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© 2003 American Society for Clinical Oncology Does Timing of Adjuvant Chemotherapy for Early Breast Cancer Influence Survival?From the Breast Unit, Royal Marsden Hospital; and the Institute of Cancer Research, London, United Kingdom. Address reprint requests to Ian E. Smith, MD, Royal Marsden Hospital, Fulham Rd, London SW3 6JJ, United Kingdom; e-mail: ian.smith{at}rmh.nthames.nhs.uk.
Purpose: Theoretically, patients with early breast cancer might benefit from starting adjuvant chemotherapy soon after surgery, and this would have important clinical implications. We have addressed this question from a large, single-center database in which the majority of patients received anthracyclines.
Patients and Methods: A total of 1,161 patients from a prospectively maintained database treated with adjuvant chemotherapy for early breast cancer at the Royal Marsden Hospital (London, United Kingdom), including 686 (59%) receiving anthracyclines, were retrospectively analyzed. The disease-free survival (DFS) and overall survival (OS) of the 368 patients starting chemotherapy within 21 days of surgery (group A) were compared with those of the 793 patients commencing chemotherapy Results: No significant difference in 5-year DFS was found between the two groups overall (70% for group A v 72% for group B; P = .4) or in any subgroup. Likewise, there was no difference in 5-year OS (82% for group A v 84% for group B; P = .2) or when the interval to the start of chemotherapy was considered as a continuous variable (P = .4). Conclusion: We have been unable to identify any significant survival benefit from starting adjuvant chemotherapy early after surgery, either overall or in any subset of patients.
THE SURVIVAL benefit of adjuvant chemotherapy for operable breast cancer is now firmly established,1 but its optimal timing after surgery remains uncertain. Adjuvant chemotherapy normally starts within a few weeks of surgery, but it is unclear whether there is any gain from starting as soon as possible or whether a delay has an adverse outcome. There are theoretical reasons to believe that starting chemotherapy early might improve survival. First, in animal models, a phase of accelerated growth of micrometastases after the removal of the primary tumor has been demonstrated,2,3 along with serum-transmissible growth factors responsible for accelerated growth of tumor at distant sites.3,4 The administration of chemotherapy or endocrine therapy preoperatively or in the perioperative period prevented this accelerated growth.5,6 Second, a delay in the initiation of systemic therapy theoretically increases the probability of the emergence of drug-resistant micrometastatic disease.7 Third, there is evidence in animal models that the removal of the primary tumor leads to an increase in angiogenesis in the vascular bed surrounding metastases,8 and it is postulated that one of the mechanisms of action of chemotherapy may be the inhibition of neoangiogenesis. Two small clinical studies have suggested that patients who received chemotherapy within 28 to 35 days of surgery had improved disease-free survival (DFS) compared with those who received chemotherapy later.9,10 More recently, a larger study analyzed the effect of timing of cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy on survival in premenopausal patients participating in the International Breast Cancer Study Group (IBCSG) trials I, II, and VI.11 This study found a significant and clinically striking improvement in 10-year DFS in a small subset of premenopausal patients with estrogen receptor (ER)–absent tumors who started chemotherapy within 21 days of surgery compared with those commencing chemotherapy 21 days or more following surgery (60% v 34%; P = .0003). No similar benefit was seen for other patients (the majority). In the current era of anthracycline-based adjuvant chemotherapy, we wished to investigate further whether there was a group of patients for whom it was particularly important to start treatment within the first 3 weeks after surgery. We have therefore reviewed a single-center database of more than 1,000 patients, the majority of whom were treated with anthracycline-based adjuvant chemotherapy.
We identified retrospectively from a prospectively maintained database 1,161 patients treated with adjuvant chemotherapy for early breast carcinoma between January 1990 and June 2001 at the Royal Marsden Hospital (London, United Kingdom), either within clinical trials or on the basis of standard service guidelines. Six hundred eighty-six of these patients received anthracycline-based chemotherapy using combinations that mainly included epirubicin 60 mg/m2 every 3 weeks for six courses (636 patients) or sometimes doxorubicin 60 mg/m2 every 3 weeks for six courses (50 patients); the remaining 475 patients received CMF or mitoxantrone and methotrexate (MM). Data were collected on known prognostic factors including age, tumor size, grade, nodal status, number of involved lymph nodes, lymphovascular invasion, and hormone receptor status. The time from surgery until the day of administration of the first cycle of adjuvant chemotherapy was recorded. The date of surgery was taken as the date of the first surgical excision of the primary tumor, whether or not a diagnostic biopsy had preceded this date. Patients were divided into two groups with respect to the initiation of adjuvant chemotherapy: those who received the first dose of chemotherapy within 21 days of surgery (group A) and those whose chemotherapy started 21 days or more after surgery (group B). Data on radiotherapy and adjuvant endocrine therapy were also recorded. Data available up to July 31, 2002, were used for this analysis. Median follow-up time was 39 months (range, 12 to 147 months). Eighty-four percent of patients also received adjuvant endocrine therapy, nearly always tamoxifen, given concurrently with the start of chemotherapy for 5 years or in a trial comparing 2 years with 5 years of treatment.
All ER assays were conducted by a laboratory that participated in the relevant UK National External Quality Assessment Scheme throughout this period. Until 1992, ER was measured by multiple-point ligand-binding and dextran-coated charcoal assay, with values obtained by Scatchard plot analysis. Between 1993 and December 1994, ER was measured using enzyme immunoassay kits (Abbott Diagnostics, Chicago, IL). In both of these assays, values of
Statistical Analysis DFS was defined as the date of first surgery (excluding diagnostic biopsy) to the date of first relapse at any site or to the appearance of a second primary breast cancer. Overall survival was measured from the date of first surgical treatment to death from any cause or to last follow-up visit. Local recurrence was defined as tumor arising in the treated breast, chest wall, or regional lymph nodes. Survival curves were calculated using the Kaplan-Meier method13 and differences assessed by the log-rank statistic.14 The Cox proportional hazards regression model was used to test for the independent effect of timing of chemotherapy after adjusting for other prognostic and treatment covariates.15 Covariates considered in the regression models included pathologic tumor size, nodal status, grade, vascular invasion, ER status, type of chemotherapy, and adjuvant endocrine therapy use. All P values were two-sided.
Patient Characteristics A total of 1,161 patients received adjuvant chemotherapy for early breast cancer between January 1990 and June 2001. Of these, 368 patients (31.7%) started chemotherapy within 21 days of surgery (group A), and 793 patients started chemotherapy 21 days or more after surgery (group B). Of the 368 patients in group A, 205 received anthracycline-based chemotherapy and 163 received either CMF or MM chemotherapy. Of the group B patients, 481 received anthracycline-based chemotherapy and 312 received CMF or MM chemotherapy.
Table 1
DFS There was no significant difference in DFS between patients starting adjuvant chemotherapy within 21 days of surgery and those commencing chemotherapy later (5-year DFS, 70% v 72%; P = .4; Fig 1  ). Likewise, there were no significant differences in DFS relating to age or ER status (Table 2). The Cox proportional hazards model was used to adjust the analysis for known prognostic factors of pathologic size, nodal status, number of involved nodes, grade, vascular invasion, ER status, type of chemotherapy, and use of adjuvant endocrine therapy. After adjusting for these factors, the effect of the surgery-chemotherapy interval remained nonsignificant (P = .5).
Overall Survival There were no differences in overall survival between groups A and B (5-year survival, 82% v 84%, respectively; P = .2; Fig 2 ). After adjustment for known prognostic factors, there remained no difference in survival between the two groups (P = .4). We were likewise unable to show that the timing of chemotherapy influenced survival significantly for subgroups related to age or ER status (Table 3).
Continuous Variable Assessment We also assessed whether any other time interval might influence outcome. One-third of the total patient population had their adjuvant chemotherapy initiated within 21 days of surgery, but the majority (65%) started adjuvant chemotherapy between day 14 and 35 after surgery (Fig 3 ). We found no effect of timing of chemotherapy on survival when the interval is considered as a continuous variable (P = .4). Likewise, we found no survival difference using either a 28-day (P = .1) or 35-day cutoff (P = .3).
Despite the experimental data discussed above,3,8 which indicate that starting adjuvant chemotherapy early might have a survival benefit in early breast cancer, we have been unable to demonstrate this clinically. In a patient population treated in a single center during a 10-year period, we found no difference in outcome relating to how soon chemotherapy was started after surgery, either overall or in any subgroup of that population. This was the case whether we used an arbitrary 21-day cutoff point or assessed time as a continuous variable. The largest previous study to address this question retrospectively analyzed data from three IBCSG trials of adjuvant CMF chemotherapy given to premenopausal, node-positive patients.11 In this analysis, there was heterogeneity in the duration and total dose of chemotherapy received. A remarkable improvement in 10-year DFS (60% v 34%) was found for a small subgroup of premenopausal patients with node-positive, ER-absent tumors receiving CMF chemotherapy (226 of 1,788 patients [13%]) within 21 days of surgery compared with those starting treatment later (hazard ratio [HR], 0.48; 95% CI, 0.33 to 0.72; P = .0003). This far exceeds anything achieved by any specific form of adjuvant therapy itself and would have important clinical implications for delivery of treatment if confirmed. No similar benefit was seen for any other subgroup of patients.
It should be noted that patients who had received adjuvant oophorectomy or other endocrine therapy were excluded from the IBCSG study, whereas 84% of our patients also received endocrine therapy (nearly always tamoxifen) given concurrently with chemotherapy. It is possible that this had a confounding effect on the influence of chemotherapy. More importantly, although our finding of no benefit from early chemotherapy included premenopausal women with ER-negative cancers, we nevertheless cannot make direct comparisons on this issue between the IBCSG study and our own because of differences in ER categorization. Throughout the period of our study, ER was measured using a biochemical cutoff for positivity of It should be noted, however, that diagnostic cutoffs for ER have changed in many centers such that what are now described as ER-negative tumors closely approximate the IBCSG description of ER-absent tumors. This is because of recent studies showing a better prognosis for tumors with as few as 1% cells staining positive when treated with tamoxifen.16 Thus the small subgroup of ER-absent tumors is increasingly relevant to contemporary practice.
In other studies, Buzdar et al17 likewise did not find any differences in DFS according to length of delay in initiation of chemotherapy. In their study of 462 patients receiving adjuvant fluorouracil, doxorubicin, and cyclophosphamide, overall 4-year DFS was 64%, 68%, 60%, and 63% for patient groups with delays of less than 10, 10 to 13, 14 to 17, or Pronzato et al10 showed improved DFS for patients starting chemotherapy within 35 days of surgery. This study examined small numbers of patients (n = 229) receiving adjuvant intravenous CMF, and survival was analyzed according to the number of cycles received, dose-intensity, and time to start of chemotherapy. All three factors were significant in a univariate analysis, but only dose-intensity and time to start of chemotherapy retained independent prognostic significance in multivariate analysis. Brooks et al9 also showed an improvement in DFS for patients with node-positive cancers receiving doxorubicin and cyclophosphamide chemotherapy within 4 weeks of surgery compared with those patients receiving delayed chemotherapy, but did not identify patient groups for whom the early chemotherapy was particularly important. In a retrospective Turkish study involving 1,167 patients receiving adjuvant chemotherapy between 1990 and 2000, it was found that time to start of adjuvant chemotherapy and time to progression were inversely related for patients receiving adjuvant chemotherapy within 4.8 months.18 No data were given on what type of chemotherapy was used or whether there were specific subgroups who benefited from starting early. In their multivariate analysis, time to initiation of chemotherapy remained an independent prognostic variable. None of these studies provided sufficient numbers and/or demographic details to allow a premenopausal ER-absent subgroup equivalent to that identified by the IBCSG to be separately analyzed. A trial of perioperative chemotherapy showed that patients receiving one course of perioperative polychemotherapy had significantly improved progression-free survival compared with patients having surgery alone, but not in patients who received additional conventional adjuvant chemotherapy subsequently.19 In this study, the timing effect of one course of perioperative fluorouracil, doxorubicin, and cyclophosphamide was analyzed in the 1,198 patients who received prolonged adjuvant systemic treatment (chemotherapy or endocrine treatment). No effect of timing was found on overall survival (HR, 0.65; 95% CI, 0.78 to 1.17; P = .65) or progression-free survival (HR, 0.94; 95% CI, 0.80 to 1.12; P = .50). In addition, no effect of timing was found on locoregional control (HR, 0.88; 95% CI, 0.59 to 1.31; P = .52). This would suggest that total dose and duration of chemotherapy are more important than the timing of the start of chemotherapy. This trial suggests that one course of perioperative chemotherapy is better than no systemic therapy at all, but does not show that the perioperative timing confers a survival advantage superior to that of standard adjuvant therapy. In conclusion, we have been unable to show any clinical benefit from commencing chemotherapy (usually anthracycline-based) early after surgery in any patient subgroup, including those we defined in the past as having ER-negative cancers. The issue remains unresolved, however, for the small subgroup with ER-absent tumors defined biochemically. Currently, this would approximate to immunohistochemically defined ER-negative tumors in an increasing number of centers, depending on cutoff. There are obvious practical and ethical difficulties in conducting a prospective randomized trial to address this issue, and the best way to proceed seems to be analysis of additional retrospective studies from large, prospectively assembled databases.
The authors indicated no potential conflicts of interest.
We thank our colleague Professor Mitch Dowsett for his expert advice on addressing the important issues of ER measurement and categorization in this manuscript, and also Alison Norton for her secretarial skills.
1. Polychemotherapy for early breast cancer: An overview of the randomised trials—Early Breast Cancer Trialists’ Collaborative Group. Lancet 352:930–942, 1998[CrossRef][Medline]
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3. Fisher B, Gunduz N, Coyle J, et al: Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Cancer Res 49:1996–2001, 1989 4. Agresti R, Tagliabue E, Ghirelli C, et al: Rescue of HER-2-positive breast carcinoma cells from dormancy by growth factors produced during wound healing. Breast Cancer Res 3:1–3, 2001[CrossRef][Medline]
5. Fisher B, Saffer E, Rudock C, et al: Effect of local or systemic treatment prior to primary tumor removal on the production and response to a serum growth-stimulating factor in mice. Cancer Res 49:2002–2004, 1989
6. Fisher B, Gunduz N, Saffer EA: Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastases. Cancer Res 43:1488–1492, 1983 7. Goldie JH, Coldman AJ: A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 63:1727–1733, 1979[Medline] 8. Folkman J: Endothelial cells and angiogenic growth factors in cancer growth and metastasis: Introduction. Cancer Metastasis Rev 9:171–174, 1990[CrossRef][Medline] 9. Brooks RJ, Jones SE, Salmon SE: Improved outcome with early treatment in an adjuvant breast cancer program. Proc Am Soc Clin Oncol 2:110, 1983 10. Pronzato P, Campora E, Amoroso D, et al: Impact of administration-related factors on outcome of adjuvant chemotherapy for primary breast cancer. Am J Clin Oncol 12:481–485, 1989[Medline]
11. Colleoni M, Bonetti M, Coates AS, et al: Early start of adjuvant chemotherapy may improve treatment outcome for premenopausal breast cancer patients with tumors not expressing estrogen receptors: The International Breast Cancer Study Group. J Clin Oncol 18:584–590, 2000
12. Saccani-Jotti G, Johnston SR, Salter J, et al: Comparison of new immunohistochemical assay for oestrogen receptor in paraffin wax embedded breast carcinoma tissue with quantitative enzyme immunoassay. J Clin Pathol 47:900–905, 1994 13. Kaplan EL, Meier P: Non parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 14. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and examples. Br J Cancer 35:1–39, 1977[Medline] 15. Cox D: Regression models and life table (with discussion). J R Stat Soc B 34:187–220, 1972
16. Harvey JM, Clark GM, Osborne CK, et al: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17:1474–1481, 1999 17. Buzdar AU, Smith TL, Powell KC, et al: Effect of timing of initiation of adjuvant chemotherapy on disease-free survival in breast cancer. Breast Cancer Res Treat 2:163–169, 1982[CrossRef][Medline]
18. Altundag MK, Celik I, Ozisik Y: Is there a range of time for initiation of adjuvant chemotherapy in patients with malignancy? Ann Oncol 11:1209, 2000 19. van der Hage JA, van de Velde CJ, Julien JP, et al: Improved survival after one course of perioperative chemotherapy in early breast cancer patients: Long-term results from the European Organization for Research and Treatment of Cancer (EORTC) Trial 10854. Eur J Cancer 37:2184–2193, 2001[CrossRef][Medline] Submitted January 13, 2003; accepted July 29, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
21 days after surgery (group B). Median follow-up time was 39 months (range, 12 to 147 months). 
2 test or Fisher’s exact test for categorical variables and the Mann-Whitney nonparametric test for continuous variables. Treatment imbalances were assessed by the 
