Susan London

SCOTTSDALE, ARIZ. – Applying a paracervical block before laparoscopic supracervical hysterectomy improves some operative outcomes but not others, Dr. Rachel L. Barr said at the annual scientific meeting of the Society of Gynecologic Surgeons.

The 132 women undergoing scheduled ambulatory surgery for presumed benign indications were randomized evenly to receive paracervical injection of bupivacaine plus epinephrine or paracervical injection of normal saline as a placebo control, each in addition to standard anesthesia.

Overall, about one-third of women were admitted to the hospital after the surgery – the trial’s primary outcome – with no significant difference between groups, reported lead investigator Dr. Rachel L. Barr, an obstetrician-gynecologist at Mount Sinai Hospital in New York. The findings were similar when restricted to women admitted specifically for pain management.

The paracervical-block group consumed about one-tenth of a tablet less of narcotics per day after surgery. They also had significantly lower estimated blood loss, although the median value was identical at 100 mL.

"The paracervical block with bupivacaine and epinephrine before laparoscopic supracervical hysterectomy is recommended to decrease the number of postoperative narcotic tablets consumed. It has the additional benefit of decreased blood loss and was found to be safe," Dr. Barr commented. "However, it was not effective at decreasing admissions for pain control."

"My first question for the authors relates to the clinical vs. statistical significance of the estimated blood loss and its variability in measurement and whether the authors considered using hematocrit in the study design," said invited discussant Dr. Clifford Wai of the division of female pelvic medicine and reconstructive surgery, University of Texas Southwestern Medical Center, Dallas.

The attending surgeon who performed all of the hysterectomies was very experienced, which likely helped achieve fairly low estimated blood loss in general, according to Dr. Barr. "So within this population, maybe the 50-mL difference between the two groups [in interquartile ranges] may not be that clinically significant."

"However, if you were to generalize this to other surgeons who maybe don’t do quite as many laparoscopic supracervical hysterectomies or on average have a higher blood loss, there may be a role for the paracervical block in helping decrease their blood loss, and you may see a larger decrease in blood loss when using the block," she added. "In addition, I think the block can be used as a tool to reduce blood loss in cases where, based on uterine size or pathology, you might predict there would be a higher blood loss, or in patients who have a lower hematocrit to begin with and refuse transfusions; this might decrease their blood loss and improve their recovery."

The investigators did not use hematocrit because they expected many patients to go home after surgery, and they do not routinely obtain a complete blood cell count in the postanesthesia care unit unless there is a clinical indication, she said at the meeting jointly sponsored by the American College of Surgeons.

"My second question is, given the limitations of the study, do the authors feel the conclusions justify a change in clinical practice?" Dr. Wai asked.

"We do now use the paracervical block with bupivacaine and epinephrine for all of our patients prior to laparoscopic supracervical hysterectomy," Dr. Barr replied.

Session attendee Dr. William W. Hurd, professor of obstetrics and gynecology at Duke University, Durham, N.C., and director of the division of reproductive endocrinology and infertility at the Duke Fertility Center, wondered, "Do you think that tiny change in pain medication would be clinically significant?"

"I do," Dr. Barr answered. "Maybe it’s not clinically significant just looking at that one value. But when you are talking to your patients preoperatively and they are asking, ‘Doctor, am I going to be taking tons of narcotics after? Am I going to get addicted?’ I think you can reassure them that over their postoperative course they might only need to take one or two tablets instead of two or three over several days. This might not seem like a lot to us, but I think that difference is reassuring to our patients."

The investigators studied patients undergoing laparoscopic supracervical hysterectomy at Mount Sinai Hospital between 2011 and 2013.

"In designing our study, we had noted that many patients at our institution were staying overnight electively in the hospital for pain management despite otherwise being stable for discharge home following laparoscopic hysterectomy," noted Dr. Barr.

The paracervical injection was performed after intubation but before the uterine manipulator was inserted or the abdominal incision was made. Admission was defined as at least one overnight stay in the hospital.

Results showed that the paracervical block and control groups were statistically indistinguishable with respect to the overall admission rate (41% vs. 28%) and the unplanned admission rate (34% vs. 27%). In the subset with an unplanned admission, 21 women were admitted for pain management: 10 in the paracervical-block group and 11 in the control group.

Use of fentanyl and use of oxycodone while in the postanesthesia care unit did not differ significantly between groups. However, in the first 14 days after surgery, the paracervical block group consumed fewer tablets of narcotics per day (0.58 vs. 0.71) and more tablets of over-the-counter analgesics per day (1.02 vs. 0.77). Mean pain scores during the first 2 postoperative days were essentially the same.

"Maybe the patients who didn’t have the block were using narcotics more to achieve a lower pain score. That’s one way to think about it," Dr. Barr proposed.

The two groups had similar rates of perioperative outcomes such as operative time and complications. Estimated median blood loss was generally low, but significantly lower in the paracervical block group.

"Out of all 132 patients, we only had 7 patients who had a blood loss greater than or equal to 500 mL, and the largest blood loss was 900 mL. Also, there were no transfusions," she pointed out.

Three patients – two in the paracervical block group and one in the control group – developed a cervical infection after surgery. All were successfully treated with oral antibiotics.

"The hysterectomies were all supracervical so the results may not apply to total hysterectomies, and we did not control for additional procedures performed at the same time," Dr. Barr noted.

Dr. Barr disclosed no relevant conflicts of interest.

SCOTTSDALE, ARIZ. – Applying a paracervical block before laparoscopic supracervical hysterectomy improves some operative outcomes but not others, Dr. Rachel L. Barr said at the annual scientific meeting of the Society of Gynecologic Surgeons.

The 132 women undergoing scheduled ambulatory surgery for presumed benign indications were randomized evenly to receive paracervical injection of bupivacaine plus epinephrine or paracervical injection of normal saline as a placebo control, each in addition to standard anesthesia.

Overall, about one-third of women were admitted to the hospital after the surgery – the trial’s primary outcome – with no significant difference between groups, reported lead investigator Dr. Rachel L. Barr, an obstetrician-gynecologist at Mount Sinai Hospital in New York. The findings were similar when restricted to women admitted specifically for pain management.

The paracervical-block group consumed about one-tenth of a tablet less of narcotics per day after surgery. They also had significantly lower estimated blood loss, although the median value was identical at 100 mL.

"The paracervical block with bupivacaine and epinephrine before laparoscopic supracervical hysterectomy is recommended to decrease the number of postoperative narcotic tablets consumed. It has the additional benefit of decreased blood loss and was found to be safe," Dr. Barr commented. "However, it was not effective at decreasing admissions for pain control."

"My first question for the authors relates to the clinical vs. statistical significance of the estimated blood loss and its variability in measurement and whether the authors considered using hematocrit in the study design," said invited discussant Dr. Clifford Wai of the division of female pelvic medicine and reconstructive surgery, University of Texas Southwestern Medical Center, Dallas.

The attending surgeon who performed all of the hysterectomies was very experienced, which likely helped achieve fairly low estimated blood loss in general, according to Dr. Barr. "So within this population, maybe the 50-mL difference between the two groups [in interquartile ranges] may not be that clinically significant."

"However, if you were to generalize this to other surgeons who maybe don’t do quite as many laparoscopic supracervical hysterectomies or on average have a higher blood loss, there may be a role for the paracervical block in helping decrease their blood loss, and you may see a larger decrease in blood loss when using the block," she added. "In addition, I think the block can be used as a tool to reduce blood loss in cases where, based on uterine size or pathology, you might predict there would be a higher blood loss, or in patients who have a lower hematocrit to begin with and refuse transfusions; this might decrease their blood loss and improve their recovery."

The investigators did not use hematocrit because they expected many patients to go home after surgery, and they do not routinely obtain a complete blood cell count in the postanesthesia care unit unless there is a clinical indication, she said at the meeting jointly sponsored by the American College of Surgeons.

"My second question is, given the limitations of the study, do the authors feel the conclusions justify a change in clinical practice?" Dr. Wai asked.

"We do now use the paracervical block with bupivacaine and epinephrine for all of our patients prior to laparoscopic supracervical hysterectomy," Dr. Barr replied.

Session attendee Dr. William W. Hurd, professor of obstetrics and gynecology at Duke University, Durham, N.C., and director of the division of reproductive endocrinology and infertility at the Duke Fertility Center, wondered, "Do you think that tiny change in pain medication would be clinically significant?"

"I do," Dr. Barr answered. "Maybe it’s not clinically significant just looking at that one value. But when you are talking to your patients preoperatively and they are asking, ‘Doctor, am I going to be taking tons of narcotics after? Am I going to get addicted?’ I think you can reassure them that over their postoperative course they might only need to take one or two tablets instead of two or three over several days. This might not seem like a lot to us, but I think that difference is reassuring to our patients."

The investigators studied patients undergoing laparoscopic supracervical hysterectomy at Mount Sinai Hospital between 2011 and 2013.

"In designing our study, we had noted that many patients at our institution were staying overnight electively in the hospital for pain management despite otherwise being stable for discharge home following laparoscopic hysterectomy," noted Dr. Barr.

The paracervical injection was performed after intubation but before the uterine manipulator was inserted or the abdominal incision was made. Admission was defined as at least one overnight stay in the hospital.

Results showed that the paracervical block and control groups were statistically indistinguishable with respect to the overall admission rate (41% vs. 28%) and the unplanned admission rate (34% vs. 27%). In the subset with an unplanned admission, 21 women were admitted for pain management: 10 in the paracervical-block group and 11 in the control group.

Use of fentanyl and use of oxycodone while in the postanesthesia care unit did not differ significantly between groups. However, in the first 14 days after surgery, the paracervical block group consumed fewer tablets of narcotics per day (0.58 vs. 0.71) and more tablets of over-the-counter analgesics per day (1.02 vs. 0.77). Mean pain scores during the first 2 postoperative days were essentially the same.

"Maybe the patients who didn’t have the block were using narcotics more to achieve a lower pain score. That’s one way to think about it," Dr. Barr proposed.

The two groups had similar rates of perioperative outcomes such as operative time and complications. Estimated median blood loss was generally low, but significantly lower in the paracervical block group.

"Out of all 132 patients, we only had 7 patients who had a blood loss greater than or equal to 500 mL, and the largest blood loss was 900 mL. Also, there were no transfusions," she pointed out.

Three patients – two in the paracervical block group and one in the control group – developed a cervical infection after surgery. All were successfully treated with oral antibiotics.

"The hysterectomies were all supracervical so the results may not apply to total hysterectomies, and we did not control for additional procedures performed at the same time," Dr. Barr noted.

Dr. Barr disclosed no relevant conflicts of interest.

SCOTTSDALE, ARIZ. – Applying a paracervical block before laparoscopic supracervical hysterectomy improves some operative outcomes but not others, Dr. Rachel L. Barr said at the annual scientific meeting of the Society of Gynecologic Surgeons.

The 132 women undergoing scheduled ambulatory surgery for presumed benign indications were randomized evenly to receive paracervical injection of bupivacaine plus epinephrine or paracervical injection of normal saline as a placebo control, each in addition to standard anesthesia.

Overall, about one-third of women were admitted to the hospital after the surgery – the trial’s primary outcome – with no significant difference between groups, reported lead investigator Dr. Rachel L. Barr, an obstetrician-gynecologist at Mount Sinai Hospital in New York. The findings were similar when restricted to women admitted specifically for pain management.

The paracervical-block group consumed about one-tenth of a tablet less of narcotics per day after surgery. They also had significantly lower estimated blood loss, although the median value was identical at 100 mL.

"The paracervical block with bupivacaine and epinephrine before laparoscopic supracervical hysterectomy is recommended to decrease the number of postoperative narcotic tablets consumed. It has the additional benefit of decreased blood loss and was found to be safe," Dr. Barr commented. "However, it was not effective at decreasing admissions for pain control."

"My first question for the authors relates to the clinical vs. statistical significance of the estimated blood loss and its variability in measurement and whether the authors considered using hematocrit in the study design," said invited discussant Dr. Clifford Wai of the division of female pelvic medicine and reconstructive surgery, University of Texas Southwestern Medical Center, Dallas.

The attending surgeon who performed all of the hysterectomies was very experienced, which likely helped achieve fairly low estimated blood loss in general, according to Dr. Barr. "So within this population, maybe the 50-mL difference between the two groups [in interquartile ranges] may not be that clinically significant."

"However, if you were to generalize this to other surgeons who maybe don’t do quite as many laparoscopic supracervical hysterectomies or on average have a higher blood loss, there may be a role for the paracervical block in helping decrease their blood loss, and you may see a larger decrease in blood loss when using the block," she added. "In addition, I think the block can be used as a tool to reduce blood loss in cases where, based on uterine size or pathology, you might predict there would be a higher blood loss, or in patients who have a lower hematocrit to begin with and refuse transfusions; this might decrease their blood loss and improve their recovery."

The investigators did not use hematocrit because they expected many patients to go home after surgery, and they do not routinely obtain a complete blood cell count in the postanesthesia care unit unless there is a clinical indication, she said at the meeting jointly sponsored by the American College of Surgeons.

"My second question is, given the limitations of the study, do the authors feel the conclusions justify a change in clinical practice?" Dr. Wai asked.

"We do now use the paracervical block with bupivacaine and epinephrine for all of our patients prior to laparoscopic supracervical hysterectomy," Dr. Barr replied.

Session attendee Dr. William W. Hurd, professor of obstetrics and gynecology at Duke University, Durham, N.C., and director of the division of reproductive endocrinology and infertility at the Duke Fertility Center, wondered, "Do you think that tiny change in pain medication would be clinically significant?"

"I do," Dr. Barr answered. "Maybe it’s not clinically significant just looking at that one value. But when you are talking to your patients preoperatively and they are asking, ‘Doctor, am I going to be taking tons of narcotics after? Am I going to get addicted?’ I think you can reassure them that over their postoperative course they might only need to take one or two tablets instead of two or three over several days. This might not seem like a lot to us, but I think that difference is reassuring to our patients."

The investigators studied patients undergoing laparoscopic supracervical hysterectomy at Mount Sinai Hospital between 2011 and 2013.

"In designing our study, we had noted that many patients at our institution were staying overnight electively in the hospital for pain management despite otherwise being stable for discharge home following laparoscopic hysterectomy," noted Dr. Barr.

The paracervical injection was performed after intubation but before the uterine manipulator was inserted or the abdominal incision was made. Admission was defined as at least one overnight stay in the hospital.

Results showed that the paracervical block and control groups were statistically indistinguishable with respect to the overall admission rate (41% vs. 28%) and the unplanned admission rate (34% vs. 27%). In the subset with an unplanned admission, 21 women were admitted for pain management: 10 in the paracervical-block group and 11 in the control group.

Use of fentanyl and use of oxycodone while in the postanesthesia care unit did not differ significantly between groups. However, in the first 14 days after surgery, the paracervical block group consumed fewer tablets of narcotics per day (0.58 vs. 0.71) and more tablets of over-the-counter analgesics per day (1.02 vs. 0.77). Mean pain scores during the first 2 postoperative days were essentially the same.

"Maybe the patients who didn’t have the block were using narcotics more to achieve a lower pain score. That’s one way to think about it," Dr. Barr proposed.

The two groups had similar rates of perioperative outcomes such as operative time and complications. Estimated median blood loss was generally low, but significantly lower in the paracervical block group.

"Out of all 132 patients, we only had 7 patients who had a blood loss greater than or equal to 500 mL, and the largest blood loss was 900 mL. Also, there were no transfusions," she pointed out.

Three patients – two in the paracervical block group and one in the control group – developed a cervical infection after surgery. All were successfully treated with oral antibiotics.

"The hysterectomies were all supracervical so the results may not apply to total hysterectomies, and we did not control for additional procedures performed at the same time," Dr. Barr noted.

Dr. Barr disclosed no relevant conflicts of interest.

SCOTTSDALE, ARIZ. – The advent of robotic technology has shifted both the approach used for hysterectomies and the involvement of residents in this surgery, suggest results of a retrospective cohort study reported at the annual meeting of the Society of Gynecologic Surgeons.

Researchers studied women undergoing hysterectomy at four hospitals that had both residents and fellows, comparing 732 surgeries from the pre-robot era (the year before the first robotic hysterectomy at the hospital) with 709 from the postrobot era (2011).

Results showed a significant decrease in the proportion of all hysterectomies that were total vaginal hysterectomies from 43% to 31%. Meanwhile, robotic hysterectomies accounted for 23% of the total by 2011.

In other findings, there was no significant change in the proportion of all hysterectomies having at least some resident involvement, according to operative reports: That value stood at 81% before robotic hysterectomy began and 82% afterward. However, in the postrobot era, residents were involved in nearly 89% of all nonrobotic hysterectomies, but only about 59% of robotic ones.

"These data provide early data on potential implications for robotic implementation," commented first author Dr. Peter C. Jeppson, a urogynecology fellow at Brown University, Providence, R.I. "At this point, the impact of the increasing diversity of hysterectomy approaches on resident education warrants further study."

"Resident involvement was based on dictated operative reports, so we do not know how much of each case was actually performed by the resident," he acknowledged at the meeting jointly sponsored by the American College of Surgeons. "However, one could argue that observing or assisting in more surgical cases provides important educational experience."

Invited discussant Dr. Shawn A. Menefee, an obstetrician-gynecologist at Kaiser Permanente, San Diego, noted, "While the rates of vaginal hysterectomy decreased in the postrobotic period, they still remained above what has been reported in the past. ... Given that resident training often reflects what technique is performed over a surgeon’s career, what impact do you believe this decrease in TVH [total vaginal hysterectomy] rates will have in the United States?"

"At this point, it’s a little bit speculative to state how this will impact the future global rates within the United States," Dr. Jeppson replied. "But I think that it is certainly possible that as the numbers decrease in training, that those numbers also decrease for postgraduates because it seems unlikely to me that residents in training, after graduating, would choose to do a procedure that they weren’t trained to do well."

Dr. Menefee noted that about one-fifth of cases were done by attendings who were urogynecologists. "Is vaginal hysterectomy becoming a procedure performed by subspecialists, and if you remove the urogynecologists at the sites, what would be the percentage of transvaginal hysterectomies performed?" he asked.

Urogynecologists performed about 40% of all hysterectomies in both eras, according to Dr. Jeppson. When these hysterectomies were removed from analyses, the share of the total that were done vaginally still fell, from 31% to 22%.

"While robotic hysterectomy offers limited-to-no benefits for benign hysterectomy, compared with other minimally invasive approaches, it does appear to impact residents’ already limited exposure. Can we adequately teach residents to safely perform multiple approaches, or do we have to choose which ones to teach?" Dr. Menefee wondered.

"My personal opinion is that we should be training residents to perform what’s best for the patients. So different patients may need a different type of surgery," Dr. Jeppson replied. "But with the restrictions placed on duty work hours and with the increasing diversity of the approaches that can be used, that may be difficult. But time will tell."

Session attendee Dr. Hal C. Lawrence III, executive vice president and CEO of the American Congress of Obstetricians and Gynecologists, asked, "What do you think we need to do as a specialty to get people back to doing vaginal surgery, which is just as effective, a whole lot less expensive, and has fewer complications?"

"I think that that will be something that we will have to address on the national level," Dr. Jeppson commented. "But having a commitment to vaginal surgery would be the place to start – there are other modalities that are important and useful, but to not abandon the proven approaches that have been established over a long period of time."

For the study, the researchers analyzed hysterectomies captured by the Fellows’ Pelvic Research Network, excluding those performed in the oncology setting and those done for emergent indications.

The women undergoing hysterectomy in the pre- and postrobot eras did not differ significantly with respect to age, body mass index, prior abdominal or pelvic surgery, insurance type, or mean uterine weight, reported Dr. Jeppson. Also, dysfunctional uterine bleeding was the most common indication for hysterectomy in both groups.

In addition to the observed decrease in vaginal hysterectomies and increase in robotic hysterectomies, there was also a significant reduction in the proportion of total abdominal hysterectomies, from 22% to 17%.

Dr. Jeppson disclosed no relevant conflicts of interest.

SCOTTSDALE, ARIZ. – The advent of robotic technology has shifted both the approach used for hysterectomies and the involvement of residents in this surgery, suggest results of a retrospective cohort study reported at the annual meeting of the Society of Gynecologic Surgeons.

Researchers studied women undergoing hysterectomy at four hospitals that had both residents and fellows, comparing 732 surgeries from the pre-robot era (the year before the first robotic hysterectomy at the hospital) with 709 from the postrobot era (2011).

Results showed a significant decrease in the proportion of all hysterectomies that were total vaginal hysterectomies from 43% to 31%. Meanwhile, robotic hysterectomies accounted for 23% of the total by 2011.

In other findings, there was no significant change in the proportion of all hysterectomies having at least some resident involvement, according to operative reports: That value stood at 81% before robotic hysterectomy began and 82% afterward. However, in the postrobot era, residents were involved in nearly 89% of all nonrobotic hysterectomies, but only about 59% of robotic ones.

"These data provide early data on potential implications for robotic implementation," commented first author Dr. Peter C. Jeppson, a urogynecology fellow at Brown University, Providence, R.I. "At this point, the impact of the increasing diversity of hysterectomy approaches on resident education warrants further study."

"Resident involvement was based on dictated operative reports, so we do not know how much of each case was actually performed by the resident," he acknowledged at the meeting jointly sponsored by the American College of Surgeons. "However, one could argue that observing or assisting in more surgical cases provides important educational experience."

Invited discussant Dr. Shawn A. Menefee, an obstetrician-gynecologist at Kaiser Permanente, San Diego, noted, "While the rates of vaginal hysterectomy decreased in the postrobotic period, they still remained above what has been reported in the past. ... Given that resident training often reflects what technique is performed over a surgeon’s career, what impact do you believe this decrease in TVH [total vaginal hysterectomy] rates will have in the United States?"

"At this point, it’s a little bit speculative to state how this will impact the future global rates within the United States," Dr. Jeppson replied. "But I think that it is certainly possible that as the numbers decrease in training, that those numbers also decrease for postgraduates because it seems unlikely to me that residents in training, after graduating, would choose to do a procedure that they weren’t trained to do well."

Dr. Menefee noted that about one-fifth of cases were done by attendings who were urogynecologists. "Is vaginal hysterectomy becoming a procedure performed by subspecialists, and if you remove the urogynecologists at the sites, what would be the percentage of transvaginal hysterectomies performed?" he asked.

Urogynecologists performed about 40% of all hysterectomies in both eras, according to Dr. Jeppson. When these hysterectomies were removed from analyses, the share of the total that were done vaginally still fell, from 31% to 22%.

"While robotic hysterectomy offers limited-to-no benefits for benign hysterectomy, compared with other minimally invasive approaches, it does appear to impact residents’ already limited exposure. Can we adequately teach residents to safely perform multiple approaches, or do we have to choose which ones to teach?" Dr. Menefee wondered.

"My personal opinion is that we should be training residents to perform what’s best for the patients. So different patients may need a different type of surgery," Dr. Jeppson replied. "But with the restrictions placed on duty work hours and with the increasing diversity of the approaches that can be used, that may be difficult. But time will tell."

Session attendee Dr. Hal C. Lawrence III, executive vice president and CEO of the American Congress of Obstetricians and Gynecologists, asked, "What do you think we need to do as a specialty to get people back to doing vaginal surgery, which is just as effective, a whole lot less expensive, and has fewer complications?"

"I think that that will be something that we will have to address on the national level," Dr. Jeppson commented. "But having a commitment to vaginal surgery would be the place to start – there are other modalities that are important and useful, but to not abandon the proven approaches that have been established over a long period of time."

For the study, the researchers analyzed hysterectomies captured by the Fellows’ Pelvic Research Network, excluding those performed in the oncology setting and those done for emergent indications.

The women undergoing hysterectomy in the pre- and postrobot eras did not differ significantly with respect to age, body mass index, prior abdominal or pelvic surgery, insurance type, or mean uterine weight, reported Dr. Jeppson. Also, dysfunctional uterine bleeding was the most common indication for hysterectomy in both groups.

In addition to the observed decrease in vaginal hysterectomies and increase in robotic hysterectomies, there was also a significant reduction in the proportion of total abdominal hysterectomies, from 22% to 17%.

Dr. Jeppson disclosed no relevant conflicts of interest.

SCOTTSDALE, ARIZ. – The advent of robotic technology has shifted both the approach used for hysterectomies and the involvement of residents in this surgery, suggest results of a retrospective cohort study reported at the annual meeting of the Society of Gynecologic Surgeons.

Researchers studied women undergoing hysterectomy at four hospitals that had both residents and fellows, comparing 732 surgeries from the pre-robot era (the year before the first robotic hysterectomy at the hospital) with 709 from the postrobot era (2011).

Results showed a significant decrease in the proportion of all hysterectomies that were total vaginal hysterectomies from 43% to 31%. Meanwhile, robotic hysterectomies accounted for 23% of the total by 2011.

In other findings, there was no significant change in the proportion of all hysterectomies having at least some resident involvement, according to operative reports: That value stood at 81% before robotic hysterectomy began and 82% afterward. However, in the postrobot era, residents were involved in nearly 89% of all nonrobotic hysterectomies, but only about 59% of robotic ones.

"These data provide early data on potential implications for robotic implementation," commented first author Dr. Peter C. Jeppson, a urogynecology fellow at Brown University, Providence, R.I. "At this point, the impact of the increasing diversity of hysterectomy approaches on resident education warrants further study."

"Resident involvement was based on dictated operative reports, so we do not know how much of each case was actually performed by the resident," he acknowledged at the meeting jointly sponsored by the American College of Surgeons. "However, one could argue that observing or assisting in more surgical cases provides important educational experience."

Invited discussant Dr. Shawn A. Menefee, an obstetrician-gynecologist at Kaiser Permanente, San Diego, noted, "While the rates of vaginal hysterectomy decreased in the postrobotic period, they still remained above what has been reported in the past. ... Given that resident training often reflects what technique is performed over a surgeon’s career, what impact do you believe this decrease in TVH [total vaginal hysterectomy] rates will have in the United States?"

"At this point, it’s a little bit speculative to state how this will impact the future global rates within the United States," Dr. Jeppson replied. "But I think that it is certainly possible that as the numbers decrease in training, that those numbers also decrease for postgraduates because it seems unlikely to me that residents in training, after graduating, would choose to do a procedure that they weren’t trained to do well."

Dr. Menefee noted that about one-fifth of cases were done by attendings who were urogynecologists. "Is vaginal hysterectomy becoming a procedure performed by subspecialists, and if you remove the urogynecologists at the sites, what would be the percentage of transvaginal hysterectomies performed?" he asked.

Urogynecologists performed about 40% of all hysterectomies in both eras, according to Dr. Jeppson. When these hysterectomies were removed from analyses, the share of the total that were done vaginally still fell, from 31% to 22%.

"While robotic hysterectomy offers limited-to-no benefits for benign hysterectomy, compared with other minimally invasive approaches, it does appear to impact residents’ already limited exposure. Can we adequately teach residents to safely perform multiple approaches, or do we have to choose which ones to teach?" Dr. Menefee wondered.

"My personal opinion is that we should be training residents to perform what’s best for the patients. So different patients may need a different type of surgery," Dr. Jeppson replied. "But with the restrictions placed on duty work hours and with the increasing diversity of the approaches that can be used, that may be difficult. But time will tell."

Session attendee Dr. Hal C. Lawrence III, executive vice president and CEO of the American Congress of Obstetricians and Gynecologists, asked, "What do you think we need to do as a specialty to get people back to doing vaginal surgery, which is just as effective, a whole lot less expensive, and has fewer complications?"

"I think that that will be something that we will have to address on the national level," Dr. Jeppson commented. "But having a commitment to vaginal surgery would be the place to start – there are other modalities that are important and useful, but to not abandon the proven approaches that have been established over a long period of time."

For the study, the researchers analyzed hysterectomies captured by the Fellows’ Pelvic Research Network, excluding those performed in the oncology setting and those done for emergent indications.

The women undergoing hysterectomy in the pre- and postrobot eras did not differ significantly with respect to age, body mass index, prior abdominal or pelvic surgery, insurance type, or mean uterine weight, reported Dr. Jeppson. Also, dysfunctional uterine bleeding was the most common indication for hysterectomy in both groups.

In addition to the observed decrease in vaginal hysterectomies and increase in robotic hysterectomies, there was also a significant reduction in the proportion of total abdominal hysterectomies, from 22% to 17%.

Dr. Jeppson disclosed no relevant conflicts of interest.

SCOTTSDALE, ARIZ. – Using a Foley catheter guide during midurethral sling surgery does not appear to reduce the risk of injury to the bladder and urethra, according to a retrospective study presented at the annual scientific meeting of the Society of Gynecologic Surgeons.

Surgeons used the guide in 24.5% of the 310 women undergoing retropubic midurethral sling surgery, reported first author Dr. Jeannine M. Miranne, an ob.gyn. at Medstar Washington Hospital Center and Georgetown University, Washington.

The rate of cystotomy was 1.3% in the guide group and 5.6% in the no-guide group, a statistically indistinguishable difference and one that remained so even after adjustment for potential confounders. None of the patients studied experienced a urethrotomy.

"Foley catheter guide use does not decrease the risk of intraoperative lower urinary tract injury. However, larger prospective studies are needed to confirm this finding, given the possibility of a type 2 error," Dr. Miranne concluded.

Session attendee Dr. Eric Sokol, an assistant professor of obstetrics and gynecology, and of urology at Stanford (Calif.) University, wondered if injury rates were affected by the specific sling used.

"What I imagine has possibly influenced your results is the fact that you have changed also the sling that you use. As I understand it, you are using a lot of Advantage Fit slings," he said. In his experience in training residents, the bladder is often inadvertently punctured when this sling is used. "When I use other slings, with a rigid handle and a bigger curve, they don’t go in the bladder. So do you think there might be an influence of the exact sling that you are using?"

"There definitely may be an influence," Dr. Miranne replied. "Unfortunately, the majority of physicians in our group used the Advantage Fit sling for approximately 90% of their cases that were included. So it’s really hard to determine whether or not that played a role in the cystotomy rate in our study. But that’s definitely something to consider when you think about cystotomy – the type of retropubic sling."

Another attendee commented that using a Foley catheter guide adds an annoying, time-consuming step to the surgery. "It wasn’t our idea, but we have used the cystoscope shaft, and we will use that to manipulate the urethra. You have to put that in anyway to scope the patient, and it saves a lot of time putting things in and taking them out," he said at the meeting, which was jointly sponsored by the American College of Surgeons.

Giving some background to the study, Dr. Miranne said that "synthetic midurethral sling has become a gold-standard surgical procedure for stress urinary incontinence. Different techniques have been introduced to decrease the risk of intraoperative lower urinary tract injury during sling placement. One such technique involves use of a rigid Foley catheter guide during retropubic sling placement."

"Although the manufacturer of the original tension-free vaginal tape continues to recommend Foley catheter guide use in its instructions, it is unclear whether use of this device decreases the risk of intraoperative lower urinary tract injury," she noted.

For the study, the investigators included women undergoing retropubic midurethral sling surgery at a single academic center during 2011 and 2012. They excluded any who underwent autologous bladder neck, transobturator, or mini-/single-incision sling surgery.

On average, the patients were 57 years old and had a body mass index of 28 kg/m², according to Dr. Miranne. Overall, 17% had previously undergone anti-incontinence surgery and 20% had previously undergone prolapse surgery, with no significant difference between groups.

Patients in the no-guide group were more likely to have anterior prolapse (95% vs. 78%) and to have a concomitant prolapse repair (65% vs. 51%). They were less likely to have a resident or fellow as first assistant in the surgery (91% vs. 99%) and to have local retropubic anesthesia (71% vs. 96%). Similar proportions had a concomitant hysterectomy.

In addition to showing no significant difference in injury rates, analyses revealed that the groups were statistically the same with respect to mean intraoperative time; mean blood loss; and mean hospital stay, which was less than 1 day for the entire cohort.

Dr. Miranne disclosed no relevant conflicts of interest.

SCOTTSDALE, ARIZ. – Using a Foley catheter guide during midurethral sling surgery does not appear to reduce the risk of injury to the bladder and urethra, according to a retrospective study presented at the annual scientific meeting of the Society of Gynecologic Surgeons.

Surgeons used the guide in 24.5% of the 310 women undergoing retropubic midurethral sling surgery, reported first author Dr. Jeannine M. Miranne, an ob.gyn. at Medstar Washington Hospital Center and Georgetown University, Washington.

The rate of cystotomy was 1.3% in the guide group and 5.6% in the no-guide group, a statistically indistinguishable difference and one that remained so even after adjustment for potential confounders. None of the patients studied experienced a urethrotomy.

"Foley catheter guide use does not decrease the risk of intraoperative lower urinary tract injury. However, larger prospective studies are needed to confirm this finding, given the possibility of a type 2 error," Dr. Miranne concluded.

Session attendee Dr. Eric Sokol, an assistant professor of obstetrics and gynecology, and of urology at Stanford (Calif.) University, wondered if injury rates were affected by the specific sling used.

"What I imagine has possibly influenced your results is the fact that you have changed also the sling that you use. As I understand it, you are using a lot of Advantage Fit slings," he said. In his experience in training residents, the bladder is often inadvertently punctured when this sling is used. "When I use other slings, with a rigid handle and a bigger curve, they don’t go in the bladder. So do you think there might be an influence of the exact sling that you are using?"

"There definitely may be an influence," Dr. Miranne replied. "Unfortunately, the majority of physicians in our group used the Advantage Fit sling for approximately 90% of their cases that were included. So it’s really hard to determine whether or not that played a role in the cystotomy rate in our study. But that’s definitely something to consider when you think about cystotomy – the type of retropubic sling."

Another attendee commented that using a Foley catheter guide adds an annoying, time-consuming step to the surgery. "It wasn’t our idea, but we have used the cystoscope shaft, and we will use that to manipulate the urethra. You have to put that in anyway to scope the patient, and it saves a lot of time putting things in and taking them out," he said at the meeting, which was jointly sponsored by the American College of Surgeons.

Giving some background to the study, Dr. Miranne said that "synthetic midurethral sling has become a gold-standard surgical procedure for stress urinary incontinence. Different techniques have been introduced to decrease the risk of intraoperative lower urinary tract injury during sling placement. One such technique involves use of a rigid Foley catheter guide during retropubic sling placement."

"Although the manufacturer of the original tension-free vaginal tape continues to recommend Foley catheter guide use in its instructions, it is unclear whether use of this device decreases the risk of intraoperative lower urinary tract injury," she noted.

For the study, the investigators included women undergoing retropubic midurethral sling surgery at a single academic center during 2011 and 2012. They excluded any who underwent autologous bladder neck, transobturator, or mini-/single-incision sling surgery.

On average, the patients were 57 years old and had a body mass index of 28 kg/m², according to Dr. Miranne. Overall, 17% had previously undergone anti-incontinence surgery and 20% had previously undergone prolapse surgery, with no significant difference between groups.

Patients in the no-guide group were more likely to have anterior prolapse (95% vs. 78%) and to have a concomitant prolapse repair (65% vs. 51%). They were less likely to have a resident or fellow as first assistant in the surgery (91% vs. 99%) and to have local retropubic anesthesia (71% vs. 96%). Similar proportions had a concomitant hysterectomy.

In addition to showing no significant difference in injury rates, analyses revealed that the groups were statistically the same with respect to mean intraoperative time; mean blood loss; and mean hospital stay, which was less than 1 day for the entire cohort.

Dr. Miranne disclosed no relevant conflicts of interest.

SCOTTSDALE, ARIZ. – Using a Foley catheter guide during midurethral sling surgery does not appear to reduce the risk of injury to the bladder and urethra, according to a retrospective study presented at the annual scientific meeting of the Society of Gynecologic Surgeons.

Surgeons used the guide in 24.5% of the 310 women undergoing retropubic midurethral sling surgery, reported first author Dr. Jeannine M. Miranne, an ob.gyn. at Medstar Washington Hospital Center and Georgetown University, Washington.

The rate of cystotomy was 1.3% in the guide group and 5.6% in the no-guide group, a statistically indistinguishable difference and one that remained so even after adjustment for potential confounders. None of the patients studied experienced a urethrotomy.

"Foley catheter guide use does not decrease the risk of intraoperative lower urinary tract injury. However, larger prospective studies are needed to confirm this finding, given the possibility of a type 2 error," Dr. Miranne concluded.

Session attendee Dr. Eric Sokol, an assistant professor of obstetrics and gynecology, and of urology at Stanford (Calif.) University, wondered if injury rates were affected by the specific sling used.

"What I imagine has possibly influenced your results is the fact that you have changed also the sling that you use. As I understand it, you are using a lot of Advantage Fit slings," he said. In his experience in training residents, the bladder is often inadvertently punctured when this sling is used. "When I use other slings, with a rigid handle and a bigger curve, they don’t go in the bladder. So do you think there might be an influence of the exact sling that you are using?"

"There definitely may be an influence," Dr. Miranne replied. "Unfortunately, the majority of physicians in our group used the Advantage Fit sling for approximately 90% of their cases that were included. So it’s really hard to determine whether or not that played a role in the cystotomy rate in our study. But that’s definitely something to consider when you think about cystotomy – the type of retropubic sling."

Another attendee commented that using a Foley catheter guide adds an annoying, time-consuming step to the surgery. "It wasn’t our idea, but we have used the cystoscope shaft, and we will use that to manipulate the urethra. You have to put that in anyway to scope the patient, and it saves a lot of time putting things in and taking them out," he said at the meeting, which was jointly sponsored by the American College of Surgeons.

Giving some background to the study, Dr. Miranne said that "synthetic midurethral sling has become a gold-standard surgical procedure for stress urinary incontinence. Different techniques have been introduced to decrease the risk of intraoperative lower urinary tract injury during sling placement. One such technique involves use of a rigid Foley catheter guide during retropubic sling placement."

"Although the manufacturer of the original tension-free vaginal tape continues to recommend Foley catheter guide use in its instructions, it is unclear whether use of this device decreases the risk of intraoperative lower urinary tract injury," she noted.

For the study, the investigators included women undergoing retropubic midurethral sling surgery at a single academic center during 2011 and 2012. They excluded any who underwent autologous bladder neck, transobturator, or mini-/single-incision sling surgery.

On average, the patients were 57 years old and had a body mass index of 28 kg/m², according to Dr. Miranne. Overall, 17% had previously undergone anti-incontinence surgery and 20% had previously undergone prolapse surgery, with no significant difference between groups.

Patients in the no-guide group were more likely to have anterior prolapse (95% vs. 78%) and to have a concomitant prolapse repair (65% vs. 51%). They were less likely to have a resident or fellow as first assistant in the surgery (91% vs. 99%) and to have local retropubic anesthesia (71% vs. 96%). Similar proportions had a concomitant hysterectomy.

In addition to showing no significant difference in injury rates, analyses revealed that the groups were statistically the same with respect to mean intraoperative time; mean blood loss; and mean hospital stay, which was less than 1 day for the entire cohort.

Dr. Miranne disclosed no relevant conflicts of interest.

SCOTTSDALE, ARIZ. – Laparoscopic hysterectomy takes longer when residents participate, but is generally as safe as when an attending physician performs the surgery alone, a study showed.

A resident was involved in 46% of the 3,441 cases that were done for benign indications between 2008 and 2011 and identified in the National Surgical Quality Improvement Program (NSQIP) database.

Patients whose surgery involved a resident had higher levels of comorbidity and were higher-risk surgical candidates, according to data presented at the annual meeting of the Society of Gynecologic Surgeons.

Compared with patients whose surgery was performed by an attending physician alone, those whose surgery involved a resident took an average of 44 minutes, or about 25% longer.

However, rates of serious adverse outcomes and death were statistically indistinguishable. The group for whom a resident was involved did have higher rates of transfusion of more than 4 U of packed red blood cells and of readmission.

"Our study is the first of its kind to study this topic in the gynecologic field in such a large sample size," said lead author Dr. Elena Igwe, a third-year obstetrician-gynecologist resident at Temple University Hospital in Philadelphia.

The longer operative time for resident-involved cases "may be accounted for by the obvious training environment of gynecologic and anesthesia residents, medical students, as well as scrub nurse students. Also, more time may have been spent if there were greater intraoperative complications such as bleeding or organ injury that were not captured by the NSQIP database," she said at the meeting, jointly sponsored by the American College of Surgeons.

"Although there was a statistically significant increase in transfusion and readmissions in the resident-involved group, there was no overall effect on morbidity or mortality. Therefore, although laparoscopic hysterectomy may take longer to accomplish with a resident involved, the clinically significant safety profile is largely unchanged," Dr. Igwe said.

Invited discussant Dr. Marie Fidela Paraiso, head of female pelvic medicine and reconstructive surgery at the Cleveland Clinic, commented, "The findings of your investigation are not surprising in that training cases require significantly longer OR times – this is the story of an academician’s life – increased transfusions (cause uncertain) and increased 30-day admits. However, it is reassuring that morbidity and severe complications and 30-day mortality are not different despite greater patient acuity in the training cohort."

She added, "Due to a limit in training hours, alternatives to hysterectomy, and a variation of tools and routes for hysterectomy, resident experience in laparoscopic hysterectomy is likely to decrease. How do you apply your findings to guide future training?" she asked.

Considerable time is required to become skilled at this surgery, Dr. Igwe replied. "If the average resident is going to do less hysterectomies during their duration as a resident, then there are two potential ways to deal with this situation. One, you can increase the length of ob.gyn. training; of course, the lack of federal funding may not make this a very attractive option. Or two, split the specialty into a track system or alternative curriculum system, where a portion of residents go into a specialized gyn. track and receive the majority of hysterectomy and other major surgery trainings, and have the privilege to perform these procedures. A general ob.gyn. residency can therefore potentially be reduced to 3 years, and these practitioners would focus on more routine ob.gyn. and preventive gynecologic care," she suggested.

"We as a society can take the initiative to do this ourselves, or insurance companies, based on the Affordable Care Act initiative and driven by outcome-based research, will make us do this based on our performances, and this may not be a pretty thing," she added.

One session attendee expressed concern about potential selection bias in the study. "It’s possible that for the more complicated cases, the attendings asked the residents to assist them, and therefore we may be unduly giving the residents credit for the increased morbidity," he said.

"That is a concern, but that’s just one of the limitations of the NSQIP database that we were not able to adjust for," Dr. Igwe said.

Another attendee commented, "Your data is reassuring, but it begs the question, we don’t know the degree to which residents were actually involved, and it makes me think ... what would be a more meaningful way to measure this issue of the interaction between resident involvement and patient morbidity?"

"If there was a way to actually record or establish how much a resident is actually doing, that would be the best thing," Dr. Igwe said.

In the study, relative to the patients operated on by attending physicians only, patients whose surgery involved a resident were on average older, were more likely to be inpatients, had higher Charlson comorbidity scores, and had higher American Society of Anesthesiologists classes.

The mean operative time was 179 minutes when a resident was involved and 135 minutes when the attending physician operated alone, reported Dr. Igwe. There was no significant difference between junior residents (those in postgraduate year 1 or 2) and senior residents (all other years).

The group having a resident involved had significantly higher rates of transfusion with more than 4 U of packed red blood cells (2.0% vs. 0.4%) and readmission (5.5% vs. 2.9%). The difference in transfusion rates was greater for junior residents than for senior residents.

However, the groups were statistically indistinguishable with respect to the proportion of patients having at least one complication, experiencing severe morbidity, dying within 30 days, developing infections or sepsis, or having thromboembolic complications.

"The limitations of this study are largely those of the NSQIP database," Dr. Igwe noted. "We were unable to control for attending surgeon experience, presence of additional trainees in the operating room, or tallying up the intraoperative complications. Also, the degree of resident participation is not clearly defined, and there is no data about the conversion rate from laparoscopic to open cases."

Dr. Igwe disclosed no relevant financial conflicts of interest.

SCOTTSDALE, ARIZ. – Laparoscopic hysterectomy takes longer when residents participate, but is generally as safe as when an attending physician performs the surgery alone, a study showed.

A resident was involved in 46% of the 3,441 cases that were done for benign indications between 2008 and 2011 and identified in the National Surgical Quality Improvement Program (NSQIP) database.

Patients whose surgery involved a resident had higher levels of comorbidity and were higher-risk surgical candidates, according to data presented at the annual meeting of the Society of Gynecologic Surgeons.

Compared with patients whose surgery was performed by an attending physician alone, those whose surgery involved a resident took an average of 44 minutes, or about 25% longer.

However, rates of serious adverse outcomes and death were statistically indistinguishable. The group for whom a resident was involved did have higher rates of transfusion of more than 4 U of packed red blood cells and of readmission.

"Our study is the first of its kind to study this topic in the gynecologic field in such a large sample size," said lead author Dr. Elena Igwe, a third-year obstetrician-gynecologist resident at Temple University Hospital in Philadelphia.

The longer operative time for resident-involved cases "may be accounted for by the obvious training environment of gynecologic and anesthesia residents, medical students, as well as scrub nurse students. Also, more time may have been spent if there were greater intraoperative complications such as bleeding or organ injury that were not captured by the NSQIP database," she said at the meeting, jointly sponsored by the American College of Surgeons.

"Although there was a statistically significant increase in transfusion and readmissions in the resident-involved group, there was no overall effect on morbidity or mortality. Therefore, although laparoscopic hysterectomy may take longer to accomplish with a resident involved, the clinically significant safety profile is largely unchanged," Dr. Igwe said.

Invited discussant Dr. Marie Fidela Paraiso, head of female pelvic medicine and reconstructive surgery at the Cleveland Clinic, commented, "The findings of your investigation are not surprising in that training cases require significantly longer OR times – this is the story of an academician’s life – increased transfusions (cause uncertain) and increased 30-day admits. However, it is reassuring that morbidity and severe complications and 30-day mortality are not different despite greater patient acuity in the training cohort."

She added, "Due to a limit in training hours, alternatives to hysterectomy, and a variation of tools and routes for hysterectomy, resident experience in laparoscopic hysterectomy is likely to decrease. How do you apply your findings to guide future training?" she asked.

Considerable time is required to become skilled at this surgery, Dr. Igwe replied. "If the average resident is going to do less hysterectomies during their duration as a resident, then there are two potential ways to deal with this situation. One, you can increase the length of ob.gyn. training; of course, the lack of federal funding may not make this a very attractive option. Or two, split the specialty into a track system or alternative curriculum system, where a portion of residents go into a specialized gyn. track and receive the majority of hysterectomy and other major surgery trainings, and have the privilege to perform these procedures. A general ob.gyn. residency can therefore potentially be reduced to 3 years, and these practitioners would focus on more routine ob.gyn. and preventive gynecologic care," she suggested.

"We as a society can take the initiative to do this ourselves, or insurance companies, based on the Affordable Care Act initiative and driven by outcome-based research, will make us do this based on our performances, and this may not be a pretty thing," she added.

One session attendee expressed concern about potential selection bias in the study. "It’s possible that for the more complicated cases, the attendings asked the residents to assist them, and therefore we may be unduly giving the residents credit for the increased morbidity," he said.

"That is a concern, but that’s just one of the limitations of the NSQIP database that we were not able to adjust for," Dr. Igwe said.

Another attendee commented, "Your data is reassuring, but it begs the question, we don’t know the degree to which residents were actually involved, and it makes me think ... what would be a more meaningful way to measure this issue of the interaction between resident involvement and patient morbidity?"

"If there was a way to actually record or establish how much a resident is actually doing, that would be the best thing," Dr. Igwe said.

In the study, relative to the patients operated on by attending physicians only, patients whose surgery involved a resident were on average older, were more likely to be inpatients, had higher Charlson comorbidity scores, and had higher American Society of Anesthesiologists classes.

The mean operative time was 179 minutes when a resident was involved and 135 minutes when the attending physician operated alone, reported Dr. Igwe. There was no significant difference between junior residents (those in postgraduate year 1 or 2) and senior residents (all other years).

The group having a resident involved had significantly higher rates of transfusion with more than 4 U of packed red blood cells (2.0% vs. 0.4%) and readmission (5.5% vs. 2.9%). The difference in transfusion rates was greater for junior residents than for senior residents.

However, the groups were statistically indistinguishable with respect to the proportion of patients having at least one complication, experiencing severe morbidity, dying within 30 days, developing infections or sepsis, or having thromboembolic complications.

"The limitations of this study are largely those of the NSQIP database," Dr. Igwe noted. "We were unable to control for attending surgeon experience, presence of additional trainees in the operating room, or tallying up the intraoperative complications. Also, the degree of resident participation is not clearly defined, and there is no data about the conversion rate from laparoscopic to open cases."

Dr. Igwe disclosed no relevant financial conflicts of interest.

SCOTTSDALE, ARIZ. – Laparoscopic hysterectomy takes longer when residents participate, but is generally as safe as when an attending physician performs the surgery alone, a study showed.

A resident was involved in 46% of the 3,441 cases that were done for benign indications between 2008 and 2011 and identified in the National Surgical Quality Improvement Program (NSQIP) database.

Patients whose surgery involved a resident had higher levels of comorbidity and were higher-risk surgical candidates, according to data presented at the annual meeting of the Society of Gynecologic Surgeons.

Compared with patients whose surgery was performed by an attending physician alone, those whose surgery involved a resident took an average of 44 minutes, or about 25% longer.

However, rates of serious adverse outcomes and death were statistically indistinguishable. The group for whom a resident was involved did have higher rates of transfusion of more than 4 U of packed red blood cells and of readmission.

"Our study is the first of its kind to study this topic in the gynecologic field in such a large sample size," said lead author Dr. Elena Igwe, a third-year obstetrician-gynecologist resident at Temple University Hospital in Philadelphia.

The longer operative time for resident-involved cases "may be accounted for by the obvious training environment of gynecologic and anesthesia residents, medical students, as well as scrub nurse students. Also, more time may have been spent if there were greater intraoperative complications such as bleeding or organ injury that were not captured by the NSQIP database," she said at the meeting, jointly sponsored by the American College of Surgeons.

"Although there was a statistically significant increase in transfusion and readmissions in the resident-involved group, there was no overall effect on morbidity or mortality. Therefore, although laparoscopic hysterectomy may take longer to accomplish with a resident involved, the clinically significant safety profile is largely unchanged," Dr. Igwe said.

Invited discussant Dr. Marie Fidela Paraiso, head of female pelvic medicine and reconstructive surgery at the Cleveland Clinic, commented, "The findings of your investigation are not surprising in that training cases require significantly longer OR times – this is the story of an academician’s life – increased transfusions (cause uncertain) and increased 30-day admits. However, it is reassuring that morbidity and severe complications and 30-day mortality are not different despite greater patient acuity in the training cohort."

She added, "Due to a limit in training hours, alternatives to hysterectomy, and a variation of tools and routes for hysterectomy, resident experience in laparoscopic hysterectomy is likely to decrease. How do you apply your findings to guide future training?" she asked.

Considerable time is required to become skilled at this surgery, Dr. Igwe replied. "If the average resident is going to do less hysterectomies during their duration as a resident, then there are two potential ways to deal with this situation. One, you can increase the length of ob.gyn. training; of course, the lack of federal funding may not make this a very attractive option. Or two, split the specialty into a track system or alternative curriculum system, where a portion of residents go into a specialized gyn. track and receive the majority of hysterectomy and other major surgery trainings, and have the privilege to perform these procedures. A general ob.gyn. residency can therefore potentially be reduced to 3 years, and these practitioners would focus on more routine ob.gyn. and preventive gynecologic care," she suggested.

"We as a society can take the initiative to do this ourselves, or insurance companies, based on the Affordable Care Act initiative and driven by outcome-based research, will make us do this based on our performances, and this may not be a pretty thing," she added.

One session attendee expressed concern about potential selection bias in the study. "It’s possible that for the more complicated cases, the attendings asked the residents to assist them, and therefore we may be unduly giving the residents credit for the increased morbidity," he said.

"That is a concern, but that’s just one of the limitations of the NSQIP database that we were not able to adjust for," Dr. Igwe said.

Another attendee commented, "Your data is reassuring, but it begs the question, we don’t know the degree to which residents were actually involved, and it makes me think ... what would be a more meaningful way to measure this issue of the interaction between resident involvement and patient morbidity?"

"If there was a way to actually record or establish how much a resident is actually doing, that would be the best thing," Dr. Igwe said.

In the study, relative to the patients operated on by attending physicians only, patients whose surgery involved a resident were on average older, were more likely to be inpatients, had higher Charlson comorbidity scores, and had higher American Society of Anesthesiologists classes.

The mean operative time was 179 minutes when a resident was involved and 135 minutes when the attending physician operated alone, reported Dr. Igwe. There was no significant difference between junior residents (those in postgraduate year 1 or 2) and senior residents (all other years).

The group having a resident involved had significantly higher rates of transfusion with more than 4 U of packed red blood cells (2.0% vs. 0.4%) and readmission (5.5% vs. 2.9%). The difference in transfusion rates was greater for junior residents than for senior residents.

However, the groups were statistically indistinguishable with respect to the proportion of patients having at least one complication, experiencing severe morbidity, dying within 30 days, developing infections or sepsis, or having thromboembolic complications.

"The limitations of this study are largely those of the NSQIP database," Dr. Igwe noted. "We were unable to control for attending surgeon experience, presence of additional trainees in the operating room, or tallying up the intraoperative complications. Also, the degree of resident participation is not clearly defined, and there is no data about the conversion rate from laparoscopic to open cases."

Dr. Igwe disclosed no relevant financial conflicts of interest.

Negative surgical margins defined by the absence of any ink on the excised tumor are adequate in most cases of early-stage breast cancer treated with breast-conserving therapy, suggest new consensus guidelines from the Society of Surgical Oncology and American Society for Radiation Oncology.

"The use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of ipsilateral breast tumor recurrence and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs," concludes the 12-member multidisciplinary panel. "The routine practice to obtain negative margin widths wider than no ink on tumor is not indicated" (J. Clin. Oncol. 2014 Feb. 10 [doi:10.1200/JCO.2013.53.3935]).

The panel used as their evidence a systematic review and a meta-analysis based on 33 studies having a total of 28,162 patients with stage I or II breast cancer who were treated with breast-conserving surgery plus whole-breast radiation therapy.

Results showed that, compared with peers having negative margins, patients having positive margins were twice as likely to experience an ipsilateral recurrence, regardless of whether they had favorable tumor biology, were given a radiation boost, or received endocrine therapy (Int. J. Radiation Oncol. Biol. Phys. 2014;88:553-64).

But taking wider margins beyond the point of no ink on tumor did not further reduce the risk of ipsilateral recurrence in the patients overall or in a variety of subsets having unfavorable features (young age, aggressive biology, lobular cancers, or tumors with an extensive intraductal component).

"Our hope is that this guideline will ultimately lead to significant reductions in the high re-excision rate for women with early-stage breast cancer undergoing breast-conserving surgery. Based on the consensus panel’s extensive review of the literature, the vast majority of re-excisions are unnecessary because disease control in the breast is excellent for women with early-stage disease when radiation and hormonal therapy and/or chemotherapy are added to a women’s treatment plan," panel cochair Dr. Meena S. Moran of Yale University, New Haven, Conn., commented in a prepared statement.

In an accompanying editorial, Dr. Reshma Jagsi, University of Michigan, Ann Arbor, and her colleagues write, "We agree with the general idea that routine reexcision of close margins (beyond no ink on tumor) is not necessary, and we expect that these guidelines will have a substantial impact on the community of practicing surgeons. Therefore, radiation oncologists should be prepared to encounter an increasing number of patients with microscopically close margins who might have undergone re-excision in previous years" (Int. J. Radiation Oncol. Biol. Phys. 2014;88:535-36).

At the same time, they note that the wording of the new guidelines gives physicians and patients latitude in individualizing decisions about whether re-excision is warranted.

"Physicians applying these guidelines must have an appreciation of the rationale for the recommendations, as well as the limitations of the evidence available, so that they can interpret and apply the guidelines appropriately. Only with a sophisticated understanding of these issues can we, as a profession, continue to deliver individualized care of consistently high quality, avoiding the sort of ‘cookbook medicine’ that serves well neither physicians nor patients," the editorialists conclude.

The studies included in the meta-analysis were published between 1965 and early 2013 and had a median or mean follow-up of at least 4 years. Patients were excluded if they received neoadjuvant chemotherapy or had only ductal carcinoma in situ.

Overall, 78% of the patients studied had negative margins, defined as no ink on the invasive tumor or any ductal carcinoma in situ component. After a median follow-up of 6.6 years, the median prevalence of ipsilateral recurrence was 5.3% overall.

Patients with positive or close margins were twice as likely to have an ipsilateral recurrence (odds ratio, 1.96). In the subset of studies that were able to separate out close margins, risk was elevated with both positive margins (OR, 2.44) and close margins (OR, 1.74).

The adverse impact of positive margins was still evident in analyses taking into account use of a radiation boost (OR, 2.45) and receipt of endocrine therapy (OR, 2.53), and among patients with favorable biology in the form of estrogen receptor–positive tumors (OR, 2.66).

When the impact of the width of the negative margin was evaluated, the risks of ipsilateral recurrence with 2-mm and 5-mm margins were statistically indistinguishable from those with 1-mm margins.

The analysis confirmed that giving systemic therapy (endocrine therapy, chemotherapy, and/or biologic therapy) reduces the risk of ipsilateral recurrence. But the evidence also suggested that in the small number of patients who do not receive this therapy, wider margins beyond no ink on tumor do not further reduce that risk.

In additional findings, there was no evidence that wider margins beyond no ink on tumor are indicated in patients having more aggressive biological subtypes of breast cancer, invasive lobular carcinoma, or tumors with an extensive intraductal component, or in patients aged 40 years or younger.

The panel also concluded that margin width should not dictate the choice of whole-breast radiation therapy delivery technique, fractionation, and boost dose.

Negative surgical margins defined by the absence of any ink on the excised tumor are adequate in most cases of early-stage breast cancer treated with breast-conserving therapy, suggest new consensus guidelines from the Society of Surgical Oncology and American Society for Radiation Oncology.

"The use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of ipsilateral breast tumor recurrence and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs," concludes the 12-member multidisciplinary panel. "The routine practice to obtain negative margin widths wider than no ink on tumor is not indicated" (J. Clin. Oncol. 2014 Feb. 10 [doi:10.1200/JCO.2013.53.3935]).

The panel used as their evidence a systematic review and a meta-analysis based on 33 studies having a total of 28,162 patients with stage I or II breast cancer who were treated with breast-conserving surgery plus whole-breast radiation therapy.

Results showed that, compared with peers having negative margins, patients having positive margins were twice as likely to experience an ipsilateral recurrence, regardless of whether they had favorable tumor biology, were given a radiation boost, or received endocrine therapy (Int. J. Radiation Oncol. Biol. Phys. 2014;88:553-64).

But taking wider margins beyond the point of no ink on tumor did not further reduce the risk of ipsilateral recurrence in the patients overall or in a variety of subsets having unfavorable features (young age, aggressive biology, lobular cancers, or tumors with an extensive intraductal component).

"Our hope is that this guideline will ultimately lead to significant reductions in the high re-excision rate for women with early-stage breast cancer undergoing breast-conserving surgery. Based on the consensus panel’s extensive review of the literature, the vast majority of re-excisions are unnecessary because disease control in the breast is excellent for women with early-stage disease when radiation and hormonal therapy and/or chemotherapy are added to a women’s treatment plan," panel cochair Dr. Meena S. Moran of Yale University, New Haven, Conn., commented in a prepared statement.

In an accompanying editorial, Dr. Reshma Jagsi, University of Michigan, Ann Arbor, and her colleagues write, "We agree with the general idea that routine reexcision of close margins (beyond no ink on tumor) is not necessary, and we expect that these guidelines will have a substantial impact on the community of practicing surgeons. Therefore, radiation oncologists should be prepared to encounter an increasing number of patients with microscopically close margins who might have undergone re-excision in previous years" (Int. J. Radiation Oncol. Biol. Phys. 2014;88:535-36).

At the same time, they note that the wording of the new guidelines gives physicians and patients latitude in individualizing decisions about whether re-excision is warranted.

"Physicians applying these guidelines must have an appreciation of the rationale for the recommendations, as well as the limitations of the evidence available, so that they can interpret and apply the guidelines appropriately. Only with a sophisticated understanding of these issues can we, as a profession, continue to deliver individualized care of consistently high quality, avoiding the sort of ‘cookbook medicine’ that serves well neither physicians nor patients," the editorialists conclude.

The studies included in the meta-analysis were published between 1965 and early 2013 and had a median or mean follow-up of at least 4 years. Patients were excluded if they received neoadjuvant chemotherapy or had only ductal carcinoma in situ.

Overall, 78% of the patients studied had negative margins, defined as no ink on the invasive tumor or any ductal carcinoma in situ component. After a median follow-up of 6.6 years, the median prevalence of ipsilateral recurrence was 5.3% overall.

Patients with positive or close margins were twice as likely to have an ipsilateral recurrence (odds ratio, 1.96). In the subset of studies that were able to separate out close margins, risk was elevated with both positive margins (OR, 2.44) and close margins (OR, 1.74).

The adverse impact of positive margins was still evident in analyses taking into account use of a radiation boost (OR, 2.45) and receipt of endocrine therapy (OR, 2.53), and among patients with favorable biology in the form of estrogen receptor–positive tumors (OR, 2.66).

When the impact of the width of the negative margin was evaluated, the risks of ipsilateral recurrence with 2-mm and 5-mm margins were statistically indistinguishable from those with 1-mm margins.

The analysis confirmed that giving systemic therapy (endocrine therapy, chemotherapy, and/or biologic therapy) reduces the risk of ipsilateral recurrence. But the evidence also suggested that in the small number of patients who do not receive this therapy, wider margins beyond no ink on tumor do not further reduce that risk.

In additional findings, there was no evidence that wider margins beyond no ink on tumor are indicated in patients having more aggressive biological subtypes of breast cancer, invasive lobular carcinoma, or tumors with an extensive intraductal component, or in patients aged 40 years or younger.

The panel also concluded that margin width should not dictate the choice of whole-breast radiation therapy delivery technique, fractionation, and boost dose.

Negative surgical margins defined by the absence of any ink on the excised tumor are adequate in most cases of early-stage breast cancer treated with breast-conserving therapy, suggest new consensus guidelines from the Society of Surgical Oncology and American Society for Radiation Oncology.

"The use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of ipsilateral breast tumor recurrence and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs," concludes the 12-member multidisciplinary panel. "The routine practice to obtain negative margin widths wider than no ink on tumor is not indicated" (J. Clin. Oncol. 2014 Feb. 10 [doi:10.1200/JCO.2013.53.3935]).

The panel used as their evidence a systematic review and a meta-analysis based on 33 studies having a total of 28,162 patients with stage I or II breast cancer who were treated with breast-conserving surgery plus whole-breast radiation therapy.

Results showed that, compared with peers having negative margins, patients having positive margins were twice as likely to experience an ipsilateral recurrence, regardless of whether they had favorable tumor biology, were given a radiation boost, or received endocrine therapy (Int. J. Radiation Oncol. Biol. Phys. 2014;88:553-64).

But taking wider margins beyond the point of no ink on tumor did not further reduce the risk of ipsilateral recurrence in the patients overall or in a variety of subsets having unfavorable features (young age, aggressive biology, lobular cancers, or tumors with an extensive intraductal component).

"Our hope is that this guideline will ultimately lead to significant reductions in the high re-excision rate for women with early-stage breast cancer undergoing breast-conserving surgery. Based on the consensus panel’s extensive review of the literature, the vast majority of re-excisions are unnecessary because disease control in the breast is excellent for women with early-stage disease when radiation and hormonal therapy and/or chemotherapy are added to a women’s treatment plan," panel cochair Dr. Meena S. Moran of Yale University, New Haven, Conn., commented in a prepared statement.

In an accompanying editorial, Dr. Reshma Jagsi, University of Michigan, Ann Arbor, and her colleagues write, "We agree with the general idea that routine reexcision of close margins (beyond no ink on tumor) is not necessary, and we expect that these guidelines will have a substantial impact on the community of practicing surgeons. Therefore, radiation oncologists should be prepared to encounter an increasing number of patients with microscopically close margins who might have undergone re-excision in previous years" (Int. J. Radiation Oncol. Biol. Phys. 2014;88:535-36).

At the same time, they note that the wording of the new guidelines gives physicians and patients latitude in individualizing decisions about whether re-excision is warranted.

"Physicians applying these guidelines must have an appreciation of the rationale for the recommendations, as well as the limitations of the evidence available, so that they can interpret and apply the guidelines appropriately. Only with a sophisticated understanding of these issues can we, as a profession, continue to deliver individualized care of consistently high quality, avoiding the sort of ‘cookbook medicine’ that serves well neither physicians nor patients," the editorialists conclude.

The studies included in the meta-analysis were published between 1965 and early 2013 and had a median or mean follow-up of at least 4 years. Patients were excluded if they received neoadjuvant chemotherapy or had only ductal carcinoma in situ.

Overall, 78% of the patients studied had negative margins, defined as no ink on the invasive tumor or any ductal carcinoma in situ component. After a median follow-up of 6.6 years, the median prevalence of ipsilateral recurrence was 5.3% overall.

Patients with positive or close margins were twice as likely to have an ipsilateral recurrence (odds ratio, 1.96). In the subset of studies that were able to separate out close margins, risk was elevated with both positive margins (OR, 2.44) and close margins (OR, 1.74).

The adverse impact of positive margins was still evident in analyses taking into account use of a radiation boost (OR, 2.45) and receipt of endocrine therapy (OR, 2.53), and among patients with favorable biology in the form of estrogen receptor–positive tumors (OR, 2.66).

When the impact of the width of the negative margin was evaluated, the risks of ipsilateral recurrence with 2-mm and 5-mm margins were statistically indistinguishable from those with 1-mm margins.

The analysis confirmed that giving systemic therapy (endocrine therapy, chemotherapy, and/or biologic therapy) reduces the risk of ipsilateral recurrence. But the evidence also suggested that in the small number of patients who do not receive this therapy, wider margins beyond no ink on tumor do not further reduce that risk.

In additional findings, there was no evidence that wider margins beyond no ink on tumor are indicated in patients having more aggressive biological subtypes of breast cancer, invasive lobular carcinoma, or tumors with an extensive intraductal component, or in patients aged 40 years or younger.

The panel also concluded that margin width should not dictate the choice of whole-breast radiation therapy delivery technique, fractionation, and boost dose.

SAN FRANCISCO – The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is a valid tool for predicting survival in patients starting second-line targeted therapy for this disease, new data show.

In fact, it outperforms the leading model derived a decade ago, researchers reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The new model uses six clinical and laboratory factors to stratify patients into prognostic risk groups. It builds on the widely used three-factor Memorial Sloan-Kettering Cancer Center (MSKCC) second-line prognostic model (J. Clin. Oncol. 2004;22:454-63).

Results of the retrospective cohort study showed that the IMDC model performed well for risk stratification in this setting, with patients in the intermediate- and high-risk groups having roughly two and six times the risk of death, respectively, compared with peers in the favorable risk group, reported Dr. Jenny J. Ko of the British Columbia Cancer Agency, Vancouver. Also, it was superior to the MSKCC model for predicting survival as assessed by three statistical tests.

"The six-factor IMDC prognostic model has been validated in and can be applied to patients previously treated with targeted therapy, in addition to previously validated populations in the first-line targeted therapy and non–clear cell setting," she commented.

"The model fits better into the context of the contemporary treatment era, where targeted therapies are used in a sequential fashion," Dr. Ko added.

The study population was heterogeneous, she acknowledged. But "this can also mean that the cohort was generalizable, as our cohort includes trial and off-trial patients, and it also includes community and academic centers."

Invited discussant Dr. Daniel Canter of the Fox Chase Cancer Center, Philadelphia, noted that the durations of second-line therapy and survival after starting this therapy were fairly short, highlighting the need for better therapies.

The choice of first-line therapy for metastatic renal cell carcinoma (mRCC) may shift in the future away from sunitinib (Sutent) and sorafenib (Nexavar), used in the vast majority of the patients studied, he noted.

"My observation is that the medical oncologists that I work with seem to be using pazopanib (Votrient) more now as a first-line therapy because of the improved toxicity," Dr. Canter noted, and doing so may ultimately affect survival. "Obviously, a future question is the role of pazopanib. And ... an algorithm to define second-line choices is clearly something where there is an opportunity for work to be done."

Dr. Ko and her team studied 1,021 consecutive patients with mRCC from 19 centers who were starting second-line targeted therapy. (About a fifth had received immunotherapy before their first-line targeted therapy and were therefore on third-line therapy of any type.)

Eighty-five percent of patients had undergone nephrectomy. Their first-line targeted therapy had most often been sunitinib (67%) or sorafenib (20%).

The second-line therapies given included sorafenib (29%), sunitinib (22%), everolimus (Afinitor) (22%), and temsirolimus (Torisel) (12%), among others.

In a multivariate analysis, five of the six IMDC factors (Karnofsky performance status less than 80%; interval between diagnosis and treatment of less than 1 year; anemia; thrombocytosis; and neutrophilia) individually predicted an elevated risk of death after starting second-line therapy, reported Dr. Ko, who disclosed no conflicts of interest related to the research. Hypercalcemia did not, but few patients had this risk factor.

The median time on second-line targeted therapy was 3.9 months, and the median overall survival after starting this therapy was 12.5 months.

Compared with patients in the favorable IMDC risk group (having none of the risk factors), patients in the intermediate-risk group (having one or two) and patients in the high-risk group (having three or more) had significantly elevated risks of death (hazard ratios, 1.89 and 5.73).

In a likelihood ratio test, comparing the two models, the chi-square value was highly significant, suggesting that inclusion of the three additional factors in the IMDC model enhanced predictive performance over that with the MSKCC model.

Finally, in a reclassification calibration analysis, the chi-square value was much lower for the IMDC model than for the MSKCC model (6.2 vs. 54.2), indicating that the observed vs. predicted number of deaths at 1 year was better for the former.

SAN FRANCISCO – The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is a valid tool for predicting survival in patients starting second-line targeted therapy for this disease, new data show.

In fact, it outperforms the leading model derived a decade ago, researchers reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The new model uses six clinical and laboratory factors to stratify patients into prognostic risk groups. It builds on the widely used three-factor Memorial Sloan-Kettering Cancer Center (MSKCC) second-line prognostic model (J. Clin. Oncol. 2004;22:454-63).

Results of the retrospective cohort study showed that the IMDC model performed well for risk stratification in this setting, with patients in the intermediate- and high-risk groups having roughly two and six times the risk of death, respectively, compared with peers in the favorable risk group, reported Dr. Jenny J. Ko of the British Columbia Cancer Agency, Vancouver. Also, it was superior to the MSKCC model for predicting survival as assessed by three statistical tests.

"The six-factor IMDC prognostic model has been validated in and can be applied to patients previously treated with targeted therapy, in addition to previously validated populations in the first-line targeted therapy and non–clear cell setting," she commented.

"The model fits better into the context of the contemporary treatment era, where targeted therapies are used in a sequential fashion," Dr. Ko added.

The study population was heterogeneous, she acknowledged. But "this can also mean that the cohort was generalizable, as our cohort includes trial and off-trial patients, and it also includes community and academic centers."

Invited discussant Dr. Daniel Canter of the Fox Chase Cancer Center, Philadelphia, noted that the durations of second-line therapy and survival after starting this therapy were fairly short, highlighting the need for better therapies.

The choice of first-line therapy for metastatic renal cell carcinoma (mRCC) may shift in the future away from sunitinib (Sutent) and sorafenib (Nexavar), used in the vast majority of the patients studied, he noted.

"My observation is that the medical oncologists that I work with seem to be using pazopanib (Votrient) more now as a first-line therapy because of the improved toxicity," Dr. Canter noted, and doing so may ultimately affect survival. "Obviously, a future question is the role of pazopanib. And ... an algorithm to define second-line choices is clearly something where there is an opportunity for work to be done."

Dr. Ko and her team studied 1,021 consecutive patients with mRCC from 19 centers who were starting second-line targeted therapy. (About a fifth had received immunotherapy before their first-line targeted therapy and were therefore on third-line therapy of any type.)

Eighty-five percent of patients had undergone nephrectomy. Their first-line targeted therapy had most often been sunitinib (67%) or sorafenib (20%).

The second-line therapies given included sorafenib (29%), sunitinib (22%), everolimus (Afinitor) (22%), and temsirolimus (Torisel) (12%), among others.

In a multivariate analysis, five of the six IMDC factors (Karnofsky performance status less than 80%; interval between diagnosis and treatment of less than 1 year; anemia; thrombocytosis; and neutrophilia) individually predicted an elevated risk of death after starting second-line therapy, reported Dr. Ko, who disclosed no conflicts of interest related to the research. Hypercalcemia did not, but few patients had this risk factor.

The median time on second-line targeted therapy was 3.9 months, and the median overall survival after starting this therapy was 12.5 months.

Compared with patients in the favorable IMDC risk group (having none of the risk factors), patients in the intermediate-risk group (having one or two) and patients in the high-risk group (having three or more) had significantly elevated risks of death (hazard ratios, 1.89 and 5.73).

In a likelihood ratio test, comparing the two models, the chi-square value was highly significant, suggesting that inclusion of the three additional factors in the IMDC model enhanced predictive performance over that with the MSKCC model.

Finally, in a reclassification calibration analysis, the chi-square value was much lower for the IMDC model than for the MSKCC model (6.2 vs. 54.2), indicating that the observed vs. predicted number of deaths at 1 year was better for the former.

SAN FRANCISCO – The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is a valid tool for predicting survival in patients starting second-line targeted therapy for this disease, new data show.

In fact, it outperforms the leading model derived a decade ago, researchers reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The new model uses six clinical and laboratory factors to stratify patients into prognostic risk groups. It builds on the widely used three-factor Memorial Sloan-Kettering Cancer Center (MSKCC) second-line prognostic model (J. Clin. Oncol. 2004;22:454-63).

Results of the retrospective cohort study showed that the IMDC model performed well for risk stratification in this setting, with patients in the intermediate- and high-risk groups having roughly two and six times the risk of death, respectively, compared with peers in the favorable risk group, reported Dr. Jenny J. Ko of the British Columbia Cancer Agency, Vancouver. Also, it was superior to the MSKCC model for predicting survival as assessed by three statistical tests.

"The six-factor IMDC prognostic model has been validated in and can be applied to patients previously treated with targeted therapy, in addition to previously validated populations in the first-line targeted therapy and non–clear cell setting," she commented.

"The model fits better into the context of the contemporary treatment era, where targeted therapies are used in a sequential fashion," Dr. Ko added.

The study population was heterogeneous, she acknowledged. But "this can also mean that the cohort was generalizable, as our cohort includes trial and off-trial patients, and it also includes community and academic centers."

Invited discussant Dr. Daniel Canter of the Fox Chase Cancer Center, Philadelphia, noted that the durations of second-line therapy and survival after starting this therapy were fairly short, highlighting the need for better therapies.

The choice of first-line therapy for metastatic renal cell carcinoma (mRCC) may shift in the future away from sunitinib (Sutent) and sorafenib (Nexavar), used in the vast majority of the patients studied, he noted.

"My observation is that the medical oncologists that I work with seem to be using pazopanib (Votrient) more now as a first-line therapy because of the improved toxicity," Dr. Canter noted, and doing so may ultimately affect survival. "Obviously, a future question is the role of pazopanib. And ... an algorithm to define second-line choices is clearly something where there is an opportunity for work to be done."

Dr. Ko and her team studied 1,021 consecutive patients with mRCC from 19 centers who were starting second-line targeted therapy. (About a fifth had received immunotherapy before their first-line targeted therapy and were therefore on third-line therapy of any type.)

Eighty-five percent of patients had undergone nephrectomy. Their first-line targeted therapy had most often been sunitinib (67%) or sorafenib (20%).

The second-line therapies given included sorafenib (29%), sunitinib (22%), everolimus (Afinitor) (22%), and temsirolimus (Torisel) (12%), among others.

In a multivariate analysis, five of the six IMDC factors (Karnofsky performance status less than 80%; interval between diagnosis and treatment of less than 1 year; anemia; thrombocytosis; and neutrophilia) individually predicted an elevated risk of death after starting second-line therapy, reported Dr. Ko, who disclosed no conflicts of interest related to the research. Hypercalcemia did not, but few patients had this risk factor.

The median time on second-line targeted therapy was 3.9 months, and the median overall survival after starting this therapy was 12.5 months.

Compared with patients in the favorable IMDC risk group (having none of the risk factors), patients in the intermediate-risk group (having one or two) and patients in the high-risk group (having three or more) had significantly elevated risks of death (hazard ratios, 1.89 and 5.73).

In a likelihood ratio test, comparing the two models, the chi-square value was highly significant, suggesting that inclusion of the three additional factors in the IMDC model enhanced predictive performance over that with the MSKCC model.

Finally, in a reclassification calibration analysis, the chi-square value was much lower for the IMDC model than for the MSKCC model (6.2 vs. 54.2), indicating that the observed vs. predicted number of deaths at 1 year was better for the former.

SAN FRANCISCO – Circulating tumor cells may be useful for ascertaining both the presence and extent of pancreatic cancer, according to the findings of a prospective cohort study reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

A "nano-Velcro" assay to find circulating tumor cells (CTCs) was evaluated prospectively in 61 patients with suspicious pancreatic masses, two-thirds of whom were found to have pancreatic adenocarcinoma.

Finding at least one CTC/2 mL of blood had 71% sensitivity and 95% specificity for the presence of pancreatic cancer, and, among the patients with cancer, finding at least two CTCs/2 mL of blood had 69% sensitivity and 96% specificity for the presence of metastases, reported Dr. Jacob S. Ankeny of the department of surgery, University of California, Los Angeles.

"I think CTCs do have a potential role in aiding in our diagnosis of pancreas cancer and in discriminating which patients are at higher risk of having metastatic disease at the time of their disease presentation," said Dr. Ankeny.

"In our study, circulating tumor cells actually outperformed CA 19-9 [cancer antigen 19-9] for differentiating locoregional vs. metastatic disease, and as a result, I think they show marked promise as a biomarker at the time of disease presentation so that we can perform pretreatment staging and implement more effective initial therapies based on patient stage," he added.

Study limitations included the small sample size and the lack of outcome data, Dr. Ankeny acknowledged. "Additionally, we had minimal inclusion of inflammatory pancreatic conditions and didn’t have any patients with acute pancreatitis. It’s known that some other inflammatory conditions actually lead to false-positive results in some other circulating tumor cell platforms."

A key challenge to using CTCs is their rarity, according to invited discussant Rebecca A. Miksad of Harvard Medical School and the Beth Israel Deaconess Medical Center, both in Boston.

"In the data presented, the difference between cancer and no cancer is one CTC; similarly, the difference between metastatic and locoregional cancer is one CTC. Because CTCs are detected only in whole numbers, these close cutoffs raise questions about the accuracy, reliability, and reproducibility; in other words, will the same result be found in repeated analysis of the same sample and in different samples from the same patient," she commented.

"CTCs in pancreatic cancer are intriguing, although the role remains unclear," Dr. Miksad concluded. "The presented CTC data has a narrow diagnostic predictive window, and we may find with further work that the utility of CTCs as a test to detect the presence of pancreatic cancer may differ from its utility to assist with staging."

The nano-Velcro assay uses antibody-coated silicon nanowires to capture circulating cells with high efficiency, Dr. Ankeny explained. The captured cells are stained immunocytochemically, scanned with fluorescence microscopy, and counted.

In the study, a tumor cell was defined as a cell measuring at least 10 microns that had a DAPI-staining nucleus, was positive for cytokeratin, and was negative for the leukocyte marker CD45.

The investigators tested duplicate 2-mL aliquots from the study patients at the time of their presentation with suspicious pancreatic masses.

The 41 patients determined to have pancreatic adenocarcinoma were roughly equally distributed across tumor stages II, III, and IV. The other 20 patients had more than half a dozen pancreatic conditions, such as intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and serous cysts.

The assay identified CTCs in 71% of the patients with cancer, reported Dr. Ankeny, who disclosed no conflicts of interest related to the research.

A single patient in the control group was found to have a CTC, meaning a false-positive result. "That was a patient with a nondiagnostic FNA [fine-needle aspiration] of a large cyst containing a large solid component," he explained. "Unfortunately, the patient went elsewhere for surgery and refused surgery, and we don’t have any follow-up pathology. So it’s a theoretical false-positive in our non–adenocarcinoma group."

At an optimal diagnostic cutoff of at least one CTC/2 mL blood, the assay had a sensitivity of 71%, a specificity of 95%, a positive predictive value of 97%, and a negative predictive value of 59% for the presence of pancreatic cancer.

The area under a receiver operating characteristic curve was 0.84 (P less than .001), indicating good discrimination between patients with and without cancer, Dr. Ankeny said.

Among the patients with cancer, at the optimal cutoff of two or more CTCs/2 mL of blood, the assay had a sensitivity of 69%, a specificity of 96%, and a positive predictive value of 92% for the presence of metastases.

The area under a receiver operating characteristic curve was 0.84 (P less than .001), indicating good discrimination between patients with and without metastases.

A subset of seven patients with presumed stage II disease based on preoperative imaging were found to have liver metastases at the time of surgery. In five of them, preoperative blood samples showed at least two CTCs/2 mL, predicting metastatic disease.

"This indicates that CTCs may be potentially useful in predicting preoperative metastasis and directing patients toward more appropriate therapies while having them avoid potentially morbid surgery," Dr. Ankeny commented.

In a final analysis, CTCs were superior to CA 19-9 for discriminating between locoregional disease and metastatic disease, with an area under the receiver operating characteristic curve of 0.87 (P less than .001) vs. 0.69 (P = .06).

Dr. Ankeny disclosed no relevant conflicts of interest. Dr. Miksad disclosed no relevant conflicts of interest.

SAN FRANCISCO – Circulating tumor cells may be useful for ascertaining both the presence and extent of pancreatic cancer, according to the findings of a prospective cohort study reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

A "nano-Velcro" assay to find circulating tumor cells (CTCs) was evaluated prospectively in 61 patients with suspicious pancreatic masses, two-thirds of whom were found to have pancreatic adenocarcinoma.

Finding at least one CTC/2 mL of blood had 71% sensitivity and 95% specificity for the presence of pancreatic cancer, and, among the patients with cancer, finding at least two CTCs/2 mL of blood had 69% sensitivity and 96% specificity for the presence of metastases, reported Dr. Jacob S. Ankeny of the department of surgery, University of California, Los Angeles.

"I think CTCs do have a potential role in aiding in our diagnosis of pancreas cancer and in discriminating which patients are at higher risk of having metastatic disease at the time of their disease presentation," said Dr. Ankeny.

"In our study, circulating tumor cells actually outperformed CA 19-9 [cancer antigen 19-9] for differentiating locoregional vs. metastatic disease, and as a result, I think they show marked promise as a biomarker at the time of disease presentation so that we can perform pretreatment staging and implement more effective initial therapies based on patient stage," he added.

Study limitations included the small sample size and the lack of outcome data, Dr. Ankeny acknowledged. "Additionally, we had minimal inclusion of inflammatory pancreatic conditions and didn’t have any patients with acute pancreatitis. It’s known that some other inflammatory conditions actually lead to false-positive results in some other circulating tumor cell platforms."

A key challenge to using CTCs is their rarity, according to invited discussant Rebecca A. Miksad of Harvard Medical School and the Beth Israel Deaconess Medical Center, both in Boston.

"In the data presented, the difference between cancer and no cancer is one CTC; similarly, the difference between metastatic and locoregional cancer is one CTC. Because CTCs are detected only in whole numbers, these close cutoffs raise questions about the accuracy, reliability, and reproducibility; in other words, will the same result be found in repeated analysis of the same sample and in different samples from the same patient," she commented.

"CTCs in pancreatic cancer are intriguing, although the role remains unclear," Dr. Miksad concluded. "The presented CTC data has a narrow diagnostic predictive window, and we may find with further work that the utility of CTCs as a test to detect the presence of pancreatic cancer may differ from its utility to assist with staging."

The nano-Velcro assay uses antibody-coated silicon nanowires to capture circulating cells with high efficiency, Dr. Ankeny explained. The captured cells are stained immunocytochemically, scanned with fluorescence microscopy, and counted.

In the study, a tumor cell was defined as a cell measuring at least 10 microns that had a DAPI-staining nucleus, was positive for cytokeratin, and was negative for the leukocyte marker CD45.

The investigators tested duplicate 2-mL aliquots from the study patients at the time of their presentation with suspicious pancreatic masses.

The 41 patients determined to have pancreatic adenocarcinoma were roughly equally distributed across tumor stages II, III, and IV. The other 20 patients had more than half a dozen pancreatic conditions, such as intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and serous cysts.

The assay identified CTCs in 71% of the patients with cancer, reported Dr. Ankeny, who disclosed no conflicts of interest related to the research.

A single patient in the control group was found to have a CTC, meaning a false-positive result. "That was a patient with a nondiagnostic FNA [fine-needle aspiration] of a large cyst containing a large solid component," he explained. "Unfortunately, the patient went elsewhere for surgery and refused surgery, and we don’t have any follow-up pathology. So it’s a theoretical false-positive in our non–adenocarcinoma group."

At an optimal diagnostic cutoff of at least one CTC/2 mL blood, the assay had a sensitivity of 71%, a specificity of 95%, a positive predictive value of 97%, and a negative predictive value of 59% for the presence of pancreatic cancer.

The area under a receiver operating characteristic curve was 0.84 (P less than .001), indicating good discrimination between patients with and without cancer, Dr. Ankeny said.

Among the patients with cancer, at the optimal cutoff of two or more CTCs/2 mL of blood, the assay had a sensitivity of 69%, a specificity of 96%, and a positive predictive value of 92% for the presence of metastases.

The area under a receiver operating characteristic curve was 0.84 (P less than .001), indicating good discrimination between patients with and without metastases.

A subset of seven patients with presumed stage II disease based on preoperative imaging were found to have liver metastases at the time of surgery. In five of them, preoperative blood samples showed at least two CTCs/2 mL, predicting metastatic disease.

"This indicates that CTCs may be potentially useful in predicting preoperative metastasis and directing patients toward more appropriate therapies while having them avoid potentially morbid surgery," Dr. Ankeny commented.

In a final analysis, CTCs were superior to CA 19-9 for discriminating between locoregional disease and metastatic disease, with an area under the receiver operating characteristic curve of 0.87 (P less than .001) vs. 0.69 (P = .06).

Dr. Ankeny disclosed no relevant conflicts of interest. Dr. Miksad disclosed no relevant conflicts of interest.

SAN FRANCISCO – Circulating tumor cells may be useful for ascertaining both the presence and extent of pancreatic cancer, according to the findings of a prospective cohort study reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

A "nano-Velcro" assay to find circulating tumor cells (CTCs) was evaluated prospectively in 61 patients with suspicious pancreatic masses, two-thirds of whom were found to have pancreatic adenocarcinoma.

Finding at least one CTC/2 mL of blood had 71% sensitivity and 95% specificity for the presence of pancreatic cancer, and, among the patients with cancer, finding at least two CTCs/2 mL of blood had 69% sensitivity and 96% specificity for the presence of metastases, reported Dr. Jacob S. Ankeny of the department of surgery, University of California, Los Angeles.

"I think CTCs do have a potential role in aiding in our diagnosis of pancreas cancer and in discriminating which patients are at higher risk of having metastatic disease at the time of their disease presentation," said Dr. Ankeny.

"In our study, circulating tumor cells actually outperformed CA 19-9 [cancer antigen 19-9] for differentiating locoregional vs. metastatic disease, and as a result, I think they show marked promise as a biomarker at the time of disease presentation so that we can perform pretreatment staging and implement more effective initial therapies based on patient stage," he added.

Study limitations included the small sample size and the lack of outcome data, Dr. Ankeny acknowledged. "Additionally, we had minimal inclusion of inflammatory pancreatic conditions and didn’t have any patients with acute pancreatitis. It’s known that some other inflammatory conditions actually lead to false-positive results in some other circulating tumor cell platforms."

A key challenge to using CTCs is their rarity, according to invited discussant Rebecca A. Miksad of Harvard Medical School and the Beth Israel Deaconess Medical Center, both in Boston.

"In the data presented, the difference between cancer and no cancer is one CTC; similarly, the difference between metastatic and locoregional cancer is one CTC. Because CTCs are detected only in whole numbers, these close cutoffs raise questions about the accuracy, reliability, and reproducibility; in other words, will the same result be found in repeated analysis of the same sample and in different samples from the same patient," she commented.

"CTCs in pancreatic cancer are intriguing, although the role remains unclear," Dr. Miksad concluded. "The presented CTC data has a narrow diagnostic predictive window, and we may find with further work that the utility of CTCs as a test to detect the presence of pancreatic cancer may differ from its utility to assist with staging."

The nano-Velcro assay uses antibody-coated silicon nanowires to capture circulating cells with high efficiency, Dr. Ankeny explained. The captured cells are stained immunocytochemically, scanned with fluorescence microscopy, and counted.

In the study, a tumor cell was defined as a cell measuring at least 10 microns that had a DAPI-staining nucleus, was positive for cytokeratin, and was negative for the leukocyte marker CD45.

The investigators tested duplicate 2-mL aliquots from the study patients at the time of their presentation with suspicious pancreatic masses.

The 41 patients determined to have pancreatic adenocarcinoma were roughly equally distributed across tumor stages II, III, and IV. The other 20 patients had more than half a dozen pancreatic conditions, such as intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and serous cysts.

The assay identified CTCs in 71% of the patients with cancer, reported Dr. Ankeny, who disclosed no conflicts of interest related to the research.

A single patient in the control group was found to have a CTC, meaning a false-positive result. "That was a patient with a nondiagnostic FNA [fine-needle aspiration] of a large cyst containing a large solid component," he explained. "Unfortunately, the patient went elsewhere for surgery and refused surgery, and we don’t have any follow-up pathology. So it’s a theoretical false-positive in our non–adenocarcinoma group."

At an optimal diagnostic cutoff of at least one CTC/2 mL blood, the assay had a sensitivity of 71%, a specificity of 95%, a positive predictive value of 97%, and a negative predictive value of 59% for the presence of pancreatic cancer.

The area under a receiver operating characteristic curve was 0.84 (P less than .001), indicating good discrimination between patients with and without cancer, Dr. Ankeny said.

Among the patients with cancer, at the optimal cutoff of two or more CTCs/2 mL of blood, the assay had a sensitivity of 69%, a specificity of 96%, and a positive predictive value of 92% for the presence of metastases.

The area under a receiver operating characteristic curve was 0.84 (P less than .001), indicating good discrimination between patients with and without metastases.

A subset of seven patients with presumed stage II disease based on preoperative imaging were found to have liver metastases at the time of surgery. In five of them, preoperative blood samples showed at least two CTCs/2 mL, predicting metastatic disease.

"This indicates that CTCs may be potentially useful in predicting preoperative metastasis and directing patients toward more appropriate therapies while having them avoid potentially morbid surgery," Dr. Ankeny commented.

In a final analysis, CTCs were superior to CA 19-9 for discriminating between locoregional disease and metastatic disease, with an area under the receiver operating characteristic curve of 0.87 (P less than .001) vs. 0.69 (P = .06).

Dr. Ankeny disclosed no relevant conflicts of interest. Dr. Miksad disclosed no relevant conflicts of interest.

SAN FRANCISCO – Only selected patients with synchronous metastases from renal cell carcinoma derive a survival benefit from a cytoreductive nephrectomy, a retrospective cohort study showed.

Researchers studied more than 1,600 patients from the International mRCC (metastatic renal cell carcinoma) Database Consortium who developed metastases while their primary tumor was still in place.

The main analyses showed that as a whole, patients who underwent cytoreductive nephrectomy lived longer than their counterparts who did not have this surgery.

However, in stratified analyses, the surgery significantly prolonged survival only among patients who had a life expectancy exceeding 12 months and patients who had three or fewer risk factors by International mRCC Database Consortium (IMDC) criteria.

Risk factors include Karnofsky performance status less than 80%, an interval between diagnosis and treatment of less than 1 year, anemia, thrombocytosis, neutrophilia, and hypercalcemia

"Overall, I think we can say that cytoreductive nephrectomy may be beneficial in the age of targeted therapy. However, not all patients should have it," commented first author Dr. Daniel Y.C. Heng of the University of Calgary (Alta.).

"Patients with four or more IMDC risk factors and patients with limited life expectancy probably shouldn’t have a cytoreductive nephrectomy," he said. "Of course, there are probably exceptions to that rule; if patients are really symptomatic in the primary, for example, or have bleeding, maybe there are exceptions.

"But I think this is a very interesting and useful way to help select our patients for cytoreductive nephrectomy. Certainly, we are awaiting the CARMENA and SURTIME phase III randomized controlled trials to prospectively evaluate this, and hopefully, we will be able to look at the IMDC risk factors to see if they can aid in patient selection in a prospectively validated way," Dr. Heng said at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Cytoreductive nephrectomy carries risks of morbidity and mortality, and some patients may be unable to go on to receive systemic therapy, noted invited discussant Dr. Daniel Canter of the Fox Chase Cancer Center, Philadelphia.

"What I take home as the most important point of this talk is that we need to make better choices and risk stratify these patients before surgery," he said.

A key question arising from the new data is whether the IMDC risk groups should be redefined, according to Dr. Canter; for example, patients with three risk factors are currently placed in the poor risk group, yet they derived significant benefit from surgery in this study. "So is there room for further refinement in this model?" he asked.

"With such a large cohort, I think that adding to this data with complication rates and perioperative mortality would certainly be important in terms of future treatment decision making," he commented.

Session attendee Dr. Adam Metwalli of the National Cancer Institute asked, "Are there specific risk factors that seem to disproportionately cluster among those who have four or five that would help to distinguish them from the ones who have zero to three?"

"By far, the most important prognostic factor is Karnofsky performance status, and that makes sense," Dr. Heng replied. "It’s partially the ‘look test’ and how you think a patient will fare. So, that by far has the biggest contribution."

Introducing the study, he noted that cytoreductive nephrectomy has previously been found to prolong survival by about 6 months in patients with metastatic renal cell carcinoma treated in the immunotherapy era.

"But of course now we are in the age of targeted therapy, with VEGF [vascular endothelial growth factor] inhibitors and mTOR [mammalian target of rapamycin] inhibitors. These are drugs that are much more active than in the era of old immunotherapy. So it begs the question, is cytoreductive nephrectomy still relevant?" Dr. Heng said.

The researchers studied 1,658 patients from 20 institutions who had mRCC with synchronous metastases, of whom 59% underwent cytoreductive nephrectomy.

They had a median age of 59 years, and about half were in the IMDC intermediate-risk group. The most common prior targeted therapy was sunitinib (Sutent), received by about three-fourths, reported Dr. Heng.

In unadjusted analyses, median overall survival was a significant 11 months longer for patients who underwent cytoreductive nephrectomy compared with their counterparts who did not (20.6 vs. 9.5 months). After adjustment for IMDC risk factors, the surgery was associated with a 40% reduction in the risk of death in the entire cohort (hazard ratio, 0.60; P less than .0001).

However, in analyses stratified by patient life expectancy, there was a significant survival benefit of cytoreductive nephrectomy only among patients expected to live 12-18 months (3.3-month incremental benefit; adjusted hazard ratio, 0.85; P = .049) or 18-24 months (5.2-month incremental benefit; adjusted hazard ratio, 0.72; P less than .0001).

Similarly, in analyses stratified by the number of risk factors present out of the six IMDC risk factors, there was a significant survival benefit of cytoreductive nephrectomy only among patients with three or fewer factors (incremental benefit of 6-10 months, P less than .005 for each).

The impact of overall tumor burden and the size of the primary tumor were not considered in this analysis but will be in subsequent analyses, according to Dr. Heng.

He disclosed that he is a consultant/adviser to Aveo, Bayer, Bristol-Myers Squibb, Novartis, and Pfizer.

SAN FRANCISCO – Only selected patients with synchronous metastases from renal cell carcinoma derive a survival benefit from a cytoreductive nephrectomy, a retrospective cohort study showed.

Researchers studied more than 1,600 patients from the International mRCC (metastatic renal cell carcinoma) Database Consortium who developed metastases while their primary tumor was still in place.

The main analyses showed that as a whole, patients who underwent cytoreductive nephrectomy lived longer than their counterparts who did not have this surgery.

However, in stratified analyses, the surgery significantly prolonged survival only among patients who had a life expectancy exceeding 12 months and patients who had three or fewer risk factors by International mRCC Database Consortium (IMDC) criteria.

Risk factors include Karnofsky performance status less than 80%, an interval between diagnosis and treatment of less than 1 year, anemia, thrombocytosis, neutrophilia, and hypercalcemia

"Overall, I think we can say that cytoreductive nephrectomy may be beneficial in the age of targeted therapy. However, not all patients should have it," commented first author Dr. Daniel Y.C. Heng of the University of Calgary (Alta.).

"Patients with four or more IMDC risk factors and patients with limited life expectancy probably shouldn’t have a cytoreductive nephrectomy," he said. "Of course, there are probably exceptions to that rule; if patients are really symptomatic in the primary, for example, or have bleeding, maybe there are exceptions.

"But I think this is a very interesting and useful way to help select our patients for cytoreductive nephrectomy. Certainly, we are awaiting the CARMENA and SURTIME phase III randomized controlled trials to prospectively evaluate this, and hopefully, we will be able to look at the IMDC risk factors to see if they can aid in patient selection in a prospectively validated way," Dr. Heng said at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Cytoreductive nephrectomy carries risks of morbidity and mortality, and some patients may be unable to go on to receive systemic therapy, noted invited discussant Dr. Daniel Canter of the Fox Chase Cancer Center, Philadelphia.

"What I take home as the most important point of this talk is that we need to make better choices and risk stratify these patients before surgery," he said.

A key question arising from the new data is whether the IMDC risk groups should be redefined, according to Dr. Canter; for example, patients with three risk factors are currently placed in the poor risk group, yet they derived significant benefit from surgery in this study. "So is there room for further refinement in this model?" he asked.

"With such a large cohort, I think that adding to this data with complication rates and perioperative mortality would certainly be important in terms of future treatment decision making," he commented.

Session attendee Dr. Adam Metwalli of the National Cancer Institute asked, "Are there specific risk factors that seem to disproportionately cluster among those who have four or five that would help to distinguish them from the ones who have zero to three?"

"By far, the most important prognostic factor is Karnofsky performance status, and that makes sense," Dr. Heng replied. "It’s partially the ‘look test’ and how you think a patient will fare. So, that by far has the biggest contribution."

Introducing the study, he noted that cytoreductive nephrectomy has previously been found to prolong survival by about 6 months in patients with metastatic renal cell carcinoma treated in the immunotherapy era.

"But of course now we are in the age of targeted therapy, with VEGF [vascular endothelial growth factor] inhibitors and mTOR [mammalian target of rapamycin] inhibitors. These are drugs that are much more active than in the era of old immunotherapy. So it begs the question, is cytoreductive nephrectomy still relevant?" Dr. Heng said.

The researchers studied 1,658 patients from 20 institutions who had mRCC with synchronous metastases, of whom 59% underwent cytoreductive nephrectomy.

They had a median age of 59 years, and about half were in the IMDC intermediate-risk group. The most common prior targeted therapy was sunitinib (Sutent), received by about three-fourths, reported Dr. Heng.

In unadjusted analyses, median overall survival was a significant 11 months longer for patients who underwent cytoreductive nephrectomy compared with their counterparts who did not (20.6 vs. 9.5 months). After adjustment for IMDC risk factors, the surgery was associated with a 40% reduction in the risk of death in the entire cohort (hazard ratio, 0.60; P less than .0001).

However, in analyses stratified by patient life expectancy, there was a significant survival benefit of cytoreductive nephrectomy only among patients expected to live 12-18 months (3.3-month incremental benefit; adjusted hazard ratio, 0.85; P = .049) or 18-24 months (5.2-month incremental benefit; adjusted hazard ratio, 0.72; P less than .0001).

Similarly, in analyses stratified by the number of risk factors present out of the six IMDC risk factors, there was a significant survival benefit of cytoreductive nephrectomy only among patients with three or fewer factors (incremental benefit of 6-10 months, P less than .005 for each).

The impact of overall tumor burden and the size of the primary tumor were not considered in this analysis but will be in subsequent analyses, according to Dr. Heng.

He disclosed that he is a consultant/adviser to Aveo, Bayer, Bristol-Myers Squibb, Novartis, and Pfizer.

SAN FRANCISCO – Only selected patients with synchronous metastases from renal cell carcinoma derive a survival benefit from a cytoreductive nephrectomy, a retrospective cohort study showed.

Researchers studied more than 1,600 patients from the International mRCC (metastatic renal cell carcinoma) Database Consortium who developed metastases while their primary tumor was still in place.

The main analyses showed that as a whole, patients who underwent cytoreductive nephrectomy lived longer than their counterparts who did not have this surgery.

However, in stratified analyses, the surgery significantly prolonged survival only among patients who had a life expectancy exceeding 12 months and patients who had three or fewer risk factors by International mRCC Database Consortium (IMDC) criteria.

Risk factors include Karnofsky performance status less than 80%, an interval between diagnosis and treatment of less than 1 year, anemia, thrombocytosis, neutrophilia, and hypercalcemia

"Overall, I think we can say that cytoreductive nephrectomy may be beneficial in the age of targeted therapy. However, not all patients should have it," commented first author Dr. Daniel Y.C. Heng of the University of Calgary (Alta.).

"Patients with four or more IMDC risk factors and patients with limited life expectancy probably shouldn’t have a cytoreductive nephrectomy," he said. "Of course, there are probably exceptions to that rule; if patients are really symptomatic in the primary, for example, or have bleeding, maybe there are exceptions.

"But I think this is a very interesting and useful way to help select our patients for cytoreductive nephrectomy. Certainly, we are awaiting the CARMENA and SURTIME phase III randomized controlled trials to prospectively evaluate this, and hopefully, we will be able to look at the IMDC risk factors to see if they can aid in patient selection in a prospectively validated way," Dr. Heng said at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Cytoreductive nephrectomy carries risks of morbidity and mortality, and some patients may be unable to go on to receive systemic therapy, noted invited discussant Dr. Daniel Canter of the Fox Chase Cancer Center, Philadelphia.

"What I take home as the most important point of this talk is that we need to make better choices and risk stratify these patients before surgery," he said.

A key question arising from the new data is whether the IMDC risk groups should be redefined, according to Dr. Canter; for example, patients with three risk factors are currently placed in the poor risk group, yet they derived significant benefit from surgery in this study. "So is there room for further refinement in this model?" he asked.

"With such a large cohort, I think that adding to this data with complication rates and perioperative mortality would certainly be important in terms of future treatment decision making," he commented.

Session attendee Dr. Adam Metwalli of the National Cancer Institute asked, "Are there specific risk factors that seem to disproportionately cluster among those who have four or five that would help to distinguish them from the ones who have zero to three?"

"By far, the most important prognostic factor is Karnofsky performance status, and that makes sense," Dr. Heng replied. "It’s partially the ‘look test’ and how you think a patient will fare. So, that by far has the biggest contribution."

Introducing the study, he noted that cytoreductive nephrectomy has previously been found to prolong survival by about 6 months in patients with metastatic renal cell carcinoma treated in the immunotherapy era.

"But of course now we are in the age of targeted therapy, with VEGF [vascular endothelial growth factor] inhibitors and mTOR [mammalian target of rapamycin] inhibitors. These are drugs that are much more active than in the era of old immunotherapy. So it begs the question, is cytoreductive nephrectomy still relevant?" Dr. Heng said.

The researchers studied 1,658 patients from 20 institutions who had mRCC with synchronous metastases, of whom 59% underwent cytoreductive nephrectomy.

They had a median age of 59 years, and about half were in the IMDC intermediate-risk group. The most common prior targeted therapy was sunitinib (Sutent), received by about three-fourths, reported Dr. Heng.

In unadjusted analyses, median overall survival was a significant 11 months longer for patients who underwent cytoreductive nephrectomy compared with their counterparts who did not (20.6 vs. 9.5 months). After adjustment for IMDC risk factors, the surgery was associated with a 40% reduction in the risk of death in the entire cohort (hazard ratio, 0.60; P less than .0001).

However, in analyses stratified by patient life expectancy, there was a significant survival benefit of cytoreductive nephrectomy only among patients expected to live 12-18 months (3.3-month incremental benefit; adjusted hazard ratio, 0.85; P = .049) or 18-24 months (5.2-month incremental benefit; adjusted hazard ratio, 0.72; P less than .0001).

Similarly, in analyses stratified by the number of risk factors present out of the six IMDC risk factors, there was a significant survival benefit of cytoreductive nephrectomy only among patients with three or fewer factors (incremental benefit of 6-10 months, P less than .005 for each).

The impact of overall tumor burden and the size of the primary tumor were not considered in this analysis but will be in subsequent analyses, according to Dr. Heng.

He disclosed that he is a consultant/adviser to Aveo, Bayer, Bristol-Myers Squibb, Novartis, and Pfizer.

SAN FRANCISCO – Patients with muscle-invasive bladder cancer who have a near-complete response to induction chemoradiation can safely skip a cystectomy, suggested a study reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Researchers led by Dr. Timur Mitin, a radiation oncologist at Massachusetts General Hospital in Boston, conducted a pooled analysis of 119 patients from two Radiation Therapy Oncology Group (RTOG) trials that tested trimodality therapy, whereby patients undergo maximal transurethral resection of the bladder tumor (TURBT), induction chemoradiation, cystoscopic evaluation of response, and consolidation chemoradiation, with or without adjuvant chemotherapy.

In contrast to the historical practice of allowing only patients having a complete response (T0) to induction chemoradiation to proceed with bladder-sparing therapy, the RTOG trials allowed patients having a near-complete response (Ta or Tis) to do the same.

Results showed that, after a median follow-up of almost 6 years, there were no significant differences between the complete and near-complete responders with respect to rates of bladder recurrence, salvage cystectomy, and overall survival, Dr. Mitin reported.

"Many physicians have been reluctant to subject patients to radical cystectomy if, after the induction chemoradiation therapy, they find a very small amount of superficial tumor, Ta or Tis," he commented. On the basis of these patients’ similarly good outcomes, "we recommend that patients with a near-complete response to the induction phase continue with their bladder-sparing therapy."

"I think this was a wonderful analysis," session cochair Dr. Jason A. Efstathiou, also of Massachusetts General Hospital, said in an interview.

"The RTOG has a long history of exploring bladder-sparing trimodality therapy as an option for select patients. If you select those patients well, as this abstract suggested – those who have a complete response or a near-complete response to induction chemoradiation – these patients do in fact very well. So we do believe that, for the right patient, trimodality therapy is an appropriate option, an option to up-front cystectomy. And I think his data [were] very reassuring: For patients who respond well to such treatment initially, they have a very good chance of doing well in the long term and even being cured," he said.

"Ultimately, what will be practice changing is the continued multidisciplinary approach to this disease, which means newly diagnosed patients with muscle-invasive disease are seen by urologic surgeons, by medical oncologists, and by radiation oncologists, and that sort of a consensus plan is developed that the patient chooses. So that movement will be practice changing," Dr. Efstathiou added. "And I think patient advocacy – patients learning of trimodality therapy as an option for up-front treatment – will also play a big role in perhaps the increased use of this management strategy."

The study patients were treated on RTOG 9906 (the first trial to relax the response criteria for allowing patients to go on to consolidation therapy) and RTOG 0233.

Pooled analyses compared 101 patients who had a complete response (T0) with 18 patients who had a near-complete response (Ta or Tis) to induction chemoradiation, all of whom were treated with bladder-sparing trimodality therapy.

Baseline demographic and clinical characteristics did not differ significantly between the complete responders and the near-complete responders, Dr. Mitin reported.

After a median follow-up of 5.9 years, the two groups did not differ significantly with respect to rates of any bladder recurrence (36% vs. 28%) or, specifically, an invasive bladder recurrence (36% vs. 20%).

The groups also were statistically indistinguishable with respect to rates of salvage cystectomy, disease-specific survival, and bladder-intact survival, as well as overall survival (72% vs. 61%).

Dr. Mitin disclosed no conflicts of interest related to the research.

SAN FRANCISCO – Patients with muscle-invasive bladder cancer who have a near-complete response to induction chemoradiation can safely skip a cystectomy, suggested a study reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Researchers led by Dr. Timur Mitin, a radiation oncologist at Massachusetts General Hospital in Boston, conducted a pooled analysis of 119 patients from two Radiation Therapy Oncology Group (RTOG) trials that tested trimodality therapy, whereby patients undergo maximal transurethral resection of the bladder tumor (TURBT), induction chemoradiation, cystoscopic evaluation of response, and consolidation chemoradiation, with or without adjuvant chemotherapy.

In contrast to the historical practice of allowing only patients having a complete response (T0) to induction chemoradiation to proceed with bladder-sparing therapy, the RTOG trials allowed patients having a near-complete response (Ta or Tis) to do the same.

Results showed that, after a median follow-up of almost 6 years, there were no significant differences between the complete and near-complete responders with respect to rates of bladder recurrence, salvage cystectomy, and overall survival, Dr. Mitin reported.

"Many physicians have been reluctant to subject patients to radical cystectomy if, after the induction chemoradiation therapy, they find a very small amount of superficial tumor, Ta or Tis," he commented. On the basis of these patients’ similarly good outcomes, "we recommend that patients with a near-complete response to the induction phase continue with their bladder-sparing therapy."

"I think this was a wonderful analysis," session cochair Dr. Jason A. Efstathiou, also of Massachusetts General Hospital, said in an interview.

"The RTOG has a long history of exploring bladder-sparing trimodality therapy as an option for select patients. If you select those patients well, as this abstract suggested – those who have a complete response or a near-complete response to induction chemoradiation – these patients do in fact very well. So we do believe that, for the right patient, trimodality therapy is an appropriate option, an option to up-front cystectomy. And I think his data [were] very reassuring: For patients who respond well to such treatment initially, they have a very good chance of doing well in the long term and even being cured," he said.

"Ultimately, what will be practice changing is the continued multidisciplinary approach to this disease, which means newly diagnosed patients with muscle-invasive disease are seen by urologic surgeons, by medical oncologists, and by radiation oncologists, and that sort of a consensus plan is developed that the patient chooses. So that movement will be practice changing," Dr. Efstathiou added. "And I think patient advocacy – patients learning of trimodality therapy as an option for up-front treatment – will also play a big role in perhaps the increased use of this management strategy."

The study patients were treated on RTOG 9906 (the first trial to relax the response criteria for allowing patients to go on to consolidation therapy) and RTOG 0233.

Pooled analyses compared 101 patients who had a complete response (T0) with 18 patients who had a near-complete response (Ta or Tis) to induction chemoradiation, all of whom were treated with bladder-sparing trimodality therapy.

Baseline demographic and clinical characteristics did not differ significantly between the complete responders and the near-complete responders, Dr. Mitin reported.

After a median follow-up of 5.9 years, the two groups did not differ significantly with respect to rates of any bladder recurrence (36% vs. 28%) or, specifically, an invasive bladder recurrence (36% vs. 20%).

The groups also were statistically indistinguishable with respect to rates of salvage cystectomy, disease-specific survival, and bladder-intact survival, as well as overall survival (72% vs. 61%).

Dr. Mitin disclosed no conflicts of interest related to the research.

SAN FRANCISCO – Patients with muscle-invasive bladder cancer who have a near-complete response to induction chemoradiation can safely skip a cystectomy, suggested a study reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Researchers led by Dr. Timur Mitin, a radiation oncologist at Massachusetts General Hospital in Boston, conducted a pooled analysis of 119 patients from two Radiation Therapy Oncology Group (RTOG) trials that tested trimodality therapy, whereby patients undergo maximal transurethral resection of the bladder tumor (TURBT), induction chemoradiation, cystoscopic evaluation of response, and consolidation chemoradiation, with or without adjuvant chemotherapy.

In contrast to the historical practice of allowing only patients having a complete response (T0) to induction chemoradiation to proceed with bladder-sparing therapy, the RTOG trials allowed patients having a near-complete response (Ta or Tis) to do the same.

Results showed that, after a median follow-up of almost 6 years, there were no significant differences between the complete and near-complete responders with respect to rates of bladder recurrence, salvage cystectomy, and overall survival, Dr. Mitin reported.

"Many physicians have been reluctant to subject patients to radical cystectomy if, after the induction chemoradiation therapy, they find a very small amount of superficial tumor, Ta or Tis," he commented. On the basis of these patients’ similarly good outcomes, "we recommend that patients with a near-complete response to the induction phase continue with their bladder-sparing therapy."

"I think this was a wonderful analysis," session cochair Dr. Jason A. Efstathiou, also of Massachusetts General Hospital, said in an interview.

"The RTOG has a long history of exploring bladder-sparing trimodality therapy as an option for select patients. If you select those patients well, as this abstract suggested – those who have a complete response or a near-complete response to induction chemoradiation – these patients do in fact very well. So we do believe that, for the right patient, trimodality therapy is an appropriate option, an option to up-front cystectomy. And I think his data [were] very reassuring: For patients who respond well to such treatment initially, they have a very good chance of doing well in the long term and even being cured," he said.

"Ultimately, what will be practice changing is the continued multidisciplinary approach to this disease, which means newly diagnosed patients with muscle-invasive disease are seen by urologic surgeons, by medical oncologists, and by radiation oncologists, and that sort of a consensus plan is developed that the patient chooses. So that movement will be practice changing," Dr. Efstathiou added. "And I think patient advocacy – patients learning of trimodality therapy as an option for up-front treatment – will also play a big role in perhaps the increased use of this management strategy."

The study patients were treated on RTOG 9906 (the first trial to relax the response criteria for allowing patients to go on to consolidation therapy) and RTOG 0233.

Pooled analyses compared 101 patients who had a complete response (T0) with 18 patients who had a near-complete response (Ta or Tis) to induction chemoradiation, all of whom were treated with bladder-sparing trimodality therapy.

Baseline demographic and clinical characteristics did not differ significantly between the complete responders and the near-complete responders, Dr. Mitin reported.

After a median follow-up of 5.9 years, the two groups did not differ significantly with respect to rates of any bladder recurrence (36% vs. 28%) or, specifically, an invasive bladder recurrence (36% vs. 20%).

The groups also were statistically indistinguishable with respect to rates of salvage cystectomy, disease-specific survival, and bladder-intact survival, as well as overall survival (72% vs. 61%).

Dr. Mitin disclosed no conflicts of interest related to the research.

SAN FRANCISCO – Use of radium-223 in men with castration-resistant prostate cancer who have bone metastases appears safe in the longer term, according to data collected 1.5 years after treatment in the ALSYMPCA trial.

Patients in the phase III trial had received placebo or up to six injections of radium-223 (Xofigo, formerly Alpharadin), a first-in-class alpha-emitting radiopharmaceutical taken up by bone, during the trial’s active treatment phase.

A total of 574 entered the trial’s follow-up program designed to look at safety with respect to bone and marrow toxicity and second cancers, lead author Dr. Sten Nilsson reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The rate of grade 3/4 myelosuppression was about 3% in the radium-223 group (compared with 1% in the placebo group), and a single patient developed aplastic anemia, reported Dr. Nilsson of the Karolinska University Hospital in Stockholm. There were no cases of treatment-related hematologic, bone, or solid organ cancers, or myelodysplastic syndrome.

"We know from the ALSYMPCA study and also from prior studies with radium-223 that it has a very benign safety profile, and we can see from this long-term follow-up that this remained during the study period," he commented. The findings "support further evaluation of combining radium-223 with other agents to treat patients with castration-resistant prostate cancer and bone metastases."

These findings "show for those of you who are concerned about long-term marrow toxicity or of the development of a second primary within that 1.5-year period, it looks like one can rest easy, that there are no surprises coming down the pike, and that indeed it looks like this is a drug that prolongs survival with a relatively low cost to patients in terms of quality of life or damage to their normal organs," said invited discussant Dr. Michael J. Morris, head of the prostate cancer section at the Memorial-Sloan Kettering Cancer Center in New York.

"The one patient who had aplastic anemia was heavily pretreated, but otherwise, there is a side effect profile that is tantalizingly close to zero at 1.5 years," he noted. "Although the drug is eliminated by virtue of the GI tract, we didn’t really see any GI toxicity that is long term, no GI second primaries and no hematologic second primaries."

At the same time, Dr. Morris called for research to address a host of unanswered questions about the efficacy of radium-223, such as the specific target in bone responsible for the survival benefit and the optimal dose to use. "If you look at a mathematical model of the geometry of the bone marrow, the heterogeneous deposition of hydroxyapatite within that geometry, and the placement of the progenitor cells, it does seem at least hypothetically that one could go much higher than this dose and still not risk significant marrow toxicity," he noted.

A session attendee commented that she has had difficulty giving chemotherapy to a few patients who had previously received radium-223. "Do you have any data or are you collecting a database on the rates of myelosuppression, febrile neutropenia, and the doses you can deliver in these patients?" she asked Dr. Nilsson.

"We don’t have any firm data, but we are looking into that," he replied. "We have patients who have participated in the ALSYMPCA trial who have received docetaxel afterwards without any major problems. Also we have some patients who have received both docetaxel and cabazitaxel afterwards. So we believe that there are no problems with doing that. But surely we need further data [to be certain]."

Another attendee asked, "What do you think the best future use of radium is – [in the progressive disease setting or earlier, in the adjuvant setting?"

"Well, the studies have been performed in progressive disease, and that is where we base our knowledge," Dr. Nilsson replied. "Of course, like with other drugs, it would be interesting to look at what happens if you move it further upward and give it earlier in the disease. There are trials now in planning or ongoing where you give radium earlier, and of course it would be very interesting to see what the results are if you combine, for example, radium with hormonal therapy in a patient who presents with bone metastatic disease."

The ALSYMPCA trial, sponsored by Bayer in collaboration with Algeta, randomized 921 men in 2:1 ratio to radium-223 or placebo, each added to best standard of care and given over a 24-week period.

The main results, previously reported, showed that the agent prolonged overall survival and the time to first symptomatic skeletal events, and was associated with fewer adverse events and a low rate of myelosuppression (N. Engl. J. Med. 2013;369:213-23). These results led to approval of radium-223 by the Food and Drug Administration for the treatment of castration-resistant metastatic prostate cancer in men with symptomatic bone metastases.

After stopping treatment, 406 patients from the radium-223 group and 168 from the placebo group entered the trial’s posttreatment follow-up program. Nearly 60% had previously received docetaxel (Taxotere), and roughly 40% were receiving bisphosphonates, usually zoledronate (Zometa).

The majority of patients – 83% and 71%, respectively – had received all of the six planned injections of study drug, reported Dr. Nilsson.

There was a high rate of withdrawal of patients during the follow-up period, 79% in the radium-223 group and 86% in the placebo group, in the majority of cases due to death.

The median duration of follow-up was 10.4 months for the radium-223 group and 7.6 months for the placebo group.

Analyses of hematologic adverse events showed that the two groups had an identical rate of grade 3/4 anemia, at 1%.

The radium-223 group had a single case of grade 3/4 aplastic anemia, diagnosed by bone marrow biopsy and considered treatment related. "This was a patient who had received samarium and chemotherapy, and repeated external beam radiotherapy to his bone metastatic disease," Dr. Nilsson noted.

In addition, there were two cases each of grade 3/4 leukopenia and neutropenia in the radium-223 group, for an overall myelosuppression rate of about 3%.

Analyses of nonhematologic adverse events showed that the radium-223 group had single cases of grade 3-5 multiorgan failure, pneumonia, and pathologic fracture, while the placebo group had a single case of grade 3-5 cardiopulmonary failure.

None of the patients were reported to have developed acute myeloid leukemia, myelodysplastic syndrome, or primary bone cancer.

Primary cancers in other organs were seen in two patients in the radium-223 group (bladder cancer and lymph node metastases not originating from prostate cancer) and three in the placebo group (two cases of skin cancer and one of rectal cancer); all were considered unrelated to the study drug, according to Dr. Nilsson.

Dr. Nilsson disclosed that he is a consultant/adviser to Algeta and Bayer HealthCare. The trial was sponsored by Bayer in collaboration with Algeta. Dr. Morris disclosed that he is a consultant to Bayer.

SAN FRANCISCO – Use of radium-223 in men with castration-resistant prostate cancer who have bone metastases appears safe in the longer term, according to data collected 1.5 years after treatment in the ALSYMPCA trial.

Patients in the phase III trial had received placebo or up to six injections of radium-223 (Xofigo, formerly Alpharadin), a first-in-class alpha-emitting radiopharmaceutical taken up by bone, during the trial’s active treatment phase.

A total of 574 entered the trial’s follow-up program designed to look at safety with respect to bone and marrow toxicity and second cancers, lead author Dr. Sten Nilsson reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The rate of grade 3/4 myelosuppression was about 3% in the radium-223 group (compared with 1% in the placebo group), and a single patient developed aplastic anemia, reported Dr. Nilsson of the Karolinska University Hospital in Stockholm. There were no cases of treatment-related hematologic, bone, or solid organ cancers, or myelodysplastic syndrome.

"We know from the ALSYMPCA study and also from prior studies with radium-223 that it has a very benign safety profile, and we can see from this long-term follow-up that this remained during the study period," he commented. The findings "support further evaluation of combining radium-223 with other agents to treat patients with castration-resistant prostate cancer and bone metastases."

These findings "show for those of you who are concerned about long-term marrow toxicity or of the development of a second primary within that 1.5-year period, it looks like one can rest easy, that there are no surprises coming down the pike, and that indeed it looks like this is a drug that prolongs survival with a relatively low cost to patients in terms of quality of life or damage to their normal organs," said invited discussant Dr. Michael J. Morris, head of the prostate cancer section at the Memorial-Sloan Kettering Cancer Center in New York.

"The one patient who had aplastic anemia was heavily pretreated, but otherwise, there is a side effect profile that is tantalizingly close to zero at 1.5 years," he noted. "Although the drug is eliminated by virtue of the GI tract, we didn’t really see any GI toxicity that is long term, no GI second primaries and no hematologic second primaries."

At the same time, Dr. Morris called for research to address a host of unanswered questions about the efficacy of radium-223, such as the specific target in bone responsible for the survival benefit and the optimal dose to use. "If you look at a mathematical model of the geometry of the bone marrow, the heterogeneous deposition of hydroxyapatite within that geometry, and the placement of the progenitor cells, it does seem at least hypothetically that one could go much higher than this dose and still not risk significant marrow toxicity," he noted.

A session attendee commented that she has had difficulty giving chemotherapy to a few patients who had previously received radium-223. "Do you have any data or are you collecting a database on the rates of myelosuppression, febrile neutropenia, and the doses you can deliver in these patients?" she asked Dr. Nilsson.

"We don’t have any firm data, but we are looking into that," he replied. "We have patients who have participated in the ALSYMPCA trial who have received docetaxel afterwards without any major problems. Also we have some patients who have received both docetaxel and cabazitaxel afterwards. So we believe that there are no problems with doing that. But surely we need further data [to be certain]."

Another attendee asked, "What do you think the best future use of radium is – [in the progressive disease setting or earlier, in the adjuvant setting?"

"Well, the studies have been performed in progressive disease, and that is where we base our knowledge," Dr. Nilsson replied. "Of course, like with other drugs, it would be interesting to look at what happens if you move it further upward and give it earlier in the disease. There are trials now in planning or ongoing where you give radium earlier, and of course it would be very interesting to see what the results are if you combine, for example, radium with hormonal therapy in a patient who presents with bone metastatic disease."

The ALSYMPCA trial, sponsored by Bayer in collaboration with Algeta, randomized 921 men in 2:1 ratio to radium-223 or placebo, each added to best standard of care and given over a 24-week period.

The main results, previously reported, showed that the agent prolonged overall survival and the time to first symptomatic skeletal events, and was associated with fewer adverse events and a low rate of myelosuppression (N. Engl. J. Med. 2013;369:213-23). These results led to approval of radium-223 by the Food and Drug Administration for the treatment of castration-resistant metastatic prostate cancer in men with symptomatic bone metastases.

After stopping treatment, 406 patients from the radium-223 group and 168 from the placebo group entered the trial’s posttreatment follow-up program. Nearly 60% had previously received docetaxel (Taxotere), and roughly 40% were receiving bisphosphonates, usually zoledronate (Zometa).

The majority of patients – 83% and 71%, respectively – had received all of the six planned injections of study drug, reported Dr. Nilsson.

There was a high rate of withdrawal of patients during the follow-up period, 79% in the radium-223 group and 86% in the placebo group, in the majority of cases due to death.

The median duration of follow-up was 10.4 months for the radium-223 group and 7.6 months for the placebo group.

Analyses of hematologic adverse events showed that the two groups had an identical rate of grade 3/4 anemia, at 1%.

The radium-223 group had a single case of grade 3/4 aplastic anemia, diagnosed by bone marrow biopsy and considered treatment related. "This was a patient who had received samarium and chemotherapy, and repeated external beam radiotherapy to his bone metastatic disease," Dr. Nilsson noted.

In addition, there were two cases each of grade 3/4 leukopenia and neutropenia in the radium-223 group, for an overall myelosuppression rate of about 3%.

Analyses of nonhematologic adverse events showed that the radium-223 group had single cases of grade 3-5 multiorgan failure, pneumonia, and pathologic fracture, while the placebo group had a single case of grade 3-5 cardiopulmonary failure.

None of the patients were reported to have developed acute myeloid leukemia, myelodysplastic syndrome, or primary bone cancer.

Primary cancers in other organs were seen in two patients in the radium-223 group (bladder cancer and lymph node metastases not originating from prostate cancer) and three in the placebo group (two cases of skin cancer and one of rectal cancer); all were considered unrelated to the study drug, according to Dr. Nilsson.

Dr. Nilsson disclosed that he is a consultant/adviser to Algeta and Bayer HealthCare. The trial was sponsored by Bayer in collaboration with Algeta. Dr. Morris disclosed that he is a consultant to Bayer.

SAN FRANCISCO – Use of radium-223 in men with castration-resistant prostate cancer who have bone metastases appears safe in the longer term, according to data collected 1.5 years after treatment in the ALSYMPCA trial.

Patients in the phase III trial had received placebo or up to six injections of radium-223 (Xofigo, formerly Alpharadin), a first-in-class alpha-emitting radiopharmaceutical taken up by bone, during the trial’s active treatment phase.

A total of 574 entered the trial’s follow-up program designed to look at safety with respect to bone and marrow toxicity and second cancers, lead author Dr. Sten Nilsson reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The rate of grade 3/4 myelosuppression was about 3% in the radium-223 group (compared with 1% in the placebo group), and a single patient developed aplastic anemia, reported Dr. Nilsson of the Karolinska University Hospital in Stockholm. There were no cases of treatment-related hematologic, bone, or solid organ cancers, or myelodysplastic syndrome.

"We know from the ALSYMPCA study and also from prior studies with radium-223 that it has a very benign safety profile, and we can see from this long-term follow-up that this remained during the study period," he commented. The findings "support further evaluation of combining radium-223 with other agents to treat patients with castration-resistant prostate cancer and bone metastases."

These findings "show for those of you who are concerned about long-term marrow toxicity or of the development of a second primary within that 1.5-year period, it looks like one can rest easy, that there are no surprises coming down the pike, and that indeed it looks like this is a drug that prolongs survival with a relatively low cost to patients in terms of quality of life or damage to their normal organs," said invited discussant Dr. Michael J. Morris, head of the prostate cancer section at the Memorial-Sloan Kettering Cancer Center in New York.

"The one patient who had aplastic anemia was heavily pretreated, but otherwise, there is a side effect profile that is tantalizingly close to zero at 1.5 years," he noted. "Although the drug is eliminated by virtue of the GI tract, we didn’t really see any GI toxicity that is long term, no GI second primaries and no hematologic second primaries."

At the same time, Dr. Morris called for research to address a host of unanswered questions about the efficacy of radium-223, such as the specific target in bone responsible for the survival benefit and the optimal dose to use. "If you look at a mathematical model of the geometry of the bone marrow, the heterogeneous deposition of hydroxyapatite within that geometry, and the placement of the progenitor cells, it does seem at least hypothetically that one could go much higher than this dose and still not risk significant marrow toxicity," he noted.

A session attendee commented that she has had difficulty giving chemotherapy to a few patients who had previously received radium-223. "Do you have any data or are you collecting a database on the rates of myelosuppression, febrile neutropenia, and the doses you can deliver in these patients?" she asked Dr. Nilsson.

"We don’t have any firm data, but we are looking into that," he replied. "We have patients who have participated in the ALSYMPCA trial who have received docetaxel afterwards without any major problems. Also we have some patients who have received both docetaxel and cabazitaxel afterwards. So we believe that there are no problems with doing that. But surely we need further data [to be certain]."

Another attendee asked, "What do you think the best future use of radium is – [in the progressive disease setting or earlier, in the adjuvant setting?"

"Well, the studies have been performed in progressive disease, and that is where we base our knowledge," Dr. Nilsson replied. "Of course, like with other drugs, it would be interesting to look at what happens if you move it further upward and give it earlier in the disease. There are trials now in planning or ongoing where you give radium earlier, and of course it would be very interesting to see what the results are if you combine, for example, radium with hormonal therapy in a patient who presents with bone metastatic disease."

The ALSYMPCA trial, sponsored by Bayer in collaboration with Algeta, randomized 921 men in 2:1 ratio to radium-223 or placebo, each added to best standard of care and given over a 24-week period.

The main results, previously reported, showed that the agent prolonged overall survival and the time to first symptomatic skeletal events, and was associated with fewer adverse events and a low rate of myelosuppression (N. Engl. J. Med. 2013;369:213-23). These results led to approval of radium-223 by the Food and Drug Administration for the treatment of castration-resistant metastatic prostate cancer in men with symptomatic bone metastases.

After stopping treatment, 406 patients from the radium-223 group and 168 from the placebo group entered the trial’s posttreatment follow-up program. Nearly 60% had previously received docetaxel (Taxotere), and roughly 40% were receiving bisphosphonates, usually zoledronate (Zometa).

The majority of patients – 83% and 71%, respectively – had received all of the six planned injections of study drug, reported Dr. Nilsson.

There was a high rate of withdrawal of patients during the follow-up period, 79% in the radium-223 group and 86% in the placebo group, in the majority of cases due to death.

The median duration of follow-up was 10.4 months for the radium-223 group and 7.6 months for the placebo group.

Analyses of hematologic adverse events showed that the two groups had an identical rate of grade 3/4 anemia, at 1%.

The radium-223 group had a single case of grade 3/4 aplastic anemia, diagnosed by bone marrow biopsy and considered treatment related. "This was a patient who had received samarium and chemotherapy, and repeated external beam radiotherapy to his bone metastatic disease," Dr. Nilsson noted.

In addition, there were two cases each of grade 3/4 leukopenia and neutropenia in the radium-223 group, for an overall myelosuppression rate of about 3%.

Analyses of nonhematologic adverse events showed that the radium-223 group had single cases of grade 3-5 multiorgan failure, pneumonia, and pathologic fracture, while the placebo group had a single case of grade 3-5 cardiopulmonary failure.

None of the patients were reported to have developed acute myeloid leukemia, myelodysplastic syndrome, or primary bone cancer.

Primary cancers in other organs were seen in two patients in the radium-223 group (bladder cancer and lymph node metastases not originating from prostate cancer) and three in the placebo group (two cases of skin cancer and one of rectal cancer); all were considered unrelated to the study drug, according to Dr. Nilsson.

Dr. Nilsson disclosed that he is a consultant/adviser to Algeta and Bayer HealthCare. The trial was sponsored by Bayer in collaboration with Algeta. Dr. Morris disclosed that he is a consultant to Bayer.