Maximizing Radiation Benefit in Breast Cancer

We read with interest the article and reviews of "Current Status of Radiation in the Treatment of Breast Cancer," which appeared in the April 2001 issue of ONCOLOGY.[1] These papers suggest that one of the most controversial areas in this field is the use of radiation in the management of nodal disease, especially in light of changing surgical approaches. Several recent articles encourage surgeons to undertake routine sentinel lymph node dissection for nonpalpable nodal disease in lieu of routine axillary lymph node dissection.[2,3]

False Node-Negative Rate

Patterns of care should keep up with the science and reduce unnecessary costs and procedures without increasing patient morbidity or reducing cure rates. Surgeons have capably undertaken this task by utilizing needle biopsies prior to surgery. Similarly, sentinel lymph node dissection in lieu of axillary lymph node dissection enables breast conservation surgery to be performed in an ambulatory setting, while decreasing false node-negative rates. False node-negative rates range from 5% to 11% for sentinel lymph node dissection[2,3] and from 30% to 40% for axillary lymph node dissection.[4] In experienced hands, the false node-negative rate in sentinel lymph node dissection depends on the following factors:

• Techniques used to identify the sentinel node-ie, single or dual targeting of nodes.
• Pathologic approaches used to evaluate the sentinel nodes-ie, number and thickness of sections and use of immunohistochemical stains.
• Pathologic approaches used to evaluate the remainder of the nodes on axillary lymph node dissection.

In addition, it should be noted that neither sentinel nor axillary lymph node dissection evaluates all first-echelon nodes.[4]

Today, systemic adjuvant therapy is the standard of care when the breast tumor exceeds 1 cm. Hence, sentinel lymph node dissection is most valuable in T1b, high-grade T1a, and ductal carcinoma in situ (DCIS) tumors, for which being node-positive will make a difference in adjuvant therapy. Most DCIS and T1a tumors do not call for nodal evaluation or nodal irradiation.

Nodal Irradiation vs Dissection

Without factoring in the above-mentioned false node-negative rates, there is a 25% to 40% risk of patients with clinical T1c, N0, M0 tumors being pathologically node-positive.[2,3] Nodal irradiation at the time of breast irradiation may eliminate the need for nodal evaluation in many cases without increasing the cost of radiation therapy. Hence, after local excision, T1c, N0, M0 tumors need optimal adjuvant radiation to the breast and lymph node chain along with systemic therapy, without sentinel or axillary lymph node dissection. Increasing data from several randomized trials and meta-analyses demonstrate that nodal irradiation improves locoregional tumor control as well as disease-free and overall survival, with a reduction in cancer mortality.[5-7]

There is a 52% and 71% risk of being pathologically node-positive in patients with clinical T2, N0, M0 tumors and T3, N0, M0 tumors, respectively.[3] These patients would best be treated with neoadjuvant and/or adjuvant chemotherapy, breast conservation without sentinel or axillary lymph node dissection, and locoregional radiation. Radiation treats the interpectoral (Rotter’s) nodes and the entire chain of axillary (levels I-III), subclavicular, and supraclavicular nodes. When indicated, the internal mammary nodes can also be included in the radiation field.

Axillary lymph node dissection deters radiation therapy to the nodes due to increased risks of breast and arm lymphedema. However, axillary lymph node dissection is indicated and therapeutic for palpable nodal disease. Axillary lymph node dissection after neoadjuvant chemotherapy for nonpalpable nodes is counterproductive unless it is done for the benefit of a scientific trial. Use of neoadjuvant chemotherapy refutes the argument that nodal information is needed to select drug combinations in aggressive breast cancer. In fact, these patients would be better served with therapy to all the draining nodes rather than a diagnostic test on some nodes, which subsequently deters adequate nodal treatment.

With identical axillary control rates,[1] replacing routine axillary lymph node dissection with nodal radiation saves the patient from a surgical procedure, which has significant cost and morbidity. Without axillary lymph node dissection, the breast surgery can be performed without patient admission, significant rehabilitation, and convalescence.

Conclusions

The challenge for the oncology community is to tailor treatment approaches to the individual patient’s cancer, so as to increase the patient’s probability of cure while reducing her physical and psychological morbidity. With many histopathologic tumor markers now available to predict the behavior of the breast cancer, the value of nodal evaluation (with its false node-negative rates) for stratification (in clinical trials), prognosis, and therapy should be questioned. We need to reconsider the policy that all invasive breast cancers require identical locoregional treatment.

References

1. Small W Jr: Current status of radiation in the treatment of breast cancer. Oncology 15:469-488, 2001.

2. Veronesi U, Galimberti V, Zurrida A, et al: Sentinel lymph node biopsy as an indicator for axillary dissection in early breast cancer. Eur J Cancer 37:455-458, 2001.

3. McMasters K, Tuttle, TM, Carison DJ, et al: Sentinel lymph node biopsy for breast cancer: A suitable alternative to routine axillary dissection in multi-institutional practice when optimal technique is used. J Clin Oncol 18:2560-2566, 2000.

4. Lawrence GA: Axillary dissection in invasive breast cancer. Oncology 12:1011, 1998.

5. Whelan TJ, Julian J, Wright J, et al: Does locoregional radiation therapy improves survival in breast cancer? A meta-analysis. J Clin Oncol 18:1220-1229, 2000.

6. Lawrence GA, Castro P, Collins B: Breast cancer: Systemic benefits of locoregional treatment. J Clin Oncol 14:1403-1404, 1996.

7. Cuzick J, Stewart H, Rutqvist L, et al: Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 12:447-453, 1994.

Authors’ Response

Drs. Lawrence and Crawford quote a very high 30% to 40% false node-negative rate in patients who undergo axillary lymph node dissection. We believe that the pathologic false-negative rate for a well-done axillary lymph node dissection should be no worse than with a sentinel lymph node dissection, and the procedure remains an excellent means of staging the axillary lymph node basin. The current recommendation for the extent of axillary dissection is to levels I and II. Multiple studies have shown that the incidence of isolated level III metastasis is less than 5%.[1,2]

Local control is maintained in 97% of patients treated with this approach,[3] strongly suggesting that "understaging" is not occurring in 40% of patients. If the authors are referring to the lack of immunohistochemical information in routine axillary specimens, the prognostic significance of these cells is uncertain enough that it is being addressed prospectively in two national trials (American College of Surgeons Oncology Group [ACOSOG] Z10 and National Surgical Adjuvant Breast and Bowel Project [NSABP] B32).

Axillary Control

The management of the axilla in breast cancer patients can be thought of in two ways: (1) obtaining prognostic information to aid in the selection of therapy, and (2) obtaining axillary control. Axillary control remains a very important goal. In a clinically negative axilla, axillary radiation probably achieves a local control rate similar to that of surgical intervention.[3]

Drs. Lawrence and Crawford suggest that nodal irradiation should be delivered to all patients with T1c, T2, and T3 lesions, without surgical evaluation of the axilla. This would expose a large number of patients without lymph node metastasis to regional nodal irradiation. The addition of a third or fourth radiation field to treat the upper axilla and clavicular area, with or without the internal mammary area, increases the morbidity of radiotherapy.

If you believe that regional nodal irradiation is beneficial to all patients, even those without lymph node metastasis, then this is a reasonable approach. We feel that the available data remain controversial, and that there are minimal data to suggest that patients without axillary lymph node metastasis and who have early disease (T1/2) benefit from regional nodal irradiation. The use of axillary dissection-preferably sentinel lymph node dissection-can provide diagnostic information that would help tailor the use of radiotherapy in this setting.

In summary, we appreciate the thoughtful comments of Drs. Lawrence and Crawford and certainly agree that not all invasive breast cancers should receive identical locoregional treatment.

WILLIAM SMALL, JR., MD
Associate Professor of Clinical Radiology
Division of Radiation Oncology
MONICA M. MORROW, MD
Professor of Surgery and Director
Lynn Sage Comprehensive Breast Cancer
Robert H. Lurie Cancer Center
of Northwestern University
Chicago, Illinois

References

1. Rosen P, Martin M, Kline D: Discontinuous or "skip" metastasis in breast carcinoma: Analysis of 1,228 axillary dissections. Ann Surg 197:276, 1983.

2. Veronesi U, Rilke F, Luini A, et al: Distribution of axillary node metastases by level of invasion. An analysis of 539 cases. Cancer 59:682, 1987.

3. Axelsson C, Mouridsen H, Zedeler K, et al: Axillary dissection of level 1 and 2 lymph nodes is important in breast cancer classification. Eur J Cancer 28A:1415, 1992.