CHICAGO – Lapatinib was not superior to trastuzumab when used as a component of neoadjuvant therapy for operable HER2-positive breast cancer in a randomized cooperative group trial. And neither was a combination of both drugs in the population overall.
About 50%-60% of the 529 patients studied had a pathological complete response (pCR) whether they received trastuzumab (Herceptin) only, lapatinib (Tykerb) only, or lapatinib plus trastuzumab, each in addition to standard chemotherapy in the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-41 trial, investigators reported.
However, patients whose tumors had a high level of HER2 overexpression on immunohistochemistry, scored as 3+ staining, were more likely to have a pCR if they received lapatinib plus trastuzumab than if they received trastuzumab alone, Dr. Andre Robidoux told attendees at the annual meeting of the American Society of Clinical Oncology.
Of note, the rate of grade 3 or worse diarrhea was higher with lapatinib alone or in combination, the investigators found. And patients in those groups were less likely to complete their treatment.
"Combined HER2-targeted therapy produced a numerically higher pCR percentage than single-agent HER2-directed therapy, but the difference was not statistically significant," said Dr. Robidoux of the Centre Hospitalier de l’Université de Montréal
"Unplanned analysis based on immunohistochemical staining intensity suggests that combined HER2-targeted therapy may be of greatest value in patients with tumors with a high degree of protein overexpression," he added.
Dual Blockade Supported
Discussant Dr. Gunter von Minckwitz of the German Breast Group and the University of Frankfurt noted that neoadjuvant trastuzumab therapy increases the likelihood of residual ductal carcinoma in situ (DCIS) at surgery, which is a negative prognostic factor for disease-free survival (J. Clin. Oncol. 2012;30:901-3). "So maybe the NSABP investigators should also analyze their data for an even more pure pCR definition," he proposed.
"We have seen now a series of studies either combining lapatinib and trastuzumab or combining trastuzumab and pertuzumab [Perjeta] showing higher pCR rates compared to patients who got only one of the anti-HER2 treatments," he maintained. "So this is the way we have to go. ... Dual blockade appears to be the most promising approach for the future."
"We have to wait, of course, to see how far the neoadjuvant results are predicting the outcome of adjuvant treatment; therefore, ALTTO and APHINITY are crucial," Dr. von Minckwitz added, referring to two trials.
"However, I believe the results from the neoadjuvant setting are quite consistent with the results that are now obtained in other settings – the adjuvant and metastatic settings. Therefore, this might open a regulatory path for conditional approval of agents in early development," as recently proposed by the Food and Drug Administration (N. Engl. J. Med. 2012 May 30).
Giving background on NSABP B-41, Dr. Robidoux noted that doxorubicin (Adriamycin) plus cyclophosphamide, followed by weekly paclitaxel plus trastuzumab, has been a standard neoadjuvant therapy for HER2-positive breast cancer since 2005. But lapatinib, an oral dual tyrosine kinase inhibitor of HER2 and the epidermal growth factor receptor (EGFR), has a different mechanism of action and shows synergy with trastuzumab.
"The next logical step was to evaluate the addition of a second agent that interrupts HER2 signaling through a different mechanism than trastuzumab," he said.
PCR Rates Indistinguishable
Women enrolled in the trial had a palpable tumor measuring at least 2 cm, a left ventricular ejection fraction of at least 50%, and HER2-positive disease, defined as gene amplification by fluorescence in situ hybridization (FISH) or a score of 3+ by immunohistochemistry.
All women received four cycles of doxorubicin plus cyclophosphamide. Thereafter, they received weekly paclitaxel plus trastuzumab only (as a control), plus lapatinib only, or plus both. They then underwent surgery and received trastuzumab postoperatively.
The main results showed that the rate of clinical complete response with lapatinib alone (69.9%) was lower than that with trastuzumab alone (82%) (P = .014). But it did not differ significantly between trastuzumab and lapatinib plus trastuzumab (76.8%).
The rates of pCR in the breast with lapatinib alone (53.2%) or lapatinib combined with trastuzumab (62%) were statistically indistinguishable from that seen with trastuzumab alone (52.5%).
This pattern was the same in subgroups having hormone receptor–positive and negative disease. However, in a finding that Dr. Robidoux called "intriguing," the pCR rate among those with 3+ immunohistochemical staining for HER2 was higher with lapatinib plus trastuzumab (71%) than with trastuzumab alone (54.7%) (P = .006).
The overall rate of grade 3 or worse toxicity was 50% with trastuzumab alone, 62% with lapatinib alone, and 61% with lapatinib plus trastuzumab. Grade 3 or worse diarrhea was by far more common in both lapatinib groups (P less than .001), but grade 3 or worse febrile neutropenia and hepatotoxicity were similarly common.
The rate of New York Heart Association class III or IV congestive heart failure was 4% with trastuzumab alone, 4% with lapatinib alone, and 1% with the combination, differences that were not statistically significant.
Patients in the trastuzumab group were more likely to complete their therapy (78%) than their counterparts in the lapatinib group (68%) and in the combination group (63%) (P = .01).
About half of patients were able to have breast-conserving surgery, whether they received trastuzumab alone (54%), lapatinib alone (46%), or both drugs (50%).
Dr. Robidoux disclosed that he is a consultant to GlaxoSmithKline and receives honoraria and research funding from GlaxoSmithKline and Roche. Dr. von Minckwitz disclosed no relevant conflicts of interest.
Lapatinib, trastuzumab, HER2-positive breast cancer, Herceptin, NSABP (National Surgical Adjuvant Breast and Bowel Project) B-41 trial, Dr. Andre Robidoux
CHICAGO – Lapatinib was not superior to trastuzumab when used as a component of neoadjuvant therapy for operable HER2-positive breast cancer in a randomized cooperative group trial. And neither was a combination of both drugs in the population overall.
About 50%-60% of the 529 patients studied had a pathological complete response (pCR) whether they received trastuzumab (Herceptin) only, lapatinib (Tykerb) only, or lapatinib plus trastuzumab, each in addition to standard chemotherapy in the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-41 trial, investigators reported.
However, patients whose tumors had a high level of HER2 overexpression on immunohistochemistry, scored as 3+ staining, were more likely to have a pCR if they received lapatinib plus trastuzumab than if they received trastuzumab alone, Dr. Andre Robidoux told attendees at the annual meeting of the American Society of Clinical Oncology.
Of note, the rate of grade 3 or worse diarrhea was higher with lapatinib alone or in combination, the investigators found. And patients in those groups were less likely to complete their treatment.
"Combined HER2-targeted therapy produced a numerically higher pCR percentage than single-agent HER2-directed therapy, but the difference was not statistically significant," said Dr. Robidoux of the Centre Hospitalier de l’Université de Montréal
"Unplanned analysis based on immunohistochemical staining intensity suggests that combined HER2-targeted therapy may be of greatest value in patients with tumors with a high degree of protein overexpression," he added.
Dual Blockade Supported
Discussant Dr. Gunter von Minckwitz of the German Breast Group and the University of Frankfurt noted that neoadjuvant trastuzumab therapy increases the likelihood of residual ductal carcinoma in situ (DCIS) at surgery, which is a negative prognostic factor for disease-free survival (J. Clin. Oncol. 2012;30:901-3). "So maybe the NSABP investigators should also analyze their data for an even more pure pCR definition," he proposed.
"We have seen now a series of studies either combining lapatinib and trastuzumab or combining trastuzumab and pertuzumab [Perjeta] showing higher pCR rates compared to patients who got only one of the anti-HER2 treatments," he maintained. "So this is the way we have to go. ... Dual blockade appears to be the most promising approach for the future."
"We have to wait, of course, to see how far the neoadjuvant results are predicting the outcome of adjuvant treatment; therefore, ALTTO and APHINITY are crucial," Dr. von Minckwitz added, referring to two trials.
"However, I believe the results from the neoadjuvant setting are quite consistent with the results that are now obtained in other settings – the adjuvant and metastatic settings. Therefore, this might open a regulatory path for conditional approval of agents in early development," as recently proposed by the Food and Drug Administration (N. Engl. J. Med. 2012 May 30).
Giving background on NSABP B-41, Dr. Robidoux noted that doxorubicin (Adriamycin) plus cyclophosphamide, followed by weekly paclitaxel plus trastuzumab, has been a standard neoadjuvant therapy for HER2-positive breast cancer since 2005. But lapatinib, an oral dual tyrosine kinase inhibitor of HER2 and the epidermal growth factor receptor (EGFR), has a different mechanism of action and shows synergy with trastuzumab.
"The next logical step was to evaluate the addition of a second agent that interrupts HER2 signaling through a different mechanism than trastuzumab," he said.
PCR Rates Indistinguishable
Women enrolled in the trial had a palpable tumor measuring at least 2 cm, a left ventricular ejection fraction of at least 50%, and HER2-positive disease, defined as gene amplification by fluorescence in situ hybridization (FISH) or a score of 3+ by immunohistochemistry.
All women received four cycles of doxorubicin plus cyclophosphamide. Thereafter, they received weekly paclitaxel plus trastuzumab only (as a control), plus lapatinib only, or plus both. They then underwent surgery and received trastuzumab postoperatively.
The main results showed that the rate of clinical complete response with lapatinib alone (69.9%) was lower than that with trastuzumab alone (82%) (P = .014). But it did not differ significantly between trastuzumab and lapatinib plus trastuzumab (76.8%).
The rates of pCR in the breast with lapatinib alone (53.2%) or lapatinib combined with trastuzumab (62%) were statistically indistinguishable from that seen with trastuzumab alone (52.5%).
This pattern was the same in subgroups having hormone receptor–positive and negative disease. However, in a finding that Dr. Robidoux called "intriguing," the pCR rate among those with 3+ immunohistochemical staining for HER2 was higher with lapatinib plus trastuzumab (71%) than with trastuzumab alone (54.7%) (P = .006).
The overall rate of grade 3 or worse toxicity was 50% with trastuzumab alone, 62% with lapatinib alone, and 61% with lapatinib plus trastuzumab. Grade 3 or worse diarrhea was by far more common in both lapatinib groups (P less than .001), but grade 3 or worse febrile neutropenia and hepatotoxicity were similarly common.
The rate of New York Heart Association class III or IV congestive heart failure was 4% with trastuzumab alone, 4% with lapatinib alone, and 1% with the combination, differences that were not statistically significant.
Patients in the trastuzumab group were more likely to complete their therapy (78%) than their counterparts in the lapatinib group (68%) and in the combination group (63%) (P = .01).
About half of patients were able to have breast-conserving surgery, whether they received trastuzumab alone (54%), lapatinib alone (46%), or both drugs (50%).
Dr. Robidoux disclosed that he is a consultant to GlaxoSmithKline and receives honoraria and research funding from GlaxoSmithKline and Roche. Dr. von Minckwitz disclosed no relevant conflicts of interest.
CHICAGO – Lapatinib was not superior to trastuzumab when used as a component of neoadjuvant therapy for operable HER2-positive breast cancer in a randomized cooperative group trial. And neither was a combination of both drugs in the population overall.
About 50%-60% of the 529 patients studied had a pathological complete response (pCR) whether they received trastuzumab (Herceptin) only, lapatinib (Tykerb) only, or lapatinib plus trastuzumab, each in addition to standard chemotherapy in the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-41 trial, investigators reported.
However, patients whose tumors had a high level of HER2 overexpression on immunohistochemistry, scored as 3+ staining, were more likely to have a pCR if they received lapatinib plus trastuzumab than if they received trastuzumab alone, Dr. Andre Robidoux told attendees at the annual meeting of the American Society of Clinical Oncology.
Of note, the rate of grade 3 or worse diarrhea was higher with lapatinib alone or in combination, the investigators found. And patients in those groups were less likely to complete their treatment.
"Combined HER2-targeted therapy produced a numerically higher pCR percentage than single-agent HER2-directed therapy, but the difference was not statistically significant," said Dr. Robidoux of the Centre Hospitalier de l’Université de Montréal
"Unplanned analysis based on immunohistochemical staining intensity suggests that combined HER2-targeted therapy may be of greatest value in patients with tumors with a high degree of protein overexpression," he added.
Dual Blockade Supported
Discussant Dr. Gunter von Minckwitz of the German Breast Group and the University of Frankfurt noted that neoadjuvant trastuzumab therapy increases the likelihood of residual ductal carcinoma in situ (DCIS) at surgery, which is a negative prognostic factor for disease-free survival (J. Clin. Oncol. 2012;30:901-3). "So maybe the NSABP investigators should also analyze their data for an even more pure pCR definition," he proposed.
"We have seen now a series of studies either combining lapatinib and trastuzumab or combining trastuzumab and pertuzumab [Perjeta] showing higher pCR rates compared to patients who got only one of the anti-HER2 treatments," he maintained. "So this is the way we have to go. ... Dual blockade appears to be the most promising approach for the future."
"We have to wait, of course, to see how far the neoadjuvant results are predicting the outcome of adjuvant treatment; therefore, ALTTO and APHINITY are crucial," Dr. von Minckwitz added, referring to two trials.
"However, I believe the results from the neoadjuvant setting are quite consistent with the results that are now obtained in other settings – the adjuvant and metastatic settings. Therefore, this might open a regulatory path for conditional approval of agents in early development," as recently proposed by the Food and Drug Administration (N. Engl. J. Med. 2012 May 30).
Giving background on NSABP B-41, Dr. Robidoux noted that doxorubicin (Adriamycin) plus cyclophosphamide, followed by weekly paclitaxel plus trastuzumab, has been a standard neoadjuvant therapy for HER2-positive breast cancer since 2005. But lapatinib, an oral dual tyrosine kinase inhibitor of HER2 and the epidermal growth factor receptor (EGFR), has a different mechanism of action and shows synergy with trastuzumab.
"The next logical step was to evaluate the addition of a second agent that interrupts HER2 signaling through a different mechanism than trastuzumab," he said.
PCR Rates Indistinguishable
Women enrolled in the trial had a palpable tumor measuring at least 2 cm, a left ventricular ejection fraction of at least 50%, and HER2-positive disease, defined as gene amplification by fluorescence in situ hybridization (FISH) or a score of 3+ by immunohistochemistry.
All women received four cycles of doxorubicin plus cyclophosphamide. Thereafter, they received weekly paclitaxel plus trastuzumab only (as a control), plus lapatinib only, or plus both. They then underwent surgery and received trastuzumab postoperatively.
The main results showed that the rate of clinical complete response with lapatinib alone (69.9%) was lower than that with trastuzumab alone (82%) (P = .014). But it did not differ significantly between trastuzumab and lapatinib plus trastuzumab (76.8%).
The rates of pCR in the breast with lapatinib alone (53.2%) or lapatinib combined with trastuzumab (62%) were statistically indistinguishable from that seen with trastuzumab alone (52.5%).
This pattern was the same in subgroups having hormone receptor–positive and negative disease. However, in a finding that Dr. Robidoux called "intriguing," the pCR rate among those with 3+ immunohistochemical staining for HER2 was higher with lapatinib plus trastuzumab (71%) than with trastuzumab alone (54.7%) (P = .006).
The overall rate of grade 3 or worse toxicity was 50% with trastuzumab alone, 62% with lapatinib alone, and 61% with lapatinib plus trastuzumab. Grade 3 or worse diarrhea was by far more common in both lapatinib groups (P less than .001), but grade 3 or worse febrile neutropenia and hepatotoxicity were similarly common.
The rate of New York Heart Association class III or IV congestive heart failure was 4% with trastuzumab alone, 4% with lapatinib alone, and 1% with the combination, differences that were not statistically significant.
Patients in the trastuzumab group were more likely to complete their therapy (78%) than their counterparts in the lapatinib group (68%) and in the combination group (63%) (P = .01).
About half of patients were able to have breast-conserving surgery, whether they received trastuzumab alone (54%), lapatinib alone (46%), or both drugs (50%).
Dr. Robidoux disclosed that he is a consultant to GlaxoSmithKline and receives honoraria and research funding from GlaxoSmithKline and Roche. Dr. von Minckwitz disclosed no relevant conflicts of interest.
Neoadjuvant Lapatinib Fails to Surpass Trastuzumab in HER2+ Breast Cancer
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Neoadjuvant Lapatinib Fails to Surpass Trastuzumab in HER2+ Breast Cancer
Legacy Keywords
Lapatinib, trastuzumab, HER2-positive breast cancer, Herceptin, NSABP (National Surgical Adjuvant Breast and Bowel Project) B-41 trial, Dr. Andre Robidoux
Legacy Keywords
Lapatinib, trastuzumab, HER2-positive breast cancer, Herceptin, NSABP (National Surgical Adjuvant Breast and Bowel Project) B-41 trial, Dr. Andre Robidoux
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AT THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY
CHICAGO – Radiation therapy dramatically improves local control in ductal carcinoma in situ, even in cases having favorable features, investigators reported.
The randomized Radiation Therapy Oncology Group (RTOG) 9804 trial was conducted among 585 women who had "good-risk" ductal carcinoma in situ (DCIS), meaning small, asymptomatic tumors of low grade and with adequate resection margins after lumpectomy.
Dr. Beryl McCormick
The main results showed that women had a significant 86% relative reduction in the risk of local failure if they received radiation therapy instead of observation. But the absolute 5-year rate of local failure was only about 3%, even without this intervention.
"We were able, using standard pathology methods and our Web-based RTOG pathology tool, to define good-risk or low-risk DCIS patients who had an extremely low event rate even with observation," said lead investigator Dr. Beryl McCormick at the annual meeting of the American Society of Clinical Oncology.
Nonetheless, "for this good-risk disease, the addition of radiation significantly reduced the risk of local failure. Clearly, we are expecting to follow this group out longer," added Dr. McCormick, a radiation oncologist and chief of the external beam radiotherapy service at Memorial Sloan-Kettering Cancer Center in New York.
"The study was a positive study," commented discussant Dr. Eun-Sil Shelley Hwang of Duke University Medical Center in Durham, N.C. "The reasons for that are debatable. On this analysis, there was a lower recurrence rate in the excision-only group than had been predicted, but what drove the positive findings was the much lower rate in the radiation therapy group."
Dr. Hwang speculated that the use of tamoxifen by about two-thirds of women may have contributed to the low rate of local recurrence seen even in the absence of radiation therapy.
"Further follow-up is required, because many of these patients [had] a short follow-up that may explain why we saw such low recurrence risks in this study," she proposed.
Women with DCIS who were above age 26 were eligible for RTOG 9804 if they had no symptoms (their tumors had been found mammographically or incidentally), had only low or intermediate tumor grade, had a tumor size of 2.5 cm or less, and had a resection margin width of at least 3 mm.
The 585 study participants were randomly assigned in balanced fashion to observation or radiation therapy, each with or without tamoxifen. (Overall, 62% received the drug.) Radiation therapy began within 12 weeks of final surgery, and consisted of 42.5-50.4 Gy, with no boost.
The main trial results showed that the actuarial 5-year rate of local failure (invasive or noninvasive) in the treated breast was 3.2% in the observation group and 0.4% in the radiation therapy group, corresponding to an 86% reduction in risk (hazard ratio, 0.14; P = .002), Dr. McCormick reported.
In the radiation therapy group, there were no local failures in the same quadrant as the original tumor; in contrast, in the observation group, two-thirds of the failures were in the same quadrant.
The two groups were statistically indistinguishable with respect to the rate of contralateral breast events, disease-free survival, and overall survival.
The rate of acute grade 3 or worse nonhematologic toxicities was similar in the observation group and radiation therapy group (4.0% vs. 4.2%, respectively), although lower-grade toxicities were more common in the latter. The rate of late grade 3 or worse radiation therapy toxicity was 0.7% in the group given this therapy.
Dr. McCormick disclosed no relevant conflicts of interest. Dr. Hwang disclosed that she is a consultant to Genomic Health and receives research funding from Merck and Novartis.
radiation therapy, breast cancer, Dr. Beryl McCormick, ductal carcinoma in situ (DCIS), Dr. Eun-Sil Shelley Hwang , ASCO, American Society of Clinical Oncology
CHICAGO – Radiation therapy dramatically improves local control in ductal carcinoma in situ, even in cases having favorable features, investigators reported.
The randomized Radiation Therapy Oncology Group (RTOG) 9804 trial was conducted among 585 women who had "good-risk" ductal carcinoma in situ (DCIS), meaning small, asymptomatic tumors of low grade and with adequate resection margins after lumpectomy.
Dr. Beryl McCormick
The main results showed that women had a significant 86% relative reduction in the risk of local failure if they received radiation therapy instead of observation. But the absolute 5-year rate of local failure was only about 3%, even without this intervention.
"We were able, using standard pathology methods and our Web-based RTOG pathology tool, to define good-risk or low-risk DCIS patients who had an extremely low event rate even with observation," said lead investigator Dr. Beryl McCormick at the annual meeting of the American Society of Clinical Oncology.
Nonetheless, "for this good-risk disease, the addition of radiation significantly reduced the risk of local failure. Clearly, we are expecting to follow this group out longer," added Dr. McCormick, a radiation oncologist and chief of the external beam radiotherapy service at Memorial Sloan-Kettering Cancer Center in New York.
"The study was a positive study," commented discussant Dr. Eun-Sil Shelley Hwang of Duke University Medical Center in Durham, N.C. "The reasons for that are debatable. On this analysis, there was a lower recurrence rate in the excision-only group than had been predicted, but what drove the positive findings was the much lower rate in the radiation therapy group."
Dr. Hwang speculated that the use of tamoxifen by about two-thirds of women may have contributed to the low rate of local recurrence seen even in the absence of radiation therapy.
"Further follow-up is required, because many of these patients [had] a short follow-up that may explain why we saw such low recurrence risks in this study," she proposed.
Women with DCIS who were above age 26 were eligible for RTOG 9804 if they had no symptoms (their tumors had been found mammographically or incidentally), had only low or intermediate tumor grade, had a tumor size of 2.5 cm or less, and had a resection margin width of at least 3 mm.
The 585 study participants were randomly assigned in balanced fashion to observation or radiation therapy, each with or without tamoxifen. (Overall, 62% received the drug.) Radiation therapy began within 12 weeks of final surgery, and consisted of 42.5-50.4 Gy, with no boost.
The main trial results showed that the actuarial 5-year rate of local failure (invasive or noninvasive) in the treated breast was 3.2% in the observation group and 0.4% in the radiation therapy group, corresponding to an 86% reduction in risk (hazard ratio, 0.14; P = .002), Dr. McCormick reported.
In the radiation therapy group, there were no local failures in the same quadrant as the original tumor; in contrast, in the observation group, two-thirds of the failures were in the same quadrant.
The two groups were statistically indistinguishable with respect to the rate of contralateral breast events, disease-free survival, and overall survival.
The rate of acute grade 3 or worse nonhematologic toxicities was similar in the observation group and radiation therapy group (4.0% vs. 4.2%, respectively), although lower-grade toxicities were more common in the latter. The rate of late grade 3 or worse radiation therapy toxicity was 0.7% in the group given this therapy.
Dr. McCormick disclosed no relevant conflicts of interest. Dr. Hwang disclosed that she is a consultant to Genomic Health and receives research funding from Merck and Novartis.
CHICAGO – Radiation therapy dramatically improves local control in ductal carcinoma in situ, even in cases having favorable features, investigators reported.
The randomized Radiation Therapy Oncology Group (RTOG) 9804 trial was conducted among 585 women who had "good-risk" ductal carcinoma in situ (DCIS), meaning small, asymptomatic tumors of low grade and with adequate resection margins after lumpectomy.
Dr. Beryl McCormick
The main results showed that women had a significant 86% relative reduction in the risk of local failure if they received radiation therapy instead of observation. But the absolute 5-year rate of local failure was only about 3%, even without this intervention.
"We were able, using standard pathology methods and our Web-based RTOG pathology tool, to define good-risk or low-risk DCIS patients who had an extremely low event rate even with observation," said lead investigator Dr. Beryl McCormick at the annual meeting of the American Society of Clinical Oncology.
Nonetheless, "for this good-risk disease, the addition of radiation significantly reduced the risk of local failure. Clearly, we are expecting to follow this group out longer," added Dr. McCormick, a radiation oncologist and chief of the external beam radiotherapy service at Memorial Sloan-Kettering Cancer Center in New York.
"The study was a positive study," commented discussant Dr. Eun-Sil Shelley Hwang of Duke University Medical Center in Durham, N.C. "The reasons for that are debatable. On this analysis, there was a lower recurrence rate in the excision-only group than had been predicted, but what drove the positive findings was the much lower rate in the radiation therapy group."
Dr. Hwang speculated that the use of tamoxifen by about two-thirds of women may have contributed to the low rate of local recurrence seen even in the absence of radiation therapy.
"Further follow-up is required, because many of these patients [had] a short follow-up that may explain why we saw such low recurrence risks in this study," she proposed.
Women with DCIS who were above age 26 were eligible for RTOG 9804 if they had no symptoms (their tumors had been found mammographically or incidentally), had only low or intermediate tumor grade, had a tumor size of 2.5 cm or less, and had a resection margin width of at least 3 mm.
The 585 study participants were randomly assigned in balanced fashion to observation or radiation therapy, each with or without tamoxifen. (Overall, 62% received the drug.) Radiation therapy began within 12 weeks of final surgery, and consisted of 42.5-50.4 Gy, with no boost.
The main trial results showed that the actuarial 5-year rate of local failure (invasive or noninvasive) in the treated breast was 3.2% in the observation group and 0.4% in the radiation therapy group, corresponding to an 86% reduction in risk (hazard ratio, 0.14; P = .002), Dr. McCormick reported.
In the radiation therapy group, there were no local failures in the same quadrant as the original tumor; in contrast, in the observation group, two-thirds of the failures were in the same quadrant.
The two groups were statistically indistinguishable with respect to the rate of contralateral breast events, disease-free survival, and overall survival.
The rate of acute grade 3 or worse nonhematologic toxicities was similar in the observation group and radiation therapy group (4.0% vs. 4.2%, respectively), although lower-grade toxicities were more common in the latter. The rate of late grade 3 or worse radiation therapy toxicity was 0.7% in the group given this therapy.
Dr. McCormick disclosed no relevant conflicts of interest. Dr. Hwang disclosed that she is a consultant to Genomic Health and receives research funding from Merck and Novartis.
Radiation Therapy Beneficial Even for 'Good-Risk' Ductal Carcinoma
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Radiation Therapy Beneficial Even for 'Good-Risk' Ductal Carcinoma
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radiation therapy, breast cancer, Dr. Beryl McCormick, ductal carcinoma in situ (DCIS), Dr. Eun-Sil Shelley Hwang , ASCO, American Society of Clinical Oncology
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radiation therapy, breast cancer, Dr. Beryl McCormick, ductal carcinoma in situ (DCIS), Dr. Eun-Sil Shelley Hwang , ASCO, American Society of Clinical Oncology
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AT THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY
CHICAGO – The new DCIS score, an offshoot of the Oncotype DX recurrence score, independently predicts the risk of ipsilateral recurrence or invasive disease in patients with ductal carcinoma in situ, according to a subgroup analysis from the prospective validation study.
The score correlated only moderately, poorly, or not at all with measures such as menopausal status and histologic grade among 327 patients with ductal carcinoma in situ (DCIS) treated with wide local excision and without radiation therapy, investigators reported.
And even after such measures were taken into account, each 50-point increase in the 100-point score was significantly associated with more than a doubling of the 10-year risk of recurrence or invasive disease in the same breast.
"The DCIS score provides independent information on ipsilateral breast risk beyond clinical and pathologic variables," lead author Dr. Sunil S. Badve said at the annual meeting of the American Society of Clinical Oncology.
"One can use the DCIS score to select patients with ... a clinically good prognosis who may have a higher DCIS score and may have a slightly [greater] risk than one would have estimated by traditional criteria," added Dr. Badve, a professor in the department of pathology and laboratory medicine and the department of internal medicine, and director of the Translational Genomics Core at Indiana University, Indianapolis.
"So particularly for the subset with a clinically good prognosis, we may be able to dissect which patients really might have a better prognosis and which patients may need to be more cautious."
Discussant Dr. Eun-Sil Shelley Hwang of Duke University Medical Center in Durham, N.C., called particular attention to the weak association between nuclear grade and DCIS Score.
"This is a very important point to make and a response to the criticism that’s often heard that the DCIS score or the Oncotype score may just be a surrogate – and a very expensive one – for proliferative index or Ki-67," she commented.
Next-generation sequencing and advances in epigenomics, proteomics, and molecular characterization of stroma are likely to make it possible to further risk-stratify DCIS in the future, according to Dr. Hwang.
"But none of this is important unless we can implement it into treatment of patients. So how this is implemented in our everyday practice will be very important to analyze – whether it impacts decision making, and whether it gives patients satisfaction with the decisions they make will also be very important to look at," she added.
"Finally, in this increasingly resource-constrained environment, cost-effectiveness issues will also be very important to analyze as we go forward," she noted.
Study analyses were based on a subset of women from the E5194 trial, a prospective study to validate the DCIS score, which contains 12 of the 21 genes included in the Oncotype DX recurrence score used in estrogen receptor–positive early-stage breast cancer.
All of the women had DCIS treated with wide local excision. They had a median age of 61 years and a median tumor size of 7 mm. Twenty-nine percent received tamoxifen. The median duration of follow-up was 8.8 years.
Results showed that the DCIS score was only moderately correlated with histologic grade (r = 0.41-0.46) and with the percentage of cells showing comedo necrosis (r = 0.49), and was poorly correlated with tumor size (r = 0.18), Dr. Badve reported. And there was no correlation with age, menopausal status, DCIS histologic pattern, or margin status.
In a multivariate analysis, each 50-point increase in DCIS score was associated with more than a doubling of the risk of a recurrence of DCIS or the occurrence of invasive disease in the ipsilateral breast (hazard ratio, 2.41; P = .02).
In addition, tumor size was an independent positive predictor of risk (HR for each 5-mm increase, 1.52; P = .01), and postmenopausal status was an independent negative predictor (HR, 0.49; P = .02).
Dr. Badve disclosed that he is a consultant to Genomic Health, which makes the assay. Dr. Hwang disclosed that she is a consultant to Genomic Health and receives research funding from Merck and Novartis.
CHICAGO – The new DCIS score, an offshoot of the Oncotype DX recurrence score, independently predicts the risk of ipsilateral recurrence or invasive disease in patients with ductal carcinoma in situ, according to a subgroup analysis from the prospective validation study.
The score correlated only moderately, poorly, or not at all with measures such as menopausal status and histologic grade among 327 patients with ductal carcinoma in situ (DCIS) treated with wide local excision and without radiation therapy, investigators reported.
And even after such measures were taken into account, each 50-point increase in the 100-point score was significantly associated with more than a doubling of the 10-year risk of recurrence or invasive disease in the same breast.
"The DCIS score provides independent information on ipsilateral breast risk beyond clinical and pathologic variables," lead author Dr. Sunil S. Badve said at the annual meeting of the American Society of Clinical Oncology.
"One can use the DCIS score to select patients with ... a clinically good prognosis who may have a higher DCIS score and may have a slightly [greater] risk than one would have estimated by traditional criteria," added Dr. Badve, a professor in the department of pathology and laboratory medicine and the department of internal medicine, and director of the Translational Genomics Core at Indiana University, Indianapolis.
"So particularly for the subset with a clinically good prognosis, we may be able to dissect which patients really might have a better prognosis and which patients may need to be more cautious."
Discussant Dr. Eun-Sil Shelley Hwang of Duke University Medical Center in Durham, N.C., called particular attention to the weak association between nuclear grade and DCIS Score.
"This is a very important point to make and a response to the criticism that’s often heard that the DCIS score or the Oncotype score may just be a surrogate – and a very expensive one – for proliferative index or Ki-67," she commented.
Next-generation sequencing and advances in epigenomics, proteomics, and molecular characterization of stroma are likely to make it possible to further risk-stratify DCIS in the future, according to Dr. Hwang.
"But none of this is important unless we can implement it into treatment of patients. So how this is implemented in our everyday practice will be very important to analyze – whether it impacts decision making, and whether it gives patients satisfaction with the decisions they make will also be very important to look at," she added.
"Finally, in this increasingly resource-constrained environment, cost-effectiveness issues will also be very important to analyze as we go forward," she noted.
Study analyses were based on a subset of women from the E5194 trial, a prospective study to validate the DCIS score, which contains 12 of the 21 genes included in the Oncotype DX recurrence score used in estrogen receptor–positive early-stage breast cancer.
All of the women had DCIS treated with wide local excision. They had a median age of 61 years and a median tumor size of 7 mm. Twenty-nine percent received tamoxifen. The median duration of follow-up was 8.8 years.
Results showed that the DCIS score was only moderately correlated with histologic grade (r = 0.41-0.46) and with the percentage of cells showing comedo necrosis (r = 0.49), and was poorly correlated with tumor size (r = 0.18), Dr. Badve reported. And there was no correlation with age, menopausal status, DCIS histologic pattern, or margin status.
In a multivariate analysis, each 50-point increase in DCIS score was associated with more than a doubling of the risk of a recurrence of DCIS or the occurrence of invasive disease in the ipsilateral breast (hazard ratio, 2.41; P = .02).
In addition, tumor size was an independent positive predictor of risk (HR for each 5-mm increase, 1.52; P = .01), and postmenopausal status was an independent negative predictor (HR, 0.49; P = .02).
Dr. Badve disclosed that he is a consultant to Genomic Health, which makes the assay. Dr. Hwang disclosed that she is a consultant to Genomic Health and receives research funding from Merck and Novartis.
CHICAGO – The new DCIS score, an offshoot of the Oncotype DX recurrence score, independently predicts the risk of ipsilateral recurrence or invasive disease in patients with ductal carcinoma in situ, according to a subgroup analysis from the prospective validation study.
The score correlated only moderately, poorly, or not at all with measures such as menopausal status and histologic grade among 327 patients with ductal carcinoma in situ (DCIS) treated with wide local excision and without radiation therapy, investigators reported.
And even after such measures were taken into account, each 50-point increase in the 100-point score was significantly associated with more than a doubling of the 10-year risk of recurrence or invasive disease in the same breast.
"The DCIS score provides independent information on ipsilateral breast risk beyond clinical and pathologic variables," lead author Dr. Sunil S. Badve said at the annual meeting of the American Society of Clinical Oncology.
"One can use the DCIS score to select patients with ... a clinically good prognosis who may have a higher DCIS score and may have a slightly [greater] risk than one would have estimated by traditional criteria," added Dr. Badve, a professor in the department of pathology and laboratory medicine and the department of internal medicine, and director of the Translational Genomics Core at Indiana University, Indianapolis.
"So particularly for the subset with a clinically good prognosis, we may be able to dissect which patients really might have a better prognosis and which patients may need to be more cautious."
Discussant Dr. Eun-Sil Shelley Hwang of Duke University Medical Center in Durham, N.C., called particular attention to the weak association between nuclear grade and DCIS Score.
"This is a very important point to make and a response to the criticism that’s often heard that the DCIS score or the Oncotype score may just be a surrogate – and a very expensive one – for proliferative index or Ki-67," she commented.
Next-generation sequencing and advances in epigenomics, proteomics, and molecular characterization of stroma are likely to make it possible to further risk-stratify DCIS in the future, according to Dr. Hwang.
"But none of this is important unless we can implement it into treatment of patients. So how this is implemented in our everyday practice will be very important to analyze – whether it impacts decision making, and whether it gives patients satisfaction with the decisions they make will also be very important to look at," she added.
"Finally, in this increasingly resource-constrained environment, cost-effectiveness issues will also be very important to analyze as we go forward," she noted.
Study analyses were based on a subset of women from the E5194 trial, a prospective study to validate the DCIS score, which contains 12 of the 21 genes included in the Oncotype DX recurrence score used in estrogen receptor–positive early-stage breast cancer.
All of the women had DCIS treated with wide local excision. They had a median age of 61 years and a median tumor size of 7 mm. Twenty-nine percent received tamoxifen. The median duration of follow-up was 8.8 years.
Results showed that the DCIS score was only moderately correlated with histologic grade (r = 0.41-0.46) and with the percentage of cells showing comedo necrosis (r = 0.49), and was poorly correlated with tumor size (r = 0.18), Dr. Badve reported. And there was no correlation with age, menopausal status, DCIS histologic pattern, or margin status.
In a multivariate analysis, each 50-point increase in DCIS score was associated with more than a doubling of the risk of a recurrence of DCIS or the occurrence of invasive disease in the ipsilateral breast (hazard ratio, 2.41; P = .02).
In addition, tumor size was an independent positive predictor of risk (HR for each 5-mm increase, 1.52; P = .01), and postmenopausal status was an independent negative predictor (HR, 0.49; P = .02).
Dr. Badve disclosed that he is a consultant to Genomic Health, which makes the assay. Dr. Hwang disclosed that she is a consultant to Genomic Health and receives research funding from Merck and Novartis.
CHICAGO – Delegates to the American Medical Association’s legislative body are not happy with the U.S. Preventive Services Task Force.
They voted overwhelmingly (322 to 93) to express "concern" over the task force’s recommendations on screening mammography and prostate-specific antigen screening. Both recommendations attracted a firestorm of criticism when they were issued – the mammography recommendation in 2009 and those on PSA testing in May.
Many delegates also said they thought that the USPSTF, a quasi-governmental group operating under the auspices of the Agency for Healthcare Research and Quality, had reached its decisions without proper input from specialty societies or experts in each field.
In a second resolution, the delegates voted to encourage the USPSTF to "implement procedures that allow for meaningful input on recommendation development from specialists and stakeholders in the topic area under study."
Alicia Ault/IMNG Medical Media
"None of the recognized experts in the field were contacted, to the best of our knowledge," said Dr. Arl Van Moore of the American College of Radiology.
Dr. Arl Van Moore Jr., a delegate from the American College of Radiology, said that neither the ACR nor any prominent breast imaging or surgical societies were contacted by the USPSTF in creating the screening mammography recommendations.
"None of the recognized experts in the field were contacted, to the best of our knowledge," said Dr. Moore, an interventional radiologist in Charlotte, N.C.
The American Urological Association delegate, Dr. William Gee, did not mince words when it came to the PSA screening guidelines.
"The [USPSTF] did not use an open process and ignored the public in reaching their conclusions," he said.
But Dr. Sally J. Trippel, a preventive medicine specialist at the Mayo Clinic and delegate from Minnesota, defended the USPSTF and its process. The task force is "about as politically independent as any national organization can get," and "about as free of conflict of interest as is possible in any organization developing guidelines for American clinicians," she said.
She quoted from task force documents showing that urologists provided peer review of the PSA evidence review. "So there were experts from urology involved in the development of that guideline," and also for the one on screening mammography.
To further show its consternation with the task force, AMA delegates also approved a report that stated that starting at age 40, women should be "eligible for screening mammography," and encouraging physicians "to regularly discuss with their individual patients the benefits and risks of screening mammography, and whether screening is appropriate for each clinical situation given that the balance of benefits and risks will be viewed differently by each patient."
Primary care delegates from the American Academy of Family Physicians and the American College of Physicians opposed the resolutions of concern against the USPSTF and the mammography report.
The AAFP supported the task force when it issued its mammography recommendations "because it was the most comprehensive pattern and set of preventive guidelines using current methodology with what was available in science at that time," said Dr. Roland Goertz, AAFP delegate.
The task force basically recommends what the AMA report urged: that physicians have discussions with their patients about risks and benefits, he said. The problem is not the USPSTF recommendations, but that they are being used to deny payment, he added.
Alicia Ault/IMNG Medical Media
Dr. William Golden, delegate from ACP, said that the AMA House of Delegates was not the correct venue to decide on clinical guidelines.
Dr. Richard Reiling, a delegate from the American College of Surgeons, said that the task force had confused patients with its mammography recommendation, and called for the AMA to convene all interested parties to craft a single guideline. The USPSTF was "wrong in presenting this report without listening to the stakeholders in the past," he said, adding, "let’s get one guideline out there."
Dr. Goertz agreed that there needed to be a common guideline.
ACP Delegate Dr. William Golden expressed the ACP’s view that the House of Delegates was not the appropriate venue for voting on particular guidelines. "The House should not be in the position of voting on what guideline is best," he said.
CHICAGO – Delegates to the American Medical Association’s legislative body are not happy with the U.S. Preventive Services Task Force.
They voted overwhelmingly (322 to 93) to express "concern" over the task force’s recommendations on screening mammography and prostate-specific antigen screening. Both recommendations attracted a firestorm of criticism when they were issued – the mammography recommendation in 2009 and those on PSA testing in May.
Many delegates also said they thought that the USPSTF, a quasi-governmental group operating under the auspices of the Agency for Healthcare Research and Quality, had reached its decisions without proper input from specialty societies or experts in each field.
In a second resolution, the delegates voted to encourage the USPSTF to "implement procedures that allow for meaningful input on recommendation development from specialists and stakeholders in the topic area under study."
Alicia Ault/IMNG Medical Media
"None of the recognized experts in the field were contacted, to the best of our knowledge," said Dr. Arl Van Moore of the American College of Radiology.
Dr. Arl Van Moore Jr., a delegate from the American College of Radiology, said that neither the ACR nor any prominent breast imaging or surgical societies were contacted by the USPSTF in creating the screening mammography recommendations.
"None of the recognized experts in the field were contacted, to the best of our knowledge," said Dr. Moore, an interventional radiologist in Charlotte, N.C.
The American Urological Association delegate, Dr. William Gee, did not mince words when it came to the PSA screening guidelines.
"The [USPSTF] did not use an open process and ignored the public in reaching their conclusions," he said.
But Dr. Sally J. Trippel, a preventive medicine specialist at the Mayo Clinic and delegate from Minnesota, defended the USPSTF and its process. The task force is "about as politically independent as any national organization can get," and "about as free of conflict of interest as is possible in any organization developing guidelines for American clinicians," she said.
She quoted from task force documents showing that urologists provided peer review of the PSA evidence review. "So there were experts from urology involved in the development of that guideline," and also for the one on screening mammography.
To further show its consternation with the task force, AMA delegates also approved a report that stated that starting at age 40, women should be "eligible for screening mammography," and encouraging physicians "to regularly discuss with their individual patients the benefits and risks of screening mammography, and whether screening is appropriate for each clinical situation given that the balance of benefits and risks will be viewed differently by each patient."
Primary care delegates from the American Academy of Family Physicians and the American College of Physicians opposed the resolutions of concern against the USPSTF and the mammography report.
The AAFP supported the task force when it issued its mammography recommendations "because it was the most comprehensive pattern and set of preventive guidelines using current methodology with what was available in science at that time," said Dr. Roland Goertz, AAFP delegate.
The task force basically recommends what the AMA report urged: that physicians have discussions with their patients about risks and benefits, he said. The problem is not the USPSTF recommendations, but that they are being used to deny payment, he added.
Alicia Ault/IMNG Medical Media
Dr. William Golden, delegate from ACP, said that the AMA House of Delegates was not the correct venue to decide on clinical guidelines.
Dr. Richard Reiling, a delegate from the American College of Surgeons, said that the task force had confused patients with its mammography recommendation, and called for the AMA to convene all interested parties to craft a single guideline. The USPSTF was "wrong in presenting this report without listening to the stakeholders in the past," he said, adding, "let’s get one guideline out there."
Dr. Goertz agreed that there needed to be a common guideline.
ACP Delegate Dr. William Golden expressed the ACP’s view that the House of Delegates was not the appropriate venue for voting on particular guidelines. "The House should not be in the position of voting on what guideline is best," he said.
CHICAGO – Delegates to the American Medical Association’s legislative body are not happy with the U.S. Preventive Services Task Force.
They voted overwhelmingly (322 to 93) to express "concern" over the task force’s recommendations on screening mammography and prostate-specific antigen screening. Both recommendations attracted a firestorm of criticism when they were issued – the mammography recommendation in 2009 and those on PSA testing in May.
Many delegates also said they thought that the USPSTF, a quasi-governmental group operating under the auspices of the Agency for Healthcare Research and Quality, had reached its decisions without proper input from specialty societies or experts in each field.
In a second resolution, the delegates voted to encourage the USPSTF to "implement procedures that allow for meaningful input on recommendation development from specialists and stakeholders in the topic area under study."
Alicia Ault/IMNG Medical Media
"None of the recognized experts in the field were contacted, to the best of our knowledge," said Dr. Arl Van Moore of the American College of Radiology.
Dr. Arl Van Moore Jr., a delegate from the American College of Radiology, said that neither the ACR nor any prominent breast imaging or surgical societies were contacted by the USPSTF in creating the screening mammography recommendations.
"None of the recognized experts in the field were contacted, to the best of our knowledge," said Dr. Moore, an interventional radiologist in Charlotte, N.C.
The American Urological Association delegate, Dr. William Gee, did not mince words when it came to the PSA screening guidelines.
"The [USPSTF] did not use an open process and ignored the public in reaching their conclusions," he said.
But Dr. Sally J. Trippel, a preventive medicine specialist at the Mayo Clinic and delegate from Minnesota, defended the USPSTF and its process. The task force is "about as politically independent as any national organization can get," and "about as free of conflict of interest as is possible in any organization developing guidelines for American clinicians," she said.
She quoted from task force documents showing that urologists provided peer review of the PSA evidence review. "So there were experts from urology involved in the development of that guideline," and also for the one on screening mammography.
To further show its consternation with the task force, AMA delegates also approved a report that stated that starting at age 40, women should be "eligible for screening mammography," and encouraging physicians "to regularly discuss with their individual patients the benefits and risks of screening mammography, and whether screening is appropriate for each clinical situation given that the balance of benefits and risks will be viewed differently by each patient."
Primary care delegates from the American Academy of Family Physicians and the American College of Physicians opposed the resolutions of concern against the USPSTF and the mammography report.
The AAFP supported the task force when it issued its mammography recommendations "because it was the most comprehensive pattern and set of preventive guidelines using current methodology with what was available in science at that time," said Dr. Roland Goertz, AAFP delegate.
The task force basically recommends what the AMA report urged: that physicians have discussions with their patients about risks and benefits, he said. The problem is not the USPSTF recommendations, but that they are being used to deny payment, he added.
Alicia Ault/IMNG Medical Media
Dr. William Golden, delegate from ACP, said that the AMA House of Delegates was not the correct venue to decide on clinical guidelines.
Dr. Richard Reiling, a delegate from the American College of Surgeons, said that the task force had confused patients with its mammography recommendation, and called for the AMA to convene all interested parties to craft a single guideline. The USPSTF was "wrong in presenting this report without listening to the stakeholders in the past," he said, adding, "let’s get one guideline out there."
Dr. Goertz agreed that there needed to be a common guideline.
ACP Delegate Dr. William Golden expressed the ACP’s view that the House of Delegates was not the appropriate venue for voting on particular guidelines. "The House should not be in the position of voting on what guideline is best," he said.
AIP: A Randomized, Double-Blind, Placebo-Controlled Study of Oral Coenzyme Q10 to Relieve Self-Reported Treatment-Related Fatigue in Newly Diagnosed Patients with Breast Cancer
Glenn J. Lesser, MD
,
Doug Case, PhD,
Nancy Stark, RN, PhD,
Susan Williford, MD,
Jeff Giguere, MD,
L. Astrid Garino, MD,
Michelle J. Naughton, PhD,
Mara Z. Vitolins, DrPH, RD,
Mark O. Lively, PhD,
Edward G. Shaw, MD, MA,
Wake Forest University Community Clinical Oncology Program Research Base
Abstract
Background
Coenzyme Q10 (CoQ10) is a common antioxidant supplement with known cardioprotective effects and potential anticancer benefits.
Objectives
We performed a randomized, double-blind, placebo-controlled study of oral CoQ10 in female breast cancer patients with the primary objective of determining CoQ10's effects on self-reported fatigue, depression, and quality of life (QOL).
Methods
Eligible women with newly diagnosed breast cancer and planned adjuvant chemotherapy were randomized to oral supplements of 300 mg CoQ10 or placebo, each combined with 300 IU vitamin E, divided into 3 daily doses. Treatment was continued for 24 weeks. Blood tests, QOL measures, and levels of plasma CoQ10 and vitamin E were obtained at baseline and at 8, 16, and 24 weeks. Mixed-effects models were used to assess treatment differences in outcomes over time.
Results
Between September 2004 and March 2009, 236 women were enrolled. Treatment arms were well balanced with respect to age (range, 28−85 years), pathologic stage (stage 0, 91%; stage I, 8%; stage II, 1%), ethnicity (white, 87%; black, 11%; Hispanic, 2%), and planned therapy. Baseline CoQ10 levels in the CoQ10 and placebo arms were 0.70 and 0.73 μg/mL, respectively; the 24-week CoQ10 levels were 1.83 and 0.79 μg/mL, respectively. There were no significant differences between the CoQ10 and placebo arms at 24 weeks for scores on the Profile of Mood States–Fatigue questionnaire (least squares means, 7.08 vs 8.24, P = .257), the Functional Assessment of Chronic Illness Therapy–Fatigue tool (37.6 vs 37.6, P = .965), the Functional Assessment of Cancer Therapy–Breast Cancer instrument (111.9 vs 110.4, P = .577), or the Center for Epidemiologic Studies–Depression scale (11.6 vs 12.3, P = .632).
Conclusions
Supplementation with conventional doses of CoQ10 led to sustained increases in plasma CoQ10 levels but did not result in improved self-reported fatigue or QOL after 24 weeks of treatment.
*For a PDF of the full article click in the link to the left of this introduction.
Wake Forest University Community Clinical Oncology Program Research Base
Abstract
Background
Coenzyme Q10 (CoQ10) is a common antioxidant supplement with known cardioprotective effects and potential anticancer benefits.
Objectives
We performed a randomized, double-blind, placebo-controlled study of oral CoQ10 in female breast cancer patients with the primary objective of determining CoQ10's effects on self-reported fatigue, depression, and quality of life (QOL).
Methods
Eligible women with newly diagnosed breast cancer and planned adjuvant chemotherapy were randomized to oral supplements of 300 mg CoQ10 or placebo, each combined with 300 IU vitamin E, divided into 3 daily doses. Treatment was continued for 24 weeks. Blood tests, QOL measures, and levels of plasma CoQ10 and vitamin E were obtained at baseline and at 8, 16, and 24 weeks. Mixed-effects models were used to assess treatment differences in outcomes over time.
Results
Between September 2004 and March 2009, 236 women were enrolled. Treatment arms were well balanced with respect to age (range, 28−85 years), pathologic stage (stage 0, 91%; stage I, 8%; stage II, 1%), ethnicity (white, 87%; black, 11%; Hispanic, 2%), and planned therapy. Baseline CoQ10 levels in the CoQ10 and placebo arms were 0.70 and 0.73 μg/mL, respectively; the 24-week CoQ10 levels were 1.83 and 0.79 μg/mL, respectively. There were no significant differences between the CoQ10 and placebo arms at 24 weeks for scores on the Profile of Mood States–Fatigue questionnaire (least squares means, 7.08 vs 8.24, P = .257), the Functional Assessment of Chronic Illness Therapy–Fatigue tool (37.6 vs 37.6, P = .965), the Functional Assessment of Cancer Therapy–Breast Cancer instrument (111.9 vs 110.4, P = .577), or the Center for Epidemiologic Studies–Depression scale (11.6 vs 12.3, P = .632).
Conclusions
Supplementation with conventional doses of CoQ10 led to sustained increases in plasma CoQ10 levels but did not result in improved self-reported fatigue or QOL after 24 weeks of treatment.
*For a PDF of the full article click in the link to the left of this introduction.
Glenn J. Lesser, MD
,
Doug Case, PhD,
Nancy Stark, RN, PhD,
Susan Williford, MD,
Jeff Giguere, MD,
L. Astrid Garino, MD,
Michelle J. Naughton, PhD,
Mara Z. Vitolins, DrPH, RD,
Mark O. Lively, PhD,
Edward G. Shaw, MD, MA,
Wake Forest University Community Clinical Oncology Program Research Base
Abstract
Background
Coenzyme Q10 (CoQ10) is a common antioxidant supplement with known cardioprotective effects and potential anticancer benefits.
Objectives
We performed a randomized, double-blind, placebo-controlled study of oral CoQ10 in female breast cancer patients with the primary objective of determining CoQ10's effects on self-reported fatigue, depression, and quality of life (QOL).
Methods
Eligible women with newly diagnosed breast cancer and planned adjuvant chemotherapy were randomized to oral supplements of 300 mg CoQ10 or placebo, each combined with 300 IU vitamin E, divided into 3 daily doses. Treatment was continued for 24 weeks. Blood tests, QOL measures, and levels of plasma CoQ10 and vitamin E were obtained at baseline and at 8, 16, and 24 weeks. Mixed-effects models were used to assess treatment differences in outcomes over time.
Results
Between September 2004 and March 2009, 236 women were enrolled. Treatment arms were well balanced with respect to age (range, 28−85 years), pathologic stage (stage 0, 91%; stage I, 8%; stage II, 1%), ethnicity (white, 87%; black, 11%; Hispanic, 2%), and planned therapy. Baseline CoQ10 levels in the CoQ10 and placebo arms were 0.70 and 0.73 μg/mL, respectively; the 24-week CoQ10 levels were 1.83 and 0.79 μg/mL, respectively. There were no significant differences between the CoQ10 and placebo arms at 24 weeks for scores on the Profile of Mood States–Fatigue questionnaire (least squares means, 7.08 vs 8.24, P = .257), the Functional Assessment of Chronic Illness Therapy–Fatigue tool (37.6 vs 37.6, P = .965), the Functional Assessment of Cancer Therapy–Breast Cancer instrument (111.9 vs 110.4, P = .577), or the Center for Epidemiologic Studies–Depression scale (11.6 vs 12.3, P = .632).
Conclusions
Supplementation with conventional doses of CoQ10 led to sustained increases in plasma CoQ10 levels but did not result in improved self-reported fatigue or QOL after 24 weeks of treatment.
*For a PDF of the full article click in the link to the left of this introduction.
AIP: A Randomized, Double-Blind, Placebo-Controlled Study of Oral Coenzyme Q10 to Relieve Self-Reported Treatment-Related Fatigue in Newly Diagnosed Patients with Breast Cancer
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AIP: A Randomized, Double-Blind, Placebo-Controlled Study of Oral Coenzyme Q10 to Relieve Self-Reported Treatment-Related Fatigue in Newly Diagnosed Patients with Breast Cancer
Fertility preservation for young women facing cancer therapy has garnered endorsements from leading medical groups in oncology and reproductive medicine, and it isn’t in the experimental stages anymore, interviews with experts suggest.
"There is more literature coming out showing that egg freezing does work," said Dr. Clarisa R. Gracia, director of fertility preservation at the University of Pennsylvania Health System, Philadelphia. "We have more data that we can show patients to say, ‘This is not as experimental as it used to be. It is improving, and it is a real option to offer.’ "
The two most common methods of fertility preservation are embryo freezing and egg freezing, according to Dr. Nicole Noyes, a New York City–based reproductive endocrinologist who specializes in infertility, in vitro fertilization (IVF), and egg freezing.
Both procedures involve the use of follicle-stimulating hormone, an injectable medication that causes maturation of multiple eggs in the woman’s ovaries as opposed to a single egg that is naturally ovulated. The stimulated eggs are then gently aspirated from the ovary and placed in a Petri dish.
From this point, either the eggs can be frozen in the unfertilized state or, alternatively, sperm is added, allowing for fertilization and, thus, the creation of embryos prior to freezing. Using either method, eggs or embryos remain cryopreserved until a pregnancy is desired, at which time they are removed from liquid nitrogen for usage. In the case of eggs, fertilization is required post thaw before transfer back to the uterus.
Single girls and women who don’t have a male partner and, thus, don’t have a source of male gamete – other than donor sperm from a bank or "friend" – most often choose egg freezing, whereas women in a committed relationship more often freeze embryos.
"In my patient population, even patients in a committed relationship often choose to freeze some of their gametes unfertilized to increase reproductive autonomy and to lower the relationship pressure – especially given all the stress," she said.
Another fertility preservation option is ovarian tissue freezing, an experimental procedure in which clinicians remove a piece of the ovary via laparoscopy and freeze it. The stored tissue can then be thawed and transplanted back into the pelvis at a later time, in the hope of achieving ovarian function with ovulation and subsequent pregnancy.
"Ovarian tissue freezing is also sometimes offered to prepubertal girls with hopes that it will later function as a source of eggs for that person. To date, there have been no pregnancies or births from tissue transplanted back after being removed at a prepubertal age," Dr. Noyes said.
The advantage of ovarian tissue freezing is that it can be performed in a few hours. The disadvantages are that it requires surgery (general anesthesia and laparoscopy or laparotomy), and there are relatively few successes at this time.
"There have been 17 live births reported worldwide from ovarian tissue freezing and transplantation" in patients who had cancer, Dr. Gracia said "While that’s a limited number, it shows that it can work, and it gives ammunition to keep referring patients to reproductive endocrinologists who are involved in fertility preservation and who are aware of what’s available."
Timing and Cancer Type Are Critical
Young women with breast cancer, gynecologic cancer, or a hematologic malignancy are the patients most often seeking fertility preservation, said Dr. Noyes. It takes an average of 17 days from the day of consult with a reproductive endocrinologist to the day of oocyte retrieval, and this can be an obstacle.
"For some malignancies, that’s too long to wait, such as for hematologic malignancies including non-Hodgkin’s lymphoma – the really sick patients who have a full tumor load," she said.
"In breast cancer cases, we generally do oocyte retrieval between surgery and chemotherapy. There’s usually a 4-6 week window there, so that usually is not an issue. The problem is, sometimes the oncologist doesn’t call you until they’re 5 weeks after their surgery to ask if you can do the oocyte retrieval in 7 days."
Bone marrow transplant patients face almost a 100% chance of ovarian failure from the pretreatment for the transplant. "Those patients are great candidates for fertility preservation," Dr. Noyes said. "Any regimen that has an alkylating agent such as cyclophosphamide (Cytoxan), those patients are at high risk. Almost all breast cancer patients get Cytoxan."
Not all female cancer patients opt for fertility preservation, however. For example, the initial treatment for Hodgkin’s lymphoma, ABVD (doxorubicin hydrochloride [Adriamycin], bleomycin, vinblastine, and dacarbazine), is a chemotherapeutic regimen with low toxicity that usually does not cause infertility.
"Many of those patients do not end up doing fertility preservation, because ultimately 90% of women with Hodgkin’s lymphoma get cured and will be able to get pregnant without a problem, as long as they try before the age of 35," Dr. Gracia said.
The problem is that "10% of women who relapse will then require a bone marrow transplant as the subsequent therapy," she continued, and no one knows who they will be. "That treatment causes infertility in over 95% of patients."
Many oncologists do not refer Hodgkin’s lymphoma patients on the assumption that all will be fine after ABVD therapy. "But if the chemotherapy regimen fails and [the patients] come back to see me, at that point the options are more limited in terms of what you can offer them. ... Their ovaries may not respond as well to treatment in order to stimulate the ovaries with injections of gonadotropin, and then retrieve eggs in order to freeze eggs or embryos."
Providing fertility preservation for patients with leukemia can be challenging, Dr. Gracia added, because they sometimes are so sick "that it’s not really safe to put them through procedures like ovarian stimulation, or egg or embryo freezing. Those are patients we are often not able to help."
Dr. Nicole Noyes
Cancer prognosis also can be a factor in deciding whether a patient is a good candidate for fertility preservation, although Dr. Noyes urged caution on that issue. "Even if a patient has stage III cancer and the survival rate is 20%, I don’t think it’s my place to judge that. ... If she is in the 20% who survive, she will not be happy if you say, ‘I didn’t do oocyte retrieval because I didn’t figure you would make it,’ " she explained.
In a survey answered by 516 oncologists, slightly less than half of respondents took "a neutral stance" on the advisability of poor-prognosis patients pursuing fertility preservation. While 23% agreed that these patients should not pursue fertility preservation, 32% disagreed; data were missing for 1%. Similarly, 51% had no opinion on posthumous parenting, only 16% expressed support, and 32% were opposed. Again, data were missing for 1%.
"Oncologists’ personal attitudes regarding posthumous reproduction were related to referral of patients with a poor prognosis," the authors wrote, noting that religious beliefs can influence physician attitudes (J. Support. Oncol. 2011 [doi: 10.1016/j.suponc.2011.09.006]).
How Old, How Young, and With Whom?
Age cutoffs for fertility preservation vary from practice to practice, but most physicians won’t perform the practice in patients older than age 46. When providing counseling about fertility preservation options, Dr. Noyes makes it a point to ask the patient if she is in a committed relationship with someone with whom she can rear a child.
"Oftentimes rather than just freezing all embryos, I’ll freeze half as unfertilized eggs and half as embryos, even if the woman is in a committed relationship," Dr. Noyes said. "This creates less pressure on the couple, and there is some reproductive autonomy if things don’t work out. The woman could still use those eggs with someone else."
Dr. Gracia once had a 49-year-old cancer patient seek her assistance with fertility preservation. "I told her, ‘You’re close to menopause and unfortunately, fertility preservation technologies will not work at your age.’ Even in situations where a woman’s fertility is already compromised, a cancer diagnosis often makes individuals even more aware of their future fertility, since treatments may take away their ability to have children."
With IVF, the efficiency is about a 6%-7% live birth rate per egg. With egg freezing, the efficiency stands at about 5% per egg, "so it’s similar to IVF, which is good," Dr. Noyes said. "We know from years and years of IVF that every egg isn’t meant to be a baby. Otherwise, the pregnancy success rate would have gone from about 30%, which it was in 1990, to almost 100% now. It improved from about 30% in 1990 to 50%-60% now."
To date, Dr. Noyes has performed fertility preservation in about 125 cancer patients, and 6 of them have returned to use the frozen eggs or embryos. "On average, they are using their preserved eggs or embryos about 3 years after preserving them," she said. "It depends on their age when they freeze the eggs or embryos. The very young girls aren’t going to be back for a decade or more."
The best candidates for ovarian tissue freezing are children, "because it’s not possible to stimulate the ovaries of a girl who hasn’t gone through puberty yet," Dr. Gracia said. "That’s really the only option they have. We also offer it to patients who are at extremely high risk for going through ovarian failure or infertility, like patients who need to get transplants or those who receive high doses of alkylating agents."
Fears of Recurrence
Some breast cancer patients ask Dr. Karine Chung, director of the Fertility Preservation Program at the University of Southern California, Los Angeles, if fertility treatments or becoming pregnant will increase the risk that the cancer may return. She tells them that "while theoretically it is a concern that becoming pregnant after breast cancer could increase the rate of recurrence, there have been a number of very well-designed, large studies that have shown that that is not the case."
"As far as whether going through IVF or ovarian stimulation increases the risk of recurrence, we don’t think so. There is very limited data looking at that, but if you compare what happens during an IVF cycle and what happens during pregnancy, an IVF cycle is a very short period of time in which a woman is exposed to high levels of estrogen, whereas pregnancy is a relatively long time in which a woman is exposed to high levels of estrogen. If pregnancy has not turned out increased recurrence, we don’t think that IVF will, either," she said.
Dr. Alison W. Loren, fellowship program director in the division of hematology/oncology at the University of Pennsylvania, Philadelphia, tells her hematology patients that there is "really no increased risk of recurrence of blood cancers, if they choose to become pregnant after their cancer treatment."
On the other hand, women who have hormone receptor–positive cancers "are generally counseled to wait at least 5 years after their cancer treatment is complete to become pregnant, but that’s not evidence based. There are concerns in cases where the fertility window is shortened. For example, if you advise a 32-year-old woman to wait 5 years after her last cancer treatment to get pregnant, you could be jeopardizing her ability to get pregnant."
Increased recurrence rates for certain types of cancer following fertility preservation were reported at the March 2102 annual meeting of the Society of Gynecologic Oncology in Austin, Tex. A study from Japan reported a recurrence rate of 24% after use of high-dose medroxyprogesterone acetate in young patients with endometrial cancer. The total number of pregnancies was 42; delivery outcomes were 19 normal deliveries, 11 cesarean sections, 2 premature deliveries, 5 spontaneous abortions, 2 induced abortions, 1 unknown, and 2 ongoing pregnancies (Gynecol. Oncol. 2012;125;S5 [doi: 10.1016/j.ygyno.2011.12.006]). A separate, multicenter study in the United States found that the risk of recurrence in patients with serous borderline ovarian tumors was 35% among patients who underwent fertility-sparing surgery, compared with 15% in other patients; at least 7 healthy infants were delivered (Gynecol. Oncol. 2012;125;S5 [doi: 10.1016/j.ygyno.2011.12.007]).
The data have not yet been published in a medical journal except as meeting abstracts, however, and Dr. Loren was reluctant to comment until more information becomes available.
Cost Can Be an Obstacle
Insurance rarely covers the cost of fertility preservation for cancer patients, and the costs can reach $20,000. Fertile Hope’s Sharing Hope Program for Women, an initiative of the Lance Armstrong Foundation, invites cancer patients to apply for discounted services and donated medications (www.fertilehope.org). Eligibility requirements include being a U.S. citizen or permanent resident with an annual household income of less than $75,000 (single) or $100,000 (married), and having not yet started fertility-damaging cancer treatments.
Other resources for patients include Fertile Action (http://fertileaction.org), which was founded by a breast cancer survivor, and MyOncofertility.org (http://myoncofertility.org), an education resource provided by the Oncofertility Consortium.
Who Has Expertise in Fertility Preservation?
New guidelines from the National Comprehensive Cancer Network establish young adult and adolescent cancer patients as a distinct group whom oncologists should routinely send for fertility counseling. Will they?
Oncologists are not necessarily knowledgeable about the options or in the habit of referring patients to reproductive endocrinologists or other clinicians who specialize in fertility, according to Dr. Chung.
"Because [the oncologists’] knowledge of fertility and ovarian function in general is somewhat limited, to have a meaningful discussion about fertility preservation options with these patients is difficult," she said.
The American Society of Clinical Oncology (J. Clin. Oncol 2006:24:2917-31). and the American Society for Reproductive Medicine (Fertil. Steril. 2005;83:1622-8) have previously recommended that all women be offered counseling and an opportunity to preserve their fertility before cancer therapy, but implementation appears to be mixed.
According to a 2009 survey of 249 oncologists who practice at academic medical centers, 95% reported routinely discussing a cancer treatment’s impact on fertility (Fertil. Steril. 2010;94:1652-6). Only 39% said they routinely referred female cancer patients to a reproductive endocrinologist or ob.gyn. who specializes in fertility, however, while 18% said they never refer their patients. Reasons most commonly cited for not referring included lack of patient interest in fertility preservation (38%), lack of time because of emergent need to start therapy (28%), and poor prognosis for future fertility (6%).
Three key factors contribute to a lack of referrals by oncologists, according to Dr. Loren: a lack of time, a lack of access to reproductive endocrinologists in the oncologist’s network/institution, and a lack of baseline knowledge about fertility preservation options.
"Many oncologists don’t know a lot about this; so they worry if they bring this up, patients are going to start asking, ‘What are my options?’ " Dr. Loren said.
"We have studied this issue specifically among clinicians who provide bone marrow transplantation to cancer patients. Lack of knowledge and lack of access to a provider are the biggest reasons that people don’t refer patients for fertility preservation," she added.
Dr. Loren advises gynecology specialists to make networking inroads with oncologists by offering to be their referral source for patients with questions about fertility preservation. This may include speaking at grand rounds and at occasional meetings of oncology faculty and staff – anything to increase awareness of options for patients. "A key to this is good communication," she said.
In a year-long pilot study carried out at the Tampa, Fla.–based Lee Moffitt Cancer Center to develop a referral system for fertility preservation in patients with newly diagnosed cancer, measures that included placement of informational brochures in the waiting room and establishment of a dedicated telephone line for referrals led to a ninefold increase in the number of calls received (J. Natl. Compr. Canc. Netw. 2011;9:1219-25). The researchers concluded that such a referral system "allows oncologists to fulfill their obligation and make informed decisions about fertility preservation, thereby improving the full cancer care continuum."
Dr. Chung, Dr. Loren, Dr. Noyes and Dr. Gracia said that they had no relevant financial disclosures.
Fertility preservation for young women facing cancer therapy has garnered endorsements from leading medical groups in oncology and reproductive medicine, and it isn’t in the experimental stages anymore, interviews with experts suggest.
"There is more literature coming out showing that egg freezing does work," said Dr. Clarisa R. Gracia, director of fertility preservation at the University of Pennsylvania Health System, Philadelphia. "We have more data that we can show patients to say, ‘This is not as experimental as it used to be. It is improving, and it is a real option to offer.’ "
The two most common methods of fertility preservation are embryo freezing and egg freezing, according to Dr. Nicole Noyes, a New York City–based reproductive endocrinologist who specializes in infertility, in vitro fertilization (IVF), and egg freezing.
Both procedures involve the use of follicle-stimulating hormone, an injectable medication that causes maturation of multiple eggs in the woman’s ovaries as opposed to a single egg that is naturally ovulated. The stimulated eggs are then gently aspirated from the ovary and placed in a Petri dish.
From this point, either the eggs can be frozen in the unfertilized state or, alternatively, sperm is added, allowing for fertilization and, thus, the creation of embryos prior to freezing. Using either method, eggs or embryos remain cryopreserved until a pregnancy is desired, at which time they are removed from liquid nitrogen for usage. In the case of eggs, fertilization is required post thaw before transfer back to the uterus.
Single girls and women who don’t have a male partner and, thus, don’t have a source of male gamete – other than donor sperm from a bank or "friend" – most often choose egg freezing, whereas women in a committed relationship more often freeze embryos.
"In my patient population, even patients in a committed relationship often choose to freeze some of their gametes unfertilized to increase reproductive autonomy and to lower the relationship pressure – especially given all the stress," she said.
Another fertility preservation option is ovarian tissue freezing, an experimental procedure in which clinicians remove a piece of the ovary via laparoscopy and freeze it. The stored tissue can then be thawed and transplanted back into the pelvis at a later time, in the hope of achieving ovarian function with ovulation and subsequent pregnancy.
"Ovarian tissue freezing is also sometimes offered to prepubertal girls with hopes that it will later function as a source of eggs for that person. To date, there have been no pregnancies or births from tissue transplanted back after being removed at a prepubertal age," Dr. Noyes said.
The advantage of ovarian tissue freezing is that it can be performed in a few hours. The disadvantages are that it requires surgery (general anesthesia and laparoscopy or laparotomy), and there are relatively few successes at this time.
"There have been 17 live births reported worldwide from ovarian tissue freezing and transplantation" in patients who had cancer, Dr. Gracia said "While that’s a limited number, it shows that it can work, and it gives ammunition to keep referring patients to reproductive endocrinologists who are involved in fertility preservation and who are aware of what’s available."
Timing and Cancer Type Are Critical
Young women with breast cancer, gynecologic cancer, or a hematologic malignancy are the patients most often seeking fertility preservation, said Dr. Noyes. It takes an average of 17 days from the day of consult with a reproductive endocrinologist to the day of oocyte retrieval, and this can be an obstacle.
"For some malignancies, that’s too long to wait, such as for hematologic malignancies including non-Hodgkin’s lymphoma – the really sick patients who have a full tumor load," she said.
"In breast cancer cases, we generally do oocyte retrieval between surgery and chemotherapy. There’s usually a 4-6 week window there, so that usually is not an issue. The problem is, sometimes the oncologist doesn’t call you until they’re 5 weeks after their surgery to ask if you can do the oocyte retrieval in 7 days."
Bone marrow transplant patients face almost a 100% chance of ovarian failure from the pretreatment for the transplant. "Those patients are great candidates for fertility preservation," Dr. Noyes said. "Any regimen that has an alkylating agent such as cyclophosphamide (Cytoxan), those patients are at high risk. Almost all breast cancer patients get Cytoxan."
Not all female cancer patients opt for fertility preservation, however. For example, the initial treatment for Hodgkin’s lymphoma, ABVD (doxorubicin hydrochloride [Adriamycin], bleomycin, vinblastine, and dacarbazine), is a chemotherapeutic regimen with low toxicity that usually does not cause infertility.
"Many of those patients do not end up doing fertility preservation, because ultimately 90% of women with Hodgkin’s lymphoma get cured and will be able to get pregnant without a problem, as long as they try before the age of 35," Dr. Gracia said.
The problem is that "10% of women who relapse will then require a bone marrow transplant as the subsequent therapy," she continued, and no one knows who they will be. "That treatment causes infertility in over 95% of patients."
Many oncologists do not refer Hodgkin’s lymphoma patients on the assumption that all will be fine after ABVD therapy. "But if the chemotherapy regimen fails and [the patients] come back to see me, at that point the options are more limited in terms of what you can offer them. ... Their ovaries may not respond as well to treatment in order to stimulate the ovaries with injections of gonadotropin, and then retrieve eggs in order to freeze eggs or embryos."
Providing fertility preservation for patients with leukemia can be challenging, Dr. Gracia added, because they sometimes are so sick "that it’s not really safe to put them through procedures like ovarian stimulation, or egg or embryo freezing. Those are patients we are often not able to help."
Dr. Nicole Noyes
Cancer prognosis also can be a factor in deciding whether a patient is a good candidate for fertility preservation, although Dr. Noyes urged caution on that issue. "Even if a patient has stage III cancer and the survival rate is 20%, I don’t think it’s my place to judge that. ... If she is in the 20% who survive, she will not be happy if you say, ‘I didn’t do oocyte retrieval because I didn’t figure you would make it,’ " she explained.
In a survey answered by 516 oncologists, slightly less than half of respondents took "a neutral stance" on the advisability of poor-prognosis patients pursuing fertility preservation. While 23% agreed that these patients should not pursue fertility preservation, 32% disagreed; data were missing for 1%. Similarly, 51% had no opinion on posthumous parenting, only 16% expressed support, and 32% were opposed. Again, data were missing for 1%.
"Oncologists’ personal attitudes regarding posthumous reproduction were related to referral of patients with a poor prognosis," the authors wrote, noting that religious beliefs can influence physician attitudes (J. Support. Oncol. 2011 [doi: 10.1016/j.suponc.2011.09.006]).
How Old, How Young, and With Whom?
Age cutoffs for fertility preservation vary from practice to practice, but most physicians won’t perform the practice in patients older than age 46. When providing counseling about fertility preservation options, Dr. Noyes makes it a point to ask the patient if she is in a committed relationship with someone with whom she can rear a child.
"Oftentimes rather than just freezing all embryos, I’ll freeze half as unfertilized eggs and half as embryos, even if the woman is in a committed relationship," Dr. Noyes said. "This creates less pressure on the couple, and there is some reproductive autonomy if things don’t work out. The woman could still use those eggs with someone else."
Dr. Gracia once had a 49-year-old cancer patient seek her assistance with fertility preservation. "I told her, ‘You’re close to menopause and unfortunately, fertility preservation technologies will not work at your age.’ Even in situations where a woman’s fertility is already compromised, a cancer diagnosis often makes individuals even more aware of their future fertility, since treatments may take away their ability to have children."
With IVF, the efficiency is about a 6%-7% live birth rate per egg. With egg freezing, the efficiency stands at about 5% per egg, "so it’s similar to IVF, which is good," Dr. Noyes said. "We know from years and years of IVF that every egg isn’t meant to be a baby. Otherwise, the pregnancy success rate would have gone from about 30%, which it was in 1990, to almost 100% now. It improved from about 30% in 1990 to 50%-60% now."
To date, Dr. Noyes has performed fertility preservation in about 125 cancer patients, and 6 of them have returned to use the frozen eggs or embryos. "On average, they are using their preserved eggs or embryos about 3 years after preserving them," she said. "It depends on their age when they freeze the eggs or embryos. The very young girls aren’t going to be back for a decade or more."
The best candidates for ovarian tissue freezing are children, "because it’s not possible to stimulate the ovaries of a girl who hasn’t gone through puberty yet," Dr. Gracia said. "That’s really the only option they have. We also offer it to patients who are at extremely high risk for going through ovarian failure or infertility, like patients who need to get transplants or those who receive high doses of alkylating agents."
Fears of Recurrence
Some breast cancer patients ask Dr. Karine Chung, director of the Fertility Preservation Program at the University of Southern California, Los Angeles, if fertility treatments or becoming pregnant will increase the risk that the cancer may return. She tells them that "while theoretically it is a concern that becoming pregnant after breast cancer could increase the rate of recurrence, there have been a number of very well-designed, large studies that have shown that that is not the case."
"As far as whether going through IVF or ovarian stimulation increases the risk of recurrence, we don’t think so. There is very limited data looking at that, but if you compare what happens during an IVF cycle and what happens during pregnancy, an IVF cycle is a very short period of time in which a woman is exposed to high levels of estrogen, whereas pregnancy is a relatively long time in which a woman is exposed to high levels of estrogen. If pregnancy has not turned out increased recurrence, we don’t think that IVF will, either," she said.
Dr. Alison W. Loren, fellowship program director in the division of hematology/oncology at the University of Pennsylvania, Philadelphia, tells her hematology patients that there is "really no increased risk of recurrence of blood cancers, if they choose to become pregnant after their cancer treatment."
On the other hand, women who have hormone receptor–positive cancers "are generally counseled to wait at least 5 years after their cancer treatment is complete to become pregnant, but that’s not evidence based. There are concerns in cases where the fertility window is shortened. For example, if you advise a 32-year-old woman to wait 5 years after her last cancer treatment to get pregnant, you could be jeopardizing her ability to get pregnant."
Increased recurrence rates for certain types of cancer following fertility preservation were reported at the March 2102 annual meeting of the Society of Gynecologic Oncology in Austin, Tex. A study from Japan reported a recurrence rate of 24% after use of high-dose medroxyprogesterone acetate in young patients with endometrial cancer. The total number of pregnancies was 42; delivery outcomes were 19 normal deliveries, 11 cesarean sections, 2 premature deliveries, 5 spontaneous abortions, 2 induced abortions, 1 unknown, and 2 ongoing pregnancies (Gynecol. Oncol. 2012;125;S5 [doi: 10.1016/j.ygyno.2011.12.006]). A separate, multicenter study in the United States found that the risk of recurrence in patients with serous borderline ovarian tumors was 35% among patients who underwent fertility-sparing surgery, compared with 15% in other patients; at least 7 healthy infants were delivered (Gynecol. Oncol. 2012;125;S5 [doi: 10.1016/j.ygyno.2011.12.007]).
The data have not yet been published in a medical journal except as meeting abstracts, however, and Dr. Loren was reluctant to comment until more information becomes available.
Cost Can Be an Obstacle
Insurance rarely covers the cost of fertility preservation for cancer patients, and the costs can reach $20,000. Fertile Hope’s Sharing Hope Program for Women, an initiative of the Lance Armstrong Foundation, invites cancer patients to apply for discounted services and donated medications (www.fertilehope.org). Eligibility requirements include being a U.S. citizen or permanent resident with an annual household income of less than $75,000 (single) or $100,000 (married), and having not yet started fertility-damaging cancer treatments.
Other resources for patients include Fertile Action (http://fertileaction.org), which was founded by a breast cancer survivor, and MyOncofertility.org (http://myoncofertility.org), an education resource provided by the Oncofertility Consortium.
Who Has Expertise in Fertility Preservation?
New guidelines from the National Comprehensive Cancer Network establish young adult and adolescent cancer patients as a distinct group whom oncologists should routinely send for fertility counseling. Will they?
Oncologists are not necessarily knowledgeable about the options or in the habit of referring patients to reproductive endocrinologists or other clinicians who specialize in fertility, according to Dr. Chung.
"Because [the oncologists’] knowledge of fertility and ovarian function in general is somewhat limited, to have a meaningful discussion about fertility preservation options with these patients is difficult," she said.
The American Society of Clinical Oncology (J. Clin. Oncol 2006:24:2917-31). and the American Society for Reproductive Medicine (Fertil. Steril. 2005;83:1622-8) have previously recommended that all women be offered counseling and an opportunity to preserve their fertility before cancer therapy, but implementation appears to be mixed.
According to a 2009 survey of 249 oncologists who practice at academic medical centers, 95% reported routinely discussing a cancer treatment’s impact on fertility (Fertil. Steril. 2010;94:1652-6). Only 39% said they routinely referred female cancer patients to a reproductive endocrinologist or ob.gyn. who specializes in fertility, however, while 18% said they never refer their patients. Reasons most commonly cited for not referring included lack of patient interest in fertility preservation (38%), lack of time because of emergent need to start therapy (28%), and poor prognosis for future fertility (6%).
Three key factors contribute to a lack of referrals by oncologists, according to Dr. Loren: a lack of time, a lack of access to reproductive endocrinologists in the oncologist’s network/institution, and a lack of baseline knowledge about fertility preservation options.
"Many oncologists don’t know a lot about this; so they worry if they bring this up, patients are going to start asking, ‘What are my options?’ " Dr. Loren said.
"We have studied this issue specifically among clinicians who provide bone marrow transplantation to cancer patients. Lack of knowledge and lack of access to a provider are the biggest reasons that people don’t refer patients for fertility preservation," she added.
Dr. Loren advises gynecology specialists to make networking inroads with oncologists by offering to be their referral source for patients with questions about fertility preservation. This may include speaking at grand rounds and at occasional meetings of oncology faculty and staff – anything to increase awareness of options for patients. "A key to this is good communication," she said.
In a year-long pilot study carried out at the Tampa, Fla.–based Lee Moffitt Cancer Center to develop a referral system for fertility preservation in patients with newly diagnosed cancer, measures that included placement of informational brochures in the waiting room and establishment of a dedicated telephone line for referrals led to a ninefold increase in the number of calls received (J. Natl. Compr. Canc. Netw. 2011;9:1219-25). The researchers concluded that such a referral system "allows oncologists to fulfill their obligation and make informed decisions about fertility preservation, thereby improving the full cancer care continuum."
Dr. Chung, Dr. Loren, Dr. Noyes and Dr. Gracia said that they had no relevant financial disclosures.
Fertility preservation for young women facing cancer therapy has garnered endorsements from leading medical groups in oncology and reproductive medicine, and it isn’t in the experimental stages anymore, interviews with experts suggest.
"There is more literature coming out showing that egg freezing does work," said Dr. Clarisa R. Gracia, director of fertility preservation at the University of Pennsylvania Health System, Philadelphia. "We have more data that we can show patients to say, ‘This is not as experimental as it used to be. It is improving, and it is a real option to offer.’ "
The two most common methods of fertility preservation are embryo freezing and egg freezing, according to Dr. Nicole Noyes, a New York City–based reproductive endocrinologist who specializes in infertility, in vitro fertilization (IVF), and egg freezing.
Both procedures involve the use of follicle-stimulating hormone, an injectable medication that causes maturation of multiple eggs in the woman’s ovaries as opposed to a single egg that is naturally ovulated. The stimulated eggs are then gently aspirated from the ovary and placed in a Petri dish.
From this point, either the eggs can be frozen in the unfertilized state or, alternatively, sperm is added, allowing for fertilization and, thus, the creation of embryos prior to freezing. Using either method, eggs or embryos remain cryopreserved until a pregnancy is desired, at which time they are removed from liquid nitrogen for usage. In the case of eggs, fertilization is required post thaw before transfer back to the uterus.
Single girls and women who don’t have a male partner and, thus, don’t have a source of male gamete – other than donor sperm from a bank or "friend" – most often choose egg freezing, whereas women in a committed relationship more often freeze embryos.
"In my patient population, even patients in a committed relationship often choose to freeze some of their gametes unfertilized to increase reproductive autonomy and to lower the relationship pressure – especially given all the stress," she said.
Another fertility preservation option is ovarian tissue freezing, an experimental procedure in which clinicians remove a piece of the ovary via laparoscopy and freeze it. The stored tissue can then be thawed and transplanted back into the pelvis at a later time, in the hope of achieving ovarian function with ovulation and subsequent pregnancy.
"Ovarian tissue freezing is also sometimes offered to prepubertal girls with hopes that it will later function as a source of eggs for that person. To date, there have been no pregnancies or births from tissue transplanted back after being removed at a prepubertal age," Dr. Noyes said.
The advantage of ovarian tissue freezing is that it can be performed in a few hours. The disadvantages are that it requires surgery (general anesthesia and laparoscopy or laparotomy), and there are relatively few successes at this time.
"There have been 17 live births reported worldwide from ovarian tissue freezing and transplantation" in patients who had cancer, Dr. Gracia said "While that’s a limited number, it shows that it can work, and it gives ammunition to keep referring patients to reproductive endocrinologists who are involved in fertility preservation and who are aware of what’s available."
Timing and Cancer Type Are Critical
Young women with breast cancer, gynecologic cancer, or a hematologic malignancy are the patients most often seeking fertility preservation, said Dr. Noyes. It takes an average of 17 days from the day of consult with a reproductive endocrinologist to the day of oocyte retrieval, and this can be an obstacle.
"For some malignancies, that’s too long to wait, such as for hematologic malignancies including non-Hodgkin’s lymphoma – the really sick patients who have a full tumor load," she said.
"In breast cancer cases, we generally do oocyte retrieval between surgery and chemotherapy. There’s usually a 4-6 week window there, so that usually is not an issue. The problem is, sometimes the oncologist doesn’t call you until they’re 5 weeks after their surgery to ask if you can do the oocyte retrieval in 7 days."
Bone marrow transplant patients face almost a 100% chance of ovarian failure from the pretreatment for the transplant. "Those patients are great candidates for fertility preservation," Dr. Noyes said. "Any regimen that has an alkylating agent such as cyclophosphamide (Cytoxan), those patients are at high risk. Almost all breast cancer patients get Cytoxan."
Not all female cancer patients opt for fertility preservation, however. For example, the initial treatment for Hodgkin’s lymphoma, ABVD (doxorubicin hydrochloride [Adriamycin], bleomycin, vinblastine, and dacarbazine), is a chemotherapeutic regimen with low toxicity that usually does not cause infertility.
"Many of those patients do not end up doing fertility preservation, because ultimately 90% of women with Hodgkin’s lymphoma get cured and will be able to get pregnant without a problem, as long as they try before the age of 35," Dr. Gracia said.
The problem is that "10% of women who relapse will then require a bone marrow transplant as the subsequent therapy," she continued, and no one knows who they will be. "That treatment causes infertility in over 95% of patients."
Many oncologists do not refer Hodgkin’s lymphoma patients on the assumption that all will be fine after ABVD therapy. "But if the chemotherapy regimen fails and [the patients] come back to see me, at that point the options are more limited in terms of what you can offer them. ... Their ovaries may not respond as well to treatment in order to stimulate the ovaries with injections of gonadotropin, and then retrieve eggs in order to freeze eggs or embryos."
Providing fertility preservation for patients with leukemia can be challenging, Dr. Gracia added, because they sometimes are so sick "that it’s not really safe to put them through procedures like ovarian stimulation, or egg or embryo freezing. Those are patients we are often not able to help."
Dr. Nicole Noyes
Cancer prognosis also can be a factor in deciding whether a patient is a good candidate for fertility preservation, although Dr. Noyes urged caution on that issue. "Even if a patient has stage III cancer and the survival rate is 20%, I don’t think it’s my place to judge that. ... If she is in the 20% who survive, she will not be happy if you say, ‘I didn’t do oocyte retrieval because I didn’t figure you would make it,’ " she explained.
In a survey answered by 516 oncologists, slightly less than half of respondents took "a neutral stance" on the advisability of poor-prognosis patients pursuing fertility preservation. While 23% agreed that these patients should not pursue fertility preservation, 32% disagreed; data were missing for 1%. Similarly, 51% had no opinion on posthumous parenting, only 16% expressed support, and 32% were opposed. Again, data were missing for 1%.
"Oncologists’ personal attitudes regarding posthumous reproduction were related to referral of patients with a poor prognosis," the authors wrote, noting that religious beliefs can influence physician attitudes (J. Support. Oncol. 2011 [doi: 10.1016/j.suponc.2011.09.006]).
How Old, How Young, and With Whom?
Age cutoffs for fertility preservation vary from practice to practice, but most physicians won’t perform the practice in patients older than age 46. When providing counseling about fertility preservation options, Dr. Noyes makes it a point to ask the patient if she is in a committed relationship with someone with whom she can rear a child.
"Oftentimes rather than just freezing all embryos, I’ll freeze half as unfertilized eggs and half as embryos, even if the woman is in a committed relationship," Dr. Noyes said. "This creates less pressure on the couple, and there is some reproductive autonomy if things don’t work out. The woman could still use those eggs with someone else."
Dr. Gracia once had a 49-year-old cancer patient seek her assistance with fertility preservation. "I told her, ‘You’re close to menopause and unfortunately, fertility preservation technologies will not work at your age.’ Even in situations where a woman’s fertility is already compromised, a cancer diagnosis often makes individuals even more aware of their future fertility, since treatments may take away their ability to have children."
With IVF, the efficiency is about a 6%-7% live birth rate per egg. With egg freezing, the efficiency stands at about 5% per egg, "so it’s similar to IVF, which is good," Dr. Noyes said. "We know from years and years of IVF that every egg isn’t meant to be a baby. Otherwise, the pregnancy success rate would have gone from about 30%, which it was in 1990, to almost 100% now. It improved from about 30% in 1990 to 50%-60% now."
To date, Dr. Noyes has performed fertility preservation in about 125 cancer patients, and 6 of them have returned to use the frozen eggs or embryos. "On average, they are using their preserved eggs or embryos about 3 years after preserving them," she said. "It depends on their age when they freeze the eggs or embryos. The very young girls aren’t going to be back for a decade or more."
The best candidates for ovarian tissue freezing are children, "because it’s not possible to stimulate the ovaries of a girl who hasn’t gone through puberty yet," Dr. Gracia said. "That’s really the only option they have. We also offer it to patients who are at extremely high risk for going through ovarian failure or infertility, like patients who need to get transplants or those who receive high doses of alkylating agents."
Fears of Recurrence
Some breast cancer patients ask Dr. Karine Chung, director of the Fertility Preservation Program at the University of Southern California, Los Angeles, if fertility treatments or becoming pregnant will increase the risk that the cancer may return. She tells them that "while theoretically it is a concern that becoming pregnant after breast cancer could increase the rate of recurrence, there have been a number of very well-designed, large studies that have shown that that is not the case."
"As far as whether going through IVF or ovarian stimulation increases the risk of recurrence, we don’t think so. There is very limited data looking at that, but if you compare what happens during an IVF cycle and what happens during pregnancy, an IVF cycle is a very short period of time in which a woman is exposed to high levels of estrogen, whereas pregnancy is a relatively long time in which a woman is exposed to high levels of estrogen. If pregnancy has not turned out increased recurrence, we don’t think that IVF will, either," she said.
Dr. Alison W. Loren, fellowship program director in the division of hematology/oncology at the University of Pennsylvania, Philadelphia, tells her hematology patients that there is "really no increased risk of recurrence of blood cancers, if they choose to become pregnant after their cancer treatment."
On the other hand, women who have hormone receptor–positive cancers "are generally counseled to wait at least 5 years after their cancer treatment is complete to become pregnant, but that’s not evidence based. There are concerns in cases where the fertility window is shortened. For example, if you advise a 32-year-old woman to wait 5 years after her last cancer treatment to get pregnant, you could be jeopardizing her ability to get pregnant."
Increased recurrence rates for certain types of cancer following fertility preservation were reported at the March 2102 annual meeting of the Society of Gynecologic Oncology in Austin, Tex. A study from Japan reported a recurrence rate of 24% after use of high-dose medroxyprogesterone acetate in young patients with endometrial cancer. The total number of pregnancies was 42; delivery outcomes were 19 normal deliveries, 11 cesarean sections, 2 premature deliveries, 5 spontaneous abortions, 2 induced abortions, 1 unknown, and 2 ongoing pregnancies (Gynecol. Oncol. 2012;125;S5 [doi: 10.1016/j.ygyno.2011.12.006]). A separate, multicenter study in the United States found that the risk of recurrence in patients with serous borderline ovarian tumors was 35% among patients who underwent fertility-sparing surgery, compared with 15% in other patients; at least 7 healthy infants were delivered (Gynecol. Oncol. 2012;125;S5 [doi: 10.1016/j.ygyno.2011.12.007]).
The data have not yet been published in a medical journal except as meeting abstracts, however, and Dr. Loren was reluctant to comment until more information becomes available.
Cost Can Be an Obstacle
Insurance rarely covers the cost of fertility preservation for cancer patients, and the costs can reach $20,000. Fertile Hope’s Sharing Hope Program for Women, an initiative of the Lance Armstrong Foundation, invites cancer patients to apply for discounted services and donated medications (www.fertilehope.org). Eligibility requirements include being a U.S. citizen or permanent resident with an annual household income of less than $75,000 (single) or $100,000 (married), and having not yet started fertility-damaging cancer treatments.
Other resources for patients include Fertile Action (http://fertileaction.org), which was founded by a breast cancer survivor, and MyOncofertility.org (http://myoncofertility.org), an education resource provided by the Oncofertility Consortium.
Who Has Expertise in Fertility Preservation?
New guidelines from the National Comprehensive Cancer Network establish young adult and adolescent cancer patients as a distinct group whom oncologists should routinely send for fertility counseling. Will they?
Oncologists are not necessarily knowledgeable about the options or in the habit of referring patients to reproductive endocrinologists or other clinicians who specialize in fertility, according to Dr. Chung.
"Because [the oncologists’] knowledge of fertility and ovarian function in general is somewhat limited, to have a meaningful discussion about fertility preservation options with these patients is difficult," she said.
The American Society of Clinical Oncology (J. Clin. Oncol 2006:24:2917-31). and the American Society for Reproductive Medicine (Fertil. Steril. 2005;83:1622-8) have previously recommended that all women be offered counseling and an opportunity to preserve their fertility before cancer therapy, but implementation appears to be mixed.
According to a 2009 survey of 249 oncologists who practice at academic medical centers, 95% reported routinely discussing a cancer treatment’s impact on fertility (Fertil. Steril. 2010;94:1652-6). Only 39% said they routinely referred female cancer patients to a reproductive endocrinologist or ob.gyn. who specializes in fertility, however, while 18% said they never refer their patients. Reasons most commonly cited for not referring included lack of patient interest in fertility preservation (38%), lack of time because of emergent need to start therapy (28%), and poor prognosis for future fertility (6%).
Three key factors contribute to a lack of referrals by oncologists, according to Dr. Loren: a lack of time, a lack of access to reproductive endocrinologists in the oncologist’s network/institution, and a lack of baseline knowledge about fertility preservation options.
"Many oncologists don’t know a lot about this; so they worry if they bring this up, patients are going to start asking, ‘What are my options?’ " Dr. Loren said.
"We have studied this issue specifically among clinicians who provide bone marrow transplantation to cancer patients. Lack of knowledge and lack of access to a provider are the biggest reasons that people don’t refer patients for fertility preservation," she added.
Dr. Loren advises gynecology specialists to make networking inroads with oncologists by offering to be their referral source for patients with questions about fertility preservation. This may include speaking at grand rounds and at occasional meetings of oncology faculty and staff – anything to increase awareness of options for patients. "A key to this is good communication," she said.
In a year-long pilot study carried out at the Tampa, Fla.–based Lee Moffitt Cancer Center to develop a referral system for fertility preservation in patients with newly diagnosed cancer, measures that included placement of informational brochures in the waiting room and establishment of a dedicated telephone line for referrals led to a ninefold increase in the number of calls received (J. Natl. Compr. Canc. Netw. 2011;9:1219-25). The researchers concluded that such a referral system "allows oncologists to fulfill their obligation and make informed decisions about fertility preservation, thereby improving the full cancer care continuum."
Dr. Chung, Dr. Loren, Dr. Noyes and Dr. Gracia said that they had no relevant financial disclosures.
Women with HER2-positive metastatic breast cancer have been given a double-edged sword, with the Food and Drug Administration granting approval to pertuzumab on Friday, June 8, as a first-line therapy.*
The addition of pertuzumab (Perjeta), a new HER2 blocker, to a standard chemotherapy combination of trastuzumab (Herceptin) and docetaxel (Taxotere) has been shown to extend progression-free survival in these patients. Overall survival data are not yet available.
Pertuzumab is a humanized monoclonal antibody, manufactured through biotechnology methods by Genentech, a subsidiary of Roche. It also blocks other HER family members, including EGFR, HER3, and HER4, and is believed to complement HER2 inhibition by trastuzumab, also made by Genentech and Roche.
The approval rides largely on the results of the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) trial. Dual HER2 blockade boosted median progression-free survival from 12.4 months in a control group treated with only the standard combination to 18.5 months in a group treated with standard therapy plus-pertuzumab. This is a statistically significant difference that corresponds to a 38% reduction in the risk for progression or death and an increase of 6.1 months in median progression-free survival. These results were published in the New England Journal of Medicine (2012;366:109-19).
For the double-blind phase III trial, 808 patients aged 18 years and older with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer were randomized either to a control group that received placebo plus trastuzumab and docetaxel or to the pertuzumab group, which received pertuzumab plus trastuzumab and docetaxel.
In their announcements of pertuzumab approval, Genentech, maker of the drug, and the FDA disclosed that production issues could affect the long-term supply of the drug.
"We expect to meet demand for Perjeta following today\'s FDA approval. We recently identified a cell growth issue that might affect our future supply of the medicine," said Patrick Y. Yang, Ph.D., head, Pharma Global Technical Operations. "We take this very seriously and are working with the FDA to ensure a consistent manufacturing process that maintains drug supply for the people who need it."
With the approval, Genentech has agreed to postmarketing commitments related to the manufacturing process for Perjeta. These include FDA review of data from the next several productions of the medicine.
The FDA limited its approval to drug product that has not been affected by production issues, according to Dr. Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research.
"Given the need for additional treatments for metastatic breast cancer, we made the decision to approve this drug today and not to delay its availability to patients pending resolution of the production issues relating to future supply," she said in the FDA announcement.
"Genentech is currently developing a plan to mitigate the effect on patients of any potential shortage of Perjeta."
An added concern is the high cost of dual HER2 inhibition at a time when oncologists are under pressure to contain costs. According to the New York Times, Genentech is putting the wholesale cost of pertuzumab at $5,900/month, which added to the typical $4,500/month costs of trastuzumab, would drive the cost of 18 months of treatment to $187,000.
Boxed Warning Put on Label
Pertuzumab is indicated in combination with trastuzumab and docetaxel for "patients with HER2-positive metastatic breast cancer who have not received prior anti–HER2 therapy or chemotherapy for metastatic disease."
The FDA announced that pertuzumab would have a boxed warning on its label. This is to alert clinicians and patients to the potential risk of death or severe effects to a fetus. "Pregnancy status must be verified prior to the start of Perjeta treatment," it said; patients should be advised "of these risks and need for effective contraception prior to starting pertuzumab."
According to the agency, the most common side effects observed with use of pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral sensory neuropathy.
Although left ventricular dysfunction was observed, the FDA said the combination of pertuzumab with standard therapy "was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction or decreases in left ventricular ejection fraction, compared with placebo in combination with trastuzumab and docetaxel.
The FDA recommended that pertuzumab be started at an initial dose of 840 mg administered as a 60-minute IV infusion, followed every 3 weeks, thereafter, by 420 mg administered as a 30- to 60-minute IV infusion. It also recommended that when trastuzumab is used with pertuzumab, trastuzumab should be started at 8 mg/kg administered as a 90-minute IV infusion, followed every 3 weeks by a dose of 6 mg/kg administered IV over 30 to 90 minutes. When docetaxel is given with pertuzumab, the recommended starting docetaxel dose is 75 mg/m2 administered as an IV infusion. If well tolerated, docetaxel may be escalated to 100 mg/m2 every 3 weeks.
Women with HER2-positive metastatic breast cancer have been given a double-edged sword, with the Food and Drug Administration granting approval to pertuzumab on Friday, June 8, as a first-line therapy.*
The addition of pertuzumab (Perjeta), a new HER2 blocker, to a standard chemotherapy combination of trastuzumab (Herceptin) and docetaxel (Taxotere) has been shown to extend progression-free survival in these patients. Overall survival data are not yet available.
Pertuzumab is a humanized monoclonal antibody, manufactured through biotechnology methods by Genentech, a subsidiary of Roche. It also blocks other HER family members, including EGFR, HER3, and HER4, and is believed to complement HER2 inhibition by trastuzumab, also made by Genentech and Roche.
The approval rides largely on the results of the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) trial. Dual HER2 blockade boosted median progression-free survival from 12.4 months in a control group treated with only the standard combination to 18.5 months in a group treated with standard therapy plus-pertuzumab. This is a statistically significant difference that corresponds to a 38% reduction in the risk for progression or death and an increase of 6.1 months in median progression-free survival. These results were published in the New England Journal of Medicine (2012;366:109-19).
For the double-blind phase III trial, 808 patients aged 18 years and older with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer were randomized either to a control group that received placebo plus trastuzumab and docetaxel or to the pertuzumab group, which received pertuzumab plus trastuzumab and docetaxel.
In their announcements of pertuzumab approval, Genentech, maker of the drug, and the FDA disclosed that production issues could affect the long-term supply of the drug.
"We expect to meet demand for Perjeta following today\'s FDA approval. We recently identified a cell growth issue that might affect our future supply of the medicine," said Patrick Y. Yang, Ph.D., head, Pharma Global Technical Operations. "We take this very seriously and are working with the FDA to ensure a consistent manufacturing process that maintains drug supply for the people who need it."
With the approval, Genentech has agreed to postmarketing commitments related to the manufacturing process for Perjeta. These include FDA review of data from the next several productions of the medicine.
The FDA limited its approval to drug product that has not been affected by production issues, according to Dr. Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research.
"Given the need for additional treatments for metastatic breast cancer, we made the decision to approve this drug today and not to delay its availability to patients pending resolution of the production issues relating to future supply," she said in the FDA announcement.
"Genentech is currently developing a plan to mitigate the effect on patients of any potential shortage of Perjeta."
An added concern is the high cost of dual HER2 inhibition at a time when oncologists are under pressure to contain costs. According to the New York Times, Genentech is putting the wholesale cost of pertuzumab at $5,900/month, which added to the typical $4,500/month costs of trastuzumab, would drive the cost of 18 months of treatment to $187,000.
Boxed Warning Put on Label
Pertuzumab is indicated in combination with trastuzumab and docetaxel for "patients with HER2-positive metastatic breast cancer who have not received prior anti–HER2 therapy or chemotherapy for metastatic disease."
The FDA announced that pertuzumab would have a boxed warning on its label. This is to alert clinicians and patients to the potential risk of death or severe effects to a fetus. "Pregnancy status must be verified prior to the start of Perjeta treatment," it said; patients should be advised "of these risks and need for effective contraception prior to starting pertuzumab."
According to the agency, the most common side effects observed with use of pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral sensory neuropathy.
Although left ventricular dysfunction was observed, the FDA said the combination of pertuzumab with standard therapy "was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction or decreases in left ventricular ejection fraction, compared with placebo in combination with trastuzumab and docetaxel.
The FDA recommended that pertuzumab be started at an initial dose of 840 mg administered as a 60-minute IV infusion, followed every 3 weeks, thereafter, by 420 mg administered as a 30- to 60-minute IV infusion. It also recommended that when trastuzumab is used with pertuzumab, trastuzumab should be started at 8 mg/kg administered as a 90-minute IV infusion, followed every 3 weeks by a dose of 6 mg/kg administered IV over 30 to 90 minutes. When docetaxel is given with pertuzumab, the recommended starting docetaxel dose is 75 mg/m2 administered as an IV infusion. If well tolerated, docetaxel may be escalated to 100 mg/m2 every 3 weeks.
* This story was updated on 11/30/2012.
Women with HER2-positive metastatic breast cancer have been given a double-edged sword, with the Food and Drug Administration granting approval to pertuzumab on Friday, June 8, as a first-line therapy.*
The addition of pertuzumab (Perjeta), a new HER2 blocker, to a standard chemotherapy combination of trastuzumab (Herceptin) and docetaxel (Taxotere) has been shown to extend progression-free survival in these patients. Overall survival data are not yet available.
Pertuzumab is a humanized monoclonal antibody, manufactured through biotechnology methods by Genentech, a subsidiary of Roche. It also blocks other HER family members, including EGFR, HER3, and HER4, and is believed to complement HER2 inhibition by trastuzumab, also made by Genentech and Roche.
The approval rides largely on the results of the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) trial. Dual HER2 blockade boosted median progression-free survival from 12.4 months in a control group treated with only the standard combination to 18.5 months in a group treated with standard therapy plus-pertuzumab. This is a statistically significant difference that corresponds to a 38% reduction in the risk for progression or death and an increase of 6.1 months in median progression-free survival. These results were published in the New England Journal of Medicine (2012;366:109-19).
For the double-blind phase III trial, 808 patients aged 18 years and older with centrally confirmed HER2-positive metastatic or locally recurrent, unresectable breast cancer were randomized either to a control group that received placebo plus trastuzumab and docetaxel or to the pertuzumab group, which received pertuzumab plus trastuzumab and docetaxel.
In their announcements of pertuzumab approval, Genentech, maker of the drug, and the FDA disclosed that production issues could affect the long-term supply of the drug.
"We expect to meet demand for Perjeta following today\'s FDA approval. We recently identified a cell growth issue that might affect our future supply of the medicine," said Patrick Y. Yang, Ph.D., head, Pharma Global Technical Operations. "We take this very seriously and are working with the FDA to ensure a consistent manufacturing process that maintains drug supply for the people who need it."
With the approval, Genentech has agreed to postmarketing commitments related to the manufacturing process for Perjeta. These include FDA review of data from the next several productions of the medicine.
The FDA limited its approval to drug product that has not been affected by production issues, according to Dr. Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research.
"Given the need for additional treatments for metastatic breast cancer, we made the decision to approve this drug today and not to delay its availability to patients pending resolution of the production issues relating to future supply," she said in the FDA announcement.
"Genentech is currently developing a plan to mitigate the effect on patients of any potential shortage of Perjeta."
An added concern is the high cost of dual HER2 inhibition at a time when oncologists are under pressure to contain costs. According to the New York Times, Genentech is putting the wholesale cost of pertuzumab at $5,900/month, which added to the typical $4,500/month costs of trastuzumab, would drive the cost of 18 months of treatment to $187,000.
Boxed Warning Put on Label
Pertuzumab is indicated in combination with trastuzumab and docetaxel for "patients with HER2-positive metastatic breast cancer who have not received prior anti–HER2 therapy or chemotherapy for metastatic disease."
The FDA announced that pertuzumab would have a boxed warning on its label. This is to alert clinicians and patients to the potential risk of death or severe effects to a fetus. "Pregnancy status must be verified prior to the start of Perjeta treatment," it said; patients should be advised "of these risks and need for effective contraception prior to starting pertuzumab."
According to the agency, the most common side effects observed with use of pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral sensory neuropathy.
Although left ventricular dysfunction was observed, the FDA said the combination of pertuzumab with standard therapy "was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction or decreases in left ventricular ejection fraction, compared with placebo in combination with trastuzumab and docetaxel.
The FDA recommended that pertuzumab be started at an initial dose of 840 mg administered as a 60-minute IV infusion, followed every 3 weeks, thereafter, by 420 mg administered as a 30- to 60-minute IV infusion. It also recommended that when trastuzumab is used with pertuzumab, trastuzumab should be started at 8 mg/kg administered as a 90-minute IV infusion, followed every 3 weeks by a dose of 6 mg/kg administered IV over 30 to 90 minutes. When docetaxel is given with pertuzumab, the recommended starting docetaxel dose is 75 mg/m2 administered as an IV infusion. If well tolerated, docetaxel may be escalated to 100 mg/m2 every 3 weeks.
SAN FRANCISCO – Regional recurrence is rare in breast cancer patients with a negative sentinel lymph node biopsy and does not appear to be associated with reduced overall survival, based on the latest results of a clinical trial including more than 5,500 patients.
"Regional recurrences were very low and remained so over the follow-up period," Dr. Kelly K. Hunt said at the annual meeting of the American Surgical Association. The 3-year cumulative incidence rate for regional recurrence was 0.003, and the rate at 5 years was 0.005. In comparison, the 3-year and 5-year rates for local recurrence were 0.013 and 0.024, respectively; the 3-year and 5-year rates for distant recurrence were 0.017 and 0.028, respectively.
Dr. Kelly K. Hunt
Sentinel lymph node (SLN) dissection has been shown to improve staging, compared with axillary lymph node dissection (ALND) alone, and reduced morbidity and improved quality of life have been associated with SLN dissection. Thus, SLN dissection has replaced ALND in clinical practice for staging of regional lymph nodes in women with clinically node-negative, early-stage breast cancer. However, studies have shown false-negative rates ranging from 5% to 17%, noted Dr. Hunt of the department of surgical oncology at the MD Anderson Cancer Center in Houston.
She and her fellow researchers analyzed data from the American College of Surgeons Oncology Group (ACOSOG) Z0010 trial, a prospective multicenter trial designed to evaluate the prognostic implications of SLN and bone marrow micrometastases in women with early-stage breast cancer.
Eligible patients had biopsy-proven T1 or T2 breast cancer with clinically negative lymph nodes and were candidates for lumpectomy and whole breast irradiation. A total of 5,539 patients were enrolled from 126 participating sites. A total of 5,200 patients were fully evaluable, and a sentinel node was identified in 5,119.
Of those, 3,904 patients had negative lymph nodes based on standard H&E staining. Of the patients with negative SLNs on H&E staining, there were 3,326 who had sufficient samples for immunohistochemical staining for cytokeratin. Ten percent of these patients had positive nodes on immunohistochemistry (IHC).
In outcomes published last year, women with H&E positive sentinel nodes had decreased survival compared with those with H&E negative sentinel nodes (JAMA 2011;306:385-93 [doi:10.1001/jama.2011.1034]).
Patients were largely postmenopausal women with ductal breast cancers. They had mostly T1 tumors, many of which were hormone receptor–positive, low to intermediate grade. The majority of patients (98%) had breast-conserving surgery, and 68% patients received hormonal therapy as part of adjuvant treatment. Most patients (92%) finished adjuvant radiation, and almost half (44%) also received systemic chemotherapy. The median follow-up was 8.4 years. There were 127 local failures, 20 regional recurrences, and 134 distant recurrences. There were 317 deaths.
"Within this small group of locoregional recurrences, we did look at the differences in the patients who had IHC-positive vs. IHC-negative sentinel nodes and we did not see any difference between those two groups," Dr. Hunt said. As a result, they combined the two groups for subsequent analyses. "We did not see a difference in recurrence rates based on IHC status, despite the fact that we would suspect that some of these patients have residual disease in the axilla based on published false-negative rates from multicenter trials."
They also examined clinical factors, pathologic factors, and treatment factors that may have affected local and regional recurrences on univariable and multivariable analyses. In both models, younger age and negative hormone receptor status predicted both a greater rate of local failures and locoregional recurrences. With respect to distant recurrence, the important factors were increasing tumor size, the presence of lymphovascular invasion, and higher tumor grade.
Older age, larger tumor size, higher tumor grade, and the presence of a local recurrence predicted reduced overall survival. The hazard rate for local recurrence alone on multivariable analysis was 6.73 (P less than .0001).
"This study reassures anyone practicing in this field ... that those early clinical judgments we all made that drove early adoption of sentinel lymph node axillary staging and early, occasionally angst-ridden decisions to forgo axillary dissection in patients with early-stage breast cancer and minimal axillary nodal disease ... that those choices were correct," said invited discussant Dr. Barbara L. Bass, the John F. and Carolyn Bookout Distinguished Endowed Chair in the department of surgery at the Methodist Hospital in Houston and a professor of surgery at Cornell University in New York.
The regional recurrence rates are particularly interesting, she noted. "It practically makes you think that the axilla – our current bedrock for decision making and staging – is in fact a hostile soil for tumor cells, compared to the breast and distant sites." She asked why the axilla was practically immune from recurrence. "Clearly, those lymph nodes in that space were still there, but tumor does not go or grow there."
Dr. Hunt said earlier studies have suggested that some nodal disease is not clinically relevant and requires no treatment. However, with SLN surgery, "the more that we look, the more we find these micrometastases, and the bias is to treat them."
With improved adjuvant therapy, "we are eradicating disease with those treatments. We know that from neoadjuvant trials as well," Dr. Hunt added. In trials at MD Anderson, after chemotherapy 25% of patients who had fine-needle biopsy at initial diagnosis have complete eradication of disease in the nodes, she said.
"Now that we understand more about the subtypes, we see that in HER-2 positive disease, we’re eradicating about 75% of the disease in regional nodes with targeted therapies." Systemic therapy has gotten better, but it also appears that there are metastases that are not clinically or biologically relevant.
Because the first site of failure is generally the only site recorded, the researchers also performed a competing risk regression model to account for patients with local, regional, and distant recurrences. Evaluating competing risks demonstrated that hormone receptor–negative disease and lack of systemic chemotherapy are associated with increased risk of local recurrence. Older age, higher tumor size, greater tumor grade, and local recurrence predicted decreased survival.
Dr. Bass observed that currently, staging is based largely on the features of the primary tumor – gene assessments, tumor markers, and so on. In light of this, she wondered how long will it will be necessary to surgically stage the clinically negative axilla in patients with early-stage disease who are treated with breast-conserving therapy.
"Do the results of this trial mean that it might be possible to forgo sentinel lymph node staging of the axilla in some patients?" she asked.
That question remains to be answered, according to Dr. Hunt. Planning is underway for a trial in early-stage breast cancer to compare SLN surgery with no treatment of the axilla. "This is based on the fact that we know that different biologic subtypes have very different local and regional recurrence patterns." So, for example, in women with HER-2 positive or triple-negative disease, the systemic treatment regimen is clear with or without nodal involvement.
The researchers reported that they have no relevant conflicts of interest.
The complete manuscript of this presentation is anticipated to be published in the Annals of Surgery pending editorial review.
SAN FRANCISCO – Regional recurrence is rare in breast cancer patients with a negative sentinel lymph node biopsy and does not appear to be associated with reduced overall survival, based on the latest results of a clinical trial including more than 5,500 patients.
"Regional recurrences were very low and remained so over the follow-up period," Dr. Kelly K. Hunt said at the annual meeting of the American Surgical Association. The 3-year cumulative incidence rate for regional recurrence was 0.003, and the rate at 5 years was 0.005. In comparison, the 3-year and 5-year rates for local recurrence were 0.013 and 0.024, respectively; the 3-year and 5-year rates for distant recurrence were 0.017 and 0.028, respectively.
Dr. Kelly K. Hunt
Sentinel lymph node (SLN) dissection has been shown to improve staging, compared with axillary lymph node dissection (ALND) alone, and reduced morbidity and improved quality of life have been associated with SLN dissection. Thus, SLN dissection has replaced ALND in clinical practice for staging of regional lymph nodes in women with clinically node-negative, early-stage breast cancer. However, studies have shown false-negative rates ranging from 5% to 17%, noted Dr. Hunt of the department of surgical oncology at the MD Anderson Cancer Center in Houston.
She and her fellow researchers analyzed data from the American College of Surgeons Oncology Group (ACOSOG) Z0010 trial, a prospective multicenter trial designed to evaluate the prognostic implications of SLN and bone marrow micrometastases in women with early-stage breast cancer.
Eligible patients had biopsy-proven T1 or T2 breast cancer with clinically negative lymph nodes and were candidates for lumpectomy and whole breast irradiation. A total of 5,539 patients were enrolled from 126 participating sites. A total of 5,200 patients were fully evaluable, and a sentinel node was identified in 5,119.
Of those, 3,904 patients had negative lymph nodes based on standard H&E staining. Of the patients with negative SLNs on H&E staining, there were 3,326 who had sufficient samples for immunohistochemical staining for cytokeratin. Ten percent of these patients had positive nodes on immunohistochemistry (IHC).
In outcomes published last year, women with H&E positive sentinel nodes had decreased survival compared with those with H&E negative sentinel nodes (JAMA 2011;306:385-93 [doi:10.1001/jama.2011.1034]).
Patients were largely postmenopausal women with ductal breast cancers. They had mostly T1 tumors, many of which were hormone receptor–positive, low to intermediate grade. The majority of patients (98%) had breast-conserving surgery, and 68% patients received hormonal therapy as part of adjuvant treatment. Most patients (92%) finished adjuvant radiation, and almost half (44%) also received systemic chemotherapy. The median follow-up was 8.4 years. There were 127 local failures, 20 regional recurrences, and 134 distant recurrences. There were 317 deaths.
"Within this small group of locoregional recurrences, we did look at the differences in the patients who had IHC-positive vs. IHC-negative sentinel nodes and we did not see any difference between those two groups," Dr. Hunt said. As a result, they combined the two groups for subsequent analyses. "We did not see a difference in recurrence rates based on IHC status, despite the fact that we would suspect that some of these patients have residual disease in the axilla based on published false-negative rates from multicenter trials."
They also examined clinical factors, pathologic factors, and treatment factors that may have affected local and regional recurrences on univariable and multivariable analyses. In both models, younger age and negative hormone receptor status predicted both a greater rate of local failures and locoregional recurrences. With respect to distant recurrence, the important factors were increasing tumor size, the presence of lymphovascular invasion, and higher tumor grade.
Older age, larger tumor size, higher tumor grade, and the presence of a local recurrence predicted reduced overall survival. The hazard rate for local recurrence alone on multivariable analysis was 6.73 (P less than .0001).
"This study reassures anyone practicing in this field ... that those early clinical judgments we all made that drove early adoption of sentinel lymph node axillary staging and early, occasionally angst-ridden decisions to forgo axillary dissection in patients with early-stage breast cancer and minimal axillary nodal disease ... that those choices were correct," said invited discussant Dr. Barbara L. Bass, the John F. and Carolyn Bookout Distinguished Endowed Chair in the department of surgery at the Methodist Hospital in Houston and a professor of surgery at Cornell University in New York.
The regional recurrence rates are particularly interesting, she noted. "It practically makes you think that the axilla – our current bedrock for decision making and staging – is in fact a hostile soil for tumor cells, compared to the breast and distant sites." She asked why the axilla was practically immune from recurrence. "Clearly, those lymph nodes in that space were still there, but tumor does not go or grow there."
Dr. Hunt said earlier studies have suggested that some nodal disease is not clinically relevant and requires no treatment. However, with SLN surgery, "the more that we look, the more we find these micrometastases, and the bias is to treat them."
With improved adjuvant therapy, "we are eradicating disease with those treatments. We know that from neoadjuvant trials as well," Dr. Hunt added. In trials at MD Anderson, after chemotherapy 25% of patients who had fine-needle biopsy at initial diagnosis have complete eradication of disease in the nodes, she said.
"Now that we understand more about the subtypes, we see that in HER-2 positive disease, we’re eradicating about 75% of the disease in regional nodes with targeted therapies." Systemic therapy has gotten better, but it also appears that there are metastases that are not clinically or biologically relevant.
Because the first site of failure is generally the only site recorded, the researchers also performed a competing risk regression model to account for patients with local, regional, and distant recurrences. Evaluating competing risks demonstrated that hormone receptor–negative disease and lack of systemic chemotherapy are associated with increased risk of local recurrence. Older age, higher tumor size, greater tumor grade, and local recurrence predicted decreased survival.
Dr. Bass observed that currently, staging is based largely on the features of the primary tumor – gene assessments, tumor markers, and so on. In light of this, she wondered how long will it will be necessary to surgically stage the clinically negative axilla in patients with early-stage disease who are treated with breast-conserving therapy.
"Do the results of this trial mean that it might be possible to forgo sentinel lymph node staging of the axilla in some patients?" she asked.
That question remains to be answered, according to Dr. Hunt. Planning is underway for a trial in early-stage breast cancer to compare SLN surgery with no treatment of the axilla. "This is based on the fact that we know that different biologic subtypes have very different local and regional recurrence patterns." So, for example, in women with HER-2 positive or triple-negative disease, the systemic treatment regimen is clear with or without nodal involvement.
The researchers reported that they have no relevant conflicts of interest.
The complete manuscript of this presentation is anticipated to be published in the Annals of Surgery pending editorial review.
SAN FRANCISCO – Regional recurrence is rare in breast cancer patients with a negative sentinel lymph node biopsy and does not appear to be associated with reduced overall survival, based on the latest results of a clinical trial including more than 5,500 patients.
"Regional recurrences were very low and remained so over the follow-up period," Dr. Kelly K. Hunt said at the annual meeting of the American Surgical Association. The 3-year cumulative incidence rate for regional recurrence was 0.003, and the rate at 5 years was 0.005. In comparison, the 3-year and 5-year rates for local recurrence were 0.013 and 0.024, respectively; the 3-year and 5-year rates for distant recurrence were 0.017 and 0.028, respectively.
Dr. Kelly K. Hunt
Sentinel lymph node (SLN) dissection has been shown to improve staging, compared with axillary lymph node dissection (ALND) alone, and reduced morbidity and improved quality of life have been associated with SLN dissection. Thus, SLN dissection has replaced ALND in clinical practice for staging of regional lymph nodes in women with clinically node-negative, early-stage breast cancer. However, studies have shown false-negative rates ranging from 5% to 17%, noted Dr. Hunt of the department of surgical oncology at the MD Anderson Cancer Center in Houston.
She and her fellow researchers analyzed data from the American College of Surgeons Oncology Group (ACOSOG) Z0010 trial, a prospective multicenter trial designed to evaluate the prognostic implications of SLN and bone marrow micrometastases in women with early-stage breast cancer.
Eligible patients had biopsy-proven T1 or T2 breast cancer with clinically negative lymph nodes and were candidates for lumpectomy and whole breast irradiation. A total of 5,539 patients were enrolled from 126 participating sites. A total of 5,200 patients were fully evaluable, and a sentinel node was identified in 5,119.
Of those, 3,904 patients had negative lymph nodes based on standard H&E staining. Of the patients with negative SLNs on H&E staining, there were 3,326 who had sufficient samples for immunohistochemical staining for cytokeratin. Ten percent of these patients had positive nodes on immunohistochemistry (IHC).
In outcomes published last year, women with H&E positive sentinel nodes had decreased survival compared with those with H&E negative sentinel nodes (JAMA 2011;306:385-93 [doi:10.1001/jama.2011.1034]).
Patients were largely postmenopausal women with ductal breast cancers. They had mostly T1 tumors, many of which were hormone receptor–positive, low to intermediate grade. The majority of patients (98%) had breast-conserving surgery, and 68% patients received hormonal therapy as part of adjuvant treatment. Most patients (92%) finished adjuvant radiation, and almost half (44%) also received systemic chemotherapy. The median follow-up was 8.4 years. There were 127 local failures, 20 regional recurrences, and 134 distant recurrences. There were 317 deaths.
"Within this small group of locoregional recurrences, we did look at the differences in the patients who had IHC-positive vs. IHC-negative sentinel nodes and we did not see any difference between those two groups," Dr. Hunt said. As a result, they combined the two groups for subsequent analyses. "We did not see a difference in recurrence rates based on IHC status, despite the fact that we would suspect that some of these patients have residual disease in the axilla based on published false-negative rates from multicenter trials."
They also examined clinical factors, pathologic factors, and treatment factors that may have affected local and regional recurrences on univariable and multivariable analyses. In both models, younger age and negative hormone receptor status predicted both a greater rate of local failures and locoregional recurrences. With respect to distant recurrence, the important factors were increasing tumor size, the presence of lymphovascular invasion, and higher tumor grade.
Older age, larger tumor size, higher tumor grade, and the presence of a local recurrence predicted reduced overall survival. The hazard rate for local recurrence alone on multivariable analysis was 6.73 (P less than .0001).
"This study reassures anyone practicing in this field ... that those early clinical judgments we all made that drove early adoption of sentinel lymph node axillary staging and early, occasionally angst-ridden decisions to forgo axillary dissection in patients with early-stage breast cancer and minimal axillary nodal disease ... that those choices were correct," said invited discussant Dr. Barbara L. Bass, the John F. and Carolyn Bookout Distinguished Endowed Chair in the department of surgery at the Methodist Hospital in Houston and a professor of surgery at Cornell University in New York.
The regional recurrence rates are particularly interesting, she noted. "It practically makes you think that the axilla – our current bedrock for decision making and staging – is in fact a hostile soil for tumor cells, compared to the breast and distant sites." She asked why the axilla was practically immune from recurrence. "Clearly, those lymph nodes in that space were still there, but tumor does not go or grow there."
Dr. Hunt said earlier studies have suggested that some nodal disease is not clinically relevant and requires no treatment. However, with SLN surgery, "the more that we look, the more we find these micrometastases, and the bias is to treat them."
With improved adjuvant therapy, "we are eradicating disease with those treatments. We know that from neoadjuvant trials as well," Dr. Hunt added. In trials at MD Anderson, after chemotherapy 25% of patients who had fine-needle biopsy at initial diagnosis have complete eradication of disease in the nodes, she said.
"Now that we understand more about the subtypes, we see that in HER-2 positive disease, we’re eradicating about 75% of the disease in regional nodes with targeted therapies." Systemic therapy has gotten better, but it also appears that there are metastases that are not clinically or biologically relevant.
Because the first site of failure is generally the only site recorded, the researchers also performed a competing risk regression model to account for patients with local, regional, and distant recurrences. Evaluating competing risks demonstrated that hormone receptor–negative disease and lack of systemic chemotherapy are associated with increased risk of local recurrence. Older age, higher tumor size, greater tumor grade, and local recurrence predicted decreased survival.
Dr. Bass observed that currently, staging is based largely on the features of the primary tumor – gene assessments, tumor markers, and so on. In light of this, she wondered how long will it will be necessary to surgically stage the clinically negative axilla in patients with early-stage disease who are treated with breast-conserving therapy.
"Do the results of this trial mean that it might be possible to forgo sentinel lymph node staging of the axilla in some patients?" she asked.
That question remains to be answered, according to Dr. Hunt. Planning is underway for a trial in early-stage breast cancer to compare SLN surgery with no treatment of the axilla. "This is based on the fact that we know that different biologic subtypes have very different local and regional recurrence patterns." So, for example, in women with HER-2 positive or triple-negative disease, the systemic treatment regimen is clear with or without nodal involvement.
The researchers reported that they have no relevant conflicts of interest.
The complete manuscript of this presentation is anticipated to be published in the Annals of Surgery pending editorial review.
SLN-Negative Breast Cancer Has Low Regional Recurrence
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SLN-Negative Breast Cancer Has Low Regional Recurrence
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breast cancer patients, negative sentinel lymph node, SLN-negative, breast cancer survival, Dr. Kelly K. Hunt
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breast cancer patients, negative sentinel lymph node, SLN-negative, breast cancer survival, Dr. Kelly K. Hunt
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FROM THE ANNUAL MEETING OF THE AMERICAN SURGICAL ASSOCIATION
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Major Finding: The 3-year cumulative incidence rate for regional recurrence of SLN-negative early-stage breast cancer was 0.003 and the rate at 5 years was 0.005. In comparison, the 3-year and 5-year rates for local recurrence were 0.013 and 0.024, respectively; the 3-year and 5-year rates for distant recurrence were 0.017 and 0.028, respectively.
Data Source: The findings come from additional analyses of data from 3,904 women who participated in the American College of Surgeons Oncology Group (ACOSOG) Z0010 trial, which was designed to evaluate the prognostic implications of SLN and bone marrow micrometastases in women with early-stage breast cancer.
Disclosures: The researchers reported that they have no relevant conflicts of interest.
CHICAGO – Women taking zoledronic acid monthly for metastatic breast cancer that has spread to the bone may be able to get by with quarterly injections after a year of standard treatment.
The first phase III trial to compare the two dosing schedules for the bisphosphonate found that less frequent therapy produced "noninferior" outcomes compared with the current standard of care, Dr. Carla Ripamonti reported at the annual meeting of the American Society of Clinical Oncology.
Zoledronic acid (Zometa) has been shown to reduce skeletal-related events for up to 2 years in such patients, and international guidelines recommend its use until they experience a substantial decrease in performance status, said Dr. Ripamonti of the National Cancer Institute in Milan, Italy. The thinking behind the current trial was that after a year of treatment, a more convenient regimen "might contribute to improved patient compliance and safety, and help reduce cost while maintaining the efficacy of the drug."
Underscoring the universality of the issue, the invited discussant, Dr. Thomas J. Smith, director of palliative medicine at Johns Hopkins University’s Sidney Kimmel Cancer Center in Baltimore, introduced his comments with the observation, "I’m a breast cancer doctor, and so I see so many people who ask, ‘Do I have to come in every month for my zoledronic acid?’ And the answer is, ‘I don’t know.’ "
Dr. Ripamonti and her coinvestigators randomized 209 women to 4 mg of zoledronic acid every 12 weeks and 216 women to 4 mg every 4 weeks in the 12-month, open-label, multicenter ZOOM trial. All participants had received 9-12 infusions prior to entering the prospective study.
At the trial’s end, 149 and 142 women, respectively, had completed treatment with no difference in the skeletal morbidity rate, the primary end point, in an intent-to-treat analysis. The mean of the ratio of skeletal events per year to time on trial was 0.26 with quarterly treatment and 0.22 with monthly dosing, she reported.
The proportion of patients with skeletal-related events, a secondary end point, also was similar at 14.8% in the quarterly group and 15.3% in the monthly group.
Both schedules were well tolerated, with little difference in adverse events, she reported. The rate of renal side effects was 4% in each arm; osteonecrosis of the jaw occurred in 4 patients on the quarterly schedule and 3 treated monthly.
An assessment of median NTx (N-telopeptides of type I collagen) levels at baseline and every 3 months on study raised some concern, in that the bone resorption marker was increased at 6 months and stayed elevated in the quarterly group, but it did not rise with standard care. This suggests that "caution is needed and longer follow-up is needed to assess whether zoledronic acid every 3 months can maintain adequate efficacy in skeletal-related events over time," said Dr. Ripamonti.
Despite the generally positive results, she noted that the trial was conducted in just one country as an open-label study, it did not have a prespecified imaging frequency, and patients were followed for only 1 year. She urged clinicians to wait for data from the double-blind, phase III Optimize-2 trial, which compared the same dose schedules. Results will be available in the next year, and then oncologists "can decide how to change our clinical practice," she said.
Dr. Smith agreed. It’s "too early" to use NTx levels, he said, recommending that clinicians wait for new data and guidelines. If quarterly dosing becomes possible, he predicted the "cost will be one-third of what it was before."
"So don’t change your current approach, but stay tuned," he told attendees.
Dr. Ripamonti said she had no relevant disclosures. Dr. Smith said he received research funds from the American Cancer Society.
CHICAGO – Women taking zoledronic acid monthly for metastatic breast cancer that has spread to the bone may be able to get by with quarterly injections after a year of standard treatment.
The first phase III trial to compare the two dosing schedules for the bisphosphonate found that less frequent therapy produced "noninferior" outcomes compared with the current standard of care, Dr. Carla Ripamonti reported at the annual meeting of the American Society of Clinical Oncology.
Zoledronic acid (Zometa) has been shown to reduce skeletal-related events for up to 2 years in such patients, and international guidelines recommend its use until they experience a substantial decrease in performance status, said Dr. Ripamonti of the National Cancer Institute in Milan, Italy. The thinking behind the current trial was that after a year of treatment, a more convenient regimen "might contribute to improved patient compliance and safety, and help reduce cost while maintaining the efficacy of the drug."
Underscoring the universality of the issue, the invited discussant, Dr. Thomas J. Smith, director of palliative medicine at Johns Hopkins University’s Sidney Kimmel Cancer Center in Baltimore, introduced his comments with the observation, "I’m a breast cancer doctor, and so I see so many people who ask, ‘Do I have to come in every month for my zoledronic acid?’ And the answer is, ‘I don’t know.’ "
Dr. Ripamonti and her coinvestigators randomized 209 women to 4 mg of zoledronic acid every 12 weeks and 216 women to 4 mg every 4 weeks in the 12-month, open-label, multicenter ZOOM trial. All participants had received 9-12 infusions prior to entering the prospective study.
At the trial’s end, 149 and 142 women, respectively, had completed treatment with no difference in the skeletal morbidity rate, the primary end point, in an intent-to-treat analysis. The mean of the ratio of skeletal events per year to time on trial was 0.26 with quarterly treatment and 0.22 with monthly dosing, she reported.
The proportion of patients with skeletal-related events, a secondary end point, also was similar at 14.8% in the quarterly group and 15.3% in the monthly group.
Both schedules were well tolerated, with little difference in adverse events, she reported. The rate of renal side effects was 4% in each arm; osteonecrosis of the jaw occurred in 4 patients on the quarterly schedule and 3 treated monthly.
An assessment of median NTx (N-telopeptides of type I collagen) levels at baseline and every 3 months on study raised some concern, in that the bone resorption marker was increased at 6 months and stayed elevated in the quarterly group, but it did not rise with standard care. This suggests that "caution is needed and longer follow-up is needed to assess whether zoledronic acid every 3 months can maintain adequate efficacy in skeletal-related events over time," said Dr. Ripamonti.
Despite the generally positive results, she noted that the trial was conducted in just one country as an open-label study, it did not have a prespecified imaging frequency, and patients were followed for only 1 year. She urged clinicians to wait for data from the double-blind, phase III Optimize-2 trial, which compared the same dose schedules. Results will be available in the next year, and then oncologists "can decide how to change our clinical practice," she said.
Dr. Smith agreed. It’s "too early" to use NTx levels, he said, recommending that clinicians wait for new data and guidelines. If quarterly dosing becomes possible, he predicted the "cost will be one-third of what it was before."
"So don’t change your current approach, but stay tuned," he told attendees.
Dr. Ripamonti said she had no relevant disclosures. Dr. Smith said he received research funds from the American Cancer Society.
CHICAGO – Women taking zoledronic acid monthly for metastatic breast cancer that has spread to the bone may be able to get by with quarterly injections after a year of standard treatment.
The first phase III trial to compare the two dosing schedules for the bisphosphonate found that less frequent therapy produced "noninferior" outcomes compared with the current standard of care, Dr. Carla Ripamonti reported at the annual meeting of the American Society of Clinical Oncology.
Zoledronic acid (Zometa) has been shown to reduce skeletal-related events for up to 2 years in such patients, and international guidelines recommend its use until they experience a substantial decrease in performance status, said Dr. Ripamonti of the National Cancer Institute in Milan, Italy. The thinking behind the current trial was that after a year of treatment, a more convenient regimen "might contribute to improved patient compliance and safety, and help reduce cost while maintaining the efficacy of the drug."
Underscoring the universality of the issue, the invited discussant, Dr. Thomas J. Smith, director of palliative medicine at Johns Hopkins University’s Sidney Kimmel Cancer Center in Baltimore, introduced his comments with the observation, "I’m a breast cancer doctor, and so I see so many people who ask, ‘Do I have to come in every month for my zoledronic acid?’ And the answer is, ‘I don’t know.’ "
Dr. Ripamonti and her coinvestigators randomized 209 women to 4 mg of zoledronic acid every 12 weeks and 216 women to 4 mg every 4 weeks in the 12-month, open-label, multicenter ZOOM trial. All participants had received 9-12 infusions prior to entering the prospective study.
At the trial’s end, 149 and 142 women, respectively, had completed treatment with no difference in the skeletal morbidity rate, the primary end point, in an intent-to-treat analysis. The mean of the ratio of skeletal events per year to time on trial was 0.26 with quarterly treatment and 0.22 with monthly dosing, she reported.
The proportion of patients with skeletal-related events, a secondary end point, also was similar at 14.8% in the quarterly group and 15.3% in the monthly group.
Both schedules were well tolerated, with little difference in adverse events, she reported. The rate of renal side effects was 4% in each arm; osteonecrosis of the jaw occurred in 4 patients on the quarterly schedule and 3 treated monthly.
An assessment of median NTx (N-telopeptides of type I collagen) levels at baseline and every 3 months on study raised some concern, in that the bone resorption marker was increased at 6 months and stayed elevated in the quarterly group, but it did not rise with standard care. This suggests that "caution is needed and longer follow-up is needed to assess whether zoledronic acid every 3 months can maintain adequate efficacy in skeletal-related events over time," said Dr. Ripamonti.
Despite the generally positive results, she noted that the trial was conducted in just one country as an open-label study, it did not have a prespecified imaging frequency, and patients were followed for only 1 year. She urged clinicians to wait for data from the double-blind, phase III Optimize-2 trial, which compared the same dose schedules. Results will be available in the next year, and then oncologists "can decide how to change our clinical practice," she said.
Dr. Smith agreed. It’s "too early" to use NTx levels, he said, recommending that clinicians wait for new data and guidelines. If quarterly dosing becomes possible, he predicted the "cost will be one-third of what it was before."
"So don’t change your current approach, but stay tuned," he told attendees.
Dr. Ripamonti said she had no relevant disclosures. Dr. Smith said he received research funds from the American Cancer Society.
Reflecting a psychological paradigm shift, a number of studies at the American Society of Clinical Oncology 2012 annual meeting focus on individuals’ inherent coping skills, sources of strength, and resilience.
One such study, from Australia, takes the important step of studying resiliency prospectively, drawing important conclusions about which cancer patients are most likely to negotiate the journey just fine, without professional psychological intervention.
Dr. Barbara Kaye Bennett of Prince of Wales Hospital in Sydney led the study of 218 women enrolled just following surgery for early-stage breast cancer. At baseline, she and her associates administered validated measures of mood, somatic symptoms, temperament, illness attitudes, and social support, following up at 1, 3, 6, 9, and 12 months with scales tracking mood and somatic changes.
More than a third of women (34%) never registered clinically relevant signs of psychological or somatic distress during a year of adjuvant treatment and adjustment. Another 15% were temporarily traumatized by the experience, but "recovered promptly and remained well," she reported in a poster displayed at ASCO June 2.
Importantly, the 49% of resilient women did not differ from those with higher psychosocial need in terms of age, marital status, tumor size, treatment modality, or treatment toxicity (nadir hemoglobin and neutrophil count). Mortality was identical, with eight patients in each group dying within 5 years post treatment.
Several factors did distinguish the two groups, including measures of neuroticism, primarily assessed in the study by the Eysenck Personality Questionnaire. Higher scores on the neuroticism scale of the EPQ were strongly, and negatively, correlated with resilience (with a correlation of –.351, P less than.001).
One of the so-called "Big Five" personality traits (openness, conscientiousness, extroversion, agreeableness, and neuroticism), neuroticism basically describes an emotionally reactive, anxious, sensitive, easily rattled temperament, widely believed to be genetic and essentially fixed throughout life.
People who score high on this measure are worriers, somatically focused and more prone than others are to pessimism, anxiety, and depressive symptoms. Resilient patients in the study, then, would be the opposite ... generally calm, optimistic, and not overly sensitive to somatic symptoms.
Other significant findings in the study lent support to the characterization of resilient patients as easy-going, unflappable people. Think of them as "Teflon" rather than "Velcro" responders to major life crises such a diagnosis of cancer and its day-to-day challenges of treatment pain, life disruption, and existential uncertainty.
In the study, they registered lower scores than nonresilient patients on the Illness Behavior Questionnaire scales of anxious concern, disease conviction (hypochondriasis, pain intensity and interference, psychological distress), psychological vs. somatic perception, affective inhibition, and mood disturbance.
Resilient patients perceived higher levels of social support than did their less-resilient peers, but social support was not actually predictive of a resilient psychological outcome. They were also more likely to have received more than 12 years of education and to work more than 20 hours a week – signs, perhaps, of an outward-focused outlook on life.
"Identifying low risk [of psychological distress] may have some important implications," said Dr. Bennett, a postdoctoral fellow in psychology, in an interview from ASCO’s meeting in Chicago. An overabundance of psychological resources for those who do not need them might "undermine [an] individual’s own resources," she noted.
Secondly, it wouldn’t make sense to "squander scarce health resources on those who may not be in need of them and who would not benefit further," if they received counseling or other forms of professional psychosocial care.
If half of patients are so resilient that they tend to do just fine on their own, it’s certainly an observation that deserves more study.
Betsy Bates Freed is a clinical psychologist in Santa Barbara, Calif., and a medical journalist.
Note: Dr. Bennett and her coauthors had no relevant disclosures.
Reflecting a psychological paradigm shift, a number of studies at the American Society of Clinical Oncology 2012 annual meeting focus on individuals’ inherent coping skills, sources of strength, and resilience.
One such study, from Australia, takes the important step of studying resiliency prospectively, drawing important conclusions about which cancer patients are most likely to negotiate the journey just fine, without professional psychological intervention.
Dr. Barbara Kaye Bennett of Prince of Wales Hospital in Sydney led the study of 218 women enrolled just following surgery for early-stage breast cancer. At baseline, she and her associates administered validated measures of mood, somatic symptoms, temperament, illness attitudes, and social support, following up at 1, 3, 6, 9, and 12 months with scales tracking mood and somatic changes.
More than a third of women (34%) never registered clinically relevant signs of psychological or somatic distress during a year of adjuvant treatment and adjustment. Another 15% were temporarily traumatized by the experience, but "recovered promptly and remained well," she reported in a poster displayed at ASCO June 2.
Importantly, the 49% of resilient women did not differ from those with higher psychosocial need in terms of age, marital status, tumor size, treatment modality, or treatment toxicity (nadir hemoglobin and neutrophil count). Mortality was identical, with eight patients in each group dying within 5 years post treatment.
Several factors did distinguish the two groups, including measures of neuroticism, primarily assessed in the study by the Eysenck Personality Questionnaire. Higher scores on the neuroticism scale of the EPQ were strongly, and negatively, correlated with resilience (with a correlation of –.351, P less than.001).
One of the so-called "Big Five" personality traits (openness, conscientiousness, extroversion, agreeableness, and neuroticism), neuroticism basically describes an emotionally reactive, anxious, sensitive, easily rattled temperament, widely believed to be genetic and essentially fixed throughout life.
People who score high on this measure are worriers, somatically focused and more prone than others are to pessimism, anxiety, and depressive symptoms. Resilient patients in the study, then, would be the opposite ... generally calm, optimistic, and not overly sensitive to somatic symptoms.
Other significant findings in the study lent support to the characterization of resilient patients as easy-going, unflappable people. Think of them as "Teflon" rather than "Velcro" responders to major life crises such a diagnosis of cancer and its day-to-day challenges of treatment pain, life disruption, and existential uncertainty.
In the study, they registered lower scores than nonresilient patients on the Illness Behavior Questionnaire scales of anxious concern, disease conviction (hypochondriasis, pain intensity and interference, psychological distress), psychological vs. somatic perception, affective inhibition, and mood disturbance.
Resilient patients perceived higher levels of social support than did their less-resilient peers, but social support was not actually predictive of a resilient psychological outcome. They were also more likely to have received more than 12 years of education and to work more than 20 hours a week – signs, perhaps, of an outward-focused outlook on life.
"Identifying low risk [of psychological distress] may have some important implications," said Dr. Bennett, a postdoctoral fellow in psychology, in an interview from ASCO’s meeting in Chicago. An overabundance of psychological resources for those who do not need them might "undermine [an] individual’s own resources," she noted.
Secondly, it wouldn’t make sense to "squander scarce health resources on those who may not be in need of them and who would not benefit further," if they received counseling or other forms of professional psychosocial care.
If half of patients are so resilient that they tend to do just fine on their own, it’s certainly an observation that deserves more study.
Betsy Bates Freed is a clinical psychologist in Santa Barbara, Calif., and a medical journalist.
Note: Dr. Bennett and her coauthors had no relevant disclosures.
Reflecting a psychological paradigm shift, a number of studies at the American Society of Clinical Oncology 2012 annual meeting focus on individuals’ inherent coping skills, sources of strength, and resilience.
One such study, from Australia, takes the important step of studying resiliency prospectively, drawing important conclusions about which cancer patients are most likely to negotiate the journey just fine, without professional psychological intervention.
Dr. Barbara Kaye Bennett of Prince of Wales Hospital in Sydney led the study of 218 women enrolled just following surgery for early-stage breast cancer. At baseline, she and her associates administered validated measures of mood, somatic symptoms, temperament, illness attitudes, and social support, following up at 1, 3, 6, 9, and 12 months with scales tracking mood and somatic changes.
More than a third of women (34%) never registered clinically relevant signs of psychological or somatic distress during a year of adjuvant treatment and adjustment. Another 15% were temporarily traumatized by the experience, but "recovered promptly and remained well," she reported in a poster displayed at ASCO June 2.
Importantly, the 49% of resilient women did not differ from those with higher psychosocial need in terms of age, marital status, tumor size, treatment modality, or treatment toxicity (nadir hemoglobin and neutrophil count). Mortality was identical, with eight patients in each group dying within 5 years post treatment.
Several factors did distinguish the two groups, including measures of neuroticism, primarily assessed in the study by the Eysenck Personality Questionnaire. Higher scores on the neuroticism scale of the EPQ were strongly, and negatively, correlated with resilience (with a correlation of –.351, P less than.001).
One of the so-called "Big Five" personality traits (openness, conscientiousness, extroversion, agreeableness, and neuroticism), neuroticism basically describes an emotionally reactive, anxious, sensitive, easily rattled temperament, widely believed to be genetic and essentially fixed throughout life.
People who score high on this measure are worriers, somatically focused and more prone than others are to pessimism, anxiety, and depressive symptoms. Resilient patients in the study, then, would be the opposite ... generally calm, optimistic, and not overly sensitive to somatic symptoms.
Other significant findings in the study lent support to the characterization of resilient patients as easy-going, unflappable people. Think of them as "Teflon" rather than "Velcro" responders to major life crises such a diagnosis of cancer and its day-to-day challenges of treatment pain, life disruption, and existential uncertainty.
In the study, they registered lower scores than nonresilient patients on the Illness Behavior Questionnaire scales of anxious concern, disease conviction (hypochondriasis, pain intensity and interference, psychological distress), psychological vs. somatic perception, affective inhibition, and mood disturbance.
Resilient patients perceived higher levels of social support than did their less-resilient peers, but social support was not actually predictive of a resilient psychological outcome. They were also more likely to have received more than 12 years of education and to work more than 20 hours a week – signs, perhaps, of an outward-focused outlook on life.
"Identifying low risk [of psychological distress] may have some important implications," said Dr. Bennett, a postdoctoral fellow in psychology, in an interview from ASCO’s meeting in Chicago. An overabundance of psychological resources for those who do not need them might "undermine [an] individual’s own resources," she noted.
Secondly, it wouldn’t make sense to "squander scarce health resources on those who may not be in need of them and who would not benefit further," if they received counseling or other forms of professional psychosocial care.
If half of patients are so resilient that they tend to do just fine on their own, it’s certainly an observation that deserves more study.
Betsy Bates Freed is a clinical psychologist in Santa Barbara, Calif., and a medical journalist.
Note: Dr. Bennett and her coauthors had no relevant disclosures.
