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Clinical Update - Breast Cancer

Clinical Update Issue 19 - April 2005 - ISSN 1328-9454

RADIATION THERAPY AND CHEMOTHERAPY VS CHEMOTHERAPY ALONE: 20-YEAR RESULTS OF THE BRITISH COLUMBIA RANDOMIZED TRIAL

Commentary by Professor David Joseph

The article:

Ragaz J, Olivotto I, Spinelli J et al. Locoregional Radiation Therapy in Patients with High-Risk Breast Cancer Receiving Adjuvant Chemotherapy: 20-Year Results of the British Columbia Randomized Trial. Journal of the National Cancer Institute 2005: 97(2): 116-126

Reviewer:

Professor David Joseph is Director of the Department of Radiation Oncology at Sir Charles Gairdner Hospital in Perth.

In this issue...

• Article summary
• What does this article add to existing clinical evidence in this area?
• How adequate was the methodology used in addressing the aims of the studies?
• What are the implications of these studies for clinical practice in Australia?

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Summary

Abbreviations

Breast Cancer-specific Survival (BCS); Cyclophosphamide, Methotrexate and 5-Fluorouracil (CMF); Chemotherapy and Radiation Therapy versus Chemotherapy Alone (C and RT vs C); Confidence Interval (CI).

Study design:

• Participants: 318 premenopausal women with breast cancer with pathologically positive axillary lymph nodes treated with modified radical mastectomy and axillary lymph node dissection
• Design: Women receiving adjuvant CMF chemotherapy were randomly assigned to receive locoregional radiation therapy (n=164) or no additional treatment (n=154) with follow-up at 20 years
• Primary endpoint: Comparison of survival outcomes for all patients
• Secondary endpoint: Comparison of patients by lymph node status: N1-3 vs N=4
• Tertiary endpoint: Non-breast cancer deaths and other toxicities

Findings

Primary endpoint:
At 20-year follow-up C and RT vs C were associated with a statistically significant improvement in survival outcomes, including:

Overall survival
(47% vs 37%; RR = 0.73*, 95% CI = 0.55 to 0.98; p = 0.03)
Disease-free survival
(48% vs 30%; RR = 0.63*, 95% CI = 0.47 to 0.83; p = 0.001)
Breast cancer-specific survival
(53% vs 38%; RR = 0.67*, 95% CI = 0.49 to 0.90; p = 0.008)
Systemic disease-free survival
(48% vs 31%; RR = 0.66*, 95% CI = 0.49 to 0.88; p = 0.004)
Event-free survival
(35% vs 25%; RR = 0.70*, 95% CI = 0.54 to 0.92; p = 0.009)
Survival free of locoregional recurrence
(90% vs 74%; RR = 0.36*, 95% CI = 0.18 to 0.71; p = 0.002)

*RRs use C as the reference category

Secondary endpoint:
Relative effects similar for women with N1-3 and N=4.

Tertiary endpoint:
Rate of non-breast cancer deaths was 8.5% among patients treated with C and RT compared to 3.8% of patients treated with C (p= 0.11). Rate of cardiac deaths was 1.8% among C and RT compared to 0.6% in C (p= 0.6). Other toxicities associated with RT included arm oedema among 9.1% of patients treated with C and RT compared to 3.2% of patients treated with C (p= 0 .04).

Conclusion

For women with node-positive breast cancer treated by modified radical mastectomy, the addition of radiotherapy to adjuvant chemotherapy improved overall survival with acceptable long-term toxicity.

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What does this article add to existing clinical evidence in this area?

This article provides updated 20-year follow-up data from the British Columbia randomised radiation trial. The trial was designed to determine the survival impact of locoregional radiation therapy in premenopausal women with lymph-node positive breast cancer treated with modified radical mastectomy and adjuvant CMF chemotherapy. Previously reported results at 15-years of follow-up showed that radiation therapy was associated with a statistically significant improvement in breast cancer survival, but overall survival improvement was of borderline statistical significance.

The 20-year follow-up data reported here show a statistically significantly improvement in all end points analysed including overall survival and systemic relapse-free survival in the chemotherapy and radiation therapy arm compared to chemotherapy alone. The benefits were similar in patients with one to three positive axillary lymph nodes and for patients with four or more positive lymph nodes.

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How adequate was the methodology used in addressing the aims of the studies?

The paper described a well-designed randomised controlled trial employing intention-to-treat analysis, close follow-up, strict definitions of outcomes, and complete determination of final status. It is unlikely that the patients or health practitioners were masked to treatment allocation, but this was offset by the types of outcomes being investigated (i.e. survival, recurrence, etc.). One weakness of the study is its relatively small sample size with consequent wide confidence intervals. The results however are consistent with the Danish pre1 and postmenopausal trials,2 which also showed better overall survival with adjuvant radiation.

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What are the implications of these studies for clinical practice in Australia?

The authors of the study considered the impact of their results on current clinical practice. One of the key questions this study generates is its applicability to patients treated with more intense adjuvant chemotherapy. The CMF regimens used in this trial and in the Danish premenopausal1 trial are no longer regarded as optimal, and it is unknown whether the observed benefits would apply to women treated with current chemotherapy.

The authors report results from other trials that highlight substantial relapse rates in high-risk patients treated with high-dose chemotherapy. They suggest that loco-regional radiotherapy may be even more important with current chemotherapy regimes because of their improved systemic effectiveness, making local failure and re-seeding relatively more significant.

The applicability to current practice is also limited by the technique used (5 fields 37.5G in 16 fractions including bilateral internal mammary node fields) and recent changes in systemic therapies. More information is needed about the adverse effects of adding modern locoregional radiation to adjuvant chemotherapy with anthracyclines and/or taxanes.

Another important issue relates to speculation that radiation therapy may be effective only after suboptimal surgery. The results of the Danish trials and previous data from the British Columbia trial (median of 11 axillary lymph nodes removed) showed that even among patients with adequate axillary surgery recurrences were reduced by at least one third. Therefore, the relative benefit of radiation therapy was substantial regardless of the number of lymph nodes removed.

The authors report a slight increase in non-breast cancer deaths. Cardiac deaths accounted for 1.8% in the chemotherapy and radiation group and 0.6% in the chemotherapy alone group. The substantial benefits in breast cancer survival outweighed the slight increase in non-breast cancer deaths, cardiac events, and other toxicities.

These data provide new information about regional radiation therapy after mastectomy for women with localised breast cancer and involved axillary lymph nodes, especially those with a higher risk of recurrence. These findings stress the importance of further research, including current randomised controlled trials that investigate this question. As the study involved only premenopausal women, caution should be taken before extrapolating the results to women of all ages.

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References

1. Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 1997;337:949-55
2. Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, et al. Postoperative radiotherapy in high-risk postmenopausal breast cancer patients given adjuvant tamoxifen. Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999;353:1641-8

Disclaimer:
Clinical Update 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 do not replace recommendations included in NBCC clinical practice guidelines.
Information contained in Clinical Update is not intended to be used as substitute for an independent health professional's advice. The NBCC does not accept any liability for any injury, loss or damage incurred by use of or reliance on the information contained in Clinical Update. The NBCC develops material based on the best available evidence however cannot guarantee and assumes no legal liability or responsibility for the currency or completeness of the information.

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