NSABP B-06

In Review

Fisher B, et al. "Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer.". The New England Journal of Medicine. 2002. 347(16):1233-1241.
PubMed • Full text • PDF

Clinical Question

In women with stage 1 or 2 invasive breast cancer is there a survival difference in women who underwent lumpectomy, lumpectomy and radiation, or total mastectomy?

Bottom Line

There is no difference in survival between women who underwent lumpectomy followed by radiation compared to total mastectomy. Furthermore, treatment lumpectomy and radiation reduces the recurrence of breast cancer compared to lumpectomy alone or total mastectomy.

Major Points

Breast cancer is the most common cancer affecting women, it is also the leading cause of cancer related death in women worldwide . Since the 1980's the incidences of breast cancer have continued to increase, however, mortality rates have declined. These changes are likely secondary to improving sensitivity and sensitivity in screening tests, and refinement of treatment modalities . Currently, the main categories of treatment of breast cancer are surgical, radiation, chemotherapeutic, hormonal, or targeted therapy .

Prior to this RCT, total mastectomies were the favoured surgical approach for breast cancers. Total mastectomies in comparison to lumpectomies are more extensive procedures, associated with increased morbidity, hospital stay, re-operation, and less favourable cosmetic results . In this RCT 2163 women with stage 1 or 2 invasive breast cancer were followed for 20 years after receiving either lumpectomy, lumpectomy and radiation, or total mastectomy. Kaplain-Meier and cumulative incidences were used to analyze disease free survival, recurrence free survival, and overall survival.

Design

• Prospective, multi-centre, randomized clinical trial
• N=2163
  • Total mastectomy (n=713)
  • Lumpectomy alone (n=719)
  • Lumpectomy and radiation (731)
• Setting: 34 NSABP member sites in United States and Canada
• Enrollment: July 22 1971 to September 6 1974
• Mean follow-up: 20 years
• Analysis: Intention-to-treat
• Primary outcome: Survival

Population

Inclusion Criteria

• Stage 1 or 2 invasive breast cancer
• Tumor ≤ 4 cm in the largest diameter

Exclusion Criteria

• Stage 3 or 4 disease
• Inflammatory breast cancer
• Non carcinoma cancers
• Skin ulceration > 2 cm
• P'eau d'orange involving more than 1/3 of the skin of the breast
• Satellite or parasternal nodes
• Lymph nodes elsewhere suspected to contain malignancy, but not proven by biopsy
• Bilateral malignancy
• Fixation of axillary nodes (over 2 cm)
• Biopsy ≤ 2 weeks prior to study registration
• Life limiting comorbidities
• Pregnant
• Breastfeeding
• Previous treatment for breast cancer
• Previous treatment for any other cancer (excluding BCC or SCC)
• High risk surgical canidates
• Systemic disease which would make long term follow up unlikely

Baseline Characteristics

Clinically Negative Nodes, Total Mastectomy

• Average age: 56.4
• Menopausal status:
  • Pre- and intra: 30.1%
  • Post: 69.9%
• Race:
  • White: 61.3%
  • Black: 34.6%
  • Other: 4.1%
• Average weight: 67.6 kg
• Breast involved:
  • Left: 51.7%
  • Right: 48.3%
• Location of breast tumour:
  • Outer half: 67.8%
  • Inner half: 22.1%
  • Subareolar: 6.2%
  • Between upper inner and outer: 1.4%
  • Between lower inner and outer: 0.3%
  • Diffuse: 0.0%
  • No mass: 0.3%
  • Unknown: 0.7%
• History of oral contraceptives: 9.6%
• Pregnancies:
  • None: 14.5%
  • ≥ 3: 48.6%
• Duration of symptoms:
  • 1 month: 13.9%
  • 1-3 months: 38.0%
  • 3 months: 47.0%
  • No symptoms: 1.0%
• Positive family history: 14.2%
  • In mothers and grandmothers: 6.5%
• History of benign breast disease: 19.9%

Interventions

• Patients were initially evaluated to determine if they had clinically negative or clinically positive nodes
  • Nodes were categorized as non palpable, palpable but insignificant, or clinically significant
• Following this categorization patients were randomized in their nodal status group
  • Clinically negative nodes
    • 33% treated by total mastectomy
    • 33% lumpectomy and regional radiation
    • 33% lumpectomy alone
  • Clinically positive nodes:
    • 50% lumpectomy and regional radiation
    • 50% total mastectomy alone
• Axillary lymph nodes were removed regardless of treatment arm
• Patients treated with lumpectomy had their tumour resected ensuring negative margins and the lower two levels of axillary nodes removes
  • If on histological exam the specimen was found to have positive margins the patient then underwent total mastectomy and continued in the study
• Patients treated with total mastectomy had the axillary nodes removed en bloc with the tumour
• 50 Gy of radiation was used, and only administered to the breast (no axillary radiation)
• Any patients with positive axillary lymph nodes also received adjuvant systemic therapy (melphalan and fluoruracil)

Outcomes

Primary Outcomes

Overall survival, lumpectomy alone vs. total mastectomy

HR 1.05; 95% CI 0.90-1.23; P=0.51

Overall survival, lumpectomy and radiation vs. total mastectomy

HR 0.97; 95% CI 0.83-1.14; P=0.74

Overall survival rate at 20 years, total mastectomy vs. lumpectomy alone vs. lumpectomy and radiation

47±2% vs. 46±2 vs. 46±2; P=0.57

Overall survival, lumpectomy with positive margins vs. lumpectomy with negative margins

HR 0.91; 95% CI, 0.77-1.06; P=0.23

Secondary Outcomes

Deaths due to breast cancer, lumpectomy and radiation vs. lumpectomy alone

HR 0.82; 95% CI, 0.68-0.99; P=0.04

Cumulative incidence of a recurrence in the ipsilateral breast in women who underwent irradiation after lumpectomy vs. lumpectomy alone at 20 years

14.3% vs. 39.2% (P<0.001)

Cumulative incidence of death from any cause at 20 years

53.5%

Cumulative incidence of death from recurrence of cancer in the contralateral breast at 20 years

40.4%

Cumulative incidence of death with no evidence of cancer 20 years

13.2%

Recurrence in the ipsilateral breast in node negative women at 20 years in those who did not receive radiation therapy vs. those who did

36.2% vs. 8.8% (P<0.001)

Recurrence in the ipsilateral breast in node positive women at 20 years in those who did not receive radiation therapy vs. those who did

44.2% vs. 17.0% (P<0.001)

Diagnosis of recurrent disease or second cancer or death without evidence of cancer in women treated with lumpectomy alone vs. total mastectomy

HR 1.05, 95% Cl, 0.92-1.21; P=0.47

Diagnosis of recurrent disease or second cancer or death without evidence of cancer in women treated with lumpectomy and irradiation vs. total mastectomy

HR 0.94, 95% Cl, 0.83-1.09; P=0.41

Disease free survival for women who underwent lumpectomy and irradiation vs. lumpectomy alone

HR 0.87, 95% CI 0.75-1.01; P=0.07)

Diagnosis of distant disease or a second cancer in women in the lumpectomy alone vs. total mastectomy

HR 1.11, 95% CI, 0.94-1.30; P=0.21

Diagnosis of distant disease or a second cancer in women in the lumpectomy and radiation vs. total mastectomy

HR, 1.01 95% CI, 0.86-1.18; P=0.95

Distant disease free survival in women treated with lumpectomy alone vs. lumpectomy and radiation with specimens with tumor-free margins

HR, 0.89; 95% CI, 0.75-1.04; P=0.15

Criticisms

In May 1994 the NSABP team published a letter to the editor in the New England Journal of Medicine , reporting misconduct of one of the investigators at St. Luc Hospital in Montréal. They reported falsification and fabrication of data affect protocols. An audit was done, 6 charts in the NSABP-06 study were found to have falsified surgery and biopsy dates in order to be included in the trial. Reanalysis was done, yielding almost identical results to the original study.

Funding

None declared