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Clinical investigation: Regional nodal failure patterns in breast cancer patients treated with mastectomy without radiotherapy
Int. J. Radiation Oncology Biol. Phys., Vol. 63, No. 5, pp. 1508 –1513, 2005 Copyright © 2005 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/05/$–see front matter
doi:10.1016/j.ijrobp.2005.05.044
CLINICAL INVESTIGATION
Breast
CLINICAL INVESTIGATION: REGIONAL NODAL FAILURE PATTERNS IN BREAST CANCER PATIENTS TREATED WITH MASTECTOMY WITHOUT RADIOTHERAPY ERIC A. STROM, M.D.,* WENDY A. WOODWARD, M.D., PH.D.,* ANGELA KATZ, M.D.,* THOMAS A. BUCHHOLZ, M.D.,* GEORGE H. PERKINS, M.D.,* ANUJA JHINGRAN, M.D.,* RICHARD THERIAULT, M.D.,† EVA SINGLETARY, M.D.,‡ AYSEGUL SAHIN, M.D.,§ AND MARSHA D. MCNEESE, M.D.* Departments of *Radiation Oncology, †Medical Oncology, ‡Surgical Oncology, and §Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX Purpose: 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. Methods and Materials: The cohort consisted of 1031 patients 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. Patient records, including pathology reports, were retrospectively reviewed. All regional recurrences (with or without distant metastasis) were recorded. Median follow-up was 116 months (range, 6 –262 months). Results: Twenty-one patients recurred within the low-mid axilla (10-year actuarial rate 3%). Of these, 16 were isolated regional failures (no chest wall failure). The risk of failure in the low-mid axilla was not significantly higher for patients with increasing numbers of involved nodes, increasing percentage of involved nodes, larger nodal size or gross extranodal extension. Only 3 of 100 patients with <10 nodes examined recurred in the low-mid axilla. Seventy-seven patients had a recurrence in the supraclavicular fossa/axillary apex (10-year actuarial rate 8%). Forty-nine were isolated regional recurrences. Significant predictors of failures in this region included >4 involved axillary lymph nodes, >20% involved axillary nodes, and the presence of gross extranodal extension (10-year actuarial rates 15%, 14%, and 19%, respectively, p < 0.0005). The extent of axillary dissection and the size of the largest involved node were not predictive of failure within the supraclavicular fossa/axillary apex. Conclusions: These results suggest that failure in the level I-II axilla is an uncommon occurrence after modified radical mastectomy and chemotherapy. Therefore, supplemental radiotherapy to the dissected axilla is not warranted for most patients. However, patients with >4 involved axillary lymph nodes, >20% involved axillary nodes, or gross extranodal extension are at increased risk of failure in the supraclavicular fossa/axillary apex and should receive radiation to undissected regions in addition to the chest wall. © 2005 Elsevier Inc. Breast cancer, Regional nodal recurrence, Mastectomy, Radiotherapy, Axilla.
INTRODUCTION The recent demonstration of a survival benefit for postmastectomy radiotherapy has left several questions unanswered. Indications for delivering adjuvant radiotherapy have been addressed in several retrospective reviews, including a report from our own institution, and are being investigated in large, randomized controlled trials (1–3). Another area of controversy that remains unanswered is the optimal radio-
therapy target. Most series, including our own, suggest that the chest wall is the most common site of locoregional recurrence and should be treated in high-risk patients (1–3). The issue of regional nodal radiation remains somewhat more controversial. The trials that demonstrated a survival benefit for postmastectomy radiotherapy did employ comprehensive regional nodal radiation; however, these trials have been criticized for several reasons, including recurrence patterns that are somewhat different from those ob-
Reprint requests to: Eric A. Strom, M.D., Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 97, Houston, TX 77030. Tel: (713) 792-3400; Fax: (713) 792-3642; E-mail: [email protected] Supported by a generous grant from the Stanford and Joan Alexander Foundation. Thomas A. Buchholz, M.D., is supported
by a USAMRMC Career Development Award from the Breast Cancer Research Program (BC980154). Acknowledgments—The authors wish to thank Jessica Erwin and Ramani Krishnan for their contribution to the database from which this analysis was conducted. Received Dec 16, 2004, and in revised form May 16, 2005. Accepted for publication May 20, 2005. 1508
Regional nodal failure patterns
served in large series in the United States (4 – 6). 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 (7). It is, therefore, crucial to define the subgroups of patients with the greatest potential to benefit from regional nodal radiation to maximize the therapeutic ratio. 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.
PATIENTS AND METHODS Between 1975 and 1994, 1805 patients were treated with doxorubicin-based adjuvant systemic therapy with or without tamoxifen after mastectomy on prospective clinical trials at the University of Texas M. D. Anderson Cancer Center (8 –13). Each protocol was reviewed and approved by an institutional review board, and each participant gave written informed consent according to institutional guidelines. Referral for postoperative radiation was at the discretion of the treating oncologists in most of these trials. This report comprises the data from the records of the 1031 patients who did not receive radiotherapy. Overall locoregional recurrence rates in these patients have been previously reported (1). 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. Patient and tumor characteristics are listed in Table 1. The median age for all patients was 48 (interquartile range 42–56). A total of 493 (48%) of the patients were premenopausal and 525 (51%) were postmenopausal; menopausal status was not recorded for 13 patients. Pathology for each patient was reviewed at M. D. Anderson Cancer Center before treatment. Information concerning pathologic findings was obtained from the M. D. Anderson pathology reports; however, pathology materials were not reexamined for the purpose of this study. 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), and 4% had other histologies (n ⫽ 44). Pathologic tumor size was determined by postoperative gross and microscopic examination. The median tumor size was 2.5 cm with an interquartile range of 1.9 –3.9 cm. The median number of nodes examined was 17 (interquartile range, 13–22), and the 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 (ⱕ2 mm), gross (⬎2 mm), present not otherwise specified, or absent. Patients underwent radical mastectomy (5) or modified radical mastectomy (1,026), including Level I and II axillary lymph node dissection, before 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. Patient follow-up consisted of physical examination, routine laboratory studies, chest x-rays, and bone scans, according to
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Table 1. Patient and tumor characteristics Characteristic T stage T1 T2 T3 TX Tumor size ⱕ1.0 cm 1.1–2.0 cm 2.1–3.0 cm 3.1–4.0 cm 4.1–5.0 cm ⬎5.0 cm Location UOQ UIQ LOQ LIQ Central-retroareolar Unknown Percentage involved nodes 0 ⱕ20% ⬎20% Unknown No. involved nodes 0 1–3 4–9 ⱖ10 No. nodes examined ⬍10 ⱖ10 Unknown Size of largest node* ⱕ1 cm 1.1–2 cm 2.1–3 cm ⬎3 cm Unknown Extranodal extension* None ⬍2 mm ⱖ2 mm Present, NOS Unknown
No.
%
337 510 102 80
33% 50% 10% 7%
45 270 279 160 69 105
4% 26% 27% 16% 7% 10%
527 116 113 55 124 96
51% 11% 11% 5% 13% 9%
142 453 424 12
15% 44% 41% 1%
142 465 263 157
14% 45% 26% 15%
100 918 13
10% 89% 1%
148 222 126 58 477
14% 22% 12% 6% 46%
573 83 141 68 25
64% 9% 16% 8% 3%
Abbreviations: NOS ⫽ not otherwise specified; UOQ ⫽ upper outer quadrant; UIQ ⫽ upper inner quadrant; LOQ ⫽ lower outer quadrant; LIQ ⫽ lower inner quadrant. * Excluding 142 node-negative patients. protocol guidelines. Ultrasound and computed tomography were not routinely ordered during the follow-up period, but were performed when indicated. Median follow-up from the date of initial histologic diagnosis for all patients alive at the time of analysis 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. All locoregional recurrences were recorded, as were the date and site of first distant metastasis. For the purpose of this study, regional nodal failures were classified as failures in the low-mid
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● Biology ● Physics
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. 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 (14, 15). Multivariate analysis was performed using Cox logistic regression analysis (14). All p values were two-tailed, with a value of ⱕ0.05 considered to be significant.
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 (crude rate, 17%). The chest wall was the most common site of locoregional failure, representing a component of failure in 67% of those experiencing a locoregional recurrence (120/180 patients). Regional nodal recurrences represented a component of failure in 53% of patients with a locoregional recurrence (95/180 patients). Twelve percent of locoregional recurrences included the low-mid axilla (21/180 patients) as a component and 43% included the supraclavicular fossa/axillary apex (77/180 patients). Seventy-nine percent 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). 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. 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. 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. Failure in the supraclavicular fossa/axillary apex Seventy-seven patients experienced a recurrence in the supraclavicular or infraclavicular fossa (10-year actuarial rate 8%). Forty-nine of these had no chest wall recurrence in addition to the supraclavicular/axillary apex recurrence. Univariate analysis for failure in the supraclavicular fossa/ axillary apex is described in Table 2. Significant predictors
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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, and the presence of gross extranodal extension (10-year actuarial rates 15%, 15%, 12%, and 19%, respectively, p ⬍ 0.0008). The extent of axillary dissection was not predictive of failure in the supraclavicular fossa/axillary apex. In subgroup analysis, among patients with one to three nodes positive, there was a trend for higher failure in the high axilla for patients with gross extranodal extension (greater than 2 mm, 4% vs. 13%, p ⫽ 0.06). Among patients with four or more positive nodes, failure rates in the supraclavicular fossa/axillary apex were also higher when gross extranodal extension was present; however, this was not statistically significant (13% vs. 22%, p ⫽ 0.2). In multivariate analysis of failure in the supraclavicular fossa/axillary apex including all variables significant in univariate analysis, 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). 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%. To examine the role of treating the supraclavicular and infraclavicular fossa for patients with T1 or T2 tumors and one to three positive nodes, we examined risk factors for failure in the supraclavicular or infraclavicular fossa. Only the number of positive nodes predicted for increased failure in the high axilla. The 10year actuarial freedom from recurrence with three positive nodes was 10% vs. 2% with two positive nodes, p ⫽ 0.004. 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), or lymphovascular space invasion (4% vs. 5%, p ⫽ 0.65). 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).
DISCUSSION The indications for regional nodal radiation to the lowmid axilla and supraclavicular fossa/axillary apex remain controversial. Our 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. However, 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
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Table 2. Univariate analysis for 10-year actuarial failure in the axilla (crude rate) Characteristic T stage T1 T2 T3 TX Tumor size ⱕ1.0 cm 1.1–2.0 cm 2.1–3.0 cm 3.1–4.0 cm 4.1–5.0 cm ⬎5.0 cm Unknown No. involved nodes 0 1–3 4–9 ⱖ10 No. nodes examined ⬍10 ⱖ10 LVSI Absent Present Percentage nodes ⱕ20% ⬎20% Size of largest node* ⱕ1 cm 1.1–2 cm 2.1–3 cm ⬎3 cm Unknown Extranodal extension* None Present, NOS, or focal Gross
SCV/ICV
p value
Low axilla 2% (6/337) 3% (10/510) 2% (2/102) 2% (1/78)
p value
7% (20/337) 10% (40/510) 7% (7/102) 9% (8/78)
NS
2% (1/45) 7% (18/270) 8% (19/270) 15% (18/160) 8% (4/69) 7% (7/103) 8% (10/105)
NS
3.6% (1/45) 2.7% (6/270) 1.4% (3/279) 5.8% (7/160) 4.2% (1/69) 2.2% (2/103) 2.2% (2/103)
NS
5% (3/142) 5% (20/465) 15% (34/263) 15% (20/157)
⬍0.0001
1% (1/142) 2.7% (10/465) 3.6% (7/263) 3.3% (3/157)
NS
8% (6/113) 8% (71/918)
NS
3.5% (3/113) 2.6% (18/918)
NS
0.0008 6.1% (35/644) 12.2% (39/364)
NS
NS 3% (13/644) 3% (7/364)
5% (21/453) 15% (52/424)
⬍0.0001
2.3% (8/453) 3.8% (11/424)
NS
5% (7/148) 8% (19/222) 11% (12/126) 13% (6/58) 8% (33/477)
NS
0% (0/148) 2.7% (5/222) 3.5% (4/126) 3.6% (1/58) 3.2% (11/477)
NS
2.2% (15/711) 2.2% (3/151) 1.8% (2/142)
NS
6% (43/711) 11% (13/151) 19% (20/142)
0.0012
Abbreviations: LVSI ⫽ lymphovascular space invasion; SCV ⫽ supraclavicular; ICV ⫽ infraclavicular; NS ⫽ not significant; NOS ⫽ not otherwise specified. * Excluding 142 node-negative patients.
receive radiation to these regions in addition to the chest wall. 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 (4 – 6). However, the patterns of locoregional recurrences observed in those trials are somewhat different than those observed in large series from the United States, including our own (1, 3). In our series, 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. 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 axil-
lary surgery employed in the Danish trials and at our institution. The median number of axillary lymph nodes examined in the Danish trials was 7 vs. a median of 17 in the current series. Whatever the reasons for the high rates of axillary recurrence observed in the Danish trials, it is clear that failures in the low-mid axilla are uncommon following the standard Level I-II axillary node dissection performed in the United States. None of the factors that we examined, including increasing numbers of involved nodes, the extent of axillary dissection, or the presence of gross extranodal extension, were predictive of recurrence in the low-mid axilla. Therefore, supplemental radiation to the mid axilla through fields such as posterior axillary boosts is not warranted in most patients. It must be noted that none of the patients in our series had matted or fixed axillary nodes, so no conclusions can be drawn about the risk of axillary failure for patients with N2 disease. The prognostic value of extranodal extension found in
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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 (16, 17). Our results 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. Our findings 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 (1, 18 –20). Patients with gross extranodal extension (ⱖ2 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. 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. 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
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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. Although several series report no increased risk of edema from the addition of a supraclavicular field (20 –22), 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 (7). The addition of radiotherapy portals to treat the regional lymphatics was also associated with increasing rates of pneumonitis. Our results 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 looking at the risk of regional nodal failure in patients treated with either mastectomy alone or conservative surgery with radiation to the “breast alone” report comparable rates of supraclavicular fossa/ axillary apex recurrence ranging from 1– 4% for patients with one, two, or three involved nodes (3, 23, 24). Given the added risks involved and the minimal chance for benefit, although there may be a small subset of patients with multiple pathologic indicators of increased disease burden in the axilla who may merit comprehensive nodal irradiation, it does not appear from our 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. Based on the results of this study, the policy at our institution 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.
REFERENCES 1. Katz A, Strom EA, Buchholz TA, et al. Locoregional recurrence patterns after mastectomy and doxorubicin-based chemotherapy: Implications for postoperative irradiation. J Clin Oncol 2000;18:2817–2827. 2. Fowble B, Gray R, Gilchrist K, et al. Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy. J Clin Oncol 1988;6:1107–1117. 3. Recht A, Gray R, Davidson NE, et al. Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: Experience of the Eastern Cooperative Oncology Group. J Clin Oncol 1999;17:1689 –1700. 4. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 1997;337: 949 –955. 5. Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999;353: 1641–1648.
6. 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. 7. 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. Buzdar AU, Blumenschein GR, Smith TL, et al. Adjuvant chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide, with or without Bacillus Calmette-Guerin and with or without irradiation in operable breast cancer. A prospective randomized trial. Cancer 1984;53:384 –389. 9. Buzdar AU, Hortobagyi GN, Marcus CE, et al. Results of adjuvant chemotherapy trials in breast cancer at M. D. Anderson Hospital and Tumor Institute. NCI Monogr 1986: 81– 85. 10. Buzdar AU, Hortobagyi GN, Smith TL, et al. Adjuvant therapy of breast cancer with or without additional treatment with alternate drugs. Cancer 1988;62:2098 –2104. 11. Buzdar AU, Kau SW, Smith TL, et al. Ten-year results of FAC adjuvant chemotherapy trial in breast cancer. Am J Clin Oncol 1989;12:123–128. 12. Buzdar AU, McNeese MD, Hortobagyi GN, et al. Is chemo-
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13.
14. 15. 16. 17.
18.
19.
therapy effective in reducing the local failure rate in patients with operable breast cancer? Cancer 1990;65:394 –399. Buzdar AU, Hortobagyi GN, Kau SW, et al. Adjuvant therapy with escalating doses of doxorubicin and cyclophosphamide with or without leukocyte alpha-interferon for stage II or III breast cancer. J Clin Oncol 1992;10:1540 –1546. Harris E, Albert A. Survivorship analysis for clinical studies. New York: Dekker; 1991. Koscielny S, Thames HD. Biased methods for estimating local and distant failure rates in breast carcinoma and a “commonsense” approach. Cancer 2001;92:2220 –2227. 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. Fisher BJ, Perera FE, Cooke AL, et al. Extracapsular axillary node extension in patients receiving adjuvant systemic therapy: An indication for radiotherapy? Int J Radiat Oncol Biol Phys 1997;38:551–559. Leonard C, Corkill M, Tompkin J, et al. Are axillary recur-
● E. A. STROM et al.
20.
21.
22.
23.
24.
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rence and overall survival affected by axillary extranodal tumor extension in breast cancer? Implications for radiation therapy. J Clin Oncol 1995;13:47–53. 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. Metz JM, Schultz DJ, Fox K, et al. Long-term outcome after postmastectomy radiation therapy for breast cancer patients at high risk for local-regional recurrence. Cancer J Sci Am 1999;5:77– 83. Bijker N, Rutgers EJ, Peterse JL, et al. Low risk of locoregional recurrence of primary breast carcinoma after treatment with a modification of the Halsted radical mastectomy and selective use of radiotherapy. Cancer 1999;85:1773–1781. Recht A, Pierce SM, Abner A, et al. Regional nodal failure after conservative surgery and radiotherapy for early-stage breast carcinoma. J Clin Oncol 1991;9:988 –996. 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.
doi:10.1016/j.ijrobp.2005.05.044
CLINICAL INVESTIGATION
Breast
CLINICAL INVESTIGATION: REGIONAL NODAL FAILURE PATTERNS IN BREAST CANCER PATIENTS TREATED WITH MASTECTOMY WITHOUT RADIOTHERAPY ERIC A. STROM, M.D.,* WENDY A. WOODWARD, M.D., PH.D.,* ANGELA KATZ, M.D.,* THOMAS A. BUCHHOLZ, M.D.,* GEORGE H. PERKINS, M.D.,* ANUJA JHINGRAN, M.D.,* RICHARD THERIAULT, M.D.,† EVA SINGLETARY, M.D.,‡ AYSEGUL SAHIN, M.D.,§ AND MARSHA D. MCNEESE, M.D.* Departments of *Radiation Oncology, †Medical Oncology, ‡Surgical Oncology, and §Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX Purpose: 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. Methods and Materials: The cohort consisted of 1031 patients 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. Patient records, including pathology reports, were retrospectively reviewed. All regional recurrences (with or without distant metastasis) were recorded. Median follow-up was 116 months (range, 6 –262 months). Results: Twenty-one patients recurred within the low-mid axilla (10-year actuarial rate 3%). Of these, 16 were isolated regional failures (no chest wall failure). The risk of failure in the low-mid axilla was not significantly higher for patients with increasing numbers of involved nodes, increasing percentage of involved nodes, larger nodal size or gross extranodal extension. Only 3 of 100 patients with <10 nodes examined recurred in the low-mid axilla. Seventy-seven patients had a recurrence in the supraclavicular fossa/axillary apex (10-year actuarial rate 8%). Forty-nine were isolated regional recurrences. Significant predictors of failures in this region included >4 involved axillary lymph nodes, >20% involved axillary nodes, and the presence of gross extranodal extension (10-year actuarial rates 15%, 14%, and 19%, respectively, p < 0.0005). The extent of axillary dissection and the size of the largest involved node were not predictive of failure within the supraclavicular fossa/axillary apex. Conclusions: These results suggest that failure in the level I-II axilla is an uncommon occurrence after modified radical mastectomy and chemotherapy. Therefore, supplemental radiotherapy to the dissected axilla is not warranted for most patients. However, patients with >4 involved axillary lymph nodes, >20% involved axillary nodes, or gross extranodal extension are at increased risk of failure in the supraclavicular fossa/axillary apex and should receive radiation to undissected regions in addition to the chest wall. © 2005 Elsevier Inc. Breast cancer, Regional nodal recurrence, Mastectomy, Radiotherapy, Axilla.
INTRODUCTION The recent demonstration of a survival benefit for postmastectomy radiotherapy has left several questions unanswered. Indications for delivering adjuvant radiotherapy have been addressed in several retrospective reviews, including a report from our own institution, and are being investigated in large, randomized controlled trials (1–3). Another area of controversy that remains unanswered is the optimal radio-
therapy target. Most series, including our own, suggest that the chest wall is the most common site of locoregional recurrence and should be treated in high-risk patients (1–3). The issue of regional nodal radiation remains somewhat more controversial. The trials that demonstrated a survival benefit for postmastectomy radiotherapy did employ comprehensive regional nodal radiation; however, these trials have been criticized for several reasons, including recurrence patterns that are somewhat different from those ob-
Reprint requests to: Eric A. Strom, M.D., Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 97, Houston, TX 77030. Tel: (713) 792-3400; Fax: (713) 792-3642; E-mail: [email protected] Supported by a generous grant from the Stanford and Joan Alexander Foundation. Thomas A. Buchholz, M.D., is supported
by a USAMRMC Career Development Award from the Breast Cancer Research Program (BC980154). Acknowledgments—The authors wish to thank Jessica Erwin and Ramani Krishnan for their contribution to the database from which this analysis was conducted. Received Dec 16, 2004, and in revised form May 16, 2005. Accepted for publication May 20, 2005. 1508
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served in large series in the United States (4 – 6). 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 (7). It is, therefore, crucial to define the subgroups of patients with the greatest potential to benefit from regional nodal radiation to maximize the therapeutic ratio. 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.
PATIENTS AND METHODS Between 1975 and 1994, 1805 patients were treated with doxorubicin-based adjuvant systemic therapy with or without tamoxifen after mastectomy on prospective clinical trials at the University of Texas M. D. Anderson Cancer Center (8 –13). Each protocol was reviewed and approved by an institutional review board, and each participant gave written informed consent according to institutional guidelines. Referral for postoperative radiation was at the discretion of the treating oncologists in most of these trials. This report comprises the data from the records of the 1031 patients who did not receive radiotherapy. Overall locoregional recurrence rates in these patients have been previously reported (1). 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. Patient and tumor characteristics are listed in Table 1. The median age for all patients was 48 (interquartile range 42–56). A total of 493 (48%) of the patients were premenopausal and 525 (51%) were postmenopausal; menopausal status was not recorded for 13 patients. Pathology for each patient was reviewed at M. D. Anderson Cancer Center before treatment. Information concerning pathologic findings was obtained from the M. D. Anderson pathology reports; however, pathology materials were not reexamined for the purpose of this study. 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), and 4% had other histologies (n ⫽ 44). Pathologic tumor size was determined by postoperative gross and microscopic examination. The median tumor size was 2.5 cm with an interquartile range of 1.9 –3.9 cm. The median number of nodes examined was 17 (interquartile range, 13–22), and the 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 (ⱕ2 mm), gross (⬎2 mm), present not otherwise specified, or absent. Patients underwent radical mastectomy (5) or modified radical mastectomy (1,026), including Level I and II axillary lymph node dissection, before 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. Patient follow-up consisted of physical examination, routine laboratory studies, chest x-rays, and bone scans, according to
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Table 1. Patient and tumor characteristics Characteristic T stage T1 T2 T3 TX Tumor size ⱕ1.0 cm 1.1–2.0 cm 2.1–3.0 cm 3.1–4.0 cm 4.1–5.0 cm ⬎5.0 cm Location UOQ UIQ LOQ LIQ Central-retroareolar Unknown Percentage involved nodes 0 ⱕ20% ⬎20% Unknown No. involved nodes 0 1–3 4–9 ⱖ10 No. nodes examined ⬍10 ⱖ10 Unknown Size of largest node* ⱕ1 cm 1.1–2 cm 2.1–3 cm ⬎3 cm Unknown Extranodal extension* None ⬍2 mm ⱖ2 mm Present, NOS Unknown
No.
%
337 510 102 80
33% 50% 10% 7%
45 270 279 160 69 105
4% 26% 27% 16% 7% 10%
527 116 113 55 124 96
51% 11% 11% 5% 13% 9%
142 453 424 12
15% 44% 41% 1%
142 465 263 157
14% 45% 26% 15%
100 918 13
10% 89% 1%
148 222 126 58 477
14% 22% 12% 6% 46%
573 83 141 68 25
64% 9% 16% 8% 3%
Abbreviations: NOS ⫽ not otherwise specified; UOQ ⫽ upper outer quadrant; UIQ ⫽ upper inner quadrant; LOQ ⫽ lower outer quadrant; LIQ ⫽ lower inner quadrant. * Excluding 142 node-negative patients. protocol guidelines. Ultrasound and computed tomography were not routinely ordered during the follow-up period, but were performed when indicated. Median follow-up from the date of initial histologic diagnosis for all patients alive at the time of analysis 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. All locoregional recurrences were recorded, as were the date and site of first distant metastasis. For the purpose of this study, regional nodal failures were classified as failures in the low-mid
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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. 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 (14, 15). Multivariate analysis was performed using Cox logistic regression analysis (14). All p values were two-tailed, with a value of ⱕ0.05 considered to be significant.
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 (crude rate, 17%). The chest wall was the most common site of locoregional failure, representing a component of failure in 67% of those experiencing a locoregional recurrence (120/180 patients). Regional nodal recurrences represented a component of failure in 53% of patients with a locoregional recurrence (95/180 patients). Twelve percent of locoregional recurrences included the low-mid axilla (21/180 patients) as a component and 43% included the supraclavicular fossa/axillary apex (77/180 patients). Seventy-nine percent 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). 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. 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. 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. Failure in the supraclavicular fossa/axillary apex Seventy-seven patients experienced a recurrence in the supraclavicular or infraclavicular fossa (10-year actuarial rate 8%). Forty-nine of these had no chest wall recurrence in addition to the supraclavicular/axillary apex recurrence. Univariate analysis for failure in the supraclavicular fossa/ axillary apex is described in Table 2. Significant predictors
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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, and the presence of gross extranodal extension (10-year actuarial rates 15%, 15%, 12%, and 19%, respectively, p ⬍ 0.0008). The extent of axillary dissection was not predictive of failure in the supraclavicular fossa/axillary apex. In subgroup analysis, among patients with one to three nodes positive, there was a trend for higher failure in the high axilla for patients with gross extranodal extension (greater than 2 mm, 4% vs. 13%, p ⫽ 0.06). Among patients with four or more positive nodes, failure rates in the supraclavicular fossa/axillary apex were also higher when gross extranodal extension was present; however, this was not statistically significant (13% vs. 22%, p ⫽ 0.2). In multivariate analysis of failure in the supraclavicular fossa/axillary apex including all variables significant in univariate analysis, 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). 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%. To examine the role of treating the supraclavicular and infraclavicular fossa for patients with T1 or T2 tumors and one to three positive nodes, we examined risk factors for failure in the supraclavicular or infraclavicular fossa. Only the number of positive nodes predicted for increased failure in the high axilla. The 10year actuarial freedom from recurrence with three positive nodes was 10% vs. 2% with two positive nodes, p ⫽ 0.004. 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), or lymphovascular space invasion (4% vs. 5%, p ⫽ 0.65). 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).
DISCUSSION The indications for regional nodal radiation to the lowmid axilla and supraclavicular fossa/axillary apex remain controversial. Our 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. However, 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
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Table 2. Univariate analysis for 10-year actuarial failure in the axilla (crude rate) Characteristic T stage T1 T2 T3 TX Tumor size ⱕ1.0 cm 1.1–2.0 cm 2.1–3.0 cm 3.1–4.0 cm 4.1–5.0 cm ⬎5.0 cm Unknown No. involved nodes 0 1–3 4–9 ⱖ10 No. nodes examined ⬍10 ⱖ10 LVSI Absent Present Percentage nodes ⱕ20% ⬎20% Size of largest node* ⱕ1 cm 1.1–2 cm 2.1–3 cm ⬎3 cm Unknown Extranodal extension* None Present, NOS, or focal Gross
SCV/ICV
p value
Low axilla 2% (6/337) 3% (10/510) 2% (2/102) 2% (1/78)
p value
7% (20/337) 10% (40/510) 7% (7/102) 9% (8/78)
NS
2% (1/45) 7% (18/270) 8% (19/270) 15% (18/160) 8% (4/69) 7% (7/103) 8% (10/105)
NS
3.6% (1/45) 2.7% (6/270) 1.4% (3/279) 5.8% (7/160) 4.2% (1/69) 2.2% (2/103) 2.2% (2/103)
NS
5% (3/142) 5% (20/465) 15% (34/263) 15% (20/157)
⬍0.0001
1% (1/142) 2.7% (10/465) 3.6% (7/263) 3.3% (3/157)
NS
8% (6/113) 8% (71/918)
NS
3.5% (3/113) 2.6% (18/918)
NS
0.0008 6.1% (35/644) 12.2% (39/364)
NS
NS 3% (13/644) 3% (7/364)
5% (21/453) 15% (52/424)
⬍0.0001
2.3% (8/453) 3.8% (11/424)
NS
5% (7/148) 8% (19/222) 11% (12/126) 13% (6/58) 8% (33/477)
NS
0% (0/148) 2.7% (5/222) 3.5% (4/126) 3.6% (1/58) 3.2% (11/477)
NS
2.2% (15/711) 2.2% (3/151) 1.8% (2/142)
NS
6% (43/711) 11% (13/151) 19% (20/142)
0.0012
Abbreviations: LVSI ⫽ lymphovascular space invasion; SCV ⫽ supraclavicular; ICV ⫽ infraclavicular; NS ⫽ not significant; NOS ⫽ not otherwise specified. * Excluding 142 node-negative patients.
receive radiation to these regions in addition to the chest wall. 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 (4 – 6). However, the patterns of locoregional recurrences observed in those trials are somewhat different than those observed in large series from the United States, including our own (1, 3). In our series, 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. 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 axil-
lary surgery employed in the Danish trials and at our institution. The median number of axillary lymph nodes examined in the Danish trials was 7 vs. a median of 17 in the current series. Whatever the reasons for the high rates of axillary recurrence observed in the Danish trials, it is clear that failures in the low-mid axilla are uncommon following the standard Level I-II axillary node dissection performed in the United States. None of the factors that we examined, including increasing numbers of involved nodes, the extent of axillary dissection, or the presence of gross extranodal extension, were predictive of recurrence in the low-mid axilla. Therefore, supplemental radiation to the mid axilla through fields such as posterior axillary boosts is not warranted in most patients. It must be noted that none of the patients in our series had matted or fixed axillary nodes, so no conclusions can be drawn about the risk of axillary failure for patients with N2 disease. The prognostic value of extranodal extension found in
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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 (16, 17). Our results 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. Our findings 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 (1, 18 –20). Patients with gross extranodal extension (ⱖ2 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. 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. 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
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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. Although several series report no increased risk of edema from the addition of a supraclavicular field (20 –22), 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 (7). The addition of radiotherapy portals to treat the regional lymphatics was also associated with increasing rates of pneumonitis. Our results 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 looking at the risk of regional nodal failure in patients treated with either mastectomy alone or conservative surgery with radiation to the “breast alone” report comparable rates of supraclavicular fossa/ axillary apex recurrence ranging from 1– 4% for patients with one, two, or three involved nodes (3, 23, 24). Given the added risks involved and the minimal chance for benefit, although there may be a small subset of patients with multiple pathologic indicators of increased disease burden in the axilla who may merit comprehensive nodal irradiation, it does not appear from our 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. Based on the results of this study, the policy at our institution 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.
REFERENCES 1. Katz A, Strom EA, Buchholz TA, et al. Locoregional recurrence patterns after mastectomy and doxorubicin-based chemotherapy: Implications for postoperative irradiation. J Clin Oncol 2000;18:2817–2827. 2. Fowble B, Gray R, Gilchrist K, et al. Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy. J Clin Oncol 1988;6:1107–1117. 3. Recht A, Gray R, Davidson NE, et al. Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: Experience of the Eastern Cooperative Oncology Group. J Clin Oncol 1999;17:1689 –1700. 4. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 1997;337: 949 –955. 5. Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999;353: 1641–1648.
6. 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. 7. 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. Buzdar AU, Blumenschein GR, Smith TL, et al. Adjuvant chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide, with or without Bacillus Calmette-Guerin and with or without irradiation in operable breast cancer. A prospective randomized trial. Cancer 1984;53:384 –389. 9. Buzdar AU, Hortobagyi GN, Marcus CE, et al. Results of adjuvant chemotherapy trials in breast cancer at M. D. Anderson Hospital and Tumor Institute. NCI Monogr 1986: 81– 85. 10. Buzdar AU, Hortobagyi GN, Smith TL, et al. Adjuvant therapy of breast cancer with or without additional treatment with alternate drugs. Cancer 1988;62:2098 –2104. 11. Buzdar AU, Kau SW, Smith TL, et al. Ten-year results of FAC adjuvant chemotherapy trial in breast cancer. Am J Clin Oncol 1989;12:123–128. 12. Buzdar AU, McNeese MD, Hortobagyi GN, et al. Is chemo-
Regional nodal failure patterns
13.
14. 15. 16. 17.
18.
19.
therapy effective in reducing the local failure rate in patients with operable breast cancer? Cancer 1990;65:394 –399. Buzdar AU, Hortobagyi GN, Kau SW, et al. Adjuvant therapy with escalating doses of doxorubicin and cyclophosphamide with or without leukocyte alpha-interferon for stage II or III breast cancer. J Clin Oncol 1992;10:1540 –1546. Harris E, Albert A. Survivorship analysis for clinical studies. New York: Dekker; 1991. Koscielny S, Thames HD. Biased methods for estimating local and distant failure rates in breast carcinoma and a “commonsense” approach. Cancer 2001;92:2220 –2227. 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. Fisher BJ, Perera FE, Cooke AL, et al. Extracapsular axillary node extension in patients receiving adjuvant systemic therapy: An indication for radiotherapy? Int J Radiat Oncol Biol Phys 1997;38:551–559. Leonard C, Corkill M, Tompkin J, et al. Are axillary recur-
● E. A. STROM et al.
20.
21.
22.
23.
24.
1513
rence and overall survival affected by axillary extranodal tumor extension in breast cancer? Implications for radiation therapy. J Clin Oncol 1995;13:47–53. 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. Metz JM, Schultz DJ, Fox K, et al. Long-term outcome after postmastectomy radiation therapy for breast cancer patients at high risk for local-regional recurrence. Cancer J Sci Am 1999;5:77– 83. Bijker N, Rutgers EJ, Peterse JL, et al. Low risk of locoregional recurrence of primary breast carcinoma after treatment with a modification of the Halsted radical mastectomy and selective use of radiotherapy. Cancer 1999;85:1773–1781. Recht A, Pierce SM, Abner A, et al. Regional nodal failure after conservative surgery and radiotherapy for early-stage breast carcinoma. J Clin Oncol 1991;9:988 –996. 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.