Role of Nodal Irradiation in Breast Cancer Carol Marquez, M.D. Associate Professor, Department of Radiation Medicine OHSU

Goals of discussion Review of randomized literature Present factors associated with axillary node involvement Discuss changing role of radiation in era of sentinel lymph node biopsy (SLNB) Give guidelines for inclusion of nodal fields Explore techniques for treatment

Review of nodal anatomy The primary drainage of the breast is to the axilla, regardless of location of primary tumor. Very few tumors will have primary drainage to internal mammary nodes. For patients with involved axillary nodes, risk of IMN involvement increases, especially with tumor in medial location.

NSABP B-04: Randomized management of the axilla Axilla treated by either surgery, XRT or observation in clinically negative nodes; in clinically positive nodes, treatment either by surgery or XRT. In clinically negative axilla, 40% of patients were found to have nodal involvement while only 18% of the TM patients developed a clinical axillary failure.

NSABP B-04: Results XRT achieved similar local control as surgery in clinically negative axilla while it was inferior to surgery in clinically positive axilla. 35% of the patients randomized to the total mastectomy arm had limited axillary dissection. Patients who had 6 or more nodes removed did not have axillary recurrence. No difference in survival with respect to treatment in either arm.

NSABP B-04: Late effects Those patients treated with radical mastectomy had almost double the risk of lymphedema than those treated with radiation therapy or total mastectomy. Increased risk of secondary lung cancers in patients on this trial compared to those on NSABP B-06 where nodal irradiation was not performed.

Incidence of lung cancer: NSABP B04

Other randomized data: French trial Randomized 658 pts with clinically negative nodes to axillary dissection (AXD) or axillary radiation. Enrollment from 1982-87. Fifteen year followup showed slight increase in axillary recurrence with XRT (3% vs. 1%). No difference in overall survival or disease free survival. JCO 22:97-101, 2004

What has changed since 1987? The use of adjuvant chemotherapy increased so the purpose of axillary dissection shifted from therapeutic to prognostic. Sentinel lymph node biopsy has largely replaced AXD as the method of nodal evaluation.

What factors predict for axillary involvement? Size: Any size tumor can have + nodes. Reports show an 11% risk of + nodes in T1a tumors, rising to 15-20% in T1b. Age: A variety of cutoffs but the younger the patient, the greater the chance of + nodes. LVSI: Risk rises to 50-60% in its presence and decreases to 15-25% without it. Histology: Ductal and lobular appear equal while tubular and medullary appear to have lower risks.

Impact of sentinel lymph node biopsy (SLNB) Evaluation of nodes became “easier”, less morbidity to patients and less extensive surgery. More extensive pathologic evaluation of nodes. Able to get nodal information prior to more extensive breast surgery (as in neoadjuvant setting).

What has SLNB taught us? Data from NSABP B-32 In 61% of patients, the + sentinel node is the only + node; therefore, even without the completion dissection, the procedure is therapeutic in 60% of patients. Risk of + non-sentinel node is increased by size of tumor and presence of LVSI. Risk of + non-sentinel node is decreased by increased number of nodes removed (>4). Morbidity is low and there is a learning curve that each surgeon (institution) needs to go through. Do not yet have results from American College of Surgeons randomized trial of completion AXD to none.

Special type= colloid, medullary or tubular Doctor, What are my chances of having a positive sentinel node? A Validated Nomogram for Risk Estimation. Bevilacqua JLB et al. JCO 25:3670-3679, 2007.

Micromets: What to do? Extensive pathologic evaluation of sentinel node(s) has allowed for new categories of positive nodes. Makes reliance on older data difficult since these categories did not exist.

Nomograms for predicting non-sentinel lymph node involvement Helpful in deciding who needs completion AXD. Rely on information that is only available after final pathology is complete. Memorial-Sloan Kettering: http://www.mskcc.org/mskcc/html/15938.cfm Stanford: http://www-stat.stanford.edu/~olshen/NSLNcalculator

Where does all this information leave us? In the era of SLNB, most patients should have nodes evaluated. Purpose of nodal evaluation and removal is still both prognostic and therapeutic. If the patient cannot have AXD or SLNB, XRT will provide adequate local control in the clinically negative axilla. The hard question: Who needs the supraclavicular nodes radiated when the completion AXD is not done?

Who needs the supraclavicular fossa treated if the completion AXD is not performed? Two retrospective reviews looking for factors predicting 4 or more nodes involved at completion dissection. MDACC found that any patient with only 1 positive node and no LVSI should be treated to the axilla only via modified tangents. (IJROBP 59:1074-79, 2004) MGH found that any patient with a micromet (<2 mm), 1 positive node, and no LVSI did not require treatment to the supraclavicular fossa. (IJROBP 65:40-44, 2006)

Who needs the supraclavicular fossa treated when the AXD is performed? Any patient with 4 or more positive nodes. The controversial group (again) is 1-3 positive nodes in either the post mastectomy or post lumpectomy setting. NCIC MA20, a trial randomizing pts with 1-3 positive nodes to breast or breast + regional radiation, has closed to accrual so results will not be available for years.

Nodal ratios: Prognostic value for local recurrence and survival Nodal ratio (NR)= # of positive nodes/ # of removed nodes. Allows for comparison of data across institutions/groups where extent of surgical dissection and pathologic evaluation of axilla may vary. Generally accepted cutoff of <25%, 25-<75%, >75%.

Canadian review of nodal ratios in T1-2 tumors with 1-3 + nodes Cancer 103:2006-14, 2005

Use of NR to determine who will benefit from regional XRT Retrospective review of 1255 node + pts with a median of 14 nodes removed after either lumpectomy or mastectomy. Since retrospective, fields of XRT varied based on discretion of physician. Chemotherapy only used in 37%. Found that regional XRT provided improvement in overall and cause specific survival in pts with medium and high nodal ratios, not for the low nodal ratio group. (IJROBP 68:662-666, 2007)

Techniques for nodal irradiation “Modified” tangents to include axilla: requires both a raising of superior border and expanding posterior border. Supraclavicular fossa: important to do CT planning to choose appropriate depth for coverage of nodes.

What do I do? No axillary surgery If no axillary surgery, I would include axilla in tangents if probability of nodal involvement is above 10%. I would include supraclavicular fossa if patient’s condition could tolerate fibrosis of lung in that field.

What do I do? SLNB but no AXD If only 1 + node and no LVSI (especially if >4 nodes removed in SLNB), I include the axilla in the tangents. If more than 1 node and/ or LVSI, I would include suprclavicular fossa.

What do I do? SLNB + AXD If 1 + node, no regional XRT. If >4 + nodes, XRT to axilla and supraclav. If >4+ nodes and upper inner quadrant, XRT to axilla, supraclav and IMN. If 2-3 nodes positive and NR>25%, XRT to axilla and supraclav. Multiple nodes with micromets seems like real cancer to me.