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Clinical Update - Breast Cancer

Clinical Update Issue 20 - May 2005 - ISSN 1328-9454

ADJUVANT CHEMOTHERAPY IN OLDER AND YOUNGER WOMEN WITH LYMPH NODE-POSITIVE BREAST CANCER

Commentary by Dr Anne Sullivan

The article:

Muss H, Woolf S, Berry D et al. Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. Journal of the American Medical Association 2005: 293(9): 1073-1081

Reviewer:

Dr Anne Sullivan is a senior visiting medical oncologist at the Sydney Cancer Centre and the Strathfield Breast Centre.  Dr Sullivan has a special interest in breast cancer.

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

Disease-free Survival (DFS); Involved Lymph Nodes (LN); Overall Survival (OS); Randomised Controlled Trial (RCT); Treatment-related Mortality (TRM)

Study design:

• Participants: 6487 women with lymph node-positive breast cancer
• Design: Retrospective review of 4 RCTs conducted between 1975 and 1999. All trials randomised patients to different regimens, doses, schedules and durations of chemotherapy and all included a more intensive treatment arm (higher dose or higher intensity schedule). Median follow up was 9.6 years.
• Primary endpoint: Comparison of DFS, OS and TRM among women in three age groups: ≤50 years (n=3506); 51–64 years (n=2439); ≥65 years (n=542).
  

Findings

Primary endpoint:

• No association between DFS and age (<65 vs ≥65) (p=0.90)
• OS worse for women ≥ 65 due to deaths from causes other than breast cancer (p<0.001)
• Older women (≥65) had higher TRM (p<0.001)
• Smaller tumour size, fewer positive lymph nodes, more chemotherapy, and tamoxifen were all statistically significantly associated with longer DFS and OS (p=<0.001)
  

Conclusion

Women irrespective of age derived similar reductions in DFS from regimens containing more intense chemotherapy. Age alone should not be a contraindication to the use of optimal chemotherapy regimens in older women in good general health.

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

This paper addresses the issue of whether older women derive a benefit from more aggressive chemotherapy compared to less aggressive chemotherapy, and whether more aggressive chemotherapy results in greater toxicity for this group. Anecdotal evidence suggests that women in this older age group are often either not given any chemotherapy or given gentler chemotherapy, for reasons related to both possible lack of efficacy and fear of excessive toxicity.

This study demonstrates that older women do derive a benefit from more intensive chemotherapy with regard to disease-free survival and breast cancer related mortality similar to that in younger women. However, overall survival in women aged 65 or older was significantly worse because of death from causes other than breast cancer. Treatment related toxicity is a concern. Compared to women 50 years of age and under, treatment-related mortality is approximately three times higher in women 51–64 years of age (0.2% vs 0.7%) and seven times higher in women aged 65 years or older (0.2% vs 1.5%).

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

The authors reviewed data from four Cancer and Leukaemia Group B randomised clinical trials that accrued patients between 1975 and 1999. These trials were chosen because (i) each looked at standard chemotherapy versus 'more intensive' chemotherapy in terms of duration, dose or dose intensity; (ii) 'more intensive' chemotherapy was potentially more toxic and (iii) each trial showed a survival benefit in terms of disease-free survival for patients with node-positive breast cancer, with an overall survival benefit seen in three of the four trials. 6487 patients were evaluable and divided into three groups according to age: ≤50 years, 51–64 years, and ≥65 years. These groups were well balanced with regard to tumour size and hormone receptor status but not number of positive lymph nodes, with the oldest age group having the largest proportion with ≥10 positive nodes.

One can assume significant selection bias for women in the oldest age group who were chosen for trial participation by virtue of their very high-risk breast cancer compared to the younger women for whom chemotherapy would have been routinely given. The authors acknowledge and discuss this. The use of tamoxifen was inconsistent in the three earlier studies and its contribution to treatment benefit is unclear. Numbers were small in the older age groups as one might expect, but statistical methods were sound.

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

This paper adds more fuel to the argument that fit, healthy, older women can benefit from best standard adjuvant chemotherapy with similar breast cancer survival benefits to those seen in younger women. However, the lack of overall survival benefit and significant increase in treatment-related mortality illustrates the need for careful assessment of older women’s fitness for such treatment. This leads to the question of how fitness can be assessed, as the women in these trials would have had to meet rigorous eligibility requirements.

These trials were performed using older, more established treatment regimes. Clearly, there has been some amelioration of toxicity over the years with the advent of supportive therapies such as colony stimulating factors and newer antiemetics. The findings underscore the need for continuing prospective randomised trials asking similar questions utilising best standard chemotherapy regimens versus possibly less toxic yet efficacious regimens with newer agents such as liposomal doxorubicin or vinorelbine.

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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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