Breast Cancer

CHICAGO – The antidepressant duloxetine reduces chronic pain from chemotherapy-induced peripheral neuropathy with fewer side effects than with current therapies, according to results of a phase III, double-blind trial.

Among evaluable patients, 59% reported less pain with duloxetine (Cymbalta), compared with 38% with placebo. A pain reduction of 30% or more – a measure considered clinically significant – was reported by 33% and 17%, respectively.

"Duloxetine 60 mg a day is the first drug to be shown to be effective in painful chemotherapy-induced peripheral neuropathy based on the results of a randomized trial," Ellen Lavoie Smith, Ph.D., said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A variety of other agents – including gabapentin and tricyclic antidepressants – have been shown to be effective in treating neuropathic pain and are routinely pressed into service in oncology practice, but have failed to demonstrate efficacy in randomized trials of peripheral neuropathy caused by chemotherapy, she noted.

"Some patients endure this painful neuropathy for months and possibly for as long as years following completion of chemotherapy," she said. "It’s chronic, it’s very distressing and it’s disabling. And there is nothing to date effective in treating this problem."

Duloxetine is approved to treat major depressive disorder, with an additional indication for chronic musculoskeletal pain added in 2010. The safety label was revised in September 2011 to include warnings for severe skin reactions including Stevens-Johnson Syndrome and erythema multiforme.

The Cancer and Leukemia Group B (CALGB) 170601 trial randomized 231 patients with painful neuropathy after receiving single-agent paclitaxel (Taxol) or oxaliplatin (Eloxatin) chemotherapy to duloxetine 30 mg for 1 week and 60 mg for 4 weeks, followed by crossover to placebo after a 1-week washout period or the same regimen in the opposite order. Pain levels were assessed weekly using the Brief Pain Inventory-Short Form (BPI-SF) in 220 patients.

The average change in BPI-SF score, the study’s primary outcome, was -1.09 in patients given duloxetine, compared with –0.33 given placebo (P = .003), reported Dr. Smith, with the University of Michigan, Ann Arbor.

During duloxetine treatment, patients also experienced a significant reduction in the BPI-SF pain interference score, a sum of seven items including interference with general activity, mood, walking, normal work, relations with people, sleep and enjoyment of life. There was no difference in duloxetine efficacy based on the specific neurotoxic chemotherapeutic agent received.

In all, 21% of patients said their pain was cut by at least one-half with duloxetine, while only 9% taking placebo did.

Interestingly, 11% of patients saw their pain increase with the serotonin-norepinephrine reuptake inhibitor, compared with 28% with placebo. The reason for the finding is unclear, Dr. Smith said in an interview.

"Pain is a very complicated thing to study," she said. "There are many things that go into it – psychosocial issues, environmental issues, cultural issues, but again, there may be patients who are more likely to respond to these drugs because their central nervous system isn’t really working normally."

Overall, duloxetine was well tolerated, but was associated with significantly more grade 2 or greater fatigue than placebo (11% vs. 3%; P = .029). Dr. Smith pointed out that the overall incidence of side effects was lower than observed in two studies of diabetes-related peripheral neuropathy, likely because they used the 60 mg dose without the lower 30 mg starting dose.

Dr. Hope Rugo, an oncologist at the University of California, San Francisco, who was not involved in the study, said one of the advantages of duloxetine is the lack of somnolence observed in the study – a side effect that is bothersome to many of her breast cancer patients taking gabapentin for chronic neuropathic pain induced by taxanes or platinum-based therapy.

Press briefing moderator Dr. Nicholas Vogelzang, head of genitourinary cancer at the Nevada Cancer Institute in Las Vegas, echoed those remarks and said that neuropathy is fairly common among his patients treated with platinum-based chemotherapy. Duloxetine is an addition to the oncologist’s armamentarium, he said, adding "I’m certainly going to use this when I get back to the office."

Dr. Smith acknowledged that not everyone responded to duloxetine, but said that the dual serotonin norepinephrine reuptake inhibitor improves compliance with chemotherapy treatment and that most patients saw improved function and quality of life.

Patients with depression were excluded from the trial, so the effect of duloxetine was not simply because of improved mood, she said. Instead, it is thought that the drug eases pain by increasing serotonin and norepinephrine, and that responders may have an abnormality in the way their brain processes pain because of lower levels of these two pain-inhibiting neurotransmitters. Future work will try to determine which patients are most likely to respond to the antidepressant.

CALBG 170601 was supported by the National Cancer Institute division of cancer prevention and Lilly Pharmaceuticals. Dr. Smith reported no conflicts of interest. A coauthor reported research funding from Merck. Dr. Rugo has received research funding from Genentech/Roche, Abraxis BioScience, and Bristol-Myers Squibb.

CHICAGO – The antidepressant duloxetine reduces chronic pain from chemotherapy-induced peripheral neuropathy with fewer side effects than with current therapies, according to results of a phase III, double-blind trial.

Among evaluable patients, 59% reported less pain with duloxetine (Cymbalta), compared with 38% with placebo. A pain reduction of 30% or more – a measure considered clinically significant – was reported by 33% and 17%, respectively.

"Duloxetine 60 mg a day is the first drug to be shown to be effective in painful chemotherapy-induced peripheral neuropathy based on the results of a randomized trial," Ellen Lavoie Smith, Ph.D., said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A variety of other agents – including gabapentin and tricyclic antidepressants – have been shown to be effective in treating neuropathic pain and are routinely pressed into service in oncology practice, but have failed to demonstrate efficacy in randomized trials of peripheral neuropathy caused by chemotherapy, she noted.

"Some patients endure this painful neuropathy for months and possibly for as long as years following completion of chemotherapy," she said. "It’s chronic, it’s very distressing and it’s disabling. And there is nothing to date effective in treating this problem."

Duloxetine is approved to treat major depressive disorder, with an additional indication for chronic musculoskeletal pain added in 2010. The safety label was revised in September 2011 to include warnings for severe skin reactions including Stevens-Johnson Syndrome and erythema multiforme.

The Cancer and Leukemia Group B (CALGB) 170601 trial randomized 231 patients with painful neuropathy after receiving single-agent paclitaxel (Taxol) or oxaliplatin (Eloxatin) chemotherapy to duloxetine 30 mg for 1 week and 60 mg for 4 weeks, followed by crossover to placebo after a 1-week washout period or the same regimen in the opposite order. Pain levels were assessed weekly using the Brief Pain Inventory-Short Form (BPI-SF) in 220 patients.

The average change in BPI-SF score, the study’s primary outcome, was -1.09 in patients given duloxetine, compared with –0.33 given placebo (P = .003), reported Dr. Smith, with the University of Michigan, Ann Arbor.

During duloxetine treatment, patients also experienced a significant reduction in the BPI-SF pain interference score, a sum of seven items including interference with general activity, mood, walking, normal work, relations with people, sleep and enjoyment of life. There was no difference in duloxetine efficacy based on the specific neurotoxic chemotherapeutic agent received.

In all, 21% of patients said their pain was cut by at least one-half with duloxetine, while only 9% taking placebo did.

Interestingly, 11% of patients saw their pain increase with the serotonin-norepinephrine reuptake inhibitor, compared with 28% with placebo. The reason for the finding is unclear, Dr. Smith said in an interview.

"Pain is a very complicated thing to study," she said. "There are many things that go into it – psychosocial issues, environmental issues, cultural issues, but again, there may be patients who are more likely to respond to these drugs because their central nervous system isn’t really working normally."

Overall, duloxetine was well tolerated, but was associated with significantly more grade 2 or greater fatigue than placebo (11% vs. 3%; P = .029). Dr. Smith pointed out that the overall incidence of side effects was lower than observed in two studies of diabetes-related peripheral neuropathy, likely because they used the 60 mg dose without the lower 30 mg starting dose.

Dr. Hope Rugo, an oncologist at the University of California, San Francisco, who was not involved in the study, said one of the advantages of duloxetine is the lack of somnolence observed in the study – a side effect that is bothersome to many of her breast cancer patients taking gabapentin for chronic neuropathic pain induced by taxanes or platinum-based therapy.

Press briefing moderator Dr. Nicholas Vogelzang, head of genitourinary cancer at the Nevada Cancer Institute in Las Vegas, echoed those remarks and said that neuropathy is fairly common among his patients treated with platinum-based chemotherapy. Duloxetine is an addition to the oncologist’s armamentarium, he said, adding "I’m certainly going to use this when I get back to the office."

Dr. Smith acknowledged that not everyone responded to duloxetine, but said that the dual serotonin norepinephrine reuptake inhibitor improves compliance with chemotherapy treatment and that most patients saw improved function and quality of life.

Patients with depression were excluded from the trial, so the effect of duloxetine was not simply because of improved mood, she said. Instead, it is thought that the drug eases pain by increasing serotonin and norepinephrine, and that responders may have an abnormality in the way their brain processes pain because of lower levels of these two pain-inhibiting neurotransmitters. Future work will try to determine which patients are most likely to respond to the antidepressant.

CALBG 170601 was supported by the National Cancer Institute division of cancer prevention and Lilly Pharmaceuticals. Dr. Smith reported no conflicts of interest. A coauthor reported research funding from Merck. Dr. Rugo has received research funding from Genentech/Roche, Abraxis BioScience, and Bristol-Myers Squibb.

CHICAGO – The antidepressant duloxetine reduces chronic pain from chemotherapy-induced peripheral neuropathy with fewer side effects than with current therapies, according to results of a phase III, double-blind trial.

Among evaluable patients, 59% reported less pain with duloxetine (Cymbalta), compared with 38% with placebo. A pain reduction of 30% or more – a measure considered clinically significant – was reported by 33% and 17%, respectively.

"Duloxetine 60 mg a day is the first drug to be shown to be effective in painful chemotherapy-induced peripheral neuropathy based on the results of a randomized trial," Ellen Lavoie Smith, Ph.D., said at a press conference at the annual meeting of the American Society of Clinical Oncology.

A variety of other agents – including gabapentin and tricyclic antidepressants – have been shown to be effective in treating neuropathic pain and are routinely pressed into service in oncology practice, but have failed to demonstrate efficacy in randomized trials of peripheral neuropathy caused by chemotherapy, she noted.

"Some patients endure this painful neuropathy for months and possibly for as long as years following completion of chemotherapy," she said. "It’s chronic, it’s very distressing and it’s disabling. And there is nothing to date effective in treating this problem."

Duloxetine is approved to treat major depressive disorder, with an additional indication for chronic musculoskeletal pain added in 2010. The safety label was revised in September 2011 to include warnings for severe skin reactions including Stevens-Johnson Syndrome and erythema multiforme.

The Cancer and Leukemia Group B (CALGB) 170601 trial randomized 231 patients with painful neuropathy after receiving single-agent paclitaxel (Taxol) or oxaliplatin (Eloxatin) chemotherapy to duloxetine 30 mg for 1 week and 60 mg for 4 weeks, followed by crossover to placebo after a 1-week washout period or the same regimen in the opposite order. Pain levels were assessed weekly using the Brief Pain Inventory-Short Form (BPI-SF) in 220 patients.

The average change in BPI-SF score, the study’s primary outcome, was -1.09 in patients given duloxetine, compared with –0.33 given placebo (P = .003), reported Dr. Smith, with the University of Michigan, Ann Arbor.

During duloxetine treatment, patients also experienced a significant reduction in the BPI-SF pain interference score, a sum of seven items including interference with general activity, mood, walking, normal work, relations with people, sleep and enjoyment of life. There was no difference in duloxetine efficacy based on the specific neurotoxic chemotherapeutic agent received.

In all, 21% of patients said their pain was cut by at least one-half with duloxetine, while only 9% taking placebo did.

Interestingly, 11% of patients saw their pain increase with the serotonin-norepinephrine reuptake inhibitor, compared with 28% with placebo. The reason for the finding is unclear, Dr. Smith said in an interview.

"Pain is a very complicated thing to study," she said. "There are many things that go into it – psychosocial issues, environmental issues, cultural issues, but again, there may be patients who are more likely to respond to these drugs because their central nervous system isn’t really working normally."

Overall, duloxetine was well tolerated, but was associated with significantly more grade 2 or greater fatigue than placebo (11% vs. 3%; P = .029). Dr. Smith pointed out that the overall incidence of side effects was lower than observed in two studies of diabetes-related peripheral neuropathy, likely because they used the 60 mg dose without the lower 30 mg starting dose.

Dr. Hope Rugo, an oncologist at the University of California, San Francisco, who was not involved in the study, said one of the advantages of duloxetine is the lack of somnolence observed in the study – a side effect that is bothersome to many of her breast cancer patients taking gabapentin for chronic neuropathic pain induced by taxanes or platinum-based therapy.

Press briefing moderator Dr. Nicholas Vogelzang, head of genitourinary cancer at the Nevada Cancer Institute in Las Vegas, echoed those remarks and said that neuropathy is fairly common among his patients treated with platinum-based chemotherapy. Duloxetine is an addition to the oncologist’s armamentarium, he said, adding "I’m certainly going to use this when I get back to the office."

Dr. Smith acknowledged that not everyone responded to duloxetine, but said that the dual serotonin norepinephrine reuptake inhibitor improves compliance with chemotherapy treatment and that most patients saw improved function and quality of life.

Patients with depression were excluded from the trial, so the effect of duloxetine was not simply because of improved mood, she said. Instead, it is thought that the drug eases pain by increasing serotonin and norepinephrine, and that responders may have an abnormality in the way their brain processes pain because of lower levels of these two pain-inhibiting neurotransmitters. Future work will try to determine which patients are most likely to respond to the antidepressant.

CALBG 170601 was supported by the National Cancer Institute division of cancer prevention and Lilly Pharmaceuticals. Dr. Smith reported no conflicts of interest. A coauthor reported research funding from Merck. Dr. Rugo has received research funding from Genentech/Roche, Abraxis BioScience, and Bristol-Myers Squibb.

CHICAGO – Two fairly new and expensive drugs for breast cancer were no more effective or safer than a drug that has been used for this disease for over a decade, finds a phase III cooperative group trial among nearly 800 women with chemotherapy-naive locally recurrent or metastatic disease.

The trial pitted the newer nab-paclitaxel (Abraxane) and ixabepilone (Ixempra) against the older paclitaxel (Taxol) as a control, each given weekly, along with bevacizumab (Avastin) given every 2 weeks, as first-line therapy.

Trial results reported at the annual meeting of the American Society of Clinical Oncology showed that progression-free survival was not superior with nab-paclitaxel and was in fact inferior with ixabepilone, translating to a 53% higher risk of progression or death relative to paclitaxel, first author Dr. Hope S. Rugo reported in a press briefing.

Moreover, rates of grade 3 or worse adverse events were higher with both of the newer agents than with the old stand-by.

"These data suggest that similar patients could be appropriately treated with weekly paclitaxel," said Dr. Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco.

"Interestingly, ixabepilone is an epothilone where preclinical and some clinical data suggest an ability to reverse resistance to the microtubule inhibitors like paclitaxel, and nab-paclitaxel has similar data," she added. "However, in this chemotherapy-naive population, these results showed equivalency or inferiority."

Susan London/IMNG Medical Media

"These are all good drugs, these are all major-league baseball players. I want them all on my team," asserted press briefing moderator Dr. Nicholas Vogelzang, chair and medical director, Developmental Therapeutics Committee, US Oncology, Comprehensive Cancer Centers of Nevada. "And when they are used to treat breast cancer, a patient should be considered for all of them, perhaps in different sequences for different patients."

The trial’s findings do not preclude use of at least nab-paclitaxel in selected patients similar to those studied or in other treatment settings, according to Dr. Rugo.

"Based on our data, it’s very unlikely that [nab-paclitaxel] is superior to paclitaxel, but it could be used as an alternative in patients who had a reason not to receive paclitaxel," such as an allergy to cremophor (paclitaxel’s solvent), or diabetes making it hard to tolerate the steroids needed as premedication, she said. Also, the drug is effective in patients with later-stage metastatic breast cancer or with cancers that have progressed on other taxanes.

Finally, nab-paclitaxel is a useful alternative in the context of drug shortages. "In the setting where paclitaxel is not readily available, nab-paclitaxel could clearly be used in its place," she said.

Of note, however, data have shown that nab-paclitaxel given at a lower dose of 100 mg/m² – one-third lower than the dose used in the trial – is less toxic. Therefore, "in patients in whom nab-paclitaxel is chosen ... we should be using the 100 mg/m² dose," Dr. Rugo recommended.

The trial, formally known as CALGB 40502/NCCTG N063H and sponsored by the National Cancer Institute, randomized 799 patients to open-label treatment with one of the three chemotherapies – paclitaxel (90 mg/m² weekly, the most commonly used dosage schedule), nab-paclitaxel (150 mg/m² weekly), or ixabepilone (16 mg/m² weekly) – plus bevacizumab every 2 weeks.

All chemotherapy was given on a 3-weeks-on, 1-week-off schedule. Patients who had a response or stable disease after six cycles could stop chemotherapy and continue with the bevacizumab alone.

With a median follow-up of 12 months, analyses showed that progression-free survival was no better with nab-paclitaxel (9.2 months; hazard ratio, 1.19; P = .12) and was actually worse with ixabepilone (7.6 months; hazard ratio, 1.53; P less than .0001) than with paclitaxel (10.6 months), Dr. Rugo reported.

The overall rate of grade 3 or worse adverse events was 55% with paclitaxel, compared with 79% with nab-paclitaxel and 59% with ixabepilone.

The rate of grade 3 or worse nonhematologic adverse events was significantly higher with the newer agents than with the older one. "We saw increased peripheral neuropathy in the experimental arms as compared with the control arms as well," Dr. Rugo noted. The rate of grade 3 or worse hematologic events was significantly higher with nab-paclitaxel and significantly lower with ixabepilone.

The findings are likely to remain relevant despite the Food and Drug Administration’s withdrawal of approval for bevacizumab, according to Dr. Rugo. "Interestingly, in our study, we obviously don’t have a control arm without bevacizumab, but the progression-free survival in the control arm was almost identical to ECOG 2100," which compared paclitaxel with and without bevacizumab. "And I think for that reason, it’s unlikely that there would be a big difference if you redid the whole study without bevacizumab," she said.

Dr. Rugo said she receives research funding from Abraxis BioScience, Bristol-Myers Squibb, and Roche/Genentech. Dr. Vogelzang said he is a consultant to Amgen, AVEO, Bayer, Celgene(U), Dendreon, Eisai, GE Healthcare, Genentech, GlaxoSmithKline, Johnson & Johnson, Keryx, Medscape, Novartis, Oncogenex, Pfizer, and Wilex; he receives honoraria from Amgen, Bayer, Clinical Care Options, Genentech, Imedex, Lilly, Lippincott, Williams, and Wilkins, Medscape, Novartis, Onyx, Pfizer, and Veridex; and he receives research funding from Algeta, Pfizer, Progenics, and Tokai Pharmaceuticals.

CHICAGO – Two fairly new and expensive drugs for breast cancer were no more effective or safer than a drug that has been used for this disease for over a decade, finds a phase III cooperative group trial among nearly 800 women with chemotherapy-naive locally recurrent or metastatic disease.

The trial pitted the newer nab-paclitaxel (Abraxane) and ixabepilone (Ixempra) against the older paclitaxel (Taxol) as a control, each given weekly, along with bevacizumab (Avastin) given every 2 weeks, as first-line therapy.

Trial results reported at the annual meeting of the American Society of Clinical Oncology showed that progression-free survival was not superior with nab-paclitaxel and was in fact inferior with ixabepilone, translating to a 53% higher risk of progression or death relative to paclitaxel, first author Dr. Hope S. Rugo reported in a press briefing.

Moreover, rates of grade 3 or worse adverse events were higher with both of the newer agents than with the old stand-by.

"These data suggest that similar patients could be appropriately treated with weekly paclitaxel," said Dr. Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco.

"Interestingly, ixabepilone is an epothilone where preclinical and some clinical data suggest an ability to reverse resistance to the microtubule inhibitors like paclitaxel, and nab-paclitaxel has similar data," she added. "However, in this chemotherapy-naive population, these results showed equivalency or inferiority."

Susan London/IMNG Medical Media

"These are all good drugs, these are all major-league baseball players. I want them all on my team," asserted press briefing moderator Dr. Nicholas Vogelzang, chair and medical director, Developmental Therapeutics Committee, US Oncology, Comprehensive Cancer Centers of Nevada. "And when they are used to treat breast cancer, a patient should be considered for all of them, perhaps in different sequences for different patients."

The trial’s findings do not preclude use of at least nab-paclitaxel in selected patients similar to those studied or in other treatment settings, according to Dr. Rugo.

"Based on our data, it’s very unlikely that [nab-paclitaxel] is superior to paclitaxel, but it could be used as an alternative in patients who had a reason not to receive paclitaxel," such as an allergy to cremophor (paclitaxel’s solvent), or diabetes making it hard to tolerate the steroids needed as premedication, she said. Also, the drug is effective in patients with later-stage metastatic breast cancer or with cancers that have progressed on other taxanes.

Finally, nab-paclitaxel is a useful alternative in the context of drug shortages. "In the setting where paclitaxel is not readily available, nab-paclitaxel could clearly be used in its place," she said.

Of note, however, data have shown that nab-paclitaxel given at a lower dose of 100 mg/m² – one-third lower than the dose used in the trial – is less toxic. Therefore, "in patients in whom nab-paclitaxel is chosen ... we should be using the 100 mg/m² dose," Dr. Rugo recommended.

The trial, formally known as CALGB 40502/NCCTG N063H and sponsored by the National Cancer Institute, randomized 799 patients to open-label treatment with one of the three chemotherapies – paclitaxel (90 mg/m² weekly, the most commonly used dosage schedule), nab-paclitaxel (150 mg/m² weekly), or ixabepilone (16 mg/m² weekly) – plus bevacizumab every 2 weeks.

All chemotherapy was given on a 3-weeks-on, 1-week-off schedule. Patients who had a response or stable disease after six cycles could stop chemotherapy and continue with the bevacizumab alone.

With a median follow-up of 12 months, analyses showed that progression-free survival was no better with nab-paclitaxel (9.2 months; hazard ratio, 1.19; P = .12) and was actually worse with ixabepilone (7.6 months; hazard ratio, 1.53; P less than .0001) than with paclitaxel (10.6 months), Dr. Rugo reported.

The overall rate of grade 3 or worse adverse events was 55% with paclitaxel, compared with 79% with nab-paclitaxel and 59% with ixabepilone.

The rate of grade 3 or worse nonhematologic adverse events was significantly higher with the newer agents than with the older one. "We saw increased peripheral neuropathy in the experimental arms as compared with the control arms as well," Dr. Rugo noted. The rate of grade 3 or worse hematologic events was significantly higher with nab-paclitaxel and significantly lower with ixabepilone.

The findings are likely to remain relevant despite the Food and Drug Administration’s withdrawal of approval for bevacizumab, according to Dr. Rugo. "Interestingly, in our study, we obviously don’t have a control arm without bevacizumab, but the progression-free survival in the control arm was almost identical to ECOG 2100," which compared paclitaxel with and without bevacizumab. "And I think for that reason, it’s unlikely that there would be a big difference if you redid the whole study without bevacizumab," she said.

Dr. Rugo said she receives research funding from Abraxis BioScience, Bristol-Myers Squibb, and Roche/Genentech. Dr. Vogelzang said he is a consultant to Amgen, AVEO, Bayer, Celgene(U), Dendreon, Eisai, GE Healthcare, Genentech, GlaxoSmithKline, Johnson & Johnson, Keryx, Medscape, Novartis, Oncogenex, Pfizer, and Wilex; he receives honoraria from Amgen, Bayer, Clinical Care Options, Genentech, Imedex, Lilly, Lippincott, Williams, and Wilkins, Medscape, Novartis, Onyx, Pfizer, and Veridex; and he receives research funding from Algeta, Pfizer, Progenics, and Tokai Pharmaceuticals.

CHICAGO – Two fairly new and expensive drugs for breast cancer were no more effective or safer than a drug that has been used for this disease for over a decade, finds a phase III cooperative group trial among nearly 800 women with chemotherapy-naive locally recurrent or metastatic disease.

The trial pitted the newer nab-paclitaxel (Abraxane) and ixabepilone (Ixempra) against the older paclitaxel (Taxol) as a control, each given weekly, along with bevacizumab (Avastin) given every 2 weeks, as first-line therapy.

Trial results reported at the annual meeting of the American Society of Clinical Oncology showed that progression-free survival was not superior with nab-paclitaxel and was in fact inferior with ixabepilone, translating to a 53% higher risk of progression or death relative to paclitaxel, first author Dr. Hope S. Rugo reported in a press briefing.

Moreover, rates of grade 3 or worse adverse events were higher with both of the newer agents than with the old stand-by.

"These data suggest that similar patients could be appropriately treated with weekly paclitaxel," said Dr. Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco.

"Interestingly, ixabepilone is an epothilone where preclinical and some clinical data suggest an ability to reverse resistance to the microtubule inhibitors like paclitaxel, and nab-paclitaxel has similar data," she added. "However, in this chemotherapy-naive population, these results showed equivalency or inferiority."

Susan London/IMNG Medical Media

"These are all good drugs, these are all major-league baseball players. I want them all on my team," asserted press briefing moderator Dr. Nicholas Vogelzang, chair and medical director, Developmental Therapeutics Committee, US Oncology, Comprehensive Cancer Centers of Nevada. "And when they are used to treat breast cancer, a patient should be considered for all of them, perhaps in different sequences for different patients."

The trial’s findings do not preclude use of at least nab-paclitaxel in selected patients similar to those studied or in other treatment settings, according to Dr. Rugo.

"Based on our data, it’s very unlikely that [nab-paclitaxel] is superior to paclitaxel, but it could be used as an alternative in patients who had a reason not to receive paclitaxel," such as an allergy to cremophor (paclitaxel’s solvent), or diabetes making it hard to tolerate the steroids needed as premedication, she said. Also, the drug is effective in patients with later-stage metastatic breast cancer or with cancers that have progressed on other taxanes.

Finally, nab-paclitaxel is a useful alternative in the context of drug shortages. "In the setting where paclitaxel is not readily available, nab-paclitaxel could clearly be used in its place," she said.

Of note, however, data have shown that nab-paclitaxel given at a lower dose of 100 mg/m² – one-third lower than the dose used in the trial – is less toxic. Therefore, "in patients in whom nab-paclitaxel is chosen ... we should be using the 100 mg/m² dose," Dr. Rugo recommended.

The trial, formally known as CALGB 40502/NCCTG N063H and sponsored by the National Cancer Institute, randomized 799 patients to open-label treatment with one of the three chemotherapies – paclitaxel (90 mg/m² weekly, the most commonly used dosage schedule), nab-paclitaxel (150 mg/m² weekly), or ixabepilone (16 mg/m² weekly) – plus bevacizumab every 2 weeks.

All chemotherapy was given on a 3-weeks-on, 1-week-off schedule. Patients who had a response or stable disease after six cycles could stop chemotherapy and continue with the bevacizumab alone.

With a median follow-up of 12 months, analyses showed that progression-free survival was no better with nab-paclitaxel (9.2 months; hazard ratio, 1.19; P = .12) and was actually worse with ixabepilone (7.6 months; hazard ratio, 1.53; P less than .0001) than with paclitaxel (10.6 months), Dr. Rugo reported.

The overall rate of grade 3 or worse adverse events was 55% with paclitaxel, compared with 79% with nab-paclitaxel and 59% with ixabepilone.

The rate of grade 3 or worse nonhematologic adverse events was significantly higher with the newer agents than with the older one. "We saw increased peripheral neuropathy in the experimental arms as compared with the control arms as well," Dr. Rugo noted. The rate of grade 3 or worse hematologic events was significantly higher with nab-paclitaxel and significantly lower with ixabepilone.

The findings are likely to remain relevant despite the Food and Drug Administration’s withdrawal of approval for bevacizumab, according to Dr. Rugo. "Interestingly, in our study, we obviously don’t have a control arm without bevacizumab, but the progression-free survival in the control arm was almost identical to ECOG 2100," which compared paclitaxel with and without bevacizumab. "And I think for that reason, it’s unlikely that there would be a big difference if you redid the whole study without bevacizumab," she said.

Dr. Rugo said she receives research funding from Abraxis BioScience, Bristol-Myers Squibb, and Roche/Genentech. Dr. Vogelzang said he is a consultant to Amgen, AVEO, Bayer, Celgene(U), Dendreon, Eisai, GE Healthcare, Genentech, GlaxoSmithKline, Johnson & Johnson, Keryx, Medscape, Novartis, Oncogenex, Pfizer, and Wilex; he receives honoraria from Amgen, Bayer, Clinical Care Options, Genentech, Imedex, Lilly, Lippincott, Williams, and Wilkins, Medscape, Novartis, Onyx, Pfizer, and Veridex; and he receives research funding from Algeta, Pfizer, Progenics, and Tokai Pharmaceuticals.

CHICAGO – Breast cancer risk is much higher than previously recognized among women who received chest radiation for Hodgkin’s lymphoma when they were children, investigators reported.

By the time these survivors are 50 years of age, breast cancer incidence is 30% – "remarkably similar" to the 31% incidence observed in the high-risk group of women with BRCA1 mutations, Chaya S. Moskowitz, Ph.D., and her colleagues determined in a study presented at the annual meeting of the American Society of Clinical Oncology.

Although the effect was less dramatic, cumulative risk also was elevated in survivors of other childhood cancers treated with chest radiation, reaching 24% overall by age 50, Dr. Moskowitz said at a press briefing. Among the general population of women in the United States, it is 4% at that benchmark, she noted.

Particularly concerning is the heightened risk observed in women who received less radiation than the current threshold at which the Children’s Oncology Group (COG) recommends breast cancer surveillance. The COG says that survivors who received 20 Gy or more of chest radiation should start annual mammograms at age 25 years or 8 years after radiotherapy, whichever comes later.

In this group, 12% of survivors will develop breast cancer by age 40, said Dr. Moskowitz, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York. The study showed that breast cancer incidence also was elevated, albeit not as dramatically – 7% by age 40 – among survivors who received 10-19 Gy of radiation.

Excess risk in those treated with 10-19 Gy warrants "consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with [more than] 20 Gy," the investigators concluded.

About 50,000 survivors received 20 Gy or more of radiation and, therefore, meet the current threshold, Dr. Moskowitz said. Lowering the threshold to include survivors who were treated with 10-19 Gy of chest radiation would add another 7,000-9,000 women.

Increasing public awareness is crucial to increasing surveillance. "Many women who were treated with chest radiation don’t know they have an increased risk of breast cancer," she said. "Their physicians may or may not know, but many physicians are not aware of the guidelines."

Moreover, many survivors don’t know their radiation exposure, and she urged them to try to find those records from long, long ago.

The analysis – a report from the Childhood Cancer Survivor Study (CCSS) and the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study – mined data on 1,268 women survivors of childhood cancers diagnosed from 1970 to 1986 and on 4,570 first-degree relatives of women who had survived at least 1 year after being diagnosed with breast cancer.

Median follow-up was 26 years in the childhood survivors, of whom 175 women were diagnosed with breast cancer as adults. Median latency was 23 years after treatment, and diagnosis was made at a median age of 38 years.

Multiple studies have shown an increased risk of breast cancer in women who received chest radiation as children, Dr. Moskowitz said. This large study has substantially longer follow-up and was surprising in the magnitude of risk it documents.

Chest radiation doses are lower today, and mantle field radiation – which had been used almost exclusively in Hodgkin’s lymphoma – is no longer used, but other regimens are still in the clinic, she added.

Another surprise from the study was that whole lung radiation, even at low doses, can heighten breast cancer risk. "Women treated with whole lung radiation have a risk of breast cancer that is higher than previous recognized and may benefit from surveillance strategies," she said.

"These are striking data and certainly warrant our careful attention," commented press briefing chair Dr. Nicholas Vogelzang, chair and medical director of the developmental therapeutics committee at the Comprehensive Cancer Centers of Nevada, Las Vegas, and cochair of the genitourinary committee for U.S. Oncology Research.

"The benefit of curing a cancer is you can live 25 or more years," he said, noting that curves for breast cancer incidence rose after 25 years in a graphic representation of the data presented. "We have an obligation to those many thousands of young women whom we treated many years ago."

The investigators said that they had no relevant financial disclosures.

CHICAGO – Breast cancer risk is much higher than previously recognized among women who received chest radiation for Hodgkin’s lymphoma when they were children, investigators reported.

By the time these survivors are 50 years of age, breast cancer incidence is 30% – "remarkably similar" to the 31% incidence observed in the high-risk group of women with BRCA1 mutations, Chaya S. Moskowitz, Ph.D., and her colleagues determined in a study presented at the annual meeting of the American Society of Clinical Oncology.

Although the effect was less dramatic, cumulative risk also was elevated in survivors of other childhood cancers treated with chest radiation, reaching 24% overall by age 50, Dr. Moskowitz said at a press briefing. Among the general population of women in the United States, it is 4% at that benchmark, she noted.

Particularly concerning is the heightened risk observed in women who received less radiation than the current threshold at which the Children’s Oncology Group (COG) recommends breast cancer surveillance. The COG says that survivors who received 20 Gy or more of chest radiation should start annual mammograms at age 25 years or 8 years after radiotherapy, whichever comes later.

In this group, 12% of survivors will develop breast cancer by age 40, said Dr. Moskowitz, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York. The study showed that breast cancer incidence also was elevated, albeit not as dramatically – 7% by age 40 – among survivors who received 10-19 Gy of radiation.

Excess risk in those treated with 10-19 Gy warrants "consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with [more than] 20 Gy," the investigators concluded.

About 50,000 survivors received 20 Gy or more of radiation and, therefore, meet the current threshold, Dr. Moskowitz said. Lowering the threshold to include survivors who were treated with 10-19 Gy of chest radiation would add another 7,000-9,000 women.

Increasing public awareness is crucial to increasing surveillance. "Many women who were treated with chest radiation don’t know they have an increased risk of breast cancer," she said. "Their physicians may or may not know, but many physicians are not aware of the guidelines."

Moreover, many survivors don’t know their radiation exposure, and she urged them to try to find those records from long, long ago.

The analysis – a report from the Childhood Cancer Survivor Study (CCSS) and the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study – mined data on 1,268 women survivors of childhood cancers diagnosed from 1970 to 1986 and on 4,570 first-degree relatives of women who had survived at least 1 year after being diagnosed with breast cancer.

Median follow-up was 26 years in the childhood survivors, of whom 175 women were diagnosed with breast cancer as adults. Median latency was 23 years after treatment, and diagnosis was made at a median age of 38 years.

Multiple studies have shown an increased risk of breast cancer in women who received chest radiation as children, Dr. Moskowitz said. This large study has substantially longer follow-up and was surprising in the magnitude of risk it documents.

Chest radiation doses are lower today, and mantle field radiation – which had been used almost exclusively in Hodgkin’s lymphoma – is no longer used, but other regimens are still in the clinic, she added.

Another surprise from the study was that whole lung radiation, even at low doses, can heighten breast cancer risk. "Women treated with whole lung radiation have a risk of breast cancer that is higher than previous recognized and may benefit from surveillance strategies," she said.

"These are striking data and certainly warrant our careful attention," commented press briefing chair Dr. Nicholas Vogelzang, chair and medical director of the developmental therapeutics committee at the Comprehensive Cancer Centers of Nevada, Las Vegas, and cochair of the genitourinary committee for U.S. Oncology Research.

"The benefit of curing a cancer is you can live 25 or more years," he said, noting that curves for breast cancer incidence rose after 25 years in a graphic representation of the data presented. "We have an obligation to those many thousands of young women whom we treated many years ago."

The investigators said that they had no relevant financial disclosures.

CHICAGO – Breast cancer risk is much higher than previously recognized among women who received chest radiation for Hodgkin’s lymphoma when they were children, investigators reported.

By the time these survivors are 50 years of age, breast cancer incidence is 30% – "remarkably similar" to the 31% incidence observed in the high-risk group of women with BRCA1 mutations, Chaya S. Moskowitz, Ph.D., and her colleagues determined in a study presented at the annual meeting of the American Society of Clinical Oncology.

Although the effect was less dramatic, cumulative risk also was elevated in survivors of other childhood cancers treated with chest radiation, reaching 24% overall by age 50, Dr. Moskowitz said at a press briefing. Among the general population of women in the United States, it is 4% at that benchmark, she noted.

Particularly concerning is the heightened risk observed in women who received less radiation than the current threshold at which the Children’s Oncology Group (COG) recommends breast cancer surveillance. The COG says that survivors who received 20 Gy or more of chest radiation should start annual mammograms at age 25 years or 8 years after radiotherapy, whichever comes later.

In this group, 12% of survivors will develop breast cancer by age 40, said Dr. Moskowitz, a biostatistician at Memorial Sloan-Kettering Cancer Center in New York. The study showed that breast cancer incidence also was elevated, albeit not as dramatically – 7% by age 40 – among survivors who received 10-19 Gy of radiation.

Excess risk in those treated with 10-19 Gy warrants "consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with [more than] 20 Gy," the investigators concluded.

About 50,000 survivors received 20 Gy or more of radiation and, therefore, meet the current threshold, Dr. Moskowitz said. Lowering the threshold to include survivors who were treated with 10-19 Gy of chest radiation would add another 7,000-9,000 women.

Increasing public awareness is crucial to increasing surveillance. "Many women who were treated with chest radiation don’t know they have an increased risk of breast cancer," she said. "Their physicians may or may not know, but many physicians are not aware of the guidelines."

Moreover, many survivors don’t know their radiation exposure, and she urged them to try to find those records from long, long ago.

The analysis – a report from the Childhood Cancer Survivor Study (CCSS) and the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study – mined data on 1,268 women survivors of childhood cancers diagnosed from 1970 to 1986 and on 4,570 first-degree relatives of women who had survived at least 1 year after being diagnosed with breast cancer.

Median follow-up was 26 years in the childhood survivors, of whom 175 women were diagnosed with breast cancer as adults. Median latency was 23 years after treatment, and diagnosis was made at a median age of 38 years.

Multiple studies have shown an increased risk of breast cancer in women who received chest radiation as children, Dr. Moskowitz said. This large study has substantially longer follow-up and was surprising in the magnitude of risk it documents.

Chest radiation doses are lower today, and mantle field radiation – which had been used almost exclusively in Hodgkin’s lymphoma – is no longer used, but other regimens are still in the clinic, she added.

Another surprise from the study was that whole lung radiation, even at low doses, can heighten breast cancer risk. "Women treated with whole lung radiation have a risk of breast cancer that is higher than previous recognized and may benefit from surveillance strategies," she said.

"These are striking data and certainly warrant our careful attention," commented press briefing chair Dr. Nicholas Vogelzang, chair and medical director of the developmental therapeutics committee at the Comprehensive Cancer Centers of Nevada, Las Vegas, and cochair of the genitourinary committee for U.S. Oncology Research.

"The benefit of curing a cancer is you can live 25 or more years," he said, noting that curves for breast cancer incidence rose after 25 years in a graphic representation of the data presented. "We have an obligation to those many thousands of young women whom we treated many years ago."

The investigators said that they had no relevant financial disclosures.

CHICAGO – T-DM1, an investigational antibody-drug conjugate, is more efficacious and less toxic than standard treatment for advanced HER2-positive breast cancer, finds the randomized phase III EMILIA trial.

In the nearly 1,000 women studied, all of whom had previously received a taxane and trastuzumab, T-DM1 reduced the risk of progression-free survival events by 35% and the risk of death by 38% when compared with capecitabine plus lapatinib, investigators reported at the annual meeting of the American Society of Clinical Oncology.

In addition, the rate of grade 3 or higher adverse events was about one-third lower with T-DM1 than with the combination therapy (41% vs. 57%).

"T-DM1 is a brand new way of treating HER2-positive breast cancer. I think it’s the first of many antibody-drug conjugates to follow that will link a potent anticancer agent to a targeted delivery system of an antibody," lead investigator Dr. Kimberly L. Blackwell predicted in a press briefing. "I think this will offer a very important therapeutic option for patients with HER2-positive metastatic breast cancer."

The manufacturer is preparing a filing with the Food and Drug Administration for approval of T-DM1 that will likely cover use in the same population eligible for the trial, namely, women in the first, second, and third lines of treatment, she added.

“I congratulate Dr. Blackwell and her colleagues for designing, implementing, and analyzing a phase III clinical trial that convincingly demonstrates the superiority of T-DM1 therapy compared to a standard reference regimen of capecitabine plus lapatinib in women with HER2-positive metastatic breast cancer that is refractory to trastuzumab,” said discussant Dr. Louis M. Weiner, director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington. “Stated simply, T-DM1 really works in this patient population. The improved survival is particularly notable since effective palliative treatment of metastatic breast cancer has rarely been associated with substantially improved survival in the refractory setting.”

“Like any significant new finding, the success of the EMILIA trial raises many new avenues for further exploration,” Dr. Weiner added. “It will be important to define new clinical niches for T-DM1 therapy in metastatic HER2-positive breast cancer with an additional emphasis on defining effective T-DM1–based drug combinations; such combinations might include chemotherapy agents, other antibodies, targeted agents against the epidermal growth factor receptor network components or other targets, or even immune therapies that liberate nascent antitumor immune responses. While it is perhaps still early, future studies to determine the value of T-DM1 use in the adjuvant setting will be warranted.”

In an interview Dr. Andrew D. Seidman of the Memorial Sloan-Kettering Cancer Center in New York praised the drug’s mechanism of action, saying, “this is a way to teach an old dog new tricks, so to speak. We have a smart bomb: We have trained trastuzumab to deliver a toxic moiety to cancer cells. It’s precision medicine, and it’s superior to the combination of two oral medications that are the current standard of treatment.”

T-DM1 "keeps breast cancer from progressing and, at least in an early analysis, appears likely to prolong survival in HER2-positive metastatic breast cancer," Dr. Seidman added. "So this is, for me, good news. I’ve had hands-on experience with the drug in our own clinical trials at Memorial Sloan-Kettering. It’s kind and gentle. So it’s very welcome."

The investigators enrolled in EMILIA 991 women with locally advanced or metastatic HER2-positive breast cancer that had been previously treated with a taxane and trastuzumab (Herceptin).

They were assigned evenly to intravenous T-DM1 (also known as trastuzumab emtansine) once every 3 weeks, or to oral, standard-dose capecitabine (Xeloda) and lapatinib (Tykerb), currently the only approved combination for trastuzumab-refractory HER2-positive metastatic breast cancer. There was no planned cross-over at progression.

Median progression-free survival, one of the trial’s primary efficacy end points, was 9.6 months with T-DM1, compared with 6.4 months with capecitabine-lapatinib (hazard ratio, 0.65; P less than .0001). Results were largely the same across patient subgroups, except for an apparent lack of benefit among women aged 65 years or older.

The progression-free survival findings triggered an interim analysis of overall survival, the trial’s other primary efficacy end point, according to Dr. Blackwell, who is a professor of medicine and assistant professor of radiation oncology at Duke Cancer Institute at Duke University, Durham, N.C.

Although T-DM1 also improved median overall survival (not reached vs. 23.3 months; hazard ratio, 0.62; P less than .0005), the difference fell just short of the predefined statistical threshold for stopping the trial.

In addition, T-DM1 was superior to capecitabine-lapatinib in terms of the overall response rate and the duration of response.

T-DM1 was associated with higher rates of grade 3 or worse thrombocytopenia (12.9% vs. 0.2%) and elevations of aspartate aminotransferase (4.3% vs. 0.8%) and alanine aminotransferase (2.9% vs. 1.4%); notably, however, cardiac toxicity (an adverse effect seen with trastuzumab) was not elevated with T-DM1. On the other hand, capecitabine-lapatinib was associated with higher rates of diarrhea (20.7% vs. 1.6%), hand-foot syndrome (16.4% vs. 0%), and vomiting (4.5% vs. 0.8%).

Patients given capecitabine-lapatinib were significantly more likely to discontinue treatment because of toxicity, according to Dr. Blackwell.

"We would hope that these data would support the availability of the drug for patients faced with HER2-positive breast cancer," she concluded.

Dr. Blackwell disclosed no relevant conflicts of interest. The trial was sponsored by Genentech, manufacturer of T-DM1. Dr. Seidman disclosed that he is a consultant to Enzon and Wyeth, and receives honoraria from Celgene, Genentech, and Genomic Health. Dr. Weiner disclosed that he is a consultant to Abbott Laboratories, Celldex, Johnson and Johnson, Merrimack, Samsung Advanced Institute of Technology, and Symphogen; owns stock in Celldex and Merrimack; receives honoraria from Bristol-Myers Squibb; and receives research funding from Samsung Advanced Institute of Technology.

*This article was updated June 4, 2012.

CHICAGO – T-DM1, an investigational antibody-drug conjugate, is more efficacious and less toxic than standard treatment for advanced HER2-positive breast cancer, finds the randomized phase III EMILIA trial.

In the nearly 1,000 women studied, all of whom had previously received a taxane and trastuzumab, T-DM1 reduced the risk of progression-free survival events by 35% and the risk of death by 38% when compared with capecitabine plus lapatinib, investigators reported at the annual meeting of the American Society of Clinical Oncology.

In addition, the rate of grade 3 or higher adverse events was about one-third lower with T-DM1 than with the combination therapy (41% vs. 57%).

"T-DM1 is a brand new way of treating HER2-positive breast cancer. I think it’s the first of many antibody-drug conjugates to follow that will link a potent anticancer agent to a targeted delivery system of an antibody," lead investigator Dr. Kimberly L. Blackwell predicted in a press briefing. "I think this will offer a very important therapeutic option for patients with HER2-positive metastatic breast cancer."

The manufacturer is preparing a filing with the Food and Drug Administration for approval of T-DM1 that will likely cover use in the same population eligible for the trial, namely, women in the first, second, and third lines of treatment, she added.

“I congratulate Dr. Blackwell and her colleagues for designing, implementing, and analyzing a phase III clinical trial that convincingly demonstrates the superiority of T-DM1 therapy compared to a standard reference regimen of capecitabine plus lapatinib in women with HER2-positive metastatic breast cancer that is refractory to trastuzumab,” said discussant Dr. Louis M. Weiner, director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington. “Stated simply, T-DM1 really works in this patient population. The improved survival is particularly notable since effective palliative treatment of metastatic breast cancer has rarely been associated with substantially improved survival in the refractory setting.”

“Like any significant new finding, the success of the EMILIA trial raises many new avenues for further exploration,” Dr. Weiner added. “It will be important to define new clinical niches for T-DM1 therapy in metastatic HER2-positive breast cancer with an additional emphasis on defining effective T-DM1–based drug combinations; such combinations might include chemotherapy agents, other antibodies, targeted agents against the epidermal growth factor receptor network components or other targets, or even immune therapies that liberate nascent antitumor immune responses. While it is perhaps still early, future studies to determine the value of T-DM1 use in the adjuvant setting will be warranted.”

In an interview Dr. Andrew D. Seidman of the Memorial Sloan-Kettering Cancer Center in New York praised the drug’s mechanism of action, saying, “this is a way to teach an old dog new tricks, so to speak. We have a smart bomb: We have trained trastuzumab to deliver a toxic moiety to cancer cells. It’s precision medicine, and it’s superior to the combination of two oral medications that are the current standard of treatment.”

T-DM1 "keeps breast cancer from progressing and, at least in an early analysis, appears likely to prolong survival in HER2-positive metastatic breast cancer," Dr. Seidman added. "So this is, for me, good news. I’ve had hands-on experience with the drug in our own clinical trials at Memorial Sloan-Kettering. It’s kind and gentle. So it’s very welcome."

The investigators enrolled in EMILIA 991 women with locally advanced or metastatic HER2-positive breast cancer that had been previously treated with a taxane and trastuzumab (Herceptin).

They were assigned evenly to intravenous T-DM1 (also known as trastuzumab emtansine) once every 3 weeks, or to oral, standard-dose capecitabine (Xeloda) and lapatinib (Tykerb), currently the only approved combination for trastuzumab-refractory HER2-positive metastatic breast cancer. There was no planned cross-over at progression.

Median progression-free survival, one of the trial’s primary efficacy end points, was 9.6 months with T-DM1, compared with 6.4 months with capecitabine-lapatinib (hazard ratio, 0.65; P less than .0001). Results were largely the same across patient subgroups, except for an apparent lack of benefit among women aged 65 years or older.

The progression-free survival findings triggered an interim analysis of overall survival, the trial’s other primary efficacy end point, according to Dr. Blackwell, who is a professor of medicine and assistant professor of radiation oncology at Duke Cancer Institute at Duke University, Durham, N.C.

Although T-DM1 also improved median overall survival (not reached vs. 23.3 months; hazard ratio, 0.62; P less than .0005), the difference fell just short of the predefined statistical threshold for stopping the trial.

In addition, T-DM1 was superior to capecitabine-lapatinib in terms of the overall response rate and the duration of response.

T-DM1 was associated with higher rates of grade 3 or worse thrombocytopenia (12.9% vs. 0.2%) and elevations of aspartate aminotransferase (4.3% vs. 0.8%) and alanine aminotransferase (2.9% vs. 1.4%); notably, however, cardiac toxicity (an adverse effect seen with trastuzumab) was not elevated with T-DM1. On the other hand, capecitabine-lapatinib was associated with higher rates of diarrhea (20.7% vs. 1.6%), hand-foot syndrome (16.4% vs. 0%), and vomiting (4.5% vs. 0.8%).

Patients given capecitabine-lapatinib were significantly more likely to discontinue treatment because of toxicity, according to Dr. Blackwell.

"We would hope that these data would support the availability of the drug for patients faced with HER2-positive breast cancer," she concluded.

Dr. Blackwell disclosed no relevant conflicts of interest. The trial was sponsored by Genentech, manufacturer of T-DM1. Dr. Seidman disclosed that he is a consultant to Enzon and Wyeth, and receives honoraria from Celgene, Genentech, and Genomic Health. Dr. Weiner disclosed that he is a consultant to Abbott Laboratories, Celldex, Johnson and Johnson, Merrimack, Samsung Advanced Institute of Technology, and Symphogen; owns stock in Celldex and Merrimack; receives honoraria from Bristol-Myers Squibb; and receives research funding from Samsung Advanced Institute of Technology.

*This article was updated June 4, 2012.

CHICAGO – T-DM1, an investigational antibody-drug conjugate, is more efficacious and less toxic than standard treatment for advanced HER2-positive breast cancer, finds the randomized phase III EMILIA trial.

In the nearly 1,000 women studied, all of whom had previously received a taxane and trastuzumab, T-DM1 reduced the risk of progression-free survival events by 35% and the risk of death by 38% when compared with capecitabine plus lapatinib, investigators reported at the annual meeting of the American Society of Clinical Oncology.

In addition, the rate of grade 3 or higher adverse events was about one-third lower with T-DM1 than with the combination therapy (41% vs. 57%).

"T-DM1 is a brand new way of treating HER2-positive breast cancer. I think it’s the first of many antibody-drug conjugates to follow that will link a potent anticancer agent to a targeted delivery system of an antibody," lead investigator Dr. Kimberly L. Blackwell predicted in a press briefing. "I think this will offer a very important therapeutic option for patients with HER2-positive metastatic breast cancer."

The manufacturer is preparing a filing with the Food and Drug Administration for approval of T-DM1 that will likely cover use in the same population eligible for the trial, namely, women in the first, second, and third lines of treatment, she added.

“I congratulate Dr. Blackwell and her colleagues for designing, implementing, and analyzing a phase III clinical trial that convincingly demonstrates the superiority of T-DM1 therapy compared to a standard reference regimen of capecitabine plus lapatinib in women with HER2-positive metastatic breast cancer that is refractory to trastuzumab,” said discussant Dr. Louis M. Weiner, director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington. “Stated simply, T-DM1 really works in this patient population. The improved survival is particularly notable since effective palliative treatment of metastatic breast cancer has rarely been associated with substantially improved survival in the refractory setting.”

“Like any significant new finding, the success of the EMILIA trial raises many new avenues for further exploration,” Dr. Weiner added. “It will be important to define new clinical niches for T-DM1 therapy in metastatic HER2-positive breast cancer with an additional emphasis on defining effective T-DM1–based drug combinations; such combinations might include chemotherapy agents, other antibodies, targeted agents against the epidermal growth factor receptor network components or other targets, or even immune therapies that liberate nascent antitumor immune responses. While it is perhaps still early, future studies to determine the value of T-DM1 use in the adjuvant setting will be warranted.”

In an interview Dr. Andrew D. Seidman of the Memorial Sloan-Kettering Cancer Center in New York praised the drug’s mechanism of action, saying, “this is a way to teach an old dog new tricks, so to speak. We have a smart bomb: We have trained trastuzumab to deliver a toxic moiety to cancer cells. It’s precision medicine, and it’s superior to the combination of two oral medications that are the current standard of treatment.”

T-DM1 "keeps breast cancer from progressing and, at least in an early analysis, appears likely to prolong survival in HER2-positive metastatic breast cancer," Dr. Seidman added. "So this is, for me, good news. I’ve had hands-on experience with the drug in our own clinical trials at Memorial Sloan-Kettering. It’s kind and gentle. So it’s very welcome."

The investigators enrolled in EMILIA 991 women with locally advanced or metastatic HER2-positive breast cancer that had been previously treated with a taxane and trastuzumab (Herceptin).

They were assigned evenly to intravenous T-DM1 (also known as trastuzumab emtansine) once every 3 weeks, or to oral, standard-dose capecitabine (Xeloda) and lapatinib (Tykerb), currently the only approved combination for trastuzumab-refractory HER2-positive metastatic breast cancer. There was no planned cross-over at progression.

Median progression-free survival, one of the trial’s primary efficacy end points, was 9.6 months with T-DM1, compared with 6.4 months with capecitabine-lapatinib (hazard ratio, 0.65; P less than .0001). Results were largely the same across patient subgroups, except for an apparent lack of benefit among women aged 65 years or older.

The progression-free survival findings triggered an interim analysis of overall survival, the trial’s other primary efficacy end point, according to Dr. Blackwell, who is a professor of medicine and assistant professor of radiation oncology at Duke Cancer Institute at Duke University, Durham, N.C.

Although T-DM1 also improved median overall survival (not reached vs. 23.3 months; hazard ratio, 0.62; P less than .0005), the difference fell just short of the predefined statistical threshold for stopping the trial.

In addition, T-DM1 was superior to capecitabine-lapatinib in terms of the overall response rate and the duration of response.

T-DM1 was associated with higher rates of grade 3 or worse thrombocytopenia (12.9% vs. 0.2%) and elevations of aspartate aminotransferase (4.3% vs. 0.8%) and alanine aminotransferase (2.9% vs. 1.4%); notably, however, cardiac toxicity (an adverse effect seen with trastuzumab) was not elevated with T-DM1. On the other hand, capecitabine-lapatinib was associated with higher rates of diarrhea (20.7% vs. 1.6%), hand-foot syndrome (16.4% vs. 0%), and vomiting (4.5% vs. 0.8%).

Patients given capecitabine-lapatinib were significantly more likely to discontinue treatment because of toxicity, according to Dr. Blackwell.

"We would hope that these data would support the availability of the drug for patients faced with HER2-positive breast cancer," she concluded.

Dr. Blackwell disclosed no relevant conflicts of interest. The trial was sponsored by Genentech, manufacturer of T-DM1. Dr. Seidman disclosed that he is a consultant to Enzon and Wyeth, and receives honoraria from Celgene, Genentech, and Genomic Health. Dr. Weiner disclosed that he is a consultant to Abbott Laboratories, Celldex, Johnson and Johnson, Merrimack, Samsung Advanced Institute of Technology, and Symphogen; owns stock in Celldex and Merrimack; receives honoraria from Bristol-Myers Squibb; and receives research funding from Samsung Advanced Institute of Technology.

*This article was updated June 4, 2012.

The American College of Radiology’s Imaging Network and the Eastern Cooperative Oncology Group have completed their merger, which was first announced in March 2011.

As of May 17, the two groups will be known as the ECOG-ACRIN Cancer Research Group. The merger became official when they completed and approved a constitution that fully integrates the governance, administrative, and scientific components of both groups.

The new ECOG-ACRIN group comprises nearly 650 institutions and 6,000 individuals from a variety of disciplines.

The Eastern Cooperative Oncology Group was one of the first clinical trial cooperative groups sponsored by the National Cancer Institute. Now, it claims to be one of the largest cancer research organizations in the United States.

The American College of Radiology’s Imaging Network has a network of investigators from 100 academic and community-based facilities in the United States and overseas.

The merger is part of an ongoing process to streamline and consolidate the NCI cooperative groups. The overhaul was spurred by a 2010 Institute of Medicine report that found the NCI clinical trials enterprise had become unwieldy. Cooperative groups also were finding themselves increasingly in the position of competing for the same limited amount of resources for cancer research.

In a joint statement issued upon completion of the merger, ECOG-ACRIN cochairs Dr. Robert L. Comis of Drexel University and Dr. Mitchell L. Schnall of the University of Pennsylvania, both in Philadelphia, said that the new group "establishes for the public and private sectors one organizational structure capable of studying the entire cancer care pathway – prevention and screening, surveillance, early detection, staging, diagnosis, treatment, follow-up, and survivorship."

The two groups also believe that they will be stronger together than they would have been individually, said the joint statement. "For example, our core pathology and imaging scientists, and their associated laboratories and extensive IT infrastructures, make it entirely possible for the Group to integrate large data sets required for biomarker-driven science," the statement said.

Dr. Comis is also chairman of the Coalition of Cancer Cooperative Groups.

When the merger was announced in 2011, the two groups said that the new entity would focus on three main areas: early detection and diagnosis; biomarker-driven phase II and phase III therapeutic studies; and "genetic, molecular, and imaging marker research to predict and monitor treatment response."

The newly merged group said that it expects to start enrolling patients in joint clinical trials soon.

The American College of Radiology’s Imaging Network and the Eastern Cooperative Oncology Group have completed their merger, which was first announced in March 2011.

As of May 17, the two groups will be known as the ECOG-ACRIN Cancer Research Group. The merger became official when they completed and approved a constitution that fully integrates the governance, administrative, and scientific components of both groups.

The new ECOG-ACRIN group comprises nearly 650 institutions and 6,000 individuals from a variety of disciplines.

The Eastern Cooperative Oncology Group was one of the first clinical trial cooperative groups sponsored by the National Cancer Institute. Now, it claims to be one of the largest cancer research organizations in the United States.

The American College of Radiology’s Imaging Network has a network of investigators from 100 academic and community-based facilities in the United States and overseas.

The merger is part of an ongoing process to streamline and consolidate the NCI cooperative groups. The overhaul was spurred by a 2010 Institute of Medicine report that found the NCI clinical trials enterprise had become unwieldy. Cooperative groups also were finding themselves increasingly in the position of competing for the same limited amount of resources for cancer research.

In a joint statement issued upon completion of the merger, ECOG-ACRIN cochairs Dr. Robert L. Comis of Drexel University and Dr. Mitchell L. Schnall of the University of Pennsylvania, both in Philadelphia, said that the new group "establishes for the public and private sectors one organizational structure capable of studying the entire cancer care pathway – prevention and screening, surveillance, early detection, staging, diagnosis, treatment, follow-up, and survivorship."

The two groups also believe that they will be stronger together than they would have been individually, said the joint statement. "For example, our core pathology and imaging scientists, and their associated laboratories and extensive IT infrastructures, make it entirely possible for the Group to integrate large data sets required for biomarker-driven science," the statement said.

Dr. Comis is also chairman of the Coalition of Cancer Cooperative Groups.

When the merger was announced in 2011, the two groups said that the new entity would focus on three main areas: early detection and diagnosis; biomarker-driven phase II and phase III therapeutic studies; and "genetic, molecular, and imaging marker research to predict and monitor treatment response."

The newly merged group said that it expects to start enrolling patients in joint clinical trials soon.

The American College of Radiology’s Imaging Network and the Eastern Cooperative Oncology Group have completed their merger, which was first announced in March 2011.

As of May 17, the two groups will be known as the ECOG-ACRIN Cancer Research Group. The merger became official when they completed and approved a constitution that fully integrates the governance, administrative, and scientific components of both groups.

The new ECOG-ACRIN group comprises nearly 650 institutions and 6,000 individuals from a variety of disciplines.

The Eastern Cooperative Oncology Group was one of the first clinical trial cooperative groups sponsored by the National Cancer Institute. Now, it claims to be one of the largest cancer research organizations in the United States.

The American College of Radiology’s Imaging Network has a network of investigators from 100 academic and community-based facilities in the United States and overseas.

The merger is part of an ongoing process to streamline and consolidate the NCI cooperative groups. The overhaul was spurred by a 2010 Institute of Medicine report that found the NCI clinical trials enterprise had become unwieldy. Cooperative groups also were finding themselves increasingly in the position of competing for the same limited amount of resources for cancer research.

In a joint statement issued upon completion of the merger, ECOG-ACRIN cochairs Dr. Robert L. Comis of Drexel University and Dr. Mitchell L. Schnall of the University of Pennsylvania, both in Philadelphia, said that the new group "establishes for the public and private sectors one organizational structure capable of studying the entire cancer care pathway – prevention and screening, surveillance, early detection, staging, diagnosis, treatment, follow-up, and survivorship."

The two groups also believe that they will be stronger together than they would have been individually, said the joint statement. "For example, our core pathology and imaging scientists, and their associated laboratories and extensive IT infrastructures, make it entirely possible for the Group to integrate large data sets required for biomarker-driven science," the statement said.

Dr. Comis is also chairman of the Coalition of Cancer Cooperative Groups.

When the merger was announced in 2011, the two groups said that the new entity would focus on three main areas: early detection and diagnosis; biomarker-driven phase II and phase III therapeutic studies; and "genetic, molecular, and imaging marker research to predict and monitor treatment response."

The newly merged group said that it expects to start enrolling patients in joint clinical trials soon.

Many primary care physicians – and even some oncologists – are unaware of common long-term side effects of four widely used breast and colorectal cancer drugs, a national survey by the National Cancer Institute reveals.

Only 6% of primary care physicians were able to identify the main long-term effects (LEs) of doxorubicin (Adriamycin), paclitaxel (Taxol), oxaliplatin (Eloxatin), and cyclophosphamide (Cytoxan), compared with 65% of oncologists surveyed.

The results are not surprising, but they underscore the need for ongoing education among all physicians who care for the more than 12 million cancer survivors in the United States, lead author Dr. Larissa Nekhlyudov said during a press briefing highlighting research to be presented at the upcoming annual meeting of the American Society of Clinical Oncology (ASCO).

"These findings emphasize that in the transition of patients from oncology to primary care settings, primary care providers should be informed about the late effects of cancer treatment so that they may be better prepared to recognize and address these among cancer survivors in their care," said Dr. Nekhlyudov, a primary care physician (PCP) with Harvard Medical School in Boston and Harvard Vanguard Medical Associates in Kenmore, Mass. "Whether this will be achieved with survivorship care plans needs to be evaluated."

The "Survey of Physician Attitudes Regarding the Care of Cancer Survivors" was launched by the National Cancer Institute in 2009, with one survey mailed to a nationally representative sample of 1,072 PCPs and the other to 1,130 medical oncologists who only cared for patients with colorectal or breast cancer.

When asked to report the five LEs they had observed and/or had seen reported in the literature for each of the four standard chemotherapy drugs, 95% of oncologists identified cardiac dysfunction as an LE of doxorubicin, compared with 55% of PCPs (P less than .0001), Dr. Nekhlyudov said.

Similarly, peripheral neuropathy was correctly identified as an LE of paclitaxel and of oxaliplatin by 97% of oncologists, but by only 27% and 22%, respectively, of PCPs (both P less than .0001).

The survey suggests, however, that some oncologists could also use additional continuing education. Premature menopause and secondary malignancies – two long-term effects associated with the alkylating agent cyclophosphamide – were identified by only 71% and 62% of oncologists, respectively, along with 15% and 17%, respectively, of PCPs.

Oncologists and PCPs mostly missed pulmonary fibrosis as a late effect for paclitaxel (5% and 6%, respectively; P = .42) or oxaliplatin (5% and. 9%, respectively; P = .0002). They did a little better in pointing out a possible association with cyclophosphamide (20.6% and 13%; P less than .0001), which has been noted in the literature, she observed.

Dr. Nekhlyudov suggested that the lack of awareness among oncologists is likely because much of the focus has been on the treatment of cancer, and only recently have physicians become aware of the importance of survivorship and the potential for late effects.

"While it is surprising that oncologists were not more aware of late effects, I think that as more and more attention is placed on cancer survivorship, oncologists will become more equipped with that information," she said.

ASCO president and press briefing comoderator Dr. Michael Link said the problem of survivorship has long been recognized in pediatric oncology, where patients frequently relocate, outgrow their pediatrician, or even deny they ever had cancer. Groups such as ASCO and the Institute of Medicine, most recently through its "Lost in Transition" report, have offered guidance for improving transitions among survivors, including the provision of a cancer care plan.

"I think the need for all of this has been highlighted in this abstract and certainly, it’s a shot across the bow with things that need to be done," he said.

In adjusted analyses, oncologists who were not board certified were less likely to identify the main LEs for all four drugs (odds ratio, 0.58).Oncologists were more likely to know their LEs if they spent 51%-90% of their time on patient care (OR, 1.87) or more than 90% of their time with patients (OR, 1.82). Age, sex, race, U.S. training, type of practice, and percentage of uninsured patients were not associated with LE awareness, Dr. Nekhlyudov said.

Previous results from the survey reported at last year’s ASCO annual meeting indicated that PCPs had low confidence in their knowledge of breast and colon cancer survivors, and reported low marks for their skills in caring for these patients. In addition, neither PCPs nor oncologists felt that a PCP-led model was ideal for survivorship care (J. Clin. Oncol. 2011;29[suppl.];abstract CRA9006).

Dr. Nekhlyudov will formally present her study at ASCO at 5:30 p.m. June 2. The abstract can be viewed at www.abstract.asco.org.

The authors reported no disclosures.

Many primary care physicians – and even some oncologists – are unaware of common long-term side effects of four widely used breast and colorectal cancer drugs, a national survey by the National Cancer Institute reveals.

Only 6% of primary care physicians were able to identify the main long-term effects (LEs) of doxorubicin (Adriamycin), paclitaxel (Taxol), oxaliplatin (Eloxatin), and cyclophosphamide (Cytoxan), compared with 65% of oncologists surveyed.

The results are not surprising, but they underscore the need for ongoing education among all physicians who care for the more than 12 million cancer survivors in the United States, lead author Dr. Larissa Nekhlyudov said during a press briefing highlighting research to be presented at the upcoming annual meeting of the American Society of Clinical Oncology (ASCO).

"These findings emphasize that in the transition of patients from oncology to primary care settings, primary care providers should be informed about the late effects of cancer treatment so that they may be better prepared to recognize and address these among cancer survivors in their care," said Dr. Nekhlyudov, a primary care physician (PCP) with Harvard Medical School in Boston and Harvard Vanguard Medical Associates in Kenmore, Mass. "Whether this will be achieved with survivorship care plans needs to be evaluated."

The "Survey of Physician Attitudes Regarding the Care of Cancer Survivors" was launched by the National Cancer Institute in 2009, with one survey mailed to a nationally representative sample of 1,072 PCPs and the other to 1,130 medical oncologists who only cared for patients with colorectal or breast cancer.

When asked to report the five LEs they had observed and/or had seen reported in the literature for each of the four standard chemotherapy drugs, 95% of oncologists identified cardiac dysfunction as an LE of doxorubicin, compared with 55% of PCPs (P less than .0001), Dr. Nekhlyudov said.

Similarly, peripheral neuropathy was correctly identified as an LE of paclitaxel and of oxaliplatin by 97% of oncologists, but by only 27% and 22%, respectively, of PCPs (both P less than .0001).

The survey suggests, however, that some oncologists could also use additional continuing education. Premature menopause and secondary malignancies – two long-term effects associated with the alkylating agent cyclophosphamide – were identified by only 71% and 62% of oncologists, respectively, along with 15% and 17%, respectively, of PCPs.

Oncologists and PCPs mostly missed pulmonary fibrosis as a late effect for paclitaxel (5% and 6%, respectively; P = .42) or oxaliplatin (5% and. 9%, respectively; P = .0002). They did a little better in pointing out a possible association with cyclophosphamide (20.6% and 13%; P less than .0001), which has been noted in the literature, she observed.

Dr. Nekhlyudov suggested that the lack of awareness among oncologists is likely because much of the focus has been on the treatment of cancer, and only recently have physicians become aware of the importance of survivorship and the potential for late effects.

"While it is surprising that oncologists were not more aware of late effects, I think that as more and more attention is placed on cancer survivorship, oncologists will become more equipped with that information," she said.

ASCO president and press briefing comoderator Dr. Michael Link said the problem of survivorship has long been recognized in pediatric oncology, where patients frequently relocate, outgrow their pediatrician, or even deny they ever had cancer. Groups such as ASCO and the Institute of Medicine, most recently through its "Lost in Transition" report, have offered guidance for improving transitions among survivors, including the provision of a cancer care plan.

"I think the need for all of this has been highlighted in this abstract and certainly, it’s a shot across the bow with things that need to be done," he said.

In adjusted analyses, oncologists who were not board certified were less likely to identify the main LEs for all four drugs (odds ratio, 0.58).Oncologists were more likely to know their LEs if they spent 51%-90% of their time on patient care (OR, 1.87) or more than 90% of their time with patients (OR, 1.82). Age, sex, race, U.S. training, type of practice, and percentage of uninsured patients were not associated with LE awareness, Dr. Nekhlyudov said.

Previous results from the survey reported at last year’s ASCO annual meeting indicated that PCPs had low confidence in their knowledge of breast and colon cancer survivors, and reported low marks for their skills in caring for these patients. In addition, neither PCPs nor oncologists felt that a PCP-led model was ideal for survivorship care (J. Clin. Oncol. 2011;29[suppl.];abstract CRA9006).

Dr. Nekhlyudov will formally present her study at ASCO at 5:30 p.m. June 2. The abstract can be viewed at www.abstract.asco.org.

The authors reported no disclosures.

Many primary care physicians – and even some oncologists – are unaware of common long-term side effects of four widely used breast and colorectal cancer drugs, a national survey by the National Cancer Institute reveals.

Only 6% of primary care physicians were able to identify the main long-term effects (LEs) of doxorubicin (Adriamycin), paclitaxel (Taxol), oxaliplatin (Eloxatin), and cyclophosphamide (Cytoxan), compared with 65% of oncologists surveyed.

The results are not surprising, but they underscore the need for ongoing education among all physicians who care for the more than 12 million cancer survivors in the United States, lead author Dr. Larissa Nekhlyudov said during a press briefing highlighting research to be presented at the upcoming annual meeting of the American Society of Clinical Oncology (ASCO).

"These findings emphasize that in the transition of patients from oncology to primary care settings, primary care providers should be informed about the late effects of cancer treatment so that they may be better prepared to recognize and address these among cancer survivors in their care," said Dr. Nekhlyudov, a primary care physician (PCP) with Harvard Medical School in Boston and Harvard Vanguard Medical Associates in Kenmore, Mass. "Whether this will be achieved with survivorship care plans needs to be evaluated."

The "Survey of Physician Attitudes Regarding the Care of Cancer Survivors" was launched by the National Cancer Institute in 2009, with one survey mailed to a nationally representative sample of 1,072 PCPs and the other to 1,130 medical oncologists who only cared for patients with colorectal or breast cancer.

When asked to report the five LEs they had observed and/or had seen reported in the literature for each of the four standard chemotherapy drugs, 95% of oncologists identified cardiac dysfunction as an LE of doxorubicin, compared with 55% of PCPs (P less than .0001), Dr. Nekhlyudov said.

Similarly, peripheral neuropathy was correctly identified as an LE of paclitaxel and of oxaliplatin by 97% of oncologists, but by only 27% and 22%, respectively, of PCPs (both P less than .0001).

The survey suggests, however, that some oncologists could also use additional continuing education. Premature menopause and secondary malignancies – two long-term effects associated with the alkylating agent cyclophosphamide – were identified by only 71% and 62% of oncologists, respectively, along with 15% and 17%, respectively, of PCPs.

Oncologists and PCPs mostly missed pulmonary fibrosis as a late effect for paclitaxel (5% and 6%, respectively; P = .42) or oxaliplatin (5% and. 9%, respectively; P = .0002). They did a little better in pointing out a possible association with cyclophosphamide (20.6% and 13%; P less than .0001), which has been noted in the literature, she observed.

Dr. Nekhlyudov suggested that the lack of awareness among oncologists is likely because much of the focus has been on the treatment of cancer, and only recently have physicians become aware of the importance of survivorship and the potential for late effects.

"While it is surprising that oncologists were not more aware of late effects, I think that as more and more attention is placed on cancer survivorship, oncologists will become more equipped with that information," she said.

ASCO president and press briefing comoderator Dr. Michael Link said the problem of survivorship has long been recognized in pediatric oncology, where patients frequently relocate, outgrow their pediatrician, or even deny they ever had cancer. Groups such as ASCO and the Institute of Medicine, most recently through its "Lost in Transition" report, have offered guidance for improving transitions among survivors, including the provision of a cancer care plan.

"I think the need for all of this has been highlighted in this abstract and certainly, it’s a shot across the bow with things that need to be done," he said.

In adjusted analyses, oncologists who were not board certified were less likely to identify the main LEs for all four drugs (odds ratio, 0.58).Oncologists were more likely to know their LEs if they spent 51%-90% of their time on patient care (OR, 1.87) or more than 90% of their time with patients (OR, 1.82). Age, sex, race, U.S. training, type of practice, and percentage of uninsured patients were not associated with LE awareness, Dr. Nekhlyudov said.

Previous results from the survey reported at last year’s ASCO annual meeting indicated that PCPs had low confidence in their knowledge of breast and colon cancer survivors, and reported low marks for their skills in caring for these patients. In addition, neither PCPs nor oncologists felt that a PCP-led model was ideal for survivorship care (J. Clin. Oncol. 2011;29[suppl.];abstract CRA9006).

Dr. Nekhlyudov will formally present her study at ASCO at 5:30 p.m. June 2. The abstract can be viewed at www.abstract.asco.org.

The authors reported no disclosures.

We have long considered completion axillary node dissection for patients with evidence of nodal metastases – and radiation following breast conserving surgery – as truths that are necessary and critical components of treatment planning for early-stage breast cancer. These treatments are not without impact, however, both in short- and long-term toxicity, as well as cost. As we begin to understand the biology that drives breast cancer growth, it has also become clear that not all treatments considered to be "standard" have a positive benefit-to-risk ratio.

A number of recently presented trials challenge the status quo, and teach us that less may indeed be sometimes better. For women who have evidence of cancer in one to two sentinel lymph nodes, and who have had breast-conserving surgery (therefore requiring radiation that includes the low axilla), the recent update to the National Comprehensive Cancer Network (NCCN) guidelines reflects these data demonstrating lack of additional benefit and increased toxicity from completion axillary dissection.

These new guidelines spare women from an increased risk of lymphedema and neuropathy, as well as delayed recovery and procedure-related pain. However, it is important to keep in mind that the inclusion criteria for these trials required breast-conserving surgery, therefore ensuring that radiation would be recommended postoperatively. For patients with more extensive disease in the axillary nodes, a full dissection is still considered the standard of care.

What should be recommended for women who have had a mastectomy and therefore do not require radiation? This is a more difficult question, as the risk of locoregional recurrence for women with a positive sentinel node who forgo radiation is unknown. For an individual patient, local radiation could be considered in the setting of minimal or limited node involvement to avoid more extensive surgery, although data for this approach are lacking.

For older patients with slow-growing, hormone-responsive, early-stage breast cancer, the risk of local recurrence is low, and the overall risk of recurrence is protracted, extending out to at least 15 years. When surgical margins are clearly negative for tumor, the question for these women is whether or not postoperative radiation is worth the time, expense, and toxicity for the expected benefit. Previous randomized data support omitting radiation for low-risk disease in women over the age of 70 who are also receiving adjuvant hormone therapy.

The data presented by Dr. Fei-Fei Liu and colleagues at the annual meeting of the American Association of Cancer Research (AACR) is the next step in identifying the biology of tumors for which radiation provides little benefit. In this series, women taking tamoxifen and whose tumors were hormone receptor–positive, did not express HER2/neu, and had low rates of proliferation as measured by Ki67, were found to have similar recurrence rates in a randomized prospective trial regardless of the use of adjuvant radiation.

This was particularly true for women over the age of 60, although there were only 103 patients in this analysis. Additional data are needed in a larger cohort with external validation of markers before this approach is incorporated into treatment guidelines. However, it is clear that a subset of women with a subset of breast cancers is unlikely to derive significant benefit from adjuvant radiation therapy for early-stage, low-proliferative, hormone receptor–positive breast cancer.

We are making progress, not only in identifying new therapies, but in learning how to more appropriately use the therapies we already have. Less is indeed sometimes better.

Dr. Rugo, associate editor of The Oncology Report, is Director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.

We have long considered completion axillary node dissection for patients with evidence of nodal metastases – and radiation following breast conserving surgery – as truths that are necessary and critical components of treatment planning for early-stage breast cancer. These treatments are not without impact, however, both in short- and long-term toxicity, as well as cost. As we begin to understand the biology that drives breast cancer growth, it has also become clear that not all treatments considered to be "standard" have a positive benefit-to-risk ratio.

A number of recently presented trials challenge the status quo, and teach us that less may indeed be sometimes better. For women who have evidence of cancer in one to two sentinel lymph nodes, and who have had breast-conserving surgery (therefore requiring radiation that includes the low axilla), the recent update to the National Comprehensive Cancer Network (NCCN) guidelines reflects these data demonstrating lack of additional benefit and increased toxicity from completion axillary dissection.

These new guidelines spare women from an increased risk of lymphedema and neuropathy, as well as delayed recovery and procedure-related pain. However, it is important to keep in mind that the inclusion criteria for these trials required breast-conserving surgery, therefore ensuring that radiation would be recommended postoperatively. For patients with more extensive disease in the axillary nodes, a full dissection is still considered the standard of care.

What should be recommended for women who have had a mastectomy and therefore do not require radiation? This is a more difficult question, as the risk of locoregional recurrence for women with a positive sentinel node who forgo radiation is unknown. For an individual patient, local radiation could be considered in the setting of minimal or limited node involvement to avoid more extensive surgery, although data for this approach are lacking.

For older patients with slow-growing, hormone-responsive, early-stage breast cancer, the risk of local recurrence is low, and the overall risk of recurrence is protracted, extending out to at least 15 years. When surgical margins are clearly negative for tumor, the question for these women is whether or not postoperative radiation is worth the time, expense, and toxicity for the expected benefit. Previous randomized data support omitting radiation for low-risk disease in women over the age of 70 who are also receiving adjuvant hormone therapy.

The data presented by Dr. Fei-Fei Liu and colleagues at the annual meeting of the American Association of Cancer Research (AACR) is the next step in identifying the biology of tumors for which radiation provides little benefit. In this series, women taking tamoxifen and whose tumors were hormone receptor–positive, did not express HER2/neu, and had low rates of proliferation as measured by Ki67, were found to have similar recurrence rates in a randomized prospective trial regardless of the use of adjuvant radiation.

This was particularly true for women over the age of 60, although there were only 103 patients in this analysis. Additional data are needed in a larger cohort with external validation of markers before this approach is incorporated into treatment guidelines. However, it is clear that a subset of women with a subset of breast cancers is unlikely to derive significant benefit from adjuvant radiation therapy for early-stage, low-proliferative, hormone receptor–positive breast cancer.

We are making progress, not only in identifying new therapies, but in learning how to more appropriately use the therapies we already have. Less is indeed sometimes better.

Dr. Rugo, associate editor of The Oncology Report, is Director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.

We have long considered completion axillary node dissection for patients with evidence of nodal metastases – and radiation following breast conserving surgery – as truths that are necessary and critical components of treatment planning for early-stage breast cancer. These treatments are not without impact, however, both in short- and long-term toxicity, as well as cost. As we begin to understand the biology that drives breast cancer growth, it has also become clear that not all treatments considered to be "standard" have a positive benefit-to-risk ratio.

A number of recently presented trials challenge the status quo, and teach us that less may indeed be sometimes better. For women who have evidence of cancer in one to two sentinel lymph nodes, and who have had breast-conserving surgery (therefore requiring radiation that includes the low axilla), the recent update to the National Comprehensive Cancer Network (NCCN) guidelines reflects these data demonstrating lack of additional benefit and increased toxicity from completion axillary dissection.

These new guidelines spare women from an increased risk of lymphedema and neuropathy, as well as delayed recovery and procedure-related pain. However, it is important to keep in mind that the inclusion criteria for these trials required breast-conserving surgery, therefore ensuring that radiation would be recommended postoperatively. For patients with more extensive disease in the axillary nodes, a full dissection is still considered the standard of care.

What should be recommended for women who have had a mastectomy and therefore do not require radiation? This is a more difficult question, as the risk of locoregional recurrence for women with a positive sentinel node who forgo radiation is unknown. For an individual patient, local radiation could be considered in the setting of minimal or limited node involvement to avoid more extensive surgery, although data for this approach are lacking.

For older patients with slow-growing, hormone-responsive, early-stage breast cancer, the risk of local recurrence is low, and the overall risk of recurrence is protracted, extending out to at least 15 years. When surgical margins are clearly negative for tumor, the question for these women is whether or not postoperative radiation is worth the time, expense, and toxicity for the expected benefit. Previous randomized data support omitting radiation for low-risk disease in women over the age of 70 who are also receiving adjuvant hormone therapy.

The data presented by Dr. Fei-Fei Liu and colleagues at the annual meeting of the American Association of Cancer Research (AACR) is the next step in identifying the biology of tumors for which radiation provides little benefit. In this series, women taking tamoxifen and whose tumors were hormone receptor–positive, did not express HER2/neu, and had low rates of proliferation as measured by Ki67, were found to have similar recurrence rates in a randomized prospective trial regardless of the use of adjuvant radiation.

This was particularly true for women over the age of 60, although there were only 103 patients in this analysis. Additional data are needed in a larger cohort with external validation of markers before this approach is incorporated into treatment guidelines. However, it is clear that a subset of women with a subset of breast cancers is unlikely to derive significant benefit from adjuvant radiation therapy for early-stage, low-proliferative, hormone receptor–positive breast cancer.

We are making progress, not only in identifying new therapies, but in learning how to more appropriately use the therapies we already have. Less is indeed sometimes better.

Dr. Rugo, associate editor of The Oncology Report, is Director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.

Accelerated partial breast radiation with MammoSite balloon brachytherapy appears to control the tumor bed more effectively than whole breast irradiation, investigators reported at the annual meeting of the American Society of Breast Surgeons.

Dr. Peter Beitsch and his colleagues compared data from the society’s MammoSite Registry with prior findings from studies of whole-breast irradiation (WBI). They said the proportion of recurrences occurring in the tumor bed was much smaller with accelerated partial breast radiation (APBI) – 28% vs. about 69% in the earlier WBI data.

"While it made common sense to a lot of us that APBI should offer better rates of local control, compared to WBI, since the radiation therapy with APBI is delivered directly to the tumor site, this is the first study to have actually proven this hypothesis," Dr. Beitsch, director of the Dallas Breast Center, said in an interview.

"WBI has been held as the ‘gold standard’ for post-lumpectomy radiation therapy, and our data may change that line of thought," he added.

Randomized trials demonstrate that lumpectomy with WBI yields survival rates equivalent to those seen with mastectomy; they also show that WBI has no impact on the ipsilateral occurrence of new "elsewhere" cancers in quadrants away from the primary tumor quadrant. Dr. Beitsch explained during a press briefing.

In all such trials, thus far, tumor bed recurrence rates have been higher than were the rates of ipsilateral "elsewhere" cancers, he said.

Now, however, 5-year actuarial data from 1,449 cases in 1,440 patients in the MammoSite registry show the opposite. The patients were treated at 97 institutions between May 2002 and July 2004. Most patients, 87%, were diagnosed with invasive breast cancer and the rest, 13%, with ductal carcinoma in situ (DCIS). Median follow up was 60 months.

Dr. Beitsch reported there have been 50 (3.5%) ipsilateral breast tumor recurrences: 14 (1.0%) at the initial tumor site and 36 (2.5%) elsewhere in the breast. The total actuarial rate of ipsilateral breast tumor recurrence was 3.61% (3.65 % for invasive disease and 3.36 % for DCIS). Tumor bed recurrences accounted for 28% of all recurrences, whereas recurrences elsewhere added up to 72%.

In contrast, historical data on whole-breast irradiation (WBI) from six studies demonstrate that tumor bed recurrences are about twice as common as recurrences elsewhere, approximately 69% vs. about 31% elsewhere, said Dr. Beitsch, co-principal investigator for the registry and lead author on the study.

The new findings contrast with a controversial retrospective study of breast brachytherapy in nearly 93,000 older women with invasive breast cancer. In that study, the mastectomy rate 5 years later was about twice as high in women treated with brachytherapy – cumulative incidence 3.95% vs. 2.18% with WBI. The difference persisted after a multivariate adjustment, with a hazard ratio of 2.19, according to a report published May 1, 2012, in JAMA.

Moreover, short-term and long-term complications, including breast pain, were significantly more common in women who had radiation delivered by brachytherapy. Overall survival was not significantly different, however, at about 87% in both groups studied, Dr. Dr. Grace L. Smith of the University of Texas M.D. Anderson Cancer Center in Houston and her coauthors reported (JAMA 2012;307:1827-37).

In a press release asserting that the new study contradicts the JAMA report, Dr. Beitsch called attention to limitations of the M.D. Anderson study: He noted that it is based on Medicare claims data, which often do not provide an accurate clinical picture. In addition, many of the end points are "soft," poorly defined and difficult to quantify, he said, adding that the reported complication rates after breast surgery and radiotherapy vary widely, and are subject to under- or over-reporting.

Finally, "the authors’ inferences of harm to patients from breast brachytherapy are speculative," he said.

The American Society of Breast Surgeons (ASBrS) is one of three groups that previously issued rebuttals to the retrospective study. In the same press release, ASBrS executive committee member Dr. Hiram S. Cody III said that ASBrS continues to support its Consensus Statement on APBI and guidelines for patient selection, which was revised Aug. 15, 2011.

"APBI appears to be safe and effective treatment for properly selected breast conservation patients," said Dr. Cody, an attending surgeon at Memorial Sloan-Kettering Cancer Center and professor of clinical surgery at Cornell University, both in New York.

"We wish to emphasize that, although the 6-year results of APBI are encouraging, they do not conclusively establish equivalence with WBI, for which the supporting data include multiple randomized trials with follow-up exceeding 20 years, and meta-analyses that conclusively link local control and survival," Dr. Cody stated.

"APBI must ultimately be held to the same standard, and a randomized trial, NSABP [National Surgical Adjuvant Breast and Bowel Project] B-39, directly compares partial breast irradiation (by interstitial catheters, balloon devices, strut-based devices, or external beam) with WBI and promises to better define the ultimate role of APBI."

Dr. Beitsch and Dr. Cody stated that they have no disclosures.

Accelerated partial breast radiation with MammoSite balloon brachytherapy appears to control the tumor bed more effectively than whole breast irradiation, investigators reported at the annual meeting of the American Society of Breast Surgeons.

Dr. Peter Beitsch and his colleagues compared data from the society’s MammoSite Registry with prior findings from studies of whole-breast irradiation (WBI). They said the proportion of recurrences occurring in the tumor bed was much smaller with accelerated partial breast radiation (APBI) – 28% vs. about 69% in the earlier WBI data.

"While it made common sense to a lot of us that APBI should offer better rates of local control, compared to WBI, since the radiation therapy with APBI is delivered directly to the tumor site, this is the first study to have actually proven this hypothesis," Dr. Beitsch, director of the Dallas Breast Center, said in an interview.

"WBI has been held as the ‘gold standard’ for post-lumpectomy radiation therapy, and our data may change that line of thought," he added.

Randomized trials demonstrate that lumpectomy with WBI yields survival rates equivalent to those seen with mastectomy; they also show that WBI has no impact on the ipsilateral occurrence of new "elsewhere" cancers in quadrants away from the primary tumor quadrant. Dr. Beitsch explained during a press briefing.

In all such trials, thus far, tumor bed recurrence rates have been higher than were the rates of ipsilateral "elsewhere" cancers, he said.

Now, however, 5-year actuarial data from 1,449 cases in 1,440 patients in the MammoSite registry show the opposite. The patients were treated at 97 institutions between May 2002 and July 2004. Most patients, 87%, were diagnosed with invasive breast cancer and the rest, 13%, with ductal carcinoma in situ (DCIS). Median follow up was 60 months.

Dr. Beitsch reported there have been 50 (3.5%) ipsilateral breast tumor recurrences: 14 (1.0%) at the initial tumor site and 36 (2.5%) elsewhere in the breast. The total actuarial rate of ipsilateral breast tumor recurrence was 3.61% (3.65 % for invasive disease and 3.36 % for DCIS). Tumor bed recurrences accounted for 28% of all recurrences, whereas recurrences elsewhere added up to 72%.

In contrast, historical data on whole-breast irradiation (WBI) from six studies demonstrate that tumor bed recurrences are about twice as common as recurrences elsewhere, approximately 69% vs. about 31% elsewhere, said Dr. Beitsch, co-principal investigator for the registry and lead author on the study.

The new findings contrast with a controversial retrospective study of breast brachytherapy in nearly 93,000 older women with invasive breast cancer. In that study, the mastectomy rate 5 years later was about twice as high in women treated with brachytherapy – cumulative incidence 3.95% vs. 2.18% with WBI. The difference persisted after a multivariate adjustment, with a hazard ratio of 2.19, according to a report published May 1, 2012, in JAMA.

Moreover, short-term and long-term complications, including breast pain, were significantly more common in women who had radiation delivered by brachytherapy. Overall survival was not significantly different, however, at about 87% in both groups studied, Dr. Dr. Grace L. Smith of the University of Texas M.D. Anderson Cancer Center in Houston and her coauthors reported (JAMA 2012;307:1827-37).

In a press release asserting that the new study contradicts the JAMA report, Dr. Beitsch called attention to limitations of the M.D. Anderson study: He noted that it is based on Medicare claims data, which often do not provide an accurate clinical picture. In addition, many of the end points are "soft," poorly defined and difficult to quantify, he said, adding that the reported complication rates after breast surgery and radiotherapy vary widely, and are subject to under- or over-reporting.

Finally, "the authors’ inferences of harm to patients from breast brachytherapy are speculative," he said.

The American Society of Breast Surgeons (ASBrS) is one of three groups that previously issued rebuttals to the retrospective study. In the same press release, ASBrS executive committee member Dr. Hiram S. Cody III said that ASBrS continues to support its Consensus Statement on APBI and guidelines for patient selection, which was revised Aug. 15, 2011.

"APBI appears to be safe and effective treatment for properly selected breast conservation patients," said Dr. Cody, an attending surgeon at Memorial Sloan-Kettering Cancer Center and professor of clinical surgery at Cornell University, both in New York.

"We wish to emphasize that, although the 6-year results of APBI are encouraging, they do not conclusively establish equivalence with WBI, for which the supporting data include multiple randomized trials with follow-up exceeding 20 years, and meta-analyses that conclusively link local control and survival," Dr. Cody stated.

"APBI must ultimately be held to the same standard, and a randomized trial, NSABP [National Surgical Adjuvant Breast and Bowel Project] B-39, directly compares partial breast irradiation (by interstitial catheters, balloon devices, strut-based devices, or external beam) with WBI and promises to better define the ultimate role of APBI."

Dr. Beitsch and Dr. Cody stated that they have no disclosures.

Accelerated partial breast radiation with MammoSite balloon brachytherapy appears to control the tumor bed more effectively than whole breast irradiation, investigators reported at the annual meeting of the American Society of Breast Surgeons.

Dr. Peter Beitsch and his colleagues compared data from the society’s MammoSite Registry with prior findings from studies of whole-breast irradiation (WBI). They said the proportion of recurrences occurring in the tumor bed was much smaller with accelerated partial breast radiation (APBI) – 28% vs. about 69% in the earlier WBI data.

"While it made common sense to a lot of us that APBI should offer better rates of local control, compared to WBI, since the radiation therapy with APBI is delivered directly to the tumor site, this is the first study to have actually proven this hypothesis," Dr. Beitsch, director of the Dallas Breast Center, said in an interview.

"WBI has been held as the ‘gold standard’ for post-lumpectomy radiation therapy, and our data may change that line of thought," he added.

Randomized trials demonstrate that lumpectomy with WBI yields survival rates equivalent to those seen with mastectomy; they also show that WBI has no impact on the ipsilateral occurrence of new "elsewhere" cancers in quadrants away from the primary tumor quadrant. Dr. Beitsch explained during a press briefing.

In all such trials, thus far, tumor bed recurrence rates have been higher than were the rates of ipsilateral "elsewhere" cancers, he said.

Now, however, 5-year actuarial data from 1,449 cases in 1,440 patients in the MammoSite registry show the opposite. The patients were treated at 97 institutions between May 2002 and July 2004. Most patients, 87%, were diagnosed with invasive breast cancer and the rest, 13%, with ductal carcinoma in situ (DCIS). Median follow up was 60 months.

Dr. Beitsch reported there have been 50 (3.5%) ipsilateral breast tumor recurrences: 14 (1.0%) at the initial tumor site and 36 (2.5%) elsewhere in the breast. The total actuarial rate of ipsilateral breast tumor recurrence was 3.61% (3.65 % for invasive disease and 3.36 % for DCIS). Tumor bed recurrences accounted for 28% of all recurrences, whereas recurrences elsewhere added up to 72%.

In contrast, historical data on whole-breast irradiation (WBI) from six studies demonstrate that tumor bed recurrences are about twice as common as recurrences elsewhere, approximately 69% vs. about 31% elsewhere, said Dr. Beitsch, co-principal investigator for the registry and lead author on the study.

The new findings contrast with a controversial retrospective study of breast brachytherapy in nearly 93,000 older women with invasive breast cancer. In that study, the mastectomy rate 5 years later was about twice as high in women treated with brachytherapy – cumulative incidence 3.95% vs. 2.18% with WBI. The difference persisted after a multivariate adjustment, with a hazard ratio of 2.19, according to a report published May 1, 2012, in JAMA.

Moreover, short-term and long-term complications, including breast pain, were significantly more common in women who had radiation delivered by brachytherapy. Overall survival was not significantly different, however, at about 87% in both groups studied, Dr. Dr. Grace L. Smith of the University of Texas M.D. Anderson Cancer Center in Houston and her coauthors reported (JAMA 2012;307:1827-37).

In a press release asserting that the new study contradicts the JAMA report, Dr. Beitsch called attention to limitations of the M.D. Anderson study: He noted that it is based on Medicare claims data, which often do not provide an accurate clinical picture. In addition, many of the end points are "soft," poorly defined and difficult to quantify, he said, adding that the reported complication rates after breast surgery and radiotherapy vary widely, and are subject to under- or over-reporting.

Finally, "the authors’ inferences of harm to patients from breast brachytherapy are speculative," he said.

The American Society of Breast Surgeons (ASBrS) is one of three groups that previously issued rebuttals to the retrospective study. In the same press release, ASBrS executive committee member Dr. Hiram S. Cody III said that ASBrS continues to support its Consensus Statement on APBI and guidelines for patient selection, which was revised Aug. 15, 2011.

"APBI appears to be safe and effective treatment for properly selected breast conservation patients," said Dr. Cody, an attending surgeon at Memorial Sloan-Kettering Cancer Center and professor of clinical surgery at Cornell University, both in New York.

"We wish to emphasize that, although the 6-year results of APBI are encouraging, they do not conclusively establish equivalence with WBI, for which the supporting data include multiple randomized trials with follow-up exceeding 20 years, and meta-analyses that conclusively link local control and survival," Dr. Cody stated.

"APBI must ultimately be held to the same standard, and a randomized trial, NSABP [National Surgical Adjuvant Breast and Bowel Project] B-39, directly compares partial breast irradiation (by interstitial catheters, balloon devices, strut-based devices, or external beam) with WBI and promises to better define the ultimate role of APBI."

Dr. Beitsch and Dr. Cody stated that they have no disclosures.