Endocrine Cancer

CORONADO, CALIF.– In an analysis of primary treatments for all stages of differentiated thyroid carcinoma, only thyroid hormone suppressive therapy was associated with both improved overall survival and disease-free survival.

Further, when examining the degree of thyroid hormone suppressive therapy (THST), aggressive THST conferred no additional survival benefit when compared with moderate THST, even when limiting the analysis to patients with distant metastatic disease, results from a long-term analysis of registry showed.

Those are key findings from an updated analysis of data from the National Thyroid Cancer Treatment Cooperative Study Group Registry, which were presented by lead study author Dr. Aubrey Carhill during the annual meeting of the American Thyroid Association.

“To date there are no prospective studies evaluating the longitudinal outcomes of initial long-term therapies in differentiated thyroid carcinoma,” said Dr. Carhill of MD Anderson Cancer Center, Houston. “In the absence of prospective trials, there has been significant reliance on retrospective studies with limited numbers of patients and low event rates as well as significant reliance on expert opinion to guide clinical practice.”

For example, current ATA guidelines for TSH suppression suggest that in long-term follow-up of patients with differentiated thyroid cancer, “those with persistent disease should have TSH levels suppressed to undetectable levels and maintained indefinitely,” Dr. Carhill said, while disease-free, higher-risk patients “should be suppressed to low-moderate levels continued between 5 and 10 years and low-risk patients should be maintained in the low-normal range. Similar levels of evidence exist to support the use of radioactive iodine and the degree of surgical extent.”

The challenge for clinicians, she continued, becomes balancing the potential risks of more aggressive therapies, such as aggressive thyroid hormone suppression, and the risks associated with long-term thyrotoxicosis with the potential benefits of treatment. “This is not always clear, especially in patients who are at very low risk for cancer-specific mortality,” she said. “There remains a need for accurate prognostication in order to identify which patients will benefit from different treatment modalities because current staging systems have limited ability to predict response to treatment.”

Formed in 1987, the National Thyroid Treatment Cooperative Study Group is a multi-institutional effort to assess long-term management of outcomes on patients with differentiated thyroid cancer. The purpose of the present study was to provide a more current analysis of the prospectively collected data, which was last analyzed in 2001. All staging is tracked according to the registry’s staging system, which is very similar to that of the American Joint Committee on Cancer’s TNM Staging System. Therapies analyzed included total/near total thyroidectomy (T/NTT) vs. a lesser extent of surgery; radioactive iodine (RAI) vs. no RAI; and increasing degrees of THST over time.

Dr. Carhill presented findings from an analysis of the effects of initial therapies in 4,941 patients treated at 11 centers in North America between 1987 and 2012. The median length of follow-up was 6 years, which translated to 34,631 person-years of documented follow-up time. The researchers used univariate and multivariate analyses to assess overall and disease-free survival. Moderate THST was defined as TSH maintained in subnormal or normal levels, while aggressive THST was defined as that maintained in undetectable or subnormal levels.

Improved overall survival was observed in stage III patients who received RAI (risk ratio, 0.66; P = .04) and in stage IV patients who received T/NTT and RAI (RR, 0.66 and 0.70, respectively; combined P = .049). Moderate but not aggressive THST was associated with significantly improved overall survival in all stages (RR, 0.13 in stage I, 0.09 in stage II, 0.13 in stage III, and 0.33 in stage IV), as well as with improved disease-free survival (RR, 0.52 in stage I, 0.40 in stage II, 0.18 in stage III, and no RR in stage IV).

In stage I patients, RAI conferred worse disease-free survival (RR, 1.79; P = .0005). “However, further propensity analysis demonstrated that there was no difference in disease-free survival when patients were stratified according to their propensity to receive radioactive iodine,” Dr. Carhill said.

To evaluate the optimal duration of THST, the researchers examined the effect of continuing degrees of suppression beyond 1, 3, and 5 years of follow-up. After 1 and 3 years of follow-up, both initial stage and moderate TSH suppression were independently predictive of improved overall survival (RR, 0.31 and 0.29, respectively). However, after 5 years of follow-up, “although initial stage remained independently predictive, there was no further benefit with any subsequent degree of TSH suppression,” Dr. Carhill said.

The study “confirms prior registry findings of a survival benefit in high-risk groups treated with T/NTT and RAI, and there is no disease-free survival benefit in low-risk groups receiving postoperative RAI,” she concluded. “We also report for the first time that in multivariate analysis of primary treatments for DTC [differentiated thyroid cancer], in all stages, only THST was associated with both improved overall survival and disease-free survival. When examining the degree of THST, aggressive THST confers no additional survival advantage as compared with moderate THST, even in patients with distant metastatic disease, which remains particularly relevant given the risks associated with long-term thyrotoxicosis.” She acknowledged certain limitations of the study, including the potential for institutional bias. “However, we feel that this is somewhat offset due to the size of the registry cohort and the number of sites involved” Dr. Carhill said.

The registry has received support from Genzyme and Pfizer. Dr. Carhill reported having no financial disclosures.

[email protected]

On Twitter @dougbrunk

CORONADO, CALIF.– In an analysis of primary treatments for all stages of differentiated thyroid carcinoma, only thyroid hormone suppressive therapy was associated with both improved overall survival and disease-free survival.

Further, when examining the degree of thyroid hormone suppressive therapy (THST), aggressive THST conferred no additional survival benefit when compared with moderate THST, even when limiting the analysis to patients with distant metastatic disease, results from a long-term analysis of registry showed.

Those are key findings from an updated analysis of data from the National Thyroid Cancer Treatment Cooperative Study Group Registry, which were presented by lead study author Dr. Aubrey Carhill during the annual meeting of the American Thyroid Association.

“To date there are no prospective studies evaluating the longitudinal outcomes of initial long-term therapies in differentiated thyroid carcinoma,” said Dr. Carhill of MD Anderson Cancer Center, Houston. “In the absence of prospective trials, there has been significant reliance on retrospective studies with limited numbers of patients and low event rates as well as significant reliance on expert opinion to guide clinical practice.”

For example, current ATA guidelines for TSH suppression suggest that in long-term follow-up of patients with differentiated thyroid cancer, “those with persistent disease should have TSH levels suppressed to undetectable levels and maintained indefinitely,” Dr. Carhill said, while disease-free, higher-risk patients “should be suppressed to low-moderate levels continued between 5 and 10 years and low-risk patients should be maintained in the low-normal range. Similar levels of evidence exist to support the use of radioactive iodine and the degree of surgical extent.”

The challenge for clinicians, she continued, becomes balancing the potential risks of more aggressive therapies, such as aggressive thyroid hormone suppression, and the risks associated with long-term thyrotoxicosis with the potential benefits of treatment. “This is not always clear, especially in patients who are at very low risk for cancer-specific mortality,” she said. “There remains a need for accurate prognostication in order to identify which patients will benefit from different treatment modalities because current staging systems have limited ability to predict response to treatment.”

Formed in 1987, the National Thyroid Treatment Cooperative Study Group is a multi-institutional effort to assess long-term management of outcomes on patients with differentiated thyroid cancer. The purpose of the present study was to provide a more current analysis of the prospectively collected data, which was last analyzed in 2001. All staging is tracked according to the registry’s staging system, which is very similar to that of the American Joint Committee on Cancer’s TNM Staging System. Therapies analyzed included total/near total thyroidectomy (T/NTT) vs. a lesser extent of surgery; radioactive iodine (RAI) vs. no RAI; and increasing degrees of THST over time.

Dr. Carhill presented findings from an analysis of the effects of initial therapies in 4,941 patients treated at 11 centers in North America between 1987 and 2012. The median length of follow-up was 6 years, which translated to 34,631 person-years of documented follow-up time. The researchers used univariate and multivariate analyses to assess overall and disease-free survival. Moderate THST was defined as TSH maintained in subnormal or normal levels, while aggressive THST was defined as that maintained in undetectable or subnormal levels.

Improved overall survival was observed in stage III patients who received RAI (risk ratio, 0.66; P = .04) and in stage IV patients who received T/NTT and RAI (RR, 0.66 and 0.70, respectively; combined P = .049). Moderate but not aggressive THST was associated with significantly improved overall survival in all stages (RR, 0.13 in stage I, 0.09 in stage II, 0.13 in stage III, and 0.33 in stage IV), as well as with improved disease-free survival (RR, 0.52 in stage I, 0.40 in stage II, 0.18 in stage III, and no RR in stage IV).

In stage I patients, RAI conferred worse disease-free survival (RR, 1.79; P = .0005). “However, further propensity analysis demonstrated that there was no difference in disease-free survival when patients were stratified according to their propensity to receive radioactive iodine,” Dr. Carhill said.

To evaluate the optimal duration of THST, the researchers examined the effect of continuing degrees of suppression beyond 1, 3, and 5 years of follow-up. After 1 and 3 years of follow-up, both initial stage and moderate TSH suppression were independently predictive of improved overall survival (RR, 0.31 and 0.29, respectively). However, after 5 years of follow-up, “although initial stage remained independently predictive, there was no further benefit with any subsequent degree of TSH suppression,” Dr. Carhill said.

The study “confirms prior registry findings of a survival benefit in high-risk groups treated with T/NTT and RAI, and there is no disease-free survival benefit in low-risk groups receiving postoperative RAI,” she concluded. “We also report for the first time that in multivariate analysis of primary treatments for DTC [differentiated thyroid cancer], in all stages, only THST was associated with both improved overall survival and disease-free survival. When examining the degree of THST, aggressive THST confers no additional survival advantage as compared with moderate THST, even in patients with distant metastatic disease, which remains particularly relevant given the risks associated with long-term thyrotoxicosis.” She acknowledged certain limitations of the study, including the potential for institutional bias. “However, we feel that this is somewhat offset due to the size of the registry cohort and the number of sites involved” Dr. Carhill said.

The registry has received support from Genzyme and Pfizer. Dr. Carhill reported having no financial disclosures.

[email protected]

On Twitter @dougbrunk

CORONADO, CALIF.– In an analysis of primary treatments for all stages of differentiated thyroid carcinoma, only thyroid hormone suppressive therapy was associated with both improved overall survival and disease-free survival.

Further, when examining the degree of thyroid hormone suppressive therapy (THST), aggressive THST conferred no additional survival benefit when compared with moderate THST, even when limiting the analysis to patients with distant metastatic disease, results from a long-term analysis of registry showed.

Those are key findings from an updated analysis of data from the National Thyroid Cancer Treatment Cooperative Study Group Registry, which were presented by lead study author Dr. Aubrey Carhill during the annual meeting of the American Thyroid Association.

“To date there are no prospective studies evaluating the longitudinal outcomes of initial long-term therapies in differentiated thyroid carcinoma,” said Dr. Carhill of MD Anderson Cancer Center, Houston. “In the absence of prospective trials, there has been significant reliance on retrospective studies with limited numbers of patients and low event rates as well as significant reliance on expert opinion to guide clinical practice.”

For example, current ATA guidelines for TSH suppression suggest that in long-term follow-up of patients with differentiated thyroid cancer, “those with persistent disease should have TSH levels suppressed to undetectable levels and maintained indefinitely,” Dr. Carhill said, while disease-free, higher-risk patients “should be suppressed to low-moderate levels continued between 5 and 10 years and low-risk patients should be maintained in the low-normal range. Similar levels of evidence exist to support the use of radioactive iodine and the degree of surgical extent.”

The challenge for clinicians, she continued, becomes balancing the potential risks of more aggressive therapies, such as aggressive thyroid hormone suppression, and the risks associated with long-term thyrotoxicosis with the potential benefits of treatment. “This is not always clear, especially in patients who are at very low risk for cancer-specific mortality,” she said. “There remains a need for accurate prognostication in order to identify which patients will benefit from different treatment modalities because current staging systems have limited ability to predict response to treatment.”

Formed in 1987, the National Thyroid Treatment Cooperative Study Group is a multi-institutional effort to assess long-term management of outcomes on patients with differentiated thyroid cancer. The purpose of the present study was to provide a more current analysis of the prospectively collected data, which was last analyzed in 2001. All staging is tracked according to the registry’s staging system, which is very similar to that of the American Joint Committee on Cancer’s TNM Staging System. Therapies analyzed included total/near total thyroidectomy (T/NTT) vs. a lesser extent of surgery; radioactive iodine (RAI) vs. no RAI; and increasing degrees of THST over time.

Dr. Carhill presented findings from an analysis of the effects of initial therapies in 4,941 patients treated at 11 centers in North America between 1987 and 2012. The median length of follow-up was 6 years, which translated to 34,631 person-years of documented follow-up time. The researchers used univariate and multivariate analyses to assess overall and disease-free survival. Moderate THST was defined as TSH maintained in subnormal or normal levels, while aggressive THST was defined as that maintained in undetectable or subnormal levels.

Improved overall survival was observed in stage III patients who received RAI (risk ratio, 0.66; P = .04) and in stage IV patients who received T/NTT and RAI (RR, 0.66 and 0.70, respectively; combined P = .049). Moderate but not aggressive THST was associated with significantly improved overall survival in all stages (RR, 0.13 in stage I, 0.09 in stage II, 0.13 in stage III, and 0.33 in stage IV), as well as with improved disease-free survival (RR, 0.52 in stage I, 0.40 in stage II, 0.18 in stage III, and no RR in stage IV).

In stage I patients, RAI conferred worse disease-free survival (RR, 1.79; P = .0005). “However, further propensity analysis demonstrated that there was no difference in disease-free survival when patients were stratified according to their propensity to receive radioactive iodine,” Dr. Carhill said.

To evaluate the optimal duration of THST, the researchers examined the effect of continuing degrees of suppression beyond 1, 3, and 5 years of follow-up. After 1 and 3 years of follow-up, both initial stage and moderate TSH suppression were independently predictive of improved overall survival (RR, 0.31 and 0.29, respectively). However, after 5 years of follow-up, “although initial stage remained independently predictive, there was no further benefit with any subsequent degree of TSH suppression,” Dr. Carhill said.

The study “confirms prior registry findings of a survival benefit in high-risk groups treated with T/NTT and RAI, and there is no disease-free survival benefit in low-risk groups receiving postoperative RAI,” she concluded. “We also report for the first time that in multivariate analysis of primary treatments for DTC [differentiated thyroid cancer], in all stages, only THST was associated with both improved overall survival and disease-free survival. When examining the degree of THST, aggressive THST confers no additional survival advantage as compared with moderate THST, even in patients with distant metastatic disease, which remains particularly relevant given the risks associated with long-term thyrotoxicosis.” She acknowledged certain limitations of the study, including the potential for institutional bias. “However, we feel that this is somewhat offset due to the size of the registry cohort and the number of sites involved” Dr. Carhill said.

The registry has received support from Genzyme and Pfizer. Dr. Carhill reported having no financial disclosures.

[email protected]

On Twitter @dougbrunk

CORONADO, CALIF. – In a large cohort of patients with differentiated thyroid cancer, the use of radioactive iodine was associated with improved disease-specific survival in those with advanced disease but not in those with papillary thyroid microcarcinoma.

“Everything in medicine is a risk-benefit balance,” lead author Dr. Ryan K. Orosco said in an interview in advance of the annual meeting of the American Thyroid Association, where the work was presented. “Any two patients that receive radioactive iodine (RAI) for differentiated thyroid cancer are likely to have different survival benefit from that therapy. This study provides a quantitative comparison of the impact of RAI in various patient subgroups.”

In one of the largest studies of its kind, Dr. Orosco of the division of head and neck surgery at the University of California, San Diego, and his associates identified 85,740 patients with differentiated thyroid carcinoma from the Surveillance, Epidemiology, and End Results database from 1973 through 2009. They used multivariate analyses to explore the association between RAI and cancer-specific survival in 149 population subgroups, controlling for age, decade of diagnosis, race, gender, tumor type, nodal involvement, metastasis stage, and RAI therapy.

More than three-quarters of the patients (78%) were female, 68% were white, their mean age at diagnosis was 46 years, and the median follow-up time was 85 months. The researchers found that nearly half of patients (43%) received RAI. By American Joint Committee on Cancer stage, RAI was used in 55% of stage I patients, 41% of stage II patients, 94% of stage III patients, and 85% of stage IV patients. In addition, 42% of patients with T1a disease and 88% of those with T4 disease received RAI.

Use of RAI was positively associated with survival in the overall cohort (hazard ratio 1.3; P = .002), while statistically significant HRs for RAI were observed in 49 population subgroups. In patients with metastatic disease, use of RAI was associated with a decreased risk for disease-specific mortality (HR range of 2.28-3.82). Protective effects of RAI were also observed in patients with regional metastases (HR 1.4-1.9), those with T3-positive tumors (HR 1.36-1.39), those with T4 tumors (HR 1.85), and in those with stage IV disease (HR 1.47-1.73).

Dr. Orosco and his associates observed a negative effect of RAI in patients with macropapillary carcinoma. Specifically, those with T1a disease had an increased likelihood of thyroid cancer–specific mortality (HR .13; P less than .001), while similar associations were seen in multiple subgroups of patients with T1a disease (HR 0.04-0.25). No statistically significant effects of RAI were observed in patients with T1b or T2 tumors.

“RAI appears to offer the best survival impact in patients with advanced differentiated thyroid carcinoma,” Dr. Orosco said. “Its use in early-stage patients should be carefully considered.”

In their abstract, the researchers noted that the findings “might help clinicians personalize RAI therapy to specific differentiated thyroid cancer populations – offering treatment in patients most likely to benefit, and sparing others unnecessary costs and potential side effects.”

Dr. Orosco acknowledged certain limitations of the study, including the fact that the SEER database does not contain details about each patient’s surgery, the dose of RAI used, other comorbidities, or data on cancer recurrence. “This study does not attempt to explore the reasons behind the apparent survival disadvantage seen in patients with T1a disease,” he said. “We don’t know exactly why early-stage patients have an increased risk of disease-specific mortality when RAI is used. Additional work is needed to explore this further.”

Dr. Orosco reported having no financial disclosures.

[email protected]

On Twitter @dougbrunk

CORONADO, CALIF. – In a large cohort of patients with differentiated thyroid cancer, the use of radioactive iodine was associated with improved disease-specific survival in those with advanced disease but not in those with papillary thyroid microcarcinoma.

“Everything in medicine is a risk-benefit balance,” lead author Dr. Ryan K. Orosco said in an interview in advance of the annual meeting of the American Thyroid Association, where the work was presented. “Any two patients that receive radioactive iodine (RAI) for differentiated thyroid cancer are likely to have different survival benefit from that therapy. This study provides a quantitative comparison of the impact of RAI in various patient subgroups.”

In one of the largest studies of its kind, Dr. Orosco of the division of head and neck surgery at the University of California, San Diego, and his associates identified 85,740 patients with differentiated thyroid carcinoma from the Surveillance, Epidemiology, and End Results database from 1973 through 2009. They used multivariate analyses to explore the association between RAI and cancer-specific survival in 149 population subgroups, controlling for age, decade of diagnosis, race, gender, tumor type, nodal involvement, metastasis stage, and RAI therapy.

More than three-quarters of the patients (78%) were female, 68% were white, their mean age at diagnosis was 46 years, and the median follow-up time was 85 months. The researchers found that nearly half of patients (43%) received RAI. By American Joint Committee on Cancer stage, RAI was used in 55% of stage I patients, 41% of stage II patients, 94% of stage III patients, and 85% of stage IV patients. In addition, 42% of patients with T1a disease and 88% of those with T4 disease received RAI.

Use of RAI was positively associated with survival in the overall cohort (hazard ratio 1.3; P = .002), while statistically significant HRs for RAI were observed in 49 population subgroups. In patients with metastatic disease, use of RAI was associated with a decreased risk for disease-specific mortality (HR range of 2.28-3.82). Protective effects of RAI were also observed in patients with regional metastases (HR 1.4-1.9), those with T3-positive tumors (HR 1.36-1.39), those with T4 tumors (HR 1.85), and in those with stage IV disease (HR 1.47-1.73).

Dr. Orosco and his associates observed a negative effect of RAI in patients with macropapillary carcinoma. Specifically, those with T1a disease had an increased likelihood of thyroid cancer–specific mortality (HR .13; P less than .001), while similar associations were seen in multiple subgroups of patients with T1a disease (HR 0.04-0.25). No statistically significant effects of RAI were observed in patients with T1b or T2 tumors.

“RAI appears to offer the best survival impact in patients with advanced differentiated thyroid carcinoma,” Dr. Orosco said. “Its use in early-stage patients should be carefully considered.”

In their abstract, the researchers noted that the findings “might help clinicians personalize RAI therapy to specific differentiated thyroid cancer populations – offering treatment in patients most likely to benefit, and sparing others unnecessary costs and potential side effects.”

Dr. Orosco acknowledged certain limitations of the study, including the fact that the SEER database does not contain details about each patient’s surgery, the dose of RAI used, other comorbidities, or data on cancer recurrence. “This study does not attempt to explore the reasons behind the apparent survival disadvantage seen in patients with T1a disease,” he said. “We don’t know exactly why early-stage patients have an increased risk of disease-specific mortality when RAI is used. Additional work is needed to explore this further.”

Dr. Orosco reported having no financial disclosures.

[email protected]

On Twitter @dougbrunk

CORONADO, CALIF. – In a large cohort of patients with differentiated thyroid cancer, the use of radioactive iodine was associated with improved disease-specific survival in those with advanced disease but not in those with papillary thyroid microcarcinoma.

“Everything in medicine is a risk-benefit balance,” lead author Dr. Ryan K. Orosco said in an interview in advance of the annual meeting of the American Thyroid Association, where the work was presented. “Any two patients that receive radioactive iodine (RAI) for differentiated thyroid cancer are likely to have different survival benefit from that therapy. This study provides a quantitative comparison of the impact of RAI in various patient subgroups.”

In one of the largest studies of its kind, Dr. Orosco of the division of head and neck surgery at the University of California, San Diego, and his associates identified 85,740 patients with differentiated thyroid carcinoma from the Surveillance, Epidemiology, and End Results database from 1973 through 2009. They used multivariate analyses to explore the association between RAI and cancer-specific survival in 149 population subgroups, controlling for age, decade of diagnosis, race, gender, tumor type, nodal involvement, metastasis stage, and RAI therapy.

More than three-quarters of the patients (78%) were female, 68% were white, their mean age at diagnosis was 46 years, and the median follow-up time was 85 months. The researchers found that nearly half of patients (43%) received RAI. By American Joint Committee on Cancer stage, RAI was used in 55% of stage I patients, 41% of stage II patients, 94% of stage III patients, and 85% of stage IV patients. In addition, 42% of patients with T1a disease and 88% of those with T4 disease received RAI.

Use of RAI was positively associated with survival in the overall cohort (hazard ratio 1.3; P = .002), while statistically significant HRs for RAI were observed in 49 population subgroups. In patients with metastatic disease, use of RAI was associated with a decreased risk for disease-specific mortality (HR range of 2.28-3.82). Protective effects of RAI were also observed in patients with regional metastases (HR 1.4-1.9), those with T3-positive tumors (HR 1.36-1.39), those with T4 tumors (HR 1.85), and in those with stage IV disease (HR 1.47-1.73).

Dr. Orosco and his associates observed a negative effect of RAI in patients with macropapillary carcinoma. Specifically, those with T1a disease had an increased likelihood of thyroid cancer–specific mortality (HR .13; P less than .001), while similar associations were seen in multiple subgroups of patients with T1a disease (HR 0.04-0.25). No statistically significant effects of RAI were observed in patients with T1b or T2 tumors.

“RAI appears to offer the best survival impact in patients with advanced differentiated thyroid carcinoma,” Dr. Orosco said. “Its use in early-stage patients should be carefully considered.”

In their abstract, the researchers noted that the findings “might help clinicians personalize RAI therapy to specific differentiated thyroid cancer populations – offering treatment in patients most likely to benefit, and sparing others unnecessary costs and potential side effects.”

Dr. Orosco acknowledged certain limitations of the study, including the fact that the SEER database does not contain details about each patient’s surgery, the dose of RAI used, other comorbidities, or data on cancer recurrence. “This study does not attempt to explore the reasons behind the apparent survival disadvantage seen in patients with T1a disease,” he said. “We don’t know exactly why early-stage patients have an increased risk of disease-specific mortality when RAI is used. Additional work is needed to explore this further.”

Dr. Orosco reported having no financial disclosures.

[email protected]

On Twitter @dougbrunk

SAN FRANCISCO – Patients undergoing thyroid or parathyroid surgery have a sharply higher risk of postoperative hematoma if they are on clopidogrel or anticoagulants – even if these agents are stopped in advance – researchers reported at the annual clinical congress of the American College of Surgeons.

“Patients with multiple factors considered high risk for postoperative hematoma formation after parathyroid or thyroid surgery should probably undergo a period of observation,” recommended lead investigator Dr. Sarah C. Oltmann, who at the time of the study was the director of endocrine surgery at Parkland Memorial Hospital, University of Texas Southwestern Medical Center, Dallas.

“The need specifically for anticoagulation in the perioperative period should really be carefully assessed, and decisions regarding their use in the perioperative period need to be made very cautiously,” she added. “This is particularly important when considering the need for an injectable bridge [anticoagulant], and discussions with the patient’s primary care provider or cardiologist should be prompted because obviously a hematoma risk of 11% [seen with injectable anticoagulants] is not insignificant.”

The researchers retrospectively studied 4,514 patients who underwent thyroid or parathyroid surgery at the center between 1994 and 2013. Most of the operations were performed by high-volume surgeons.

Overall, 25% of patients were using an antiplatelet agent and 3% were using an anticoagulant agent, defined in the study as current use or use up to 5-7 days before surgery. “We felt that there may be some alteration of hemostasis both at the time of surgery and in the days following surgery if they were resumed on their home meds,” explained Dr. Oltmann, who is now a clinical instructor of surgery at the University of Wisconsin–Madison.

Overall, 0.5% of patients developed a postoperative hematoma, with the majority of these events occurring in the first 24 hours. Three-fourths of the affected patients had to undergo repeat surgery.

In multivariate analyses, clopidogrel (Plavix) users had 5.6 times the odds of developing a hematoma. But neither lower-dose aspirin (less than 325 mg daily) alone nor higher-dose aspirin alone was associated with this complication.

Hematoma odds were elevated by an even greater extent, 7.5 and 29.5 times, for patients using oral and injectable anticoagulants, respectively. (Subcutaneous heparin was not included among injectable anticoagulants because surgeons at the center seldom use it in this setting, according to Dr. Oltmann.)

Patients also had increased odds of hematoma if they underwent thyroid surgery as compared with parathyroid surgery (odds ratio, 7.9), and had a bilateral procedure as compared with a unilateral one (OR, 4.9).

“Additional studies are needed to better clarify both the risk-benefit ratio of injectable anticoagulation in this patient population and potentially being able to better risk-stratify which patients would be better served with a period of overnight observation,” Dr. Oltmann concluded.

Invited discussant Dr. Raymon H. Grogan, director of the endocrine surgery research program at University of Chicago Medicine, commented, “I think this work represents a level of detail and granularity in regard to anticoagulants that we haven’t seen before in this literature, so it’s really important for us to see these data.

“We tend to get lulled into a false sense of security when we talk about complications related to thyroidectomy because they are so rare. But the truth of the matter is that this is a complication that causes deaths. A recent Nationwide Inpatient Sample study showed that about 1.3% of people who developed a hematoma will actually die in the United States, which is not an insignificant number of people who will die from a complication that’s directly caused by something we’ve done as surgeons,” he said.

Patients often have other risk factors for hematoma, Dr. Grogan noted. Therefore, he wondered, “Who can actually be sent home as a same-day patient after thyroidectomy? … When you combine your … people on these medications, along with all these other risk factors, as well as the risk of significant hypocalcemia postop, it starts to get to the point where, is it really safe to send anyone home the same day after thyroidectomy, given this overwhelming number of different factors that could cause problems?”

“That’s something we all struggle with to a certain degree, trying to be able to best determine who is safe to go home at night and who is not,” Dr. Oltmann replied, noting that risk in the study was greatest for the small proportion of patients on anticoagulants. “So I think a patient who is on some form of anticoagulant, I would definitely have significant reservations about sending home on the same day. They would be somebody I would at least want to keep overnight.”

“As far as the other variables – Graves disease, the size of the tumor, some people would also argue smoking and poorly controlled hypertension – it really becomes a conversation between the surgeon and the patient to know how reliable is the patient, how do you feel the operation went. … Hopefully, the next step is being able to find a way to weigh these different factors to be able to figure out, well, if my patient has A, B, and C, I must observe versus if they don’t, this might be somebody I can send home.”

Another attendee asked, “How do you [handle] aspirin use, given that it’s low risk as seen in your data set? How do you preop the patients, [do you] ask them to stop any low-risk agents, such as aspirin, or if they take the combination of aspirin and Plavix, which one do you hold and which do you continue in your practice?”

“After kind of combing through this data and becoming very familiar with it, I feel very comfortable with continuing aspirin use through the perioperative period,” Dr. Oltmann commented.

“For Plavix, obviously, you just have to juggle the risk-benefit ratio of why they are on that medication,” she said. “I think the most compelling situation is for our patients with atrial fibrillation, with the primary care provider wanting to … have them done on a Lovenox [enoxaparin] bridge, and now having some sort of objective data to get back with them and say, ‘Listen, they have an 11% risk of this really bad complication. Do you really think their risk of stroke trumps that?’ In most patients, that’s not the case, and I think [these data are] finally going to be able to give us some ammunition in that particular battle.”

Dr. Oltmann disclosed that she had no relevant conflicts of interest.

SAN FRANCISCO – Patients undergoing thyroid or parathyroid surgery have a sharply higher risk of postoperative hematoma if they are on clopidogrel or anticoagulants – even if these agents are stopped in advance – researchers reported at the annual clinical congress of the American College of Surgeons.

“Patients with multiple factors considered high risk for postoperative hematoma formation after parathyroid or thyroid surgery should probably undergo a period of observation,” recommended lead investigator Dr. Sarah C. Oltmann, who at the time of the study was the director of endocrine surgery at Parkland Memorial Hospital, University of Texas Southwestern Medical Center, Dallas.

“The need specifically for anticoagulation in the perioperative period should really be carefully assessed, and decisions regarding their use in the perioperative period need to be made very cautiously,” she added. “This is particularly important when considering the need for an injectable bridge [anticoagulant], and discussions with the patient’s primary care provider or cardiologist should be prompted because obviously a hematoma risk of 11% [seen with injectable anticoagulants] is not insignificant.”

The researchers retrospectively studied 4,514 patients who underwent thyroid or parathyroid surgery at the center between 1994 and 2013. Most of the operations were performed by high-volume surgeons.

Overall, 25% of patients were using an antiplatelet agent and 3% were using an anticoagulant agent, defined in the study as current use or use up to 5-7 days before surgery. “We felt that there may be some alteration of hemostasis both at the time of surgery and in the days following surgery if they were resumed on their home meds,” explained Dr. Oltmann, who is now a clinical instructor of surgery at the University of Wisconsin–Madison.

Overall, 0.5% of patients developed a postoperative hematoma, with the majority of these events occurring in the first 24 hours. Three-fourths of the affected patients had to undergo repeat surgery.

In multivariate analyses, clopidogrel (Plavix) users had 5.6 times the odds of developing a hematoma. But neither lower-dose aspirin (less than 325 mg daily) alone nor higher-dose aspirin alone was associated with this complication.

Hematoma odds were elevated by an even greater extent, 7.5 and 29.5 times, for patients using oral and injectable anticoagulants, respectively. (Subcutaneous heparin was not included among injectable anticoagulants because surgeons at the center seldom use it in this setting, according to Dr. Oltmann.)

Patients also had increased odds of hematoma if they underwent thyroid surgery as compared with parathyroid surgery (odds ratio, 7.9), and had a bilateral procedure as compared with a unilateral one (OR, 4.9).

“Additional studies are needed to better clarify both the risk-benefit ratio of injectable anticoagulation in this patient population and potentially being able to better risk-stratify which patients would be better served with a period of overnight observation,” Dr. Oltmann concluded.

Invited discussant Dr. Raymon H. Grogan, director of the endocrine surgery research program at University of Chicago Medicine, commented, “I think this work represents a level of detail and granularity in regard to anticoagulants that we haven’t seen before in this literature, so it’s really important for us to see these data.

“We tend to get lulled into a false sense of security when we talk about complications related to thyroidectomy because they are so rare. But the truth of the matter is that this is a complication that causes deaths. A recent Nationwide Inpatient Sample study showed that about 1.3% of people who developed a hematoma will actually die in the United States, which is not an insignificant number of people who will die from a complication that’s directly caused by something we’ve done as surgeons,” he said.

Patients often have other risk factors for hematoma, Dr. Grogan noted. Therefore, he wondered, “Who can actually be sent home as a same-day patient after thyroidectomy? … When you combine your … people on these medications, along with all these other risk factors, as well as the risk of significant hypocalcemia postop, it starts to get to the point where, is it really safe to send anyone home the same day after thyroidectomy, given this overwhelming number of different factors that could cause problems?”

“That’s something we all struggle with to a certain degree, trying to be able to best determine who is safe to go home at night and who is not,” Dr. Oltmann replied, noting that risk in the study was greatest for the small proportion of patients on anticoagulants. “So I think a patient who is on some form of anticoagulant, I would definitely have significant reservations about sending home on the same day. They would be somebody I would at least want to keep overnight.”

“As far as the other variables – Graves disease, the size of the tumor, some people would also argue smoking and poorly controlled hypertension – it really becomes a conversation between the surgeon and the patient to know how reliable is the patient, how do you feel the operation went. … Hopefully, the next step is being able to find a way to weigh these different factors to be able to figure out, well, if my patient has A, B, and C, I must observe versus if they don’t, this might be somebody I can send home.”

Another attendee asked, “How do you [handle] aspirin use, given that it’s low risk as seen in your data set? How do you preop the patients, [do you] ask them to stop any low-risk agents, such as aspirin, or if they take the combination of aspirin and Plavix, which one do you hold and which do you continue in your practice?”

“After kind of combing through this data and becoming very familiar with it, I feel very comfortable with continuing aspirin use through the perioperative period,” Dr. Oltmann commented.

“For Plavix, obviously, you just have to juggle the risk-benefit ratio of why they are on that medication,” she said. “I think the most compelling situation is for our patients with atrial fibrillation, with the primary care provider wanting to … have them done on a Lovenox [enoxaparin] bridge, and now having some sort of objective data to get back with them and say, ‘Listen, they have an 11% risk of this really bad complication. Do you really think their risk of stroke trumps that?’ In most patients, that’s not the case, and I think [these data are] finally going to be able to give us some ammunition in that particular battle.”

Dr. Oltmann disclosed that she had no relevant conflicts of interest.

SAN FRANCISCO – Patients undergoing thyroid or parathyroid surgery have a sharply higher risk of postoperative hematoma if they are on clopidogrel or anticoagulants – even if these agents are stopped in advance – researchers reported at the annual clinical congress of the American College of Surgeons.

“Patients with multiple factors considered high risk for postoperative hematoma formation after parathyroid or thyroid surgery should probably undergo a period of observation,” recommended lead investigator Dr. Sarah C. Oltmann, who at the time of the study was the director of endocrine surgery at Parkland Memorial Hospital, University of Texas Southwestern Medical Center, Dallas.

“The need specifically for anticoagulation in the perioperative period should really be carefully assessed, and decisions regarding their use in the perioperative period need to be made very cautiously,” she added. “This is particularly important when considering the need for an injectable bridge [anticoagulant], and discussions with the patient’s primary care provider or cardiologist should be prompted because obviously a hematoma risk of 11% [seen with injectable anticoagulants] is not insignificant.”

The researchers retrospectively studied 4,514 patients who underwent thyroid or parathyroid surgery at the center between 1994 and 2013. Most of the operations were performed by high-volume surgeons.

Overall, 25% of patients were using an antiplatelet agent and 3% were using an anticoagulant agent, defined in the study as current use or use up to 5-7 days before surgery. “We felt that there may be some alteration of hemostasis both at the time of surgery and in the days following surgery if they were resumed on their home meds,” explained Dr. Oltmann, who is now a clinical instructor of surgery at the University of Wisconsin–Madison.

Overall, 0.5% of patients developed a postoperative hematoma, with the majority of these events occurring in the first 24 hours. Three-fourths of the affected patients had to undergo repeat surgery.

In multivariate analyses, clopidogrel (Plavix) users had 5.6 times the odds of developing a hematoma. But neither lower-dose aspirin (less than 325 mg daily) alone nor higher-dose aspirin alone was associated with this complication.

Hematoma odds were elevated by an even greater extent, 7.5 and 29.5 times, for patients using oral and injectable anticoagulants, respectively. (Subcutaneous heparin was not included among injectable anticoagulants because surgeons at the center seldom use it in this setting, according to Dr. Oltmann.)

Patients also had increased odds of hematoma if they underwent thyroid surgery as compared with parathyroid surgery (odds ratio, 7.9), and had a bilateral procedure as compared with a unilateral one (OR, 4.9).

“Additional studies are needed to better clarify both the risk-benefit ratio of injectable anticoagulation in this patient population and potentially being able to better risk-stratify which patients would be better served with a period of overnight observation,” Dr. Oltmann concluded.

Invited discussant Dr. Raymon H. Grogan, director of the endocrine surgery research program at University of Chicago Medicine, commented, “I think this work represents a level of detail and granularity in regard to anticoagulants that we haven’t seen before in this literature, so it’s really important for us to see these data.

“We tend to get lulled into a false sense of security when we talk about complications related to thyroidectomy because they are so rare. But the truth of the matter is that this is a complication that causes deaths. A recent Nationwide Inpatient Sample study showed that about 1.3% of people who developed a hematoma will actually die in the United States, which is not an insignificant number of people who will die from a complication that’s directly caused by something we’ve done as surgeons,” he said.

Patients often have other risk factors for hematoma, Dr. Grogan noted. Therefore, he wondered, “Who can actually be sent home as a same-day patient after thyroidectomy? … When you combine your … people on these medications, along with all these other risk factors, as well as the risk of significant hypocalcemia postop, it starts to get to the point where, is it really safe to send anyone home the same day after thyroidectomy, given this overwhelming number of different factors that could cause problems?”

“That’s something we all struggle with to a certain degree, trying to be able to best determine who is safe to go home at night and who is not,” Dr. Oltmann replied, noting that risk in the study was greatest for the small proportion of patients on anticoagulants. “So I think a patient who is on some form of anticoagulant, I would definitely have significant reservations about sending home on the same day. They would be somebody I would at least want to keep overnight.”

“As far as the other variables – Graves disease, the size of the tumor, some people would also argue smoking and poorly controlled hypertension – it really becomes a conversation between the surgeon and the patient to know how reliable is the patient, how do you feel the operation went. … Hopefully, the next step is being able to find a way to weigh these different factors to be able to figure out, well, if my patient has A, B, and C, I must observe versus if they don’t, this might be somebody I can send home.”

Another attendee asked, “How do you [handle] aspirin use, given that it’s low risk as seen in your data set? How do you preop the patients, [do you] ask them to stop any low-risk agents, such as aspirin, or if they take the combination of aspirin and Plavix, which one do you hold and which do you continue in your practice?”

“After kind of combing through this data and becoming very familiar with it, I feel very comfortable with continuing aspirin use through the perioperative period,” Dr. Oltmann commented.

“For Plavix, obviously, you just have to juggle the risk-benefit ratio of why they are on that medication,” she said. “I think the most compelling situation is for our patients with atrial fibrillation, with the primary care provider wanting to … have them done on a Lovenox [enoxaparin] bridge, and now having some sort of objective data to get back with them and say, ‘Listen, they have an 11% risk of this really bad complication. Do you really think their risk of stroke trumps that?’ In most patients, that’s not the case, and I think [these data are] finally going to be able to give us some ammunition in that particular battle.”

Dr. Oltmann disclosed that she had no relevant conflicts of interest.

BOSTON – With a little chemical or genetic snooping, or both, clinicians may be able to pinpoint the source of nearly all metastatic neuroendocrine tumors of the small bowel or pancreas.

By looking at expression patterns of four genes, investigators were able to determine that a surgically obtained metastatic neuroendocrine tumor (NET) originated in the small bowel with more than 96% accuracy, and, with the use of an immunohistochemistry algorithm, they identified the pancreas as the primary source of metastases in 10 of 10 cases.

"All the NETs that were misclassified by one method were correctly identified by the other method," said Dr. Jessica Maxwell of the department of surgery at the University of Iowa Hospitals and Clinics in Iowa City.

In about 15%-20% of cases of metastatic NETs, the primary tumor site is unknown, but is most likely to be in the small bowel or pancreas. Failure to identify the primary tumor site, despite optimal work-up, could delay referral for surgery or complicate choice of systemic medical therapies, she said at the annual meeting of the American Association of Endocrine Surgeons.

The authors tested the mettle of immunohistochemistry and gene expression classification (GEC) methods on 136 metastatic NETs collected intraoperatively from 97 patients with small-bowel NETs (38 with metastases to liver and 59 with metastases to lymph nodes) and 39 with pancreatic NETs (17 liver and 22 lymph node metastases).

The GEC uses quantitative or "real-time" polymerase chain reaction (qPCR) to evaluate expression of four key genes, encoding for the secretin receptor (SCTR), oxytocin receptor (OXTR), bombesin-like receptor-3 (BRS3), and opioid receptor kappa-1 (OPRK1).

The differential patterns of gene expression mark the metastases as originating either in the pancreas or small bowel.

They also tested a two-tiered immunohistochemistry algorithm using the markers CDX2, PAX6, and ISLET1 for tier 1, and PrAP, PRm NESP55, and PDX1 in tier 2. They tested the algorithm on six primary tumors and validated their findings on 37 metastases.

The immunohistochemistry method can identify a primary tumor site with as few as three markers, but if the findings are indeterminate, the addition of the four tier 2 markers can help to nail down the tumor site, Dr. Maxwell said.

They found that the GEC accurately identified 94 of 97 small bowel NETs (96.9%), and 34 of 39 pancreatic NETS (87.2%).

In contrast, the immunohistochemistry algorithm correctly identified the primary site in 23 of 27 small bowel metastases (85.2%), and in 10 of 10 (100%) pancreatic metastases.

When the methods were compared head to head in 27 metastases, GEC had a 96.2% overall accuracy and immunohistochemistry an 85.2% accuracy.

As noted before, the methods were complementary, with all NETs misclassified by one method called accurately by the other.

The investigators suggest that because the methods are highly accurate and complementary, they may best be used sequentially, starting with immunohistochemistry which is both inexpensive and widely available, and if immunohistochemistry fails, moving on to GEC.

"Sequential use allows for identification of nearly all metastatic neuroendocrine tumors from small bowel or pancreatic sites," Dr. Maxwell said.

In the discussion, Dr. Eren Berber of the Center for Endocrine Surgery at the Cleveland Clinic, who was not involved in the study, questioned whether knowing the primary site had any practical implications for surgeons.

Dr. Maxwell noted that some pancreatic NETs are not detected by preoperative studies and that given the risks of pancreatectomy or pancreaticoduodenectomy, accurately identifying the source of an NET may be helpful for patient counseling and preoperative planning.

The study was supported by a grant from the National Institutes of Health. Dr. Maxwell and Dr. Berber reported having no financial disclosures.

BOSTON – With a little chemical or genetic snooping, or both, clinicians may be able to pinpoint the source of nearly all metastatic neuroendocrine tumors of the small bowel or pancreas.

By looking at expression patterns of four genes, investigators were able to determine that a surgically obtained metastatic neuroendocrine tumor (NET) originated in the small bowel with more than 96% accuracy, and, with the use of an immunohistochemistry algorithm, they identified the pancreas as the primary source of metastases in 10 of 10 cases.

"All the NETs that were misclassified by one method were correctly identified by the other method," said Dr. Jessica Maxwell of the department of surgery at the University of Iowa Hospitals and Clinics in Iowa City.

In about 15%-20% of cases of metastatic NETs, the primary tumor site is unknown, but is most likely to be in the small bowel or pancreas. Failure to identify the primary tumor site, despite optimal work-up, could delay referral for surgery or complicate choice of systemic medical therapies, she said at the annual meeting of the American Association of Endocrine Surgeons.

The authors tested the mettle of immunohistochemistry and gene expression classification (GEC) methods on 136 metastatic NETs collected intraoperatively from 97 patients with small-bowel NETs (38 with metastases to liver and 59 with metastases to lymph nodes) and 39 with pancreatic NETs (17 liver and 22 lymph node metastases).

The GEC uses quantitative or "real-time" polymerase chain reaction (qPCR) to evaluate expression of four key genes, encoding for the secretin receptor (SCTR), oxytocin receptor (OXTR), bombesin-like receptor-3 (BRS3), and opioid receptor kappa-1 (OPRK1).

The differential patterns of gene expression mark the metastases as originating either in the pancreas or small bowel.

They also tested a two-tiered immunohistochemistry algorithm using the markers CDX2, PAX6, and ISLET1 for tier 1, and PrAP, PRm NESP55, and PDX1 in tier 2. They tested the algorithm on six primary tumors and validated their findings on 37 metastases.

The immunohistochemistry method can identify a primary tumor site with as few as three markers, but if the findings are indeterminate, the addition of the four tier 2 markers can help to nail down the tumor site, Dr. Maxwell said.

They found that the GEC accurately identified 94 of 97 small bowel NETs (96.9%), and 34 of 39 pancreatic NETS (87.2%).

In contrast, the immunohistochemistry algorithm correctly identified the primary site in 23 of 27 small bowel metastases (85.2%), and in 10 of 10 (100%) pancreatic metastases.

When the methods were compared head to head in 27 metastases, GEC had a 96.2% overall accuracy and immunohistochemistry an 85.2% accuracy.

As noted before, the methods were complementary, with all NETs misclassified by one method called accurately by the other.

The investigators suggest that because the methods are highly accurate and complementary, they may best be used sequentially, starting with immunohistochemistry which is both inexpensive and widely available, and if immunohistochemistry fails, moving on to GEC.

"Sequential use allows for identification of nearly all metastatic neuroendocrine tumors from small bowel or pancreatic sites," Dr. Maxwell said.

In the discussion, Dr. Eren Berber of the Center for Endocrine Surgery at the Cleveland Clinic, who was not involved in the study, questioned whether knowing the primary site had any practical implications for surgeons.

Dr. Maxwell noted that some pancreatic NETs are not detected by preoperative studies and that given the risks of pancreatectomy or pancreaticoduodenectomy, accurately identifying the source of an NET may be helpful for patient counseling and preoperative planning.

The study was supported by a grant from the National Institutes of Health. Dr. Maxwell and Dr. Berber reported having no financial disclosures.

BOSTON – With a little chemical or genetic snooping, or both, clinicians may be able to pinpoint the source of nearly all metastatic neuroendocrine tumors of the small bowel or pancreas.

By looking at expression patterns of four genes, investigators were able to determine that a surgically obtained metastatic neuroendocrine tumor (NET) originated in the small bowel with more than 96% accuracy, and, with the use of an immunohistochemistry algorithm, they identified the pancreas as the primary source of metastases in 10 of 10 cases.

"All the NETs that were misclassified by one method were correctly identified by the other method," said Dr. Jessica Maxwell of the department of surgery at the University of Iowa Hospitals and Clinics in Iowa City.

In about 15%-20% of cases of metastatic NETs, the primary tumor site is unknown, but is most likely to be in the small bowel or pancreas. Failure to identify the primary tumor site, despite optimal work-up, could delay referral for surgery or complicate choice of systemic medical therapies, she said at the annual meeting of the American Association of Endocrine Surgeons.

The authors tested the mettle of immunohistochemistry and gene expression classification (GEC) methods on 136 metastatic NETs collected intraoperatively from 97 patients with small-bowel NETs (38 with metastases to liver and 59 with metastases to lymph nodes) and 39 with pancreatic NETs (17 liver and 22 lymph node metastases).

The GEC uses quantitative or "real-time" polymerase chain reaction (qPCR) to evaluate expression of four key genes, encoding for the secretin receptor (SCTR), oxytocin receptor (OXTR), bombesin-like receptor-3 (BRS3), and opioid receptor kappa-1 (OPRK1).

The differential patterns of gene expression mark the metastases as originating either in the pancreas or small bowel.

They also tested a two-tiered immunohistochemistry algorithm using the markers CDX2, PAX6, and ISLET1 for tier 1, and PrAP, PRm NESP55, and PDX1 in tier 2. They tested the algorithm on six primary tumors and validated their findings on 37 metastases.

The immunohistochemistry method can identify a primary tumor site with as few as three markers, but if the findings are indeterminate, the addition of the four tier 2 markers can help to nail down the tumor site, Dr. Maxwell said.

They found that the GEC accurately identified 94 of 97 small bowel NETs (96.9%), and 34 of 39 pancreatic NETS (87.2%).

In contrast, the immunohistochemistry algorithm correctly identified the primary site in 23 of 27 small bowel metastases (85.2%), and in 10 of 10 (100%) pancreatic metastases.

When the methods were compared head to head in 27 metastases, GEC had a 96.2% overall accuracy and immunohistochemistry an 85.2% accuracy.

As noted before, the methods were complementary, with all NETs misclassified by one method called accurately by the other.

The investigators suggest that because the methods are highly accurate and complementary, they may best be used sequentially, starting with immunohistochemistry which is both inexpensive and widely available, and if immunohistochemistry fails, moving on to GEC.

"Sequential use allows for identification of nearly all metastatic neuroendocrine tumors from small bowel or pancreatic sites," Dr. Maxwell said.

In the discussion, Dr. Eren Berber of the Center for Endocrine Surgery at the Cleveland Clinic, who was not involved in the study, questioned whether knowing the primary site had any practical implications for surgeons.

Dr. Maxwell noted that some pancreatic NETs are not detected by preoperative studies and that given the risks of pancreatectomy or pancreaticoduodenectomy, accurately identifying the source of an NET may be helpful for patient counseling and preoperative planning.

The study was supported by a grant from the National Institutes of Health. Dr. Maxwell and Dr. Berber reported having no financial disclosures.

CHICAGO – The investigational drug lenvatinib significantly prolonged progression-free survival and produced high response rates compared with placebo in patients with iodine-refractory differentiated thyroid cancer.

In a randomized trial, the median progression-free survival (PFS) among patients assigned to lenvatinib was 18.3 months, compared with 3.6 months for placebo. The hazard ratio for lenvatinib was 0.21 (P less than .0001), Dr. Martin Schlumberger reported at the annual meeting of the American Society of Clinical Oncology.

"We had a high objective response rate – about 65% – with some complete responses. Interestingly, the time to objective response was only 2 months, so responses occur very quickly after the first treatment," Dr. Schlumberger, a professor of oncology at the University Paris-Sud, France, said at a media briefing prior to his presentation of the data in a plenary session.

"It’s really rewarding to see another active drug in this disease, where a year ago we really had no active therapy," commented Dr. Gregory A. Masters from the Helen F. Graham Cancer Center in Newark, Delaware.

Dr. Masters moderated the briefing but was not involved in the study.

Patients with relapsed or refractory differentiated thyroid cancer that is resistant to treatment with iodine-131 (¹³¹I) have few treatment choices and a 10-year survival rate of just 10%, Dr. Schlumberger noted.

There is evidence, however, showing that vascular endothelial growth factor (VEGF) signaling is associated with aggressive thyroid cancer and its propensity for metastasis, prompting researchers to explore VEGF-receptor inhibitors.

Lenvatinib is an oral multi–tyrosine kinase inhibitor of VEGF receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor–alpha, and the RET and KIT kinases.

In a phase II study, the drug showed clinical activity against ¹³¹I-refractory differentiated thyroid cancer, prompting investigators to launch the phase III SELECT trial (Study of E7080 Lenvatinib in Differentiated Cancer of the Thyroid) in this population.

They enrolled 392 patients with measurable disease and evidence of progression within the previous 13 months of treatment, which could include one prior VEGF or VEGF-receptor inhibitor.

The patients were randomized on a 2:1 basis to either oral lenvatinib 24 mg daily or placebo, with treatment continuing until disease progression according to RECIST (Response Evaluation Criteria in Solid Tumor) criteria. At the time of confirmed disease progression, patients originally assigned to placebo could be crossed over to the active drug.

As noted above, median PFS was significantly better for the 261 patients assigned to lenvatinib, at 18.3 months, vs. 3.6 months for the 121 assigned to placebo. The median PFS for patients who had previously received another VEGF inhibitor was 15.1 months, compared with 18.7 months for those who had not been treated with an anti-VEGF agent (P value not shown). Median overall survival has not yet been reached.

The overall response rates were 65% for lenvatinib, versus 2% for placebo (P less than .0001). In the lenvatinib group, there were 4 complete responses, 165 partial responses, 40 cases with stable disease of at least 23 weeks’ duration, and 18 cases of progressive disease. Among placebo-treated patients, there were no complete responses, 2 partial responses, 39 cases of stable disease, and 52 of progressive disease. Only 1.5% of patients, all in the lenvatinib group, had a complete response, compared with none in the placebo group.

The median time to an objective response was 2 months. The median duration of response had not been reached by the last analysis. Approximately 75% of responders had an objective response last for more than 9.4 months, Dr. Schlumberger said.

As is common with other VEGF inhibitors, treatment-emergent adverse events were common, occurring in 97% of patients treated with lenvatinib, compared with 60% of patients on placebo.

The most common events were hypertension, occurring in 68% of patients vs. 9% on placebo, diarrhea (60% vs. 8%), fatigue/asthenia (59% vs. 28%), decreased appetite (50% vs. 12%), and nausea/vomiting (51% vs. 24%).

Adverse events requiring dose reductions occurred in 68% of patients on lenvatinib, dose interruptions in 82%, and discontinuation in 14%. In contrast, only 5% of patients on placebo had a dose reduction, 18% had an interruption, and 5% discontinued therapy.

Also of concern to investigators was the fact that of the 20 patients on lenvatinib who died during the trial, 6 of the deaths were determined by investigators to be treatment related. One of these patients died from a hemorrhagic stroke, one from a pulmonary embolism, and four from general health deterioration.

Hematologic complications are a class effect of the anti-VEGF tyrosine kinase inhibitors, said coauthor Dr. Lori Wirth, medical director of the center for head and neck cancers at Massachusetts General Hospital, Boston.

"The other thing about the toxicity profile overall is that it’s an extremely important thing to consider in patients with thyroid cancer, because many patients do have quite indolent disease. But the patients who were enrolled in the placebo arm had a progression-free survival of less than 4 months, and these are the people who go on to die from their disease when it’s that rapidly progressive. So we do need effective treatments that, unfortunately, do come with some toxicities," she said in an interview.

Although the toxicities of therapy were "considerable," most could be managed through either dose adjustment or additional medications, Dr. Schlumberger said.

The study was sponsored by Eisai. Dr. Schlumberger disclosed receiving honoraria and research funding and acting in an advisory role to the company. Dr. Masters and Dr. Wirth reported having no relevant relationships to disclose.

CHICAGO – The investigational drug lenvatinib significantly prolonged progression-free survival and produced high response rates compared with placebo in patients with iodine-refractory differentiated thyroid cancer.

In a randomized trial, the median progression-free survival (PFS) among patients assigned to lenvatinib was 18.3 months, compared with 3.6 months for placebo. The hazard ratio for lenvatinib was 0.21 (P less than .0001), Dr. Martin Schlumberger reported at the annual meeting of the American Society of Clinical Oncology.

"We had a high objective response rate – about 65% – with some complete responses. Interestingly, the time to objective response was only 2 months, so responses occur very quickly after the first treatment," Dr. Schlumberger, a professor of oncology at the University Paris-Sud, France, said at a media briefing prior to his presentation of the data in a plenary session.

"It’s really rewarding to see another active drug in this disease, where a year ago we really had no active therapy," commented Dr. Gregory A. Masters from the Helen F. Graham Cancer Center in Newark, Delaware.

Dr. Masters moderated the briefing but was not involved in the study.

Patients with relapsed or refractory differentiated thyroid cancer that is resistant to treatment with iodine-131 (¹³¹I) have few treatment choices and a 10-year survival rate of just 10%, Dr. Schlumberger noted.

There is evidence, however, showing that vascular endothelial growth factor (VEGF) signaling is associated with aggressive thyroid cancer and its propensity for metastasis, prompting researchers to explore VEGF-receptor inhibitors.

Lenvatinib is an oral multi–tyrosine kinase inhibitor of VEGF receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor–alpha, and the RET and KIT kinases.

In a phase II study, the drug showed clinical activity against ¹³¹I-refractory differentiated thyroid cancer, prompting investigators to launch the phase III SELECT trial (Study of E7080 Lenvatinib in Differentiated Cancer of the Thyroid) in this population.

They enrolled 392 patients with measurable disease and evidence of progression within the previous 13 months of treatment, which could include one prior VEGF or VEGF-receptor inhibitor.

The patients were randomized on a 2:1 basis to either oral lenvatinib 24 mg daily or placebo, with treatment continuing until disease progression according to RECIST (Response Evaluation Criteria in Solid Tumor) criteria. At the time of confirmed disease progression, patients originally assigned to placebo could be crossed over to the active drug.

As noted above, median PFS was significantly better for the 261 patients assigned to lenvatinib, at 18.3 months, vs. 3.6 months for the 121 assigned to placebo. The median PFS for patients who had previously received another VEGF inhibitor was 15.1 months, compared with 18.7 months for those who had not been treated with an anti-VEGF agent (P value not shown). Median overall survival has not yet been reached.

The overall response rates were 65% for lenvatinib, versus 2% for placebo (P less than .0001). In the lenvatinib group, there were 4 complete responses, 165 partial responses, 40 cases with stable disease of at least 23 weeks’ duration, and 18 cases of progressive disease. Among placebo-treated patients, there were no complete responses, 2 partial responses, 39 cases of stable disease, and 52 of progressive disease. Only 1.5% of patients, all in the lenvatinib group, had a complete response, compared with none in the placebo group.

The median time to an objective response was 2 months. The median duration of response had not been reached by the last analysis. Approximately 75% of responders had an objective response last for more than 9.4 months, Dr. Schlumberger said.

As is common with other VEGF inhibitors, treatment-emergent adverse events were common, occurring in 97% of patients treated with lenvatinib, compared with 60% of patients on placebo.

The most common events were hypertension, occurring in 68% of patients vs. 9% on placebo, diarrhea (60% vs. 8%), fatigue/asthenia (59% vs. 28%), decreased appetite (50% vs. 12%), and nausea/vomiting (51% vs. 24%).

Adverse events requiring dose reductions occurred in 68% of patients on lenvatinib, dose interruptions in 82%, and discontinuation in 14%. In contrast, only 5% of patients on placebo had a dose reduction, 18% had an interruption, and 5% discontinued therapy.

Also of concern to investigators was the fact that of the 20 patients on lenvatinib who died during the trial, 6 of the deaths were determined by investigators to be treatment related. One of these patients died from a hemorrhagic stroke, one from a pulmonary embolism, and four from general health deterioration.

Hematologic complications are a class effect of the anti-VEGF tyrosine kinase inhibitors, said coauthor Dr. Lori Wirth, medical director of the center for head and neck cancers at Massachusetts General Hospital, Boston.

"The other thing about the toxicity profile overall is that it’s an extremely important thing to consider in patients with thyroid cancer, because many patients do have quite indolent disease. But the patients who were enrolled in the placebo arm had a progression-free survival of less than 4 months, and these are the people who go on to die from their disease when it’s that rapidly progressive. So we do need effective treatments that, unfortunately, do come with some toxicities," she said in an interview.

Although the toxicities of therapy were "considerable," most could be managed through either dose adjustment or additional medications, Dr. Schlumberger said.

The study was sponsored by Eisai. Dr. Schlumberger disclosed receiving honoraria and research funding and acting in an advisory role to the company. Dr. Masters and Dr. Wirth reported having no relevant relationships to disclose.

CHICAGO – The investigational drug lenvatinib significantly prolonged progression-free survival and produced high response rates compared with placebo in patients with iodine-refractory differentiated thyroid cancer.

In a randomized trial, the median progression-free survival (PFS) among patients assigned to lenvatinib was 18.3 months, compared with 3.6 months for placebo. The hazard ratio for lenvatinib was 0.21 (P less than .0001), Dr. Martin Schlumberger reported at the annual meeting of the American Society of Clinical Oncology.

"We had a high objective response rate – about 65% – with some complete responses. Interestingly, the time to objective response was only 2 months, so responses occur very quickly after the first treatment," Dr. Schlumberger, a professor of oncology at the University Paris-Sud, France, said at a media briefing prior to his presentation of the data in a plenary session.

"It’s really rewarding to see another active drug in this disease, where a year ago we really had no active therapy," commented Dr. Gregory A. Masters from the Helen F. Graham Cancer Center in Newark, Delaware.

Dr. Masters moderated the briefing but was not involved in the study.

Patients with relapsed or refractory differentiated thyroid cancer that is resistant to treatment with iodine-131 (¹³¹I) have few treatment choices and a 10-year survival rate of just 10%, Dr. Schlumberger noted.

There is evidence, however, showing that vascular endothelial growth factor (VEGF) signaling is associated with aggressive thyroid cancer and its propensity for metastasis, prompting researchers to explore VEGF-receptor inhibitors.

Lenvatinib is an oral multi–tyrosine kinase inhibitor of VEGF receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor–alpha, and the RET and KIT kinases.

In a phase II study, the drug showed clinical activity against ¹³¹I-refractory differentiated thyroid cancer, prompting investigators to launch the phase III SELECT trial (Study of E7080 Lenvatinib in Differentiated Cancer of the Thyroid) in this population.

They enrolled 392 patients with measurable disease and evidence of progression within the previous 13 months of treatment, which could include one prior VEGF or VEGF-receptor inhibitor.

The patients were randomized on a 2:1 basis to either oral lenvatinib 24 mg daily or placebo, with treatment continuing until disease progression according to RECIST (Response Evaluation Criteria in Solid Tumor) criteria. At the time of confirmed disease progression, patients originally assigned to placebo could be crossed over to the active drug.

As noted above, median PFS was significantly better for the 261 patients assigned to lenvatinib, at 18.3 months, vs. 3.6 months for the 121 assigned to placebo. The median PFS for patients who had previously received another VEGF inhibitor was 15.1 months, compared with 18.7 months for those who had not been treated with an anti-VEGF agent (P value not shown). Median overall survival has not yet been reached.

The overall response rates were 65% for lenvatinib, versus 2% for placebo (P less than .0001). In the lenvatinib group, there were 4 complete responses, 165 partial responses, 40 cases with stable disease of at least 23 weeks’ duration, and 18 cases of progressive disease. Among placebo-treated patients, there were no complete responses, 2 partial responses, 39 cases of stable disease, and 52 of progressive disease. Only 1.5% of patients, all in the lenvatinib group, had a complete response, compared with none in the placebo group.

The median time to an objective response was 2 months. The median duration of response had not been reached by the last analysis. Approximately 75% of responders had an objective response last for more than 9.4 months, Dr. Schlumberger said.

As is common with other VEGF inhibitors, treatment-emergent adverse events were common, occurring in 97% of patients treated with lenvatinib, compared with 60% of patients on placebo.

The most common events were hypertension, occurring in 68% of patients vs. 9% on placebo, diarrhea (60% vs. 8%), fatigue/asthenia (59% vs. 28%), decreased appetite (50% vs. 12%), and nausea/vomiting (51% vs. 24%).

Adverse events requiring dose reductions occurred in 68% of patients on lenvatinib, dose interruptions in 82%, and discontinuation in 14%. In contrast, only 5% of patients on placebo had a dose reduction, 18% had an interruption, and 5% discontinued therapy.

Also of concern to investigators was the fact that of the 20 patients on lenvatinib who died during the trial, 6 of the deaths were determined by investigators to be treatment related. One of these patients died from a hemorrhagic stroke, one from a pulmonary embolism, and four from general health deterioration.

Hematologic complications are a class effect of the anti-VEGF tyrosine kinase inhibitors, said coauthor Dr. Lori Wirth, medical director of the center for head and neck cancers at Massachusetts General Hospital, Boston.

"The other thing about the toxicity profile overall is that it’s an extremely important thing to consider in patients with thyroid cancer, because many patients do have quite indolent disease. But the patients who were enrolled in the placebo arm had a progression-free survival of less than 4 months, and these are the people who go on to die from their disease when it’s that rapidly progressive. So we do need effective treatments that, unfortunately, do come with some toxicities," she said in an interview.

Although the toxicities of therapy were "considerable," most could be managed through either dose adjustment or additional medications, Dr. Schlumberger said.

The study was sponsored by Eisai. Dr. Schlumberger disclosed receiving honoraria and research funding and acting in an advisory role to the company. Dr. Masters and Dr. Wirth reported having no relevant relationships to disclose.

The somatostatin analogue pasireotide reduced postoperative pancreatic fistula leak or abscess by 56%, compared with placebo, a randomized study has determined.

Pasireotide (Signifor) was effective after both pancreaticoduodenectomy and distal pancreatectomy, whether or not the pancreatic duct was dilated, Dr. Peter J. Allen and his colleagues wrote in the May 21 issue of the New England Journal of Medicine (N. Engl. J. Med. 2014;370:2014-22).

In those patients who did develop fistulas or leaks, pasireotide was associated with fewer grade 3 occurrences.

"These results suggest that ... not only were many leaks and fistulas prevented, but when they did occur they were less clinically relevant," wrote Dr. Allen of the Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

The study randomized 300 patients to subcutaneous injections of either placebo or pasireotide twice daily for 7 days after pancreatic surgery. The primary endpoint was the development of a pancreatic leak, fistula, or abscess of at least grade 3. Secondary endpoints included the overall rate of pancreatic complications (all grades) and the rate of grade B or grade C pancreatic fistula.

Patients were a mean of 64 years old. Most (73%) underwent a pancreaticoduodenectomy. The average length of stay for these patients was about 10 days. The active group received 900 mcg of pasireotide subcutaneously twice daily for 7 days, beginning on the morning of surgery.

Mean postoperative serum glucose levels were significantly higher in patients taking pasireotide (258 mg/dL vs. 215 mg/dL). Readmission occurred in significantly fewer pasireotide patients (17% vs. 29%).

Significantly fewer of those taking the active drug were able to finish the entire course of 14 doses (76% vs. 86% given placebo). The lower completion rate was mostly due to nausea and vomiting, which caused 26 patients in the active group and 3 in the placebo group to withdraw from the study.

A leak or fistula of grade 3 or higher developed in 45 patients. The outcome was significantly less common among those taking pasireotide than among those on placebo (9% vs. 21%; relative risk, 0.44). "This corresponded to an absolute risk reduction of 11.7 percentage points," with a number needed to treat of 8, the investigators said.

Pasireotide was significantly more effective than placebo in surgical subgroups, including pancreaticoduodenectomy (RR, 0.49) and distal pancreatectomy (RR, 0.32). The effect was also positive whether the pancreatic duct was dilated (RR, 0.11) or nondilated (RR, 0.55).

The secondary outcome (grade B or C postoperative fistula) occurred in 37 patients (12%). In the pasireotide group, there were 12 grade B fistulas and no grade C fistulas. In the placebo group, there were 20 grade B and 5 grade C fistulas.

Overall 60-day mortality was 0.7% (one death in each treatment group). Grade 3 and 4 complications were common, occurring in 92% of the pasireotide group and 90% of the placebo group. Most of these were expected postoperative serum abnormalities.

The investigators said that the other approved somatostatin analogue, octreotide, has not been clearly associated with pancreatic leak reduction. They suggested that pasireotide may be more effective because it has a longer half-life and binds to four of the five somatostatin-receptor subtypes, rather than just two, as octreotide does.

They added that the octreotide studies were conducted before 2005, when there was no consistent definition of postoperative pancreatic fistula. Therefore, they concluded, the extant data cannot be used to identify octreotide efficacy in this application.

Pasireotide, which is made by Novartis Pharmaceuticals, is currently approved as an injection for the treatment of Cushing’s disease patients who cannot be helped through surgery.

Novartis Pharmaceuticals sponsored the trial. Dr. Allen received Novartis grant funding but had no other financial ties with the company.

[email protected]

The somatostatin analogue pasireotide reduced postoperative pancreatic fistula leak or abscess by 56%, compared with placebo, a randomized study has determined.

Pasireotide (Signifor) was effective after both pancreaticoduodenectomy and distal pancreatectomy, whether or not the pancreatic duct was dilated, Dr. Peter J. Allen and his colleagues wrote in the May 21 issue of the New England Journal of Medicine (N. Engl. J. Med. 2014;370:2014-22).

In those patients who did develop fistulas or leaks, pasireotide was associated with fewer grade 3 occurrences.

"These results suggest that ... not only were many leaks and fistulas prevented, but when they did occur they were less clinically relevant," wrote Dr. Allen of the Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

The study randomized 300 patients to subcutaneous injections of either placebo or pasireotide twice daily for 7 days after pancreatic surgery. The primary endpoint was the development of a pancreatic leak, fistula, or abscess of at least grade 3. Secondary endpoints included the overall rate of pancreatic complications (all grades) and the rate of grade B or grade C pancreatic fistula.

Patients were a mean of 64 years old. Most (73%) underwent a pancreaticoduodenectomy. The average length of stay for these patients was about 10 days. The active group received 900 mcg of pasireotide subcutaneously twice daily for 7 days, beginning on the morning of surgery.

Mean postoperative serum glucose levels were significantly higher in patients taking pasireotide (258 mg/dL vs. 215 mg/dL). Readmission occurred in significantly fewer pasireotide patients (17% vs. 29%).

Significantly fewer of those taking the active drug were able to finish the entire course of 14 doses (76% vs. 86% given placebo). The lower completion rate was mostly due to nausea and vomiting, which caused 26 patients in the active group and 3 in the placebo group to withdraw from the study.

A leak or fistula of grade 3 or higher developed in 45 patients. The outcome was significantly less common among those taking pasireotide than among those on placebo (9% vs. 21%; relative risk, 0.44). "This corresponded to an absolute risk reduction of 11.7 percentage points," with a number needed to treat of 8, the investigators said.

Pasireotide was significantly more effective than placebo in surgical subgroups, including pancreaticoduodenectomy (RR, 0.49) and distal pancreatectomy (RR, 0.32). The effect was also positive whether the pancreatic duct was dilated (RR, 0.11) or nondilated (RR, 0.55).

The secondary outcome (grade B or C postoperative fistula) occurred in 37 patients (12%). In the pasireotide group, there were 12 grade B fistulas and no grade C fistulas. In the placebo group, there were 20 grade B and 5 grade C fistulas.

Overall 60-day mortality was 0.7% (one death in each treatment group). Grade 3 and 4 complications were common, occurring in 92% of the pasireotide group and 90% of the placebo group. Most of these were expected postoperative serum abnormalities.

The investigators said that the other approved somatostatin analogue, octreotide, has not been clearly associated with pancreatic leak reduction. They suggested that pasireotide may be more effective because it has a longer half-life and binds to four of the five somatostatin-receptor subtypes, rather than just two, as octreotide does.

They added that the octreotide studies were conducted before 2005, when there was no consistent definition of postoperative pancreatic fistula. Therefore, they concluded, the extant data cannot be used to identify octreotide efficacy in this application.

Pasireotide, which is made by Novartis Pharmaceuticals, is currently approved as an injection for the treatment of Cushing’s disease patients who cannot be helped through surgery.

Novartis Pharmaceuticals sponsored the trial. Dr. Allen received Novartis grant funding but had no other financial ties with the company.

[email protected]

The somatostatin analogue pasireotide reduced postoperative pancreatic fistula leak or abscess by 56%, compared with placebo, a randomized study has determined.

Pasireotide (Signifor) was effective after both pancreaticoduodenectomy and distal pancreatectomy, whether or not the pancreatic duct was dilated, Dr. Peter J. Allen and his colleagues wrote in the May 21 issue of the New England Journal of Medicine (N. Engl. J. Med. 2014;370:2014-22).

In those patients who did develop fistulas or leaks, pasireotide was associated with fewer grade 3 occurrences.

"These results suggest that ... not only were many leaks and fistulas prevented, but when they did occur they were less clinically relevant," wrote Dr. Allen of the Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

The study randomized 300 patients to subcutaneous injections of either placebo or pasireotide twice daily for 7 days after pancreatic surgery. The primary endpoint was the development of a pancreatic leak, fistula, or abscess of at least grade 3. Secondary endpoints included the overall rate of pancreatic complications (all grades) and the rate of grade B or grade C pancreatic fistula.

Patients were a mean of 64 years old. Most (73%) underwent a pancreaticoduodenectomy. The average length of stay for these patients was about 10 days. The active group received 900 mcg of pasireotide subcutaneously twice daily for 7 days, beginning on the morning of surgery.

Mean postoperative serum glucose levels were significantly higher in patients taking pasireotide (258 mg/dL vs. 215 mg/dL). Readmission occurred in significantly fewer pasireotide patients (17% vs. 29%).

Significantly fewer of those taking the active drug were able to finish the entire course of 14 doses (76% vs. 86% given placebo). The lower completion rate was mostly due to nausea and vomiting, which caused 26 patients in the active group and 3 in the placebo group to withdraw from the study.

A leak or fistula of grade 3 or higher developed in 45 patients. The outcome was significantly less common among those taking pasireotide than among those on placebo (9% vs. 21%; relative risk, 0.44). "This corresponded to an absolute risk reduction of 11.7 percentage points," with a number needed to treat of 8, the investigators said.

Pasireotide was significantly more effective than placebo in surgical subgroups, including pancreaticoduodenectomy (RR, 0.49) and distal pancreatectomy (RR, 0.32). The effect was also positive whether the pancreatic duct was dilated (RR, 0.11) or nondilated (RR, 0.55).

The secondary outcome (grade B or C postoperative fistula) occurred in 37 patients (12%). In the pasireotide group, there were 12 grade B fistulas and no grade C fistulas. In the placebo group, there were 20 grade B and 5 grade C fistulas.

Overall 60-day mortality was 0.7% (one death in each treatment group). Grade 3 and 4 complications were common, occurring in 92% of the pasireotide group and 90% of the placebo group. Most of these were expected postoperative serum abnormalities.

The investigators said that the other approved somatostatin analogue, octreotide, has not been clearly associated with pancreatic leak reduction. They suggested that pasireotide may be more effective because it has a longer half-life and binds to four of the five somatostatin-receptor subtypes, rather than just two, as octreotide does.

They added that the octreotide studies were conducted before 2005, when there was no consistent definition of postoperative pancreatic fistula. Therefore, they concluded, the extant data cannot be used to identify octreotide efficacy in this application.

Pasireotide, which is made by Novartis Pharmaceuticals, is currently approved as an injection for the treatment of Cushing’s disease patients who cannot be helped through surgery.

Novartis Pharmaceuticals sponsored the trial. Dr. Allen received Novartis grant funding but had no other financial ties with the company.

[email protected]

BOSTON – Extensive surgery beyond lobectomy offers no survival advantage for small papillary thyroid cancers, according to a large database analysis.

Total thyroidectomy was not associated with an overall survival benefit over lobectomy for papillary thyroid cancers sized 1-2 cm (hazard ratio, 1.05; P = .61) or 2.1-4.0 cm (HR, 0.89; P = .21), even after adjusting for multiple patient and pathologic factors.

"Despite guidelines, our results call into question whether tumor size 1-4 cm should be an absolute determinant for extent of surgery," Dr. Mohamed Abdelgadir Adam said at the annual meeting of the American Surgical Association.

Current American Thyroid Association guidelines recommend lobectomy for tumors less than 1 cm in size and total thyroidectomy for those exceeding 1 cm.

Patrice Wendling/Frontline Medical News

"Using total thyroidectomy based on tumor size alone may unnecessarily subject patients to increased risks of complications without a survival benefit," he said. "In addition to tumor size up to 4 cm, other factors are important for determining extent of surgery such as nodal and distant metastases and patient preference."

The extent of surgery for papillary thyroid cancer, however, remains controversial. Recent analyses (Arch. Otolaryngol. Head Neck Surg. 2010;136:1055-61) have shown no survival difference between lobectomy and total thyroidectomy, while an earlier landmark study found improved overall survival with total thyroidectomy for tumors 1 cm or more (Ann. Surg. 2007;246;375-81). The latter study, however, has been criticized because it did not take into account patient comorbidities, multifocality, extrathyroidal extension, or completeness of resection, said Dr. Adam of Duke University School of Medicine, Durham, N.C.

The current analysis adjusted for age, gender, race, annual income, insurance status, hospital volume, patient comorbidities, tumor multifocality, extrathyroidal extension, lymph node involvement, metastases, surgical margins, and radioactive iodine ablation.

Discussant Dr. Blake Cady, professor emeritus of surgery at Harvard Medical School and Massachusetts General Hospital in Boston, said the current report is an important contribution to the controversy. It also supports his own bias against overtreatment of these mostly young patients with total thyroidectomy, which necessitates long-term medication and is accompanied by almost routine use of radioactive iodine, despite no evidence it improves outcomes in low-risk patients.

"In no other human cancer with a 99% 20-year survival is a policy of routine total primary organ removal practiced and routine systemic therapy used," he said. "Therefore, this report may help to scale back toward a more measured balance between treatment and morbidity."

Study coauthor Dr. Julie Ann Sosa, chief of endocrine surgery at Duke, challenged the audience to promote the growing body of evidence supporting equivalence in overall survival, such as a recent study described as coming the closest to a head-to-head comparison and having the longest follow-up at 18 years. It showed equivalence between lobectomy, without radioactive iodine, and total thyroidectomy for overall, progression-free, and disease-specific survival and risk of recurrence in tumors 40 mm or less (World J. Surg. 2014;38:68-79.

"In light of these data, I think it is probably high time for guidelines to potentially reconsider this issue," she said, noting that the American Thyroid Association will issue new guidelines later this spring or summer.

Dr. Sosa also advocated for "a more sophisticated approach" to preoperative evaluation and risk stratification for papillary thyroid cancer that distinguishes between low-, medium-, and high-risk tumors. The Duke study did not exclude most high-risk tumors, but rather adjusted for high-risk characteristics such as extrathyroidal extension, lymph node involvement, and distant metastases.

"When you adjust for these high-risk characteristics, the afforded overall survival benefit disappears," she said. "So what I think we would argue is that there is equivalence in outcome for the majority of patients for low- and medium-risk tumors. But for those patients who have high-risk tumors, as defined by some of these high-risk characteristics, then I think all of us would agree that total thyroidectomy, with or without radioactive iodine, would be indicated."

The study involved 61,775 patients in the National Cancer Database who underwent total thyroidectomy (n = 54,926) or lobectomy with or without isthmusectomy (n = 6,849) for papillary thyroid cancer from 1998 to 2006. Compared with the lobectomy group, the thyroidectomy group had more tumor multifocality (44% vs. 29%), positive surgical margins (27% vs. 7%), distant metastases (1% vs. 0.4%), and radioactive iodine (65% vs. 33%; P value less than .01 for all).

In multivariable analysis, nodal and distant metastases were associated with compromised survival, Dr. Adam said.

The complete manuscript of this study and its presentation at the American Surgical Association’s 134^th Annual Meeting, April 2014 in Boston, is anticipated to be published in the Annals of Surgery, pending editorial review.

The authors reported no conflicting interests

[email protected]

BOSTON – Extensive surgery beyond lobectomy offers no survival advantage for small papillary thyroid cancers, according to a large database analysis.

Total thyroidectomy was not associated with an overall survival benefit over lobectomy for papillary thyroid cancers sized 1-2 cm (hazard ratio, 1.05; P = .61) or 2.1-4.0 cm (HR, 0.89; P = .21), even after adjusting for multiple patient and pathologic factors.

"Despite guidelines, our results call into question whether tumor size 1-4 cm should be an absolute determinant for extent of surgery," Dr. Mohamed Abdelgadir Adam said at the annual meeting of the American Surgical Association.

Current American Thyroid Association guidelines recommend lobectomy for tumors less than 1 cm in size and total thyroidectomy for those exceeding 1 cm.

Patrice Wendling/Frontline Medical News

"Using total thyroidectomy based on tumor size alone may unnecessarily subject patients to increased risks of complications without a survival benefit," he said. "In addition to tumor size up to 4 cm, other factors are important for determining extent of surgery such as nodal and distant metastases and patient preference."

The extent of surgery for papillary thyroid cancer, however, remains controversial. Recent analyses (Arch. Otolaryngol. Head Neck Surg. 2010;136:1055-61) have shown no survival difference between lobectomy and total thyroidectomy, while an earlier landmark study found improved overall survival with total thyroidectomy for tumors 1 cm or more (Ann. Surg. 2007;246;375-81). The latter study, however, has been criticized because it did not take into account patient comorbidities, multifocality, extrathyroidal extension, or completeness of resection, said Dr. Adam of Duke University School of Medicine, Durham, N.C.

The current analysis adjusted for age, gender, race, annual income, insurance status, hospital volume, patient comorbidities, tumor multifocality, extrathyroidal extension, lymph node involvement, metastases, surgical margins, and radioactive iodine ablation.

Discussant Dr. Blake Cady, professor emeritus of surgery at Harvard Medical School and Massachusetts General Hospital in Boston, said the current report is an important contribution to the controversy. It also supports his own bias against overtreatment of these mostly young patients with total thyroidectomy, which necessitates long-term medication and is accompanied by almost routine use of radioactive iodine, despite no evidence it improves outcomes in low-risk patients.

"In no other human cancer with a 99% 20-year survival is a policy of routine total primary organ removal practiced and routine systemic therapy used," he said. "Therefore, this report may help to scale back toward a more measured balance between treatment and morbidity."

Study coauthor Dr. Julie Ann Sosa, chief of endocrine surgery at Duke, challenged the audience to promote the growing body of evidence supporting equivalence in overall survival, such as a recent study described as coming the closest to a head-to-head comparison and having the longest follow-up at 18 years. It showed equivalence between lobectomy, without radioactive iodine, and total thyroidectomy for overall, progression-free, and disease-specific survival and risk of recurrence in tumors 40 mm or less (World J. Surg. 2014;38:68-79.

"In light of these data, I think it is probably high time for guidelines to potentially reconsider this issue," she said, noting that the American Thyroid Association will issue new guidelines later this spring or summer.

Dr. Sosa also advocated for "a more sophisticated approach" to preoperative evaluation and risk stratification for papillary thyroid cancer that distinguishes between low-, medium-, and high-risk tumors. The Duke study did not exclude most high-risk tumors, but rather adjusted for high-risk characteristics such as extrathyroidal extension, lymph node involvement, and distant metastases.

"When you adjust for these high-risk characteristics, the afforded overall survival benefit disappears," she said. "So what I think we would argue is that there is equivalence in outcome for the majority of patients for low- and medium-risk tumors. But for those patients who have high-risk tumors, as defined by some of these high-risk characteristics, then I think all of us would agree that total thyroidectomy, with or without radioactive iodine, would be indicated."

The study involved 61,775 patients in the National Cancer Database who underwent total thyroidectomy (n = 54,926) or lobectomy with or without isthmusectomy (n = 6,849) for papillary thyroid cancer from 1998 to 2006. Compared with the lobectomy group, the thyroidectomy group had more tumor multifocality (44% vs. 29%), positive surgical margins (27% vs. 7%), distant metastases (1% vs. 0.4%), and radioactive iodine (65% vs. 33%; P value less than .01 for all).

In multivariable analysis, nodal and distant metastases were associated with compromised survival, Dr. Adam said.

The complete manuscript of this study and its presentation at the American Surgical Association’s 134^th Annual Meeting, April 2014 in Boston, is anticipated to be published in the Annals of Surgery, pending editorial review.

The authors reported no conflicting interests

[email protected]

BOSTON – Extensive surgery beyond lobectomy offers no survival advantage for small papillary thyroid cancers, according to a large database analysis.

Total thyroidectomy was not associated with an overall survival benefit over lobectomy for papillary thyroid cancers sized 1-2 cm (hazard ratio, 1.05; P = .61) or 2.1-4.0 cm (HR, 0.89; P = .21), even after adjusting for multiple patient and pathologic factors.

"Despite guidelines, our results call into question whether tumor size 1-4 cm should be an absolute determinant for extent of surgery," Dr. Mohamed Abdelgadir Adam said at the annual meeting of the American Surgical Association.

Current American Thyroid Association guidelines recommend lobectomy for tumors less than 1 cm in size and total thyroidectomy for those exceeding 1 cm.

Patrice Wendling/Frontline Medical News

"Using total thyroidectomy based on tumor size alone may unnecessarily subject patients to increased risks of complications without a survival benefit," he said. "In addition to tumor size up to 4 cm, other factors are important for determining extent of surgery such as nodal and distant metastases and patient preference."

The extent of surgery for papillary thyroid cancer, however, remains controversial. Recent analyses (Arch. Otolaryngol. Head Neck Surg. 2010;136:1055-61) have shown no survival difference between lobectomy and total thyroidectomy, while an earlier landmark study found improved overall survival with total thyroidectomy for tumors 1 cm or more (Ann. Surg. 2007;246;375-81). The latter study, however, has been criticized because it did not take into account patient comorbidities, multifocality, extrathyroidal extension, or completeness of resection, said Dr. Adam of Duke University School of Medicine, Durham, N.C.

The current analysis adjusted for age, gender, race, annual income, insurance status, hospital volume, patient comorbidities, tumor multifocality, extrathyroidal extension, lymph node involvement, metastases, surgical margins, and radioactive iodine ablation.

Discussant Dr. Blake Cady, professor emeritus of surgery at Harvard Medical School and Massachusetts General Hospital in Boston, said the current report is an important contribution to the controversy. It also supports his own bias against overtreatment of these mostly young patients with total thyroidectomy, which necessitates long-term medication and is accompanied by almost routine use of radioactive iodine, despite no evidence it improves outcomes in low-risk patients.

"In no other human cancer with a 99% 20-year survival is a policy of routine total primary organ removal practiced and routine systemic therapy used," he said. "Therefore, this report may help to scale back toward a more measured balance between treatment and morbidity."

Study coauthor Dr. Julie Ann Sosa, chief of endocrine surgery at Duke, challenged the audience to promote the growing body of evidence supporting equivalence in overall survival, such as a recent study described as coming the closest to a head-to-head comparison and having the longest follow-up at 18 years. It showed equivalence between lobectomy, without radioactive iodine, and total thyroidectomy for overall, progression-free, and disease-specific survival and risk of recurrence in tumors 40 mm or less (World J. Surg. 2014;38:68-79.

"In light of these data, I think it is probably high time for guidelines to potentially reconsider this issue," she said, noting that the American Thyroid Association will issue new guidelines later this spring or summer.

Dr. Sosa also advocated for "a more sophisticated approach" to preoperative evaluation and risk stratification for papillary thyroid cancer that distinguishes between low-, medium-, and high-risk tumors. The Duke study did not exclude most high-risk tumors, but rather adjusted for high-risk characteristics such as extrathyroidal extension, lymph node involvement, and distant metastases.

"When you adjust for these high-risk characteristics, the afforded overall survival benefit disappears," she said. "So what I think we would argue is that there is equivalence in outcome for the majority of patients for low- and medium-risk tumors. But for those patients who have high-risk tumors, as defined by some of these high-risk characteristics, then I think all of us would agree that total thyroidectomy, with or without radioactive iodine, would be indicated."

The study involved 61,775 patients in the National Cancer Database who underwent total thyroidectomy (n = 54,926) or lobectomy with or without isthmusectomy (n = 6,849) for papillary thyroid cancer from 1998 to 2006. Compared with the lobectomy group, the thyroidectomy group had more tumor multifocality (44% vs. 29%), positive surgical margins (27% vs. 7%), distant metastases (1% vs. 0.4%), and radioactive iodine (65% vs. 33%; P value less than .01 for all).

In multivariable analysis, nodal and distant metastases were associated with compromised survival, Dr. Adam said.

The complete manuscript of this study and its presentation at the American Surgical Association’s 134^th Annual Meeting, April 2014 in Boston, is anticipated to be published in the Annals of Surgery, pending editorial review.

The authors reported no conflicting interests

[email protected]

Elevated growth hormone levels had a negative impact on remission in acromegaly patients undergoing transsphenoidal adenomectomies, researchers from Emory University in Atlanta concluded after a retrospective, multivariate analysis of case studies.

To determine the impact of preoperative growth hormone (GH), Dr. Jeremy Anthony and his associates examined the case files of 79 acromegaly patients who underwent transsphenoidal adenomectomy between 1994 and 2013 at Emory and assigned them to two groups on the basis of their preoperative GH levels, using 40 ng/mL as the cutoff.

Biochemical remission was defined as normal insulin-like growth factor 1 (IGF-1) during follow-up of more than 3 months in the absence of adjuvant therapy. The results were released at the annual meeting of the American Association of Clinical Endocrinologists on May 15 in Las Vegas.

Group A, with preoperative GH levels greater than 40 ng/mL, comprised 19 patients with a mean age of 43 years and an average follow-up of 38 months. They had larger, more invasive tumors, higher preoperative IGF-1 levels, higher immediate postoperative GH, and more residual tumors at 3 months, compared with the 60 patients in group B, who had preop GH levels of 40 ng/mL or less, a mean age of 47 years, and 43 months of follow-up.

In group A, three patients (15%) had remission at 3 months, but two patients had recurrence within 2 years. In group B, 35 patients (58%) had remission at 3 months with no recurrence during follow-up.

On univariate analysis, lower preoperative GH was a predictor of remission. In a multivariate analysis, however, lack of cavernous sinus invasion was the only predictor of remission.

"The relationship of GH elevation and cavernous sinus invasion should be further defined, as should the molecular fingerprint and the potential role of preoperative medical treatment in this group of patients," Dr. Anthony and his associates wrote.

No disclosures were reported.

[email protected]

Elevated growth hormone levels had a negative impact on remission in acromegaly patients undergoing transsphenoidal adenomectomies, researchers from Emory University in Atlanta concluded after a retrospective, multivariate analysis of case studies.

To determine the impact of preoperative growth hormone (GH), Dr. Jeremy Anthony and his associates examined the case files of 79 acromegaly patients who underwent transsphenoidal adenomectomy between 1994 and 2013 at Emory and assigned them to two groups on the basis of their preoperative GH levels, using 40 ng/mL as the cutoff.

Biochemical remission was defined as normal insulin-like growth factor 1 (IGF-1) during follow-up of more than 3 months in the absence of adjuvant therapy. The results were released at the annual meeting of the American Association of Clinical Endocrinologists on May 15 in Las Vegas.

Group A, with preoperative GH levels greater than 40 ng/mL, comprised 19 patients with a mean age of 43 years and an average follow-up of 38 months. They had larger, more invasive tumors, higher preoperative IGF-1 levels, higher immediate postoperative GH, and more residual tumors at 3 months, compared with the 60 patients in group B, who had preop GH levels of 40 ng/mL or less, a mean age of 47 years, and 43 months of follow-up.

In group A, three patients (15%) had remission at 3 months, but two patients had recurrence within 2 years. In group B, 35 patients (58%) had remission at 3 months with no recurrence during follow-up.

On univariate analysis, lower preoperative GH was a predictor of remission. In a multivariate analysis, however, lack of cavernous sinus invasion was the only predictor of remission.

"The relationship of GH elevation and cavernous sinus invasion should be further defined, as should the molecular fingerprint and the potential role of preoperative medical treatment in this group of patients," Dr. Anthony and his associates wrote.

No disclosures were reported.

[email protected]

Elevated growth hormone levels had a negative impact on remission in acromegaly patients undergoing transsphenoidal adenomectomies, researchers from Emory University in Atlanta concluded after a retrospective, multivariate analysis of case studies.

To determine the impact of preoperative growth hormone (GH), Dr. Jeremy Anthony and his associates examined the case files of 79 acromegaly patients who underwent transsphenoidal adenomectomy between 1994 and 2013 at Emory and assigned them to two groups on the basis of their preoperative GH levels, using 40 ng/mL as the cutoff.

Biochemical remission was defined as normal insulin-like growth factor 1 (IGF-1) during follow-up of more than 3 months in the absence of adjuvant therapy. The results were released at the annual meeting of the American Association of Clinical Endocrinologists on May 15 in Las Vegas.

Group A, with preoperative GH levels greater than 40 ng/mL, comprised 19 patients with a mean age of 43 years and an average follow-up of 38 months. They had larger, more invasive tumors, higher preoperative IGF-1 levels, higher immediate postoperative GH, and more residual tumors at 3 months, compared with the 60 patients in group B, who had preop GH levels of 40 ng/mL or less, a mean age of 47 years, and 43 months of follow-up.

In group A, three patients (15%) had remission at 3 months, but two patients had recurrence within 2 years. In group B, 35 patients (58%) had remission at 3 months with no recurrence during follow-up.

On univariate analysis, lower preoperative GH was a predictor of remission. In a multivariate analysis, however, lack of cavernous sinus invasion was the only predictor of remission.

"The relationship of GH elevation and cavernous sinus invasion should be further defined, as should the molecular fingerprint and the potential role of preoperative medical treatment in this group of patients," Dr. Anthony and his associates wrote.

No disclosures were reported.

[email protected]

SAN FRANCISCO – A new chemotherapy regimen of capecitabine and temozolomide was highly active against advanced treatment-resistant neuroendocrine tumors, based on the interim results of a phase II trial.

Tumors shrank in 43% of the 28 patients with various types of differentiated metastatic neuroendocrine tumors given the regimen, which is abbreviated CAPTEM. Disease stabilized in 54%.

Responses were durable, with a median progression-free survival approaching 2 years, reported lead investigator Dr. Robert Fine of the department of medicine at New York Presbyterian Hospital–Columbia University Medical Center.

"In this study, we’re seeing patients who had been given 6 months to live and are still alive 8 years after starting CAPTEM," he said in a prepared statement. "The regimen was effective even in patients with tumors that hadn’t responded to any other standard treatment, including chemotherapy, high-dose octreotide, small molecule inhibitors, radiation, or surgery."

For example, 42% of the patients with carcinoid tumors had a complete or partial response, and the others had stabilization of their disease. Median progression-free survival in this subset exceeded 31 months.

"Pituitary tumors were extraordinarily sensitive – end-stage people on respirators who were intubated with pituitary masses [compressing the spinal cord] were 100% responsive to the regimen, he said. Two of three patients had a complete response and were able to come off the ventilator and remain disease free with ongoing treatment at nearly 4 years out. The other patient had a partial response.

Toxicities were mild, and none of the patients had to be hospitalized or died as a result of the treatment, Dr. Fine commented in a press briefing before the results were presented at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Dr. Smitha S. Krishnamurthi of Case Western Reserve University, Cleveland, who was the press briefing moderator, concurred that the regimen offers a new treatment option to patients who have exhausted the standard options.

"This regimen of CAPTEM vs. TEM (temozolomide) is under study now in a cooperative group trial for patients with pancreatic neuroendocrine cancer," she noted.

Dr. Fine and his team enrolled patients in the trial who had well- or moderately differentiated neuroendocrine tumors and either experienced progression despite standard therapy with high-dose octreotide (Sandostatin) or were ineligible for this treatment because of a negative octreotide scan. Other prior treatments, with the exception of the two drugs being studied, were allowed.

CAPTEM contains capecitabine (Xeloda), currently approved by the Food and Drug Administration for the treatment of breast and colorectal cancers, and temozolomide (Temodar), currently approved for the treatment of anaplastic astrocytoma and glioblastoma multiforme.

The drugs are given in sequence to maximize efficacy, according to Dr. Fine, as the capecitabine depletes tumor thymidine stores, which dramatically potentiates the antitumor effect of the temozolomide.

Of the 28 patients, 12 had carcinoid tumors, 11 had pancreatic tumors, 3 had pituitary tumors, and 2 had medullary thyroid tumors.

The patients were treated with CAPTEM on 28-day cycles, with capecitabine alone for 9 days, both capecitabine and temozolomide for 5 days, and the next 14 days off.

Overall, 11% of patients had a complete response, 32% had a partial response, 54% had stable disease, and 3% had progressive disease. These values translated to a response rate of 43% and a clinical benefit rate of 97%.

Median progression-free survival exceeded 22 months, and median overall survival, although still maturing, exceeded 29 months.

"The toxicities were extraordinarily light," commented Dr. Fine, who disclosed that he receives research funding from Merck.

The most common grade 3 or 4 toxicities were lymphopenia (seen in 35% of patients), hyperglycemia (6%), thrombocytopenia (3%), and diarrhea (3%).

None of the patients were hospitalized, developed opportunistic infections, or died as a result of CAPTEM treatment.

SAN FRANCISCO – A new chemotherapy regimen of capecitabine and temozolomide was highly active against advanced treatment-resistant neuroendocrine tumors, based on the interim results of a phase II trial.

Tumors shrank in 43% of the 28 patients with various types of differentiated metastatic neuroendocrine tumors given the regimen, which is abbreviated CAPTEM. Disease stabilized in 54%.

Responses were durable, with a median progression-free survival approaching 2 years, reported lead investigator Dr. Robert Fine of the department of medicine at New York Presbyterian Hospital–Columbia University Medical Center.

"In this study, we’re seeing patients who had been given 6 months to live and are still alive 8 years after starting CAPTEM," he said in a prepared statement. "The regimen was effective even in patients with tumors that hadn’t responded to any other standard treatment, including chemotherapy, high-dose octreotide, small molecule inhibitors, radiation, or surgery."

For example, 42% of the patients with carcinoid tumors had a complete or partial response, and the others had stabilization of their disease. Median progression-free survival in this subset exceeded 31 months.

"Pituitary tumors were extraordinarily sensitive – end-stage people on respirators who were intubated with pituitary masses [compressing the spinal cord] were 100% responsive to the regimen, he said. Two of three patients had a complete response and were able to come off the ventilator and remain disease free with ongoing treatment at nearly 4 years out. The other patient had a partial response.

Toxicities were mild, and none of the patients had to be hospitalized or died as a result of the treatment, Dr. Fine commented in a press briefing before the results were presented at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Dr. Smitha S. Krishnamurthi of Case Western Reserve University, Cleveland, who was the press briefing moderator, concurred that the regimen offers a new treatment option to patients who have exhausted the standard options.

"This regimen of CAPTEM vs. TEM (temozolomide) is under study now in a cooperative group trial for patients with pancreatic neuroendocrine cancer," she noted.

Dr. Fine and his team enrolled patients in the trial who had well- or moderately differentiated neuroendocrine tumors and either experienced progression despite standard therapy with high-dose octreotide (Sandostatin) or were ineligible for this treatment because of a negative octreotide scan. Other prior treatments, with the exception of the two drugs being studied, were allowed.

CAPTEM contains capecitabine (Xeloda), currently approved by the Food and Drug Administration for the treatment of breast and colorectal cancers, and temozolomide (Temodar), currently approved for the treatment of anaplastic astrocytoma and glioblastoma multiforme.

The drugs are given in sequence to maximize efficacy, according to Dr. Fine, as the capecitabine depletes tumor thymidine stores, which dramatically potentiates the antitumor effect of the temozolomide.

Of the 28 patients, 12 had carcinoid tumors, 11 had pancreatic tumors, 3 had pituitary tumors, and 2 had medullary thyroid tumors.

The patients were treated with CAPTEM on 28-day cycles, with capecitabine alone for 9 days, both capecitabine and temozolomide for 5 days, and the next 14 days off.

Overall, 11% of patients had a complete response, 32% had a partial response, 54% had stable disease, and 3% had progressive disease. These values translated to a response rate of 43% and a clinical benefit rate of 97%.

Median progression-free survival exceeded 22 months, and median overall survival, although still maturing, exceeded 29 months.

"The toxicities were extraordinarily light," commented Dr. Fine, who disclosed that he receives research funding from Merck.

The most common grade 3 or 4 toxicities were lymphopenia (seen in 35% of patients), hyperglycemia (6%), thrombocytopenia (3%), and diarrhea (3%).

None of the patients were hospitalized, developed opportunistic infections, or died as a result of CAPTEM treatment.

SAN FRANCISCO – A new chemotherapy regimen of capecitabine and temozolomide was highly active against advanced treatment-resistant neuroendocrine tumors, based on the interim results of a phase II trial.

Tumors shrank in 43% of the 28 patients with various types of differentiated metastatic neuroendocrine tumors given the regimen, which is abbreviated CAPTEM. Disease stabilized in 54%.

Responses were durable, with a median progression-free survival approaching 2 years, reported lead investigator Dr. Robert Fine of the department of medicine at New York Presbyterian Hospital–Columbia University Medical Center.

"In this study, we’re seeing patients who had been given 6 months to live and are still alive 8 years after starting CAPTEM," he said in a prepared statement. "The regimen was effective even in patients with tumors that hadn’t responded to any other standard treatment, including chemotherapy, high-dose octreotide, small molecule inhibitors, radiation, or surgery."

For example, 42% of the patients with carcinoid tumors had a complete or partial response, and the others had stabilization of their disease. Median progression-free survival in this subset exceeded 31 months.

"Pituitary tumors were extraordinarily sensitive – end-stage people on respirators who were intubated with pituitary masses [compressing the spinal cord] were 100% responsive to the regimen, he said. Two of three patients had a complete response and were able to come off the ventilator and remain disease free with ongoing treatment at nearly 4 years out. The other patient had a partial response.

Toxicities were mild, and none of the patients had to be hospitalized or died as a result of the treatment, Dr. Fine commented in a press briefing before the results were presented at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Dr. Smitha S. Krishnamurthi of Case Western Reserve University, Cleveland, who was the press briefing moderator, concurred that the regimen offers a new treatment option to patients who have exhausted the standard options.

"This regimen of CAPTEM vs. TEM (temozolomide) is under study now in a cooperative group trial for patients with pancreatic neuroendocrine cancer," she noted.

Dr. Fine and his team enrolled patients in the trial who had well- or moderately differentiated neuroendocrine tumors and either experienced progression despite standard therapy with high-dose octreotide (Sandostatin) or were ineligible for this treatment because of a negative octreotide scan. Other prior treatments, with the exception of the two drugs being studied, were allowed.

CAPTEM contains capecitabine (Xeloda), currently approved by the Food and Drug Administration for the treatment of breast and colorectal cancers, and temozolomide (Temodar), currently approved for the treatment of anaplastic astrocytoma and glioblastoma multiforme.

The drugs are given in sequence to maximize efficacy, according to Dr. Fine, as the capecitabine depletes tumor thymidine stores, which dramatically potentiates the antitumor effect of the temozolomide.

Of the 28 patients, 12 had carcinoid tumors, 11 had pancreatic tumors, 3 had pituitary tumors, and 2 had medullary thyroid tumors.

The patients were treated with CAPTEM on 28-day cycles, with capecitabine alone for 9 days, both capecitabine and temozolomide for 5 days, and the next 14 days off.

Overall, 11% of patients had a complete response, 32% had a partial response, 54% had stable disease, and 3% had progressive disease. These values translated to a response rate of 43% and a clinical benefit rate of 97%.

Median progression-free survival exceeded 22 months, and median overall survival, although still maturing, exceeded 29 months.

"The toxicities were extraordinarily light," commented Dr. Fine, who disclosed that he receives research funding from Merck.

The most common grade 3 or 4 toxicities were lymphopenia (seen in 35% of patients), hyperglycemia (6%), thrombocytopenia (3%), and diarrhea (3%).

None of the patients were hospitalized, developed opportunistic infections, or died as a result of CAPTEM treatment.

SAN FRANCISCO – Measurements of prolactin levels during inferior petrosal sinus sampling did not help localize pituitary adenomas in patients with Cushing’s disease in a study of 28 patients, contradicting findings from a previous study of 28 patients.

The value of prolactin measurements in tumor localization using inferior petrosal sinus sampling (IPSS) remains unclear and needs further study in a larger, prospective study, Dr. Susmeeta T. Sharma said at the Endocrine Society’s Annual Meeting. The current and previous studies were retrospective analyses.

Although IPSS has been considered the standard test in patients with ACTH-dependent Cushing’s syndrome to differentiate between ectopic ACTH secretion and Cushing’s disease, there has been controversy about its value in localizing adenomas within the pituitary gland once a biochemical diagnosis of Cushing’s disease has been made. Various studies that used an intersinus ACTH ratio of 1.4 or greater before or after corticotropin-releasing hormone (CRH) stimulation have reported success rates as low as 50% and as high as 100% for tumor location.

A previous retrospective study of 28 patients with Cushing’s disease reported that adjusting the ACTH intersinus gradient by levels of prolactin before or after CRH stimulation, and combining the prolactin-adjusted ACTH intersinus ratio, improved pituitary adenoma localization. Magnetic resonance imaging (MRI) alone correctly localized the pituitary adenoma in 17 patients (61%), a prolactin-adjusted ACTH intersinus ratio of at least 1.4 improved the localization rate to 21 patients (75%), and combining MRI and the prolactin-adjusted ACTH intersinus ratio improved localization further to 23 patients, or 82% (Clin. Endocrinol. 2012;77:268-74).

The findings inspired the current retrospective study. The investigators looked at prolactin levels measured in stored petrosal and peripheral venous samples at baseline and at the time of peak ACTH levels after CRH stimulation for 28 patients with Cushing’s disease and ACTH-positive pituitary adenomas who underwent IPSS in 2007-2013. The investigators calculated prolactin-adjusted values by dividing each ACTH value by the concomitant ipsilateral prolactin value. They used an intersinus ACTH ratio of 1.4 or greater to predict tumor location.

At surgery, 26 patients had a single lateral tumor (meaning its epicenter was not in the midline), 1 patient had a central microadenoma, and 1 patient had a macroadenoma, reported Dr. Sharma of the National Institute of Child Health and Human Development, Bethesda, Md.

MRI findings accurately identified the location of 21 of the 26 lateral tumors (81%), compared with accurate localization in 18 patients using either the unadjusted ACTH intersinus ratio or the prolactin-adjusted ACTH intersinus ratio (69% for each), she said.

Incorrect tumor localization occurred with one patient using MRI alone and seven patients using either ratio. In four patients whose tumors could not be localized by MRI, the uncorrected and prolactin-adjusted ratios localized one tumor correctly and three tumors incorrectly. Only MRI correctly localized the one central microadenoma.

"We did not find any difference in localization rates by measurement of prolactin during IPSS," she said. The small size of the study and its retrospective design invite further research in a more robust study.

Dr. Sharma reported having no financial disclosures.

[email protected]

On Twitter @sherryboschert

SAN FRANCISCO – Measurements of prolactin levels during inferior petrosal sinus sampling did not help localize pituitary adenomas in patients with Cushing’s disease in a study of 28 patients, contradicting findings from a previous study of 28 patients.

The value of prolactin measurements in tumor localization using inferior petrosal sinus sampling (IPSS) remains unclear and needs further study in a larger, prospective study, Dr. Susmeeta T. Sharma said at the Endocrine Society’s Annual Meeting. The current and previous studies were retrospective analyses.

Although IPSS has been considered the standard test in patients with ACTH-dependent Cushing’s syndrome to differentiate between ectopic ACTH secretion and Cushing’s disease, there has been controversy about its value in localizing adenomas within the pituitary gland once a biochemical diagnosis of Cushing’s disease has been made. Various studies that used an intersinus ACTH ratio of 1.4 or greater before or after corticotropin-releasing hormone (CRH) stimulation have reported success rates as low as 50% and as high as 100% for tumor location.

A previous retrospective study of 28 patients with Cushing’s disease reported that adjusting the ACTH intersinus gradient by levels of prolactin before or after CRH stimulation, and combining the prolactin-adjusted ACTH intersinus ratio, improved pituitary adenoma localization. Magnetic resonance imaging (MRI) alone correctly localized the pituitary adenoma in 17 patients (61%), a prolactin-adjusted ACTH intersinus ratio of at least 1.4 improved the localization rate to 21 patients (75%), and combining MRI and the prolactin-adjusted ACTH intersinus ratio improved localization further to 23 patients, or 82% (Clin. Endocrinol. 2012;77:268-74).

The findings inspired the current retrospective study. The investigators looked at prolactin levels measured in stored petrosal and peripheral venous samples at baseline and at the time of peak ACTH levels after CRH stimulation for 28 patients with Cushing’s disease and ACTH-positive pituitary adenomas who underwent IPSS in 2007-2013. The investigators calculated prolactin-adjusted values by dividing each ACTH value by the concomitant ipsilateral prolactin value. They used an intersinus ACTH ratio of 1.4 or greater to predict tumor location.

At surgery, 26 patients had a single lateral tumor (meaning its epicenter was not in the midline), 1 patient had a central microadenoma, and 1 patient had a macroadenoma, reported Dr. Sharma of the National Institute of Child Health and Human Development, Bethesda, Md.

MRI findings accurately identified the location of 21 of the 26 lateral tumors (81%), compared with accurate localization in 18 patients using either the unadjusted ACTH intersinus ratio or the prolactin-adjusted ACTH intersinus ratio (69% for each), she said.

Incorrect tumor localization occurred with one patient using MRI alone and seven patients using either ratio. In four patients whose tumors could not be localized by MRI, the uncorrected and prolactin-adjusted ratios localized one tumor correctly and three tumors incorrectly. Only MRI correctly localized the one central microadenoma.

"We did not find any difference in localization rates by measurement of prolactin during IPSS," she said. The small size of the study and its retrospective design invite further research in a more robust study.

Dr. Sharma reported having no financial disclosures.

[email protected]

On Twitter @sherryboschert

SAN FRANCISCO – Measurements of prolactin levels during inferior petrosal sinus sampling did not help localize pituitary adenomas in patients with Cushing’s disease in a study of 28 patients, contradicting findings from a previous study of 28 patients.

The value of prolactin measurements in tumor localization using inferior petrosal sinus sampling (IPSS) remains unclear and needs further study in a larger, prospective study, Dr. Susmeeta T. Sharma said at the Endocrine Society’s Annual Meeting. The current and previous studies were retrospective analyses.

Although IPSS has been considered the standard test in patients with ACTH-dependent Cushing’s syndrome to differentiate between ectopic ACTH secretion and Cushing’s disease, there has been controversy about its value in localizing adenomas within the pituitary gland once a biochemical diagnosis of Cushing’s disease has been made. Various studies that used an intersinus ACTH ratio of 1.4 or greater before or after corticotropin-releasing hormone (CRH) stimulation have reported success rates as low as 50% and as high as 100% for tumor location.

A previous retrospective study of 28 patients with Cushing’s disease reported that adjusting the ACTH intersinus gradient by levels of prolactin before or after CRH stimulation, and combining the prolactin-adjusted ACTH intersinus ratio, improved pituitary adenoma localization. Magnetic resonance imaging (MRI) alone correctly localized the pituitary adenoma in 17 patients (61%), a prolactin-adjusted ACTH intersinus ratio of at least 1.4 improved the localization rate to 21 patients (75%), and combining MRI and the prolactin-adjusted ACTH intersinus ratio improved localization further to 23 patients, or 82% (Clin. Endocrinol. 2012;77:268-74).

The findings inspired the current retrospective study. The investigators looked at prolactin levels measured in stored petrosal and peripheral venous samples at baseline and at the time of peak ACTH levels after CRH stimulation for 28 patients with Cushing’s disease and ACTH-positive pituitary adenomas who underwent IPSS in 2007-2013. The investigators calculated prolactin-adjusted values by dividing each ACTH value by the concomitant ipsilateral prolactin value. They used an intersinus ACTH ratio of 1.4 or greater to predict tumor location.

At surgery, 26 patients had a single lateral tumor (meaning its epicenter was not in the midline), 1 patient had a central microadenoma, and 1 patient had a macroadenoma, reported Dr. Sharma of the National Institute of Child Health and Human Development, Bethesda, Md.

MRI findings accurately identified the location of 21 of the 26 lateral tumors (81%), compared with accurate localization in 18 patients using either the unadjusted ACTH intersinus ratio or the prolactin-adjusted ACTH intersinus ratio (69% for each), she said.

Incorrect tumor localization occurred with one patient using MRI alone and seven patients using either ratio. In four patients whose tumors could not be localized by MRI, the uncorrected and prolactin-adjusted ratios localized one tumor correctly and three tumors incorrectly. Only MRI correctly localized the one central microadenoma.

"We did not find any difference in localization rates by measurement of prolactin during IPSS," she said. The small size of the study and its retrospective design invite further research in a more robust study.

Dr. Sharma reported having no financial disclosures.

[email protected]

On Twitter @sherryboschert