March 11, 2011 (Hollywood, Florida) — New systemic treatment options for women with metastatic disease highlight the recently updated breast cancer guideline from the National Comprehensive Cancer Network (NCCN), which was presented here at the NCCN 16th Annual Conference.
However, the headlining element of the guideline might be described as controversial; the breast cancer panel made recommendations on issues such as forgoing axillary lymph node dissection (despite positive nodes) and the use of bevacizumab in advanced disease.
The NCCN's guidance on systemic treatment for recurrent or stage IV disease has added 2 new drugs, both of which were recently approved by the US Food and Drug Administration (FDA) — denosumab (Xgeva, Amgen) for the prevention of skeletal-related events (SREs) and eribulin (Halaven, Eisai), the new chemotherapy for women with heavily pretreated metastatic disease.
The changes were discussed by the chair of the NCCN breast cancer panel, Robert Carlson, MD, from the Stanford Comprehensive Cancer Center in Palo Alto, California.
Denosumab Offers Another Option
The novel biologic denosumab is now an option for the prevention of SREs; the other options include the bisphosphonates zolendronic acid and pamidronate.
SREs are "frequent" events in metastatic breast cancer and include pathologic bone fracture; they occur in more than 50% of women within 24 months, said Dr. Carlson. In addition, more than 40% of women will need radiation therapy because of skeletal metastasis in that time period.
Pamidronate was the first agent approved for the prevention of SREs, followed by zoledronic acid, which was "slightly superior" to its predecessor in preventing lytic metastasis and equally effective in preventing nonlytic metastasis, Dr. Carlson noted.
Now, denosumab, which is administered subcutaneously, has been shown to be "slightly superior" to zoledronic acid in preventing SREs in advanced breast cancer, he said. Dr. Carlson was referring to data from a pivotal Amgen-sponsored study that led to the approval of the drug for this indication late last year.
The study found that, compared with zoledronic acid, denosumab significantly delayed the time to first on-study SRE by 18%, and the time to multiple on-study SREs by 23%, with hazard ratios of 0.82 and 0.77, respectively. The time-to-first-SRE data demonstrated both the noninferiority (P < .001) and superiority (P = .01) of denosumab over zoledronic acid, noted Dr. Carlson.
Denosumab also has a "more favorable toxicity" for the "vast majority of toxicities" than zoledronic acid, he noted. Hypercalcemia and renal failure are among the toxicities that are less common with denosumab.
The lack of renal adverse effects is very important for some patients, suggest the authors of the comparative study published last year (J Clin Oncol. 2010;28:5132-5139).
"Denosumab represents a therapeutic option for patients with bone metastases who have chronic renal failure and renal insufficiency and for those with metastatic breast cancer receiving nephrotoxic platinum-based chemotherapy regimens," the authors of that study write.
In patients with metastatic disease, the NCCN panel recommends giving chemotherapy or endocrine therapy plus 1 of the 3 bone agents, along with calcium and vitamin D supplementation. These patients should have an expected survival of 3 months or more and adequate renal function. The guideline also calls for a dental examination and preventive dentistry prior to therapy, because of the risk of osteonecrosis of the jaw with these bone agents.
Finally, the guideline acknowledges that the "optimal schedule and duration" of the 3 bone agents are "unknown."
In his presentation about denosumab, Dr. Carlson did not discuss the cost of the various bone drugs. However, because of its relatively high cost, denosumab was recently questioned as having "debatable value," despite its advantages over zoledronic acid, in a Journal of Clinical Oncology editorial, as reported by Medscape Medical News.
Eribulin for Heavily Pretreated Metastatic Disease
For women with advanced disease, eribulin has been added as a "preferred single agent" in the guideline section on chemotherapy regimens. Eribulin, a microtubule inhibitor, is the first chemotherapy to show a statistically significant improvement in survival in women with heavily pretreated metastatic breast cancer, compared with control subjects, who received "treatment by physician's choice."
The NCCN endorses a treatment schedule for eribulin of 1.4 mg/m2 intravenously for 2 to 5 minutes on days 1 to 8 of a 21-day cycle.
The data on eribulin come from the pivotal EMBRACE phase 3 trial, which was published recently. These data led to the FDA approval of eribulin in November 2010.
Dr. Carlson noted that eribulin is indicated "for the treatment of patients with metastatic breast cancer who have previously received at least 2 chemotherapeutic regimens for the treatment of metastatic disease. Previous therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting."
There are "limited options" for these women, said Dr. Carlson in a press statement, which makes eribulin a "noteworthy treatment" that is now incorporated in the guideline.
NCCN on Axillary Dissection
The guideline has new information about the use of axillary lymph node dissection in certain women with early breast cancer and a minimal number of positive nodes, said Dr. Carlson.
The source of the guidance comes from a recently published randomized trial from the American College of Surgeons Oncology Group (ACSOG Z0011).
The guidance indicates that axillary lymph node dissection results in "more morbidity, no improvement in locoregional recurrence rates, and no difference in overall survival," compared with sentinel lymph node dissection alone, in women with clinical T1/T2 invasive breast cancer and 1 or 2 sentinel lymph nodes; the women also all received breast-conserving surgery, whole-breast irradiation, and adjuvant systemic therapy.
However, the new guidance is only a footnote in the NCCN document, said Dr. Carlson. "The panel declined to include the recommendation in the main portion of the guideline," he explained.
Why? Because the ACSOG Z0011 was designed as a 1900-patient study but only enrolled about 450 patients because of slow accrual.
Despite the study's faults, its findings have resulted in "at least 1 NCCN center" changing its protocol for these women. At the same time, "at least 1 NCCN center has not," said Dr. Carlson.
The idea of leaving behind any cancer at all, even small amounts in a minimal number of lymph nodes, seems "counterintuitive," admitted the ACSOG Z0011 lead investigator when the data were first presented in 2010. However, other experts have since speculated that "adjuvant radiation and systemic therapy likely treated the low-volume nodal metastasis in this study."
NCCN Casts Its Bevacizumab Vote
The NCCN breast cancer panel has voted unanimously to retain its recommendation that bevacizumab (Avastin, Genentech/Roche) be used in combination with chemotherapy in advanced breast cancer, Dr. Carlson reported.
He explained that the FDA has voted to rescind the breast cancer indication for the targeted therapy but that the manufacturer is appealing the decision. "The FDA indication, as we speak today, for breast cancer still exists," he reminded the NCCN audience.
The NCCN guidance reads: "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."
The majority of the NCCN audience was not in favor of the FDA's decision to remove the breast cancer indication for bevacizumab. Using hand-held devices that are increasingly popular at medical meetings, the audience voted on the matter — 59% were opposed to the FDA decision and 41% were in agreement.
CYP2D6: Silence Speaks Volumes
Dr. Carlson also reviewed a subject about which the guideline is "silent." Namely, testing for CYP2D6 polymorphisms, which identify women who are less likely to respond to tamoxifen when it is used to reduce the risk for recurrence after treatment for early-stage breast cancer.
The "available studies are inconsistent" noted Dr. Carlson. Thus, the panel has chosen not to make a recommendation about using this marker to estimate how patients will respond to tamoxifen.
"You should interpret the silence as a recommendation not to [test for the polymorphisms]," he said.
Dr. Carlson reports receiving grant/research support from AstraZeneca, Genentech, and Sanofi-Aventis; and being a member of a Data Safety Monitoring Board for Pfizer.
National Comprehensive Cancer Network (NCCN) 16th Annual Conference. Presented March 10, 2011.
However, the headlining element of the guideline might be described as controversial; the breast cancer panel made recommendations on issues such as forgoing axillary lymph node dissection (despite positive nodes) and the use of bevacizumab in advanced disease.
The NCCN's guidance on systemic treatment for recurrent or stage IV disease has added 2 new drugs, both of which were recently approved by the US Food and Drug Administration (FDA) — denosumab (Xgeva, Amgen) for the prevention of skeletal-related events (SREs) and eribulin (Halaven, Eisai), the new chemotherapy for women with heavily pretreated metastatic disease.
The changes were discussed by the chair of the NCCN breast cancer panel, Robert Carlson, MD, from the Stanford Comprehensive Cancer Center in Palo Alto, California.
Denosumab Offers Another Option
The novel biologic denosumab is now an option for the prevention of SREs; the other options include the bisphosphonates zolendronic acid and pamidronate.
SREs are "frequent" events in metastatic breast cancer and include pathologic bone fracture; they occur in more than 50% of women within 24 months, said Dr. Carlson. In addition, more than 40% of women will need radiation therapy because of skeletal metastasis in that time period.
Pamidronate was the first agent approved for the prevention of SREs, followed by zoledronic acid, which was "slightly superior" to its predecessor in preventing lytic metastasis and equally effective in preventing nonlytic metastasis, Dr. Carlson noted.
Now, denosumab, which is administered subcutaneously, has been shown to be "slightly superior" to zoledronic acid in preventing SREs in advanced breast cancer, he said. Dr. Carlson was referring to data from a pivotal Amgen-sponsored study that led to the approval of the drug for this indication late last year.
The study found that, compared with zoledronic acid, denosumab significantly delayed the time to first on-study SRE by 18%, and the time to multiple on-study SREs by 23%, with hazard ratios of 0.82 and 0.77, respectively. The time-to-first-SRE data demonstrated both the noninferiority (P < .001) and superiority (P = .01) of denosumab over zoledronic acid, noted Dr. Carlson.
Denosumab also has a "more favorable toxicity" for the "vast majority of toxicities" than zoledronic acid, he noted. Hypercalcemia and renal failure are among the toxicities that are less common with denosumab.
The lack of renal adverse effects is very important for some patients, suggest the authors of the comparative study published last year (J Clin Oncol. 2010;28:5132-5139).
"Denosumab represents a therapeutic option for patients with bone metastases who have chronic renal failure and renal insufficiency and for those with metastatic breast cancer receiving nephrotoxic platinum-based chemotherapy regimens," the authors of that study write.
In patients with metastatic disease, the NCCN panel recommends giving chemotherapy or endocrine therapy plus 1 of the 3 bone agents, along with calcium and vitamin D supplementation. These patients should have an expected survival of 3 months or more and adequate renal function. The guideline also calls for a dental examination and preventive dentistry prior to therapy, because of the risk of osteonecrosis of the jaw with these bone agents.
Finally, the guideline acknowledges that the "optimal schedule and duration" of the 3 bone agents are "unknown."
In his presentation about denosumab, Dr. Carlson did not discuss the cost of the various bone drugs. However, because of its relatively high cost, denosumab was recently questioned as having "debatable value," despite its advantages over zoledronic acid, in a Journal of Clinical Oncology editorial, as reported by Medscape Medical News.
Eribulin for Heavily Pretreated Metastatic Disease
For women with advanced disease, eribulin has been added as a "preferred single agent" in the guideline section on chemotherapy regimens. Eribulin, a microtubule inhibitor, is the first chemotherapy to show a statistically significant improvement in survival in women with heavily pretreated metastatic breast cancer, compared with control subjects, who received "treatment by physician's choice."
The NCCN endorses a treatment schedule for eribulin of 1.4 mg/m2 intravenously for 2 to 5 minutes on days 1 to 8 of a 21-day cycle.
The data on eribulin come from the pivotal EMBRACE phase 3 trial, which was published recently. These data led to the FDA approval of eribulin in November 2010.
Dr. Carlson noted that eribulin is indicated "for the treatment of patients with metastatic breast cancer who have previously received at least 2 chemotherapeutic regimens for the treatment of metastatic disease. Previous therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting."
There are "limited options" for these women, said Dr. Carlson in a press statement, which makes eribulin a "noteworthy treatment" that is now incorporated in the guideline.
NCCN on Axillary Dissection
The guideline has new information about the use of axillary lymph node dissection in certain women with early breast cancer and a minimal number of positive nodes, said Dr. Carlson.
The source of the guidance comes from a recently published randomized trial from the American College of Surgeons Oncology Group (ACSOG Z0011).
The guidance indicates that axillary lymph node dissection results in "more morbidity, no improvement in locoregional recurrence rates, and no difference in overall survival," compared with sentinel lymph node dissection alone, in women with clinical T1/T2 invasive breast cancer and 1 or 2 sentinel lymph nodes; the women also all received breast-conserving surgery, whole-breast irradiation, and adjuvant systemic therapy.
However, the new guidance is only a footnote in the NCCN document, said Dr. Carlson. "The panel declined to include the recommendation in the main portion of the guideline," he explained.
Why? Because the ACSOG Z0011 was designed as a 1900-patient study but only enrolled about 450 patients because of slow accrual.
Despite the study's faults, its findings have resulted in "at least 1 NCCN center" changing its protocol for these women. At the same time, "at least 1 NCCN center has not," said Dr. Carlson.
The idea of leaving behind any cancer at all, even small amounts in a minimal number of lymph nodes, seems "counterintuitive," admitted the ACSOG Z0011 lead investigator when the data were first presented in 2010. However, other experts have since speculated that "adjuvant radiation and systemic therapy likely treated the low-volume nodal metastasis in this study."
NCCN Casts Its Bevacizumab Vote
The NCCN breast cancer panel has voted unanimously to retain its recommendation that bevacizumab (Avastin, Genentech/Roche) be used in combination with chemotherapy in advanced breast cancer, Dr. Carlson reported.
He explained that the FDA has voted to rescind the breast cancer indication for the targeted therapy but that the manufacturer is appealing the decision. "The FDA indication, as we speak today, for breast cancer still exists," he reminded the NCCN audience.
The NCCN guidance reads: "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."
The majority of the NCCN audience was not in favor of the FDA's decision to remove the breast cancer indication for bevacizumab. Using hand-held devices that are increasingly popular at medical meetings, the audience voted on the matter — 59% were opposed to the FDA decision and 41% were in agreement.
CYP2D6: Silence Speaks Volumes
Dr. Carlson also reviewed a subject about which the guideline is "silent." Namely, testing for CYP2D6 polymorphisms, which identify women who are less likely to respond to tamoxifen when it is used to reduce the risk for recurrence after treatment for early-stage breast cancer.
The "available studies are inconsistent" noted Dr. Carlson. Thus, the panel has chosen not to make a recommendation about using this marker to estimate how patients will respond to tamoxifen.
"You should interpret the silence as a recommendation not to [test for the polymorphisms]," he said.
Dr. Carlson reports receiving grant/research support from AstraZeneca, Genentech, and Sanofi-Aventis; and being a member of a Data Safety Monitoring Board for Pfizer.
National Comprehensive Cancer Network (NCCN) 16th Annual Conference. Presented March 10, 2011.
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