Annals of Oncology Advance Access published online on October 17, 2007
Annals of Oncology, doi:10.1093/annonc/mdm475
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2007 European Society for Medical Oncology
Timing of adjuvant chemotherapy and tamoxifen in women with breast cancer: findings from two consecutive trials of Gruppo Oncologico Nord-Ovest–Mammella Intergruppo (GONO–MIG) Group
1 Oncologia Medica A
2 Epidemiologia Clinica, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, Genova
3 Presidio Ospedaliero C. Poma, Viale Albertoni, Mantova
4 Ospedale S. Chiara, Via Roma, Pisa
5 Ospedale Civile, Via E. De Nicola, Sassari
6 DH Oncologico—Ospedale S. Anna, Via Ventimiglia, Torino
7 Divisione Ginecologia ed Ostetricia C, Ospedale S. Anna, Corso Spezia, Torino
8 Senologia Chirurgica, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, Genova, Italy
* Correspondence to: Dr L. Del Mastro, Oncologia Medica A, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, 10, 16132 Genova, Italy. Tel: +39-010-5600666; Fax: +39-010-5600850; E-mail: lucia.delmastro{at}istge.it
 |
Abstract |
|---|
 Top Abstract introductionpatients and methodsresultsdiscussionfundingappendix 1AcknowledgementsReferences |
|---|
Background: The timing of adjuvant chemotherapy and tamoxifen (TAM) has been investigated only in postmenopausal breast cancer women. We analyzed the outcome of both pre- and postmenopausal women who entered two randomized trials (Gruppo Oncologico Nord-Ovest–Mammella Intergruppo studies) on adjuvant chemotherapy and received either concomitant or sequential TAM.
Patients and methods: Patients who received anthracycline-based regimens and either concomitant or sequential TAM were eligible. The primary end point was overall survival (OS). Hazard ratios (HRs) of death or recurrence for treatment comparisons were estimated by Cox proportional hazards regression models.
Results: Among the 1096 eligible patients, 507 (46.3%) and 589 (53.7%) received concomitant and sequential TAM, respectively. The median follow-up time was 6.6 years. Ten-year OS was 83% [95% confidence interval (CI) 78–88] and 80% (95% CI 74% to 86%) in the concomitant and sequential groups, respectively. Multivariate analyses confirmed no significant difference in the hazard of death (HR = 1.13; 95% CI 0.78–1.64; P = 0.534) and recurrence (HR = 1.03; 95% CI 0.80–1.33; P = 0.88) between the two groups. A decreasing trend (P = 0.015) in HR of death with increasing age was observed indicating that concomitant therapy might be more effective than sequential therapy in young patients.
Conclusions: We observed no outcome difference between sequential and concomitant chemo-endocrine therapy. The potential advantage of concomitant TAM in young patients needs to be further addressed in prospective trials.
adjuvant therapy, breast cancer, chemotherapy, tamoxifen, timing
|
introduction |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionfundingappendix 1AcknowledgementsReferences |
|---|
Because nearly 80% of breast cancers are endocrine-responsive tumors [1], the majority of patients candidates for adjuvant chemotherapy are also candidates for endocrine therapy. The optimal timing for the integration of these two treatments has not been widely investigated, leading to adopting different timing (i.e. concomitant versus sequential) also in recent trials of adjuvant chemotherapy [2, 3]. A potential advantage of concomitant administration is the avoidance of the possible detrimental effect of the delay in the start of tamoxifen (TAM) in endocrine-responsive patients [4]. On the other hand, preclinical studies indicated a negative interaction of TAM and chemotherapy when given concomitantly [5]. Randomized trials available on this issue were restricted to postmenopausal women and reported conflicting results, with no difference between concomitant and sequential administration in two trials [6, 7] and a superiority of sequential as compared with concomitant administration in another trial [8]. So far, no study has evaluated the timing of chemo-endocrine therapy in premenopausal patients.
To contribute at clarifying the issue of the best timing of chemo-endocrine therapy, both in postmenopausal and premenopausal patients, we retrospectively analyzed the outcome of patients who entered in two phase III trials of adjuvant chemotherapy and received TAM concomitantly or sequentially to chemotherapy.
|
patients and methods |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionfundingappendix 1AcknowledgementsReferences |
|---|
patient population
For this retrospective study, patients were selected among those enrolled in two consecutive randomized clinical trials previously conducted by the Gruppo Oncologico Nord-Ovest–Mammella Intergroup (GONO–MIG). Main eligibility criteria of the trials (MIG-1 and MIG-5) were as follows: histologically confirmed breast cancer treated with radical mastectomy or breast-conserving surgery and complete ipsilateral axillary lymph node dissection; no clinical or radiological evidence of distant metastases; age 70 years or younger and surgery carried out no >5 weeks before randomization. Specific criteria for the first trial (MIG-1) were node-positive disease with no >10 involved nodes or node-negative disease but at high risk of recurrence, defined as the presence of one or more of the following criteria: age
35 years, negative estrogen receptor (ER) and progesterone receptor (PgR) status, pathological tumor size (T) 
2 cm, poor histological grade and/or a high proliferative rate. Specific criterion for the second trial (MIG-5) was node-positive disease with <10 nodes involved. As previously reported [9], premenopausal status was defined by the occurrence of a menstrual period within 6 months before random assignment in MIG-1 and MIG-5 studies. To be defined as premenopausal, those women younger than 50 years who had undergone hysterectomy were required to have premenopausal levels of luteinizing hormone or follicle-stimulating hormone.
Both MIG-1 and MIG-5 trials were conducted in accordance with the International Good Clinical Practice principles and local ethical and regulatory requirements. Both studies were approved by the internal review board of the coordinating center, the National Cancer Research Institute in Genoa, Italy. Written informed consent was obtained from all patients before enrollment in either trial.
Randomization and data collection were carried out at the trial center of the National Cancer Research Institute in Genoa, Italy. Twenty-one and 30 centers participated in MIG-1 and MIG-5 studies, respectively.
study design and treatment regimens
In the first trial (MIG-1), patients were randomly assigned to receive either six courses of FEC21 (5-fluorouracil 600 mg/m2, epirubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days) or six courses of dose-dense FEC14 (same treatment as FEC21 but every 14 days with granulocyte colony-stimulating factor support) [9]. In the second trial (MIG-5), patients were randomly assigned to receive either the FEC21 treatment as described above or four courses of ET (epirubicin 90 mg/m2 and paclitaxel 175 mg/m2 every 21 days) [10]. In both trials, TAM (20 mg/day for 5 years) was given to premenopausal and postmenopausal patients with ER- and/or PgR-positive tumors. TAM was given either after completion of the chemotherapy or concomitantly at physician discretion.
For the present study, only patients with positive ER and/or PgR who received TAM and anyone of the chemotherapy regimens described above were selected. Hormonal receptor status was defined as positive when >10% positive cells were revealed by immunohistochemistry or when 10 fmol/mg cytosol proteins were detected by dextran-coated charcoal assay. Patients with a tumor negative for both ER and PgR and patients who did not receive TAM were excluded (Figure 1).
|
Eligible patients were divided into two groups depending on the timing of TAM administration. Patients were assigned to the concomitant group if TAM was given within 23 days of the first cycle of chemotherapy; patients who started TAM after completion of chemotherapy or at the most 7 days before the last cycle were assigned to the sequential group. Eighty-seven patients who had starting dates of TAM and/or chemotherapy not meeting these criteria could not be attributed to either one of the two groups. They were thus excluded from the study population which finally included 1096 patients. An additional analysis, anyway, was carried out with these 87 patients included. Among these 87 patients, those who received TAM with concomitant chemotherapy for at least two cycles were assigned to the concomitant group and the others to the sequential group.
end points and statistical analysis
The primary study end point was overall survival (OS), as estimated from the date of surgery to the date of last contact or death from any cause. The secondary end point was event-free survival (EFS), as estimated from the date of surgery to the date of occurrence of any of local relapse, distant relapse, contralateral primary cancer or death from any cause, whichever occurred first.
For each prognostic factor, heterogeneity between the two study groups in the distribution of the patients within subgroups was estimated by the Pearson chi-square test.
OS and EFS were obtained from Kaplan–Meier analyses, and the primary comparison between the two groups was carried out using the log-rank test. For each prognostic factor, stratified univariate analyses and log-rank tests were also used to assess statistical differences between the two treatment regimens.
Cox's model was used for multivariate analyses to assess the independent prognostic role of each prognostic factor, while adjusting for the effect of the other factors. The variables included in the models as covariates were random study assignment (FEC14, FEC21 or ET), age (40 years, 41–50 years, 51–60 years or >60 years), menopausal status (pre or post), pathological T (pT1 or >pT1), grading (G1, G2 or G3), number of positive lymph nodes (0 node, 1–3 nodes or >3 nodes), number of patients enrolled by center (40 patients, 41–100 patients or >100 patients) and hormonal receptor status (ER+/PgR–, ER–/PgR+ or ER+/PgR+). In order to assess the presence of confounding due to changes in the use of concomitant versus sequential chemo-endocrine therapy over time, the year of randomization was included in the model as well. However, the collinearity with the variable ‘random assignment’ led to instability of the estimates. Since no prognostic effect of the variable ‘year of randomization’ was seen, it was not included in the final models. Hazard ratios (HRs) for each variable were obtained by exponentiating the coefficients estimated by the Cox models. Modifications of the relative effect of concomitant as compared with sequential endocrine therapy across the strata of each covariate were assessed by introducing the appropriate interaction terms in the model. These covariates by treatment interaction terms were introduced in the model one at a time. The likelihood ratio test was used to evaluate the statistical significance of each interaction term. The results of the multivariate and subgroup analyses are graphically summarized using the Forest plot as indicated by Cuzick [11]. All statistical tests were two-sided and were carried out using the SPSS package (version 13.0 for Windows).
Because early commencement of TAM (concomitant strategy) may be particularly important in patients with highly endocrine-responsive tumors, we explored the trend in treatment effect differences as a function of ER level, by using the nonparametric subpopulation treatment effect pattern plot (STEPP) method [12]. To carry out this analysis, the sliding window option was chosen [10]. Overlapping groups of patients were created on the basis of the number of ER-positive tumor cells. Subpopulations of 
200 patients (±3.21) were created, and 10 patients (±1.2) were replaced as the window moved along the ER axis. Thus, from left to right, each subsequent subpopulation was formed by dropping the 10 patients with the lowest content of ER-positive cells and including the 10 patients with the next higher ER value. Treatment effect difference within each subgroup was estimated by a Cox's proportional hazards model including all covariates significantly contributing to the likelihood of the model in the entire dataset. HRs were obtained as described above. Patients were eligible for this analysis if the concentration of ER in the primary tumor was determined by immunohistochemistry.
|
results |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionfundingappendix 1AcknowledgementsReferences |
|---|
patient characteristics
In the MIG-1 trial, 1214 patients were randomized from 1 November 1992 to 30 June 1997. In the MIG-5 trial, 1055 patients were randomized from 10 November 1996 to 24 January 2001. From these 2269 patients, 1096 (48.3%) patients were eligible and considered for the present analysis according to the criteria reported in Figure 1. No main difference was observed between patient populations selected for the present study and the overall population of each trial (data not shown), with the obvious exception of the percentage of patients with hormonal receptor-positive tumors which was higher (100% of patients) in the population selected for this study as compared with the overall population of both MIG-1 (59% of patients with ER- and/or PgR-positive tumors) and MIG-5 (69% of patients with ER- and/or PgR-positive tumors) studies.
Among the 1096 selected patients, 507 (46.3%) were included in the concomitant group and 589 (53.7%) in the sequential group.
The median observation time from surgery to death or censoring was 6.6 years (range: 34 days to 11.7 years). Nine hundred and eighty-four patients (89.8%) were alive at the end of the study with a median follow-up of 6.8 years (7.2 years for the concomitant group and 6.5 years for the sequential group). Among those patients, 838 (85.2%) were free of disease and 136 (13.8%) were not. Overall, an event (relapse or death) was recorded for 258 patients (23.5%).
Main patient and tumor characteristics are summarized in Table 1. Some statistically significant differences were seen between the two groups of hormonal therapy (concomitant versus sequential): patients in the sequential group had been enrolled more often in the MIG-5 trial (P < 0.001), had more often a G3 tumor (P = 0.001) and three or more positive axillary lymph nodes (P = 0.022) and had been enrolled in the adjuvant trial more often by a center randomizing >100 patients (P < 0.001). Concomitant chemo-endocrine therapy was used more often in patients enrolled before 1996 (63% of the cases), while the opposite was true for patients enrolled from 1996 to 2000. When the odds of being treated with sequential as compared with concomitant therapy were modeled in a multivariate logistic regression as a function of all the variables mentioned above, the association with those five variables remained unchanged (data not shown), indicating that the association with tumor grade and nodal status was independent of the chemotherapy scheme, the year of randomization and the center where the patient had been enrolled.
|
OS and EFS
By 31 December 2004, 122 deaths had been recorded, 57 in the concomitant group and 65 in the sequential group. No significant difference in OS was seen between the two groups (P = 0.384). Cumulative OS at 5 years (Figure 2A) was 94% (95% confidence interval (CI) 92–96) in both the concomitant and the sequential groups. At 10 years, this value decreased to 83% (95% CI 78–88) in the concomitant group and to 80% (95% CI 74–86) in the sequential group. Overall, 258 events had been recorded: 124 (48%) in the concomitant group and 134 (52%) in the sequential group. Cumulative 5-year EFS (Figure 2B) was 80% (95% CI 76–84) in the concomitant group and 79% (95% CI 75–83) in the sequential group. Cumulative 10-year EFS was 63% (95% CI 56–70) in the concomitant group and 54% (95% CI 42–66) in the sequential group (P = 0.570).
|
When the comparison between the two groups was adjusted for type of study, age, menopausal status, pathological T, tumor grade, nodal status, number of patients by center or hormonal receptor status (Table 2), no statistically significant difference was observed with respect to either OS or EFS.
|
multivariate and subgroup analyses
In multivariate analyses, age, menopausal status, tumor grade, pathological T, hormonal receptor status and number of metastatic nodes were independently associated with OS and/or EFS (data not shown). After adjustment for all these prognostic factors as well as for the type of adjuvant trial (MIG-1 or MIG-5) and the number of patients enrolled by center, we did not find any significant difference in the hazard of death between the sequential group and the concomitant group in the overall population (HR = 1.03; 95% CI 0.80–1.33; P = 0.516; Figure 3). A similar lack of effect on the EFS was observed (HR = 1.03; 95% CI 0.80–1.33; P = 0.822). Similar results were obtained when the 87 patients, who had starting dates of TAM and/or chemotherapy not meeting the main criteria for timing definition, were included in the analysis (HR of death: 1.12; 95% CI 0.78–1.60; P = 0.534 and HR of recurrence: 1.03; 95% CI 0.81–1.32; P = 0.803). Adjustment for year of randomization did not change the estimates of the relative treatment effect (data not shown).
|
Subgroup analyses of OS and EFS comparing the sequential group versus the concomitant group within strata formed by each prognostic factor showed no evidence of interaction between the type of hormonal treatment and adjuvant trial, menopausal status, pathological T, tumor grade, number of positive lymph node, number of patients enrolled by center or receptor status (Figure 3). Conversely, an indication of a possible interaction between timing of hormonal treatment and age, and possibly menopausal status, was seen; the significant decreasing trend (P = 0.015 for age and P = 0.108 for menopausal status) in HR with increasing age indicates that concomitant therapy, when compared with sequential therapy, might be more effective in younger age groups (
40 years) and less effective in older age groups. A similar indication that concomitant therapy might influence EFS according to the age was also observed and again appeared to be restricted to the group of youngest patients, the decreasing trend in HR being less significant (P = 0.063).
STEPP analysis of HR pattern according to ER level
For this analysis, 82 patients (7.5%) were excluded because they were classified as ER positive but the ER level was not reported. Other 21 patients (1.9%) were excluded because the ER status was assessed by dextran-coated charcoal assay instead of immunohistochemistry. The final STEPP analysis was thus conducted on 993 patients. No difference in the main prognostic factors was observed between this selected population and the whole population of 1096 patients (data not shown). Multivariate treatment HR estimates (y-axis, sequential therapy versus concomitant therapy) were obtained from Cox's regression models. The covariates included in the models were those independently associated with OS: age, menopausal status, tumor grade, pathological T and number of metastatic lymph nodes. Results of the STEPP analysis are reported in Figure 4.
|
Although some variations were observed with HR values favoring the concomitant therapy both in patients with the lowest and in patients with the highest ER levels, and the sequential therapy in patients with intermediate ER level, the trend was not monotonic.
|
discussion |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionfundingappendix 1AcknowledgementsReferences |
|---|
In current clinical practice, adjuvant chemotherapy and hormonal therapy are given sequentially, with hormonal therapy following chemotherapy [13]. Although this practice is considered as a standard, there is no strong evidence as to whether there is any significant difference in long-term outcome between concomitant and sequential chemo-endocrine therapy [14].
Among the phase III studies addressing the timing of chemo-endocrine therapy, only one was extensively reported and showed no difference between concomitant and sequential treatment [6]. The preliminary report of Sertoli et al. confirmed the absence of difference between the two different timing of administering chemotherapy and endocrine therapy [7]. The study of Albain et al. [8] gave so far the major contribution to the debate, although it is not yet available as a full report. The study showed that in the context of a cyclophosphamide, doxorubicin, 5-fluorouracil regimen, the sequential administration of TAM is superior to the concomitant one in terms of EFS but not in terms of OS. After the first presentation of the study in 1997 [15], the clinical practice did change and the sequential strategy became the standard treatment. Nevertheless, the results of the study of Albain et al. cannot be considered as the conclusive indication of the best timing of chemo-endocrine therapy. In fact, the study power was not very high and no confirmatory trials are available yet. In addition, the three studies mentioned above [6–8] evaluated the timing of chemo-endocrine therapy only in postmenopausal patients; thus their findings may not be extended to younger women.
Our retrospective study confirmed the change over time in clinical practice, regarding the timing of chemo-endocrine therapy and such a change may explain the significantly higher percentage of patients receiving the sequential treatment in the MIG-5 trial, i.e. the most recent study. Moreover, a slightly higher proportion of patients in the sequential group had >3 positive nodes (11.7% versus 17.6% in concomitant and sequential groups, respectively) and a poorly differentiated tumor (10.0% versus 16.9% in concomitant and sequential groups, respectively). The potential major benefit of chemotherapy for these high-risk patients may have prompted clinicians to privilege chemotherapy and to give TAM afterwards. The possible unfavorable impact of these poor prognostic factors on the prognosis of the sequential group was corrected by the multivariate analysis, which was adjusted for such factors.
A weakness of both MIG-1 and MIG-5 trials was that the epirubicin dose used in the FEC regimen (i.e. 60 mg/m2) was less than the current standard dose of 100 mg/m2. However, when the trials were being planned, data on the superiority of higher doses of epirubicin were not available [16]. In any case, the dose of epirubicin was the same in concomitant and sequential groups and thus should not affect the results of this study.
Our results did not evidence any significant difference between patients receiving TAM concomitantly or sequentially to chemotherapy, with respect to either OS or EFS. Nevertheless, our data provide the noteworthy indication of a potential interaction between timing of endocrine therapy and patient age. In terms of OS, a significant decreasing trend in HR (P = 0.015) with increasing age was observed, thus indicating that concomitant therapy, as compared with sequential therapy, might be more effective in younger patients. A potential explanation of this finding is that the early commencement of TAM could counterbalance the bad prognosis reported in young premenopausal patients with ER-positive tumors who are treated with chemotherapy alone. For this group of patients, the expression of ER has been associated with an increased risk of recurrence and/or death as compared with patients having ER-negative tumors [17].
The results of the STEPP analysis did not show a clear difference between sequential and concomitant therapy in subgroups of patients with different ER level. Both in patients with the lowest and in patients with the highest ER levels, HR values seem to favor the concomitant therapy. In patients with intermediate ER level, some benefit of the sequential regimen is observed. A longer follow-up is necessary to reliably assess a potentially different effect of concomitant and sequential strategies in patients with different ER level. In fact, especially in patients with high ER values (from 75% and above), the number of events was low (median: 15; range: 11–20) as compared with the number of events in patient's groups with low ER level (median: 25; range: 19–29).
A limitation of our study is the short median follow-up time (6.6 years). In endocrine-responsive disease, events take long time to appear [14] and, as a consequence, in order to detect small differences between alternative treatment strategies, long follow-up is needed. Our results showed that at 5 years there are no difference in terms of both OS (94% in both groups) and EFS (80% in the concomitant group and 79% in the sequential group), while a trend in favor of concomitant group starts to appear at 10 years (OS: 83% and 80% in concomitant and sequential groups, respectively; EFS: 63% and 54% in concomitant and sequential groups, respectively). A longer follow-up time is necessary to confirm or rule out a potential small difference in favor of the concomitant approach.
With the limitations of its retrospective nature, our study indicates that no major difference in outcome exists between concomitant and sequential administration of TAM and chemotherapy in the whole population of endocrine-responsive breast cancer patients. The potential advantage observed in young patients and in patients with high ER level tumors in giving TAM in concomitance to chemotherapy rather than sequentially needs to be further addressed in prospective trials.
|
funding |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionfundingappendix 1AcknowledgementsReferences |
|---|
Associazione Italiana per la Ricerca sul Cancro.
|
appendix 1 |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionfundingappendix 1AcknowledgementsReferences |
|---|
The following members of the GONO–MIG group also participated to the study: Ospedale S. Lazzaro, Alba (CN), Italy: Porcile G.; Ospedale Civile, ASTI, Italy: Testore F.; Ospedale Oncologico ‘G. Businco’, Cagliari, Italy: Mascia V., De Fraia E.; Ospedale S. Spirito, Casale Monferrato, Italy: Botta M.; Ospedale S. Croce e Carle, Cuneo, Italy: Merlano M.; Ospedale Sampierdarena, Genova, Italy: Mencoboni M.; Ospedale Civile, Sanremo (IM), Italy: Campora E.; Ospedale S. Paolo, Savona, Italy: Brema F.; Ospedale Sestri Levante (Ge), Italy: Lavarello A.; Ospedale S. Anna, Divisione B, Torino, Italy: Campogrande M.; Ospedale Galliera, Genova, Italy: Caroti C.; Ospedale Civile, Livorno, Italy: Falcone A.; Ospedale S. Leopoldo Mandic, Merate, Italy: Banducci S.; Ospedale S. Raffaele, Milano, Italy: Villa E., Aldrighetti D.; IRCSS S. Matteo, Pavia, Italy: Danova M.; Ospedale S. Corona, Pietra Ligure (Ge), Italy: Folco U.; DH Oncologico, Policlinico Umberto I, Roma, Italy: Cortesi E., D'Auria G; Ospedale SS. Annunziata, Sassari, Italy: Olmeo N, Pazzola A; Centro Oncologico, Trieste, Italy: Mustacchi G., Dellach C.
|
Acknowledgements |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionfundingappendix 1AcknowledgementsReferences |
|---|
The authors thank S. Pastorino for data collection and management.
|
Footnotes |
|---|
Present address: Oncologia Medica, Ospedale Sacro Cuore, Via Sempreboni, Negrar, Verona, Italy 
Received for publication July 6, 2007. Revision received September 7, 2007. Accepted for publication September 10, 2007.
|
References |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionfundingappendix 1AcknowledgementsReferences |
|---|
1. Li CI, Daling JR, Malone KE. Incidence of invasive breast cancer by hormone receptor status from 1992 to 1998. J Clin Oncol (2003) 21:28–34.
2. Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol (2003) 21:976–983.
3. Mamounas EP, Bryant J, Lembersky B, et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol (2005) 23:3686–3696.
4. Colleoni M, Li S, Gelber RD, et al. Timing of CMF chemotherapy in combination with tamoxifen in post-menopausal women with breast cancer: role of endocrine responsiveness of the tumor. Ann Oncol (2005) 16:716–725.
5. Osborne CK. Interactions of tamoxifen with cytotoxic chemotherapy for breast cancer. In: Long Term Tamoxifen for Breast Cancer—Jordan VC, ed. (1994) Madison, WI: University of Wisconsin Press. 181–198.
6. Pico C, Martin M, Jara C, et al. Epirubicin-cyclophosphamide adjuvant chemotherapy plus tamoxifen administered concurrently versus sequentially: randomized phase III trial in postmenopausal node-positive breast cancer patients. A GEICAM 9401 study. Ann Oncol (2004) 15:79–87.
7. Sertoli MR, Pronzato P, Venturini M, et al. A randomized study of concurrent versus sequential adjuvant chemotherapy and tamoxifen in stage II breast cancer. Proc Am Soc Clin Oncol (2002) 21. 46a (Abstr 182).
8. Albain KS, Green SJ, Ravdin PM, et al. Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol (2002) 21:37a. (Abstr 143).
9. Venturini M, Del Mastro L, Aitini E, et al. Dose-dense adjuvant chemeotherapy in early breast cancer patients: results from a randomized trial. J Natl Cancer Inst (2005) 97:1724–1733.
10. Venturini M, Del Mastro L, Durando A, et al. First results of cooperative MIG5 study, a randomized trial in node positive early breast cancer patients. Ann Oncol (2006) 17(Suppl 11):xi15. (Abstr A42).
11. Cuzick J. Forest plots and the interpretation of subgroups. Lancet (2005) 365:1308.[CrossRef][Web of Science][Medline]
12. Bonetti M, Gelber RD. A graphical method to assess treatment-covariate interactions using the Cox model on subsets of the data. Stat Med (2000) 19:2595–2609.[CrossRef][Web of Science][Medline]
13. National comprehensive cancer network clinical practice guidelines in oncology Breast Cancer. Version 1.2007 http://www.nccn.org/professional/physician_gls/PDF/breast.prd (15 February 2007, date last accessed).
14. Early Breast Cancer Trialists' Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet (2005) 365:1687–1717.[CrossRef][Web of Science][Medline]
15. Albain K, Green S, Osborne K, et al. Tamoxifen (T) versus cyclophosphamide, adriamycin and 5-FU plus either concurrent or sequential T in post-menopausal receptor (+), node (+) breast cancer: a Southwest Oncology Group phase III intergroup trial (SWOG-8814-INT0100). Proc Am Soc Clin Oncol (1997) 16:128a. (Abstr 450).
16. French Adjuvant Study Group. Benefit of high-dose epirubicin regimen in adjuvant chemotherapy for node positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol (2001) 19:602–611.
17. Aebi S, Gelber R, Castiglione-Gertsch M, et al. Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer? Lancet (2000) 355:1869–1874.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. R. Smith Rapid Testosterone Cycling and Chemotherapy for Prostate Cancer: A Way Forward or Return to the Past? J. Clin. Oncol., June 20, 2008; 26(18): 2932 - 2933. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||