Level Ia evidence: prospective randomized surgical trials in breast cancer

1. Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. Fisher B, Jeong JH, Anderson S, et al. N Engl J Med 2002;347:567–75.

Hypothesis : Less radical surgery with or without RT is as effective as the Halstead radical mastectomy (RM) in primary operable breast cancer.

Published abstract : BACKGROUND: In women with breast cancer, the role of radical mastectomy, as compared with less extensive surgery, has been a matter of debate. We report 25-year findings of a randomized trial initiated in 1971 to determine whether less extensive surgery with or without radiation therapy was as effective as the Halsted radical mastectomy. METHODS: A total of 1079 women with clinically negative axillary nodes underwent radical mastectomy, total mastectomy without axillary dissection but with postoperative irradiation, or total mastectomy plus axillary dissection only if their nodes became positive. A total of 586 women with clinically positive axillary nodes either underwent radical mastectomy or underwent total mastectomy without axillary dissection but with postoperative irradiation. Kaplan-Meier and cumulative-incidence estimates of outcome were obtained. RESULTS: No significant differences were observed among the 3 groups of women with negative nodes or between the 2 groups of women with positive nodes with respect to disease-free survival, relapse-free survival, distant disease-free survival, or overall survival. Among women with negative nodes, the hazard ratio for death among those who were treated with total mastectomy and radiation as compared with those who underwent radical mastectomy was 1.08 (95% confidence interval, 0.91 to 1.28; P = .38), and the hazard ratio for death among those who had total mastectomy without radiation as compared with those who underwent radical mastectomy was 1.03 (95% confidence interval, 0.87 to 1.23; P = .72). Among women with positive nodes, the hazard ratio for death among those who underwent total mastectomy and radiation as compared with those who underwent radical mastectomy was 1.06 (95% confidence interval, 0.89 to 1.27; P = .49). CONCLUSIONS: The findings validate earlier results showing no advantage from radical mastectomy. Although differences of a few percentage points cannot be excluded, the findings fail to show a significant survival advantage from removing occult positive nodes at the time of initial surgery or from radiation therapy. (Copyright 2002, Massachusetts Medical Society. All rights reserved. Reprinted with permission.)

Editor’s summary and comments : The NSABP B-04 trial compared less extensive operations (TM) with or without RT to traditional RM in women with primary operable breast cancer, and with long-term follow-up, no differences in any survival outcomes were observed. NSABP B-04 has been fundamental in shaping the approach to breast cancer treatment for the last 35 years as its findings supported the “systemic” disease hypothesis, which proposed that alterations in local therapy were unlikely to impact survival. The proof of principle that more radical treatment did not increase cure rate opened the door for subsequent trials of BCT.

Of note, 40% of the clinically node-negative patients in the RM arm of NSABP B-04 had nodal involvement on final pathology, but only 18% of those in the no axillary lymph node dissection (ALND) arm developed clinical axillary recurrence requiring delayed ALND. This result, coupled with the lack of survival differences observed between arms, led to ALND being regarded as a staging rather than a therapeutic procedure. For this reason, the role of completion dissection after a positive sentinel node biopsy (SLNB) is a source of debate, but when considering the role of B04 in defining appropriate treatment of the axilla, it is important to recall that no systemic therapy was used in the trial, and by modern standards B04 was underpowered to detect a small (less than 10%) benefit in survival related to ALND.

2. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. Fisher B, Anderson S, Bryant J, et al. N Engl J Med 2002;347:1233–41.

Hypothesis : BCT with RT is equivalent to TM.

Published abstract : BACKGROUND: In 1976, we initiated a randomized trial to determine whether lumpectomy with or without radiation therapy was as effective as total mastectomy for the treatment of invasive breast cancer. METHODS: A total of 1851 women for whom follow-up data were available and nodal status was known underwent randomly assigned treatment consisting of total mastectomy, lumpectomy alone, or lumpectomy and breast irradiation. Kaplan-Meier and cumulative-incidence estimates of the outcome were obtained. RESULTS: The cumulative incidence of recurrent tumor in the ipsilateral breast was 14.3% in the women who underwent lumpectomy and breast irradiation, as compared with 39.2% in the women who underwent lumpectomy without irradiation ( P <.001). No significant differences were observed among the 3 groups of women with respect to disease-free survival, distant disease-free survival, or overall survival. The hazard ratio for death among the women who underwent lumpectomy alone, as compared with those who underwent total mastectomy, was 1.05 (95% confidence interval, 0.90 to 1.23; P = .51). The hazard ratio for death among the women who underwent lumpectomy followed by breast irradiation, as compared with those who underwent total mastectomy, was 0.97 (95% confidence interval, 0.83 to 1.14; P = .74). Among the lumpectomy-treated women whose surgical specimens had tumor-free margins, the hazard ratio for death among the women who underwent postoperative breast irradiation, as compared with those who did not, was 0.91 (95% confidence interval, 0.77 to 1.06; P = .23). Radiation therapy was associated with a marginally significant decrease in deaths due to breast cancer. This decrease was partially offset by an increase in deaths from other causes. CONCLUSIONS: Lumpectomy followed by breast irradiation continues to be appropriate therapy for women with breast cancer, provided that the margins of resected specimens are free of tumor and an acceptable cosmetic result can be obtained. (Copyright 2002, Massachusetts Medical Society. All rights reserved. Reprinted with permission.)

Editor’s summary and comments : NSABP-06 was designed to evaluate the efficacy of BCT with and without RT in women with tumors smaller than 4 cm in diameter. The trial is one of several large studies evaluating the role of BCT and now reporting follow-up at 13 to 20 years after randomization. The findings reported here are similar to those previously published; no differences in survival exist between the treatment groups. The use of adjuvant RT did significantly reduce IBTR in both node-positive and node-negative patients undergoing lumpectomy, and recurrence in patients treated without RT occurred earlier (73% within 5 years of surgery) than in those treated with RT (40% within 5 years of surgery). In comparing NSABP B-06 to the Milan, EORTC 10801, and National Cancer Institute (NCI) trials ( Table 1 ), it is important to realize that excision to negative margins was not required for the NCI and EORTC 10801 studies, resulting in higher rates of IBTR, and confirming that complete surgical resection with negative (no tumor on ink) margins is an essential component of BCT.

In NSABP B-06, only patients with positive axillary nodes received adjuvant chemotherapy. This treatment combined with RT resulted in 50% fewer IBTRs (8.8%) than seen with RT alone in the lower risk node-negative patients (17%), indicating that chemotherapy can act synergistically with RT to prevent a subset of local recurrences.

3. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival : an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group (EBCTG). Lancet 2006;366 : 2087–106.

Hypothesis : Differences in local regional recurrence (LRR) resulting from more versus less local therapy result in long-term survival differences.

Published abstract : BACKGROUND: In early breast cancer, variations in local treatment that substantially affect the risk of locoregional recurrence could also affect long-term breast cancer mortality. To examine this relationship, collaborative meta-analyses were undertaken, based on individual patient data, of the relevant randomized trials that began by 1995. METHODS: Information was available on 42,000 women in 78 randomized treatment comparisons (radiotherapy vs no radiotherapy, 23,500; more vs less surgery, 9300; more surgery vs radiotherapy, 9300). Twenty-four types of local treatment comparison were identified. To help relate the effect on local (ie, locoregional) recurrence to that on breast cancer mortality, these were grouped according to whether or not the 5-year local recurrence risk exceeded 10% (<10%, 17,000 women; >10%, 25,000 women). FINDINGS: About three-quarters of the eventual local recurrence risk occurred during the first 5 years. In the comparisons that involved little (<10%) difference in 5-year local recurrence risk there was little difference in 15-year breast cancer mortality. Among the 25,000 women in the comparisons that involved substantial (>10%) differences, however, 5-year local recurrence risks were 7% active versus 26% control (absolute reduction 19%), and 15-year breast cancer mortality risks were 44·6% versus 49·5% (absolute reduction 5·0%, SE 0·8, 2 p <.001). These 25,000 women included 7300 with breast-conserving surgery (BCS) in trials of radiotherapy (generally just to the conserved breast), with 5-year local recurrence risks (mainly in the conserved breast, as most had axillary clearance and node-negative disease) 7% versus 26% (reduction 19%), and 15-year breast cancer mortality risks 30.5% versus 35.9% (reduction 5.4%, SE 1.7, 2 p = .0002; overall mortality reduction 5.3%, SE 1.8, 2 p = .005). They also included 8500 with mastectomy, axillary clearance, and node-positive disease in trials of radiotherapy (generally to the chest wall and regional lymph nodes), with similar absolute gains from radiotherapy; 5-year local recurrence risks (mainly at these sites) 6% versus 23% (reduction 17%), and 15-year breast cancer mortality risks 54.7% versus 60.1% (reduction 5.4%, SE 1.3, 2 p = .0002; overall mortality reduction 4.4%, SE 1.2, 2 p = .0009). Radiotherapy produced similar proportional reductions in local recurrence in all women (irrespective of age or tumor characteristics) and in all major trials of radiotherapy versus not (recent or older; with or without systemic therapy), so large absolute reductions in local recurrence were seen only if the control risk was large. To help assess the life-threatening side effects of radiotherapy, the trials of radiotherapy versus not were combined with those of radiotherapy versus more surgery. There was, at least with some of the older radiotherapy regimens, a significant excess incidence of contralateral breast cancer (rate ratio 1.18, SE 0.06, 2 p = .002) and a significant excess of non-breast cancer mortality in irradiated women (rate ratio 1.12, SE 0.04, 2 p = .001). Both were slight during the first 5 years, but continued after year 15. The excess mortality was mainly from heart disease (rate ratio 1.27, SE 0.07, 2 p = .0001) and lung cancer (rate ratio 1.78, SE 0.22, 2 p = .0004). INTERPRETATION: In these trials, avoidance of a local recurrence in the conserved breast after BCS and avoidance of a local recurrence elsewhere (eg, the chest wall or regional nodes) after mastectomy were of comparable relevance to 15-year breast cancer mortality. Differences in local treatment that substantially affect local recurrence rates would, in the hypothetical absence of any other causes of death, avoid about one breast cancer death over the next 15 years for every 4 local recurrences avoided, and should reduce 15-year overall mortality. (Copyright 2006, Elsevier. Reprinted with permission.)

Editor’s summary and comments : The Early Breast Cancer Trialists’ Collaborative Group (EBCTG) has centrally reviewed individual patient data every 5 years since 1985 to study the effects of RT and the extent of surgery on local control and cause-specific mortality in early breast cancer. An important new finding in the 15-year review is that differences in local recurrence of greater than 10% at 5 years result in statistically significant differences in OS at 15 years. The ratio of absolute effect is 4 to 1 (ie, for every 4 local recurrences prevented, 1 life is saved).

This principle is reflected in analyses addressing lumpectomy with or without RT, an adjuvant therapy resulting in an absolute risk reduction (ARR) of 19% in IBTR and 5.4% in breast cancer–specific mortality in this meta-analysis. Node-positive mastectomy patients similarly experienced large risk reductions in 5-year local recurrence with adjuvant RT (23% vs 6%), translating into a 15-year ARR in breast cancer–specific mortality of 5.4%. Survival outcomes in node-negative patients treated with modified radical mastectomy (MRM) were not improved with RT, a reflection of the small difference in local control between groups (ARR 4%). Subgroup analyses did not identify BCT patients who failed to benefit from adjuvant RT.

Another finding of the meta-analysis was that adjuvant RT results in a small increase in long-term mortality related to contralateral breast cancer, heart disease, and lung cancer. The increase in these events was 1.3% at 15 years and did not exceed the benefit of RT on breast cancer-specific survival. The impact of modern chemotherapy and RT regimens on these outcomes requires further study.

Level Ia evidence: prospective randomized trials in evaluation and management of the axilla

4. Sentinel-lymph node biopsy as a staging procedure in breast cancer: update of a randomized controlled trial. Veronesi U, Paganelli G, Viale G, et al. Lancet Oncol 2006;6:983–90.

Hypothesis : SLNB is equivalent to ALND in node-negative patients.

Published abstract : BACKGROUND: In women with breast cancer, sentinel-lymph-node biopsy (SLNB) provides information that allows surgeons to avoid axillary-lymph-node dissection (ALND) if the SLN does not have metastasis, and has a favorable effect on quality of life. Results of our previous trial showed that SLNB accurately screens the ALN for metastasis in breast cancers of diameter 2 mm or less. We aimed to update this trial with results from longer follow-up. METHODS: Women with breast tumors of diameter 2 cm or less were randomly assigned after breast-conserving surgery either to SLNB and total ALND (ALND group), or to SLNB followed by ALND only if the SLN was involved (SLN group). Analysis was restricted to patients whose tumor characteristics met eligibility criteria after treatment. The major end points were the number of axillary metastases in women in the SLN group with negative SLNs, staging power of SLNB, and disease-free and overall survival. FINDINGS: Of the 257 patients in the ALND group, 83 (32%) had a positive SLN and 174 (68%) had a negative SLN; 8 of those with negative SLNs were found to have false-negative SLNs. Of the 259 patients in the SLN group, 92 (36%) had a positive SLN and 167 (65%) had a negative SLN. One case of overt clinical axillary metastasis was seen in the follow-up of the 167 women in the SLN group who did not receive ALND (ie, one false-negative). After a median follow-up of 79 months (range 15–97), 34 events associated with breast cancer occurred: 18 in the ALND group, and 16 in the SLN group (log-rank p = .6). The overall 5-year survival of all patients was 96.4% (95% CI 94.1–98.7) in the ALND group and 98.4% (96.9–100) in the SLN group (log-rank p = .1). INTERPRETATIONS: SLNB can allow total ALND to be avoided in patients with negative SLNs, while reducing postoperative morbidity and the costs of hospital stay. The findings that only one overt axillary metastasis occurred during follow-up of patients who did not receive ALND (whereas 8 cases were expected) could be explained by various hypotheses, including those from cancer-stem-cell research. (Copyright 2006, Elsevier. Reprinted with permission.)

Editor’s summary and comments : SLN mapping in breast cancer was described by Giuliano and colleagues in 1994, and subsequently shown to predict axillary nodal status in 95.6% of patients. In the NSABP B-32 trial of 5611 patients, more than 97% of patients had an SLN detected and removed using lymphoscintigraphy, blue dye, and palpation; accuracy was 97.1%, confirming feasibility of the technique. In the ACOSOG Z10 trial involving a similar number of patients, no difference in SLN detection rate was observed when tracing was performed with blue dye alone, isotope alone, or the combination of blue dye and isotope.

The Milan trial randomized 516 patients with T1 tumors undergoing quadrantectomy with planned adjuvant RT to either SLNB followed by ALND or to SLNB followed by completion ALND (cALND) only if the SLN contained metastases. Concordant with earlier reports, the accuracy of SLN in patients undergoing ALND was 96.9%; in addition, patients in the SLNB group had a decrease in both short- and long-term morbidity. Quality of life benefits have been confirmed in subsequent trials designed to specifically address this question.

To date, oncologic outcomes appear identical in the 2 arms of the Milan Institute trial, although the relatively small size of the patient cohort limits its power to show small differences in survival. Results of NSABP B-32, which enrolled a significantly larger number of patients than the Milan Institute or the underpowered Sentinella/GIVOM study, should, when mature, provide additional data regarding associated disease-free survival (DFS) and OS outcomes.

After a median follow-up of 79 months, only one case of overt clinical axillary metastasis was observed in the SLNB arm of the Italian study, although 8 false negatives would be expected based on technical outcomes. This result demonstrated, as in NSABP-B04, that not all nodal metastases become clinically evident. In addition, a subset analysis of the 60 patients with isolated micrometastatic disease in the SLN showed that only 17% of these patients had other axillary nodal metastases, providing additional evidence that cALND may not be warranted in all such cases. Retrospective studies have been performed to stratify the risk of additional positive lymph nodes in this subgroup of patients, with the goal of identifying a population for whom observation may be appropriate management.

Level Ia evidence: prospective randomized trials in evaluation and management of the axilla

4. Sentinel-lymph node biopsy as a staging procedure in breast cancer: update of a randomized controlled trial. Veronesi U, Paganelli G, Viale G, et al. Lancet Oncol 2006;6:983–90.

Hypothesis : SLNB is equivalent to ALND in node-negative patients.

Published abstract : BACKGROUND: In women with breast cancer, sentinel-lymph-node biopsy (SLNB) provides information that allows surgeons to avoid axillary-lymph-node dissection (ALND) if the SLN does not have metastasis, and has a favorable effect on quality of life. Results of our previous trial showed that SLNB accurately screens the ALN for metastasis in breast cancers of diameter 2 mm or less. We aimed to update this trial with results from longer follow-up. METHODS: Women with breast tumors of diameter 2 cm or less were randomly assigned after breast-conserving surgery either to SLNB and total ALND (ALND group), or to SLNB followed by ALND only if the SLN was involved (SLN group). Analysis was restricted to patients whose tumor characteristics met eligibility criteria after treatment. The major end points were the number of axillary metastases in women in the SLN group with negative SLNs, staging power of SLNB, and disease-free and overall survival. FINDINGS: Of the 257 patients in the ALND group, 83 (32%) had a positive SLN and 174 (68%) had a negative SLN; 8 of those with negative SLNs were found to have false-negative SLNs. Of the 259 patients in the SLN group, 92 (36%) had a positive SLN and 167 (65%) had a negative SLN. One case of overt clinical axillary metastasis was seen in the follow-up of the 167 women in the SLN group who did not receive ALND (ie, one false-negative). After a median follow-up of 79 months (range 15–97), 34 events associated with breast cancer occurred: 18 in the ALND group, and 16 in the SLN group (log-rank p = .6). The overall 5-year survival of all patients was 96.4% (95% CI 94.1–98.7) in the ALND group and 98.4% (96.9–100) in the SLN group (log-rank p = .1). INTERPRETATIONS: SLNB can allow total ALND to be avoided in patients with negative SLNs, while reducing postoperative morbidity and the costs of hospital stay. The findings that only one overt axillary metastasis occurred during follow-up of patients who did not receive ALND (whereas 8 cases were expected) could be explained by various hypotheses, including those from cancer-stem-cell research. (Copyright 2006, Elsevier. Reprinted with permission.)

Editor’s summary and comments : SLN mapping in breast cancer was described by Giuliano and colleagues in 1994, and subsequently shown to predict axillary nodal status in 95.6% of patients. In the NSABP B-32 trial of 5611 patients, more than 97% of patients had an SLN detected and removed using lymphoscintigraphy, blue dye, and palpation; accuracy was 97.1%, confirming feasibility of the technique. In the ACOSOG Z10 trial involving a similar number of patients, no difference in SLN detection rate was observed when tracing was performed with blue dye alone, isotope alone, or the combination of blue dye and isotope.

The Milan trial randomized 516 patients with T1 tumors undergoing quadrantectomy with planned adjuvant RT to either SLNB followed by ALND or to SLNB followed by completion ALND (cALND) only if the SLN contained metastases. Concordant with earlier reports, the accuracy of SLN in patients undergoing ALND was 96.9%; in addition, patients in the SLNB group had a decrease in both short- and long-term morbidity. Quality of life benefits have been confirmed in subsequent trials designed to specifically address this question.

To date, oncologic outcomes appear identical in the 2 arms of the Milan Institute trial, although the relatively small size of the patient cohort limits its power to show small differences in survival. Results of NSABP B-32, which enrolled a significantly larger number of patients than the Milan Institute or the underpowered Sentinella/GIVOM study, should, when mature, provide additional data regarding associated disease-free survival (DFS) and OS outcomes.

After a median follow-up of 79 months, only one case of overt clinical axillary metastasis was observed in the SLNB arm of the Italian study, although 8 false negatives would be expected based on technical outcomes. This result demonstrated, as in NSABP-B04, that not all nodal metastases become clinically evident. In addition, a subset analysis of the 60 patients with isolated micrometastatic disease in the SLN showed that only 17% of these patients had other axillary nodal metastases, providing additional evidence that cALND may not be warranted in all such cases. Retrospective studies have been performed to stratify the risk of additional positive lymph nodes in this subgroup of patients, with the goal of identifying a population for whom observation may be appropriate management.

Level Ia evidence: prospective randomized trials addressing adjuvant radiation of the breast

5. Prevention of invasive breast cancer in women with ductal carcinoma in situ : an update of the National Surgical Adjuvant Breast and Bowel Project experience. Fisher B, Land S, Mamounas E, et al. Semin Oncol 2001;28:400–18.

Hypothesis : RT after excision of ductal carcinoma in situ (DCIS) reduces IBTR.

Published abstract : The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted 2 sequential randomized clinical trials to aid in resolving uncertainty about the treatment of women with small, localized, mammographically detected ductal carcinoma in situ (DCIS). After removal of the tumor and normal breast tissue so that specimen margins were histologically tumor-free (lumpectomy), 818 patients in the B-17 trial were randomly assigned to receive either radiation therapy to the ipsilateral breast or no radiation therapy. B-24, the second study, which involved 1804 women, tested the hypothesis that, in DCIS patients with or without positive tumor specimen margins, lumpectomy, radiation, and tamoxifen (TAM) would be more effective than lumpectomy, radiation, and placebo in preventing invasive and noninvasive ipsilateral breast tumor recurrences (IBTRs), contralateral breast tumors (CBTs), and tumors at metastatic sites. The findings in this report continue to demonstrate through 12 years of follow-up that radiation after lumpectomy reduces the incidence rate of all IBTRs by 58%. They also demonstrate that the administration of TAM after lumpectomy and radiation therapy results in a significant decrease in the rate of all breast cancer events, particularly in invasive cancer. The findings from the B-17 and B-24 studies are related to those from the NSABP prevention (P-1) trial, which demonstrated a 50% reduction in the risk of invasive cancer in women with a history of atypical ductal hyperplasia (ADH) or lobular carcinoma in situ (LCIS) and a reduction in the incidence of both DCIS and LCIS in women without a history of those tumors. The B-17 findings demonstrated that patients treated with lumpectomy alone were at greater risk for invasive cancer than were women in P-1 who had a history of ADH or LCIS and who received no radiation therapy or TAM. Although women who received radiation benefited from that therapy, they remained at higher risk for invasive cancer than women in P-1 who had a history of LCIS and who received placebo or TAM. Thus, if it is accepted from the P-1 findings that women at increased risk for invasive cancer are candidates for an intervention such as TAM, then it would seem that women with a history of DCIS should also be considered for such therapy in addition to radiation therapy. That statement does not imply that, as a result of the findings presented here, all DCIS patients should receive radiation and TAM. It does suggest, however, that, in the treatment of DCIS, the appropriate use of current and better therapeutic agents that become available could diminish the significance of breast cancer as a public health problem. (Copyright 2001, Elsevier. Reprinted with permission.)

Editor’s summary and comments : NSABP-17 is 1 of 4 major randomized controlled trials that address the role of adjuvant RT in local control of DCIS ( Table 2 ). Outcomes after 12 years demonstrated a 55% relative risk reduction in IBTR following RT. Five years after randomization, the benefit of RT appeared greatest in reducing invasive recurrences, but with longer follow-up there was equal reduction in rates of intraductal and invasive cancers. Radiation had no effect on the secondary survival end points in this study, which is not powered to identify such changes.

Table 2

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