Clinical Update - Breast Cancer
Impact on survival of time from definitive surgery to initiation of adjuvant chemotherapy for early-stage breast cancer
Commentary by Dr Nicole McCarthy
The article
Lohrisch C, Paltiel C, Gelmon K et al. Impact on survival of time from definitive surgery to initiation of adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol 2006;24(30):4888−94
Summary | Commentary
Reviewer
Dr Nicole McCarthy is a medical oncologist at the Royal Brisbane & Women's Hospital and Wesley Hospital, Queensland.
Impact on survival of time from definitive surgery to initiation of adjuvant chemotherapy for early-stage breast cancer
Summary
Abbreviations
Confidence Interval (CI), Disease-Free Survival (DFS), Hazard Ratio (HR), International Breast Cancer Study Group (IBCSG), Overall Survival (OS), Relapse-Free Survival (RFS)
Study design
This study retrospectively reviewed 2594 patients with stage I and II breast cancer receiving adjuvant chemotherapy who were referred to the British Columbia Cancer Agency between 1989 and 1998. The patients were grouped by time from definitive surgery to start of adjuvant chemotherapy into four cohorts: ≤ 4 weeks (n=993), >4 to 8 weeks (n=1272), >8 to 12 weeks (n=217), and >12 to 24 weeks (n=112). The primary outcomes of interest were breast cancer RFS and OS.
Findings
The rates of breast cancer RFS and OS at 5 years are presented in Table 1.
Table 1. Rates of breast cancer RFS and OS according to interval from surgery to chemotherapy.
|
Interval from surgery to chemotherapy |
p (log-rank) |
|||
0-4 weeks |
>4-8 weeks |
>8-12 weeks |
>12-24 weeks |
||
5-year RFS |
74% |
79% |
82% |
69% |
0.004 |
5-year OS |
84% |
85% |
89% |
78% |
0.013 |
The OS for the group with interval from surgery to chemotherapy >12-24 weeks was significantly worse compared to the other three groups (HR: 1.5; 95% CI: 1.07, 2.10; p=0.017).
Conclusion
The authors suggested that adjuvant chemotherapy is equally effective up to 12 weeks after definitive surgery but delays of more than 12 weeks after definitive surgery may compromise RFS and OS.
Commentary
What does this article add to existing clinical evidence in this area?
The optimal time to commence adjuvant chemotherapy for early stage breast cancer is unknown. Adjuvant chemotherapy usually starts within 1 month of surgery, but it is unclear whether starting earlier is better, or whether delaying it till later will have a negative impact on survival. Seven prior studies have addressed this question. Two small studies from the 1980s reported improved DFS for patients receiving chemotherapy within 4–5 weeks compared with later.1–2 A retrospective Turkish study found that the time to starting adjuvant chemotherapy and time to progression were inversely related for patients receiving adjuvant chemotherapy within 4.8 months.3 However, other studies have not been able to demonstrate such benefits. A review from MD Anderson showed delays of 9, 10–13,14–17,18+ weeks did not affect DFS and a larger retrospective study from the Danish Breast Cancer Cooperative Group also found no difference in outcome for 7500 patients starting chemotherapy up to 13 weeks after surgery.4-5 Attempts have been made to demonstrate subgroups that may benefit from early commencement of adjuvant chemotherapy. IBCSG analysed the effect of timing of cyclophosphamide, methotrexate and fluorouracil on survival in premenopausal women treated on IBCSG Trials I, II and VI, and showed a striking improvement in DFS only in a small subset of oestrogen receptor negative patients who started chemotherapy within 3 weeks after definitive surgery compared with ≥3 weeks.5 This finding was not able to be reproduced in a review from the Royal Marsden Hospital.7
This retrospective review from the British Columbia Cancer Agency provides further evidence that adjuvant chemotherapy can be delivered without compromising efficacy up to 12 weeks after definitive surgery. It is one of the first studies to demonstrate that starting adjuvant chemotherapy more than 12 weeks after surgery is associated with inferior survival (HR: 1.6; 95% CI: 1.2, 2.3; p=0.005).
How was the methodology used in addressing the aims of this study?
This study is a population-based analysis of the impact of time to initiation of adjuvant chemotherapy on the risks of relapse and death, using multivariable models to account for the effects of known prognostic factors such as age, tumour size, grade, axillary node status, lymphovascular invasion and oestrogen receptor status and anthracycline use. There was no difference in outcomes between the three groups starting adjuvant chemotherapy within 12 weeks or less, but the group starting later than 12 weeks did significantly worse. In the absence of a ‘no chemotherapy’ comparator, it is impossible to say whether the benefit of chemotherapy was lost or merely attenuated by the delay.
This study is limited by the flaws inherent in its retrospective observational design. Imbalances in known and unknown prognostic factors may have influenced the observed results. The study reviews standard clinical practice during the specific time period reviewed. Some of the limitations acknowledged by the authors include:
- 56% of patients had oestrogen receptor positive disease – biasing the sample towards patients with oestrogen receptor negative disease who are more likely to be offered chemotherapy
- patients starting adjuvant chemotherapy within 4 weeks were most likely to have involved lymph nodes
- only 38% received tamoxifen: 68% of the population were <50 yrs old and tamoxifen was not recommended for premenopausal women in the early years of the study
- anthracycline-based chemotherapy was not recommended for node negative disease in the early years of the study
- the proportion of patients receiving an anthracycline was lower in groups starting chemotherapy later
- HER2 status was not known
- the dose intensity of the chemotherapy delivered was unknown.
What are the implications of this study for clinical practice in Australia?
Overall, the results of this study are remarkably consistent with other large retrospective reviews suggesting that starting chemotherapy within 3 months of definitive surgery is adequate, but delays beyond 3 months compromise survival. This should be in keeping with standard practice in most Australian centres and provides a benchmark for the time to start adjuvant chemotherapy. Twelve weeks allows women a significant period of time in which to gather information, consider options and take an active role in decision making if desired. It is unlikely that large prospective randomised trials will be performed to answer this important question definitively and the impact of timing of adjuvant chemotherapy on high risk subgroups remains unclear and of ongoing concern.
References
1. Brooks RJ, Jones SE, Salmon SE et al. Improved outcome with early treatment in an adjuvant breast cancer program. Proc Am Soc Clin Oncol 1983;2(110):C-431.
2. 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 1989;12:481−5.
3.Altundag MK, Celik I, Ozisik Y. Is there a range of time for initiation of adjuvant chemotherapy in patients with malignancy? Ann Oncol 2000;11:1209.
4.Buzdar AU, Smith TL, Powell KC, Blumenschein GR, Gehan EA. Effect of timing of initiation of adjuvant chemotherapy on disease-free survival in breast cancer. Breast Cancer Res Treat 1982;2:163−9.
5.Cold S, Düring M, Ewertz M, et al. Does timing of adjuvant chemotherapy influence the prognosis after early breast cancer? Results of the Danish Breast Cancer Cooperative Group (DBCG). Br J Cancer 2005;93:627−32.
6.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 2000;18:584−90.
7.Shannon C, Ashley S, Smith IE. Does timing of adjuvant chemotherapy for early breast cancer influence survival? J Clin Oncol 2003;21:3792−7.
Editor: Dr Karen Luxford, Deputy Director NBCC.
Editorial Committee: Mr John Collins - Surgeon,
Dr Sue-Anne McLachlan - Medical Oncologist,
Dr Sue Pendlebury - Radiation Oncologist,
A/Prof Martin Stockler - Medical Oncologist, Ms Jo Keyser - Specialist Breast Nurse, Dr Sally Meade - Breast Surgeon, Dr Warwick Lee - Radiologist, Dr Penny Schofield - Senior Research Fellow.
Disclaimer
Clinical Update - Breast Cancer is produced by the National Breast Cancer Centre (NBCC) and is intended to provide health professionals with timely expert commentary on new research in breast cancer. Commentaries included in Clinical Update - Breast Cancer do not replace recommendations included in NBCC clinical practice guidelines.
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