NSABP B-04

Fisher B, Jeong JH, Anderson S, Bryant J, Fisher ER, Wolmark N. Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med. 2002;347(8):567-575. doi:10.1056/NEJMoa020128

Clinical Question

In patients with invasive breast cancer, does less extensive surgery (vs Halsted radical mastectomy) lead to equivalent outcomes?

Bottom Line

The modern total (simple) mastectomy provides equivalent oncologic outcomes to the radical mastectomy with regards to the breast.

While the patient population is no longer consistent with the majority of breast cancer presentations which are earlier stage due to improvements in screening and diagnosis, and recurrence rates have declined due to improvements in systemic therapy, particularly the introduction of endocrine therapy, it laid the groundwork for de-escalation of breast cancer therapy and gave important information about the timing of both local and distant recurrence which informs trial follow up timing to this day.

Major Points

In clinically node negative patients, axillary dissection does not improve survival when compared to adjuvant radiation or omission of axillary surgery. In clinically node positive patients, simple mastectomy and radiations yield similar outcomes as radical mastectomy. Adjuvant radiation may decrease local recurrence but does not improve survival or distant recurrence.

Important findings include that 40% of the women with clinically negative nodes who underwent radical mastectomy were found to have positive nodes, indicating that complete clearance of lymph nodes is not essential for adequate disease control and paving the way for ACOSOG Z011 . In addition, 25% of all first distant recurrences and 50% of all contralateral breast cancers occurred after 5 years, highlighting the need for longer term follow up in future trials.

Design

• Multicenter, randomized, controlled trial
• N = 1665
• Setting: 34 centers across the United States
• Enrollment: July 1971 and September 1974
• Mean follow-up: 25 years

Population

Inclusion Criteria

• Women with primarily operable breast cancer

Exclusion Criteria

• Fixation to the chest wall or axilla
• Arm edema
• Pregnant or lactating
• Prior breast cancer treatment
• Concomitant cancer (other than effectively managed basal or squamous cell)
• Inflammatory breast cancer or skin ulceration > 2 cm
• Matted / fixed lymph nodes
• Poor surgical risk

Baseline Characteristics

• None of the women received adjuvant systemic therapy
• 70% of women were 50 or older
• Mean tumor diameter was 3.3 cm +/- 2.0 cm
• 87% follow up or knowledge of prior death at 25 years, well balanced between groups.

Interventions

• 1079 women with clinically negative nodes:
  • Radical mastectomy
  • Total mastectomy without axillary dissection but with adjuvant radiation
  • Total mastectomy with axillary dissection only if their nodes became positive
• 586 women with clinically positive axillary nodes:
  • Radical mastectomy
  • Total mastectomy without axillary dissection but with adjuvant radiation

Outcomes

• Women with negative nodes

Disease-free survival

Radical mastectomy 19% ±2

Total mastectomy and radiation 13% ±2 (HR 1.06; 95% CI, 0.90 to 1.25; P=0.49)

Total mastectomy 19% ± 2 (compared to radical-mastectomy HR 1.07; % CI, 0.91 to 1.27; P=0.39)(compared to mastectomy + RT HR 1.02; 95% CI, 0.87 to 1.21; P=0.78)

Relapse-free survival

Radical mastectomy 53% ±3

Total mastectomy with radiation 52% ±4 (HR 0.96; 95% CI 0.76 to 1.2; P=0.74)

Total mastectomy 50% ±3 (Compared to radical mastectomy HR 1.14; 95% CI 0.91 to 1.42; P=-.27)(Compared to mastectomy + RT HR 1.18; 95% CI 0.94 to 1.48; P=0.15)

Local recurrence

Lowest among women with mastectomy + RT (P=0.002)

Distant recurrence

No difference (P=0.61)

• 68.2% of breast-cancer related events occurred within the first 5 years
• No difference in distant-disease free survival (P=0.63)
• No difference in overall survival (P=0.68)

• Women with positive nodes

Disease-free survival among negative node groups

Radical-mastectomy group 11% ±2 vs 10% ±2 for total mastectomy + radiation therapy (HR 1.12; 95% CI, 0.94 to 1.33; P=0.20)

Relapse-free survival

Radical mastectomy 36% ±3 vs 33% ±3 for total mastectomy + radiation therapy (HR 1.09; 95% CI, 0.89to 1.35; P=0.40)

Locoregional recurrence

No difference in combined locoregional recurrence (P=0.67)

Lower local recurrence in radiation but no difference in regional or distant recurrence.

Distant recurrence

No difference (P=0.61)

Distant disease-free survival

Radical mastectomy 32% ±3 and mastectomy + RT 29% ±3 (HR 1.07; 95% CI 0.87 to 1.32; P=0.51)

Overall survival

Radical mastectomy 14% ±2 and mastectomy + RT14% ±2 (HR 1.06; 95% CI 0.89 to 1.27; P=0.49)

• 81.7% of breast-cancer related events occurred within the first 5 years.

Criticisms

• At present, this study lacks granularity with regard to biomarker status and menopausal status and lacks some degree of relevance due to advances in systemic therapy, particularly endocrine therapy and radiation therapy.