In this study, no differences in OS and DFS between concurrent and sequential adjuvant chemo- and hormone therapies in node-positive breast cancer patients were observed. This trial was conceived on the basis of two contrasting hypotheses underlying the concurrent or sequential administration of hormone therapy and chemotherapy in the adjuvant treatment of early breast cancer. The concurrent modality could avoid any delay in prompting synergistic pharmacological interactions; the sequential modality could circumvent the expected kinetic antagonism of chemotherapy and hormone therapy. The results of this study fail to support either hypothesis.
Some limitations of the study must be considered because they are, at least in part, a reflection of the assumptions and attitudes of the time when the study was designed. First, the size of the study is inadequate by today’s standards. In fact, the study had the statistical power (ie, >80%) to detect a 36% reduction in death rate and a 32% reduction in recurrence rate, and we now know that an effect of this magnitude is a rare event (1
). As a consequence, any negative finding in this study must be interpreted in the light of its low statistical power.
The problem of low statistical power in this study is enhanced by the occurrence of 23 deaths that were not preceded by a report of progression. Deaths unrelated to breast cancer might have diluted not only OS but also DFS comparisons. Even though the distribution of these 23 deaths was similar in the two groups (11 and 12 in the concurrent and sequential group, respectively), it is possible to speculate that the convergence of the DFS and OS curves with increasing follow-up may be due, at least in part, to the diluting effect of these deaths. According to standard statistical practices, it is not possible to ignore these deaths by censoring these patients at the time of death because of the risk of bias and because some of these case patients may indeed have suffered an unreported relapse. The latter hypothesis is supported by the fact that most of these patients were in their early 60s when they died (median age at death = 63 years), an age when deaths from competing risks are much less frequent than deaths from breast cancer in a high-risk population such as the one in this study (10-year DFS approximately 50%).
Second, patients were eligible for this study regardless of their hormone receptor status, an understandable omission, considering that the study was conceived before the first Early Breast Cancer Trialists’ Collaborative Group overview (published in 1988), in which tamoxifen was reported effective in women 50 aged years or older (23
). It was only in 1998 that the Oxford Overview (24
) definitely attributed true predictive value to estrogen receptor status. Therefore, a major weakness of our study is represented by the inclusion of one-fourth of patients with negative hormone receptor status and one-fourth of patients with unknown hormone receptor status.
As a consequence, the hazard ratio of 0.64 and 0.68 (for OS and DFS, respectively), which could be detected with a statistical power of 80% in the entire study population, should be entirely driven by the approximately two-thirds of patients with tumors sensitive to hormonal treatments: The reductions in the hazard of relapse and of death in this subgroup that were necessary to obtain these overall effects were 47% and 53%, respectively, much larger than the difference one might reasonably expect when comparing sequential and concurrent tamoxifen.
The subgroup analyses were planned in advance and included in the original study protocol. However, given the number of tests performed (n = 10) and the small size of the study, none of them achieved the critical P value required for statistical significance after correction for multiplicity (P = .005). When the analysis was restricted to the hormone receptor–positive patients, a 40% increase in the risk of relapse was seen in the sequential arm, with a similar difference in OS, but the test for interaction was not statistically significant (P = .41 and P = .52 for DFS and OS, respectively). Although this finding cannot provide evidence to support the superiority of one treatment over the other, it suggests that concurrent tamoxifen might not be detrimental (sequential vs concurrent arm: HR of relapse = 1.40, 95% CI = 0.96 to 2.04 and HR of death = 1.27, 95% CI = 0.83 to 1.94). Two other planned subgroup analyses, by tumor size and by nodal status, corroborate the same interpretation. Indeed, in both analyses, a statistically significant treatment–covariate interaction was found for DFS (P = .040 and P = .039 for nodal and tumor size status comparisons, respectively; not statistically significant with Bonferroni correction), suggesting that the sequential regimen may be less effective than the concurrent one in at least two high-risk subgroups (HR of relapse = 1.38, 95% CI = 0.99 to 1.94 in the pT ≥2 group and HR of relapse = 2.04, 95% CI = 1.13 to 3.70 in patients with ≥10 metastatic axillary lymph nodes). These results are mirrored in OS analyses.
Two other randomized studies similarly assessed the administration of chemo- and hormone therapy (25
). In the Spanish Breast Cancer Research Group (GEICAM) study (25
), a randomized trial involving node-positive postmenopausal women not selected by hormone receptor status or with unknown status, tamoxifen was administered concurrently or sequentially with epirubicin–cyclophosphamide adjuvant chemotherapy. After a follow-up of 4.6 years, the GEICAM study (25
), which started in 1995, did not detect any statistically significant difference in outcome between concurrent and sequential administration. However, considering the number of events detected (52 OS and 96 DFS events), the statistical power of the GEICAM study is very low, and this weakness strongly reduces the relevance of the observation.
Conversely, the preliminary analysis of the Southwest Oncology Group (SWOG) 8814 trial, presented in 2002, showed a statistically significant improvement in DFS in the sequential arm over the concurrent arm (27
). That large trial, started in 1989, compared three arms: chemotherapy (cyclophosphamide, doxorubicin and 5-fluorouracil [CAF]) given concurrently or sequentially with tamoxifen vs tamoxifen alone. A study of such magnitude (ie, 89% statistical power to detect a 33% increase in the HR for concurrent vs sequential administration, for α = .05, one-sided) and one that is focused on a specific set of node-positive patients (ie, hormone receptor positive and postmenopausal) represents the ideal setting for assessing the relative role of sequential vs concurrent combination of chemotherapy and hormone therapy. After the presentation of the SWOG trial results (27
), clinical practice did change, and the general consensus among clinical oncologists was to administer the two treatments sequentially (28
). Furthermore, on the basis of the SWOG preliminary results, the 2005 St Gallen consensus recommended that patients receiving chemotherapy should not start tamoxifen until completion of treatment (29
). However, the final results of the SWOG trial, with a median follow-up of 8.9 years, did not fully support the findings of the preliminary SWOG analysis (26
). We caution that a longer follow-up could eventually reduce the advantage, as happened for this study. In fact, the findings of our interim analyses were reversed after longer follow-up. Early data suggested that the concurrent arm was better (18
), whereas this advantage was greatly reduced later (21
). Even in the present report, the DFS curves progressively diverge until the eighth year of observation and then converge at the end of follow-up; a similar trend was observed for OS.
Although in the SWOG study the authors championed the use of anthracycline-based chemotherapy followed by tamoxifen in clinical practice, they failed to prove a clear superiority of the sequential treatment over the concurrent one, because the OS and DFS analyses did not reach the statistical significance (HR = 0.90, 95% CI = 0.73 to 1.10, P
= .30 and HR = 0.84, 95% CI = 0.70 to 1.01, P
= .06, for OS and DFS, respectively) (26
). Nevertheless, the combined therapy of CAF and tamoxifen (given either sequentially or concurrently) was superior to tamoxifen alone in terms of DFS (HR = 0.76, 95% CI = 0.64 to 0.91, P
= .002) (26
). Therefore, the SWOG study upheld the legacy of previous trials with respect to the superiority of chemo- and hormone therapy over hormone therapy alone, when an anthracycline-containing regimen was used, but did not favor any specific modality for administering the drugs (30
To date, neither this study nor the GEICAM (25
) or SWOG (26
) studies have been able to clearly indicate the best timing for administering the chemotherapy and hormone therapy combination. When these three studies were pooled together in the Oxford Overview (unpublished data; presented at the 2008 San Antonio Breast Cancer Meeting), no difference was seen between the use of tamoxifen given concurrently or sequentially after chemotherapy (9
Recently, the role of concurrent or sequential treatment was retrospectively investigated in pre- and post-menopausal hormone receptor–positive patients, who were accrued to two more recent randomized adjuvant trials at our Institutes (32
). Although there was no statistically significant difference in either OS or event-free survival between patients receiving tamoxifen concurrently with or sequentially to chemotherapy, a statistically significant decreasing trend in the hazard of death (P
= .015) for sequential therapy was associated with increasing age. This finding suggests that concurrent therapy might be more effective than sequential therapy in younger patients and/or in premenopausal patients. The authors speculated that starting tamoxifen as soon as possible together with chemotherapy could counterbalance the poor prognosis reported in young premenopausal patients with estrogen receptor–positive tumors, who are treated with chemotherapy alone (32
To our knowledge, only this study prospectively investigated the timing of the two modalities in premenopausal patients, but because of its design, this study does not provide sufficient evidence to support or reject either aforementioned hypothesis. Therefore, we believe that the definition of the best timing of chemo- and hormone therapy in premenopausal patients is a pending subject, given the concern of many clinicians to delay the endocrine treatment.
Both our study and the SWOG study (26
) used an anthracycline-based chemotherapy regimen of longer duration compared with the modern chemotherapy standards. In addition, the chemotherapy regimen chosen for our trial is not comparable to the current standard in terms of schedule, dosage, and drugs. These variables probably affected the survival of the study population, even if the overall poor outcomes observed in trials started in the 1980s were also affected by the less than adequate staging available at the time.
In our report, nausea and vomiting (G3–G4 in approximately 60% of subjects) represented the dose-limiting factors. This is not surprising considering the high emetogenic activity of anthracycline-based regimens in the absence of premedication with modern antiemetic drugs (5-HT3
antagonists), which were unavailable at the time of this trial. It is noteworthy that although an increased risk of thromboembolic complications with concurrent tamoxifen and chemotherapy was reported by others (35
), no differences in toxic effects were seen in this trial or in the GEICAM (25
) and SWOG (26
) trials. Even if we were aware of the cardiovascular risks (36
) no relevant toxic effect was associated with the concurrent treatment either in this study or in our dose-density phase III trials, in which patients were similarly treated with concomitant or sequential tamoxifen (17
No data are available so far about the best timing of administration of chemotherapy and aromatase inhibitors in early breast cancer. These drugs represent the other major form of adjuvant endocrine therapy. In view of their different pharmacodynamics and pharmacokinetics compared with tamoxifen, the results of studies evaluating the timing of chemotherapy and tamoxifen cannot be applied to aromatase inhibitors (26
). Because aromatase inhibitors are particularly active in switching off the proliferation and taxanes are particularly active in highly proliferating cancers, concerns about their concurrent administration exist. However, in vivo synergism between these drugs could not be excluded. Intriguingly, Watanabe et al. (38
) recently observed that the rate of pathological complete response obtained by neoadjuvant concurrent administration of an aromatase inhibitor (anastrozole) and chemotherapy (CEF followed by paclitaxel) was not lower than those of previous chemotherapy only trials. The antagonism of these clashing hypotheses (ie, antagonism or synergism) recapitulates the same rationale behind this study.
In conclusion, the debate about the best timing for adjuvant chemo- and hormone therapy is far from resolved, even considering that new chemotherapeutic, biological, and endocrine agents are presently available.