents who represented a weighted sample of 106,001 physicians nationally. Some 42% were general internists, 41% were family physicians, and 17% were obstetrician-gynecologists.

Nearly three-fourths of the physicians worked in group practices. When asked about their sources of information on cancer screening, the most common were the American Cancer Society (66% listed it among their top three), the USPSTF (53%), the National Institutes of Health and National Cancer Institute (33%), and the American College of Obstetricians and Gynecologists (31%).

In a finding that Dr. Baldwin described as highly surprising, 33% of physicians believed that transvaginal ultrasound, the CA-125 test, or both were effective for ovarian cancer screening in average-risk women.

For low-risk patients, 72% of physicians were adherent to screening recommendations (defined as almost never offering or ordering either screening test); for medium-risk patients, 35% were adherent.

On the flip side, 6% of physicians said they would almost always offer or order a screening test for a low-risk patient, and 24% said they would almost always do so for a medium-risk patient.

In multivariate analyses, physicians were less likely to be adherent to recommendations against screening if the patient was at medium risk or requested testing, or they had been in practice for at least 10 years, Dr. Baldwin reported.

On the other hand, physicians were more likely to be adherent if they high-listed USPSTF as an information source, did not have any personal or family experience with cancer, were involved with clinical teaching, or were in a group practice.

However, when belief about the effectiveness of the screening tests was added to the other physician factors, physicians believing them to be effective were less likely to adhere to recommendations than their peers believing them to be ineffective.

Also, three of the other factors – years in practice, high-listing the USPSTF, and group practice – were no longer significantly related to adherence. "So basically, those associations were mediated by the degree to which those groups believed in the effectiveness of these tests," she explained.

"We don’t really understand why a third of physicians believe that these are effective ovarian cancer screening tests," Dr. Baldwin commented. "But use of the USPSTF recommendations, and practice in settings that promote interactions between physicians, like group practices, may help dispel misconceptions about the effectiveness of the ovarian cancer screening tests."

"Further research is definitely needed to try to understand what’s going on with these misconceptions and the contribution of potential risk assessment errors to this screening," she concluded.

Dr. Baldwin reported that she had no relevant financial conflicts of interest.

SEATTLE – Women at average risk are often screened for ovarian cancer, even though national guidelines recommend against this practice, based on a study reported at the annual meeting of the North American Primary Care Research Group.

In a cross-sectional survey of 1,088 primary care physicians presented with examples cases, 72% said they would almost never offer low-risk women transvaginal ultrasound or the cancer antigen (CA)-125 blood test, and 35% said they would almost never do so for medium-risk women.

Of concern, 30% of physicians overall said they would almost always offer or order the tests for such women.

"Screening is actually not recommended for either of these groups, suggesting that physicians are either not accurately assessing the risk or that they are choosing to offer or order the test despite recommendations to the contrary," commented lead investigator Dr. Laura-Mae Baldwin.

Besides risk assessment, a mistaken belief that the tests are effective for screening in average-risk women – endorsed by a third of the physicians – was the next strongest predictor of nonadherence to guidelines.

In fact, transvaginal ultrasound and the CA-125 test have high false-positive rates and low positive predictive values when used for ovarian cancer screening, according to Dr. Baldwin, who is a professor of family medicine and director of the Family Medicine Research Section at the University of Washington, Seattle.

"There is no professional organization or government agency that currently recommends routine ovarian cancer screening," she noted. "The U.S. Preventive Services Task Force (USPSTF) actually gives it a D grade, meaning that the harms exceed the benefits, and they recommend against the test."

"But as we know, physicians have demonstrated enthusiasm for some cancer screening tests that don’t have clear proven benefit, and we thought it might be possible that women may be exposed to the potential harms of ovarian cancer screening despite these recommendations," she said.

The investigators sent vignette-based surveys to a cross-sectional sample of U.S. primary care physicians selected from American Medical Association Physician Masterfiles.

The vignettes portrayed women at low, medium, and high risk for ovarian cancer. Respondents were asked, for the patient described, how often they would offer or order each of a list of tests for cancer screening, and were given response options of almost always, sometimes, and almost never.

"We excluded the physicians who had vignettes of women at high risk for ovarian cancer because there are some recommendations that suggest that it may be appropriate to screen in those women, so we wanted really to look at a group that had a more average risk of ovarian cancer," Dr. Baldwin explained.

Results were based on 1,088 respondents who represented a weighted sample of 106,001 physicians nationally. Some 42% were general internists, 41% were family physicians, and 17% were obstetrician-gynecologists.

Nearly three-fourths of the physicians worked in group practices. When asked about their sources of information on cancer screening, the most common were the American Cancer Society (66% listed it among their top three), the USPSTF (53%), the National Institutes of Health and National Cancer Institute (33%), and the American College of Obstetricians and Gynecologists (31%).

In a finding that Dr. Baldwin described as highly surprising, 33% of physicians believed that transvaginal ultrasound, the CA-125 test, or both were effective for ovarian cancer screening in average-risk women.

For low-risk patients, 72% of physicians were adherent to screening recommendations (defined as almost never offering or ordering either screening test); for medium-risk patients, 35% were adherent.

On the flip side, 6% of physicians said they would almost always offer or order a screening test for a low-risk patient, and 24% said they would almost always do so for a medium-risk patient.

In multivariate analyses, physicians were less likely to be adherent to recommendations against screening if the patient was at medium risk or requested testing, or they had been in practice for at least 10 years, Dr. Baldwin reported.

On the other hand, physicians were more likely to be adherent if they high-listed USPSTF as an information source, did not have any personal or family experience with cancer, were involved with clinical teaching, or were in a group practice.

However, when belief about the effectiveness of the screening tests was added to the other physician factors, physicians believing them to be effective were less likely to adhere to recommendations than their peers believing them to be ineffective.

Also, three of the other factors – years in practice, high-listing the USPSTF, and group practice – were no longer significantly related to adherence. "So basically, those associations were mediated by the degree to which those groups believed in the effectiveness of these tests," she explained.

"We don’t really understand why a third of physicians believe that these are effective ovarian cancer screening tests," Dr. Baldwin commented. "But use of the USPSTF recommendations, and practice in settings that promote interactions between physicians, like group practices, may help dispel misconceptions about the effectiveness of the ovarian cancer screening tests."

"Further research is definitely needed to try to understand what’s going on with these misconceptions and the contribution of potential risk assessment errors to this screening," she concluded.

Dr. Baldwin reported that she had no relevant financial conflicts of interest.

SEATTLE – Women at average risk are often screened for ovarian cancer, even though national guidelines recommend against this practice, based on a study reported at the annual meeting of the North American Primary Care Research Group.

In a cross-sectional survey of 1,088 primary care physicians presented with examples cases, 72% said they would almost never offer low-risk women transvaginal ultrasound or the cancer antigen (CA)-125 blood test, and 35% said they would almost never do so for medium-risk women.

Of concern, 30% of physicians overall said they would almost always offer or order the tests for such women.

"Screening is actually not recommended for either of these groups, suggesting that physicians are either not accurately assessing the risk or that they are choosing to offer or order the test despite recommendations to the contrary," commented lead investigator Dr. Laura-Mae Baldwin.

Besides risk assessment, a mistaken belief that the tests are effective for screening in average-risk women – endorsed by a third of the physicians – was the next strongest predictor of nonadherence to guidelines.

In fact, transvaginal ultrasound and the CA-125 test have high false-positive rates and low positive predictive values when used for ovarian cancer screening, according to Dr. Baldwin, who is a professor of family medicine and director of the Family Medicine Research Section at the University of Washington, Seattle.

"There is no professional organization or government agency that currently recommends routine ovarian cancer screening," she noted. "The U.S. Preventive Services Task Force (USPSTF) actually gives it a D grade, meaning that the harms exceed the benefits, and they recommend against the test."

"But as we know, physicians have demonstrated enthusiasm for some cancer screening tests that don’t have clear proven benefit, and we thought it might be possible that women may be exposed to the potential harms of ovarian cancer screening despite these recommendations," she said.

The investigators sent vignette-based surveys to a cross-sectional sample of U.S. primary care physicians selected from American Medical Association Physician Masterfiles.

The vignettes portrayed women at low, medium, and high risk for ovarian cancer. Respondents were asked, for the patient described, how often they would offer or order each of a list of tests for cancer screening, and were given response options of almost always, sometimes, and almost never.

"We excluded the physicians who had vignettes of women at high risk for ovarian cancer because there are some recommendations that suggest that it may be appropriate to screen in those women, so we wanted really to look at a group that had a more average risk of ovarian cancer," Dr. Baldwin explained.

Results were based on 1,088 respondents who represented a weighted sample of 106,001 physicians nationally. Some 42% were general internists, 41% were family physicians, and 17% were obstetrician-gynecologists.

Nearly three-fourths of the physicians worked in group practices. When asked about their sources of information on cancer screening, the most common were the American Cancer Society (66% listed it among their top three), the USPSTF (53%), the National Institutes of Health and National Cancer Institute (33%), and the American College of Obstetricians and Gynecologists (31%).

In a finding that Dr. Baldwin described as highly surprising, 33% of physicians believed that transvaginal ultrasound, the CA-125 test, or both were effective for ovarian cancer screening in average-risk women.

For low-risk patients, 72% of physicians were adherent to screening recommendations (defined as almost never offering or ordering either screening test); for medium-risk patients, 35% were adherent.

On the flip side, 6% of physicians said they would almost always offer or order a screening test for a low-risk patient, and 24% said they would almost always do so for a medium-risk patient.

In multivariate analyses, physicians were less likely to be adherent to recommendations against screening if the patient was at medium risk or requested testing, or they had been in practice for at least 10 years, Dr. Baldwin reported.

On the other hand, physicians were more likely to be adherent if they high-listed USPSTF as an information source, did not have any personal or family experience with cancer, were involved with clinical teaching, or were in a group practice.

However, when belief about the effectiveness of the screening tests was added to the other physician factors, physicians believing them to be effective were less likely to adhere to recommendations than their peers believing them to be ineffective.

Also, three of the other factors – years in practice, high-listing the USPSTF, and group practice – were no longer significantly related to adherence. "So basically, those associations were mediated by the degree to which those groups believed in the effectiveness of these tests," she explained.

"We don’t really understand why a third of physicians believe that these are effective ovarian cancer screening tests," Dr. Baldwin commented. "But use of the USPSTF recommendations, and practice in settings that promote interactions between physicians, like group practices, may help dispel misconceptions about the effectiveness of the ovarian cancer screening tests."

"Further research is definitely needed to try to understand what’s going on with these misconceptions and the contribution of potential risk assessment errors to this screening," she concluded.

Dr. Baldwin reported that she had no relevant financial conflicts of interest.

SEATTLE – Women at average risk are often screened for ovarian cancer, even though national guidelines recommend against this practice, based on a study reported at the annual meeting of the North American Primary Care Research Group.

In a cross-sectional survey of 1,088 primary care physicians presented with examples cases, 72% said they would almost never offer low-risk women transvaginal ultrasound or the cancer antigen (CA)-125 blood test, and 35% said they would almost never do so for medium-risk women.

Of concern, 30% of physicians overall said they would almost always offer or order the tests for such women.

"Screening is actually not recommended for either of these groups, suggesting that physicians are either not accurately assessing the risk or that they are choosing to offer or order the test despite recommendations to the contrary," commented lead investigator Dr. Laura-Mae Baldwin.

Besides risk assessment, a mistaken belief that the tests are effective for screening in average-risk women – endorsed by a third of the physicians – was the next strongest predictor of nonadherence to guidelines.

In fact, transvaginal ultrasound and the CA-125 test have high false-positive rates and low positive predictive values when used for ovarian cancer screening, according to Dr. Baldwin, who is a professor of family medicine and director of the Family Medicine Research Section at the University of Washington, Seattle.

"There is no professional organization or government agency that currently recommends routine ovarian cancer screening," she noted. "The U.S. Preventive Services Task Force (USPSTF) actually gives it a D grade, meaning that the harms exceed the benefits, and they recommend against the test."

"But as we know, physicians have demonstrated enthusiasm for some cancer screening tests that don’t have clear proven benefit, and we thought it might be possible that women may be exposed to the potential harms of ovarian cancer screening despite these recommendations," she said.

The investigators sent vignette-based surveys to a cross-sectional sample of U.S. primary care physicians selected from American Medical Association Physician Masterfiles.

The vignettes portrayed women at low, medium, and high risk for ovarian cancer. Respondents were asked, for the patient described, how often they would offer or order each of a list of tests for cancer screening, and were given response options of almost always, sometimes, and almost never.

"We excluded the physicians who had vignettes of women at high risk for ovarian cancer because there are some recommendations that suggest that it may be appropriate to screen in those women, so we wanted really to look at a group that had a more average risk of ovarian cancer," Dr. Baldwin explained.

Results were based on 1,088 respondents who represented a weighted sample of 106,001 physicians nationally. Some 42% were general internists, 41% were family physicians, and 17% were obstetrician-gynecologists.

Nearly three-fourths of the physicians worked in group practices. When asked about their sources of information on cancer screening, the most common were the American Cancer Society (66% listed it among their top three), the USPSTF (53%), the National Institutes of Health and National Cancer Institute (33%), and the American College of Obstetricians and Gynecologists (31%).

In a finding that Dr. Baldwin described as highly surprising, 33% of physicians believed that transvaginal ultrasound, the CA-125 test, or both were effective for ovarian cancer screening in average-risk women.

For low-risk patients, 72% of physicians were adherent to screening recommendations (defined as almost never offering or ordering either screening test); for medium-risk patients, 35% were adherent.

On the flip side, 6% of physicians said they would almost always offer or order a screening test for a low-risk patient, and 24% said they would almost always do so for a medium-risk patient.

In multivariate analyses, physicians were less likely to be adherent to recommendations against screening if the patient was at medium risk or requested testing, or they had been in practice for at least 10 years, Dr. Baldwin reported.

On the other hand, physicians were more likely to be adherent if they high-listed USPSTF as an information source, did not have any personal or family experience with cancer, were involved with clinical teaching, or were in a group practice.

However, when belief about the effectiveness of the screening tests was added to the other physician factors, physicians believing them to be effective were less likely to adhere to recommendations than their peers believing them to be ineffective.

Also, three of the other factors – years in practice, high-listing the USPSTF, and group practice – were no longer significantly related to adherence. "So basically, those associations were mediated by the degree to which those groups believed in the effectiveness of these tests," she explained.

"We don’t really understand why a third of physicians believe that these are effective ovarian cancer screening tests," Dr. Baldwin commented. "But use of the USPSTF recommendations, and practice in settings that promote interactions between physicians, like group practices, may help dispel misconceptions about the effectiveness of the ovarian cancer screening tests."

"Further research is definitely needed to try to understand what’s going on with these misconceptions and the contribution of potential risk assessment errors to this screening," she concluded.

Dr. Baldwin reported that she had no relevant financial conflicts of interest.

SEATTLE – Women at average risk are often screened for ovarian cancer, even though national guidelines recommend against this practice, based on a study reported at the annual meeting of the North American Primary Care Research Group.

In a cross-sectional survey of 1,088 primary care physicians presented with examples cases, 72% said they would almost never offer low-risk women transvaginal ultrasound or the cancer antigen (CA)-125 blood test, and 35% said they would almost never do so for medium-risk women.

Of concern, 30% of physicians overall said they would almost always offer or order the tests for such women.

"Screening is actually not recommended for either of these groups, suggesting that physicians are either not accurately assessing the risk or that they are choosing to offer or order the test despite recommendations to the contrary," commented lead investigator Dr. Laura-Mae Baldwin.

Besides risk assessment, a mistaken belief that the tests are effective for screening in average-risk women – endorsed by a third of the physicians – was the next strongest predictor of nonadherence to guidelines.

In fact, transvaginal ultrasound and the CA-125 test have high false-positive rates and low positive predictive values when used for ovarian cancer screening, according to Dr. Baldwin, who is a professor of family medicine and director of the Family Medicine Research Section at the University of Washington, Seattle.

"There is no professional organization or government agency that currently recommends routine ovarian cancer screening," she noted. "The U.S. Preventive Services Task Force (USPSTF) actually gives it a D grade, meaning that the harms exceed the benefits, and they recommend against the test."

"But as we know, physicians have demonstrated enthusiasm for some cancer screening tests that don’t have clear proven benefit, and we thought it might be possible that women may be exposed to the potential harms of ovarian cancer screening despite these recommendations," she said.

The investigators sent vignette-based surveys to a cross-sectional sample of U.S. primary care physicians selected from American Medical Association Physician Masterfiles.

The vignettes portrayed women at low, medium, and high risk for ovarian cancer. Respondents were asked, for the patient described, how often they would offer or order each of a list of tests for cancer screening, and were given response options of almost always, sometimes, and almost never.

"We excluded the physicians who had vignettes of women at high risk for ovarian cancer because there are some recommendations that suggest that it may be appropriate to screen in those women, so we wanted really to look at a group that had a more average risk of ovarian cancer," Dr. Baldwin explained.

Results were based on 1,088 respondents who represented a weighted sample of 106,001 physicians nationally. Some 42% were general internists, 41% were family physicians, and 17% were obstetrician-gynecologists.

Nearly three-fourths of the physicians worked in group practices. When asked about their sources of information on cancer screening, the most common were the American Cancer Society (66% listed it among their top three), the USPSTF (53%), the National Institutes of Health and National Cancer Institute (33%), and the American College of Obstetricians and Gynecologists (31%).

In a finding that Dr. Baldwin described as highly surprising, 33% of physicians believed that transvaginal ultrasound, the CA-125 test, or both were effective for ovarian cancer screening in average-risk women.

For low-risk patients, 72% of physicians were adherent to screening recommendations (defined as almost never offering or ordering either screening test); for medium-risk patients, 35% were adherent.

On the flip side, 6% of physicians said they would almost always offer or order a screening test for a low-risk patient, and 24% said they would almost always do so for a medium-risk patient.

In multivariate analyses, physicians were less likely to be adherent to recommendations against screening if the patient was at medium risk or requested testing, or they had been in practice for at least 10 years, Dr. Baldwin reported.

On the other hand, physicians were more likely to be adherent if they high-listed USPSTF as an information source, did not have any personal or family experience with cancer, were involved with clinical teaching, or were in a group practice.

However, when belief about the effectiveness of the screening tests was added to the other physician factors, physicians believing them to be effective were less likely to adhere to recommendations than their peers believing them to be ineffective.

Also, three of the other factors – years in practice, high-listing the USPSTF, and group practice – were no longer significantly related to adherence. "So basically, those associations were mediated by the degree to which those groups believed in the effectiveness of these tests," she explained.

"We don’t really understand why a third of physicians believe that these are effective ovarian cancer screening tests," Dr. Baldwin commented. "But use of the USPSTF recommendations, and practice in settings that promote interactions between physicians, like group practices, may help dispel misconceptions about the effectiveness of the ovarian cancer screening tests."

"Further research is definitely needed to try to understand what’s going on with these misconceptions and the contribution of potential risk assessment errors to this screening," she concluded.

Dr. Baldwin reported that she had no relevant financial conflicts of interest.

Major Finding: Statin users had a 27% lower risk of developing Parkinson's disease than did nonusers.

Data Source: A population-based historical cohort study of 94,308 patients from one region of Israel.

Disclosures: Dr. Lahad reported that he had no relevant conflicts of interest.

SEATTLE – Statin use was associated with protection against the development of Parkinson's disease in a population-based historical cohort study of 94,308 middle-aged and older adults in Israel.

Statin users, who accounted for one-third of the cohort, had a 27% lower risk of Parkinson's disease (PD), compared with nonusers, after adjustment for potential confounders.

“Statins, in addition to lowering cholesterol levels and reducing cardiovascular risk, may have a protective effect on the incidence” of PD, Dr. Amnon Lahad said at the meeting

PD, a central nervous system degenerative disease, “may react like other cardiovascular diseases in responding to statins,” he said, speculating that ischemia plays a role in its pathogenesis, much as it does for dementia. “It is probably at the level of the microvasculature. We don't really know how to test [for it], but it's there.”

Half a dozen studies have assessed the association between statins and PD in recent years, but their conclusions have been inconsistent. Most have found that statin use confers increased risk, with a subset suggesting that this association is mediated through cholesterol levels, making statins simply a confounder, said Dr. Lahad, chairman of the department of family medicine at the Hebrew University of Jerusalem.

He and his colleagues searched the database of the largest health maintenance organization in Israel to identify all patients older than 45 years in a single administrative region during 2001-2007. They excluded patients who had PD or took statins before the study period, used neuroleptic drugs at any time, changed health insurance, or did not have a record of LDL cholesterol values.

Statin use and chronic illnesses were also ascertained from the database. Family history on PD was not available, and body mass index was not used because it was inconsistently recorded, according to Dr. Lahad.

Analyses were based on 94,308 patients, he reported. The cohort was nearly equally divided by sex. About a fifth of patients had low socioeconomic status, as indicated in the database by the waiving of their copayment for prescriptions.

Substantial proportions of the cohort smoked (20%) and had diabetes (22%), hypertension (51%), or ischemic heart disease (19%), or had previously experienced a stroke (8%).

Some 32% of the patients were classified as statin users because they filled at least six monthly statin prescriptions during a 9-month period. The rest were classified as nonusers.

Overall, 1.1% of the cohort developed PD during the study period, as ascertained from their filling of at least two monthly prescriptions for an antiparkinsonian medication.

In a Cox regression analysis, the risk of PD was elevated for men compared with women (hazard ratio, 1.57; P less than .0001), for patients with low socioeconomic status compared with their better-off peers (HR, 1.33; P less than .0001), and for patients who had experienced a stroke compared with those who had not (HR, 1.96; P less than .0001).

“Surprisingly, the other diseases or conditions [hypertension, ischemic heart disease, diabetes, and smoking] were not related, even in a pretty big group,” to PD, Dr. Lahad said. “The most surprising is smoking, which in the literature is connected.”

LDL cholesterol level at baseline was not significantly associated with the risk of PD. However, there was a trend for an increased risk of PD with an LDL level greater than 100 mg/dL, and a lower risk of the disease in those with LDL levels greater than about 160 mg/dL.

When statin use was added to the analysis, statin users had a one-fourth reduction in the risk of PD relative to nonusers (HR, 0.73; P = .001), and the other significant associations persisted.

However, when the investigators accounted for statin use, the individuals with the highest LDL cholesterol levels no longer had a reduced risk of the disease. “It probably was the effect that this group got statins much more often, so it did protect them,” Dr. Lahad speculated. “And it showed, without the statin, purely the effect of the cholesterol.”

The risk of PD fell with an increasing duration of statin use (as assessed from the number of prescriptions and months of use). But in this case, the association was weaker. “It was a trend; it wasn't by itself significant,” he noted.

“Of course, it's not a randomized controlled trial,” Dr. Lahad acknowledged, so it is possible that other factors explain the observed association. “But at least we don't find the alarming finding of previous studies that show that statins are connected to an increase in morbidity.”

Major Finding: Statin users had a 27% lower risk of developing Parkinson's disease than did nonusers.

Data Source: A population-based historical cohort study of 94,308 patients from one region of Israel.

Disclosures: Dr. Lahad reported that he had no relevant conflicts of interest.

SEATTLE – Statin use was associated with protection against the development of Parkinson's disease in a population-based historical cohort study of 94,308 middle-aged and older adults in Israel.

Statin users, who accounted for one-third of the cohort, had a 27% lower risk of Parkinson's disease (PD), compared with nonusers, after adjustment for potential confounders.

“Statins, in addition to lowering cholesterol levels and reducing cardiovascular risk, may have a protective effect on the incidence” of PD, Dr. Amnon Lahad said at the meeting

PD, a central nervous system degenerative disease, “may react like other cardiovascular diseases in responding to statins,” he said, speculating that ischemia plays a role in its pathogenesis, much as it does for dementia. “It is probably at the level of the microvasculature. We don't really know how to test [for it], but it's there.”

Half a dozen studies have assessed the association between statins and PD in recent years, but their conclusions have been inconsistent. Most have found that statin use confers increased risk, with a subset suggesting that this association is mediated through cholesterol levels, making statins simply a confounder, said Dr. Lahad, chairman of the department of family medicine at the Hebrew University of Jerusalem.

He and his colleagues searched the database of the largest health maintenance organization in Israel to identify all patients older than 45 years in a single administrative region during 2001-2007. They excluded patients who had PD or took statins before the study period, used neuroleptic drugs at any time, changed health insurance, or did not have a record of LDL cholesterol values.

Statin use and chronic illnesses were also ascertained from the database. Family history on PD was not available, and body mass index was not used because it was inconsistently recorded, according to Dr. Lahad.

Analyses were based on 94,308 patients, he reported. The cohort was nearly equally divided by sex. About a fifth of patients had low socioeconomic status, as indicated in the database by the waiving of their copayment for prescriptions.

Substantial proportions of the cohort smoked (20%) and had diabetes (22%), hypertension (51%), or ischemic heart disease (19%), or had previously experienced a stroke (8%).

Some 32% of the patients were classified as statin users because they filled at least six monthly statin prescriptions during a 9-month period. The rest were classified as nonusers.

Overall, 1.1% of the cohort developed PD during the study period, as ascertained from their filling of at least two monthly prescriptions for an antiparkinsonian medication.

In a Cox regression analysis, the risk of PD was elevated for men compared with women (hazard ratio, 1.57; P less than .0001), for patients with low socioeconomic status compared with their better-off peers (HR, 1.33; P less than .0001), and for patients who had experienced a stroke compared with those who had not (HR, 1.96; P less than .0001).

“Surprisingly, the other diseases or conditions [hypertension, ischemic heart disease, diabetes, and smoking] were not related, even in a pretty big group,” to PD, Dr. Lahad said. “The most surprising is smoking, which in the literature is connected.”

LDL cholesterol level at baseline was not significantly associated with the risk of PD. However, there was a trend for an increased risk of PD with an LDL level greater than 100 mg/dL, and a lower risk of the disease in those with LDL levels greater than about 160 mg/dL.

When statin use was added to the analysis, statin users had a one-fourth reduction in the risk of PD relative to nonusers (HR, 0.73; P = .001), and the other significant associations persisted.

However, when the investigators accounted for statin use, the individuals with the highest LDL cholesterol levels no longer had a reduced risk of the disease. “It probably was the effect that this group got statins much more often, so it did protect them,” Dr. Lahad speculated. “And it showed, without the statin, purely the effect of the cholesterol.”

The risk of PD fell with an increasing duration of statin use (as assessed from the number of prescriptions and months of use). But in this case, the association was weaker. “It was a trend; it wasn't by itself significant,” he noted.

“Of course, it's not a randomized controlled trial,” Dr. Lahad acknowledged, so it is possible that other factors explain the observed association. “But at least we don't find the alarming finding of previous studies that show that statins are connected to an increase in morbidity.”

Major Finding: Statin users had a 27% lower risk of developing Parkinson's disease than did nonusers.

Data Source: A population-based historical cohort study of 94,308 patients from one region of Israel.

Disclosures: Dr. Lahad reported that he had no relevant conflicts of interest.

SEATTLE – Statin use was associated with protection against the development of Parkinson's disease in a population-based historical cohort study of 94,308 middle-aged and older adults in Israel.

Statin users, who accounted for one-third of the cohort, had a 27% lower risk of Parkinson's disease (PD), compared with nonusers, after adjustment for potential confounders.

“Statins, in addition to lowering cholesterol levels and reducing cardiovascular risk, may have a protective effect on the incidence” of PD, Dr. Amnon Lahad said at the meeting

PD, a central nervous system degenerative disease, “may react like other cardiovascular diseases in responding to statins,” he said, speculating that ischemia plays a role in its pathogenesis, much as it does for dementia. “It is probably at the level of the microvasculature. We don't really know how to test [for it], but it's there.”

Half a dozen studies have assessed the association between statins and PD in recent years, but their conclusions have been inconsistent. Most have found that statin use confers increased risk, with a subset suggesting that this association is mediated through cholesterol levels, making statins simply a confounder, said Dr. Lahad, chairman of the department of family medicine at the Hebrew University of Jerusalem.

He and his colleagues searched the database of the largest health maintenance organization in Israel to identify all patients older than 45 years in a single administrative region during 2001-2007. They excluded patients who had PD or took statins before the study period, used neuroleptic drugs at any time, changed health insurance, or did not have a record of LDL cholesterol values.

Statin use and chronic illnesses were also ascertained from the database. Family history on PD was not available, and body mass index was not used because it was inconsistently recorded, according to Dr. Lahad.

Analyses were based on 94,308 patients, he reported. The cohort was nearly equally divided by sex. About a fifth of patients had low socioeconomic status, as indicated in the database by the waiving of their copayment for prescriptions.

Substantial proportions of the cohort smoked (20%) and had diabetes (22%), hypertension (51%), or ischemic heart disease (19%), or had previously experienced a stroke (8%).

Some 32% of the patients were classified as statin users because they filled at least six monthly statin prescriptions during a 9-month period. The rest were classified as nonusers.

Overall, 1.1% of the cohort developed PD during the study period, as ascertained from their filling of at least two monthly prescriptions for an antiparkinsonian medication.

In a Cox regression analysis, the risk of PD was elevated for men compared with women (hazard ratio, 1.57; P less than .0001), for patients with low socioeconomic status compared with their better-off peers (HR, 1.33; P less than .0001), and for patients who had experienced a stroke compared with those who had not (HR, 1.96; P less than .0001).

“Surprisingly, the other diseases or conditions [hypertension, ischemic heart disease, diabetes, and smoking] were not related, even in a pretty big group,” to PD, Dr. Lahad said. “The most surprising is smoking, which in the literature is connected.”

LDL cholesterol level at baseline was not significantly associated with the risk of PD. However, there was a trend for an increased risk of PD with an LDL level greater than 100 mg/dL, and a lower risk of the disease in those with LDL levels greater than about 160 mg/dL.

When statin use was added to the analysis, statin users had a one-fourth reduction in the risk of PD relative to nonusers (HR, 0.73; P = .001), and the other significant associations persisted.

However, when the investigators accounted for statin use, the individuals with the highest LDL cholesterol levels no longer had a reduced risk of the disease. “It probably was the effect that this group got statins much more often, so it did protect them,” Dr. Lahad speculated. “And it showed, without the statin, purely the effect of the cholesterol.”

The risk of PD fell with an increasing duration of statin use (as assessed from the number of prescriptions and months of use). But in this case, the association was weaker. “It was a trend; it wasn't by itself significant,” he noted.

“Of course, it's not a randomized controlled trial,” Dr. Lahad acknowledged, so it is possible that other factors explain the observed association. “But at least we don't find the alarming finding of previous studies that show that statins are connected to an increase in morbidity.”

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 meeting.

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,” Dr. Culver 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.

'If the symptoms are relatively mild or modest … then I think observation is completely reasonable.'

Source DR. CULVER

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 meeting.

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,” Dr. Culver 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.

'If the symptoms are relatively mild or modest … then I think observation is completely reasonable.'

Source DR. CULVER

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 meeting.

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,” Dr. Culver 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.

'If the symptoms are relatively mild or modest … then I think observation is completely reasonable.'

Source DR. CULVER

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.