NCCN Breast Guidelines Stand by Bevacizumab

HOLLYWOOD, FLA. – The National Comprehensive Cancer Network is sticking by its endorsement of bevacizumab in combination with paclitaxel for the treatment of metastatic breast cancer.

Dr. Robert W. Carlson announced that the network’s breast cancer panel voted to retain the guideline recommendation after holding multiple "marathon" meetings to review data behind the Food and Drug Administration’s controversial decision to withdraw marketing approval for bevacizumab (Avastin) in metastatic breast cancer.

"The data observed in the [E2100 trial] really had not changed from its approval previously, and we thought that if the data were compelling 2 years ago, why isn’t it compelling enough today?" explained Dr. Carlson of Stanford (Calif.) University, chair of the 27-member panel, at the annual conference of the National Comprehensive Cancer Network

Bevacizumab received accelerated approval in 2008 based on results of the E2100 trial, which showed a statistically significant increase in progression-free survival but not overall survival. When subsequent trials did not match these results or show an improvement in overall survival, the FDA’s Oncologic Drugs Advisory Committee voted unanimously that the indication ought to be withdrawn.

The Food and Drug Administration announced in December that it would do so. A more than 20% increase in grade 3-5 toxicity relative to paclitaxel alone suggests the benefits of the drug do not outweigh the risks, according to the agency, which has scheduled a hearing June 28-29, 2011, to consider an appeal by drugmaker Genentech (owned by Roche).

In a footnote to a listing of preferred chemotherapy regimens for metastatic breast cancer in the updated NCCN guidelines, the breast cancer panel states: "Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel."

Other important updates to the breast cancer guidelines follow.

Axillary Lymph Node Dissection

The panel stopped short of endorsing omission of complete axillary lymph node dissection (ALND) in patients with early breast cancer who are found to be node positive or have unidentified nodal involvement after sentinel lymph node dissection (SLND).

After reviewing the American College of Surgeons Oncology Group (ACOSOG) Z011 study, which found no improvement in outcomes with the additional procedure (J. Clin. Oncol. 28:18s, 2010 [suppl; abstr CRA506]), the NCCN panel issued a "guidance" via the following footnote in the new guidelines: "The data from a single randomized trial suggests complete axillary lymph node dissection in women with clinically node negative T/1-2 tumors, fewer than 3 involved sentinel lymph nodes, and undergoing breast conserving surgery and whole breast radiation results in more morbidity, no improvement in local regional recurrence rates, and no difference in overall survival compared with sentinel lymph node procedure alone."

While the statistical and absolute numerical advantage in the observed survival curves clearly favored skipping the additional procedure, the panel declined to recommend against ALND because the study accrued only 450 of the planned 1,900 patients, according to Dr. Carlson. Nonetheless, he acknowledged that results are already changing clinical practice.

"There’s no reason to suspect that the trend wouldn’t have continued with sufficient accrual," he said. "In fact, as a result of the study, there is at least one NCCN institution that has abandoned axillary node dissection in this highly selective group of patients."

Eribulin as Third-Line Monotherapy

Based on the findings of the phase III EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs. E7389) trial, the guidelines panel included eribulin (Halaven), a synthetic microtubule blocker, on the list of preferred single-agent treatments for metastatic or recurrent breast cancer. It is FDA approved in patients previously treated with both a taxane-based therapy and an anthracycline-based treatment.

The addition of this agent to the treatment algorithm is especially noteworthy, Dr. Carlson said, "considering the limited options for women with metastatic breast cancer who have already received other therapies."

The median overall survival of women randomized to eribulin in the EMBRACE trial was 13.12 months, compared with 10.65 in the comparator group of women treated with their doctors’ choice of chemotherapy (Lancet 2011 March 3 [doi:10.1016/S0140-6736(11)60070-6]). Despite the statistically significant improvement in overall survival, there was no progression-free survival advantage with eribulin treatment – a result that Dr. Carlson deemed "confusing."

The apparent contradiction "gives me a lot of concern that we may not know what we are measuring when we measure progression-free survival," he said.

Denosumab for Skeletal Protection

Recently approved by the FDA for the prevention of skeletal events in advanced breast cancer patients with bone metastases, the monoclonal antibody denosumab (Xgeva) joins zoledronic acid (Zometa) and pamidronate (Aredia) as supportive care options in the updated guidelines. The recommendation is based on the findings of a phase III trial in which denosumab reduced the risks of experiencing a first skeletal event by 18% and multiple skeletal-related events by 23% relative to zoledronic acid (J. Clin. Oncol. 2010;10:5132-9)

Although treatment with denosumab did not improve overall survival or progression-free survival, the impact of the drug in reducing such events as fractures and bone pain could potentially minimize the need for surgery or radiation for skeletal complications and as such substantially improves patients’ quality of life, Dr. Carlson stressed.

Role of Biomarkers

While affirming the importance of determining the status of the estrogen receptor (ER), progesterone receptor (PR), and HER2 in the initial or recurrent work-up for stage IV disease, the revised guidelines do not address testing for CYP2D6 biomarkers prior to prescribing tamoxifen.

Although it has been suggested that testing for variations in the CYP2D6 gene can identify poor metabolizers of tamoxifen who will not benefit from the drug’s protective effects, "the biologic evidence is inconsistent and confusing," Dr. Carlson stated. As such, he noted, "the guidelines are silent on the issue of [CYP2D6] testing, which clinicians should interpret as a recommendation not to do it."

The updated NCCN Guidelines for Breast Cancer are available free of charge at the NCCN website.

Dr. Carlson disclosed receiving grant and research support from AstraZeneca Pharmaceuticals, Genentech, Pfizer, and Sanofi-Aventis US.

HOLLYWOOD, FLA. – The National Comprehensive Cancer Network is sticking by its endorsement of bevacizumab in combination with paclitaxel for the treatment of metastatic breast cancer.

Dr. Robert W. Carlson announced that the network’s breast cancer panel voted to retain the guideline recommendation after holding multiple "marathon" meetings to review data behind the Food and Drug Administration’s controversial decision to withdraw marketing approval for bevacizumab (Avastin) in metastatic breast cancer.

"The data observed in the [E2100 trial] really had not changed from its approval previously, and we thought that if the data were compelling 2 years ago, why isn’t it compelling enough today?" explained Dr. Carlson of Stanford (Calif.) University, chair of the 27-member panel, at the annual conference of the National Comprehensive Cancer Network

Bevacizumab received accelerated approval in 2008 based on results of the E2100 trial, which showed a statistically significant increase in progression-free survival but not overall survival. When subsequent trials did not match these results or show an improvement in overall survival, the FDA’s Oncologic Drugs Advisory Committee voted unanimously that the indication ought to be withdrawn.

The Food and Drug Administration announced in December that it would do so. A more than 20% increase in grade 3-5 toxicity relative to paclitaxel alone suggests the benefits of the drug do not outweigh the risks, according to the agency, which has scheduled a hearing June 28-29, 2011, to consider an appeal by drugmaker Genentech (owned by Roche).

In a footnote to a listing of preferred chemotherapy regimens for metastatic breast cancer in the updated NCCN guidelines, the breast cancer panel states: "Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel."

Other important updates to the breast cancer guidelines follow.

Axillary Lymph Node Dissection

The panel stopped short of endorsing omission of complete axillary lymph node dissection (ALND) in patients with early breast cancer who are found to be node positive or have unidentified nodal involvement after sentinel lymph node dissection (SLND).

After reviewing the American College of Surgeons Oncology Group (ACOSOG) Z011 study, which found no improvement in outcomes with the additional procedure (J. Clin. Oncol. 28:18s, 2010 [suppl; abstr CRA506]), the NCCN panel issued a "guidance" via the following footnote in the new guidelines: "The data from a single randomized trial suggests complete axillary lymph node dissection in women with clinically node negative T/1-2 tumors, fewer than 3 involved sentinel lymph nodes, and undergoing breast conserving surgery and whole breast radiation results in more morbidity, no improvement in local regional recurrence rates, and no difference in overall survival compared with sentinel lymph node procedure alone."

While the statistical and absolute numerical advantage in the observed survival curves clearly favored skipping the additional procedure, the panel declined to recommend against ALND because the study accrued only 450 of the planned 1,900 patients, according to Dr. Carlson. Nonetheless, he acknowledged that results are already changing clinical practice.

"There’s no reason to suspect that the trend wouldn’t have continued with sufficient accrual," he said. "In fact, as a result of the study, there is at least one NCCN institution that has abandoned axillary node dissection in this highly selective group of patients."

Eribulin as Third-Line Monotherapy

Based on the findings of the phase III EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs. E7389) trial, the guidelines panel included eribulin (Halaven), a synthetic microtubule blocker, on the list of preferred single-agent treatments for metastatic or recurrent breast cancer. It is FDA approved in patients previously treated with both a taxane-based therapy and an anthracycline-based treatment.

The addition of this agent to the treatment algorithm is especially noteworthy, Dr. Carlson said, "considering the limited options for women with metastatic breast cancer who have already received other therapies."

The median overall survival of women randomized to eribulin in the EMBRACE trial was 13.12 months, compared with 10.65 in the comparator group of women treated with their doctors’ choice of chemotherapy (Lancet 2011 March 3 [doi:10.1016/S0140-6736(11)60070-6]). Despite the statistically significant improvement in overall survival, there was no progression-free survival advantage with eribulin treatment – a result that Dr. Carlson deemed "confusing."

The apparent contradiction "gives me a lot of concern that we may not know what we are measuring when we measure progression-free survival," he said.

Denosumab for Skeletal Protection

Recently approved by the FDA for the prevention of skeletal events in advanced breast cancer patients with bone metastases, the monoclonal antibody denosumab (Xgeva) joins zoledronic acid (Zometa) and pamidronate (Aredia) as supportive care options in the updated guidelines. The recommendation is based on the findings of a phase III trial in which denosumab reduced the risks of experiencing a first skeletal event by 18% and multiple skeletal-related events by 23% relative to zoledronic acid (J. Clin. Oncol. 2010;10:5132-9)

Although treatment with denosumab did not improve overall survival or progression-free survival, the impact of the drug in reducing such events as fractures and bone pain could potentially minimize the need for surgery or radiation for skeletal complications and as such substantially improves patients’ quality of life, Dr. Carlson stressed.

Role of Biomarkers

While affirming the importance of determining the status of the estrogen receptor (ER), progesterone receptor (PR), and HER2 in the initial or recurrent work-up for stage IV disease, the revised guidelines do not address testing for CYP2D6 biomarkers prior to prescribing tamoxifen.

Although it has been suggested that testing for variations in the CYP2D6 gene can identify poor metabolizers of tamoxifen who will not benefit from the drug’s protective effects, "the biologic evidence is inconsistent and confusing," Dr. Carlson stated. As such, he noted, "the guidelines are silent on the issue of [CYP2D6] testing, which clinicians should interpret as a recommendation not to do it."

The updated NCCN Guidelines for Breast Cancer are available free of charge at the NCCN website.

Dr. Carlson disclosed receiving grant and research support from AstraZeneca Pharmaceuticals, Genentech, Pfizer, and Sanofi-Aventis US.

HOLLYWOOD, FLA. – The National Comprehensive Cancer Network is sticking by its endorsement of bevacizumab in combination with paclitaxel for the treatment of metastatic breast cancer.

Dr. Robert W. Carlson announced that the network’s breast cancer panel voted to retain the guideline recommendation after holding multiple "marathon" meetings to review data behind the Food and Drug Administration’s controversial decision to withdraw marketing approval for bevacizumab (Avastin) in metastatic breast cancer.

"The data observed in the [E2100 trial] really had not changed from its approval previously, and we thought that if the data were compelling 2 years ago, why isn’t it compelling enough today?" explained Dr. Carlson of Stanford (Calif.) University, chair of the 27-member panel, at the annual conference of the National Comprehensive Cancer Network

Bevacizumab received accelerated approval in 2008 based on results of the E2100 trial, which showed a statistically significant increase in progression-free survival but not overall survival. When subsequent trials did not match these results or show an improvement in overall survival, the FDA’s Oncologic Drugs Advisory Committee voted unanimously that the indication ought to be withdrawn.

The Food and Drug Administration announced in December that it would do so. A more than 20% increase in grade 3-5 toxicity relative to paclitaxel alone suggests the benefits of the drug do not outweigh the risks, according to the agency, which has scheduled a hearing June 28-29, 2011, to consider an appeal by drugmaker Genentech (owned by Roche).

In a footnote to a listing of preferred chemotherapy regimens for metastatic breast cancer in the updated NCCN guidelines, the breast cancer panel states: "Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel."

Other important updates to the breast cancer guidelines follow.

Axillary Lymph Node Dissection

The panel stopped short of endorsing omission of complete axillary lymph node dissection (ALND) in patients with early breast cancer who are found to be node positive or have unidentified nodal involvement after sentinel lymph node dissection (SLND).

After reviewing the American College of Surgeons Oncology Group (ACOSOG) Z011 study, which found no improvement in outcomes with the additional procedure (J. Clin. Oncol. 28:18s, 2010 [suppl; abstr CRA506]), the NCCN panel issued a "guidance" via the following footnote in the new guidelines: "The data from a single randomized trial suggests complete axillary lymph node dissection in women with clinically node negative T/1-2 tumors, fewer than 3 involved sentinel lymph nodes, and undergoing breast conserving surgery and whole breast radiation results in more morbidity, no improvement in local regional recurrence rates, and no difference in overall survival compared with sentinel lymph node procedure alone."

While the statistical and absolute numerical advantage in the observed survival curves clearly favored skipping the additional procedure, the panel declined to recommend against ALND because the study accrued only 450 of the planned 1,900 patients, according to Dr. Carlson. Nonetheless, he acknowledged that results are already changing clinical practice.

"There’s no reason to suspect that the trend wouldn’t have continued with sufficient accrual," he said. "In fact, as a result of the study, there is at least one NCCN institution that has abandoned axillary node dissection in this highly selective group of patients."

Eribulin as Third-Line Monotherapy

Based on the findings of the phase III EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs. E7389) trial, the guidelines panel included eribulin (Halaven), a synthetic microtubule blocker, on the list of preferred single-agent treatments for metastatic or recurrent breast cancer. It is FDA approved in patients previously treated with both a taxane-based therapy and an anthracycline-based treatment.

The addition of this agent to the treatment algorithm is especially noteworthy, Dr. Carlson said, "considering the limited options for women with metastatic breast cancer who have already received other therapies."

The median overall survival of women randomized to eribulin in the EMBRACE trial was 13.12 months, compared with 10.65 in the comparator group of women treated with their doctors’ choice of chemotherapy (Lancet 2011 March 3 [doi:10.1016/S0140-6736(11)60070-6]). Despite the statistically significant improvement in overall survival, there was no progression-free survival advantage with eribulin treatment – a result that Dr. Carlson deemed "confusing."

The apparent contradiction "gives me a lot of concern that we may not know what we are measuring when we measure progression-free survival," he said.

Denosumab for Skeletal Protection

Recently approved by the FDA for the prevention of skeletal events in advanced breast cancer patients with bone metastases, the monoclonal antibody denosumab (Xgeva) joins zoledronic acid (Zometa) and pamidronate (Aredia) as supportive care options in the updated guidelines. The recommendation is based on the findings of a phase III trial in which denosumab reduced the risks of experiencing a first skeletal event by 18% and multiple skeletal-related events by 23% relative to zoledronic acid (J. Clin. Oncol. 2010;10:5132-9)

Although treatment with denosumab did not improve overall survival or progression-free survival, the impact of the drug in reducing such events as fractures and bone pain could potentially minimize the need for surgery or radiation for skeletal complications and as such substantially improves patients’ quality of life, Dr. Carlson stressed.

Role of Biomarkers

While affirming the importance of determining the status of the estrogen receptor (ER), progesterone receptor (PR), and HER2 in the initial or recurrent work-up for stage IV disease, the revised guidelines do not address testing for CYP2D6 biomarkers prior to prescribing tamoxifen.

Although it has been suggested that testing for variations in the CYP2D6 gene can identify poor metabolizers of tamoxifen who will not benefit from the drug’s protective effects, "the biologic evidence is inconsistent and confusing," Dr. Carlson stated. As such, he noted, "the guidelines are silent on the issue of [CYP2D6] testing, which clinicians should interpret as a recommendation not to do it."

The updated NCCN Guidelines for Breast Cancer are available free of charge at the NCCN website.

Dr. Carlson disclosed receiving grant and research support from AstraZeneca Pharmaceuticals, Genentech, Pfizer, and Sanofi-Aventis US.