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Old 07-07-2010, 09:37 AM   #1
Hopeful
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Join Date: Aug 2006
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'Less Is More' in Local Therapy for Early-Stage Breast Cancer

2010 Jul 7, Lee Schwartzberg, MD, Editor-in-Chief

This year's ASCO meeting had expectations running high that new standards of care for breast cancer would be established. Interestingly, the changes coming out of the major presentations related more to surgical and radiation oncologic approaches than to medical oncology interventions. Indeed, some of our longest-held assumptions about local-regional therapy of early-stage breast cancer were challenged by the provocative data presented.

Local therapy for early-stage breast cancer: Less is more?

Sentinel lymph node biopsy (SLNB) rapidly became the standard of care in the late 1990s, sparing women with negative nodes the morbidity of axillary dissection and offering the possibility of less lymphedema and preserved arm motion in the long term. Still, there were many questions remaining once the technical challenge of training surgeons to do the technique properly was completed: What happens to patients who have SLNs that are negative and who do not undergo axillary dissection? If the SLN is positive by immunohistochemistry (IHC) after the fact, should a second surgical procedure for axillary dissection be performed? How often are additional axillary lymph nodes positive if SLNs are positive? Does prevention of local-regional relapse depend on removing all nodes? Does bone marrow sampling improve prognostic information when coupled with SLNB?

Thankfully, a number of trials launched a decade ago to answer these questions have now been completed, and many were presented at ASCO 2010, giving us a much clearer picture of appropriate local-regional care.

SLNB

ACOSOG Z0010. The ACOSOG Z0010 trial addressed the clinical significance of occult metastases identified by IHC in both lymph nodes and in bone marrow. Previous studies had suggested that a small number of tumor cells detected in either of these sites could negatively influence prognosis. The patient population included women with clinical T1-2 and N0 disease who were scheduled for lumpectomy and radiation. The majority received adjuvant systemic therapy. Women with lymph nodes that were positive by IHC evaluation after surgery did not undergo axillary dissection.

By IHC techniques, 10% of patients had IHC-positive SLNs, and only 3% of bone marrow samples were positive. No difference in disease-free survival (DFS) was seen between patients with IHC-negative SLNs and those with IHC-positive SLNs, but H&E-positive SLNs were associated with a reduced 5-year DFS. IHC-positive bone marrow, although rare, was also associated with reduced DFS, suggesting that these cells contribute to metastases. In multivariate analyses, IHC-positive SLN status did not affect DFS or overall survival (OS), but IHC-positive bone marrow was associated with reduced OS. Increasing tumor size correlated with increased risk of having either H&E-positive or IHC-positive SLNs, but it did not correlate with the risk for bone marrow IHC positivity. OS rates for all groups were excellent at 5 years, at 93% for women with H&E-negative SLNs and 96% for those with SLNs that were H&E negative, IHC positive, or IHC negative. The authors suggested that routine IHC analysis of SLNs need not be performed, since axillary lymph node dissection (ALND) was not done and IHC positivity did not alter prognosis.

NSABP B-32. The phase III NSABP B-32 trial examined the therapeutic effect of removing axillary lymph nodes.2 By way of background, removal of axillary lymph nodes seemed in the past to confer a small degree of improved survival, suggesting a therapeutic benefit. Since a negative SLNB result assumes a false-negative result in some patients, the question arose as to whether SLNB without ALND impairs DFS or OS. Although stopping the work-up after a negative SLNB result has become the standard of care, the evidence supporting this approach has been scant and intuitive. The NSABP B-32 trial demonstrated no significant difference, in terms of both DFS and OS, between patients who underwent SLNB alone and those who were randomized to SLNB plus ALND. The incidence of axillary recurrence was remarkably low in both groups. However, morbidity was reduced in the SLNB-alone group across all determinations, including arm volume, degree of shoulder abduction, arm numbness, and arm tingling, making SLNB alone the definitive procedure of choice.

ACOSOG Z0011. The ACOSOG Z0011 trial was the most provocative study presented in the early-stage breast cancer oral session. The hypothesis for this trial was that SLNB alone would provide similar local-regional control and survival as ALND for women with an SLN that was H&E positive. The hypothesis was tested in women with clinical T1-2, N0 breast cancer who were scheduled for lumpectomy and whole-breast radiation therapy and who had up to two positive SLNs by H&E.

The study did not meet its projected accrual goals and closed early. Overall, 891 women were randomized, and nearly all patients received adjuvant systemic therapy. The median number of lymph nodes removed for the ALND group was 10, compared with 2 lymph nodes for the SLNB group. Among the women treated with ALND, 27% had additional positive lymph nodes removed after SLNB. Axillary recurrence was observed in less than 1% of patients in either group, and there was no significant difference in the rate of local-regional recurrence between the two groups: the rate was 2.8% in the SLNB-alone group and 4.1% in the ALND group. There was no significant difference in DFS or OS based on the type of operation received. Older age, negative estrogen-receptor status, and no use of adjuvant therapy had a negative impact on OS in multivariate analysis. The authors concluded that the ACOSOG Z0011 study did not support the use of routine ALND in early, nodal-metastatic breast cancer detected by SLNB.

What are the take-home messages from these trials? It seems clear that in the modern era of early-stage breast cancer, defined as clinically smaller tumors with fewer positive nodes, the use of lumpectomy plus radiation therapy and the nearly universal administration of adjuvant systemic therapy render axillary dissection less and less important. This appears to be true whether axillary clearance is seen as a therapeutic maneuver or as a prognostic indicator. These three studies identify stepwise situations where ALND is not needed: in the IHC-positive or -negative situation, as seen in Z0010; in the H&E-negative situation, as seen in NSABP B32; and even in the circumstance of H&E-positive lymph nodes, as seen in ACOSOG Z0011, assuming only one or two SLNs are positive.

The implications are significant. Whereas only 15 years ago, all women with breast cancer underwent a full ALND, and now only those with positive SLNs undergo this procedure, it appears likely that this operation will become a rarity. In my own practice, I will immediately advocate against completion ALND in patients found to have IHC-positive SLNs or micrometastases in final histologic sections. Selected women with H&E-positive SLNs may also be spared a full operation.

Radiation Therapy in Early-Stage Breast Cancer

Another critical question revolves around the benefit of radiation therapy for older women undergoing lumpectomy. This is a large group of patients who often receive combined-modality therapy without a lot of evidence supporting the practice. The CALGB trial 9343 attempted to answer the question of the benefit of radiation therapy in women who were >70 years of age and had T1, N0 breast cancer, were estrogen-receptor positive, and were receiving tamoxifen. Women were randomized to receive either tamoxifen alone after lumpectomy or tamoxifen plus radiation therapy. Interestingly, two-thirds of the women in this trial had no axillary dissection. Results were reported after 12 years of follow-up.

As expected, the incidence of ipsilateral breast tumor recurrence was reduced with radiation, from 9% to 2%. However, there were no other benefits to radiation. This included no difference in ultimate mastectomy rates between the groups. Only 3% of patients had axillary recurrence. The incidence of second primary breast cancers was the same in both groups. There was no difference in OS, in the rate of distant recurrence, or in the rate of breast-cancer−specific survival. The authors concluded that there was no reason to recommend radiation therapy to the whole breast after lumpectomy in women over the age of 70 whose tumors were estrogen-receptor positive and who were receiving tamoxifen. This makes intuitive sense, since these good-prognosis patients are much more likely than younger women to experience morbidity from the radiation therapy.

In summary, ASCO 2010 was indeed practice changing for the approach to early-stage breast cancer. The trend toward doing less to accomplish the same excellent outcome, begun with the era of lumpectomy 30 years ago, continues forward. Our conventional beliefs regarding the removal of axillary lymph nodes and the use of radiation therapy have undergone marked reevaluation as a result of these landmark trials.

References

1. Cote R, Guliano AE, Hawes KV, et Al. ACOSOG Z0010: a multicenter prognostic study of sentinel node (SN) and bone marrow (BM) micrometastases in women with clinical T1/T2 N0 M0 breast cancer. J Clin Oncol. 2010;28(18 suppl):abstract CRA504.

2. Krag DN, Anderson SJ, Julian TB, et al. Primary outcome results of NSABP B-32, a randomized phase III clinical trial to compare sentinel node resection (SNR) to conventional axillary dissection (AD) in clinically node-negative breast cancer patients. J Clin Oncol. 2010;28(18 suppl):abstract LBA505.

3. Guliano AE, McCall LM, Beitsch D, et al. ACOSOG Z0011: a randomized trial of axillary node dissection in women with clinical T1-2 N0 M0 breast cancer who have a positive sentinel node. J Clin Oncol. 2010;28(18 suppl):abstract CRA506.

4. Hughes KS, Schnaper LA, Cirrincione C, etal. Comparison of lumpectomy plus tamoxifen with or without irradiation in women 70 or older with clinical stage I, ER+ breast carcinoma. J Clin Oncol. 2010;28(15 suppl):abstract 507.

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