Clinical investigations
Breast
Selecting breast cancer patients with T1-T2 tumors and one to three positive axillary nodes at high postmastectomy locoregional recurrence risk for adjuvant radiotherapy

Oral presentation at the Canadian Association of Radiation Oncologists’ Annual Meeting, September 9–12, 2004, Halifax, NS, Canada.
https://doi.org/10.1016/j.ijrobp.2004.08.009Get rights and content

Purpose: To define the individual factors and combinations of factors associated with increased risk of locoregional recurrence (LRR) that may justify postmastectomy radiotherapy (PMRT) in patients with T1–T2 breast cancer and one to three positive nodes.

Methods and Materials: The study cohort comprised 821 women referred to the British Columbia Cancer Agency between 1989 and 1997 with pathologic T1-T2 breast cancer and one to three positive nodes treated with mastectomy without adjuvant RT. The 10-year Kaplan-Meier estimates of isolated LRR and LRR with or without simultaneous distant recurrence (LRR ± SDR) were analyzed according to age, histologic findings, tumor location, size, and grade, lymphovascular invasion status, estrogen receptor (ER) status, margin status, number of positive nodes, number of nodes removed, percentage of positive nodes, and systemic therapy use. Multivariate analyses were performed using Cox proportional hazards modeling. A risk classification model was developed using combinations of the statistically significant factors identified on multivariate analysis.

Results: The median follow-up was 7.7 years. Systemic therapy was used in 94% of patients. Overall, the 10-year Kaplan-Meier isolated LRR and LRR ± SDR rate was 12.7% and 15.9%, respectively. Without PMRT, a 10-year LRR risk of >20% was identified in women with one to three positive nodes plus at least one of the following factors: age <45 years, Stage T2, histologic Grade 3, ER-negative disease, medial location, more than one positive node, or >25% of nodes positive (all p < 0.05 on univariate analysis). On multivariate analysis, age <45 years, >25% of nodes positive, medial tumor location, and ER-negative status were statistically significant predictors of isolated LRR and LRR ± SDR. In the classification model, the first split was according to age (<45 years vs. ≥45 years), with 29.3% vs. 13.7% developing LRR ± SDR (p < 0.0001). Of 123 women <45 years, the presence of >25% of nodes positive was associated with a risk of LRR ± SDR of 58.0% compared with 23.8% for those with ≤25% of nodes positive (p = 0.01). Of 698 women >45 years, the presence of >25% of nodes positive also conferred a greater LRR ± SDR risk (26.7%) compared with women with ≤25% of nodes positive (10.8%; p < 0.0001). In women >45 years with ≤25% of nodes positive, tumor location and ER status were factors that could be used to further distinguish low-risk from higher risk subsets.

Conclusion: Clinical and pathologic factors can identify women with T1-T2 breast cancer and one to three positive nodes at high LRR risk after mastectomy. Age <45 years, >25% of nodes positive, a medial tumor location, and ER-negative status were statistically significant independent factors associated with greater LRR, meriting consideration and discussion of PMRT. Combinations of these factors further augmented the LRR risk, warranting recommendation of PMRT to optimize locoregional control and potentially improve survival. The absence of high-risk factors identifies women who may reasonably be spared the morbidity of PMRT.

Introduction

The role of postmastectomy radiotherapy (PMRT) in breast cancer patients with T1-T2 tumors and one to three positive axillary nodes is among the most controversial issues in adjuvant breast cancer management facing radiation oncologists today. PMRT, which generally encompasses the chest wall and regional lymph nodes, has been demonstrated to improve locoregional control in patients with high-risk breast cancer (1, 2, 3). In the absence of adjuvant systemic therapy, trials have not demonstrated improved survival with PMRT compared with surgery alone (1, 2). In the past two decades, systemic therapy for breast cancer has evolved, with broader indications for adjuvant chemotherapy and hormonal therapy (4, 5). Recently, three randomized trials (6, 7, 8) and a meta-analysis (3) demonstrated that PMRT improved not only locoregional control, but also survival, among patients with high-risk disease treated with systemic therapy. The results of these trials have prompted reevaluation of prior policies and launched a number of position statements and treatment guidelines addressing the role of PMRT in modern practice (9, 10, 11, 12, 13, 14).

Although consensus has been reached that PMRT is indicated for patients with advanced primary tumors >5 cm or four or more positive axillary nodes, the role of PMRT in patients with tumors ≤5 cm and one to three positive axillary nodes is controversial (9, 10, 11, 12, 13, 14). In the Danish Breast Cancer Cooperative Group 82b and 82c trials, the locoregional recurrence (LRR) rate without PMRT of approximately 30% at 10 years (7, 8) was considerably greater than rates observed in the British Columbia Cancer Agency (BCCA) trial (16% at 10 years and 33% at 15 years) (6) and in cohort studies of patients enrolled in systemic therapy trials (12–20% at 10 years) (15, 16, 17, 18, 19, 20). This discrepancy has been attributed to heterogeneous practices in axillary staging, systemic therapy, and patient selection (6, 7, 8, 9, 10, 11, 12, 13, 14). The relative reduction in LRR of approximately two-thirds associated with PMRT is of a similar magnitude in women with one to three positive nodes compared with women with four or more positive (1, 2, 3, 6, 7, 8). However, the absolute reduction in LRR with PMRT would be smaller if the baseline risk of LRR were lower in this subgroup, and the associated survival implication is unclear.

Owing to the inconsistencies in the available evidence, the role of PMRT in women with one to three positive nodes is currently undefined. It is, thus, disappointing that an Intergroup trial designed to address this question directly by randomizing patients with one to three positive nodes to locoregional PMRT or observation was prematurely closed because of a lack of accrual (21). The reasons for the trial’s poor accrual were likely multifactorial, but may have included patient refusal, physician biases, and divergent opinions and practice patterns. In a Canadian study comparing regional RT use before and after the publication of the Danish Breast Cancer Cooperative Group and BCCA trials in 1997, Chua et al. (22) reported that among women with one to three positive nodes, regional PMRT use increased from 32% to 54%. Similar findings were apparent in a survey of radiation oncologists in the United States and Europe that reported that 50% of European responders and 55% of American responders indicated they would use PMRT in patients with one to three positive nodes (23). The selection criteria in using or withholding PMRT among these clinicians were not specified.

Because PMRT optimizes locoregional control and may affect survival (3, 6, 7, 8), strategies that use patient and pathologic characteristics, other than tumor and nodal stage, to distinguish subsets at high risk of LRR (justifying use of PMRT) from those at sufficiently low risk of LRR (who may be spared PMRT) warrant investigation. This study reports an analysis of the individual prognostic factors and combinations associated with a high risk of LRR in patients with T1-T2 breast cancer and one to three positive nodes that may be used to select patients for adjuvant RT.

Section snippets

Methods and materials

The Breast Cancer Outcomes Unit database of the BCCA identified 1117 women diagnosed between January 1, 1989 and December 31, 1997 and referred with pT1-T2 breast cancer and one to three positive axillary nodes who were treated with mastectomy. The analysis excluded patients with established indications for PMRT, including pT3-T4 tumors and/or four or more positive nodes, patients presenting with distant metastasis, and patients with unknown pTN stage. Because our objective was to evaluate the

Results

The median follow-up time was 7.7 years. The median patient age at diagnosis was 62 years (range, 26–94 years).

Discussion

Advances in locoregional and systemic therapies in the past two decades have revolutionized breast cancer management. Recent trials have demonstrated that, in women receiving systemic therapy, PMRT improves not only locoregional control, but also disease-free and overall survival (3, 6, 7, 8). This survival benefit supports the hypothesis that when distant micrometastasis is controlled by systemic therapy and the locoregional tumor burden is reduced by RT, the effects combine to enhance disease

Conclusion

Patients with T1-T2 tumors and one to three positive nodes in this population-based analysis experienced overall LRR risk of 13–16% at 10 years. Although the magnitude of this risk may not be sufficiently great to justify routine PMRT in all patients, subgroups with age <45 years, >25% positive nodes, medial tumor location, and ER-negative disease experienced LRR of >20%. Women with these individual characteristics should be considered for PMRT. Combinations of these prognostic factors

References (43)

  • S.J. Feigenberg et al.

    Postmastectomy radiotherapyPatterns of recurrence and long-term disease control using electrons

    Int J Radiat Oncol Biol Phys

    (2003)
  • Effects of radiotherapy and surgery in breast cancerAn overview of the randomized trials

    N Engl J Med

    (1995)
  • Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancerAn overview of the randomised trials

    Lancet

    (2000)
  • T.J. Whelan et al.

    Does locoregional radiotherapy improve survival in breast cancer? A meta-analysis

    J Clin Oncol

    (2000)
  • Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women

    Lancet

    (1992)
  • Tamoxifen for early breast cancerAn overview of the randomised trials

    Lancet

    (1998)
  • J. Ragaz et al.

    Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer

    N Engl J Med

    (1997)
  • M. Overgaard et al.

    Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapyDanish Breast Cancer Cooperative Group 82b Trial

    N Engl J Med

    (1997)
  • S. Hellman

    Stopping metastases at their source

    N Engl J Med

    (1997)
  • A. Recht et al.

    Postmastectomy radiotherapyQuestions for the twenty-first century

    J Clin Oncol

    (1998)
  • M.E. Taylor et al.

    Postmastectomy radiotherapyACR Appropriateness Criteria

    Radiology

    (2000)
  • Cited by (0)

    View full text