3. Departments of Radiation Oncology, Medical
Oncology, Surgical Oncology, and Pathology
The University of Texas M. D. Anderson Cancer
Center, Houston, TX
Int. J. Radiation Oncology Biol. Phys.
4. REGIONAL NODAL FAILURE PATTERNS IN
BREAST CANCER PATIENTS TREATED WITH
MASTECTOMY WITHOUT RADIOTHERAPY
5. AIM
The purpose of this study was to describe regional
nodal failure patterns in patients who had undergone
mastectomy with axillary dissection to define
subgroups of patients who might benefit from
supplemental regional nodal radiation to the axilla or
supraclavicular fossa/axillary apex.
6. INTRODUCTION
The chest wall is the most common site of locoregional
recurrence and should be treated.
The issue of regional nodal radiation remains
somewhat more controversial.
7. Regional nodal failures can be a source to seed distant
metastasis and generally portend a poor prognosis. On
the other hand, adjuvant treatment to the regional
lymphatics increases the risk of treatment
complications, including lymphedema and
pneumonitis.
Halverson KJ, Taylor ME, Perez CA, et al. Regional nodal management and patterns
of failure following conservative surgery and radiation therapy for stage I and II
breast cancer. Int J Radiat Oncol Biol Phys 1993;26:593–599.
8. The purpose of this study was to determine regional
nodal failure patterns to define subgroups of patients
who might benefit from supplemental regional nodal
irradiation to the mid-axilla or supraclavicular
fossa/axillary apex.
9. MATERIALS AND METHODS
n=1031
Treated with mastectomy (including a level I-II
axillary dissection) and doxorubicin-based
systemic therapy without radiation on five clinical
trials at M.D. Anderson Cancer Center.
All regional recurrences (with or without distant
metastasis) were recorded.
Median follow-up was 116 months (range, 6–262
months).
10. PATIENTS
Eligibility criteria for these trials included resectable
Stage II and IIIA disease.
Patients older than age 75, those with evidence of
distant dissemination at diagnosis, and those with a
prior or concurrent malignancy were not eligible for
inclusion in these trials.
11. PATIENTS…
The median age for all patients was 48 (interquartile
range 42–56).
493 (48%) of the patients were premenopausal
525 (51%) were postmenopausal
Menopausal status was not recorded for 13 patients.
12. Ninety-one percent of patients (n=932) had invasive
ductal or mixed invasive ductal and lobular carcinoma
5% had invasive pure lobular carcinoma (n=55)
4% had other histologies (n=44).
The median tumor size was 2.5 cm with an
interquartile range of 1.9 –3.9 cm.
13. Median number of nodes examined was 17
(interquartile range, 13–22)
Median number of involved nodes was 3 (interquartile
range, 1–6).
A total of 1,918 (89%) had 10 or more nodes examined.
Nine patients (1%) had fewer than 5 nodes removed,
and 91 patients (9%) had between 5 and 9 nodes
removed.
Extranodal extension was described as focal (<2 mm),
gross (>2 mm), present not otherwise specified, or
absent.
14. TREATMENT
Patients underwent radical mastectomy (5) or
modified radical mastectomy (1,026), including Level I
and II axillary lymph node dissection
Adjuvant systemic therapy, which consisted of
combination chemotherapy including doxorubicin.
In addition to chemotherapy, 318 patients (31%) who
were estrogen receptor– or progesterone receptor–
positive also received tamoxifen.
15. FOLLOW UP
Median follow-up was 116 months (range, 6–262
months).
A total of 766 patients were evaluable at 5 years and
370 at 10 years.
Thirteen patients were lost to follow-up within less
than 3 years of treatment (range, 6–35 months). Of
these, 11 were alive without evidence of disease and 2
were alive with disease as of the last date of contact.
16. Regional nodal failures were classified as failures in the
low-mid axilla vs. those in the supraclavicular
fossa/axillary apex.
The intent of this classification was to separate failures
according to the corresponding radiation therapy
fields that would encompass the region of interest.
17. STATISTICS
Ten-year actuarial rates of locoregional recurrence
with or without prior or simultaneous distant
metastasis were calculated by the Kaplan-Meier
method, with comparisons among groups performed
using two-sided log–rank tests.
Multivariate analysis was performed using Cox logistic
regression analysis. All p values were two-tailed, with a
value of 0.05 considered to be significant.
18. Patient and tumor characteristics
T stage
T1 337 33%
T2 510 50%
T3 102 10%
TX 80 7%
Tumor size
<1.0 cm 45 4%
1.1–2.0 cm 270 26%
2.1–3.0 cm 279 27%
3.1–4.0 cm 160 16%
4.1–5.0 cm 69 7%
>5.0 cm 105 10%
21. Patient and tumor characteristics...
Size of largest node
<1 cm 148 14%
1.1–2 cm 222 22%
2.1–3 cm 126 12%
>3 cm 58 6%
Unknown 477 46%
Extranodal extension
None 573 64%
<2 mm 83 9%
>2 mm 141 16%
Present, NOS 68 8%
Unknown 25 3%
22. RESULTS
Overall survival and disease-free survival for all
patients at 10 years were 65% and 55%, respectively.
The 10-year actuarial rate of distant metastasis-free
survival was 64%.
The actuarial rate of locoregional recurrence (with or
without distant metastasis) for the entire cohort was
19% at 10 years.
23. RESULTS…
The chest wall was the most common site of
locoregional failure -67%(120/180 patients).
Regional nodal recurrences represented a component
of failure in 53% of patients with a locoregional
recurrence (95/180 patients).
24. RESULTS…
12% percentof locoregional recurrences included the
low-mid axilla (21/180 patients) as a component and
43% included the supraclavicular fossa/axillary apex
(77/180 patients).
79% of recurrences were biopsy proven.
The median interval to chest wall recurrence was 27
months, which was shorter than the interval to
detection of regional nodal recurrence (median, 38
months).
25. Failure in the low-mid axilla
Only 21 of 1,031 patients recurred within the low-mid
axilla (10-year actuarial rate 3%).
Five of these patients had a chest wall failure in
addition to their low-mid axillary recurrence. None of
the factors examined in univariate analysis predicted
for increased rates of failure in the lowmid axilla.
26. Failure in the low-mid axilla...
The risk of failure in the dissected axilla was not
significantly higher for patients with increasing
numbers of involved axillary lymph nodes, increasing
percentage of involved axillary lymph nodes, larger
nodal size, or gross extranodal extension than for
patients without these features.
27. Failure in the low-mid axilla...
Only 2 of 141 patients with gross extranodal extension
experienced a failure in the low-mid axilla (10-year
actuarial rates 2%).
The extent of axillary dissection was also not predictive
of the risk of axillary failure. Only 3 of 100 patients
with <10 nodes and 0 of 9 with <5 nodes examined
recurred in the low-mid axilla.
28. Failure in the supraclavicular
fossa/axillary apex
77 patients experienced a recurrence in the
supraclavicular or infraclavicular fossa (10-year
actuarial rate 8%).
49 of these had no chest wall recurrence in addition to
the supraclavicular/axillary apex recurrence.
29. Failure in the supraclavicular
fossa/axillary apex...
Significant predictors of failures in this region
included:-
involvement of four or more axillary lymph nodes
greater than 20% involved axillary lymph nodes
presence of lymphovascular space invasion
presence of gross extranodal extension.
30. Failure in the supraclavicular
fossa/axillary apex...
In multivariate analysis of failure in the supraclavicular
fossa/axillary apex, presence of lymphovascular space
invasion and the percentage of positive nodes
predicted for higher failure rates (hazard ratio, 1.89
and 1.01; p 0.007 and 0.0017).
31. Failure in the supraclavicular
fossa/axillary apex...
For patients with T1/T2 disease and one to three
positive nodes, the overall risk of recurring in
supraclavicular or infraclavicular fossa for this cohort
is very low; 10-year actuarial rate 5%.
32. Failure in the supraclavicular
fossa/axillary apex...
Only the number of positive nodes predicted for
increased failure in the high axilla. The 10- year
actuarial freedom from recurrence with three positive
nodes was 10% vs. 2% with two positive nodes, p
0.004.
33. Failure in the supraclavicular
fossa/axillary apex...
There was no statistically significant difference in high
axillary recurrence rates (supraclavicular or
infraclavicular fossa) with
greater than 20% involved axillary lymph nodes (9%
vs. 4%, p 0.15),
the presence of gross extranodal extension (11% vs. 4%,
p 0.21),
<10 nodes removed (5% vs. 4%, p 0.97),
largest axillary node >2 cm (6% vs. 4%, p 0.26),
lymphovascular space invasion (4% vs. 5%, p 0.65).
34. Failure in the supraclavicular
fossa/axillary apex...
However, patients with an increasing number of these
factors had a higher failure rate in the supraclavicular
or infraclavicular fossa at 10 years than those with no
risk factors
four factors, 40%
three factors, 9%
two factors, 6%
one factor, 5%
no factors, 2.5%; p 0.001).
35. Univariate analysis for 10-year actuarial failure in the axilla (crude rate)
Characteristic SCV/ICV p value Low axilla p value
T stage
T1 7% (20/337) NS 2% (6/337) NS
T2 10% (40/510) 3% (10/510)
T3 7% (7/102) 2% (2/102)
TX 9% (8/78) 2% (1/78)
Tumor size
<1.0 cm 2% (1/45) NS 3.6% (1/45) NS
1.1–2.0 cm 7% (18/270) 2.7% (6/270)
2.1–3.0 cm 8% (19/270) 1.4% (3/279)
3.1–4.0 cm 15% (18/160) 5.8% (7/160)
4.1–5.0 cm 8% (4/69) 4.2% (1/69)
>5.0 cm 7% (7/103) 2.2% (2/103)
Unknown 8% (10/105) 2.2% (2/103)
37. Univariate analysis for 10-year actuarial failure in the axilla (crude rate)
Characteristic SCV/ICV p value Low axilla p value
Percentage nodes
<20% 5% (21/453) <0.0001 2.3% (8/453) NS
>20% 15% (52/424) 3.8% (11/424)
Size of largest node
<1 cm 5% (7/148) NS 0% (0/148) NS
1.1–2 cm 8% (19/222) 2.7% (5/222)
2.1–3 cm 11% (12/126) 3.5% (4/126)
>3 cm 13% (6/58) 3.6% (1/58)
Unknown 8% (33/477) 3.2% (11/477)
Extranodal extension
None 6% (43/711) 0.0012 2.2% (15/711) NS
Present, NOS, or focal 11% (13/151) 2.2% (3/151)
Gross 19% (20/142) 1.8% (2/142)
38. DISCUSSION
The indications for regional nodal radiation to the
lowmid axilla and supraclavicular fossa/axillary apex
remain controversial. Results suggest that failure in
the low-mid axilla is an uncommon occurrence and
that supplemental radiotherapy to the dissected
portion of the axilla is not warranted for most patients.
39. DISCUSSION…
Patients with four or more involved axillary lymph
nodes, 20% involved axillary nodes,
lymphovascular space invasion, or gross
extranodal extension are at increased risk of failure
in the undissected supraclavicular fossa/axillary apex
and should receive radiation to these regions in
addition to the chest wall.
40. DISCUSSION…
Many have argued for comprehensive regional nodal
radiation in all patients treated with postmastectomy
radiotherapy, because the three large, randomized
trials that demonstrated a survival benefit to
postmastectomy radiation employed comprehensive
regional nodal radiation.
Danish BreastCancer Cooperative Group 82b Trial. N Engl J Med 1997;337:949–955.
Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet
1999;353:1641–1648.
Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-
positive premenopausal women with breast cancer. N Engl J Med 1997;337:956 –962.
41. DISCUSSION…
In this study, the chest wall was the most common site
of locoregional recurrence, followed by the
supraclavicular fossa/axillary apex. Failures in the
dissected axilla were relatively rare, representing a
component of failure in only 14% of patients with a
locoregional recurrence.
42. DISCUSSION…
In contrast, 45% of patients with a locoregional
recurrence in the Danish 82b and 82c trials had
axillary recurrences. These differences may be
attributable to the differences in the axillary surgery
employed in the Danish trials. The median number of
axillary lymph nodes examined in the Danish trials
was 7 vs. a median of 17 in the current series.
43. DISCUSSION…
The prognostic value of extranodal extension found in
axillary lymph node dissections for breast cancer has been
particularly controversial. Several reports have suggested
that the presence of extranodal extension, which is
correlated with the number of involved axillary lymph
nodes, was not a significant independent predictor of
locoregional recurrence or overall survival.
Donegan WL, Stine SB, Samter TG. Implications of extracapsular nodal metastases for
treatment and prognosis of breast cancer. Cancer 1993;72:778 –782.
Hetelekidis S, Schnitt SJ, Silver B, et al. The significance of extracapsular extension of axillary
lymph node metastases in early-stage breast cancer. Int J Radiat Oncol Biol Phys 2000; 46:31–
34.
44. DISCUSSION…
Results of this study suggest that extranodal extension
is a marker for aggressive disease with a high
propensity to locoregional recurrence rather than an
indication that disease has been left behind in the
axilla. Most of the recurrences in patients with
extranodal extension involve the chest wall and
supraclavicular fossa/ axillary apex, which are the most
common sites of locoregional failure overall after
mastectomy. Failures in the lowmid axilla are rare even
in the setting of gross extranodal extension.
45. Findings of this study are consistent with those from
several other institutions, which report a 4–7% risk of
axillary failure after surgery and adjuvant therapy for
patients with extranodal extension.
Pierce LJ, Oberman HA, Strawderman MH, et al. Microscopic extracapsular extension in
the axilla: Is this an indication for axillary radiotherapy? Int J Radiat Oncol Biol Phys
1995;33: 253–259.
46. Patients with gross extranodal extension (>2 mm)
may, therefore, benefit from adjuvant radiotherapy to
the chest wall and supraclavicular fossa/axillary apex.
Supplemental radiation to the low-mid axilla, on the
other hand, is not indicated.
47. In addition to gross extranodal extension, other
predictors of locoregional recurrence in the
supraclavicular fossa/ axillary apex include the
presence of four or more involved axillary lymph nodes
or 20% involved axillary lymph nodes. Patients with
these tumor characteristics have a 15– 20% risk of
failure in the supraclavicular fossa/axillary apex, and
should, therefore, be offered adjuvant radiation
therapy to this region as well as the chest wall.
48. The use of supplemental radiation fields to cover the
supraclavicular fossa/axillary apex for patients with
one, two, or three involved axillary lymph nodes
remains controversial. Although patient prognosis
after supraclavicular failure is poor, the addition of a
radiation portal to cover the supraclavicular
fossa/axillary apex may substantially increase the risk
of treatment related complications, such as
lymphedema and pneumonitis.
49. Although several series report no increased risk of edema
from the addition of a supraclavicular field, Halverson et al.
reported a 24% rate of lymphedema for patients treated
with radiotherapy to the breast and supraclavicular
fossa/axillary apex after conservative surgery and axillary
node dissection.
The addition of radiotherapy portals to treat the regional
lymphatics was also associated with increasing rates of
pneumonitis.
Pierce LJ, Oberman HA, Strawderman MH, et al. Microscopic extracapsular extension in
the axilla: Is this an indication for axillary radiotherapy? Int J Radiat Oncol Biol Phys
1995;33: 253–259.
50. Results of this study demonstrate only a 5% actuarial
rate of supraclavicular fossa/axillary apex recurrence at
10 years for patients with one, two, or three involved
axillary lymph nodes. Other studies report comparable
rates of supraclavicular fossa/ axillary apex recurrence
ranging from 1–4% for patients with one, two, or three
involved nodes.
Vicini FA, Horwitz EM, Lacerna MD, et al. The role of regional nodal irradiation in the
management of patients with early-stage breast cancer treated with breast-conserving
therapy. Int J Radiat Oncol Biol Phys 1997;39:1069 –1076.
51. Given the added risks involved and the minimal
chance for benefit, it does not appear from data that
the use of an additional radiotherapy portal to treat
the supraclavicular fossa/axillary apex is warranted in
most patients with fewer than four involved axillary
lymph nodes.
52. Based on the results of this study, the policy is to treat
the supraclavicular fossa/axillary apex in patients with
four or more involved axillary lymph nodes, >20%
involved axillary nodes, or gross extranodal extension.
Supplementation to the dissected axilla is not
routinely used for patients with operable breast
cancer.
