sarah
05-31-2006, 10:15 AM
From Medscape: (sorry if this has already been posted)
http://www.medscape.com/viewarticle/532396
Optimizing Adjuvant Treatment for Patients With HER2-Positive Breast Cancer: An Expert Interview With Dr. Clifford Hudis
Medscape Hematology-Oncology. 2006;9(1) ©2006 Medscape
Posted 05/23/2006
http://images.medscape.com/pi/global/ornaments/spacer.gifEditor's Note:
Results from 4 major trials[1-3] demonstrating a clear benefit with the addition of trastuzumab to adjuvant therapy for patients with HER2-positive breast cancer have also raised a number of associated questions. Among the clinical issues that have emerged are concerns over cardiac safety, questions of optimal sequencing and duration, and evolving data from studies of chemotherapy regimens, including whether to use dose-dense schedules and whether it is safe to exclude anthracyclines in certain patients. To better understand how such questions affect current practice, as well as to explore directions for future research, Nancy Lin, MD, of Harvard Medical School and Dana-Farber Cancer Institute, on behalf of Medscape, spoke with Clifford Hudis, MD, Chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, New York, NY, and Associate Professor of Medicine at the Joan and Sanford I. Weill Medical College at Cornell University, New York, NY.
Medscape: There are now 4 major trials[1-3] demonstrating improved disease-free survival with the addition of trastuzumab in the adjuvant setting. What were the key differences between the trials?
Dr. Hudis: The very first trial, which was led by the NSABP [National Surgical Adjuvant Breast and Bowel Project],[1] was the simplest one: doxorubicin and cyclosphosphamide (AC) followed by paclitaxel, all given conventionally with or without trastuzumab. A very similar trial, the Intergroup 9831 trial led by the North Central Group,[1] looked at essentially the same thing, AC-paclitaxel, the only wrinkle being that it used low-dose weekly paclitaxel rather than conventional high-dose paclitaxel given every 3 weeks. It also included a novel third arm in which trastuzumab was not given with the paclitaxel but was delayed until the end of chemotherapy. The third trial was the BCIRG 006 trial,[2] which substituted docetaxel in place of paclitaxel, and included a novel third arm that used carboplatin and docetaxel with trastuzumab and omitted the anthracycline. The fourth of these large trials was HERA [Herceptin Adjuvant].[3] In HERA, a minimal chemotherapy regimen equal to 4 cycles of AC was required, and all therapy, including radiation, had to be completed before patients received trastuzumab. In that trial, patients received 0, 1, or 2 years of trastuzumab after adjuvant chemotherapy.
Before we get into these studies, I think it is worth pointing out that ECOG [Eastern Cooperative Oncology Group] 1199,[4] a large randomized trial looking at AC followed by taxanes, largely minimized any potential differences between the use of weekly or every-3-week paclitaxel, as well as the choice of docetaxel or paclitaxel. There are some subtleties to the trial and there are trends in various subsets, but by and large, what that study says is that we can consider the first 3 adjuvant trastuzumab trials as asking essentially the same question: Does the AC-taxane backbone perform better when trastuzumab is added concurrently to the taxane? The answer from all 3 of those studies is yes.
In the combined analysis of the NSABP and the North Central study,[1] which looked at the concurrent use of paclitaxel and trastuzumab vs paclitaxel alone, there was about a 50% risk reduction for recurrence events with the addition of trastuzumab. In the BCIRG trial,[2] the addition of trastuzumab to the AC-docetaxel backbone lowered the risk for recurrence by about 50%. So these results are really consistent.
Where things get a little more subtle is through a closer examination of the other parts of these trials. For example, in the North Central study, if we look at the analysis for recurrence with delayed trastuzumab, there is no evidence at this time that adding trastuzumab after AC-paclitaxel improved outcomes -- though I think the analysis is currently underpowered. Standing alone, the results suggest that concurrent use is clearly better. However, if we then look at HERA, in which all the patients were treated with delayed trastuzumab, there is about a 46% risk reduction for recurrence. Those 2 results are at odds -- but the HERA trial is much larger. So I think for the moment that we can't use the North Central study to argue strongly against delaying trastuzumab, but we certainly want to watch this question.
The third point that I would make is that in the BCIRG trial, the carboplatin, docetaxel, and trastuzumab arm improved outcome compared with the control arm, but it is possible that it was less effective than the AC-docetaxel/trastuzumab arm. That comparison is underpowered at present, but we should pay attention to the results as the data mature.
The optimal duration of trastuzumab therapy is another major issue, and we are all waiting anxiously for the 2-year vs 1-year data that will emerge from HERA. In the meantime, there is a small bit of evidence from the FinHER trial regarding shorter durations of trastuzumab.[5] You will recall that that was a trial looking at chemotherapy with vinorelbine or with docetaxel. In the subset of patients who had HER2-positive disease and were randomized to receive trastuzumab or not, giving just 9 weeks of trastuzumab with the nonanthracycline chemotherapy achieved about a 58% risk reduction and an improvement in overall survival.
Still, we do not have any direct comparisons between that short duration and 1 year of therapy. There is a French NCI trial that is going to look at 6 months vs 1 year of trastuzumab. Of course, if 2 years of trastuzumab in the HERA trial are better than 1 year, we will be left with a real question about whether we need to give trastuzumab for an even longer duration, and that will, at the same time, be tempered by the possibility that concurrent use with chemotherapy makes up for duration of use.
On the other side of the optimal duration question is the cardiac toxicity concern. Here, I think that all the dust has not completely settled. It is clear that when we add trastuzumab in these adjuvant trials, we have increases that are significant in the number of cardiac events, but it is not as clear to me that we have optimally identified those cardiac events that truly matter. For example, what we don't yet know is what, if any, long-term consequences there may be from the mild and possibly temporary declines in ejection fraction that we were detecting because of our careful scrutiny.
[b]Medscape: Going back to the BCIRG study, are there patients for whom you would consider a nonanthracycline-containing regimen, such as adjuvant docetaxel, carboplatin, and trastuzumab? What would you like to see before you use this approach more widely?
Dr. Hudis: I think this is a really big issue right now. There is a long-standing history of focus on topoisomerase 2-alpha (TOPO2) and anthracycline sensitivity, and the results in the past have been somewhat mixed. The BCIRG investigators have appropriately looked for markers of benefit from the anthracycline and have suggested in a large subset analysis that TOPO2 coamplification along with HER2 amplification could indicate a subset of patients who definitely need the anthracycline, and, conversely, that the majority of patients who lack TOPO2 coamplification might possibly be just as well treated without the anthracycline. I think this is something that we need to look at carefully in the coming years. However, because there is no broadly available TOPO2 test and these data have not yet been corroborated independently, I would be very cautious about withholding anthracycline in the average patient.
Now what about the patient who comes in with a preexisting cardiac issue and yet has a high-risk HER2-positive breast cancer? My sense right now is that without being able to do TOPO2 testing, you would err in the direction of giving the anthracycline. Another problem, which I think many medical oncologists don't always put to the forefront, is that if a patient has that degree of cardiac dysfunction, then the marginal benefit achieved with adjuvant therapy may not be so large anyway.
So the simple answer to your question is that right now there is no globally identifiable group of patients in whom the carboplatin-docetaxel regimen would be routinely appropriate. I do think that it is a good option for individual patients in specific circumstances.
Medscape: What about the use of dose-dense chemotherapy with trastuzumab?
Dr. Hudis: The first question to consider is whether dose-dense chemotherapy is more toxic than conventionally scheduled every-3-week regimens. The 6.5-year follow-up of the pivotal trial for that concept, CALGB [Cancer and Leukemia Group B] 9741,[6] actually identified numerically fewer cases of cardiac events of all types in the dose-dense arm compared with the conventional-schedule arm. Specifically, with every-2-week scheduling, there were 12 cases of grade 3 or 4 long-term cardiac toxicity in about 1000 patients. With every-3-week scheduling, there were 24 cases in about 1000 patients. The only acute cardiac death in the trial during treatment occurred with single-agent doxorubicin given every 3 weeks. I mention this because one needs to have a sense of a baseline, and interestingly, the baseline evidence is that there is no increase in cardiac events with every-2-week scheduling.
Having said that, we then noted that, especially in ER [estrogen receptor]-negative breast cancer, dose-dense scheduling is associated with a significant improvement in disease-free survival of 3 years. Quite frankly, when one looks at ER-negative breast cancer, the absolute benefit at 3 years is in the same league as the benefit of trastuzumab.
Dr. Chau Dang on our service performed a phase 2 study of dose-dense AC-paclitaxel given exactly as in trial 9741. We initiated trastuzumab at the second week after the last dose of AC, that is, with the first dose of paclitaxel, and we built in the same intensive cardiac monitoring as in the Intergroup studies. Although the study is not 100% complete, all patients have finished chemotherapy, and the majority of patients are completing trastuzumab. To date, there have been no cardiac deaths and 1 case of heart failure. Given that, we currently are developing confidence that this regimen is as safe as the more broadly used every 3-week regimen.
Medscape: On the basis of the data thus far, for which patients would you recommend trastuzumab in the adjuvant setting?
Dr. Hudis: At first blush, we consider the addition of trastuzumab in anyone who needs chemotherapy for whatever standard reasons and has HER2-positive disease. That is a broader use, frankly, than the eligibility criteria for the various studies would have suggested. The exception to that, of course, is HERA, which enrolled a significant proportion of node-negative patients.
What is a little bit sobering to my point of view is the fact that when one looks at the raw number of events in the 9831 trial in the node-negative subset, it is actually quite small. I think that the marginal benefit of trastuzumab in that lowest risk cohort is something that we are going to want more information about as these studies mature.
Medscape: What future directions are being explored to further improve outcomes in patients with HER2-positive breast cancer?
Dr. Hudis: Clearly there are cases of HER2-positive breast cancer that progress despite trastuzumab treatment. So understanding the mechanisms of resistance and addressing those mechanisms are important tasks for us right now. There are also several investigational agents that I find interesting.
The first is lapatinib, an oral tyrosine kinase inhibitor that appears to be active in patients who have already been treated with trastuzumab and in untreated patients who have HER2-positive breast cancer. Plans are already in place to test lapatinib in both the metastatic and adjuvant settings.
On our service, we are very enthused about a geldanamycin derivative called 17AAG. This is a heat shock protein [Hsp] 90 poison, which essentially downregulates HER2 along with a variety of other client proteins of Hsp90, some of which are a part of the HER2 signal-transduction pathway. This drug may also be much more than a HER2 targeting agent. We have seen very exciting evidence of activity in phase 1 studies for this drug in the subset of patients who have metastatic, HER2-positive, extensively trastuzumab-pretreated disease -- and are really enthused about developing this agent further.
I do think that with what we have learned about HER2, we now have opportunities to develop additional, exciting targeted therapeutics that may broaden the effect of trastuzumab.
References
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673-1684. Abstract (http://www.medscape.com/medline/abstract/16236738)
Slamon D, Eiermann W, Robert N, et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC --> T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC --> TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Breast Cancer Res Treat. 2005;94(suppl1):S5. Abstract 1.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-1672. Abstract (http://www.medscape.com/medline/abstract/16236737)
Sparano JA, Wang M, Martino S, et al. Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in patients with axillary node-positive of high-risk node-negative breast cancer: results of North American Breast Cancer Intergroup Trial E1199. Breast Cancer Res Treat. 2005;94(suppl1). Abstract 48.
Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006;354:809-820. Abstract (http://www.medscape.com/medline/abstract/16495393)
Hudis C, Citron M, Berry D, et al. Five year follow-up of INT C9741: dose-dense (DD) chemotherapy is safe and effective. Breast Cancer Res Treat. 2005;94(suppl1):S20. Abstract 41.
http://www.medscape.com/viewarticle/532396
Optimizing Adjuvant Treatment for Patients With HER2-Positive Breast Cancer: An Expert Interview With Dr. Clifford Hudis
Medscape Hematology-Oncology. 2006;9(1) ©2006 Medscape
Posted 05/23/2006
http://images.medscape.com/pi/global/ornaments/spacer.gifEditor's Note:
Results from 4 major trials[1-3] demonstrating a clear benefit with the addition of trastuzumab to adjuvant therapy for patients with HER2-positive breast cancer have also raised a number of associated questions. Among the clinical issues that have emerged are concerns over cardiac safety, questions of optimal sequencing and duration, and evolving data from studies of chemotherapy regimens, including whether to use dose-dense schedules and whether it is safe to exclude anthracyclines in certain patients. To better understand how such questions affect current practice, as well as to explore directions for future research, Nancy Lin, MD, of Harvard Medical School and Dana-Farber Cancer Institute, on behalf of Medscape, spoke with Clifford Hudis, MD, Chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, New York, NY, and Associate Professor of Medicine at the Joan and Sanford I. Weill Medical College at Cornell University, New York, NY.
Medscape: There are now 4 major trials[1-3] demonstrating improved disease-free survival with the addition of trastuzumab in the adjuvant setting. What were the key differences between the trials?
Dr. Hudis: The very first trial, which was led by the NSABP [National Surgical Adjuvant Breast and Bowel Project],[1] was the simplest one: doxorubicin and cyclosphosphamide (AC) followed by paclitaxel, all given conventionally with or without trastuzumab. A very similar trial, the Intergroup 9831 trial led by the North Central Group,[1] looked at essentially the same thing, AC-paclitaxel, the only wrinkle being that it used low-dose weekly paclitaxel rather than conventional high-dose paclitaxel given every 3 weeks. It also included a novel third arm in which trastuzumab was not given with the paclitaxel but was delayed until the end of chemotherapy. The third trial was the BCIRG 006 trial,[2] which substituted docetaxel in place of paclitaxel, and included a novel third arm that used carboplatin and docetaxel with trastuzumab and omitted the anthracycline. The fourth of these large trials was HERA [Herceptin Adjuvant].[3] In HERA, a minimal chemotherapy regimen equal to 4 cycles of AC was required, and all therapy, including radiation, had to be completed before patients received trastuzumab. In that trial, patients received 0, 1, or 2 years of trastuzumab after adjuvant chemotherapy.
Before we get into these studies, I think it is worth pointing out that ECOG [Eastern Cooperative Oncology Group] 1199,[4] a large randomized trial looking at AC followed by taxanes, largely minimized any potential differences between the use of weekly or every-3-week paclitaxel, as well as the choice of docetaxel or paclitaxel. There are some subtleties to the trial and there are trends in various subsets, but by and large, what that study says is that we can consider the first 3 adjuvant trastuzumab trials as asking essentially the same question: Does the AC-taxane backbone perform better when trastuzumab is added concurrently to the taxane? The answer from all 3 of those studies is yes.
In the combined analysis of the NSABP and the North Central study,[1] which looked at the concurrent use of paclitaxel and trastuzumab vs paclitaxel alone, there was about a 50% risk reduction for recurrence events with the addition of trastuzumab. In the BCIRG trial,[2] the addition of trastuzumab to the AC-docetaxel backbone lowered the risk for recurrence by about 50%. So these results are really consistent.
Where things get a little more subtle is through a closer examination of the other parts of these trials. For example, in the North Central study, if we look at the analysis for recurrence with delayed trastuzumab, there is no evidence at this time that adding trastuzumab after AC-paclitaxel improved outcomes -- though I think the analysis is currently underpowered. Standing alone, the results suggest that concurrent use is clearly better. However, if we then look at HERA, in which all the patients were treated with delayed trastuzumab, there is about a 46% risk reduction for recurrence. Those 2 results are at odds -- but the HERA trial is much larger. So I think for the moment that we can't use the North Central study to argue strongly against delaying trastuzumab, but we certainly want to watch this question.
The third point that I would make is that in the BCIRG trial, the carboplatin, docetaxel, and trastuzumab arm improved outcome compared with the control arm, but it is possible that it was less effective than the AC-docetaxel/trastuzumab arm. That comparison is underpowered at present, but we should pay attention to the results as the data mature.
The optimal duration of trastuzumab therapy is another major issue, and we are all waiting anxiously for the 2-year vs 1-year data that will emerge from HERA. In the meantime, there is a small bit of evidence from the FinHER trial regarding shorter durations of trastuzumab.[5] You will recall that that was a trial looking at chemotherapy with vinorelbine or with docetaxel. In the subset of patients who had HER2-positive disease and were randomized to receive trastuzumab or not, giving just 9 weeks of trastuzumab with the nonanthracycline chemotherapy achieved about a 58% risk reduction and an improvement in overall survival.
Still, we do not have any direct comparisons between that short duration and 1 year of therapy. There is a French NCI trial that is going to look at 6 months vs 1 year of trastuzumab. Of course, if 2 years of trastuzumab in the HERA trial are better than 1 year, we will be left with a real question about whether we need to give trastuzumab for an even longer duration, and that will, at the same time, be tempered by the possibility that concurrent use with chemotherapy makes up for duration of use.
On the other side of the optimal duration question is the cardiac toxicity concern. Here, I think that all the dust has not completely settled. It is clear that when we add trastuzumab in these adjuvant trials, we have increases that are significant in the number of cardiac events, but it is not as clear to me that we have optimally identified those cardiac events that truly matter. For example, what we don't yet know is what, if any, long-term consequences there may be from the mild and possibly temporary declines in ejection fraction that we were detecting because of our careful scrutiny.
[b]Medscape: Going back to the BCIRG study, are there patients for whom you would consider a nonanthracycline-containing regimen, such as adjuvant docetaxel, carboplatin, and trastuzumab? What would you like to see before you use this approach more widely?
Dr. Hudis: I think this is a really big issue right now. There is a long-standing history of focus on topoisomerase 2-alpha (TOPO2) and anthracycline sensitivity, and the results in the past have been somewhat mixed. The BCIRG investigators have appropriately looked for markers of benefit from the anthracycline and have suggested in a large subset analysis that TOPO2 coamplification along with HER2 amplification could indicate a subset of patients who definitely need the anthracycline, and, conversely, that the majority of patients who lack TOPO2 coamplification might possibly be just as well treated without the anthracycline. I think this is something that we need to look at carefully in the coming years. However, because there is no broadly available TOPO2 test and these data have not yet been corroborated independently, I would be very cautious about withholding anthracycline in the average patient.
Now what about the patient who comes in with a preexisting cardiac issue and yet has a high-risk HER2-positive breast cancer? My sense right now is that without being able to do TOPO2 testing, you would err in the direction of giving the anthracycline. Another problem, which I think many medical oncologists don't always put to the forefront, is that if a patient has that degree of cardiac dysfunction, then the marginal benefit achieved with adjuvant therapy may not be so large anyway.
So the simple answer to your question is that right now there is no globally identifiable group of patients in whom the carboplatin-docetaxel regimen would be routinely appropriate. I do think that it is a good option for individual patients in specific circumstances.
Medscape: What about the use of dose-dense chemotherapy with trastuzumab?
Dr. Hudis: The first question to consider is whether dose-dense chemotherapy is more toxic than conventionally scheduled every-3-week regimens. The 6.5-year follow-up of the pivotal trial for that concept, CALGB [Cancer and Leukemia Group B] 9741,[6] actually identified numerically fewer cases of cardiac events of all types in the dose-dense arm compared with the conventional-schedule arm. Specifically, with every-2-week scheduling, there were 12 cases of grade 3 or 4 long-term cardiac toxicity in about 1000 patients. With every-3-week scheduling, there were 24 cases in about 1000 patients. The only acute cardiac death in the trial during treatment occurred with single-agent doxorubicin given every 3 weeks. I mention this because one needs to have a sense of a baseline, and interestingly, the baseline evidence is that there is no increase in cardiac events with every-2-week scheduling.
Having said that, we then noted that, especially in ER [estrogen receptor]-negative breast cancer, dose-dense scheduling is associated with a significant improvement in disease-free survival of 3 years. Quite frankly, when one looks at ER-negative breast cancer, the absolute benefit at 3 years is in the same league as the benefit of trastuzumab.
Dr. Chau Dang on our service performed a phase 2 study of dose-dense AC-paclitaxel given exactly as in trial 9741. We initiated trastuzumab at the second week after the last dose of AC, that is, with the first dose of paclitaxel, and we built in the same intensive cardiac monitoring as in the Intergroup studies. Although the study is not 100% complete, all patients have finished chemotherapy, and the majority of patients are completing trastuzumab. To date, there have been no cardiac deaths and 1 case of heart failure. Given that, we currently are developing confidence that this regimen is as safe as the more broadly used every 3-week regimen.
Medscape: On the basis of the data thus far, for which patients would you recommend trastuzumab in the adjuvant setting?
Dr. Hudis: At first blush, we consider the addition of trastuzumab in anyone who needs chemotherapy for whatever standard reasons and has HER2-positive disease. That is a broader use, frankly, than the eligibility criteria for the various studies would have suggested. The exception to that, of course, is HERA, which enrolled a significant proportion of node-negative patients.
What is a little bit sobering to my point of view is the fact that when one looks at the raw number of events in the 9831 trial in the node-negative subset, it is actually quite small. I think that the marginal benefit of trastuzumab in that lowest risk cohort is something that we are going to want more information about as these studies mature.
Medscape: What future directions are being explored to further improve outcomes in patients with HER2-positive breast cancer?
Dr. Hudis: Clearly there are cases of HER2-positive breast cancer that progress despite trastuzumab treatment. So understanding the mechanisms of resistance and addressing those mechanisms are important tasks for us right now. There are also several investigational agents that I find interesting.
The first is lapatinib, an oral tyrosine kinase inhibitor that appears to be active in patients who have already been treated with trastuzumab and in untreated patients who have HER2-positive breast cancer. Plans are already in place to test lapatinib in both the metastatic and adjuvant settings.
On our service, we are very enthused about a geldanamycin derivative called 17AAG. This is a heat shock protein [Hsp] 90 poison, which essentially downregulates HER2 along with a variety of other client proteins of Hsp90, some of which are a part of the HER2 signal-transduction pathway. This drug may also be much more than a HER2 targeting agent. We have seen very exciting evidence of activity in phase 1 studies for this drug in the subset of patients who have metastatic, HER2-positive, extensively trastuzumab-pretreated disease -- and are really enthused about developing this agent further.
I do think that with what we have learned about HER2, we now have opportunities to develop additional, exciting targeted therapeutics that may broaden the effect of trastuzumab.
References
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673-1684. Abstract (http://www.medscape.com/medline/abstract/16236738)
Slamon D, Eiermann W, Robert N, et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC --> T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC --> TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Breast Cancer Res Treat. 2005;94(suppl1):S5. Abstract 1.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-1672. Abstract (http://www.medscape.com/medline/abstract/16236737)
Sparano JA, Wang M, Martino S, et al. Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in patients with axillary node-positive of high-risk node-negative breast cancer: results of North American Breast Cancer Intergroup Trial E1199. Breast Cancer Res Treat. 2005;94(suppl1). Abstract 48.
Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006;354:809-820. Abstract (http://www.medscape.com/medline/abstract/16495393)
Hudis C, Citron M, Berry D, et al. Five year follow-up of INT C9741: dose-dense (DD) chemotherapy is safe and effective. Breast Cancer Res Treat. 2005;94(suppl1):S20. Abstract 41.