Diana Mahoney

SAN ANTONIO – Laparoscopic liver resection is a safe and effective option for hepatocellular carcinoma in patients with cirrhosis, a study has shown.

Multiple meta-analyses, case-cohort matched series, and single-center series have shown that laparoscopic hepatic resection (LHR) significantly reduces operative blood loss, risk of postoperative complications, duration of hospital stay, days of narcotic use, and days until oral intake, Kanazawa Akishige, Ph.D., said at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

However, cirrhotic patients with hepatocellular carcinoma (HCC) are at increased risk for complications such as perioperative hemorrhage and postoperative ascites; as a result, they may have longer hospital stays. To determine whether LHR is safe, effective, and feasible in these patients, Dr. Akishige and colleagues at Osaka City General Hospital in Japan identified 245 patients who underwent liver resection for HCC between February 2006 and August 2010.

The investigators then studied the 90 patients in the series who had complete liver cirrhosis and underwent a partial hepatectomy. Of the 90 patients, 62 underwent hepatectomy via laparotomy and 28 had LHR, Dr. Akishige said, noting that both approaches employed an ultrasonic surgical aspirator and soft coagulation. Preoperatively, the two groups had comparable liver reserve function, assessed via indocyanine green retention rate at 15 minutes (ICG R15).

The results showed no significant difference in procedure time between the two groups, however "there was significantly less blood loss during surgery in the laparoscopy group than in the laparotomy group," Dr. Akishige said, reporting that 16 patients in the open group and no patients in the minimally invasive group required transfusion of red cell concentrates.

Additionally, rates of postoperative mortality and morbidity were significantly higher in the laparotomy group. "Two patients in the open group died, and 29 [46.8%] experienced postoperative morbidity, whereas there was no mortality or morbidity in the laparoscopy group," he said.

The specific causes of morbidity in the patients who underwent the open procedure included ascites (9), biliary collection (9), surgical site infection (6), intraabdominal abscess (4), and respiratory complications (1), Dr. Akishige reported. Due in large part to the increased morbidity, the mean duration of hospital stay in the laparotomy group was 35 days, compared with 12 days in patients who underwent the laparoscopic procedure, he said.

Among the specific advantages of LHR that contributed to earlier recovery and shorter hospital stays in cirrhotic patients are the fact that the minimally invasive approach minimizes abdominal injury, improves diaphragmatic kinetics, preserves collateral venous drainage, and leads to less postoperative ascites, according to Dr. Akishige.

"Our results show that the procedure is safe and feasible for the treatment of [HCC] in patients with cirrhosis and is associated with good short-term outcomes," he said.

Dr. Akishige disclosed no relevant conflicts of interest.

SAN ANTONIO – Laparoscopic liver resection is a safe and effective option for hepatocellular carcinoma in patients with cirrhosis, a study has shown.

Multiple meta-analyses, case-cohort matched series, and single-center series have shown that laparoscopic hepatic resection (LHR) significantly reduces operative blood loss, risk of postoperative complications, duration of hospital stay, days of narcotic use, and days until oral intake, Kanazawa Akishige, Ph.D., said at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

However, cirrhotic patients with hepatocellular carcinoma (HCC) are at increased risk for complications such as perioperative hemorrhage and postoperative ascites; as a result, they may have longer hospital stays. To determine whether LHR is safe, effective, and feasible in these patients, Dr. Akishige and colleagues at Osaka City General Hospital in Japan identified 245 patients who underwent liver resection for HCC between February 2006 and August 2010.

The investigators then studied the 90 patients in the series who had complete liver cirrhosis and underwent a partial hepatectomy. Of the 90 patients, 62 underwent hepatectomy via laparotomy and 28 had LHR, Dr. Akishige said, noting that both approaches employed an ultrasonic surgical aspirator and soft coagulation. Preoperatively, the two groups had comparable liver reserve function, assessed via indocyanine green retention rate at 15 minutes (ICG R15).

The results showed no significant difference in procedure time between the two groups, however "there was significantly less blood loss during surgery in the laparoscopy group than in the laparotomy group," Dr. Akishige said, reporting that 16 patients in the open group and no patients in the minimally invasive group required transfusion of red cell concentrates.

Additionally, rates of postoperative mortality and morbidity were significantly higher in the laparotomy group. "Two patients in the open group died, and 29 [46.8%] experienced postoperative morbidity, whereas there was no mortality or morbidity in the laparoscopy group," he said.

The specific causes of morbidity in the patients who underwent the open procedure included ascites (9), biliary collection (9), surgical site infection (6), intraabdominal abscess (4), and respiratory complications (1), Dr. Akishige reported. Due in large part to the increased morbidity, the mean duration of hospital stay in the laparotomy group was 35 days, compared with 12 days in patients who underwent the laparoscopic procedure, he said.

Among the specific advantages of LHR that contributed to earlier recovery and shorter hospital stays in cirrhotic patients are the fact that the minimally invasive approach minimizes abdominal injury, improves diaphragmatic kinetics, preserves collateral venous drainage, and leads to less postoperative ascites, according to Dr. Akishige.

"Our results show that the procedure is safe and feasible for the treatment of [HCC] in patients with cirrhosis and is associated with good short-term outcomes," he said.

Dr. Akishige disclosed no relevant conflicts of interest.

SAN ANTONIO – Laparoscopic liver resection is a safe and effective option for hepatocellular carcinoma in patients with cirrhosis, a study has shown.

Multiple meta-analyses, case-cohort matched series, and single-center series have shown that laparoscopic hepatic resection (LHR) significantly reduces operative blood loss, risk of postoperative complications, duration of hospital stay, days of narcotic use, and days until oral intake, Kanazawa Akishige, Ph.D., said at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

However, cirrhotic patients with hepatocellular carcinoma (HCC) are at increased risk for complications such as perioperative hemorrhage and postoperative ascites; as a result, they may have longer hospital stays. To determine whether LHR is safe, effective, and feasible in these patients, Dr. Akishige and colleagues at Osaka City General Hospital in Japan identified 245 patients who underwent liver resection for HCC between February 2006 and August 2010.

The investigators then studied the 90 patients in the series who had complete liver cirrhosis and underwent a partial hepatectomy. Of the 90 patients, 62 underwent hepatectomy via laparotomy and 28 had LHR, Dr. Akishige said, noting that both approaches employed an ultrasonic surgical aspirator and soft coagulation. Preoperatively, the two groups had comparable liver reserve function, assessed via indocyanine green retention rate at 15 minutes (ICG R15).

The results showed no significant difference in procedure time between the two groups, however "there was significantly less blood loss during surgery in the laparoscopy group than in the laparotomy group," Dr. Akishige said, reporting that 16 patients in the open group and no patients in the minimally invasive group required transfusion of red cell concentrates.

Additionally, rates of postoperative mortality and morbidity were significantly higher in the laparotomy group. "Two patients in the open group died, and 29 [46.8%] experienced postoperative morbidity, whereas there was no mortality or morbidity in the laparoscopy group," he said.

The specific causes of morbidity in the patients who underwent the open procedure included ascites (9), biliary collection (9), surgical site infection (6), intraabdominal abscess (4), and respiratory complications (1), Dr. Akishige reported. Due in large part to the increased morbidity, the mean duration of hospital stay in the laparotomy group was 35 days, compared with 12 days in patients who underwent the laparoscopic procedure, he said.

Among the specific advantages of LHR that contributed to earlier recovery and shorter hospital stays in cirrhotic patients are the fact that the minimally invasive approach minimizes abdominal injury, improves diaphragmatic kinetics, preserves collateral venous drainage, and leads to less postoperative ascites, according to Dr. Akishige.

"Our results show that the procedure is safe and feasible for the treatment of [HCC] in patients with cirrhosis and is associated with good short-term outcomes," he said.

Dr. Akishige disclosed no relevant conflicts of interest.

SAN ANTONIO – Laparoscopic liver resection provides significant intraoperative and postoperative benefits, compared with open hepatic resection, in patients with benign and malignant tumors and it does not compromise 5-year outcomes in hepatocellular carcinoma or colorectal cancer metastases, said Dr. David A. Geller, codirector of the liver cancer center at the University of Pittsburgh Medical Center.

Not yet considered standard of care, "laparoscopic hepatic resection [LHR] has now been performed in more than 4,000 patients worldwide, and the benefits when compared with open hepatic resection [OHR] include decreased operating room time, less pain, less narcotic use, shorter length of stay, less blood loss when matched for size of tumor and extent of the operation performed, faster oral intake, and a Band-Aid–sized incision," Dr. Geller concluded from a review of the available literature. The studies included meta-analyses, case cohort matched series, and single-center series from more than 20 centers.

"Most importantly, there are no oncologic disadvantages," he said. "If we were giving patients a small incision and shortening their recovery but sacrificing margins or recurrences, then it wouldn’t be worthwhile."

The first comprehensive literature review on the LHR procedure was published in the Annals of Surgery in 2009; it showed the procedure to be "safe with acceptable morbidity and mortality for both minor and major hepatic resections," said Dr. Geller, who coauthored the study (Ann. Surg. 2009;250:842-8).

Of 2,804 minimally invasive liver resections included in that analysis, the overall mortality was 0.3%, and "morbidity was 10.5% with no intraoperative deaths," Dr. Geller reported at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

For cancer resections, which constituted 50% of the total resections, "negative surgical margins were achieved in 82%-100% of the reported series, and the overall and disease-free survival at 3 years in the colorectal metastasis patients and at 5 years in the hepatocellular carcinoma patients matched – or was better than – that seen in open liver resection series," he said.

Acknowledging the likelihood of a bias for carefully selected patients with laparoscopic procedures, "the results still confirm that in well-selected patients, and in the hands of technically skilled surgeons who have training in both minimally invasive surgery and formal liver procedures, it is a safe operation," Dr. Geller concluded.

The following studies corroborate and extend the early findings, he said:

• An updated meta-analysis of relevant studies evaluating long-term outcomes of LHR and OHR for benign and malignant tumors demonstrated that patients undergoing LHR for malignant tumors had a significantly reduced hazard ratio for death, less operative blood loss, and fewer postoperative complications than did patients in the OHR group, with no significant difference in the rate of recurrence compared with the OHR patients (Arch. Surg. 2010;145:1109-18).

• In a review of 31 case-cohort matched studies that directly compared LHR with OHR in nearly 2,500 patients, and an institutional series of 314 patients, Dr. Geller and colleagues showed that, in addition to the previously reported safety and efficacy findings and patient benefits, the minimally invasive approach was economically advantageous, despite the increased cost associated with disposable instruments, because of the reduced incidence of complications and significantly shorter hospital stays (Arch. Surg. 2011;146:348-56).

There are currently no level 1, randomized, controlled trials comparing LHR and OHR, "and there probably never will be, both because it would be difficult to accrue enough patients to detect a difference in the complications and because it’s very much patient driven, and patients are unlikely to choose to undergo the open procedure when the reported outcomes of the minimally invasive procedure have been so positive," said Dr. Geller.

"The body of literature available to date indicates that, in experienced hands, [LHR] for both benign and malignant lesions is safe and feasible, is associated with significant short-term patient benefits, is economically reasonable, and does not compromise oncologic principles." As such, he noted, "laparoscopic hepatic resection should be considered an important tool in the liver resection armamentarium."

Dr. Geller reported having no relevant financial conflicts of interest.

SAN ANTONIO – Laparoscopic liver resection provides significant intraoperative and postoperative benefits, compared with open hepatic resection, in patients with benign and malignant tumors and it does not compromise 5-year outcomes in hepatocellular carcinoma or colorectal cancer metastases, said Dr. David A. Geller, codirector of the liver cancer center at the University of Pittsburgh Medical Center.

Not yet considered standard of care, "laparoscopic hepatic resection [LHR] has now been performed in more than 4,000 patients worldwide, and the benefits when compared with open hepatic resection [OHR] include decreased operating room time, less pain, less narcotic use, shorter length of stay, less blood loss when matched for size of tumor and extent of the operation performed, faster oral intake, and a Band-Aid–sized incision," Dr. Geller concluded from a review of the available literature. The studies included meta-analyses, case cohort matched series, and single-center series from more than 20 centers.

"Most importantly, there are no oncologic disadvantages," he said. "If we were giving patients a small incision and shortening their recovery but sacrificing margins or recurrences, then it wouldn’t be worthwhile."

The first comprehensive literature review on the LHR procedure was published in the Annals of Surgery in 2009; it showed the procedure to be "safe with acceptable morbidity and mortality for both minor and major hepatic resections," said Dr. Geller, who coauthored the study (Ann. Surg. 2009;250:842-8).

Of 2,804 minimally invasive liver resections included in that analysis, the overall mortality was 0.3%, and "morbidity was 10.5% with no intraoperative deaths," Dr. Geller reported at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

For cancer resections, which constituted 50% of the total resections, "negative surgical margins were achieved in 82%-100% of the reported series, and the overall and disease-free survival at 3 years in the colorectal metastasis patients and at 5 years in the hepatocellular carcinoma patients matched – or was better than – that seen in open liver resection series," he said.

Acknowledging the likelihood of a bias for carefully selected patients with laparoscopic procedures, "the results still confirm that in well-selected patients, and in the hands of technically skilled surgeons who have training in both minimally invasive surgery and formal liver procedures, it is a safe operation," Dr. Geller concluded.

The following studies corroborate and extend the early findings, he said:

• An updated meta-analysis of relevant studies evaluating long-term outcomes of LHR and OHR for benign and malignant tumors demonstrated that patients undergoing LHR for malignant tumors had a significantly reduced hazard ratio for death, less operative blood loss, and fewer postoperative complications than did patients in the OHR group, with no significant difference in the rate of recurrence compared with the OHR patients (Arch. Surg. 2010;145:1109-18).

• In a review of 31 case-cohort matched studies that directly compared LHR with OHR in nearly 2,500 patients, and an institutional series of 314 patients, Dr. Geller and colleagues showed that, in addition to the previously reported safety and efficacy findings and patient benefits, the minimally invasive approach was economically advantageous, despite the increased cost associated with disposable instruments, because of the reduced incidence of complications and significantly shorter hospital stays (Arch. Surg. 2011;146:348-56).

There are currently no level 1, randomized, controlled trials comparing LHR and OHR, "and there probably never will be, both because it would be difficult to accrue enough patients to detect a difference in the complications and because it’s very much patient driven, and patients are unlikely to choose to undergo the open procedure when the reported outcomes of the minimally invasive procedure have been so positive," said Dr. Geller.

"The body of literature available to date indicates that, in experienced hands, [LHR] for both benign and malignant lesions is safe and feasible, is associated with significant short-term patient benefits, is economically reasonable, and does not compromise oncologic principles." As such, he noted, "laparoscopic hepatic resection should be considered an important tool in the liver resection armamentarium."

Dr. Geller reported having no relevant financial conflicts of interest.

SAN ANTONIO – Laparoscopic liver resection provides significant intraoperative and postoperative benefits, compared with open hepatic resection, in patients with benign and malignant tumors and it does not compromise 5-year outcomes in hepatocellular carcinoma or colorectal cancer metastases, said Dr. David A. Geller, codirector of the liver cancer center at the University of Pittsburgh Medical Center.

Not yet considered standard of care, "laparoscopic hepatic resection [LHR] has now been performed in more than 4,000 patients worldwide, and the benefits when compared with open hepatic resection [OHR] include decreased operating room time, less pain, less narcotic use, shorter length of stay, less blood loss when matched for size of tumor and extent of the operation performed, faster oral intake, and a Band-Aid–sized incision," Dr. Geller concluded from a review of the available literature. The studies included meta-analyses, case cohort matched series, and single-center series from more than 20 centers.

"Most importantly, there are no oncologic disadvantages," he said. "If we were giving patients a small incision and shortening their recovery but sacrificing margins or recurrences, then it wouldn’t be worthwhile."

The first comprehensive literature review on the LHR procedure was published in the Annals of Surgery in 2009; it showed the procedure to be "safe with acceptable morbidity and mortality for both minor and major hepatic resections," said Dr. Geller, who coauthored the study (Ann. Surg. 2009;250:842-8).

Of 2,804 minimally invasive liver resections included in that analysis, the overall mortality was 0.3%, and "morbidity was 10.5% with no intraoperative deaths," Dr. Geller reported at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

For cancer resections, which constituted 50% of the total resections, "negative surgical margins were achieved in 82%-100% of the reported series, and the overall and disease-free survival at 3 years in the colorectal metastasis patients and at 5 years in the hepatocellular carcinoma patients matched – or was better than – that seen in open liver resection series," he said.

Acknowledging the likelihood of a bias for carefully selected patients with laparoscopic procedures, "the results still confirm that in well-selected patients, and in the hands of technically skilled surgeons who have training in both minimally invasive surgery and formal liver procedures, it is a safe operation," Dr. Geller concluded.

The following studies corroborate and extend the early findings, he said:

• An updated meta-analysis of relevant studies evaluating long-term outcomes of LHR and OHR for benign and malignant tumors demonstrated that patients undergoing LHR for malignant tumors had a significantly reduced hazard ratio for death, less operative blood loss, and fewer postoperative complications than did patients in the OHR group, with no significant difference in the rate of recurrence compared with the OHR patients (Arch. Surg. 2010;145:1109-18).

• In a review of 31 case-cohort matched studies that directly compared LHR with OHR in nearly 2,500 patients, and an institutional series of 314 patients, Dr. Geller and colleagues showed that, in addition to the previously reported safety and efficacy findings and patient benefits, the minimally invasive approach was economically advantageous, despite the increased cost associated with disposable instruments, because of the reduced incidence of complications and significantly shorter hospital stays (Arch. Surg. 2011;146:348-56).

There are currently no level 1, randomized, controlled trials comparing LHR and OHR, "and there probably never will be, both because it would be difficult to accrue enough patients to detect a difference in the complications and because it’s very much patient driven, and patients are unlikely to choose to undergo the open procedure when the reported outcomes of the minimally invasive procedure have been so positive," said Dr. Geller.

"The body of literature available to date indicates that, in experienced hands, [LHR] for both benign and malignant lesions is safe and feasible, is associated with significant short-term patient benefits, is economically reasonable, and does not compromise oncologic principles." As such, he noted, "laparoscopic hepatic resection should be considered an important tool in the liver resection armamentarium."

Dr. Geller reported having no relevant financial conflicts of interest.

SAN ANTONIO – Laparoscopic liver resection provides significant intraoperative and postoperative benefits, compared with open hepatic resection, in patients with benign and malignant tumors and it does not compromise 5-year outcomes in hepatocellular carcinoma or colorectal cancer metastases, said Dr. David A. Geller, codirector of the liver cancer center at the University of Pittsburgh Medical Center.

Not yet considered standard of care, "laparoscopic hepatic resection [LHR] has now been performed in more than 4,000 patients worldwide, and the benefits when compared with open hepatic resection [OHR] include decreased operating room time, less pain, less narcotic use, shorter length of stay, less blood loss when matched for size of tumor and extent of the operation performed, faster oral intake, and a Band-Aid–sized incision," Dr. Geller concluded from a review of the available literature. The studies included meta-analyses, case cohort matched series, and single-center series from more than 20 centers.

"Most importantly, there are no oncologic disadvantages," he said. "If we were giving patients a small incision and shortening their recovery but sacrificing margins or recurrences, then it wouldn’t be worthwhile."

The first comprehensive literature review on the LHR procedure was published in the Annals of Surgery in 2009; it showed the procedure to be "safe with acceptable morbidity and mortality for both minor and major hepatic resections," said Dr. Geller, who coauthored the study (Ann. Surg. 2009;250:842-8).

Of 2,804 minimally invasive liver resections included in that analysis, the overall mortality was 0.3%, and "morbidity was 10.5% with no intraoperative deaths," Dr. Geller reported at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

For cancer resections, which constituted 50% of the total resections, "negative surgical margins were achieved in 82%-100% of the reported series, and the overall and disease-free survival at 3 years in the colorectal metastasis patients and at 5 years in the hepatocellular carcinoma patients matched – or was better than – that seen in open liver resection series," he said.

Acknowledging the likelihood of a bias for carefully selected patients with laparoscopic procedures, "the results still confirm that in well-selected patients, and in the hands of technically skilled surgeons who have training in both minimally invasive surgery and formal liver procedures, it is a safe operation," Dr. Geller concluded.

The following studies corroborate and extend the early findings, he said:

• An updated meta-analysis of relevant studies evaluating long-term outcomes of LHR and OHR for benign and malignant tumors demonstrated that patients undergoing LHR for malignant tumors had a significantly reduced hazard ratio for death, less operative blood loss, and fewer postoperative complications than did patients in the OHR group, with no significant difference in the rate of recurrence compared with the OHR patients (Arch. Surg. 2010;145:1109-18).

• In a review of 31 case-cohort matched studies that directly compared LHR with OHR in nearly 2,500 patients, and an institutional series of 314 patients, Dr. Geller and colleagues showed that, in addition to the previously reported safety and efficacy findings and patient benefits, the minimally invasive approach was economically advantageous, despite the increased cost associated with disposable instruments, because of the reduced incidence of complications and significantly shorter hospital stays (Arch. Surg. 2011;146:348-56).

There are currently no level 1, randomized, controlled trials comparing LHR and OHR, "and there probably never will be, both because it would be difficult to accrue enough patients to detect a difference in the complications and because it’s very much patient driven, and patients are unlikely to choose to undergo the open procedure when the reported outcomes of the minimally invasive procedure have been so positive," said Dr. Geller.

"The body of literature available to date indicates that, in experienced hands, [LHR] for both benign and malignant lesions is safe and feasible, is associated with significant short-term patient benefits, is economically reasonable, and does not compromise oncologic principles." As such, he noted, "laparoscopic hepatic resection should be considered an important tool in the liver resection armamentarium."

Dr. Geller reported having no relevant financial conflicts of interest.

SAN ANTONIO – Laparoscopic liver resection provides significant intraoperative and postoperative benefits, compared with open hepatic resection, in patients with benign and malignant tumors and it does not compromise 5-year outcomes in hepatocellular carcinoma or colorectal cancer metastases, said Dr. David A. Geller, codirector of the liver cancer center at the University of Pittsburgh Medical Center.

Not yet considered standard of care, "laparoscopic hepatic resection [LHR] has now been performed in more than 4,000 patients worldwide, and the benefits when compared with open hepatic resection [OHR] include decreased operating room time, less pain, less narcotic use, shorter length of stay, less blood loss when matched for size of tumor and extent of the operation performed, faster oral intake, and a Band-Aid–sized incision," Dr. Geller concluded from a review of the available literature. The studies included meta-analyses, case cohort matched series, and single-center series from more than 20 centers.

"Most importantly, there are no oncologic disadvantages," he said. "If we were giving patients a small incision and shortening their recovery but sacrificing margins or recurrences, then it wouldn’t be worthwhile."

The first comprehensive literature review on the LHR procedure was published in the Annals of Surgery in 2009; it showed the procedure to be "safe with acceptable morbidity and mortality for both minor and major hepatic resections," said Dr. Geller, who coauthored the study (Ann. Surg. 2009;250:842-8).

Of 2,804 minimally invasive liver resections included in that analysis, the overall mortality was 0.3%, and "morbidity was 10.5% with no intraoperative deaths," Dr. Geller reported at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

For cancer resections, which constituted 50% of the total resections, "negative surgical margins were achieved in 82%-100% of the reported series, and the overall and disease-free survival at 3 years in the colorectal metastasis patients and at 5 years in the hepatocellular carcinoma patients matched – or was better than – that seen in open liver resection series," he said.

Acknowledging the likelihood of a bias for carefully selected patients with laparoscopic procedures, "the results still confirm that in well-selected patients, and in the hands of technically skilled surgeons who have training in both minimally invasive surgery and formal liver procedures, it is a safe operation," Dr. Geller concluded.

The following studies corroborate and extend the early findings, he said:

• An updated meta-analysis of relevant studies evaluating long-term outcomes of LHR and OHR for benign and malignant tumors demonstrated that patients undergoing LHR for malignant tumors had a significantly reduced hazard ratio for death, less operative blood loss, and fewer postoperative complications than did patients in the OHR group, with no significant difference in the rate of recurrence compared with the OHR patients (Arch. Surg. 2010;145:1109-18).

• In a review of 31 case-cohort matched studies that directly compared LHR with OHR in nearly 2,500 patients, and an institutional series of 314 patients, Dr. Geller and colleagues showed that, in addition to the previously reported safety and efficacy findings and patient benefits, the minimally invasive approach was economically advantageous, despite the increased cost associated with disposable instruments, because of the reduced incidence of complications and significantly shorter hospital stays (Arch. Surg. 2011;146:348-56).

There are currently no level 1, randomized, controlled trials comparing LHR and OHR, "and there probably never will be, both because it would be difficult to accrue enough patients to detect a difference in the complications and because it’s very much patient driven, and patients are unlikely to choose to undergo the open procedure when the reported outcomes of the minimally invasive procedure have been so positive," said Dr. Geller.

"The body of literature available to date indicates that, in experienced hands, [LHR] for both benign and malignant lesions is safe and feasible, is associated with significant short-term patient benefits, is economically reasonable, and does not compromise oncologic principles." As such, he noted, "laparoscopic hepatic resection should be considered an important tool in the liver resection armamentarium."

Dr. Geller reported having no relevant financial conflicts of interest.

SAN ANTONIO – Laparoscopic liver resection provides significant intraoperative and postoperative benefits, compared with open hepatic resection, in patients with benign and malignant tumors and it does not compromise 5-year outcomes in hepatocellular carcinoma or colorectal cancer metastases, said Dr. David A. Geller, codirector of the liver cancer center at the University of Pittsburgh Medical Center.

Not yet considered standard of care, "laparoscopic hepatic resection [LHR] has now been performed in more than 4,000 patients worldwide, and the benefits when compared with open hepatic resection [OHR] include decreased operating room time, less pain, less narcotic use, shorter length of stay, less blood loss when matched for size of tumor and extent of the operation performed, faster oral intake, and a Band-Aid–sized incision," Dr. Geller concluded from a review of the available literature. The studies included meta-analyses, case cohort matched series, and single-center series from more than 20 centers.

"Most importantly, there are no oncologic disadvantages," he said. "If we were giving patients a small incision and shortening their recovery but sacrificing margins or recurrences, then it wouldn’t be worthwhile."

The first comprehensive literature review on the LHR procedure was published in the Annals of Surgery in 2009; it showed the procedure to be "safe with acceptable morbidity and mortality for both minor and major hepatic resections," said Dr. Geller, who coauthored the study (Ann. Surg. 2009;250:842-8).

Of 2,804 minimally invasive liver resections included in that analysis, the overall mortality was 0.3%, and "morbidity was 10.5% with no intraoperative deaths," Dr. Geller reported at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons.

For cancer resections, which constituted 50% of the total resections, "negative surgical margins were achieved in 82%-100% of the reported series, and the overall and disease-free survival at 3 years in the colorectal metastasis patients and at 5 years in the hepatocellular carcinoma patients matched – or was better than – that seen in open liver resection series," he said.

Acknowledging the likelihood of a bias for carefully selected patients with laparoscopic procedures, "the results still confirm that in well-selected patients, and in the hands of technically skilled surgeons who have training in both minimally invasive surgery and formal liver procedures, it is a safe operation," Dr. Geller concluded.

The following studies corroborate and extend the early findings, he said:

• An updated meta-analysis of relevant studies evaluating long-term outcomes of LHR and OHR for benign and malignant tumors demonstrated that patients undergoing LHR for malignant tumors had a significantly reduced hazard ratio for death, less operative blood loss, and fewer postoperative complications than did patients in the OHR group, with no significant difference in the rate of recurrence compared with the OHR patients (Arch. Surg. 2010;145:1109-18).

• In a review of 31 case-cohort matched studies that directly compared LHR with OHR in nearly 2,500 patients, and an institutional series of 314 patients, Dr. Geller and colleagues showed that, in addition to the previously reported safety and efficacy findings and patient benefits, the minimally invasive approach was economically advantageous, despite the increased cost associated with disposable instruments, because of the reduced incidence of complications and significantly shorter hospital stays (Arch. Surg. 2011;146:348-56).

There are currently no level 1, randomized, controlled trials comparing LHR and OHR, "and there probably never will be, both because it would be difficult to accrue enough patients to detect a difference in the complications and because it’s very much patient driven, and patients are unlikely to choose to undergo the open procedure when the reported outcomes of the minimally invasive procedure have been so positive," said Dr. Geller.

"The body of literature available to date indicates that, in experienced hands, [LHR] for both benign and malignant lesions is safe and feasible, is associated with significant short-term patient benefits, is economically reasonable, and does not compromise oncologic principles." As such, he noted, "laparoscopic hepatic resection should be considered an important tool in the liver resection armamentarium."

Dr. Geller reported having no relevant financial conflicts of interest.

Testing for epidermal growth factor receptor mutations is an important step in the evaluation process for systemic therapy in patients with metastatic or recurrent non–small cell lung cancer according to updated recommendations issued by the American Society of Clinical Oncology and the National Comprehensive Cancer Network.

ASCO issued a provisional clinical opinion (PCO) on April 7 that patients with advanced non–small cell lung cancer (NSCLC) who are being considered for treatment with one of the tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR) should undergo EGFR-mutation testing.

Oncologists have learned that NSCLC is "really a collection of genetically distinct diseases," ASCO’s PCO panel cochair Dr. Vicki L. Keedy of Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said in a press release. The goal is to "treat patients with drugs that target the molecular drivers of their specific tumors rather than using a one-size-fits-all approach."

The NCCN earlier updated its clinical management guidelines to include a category 1 recommendation that EGFR testing should be undertaken after histologic diagnosis of adenocarcinoma, large cell carcinoma, or undifferentiated carcinoma.

The NCCN recommendation does not extend to patients with squamous cell lung cancer, because the incidence of EGFR mutation in this patient subgroup is less than 3.6%, Dr. David S. Ettinger said in March at the organization’s annual conference.

Both groups based their endorsements on studies demonstrating that mutations in two regions of EGFR gene appear to predict tumor response to chemotherapy in general, and to TKIs specifically.

Among the research priorities that were identified by ASCO, Dr. Keedy noted the trials that are designed to discern whether first-line treatment with a TKI in EGFR mutation–negative patients delays chemotherapy or affects outcome; whether chemotherapy prior to TKI treatment in EGFR mutation–positive patients affects outcome; and whether there are clinically significant differences between erlotinib (Tarceva) and gefitinib (Iressa) among EGFR mutation–positive patients.

The last question is of particular interest, because gefitinib is not Food and Drug Administration approved outside a special program in the United States, whereas erlotinib is currently approved as second-line therapy, she said.

Dr. Ettinger, chair of the NCCN’s NSCLC guideline panel and professor of oncology at Johns Hopkins University in Baltimore, cited findings from the landmark IPASS (Iressa Pan-Asia Study) investigation that compared progression-free and overall survival in 1,217 East Asian patients with advanced NSCLC that was treated with the gefitinib or standard carboplatin and paclitaxel chemotherapy.

IPASS demonstrated that EGFR mutation strongly predicted a lower risk of progression on gefitinib vs. chemotherapy (hazard ratio, 0.48), whereas wild-type EGFR predicted a higher risk of progression on gefitinib relative to chemotherapy (HR, 2.85) (N. Engl. J. Med. 2009;361:947-57).

Similarly, in a pooled analysis of clinical outcomes of NSCLC patients who were treated with erlotinib, EGFR mutations were associated with a median progression-free survival of 13.2 vs. 5.9 months (J. Cell. Mol. Med. 2010;14:51-69). Neither study demonstrated a difference in overall survival among treated patients with and without EGFR mutations, Dr. Ettinger said.

The updated NCCN guidelines also state that the sequencing of KRAS (a G protein involved in the EGFR-related signal transmission) could be useful for the selection of patients as candidates for TKI therapy. The KRAS gene can harbor oncogenic mutations that may render a tumor resistant to EGFR-targeting agents, Dr. Ettinger explained, noting that studies have shown that a KRAS mutation in patients with NSCLC "confers a high level of resistance" to TKIs.

Although the data – which primarily come from retrospective reviews with small sample sizes – are insufficient to make a determination about an association between KRAS mutation status and survival, he said, they are sufficient to warrant a category 2A recommendation for sequencing, as well as a recommendation that patients with a known KRAS mutation should undergo first-line therapy with an agent other than a TKI.

Individuals who test negative for EGFR and KRAS should also be screened for a mutation of the anaplastic lymphoma kinase (ALK) fusion gene, Dr. Ettinger said. "Patients who screen positive may not benefit from EGFR TKIs, but they may be good candidates for an ALK-targeted therapy," he said, noting that the investigational ALK-targeting drug crizotinib, in particular, has demonstrated positive results in early studies of NSCLC patients with echinoderm microtubule-associated proteinlike 4 (EML4)-ALK translocations (N. Engl. J. Med. 2010;363:1693-703).

With respect to first-line systemic therapy, patients with adenocarcinoma, large cell carcinoma, or NSCLC "not otherwise specified" who have an Eastern Cooperative Oncology Group/World Health Organization performance status grade of 0-4 and who test positive for the EGFR mutation prior to first-line therapy should be treated with erlotinib, according to the NCCN guidelines. Alternatively, the guidelines state that gefitinib can be used in place of erlotinib "in areas of the world where it is available."

For patients in whom the EGFR mutation is discovered during chemotherapy, the guidelines recommend either adding erlotinib to the current chemotherapy protocol or switching to erlotinib as maintenance treatment."

For patients whose EGFR status is negative or unknown, even in the presence of clinical characteristics that might be suggestive of a mutation (for example, female, nonsmoker, Asian race), conventional chemotherapy is recommended, Dr. Ettinger said.

The updated NCCN guidelines for NSCLC are posted at www.nccn.org.

The guidelines take a conservative stance on the National Lung Screening Trial finding that screening with low-dose helical CT was associated with a 20% reduction in lung cancer deaths vs. screening with standard chest x-ray. Despite this positive finding, "the NCCN panel does not recommend the routine use of screening CT as a standard clinical practice," said Dr. Ettinger; more conclusive data from ongoing national trials are needed to define the associated risks and benefits. "High-risk patients should participate in a clinical trial evaluating CT screening or go to a center of excellence to discuss the potential risks and benefits of a screening CT," Dr. Ettinger said.

Other notable updates include the following:

• The addition of EBUS (endobronchial ultrasound) as a work-up recommendation.

• The recommendation that bevacizumab (Avastin) and chemotherapy or chemotherapy alone is indicated in performance status 0-1 patients with advanced or recurrent NSCLC, and that bevacizumab should be given until disease progression.

• The recommendation against systemic chemotherapy in performance status 3-4 NSCLC patients.

• The guidance that chemoradiation is better than chemotherapy alone in locally advanced NSCLC, and that concurrent chemoradiation is better than sequential chemoradiation.

• The addition of denosumab (Xgeva) as a treatment option for patients with bone metastases.

• The recommendation favoring cisplatin/pemetrexed (Alimta) vs. cisplatin/gemcitabine (Gemzar) in patients with nonsquamous histology.

• The recommendation against adding a third cytotoxic drug, with the exception of bevacizumab or cetuximab (Erbitux), in treatment-naive performance status 0-1 NSCLC patients.

• The guidance that cisplatin-based combinations are better than best supportive care in advanced, incurable disease, with improvement in median survival and 1-year survival rates.

The ASCO PCO is available online.

In an editorial that accompanied ASCO’s PCO announcement, Dr. Paul A. Bunn Jr. and Dr. Robert C. Doebele of the University of Colorado Cancer Center in Aurora wrote that the growing clinical importance of molecularly defined subgroups of adenocarcinoma signals a "new era of personalized medicine for patients with advanced lung cancer, in which it will be imperative to match the specific mutations of a patient’s tumor with a specific therapy."

The implementation of routine, simultaneous testing of multiple markers will likely be conducted on all patients prior to treatment initiation, regardless of clinical features, they stated, acknowledging certain procedural challenges, including obtaining adequate tumor material at the time of diagnostic biopsy and developing testing platforms "that simultaneously analyze for the presence of somatic mutations, gene fusions, or other genetic challenges."

Dr. Ettinger has consultancy agreements with the following companies: Biodesix, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Genentech, Merck, Novartis Pharmaceuticals, Poniard Pharmaceuticals, Prometheus Laboratories, Shin Nippon Biomedical Laboratories, and Telik. Dr. Keedy receives commercial research support from Ariad Pharmaceuticals, Ziopharm Oncology, and Amgen Oncology Therapeutics. Dr. Bunn has a consultant or advisory role with Amgen, AstraZeneca, Abraxis, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Syndax, Biodesix, Allos Therapeutics, Novartis, OSI/Genentech/Roche, Poniard, and Sanofi-Aventis. Dr. Doebele disclosed research funding from Lilly, ImClone Systems, and Pfizer.

Testing for epidermal growth factor receptor mutations is an important step in the evaluation process for systemic therapy in patients with metastatic or recurrent non–small cell lung cancer according to updated recommendations issued by the American Society of Clinical Oncology and the National Comprehensive Cancer Network.

ASCO issued a provisional clinical opinion (PCO) on April 7 that patients with advanced non–small cell lung cancer (NSCLC) who are being considered for treatment with one of the tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR) should undergo EGFR-mutation testing.

Oncologists have learned that NSCLC is "really a collection of genetically distinct diseases," ASCO’s PCO panel cochair Dr. Vicki L. Keedy of Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said in a press release. The goal is to "treat patients with drugs that target the molecular drivers of their specific tumors rather than using a one-size-fits-all approach."

The NCCN earlier updated its clinical management guidelines to include a category 1 recommendation that EGFR testing should be undertaken after histologic diagnosis of adenocarcinoma, large cell carcinoma, or undifferentiated carcinoma.

The NCCN recommendation does not extend to patients with squamous cell lung cancer, because the incidence of EGFR mutation in this patient subgroup is less than 3.6%, Dr. David S. Ettinger said in March at the organization’s annual conference.

Both groups based their endorsements on studies demonstrating that mutations in two regions of EGFR gene appear to predict tumor response to chemotherapy in general, and to TKIs specifically.

Among the research priorities that were identified by ASCO, Dr. Keedy noted the trials that are designed to discern whether first-line treatment with a TKI in EGFR mutation–negative patients delays chemotherapy or affects outcome; whether chemotherapy prior to TKI treatment in EGFR mutation–positive patients affects outcome; and whether there are clinically significant differences between erlotinib (Tarceva) and gefitinib (Iressa) among EGFR mutation–positive patients.

The last question is of particular interest, because gefitinib is not Food and Drug Administration approved outside a special program in the United States, whereas erlotinib is currently approved as second-line therapy, she said.

Dr. Ettinger, chair of the NCCN’s NSCLC guideline panel and professor of oncology at Johns Hopkins University in Baltimore, cited findings from the landmark IPASS (Iressa Pan-Asia Study) investigation that compared progression-free and overall survival in 1,217 East Asian patients with advanced NSCLC that was treated with the gefitinib or standard carboplatin and paclitaxel chemotherapy.

IPASS demonstrated that EGFR mutation strongly predicted a lower risk of progression on gefitinib vs. chemotherapy (hazard ratio, 0.48), whereas wild-type EGFR predicted a higher risk of progression on gefitinib relative to chemotherapy (HR, 2.85) (N. Engl. J. Med. 2009;361:947-57).

Similarly, in a pooled analysis of clinical outcomes of NSCLC patients who were treated with erlotinib, EGFR mutations were associated with a median progression-free survival of 13.2 vs. 5.9 months (J. Cell. Mol. Med. 2010;14:51-69). Neither study demonstrated a difference in overall survival among treated patients with and without EGFR mutations, Dr. Ettinger said.

The updated NCCN guidelines also state that the sequencing of KRAS (a G protein involved in the EGFR-related signal transmission) could be useful for the selection of patients as candidates for TKI therapy. The KRAS gene can harbor oncogenic mutations that may render a tumor resistant to EGFR-targeting agents, Dr. Ettinger explained, noting that studies have shown that a KRAS mutation in patients with NSCLC "confers a high level of resistance" to TKIs.

Although the data – which primarily come from retrospective reviews with small sample sizes – are insufficient to make a determination about an association between KRAS mutation status and survival, he said, they are sufficient to warrant a category 2A recommendation for sequencing, as well as a recommendation that patients with a known KRAS mutation should undergo first-line therapy with an agent other than a TKI.

Individuals who test negative for EGFR and KRAS should also be screened for a mutation of the anaplastic lymphoma kinase (ALK) fusion gene, Dr. Ettinger said. "Patients who screen positive may not benefit from EGFR TKIs, but they may be good candidates for an ALK-targeted therapy," he said, noting that the investigational ALK-targeting drug crizotinib, in particular, has demonstrated positive results in early studies of NSCLC patients with echinoderm microtubule-associated proteinlike 4 (EML4)-ALK translocations (N. Engl. J. Med. 2010;363:1693-703).

With respect to first-line systemic therapy, patients with adenocarcinoma, large cell carcinoma, or NSCLC "not otherwise specified" who have an Eastern Cooperative Oncology Group/World Health Organization performance status grade of 0-4 and who test positive for the EGFR mutation prior to first-line therapy should be treated with erlotinib, according to the NCCN guidelines. Alternatively, the guidelines state that gefitinib can be used in place of erlotinib "in areas of the world where it is available."

For patients in whom the EGFR mutation is discovered during chemotherapy, the guidelines recommend either adding erlotinib to the current chemotherapy protocol or switching to erlotinib as maintenance treatment."

For patients whose EGFR status is negative or unknown, even in the presence of clinical characteristics that might be suggestive of a mutation (for example, female, nonsmoker, Asian race), conventional chemotherapy is recommended, Dr. Ettinger said.

The updated NCCN guidelines for NSCLC are posted at www.nccn.org.

The guidelines take a conservative stance on the National Lung Screening Trial finding that screening with low-dose helical CT was associated with a 20% reduction in lung cancer deaths vs. screening with standard chest x-ray. Despite this positive finding, "the NCCN panel does not recommend the routine use of screening CT as a standard clinical practice," said Dr. Ettinger; more conclusive data from ongoing national trials are needed to define the associated risks and benefits. "High-risk patients should participate in a clinical trial evaluating CT screening or go to a center of excellence to discuss the potential risks and benefits of a screening CT," Dr. Ettinger said.

Other notable updates include the following:

• The addition of EBUS (endobronchial ultrasound) as a work-up recommendation.

• The recommendation that bevacizumab (Avastin) and chemotherapy or chemotherapy alone is indicated in performance status 0-1 patients with advanced or recurrent NSCLC, and that bevacizumab should be given until disease progression.

• The recommendation against systemic chemotherapy in performance status 3-4 NSCLC patients.

• The guidance that chemoradiation is better than chemotherapy alone in locally advanced NSCLC, and that concurrent chemoradiation is better than sequential chemoradiation.

• The addition of denosumab (Xgeva) as a treatment option for patients with bone metastases.

• The recommendation favoring cisplatin/pemetrexed (Alimta) vs. cisplatin/gemcitabine (Gemzar) in patients with nonsquamous histology.

• The recommendation against adding a third cytotoxic drug, with the exception of bevacizumab or cetuximab (Erbitux), in treatment-naive performance status 0-1 NSCLC patients.

• The guidance that cisplatin-based combinations are better than best supportive care in advanced, incurable disease, with improvement in median survival and 1-year survival rates.

The ASCO PCO is available online.

In an editorial that accompanied ASCO’s PCO announcement, Dr. Paul A. Bunn Jr. and Dr. Robert C. Doebele of the University of Colorado Cancer Center in Aurora wrote that the growing clinical importance of molecularly defined subgroups of adenocarcinoma signals a "new era of personalized medicine for patients with advanced lung cancer, in which it will be imperative to match the specific mutations of a patient’s tumor with a specific therapy."

The implementation of routine, simultaneous testing of multiple markers will likely be conducted on all patients prior to treatment initiation, regardless of clinical features, they stated, acknowledging certain procedural challenges, including obtaining adequate tumor material at the time of diagnostic biopsy and developing testing platforms "that simultaneously analyze for the presence of somatic mutations, gene fusions, or other genetic challenges."

Dr. Ettinger has consultancy agreements with the following companies: Biodesix, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Genentech, Merck, Novartis Pharmaceuticals, Poniard Pharmaceuticals, Prometheus Laboratories, Shin Nippon Biomedical Laboratories, and Telik. Dr. Keedy receives commercial research support from Ariad Pharmaceuticals, Ziopharm Oncology, and Amgen Oncology Therapeutics. Dr. Bunn has a consultant or advisory role with Amgen, AstraZeneca, Abraxis, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Syndax, Biodesix, Allos Therapeutics, Novartis, OSI/Genentech/Roche, Poniard, and Sanofi-Aventis. Dr. Doebele disclosed research funding from Lilly, ImClone Systems, and Pfizer.

Testing for epidermal growth factor receptor mutations is an important step in the evaluation process for systemic therapy in patients with metastatic or recurrent non–small cell lung cancer according to updated recommendations issued by the American Society of Clinical Oncology and the National Comprehensive Cancer Network.

ASCO issued a provisional clinical opinion (PCO) on April 7 that patients with advanced non–small cell lung cancer (NSCLC) who are being considered for treatment with one of the tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR) should undergo EGFR-mutation testing.

Oncologists have learned that NSCLC is "really a collection of genetically distinct diseases," ASCO’s PCO panel cochair Dr. Vicki L. Keedy of Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said in a press release. The goal is to "treat patients with drugs that target the molecular drivers of their specific tumors rather than using a one-size-fits-all approach."

The NCCN earlier updated its clinical management guidelines to include a category 1 recommendation that EGFR testing should be undertaken after histologic diagnosis of adenocarcinoma, large cell carcinoma, or undifferentiated carcinoma.

The NCCN recommendation does not extend to patients with squamous cell lung cancer, because the incidence of EGFR mutation in this patient subgroup is less than 3.6%, Dr. David S. Ettinger said in March at the organization’s annual conference.

Both groups based their endorsements on studies demonstrating that mutations in two regions of EGFR gene appear to predict tumor response to chemotherapy in general, and to TKIs specifically.

Among the research priorities that were identified by ASCO, Dr. Keedy noted the trials that are designed to discern whether first-line treatment with a TKI in EGFR mutation–negative patients delays chemotherapy or affects outcome; whether chemotherapy prior to TKI treatment in EGFR mutation–positive patients affects outcome; and whether there are clinically significant differences between erlotinib (Tarceva) and gefitinib (Iressa) among EGFR mutation–positive patients.

The last question is of particular interest, because gefitinib is not Food and Drug Administration approved outside a special program in the United States, whereas erlotinib is currently approved as second-line therapy, she said.

Dr. Ettinger, chair of the NCCN’s NSCLC guideline panel and professor of oncology at Johns Hopkins University in Baltimore, cited findings from the landmark IPASS (Iressa Pan-Asia Study) investigation that compared progression-free and overall survival in 1,217 East Asian patients with advanced NSCLC that was treated with the gefitinib or standard carboplatin and paclitaxel chemotherapy.

IPASS demonstrated that EGFR mutation strongly predicted a lower risk of progression on gefitinib vs. chemotherapy (hazard ratio, 0.48), whereas wild-type EGFR predicted a higher risk of progression on gefitinib relative to chemotherapy (HR, 2.85) (N. Engl. J. Med. 2009;361:947-57).

Similarly, in a pooled analysis of clinical outcomes of NSCLC patients who were treated with erlotinib, EGFR mutations were associated with a median progression-free survival of 13.2 vs. 5.9 months (J. Cell. Mol. Med. 2010;14:51-69). Neither study demonstrated a difference in overall survival among treated patients with and without EGFR mutations, Dr. Ettinger said.

The updated NCCN guidelines also state that the sequencing of KRAS (a G protein involved in the EGFR-related signal transmission) could be useful for the selection of patients as candidates for TKI therapy. The KRAS gene can harbor oncogenic mutations that may render a tumor resistant to EGFR-targeting agents, Dr. Ettinger explained, noting that studies have shown that a KRAS mutation in patients with NSCLC "confers a high level of resistance" to TKIs.

Although the data – which primarily come from retrospective reviews with small sample sizes – are insufficient to make a determination about an association between KRAS mutation status and survival, he said, they are sufficient to warrant a category 2A recommendation for sequencing, as well as a recommendation that patients with a known KRAS mutation should undergo first-line therapy with an agent other than a TKI.

Individuals who test negative for EGFR and KRAS should also be screened for a mutation of the anaplastic lymphoma kinase (ALK) fusion gene, Dr. Ettinger said. "Patients who screen positive may not benefit from EGFR TKIs, but they may be good candidates for an ALK-targeted therapy," he said, noting that the investigational ALK-targeting drug crizotinib, in particular, has demonstrated positive results in early studies of NSCLC patients with echinoderm microtubule-associated proteinlike 4 (EML4)-ALK translocations (N. Engl. J. Med. 2010;363:1693-703).

With respect to first-line systemic therapy, patients with adenocarcinoma, large cell carcinoma, or NSCLC "not otherwise specified" who have an Eastern Cooperative Oncology Group/World Health Organization performance status grade of 0-4 and who test positive for the EGFR mutation prior to first-line therapy should be treated with erlotinib, according to the NCCN guidelines. Alternatively, the guidelines state that gefitinib can be used in place of erlotinib "in areas of the world where it is available."

For patients in whom the EGFR mutation is discovered during chemotherapy, the guidelines recommend either adding erlotinib to the current chemotherapy protocol or switching to erlotinib as maintenance treatment."

For patients whose EGFR status is negative or unknown, even in the presence of clinical characteristics that might be suggestive of a mutation (for example, female, nonsmoker, Asian race), conventional chemotherapy is recommended, Dr. Ettinger said.

The updated NCCN guidelines for NSCLC are posted at www.nccn.org.

The guidelines take a conservative stance on the National Lung Screening Trial finding that screening with low-dose helical CT was associated with a 20% reduction in lung cancer deaths vs. screening with standard chest x-ray. Despite this positive finding, "the NCCN panel does not recommend the routine use of screening CT as a standard clinical practice," said Dr. Ettinger; more conclusive data from ongoing national trials are needed to define the associated risks and benefits. "High-risk patients should participate in a clinical trial evaluating CT screening or go to a center of excellence to discuss the potential risks and benefits of a screening CT," Dr. Ettinger said.

Other notable updates include the following:

• The addition of EBUS (endobronchial ultrasound) as a work-up recommendation.

• The recommendation that bevacizumab (Avastin) and chemotherapy or chemotherapy alone is indicated in performance status 0-1 patients with advanced or recurrent NSCLC, and that bevacizumab should be given until disease progression.

• The recommendation against systemic chemotherapy in performance status 3-4 NSCLC patients.

• The guidance that chemoradiation is better than chemotherapy alone in locally advanced NSCLC, and that concurrent chemoradiation is better than sequential chemoradiation.

• The addition of denosumab (Xgeva) as a treatment option for patients with bone metastases.

• The recommendation favoring cisplatin/pemetrexed (Alimta) vs. cisplatin/gemcitabine (Gemzar) in patients with nonsquamous histology.

• The recommendation against adding a third cytotoxic drug, with the exception of bevacizumab or cetuximab (Erbitux), in treatment-naive performance status 0-1 NSCLC patients.

• The guidance that cisplatin-based combinations are better than best supportive care in advanced, incurable disease, with improvement in median survival and 1-year survival rates.

The ASCO PCO is available online.

In an editorial that accompanied ASCO’s PCO announcement, Dr. Paul A. Bunn Jr. and Dr. Robert C. Doebele of the University of Colorado Cancer Center in Aurora wrote that the growing clinical importance of molecularly defined subgroups of adenocarcinoma signals a "new era of personalized medicine for patients with advanced lung cancer, in which it will be imperative to match the specific mutations of a patient’s tumor with a specific therapy."

The implementation of routine, simultaneous testing of multiple markers will likely be conducted on all patients prior to treatment initiation, regardless of clinical features, they stated, acknowledging certain procedural challenges, including obtaining adequate tumor material at the time of diagnostic biopsy and developing testing platforms "that simultaneously analyze for the presence of somatic mutations, gene fusions, or other genetic challenges."

Dr. Ettinger has consultancy agreements with the following companies: Biodesix, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Genentech, Merck, Novartis Pharmaceuticals, Poniard Pharmaceuticals, Prometheus Laboratories, Shin Nippon Biomedical Laboratories, and Telik. Dr. Keedy receives commercial research support from Ariad Pharmaceuticals, Ziopharm Oncology, and Amgen Oncology Therapeutics. Dr. Bunn has a consultant or advisory role with Amgen, AstraZeneca, Abraxis, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Syndax, Biodesix, Allos Therapeutics, Novartis, OSI/Genentech/Roche, Poniard, and Sanofi-Aventis. Dr. Doebele disclosed research funding from Lilly, ImClone Systems, and Pfizer.

Primary angiitis of the central nervous system in children, which encompasses a spectrum of progressive and nonprogressive large- and small-vessel inflammatory brain diseases, has been linked in recent years to a range of neurologic conditions, such as refractory status epilepticus, movement disorders, severe cognitive dysfunction, optic neuritis, and psychiatric symptoms in previously healthy children, according to Dr. Susanne Benseler, director of the Childhood CNS Vasculitis Program at the Hospital for Sick Children in Toronto.

Although an accurate, timely diagnosis is essential for optimizing neurologic outcomes in this reversible disease, overlapping clinical features with noninflammatory brain conditions – such as vasoconstrictive disorders and neuronal antibody–associated conditions – can complicate the diagnosis and lead to treatment delays, as well as potentially devastating consequences, Dr. Benseler said at the joint annual meeting of the Canadian Rheumatology Association and the Mexican Congress of Rheumatology.

In this column, Dr. Benseler answers questions about the management of primary angiitis of the central nervous system in children (cPACNS) and offers a diagnostic algorithm that allows for rapid evaluation and initiation of targeted therapy.

QUESTION: What is the incidence of cPACNS in the general population?

Dr. Benseler: Primary central nervous system vasculitis in children includes progressive and nonprogressive, angiography-positive, large-vessel vasculitis, small-vessel vasculitis, and most recently, primary CNS venulitis. Because it has only recently been described in case reports and case series, the true incidence of cPACNS remains unknown, but as recognition of the condition increases, so does the number of cases that are diagnosed and treated appropriately. For example, we currently have no idea how many kids presenting with status epilepticus have CNS vasculitis. We can assume that the number is large, however, because once we began looking for vasculitis in these children, we have been diagnosing it in case after case.

QUESTION: What are some of the risk factors for the development of the disease?

Dr. Benseler: Primary childhood CNS vasculitis develops in heretofore perfectly healthy children. Preceding viral illness may play a role. However, no true risk factors have been identified so far. It does not run in families, and it does not reflect any "weakness" of the immune system. It is the exact opposite.

QUESTION: How is cPACNS diagnosed, and what are some of the more pressing diagnostic challenges?

Dr. Benseler: The diagnosis is based on an algorithm of clinical features, including the presence of newly acquired neurologic deficits and/or psychiatric symptoms; such serum inflammatory markers as C-reactive protein, erythrocyte sedimentation rate, and von Willebrand’s factor antigen; the absence of neuronal autoantibodies in the cerebrospinal fluid; evidence of ischemic or inflammatory parenchymal disease on MRI; and evidence of CNS vascular disease on angiography or brain biopsy (Curr. Opin. Rheumatol. 2010;22: 590-7). At the same time, causes of secondary vasculitis, noninflammatory vasculopathies, and nonvasculitic inflammatory brain diseases have to be excluded.

QUESTION: Should elective brain biopsies be done routinely in patients with suspected cPACNS, or is there a specific subgroup of children in whom the procedure is most appropriate?

Dr. Benseler: Following the diagnostic algorithm, brain biopsies should be considered in children in whom the treating physician has a strong clinical suspicion of an inflammatory brain disease in the absence of vasculitis on angiography.

QUESTION: You have noted that the spectrum of the disease in children comprises progressive and nonprogressive forms. Are there differences that are apparent at diagnosis that might help clinicians distinguish between the two forms, and how would this affect management?

Dr. Benseler: We have reported the clinical, laboratory, and imaging characteristics of both subtypes. Children with nonprogressive disease present with strokes in the absence of significant inflammatory markers. The vascular wall of the distal internal carotid artery and/or proximal middle cerebral artery and/or anterior cerebral artery are inflamed and thickened on gadolinium-enhanced MRI angiography. The lumen is narrowed, causing ischemic strokes in the vascular territory, which typically includes the basal ganglia. These kids are started on antithrombotic therapy in addition to a 3-month course of high-dose corticosteroids.

In contrast, children with progressive CNS vasculitis present with additional diffuse deficits, and have evidence of inflammatory markers and angiographic abnormalities affecting multiple vessel segments, including the distal vessels. Children are diagnosed based on their angiographic appearance and are treated with the same protocol that we have reported for small-vessel vasculitis, which includes 6 months of cyclophosphamide, monthly pulses plus high-dose steroids, followed by 18 months of mycophenolate maintenance therapy with tapering doses of steroids (Lancet Neurol. 2010;9:1078-84).

QUESTION: What are some of the key management considerations for cPACNS?

Dr. Benseler: The management of CNS vasculitis has multiple components, including drug theory for inflammation; symptom therapy, such as antiseizure medications, selective serotonin reuptake inhibitors, and other drugs; supportive medications, such as vitamin D and pneumocystis jiroveci pneumonia prophylaxis; rehabilitation; family support; and school-adjustment counseling.

Dr. Benseler is also associate professor of pediatrics in the division of rheumatology and an associate scientist in Child Health Evaluative Sciences in the Research Institute at the University of Toronto. She has no conflicts of interest to disclose.

Primary angiitis of the central nervous system in children, which encompasses a spectrum of progressive and nonprogressive large- and small-vessel inflammatory brain diseases, has been linked in recent years to a range of neurologic conditions, such as refractory status epilepticus, movement disorders, severe cognitive dysfunction, optic neuritis, and psychiatric symptoms in previously healthy children, according to Dr. Susanne Benseler, director of the Childhood CNS Vasculitis Program at the Hospital for Sick Children in Toronto.

Although an accurate, timely diagnosis is essential for optimizing neurologic outcomes in this reversible disease, overlapping clinical features with noninflammatory brain conditions – such as vasoconstrictive disorders and neuronal antibody–associated conditions – can complicate the diagnosis and lead to treatment delays, as well as potentially devastating consequences, Dr. Benseler said at the joint annual meeting of the Canadian Rheumatology Association and the Mexican Congress of Rheumatology.

In this column, Dr. Benseler answers questions about the management of primary angiitis of the central nervous system in children (cPACNS) and offers a diagnostic algorithm that allows for rapid evaluation and initiation of targeted therapy.

QUESTION: What is the incidence of cPACNS in the general population?

Dr. Benseler: Primary central nervous system vasculitis in children includes progressive and nonprogressive, angiography-positive, large-vessel vasculitis, small-vessel vasculitis, and most recently, primary CNS venulitis. Because it has only recently been described in case reports and case series, the true incidence of cPACNS remains unknown, but as recognition of the condition increases, so does the number of cases that are diagnosed and treated appropriately. For example, we currently have no idea how many kids presenting with status epilepticus have CNS vasculitis. We can assume that the number is large, however, because once we began looking for vasculitis in these children, we have been diagnosing it in case after case.

QUESTION: What are some of the risk factors for the development of the disease?

Dr. Benseler: Primary childhood CNS vasculitis develops in heretofore perfectly healthy children. Preceding viral illness may play a role. However, no true risk factors have been identified so far. It does not run in families, and it does not reflect any "weakness" of the immune system. It is the exact opposite.

QUESTION: How is cPACNS diagnosed, and what are some of the more pressing diagnostic challenges?

Dr. Benseler: The diagnosis is based on an algorithm of clinical features, including the presence of newly acquired neurologic deficits and/or psychiatric symptoms; such serum inflammatory markers as C-reactive protein, erythrocyte sedimentation rate, and von Willebrand’s factor antigen; the absence of neuronal autoantibodies in the cerebrospinal fluid; evidence of ischemic or inflammatory parenchymal disease on MRI; and evidence of CNS vascular disease on angiography or brain biopsy (Curr. Opin. Rheumatol. 2010;22: 590-7). At the same time, causes of secondary vasculitis, noninflammatory vasculopathies, and nonvasculitic inflammatory brain diseases have to be excluded.

QUESTION: Should elective brain biopsies be done routinely in patients with suspected cPACNS, or is there a specific subgroup of children in whom the procedure is most appropriate?

Dr. Benseler: Following the diagnostic algorithm, brain biopsies should be considered in children in whom the treating physician has a strong clinical suspicion of an inflammatory brain disease in the absence of vasculitis on angiography.

QUESTION: You have noted that the spectrum of the disease in children comprises progressive and nonprogressive forms. Are there differences that are apparent at diagnosis that might help clinicians distinguish between the two forms, and how would this affect management?

Dr. Benseler: We have reported the clinical, laboratory, and imaging characteristics of both subtypes. Children with nonprogressive disease present with strokes in the absence of significant inflammatory markers. The vascular wall of the distal internal carotid artery and/or proximal middle cerebral artery and/or anterior cerebral artery are inflamed and thickened on gadolinium-enhanced MRI angiography. The lumen is narrowed, causing ischemic strokes in the vascular territory, which typically includes the basal ganglia. These kids are started on antithrombotic therapy in addition to a 3-month course of high-dose corticosteroids.

In contrast, children with progressive CNS vasculitis present with additional diffuse deficits, and have evidence of inflammatory markers and angiographic abnormalities affecting multiple vessel segments, including the distal vessels. Children are diagnosed based on their angiographic appearance and are treated with the same protocol that we have reported for small-vessel vasculitis, which includes 6 months of cyclophosphamide, monthly pulses plus high-dose steroids, followed by 18 months of mycophenolate maintenance therapy with tapering doses of steroids (Lancet Neurol. 2010;9:1078-84).

QUESTION: What are some of the key management considerations for cPACNS?

Dr. Benseler: The management of CNS vasculitis has multiple components, including drug theory for inflammation; symptom therapy, such as antiseizure medications, selective serotonin reuptake inhibitors, and other drugs; supportive medications, such as vitamin D and pneumocystis jiroveci pneumonia prophylaxis; rehabilitation; family support; and school-adjustment counseling.

Dr. Benseler is also associate professor of pediatrics in the division of rheumatology and an associate scientist in Child Health Evaluative Sciences in the Research Institute at the University of Toronto. She has no conflicts of interest to disclose.

Primary angiitis of the central nervous system in children, which encompasses a spectrum of progressive and nonprogressive large- and small-vessel inflammatory brain diseases, has been linked in recent years to a range of neurologic conditions, such as refractory status epilepticus, movement disorders, severe cognitive dysfunction, optic neuritis, and psychiatric symptoms in previously healthy children, according to Dr. Susanne Benseler, director of the Childhood CNS Vasculitis Program at the Hospital for Sick Children in Toronto.

Although an accurate, timely diagnosis is essential for optimizing neurologic outcomes in this reversible disease, overlapping clinical features with noninflammatory brain conditions – such as vasoconstrictive disorders and neuronal antibody–associated conditions – can complicate the diagnosis and lead to treatment delays, as well as potentially devastating consequences, Dr. Benseler said at the joint annual meeting of the Canadian Rheumatology Association and the Mexican Congress of Rheumatology.

In this column, Dr. Benseler answers questions about the management of primary angiitis of the central nervous system in children (cPACNS) and offers a diagnostic algorithm that allows for rapid evaluation and initiation of targeted therapy.

QUESTION: What is the incidence of cPACNS in the general population?

Dr. Benseler: Primary central nervous system vasculitis in children includes progressive and nonprogressive, angiography-positive, large-vessel vasculitis, small-vessel vasculitis, and most recently, primary CNS venulitis. Because it has only recently been described in case reports and case series, the true incidence of cPACNS remains unknown, but as recognition of the condition increases, so does the number of cases that are diagnosed and treated appropriately. For example, we currently have no idea how many kids presenting with status epilepticus have CNS vasculitis. We can assume that the number is large, however, because once we began looking for vasculitis in these children, we have been diagnosing it in case after case.

QUESTION: What are some of the risk factors for the development of the disease?

Dr. Benseler: Primary childhood CNS vasculitis develops in heretofore perfectly healthy children. Preceding viral illness may play a role. However, no true risk factors have been identified so far. It does not run in families, and it does not reflect any "weakness" of the immune system. It is the exact opposite.

QUESTION: How is cPACNS diagnosed, and what are some of the more pressing diagnostic challenges?

Dr. Benseler: The diagnosis is based on an algorithm of clinical features, including the presence of newly acquired neurologic deficits and/or psychiatric symptoms; such serum inflammatory markers as C-reactive protein, erythrocyte sedimentation rate, and von Willebrand’s factor antigen; the absence of neuronal autoantibodies in the cerebrospinal fluid; evidence of ischemic or inflammatory parenchymal disease on MRI; and evidence of CNS vascular disease on angiography or brain biopsy (Curr. Opin. Rheumatol. 2010;22: 590-7). At the same time, causes of secondary vasculitis, noninflammatory vasculopathies, and nonvasculitic inflammatory brain diseases have to be excluded.

QUESTION: Should elective brain biopsies be done routinely in patients with suspected cPACNS, or is there a specific subgroup of children in whom the procedure is most appropriate?

Dr. Benseler: Following the diagnostic algorithm, brain biopsies should be considered in children in whom the treating physician has a strong clinical suspicion of an inflammatory brain disease in the absence of vasculitis on angiography.

QUESTION: You have noted that the spectrum of the disease in children comprises progressive and nonprogressive forms. Are there differences that are apparent at diagnosis that might help clinicians distinguish between the two forms, and how would this affect management?

Dr. Benseler: We have reported the clinical, laboratory, and imaging characteristics of both subtypes. Children with nonprogressive disease present with strokes in the absence of significant inflammatory markers. The vascular wall of the distal internal carotid artery and/or proximal middle cerebral artery and/or anterior cerebral artery are inflamed and thickened on gadolinium-enhanced MRI angiography. The lumen is narrowed, causing ischemic strokes in the vascular territory, which typically includes the basal ganglia. These kids are started on antithrombotic therapy in addition to a 3-month course of high-dose corticosteroids.

In contrast, children with progressive CNS vasculitis present with additional diffuse deficits, and have evidence of inflammatory markers and angiographic abnormalities affecting multiple vessel segments, including the distal vessels. Children are diagnosed based on their angiographic appearance and are treated with the same protocol that we have reported for small-vessel vasculitis, which includes 6 months of cyclophosphamide, monthly pulses plus high-dose steroids, followed by 18 months of mycophenolate maintenance therapy with tapering doses of steroids (Lancet Neurol. 2010;9:1078-84).

QUESTION: What are some of the key management considerations for cPACNS?

Dr. Benseler: The management of CNS vasculitis has multiple components, including drug theory for inflammation; symptom therapy, such as antiseizure medications, selective serotonin reuptake inhibitors, and other drugs; supportive medications, such as vitamin D and pneumocystis jiroveci pneumonia prophylaxis; rehabilitation; family support; and school-adjustment counseling.

Dr. Benseler is also associate professor of pediatrics in the division of rheumatology and an associate scientist in Child Health Evaluative Sciences in the Research Institute at the University of Toronto. She has no conflicts of interest to disclose.

Primary angiitis of the central nervous system in children, which encompasses a spectrum of progressive and nonprogressive large- and small-vessel inflammatory brain diseases, has been linked in recent years to a range of neurologic conditions, such as refractory status epilepticus, movement disorders, severe cognitive dysfunction, optic neuritis, and psychiatric symptoms in previously healthy children, according to Dr. Susanne Benseler, director of the Childhood CNS Vasculitis Program at the Hospital for Sick Children in Toronto.

Although an accurate, timely diagnosis is essential for optimizing neurologic outcomes in this reversible disease, overlapping clinical features with noninflammatory brain conditions – such as vasoconstrictive disorders and neuronal antibody–associated conditions – can complicate the diagnosis and lead to treatment delays, as well as potentially devastating consequences, Dr. Benseler said at the joint annual meeting of the Canadian Rheumatology Association and the Mexican Congress of Rheumatology.

In this column, Dr. Benseler answers questions about the management of primary angiitis of the central nervous system in children (cPACNS) and offers a diagnostic algorithm that allows for rapid evaluation and initiation of targeted therapy.

QUESTION: What is the incidence of cPACNS in the general population?

Dr. Benseler: Primary central nervous system vasculitis in children includes progressive and nonprogressive, angiography-positive, large-vessel vasculitis, small-vessel vasculitis, and most recently, primary CNS venulitis. Because it has only recently been described in case reports and case series, the true incidence of cPACNS remains unknown, but as recognition of the condition increases, so does the number of cases that are diagnosed and treated appropriately. For example, we currently have no idea how many kids presenting with status epilepticus have CNS vasculitis. We can assume that the number is large, however, because once we began looking for vasculitis in these children, we have been diagnosing it in case after case.

QUESTION: What are some of the risk factors for the development of the disease?

Dr. Benseler: Primary childhood CNS vasculitis develops in heretofore perfectly healthy children. Preceding viral illness may play a role. However, no true risk factors have been identified so far. It does not run in families, and it does not reflect any "weakness" of the immune system. It is the exact opposite.

QUESTION: How is cPACNS diagnosed, and what are some of the more pressing diagnostic challenges?

Dr. Benseler: The diagnosis is based on an algorithm of clinical features, including the presence of newly acquired neurologic deficits and/or psychiatric symptoms; such serum inflammatory markers as C-reactive protein, erythrocyte sedimentation rate, and von Willebrand’s factor antigen; the absence of neuronal autoantibodies in the cerebrospinal fluid; evidence of ischemic or inflammatory parenchymal disease on MRI; and evidence of CNS vascular disease on angiography or brain biopsy (Curr. Opin. Rheumatol. 2010;22: 590-7). At the same time, causes of secondary vasculitis, noninflammatory vasculopathies, and nonvasculitic inflammatory brain diseases have to be excluded.

QUESTION: Should elective brain biopsies be done routinely in patients with suspected cPACNS, or is there a specific subgroup of children in whom the procedure is most appropriate?

Dr. Benseler: Following the diagnostic algorithm, brain biopsies should be considered in children in whom the treating physician has a strong clinical suspicion of an inflammatory brain disease in the absence of vasculitis on angiography.

QUESTION: You have noted that the spectrum of the disease in children comprises progressive and nonprogressive forms. Are there differences that are apparent at diagnosis that might help clinicians distinguish between the two forms, and how would this affect management?

Dr. Benseler: We have reported the clinical, laboratory, and imaging characteristics of both subtypes. Children with nonprogressive disease present with strokes in the absence of significant inflammatory markers. The vascular wall of the distal internal carotid artery and/or proximal middle cerebral artery and/or anterior cerebral artery are inflamed and thickened on gadolinium-enhanced MRI angiography. The lumen is narrowed, causing ischemic strokes in the vascular territory, which typically includes the basal ganglia. These kids are started on antithrombotic therapy in addition to a 3-month course of high-dose corticosteroids.

In contrast, children with progressive CNS vasculitis present with additional diffuse deficits, and have evidence of inflammatory markers and angiographic abnormalities affecting multiple vessel segments, including the distal vessels. Children are diagnosed based on their angiographic appearance and are treated with the same protocol that we have reported for small-vessel vasculitis, which includes 6 months of cyclophosphamide, monthly pulses plus high-dose steroids, followed by 18 months of mycophenolate maintenance therapy with tapering doses of steroids (Lancet Neurol. 2010;9:1078-84).

QUESTION: What are some of the key management considerations for cPACNS?

Dr. Benseler: The management of CNS vasculitis has multiple components, including drug theory for inflammation; symptom therapy, such as antiseizure medications, selective serotonin reuptake inhibitors, and other drugs; supportive medications, such as vitamin D and pneumocystis jiroveci pneumonia prophylaxis; rehabilitation; family support; and school-adjustment counseling.

This column, "Ask the Expert," regularly appears in Rheumatology News, an Elsevier publication. Dr. Benseler is also associate professor of pediatrics in the division of rheumatology and an associate scientist in Child Health Evaluative Sciences in the Research Institute at the University of Toronto. She has no conflicts of interest to disclose.

Primary angiitis of the central nervous system in children, which encompasses a spectrum of progressive and nonprogressive large- and small-vessel inflammatory brain diseases, has been linked in recent years to a range of neurologic conditions, such as refractory status epilepticus, movement disorders, severe cognitive dysfunction, optic neuritis, and psychiatric symptoms in previously healthy children, according to Dr. Susanne Benseler, director of the Childhood CNS Vasculitis Program at the Hospital for Sick Children in Toronto.

Although an accurate, timely diagnosis is essential for optimizing neurologic outcomes in this reversible disease, overlapping clinical features with noninflammatory brain conditions – such as vasoconstrictive disorders and neuronal antibody–associated conditions – can complicate the diagnosis and lead to treatment delays, as well as potentially devastating consequences, Dr. Benseler said at the joint annual meeting of the Canadian Rheumatology Association and the Mexican Congress of Rheumatology.

In this column, Dr. Benseler answers questions about the management of primary angiitis of the central nervous system in children (cPACNS) and offers a diagnostic algorithm that allows for rapid evaluation and initiation of targeted therapy.

QUESTION: What is the incidence of cPACNS in the general population?

Dr. Benseler: Primary central nervous system vasculitis in children includes progressive and nonprogressive, angiography-positive, large-vessel vasculitis, small-vessel vasculitis, and most recently, primary CNS venulitis. Because it has only recently been described in case reports and case series, the true incidence of cPACNS remains unknown, but as recognition of the condition increases, so does the number of cases that are diagnosed and treated appropriately. For example, we currently have no idea how many kids presenting with status epilepticus have CNS vasculitis. We can assume that the number is large, however, because once we began looking for vasculitis in these children, we have been diagnosing it in case after case.

QUESTION: What are some of the risk factors for the development of the disease?

Dr. Benseler: Primary childhood CNS vasculitis develops in heretofore perfectly healthy children. Preceding viral illness may play a role. However, no true risk factors have been identified so far. It does not run in families, and it does not reflect any "weakness" of the immune system. It is the exact opposite.

QUESTION: How is cPACNS diagnosed, and what are some of the more pressing diagnostic challenges?

Dr. Benseler: The diagnosis is based on an algorithm of clinical features, including the presence of newly acquired neurologic deficits and/or psychiatric symptoms; such serum inflammatory markers as C-reactive protein, erythrocyte sedimentation rate, and von Willebrand’s factor antigen; the absence of neuronal autoantibodies in the cerebrospinal fluid; evidence of ischemic or inflammatory parenchymal disease on MRI; and evidence of CNS vascular disease on angiography or brain biopsy (Curr. Opin. Rheumatol. 2010;22: 590-7). At the same time, causes of secondary vasculitis, noninflammatory vasculopathies, and nonvasculitic inflammatory brain diseases have to be excluded.

QUESTION: Should elective brain biopsies be done routinely in patients with suspected cPACNS, or is there a specific subgroup of children in whom the procedure is most appropriate?

Dr. Benseler: Following the diagnostic algorithm, brain biopsies should be considered in children in whom the treating physician has a strong clinical suspicion of an inflammatory brain disease in the absence of vasculitis on angiography.

QUESTION: You have noted that the spectrum of the disease in children comprises progressive and nonprogressive forms. Are there differences that are apparent at diagnosis that might help clinicians distinguish between the two forms, and how would this affect management?

Dr. Benseler: We have reported the clinical, laboratory, and imaging characteristics of both subtypes. Children with nonprogressive disease present with strokes in the absence of significant inflammatory markers. The vascular wall of the distal internal carotid artery and/or proximal middle cerebral artery and/or anterior cerebral artery are inflamed and thickened on gadolinium-enhanced MRI angiography. The lumen is narrowed, causing ischemic strokes in the vascular territory, which typically includes the basal ganglia. These kids are started on antithrombotic therapy in addition to a 3-month course of high-dose corticosteroids.

In contrast, children with progressive CNS vasculitis present with additional diffuse deficits, and have evidence of inflammatory markers and angiographic abnormalities affecting multiple vessel segments, including the distal vessels. Children are diagnosed based on their angiographic appearance and are treated with the same protocol that we have reported for small-vessel vasculitis, which includes 6 months of cyclophosphamide, monthly pulses plus high-dose steroids, followed by 18 months of mycophenolate maintenance therapy with tapering doses of steroids (Lancet Neurol. 2010;9:1078-84).

QUESTION: What are some of the key management considerations for cPACNS?

Dr. Benseler: The management of CNS vasculitis has multiple components, including drug theory for inflammation; symptom therapy, such as antiseizure medications, selective serotonin reuptake inhibitors, and other drugs; supportive medications, such as vitamin D and pneumocystis jiroveci pneumonia prophylaxis; rehabilitation; family support; and school-adjustment counseling.

This column, "Ask the Expert," regularly appears in Rheumatology News, an Elsevier publication. Dr. Benseler is also associate professor of pediatrics in the division of rheumatology and an associate scientist in Child Health Evaluative Sciences in the Research Institute at the University of Toronto. She has no conflicts of interest to disclose.

Primary angiitis of the central nervous system in children, which encompasses a spectrum of progressive and nonprogressive large- and small-vessel inflammatory brain diseases, has been linked in recent years to a range of neurologic conditions, such as refractory status epilepticus, movement disorders, severe cognitive dysfunction, optic neuritis, and psychiatric symptoms in previously healthy children, according to Dr. Susanne Benseler, director of the Childhood CNS Vasculitis Program at the Hospital for Sick Children in Toronto.

Although an accurate, timely diagnosis is essential for optimizing neurologic outcomes in this reversible disease, overlapping clinical features with noninflammatory brain conditions – such as vasoconstrictive disorders and neuronal antibody–associated conditions – can complicate the diagnosis and lead to treatment delays, as well as potentially devastating consequences, Dr. Benseler said at the joint annual meeting of the Canadian Rheumatology Association and the Mexican Congress of Rheumatology.

In this column, Dr. Benseler answers questions about the management of primary angiitis of the central nervous system in children (cPACNS) and offers a diagnostic algorithm that allows for rapid evaluation and initiation of targeted therapy.

QUESTION: What is the incidence of cPACNS in the general population?

Dr. Benseler: Primary central nervous system vasculitis in children includes progressive and nonprogressive, angiography-positive, large-vessel vasculitis, small-vessel vasculitis, and most recently, primary CNS venulitis. Because it has only recently been described in case reports and case series, the true incidence of cPACNS remains unknown, but as recognition of the condition increases, so does the number of cases that are diagnosed and treated appropriately. For example, we currently have no idea how many kids presenting with status epilepticus have CNS vasculitis. We can assume that the number is large, however, because once we began looking for vasculitis in these children, we have been diagnosing it in case after case.

QUESTION: What are some of the risk factors for the development of the disease?

Dr. Benseler: Primary childhood CNS vasculitis develops in heretofore perfectly healthy children. Preceding viral illness may play a role. However, no true risk factors have been identified so far. It does not run in families, and it does not reflect any "weakness" of the immune system. It is the exact opposite.

QUESTION: How is cPACNS diagnosed, and what are some of the more pressing diagnostic challenges?

Dr. Benseler: The diagnosis is based on an algorithm of clinical features, including the presence of newly acquired neurologic deficits and/or psychiatric symptoms; such serum inflammatory markers as C-reactive protein, erythrocyte sedimentation rate, and von Willebrand’s factor antigen; the absence of neuronal autoantibodies in the cerebrospinal fluid; evidence of ischemic or inflammatory parenchymal disease on MRI; and evidence of CNS vascular disease on angiography or brain biopsy (Curr. Opin. Rheumatol. 2010;22: 590-7). At the same time, causes of secondary vasculitis, noninflammatory vasculopathies, and nonvasculitic inflammatory brain diseases have to be excluded.

QUESTION: Should elective brain biopsies be done routinely in patients with suspected cPACNS, or is there a specific subgroup of children in whom the procedure is most appropriate?

Dr. Benseler: Following the diagnostic algorithm, brain biopsies should be considered in children in whom the treating physician has a strong clinical suspicion of an inflammatory brain disease in the absence of vasculitis on angiography.

QUESTION: You have noted that the spectrum of the disease in children comprises progressive and nonprogressive forms. Are there differences that are apparent at diagnosis that might help clinicians distinguish between the two forms, and how would this affect management?

Dr. Benseler: We have reported the clinical, laboratory, and imaging characteristics of both subtypes. Children with nonprogressive disease present with strokes in the absence of significant inflammatory markers. The vascular wall of the distal internal carotid artery and/or proximal middle cerebral artery and/or anterior cerebral artery are inflamed and thickened on gadolinium-enhanced MRI angiography. The lumen is narrowed, causing ischemic strokes in the vascular territory, which typically includes the basal ganglia. These kids are started on antithrombotic therapy in addition to a 3-month course of high-dose corticosteroids.

In contrast, children with progressive CNS vasculitis present with additional diffuse deficits, and have evidence of inflammatory markers and angiographic abnormalities affecting multiple vessel segments, including the distal vessels. Children are diagnosed based on their angiographic appearance and are treated with the same protocol that we have reported for small-vessel vasculitis, which includes 6 months of cyclophosphamide, monthly pulses plus high-dose steroids, followed by 18 months of mycophenolate maintenance therapy with tapering doses of steroids (Lancet Neurol. 2010;9:1078-84).

QUESTION: What are some of the key management considerations for cPACNS?

Dr. Benseler: The management of CNS vasculitis has multiple components, including drug theory for inflammation; symptom therapy, such as antiseizure medications, selective serotonin reuptake inhibitors, and other drugs; supportive medications, such as vitamin D and pneumocystis jiroveci pneumonia prophylaxis; rehabilitation; family support; and school-adjustment counseling.

This column, "Ask the Expert," regularly appears in Rheumatology News, an Elsevier publication. Dr. Benseler is also associate professor of pediatrics in the division of rheumatology and an associate scientist in Child Health Evaluative Sciences in the Research Institute at the University of Toronto. She has no conflicts of interest to disclose.

HOLLYWOOD, FLA. – Updated prostate cancer guidelines from the National Comprehensive Cancer Network call for more stringent monitoring of low-risk and very-low-risk patients who have opted for active surveillance.

The more rigorous protocol should help allay patient anxiety about "watchful waiting," while minimizing the likelihood of overtreatment and its associated risks and side affects, Dr. James L. Mohler explained at the NCCN annual conference.

Based primarily on expert consensus rather than new evidence from clinical trials, the recommendations include the following:

• Prostate-specific antigen (PSA) testing at least every 6 months and as often as every 3 months.

• Digital rectal examination (DRE) at least every 12 months and as often as every 6 months.

• Repeat needle biopsy within 18 months for patients in whom the initial biopsy was 10 or more cores.

• Repeat initial biopsy within 6 months for patients in whom the initial biopsy was fewer than 10 cores.

• Consideration of a repeat biopsy for all patients as often as 12 months.

Previously, the NCCN had called for PSA testing and DREs as frequently as every 6 and 12 months, respectively, and deemed repeat needle biopsies to be optional within 6-18 months, depending on the number of cores initially biopsied, said Dr. Mohler.

Although the revised recommendations are more specific, they are still limited by the lack of quality evidence to support them, he said, noting that the first-ever North American phase III trial to compare active surveillance with mainstay prostate cancer treatments – the ongoing START (Surveillance Therapy Against Radical Treatment) study – is having trouble meeting enrollment goals because patients perceive active surveillance as "doing nothing."

In 2010, the NCCN prostate cancer guidelines recommended active surveillance as the only option for men with low-risk prostate cancer who had an estimated life expectancy less than 10 years and for men with very-low-risk prostate cancer (a newly defined patient subset) with a life expectancy less than 20 years, said Dr. Mohler, chair of the department of urology at Roswell Park Cancer Institute in Buffalo, N.Y.

Patients in the low-risk category are those with a stage T1-T2a tumor, a Gleason score of 2-6, and a PSA level less than 10 ng/mL, whereas very-low-risk patients are those with a stage T1a tumor, a Gleason score of 6 or less, a PSA level less than 10 ng/mL, fewer than three positive biopsy cores with no more than 50% cancer in each, and a PSA density below 0.15 ng/mL per gram, he explained.

Sipuleucel-T, Cabazitaxel included

The updated guidelines also outline new recommendations for systemic treatment of castration-recurrent metastatic prostate cancer, including salvage therapy with sipuleucel-T (Provenge) for asymptomatic or minimally symptomatic disease and cabazitaxel (Jevtana) as a second-line treatment option for patients who develop resistance to docetaxel (Taxotere), Dr. Mohler said.

The sipuleucel-T recommendation is based, in large part, on the recently reported findings of the phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial that showed significantly improved overall survival – although not progression-free survival – among men who were randomized to the autologous active cellular immunotherapy, compared with placebo (N. Engl. J. Med. 2010;363:411-22), Dr. Mohler said. The category 1 recommendation applies to minimally symptomatic men with an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, a life expectancy greater than 6 months, and no visceral metastases. Sipuleucel-T is not recommended for men with symptomatic disease, for whom chemotherapy with docetaxel and prednisone remains appropriate, he said.

Men with advanced prostate cancer who are not helped by docetaxel may be candidates for treatment with cabazitaxel, a second-generation taxane, according to the revised guideline. In a phase III randomized trial, treatment with the microtubule inhibitor along with prednisone led to prolonged overall and progression-free survival and improved PSA and radiologic responses, compared with mitoxantrone (Novantrone) and prednisone, said Dr. Mohler (Lancet 2010;376:1147-54). Because of an increased risk of neutropenia and other adverse effects, "treatment should be reserved for patients without severe neuropathy or impaired liver, kidney, or bone marrow function," he said.

Denosumab an Option for Bone Mets

The revised guideline also updates the recommendation for the prevention of skeletal-related events in patients with advanced prostate cancer that has metastasized to the bone with the addition of the anti-RANKL (receptor-activated nuclear factor–kappaB ligand) monoclonal antibody denosumab (Xgeva) as an alternative to zoledronic acid (Zometa).

"In men with castration-recurrent prostate cancer who have bone metastases, denosumab was shown to be superior to zoledronic acid in preventing disease-related skeletal complications, including fracture, spinal cord compression, or the need for surgery or radiation therapy to bone," Dr. Mohler said, referring to the results of a phase III randomized study (Lancet. 2011;377:813-22).

Unlike zoledronic acid, which is administered intravenously and can potentially affect renal function, denosumab is given subcutaneously and does not affect kidney function, he said; as such, it represents a "novel treatment option."

The updated NCCN prostate cancer guidelines are available at www.nccn.org. Dr. Mohler is a cofounder and chief medical officer of AndroBioSys Inc. in Buffalo, N.Y.

HOLLYWOOD, FLA. – Updated prostate cancer guidelines from the National Comprehensive Cancer Network call for more stringent monitoring of low-risk and very-low-risk patients who have opted for active surveillance.

The more rigorous protocol should help allay patient anxiety about "watchful waiting," while minimizing the likelihood of overtreatment and its associated risks and side affects, Dr. James L. Mohler explained at the NCCN annual conference.

Based primarily on expert consensus rather than new evidence from clinical trials, the recommendations include the following:

• Prostate-specific antigen (PSA) testing at least every 6 months and as often as every 3 months.

• Digital rectal examination (DRE) at least every 12 months and as often as every 6 months.

• Repeat needle biopsy within 18 months for patients in whom the initial biopsy was 10 or more cores.

• Repeat initial biopsy within 6 months for patients in whom the initial biopsy was fewer than 10 cores.

• Consideration of a repeat biopsy for all patients as often as 12 months.

Previously, the NCCN had called for PSA testing and DREs as frequently as every 6 and 12 months, respectively, and deemed repeat needle biopsies to be optional within 6-18 months, depending on the number of cores initially biopsied, said Dr. Mohler.

Although the revised recommendations are more specific, they are still limited by the lack of quality evidence to support them, he said, noting that the first-ever North American phase III trial to compare active surveillance with mainstay prostate cancer treatments – the ongoing START (Surveillance Therapy Against Radical Treatment) study – is having trouble meeting enrollment goals because patients perceive active surveillance as "doing nothing."

In 2010, the NCCN prostate cancer guidelines recommended active surveillance as the only option for men with low-risk prostate cancer who had an estimated life expectancy less than 10 years and for men with very-low-risk prostate cancer (a newly defined patient subset) with a life expectancy less than 20 years, said Dr. Mohler, chair of the department of urology at Roswell Park Cancer Institute in Buffalo, N.Y.

Patients in the low-risk category are those with a stage T1-T2a tumor, a Gleason score of 2-6, and a PSA level less than 10 ng/mL, whereas very-low-risk patients are those with a stage T1a tumor, a Gleason score of 6 or less, a PSA level less than 10 ng/mL, fewer than three positive biopsy cores with no more than 50% cancer in each, and a PSA density below 0.15 ng/mL per gram, he explained.

Sipuleucel-T, Cabazitaxel included

The updated guidelines also outline new recommendations for systemic treatment of castration-recurrent metastatic prostate cancer, including salvage therapy with sipuleucel-T (Provenge) for asymptomatic or minimally symptomatic disease and cabazitaxel (Jevtana) as a second-line treatment option for patients who develop resistance to docetaxel (Taxotere), Dr. Mohler said.

The sipuleucel-T recommendation is based, in large part, on the recently reported findings of the phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial that showed significantly improved overall survival – although not progression-free survival – among men who were randomized to the autologous active cellular immunotherapy, compared with placebo (N. Engl. J. Med. 2010;363:411-22), Dr. Mohler said. The category 1 recommendation applies to minimally symptomatic men with an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, a life expectancy greater than 6 months, and no visceral metastases. Sipuleucel-T is not recommended for men with symptomatic disease, for whom chemotherapy with docetaxel and prednisone remains appropriate, he said.

Men with advanced prostate cancer who are not helped by docetaxel may be candidates for treatment with cabazitaxel, a second-generation taxane, according to the revised guideline. In a phase III randomized trial, treatment with the microtubule inhibitor along with prednisone led to prolonged overall and progression-free survival and improved PSA and radiologic responses, compared with mitoxantrone (Novantrone) and prednisone, said Dr. Mohler (Lancet 2010;376:1147-54). Because of an increased risk of neutropenia and other adverse effects, "treatment should be reserved for patients without severe neuropathy or impaired liver, kidney, or bone marrow function," he said.

Denosumab an Option for Bone Mets

The revised guideline also updates the recommendation for the prevention of skeletal-related events in patients with advanced prostate cancer that has metastasized to the bone with the addition of the anti-RANKL (receptor-activated nuclear factor–kappaB ligand) monoclonal antibody denosumab (Xgeva) as an alternative to zoledronic acid (Zometa).

"In men with castration-recurrent prostate cancer who have bone metastases, denosumab was shown to be superior to zoledronic acid in preventing disease-related skeletal complications, including fracture, spinal cord compression, or the need for surgery or radiation therapy to bone," Dr. Mohler said, referring to the results of a phase III randomized study (Lancet. 2011;377:813-22).

Unlike zoledronic acid, which is administered intravenously and can potentially affect renal function, denosumab is given subcutaneously and does not affect kidney function, he said; as such, it represents a "novel treatment option."

The updated NCCN prostate cancer guidelines are available at www.nccn.org. Dr. Mohler is a cofounder and chief medical officer of AndroBioSys Inc. in Buffalo, N.Y.

HOLLYWOOD, FLA. – Updated prostate cancer guidelines from the National Comprehensive Cancer Network call for more stringent monitoring of low-risk and very-low-risk patients who have opted for active surveillance.

The more rigorous protocol should help allay patient anxiety about "watchful waiting," while minimizing the likelihood of overtreatment and its associated risks and side affects, Dr. James L. Mohler explained at the NCCN annual conference.

Based primarily on expert consensus rather than new evidence from clinical trials, the recommendations include the following:

• Prostate-specific antigen (PSA) testing at least every 6 months and as often as every 3 months.

• Digital rectal examination (DRE) at least every 12 months and as often as every 6 months.

• Repeat needle biopsy within 18 months for patients in whom the initial biopsy was 10 or more cores.

• Repeat initial biopsy within 6 months for patients in whom the initial biopsy was fewer than 10 cores.

• Consideration of a repeat biopsy for all patients as often as 12 months.

Previously, the NCCN had called for PSA testing and DREs as frequently as every 6 and 12 months, respectively, and deemed repeat needle biopsies to be optional within 6-18 months, depending on the number of cores initially biopsied, said Dr. Mohler.

Although the revised recommendations are more specific, they are still limited by the lack of quality evidence to support them, he said, noting that the first-ever North American phase III trial to compare active surveillance with mainstay prostate cancer treatments – the ongoing START (Surveillance Therapy Against Radical Treatment) study – is having trouble meeting enrollment goals because patients perceive active surveillance as "doing nothing."

In 2010, the NCCN prostate cancer guidelines recommended active surveillance as the only option for men with low-risk prostate cancer who had an estimated life expectancy less than 10 years and for men with very-low-risk prostate cancer (a newly defined patient subset) with a life expectancy less than 20 years, said Dr. Mohler, chair of the department of urology at Roswell Park Cancer Institute in Buffalo, N.Y.

Patients in the low-risk category are those with a stage T1-T2a tumor, a Gleason score of 2-6, and a PSA level less than 10 ng/mL, whereas very-low-risk patients are those with a stage T1a tumor, a Gleason score of 6 or less, a PSA level less than 10 ng/mL, fewer than three positive biopsy cores with no more than 50% cancer in each, and a PSA density below 0.15 ng/mL per gram, he explained.

Sipuleucel-T, Cabazitaxel included

The updated guidelines also outline new recommendations for systemic treatment of castration-recurrent metastatic prostate cancer, including salvage therapy with sipuleucel-T (Provenge) for asymptomatic or minimally symptomatic disease and cabazitaxel (Jevtana) as a second-line treatment option for patients who develop resistance to docetaxel (Taxotere), Dr. Mohler said.

The sipuleucel-T recommendation is based, in large part, on the recently reported findings of the phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial that showed significantly improved overall survival – although not progression-free survival – among men who were randomized to the autologous active cellular immunotherapy, compared with placebo (N. Engl. J. Med. 2010;363:411-22), Dr. Mohler said. The category 1 recommendation applies to minimally symptomatic men with an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, a life expectancy greater than 6 months, and no visceral metastases. Sipuleucel-T is not recommended for men with symptomatic disease, for whom chemotherapy with docetaxel and prednisone remains appropriate, he said.

Men with advanced prostate cancer who are not helped by docetaxel may be candidates for treatment with cabazitaxel, a second-generation taxane, according to the revised guideline. In a phase III randomized trial, treatment with the microtubule inhibitor along with prednisone led to prolonged overall and progression-free survival and improved PSA and radiologic responses, compared with mitoxantrone (Novantrone) and prednisone, said Dr. Mohler (Lancet 2010;376:1147-54). Because of an increased risk of neutropenia and other adverse effects, "treatment should be reserved for patients without severe neuropathy or impaired liver, kidney, or bone marrow function," he said.

Denosumab an Option for Bone Mets

The revised guideline also updates the recommendation for the prevention of skeletal-related events in patients with advanced prostate cancer that has metastasized to the bone with the addition of the anti-RANKL (receptor-activated nuclear factor–kappaB ligand) monoclonal antibody denosumab (Xgeva) as an alternative to zoledronic acid (Zometa).

"In men with castration-recurrent prostate cancer who have bone metastases, denosumab was shown to be superior to zoledronic acid in preventing disease-related skeletal complications, including fracture, spinal cord compression, or the need for surgery or radiation therapy to bone," Dr. Mohler said, referring to the results of a phase III randomized study (Lancet. 2011;377:813-22).

Unlike zoledronic acid, which is administered intravenously and can potentially affect renal function, denosumab is given subcutaneously and does not affect kidney function, he said; as such, it represents a "novel treatment option."

The updated NCCN prostate cancer guidelines are available at www.nccn.org. Dr. Mohler is a cofounder and chief medical officer of AndroBioSys Inc. in Buffalo, N.Y.

HOLLYWOOD, FLA. – Updated prostate cancer guidelines from the National Comprehensive Cancer Network call for more stringent monitoring of low-risk and very-low-risk patients who have opted for active surveillance.

The more rigorous protocol should help allay patient anxiety about "watchful waiting," while minimizing the likelihood of overtreatment and its associated risks and side affects, Dr. James L. Mohler explained at the NCCN annual conference.

Based primarily on expert consensus rather than new evidence from clinical trials, the recommendations include the following:

• Prostate-specific antigen (PSA) testing at least every 6 months and as often as every 3 months.

• Digital rectal examination (DRE) at least every 12 months and as often as every 6 months.

• Repeat needle biopsy within 18 months for patients in whom the initial biopsy was 10 or more cores.

• Repeat initial biopsy within 6 months for patients in whom the initial biopsy was fewer than 10 cores.

• Consideration of a repeat biopsy for all patients as often as 12 months.

Previously, the NCCN had called for PSA testing and DREs as frequently as every 6 and 12 months, respectively, and deemed repeat needle biopsies to be optional within 6-18 months, depending on the number of cores initially biopsied, said Dr. Mohler.

Although the revised recommendations are more specific, they are still limited by the lack of quality evidence to support them, he said, noting that the first-ever North American phase III trial to compare active surveillance with mainstay prostate cancer treatments – the ongoing START (Surveillance Therapy Against Radical Treatment) study – is having trouble meeting enrollment goals because patients perceive active surveillance as "doing nothing."

In 2010, the NCCN prostate cancer guidelines recommended active surveillance as the only option for men with low-risk prostate cancer who had an estimated life expectancy less than 10 years and for men with very-low-risk prostate cancer (a newly defined patient subset) with a life expectancy less than 20 years, said Dr. Mohler, chair of the department of urology at Roswell Park Cancer Institute in Buffalo, N.Y.

Patients in the low-risk category are those with a stage T1-T2a tumor, a Gleason score of 2-6, and a PSA level less than 10 ng/mL, whereas very-low-risk patients are those with a stage T1a tumor, a Gleason score of 6 or less, a PSA level less than 10 ng/mL, fewer than three positive biopsy cores with no more than 50% cancer in each, and a PSA density below 0.15 ng/mL per gram, he explained.

Sipuleucel-T, Cabazitaxel included

The updated guidelines also outline new recommendations for systemic treatment of castration-recurrent metastatic prostate cancer, including salvage therapy with sipuleucel-T (Provenge) for asymptomatic or minimally symptomatic disease and cabazitaxel (Jevtana) as a second-line treatment option for patients who develop resistance to docetaxel (Taxotere), Dr. Mohler said.

The sipuleucel-T recommendation is based, in large part, on the recently reported findings of the phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial that showed significantly improved overall survival – although not progression-free survival – among men who were randomized to the autologous active cellular immunotherapy, compared with placebo (N. Engl. J. Med. 2010;363:411-22), Dr. Mohler said. The category 1 recommendation applies to minimally symptomatic men with an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, a life expectancy greater than 6 months, and no visceral metastases. Sipuleucel-T is not recommended for men with symptomatic disease, for whom chemotherapy with docetaxel and prednisone remains appropriate, he said.

Men with advanced prostate cancer who are not helped by docetaxel may be candidates for treatment with cabazitaxel, a second-generation taxane, according to the revised guideline. In a phase III randomized trial, treatment with the microtubule inhibitor along with prednisone led to prolonged overall and progression-free survival and improved PSA and radiologic responses, compared with mitoxantrone (Novantrone) and prednisone, said Dr. Mohler (Lancet 2010;376:1147-54). Because of an increased risk of neutropenia and other adverse effects, "treatment should be reserved for patients without severe neuropathy or impaired liver, kidney, or bone marrow function," he said.

Denosumab an Option for Bone Mets

The revised guideline also updates the recommendation for the prevention of skeletal-related events in patients with advanced prostate cancer that has metastasized to the bone with the addition of the anti-RANKL (receptor-activated nuclear factor–kappaB ligand) monoclonal antibody denosumab (Xgeva) as an alternative to zoledronic acid (Zometa).

"In men with castration-recurrent prostate cancer who have bone metastases, denosumab was shown to be superior to zoledronic acid in preventing disease-related skeletal complications, including fracture, spinal cord compression, or the need for surgery or radiation therapy to bone," Dr. Mohler said, referring to the results of a phase III randomized study (Lancet. 2011;377:813-22).

Unlike zoledronic acid, which is administered intravenously and can potentially affect renal function, denosumab is given subcutaneously and does not affect kidney function, he said; as such, it represents a "novel treatment option."

The updated NCCN prostate cancer guidelines are available at www.nccn.org. Dr. Mohler is a cofounder and chief medical officer of AndroBioSys Inc. in Buffalo, N.Y.

HOLLYWOOD, FLA. – Updated prostate cancer guidelines from the National Comprehensive Cancer Network call for more stringent monitoring of low-risk and very-low-risk patients who have opted for active surveillance.

The more rigorous protocol should help allay patient anxiety about "watchful waiting," while minimizing the likelihood of overtreatment and its associated risks and side affects, Dr. James L. Mohler explained at the NCCN annual conference.

Based primarily on expert consensus rather than new evidence from clinical trials, the recommendations include the following:

• Prostate-specific antigen (PSA) testing at least every 6 months and as often as every 3 months.

• Digital rectal examination (DRE) at least every 12 months and as often as every 6 months.

• Repeat needle biopsy within 18 months for patients in whom the initial biopsy was 10 or more cores.

• Repeat initial biopsy within 6 months for patients in whom the initial biopsy was fewer than 10 cores.

• Consideration of a repeat biopsy for all patients as often as 12 months.

Previously, the NCCN had called for PSA testing and DREs as frequently as every 6 and 12 months, respectively, and deemed repeat needle biopsies to be optional within 6-18 months, depending on the number of cores initially biopsied, said Dr. Mohler.

Although the revised recommendations are more specific, they are still limited by the lack of quality evidence to support them, he said, noting that the first-ever North American phase III trial to compare active surveillance with mainstay prostate cancer treatments – the ongoing START (Surveillance Therapy Against Radical Treatment) study – is having trouble meeting enrollment goals because patients perceive active surveillance as "doing nothing."

In 2010, the NCCN prostate cancer guidelines recommended active surveillance as the only option for men with low-risk prostate cancer who had an estimated life expectancy less than 10 years and for men with very-low-risk prostate cancer (a newly defined patient subset) with a life expectancy less than 20 years, said Dr. Mohler, chair of the department of urology at Roswell Park Cancer Institute in Buffalo, N.Y.

Patients in the low-risk category are those with a stage T1-T2a tumor, a Gleason score of 2-6, and a PSA level less than 10 ng/mL, whereas very-low-risk patients are those with a stage T1a tumor, a Gleason score of 6 or less, a PSA level less than 10 ng/mL, fewer than three positive biopsy cores with no more than 50% cancer in each, and a PSA density below 0.15 ng/mL per gram, he explained.

Sipuleucel-T, Cabazitaxel included

The updated guidelines also outline new recommendations for systemic treatment of castration-recurrent metastatic prostate cancer, including salvage therapy with sipuleucel-T (Provenge) for asymptomatic or minimally symptomatic disease and cabazitaxel (Jevtana) as a second-line treatment option for patients who develop resistance to docetaxel (Taxotere), Dr. Mohler said.

The sipuleucel-T recommendation is based, in large part, on the recently reported findings of the phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial that showed significantly improved overall survival – although not progression-free survival – among men who were randomized to the autologous active cellular immunotherapy, compared with placebo (N. Engl. J. Med. 2010;363:411-22), Dr. Mohler said. The category 1 recommendation applies to minimally symptomatic men with an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, a life expectancy greater than 6 months, and no visceral metastases. Sipuleucel-T is not recommended for men with symptomatic disease, for whom chemotherapy with docetaxel and prednisone remains appropriate, he said.

Men with advanced prostate cancer who are not helped by docetaxel may be candidates for treatment with cabazitaxel, a second-generation taxane, according to the revised guideline. In a phase III randomized trial, treatment with the microtubule inhibitor along with prednisone led to prolonged overall and progression-free survival and improved PSA and radiologic responses, compared with mitoxantrone (Novantrone) and prednisone, said Dr. Mohler (Lancet 2010;376:1147-54). Because of an increased risk of neutropenia and other adverse effects, "treatment should be reserved for patients without severe neuropathy or impaired liver, kidney, or bone marrow function," he said.

Denosumab an Option for Bone Mets

The revised guideline also updates the recommendation for the prevention of skeletal-related events in patients with advanced prostate cancer that has metastasized to the bone with the addition of the anti-RANKL (receptor-activated nuclear factor–kappaB ligand) monoclonal antibody denosumab (Xgeva) as an alternative to zoledronic acid (Zometa).

"In men with castration-recurrent prostate cancer who have bone metastases, denosumab was shown to be superior to zoledronic acid in preventing disease-related skeletal complications, including fracture, spinal cord compression, or the need for surgery or radiation therapy to bone," Dr. Mohler said, referring to the results of a phase III randomized study (Lancet. 2011;377:813-22).

Unlike zoledronic acid, which is administered intravenously and can potentially affect renal function, denosumab is given subcutaneously and does not affect kidney function, he said; as such, it represents a "novel treatment option."

The updated NCCN prostate cancer guidelines are available at www.nccn.org. Dr. Mohler is a cofounder and chief medical officer of AndroBioSys Inc. in Buffalo, N.Y.

HOLLYWOOD, FLA. – Updated prostate cancer guidelines from the National Comprehensive Cancer Network call for more stringent monitoring of low-risk and very-low-risk patients who have opted for active surveillance.

The more rigorous protocol should help allay patient anxiety about "watchful waiting," while minimizing the likelihood of overtreatment and its associated risks and side affects, Dr. James L. Mohler explained at the NCCN annual conference.

Based primarily on expert consensus rather than new evidence from clinical trials, the recommendations include the following:

• Prostate-specific antigen (PSA) testing at least every 6 months and as often as every 3 months.

• Digital rectal examination (DRE) at least every 12 months and as often as every 6 months.

• Repeat needle biopsy within 18 months for patients in whom the initial biopsy was 10 or more cores.

• Repeat initial biopsy within 6 months for patients in whom the initial biopsy was fewer than 10 cores.

• Consideration of a repeat biopsy for all patients as often as 12 months.

Previously, the NCCN had called for PSA testing and DREs as frequently as every 6 and 12 months, respectively, and deemed repeat needle biopsies to be optional within 6-18 months, depending on the number of cores initially biopsied, said Dr. Mohler.

Although the revised recommendations are more specific, they are still limited by the lack of quality evidence to support them, he said, noting that the first-ever North American phase III trial to compare active surveillance with mainstay prostate cancer treatments – the ongoing START (Surveillance Therapy Against Radical Treatment) study – is having trouble meeting enrollment goals because patients perceive active surveillance as "doing nothing."

In 2010, the NCCN prostate cancer guidelines recommended active surveillance as the only option for men with low-risk prostate cancer who had an estimated life expectancy less than 10 years and for men with very-low-risk prostate cancer (a newly defined patient subset) with a life expectancy less than 20 years, said Dr. Mohler, chair of the department of urology at Roswell Park Cancer Institute in Buffalo, N.Y.

Patients in the low-risk category are those with a stage T1-T2a tumor, a Gleason score of 2-6, and a PSA level less than 10 ng/mL, whereas very-low-risk patients are those with a stage T1a tumor, a Gleason score of 6 or less, a PSA level less than 10 ng/mL, fewer than three positive biopsy cores with no more than 50% cancer in each, and a PSA density below 0.15 ng/mL per gram, he explained.

Sipuleucel-T, Cabazitaxel included

The updated guidelines also outline new recommendations for systemic treatment of castration-recurrent metastatic prostate cancer, including salvage therapy with sipuleucel-T (Provenge) for asymptomatic or minimally symptomatic disease and cabazitaxel (Jevtana) as a second-line treatment option for patients who develop resistance to docetaxel (Taxotere), Dr. Mohler said.

The sipuleucel-T recommendation is based, in large part, on the recently reported findings of the phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial that showed significantly improved overall survival – although not progression-free survival – among men who were randomized to the autologous active cellular immunotherapy, compared with placebo (N. Engl. J. Med. 2010;363:411-22), Dr. Mohler said. The category 1 recommendation applies to minimally symptomatic men with an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, a life expectancy greater than 6 months, and no visceral metastases. Sipuleucel-T is not recommended for men with symptomatic disease, for whom chemotherapy with docetaxel and prednisone remains appropriate, he said.

Men with advanced prostate cancer who are not helped by docetaxel may be candidates for treatment with cabazitaxel, a second-generation taxane, according to the revised guideline. In a phase III randomized trial, treatment with the microtubule inhibitor along with prednisone led to prolonged overall and progression-free survival and improved PSA and radiologic responses, compared with mitoxantrone (Novantrone) and prednisone, said Dr. Mohler (Lancet 2010;376:1147-54). Because of an increased risk of neutropenia and other adverse effects, "treatment should be reserved for patients without severe neuropathy or impaired liver, kidney, or bone marrow function," he said.

Denosumab an Option for Bone Mets

The revised guideline also updates the recommendation for the prevention of skeletal-related events in patients with advanced prostate cancer that has metastasized to the bone with the addition of the anti-RANKL (receptor-activated nuclear factor–kappaB ligand) monoclonal antibody denosumab (Xgeva) as an alternative to zoledronic acid (Zometa).

"In men with castration-recurrent prostate cancer who have bone metastases, denosumab was shown to be superior to zoledronic acid in preventing disease-related skeletal complications, including fracture, spinal cord compression, or the need for surgery or radiation therapy to bone," Dr. Mohler said, referring to the results of a phase III randomized study (Lancet. 2011;377:813-22).

Unlike zoledronic acid, which is administered intravenously and can potentially affect renal function, denosumab is given subcutaneously and does not affect kidney function, he said; as such, it represents a "novel treatment option."

The updated NCCN prostate cancer guidelines are available at www.nccn.org. Dr. Mohler is a cofounder and chief medical officer of AndroBioSys Inc. in Buffalo, N.Y.

Major Finding: Patients with early rheumatoid arthritis rarely have radiographic progression within the first 2 years of the disease.

Data Source: Analysis of clinical indicators and radiographic progression in 529 patients from the SONORA observational early rheumatoid arthritis cohort.

Disclosures: Ms. Chen said she had no relevant financial disclosures.

CANCUN, MEXICO – Most patients with early rheumatoid arthritis do not have radiographic progression within the first 2 years of the disease, a study has shown.

Additionally, the risk of continuous radiographic progression during this period can be predicted using certain baseline indicators of disease activity, Maggie Hong Chen reported at the meeting.

An analysis of data from the Study of New-Onset Rheumatoid Arthritis (SONORA) cohort using the original Sharp method to score radiographic progression over 2 years identified the following four patterns among the 529 early arthritis patients included in the investigation: never progressed, progressed at year 1 only; progressed at year 2 only, and progressed at both year 1 and year 2, said Ms. Chen, a research fellow in the University Health Network Research Institute of the University of Toronto.

For the analysis, radiographic progression was defined as a change in total Sharp score of at least 3.5 within a year, she noted.

Of the 529 patients – all of whom were diagnosed with early rheumatoid arthritis based on symptom duration of 3-12 months and who had hand radiographs obtained at baseline, 1 year, and 2 years – 457 patients (86%) had no progression, Ms. Chen reported.

Radiographic progression in the patients at year 1, year 2, and both years 1 and 2 was observed in 18 patients (3.4%), 40 patients (7.6%), and 14 (2.6%), respectively, she said.

The investigators evaluated multiple potential clinical indicators of progression, including baseline Sharp score, baseline levels of C-reactive protein (CRP), answers to the Health Assessment Questionnaire (HAQ), swollen joint count, disease duration, anticyclic citrullinated peptide (anti-CCP) antibody status, gender, and rheumatoid factor (RF) status, as well as smoking history.

Of these potential indicators, “baseline Sharp score was a statistically significant indicator of whether the subject would progress within the 2-year period,” Ms. Chen stated, noting that, in the no-progression group, the mean baseline Sharp score was 4.06, compared with 9.33 in the 1-year progression group, 8.28 in the 2-year progression group, and 14.0 among the patients with progression both years.

Significant differences were also observed between the patterns for CRP score, baseline HAQ, swollen joint count, and anti-CCP positive status, according to Ms. Chen.

“Subjects who had no radiographic progression within the 2-year period were younger with a lower swollen joint count, a lower disease activity score [DAS], and lower CRP. They were also negative for anti-CCP and RF at baseline,” she said.

The findings of the study provide insight into the patterns and characteristics of radiographic damage in patients with early rheumatoid arthritis, “and they may also contribute to clinical decision making,” according to Ms. Chen.

The identified indicators can help rheumatologists identify patients at highest risk of continuous radiographic progression and manage them accordingly, potentially with more aggressive therapy if warranted, she said.

Major Finding: Patients with early rheumatoid arthritis rarely have radiographic progression within the first 2 years of the disease.

Data Source: Analysis of clinical indicators and radiographic progression in 529 patients from the SONORA observational early rheumatoid arthritis cohort.

Disclosures: Ms. Chen said she had no relevant financial disclosures.

CANCUN, MEXICO – Most patients with early rheumatoid arthritis do not have radiographic progression within the first 2 years of the disease, a study has shown.

Additionally, the risk of continuous radiographic progression during this period can be predicted using certain baseline indicators of disease activity, Maggie Hong Chen reported at the meeting.

An analysis of data from the Study of New-Onset Rheumatoid Arthritis (SONORA) cohort using the original Sharp method to score radiographic progression over 2 years identified the following four patterns among the 529 early arthritis patients included in the investigation: never progressed, progressed at year 1 only; progressed at year 2 only, and progressed at both year 1 and year 2, said Ms. Chen, a research fellow in the University Health Network Research Institute of the University of Toronto.

For the analysis, radiographic progression was defined as a change in total Sharp score of at least 3.5 within a year, she noted.

Of the 529 patients – all of whom were diagnosed with early rheumatoid arthritis based on symptom duration of 3-12 months and who had hand radiographs obtained at baseline, 1 year, and 2 years – 457 patients (86%) had no progression, Ms. Chen reported.

Radiographic progression in the patients at year 1, year 2, and both years 1 and 2 was observed in 18 patients (3.4%), 40 patients (7.6%), and 14 (2.6%), respectively, she said.

The investigators evaluated multiple potential clinical indicators of progression, including baseline Sharp score, baseline levels of C-reactive protein (CRP), answers to the Health Assessment Questionnaire (HAQ), swollen joint count, disease duration, anticyclic citrullinated peptide (anti-CCP) antibody status, gender, and rheumatoid factor (RF) status, as well as smoking history.

Of these potential indicators, “baseline Sharp score was a statistically significant indicator of whether the subject would progress within the 2-year period,” Ms. Chen stated, noting that, in the no-progression group, the mean baseline Sharp score was 4.06, compared with 9.33 in the 1-year progression group, 8.28 in the 2-year progression group, and 14.0 among the patients with progression both years.

Significant differences were also observed between the patterns for CRP score, baseline HAQ, swollen joint count, and anti-CCP positive status, according to Ms. Chen.

“Subjects who had no radiographic progression within the 2-year period were younger with a lower swollen joint count, a lower disease activity score [DAS], and lower CRP. They were also negative for anti-CCP and RF at baseline,” she said.

The findings of the study provide insight into the patterns and characteristics of radiographic damage in patients with early rheumatoid arthritis, “and they may also contribute to clinical decision making,” according to Ms. Chen.

The identified indicators can help rheumatologists identify patients at highest risk of continuous radiographic progression and manage them accordingly, potentially with more aggressive therapy if warranted, she said.

Major Finding: Patients with early rheumatoid arthritis rarely have radiographic progression within the first 2 years of the disease.

Data Source: Analysis of clinical indicators and radiographic progression in 529 patients from the SONORA observational early rheumatoid arthritis cohort.

Disclosures: Ms. Chen said she had no relevant financial disclosures.

CANCUN, MEXICO – Most patients with early rheumatoid arthritis do not have radiographic progression within the first 2 years of the disease, a study has shown.

Additionally, the risk of continuous radiographic progression during this period can be predicted using certain baseline indicators of disease activity, Maggie Hong Chen reported at the meeting.

An analysis of data from the Study of New-Onset Rheumatoid Arthritis (SONORA) cohort using the original Sharp method to score radiographic progression over 2 years identified the following four patterns among the 529 early arthritis patients included in the investigation: never progressed, progressed at year 1 only; progressed at year 2 only, and progressed at both year 1 and year 2, said Ms. Chen, a research fellow in the University Health Network Research Institute of the University of Toronto.

For the analysis, radiographic progression was defined as a change in total Sharp score of at least 3.5 within a year, she noted.

Of the 529 patients – all of whom were diagnosed with early rheumatoid arthritis based on symptom duration of 3-12 months and who had hand radiographs obtained at baseline, 1 year, and 2 years – 457 patients (86%) had no progression, Ms. Chen reported.

Radiographic progression in the patients at year 1, year 2, and both years 1 and 2 was observed in 18 patients (3.4%), 40 patients (7.6%), and 14 (2.6%), respectively, she said.

The investigators evaluated multiple potential clinical indicators of progression, including baseline Sharp score, baseline levels of C-reactive protein (CRP), answers to the Health Assessment Questionnaire (HAQ), swollen joint count, disease duration, anticyclic citrullinated peptide (anti-CCP) antibody status, gender, and rheumatoid factor (RF) status, as well as smoking history.

Of these potential indicators, “baseline Sharp score was a statistically significant indicator of whether the subject would progress within the 2-year period,” Ms. Chen stated, noting that, in the no-progression group, the mean baseline Sharp score was 4.06, compared with 9.33 in the 1-year progression group, 8.28 in the 2-year progression group, and 14.0 among the patients with progression both years.

Significant differences were also observed between the patterns for CRP score, baseline HAQ, swollen joint count, and anti-CCP positive status, according to Ms. Chen.

“Subjects who had no radiographic progression within the 2-year period were younger with a lower swollen joint count, a lower disease activity score [DAS], and lower CRP. They were also negative for anti-CCP and RF at baseline,” she said.

The findings of the study provide insight into the patterns and characteristics of radiographic damage in patients with early rheumatoid arthritis, “and they may also contribute to clinical decision making,” according to Ms. Chen.

The identified indicators can help rheumatologists identify patients at highest risk of continuous radiographic progression and manage them accordingly, potentially with more aggressive therapy if warranted, she said.