Susan London

CHICAGO – The mTOR inhibitor everolimus appears to be effective at overcoming trastuzumab resistance in patients with advanced HER2-positive breast cancer, based on findings from the BOLERO-3 trial.

The 572 patients studied all had locally advanced or metastatic HER2-positive breast cancer that had progressed despite trastuzumab therapy.

The main trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that when everolimus (Afinitor) was added to trastuzumab and vinorelbine, it reduced the risk of progression or death by 22% compared with placebo, a difference amounting to about a 1-month benefit.

As expected, patients receiving everolimus had higher rates of certain grade 3/4 adverse events, such as stomatitis, but the two groups did not differ with respect to quality of life. Overall survival results are not yet mature.

"This is the first phase III study showing the benefit of mTOR [mammalian target of rapamycin] pathway inhibition in HER2-positive breast cancer. Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy," commented first author Dr. Ruth O’Regan, director of translational breast cancer research at the Winship Cancer Institute of Emory University in Atlanta. "The combination of everolimus with vinorelbine and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer."

"The ongoing BOLERO-1 trial will evaluate the addition of everolimus to chemotherapy and trastuzumab in the first-line setting," she added.

Session attendee Dr. Jose Baselga, physician-in-chief of Memorial Hospital at the Memorial Sloan-Kettering Cancer Center in New York, said, "In looking at the data, the first reaction I have is that you have two groups: the ER [estrogen receptor]-positives and the ER-negatives. And I’m just wondering whether this theme of mTOR and ER, this cross-talk, is so important, that whether even in the HER2-positives, we need to address the issue of ER blockade at the same time, because if the study had been only in the ER-negatives, this would have been a massively positive trial."

"It is possible that when you inhibit mTOR, in that situation, that perhaps we do need to also inhibit ER," Dr. O’Regan agreed. "It’s a fairly large trial, and the [progression-free survival] lines cross completely in the hormone receptor–positive group. So that’s a very good question. I think maybe it’s worthwhile looking at HER2, mTOR, estrogen receptor blockade in another trial."

Dr. Steven Vogl, a medical oncologist in the Bronx, N.Y., asked whether BOLERO-1 is powered to look at ER-positive and ER-negative patients individually. "Your benefit was small and probably confined to only the ER-negative patients. It would be nice to know how big the benefit is in those patients and to have a second trial showing us that we need to give everolimus to these patients only if they are ER negative."

Dr. O’Regan said she did not know whether BOLERO-1 was adequately powered to answer that question. "I doubt it is, in reality, but I think we will get some interesting data. If we find the same thing in that study, that will be something certainly we can take forward," she said.

Dr. Alan Astrow, of the Maimonides Medical Center in Brooklyn, N.Y., who also attended the session, noted that the new data suggest that everolimus now presents a third treatment option in this patient population, in addition to pertuzumab (Perjeta) and TDM-1 (Kadcyla). "So what are your thoughts about further development of this drug now that we have other drugs available?" he asked.

"At this point, it would probably be third-line after those agents in the metastatic setting," Dr. O’Regan replied. "The question is, where do you put it in regard to lapatinib? And are we going to have to start looking at ER-negative versus ER-positive differences – would you put this combination up higher in the ER-negative, HER2-positive group? There are a lot of questions that we just don’t know the answer to right now."

Session comoderator Dr. Rebecca Alexander Dent, an oncologist with Duke-NUS in Singapore, the University of Toronto, and the Sunnybrook Odette Cancer Center in Toronto, said, "Obviously, the doses [of everolimus] that have been used in trials are somewhat different. Can you comment on what kind of impact that might make or how we should move forward with that?"

Dr. O’Regan said the 5-mg dose used was based on phase I data, whereas other trials, such as BOLERO-1, are using a 10-mg dose. "Obviously, we don’t know if we had used a higher dose if we would have had a greater progression-free survival difference, but it would definitely increase the toxicity," she said; the optimal dose may depend on whether it is given with chemotherapy.

The patients in the BOLERO-3 trial were randomized evenly to daily everolimus versus daily placebo, each added to weekly trastuzumab (Herceptin) and vinorelbine.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive, HER2-positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

A fourth of patients had previously received lapatinib (Tykerb). The large majority had received one or two prior lines of therapy for metastatic disease.

Median progression-free survival was 1.22 months longer with everolimus (7.00 vs 5.78 months; hazard ratio, 0.78; P = .0067).

The overall rate of response did not differ significantly between the everolimus and placebo groups (41% vs. 37%).

The everolimus arm had higher rates than the placebo group for grade 3/4 stomatitis (13% vs. 1%), fatigue (12% vs. 4%), and hematologic adverse events. But the groups were statistically indistinguishable with respect to the time to definitive deterioration of global health status.

The rate of death was 36% with everolimus and 41% with placebo, a nonsignificant difference, although longer follow-up is needed for definitive overall survival data.

The trial was sponsored by Novartis, the maker of Afinitor. Dr. O’Regan disclosed that she is a consultant to Novartis, and receives research funding from Genentech, the maker of Kadcyla and Perjeta, and Novartis.

CHICAGO – The mTOR inhibitor everolimus appears to be effective at overcoming trastuzumab resistance in patients with advanced HER2-positive breast cancer, based on findings from the BOLERO-3 trial.

The 572 patients studied all had locally advanced or metastatic HER2-positive breast cancer that had progressed despite trastuzumab therapy.

The main trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that when everolimus (Afinitor) was added to trastuzumab and vinorelbine, it reduced the risk of progression or death by 22% compared with placebo, a difference amounting to about a 1-month benefit.

As expected, patients receiving everolimus had higher rates of certain grade 3/4 adverse events, such as stomatitis, but the two groups did not differ with respect to quality of life. Overall survival results are not yet mature.

"This is the first phase III study showing the benefit of mTOR [mammalian target of rapamycin] pathway inhibition in HER2-positive breast cancer. Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy," commented first author Dr. Ruth O’Regan, director of translational breast cancer research at the Winship Cancer Institute of Emory University in Atlanta. "The combination of everolimus with vinorelbine and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer."

"The ongoing BOLERO-1 trial will evaluate the addition of everolimus to chemotherapy and trastuzumab in the first-line setting," she added.

Session attendee Dr. Jose Baselga, physician-in-chief of Memorial Hospital at the Memorial Sloan-Kettering Cancer Center in New York, said, "In looking at the data, the first reaction I have is that you have two groups: the ER [estrogen receptor]-positives and the ER-negatives. And I’m just wondering whether this theme of mTOR and ER, this cross-talk, is so important, that whether even in the HER2-positives, we need to address the issue of ER blockade at the same time, because if the study had been only in the ER-negatives, this would have been a massively positive trial."

"It is possible that when you inhibit mTOR, in that situation, that perhaps we do need to also inhibit ER," Dr. O’Regan agreed. "It’s a fairly large trial, and the [progression-free survival] lines cross completely in the hormone receptor–positive group. So that’s a very good question. I think maybe it’s worthwhile looking at HER2, mTOR, estrogen receptor blockade in another trial."

Dr. Steven Vogl, a medical oncologist in the Bronx, N.Y., asked whether BOLERO-1 is powered to look at ER-positive and ER-negative patients individually. "Your benefit was small and probably confined to only the ER-negative patients. It would be nice to know how big the benefit is in those patients and to have a second trial showing us that we need to give everolimus to these patients only if they are ER negative."

Dr. O’Regan said she did not know whether BOLERO-1 was adequately powered to answer that question. "I doubt it is, in reality, but I think we will get some interesting data. If we find the same thing in that study, that will be something certainly we can take forward," she said.

Dr. Alan Astrow, of the Maimonides Medical Center in Brooklyn, N.Y., who also attended the session, noted that the new data suggest that everolimus now presents a third treatment option in this patient population, in addition to pertuzumab (Perjeta) and TDM-1 (Kadcyla). "So what are your thoughts about further development of this drug now that we have other drugs available?" he asked.

"At this point, it would probably be third-line after those agents in the metastatic setting," Dr. O’Regan replied. "The question is, where do you put it in regard to lapatinib? And are we going to have to start looking at ER-negative versus ER-positive differences – would you put this combination up higher in the ER-negative, HER2-positive group? There are a lot of questions that we just don’t know the answer to right now."

Session comoderator Dr. Rebecca Alexander Dent, an oncologist with Duke-NUS in Singapore, the University of Toronto, and the Sunnybrook Odette Cancer Center in Toronto, said, "Obviously, the doses [of everolimus] that have been used in trials are somewhat different. Can you comment on what kind of impact that might make or how we should move forward with that?"

Dr. O’Regan said the 5-mg dose used was based on phase I data, whereas other trials, such as BOLERO-1, are using a 10-mg dose. "Obviously, we don’t know if we had used a higher dose if we would have had a greater progression-free survival difference, but it would definitely increase the toxicity," she said; the optimal dose may depend on whether it is given with chemotherapy.

The patients in the BOLERO-3 trial were randomized evenly to daily everolimus versus daily placebo, each added to weekly trastuzumab (Herceptin) and vinorelbine.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive, HER2-positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

A fourth of patients had previously received lapatinib (Tykerb). The large majority had received one or two prior lines of therapy for metastatic disease.

Median progression-free survival was 1.22 months longer with everolimus (7.00 vs 5.78 months; hazard ratio, 0.78; P = .0067).

The overall rate of response did not differ significantly between the everolimus and placebo groups (41% vs. 37%).

The everolimus arm had higher rates than the placebo group for grade 3/4 stomatitis (13% vs. 1%), fatigue (12% vs. 4%), and hematologic adverse events. But the groups were statistically indistinguishable with respect to the time to definitive deterioration of global health status.

The rate of death was 36% with everolimus and 41% with placebo, a nonsignificant difference, although longer follow-up is needed for definitive overall survival data.

The trial was sponsored by Novartis, the maker of Afinitor. Dr. O’Regan disclosed that she is a consultant to Novartis, and receives research funding from Genentech, the maker of Kadcyla and Perjeta, and Novartis.

CHICAGO – The mTOR inhibitor everolimus appears to be effective at overcoming trastuzumab resistance in patients with advanced HER2-positive breast cancer, based on findings from the BOLERO-3 trial.

The 572 patients studied all had locally advanced or metastatic HER2-positive breast cancer that had progressed despite trastuzumab therapy.

The main trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that when everolimus (Afinitor) was added to trastuzumab and vinorelbine, it reduced the risk of progression or death by 22% compared with placebo, a difference amounting to about a 1-month benefit.

As expected, patients receiving everolimus had higher rates of certain grade 3/4 adverse events, such as stomatitis, but the two groups did not differ with respect to quality of life. Overall survival results are not yet mature.

"This is the first phase III study showing the benefit of mTOR [mammalian target of rapamycin] pathway inhibition in HER2-positive breast cancer. Targeting mTOR is a viable approach to maximize the benefit of trastuzumab-based therapy," commented first author Dr. Ruth O’Regan, director of translational breast cancer research at the Winship Cancer Institute of Emory University in Atlanta. "The combination of everolimus with vinorelbine and trastuzumab can be considered an appropriate option for some patients with trastuzumab-resistant HER2-positive breast cancer."

"The ongoing BOLERO-1 trial will evaluate the addition of everolimus to chemotherapy and trastuzumab in the first-line setting," she added.

Session attendee Dr. Jose Baselga, physician-in-chief of Memorial Hospital at the Memorial Sloan-Kettering Cancer Center in New York, said, "In looking at the data, the first reaction I have is that you have two groups: the ER [estrogen receptor]-positives and the ER-negatives. And I’m just wondering whether this theme of mTOR and ER, this cross-talk, is so important, that whether even in the HER2-positives, we need to address the issue of ER blockade at the same time, because if the study had been only in the ER-negatives, this would have been a massively positive trial."

"It is possible that when you inhibit mTOR, in that situation, that perhaps we do need to also inhibit ER," Dr. O’Regan agreed. "It’s a fairly large trial, and the [progression-free survival] lines cross completely in the hormone receptor–positive group. So that’s a very good question. I think maybe it’s worthwhile looking at HER2, mTOR, estrogen receptor blockade in another trial."

Dr. Steven Vogl, a medical oncologist in the Bronx, N.Y., asked whether BOLERO-1 is powered to look at ER-positive and ER-negative patients individually. "Your benefit was small and probably confined to only the ER-negative patients. It would be nice to know how big the benefit is in those patients and to have a second trial showing us that we need to give everolimus to these patients only if they are ER negative."

Dr. O’Regan said she did not know whether BOLERO-1 was adequately powered to answer that question. "I doubt it is, in reality, but I think we will get some interesting data. If we find the same thing in that study, that will be something certainly we can take forward," she said.

Dr. Alan Astrow, of the Maimonides Medical Center in Brooklyn, N.Y., who also attended the session, noted that the new data suggest that everolimus now presents a third treatment option in this patient population, in addition to pertuzumab (Perjeta) and TDM-1 (Kadcyla). "So what are your thoughts about further development of this drug now that we have other drugs available?" he asked.

"At this point, it would probably be third-line after those agents in the metastatic setting," Dr. O’Regan replied. "The question is, where do you put it in regard to lapatinib? And are we going to have to start looking at ER-negative versus ER-positive differences – would you put this combination up higher in the ER-negative, HER2-positive group? There are a lot of questions that we just don’t know the answer to right now."

Session comoderator Dr. Rebecca Alexander Dent, an oncologist with Duke-NUS in Singapore, the University of Toronto, and the Sunnybrook Odette Cancer Center in Toronto, said, "Obviously, the doses [of everolimus] that have been used in trials are somewhat different. Can you comment on what kind of impact that might make or how we should move forward with that?"

Dr. O’Regan said the 5-mg dose used was based on phase I data, whereas other trials, such as BOLERO-1, are using a 10-mg dose. "Obviously, we don’t know if we had used a higher dose if we would have had a greater progression-free survival difference, but it would definitely increase the toxicity," she said; the optimal dose may depend on whether it is given with chemotherapy.

The patients in the BOLERO-3 trial were randomized evenly to daily everolimus versus daily placebo, each added to weekly trastuzumab (Herceptin) and vinorelbine.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive, HER2-positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

A fourth of patients had previously received lapatinib (Tykerb). The large majority had received one or two prior lines of therapy for metastatic disease.

Median progression-free survival was 1.22 months longer with everolimus (7.00 vs 5.78 months; hazard ratio, 0.78; P = .0067).

The overall rate of response did not differ significantly between the everolimus and placebo groups (41% vs. 37%).

The everolimus arm had higher rates than the placebo group for grade 3/4 stomatitis (13% vs. 1%), fatigue (12% vs. 4%), and hematologic adverse events. But the groups were statistically indistinguishable with respect to the time to definitive deterioration of global health status.

The rate of death was 36% with everolimus and 41% with placebo, a nonsignificant difference, although longer follow-up is needed for definitive overall survival data.

The trial was sponsored by Novartis, the maker of Afinitor. Dr. O’Regan disclosed that she is a consultant to Novartis, and receives research funding from Genentech, the maker of Kadcyla and Perjeta, and Novartis.

CHICAGO – The multigene PAM50 assay identifies postmenopausal women with node-positive early breast cancer who have a low risk of distant metastases and may be able to skip adjuvant chemotherapy.

The 543 women studied had one to three positive nodes and low- or intermediate-grade tumors; all received adjuvant endocrine therapy but no chemotherapy in a pair of randomized trials: the ABCSG-8 (Austrian Breast Cancer Study Group 8) trial and the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial.

Results showed that three PAM50 parameters – the risk of recurrence (ROR) score, ROR risk group, and intrinsic subtype – significantly added to clinicopathologic factors in predicting the 10-year risk of metastases.

"A significant proportion of early breast cancer patients with only one positive node has a limited long-term risk of metastases, as well as at least some patients with two or three positive nodes," first author Dr. Michael Gnant commented in presenting the findings at the annual meeting of the American Society of Clinical Oncology.

In particular, among patients with only one positive node, those falling into the ROR low-risk group (41% of the one-node subset) and those having the luminal A intrinsic subtype (71% of the one-node subset) had 10-year risks of metastases that were less than 9%.

"Based on their low risk of metastases, these patients could – and I would personally add should – be spared the side effects of adjuvant chemotherapy despite having node-positive early breast cancer," maintained Dr. Gnant, who is a professor of surgery at the Medical University of Vienna, Austria.

"In the adjuvant treatment of hormone receptor–positive breast cancer, we every day face the dilemma of undertreatment versus overtreatment. Assessing an individual patient’s risk of metastasis as accurately as possible is an important goal in early breast cancer, and it directly impacts on treatment decisions," he added. "Still, risk assessment is mainly based on clinicopathological variables, of which nodal status is considered to be most important. As a consequence, most node-positive patients with hormone receptor–positive breast cancer globally still receive adjuvant chemotherapy."

In the study, the researchers assessed the added prognostic value derived from NanoString Technologies’ PAM50, a 50-gene assay designed to identify intrinsic subtypes of breast cancer. The subtypes are combined with a proliferation score and tumor size to yield the ROR score, and scores are used to classify patients into ROR-based risk groups.

The clinical usefulness of the PAM50 assay and other similar molecular assays, such as Genomic Health’s Oncotype DX and Agendia’s MammaPrint, has not been defined in node-positive patients, he noted.

The node-positive patients studied were drawn from the ABCSG-8 and ATAC trials. The former trial assigned women either to tamoxifen for 5 years or to 2 years of tamoxifen followed by 3 years of the aromatase inhibitor anastrozole (Arimidex); the latter assigned patients to 5 years of adjuvant anastrozole alone, tamoxifen alone, or the (subsequently discontinued) combination.

For each patient, the investigators analyzed tumor tissue to determine the PAM50 ROR score, ROR risk group, and intrinsic subtype. In addition, they derived the clinical treatment score, which is an overall integrated measure of clinicopathologic factors.

The median follow-up was 11 years, according to Dr. Gnant. As the ROR score increased from 0 to 100, so did the 10-year risk of metastases.

When added to the clinical treatment score alone, the ROR score significantly improved on the prediction of metastasis (chi-square for the difference in likelihood ratios, 32.45; P less than .0001).

The ROR risk groups also stratified patients well. The risk of metastases was about 30% in the high-risk group, 14% in the intermediate-risk group, and 8% in the low-risk group.

When added to the clinical treatment score, the luminal subtype significantly improved on prediction of metastasis (chi-square for the difference in likelihood ratios, 20.48; P less than .0001).

The estimated 10-year risk of metastasis was 11% in the luminal A group and 31% in the luminal B group.

In a combined analysis, the risk of metastases was less than 10% in several subsets of patients: those with one or two positive nodes in the ROR low-risk group (6.6% and 7.2% risks, respectively) and those with one positive node having the luminal A subtype (8.4% risk).

Finally, each factor – ROR score, ROR risk group, and intrinsic subtype – significantly improved on the prediction of risk above and beyond clinicopathologic factors in patients with one positive node, two positive nodes, and two or three positive nodes individually.

One session attendee asked, "Was there any opportunity to look at the interaction [of PAM50 parameters] with therapy?"

"Given the rather limited overall difference between anastrozole and tamoxifen both in the ATAC trial and in the sequencing study, ABCSG-8 – tamoxifen versus tamoxifen followed by anastrozole – I don’t think that we can reasonably comment on the interaction between these scores and treatment," Dr. Gnant replied.

Another attendee, Dr. Carlos Arteaga of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., asked, "Until we all start doing these genomic tests, can you tell us whether the Ki-67 had equal power in your study? It’s a simple test, and we are all using 14% as a cutoff for luminal A and B [intrinsic subtypes]. How did that pan out in this cohort?

"We are trying to have central review for Ki-67 and bring it into the multivariate model. Hopefully, later this year we will be able to answer that question," Dr. Gnant replied.

Dr. Gnant disclosed ties to several companies including Sanofi-Aventis, Novartis, and Roche, as well as NanoString Technologies, the maker of the PAM50 assay.

CHICAGO – The multigene PAM50 assay identifies postmenopausal women with node-positive early breast cancer who have a low risk of distant metastases and may be able to skip adjuvant chemotherapy.

The 543 women studied had one to three positive nodes and low- or intermediate-grade tumors; all received adjuvant endocrine therapy but no chemotherapy in a pair of randomized trials: the ABCSG-8 (Austrian Breast Cancer Study Group 8) trial and the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial.

Results showed that three PAM50 parameters – the risk of recurrence (ROR) score, ROR risk group, and intrinsic subtype – significantly added to clinicopathologic factors in predicting the 10-year risk of metastases.

"A significant proportion of early breast cancer patients with only one positive node has a limited long-term risk of metastases, as well as at least some patients with two or three positive nodes," first author Dr. Michael Gnant commented in presenting the findings at the annual meeting of the American Society of Clinical Oncology.

In particular, among patients with only one positive node, those falling into the ROR low-risk group (41% of the one-node subset) and those having the luminal A intrinsic subtype (71% of the one-node subset) had 10-year risks of metastases that were less than 9%.

"Based on their low risk of metastases, these patients could – and I would personally add should – be spared the side effects of adjuvant chemotherapy despite having node-positive early breast cancer," maintained Dr. Gnant, who is a professor of surgery at the Medical University of Vienna, Austria.

"In the adjuvant treatment of hormone receptor–positive breast cancer, we every day face the dilemma of undertreatment versus overtreatment. Assessing an individual patient’s risk of metastasis as accurately as possible is an important goal in early breast cancer, and it directly impacts on treatment decisions," he added. "Still, risk assessment is mainly based on clinicopathological variables, of which nodal status is considered to be most important. As a consequence, most node-positive patients with hormone receptor–positive breast cancer globally still receive adjuvant chemotherapy."

In the study, the researchers assessed the added prognostic value derived from NanoString Technologies’ PAM50, a 50-gene assay designed to identify intrinsic subtypes of breast cancer. The subtypes are combined with a proliferation score and tumor size to yield the ROR score, and scores are used to classify patients into ROR-based risk groups.

The clinical usefulness of the PAM50 assay and other similar molecular assays, such as Genomic Health’s Oncotype DX and Agendia’s MammaPrint, has not been defined in node-positive patients, he noted.

The node-positive patients studied were drawn from the ABCSG-8 and ATAC trials. The former trial assigned women either to tamoxifen for 5 years or to 2 years of tamoxifen followed by 3 years of the aromatase inhibitor anastrozole (Arimidex); the latter assigned patients to 5 years of adjuvant anastrozole alone, tamoxifen alone, or the (subsequently discontinued) combination.

For each patient, the investigators analyzed tumor tissue to determine the PAM50 ROR score, ROR risk group, and intrinsic subtype. In addition, they derived the clinical treatment score, which is an overall integrated measure of clinicopathologic factors.

The median follow-up was 11 years, according to Dr. Gnant. As the ROR score increased from 0 to 100, so did the 10-year risk of metastases.

When added to the clinical treatment score alone, the ROR score significantly improved on the prediction of metastasis (chi-square for the difference in likelihood ratios, 32.45; P less than .0001).

The ROR risk groups also stratified patients well. The risk of metastases was about 30% in the high-risk group, 14% in the intermediate-risk group, and 8% in the low-risk group.

When added to the clinical treatment score, the luminal subtype significantly improved on prediction of metastasis (chi-square for the difference in likelihood ratios, 20.48; P less than .0001).

The estimated 10-year risk of metastasis was 11% in the luminal A group and 31% in the luminal B group.

In a combined analysis, the risk of metastases was less than 10% in several subsets of patients: those with one or two positive nodes in the ROR low-risk group (6.6% and 7.2% risks, respectively) and those with one positive node having the luminal A subtype (8.4% risk).

Finally, each factor – ROR score, ROR risk group, and intrinsic subtype – significantly improved on the prediction of risk above and beyond clinicopathologic factors in patients with one positive node, two positive nodes, and two or three positive nodes individually.

One session attendee asked, "Was there any opportunity to look at the interaction [of PAM50 parameters] with therapy?"

"Given the rather limited overall difference between anastrozole and tamoxifen both in the ATAC trial and in the sequencing study, ABCSG-8 – tamoxifen versus tamoxifen followed by anastrozole – I don’t think that we can reasonably comment on the interaction between these scores and treatment," Dr. Gnant replied.

Another attendee, Dr. Carlos Arteaga of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., asked, "Until we all start doing these genomic tests, can you tell us whether the Ki-67 had equal power in your study? It’s a simple test, and we are all using 14% as a cutoff for luminal A and B [intrinsic subtypes]. How did that pan out in this cohort?

"We are trying to have central review for Ki-67 and bring it into the multivariate model. Hopefully, later this year we will be able to answer that question," Dr. Gnant replied.

Dr. Gnant disclosed ties to several companies including Sanofi-Aventis, Novartis, and Roche, as well as NanoString Technologies, the maker of the PAM50 assay.

CHICAGO – The multigene PAM50 assay identifies postmenopausal women with node-positive early breast cancer who have a low risk of distant metastases and may be able to skip adjuvant chemotherapy.

The 543 women studied had one to three positive nodes and low- or intermediate-grade tumors; all received adjuvant endocrine therapy but no chemotherapy in a pair of randomized trials: the ABCSG-8 (Austrian Breast Cancer Study Group 8) trial and the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial.

Results showed that three PAM50 parameters – the risk of recurrence (ROR) score, ROR risk group, and intrinsic subtype – significantly added to clinicopathologic factors in predicting the 10-year risk of metastases.

"A significant proportion of early breast cancer patients with only one positive node has a limited long-term risk of metastases, as well as at least some patients with two or three positive nodes," first author Dr. Michael Gnant commented in presenting the findings at the annual meeting of the American Society of Clinical Oncology.

In particular, among patients with only one positive node, those falling into the ROR low-risk group (41% of the one-node subset) and those having the luminal A intrinsic subtype (71% of the one-node subset) had 10-year risks of metastases that were less than 9%.

"Based on their low risk of metastases, these patients could – and I would personally add should – be spared the side effects of adjuvant chemotherapy despite having node-positive early breast cancer," maintained Dr. Gnant, who is a professor of surgery at the Medical University of Vienna, Austria.

"In the adjuvant treatment of hormone receptor–positive breast cancer, we every day face the dilemma of undertreatment versus overtreatment. Assessing an individual patient’s risk of metastasis as accurately as possible is an important goal in early breast cancer, and it directly impacts on treatment decisions," he added. "Still, risk assessment is mainly based on clinicopathological variables, of which nodal status is considered to be most important. As a consequence, most node-positive patients with hormone receptor–positive breast cancer globally still receive adjuvant chemotherapy."

In the study, the researchers assessed the added prognostic value derived from NanoString Technologies’ PAM50, a 50-gene assay designed to identify intrinsic subtypes of breast cancer. The subtypes are combined with a proliferation score and tumor size to yield the ROR score, and scores are used to classify patients into ROR-based risk groups.

The clinical usefulness of the PAM50 assay and other similar molecular assays, such as Genomic Health’s Oncotype DX and Agendia’s MammaPrint, has not been defined in node-positive patients, he noted.

The node-positive patients studied were drawn from the ABCSG-8 and ATAC trials. The former trial assigned women either to tamoxifen for 5 years or to 2 years of tamoxifen followed by 3 years of the aromatase inhibitor anastrozole (Arimidex); the latter assigned patients to 5 years of adjuvant anastrozole alone, tamoxifen alone, or the (subsequently discontinued) combination.

For each patient, the investigators analyzed tumor tissue to determine the PAM50 ROR score, ROR risk group, and intrinsic subtype. In addition, they derived the clinical treatment score, which is an overall integrated measure of clinicopathologic factors.

The median follow-up was 11 years, according to Dr. Gnant. As the ROR score increased from 0 to 100, so did the 10-year risk of metastases.

When added to the clinical treatment score alone, the ROR score significantly improved on the prediction of metastasis (chi-square for the difference in likelihood ratios, 32.45; P less than .0001).

The ROR risk groups also stratified patients well. The risk of metastases was about 30% in the high-risk group, 14% in the intermediate-risk group, and 8% in the low-risk group.

When added to the clinical treatment score, the luminal subtype significantly improved on prediction of metastasis (chi-square for the difference in likelihood ratios, 20.48; P less than .0001).

The estimated 10-year risk of metastasis was 11% in the luminal A group and 31% in the luminal B group.

In a combined analysis, the risk of metastases was less than 10% in several subsets of patients: those with one or two positive nodes in the ROR low-risk group (6.6% and 7.2% risks, respectively) and those with one positive node having the luminal A subtype (8.4% risk).

Finally, each factor – ROR score, ROR risk group, and intrinsic subtype – significantly improved on the prediction of risk above and beyond clinicopathologic factors in patients with one positive node, two positive nodes, and two or three positive nodes individually.

One session attendee asked, "Was there any opportunity to look at the interaction [of PAM50 parameters] with therapy?"

"Given the rather limited overall difference between anastrozole and tamoxifen both in the ATAC trial and in the sequencing study, ABCSG-8 – tamoxifen versus tamoxifen followed by anastrozole – I don’t think that we can reasonably comment on the interaction between these scores and treatment," Dr. Gnant replied.

Another attendee, Dr. Carlos Arteaga of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., asked, "Until we all start doing these genomic tests, can you tell us whether the Ki-67 had equal power in your study? It’s a simple test, and we are all using 14% as a cutoff for luminal A and B [intrinsic subtypes]. How did that pan out in this cohort?

"We are trying to have central review for Ki-67 and bring it into the multivariate model. Hopefully, later this year we will be able to answer that question," Dr. Gnant replied.

Dr. Gnant disclosed ties to several companies including Sanofi-Aventis, Novartis, and Roche, as well as NanoString Technologies, the maker of the PAM50 assay.

CHICAGO – The combination of pomalidomide and low-dose dexamethasone is superior to high-dose dexamethasone monotherapy for treating patients with relapsed and refractory multiple myeloma, based on updated results from the multicenter, randomized MM-003 trial.

Among the 455 patients studied in the trial, those assigned to the combination therapy had a 52% lower risk of progression or death and a 26% lower risk of death alone when compared with peers assigned to single-agent high-dose dexamethasone.

The two regimens had much the same toxicity profile, although the combination was associated with a higher rate of grade 3/4 hematologic toxicity.

"Pomalidomide in combination with low-dose dexamethasone should be considered as a new standard of care for treatment of relapsed and refractory multiple myeloma patients after treatment with lenalidomide and bortezomib," presenting author Dr. Katja C. Weisel commented at the annual meeting of the American Society of Clinical Oncology.

All of the patients enrolled in the MM-003 trial had received at least two prior therapies and had disease refractory to their last therapy, according to Dr. Weisel, a hematologist-oncologist with the University Hospital Tübingen, Germany. All had experienced a failure of both Millennium’s bortezomib (Velcade) and Celgene’s lenalidomide (Revlimid).

The patients were randomized 2:1 to receive low-dose dexamethasone plus Celgene’s pomalidomide (Pomalyst), an antiangiogenic and immune-modulating agent, or high-dose dexamethasone alone. Patients given pomalidomide or who had a history of deep vein thrombosis were given thromboprophylaxis.

Patients who experienced progression on high-dose dexamethasone entered the companion MM-003C trial, in which they were given pomalidomide.

Initial trial results after a median follow-up of 4 months, which were previously reported, showed there were significantly better progression-free survival and overall survival with the combination. These results led to a recommendation by the trial’s monitoring committee that all patients in the high-dose dexamethasone group be given access to pomalidomide regardless of whether they had progression. In all, half of the patients in that group received pomalidomide after high-dose dexamethasone due to either this recommendation or entry into the companion trial.

In the updated analysis, now with a median follow-up of 10 months, progression-free survival was still significantly better with pomalidomide plus low-dose dexamethasone than with high-dose dexamethasone (4.0 vs. 1.9 months; hazard ratio, 0.48; P less than .001).

Overall survival was also still significantly better with the combination (12.7 vs. 8.1 months; HR, 0.74; P = .028).

"This overall survival benefit was maintained despite a high crossover rate, in 50% of the patients. ... In addition, all patients who were still alive at this time in the high-dose dexamethasone group had received pomalidomide as a salvage treatment," Dr. Weisel noted.

The progression-free survival and overall survival benefits were generally similar across subgroups of patients whose disease was refractory to both lenalidomide and bortezomib, who had received lenalidomide as their last prior therapy, and who had received bortezomib as their last prior therapy.

"The safety profile of pomalidomide is predictable and manageable, and the drug with its oral application is generally well tolerated in this heavily pretreated patient group," Dr. Weisel commented.

The main toxicity with the combination was hematologic toxicity: The rate of grade 3/4 neutropenia was 48% with the combination, compared with 16% with high-dose dexamethasone. The combination group and the high-dose dexamethasone group had essentially the same rates of grade 3/4 deep vein thrombosis and pulmonary embolism (1% and 0%, respectively), peripheral neuropathy (1% and 1%), and discontinuation due to adverse events (9% and 10%).

Dr. Weisel disclosed that she is a consultant to and receives honoraria from Celgene and Janssen.

CHICAGO – The combination of pomalidomide and low-dose dexamethasone is superior to high-dose dexamethasone monotherapy for treating patients with relapsed and refractory multiple myeloma, based on updated results from the multicenter, randomized MM-003 trial.

Among the 455 patients studied in the trial, those assigned to the combination therapy had a 52% lower risk of progression or death and a 26% lower risk of death alone when compared with peers assigned to single-agent high-dose dexamethasone.

The two regimens had much the same toxicity profile, although the combination was associated with a higher rate of grade 3/4 hematologic toxicity.

"Pomalidomide in combination with low-dose dexamethasone should be considered as a new standard of care for treatment of relapsed and refractory multiple myeloma patients after treatment with lenalidomide and bortezomib," presenting author Dr. Katja C. Weisel commented at the annual meeting of the American Society of Clinical Oncology.

All of the patients enrolled in the MM-003 trial had received at least two prior therapies and had disease refractory to their last therapy, according to Dr. Weisel, a hematologist-oncologist with the University Hospital Tübingen, Germany. All had experienced a failure of both Millennium’s bortezomib (Velcade) and Celgene’s lenalidomide (Revlimid).

The patients were randomized 2:1 to receive low-dose dexamethasone plus Celgene’s pomalidomide (Pomalyst), an antiangiogenic and immune-modulating agent, or high-dose dexamethasone alone. Patients given pomalidomide or who had a history of deep vein thrombosis were given thromboprophylaxis.

Patients who experienced progression on high-dose dexamethasone entered the companion MM-003C trial, in which they were given pomalidomide.

Initial trial results after a median follow-up of 4 months, which were previously reported, showed there were significantly better progression-free survival and overall survival with the combination. These results led to a recommendation by the trial’s monitoring committee that all patients in the high-dose dexamethasone group be given access to pomalidomide regardless of whether they had progression. In all, half of the patients in that group received pomalidomide after high-dose dexamethasone due to either this recommendation or entry into the companion trial.

In the updated analysis, now with a median follow-up of 10 months, progression-free survival was still significantly better with pomalidomide plus low-dose dexamethasone than with high-dose dexamethasone (4.0 vs. 1.9 months; hazard ratio, 0.48; P less than .001).

Overall survival was also still significantly better with the combination (12.7 vs. 8.1 months; HR, 0.74; P = .028).

"This overall survival benefit was maintained despite a high crossover rate, in 50% of the patients. ... In addition, all patients who were still alive at this time in the high-dose dexamethasone group had received pomalidomide as a salvage treatment," Dr. Weisel noted.

The progression-free survival and overall survival benefits were generally similar across subgroups of patients whose disease was refractory to both lenalidomide and bortezomib, who had received lenalidomide as their last prior therapy, and who had received bortezomib as their last prior therapy.

"The safety profile of pomalidomide is predictable and manageable, and the drug with its oral application is generally well tolerated in this heavily pretreated patient group," Dr. Weisel commented.

The main toxicity with the combination was hematologic toxicity: The rate of grade 3/4 neutropenia was 48% with the combination, compared with 16% with high-dose dexamethasone. The combination group and the high-dose dexamethasone group had essentially the same rates of grade 3/4 deep vein thrombosis and pulmonary embolism (1% and 0%, respectively), peripheral neuropathy (1% and 1%), and discontinuation due to adverse events (9% and 10%).

Dr. Weisel disclosed that she is a consultant to and receives honoraria from Celgene and Janssen.

CHICAGO – The combination of pomalidomide and low-dose dexamethasone is superior to high-dose dexamethasone monotherapy for treating patients with relapsed and refractory multiple myeloma, based on updated results from the multicenter, randomized MM-003 trial.

Among the 455 patients studied in the trial, those assigned to the combination therapy had a 52% lower risk of progression or death and a 26% lower risk of death alone when compared with peers assigned to single-agent high-dose dexamethasone.

The two regimens had much the same toxicity profile, although the combination was associated with a higher rate of grade 3/4 hematologic toxicity.

"Pomalidomide in combination with low-dose dexamethasone should be considered as a new standard of care for treatment of relapsed and refractory multiple myeloma patients after treatment with lenalidomide and bortezomib," presenting author Dr. Katja C. Weisel commented at the annual meeting of the American Society of Clinical Oncology.

All of the patients enrolled in the MM-003 trial had received at least two prior therapies and had disease refractory to their last therapy, according to Dr. Weisel, a hematologist-oncologist with the University Hospital Tübingen, Germany. All had experienced a failure of both Millennium’s bortezomib (Velcade) and Celgene’s lenalidomide (Revlimid).

The patients were randomized 2:1 to receive low-dose dexamethasone plus Celgene’s pomalidomide (Pomalyst), an antiangiogenic and immune-modulating agent, or high-dose dexamethasone alone. Patients given pomalidomide or who had a history of deep vein thrombosis were given thromboprophylaxis.

Patients who experienced progression on high-dose dexamethasone entered the companion MM-003C trial, in which they were given pomalidomide.

Initial trial results after a median follow-up of 4 months, which were previously reported, showed there were significantly better progression-free survival and overall survival with the combination. These results led to a recommendation by the trial’s monitoring committee that all patients in the high-dose dexamethasone group be given access to pomalidomide regardless of whether they had progression. In all, half of the patients in that group received pomalidomide after high-dose dexamethasone due to either this recommendation or entry into the companion trial.

In the updated analysis, now with a median follow-up of 10 months, progression-free survival was still significantly better with pomalidomide plus low-dose dexamethasone than with high-dose dexamethasone (4.0 vs. 1.9 months; hazard ratio, 0.48; P less than .001).

Overall survival was also still significantly better with the combination (12.7 vs. 8.1 months; HR, 0.74; P = .028).

"This overall survival benefit was maintained despite a high crossover rate, in 50% of the patients. ... In addition, all patients who were still alive at this time in the high-dose dexamethasone group had received pomalidomide as a salvage treatment," Dr. Weisel noted.

The progression-free survival and overall survival benefits were generally similar across subgroups of patients whose disease was refractory to both lenalidomide and bortezomib, who had received lenalidomide as their last prior therapy, and who had received bortezomib as their last prior therapy.

"The safety profile of pomalidomide is predictable and manageable, and the drug with its oral application is generally well tolerated in this heavily pretreated patient group," Dr. Weisel commented.

The main toxicity with the combination was hematologic toxicity: The rate of grade 3/4 neutropenia was 48% with the combination, compared with 16% with high-dose dexamethasone. The combination group and the high-dose dexamethasone group had essentially the same rates of grade 3/4 deep vein thrombosis and pulmonary embolism (1% and 0%, respectively), peripheral neuropathy (1% and 1%), and discontinuation due to adverse events (9% and 10%).

Dr. Weisel disclosed that she is a consultant to and receives honoraria from Celgene and Janssen.

PHOENIX – Two differing surgical approaches for early rectal cancer – radical resection and local resection—appear to be essentially equivalent treatment options, finds a systematic review and meta-analysis.

The conclusion is based on an analysis of morbidity and mortality data from 13 studies with a total of 2,855 patients with stage T1N0M0 rectal adenocarcinoma. All of the studies were published after 1979, when total mesorectal excision and modern local resection techniques were being used.

There are "improved results with the newer techniques of TEMS [transanal endoscopic microsurgery] and TAMIS [transanal minimally invasive surgery], as well as comparable outcomes when we adjust for the fact that there is a bit of a selection bias in the literature for lower-third lesions to be performed by local resection," lead investigator Dr. Sami A. Chadi reported at the annual meeting of the American Society of Colon and Rectal Surgeons.

"We know that quality of life data is better with local resection," he commented. Relative to radical resection, local resection was associated with an 87% lower risk of postoperative complications, a 69% lower risk of perioperative mortality, and an 83% lower risk of permanent ostomy.

On the other hand, local resection also was associated with a 46% higher likelihood of death at 5 years. Survival no longer differed significantly, however, when analyses took into account the greater use of local resection for cancers located in the lower third of the rectum.

"The implication is that we have established clinical equipoise between groups with T1N0M0 adenocarcinoma of the rectum, thus prompting the need for a prospective randomized, controlled trial on these two procedures," he maintained. "We do need further data to assess whether or not there is a role for neoadjuvant or adjuvant therapy in these groups." Ongoing studies are assessing the role of therapy, as well as the potential for local resection to be performed for T2 lesions.

Dr. Chadi, a surgeon with the University of Western Ontario in London, and his colleagues analyzed data from 12 observational studies and one randomized, controlled trial among patients with T1N0M0 cancer.

The 5-year rate of overall survival was poorer with local resection (relative risk, 1.46), with the difference between groups corresponding to 72 more deaths per 1,000 patients in the local resection group, according to Dr. Chadi, who disclosed no conflicts of interest related to the research.

However, this difference was largely driven by transanal excision (TAE) local procedures. There was no significant difference in this outcome for TEMS local procedures as compared with radical resection.

The researchers also repeated the survival analysis with an adjustment for cancers in the lower third of the rectum. In these patients, the surgical choice is more often local resection, potentially leading to selection bias.

When the ratio of lower-third cancers was equal in both the radical and local resection groups, there was no longer a significant difference in 5-year overall survival.

Compared with radical resection, local resection yielded a lower risk of postoperative complications (rate ratio, 0.13), with the difference corresponding to 129 fewer complications per 1,000 patients in the local resection group. The difference was significant for both TAE and TEMS individually as compared with radical resection.

Local resection also was associated with a lower risk of perioperative mortality (rate ratio, 0.31), with the difference corresponding to 11 fewer deaths per 1,000 patients in the local resection group, and a lower risk of permanent ostomy (risk ratio, 0.17), with the difference corresponding to 225 fewer permanent ostomies per 1,000 patients in the local resection group.

PHOENIX – Two differing surgical approaches for early rectal cancer – radical resection and local resection—appear to be essentially equivalent treatment options, finds a systematic review and meta-analysis.

The conclusion is based on an analysis of morbidity and mortality data from 13 studies with a total of 2,855 patients with stage T1N0M0 rectal adenocarcinoma. All of the studies were published after 1979, when total mesorectal excision and modern local resection techniques were being used.

There are "improved results with the newer techniques of TEMS [transanal endoscopic microsurgery] and TAMIS [transanal minimally invasive surgery], as well as comparable outcomes when we adjust for the fact that there is a bit of a selection bias in the literature for lower-third lesions to be performed by local resection," lead investigator Dr. Sami A. Chadi reported at the annual meeting of the American Society of Colon and Rectal Surgeons.

"We know that quality of life data is better with local resection," he commented. Relative to radical resection, local resection was associated with an 87% lower risk of postoperative complications, a 69% lower risk of perioperative mortality, and an 83% lower risk of permanent ostomy.

On the other hand, local resection also was associated with a 46% higher likelihood of death at 5 years. Survival no longer differed significantly, however, when analyses took into account the greater use of local resection for cancers located in the lower third of the rectum.

"The implication is that we have established clinical equipoise between groups with T1N0M0 adenocarcinoma of the rectum, thus prompting the need for a prospective randomized, controlled trial on these two procedures," he maintained. "We do need further data to assess whether or not there is a role for neoadjuvant or adjuvant therapy in these groups." Ongoing studies are assessing the role of therapy, as well as the potential for local resection to be performed for T2 lesions.

Dr. Chadi, a surgeon with the University of Western Ontario in London, and his colleagues analyzed data from 12 observational studies and one randomized, controlled trial among patients with T1N0M0 cancer.

The 5-year rate of overall survival was poorer with local resection (relative risk, 1.46), with the difference between groups corresponding to 72 more deaths per 1,000 patients in the local resection group, according to Dr. Chadi, who disclosed no conflicts of interest related to the research.

However, this difference was largely driven by transanal excision (TAE) local procedures. There was no significant difference in this outcome for TEMS local procedures as compared with radical resection.

The researchers also repeated the survival analysis with an adjustment for cancers in the lower third of the rectum. In these patients, the surgical choice is more often local resection, potentially leading to selection bias.

When the ratio of lower-third cancers was equal in both the radical and local resection groups, there was no longer a significant difference in 5-year overall survival.

Compared with radical resection, local resection yielded a lower risk of postoperative complications (rate ratio, 0.13), with the difference corresponding to 129 fewer complications per 1,000 patients in the local resection group. The difference was significant for both TAE and TEMS individually as compared with radical resection.

Local resection also was associated with a lower risk of perioperative mortality (rate ratio, 0.31), with the difference corresponding to 11 fewer deaths per 1,000 patients in the local resection group, and a lower risk of permanent ostomy (risk ratio, 0.17), with the difference corresponding to 225 fewer permanent ostomies per 1,000 patients in the local resection group.

PHOENIX – Two differing surgical approaches for early rectal cancer – radical resection and local resection—appear to be essentially equivalent treatment options, finds a systematic review and meta-analysis.

The conclusion is based on an analysis of morbidity and mortality data from 13 studies with a total of 2,855 patients with stage T1N0M0 rectal adenocarcinoma. All of the studies were published after 1979, when total mesorectal excision and modern local resection techniques were being used.

There are "improved results with the newer techniques of TEMS [transanal endoscopic microsurgery] and TAMIS [transanal minimally invasive surgery], as well as comparable outcomes when we adjust for the fact that there is a bit of a selection bias in the literature for lower-third lesions to be performed by local resection," lead investigator Dr. Sami A. Chadi reported at the annual meeting of the American Society of Colon and Rectal Surgeons.

"We know that quality of life data is better with local resection," he commented. Relative to radical resection, local resection was associated with an 87% lower risk of postoperative complications, a 69% lower risk of perioperative mortality, and an 83% lower risk of permanent ostomy.

On the other hand, local resection also was associated with a 46% higher likelihood of death at 5 years. Survival no longer differed significantly, however, when analyses took into account the greater use of local resection for cancers located in the lower third of the rectum.

"The implication is that we have established clinical equipoise between groups with T1N0M0 adenocarcinoma of the rectum, thus prompting the need for a prospective randomized, controlled trial on these two procedures," he maintained. "We do need further data to assess whether or not there is a role for neoadjuvant or adjuvant therapy in these groups." Ongoing studies are assessing the role of therapy, as well as the potential for local resection to be performed for T2 lesions.

Dr. Chadi, a surgeon with the University of Western Ontario in London, and his colleagues analyzed data from 12 observational studies and one randomized, controlled trial among patients with T1N0M0 cancer.

The 5-year rate of overall survival was poorer with local resection (relative risk, 1.46), with the difference between groups corresponding to 72 more deaths per 1,000 patients in the local resection group, according to Dr. Chadi, who disclosed no conflicts of interest related to the research.

However, this difference was largely driven by transanal excision (TAE) local procedures. There was no significant difference in this outcome for TEMS local procedures as compared with radical resection.

The researchers also repeated the survival analysis with an adjustment for cancers in the lower third of the rectum. In these patients, the surgical choice is more often local resection, potentially leading to selection bias.

When the ratio of lower-third cancers was equal in both the radical and local resection groups, there was no longer a significant difference in 5-year overall survival.

Compared with radical resection, local resection yielded a lower risk of postoperative complications (rate ratio, 0.13), with the difference corresponding to 129 fewer complications per 1,000 patients in the local resection group. The difference was significant for both TAE and TEMS individually as compared with radical resection.

Local resection also was associated with a lower risk of perioperative mortality (rate ratio, 0.31), with the difference corresponding to 11 fewer deaths per 1,000 patients in the local resection group, and a lower risk of permanent ostomy (risk ratio, 0.17), with the difference corresponding to 225 fewer permanent ostomies per 1,000 patients in the local resection group.

CHICAGO – Patients with advanced ovarian cancer may now have a less toxic but acceptably efficacious option when it comes to first-line chemotherapy, based on the final results of the Multicenter Italian Trials in Ovarian Cancer collaborative group’s trial 7 (MITO-7).

A total of 822 women were randomized to receive either the standard every-3-week regimen of chemotherapy – carboplatin with area under the curve (AUC 6) plus paclitaxel 175 mg/m² on day 1 every 21 days for six cycles – or to get a weekly regimen – carboplatin AUC 2 plus paclitaxel 60 mg/m² weekly for 18 administrations.

Trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that the weekly group did not have better progression-free or overall survival than did the group treated once every 3 weeks. But the weekly group did have lower rates of toxicities such as alopecia, neuropathy, and febrile neutropenia, as well as a better quality of life.

"Given the observed confidence intervals of progression-free survival, MITO-7 quality of life and toxicity data further support the use of a weekly schedule as first-line therapy for advanced ovarian cancer," commented lead investigator Dr. Sandro Pignata, a urogynecologist with Italy’s National Cancer Institute in Naples.

The patients studied by Dr. Pignata’s team had FIGO stage IC to IV ovarian, fallopian tube, or primary peritoneal cancer and had not previously received chemotherapy. Most were treated on the Italian MITO-7 trial, although some were treated on the Italian MANGO trial or the French ARCAGY GINECO trial.

The proportion receiving all planned cycles of chemotherapy was 85% in the weekly group and 91% in the 3-weekly group, he reported.

With a median follow-up of 19.9 months, the rate of progression-free survival was 18.8 months and 16.5 months, respectively, a nonsignificant difference. The findings were the same in subgroup analyses. There was also no significant difference in overall survival.

Quality of life measured with the FACT-O TOI (Functional Assessment of Cancer Therapy, for ovarian cancer, Trial Outcome Index) during the first 9 weeks of therapy (the trial’s other primary endpoint) was significantly better in the weekly treatment group.

With the weekly regimen, scores worsened slightly 1 week after the first administration but remained stable thereafter, according to Dr. Pignata. In contrast, with the 3-weekly regimen, scores worsened 1 week after each course of chemotherapy.

In terms of adverse events, the weekly group had significantly lower rates of grade 3 or worse neutropenia (39% vs. 50%), febrile neutropenia (less than 1% vs. 3%), thrombocytopenia (1% vs. 7%), and renal toxicity (0% vs. 2%); grade 2 alopecia (28% vs. 58%); and grade 2 or higher neuropathy (6% vs. 16%).

"The rate of severe allergic reaction or any-grade allergic reaction was not statistically significantly different," he pointed out. Also, "I want to underline that a significant proportion of patients treated with this weekly regimen...completed 18 weeks of therapy without losing their hair."

Dr. Pignata disclosed no relevant conflicts of interest.

CHICAGO – Patients with advanced ovarian cancer may now have a less toxic but acceptably efficacious option when it comes to first-line chemotherapy, based on the final results of the Multicenter Italian Trials in Ovarian Cancer collaborative group’s trial 7 (MITO-7).

A total of 822 women were randomized to receive either the standard every-3-week regimen of chemotherapy – carboplatin with area under the curve (AUC 6) plus paclitaxel 175 mg/m² on day 1 every 21 days for six cycles – or to get a weekly regimen – carboplatin AUC 2 plus paclitaxel 60 mg/m² weekly for 18 administrations.

Trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that the weekly group did not have better progression-free or overall survival than did the group treated once every 3 weeks. But the weekly group did have lower rates of toxicities such as alopecia, neuropathy, and febrile neutropenia, as well as a better quality of life.

"Given the observed confidence intervals of progression-free survival, MITO-7 quality of life and toxicity data further support the use of a weekly schedule as first-line therapy for advanced ovarian cancer," commented lead investigator Dr. Sandro Pignata, a urogynecologist with Italy’s National Cancer Institute in Naples.

The patients studied by Dr. Pignata’s team had FIGO stage IC to IV ovarian, fallopian tube, or primary peritoneal cancer and had not previously received chemotherapy. Most were treated on the Italian MITO-7 trial, although some were treated on the Italian MANGO trial or the French ARCAGY GINECO trial.

The proportion receiving all planned cycles of chemotherapy was 85% in the weekly group and 91% in the 3-weekly group, he reported.

With a median follow-up of 19.9 months, the rate of progression-free survival was 18.8 months and 16.5 months, respectively, a nonsignificant difference. The findings were the same in subgroup analyses. There was also no significant difference in overall survival.

Quality of life measured with the FACT-O TOI (Functional Assessment of Cancer Therapy, for ovarian cancer, Trial Outcome Index) during the first 9 weeks of therapy (the trial’s other primary endpoint) was significantly better in the weekly treatment group.

With the weekly regimen, scores worsened slightly 1 week after the first administration but remained stable thereafter, according to Dr. Pignata. In contrast, with the 3-weekly regimen, scores worsened 1 week after each course of chemotherapy.

In terms of adverse events, the weekly group had significantly lower rates of grade 3 or worse neutropenia (39% vs. 50%), febrile neutropenia (less than 1% vs. 3%), thrombocytopenia (1% vs. 7%), and renal toxicity (0% vs. 2%); grade 2 alopecia (28% vs. 58%); and grade 2 or higher neuropathy (6% vs. 16%).

"The rate of severe allergic reaction or any-grade allergic reaction was not statistically significantly different," he pointed out. Also, "I want to underline that a significant proportion of patients treated with this weekly regimen...completed 18 weeks of therapy without losing their hair."

Dr. Pignata disclosed no relevant conflicts of interest.

CHICAGO – Patients with advanced ovarian cancer may now have a less toxic but acceptably efficacious option when it comes to first-line chemotherapy, based on the final results of the Multicenter Italian Trials in Ovarian Cancer collaborative group’s trial 7 (MITO-7).

A total of 822 women were randomized to receive either the standard every-3-week regimen of chemotherapy – carboplatin with area under the curve (AUC 6) plus paclitaxel 175 mg/m² on day 1 every 21 days for six cycles – or to get a weekly regimen – carboplatin AUC 2 plus paclitaxel 60 mg/m² weekly for 18 administrations.

Trial results, reported at the annual meeting of the American Society of Clinical Oncology, showed that the weekly group did not have better progression-free or overall survival than did the group treated once every 3 weeks. But the weekly group did have lower rates of toxicities such as alopecia, neuropathy, and febrile neutropenia, as well as a better quality of life.

"Given the observed confidence intervals of progression-free survival, MITO-7 quality of life and toxicity data further support the use of a weekly schedule as first-line therapy for advanced ovarian cancer," commented lead investigator Dr. Sandro Pignata, a urogynecologist with Italy’s National Cancer Institute in Naples.

The patients studied by Dr. Pignata’s team had FIGO stage IC to IV ovarian, fallopian tube, or primary peritoneal cancer and had not previously received chemotherapy. Most were treated on the Italian MITO-7 trial, although some were treated on the Italian MANGO trial or the French ARCAGY GINECO trial.

The proportion receiving all planned cycles of chemotherapy was 85% in the weekly group and 91% in the 3-weekly group, he reported.

With a median follow-up of 19.9 months, the rate of progression-free survival was 18.8 months and 16.5 months, respectively, a nonsignificant difference. The findings were the same in subgroup analyses. There was also no significant difference in overall survival.

Quality of life measured with the FACT-O TOI (Functional Assessment of Cancer Therapy, for ovarian cancer, Trial Outcome Index) during the first 9 weeks of therapy (the trial’s other primary endpoint) was significantly better in the weekly treatment group.

With the weekly regimen, scores worsened slightly 1 week after the first administration but remained stable thereafter, according to Dr. Pignata. In contrast, with the 3-weekly regimen, scores worsened 1 week after each course of chemotherapy.

In terms of adverse events, the weekly group had significantly lower rates of grade 3 or worse neutropenia (39% vs. 50%), febrile neutropenia (less than 1% vs. 3%), thrombocytopenia (1% vs. 7%), and renal toxicity (0% vs. 2%); grade 2 alopecia (28% vs. 58%); and grade 2 or higher neuropathy (6% vs. 16%).

"The rate of severe allergic reaction or any-grade allergic reaction was not statistically significantly different," he pointed out. Also, "I want to underline that a significant proportion of patients treated with this weekly regimen...completed 18 weeks of therapy without losing their hair."

Dr. Pignata disclosed no relevant conflicts of interest.

PHOENIX – Patients with inflammatory bowel disease undergoing major abdominal surgery have a persistent elevation of the risk of blood clots postoperatively that warrants extended prophylaxis similar to that recommended for patients with colorectal cancer, new data suggest.

Investigators led by Dr. Molly Gross, a colorectal surgeon at the University of Utah in Salt Lake City, retrospectively analyzed data from the National Surgical Quality Improvement Program (NSQIP) database, assessing rates of venous thromboembolism (VTE) among nearly 46,000 patients with inflammatory bowel disease (IBD) or colorectal cancer who had major abdominal surgery.

Study results, reported at the annual meeting of the American Society of Colon and Rectal Surgeons, showed that the IBD group had a 35% higher adjusted risk of VTE at 30 days relative to the colorectal cancer group. Also, the majority of the events in the IBD group occurred a week or more after surgery, by which time most patients would have been leaving the hospital or already home.

"The National Comprehensive Cancer Network (NCCN) currently recommends that colorectal cancer patients undergoing major abdominal surgery receive up to 4 weeks of postoperative out-of-hospital prophylaxis with either subcutaneous heparin or Lovenox [enoxaparin]," Dr. Gross commented. "There are currently no such recommendations for IBD patients undergoing similar operations."

Taken together, the study’s findings "lead to our conclusion that postdischarge VTE prophylaxis recommendations for IBD patients should mirror those for colorectal cancer patients," she maintained. "This would suggest a change in clinical practice to extend out-of-hospital VTE prophylaxis in IBD patients."

"You have done excellent work, and I congratulate you on the statistical rigor that’s quite evident in your study," said Dr. Justin Lee, of St. Elizabeth’s Medical Center in Brighton, Mass., who was invited to discuss the study.

However, he questioned the low absolute 30-day rates of VTE seen in the study – 2.7% in the IBD group and 2.1% in the colorectal cancer group – as compared with those reported in other studies.

The NCCN guidelines for patients with colorectal cancer "are based on large prospective studies considered to be closer to real-time data than NSQIP. If you look at those studies, they show anywhere from a 7% to 12% 30-day rate of deep vein thrombosis in colorectal cancer patients. And if you treat them with long-term prophylaxis within 30 days after surgery, it brings the rate down to 4% or 4.5%," he explained – about twice that in the presented study.

"How do you reconcile [these rates]?" Dr. Lee asked. "And should you apply your recommended 30-day postop prophylaxis to all IBD surgical patients when in fact the 2.7% is actually lower than the literature-quoted rate of deep vein thrombosis" in patients with colorectal cancer on anticoagulation?

Dr. Gross speculated that the difference in rates between the cancer studies and the current study was multifactorial in origin, stemming from differing study designs (randomized controlled trial vs. retrospective review), differing surgical populations (patients undergoing open surgery only in an older era vs. patients undergoing open or laparoscopic surgery in the current era), and uncertainty in their study about how many patients with colorectal cancer received extended prophylaxis.

Given the generally low rates of VTE events, "it would be difficult to adequately power a large randomized controlled trial," she added. "So we are kind of making a lot of assumptions that we hope we could decrease morbidity and mortality in IBD patients without significantly causing increased cost or bleeding complications" by using extended prophylaxis.

Dr. John Migaly of the Duke University Medical Center in Durham, N.C., who comoderated the session, noted that the incidence of VTE after surgery showed a sharp drop-off at approximately day 20. "That would be about 2 weeks after discharge. Is there an optimal length, in your opinion, of VTE prophylaxis, instead of just saying 4 weeks is fine?" he asked.

The investigators based that 4-week recommendation on the conclusions of a trial among oncology patients (N. Engl. J. Med. 2002;346:975-80), according to Dr. Gross. "It is probably variable based on patient condition: how much they are ambulating, how much they are back to their regular status, and how active their IBD is. So I think it would be difficult to come up with an ideal for every patient; that [4 weeks] is an arbitrary number created from that study."

For the study, Dr. Gross’ team analyzed data from the NSQIP database for the years 2005 through 2010, restricting analyses to 8,888 patients with IBD and 37,076 patients with colorectal cancer who had major abdominal surgery.

"Previous studies looking at IBD and VTE risk included perineal and benign anorectal procedures, as well as open procedures," Dr. Gross noted. "But we only included open and laparoscopic abdominal procedures that involved resection of bowel."

The 30-day rate of VTE (deep vein thrombosis and/or pulmonary embolism) was significantly higher in the IBD group than in the colorectal cancer group (2.7% vs. 2.1%, P less than .001).

In a multivariate analysis, relative to their peers with colorectal cancer, patients with IBD still had a significantly elevated risk of this outcome (odds ratio, 1.35; P = .005).

"The [temporal] distribution of VTE events in IBD patients mirrors that in colorectal cancer patients," commented Dr. Gross, who disclosed no conflicts of interest related to the research; in both groups, events continued to occur out to 30 days.

In the IBD group, fully 55% of events occurred on day 7 or later. "At this time, most patients will have been discharged or will be discharged soon," she pointed out.

PHOENIX – Patients with inflammatory bowel disease undergoing major abdominal surgery have a persistent elevation of the risk of blood clots postoperatively that warrants extended prophylaxis similar to that recommended for patients with colorectal cancer, new data suggest.

Investigators led by Dr. Molly Gross, a colorectal surgeon at the University of Utah in Salt Lake City, retrospectively analyzed data from the National Surgical Quality Improvement Program (NSQIP) database, assessing rates of venous thromboembolism (VTE) among nearly 46,000 patients with inflammatory bowel disease (IBD) or colorectal cancer who had major abdominal surgery.

Study results, reported at the annual meeting of the American Society of Colon and Rectal Surgeons, showed that the IBD group had a 35% higher adjusted risk of VTE at 30 days relative to the colorectal cancer group. Also, the majority of the events in the IBD group occurred a week or more after surgery, by which time most patients would have been leaving the hospital or already home.

"The National Comprehensive Cancer Network (NCCN) currently recommends that colorectal cancer patients undergoing major abdominal surgery receive up to 4 weeks of postoperative out-of-hospital prophylaxis with either subcutaneous heparin or Lovenox [enoxaparin]," Dr. Gross commented. "There are currently no such recommendations for IBD patients undergoing similar operations."

Taken together, the study’s findings "lead to our conclusion that postdischarge VTE prophylaxis recommendations for IBD patients should mirror those for colorectal cancer patients," she maintained. "This would suggest a change in clinical practice to extend out-of-hospital VTE prophylaxis in IBD patients."

"You have done excellent work, and I congratulate you on the statistical rigor that’s quite evident in your study," said Dr. Justin Lee, of St. Elizabeth’s Medical Center in Brighton, Mass., who was invited to discuss the study.

However, he questioned the low absolute 30-day rates of VTE seen in the study – 2.7% in the IBD group and 2.1% in the colorectal cancer group – as compared with those reported in other studies.

The NCCN guidelines for patients with colorectal cancer "are based on large prospective studies considered to be closer to real-time data than NSQIP. If you look at those studies, they show anywhere from a 7% to 12% 30-day rate of deep vein thrombosis in colorectal cancer patients. And if you treat them with long-term prophylaxis within 30 days after surgery, it brings the rate down to 4% or 4.5%," he explained – about twice that in the presented study.

"How do you reconcile [these rates]?" Dr. Lee asked. "And should you apply your recommended 30-day postop prophylaxis to all IBD surgical patients when in fact the 2.7% is actually lower than the literature-quoted rate of deep vein thrombosis" in patients with colorectal cancer on anticoagulation?

Dr. Gross speculated that the difference in rates between the cancer studies and the current study was multifactorial in origin, stemming from differing study designs (randomized controlled trial vs. retrospective review), differing surgical populations (patients undergoing open surgery only in an older era vs. patients undergoing open or laparoscopic surgery in the current era), and uncertainty in their study about how many patients with colorectal cancer received extended prophylaxis.

Given the generally low rates of VTE events, "it would be difficult to adequately power a large randomized controlled trial," she added. "So we are kind of making a lot of assumptions that we hope we could decrease morbidity and mortality in IBD patients without significantly causing increased cost or bleeding complications" by using extended prophylaxis.

Dr. John Migaly of the Duke University Medical Center in Durham, N.C., who comoderated the session, noted that the incidence of VTE after surgery showed a sharp drop-off at approximately day 20. "That would be about 2 weeks after discharge. Is there an optimal length, in your opinion, of VTE prophylaxis, instead of just saying 4 weeks is fine?" he asked.

The investigators based that 4-week recommendation on the conclusions of a trial among oncology patients (N. Engl. J. Med. 2002;346:975-80), according to Dr. Gross. "It is probably variable based on patient condition: how much they are ambulating, how much they are back to their regular status, and how active their IBD is. So I think it would be difficult to come up with an ideal for every patient; that [4 weeks] is an arbitrary number created from that study."

For the study, Dr. Gross’ team analyzed data from the NSQIP database for the years 2005 through 2010, restricting analyses to 8,888 patients with IBD and 37,076 patients with colorectal cancer who had major abdominal surgery.

"Previous studies looking at IBD and VTE risk included perineal and benign anorectal procedures, as well as open procedures," Dr. Gross noted. "But we only included open and laparoscopic abdominal procedures that involved resection of bowel."

The 30-day rate of VTE (deep vein thrombosis and/or pulmonary embolism) was significantly higher in the IBD group than in the colorectal cancer group (2.7% vs. 2.1%, P less than .001).

In a multivariate analysis, relative to their peers with colorectal cancer, patients with IBD still had a significantly elevated risk of this outcome (odds ratio, 1.35; P = .005).

"The [temporal] distribution of VTE events in IBD patients mirrors that in colorectal cancer patients," commented Dr. Gross, who disclosed no conflicts of interest related to the research; in both groups, events continued to occur out to 30 days.

In the IBD group, fully 55% of events occurred on day 7 or later. "At this time, most patients will have been discharged or will be discharged soon," she pointed out.

PHOENIX – Patients with inflammatory bowel disease undergoing major abdominal surgery have a persistent elevation of the risk of blood clots postoperatively that warrants extended prophylaxis similar to that recommended for patients with colorectal cancer, new data suggest.

Investigators led by Dr. Molly Gross, a colorectal surgeon at the University of Utah in Salt Lake City, retrospectively analyzed data from the National Surgical Quality Improvement Program (NSQIP) database, assessing rates of venous thromboembolism (VTE) among nearly 46,000 patients with inflammatory bowel disease (IBD) or colorectal cancer who had major abdominal surgery.

Study results, reported at the annual meeting of the American Society of Colon and Rectal Surgeons, showed that the IBD group had a 35% higher adjusted risk of VTE at 30 days relative to the colorectal cancer group. Also, the majority of the events in the IBD group occurred a week or more after surgery, by which time most patients would have been leaving the hospital or already home.

"The National Comprehensive Cancer Network (NCCN) currently recommends that colorectal cancer patients undergoing major abdominal surgery receive up to 4 weeks of postoperative out-of-hospital prophylaxis with either subcutaneous heparin or Lovenox [enoxaparin]," Dr. Gross commented. "There are currently no such recommendations for IBD patients undergoing similar operations."

Taken together, the study’s findings "lead to our conclusion that postdischarge VTE prophylaxis recommendations for IBD patients should mirror those for colorectal cancer patients," she maintained. "This would suggest a change in clinical practice to extend out-of-hospital VTE prophylaxis in IBD patients."

"You have done excellent work, and I congratulate you on the statistical rigor that’s quite evident in your study," said Dr. Justin Lee, of St. Elizabeth’s Medical Center in Brighton, Mass., who was invited to discuss the study.

However, he questioned the low absolute 30-day rates of VTE seen in the study – 2.7% in the IBD group and 2.1% in the colorectal cancer group – as compared with those reported in other studies.

The NCCN guidelines for patients with colorectal cancer "are based on large prospective studies considered to be closer to real-time data than NSQIP. If you look at those studies, they show anywhere from a 7% to 12% 30-day rate of deep vein thrombosis in colorectal cancer patients. And if you treat them with long-term prophylaxis within 30 days after surgery, it brings the rate down to 4% or 4.5%," he explained – about twice that in the presented study.

"How do you reconcile [these rates]?" Dr. Lee asked. "And should you apply your recommended 30-day postop prophylaxis to all IBD surgical patients when in fact the 2.7% is actually lower than the literature-quoted rate of deep vein thrombosis" in patients with colorectal cancer on anticoagulation?

Dr. Gross speculated that the difference in rates between the cancer studies and the current study was multifactorial in origin, stemming from differing study designs (randomized controlled trial vs. retrospective review), differing surgical populations (patients undergoing open surgery only in an older era vs. patients undergoing open or laparoscopic surgery in the current era), and uncertainty in their study about how many patients with colorectal cancer received extended prophylaxis.

Given the generally low rates of VTE events, "it would be difficult to adequately power a large randomized controlled trial," she added. "So we are kind of making a lot of assumptions that we hope we could decrease morbidity and mortality in IBD patients without significantly causing increased cost or bleeding complications" by using extended prophylaxis.

Dr. John Migaly of the Duke University Medical Center in Durham, N.C., who comoderated the session, noted that the incidence of VTE after surgery showed a sharp drop-off at approximately day 20. "That would be about 2 weeks after discharge. Is there an optimal length, in your opinion, of VTE prophylaxis, instead of just saying 4 weeks is fine?" he asked.

The investigators based that 4-week recommendation on the conclusions of a trial among oncology patients (N. Engl. J. Med. 2002;346:975-80), according to Dr. Gross. "It is probably variable based on patient condition: how much they are ambulating, how much they are back to their regular status, and how active their IBD is. So I think it would be difficult to come up with an ideal for every patient; that [4 weeks] is an arbitrary number created from that study."

For the study, Dr. Gross’ team analyzed data from the NSQIP database for the years 2005 through 2010, restricting analyses to 8,888 patients with IBD and 37,076 patients with colorectal cancer who had major abdominal surgery.

"Previous studies looking at IBD and VTE risk included perineal and benign anorectal procedures, as well as open procedures," Dr. Gross noted. "But we only included open and laparoscopic abdominal procedures that involved resection of bowel."

The 30-day rate of VTE (deep vein thrombosis and/or pulmonary embolism) was significantly higher in the IBD group than in the colorectal cancer group (2.7% vs. 2.1%, P less than .001).

In a multivariate analysis, relative to their peers with colorectal cancer, patients with IBD still had a significantly elevated risk of this outcome (odds ratio, 1.35; P = .005).

"The [temporal] distribution of VTE events in IBD patients mirrors that in colorectal cancer patients," commented Dr. Gross, who disclosed no conflicts of interest related to the research; in both groups, events continued to occur out to 30 days.

In the IBD group, fully 55% of events occurred on day 7 or later. "At this time, most patients will have been discharged or will be discharged soon," she pointed out.

CHICAGO – In platinum-sensitive relapsed serous ovarian cancer patients, maintenance olaparib therapy was of most benefit among women with a BRCA mutation, based on results from a randomized phase II trial reported at the annual meeting of the American Society of Clinical Oncology.

The 265 women enrolled in the study had responded to platinum chemotherapy and were assigned evenly to olaparib – an investigational inhibitor of poly(ADP-ribose) polymerase (PARP) – or placebo for maintenance therapy.

Relative to placebo, olaparib reduced the risk of progression or death by a significant 82% (hazard ratio, 0.18) among patients with BRCA mutations and by a lesser but still significant 47% (HR, 0.53) in patients without BRCA mutations, reported first author Dr. Jonathan Ledermann, a professor of medical oncology in the UCL Cancer Institute, University College London.

There was also a greater carryover benefit of olaparib in the BRCA mutation–positive subset, in that they had a longer time to progression or death after the next therapy they received.

"As a result of these compelling data, phase III confirmatory trials are now starting in patients with BRCA mutations later this year," Dr. Lederman said.

Overall, 51% of patients enrolled in the trial, formally known as Study 19 and sponsored by AstraZeneca (the manufacturer of olaparib), had a known deleterious BRCA germline mutation or a BRCA mutation in their tumor.

The main results, previously published, showed that maintenance olaparib prolonged progression-free survival in the trial population overall, with a hazard ratio of 0.35 (N. Engl. J. Med. 2012;366:1382-92). There was no significant gain in overall survival as of an interim analysis, but there was a suggestion of benefit for patients with a BRCA mutation.

Among the BRCA mutation–positive subset, median progression-free survival was 11.2 months with olaparib versus 4.3 months with placebo (HR, 0.18; P less than .00001). Among the BRCA mutation–negative group, median progression-free survival was 5.6 months with olaparib versus 5.5 months with placebo (HR, 0.53; P less than .007).

There was still no overall survival advantage of olaparib in the trial population as a whole, but 23% of patients in the placebo group were switched to a PARP inhibitor. "This may be sufficient ... to actually have a confounding effect on the overall survival of these patients," Dr. Ledermann commented. There was a trend toward better overall survival with olaparib in the BRCA mutation–positive subset.

In addition, olaparib was superior to placebo in terms of the time from randomization to progression after a second, subsequent therapy, both among the BRCA mutation–positive subset (23.8 vs. 15.3 months; HR, 0.46; P less than .0003) and among the BRCA mutation–negative subset (17.1 vs. 14.7 months; HR, 0.64; P = .03).

"This I think translates into a clinically meaningful benefit, in that the effect if you like of olaparib is carried over beyond progression, to the time that they fail a second subsequent therapy," Dr. Ledermann said.

There was no significant difference in quality of life between the olaparib and placebo groups among women having a BRCA mutation.

Tolerability of olaparib did not differ significantly between women with the BRCA mutation–positive subset and the overall trial population. The leading adverse events in the former were low-grade nausea (seen in 73%) and fatigue (seen in 54%).

Dr. Ledermann disclosed that he receives travel grants from AstraZeneca. The trial was sponsored by AstraZeneca.

CHICAGO – In platinum-sensitive relapsed serous ovarian cancer patients, maintenance olaparib therapy was of most benefit among women with a BRCA mutation, based on results from a randomized phase II trial reported at the annual meeting of the American Society of Clinical Oncology.

The 265 women enrolled in the study had responded to platinum chemotherapy and were assigned evenly to olaparib – an investigational inhibitor of poly(ADP-ribose) polymerase (PARP) – or placebo for maintenance therapy.

Relative to placebo, olaparib reduced the risk of progression or death by a significant 82% (hazard ratio, 0.18) among patients with BRCA mutations and by a lesser but still significant 47% (HR, 0.53) in patients without BRCA mutations, reported first author Dr. Jonathan Ledermann, a professor of medical oncology in the UCL Cancer Institute, University College London.

There was also a greater carryover benefit of olaparib in the BRCA mutation–positive subset, in that they had a longer time to progression or death after the next therapy they received.

"As a result of these compelling data, phase III confirmatory trials are now starting in patients with BRCA mutations later this year," Dr. Lederman said.

Overall, 51% of patients enrolled in the trial, formally known as Study 19 and sponsored by AstraZeneca (the manufacturer of olaparib), had a known deleterious BRCA germline mutation or a BRCA mutation in their tumor.

The main results, previously published, showed that maintenance olaparib prolonged progression-free survival in the trial population overall, with a hazard ratio of 0.35 (N. Engl. J. Med. 2012;366:1382-92). There was no significant gain in overall survival as of an interim analysis, but there was a suggestion of benefit for patients with a BRCA mutation.

Among the BRCA mutation–positive subset, median progression-free survival was 11.2 months with olaparib versus 4.3 months with placebo (HR, 0.18; P less than .00001). Among the BRCA mutation–negative group, median progression-free survival was 5.6 months with olaparib versus 5.5 months with placebo (HR, 0.53; P less than .007).

There was still no overall survival advantage of olaparib in the trial population as a whole, but 23% of patients in the placebo group were switched to a PARP inhibitor. "This may be sufficient ... to actually have a confounding effect on the overall survival of these patients," Dr. Ledermann commented. There was a trend toward better overall survival with olaparib in the BRCA mutation–positive subset.

In addition, olaparib was superior to placebo in terms of the time from randomization to progression after a second, subsequent therapy, both among the BRCA mutation–positive subset (23.8 vs. 15.3 months; HR, 0.46; P less than .0003) and among the BRCA mutation–negative subset (17.1 vs. 14.7 months; HR, 0.64; P = .03).

"This I think translates into a clinically meaningful benefit, in that the effect if you like of olaparib is carried over beyond progression, to the time that they fail a second subsequent therapy," Dr. Ledermann said.

There was no significant difference in quality of life between the olaparib and placebo groups among women having a BRCA mutation.

Tolerability of olaparib did not differ significantly between women with the BRCA mutation–positive subset and the overall trial population. The leading adverse events in the former were low-grade nausea (seen in 73%) and fatigue (seen in 54%).

Dr. Ledermann disclosed that he receives travel grants from AstraZeneca. The trial was sponsored by AstraZeneca.

CHICAGO – In platinum-sensitive relapsed serous ovarian cancer patients, maintenance olaparib therapy was of most benefit among women with a BRCA mutation, based on results from a randomized phase II trial reported at the annual meeting of the American Society of Clinical Oncology.

The 265 women enrolled in the study had responded to platinum chemotherapy and were assigned evenly to olaparib – an investigational inhibitor of poly(ADP-ribose) polymerase (PARP) – or placebo for maintenance therapy.

Relative to placebo, olaparib reduced the risk of progression or death by a significant 82% (hazard ratio, 0.18) among patients with BRCA mutations and by a lesser but still significant 47% (HR, 0.53) in patients without BRCA mutations, reported first author Dr. Jonathan Ledermann, a professor of medical oncology in the UCL Cancer Institute, University College London.

There was also a greater carryover benefit of olaparib in the BRCA mutation–positive subset, in that they had a longer time to progression or death after the next therapy they received.

"As a result of these compelling data, phase III confirmatory trials are now starting in patients with BRCA mutations later this year," Dr. Lederman said.

Overall, 51% of patients enrolled in the trial, formally known as Study 19 and sponsored by AstraZeneca (the manufacturer of olaparib), had a known deleterious BRCA germline mutation or a BRCA mutation in their tumor.

The main results, previously published, showed that maintenance olaparib prolonged progression-free survival in the trial population overall, with a hazard ratio of 0.35 (N. Engl. J. Med. 2012;366:1382-92). There was no significant gain in overall survival as of an interim analysis, but there was a suggestion of benefit for patients with a BRCA mutation.

Among the BRCA mutation–positive subset, median progression-free survival was 11.2 months with olaparib versus 4.3 months with placebo (HR, 0.18; P less than .00001). Among the BRCA mutation–negative group, median progression-free survival was 5.6 months with olaparib versus 5.5 months with placebo (HR, 0.53; P less than .007).

There was still no overall survival advantage of olaparib in the trial population as a whole, but 23% of patients in the placebo group were switched to a PARP inhibitor. "This may be sufficient ... to actually have a confounding effect on the overall survival of these patients," Dr. Ledermann commented. There was a trend toward better overall survival with olaparib in the BRCA mutation–positive subset.

In addition, olaparib was superior to placebo in terms of the time from randomization to progression after a second, subsequent therapy, both among the BRCA mutation–positive subset (23.8 vs. 15.3 months; HR, 0.46; P less than .0003) and among the BRCA mutation–negative subset (17.1 vs. 14.7 months; HR, 0.64; P = .03).

"This I think translates into a clinically meaningful benefit, in that the effect if you like of olaparib is carried over beyond progression, to the time that they fail a second subsequent therapy," Dr. Ledermann said.

There was no significant difference in quality of life between the olaparib and placebo groups among women having a BRCA mutation.

Tolerability of olaparib did not differ significantly between women with the BRCA mutation–positive subset and the overall trial population. The leading adverse events in the former were low-grade nausea (seen in 73%) and fatigue (seen in 54%).

Dr. Ledermann disclosed that he receives travel grants from AstraZeneca. The trial was sponsored by AstraZeneca.

PHOENIX – The longer a laparoscopic colectomy for cancer takes, the less its advantages over an open colectomy in terms of morbidity and mortality, researchers reported at the annual meeting of the American Society of Colon and Rectal Surgeons.

A team led by Dr. Matthew Bailey, a surgery resident at the University of Kentucky in Lexington, queried the National Surgical Quality Improvement Program (NSQIP) database to identify more than 4,000 patients undergoing right colectomy because of colorectal malignancy.

Results showed that compared with their peers having an open operation lasting 3 hours or less, patients having a laparoscopic operation of this duration were less likely to develop complications and to die. However, when the operations lasted more than 3 hours, there was no longer any significant difference.

Within the laparoscopic group, patients were more likely to have a procedure lasting longer than 3 hours if they had recently received radiation therapy, were morbidly obese, or had peripheral vascular disease.

"We recommend that surgeons consider an open approach if the patient has risk factors for an operative duration greater than 3 hours," Dr. Bailey said. "We also recommend surgeons consider conversion to an open approach when it is anticipated that a laparoscopic right colectomy will exceed 3 hours."

Dr. Walter Peters of Columbia (Mo.) Surgical Associates, who comoderated the session, asked, "Were the laparoscopic procedures lasting more than 3 hours concentrated in a few institutions, or were they spread across the entire NSQIP database?"

The investigators did not assess the institutional distribution, and it may not be possible to tease that information out of NSQIP, Dr. Bailey replied.

Session attendee Dr. Eric Haas, of Colorectal Surgical Associates in Houston asked what percentage of patients had a conversion from laparoscopic to open procedures and whether analyses were conducted according to intention to treat.

"NSQIP unfortunately does not allow you to discern that, there’s no CPT [Current Procedural Terminology] code for conversion," Dr. Bailey said. "We can only assume that cases that were converted laparoscopic to open were most likely ultimately coded as open. So there was no way to perform an intent-to-treat analysis."

Dr. Haas also noted that surgeon experience with laparoscopy may have played a role. "In my own experience, certainly at the beginning of the learning curve phase, I would take 3, maybe 4 hours. And the one risk factor that you can’t put [in analyses] is surgeon," he said. "So were these 3-hour cases because of the learning curve, or were they true 3-hour cases because of the patient factors?"

The NSQIP database captures the surgeon who dictates the operative report and the level of training, the highest-level resident involved, and the specialty of the surgeon (although colorectal surgery is not among the options), according to Dr. Bailey. Still, it is generally not possible to determine who did all or most of the operation.

"We did look at operative time, and it was around 138 minutes, plus-minus, for a laparoscopic right colectomy, with the reported literature being around 187 minutes. So I’m not sure if the reported literature is dated or if, in these over 200 hospitals across the nation, this is realistic of current practice trends," he said.

"The study shows that patients are probably going to have increased complications with longer surgery, whether it’s laparoscopic or open," Dr. Timothy Geiger of Vanderbilt University Medical Center, Nashville, Tenn., the session’s other comoderator, said in an interview. "It was a good study, but it needs a little bit more in-depth look, especially at things like redosing of antibiotics, whether that is done in an appropriate manner. But otherwise, it’s a great kind of intro for us to look at this."

Giving some background to the research, Dr. Bailey noted, "The use of laparoscopy in colon cancer has been shown to be equivalent to open surgery in survival and oncologic outcomes. The question of whether operative time negatively impacts laparoscopic outcomes compared to open surgery outcomes requires further investigation if we are to endorse a laparoscopic approach regardless of procedure length. We postulated that there is an operative duration where the benefits of a laparoscopic approach are negated."

The investigators analyzed data from the NSQIP database for the years 2005 through 2010, identifying patients who had a right colectomy for cancer and excluding those treated on an emergent basis, or having secondary procedures other than enterolysis or mobilization of the splenic flexure.

Analyses were based on 2,141 patients in the laparoscopic group and 2,132 patients in the open group. Procedures lasted longer than 3 hours in 18% of the former and 11% of the latter.

Compared with the open group, the laparoscopic group was younger and had lower American Society of Anesthesiologists scores, higher serum albumin levels, and lower prothrombin time and platelet count.

In unadjusted analysis among patients whose operations lasted 3 hours or less, the laparoscopic group fared better than did the open group in terms of 30-day mortality (1.1% vs 2.6%, P less than .001), cardiopulmonary and cerebrovascular complications (5.4% vs. 8.4%, P less than .001), and infectious complications (9.2% vs. 13.3%, P less than .001).

In contrast, among patients whose operations lasted more than 3 hours, differences in these outcomes were not significant. If anything, there was a trend toward a higher rate of infectious complications with laparoscopy.

To assess the role of preoperative risk factors, the investigators looked at NSQIP estimates of morbidity and mortality for all gastrointestinal and abdominal surgery by operative duration and including 37 preoperative risk factors, and found patterns differing from those in the study cohort.

Specifically, these estimates suggested mortality was consistently lower for procedures lasting more then 3 hours, whether laparoscopic or open. And the risk of infectious complications was constant for each type and less for laparoscopy, regardless of the operative duration.

Thus, "there is something other than preoperative risk factors causing an increase in mortality" with longer operative time for laparoscopic procedures in the study cohort, said Dr. Bailey, who disclosed no conflicts of interest related to the research. Also, "the increased infectious complications that we demonstrated are not related to the morbidity risk."

Patients in the laparoscopic group had a significantly higher risk of surgery lasting more than 3 hours if they had recently received radiation therapy (odds ratio, 6.5), were morbidly obese (3.0), or had peripheral vascular disease (2.5).

Hospital length of stay was consistently shorter with the laparoscopic approach, regardless of how long the operation lasted, according to Dr. Bailey.

PHOENIX – The longer a laparoscopic colectomy for cancer takes, the less its advantages over an open colectomy in terms of morbidity and mortality, researchers reported at the annual meeting of the American Society of Colon and Rectal Surgeons.

A team led by Dr. Matthew Bailey, a surgery resident at the University of Kentucky in Lexington, queried the National Surgical Quality Improvement Program (NSQIP) database to identify more than 4,000 patients undergoing right colectomy because of colorectal malignancy.

Results showed that compared with their peers having an open operation lasting 3 hours or less, patients having a laparoscopic operation of this duration were less likely to develop complications and to die. However, when the operations lasted more than 3 hours, there was no longer any significant difference.

Within the laparoscopic group, patients were more likely to have a procedure lasting longer than 3 hours if they had recently received radiation therapy, were morbidly obese, or had peripheral vascular disease.

"We recommend that surgeons consider an open approach if the patient has risk factors for an operative duration greater than 3 hours," Dr. Bailey said. "We also recommend surgeons consider conversion to an open approach when it is anticipated that a laparoscopic right colectomy will exceed 3 hours."

Dr. Walter Peters of Columbia (Mo.) Surgical Associates, who comoderated the session, asked, "Were the laparoscopic procedures lasting more than 3 hours concentrated in a few institutions, or were they spread across the entire NSQIP database?"

The investigators did not assess the institutional distribution, and it may not be possible to tease that information out of NSQIP, Dr. Bailey replied.

Session attendee Dr. Eric Haas, of Colorectal Surgical Associates in Houston asked what percentage of patients had a conversion from laparoscopic to open procedures and whether analyses were conducted according to intention to treat.

"NSQIP unfortunately does not allow you to discern that, there’s no CPT [Current Procedural Terminology] code for conversion," Dr. Bailey said. "We can only assume that cases that were converted laparoscopic to open were most likely ultimately coded as open. So there was no way to perform an intent-to-treat analysis."

Dr. Haas also noted that surgeon experience with laparoscopy may have played a role. "In my own experience, certainly at the beginning of the learning curve phase, I would take 3, maybe 4 hours. And the one risk factor that you can’t put [in analyses] is surgeon," he said. "So were these 3-hour cases because of the learning curve, or were they true 3-hour cases because of the patient factors?"

The NSQIP database captures the surgeon who dictates the operative report and the level of training, the highest-level resident involved, and the specialty of the surgeon (although colorectal surgery is not among the options), according to Dr. Bailey. Still, it is generally not possible to determine who did all or most of the operation.

"We did look at operative time, and it was around 138 minutes, plus-minus, for a laparoscopic right colectomy, with the reported literature being around 187 minutes. So I’m not sure if the reported literature is dated or if, in these over 200 hospitals across the nation, this is realistic of current practice trends," he said.

"The study shows that patients are probably going to have increased complications with longer surgery, whether it’s laparoscopic or open," Dr. Timothy Geiger of Vanderbilt University Medical Center, Nashville, Tenn., the session’s other comoderator, said in an interview. "It was a good study, but it needs a little bit more in-depth look, especially at things like redosing of antibiotics, whether that is done in an appropriate manner. But otherwise, it’s a great kind of intro for us to look at this."

Giving some background to the research, Dr. Bailey noted, "The use of laparoscopy in colon cancer has been shown to be equivalent to open surgery in survival and oncologic outcomes. The question of whether operative time negatively impacts laparoscopic outcomes compared to open surgery outcomes requires further investigation if we are to endorse a laparoscopic approach regardless of procedure length. We postulated that there is an operative duration where the benefits of a laparoscopic approach are negated."

The investigators analyzed data from the NSQIP database for the years 2005 through 2010, identifying patients who had a right colectomy for cancer and excluding those treated on an emergent basis, or having secondary procedures other than enterolysis or mobilization of the splenic flexure.

Analyses were based on 2,141 patients in the laparoscopic group and 2,132 patients in the open group. Procedures lasted longer than 3 hours in 18% of the former and 11% of the latter.

Compared with the open group, the laparoscopic group was younger and had lower American Society of Anesthesiologists scores, higher serum albumin levels, and lower prothrombin time and platelet count.

In unadjusted analysis among patients whose operations lasted 3 hours or less, the laparoscopic group fared better than did the open group in terms of 30-day mortality (1.1% vs 2.6%, P less than .001), cardiopulmonary and cerebrovascular complications (5.4% vs. 8.4%, P less than .001), and infectious complications (9.2% vs. 13.3%, P less than .001).

In contrast, among patients whose operations lasted more than 3 hours, differences in these outcomes were not significant. If anything, there was a trend toward a higher rate of infectious complications with laparoscopy.

To assess the role of preoperative risk factors, the investigators looked at NSQIP estimates of morbidity and mortality for all gastrointestinal and abdominal surgery by operative duration and including 37 preoperative risk factors, and found patterns differing from those in the study cohort.

Specifically, these estimates suggested mortality was consistently lower for procedures lasting more then 3 hours, whether laparoscopic or open. And the risk of infectious complications was constant for each type and less for laparoscopy, regardless of the operative duration.

Thus, "there is something other than preoperative risk factors causing an increase in mortality" with longer operative time for laparoscopic procedures in the study cohort, said Dr. Bailey, who disclosed no conflicts of interest related to the research. Also, "the increased infectious complications that we demonstrated are not related to the morbidity risk."

Patients in the laparoscopic group had a significantly higher risk of surgery lasting more than 3 hours if they had recently received radiation therapy (odds ratio, 6.5), were morbidly obese (3.0), or had peripheral vascular disease (2.5).

Hospital length of stay was consistently shorter with the laparoscopic approach, regardless of how long the operation lasted, according to Dr. Bailey.

PHOENIX – The longer a laparoscopic colectomy for cancer takes, the less its advantages over an open colectomy in terms of morbidity and mortality, researchers reported at the annual meeting of the American Society of Colon and Rectal Surgeons.

A team led by Dr. Matthew Bailey, a surgery resident at the University of Kentucky in Lexington, queried the National Surgical Quality Improvement Program (NSQIP) database to identify more than 4,000 patients undergoing right colectomy because of colorectal malignancy.

Results showed that compared with their peers having an open operation lasting 3 hours or less, patients having a laparoscopic operation of this duration were less likely to develop complications and to die. However, when the operations lasted more than 3 hours, there was no longer any significant difference.

Within the laparoscopic group, patients were more likely to have a procedure lasting longer than 3 hours if they had recently received radiation therapy, were morbidly obese, or had peripheral vascular disease.

"We recommend that surgeons consider an open approach if the patient has risk factors for an operative duration greater than 3 hours," Dr. Bailey said. "We also recommend surgeons consider conversion to an open approach when it is anticipated that a laparoscopic right colectomy will exceed 3 hours."

Dr. Walter Peters of Columbia (Mo.) Surgical Associates, who comoderated the session, asked, "Were the laparoscopic procedures lasting more than 3 hours concentrated in a few institutions, or were they spread across the entire NSQIP database?"

The investigators did not assess the institutional distribution, and it may not be possible to tease that information out of NSQIP, Dr. Bailey replied.

Session attendee Dr. Eric Haas, of Colorectal Surgical Associates in Houston asked what percentage of patients had a conversion from laparoscopic to open procedures and whether analyses were conducted according to intention to treat.

"NSQIP unfortunately does not allow you to discern that, there’s no CPT [Current Procedural Terminology] code for conversion," Dr. Bailey said. "We can only assume that cases that were converted laparoscopic to open were most likely ultimately coded as open. So there was no way to perform an intent-to-treat analysis."

Dr. Haas also noted that surgeon experience with laparoscopy may have played a role. "In my own experience, certainly at the beginning of the learning curve phase, I would take 3, maybe 4 hours. And the one risk factor that you can’t put [in analyses] is surgeon," he said. "So were these 3-hour cases because of the learning curve, or were they true 3-hour cases because of the patient factors?"

The NSQIP database captures the surgeon who dictates the operative report and the level of training, the highest-level resident involved, and the specialty of the surgeon (although colorectal surgery is not among the options), according to Dr. Bailey. Still, it is generally not possible to determine who did all or most of the operation.

"We did look at operative time, and it was around 138 minutes, plus-minus, for a laparoscopic right colectomy, with the reported literature being around 187 minutes. So I’m not sure if the reported literature is dated or if, in these over 200 hospitals across the nation, this is realistic of current practice trends," he said.

"The study shows that patients are probably going to have increased complications with longer surgery, whether it’s laparoscopic or open," Dr. Timothy Geiger of Vanderbilt University Medical Center, Nashville, Tenn., the session’s other comoderator, said in an interview. "It was a good study, but it needs a little bit more in-depth look, especially at things like redosing of antibiotics, whether that is done in an appropriate manner. But otherwise, it’s a great kind of intro for us to look at this."

Giving some background to the research, Dr. Bailey noted, "The use of laparoscopy in colon cancer has been shown to be equivalent to open surgery in survival and oncologic outcomes. The question of whether operative time negatively impacts laparoscopic outcomes compared to open surgery outcomes requires further investigation if we are to endorse a laparoscopic approach regardless of procedure length. We postulated that there is an operative duration where the benefits of a laparoscopic approach are negated."

The investigators analyzed data from the NSQIP database for the years 2005 through 2010, identifying patients who had a right colectomy for cancer and excluding those treated on an emergent basis, or having secondary procedures other than enterolysis or mobilization of the splenic flexure.

Analyses were based on 2,141 patients in the laparoscopic group and 2,132 patients in the open group. Procedures lasted longer than 3 hours in 18% of the former and 11% of the latter.

Compared with the open group, the laparoscopic group was younger and had lower American Society of Anesthesiologists scores, higher serum albumin levels, and lower prothrombin time and platelet count.

In unadjusted analysis among patients whose operations lasted 3 hours or less, the laparoscopic group fared better than did the open group in terms of 30-day mortality (1.1% vs 2.6%, P less than .001), cardiopulmonary and cerebrovascular complications (5.4% vs. 8.4%, P less than .001), and infectious complications (9.2% vs. 13.3%, P less than .001).

In contrast, among patients whose operations lasted more than 3 hours, differences in these outcomes were not significant. If anything, there was a trend toward a higher rate of infectious complications with laparoscopy.

To assess the role of preoperative risk factors, the investigators looked at NSQIP estimates of morbidity and mortality for all gastrointestinal and abdominal surgery by operative duration and including 37 preoperative risk factors, and found patterns differing from those in the study cohort.

Specifically, these estimates suggested mortality was consistently lower for procedures lasting more then 3 hours, whether laparoscopic or open. And the risk of infectious complications was constant for each type and less for laparoscopy, regardless of the operative duration.

Thus, "there is something other than preoperative risk factors causing an increase in mortality" with longer operative time for laparoscopic procedures in the study cohort, said Dr. Bailey, who disclosed no conflicts of interest related to the research. Also, "the increased infectious complications that we demonstrated are not related to the morbidity risk."

Patients in the laparoscopic group had a significantly higher risk of surgery lasting more than 3 hours if they had recently received radiation therapy (odds ratio, 6.5), were morbidly obese (3.0), or had peripheral vascular disease (2.5).

Hospital length of stay was consistently shorter with the laparoscopic approach, regardless of how long the operation lasted, according to Dr. Bailey.

SAN FRANCISCO – Psychiatrists are likely to assume greater responsibility in managing cardiovascular disease risk factors among their patients with serious mental illness, according to Dr. Lydia A. Chwastiak, associate professor at the University of Washington in Seattle.

People with serious mental illness die an average of 8 years younger than the rest of the population, with most of these premature deaths tied to cardiovascular disease, she noted at the annual meeting of the American Psychiatric Association.

"We have to really think, as psychiatrists treating patients with high cardiovascular risk, should we be doing more and, if so, what should we be doing," she said. "There is an emerging group of psychiatrists and other physicians working in integrated care who have argued for an expanded role of prescribing for psychiatrists in managing disorders such as dyslipidemia."

When it comes to smoking in patients with schizophrenia, clinical practice guidelines recommend bupropion with or without nicotine replacement therapy to promote cessation.

A recent Cochrane review established that compared with placebo, bupropion increased the likelihood of cessation by threefold. The review found that varenicline increased the likelihood nearly fivefold in this population (Cochrane Database Syst. Rev. 2013;2:CD007253).

Neither drug elevated the rate of depression or positive or negative symptoms of schizophrenia, and bupropion did not elevate the rate of suicide. But varenicline possibly led to an increase in suicide intent, "so that is sort of a qualified recommendation that more research is needed and fortunately, there are ongoing trials," Dr. Chwastiak said.

Importantly, about one-third of the trials included in the review looked at smoking reduction as opposed to cessation. "What seems to be emerging is this more of a harm-reduction model, [a view] that heavier smoking confers more risk, and there is also emerging evidence that people who are able to reduce eventually are more likely to quit. So there is support for interventions that even reduce the amount of smoking," she said.

Overall, research has suggested nicotine replacement therapy alone might prove effective. Research also supports a contingency reinforcement approach, in which patients are paid to quit and abstain thereafter.

When it comes to managing dyslipidemia, reassuringly, patients with serious mental illness have a beneficial lipid response to statins similar to that of patients in the general population (Ann. Clin. Psychiatry 2013;25:141-8).

"Given that the statins appear to be as effective among people with schizophrenia, we need to think about the issues around prescribing statins," Dr. Chwastiak advised. Specifically, physicians must sort through the cytochrome P450 interactions of the various agents and choose ones that are less likely to interact with psychiatric medications.

"When we think about pharmacologic interventions [to manage cardiovascular risk factors], probably the best evidence we have really is for switching the antipsychotic medications that we are prescribing," she said.

As shown in the Comparison of Antipsychotics for Metabolic Problems trial among patients with schizophrenia or schizoaffective disorder who had adverse metabolic profiles from their medications, switching from the existing medication – olanzapine, quetiapine, or risperidone – to aripiprazole improved lipid profiles and promoted weight loss at 24 weeks (Am. J. Psychiatry 2011;168:947-56).

Importantly, switching did not increase the risk of psychiatric decompensation; however, the patients in the trial had rigorous clinical follow-up, and some did stop their treatment.

"The take-home message is that these were patients who were very closely monitored, so when medications are switched, there is a need to really monitor people both in terms of psychiatric symptoms as well as metabolic parameters," said Dr. Chwastiak, who disclosed no conflicts of interest related to her presentation.

Unfortunately, studies thus far have not found switching to improve glycemic control, although the resultant modest weight loss seen after switching can improve that outcome (as well as blood pressure control).

The only agent proven effective here is metformin, which attenuated the rise in hemoglobin A_1c levels among patients taking clozapine long term (Schizophr. Res. 2009;113:19-26).

"There is a lot of work to be done on how to manage glycemic control," Dr. Chwastiak said. "And really, there are no interventions with demonstrated effectiveness targeting diabetes or hypertension in people with serious mental illness."

A recent systematic review found that adding aripiprazole to clozapine improved total cholesterol levels, and adding topiramate to olanzapine resulted in a smaller increase in low-density lipoprotein cholesterol levels in patients with serious mental illness (AHRQ publication 12-EHC063-EF, April 2013).

"One of the interesting conclusions from this systematic review was that behavioral interventions – the lifestyle modifications – don’t seem to be any better than usual care in reducing low-density lipoprotein," Dr. Chwastiak said.

But the relevant studies were small and likely underpowered. "I don’t want that to be discouraging, suggesting that we shouldn’t be thinking about lifestyle modifications," she said. "There’s definitely improvements in cardiovascular fitness and weight reduction that really confer a benefit in terms of cardiovascular mortality."

SAN FRANCISCO – Psychiatrists are likely to assume greater responsibility in managing cardiovascular disease risk factors among their patients with serious mental illness, according to Dr. Lydia A. Chwastiak, associate professor at the University of Washington in Seattle.

People with serious mental illness die an average of 8 years younger than the rest of the population, with most of these premature deaths tied to cardiovascular disease, she noted at the annual meeting of the American Psychiatric Association.

"We have to really think, as psychiatrists treating patients with high cardiovascular risk, should we be doing more and, if so, what should we be doing," she said. "There is an emerging group of psychiatrists and other physicians working in integrated care who have argued for an expanded role of prescribing for psychiatrists in managing disorders such as dyslipidemia."

When it comes to smoking in patients with schizophrenia, clinical practice guidelines recommend bupropion with or without nicotine replacement therapy to promote cessation.

A recent Cochrane review established that compared with placebo, bupropion increased the likelihood of cessation by threefold. The review found that varenicline increased the likelihood nearly fivefold in this population (Cochrane Database Syst. Rev. 2013;2:CD007253).

Neither drug elevated the rate of depression or positive or negative symptoms of schizophrenia, and bupropion did not elevate the rate of suicide. But varenicline possibly led to an increase in suicide intent, "so that is sort of a qualified recommendation that more research is needed and fortunately, there are ongoing trials," Dr. Chwastiak said.

Importantly, about one-third of the trials included in the review looked at smoking reduction as opposed to cessation. "What seems to be emerging is this more of a harm-reduction model, [a view] that heavier smoking confers more risk, and there is also emerging evidence that people who are able to reduce eventually are more likely to quit. So there is support for interventions that even reduce the amount of smoking," she said.

Overall, research has suggested nicotine replacement therapy alone might prove effective. Research also supports a contingency reinforcement approach, in which patients are paid to quit and abstain thereafter.

When it comes to managing dyslipidemia, reassuringly, patients with serious mental illness have a beneficial lipid response to statins similar to that of patients in the general population (Ann. Clin. Psychiatry 2013;25:141-8).

"Given that the statins appear to be as effective among people with schizophrenia, we need to think about the issues around prescribing statins," Dr. Chwastiak advised. Specifically, physicians must sort through the cytochrome P450 interactions of the various agents and choose ones that are less likely to interact with psychiatric medications.

"When we think about pharmacologic interventions [to manage cardiovascular risk factors], probably the best evidence we have really is for switching the antipsychotic medications that we are prescribing," she said.

As shown in the Comparison of Antipsychotics for Metabolic Problems trial among patients with schizophrenia or schizoaffective disorder who had adverse metabolic profiles from their medications, switching from the existing medication – olanzapine, quetiapine, or risperidone – to aripiprazole improved lipid profiles and promoted weight loss at 24 weeks (Am. J. Psychiatry 2011;168:947-56).

Importantly, switching did not increase the risk of psychiatric decompensation; however, the patients in the trial had rigorous clinical follow-up, and some did stop their treatment.

"The take-home message is that these were patients who were very closely monitored, so when medications are switched, there is a need to really monitor people both in terms of psychiatric symptoms as well as metabolic parameters," said Dr. Chwastiak, who disclosed no conflicts of interest related to her presentation.

Unfortunately, studies thus far have not found switching to improve glycemic control, although the resultant modest weight loss seen after switching can improve that outcome (as well as blood pressure control).

The only agent proven effective here is metformin, which attenuated the rise in hemoglobin A_1c levels among patients taking clozapine long term (Schizophr. Res. 2009;113:19-26).

"There is a lot of work to be done on how to manage glycemic control," Dr. Chwastiak said. "And really, there are no interventions with demonstrated effectiveness targeting diabetes or hypertension in people with serious mental illness."

A recent systematic review found that adding aripiprazole to clozapine improved total cholesterol levels, and adding topiramate to olanzapine resulted in a smaller increase in low-density lipoprotein cholesterol levels in patients with serious mental illness (AHRQ publication 12-EHC063-EF, April 2013).

"One of the interesting conclusions from this systematic review was that behavioral interventions – the lifestyle modifications – don’t seem to be any better than usual care in reducing low-density lipoprotein," Dr. Chwastiak said.

But the relevant studies were small and likely underpowered. "I don’t want that to be discouraging, suggesting that we shouldn’t be thinking about lifestyle modifications," she said. "There’s definitely improvements in cardiovascular fitness and weight reduction that really confer a benefit in terms of cardiovascular mortality."

SAN FRANCISCO – Psychiatrists are likely to assume greater responsibility in managing cardiovascular disease risk factors among their patients with serious mental illness, according to Dr. Lydia A. Chwastiak, associate professor at the University of Washington in Seattle.

People with serious mental illness die an average of 8 years younger than the rest of the population, with most of these premature deaths tied to cardiovascular disease, she noted at the annual meeting of the American Psychiatric Association.

"We have to really think, as psychiatrists treating patients with high cardiovascular risk, should we be doing more and, if so, what should we be doing," she said. "There is an emerging group of psychiatrists and other physicians working in integrated care who have argued for an expanded role of prescribing for psychiatrists in managing disorders such as dyslipidemia."

When it comes to smoking in patients with schizophrenia, clinical practice guidelines recommend bupropion with or without nicotine replacement therapy to promote cessation.

A recent Cochrane review established that compared with placebo, bupropion increased the likelihood of cessation by threefold. The review found that varenicline increased the likelihood nearly fivefold in this population (Cochrane Database Syst. Rev. 2013;2:CD007253).

Neither drug elevated the rate of depression or positive or negative symptoms of schizophrenia, and bupropion did not elevate the rate of suicide. But varenicline possibly led to an increase in suicide intent, "so that is sort of a qualified recommendation that more research is needed and fortunately, there are ongoing trials," Dr. Chwastiak said.

Importantly, about one-third of the trials included in the review looked at smoking reduction as opposed to cessation. "What seems to be emerging is this more of a harm-reduction model, [a view] that heavier smoking confers more risk, and there is also emerging evidence that people who are able to reduce eventually are more likely to quit. So there is support for interventions that even reduce the amount of smoking," she said.

Overall, research has suggested nicotine replacement therapy alone might prove effective. Research also supports a contingency reinforcement approach, in which patients are paid to quit and abstain thereafter.

When it comes to managing dyslipidemia, reassuringly, patients with serious mental illness have a beneficial lipid response to statins similar to that of patients in the general population (Ann. Clin. Psychiatry 2013;25:141-8).

"Given that the statins appear to be as effective among people with schizophrenia, we need to think about the issues around prescribing statins," Dr. Chwastiak advised. Specifically, physicians must sort through the cytochrome P450 interactions of the various agents and choose ones that are less likely to interact with psychiatric medications.

"When we think about pharmacologic interventions [to manage cardiovascular risk factors], probably the best evidence we have really is for switching the antipsychotic medications that we are prescribing," she said.

As shown in the Comparison of Antipsychotics for Metabolic Problems trial among patients with schizophrenia or schizoaffective disorder who had adverse metabolic profiles from their medications, switching from the existing medication – olanzapine, quetiapine, or risperidone – to aripiprazole improved lipid profiles and promoted weight loss at 24 weeks (Am. J. Psychiatry 2011;168:947-56).

Importantly, switching did not increase the risk of psychiatric decompensation; however, the patients in the trial had rigorous clinical follow-up, and some did stop their treatment.

"The take-home message is that these were patients who were very closely monitored, so when medications are switched, there is a need to really monitor people both in terms of psychiatric symptoms as well as metabolic parameters," said Dr. Chwastiak, who disclosed no conflicts of interest related to her presentation.

Unfortunately, studies thus far have not found switching to improve glycemic control, although the resultant modest weight loss seen after switching can improve that outcome (as well as blood pressure control).

The only agent proven effective here is metformin, which attenuated the rise in hemoglobin A_1c levels among patients taking clozapine long term (Schizophr. Res. 2009;113:19-26).

"There is a lot of work to be done on how to manage glycemic control," Dr. Chwastiak said. "And really, there are no interventions with demonstrated effectiveness targeting diabetes or hypertension in people with serious mental illness."

A recent systematic review found that adding aripiprazole to clozapine improved total cholesterol levels, and adding topiramate to olanzapine resulted in a smaller increase in low-density lipoprotein cholesterol levels in patients with serious mental illness (AHRQ publication 12-EHC063-EF, April 2013).

"One of the interesting conclusions from this systematic review was that behavioral interventions – the lifestyle modifications – don’t seem to be any better than usual care in reducing low-density lipoprotein," Dr. Chwastiak said.

But the relevant studies were small and likely underpowered. "I don’t want that to be discouraging, suggesting that we shouldn’t be thinking about lifestyle modifications," she said. "There’s definitely improvements in cardiovascular fitness and weight reduction that really confer a benefit in terms of cardiovascular mortality."