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Synopsis of ASCO findings
Although 2007 was not a year for “blockbuster” advances in the management of breast cancer, the 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO) nonetheless featured many important reports on trials of breast cancer therapy for both advanced and early-stage breast cancer. In clinical management of early-stage breast cancer, there were important updates from major adjuvant trials, including ongoing analyses of toxicity and efficacy. For the most part, these observations reinforced prevailing clinical practice and understanding.
Taxanes: Schedules and Drugs
Sparano[1] presented an update of the ECOG 1199 trial, a randomized trial of doxorubicin and cyclophosphamide (AC) chemotherapy followed by 1 of 4 taxane-based treatments — paclitaxel given either weekly or every 3 weeks, or docetaxel given either weekly or every 3 weeks (Table).
Consistent with previous reports, the updated data showed that most of these regimens could be delivered effectively; only weekly docetaxel was associated with < 80% dose delivery. The side-effect profiles of the various treatments differed in ways predictable from extensive use of these regimens in breast cancer. For example, every-3-weeks docetaxel produced the highest rates of neutropenia and febrile neutropenia, whereas weekly paclitaxel had the highest rate of neuropathy.
The primary study end point was a comparison of paclitaxel vs docetaxel and a comparison of weekly vs every-3-weeks therapy, based on the 2 x 2 randomization scheme. The primary end points were all negative -- that is, there was no overall difference between the taxanes or the schedules in the aggregate.
However, analysis of each of the 4 treatment arms does suggest emerging winners and losers. In particular, weekly paclitaxel and every-3-weeks docetaxel had the lowest rates of disease recurrence, whereas weekly paclitaxel had the highest 5-year overall survival and was the only treatment with statistically significant improvement in overall survival compared with every-3-weeks paclitaxel.
Table. Updated Results of ECOG 1199
Taxane Paclitaxel Paclitaxel Docetaxel Docetaxel
Schedule Weekly Every 3 Weeks Weekly Every 3 Weeks
% cycles completed 88% 95% 75% 87%
Febrile neutropenia 1% < 1% 1% 16%
Grade 2-4 neuropathy 27% 20% 16% 16%
Myalgia 2% 7% 1% 6%
5-year DFS 81.5% 7.9% 77.6% 81.2%
5-year OS 89.7% 86.5% 86.2% 87.3%
DFS = disease-free survival; OS = overall survival.
This is now one of several trials that has shown that the every-3-weeks schedule of AC followed by paclitaxel (P) (AC → P) is an inferior treatment program. In CALGB 9741, every-2-weeks AC → P was shown to be superior to an every-3-weeks regimen.[2] Similarly, the US Oncology group[3] reported an update at ASCO of their trial of AC → P given every 3 weeks vs AP every 3 weeks → weekly paclitaxel and showed a better disease-free survival (DFS) with the AP → P arm compared with the every-3-weeks AC → P arm. It remains unclear whether AC → weekly paclitaxel or "dose-dense" AC → paclitaxel would be optimal.
Finally, this study result underscores one of the perils of 2 x 2 randomization designs. The assumption in a 2 x 2 randomization is that there is no interaction between the 2 layers of the randomization options. That allows for 2 questions to be asked for the "price" of 1 clinical trial. However, in E1199, there clearly was an interaction between each of the 2 randomization options -- taxane agent and taxane schedule -- with weekly paclitaxel or every-3-weeks docetaxel being the preferred options for best efficacy. With fewer numbers of patients, such a study finding may not have emerged.
Weekly Taxanes: Lessons From Metastatic Disease
Weekly taxane therapy also received a boost from reports of trials in the metastatic setting at ASCO 2007. The Anglo-Celtic Trial IV[4] compared response rates in patients given paclitaxel on a weekly or every-3-weeks treatment schedule and demonstrated an improvement from 27% to 42% with the more frequent dosing. The differences in time to progression were more modest. However, the study delivered only 3 months of chemotherapy and did not treat patients until the time of tumor progression; thus, it is more difficult to interpret the time-to-progression data.
Benefit of Taxanes in Estrogen Receptor (ER)-Positive Breast Cancer
An ongoing discussion has centered on the importance of adjuvant taxane-based chemotherapy among women with ER-positive breast cancer. Retrospective results from the CALGB have suggested that the major gains from the addition of taxane treatment to AC chemotherapy emerged in women with ER-negative tumors and that the gains in ER-positive patients were marginal, if present at all. Two presentations from other collaborative groups touched on this issue at ASCO 2007.
In ECOG 1199,[1] study outcomes were analyzed as a function of tumor ER status. The proportional gains for the addition of weekly paclitaxel or every-3-weeks docetaxel were achieved in both ER-positive and ER-negative tumors, suggesting that ER status alone does not determine possible improvement with taxane therapy.
A late-breaking presentation by Martin analyzed the role of ER status in predicting outcomes among patients receiving adjuvant docetaxel in the BCIRG 001 (5-fluorouracil, doxorubicin, and cyclophosphamide [FAC] vs docetaxel, doxorubicin, and cyclophosphamide [TAC]) and PACS 01 (5-fluorouracil, epirubicin, and cyclophosphamide [FEC] vs FEC followed by docetaxel) trials. The addition of docetaxel to patients with either ER-positive or ER-negative tumors led to improvements in DFS in those trials. The proportional benefits -- a 30% reduction in risk of recurrence -- were equal in ER-positive and ER-negative cases. However, because women with ER-positive tumors tend to have a better near-term prognosis, the absolute gains of adding docetaxel were greater in women with ER-negative tumors (approximately 7% to 11% reduction in the risk of recurrence) than in women with ER-positive cancers (4% to 5% reduction in the risk of recurrence).
These data fit with other studies suggesting that marginal gains through better chemotherapy in ER-positive breast cancers are smaller in absolute terms than in ER-negative breast cancers. Of note, none of the reported trials provided an update on the key issue, which is to factor in other markers of risk and treatment benefit such as HER2 status. In the CALGB experience, adding taxanes to ER-positive, HER2-positive tumors did yield clinical improvement, whereas in ER-positive, HER2-negative tumors, such gains were not discernible.
Adjuvant Trastuzumab: The Beat Goes On
Two presentations highlighted the latest data on the use of adjuvant trastuzumab. Perez[5] provided an update on the clinical efficacy from the combined analysis of NSABP B-31 and NCCTG N9831, the 2 North American trials, whereas Rastogi[6] delivered an update on cardiotoxicity from NSABP B-31.
Ongoing follow up of the adjuvant trastuzumab trials, in which patients received AC followed by paclitaxel, with or without the addition of trastuzumab, shows persistent and durable benefits. The difference in DFS through 4 years of follow-up is 13% in absolute terms (73% without trastuzumab, 86% with trastuzumab), reflecting a 50% relative reduction in risk of recurrence.
Despite the fact that 20% of patients eventually crossed over from nontrastuzumab to trastuzumab treatment, and despite the availability of trastuzumab for the treatment of metastatic recurrence, there remains a significant survival difference as well (89% vs 93% at 4 years) with the addition of trastuzumab. Subset analyses confirm the previous results that all clinical subsets -- defined by patient age, tumor size, nodal status, and ER status -- derive benefit from adjuvant trastuzumab.
One important lingering concern about adjuvant trastuzumab therapy has been the issue of cardiotoxicity. Because of apprehension about cardiac dysfunction as a consequence of trastuzumab treatment, women in the adjuvant trastuzumab trials were required to have left ventricular ejection fraction (LVEF) > 50% at baseline and were monitored serially for changes in LVEF with repeat determinations at months 3, 6, 9, 12, and 18.
Updated information from both the N9831 and NSABP trials was reassuring, as the risk of cardiotoxicity appears to plateau after years 1-2 of therapy. The risk is flat beyond that point, with a total risk of 2.5% in the N9831 group and 3.9% in the NSABP trial. These numbers compare with 0.5% to 1.0% of patients who develop heart failure with chemotherapy alone. The majority of trastuzumab-associated cases of congestive heart failure resolved with medical intervention and discontinuation of trastuzumab. Unfortunately, it is also clear that a very small fraction of women have ongoing symptomatic heart failure from trastuzumab.
Two other points regarding cardiotoxicity emerged. First, there appear to be identifiable risk factors including pre-existing hypertension, age > 60 years, and borderline ejection fraction at baseline. Second, the long-term risks of cardiac injury remain unknown. To date, we have only 3-5 years of follow-up on average. Because any cardiac injury could predispose to later cardiac problems, it is too soon to determine whether an increased risk of cardiac disease in these patients might be noted later. Left-side chest radiation did not appear to increase the risk of cardiomyopathy. However, radiation therapy causes heart failure through accelerated atherosclerosis, manifesting 10-15 years after treatment, and has both a different mechanism and time course compared with the cardiac problems related to trastuzumab.
Thus, although these intermediate-term safety data for adjuvant trastuzumab are generally reassuring, it will only be in the years ahead that the full impact of trastuzumab on late cardiac function will be measurable.
Supported by an independent educational grant from sanofi-aventis
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