- Email: [email protected]
Internal mammary nodal irradiation in conservatively-managed breast cancer patients: is there a benefit?
Int. J. Radiation Oncology Biol. Phys., Vol. 44, No. 5, pp. 997–1003, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/99/$–see front matter
PII S0360-3016(99)00135-2
CLINICAL INVESTIGATION
Breast
INTERNAL MAMMARY NODAL IRRADIATION IN CONSERVATIVELYMANAGED BREAST CANCER PATIENTS: IS THERE A BENEFIT? EDWARD OBEDIAN, M.D.
AND
BRUCE G. HAFFTY, M.D.
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT Purpose: Recent randomized trials have demonstrated a significant benefit to postmastectomy radiation in node-positive breast cancer patients. The contribution of internal mammary nodal radiation (IMNR) to this benefit remains controversial, and in conservatively-treated patients (CS ⴙ RT), may compromise cosmesis and contribute to morbidity. The purpose of this retrospective analysis is to evaluate outcome as a function of IMNR in a cohort of breast cancer patients treated with CS ⴙ RT. Patients and Methods: Between January 1970 and December 1990, 984 patients with invasive breast cancer were treated at our facility with CS ⴙ RT, and serve as the base for this study. Of these patients, 399 patients had pathologically-negative lymph nodes, 167 (17%) had pathologically-involved lymph nodes, and 381 did not undergo lymph node dissection. The majority of node-positive patients received adjuvant systemic therapy (94%) and were treated with tangential fields matched to a separate supraclavicular field (95%) with or without IMNR. For this analysis, patients were divided into two groups: those treated by intentionally targeting the internal mammary nodes (IM-yes, n ⴝ 535) and without intentionally targeting the internal mammary nodes (IM-no, n ⴝ 411). In the IM-no group, the medial border was typically placed at midline. The decision not to use a separate internal mammary field was a result of a change in treatment policy over time, and generally not based on number of nodes or tumor location. Results: As of August 1998, with a median follow-up of 13 years, the overall survival at 10 years is 76%, the distant disease-free survival is 81%, and the breast relapse-free survival is 88%. There were no significant differences between the IM-yes and IM-no groups with respect to age, ER/PR status, or use of adjuvant chemotherapy or hormone therapy. There were more patients with T2 tumors, positive nodes, medial lesions, indeterminate margins, and slightly longer follow-up in the IM-yes group compared to the IM-no group. Although there was a trend toward better outcome in the IM-no group, there were no significant differences between the IM-yes and IM-no groups with respect to overall survival (72% IM-yes vs. 84% IM-no, p ⴝ NS) or distant metastasis-free survival (64% IM-yes vs. 82% IM-no, p ⴝ NS). Subset analysis showed no benefit in the IM-yes group regardless of age, number of nodes, or location. Conclusion: In this retrospective analysis, no benefit could be attributed to IMNR in conservatively-treated breast cancer patients, even if node-positive or medial in location. Until results of an ongoing EORTC randomized trial addressing this issue are available, these data suggest that it is acceptable to continue to treat node-positive conservatively-managed patients to tangential fields usually matched to a supraclavicular field, but without a separate internal mammary field. © 1999 Elsevier Science Inc. Breast cancer, Radiation therapy, Internal mammary lymph nodes.
INTRODUCTION
therapy (RT) in patients with Stage II and III breast cancer (14, 15). In both trials, patients were treated with cytotoxic chemotherapy and were randomized to receive or not receive RT using a five-field technique, which included a separate IMN field. Whether IMNR significantly contributed to the survival advantage is unclear. Such a result, however, poses important implications for node positive patients undergoing a breast conserving treatment approach (CS ⫹ RT). Should IMNR be considered in these patients? The potential risks of IMNR in conservatively-treated patients potentially include compromised cosmetic outcomes as well as cardiopulmonary complications, especially if
The role of regional nodal irradiation in node-positive breast cancer patients is controversial (1– 4). In the past, some studies reported a benefit (5–9), whereas other studies failed to confirm these findings (10 –12). Decreased survival rates have also been associated with regional nodal irradiation, especially internal mammary nodal radiation (IMNR), presumably secondary to older techniques delivering relatively high doses to the underlying normal cardiac and pulmonary structures (13). Recent randomized trials, however, have demonstrated a significant survival advantage to postmastectomy radiation Reprint requests to: Bruce G. Haffty, M.D., Department of Therapeutic Radiology, Yale University School of Medicine, P.O. Box 208040, New Haven, CT 06520-8040. Tel: (203) 785-2959;
Fax: (203) 785-4622; E-mail: [email protected] Accepted for publication 30 March 1999. 997
998
I. J. Radiation Oncology
●
Biology
●
Physics
combined with chemotherapeutic agents employing adriamycin- or taxol-based regimens with or without dose intensification. At Yale-New Haven Hospital (YNHH), the conservative management of breast cancer has been utilized with increasing frequency over the past 25 years. In earlier years (1970 through the mid-1980s), IMN were routinely targeted with either deep tangential fields or separate IM fields. Currently, the standard treatment practice at our institution is not to intentionally target the IMN in patients undergoing CS ⫹ RT. In light of the recent randomized trials, however, the utility of elective IMNR in patients must be reassessed. The change in treatment policy over time at our institution affords us a unique opportunity to evaluate the potential benefit of IM irradiation. The purpose of this retrospective analysis is to evaluate outcome in a large cohort of breast cancer patients undergoing CS ⫹ RT as a function of IMNR. Acknowledging the limitations of such retrospective analysis, until prospective randomized data become available, this experience represents one of the largest reported series directly addressing this issue in conservatively treated breast cancer patients. PATIENTS AND MATERIALS Between January 1970 and December 1990, 984 patients with early-stage invasive breast cancer have undergone conservative management at YNHH, and serve as the population base for this study. All patients were treated by wide local excision with or without axillary nodal dissection, followed by radiation therapy to the intact breast and regional nodes as outlined below. Among these, 167 patients had pathologically involved axillary nodal metastases, 399 had pathologically negative nodes and 381 did not undergo axillary dissection, reflecting treatment policies during the earlier years of the study. Patient charts were retrospectively reviewed. All patient data including demographic, staging, pathologic, treatment, and outcome parameters were entered into a computerized database (Prodas, Conceptual Software Inc.). In the current study, specific attention was directed to the radiation therapy technique employed, which is summarized in Table 1. Patients were treated with tangential breast fields with or without supraclavicular/axillary and/or IMN fields. The majority of node-positive patients (95%) were treated with a separate supraclavicular or supraclavicular and axillary field. The isocenter of this field was set at the match line to the tangential fields half blocked at the central axis to avoid divergence into the tangential field. The medial border was set at the patient’s midline and angled 15 degrees off the spinal cord. The dose was specified to a depth of 3 cm, and the median dose to this field was 4,600 cGy. In earlier years, the majority of patients were also treated with a separate IMN field, regardless of whether they were node-positive, node-negative, or in the no axillary dissection group. The IMN field was generally 6-cm wide, typically set 1 cm across midline to the contralateral breast, and
Volume 44, Number 5, 1999
Table 1. Treatment technique and doses Treatment technique
All patients
IM-yes
IM-no
n Tangents alone Tangents ⫹ supraclavicular Tangents ⫹ supraclav ⫹ axilla Tangents ⫹ supraclav ⫹ IMN Tangents ⫹ supraclav ⫹ axilla ⫹ IMN Median dose (range, Gy): Intact breast Tangents Supraclavicular nodal region Internal mammary nodal region
946 (100%) 221 (23%)
535 (100%) 1 (0.2%)
411 (100%) 220 (54%)
106 (11%)
9 (1.7%)
97 (24%)
128 (13%)
41 (7.7%)
87 (21%)
229 (24%)
229 (43%)
0
225 (24%)
225 (48%)
0
64 (40–96) 50 (20–70)
64 (40–96) 48 (20–70)
64 (46–82) 52 (32–64)
46 (0–62)
46 (0–55)
44 (0–62)
46 (0–62)
46 (20–54)
0
5 cm toward the ipsilateral side. The field was treated en face with mixed photons and electrons (usually 6 MV photons with 13 MeV electrons). In a minority of patients, orthovoltage photons were employed in lieu of electrons. In a small number of patients (56/535 or 10%), the IMN chain was included in “deep tangent” fields, with the medial border placed 3–5 cm to the contralateral side. The median dose delivered to the IMN field was 4,600 cGy specified at a depth of 3 cm. Although CT scanning and/or lymphoscintigraphy were not performed during this time period, these landmarks were standard, and presumably included the internal mammary chain in the majority of patients. In the mid-1980s, a rapid shift in the treatment technique took place, in that separate IMN fields were no longer routinely employed. In addition, although the entire breast tissue was covered, no specific attempt was generally made to use “deep tangents” to obtain adequate coverage of the IMN region. The decision not to intentionally target the IMN region was a result of a change in treatment policy over time, and generally not based on the number of involved axillary nodes or tumor location. In patients treated without a separate IMN field, the medial border of the tangential fields was typically placed at the patient’s midline. This change in treatment technique over time afforded us a unique opportunity to evaluate the potential benefit, or lack thereof, of intentionally irradiating the IMN in nodepositive conservatively-treated breast cancer patients. For this analysis, the patients were divided into two groups: those treated with deep tangential or separate IM fields (IM-yes, n ⫽ 535), and those treated without intentionally targeting the IMN (IM-no, n ⫽ 411). The two groups of patients were compared with respect to age, T-stage, number of axillary nodes involved, number of axillary nodes dissected, location of the tumor (right vs. left breast and upper outer quadrant vs. lower outer quadrant vs. upper inner quadrant vs. lower inner quadrant vs. central
Internal mammary nodal irradiation with BCS ⫹ RT
●
E. OBEDIAN
AND
B. G. HAFFTY
999
Table 2. Patient characteristics
n Median follow-up (range, years) Median age (range, years) Age ⬎ 50 Age ⬍ 50 T-stage T1 T2 T3 Status of axillary node dissection Node negative Node positive 1–3 ⬎ /4 No. axillary nodes dissected median (range) Margins Unknown Negative Close Positive Receptor status ER⫺ ER⫹ PR⫺ PR⫹ Location of tumor Right breast Left breast Location of lesion Medial (inner quadrant ⫹ central) Outer quadrant Adjuvant systemic therapy No Yes Chemotherapy No Yes Hormone therapy No Yes
All patients
IM-yes
IM-no
(p-value)
946 13 (7–37) 57 (20–86) 654 292
535 15 (7–37) 58 (20–86) 361 (67%) 174 (33%)
411 11.5 (7–25) 57 (26–85) 293 (71%) 118 (29%)
690 249 7
375 (70%) 164 (29%) 5 (1%)
315 (77%) 85 (22%) 2 (1%)
399
162 (62%)
237 (78%)
113 53
62 (24%) 37 (14%)
51 (17%) 16 (5%)
15 (4–31)
15 (4–29)
16 (8–31)
487 277 47 55
353 (72%) 92 (19%) 21 (4%) 26 (5%)
134 (36%) 185 (49%) 26 (7%) 29 (8%)
p ⬍ 0.001
215 423 245 307
120 (33%) 243 (67%) 126 (40%) 193 (60%)
95 (35%) 180 (65%) 119 (51%) 114 (53%)
0.73
461 481
267 (50%) 266 (50%)
194 (51%) 215 (49%)
0.40
784 560
236 (44%) 297 (56%)
148 (36%) 263 (64%)
p ⫽ 0.01
622 323
367 (69%) 167 (31%)
255 (62%) 156 (38%)
p ⫽ 0.03
765 179
441 (81%) 92 (17%)
324 (79%) 87 (21%)
0.125
755 186
431 (81%) 102 (19%)
324 (79%) 84 (21%)
0.59
0.001 0.16
0.01
p ⫽ 0.05 0.77
lesions), margin status, ER/PR status, use of adjuvant systemic therapy (chemotherapy and/or hormonal therapy), and method of tumor detection (mammography and/or physical examination). Of note, 94% of node-positive patients received adjuvant systemic therapy. The chemotherapy regimen employed was CMF in the majority of patients, with less than 10% receiving adriamycin-based therapy. Dates of local recurrence, nodal recurrence, and distant metastases, as well as dates of death and dates last seen alive, were all documented. From this information, overall survival (OS), breast relapse-free survival (BRFS), and distant metastasis-free survival (DMRFS) rates were calculated using the life table method. Survival rates were calculated from the date of breast cancer diagnosis to the date last seen, or to the date of death, whichever came earlier. All tests for statistical significance were performed using the Mantel-
Haensel model for survival curves and the Chi-square test for categorical variables (16). RESULTS Patient characteristics are listed in Table 2. As of August 1998, the median follow-up is 13 years for the entire cohort of patients. The OS, BRFS, and DMRFS rates at 10 years are 76%, 88%, and 81%, respectively (Fig.1). The clinical outcomes, including sites of recurrent disease in the patient population studied, are listed in Table 3. There were no statistically significant differences between the IM-yes and IM-no groups with respect to age, ER/PR status, or use of adjuvant chemotherapy or hormonal therapy. There was a slightly longer follow-up in the IM-yes group, and more patients with medial tumors and positive
1000
I. J. Radiation Oncology
●
Biology
●
Physics
Volume 44, Number 5, 1999
Fig. 1. OS, BRFS, and DMFS: all patients.
Fig. 2. OS: IM-yes versus IM-no.
axillary lymph nodes. In addition, because more patients in the IM-yes group were treated in an earlier era, there were more patients with indeterminate pathologic margin status in the IM-yes group (p ⬍ 0.001) compared to the IM-no group. Patients in the IM-no group were more likely to have T1 tumors (p ⫽ 0.01) and less likely to receive adjuvant systemic therapy (chemotherapy ⫹ hormone therapy, p ⫽ 0.03). There were no significant differences between the IM-yes and IM-no group at 10 years with respect to OS (72% IM-yes vs. 84% IM-no, p ⫽ NS, Fig. 2) or DMFS (77% IM-yes vs. 87% IM-no, p ⫽ NS, Fig. 3). Patients in the IM-no group, however, had significantly higher BRFS rates at 10 years than patients in the IM-yes group (84% IM-yes vs. 94% IM-no, p ⬍ 0.001, Fig. 4). This difference in breast relapse rate is likely due to increased attention to the status of the surgical margins and increased use of systemic therapy in later years, when internal mammary radiation was less likely to be utilized. It was evident from the above that there were no substantial benefits noted in the IM-yes group of patients. Subset analyses were done to determine if there was an advantage to IMNR in any subgroup likely to derive a benefit from such treatment. Subset analysis in the node-positive patients
revealed that although there was a trend toward better outcome in the IM-no group, there were no significant differences between the IM-yes and IM-no groups at 10 years with respect to OS (68% IM-yes vs. 76% IM-no, Fig. 5), BRFS (85% IM-yes vs. 96% IM-no), or DMFS (64% IM-yes vs. 82% IM-no, p ⬍ 0.2) (Figure 6). To further determine if any subsets of patients specifically benefited from IMNR, subset analyses were performed evaluating patients by age (⬍ 50 vs. ⱖ 50), number of positive nodes (1–3 vs. 4 or more), location of tumor (medial vs. lateral lesions and right vs. left breast), and the combination of medial/central lesions and positive nodes. Finally, a subset analysis of those patients treated to the internal mammary chain by a separate field or by inclusion of the internal mammary chain in “deep tangents” was performed. Most of the subset analyses showed a trend toward a more favorable outcome in the IM-no group, and none showed a benefit to the IM-yes group.
Table 3. Clinical outcomes of node-positive patients
Clinical status A, WD A, NED D, WD D, NED Site of recurrence None Breast only Nodes only Distant only Breast & nodes Breast & distant Nodes & distant
Total
IM-yes
IM-no
42 693 123 88
27 (5%) 345 (64%) 96 (18%) 67 (13%)
15 (4%) 348 (85%) 27 (7%) 21 (5%)
724 82 12 119 1 5 3
366 (68%) 358 (87%) 65 (12%) 17 (4%) 9 (2%) 3 (0.7%) 86 (16%) 33 (8%) 1 (0.2%) 0 (0%) 5 (1%) 0 (0%) 3 (0.6%) 0 (0%)
DISCUSSION The value of regional nodal irradiation for improved local control in node-positive breast cancer patients has been recognized for decades (1–9). Nevertheless, the routine use of adjuvant regional nodal irradiation fell out of favor due to conflicting reports, potential excessive cardiopulmonary toxicity, and the documented benefits of systemic therapy.
p-value p ⬍ 0.001
p ⬍ 0.001
A ⫽ alive; WD ⫽ with disease; NED ⫽ no evidence of disease; D ⫽ dead.
Fig. 3. DMFS: IM-yes versus IM-no.
Internal mammary nodal irradiation with BCS ⫹ RT
●
E. OBEDIAN
AND
B. G. HAFFTY
1001
Fig. 4. BRFS: IM-yes versus IM-no.
Fig. 6. Node-positive patients. DMFS: IM-yes versus IM-no.
However, two recent randomized trials (14, 15) with large patient numbers and long-term follow-up have sparked a renewed debate regarding the role of regional radiotherapy in node-positive breast cancer patients. Both of these trials applied techniques which utilized a separate IMN field. Given the results of these randomized trials, and the potential benefits of regional nodal irradiation to both mastectomy and conservatively-treated patients, current treatment practices must be evaluated. Because many centers do not routinely target the IMN in node-positive breast cancer patients, modifications in treatment technique may be warranted. Until the results of an ongoing EORTC trial, which is randomizing patients to breast tangential fields ⫹ IMNR ⫹ supraclavicular radiotherapy versus tangential fields alone becomes available, we must rely on retrospective data, such as those presented here, upon which to base clinical decision-making. Although retrospective, our data demonstrate no significant benefit to IMNR. It should be noted, however, that when IM nodes are not intentionally targeted with a separate field, a proportion of the IM nodes are often included in the tangential and/or the supraclavicular fields. Lymphoscintigraphic studies by Recht et al. have revealed that 80% of IM nodes are located within the first three intercostal spaces, and 50% of all IMNs are located within 1 cm from midline (17, 18). Therefore, our current practice of treating nodepositive patients with tangential fields with a medial border
at midline matched to a supraclavicular field may in fact have included a significant portion of the potentially critical IMNs (19). This analysis, however, is confounded by differences in staging, margin status, and use of adjuvant systemic therapy between the two groups. Patients in whom the internal mammary nodes were not intentionally targeted were treated in a more modern era, and were therefore more likely to receive adjuvant systemic therapy and less likely to have indeterminate pathologic margins, which may explain the difference observed in BRFS. In addition, earlier stage of disease (smaller T-sizes and less involved lymph nodes) in the IM-no group gives these patients a more favorable prognosis. Subset analyses, however, failed to identify any groups in which IMNR was particularly beneficial. Even among nodepositive patients in our study, the use of IMNR did not appear to confer a survival advantage. This held true even in patients with four or more positive nodes. IMNR also did not appear to improve outcome in patients with medial breast tumors. Although this conflicts with some series (20 –22), but concurs with other reports (10, 11, 23), as mentioned before, the tangential and supraclavicular fields may have included a proportion of the IMN. In addition, almost all node-positive patients in our series received adjuvant systemic therapy. Acknowledging the limitations of this retrospective analysis, no benefit could be attributed to a separate IMN field in any subset analyzed. A recent meta-analysis of randomized trials comparing CS ⫹ RT with mastectomy reported a survival advantage to CS ⫹ RT over mastectomy in selected node-positive patients (24). In this meta-analysis, those node-positive patients treated with CS ⫹ RT fared better than mastectomy patients who did not receive radiation therapy. It is noteworthy that this benefit was also observed in trials which employed radiation techniques that did not intentionally target the IMN. These results imply that the conservativelytreated patients may have derived a benefit from radiation to the breast/chest wall and not specifically from IMNR (25). The results from our series also suggest that intentional targeting of the IMN may not be necessary to derive the benefit of regional nodal irradiation. IMNR has been associated with compromised cosmetic
Fig. 5. Node-positive patients. OS: IM-yes versus IM-no.
1002
I. J. Radiation Oncology
●
Biology
●
Physics
Fig. 7. Demonstration of matchline fibrosis in a patient treated with a separate internal mammary field.
outcome and cardiopulmonary toxicity. With a separate IMN field, matchline fibrosis between the tangential and internal mammary field may compromise cosmetic outcome. Figure 7 demonstrates matchline fibrosis associated with use of a separate IM field. Although in this study we did not address the issue of coronary artery disease, pneumonitis or other complications which may be attributed to IMNR, patients in the IM-no group had an overall survival equivalent to, if not better than, patients in the IM-yes
Volume 44, Number 5, 1999
group. Recent studies suggest, however, that if modern techniques and careful treatment planning approaches are employed, significant cardiac and/or pulmonary complications can be avoided (26, 27). We acknowledge the limitations associated with this retrospective analysis. Given the available literature, its controversies and uncertainties, there is no clearly defined standard of care with respect to the appropriate treatment or exclusion of the internal mammary chain in the management of breast cancer. Based on the radiation oncologist’s own interpretation and biases, there may be clinical situations where one may choose to specifically target the IMN. In these instances, our current practice is to obtain a treatment planning CT scan and attempt to include the IMN using deep tangents with specific attention to minimizing the volume of heart and lung in the field. Alternatively, a separate en face or angled IMN field could be treated, if necessary, using electrons and/or mixed photons/electrons (19, 28). In either case, care should be taken to minimize the amount of normal heart and lung in the field, particularly in patients receiving cytotoxic chemotherapy. In summary, no significant advantage in this retrospective analysis could be attributed to IMNR in conservativelytreated breast cancer patients even for medial or nodepositive tumors. This is significant given that there are no mature prospective randomized trials comparing postoperative RT with and without IMN fields. Until the results of an ongoing EORTC randomized trial addressing this issue become available, it appears from this retrospective analysis that it remains acceptable clinical practice to continue to treat node-negative and node-positive conservatively-managed patients with tangential fields with or without a matched supraclavicular field. Our study does not support the necessity of employing a separate internal mammary field. In those cases where, at the discretion of the radiation oncologist, deliberate targeting of the IMN is warranted, careful CT-based treatment planning techniques may be employed to minimize the amount of normal heart and lung in the treatment field.
REFERENCES 1. Fowble B, Solin LJ, Schultz DJ, et al. Frequency, sites of relapse, and outcome of regional node failure following conservative surgery and radiation for early breast cancer. Int J Radiat Oncol Biol Phys 1989;17:703–710. 2. 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. 3. 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. 4. Haffty BG, Fischer D, Fischer JJ. Regional nodal irradiation in the conservative treatment of breast cancer. Int J Radiat Oncol Biol Phys 1990;19:859 – 865. 5. Arriagada R, Rutqvist LE, Mattsson A, et al. Adequate
6.
7.
8.
9.
locoregional treatment for early breast cancer may prevent secondary dissemination. J Clin Oncol 1995;13:2869 – 2878. Wallgren A, Arner O, Bergstrom J, et al. Radiation therapy in operable breast cancer: Results from the Stockholm trial on adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 1986;12: 533–537. Wallgren A, Arner O, Bergstrom J, et al. The value of preoperative radiotherapy in operable mammary carcinoma. Int J Radiat Oncol Biol Phys 1980;6:287–290. Host H, Brenhovd IO, Loeb M. Postoperative radiotherapy in breast cancer—long-term results from the Oslo study. Int J Radiat Oncol Biol Phys 1986;12:727–732. Fletcher GH, McNeese MD, Oswald MJ. Long-range results for breast cancer patients treated by radical mastectomy and
Internal mammary nodal irradiation with BCS ⫹ RT
10.
11. 12. 13. 14.
15. 16. 17.
18. 19.
postoperative radiation without adjuvant chemotherapy: An update. Int J Radiat Oncol Biol Phys 1989;17:11–14. Fisher B, Redmond C, Fisher ER, et al. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med 1985;312:674 – 681. Fisher B, Wolmark N, Redmond C, et al. Findings from NSABP protocol no. Bl-04. Cancer 1981;48:1863–1872. Yarnold JR. Selective avoidance of lymphatic irradiation in the conservative management of breast cancer. Radiother Oncol 1984;2:79 –92. Cuzick J, Stewart H, Peto R, et al. Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer. Cancer Treat Rep 1987;71:15–29. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949 –955. 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. Cox DR. Regression models and life tables. JR Stat Soc 1992;B34:187–220. Recht A, Siddon RL, Kaplan, et al. Three-dimensional internal mammary lymphoscintigraphy: Implications for radiation therapy treatment planning for breast carcinoma. Int J Radiat Oncol Biol Phys 1988;14:477– 481. Kaplan WD, Andersen JW, Siddon RL, et al. The threedimensional localization of internal mammary lymph nodes by radionuclide lymphoscintigraphy. J Nucl Med 1988;29:473– 478. Marks LB, Heber ME, Bentel B, et al. To treat or not to treat
20.
21.
22.
23.
24.
25.
26.
27. 28.
●
E. OBEDIAN
AND
B. G. HAFFTY
1003
the internal mammary nodes: A possible compromise. Int J Radiat Oncol Biol Phys 1994;29:903–909. Le MG, Arriagada R, de Vathaire F, et al. Can internal mammary chain treatment decrease the risk of death for patients with medial breast cancers and positive axillary lymph nodes? Cancer 1990;66:2313–2318. Arriagada R, Le MG, Mouriesse L, et al. Long-term effect of internal mammary chain treatment. Results of a multivariate analysis of 1195 patients with operable breast cancer and positive axillary nodes. Radiother Oncol 1988;11:213–222. Fletcher GH, Montague ED. Does adequate irradiation of the internal mammary chain and supraclavicular nodes improve survival rates? Int J Radiat Oncol Biol Phys 1978;4: 481– 492. Veronesi U, Cascinelli N, Greco M, et al. Prognosis of breast cancer patients after mastectomy and dissection of internal mammary nodes. Ann Surg 1985;202:702–707. Morris AD, Morris RD, Wilson JF, et al. Breast-conserving therapy vs mastectomy in early-stage breast cancer: A metaanalysis of 10-year survival. Cancer J Sci Am 1997;3:6 –12. Haffty BG, Ward BA. Is breast-conserving surgery with radiation superior to mastectomy in selected patients? Cancer J Sci Am 1997;3:2–3. 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 1994;12:447– 453. Pierce LJ, Lichter AS. Postmastectomy radiotherapy: More than locoregional control. J Clin Oncol 1994;12:444 – 446. Kuske RR. Diagnosis and management of inflammatory breast cancer. Semin Radiat Oncol 1994;4:270 –282.
PII S0360-3016(99)00135-2
CLINICAL INVESTIGATION
Breast
INTERNAL MAMMARY NODAL IRRADIATION IN CONSERVATIVELYMANAGED BREAST CANCER PATIENTS: IS THERE A BENEFIT? EDWARD OBEDIAN, M.D.
AND
BRUCE G. HAFFTY, M.D.
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT Purpose: Recent randomized trials have demonstrated a significant benefit to postmastectomy radiation in node-positive breast cancer patients. The contribution of internal mammary nodal radiation (IMNR) to this benefit remains controversial, and in conservatively-treated patients (CS ⴙ RT), may compromise cosmesis and contribute to morbidity. The purpose of this retrospective analysis is to evaluate outcome as a function of IMNR in a cohort of breast cancer patients treated with CS ⴙ RT. Patients and Methods: Between January 1970 and December 1990, 984 patients with invasive breast cancer were treated at our facility with CS ⴙ RT, and serve as the base for this study. Of these patients, 399 patients had pathologically-negative lymph nodes, 167 (17%) had pathologically-involved lymph nodes, and 381 did not undergo lymph node dissection. The majority of node-positive patients received adjuvant systemic therapy (94%) and were treated with tangential fields matched to a separate supraclavicular field (95%) with or without IMNR. For this analysis, patients were divided into two groups: those treated by intentionally targeting the internal mammary nodes (IM-yes, n ⴝ 535) and without intentionally targeting the internal mammary nodes (IM-no, n ⴝ 411). In the IM-no group, the medial border was typically placed at midline. The decision not to use a separate internal mammary field was a result of a change in treatment policy over time, and generally not based on number of nodes or tumor location. Results: As of August 1998, with a median follow-up of 13 years, the overall survival at 10 years is 76%, the distant disease-free survival is 81%, and the breast relapse-free survival is 88%. There were no significant differences between the IM-yes and IM-no groups with respect to age, ER/PR status, or use of adjuvant chemotherapy or hormone therapy. There were more patients with T2 tumors, positive nodes, medial lesions, indeterminate margins, and slightly longer follow-up in the IM-yes group compared to the IM-no group. Although there was a trend toward better outcome in the IM-no group, there were no significant differences between the IM-yes and IM-no groups with respect to overall survival (72% IM-yes vs. 84% IM-no, p ⴝ NS) or distant metastasis-free survival (64% IM-yes vs. 82% IM-no, p ⴝ NS). Subset analysis showed no benefit in the IM-yes group regardless of age, number of nodes, or location. Conclusion: In this retrospective analysis, no benefit could be attributed to IMNR in conservatively-treated breast cancer patients, even if node-positive or medial in location. Until results of an ongoing EORTC randomized trial addressing this issue are available, these data suggest that it is acceptable to continue to treat node-positive conservatively-managed patients to tangential fields usually matched to a supraclavicular field, but without a separate internal mammary field. © 1999 Elsevier Science Inc. Breast cancer, Radiation therapy, Internal mammary lymph nodes.
INTRODUCTION
therapy (RT) in patients with Stage II and III breast cancer (14, 15). In both trials, patients were treated with cytotoxic chemotherapy and were randomized to receive or not receive RT using a five-field technique, which included a separate IMN field. Whether IMNR significantly contributed to the survival advantage is unclear. Such a result, however, poses important implications for node positive patients undergoing a breast conserving treatment approach (CS ⫹ RT). Should IMNR be considered in these patients? The potential risks of IMNR in conservatively-treated patients potentially include compromised cosmetic outcomes as well as cardiopulmonary complications, especially if
The role of regional nodal irradiation in node-positive breast cancer patients is controversial (1– 4). In the past, some studies reported a benefit (5–9), whereas other studies failed to confirm these findings (10 –12). Decreased survival rates have also been associated with regional nodal irradiation, especially internal mammary nodal radiation (IMNR), presumably secondary to older techniques delivering relatively high doses to the underlying normal cardiac and pulmonary structures (13). Recent randomized trials, however, have demonstrated a significant survival advantage to postmastectomy radiation Reprint requests to: Bruce G. Haffty, M.D., Department of Therapeutic Radiology, Yale University School of Medicine, P.O. Box 208040, New Haven, CT 06520-8040. Tel: (203) 785-2959;
Fax: (203) 785-4622; E-mail: [email protected] Accepted for publication 30 March 1999. 997
998
I. J. Radiation Oncology
●
Biology
●
Physics
combined with chemotherapeutic agents employing adriamycin- or taxol-based regimens with or without dose intensification. At Yale-New Haven Hospital (YNHH), the conservative management of breast cancer has been utilized with increasing frequency over the past 25 years. In earlier years (1970 through the mid-1980s), IMN were routinely targeted with either deep tangential fields or separate IM fields. Currently, the standard treatment practice at our institution is not to intentionally target the IMN in patients undergoing CS ⫹ RT. In light of the recent randomized trials, however, the utility of elective IMNR in patients must be reassessed. The change in treatment policy over time at our institution affords us a unique opportunity to evaluate the potential benefit of IM irradiation. The purpose of this retrospective analysis is to evaluate outcome in a large cohort of breast cancer patients undergoing CS ⫹ RT as a function of IMNR. Acknowledging the limitations of such retrospective analysis, until prospective randomized data become available, this experience represents one of the largest reported series directly addressing this issue in conservatively treated breast cancer patients. PATIENTS AND MATERIALS Between January 1970 and December 1990, 984 patients with early-stage invasive breast cancer have undergone conservative management at YNHH, and serve as the population base for this study. All patients were treated by wide local excision with or without axillary nodal dissection, followed by radiation therapy to the intact breast and regional nodes as outlined below. Among these, 167 patients had pathologically involved axillary nodal metastases, 399 had pathologically negative nodes and 381 did not undergo axillary dissection, reflecting treatment policies during the earlier years of the study. Patient charts were retrospectively reviewed. All patient data including demographic, staging, pathologic, treatment, and outcome parameters were entered into a computerized database (Prodas, Conceptual Software Inc.). In the current study, specific attention was directed to the radiation therapy technique employed, which is summarized in Table 1. Patients were treated with tangential breast fields with or without supraclavicular/axillary and/or IMN fields. The majority of node-positive patients (95%) were treated with a separate supraclavicular or supraclavicular and axillary field. The isocenter of this field was set at the match line to the tangential fields half blocked at the central axis to avoid divergence into the tangential field. The medial border was set at the patient’s midline and angled 15 degrees off the spinal cord. The dose was specified to a depth of 3 cm, and the median dose to this field was 4,600 cGy. In earlier years, the majority of patients were also treated with a separate IMN field, regardless of whether they were node-positive, node-negative, or in the no axillary dissection group. The IMN field was generally 6-cm wide, typically set 1 cm across midline to the contralateral breast, and
Volume 44, Number 5, 1999
Table 1. Treatment technique and doses Treatment technique
All patients
IM-yes
IM-no
n Tangents alone Tangents ⫹ supraclavicular Tangents ⫹ supraclav ⫹ axilla Tangents ⫹ supraclav ⫹ IMN Tangents ⫹ supraclav ⫹ axilla ⫹ IMN Median dose (range, Gy): Intact breast Tangents Supraclavicular nodal region Internal mammary nodal region
946 (100%) 221 (23%)
535 (100%) 1 (0.2%)
411 (100%) 220 (54%)
106 (11%)
9 (1.7%)
97 (24%)
128 (13%)
41 (7.7%)
87 (21%)
229 (24%)
229 (43%)
0
225 (24%)
225 (48%)
0
64 (40–96) 50 (20–70)
64 (40–96) 48 (20–70)
64 (46–82) 52 (32–64)
46 (0–62)
46 (0–55)
44 (0–62)
46 (0–62)
46 (20–54)
0
5 cm toward the ipsilateral side. The field was treated en face with mixed photons and electrons (usually 6 MV photons with 13 MeV electrons). In a minority of patients, orthovoltage photons were employed in lieu of electrons. In a small number of patients (56/535 or 10%), the IMN chain was included in “deep tangent” fields, with the medial border placed 3–5 cm to the contralateral side. The median dose delivered to the IMN field was 4,600 cGy specified at a depth of 3 cm. Although CT scanning and/or lymphoscintigraphy were not performed during this time period, these landmarks were standard, and presumably included the internal mammary chain in the majority of patients. In the mid-1980s, a rapid shift in the treatment technique took place, in that separate IMN fields were no longer routinely employed. In addition, although the entire breast tissue was covered, no specific attempt was generally made to use “deep tangents” to obtain adequate coverage of the IMN region. The decision not to intentionally target the IMN region was a result of a change in treatment policy over time, and generally not based on the number of involved axillary nodes or tumor location. In patients treated without a separate IMN field, the medial border of the tangential fields was typically placed at the patient’s midline. This change in treatment technique over time afforded us a unique opportunity to evaluate the potential benefit, or lack thereof, of intentionally irradiating the IMN in nodepositive conservatively-treated breast cancer patients. For this analysis, the patients were divided into two groups: those treated with deep tangential or separate IM fields (IM-yes, n ⫽ 535), and those treated without intentionally targeting the IMN (IM-no, n ⫽ 411). The two groups of patients were compared with respect to age, T-stage, number of axillary nodes involved, number of axillary nodes dissected, location of the tumor (right vs. left breast and upper outer quadrant vs. lower outer quadrant vs. upper inner quadrant vs. lower inner quadrant vs. central
Internal mammary nodal irradiation with BCS ⫹ RT
●
E. OBEDIAN
AND
B. G. HAFFTY
999
Table 2. Patient characteristics
n Median follow-up (range, years) Median age (range, years) Age ⬎ 50 Age ⬍ 50 T-stage T1 T2 T3 Status of axillary node dissection Node negative Node positive 1–3 ⬎ /4 No. axillary nodes dissected median (range) Margins Unknown Negative Close Positive Receptor status ER⫺ ER⫹ PR⫺ PR⫹ Location of tumor Right breast Left breast Location of lesion Medial (inner quadrant ⫹ central) Outer quadrant Adjuvant systemic therapy No Yes Chemotherapy No Yes Hormone therapy No Yes
All patients
IM-yes
IM-no
(p-value)
946 13 (7–37) 57 (20–86) 654 292
535 15 (7–37) 58 (20–86) 361 (67%) 174 (33%)
411 11.5 (7–25) 57 (26–85) 293 (71%) 118 (29%)
690 249 7
375 (70%) 164 (29%) 5 (1%)
315 (77%) 85 (22%) 2 (1%)
399
162 (62%)
237 (78%)
113 53
62 (24%) 37 (14%)
51 (17%) 16 (5%)
15 (4–31)
15 (4–29)
16 (8–31)
487 277 47 55
353 (72%) 92 (19%) 21 (4%) 26 (5%)
134 (36%) 185 (49%) 26 (7%) 29 (8%)
p ⬍ 0.001
215 423 245 307
120 (33%) 243 (67%) 126 (40%) 193 (60%)
95 (35%) 180 (65%) 119 (51%) 114 (53%)
0.73
461 481
267 (50%) 266 (50%)
194 (51%) 215 (49%)
0.40
784 560
236 (44%) 297 (56%)
148 (36%) 263 (64%)
p ⫽ 0.01
622 323
367 (69%) 167 (31%)
255 (62%) 156 (38%)
p ⫽ 0.03
765 179
441 (81%) 92 (17%)
324 (79%) 87 (21%)
0.125
755 186
431 (81%) 102 (19%)
324 (79%) 84 (21%)
0.59
0.001 0.16
0.01
p ⫽ 0.05 0.77
lesions), margin status, ER/PR status, use of adjuvant systemic therapy (chemotherapy and/or hormonal therapy), and method of tumor detection (mammography and/or physical examination). Of note, 94% of node-positive patients received adjuvant systemic therapy. The chemotherapy regimen employed was CMF in the majority of patients, with less than 10% receiving adriamycin-based therapy. Dates of local recurrence, nodal recurrence, and distant metastases, as well as dates of death and dates last seen alive, were all documented. From this information, overall survival (OS), breast relapse-free survival (BRFS), and distant metastasis-free survival (DMRFS) rates were calculated using the life table method. Survival rates were calculated from the date of breast cancer diagnosis to the date last seen, or to the date of death, whichever came earlier. All tests for statistical significance were performed using the Mantel-
Haensel model for survival curves and the Chi-square test for categorical variables (16). RESULTS Patient characteristics are listed in Table 2. As of August 1998, the median follow-up is 13 years for the entire cohort of patients. The OS, BRFS, and DMRFS rates at 10 years are 76%, 88%, and 81%, respectively (Fig.1). The clinical outcomes, including sites of recurrent disease in the patient population studied, are listed in Table 3. There were no statistically significant differences between the IM-yes and IM-no groups with respect to age, ER/PR status, or use of adjuvant chemotherapy or hormonal therapy. There was a slightly longer follow-up in the IM-yes group, and more patients with medial tumors and positive
1000
I. J. Radiation Oncology
●
Biology
●
Physics
Volume 44, Number 5, 1999
Fig. 1. OS, BRFS, and DMFS: all patients.
Fig. 2. OS: IM-yes versus IM-no.
axillary lymph nodes. In addition, because more patients in the IM-yes group were treated in an earlier era, there were more patients with indeterminate pathologic margin status in the IM-yes group (p ⬍ 0.001) compared to the IM-no group. Patients in the IM-no group were more likely to have T1 tumors (p ⫽ 0.01) and less likely to receive adjuvant systemic therapy (chemotherapy ⫹ hormone therapy, p ⫽ 0.03). There were no significant differences between the IM-yes and IM-no group at 10 years with respect to OS (72% IM-yes vs. 84% IM-no, p ⫽ NS, Fig. 2) or DMFS (77% IM-yes vs. 87% IM-no, p ⫽ NS, Fig. 3). Patients in the IM-no group, however, had significantly higher BRFS rates at 10 years than patients in the IM-yes group (84% IM-yes vs. 94% IM-no, p ⬍ 0.001, Fig. 4). This difference in breast relapse rate is likely due to increased attention to the status of the surgical margins and increased use of systemic therapy in later years, when internal mammary radiation was less likely to be utilized. It was evident from the above that there were no substantial benefits noted in the IM-yes group of patients. Subset analyses were done to determine if there was an advantage to IMNR in any subgroup likely to derive a benefit from such treatment. Subset analysis in the node-positive patients
revealed that although there was a trend toward better outcome in the IM-no group, there were no significant differences between the IM-yes and IM-no groups at 10 years with respect to OS (68% IM-yes vs. 76% IM-no, Fig. 5), BRFS (85% IM-yes vs. 96% IM-no), or DMFS (64% IM-yes vs. 82% IM-no, p ⬍ 0.2) (Figure 6). To further determine if any subsets of patients specifically benefited from IMNR, subset analyses were performed evaluating patients by age (⬍ 50 vs. ⱖ 50), number of positive nodes (1–3 vs. 4 or more), location of tumor (medial vs. lateral lesions and right vs. left breast), and the combination of medial/central lesions and positive nodes. Finally, a subset analysis of those patients treated to the internal mammary chain by a separate field or by inclusion of the internal mammary chain in “deep tangents” was performed. Most of the subset analyses showed a trend toward a more favorable outcome in the IM-no group, and none showed a benefit to the IM-yes group.
Table 3. Clinical outcomes of node-positive patients
Clinical status A, WD A, NED D, WD D, NED Site of recurrence None Breast only Nodes only Distant only Breast & nodes Breast & distant Nodes & distant
Total
IM-yes
IM-no
42 693 123 88
27 (5%) 345 (64%) 96 (18%) 67 (13%)
15 (4%) 348 (85%) 27 (7%) 21 (5%)
724 82 12 119 1 5 3
366 (68%) 358 (87%) 65 (12%) 17 (4%) 9 (2%) 3 (0.7%) 86 (16%) 33 (8%) 1 (0.2%) 0 (0%) 5 (1%) 0 (0%) 3 (0.6%) 0 (0%)
DISCUSSION The value of regional nodal irradiation for improved local control in node-positive breast cancer patients has been recognized for decades (1–9). Nevertheless, the routine use of adjuvant regional nodal irradiation fell out of favor due to conflicting reports, potential excessive cardiopulmonary toxicity, and the documented benefits of systemic therapy.
p-value p ⬍ 0.001
p ⬍ 0.001
A ⫽ alive; WD ⫽ with disease; NED ⫽ no evidence of disease; D ⫽ dead.
Fig. 3. DMFS: IM-yes versus IM-no.
Internal mammary nodal irradiation with BCS ⫹ RT
●
E. OBEDIAN
AND
B. G. HAFFTY
1001
Fig. 4. BRFS: IM-yes versus IM-no.
Fig. 6. Node-positive patients. DMFS: IM-yes versus IM-no.
However, two recent randomized trials (14, 15) with large patient numbers and long-term follow-up have sparked a renewed debate regarding the role of regional radiotherapy in node-positive breast cancer patients. Both of these trials applied techniques which utilized a separate IMN field. Given the results of these randomized trials, and the potential benefits of regional nodal irradiation to both mastectomy and conservatively-treated patients, current treatment practices must be evaluated. Because many centers do not routinely target the IMN in node-positive breast cancer patients, modifications in treatment technique may be warranted. Until the results of an ongoing EORTC trial, which is randomizing patients to breast tangential fields ⫹ IMNR ⫹ supraclavicular radiotherapy versus tangential fields alone becomes available, we must rely on retrospective data, such as those presented here, upon which to base clinical decision-making. Although retrospective, our data demonstrate no significant benefit to IMNR. It should be noted, however, that when IM nodes are not intentionally targeted with a separate field, a proportion of the IM nodes are often included in the tangential and/or the supraclavicular fields. Lymphoscintigraphic studies by Recht et al. have revealed that 80% of IM nodes are located within the first three intercostal spaces, and 50% of all IMNs are located within 1 cm from midline (17, 18). Therefore, our current practice of treating nodepositive patients with tangential fields with a medial border
at midline matched to a supraclavicular field may in fact have included a significant portion of the potentially critical IMNs (19). This analysis, however, is confounded by differences in staging, margin status, and use of adjuvant systemic therapy between the two groups. Patients in whom the internal mammary nodes were not intentionally targeted were treated in a more modern era, and were therefore more likely to receive adjuvant systemic therapy and less likely to have indeterminate pathologic margins, which may explain the difference observed in BRFS. In addition, earlier stage of disease (smaller T-sizes and less involved lymph nodes) in the IM-no group gives these patients a more favorable prognosis. Subset analyses, however, failed to identify any groups in which IMNR was particularly beneficial. Even among nodepositive patients in our study, the use of IMNR did not appear to confer a survival advantage. This held true even in patients with four or more positive nodes. IMNR also did not appear to improve outcome in patients with medial breast tumors. Although this conflicts with some series (20 –22), but concurs with other reports (10, 11, 23), as mentioned before, the tangential and supraclavicular fields may have included a proportion of the IMN. In addition, almost all node-positive patients in our series received adjuvant systemic therapy. Acknowledging the limitations of this retrospective analysis, no benefit could be attributed to a separate IMN field in any subset analyzed. A recent meta-analysis of randomized trials comparing CS ⫹ RT with mastectomy reported a survival advantage to CS ⫹ RT over mastectomy in selected node-positive patients (24). In this meta-analysis, those node-positive patients treated with CS ⫹ RT fared better than mastectomy patients who did not receive radiation therapy. It is noteworthy that this benefit was also observed in trials which employed radiation techniques that did not intentionally target the IMN. These results imply that the conservativelytreated patients may have derived a benefit from radiation to the breast/chest wall and not specifically from IMNR (25). The results from our series also suggest that intentional targeting of the IMN may not be necessary to derive the benefit of regional nodal irradiation. IMNR has been associated with compromised cosmetic
Fig. 5. Node-positive patients. OS: IM-yes versus IM-no.
1002
I. J. Radiation Oncology
●
Biology
●
Physics
Fig. 7. Demonstration of matchline fibrosis in a patient treated with a separate internal mammary field.
outcome and cardiopulmonary toxicity. With a separate IMN field, matchline fibrosis between the tangential and internal mammary field may compromise cosmetic outcome. Figure 7 demonstrates matchline fibrosis associated with use of a separate IM field. Although in this study we did not address the issue of coronary artery disease, pneumonitis or other complications which may be attributed to IMNR, patients in the IM-no group had an overall survival equivalent to, if not better than, patients in the IM-yes
Volume 44, Number 5, 1999
group. Recent studies suggest, however, that if modern techniques and careful treatment planning approaches are employed, significant cardiac and/or pulmonary complications can be avoided (26, 27). We acknowledge the limitations associated with this retrospective analysis. Given the available literature, its controversies and uncertainties, there is no clearly defined standard of care with respect to the appropriate treatment or exclusion of the internal mammary chain in the management of breast cancer. Based on the radiation oncologist’s own interpretation and biases, there may be clinical situations where one may choose to specifically target the IMN. In these instances, our current practice is to obtain a treatment planning CT scan and attempt to include the IMN using deep tangents with specific attention to minimizing the volume of heart and lung in the field. Alternatively, a separate en face or angled IMN field could be treated, if necessary, using electrons and/or mixed photons/electrons (19, 28). In either case, care should be taken to minimize the amount of normal heart and lung in the field, particularly in patients receiving cytotoxic chemotherapy. In summary, no significant advantage in this retrospective analysis could be attributed to IMNR in conservativelytreated breast cancer patients even for medial or nodepositive tumors. This is significant given that there are no mature prospective randomized trials comparing postoperative RT with and without IMN fields. Until the results of an ongoing EORTC randomized trial addressing this issue become available, it appears from this retrospective analysis that it remains acceptable clinical practice to continue to treat node-negative and node-positive conservatively-managed patients with tangential fields with or without a matched supraclavicular field. Our study does not support the necessity of employing a separate internal mammary field. In those cases where, at the discretion of the radiation oncologist, deliberate targeting of the IMN is warranted, careful CT-based treatment planning techniques may be employed to minimize the amount of normal heart and lung in the treatment field.
REFERENCES 1. Fowble B, Solin LJ, Schultz DJ, et al. Frequency, sites of relapse, and outcome of regional node failure following conservative surgery and radiation for early breast cancer. Int J Radiat Oncol Biol Phys 1989;17:703–710. 2. 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. 3. 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. 4. Haffty BG, Fischer D, Fischer JJ. Regional nodal irradiation in the conservative treatment of breast cancer. Int J Radiat Oncol Biol Phys 1990;19:859 – 865. 5. Arriagada R, Rutqvist LE, Mattsson A, et al. Adequate
6.
7.
8.
9.
locoregional treatment for early breast cancer may prevent secondary dissemination. J Clin Oncol 1995;13:2869 – 2878. Wallgren A, Arner O, Bergstrom J, et al. Radiation therapy in operable breast cancer: Results from the Stockholm trial on adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 1986;12: 533–537. Wallgren A, Arner O, Bergstrom J, et al. The value of preoperative radiotherapy in operable mammary carcinoma. Int J Radiat Oncol Biol Phys 1980;6:287–290. Host H, Brenhovd IO, Loeb M. Postoperative radiotherapy in breast cancer—long-term results from the Oslo study. Int J Radiat Oncol Biol Phys 1986;12:727–732. Fletcher GH, McNeese MD, Oswald MJ. Long-range results for breast cancer patients treated by radical mastectomy and
Internal mammary nodal irradiation with BCS ⫹ RT
10.
11. 12. 13. 14.
15. 16. 17.
18. 19.
postoperative radiation without adjuvant chemotherapy: An update. Int J Radiat Oncol Biol Phys 1989;17:11–14. Fisher B, Redmond C, Fisher ER, et al. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med 1985;312:674 – 681. Fisher B, Wolmark N, Redmond C, et al. Findings from NSABP protocol no. Bl-04. Cancer 1981;48:1863–1872. Yarnold JR. Selective avoidance of lymphatic irradiation in the conservative management of breast cancer. Radiother Oncol 1984;2:79 –92. Cuzick J, Stewart H, Peto R, et al. Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer. Cancer Treat Rep 1987;71:15–29. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949 –955. 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. Cox DR. Regression models and life tables. JR Stat Soc 1992;B34:187–220. Recht A, Siddon RL, Kaplan, et al. Three-dimensional internal mammary lymphoscintigraphy: Implications for radiation therapy treatment planning for breast carcinoma. Int J Radiat Oncol Biol Phys 1988;14:477– 481. Kaplan WD, Andersen JW, Siddon RL, et al. The threedimensional localization of internal mammary lymph nodes by radionuclide lymphoscintigraphy. J Nucl Med 1988;29:473– 478. Marks LB, Heber ME, Bentel B, et al. To treat or not to treat
20.
21.
22.
23.
24.
25.
26.
27. 28.
●
E. OBEDIAN
AND
B. G. HAFFTY
1003
the internal mammary nodes: A possible compromise. Int J Radiat Oncol Biol Phys 1994;29:903–909. Le MG, Arriagada R, de Vathaire F, et al. Can internal mammary chain treatment decrease the risk of death for patients with medial breast cancers and positive axillary lymph nodes? Cancer 1990;66:2313–2318. Arriagada R, Le MG, Mouriesse L, et al. Long-term effect of internal mammary chain treatment. Results of a multivariate analysis of 1195 patients with operable breast cancer and positive axillary nodes. Radiother Oncol 1988;11:213–222. Fletcher GH, Montague ED. Does adequate irradiation of the internal mammary chain and supraclavicular nodes improve survival rates? Int J Radiat Oncol Biol Phys 1978;4: 481– 492. Veronesi U, Cascinelli N, Greco M, et al. Prognosis of breast cancer patients after mastectomy and dissection of internal mammary nodes. Ann Surg 1985;202:702–707. Morris AD, Morris RD, Wilson JF, et al. Breast-conserving therapy vs mastectomy in early-stage breast cancer: A metaanalysis of 10-year survival. Cancer J Sci Am 1997;3:6 –12. Haffty BG, Ward BA. Is breast-conserving surgery with radiation superior to mastectomy in selected patients? Cancer J Sci Am 1997;3:2–3. 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 1994;12:447– 453. Pierce LJ, Lichter AS. Postmastectomy radiotherapy: More than locoregional control. J Clin Oncol 1994;12:444 – 446. Kuske RR. Diagnosis and management of inflammatory breast cancer. Semin Radiat Oncol 1994;4:270 –282.