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Long-term outcome in patients with four or more positive lymph nodes treated with conservative surgery and radiation therapy
Int. J. Radiation
Biol.
Phys., Vol. 35, No. 4. pp. 679~-685. 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0360.3016/96 $lS.OO + .OO
PII: SO360-3016( 96)00015-6
ELSEVIER
l
Oncology
Clinical
Original
Contribution
LONG-TERM OUTCOME IN PATIENTS WITH FOUR OR MORE POSITIVE LYMPH NODES TREATED WITH CONSERVATIVE SURGERY AND RADIATION THERAPY KIRAN
MEHTA,
M.D. AND BRUCE G. HAFITY, M.D.
Department of Therapeutic Radiology, Yale University School of Medicine. New Haven, CT 06520 Purpose: The purpose of this study was to review management strategies with respect to systemic therapy, radiation therapy treatment techniques, and patient outcome (local regional control, distant metastases, and overall survival) in patients undergoing conservative surgery and radiation therapy (CS + RT) who had four or more lymph nodes involved at the time of original diagnosis. Methods and Materials: Of 1040 patients undergoing CS + RT at our institution prior to December 1989, 579 patients underwent axillary lymph node dissection. Of those patients undergoing axillary lymph node dissection, 167 had positive nodes and 51 of these patients had four or more positive lymph nodes involved and serve as the patient population base for this study. All patients received radiation therapy to the intact breast using tangential fields with subsequent electron beam boost to the tumor bed to a total median dose of 64 Gy. The majority of patients received regional nodal irradiation as follows: 40 patients received RT to the supraclavicular region without axilla to a median dose of 46 Gy, 10 patients received radiation to the supraclavlcular region and axllla to a median dose of 46 Gy. Thirty of the 51 patients received a separate internal mammary port with a mixed beam of photons and electrons. One patient received radiation to the tangents alone without regional nodal irradiation. Adjuvant systemic therapy was used in 49 of the 51 patients (96% ) with 27 patients receiving chemotherapy alone, 14 patients receiving cytotoxic chemotherapy and tamoxlfen, and 8 patients receiving tamoxifen alone. Results: As of December 1994, with a minimum evaluable follow-up of 5 years and a median follow-up of 9.29 years, there have been 18 distant relapses, 2 nodal relapses, and 5 breast relapses. Actuarial statistics reveal a lo-year distant metastases-free rate of 65%, lo-year nodal recurrence-free rate of 96%, and a loyear breast recurrence-free rate of 82%. All five patients who sustained a breast relapse were successfully salvaged with mastectomy. Both patients with nodal relapses (one supraclavicular and one axillarylsupraclavicular) failed within the irradiated volume. Of the 40 patients treated to the supraclavlcular fossa (omitting complete axillary radiation), none failed in the dissected axllla. With a median follow-up of nearly 10 years, 29 of the 51 patients (57%) remain alive without evidence of disease, 15 (29%) have died with disease, 2 (4%) remain alive with disease, and 5 (10%) have died without evidence of disease. Overall actuarial lo-year survival for these 51 patients is 58%. Conclusions: We conclude that in patients found to have four or more positive lymph nodes at the time of axlllary lymph node dissection, conservative surgery followed by radiation therapy to the intact breast with appropriate adjuvant systemic therapy results in a reasonable long-term survival with a high rate of local regional control. Omission of axillary radiation in this subset of patients appears appropriate because there were no axillary failures among the 41 dissected but unirradiated axillae. Breast cancer, Lymph nodes, Irradiation,
Conservative
INTRODUCTION
surgery, Chemotherapy.
Breast conservation with lumpectomy followed by radiation therapy to the intact breast is now widely accepted as an alternative to mastectomy for the majority of women with operable breast cancer. It has clearly been demonstrated in retrospective series as well as prospective randomized trials that patients with pathologically negative,
as well as patients with pathologically involved, axillary lymph nodes can be treated conservatively and enjoy a survival rate equivalent to their counterparts undergoing modified radical mastectomy (5, 7, 12). Those patients who have a pathologically negative axilla following axillary dissection may be adequately treated with tangential fields directed at the intact breast without regional nodal irradiation. There is considerable controversy and unset-
Reprint requests to: Bruce G. Haffty, M.D., Department of Therapeutic Radiology. Yale University School of Medicine,
P.O. Box 208040, New Haven, CT 06.520-8040. Accepted for publication 29 December 1995.40. 679
680
1. J. Radiation
Oncology
0 Biology
0 Physics
tled issues regarding optimal treatment techiques and outcome in patients with positive nodes undergoing breast conservation therapy ( 2, 6- 16). The purpose of the current study was to review our institution’s treatment policy and outcome in patients with four or more pathologically involved lymph nodes undergoing conservative surgery and radiation therapy. Specifically, we reveiwed our management practices with respect to the integration of systemic therapy and radiation therapy with particular attention to radiation therapy treatment techniques, patterns of failure, and long-term outcome in this group of patients. METHODS
AND
MATERIALS
A total of 1040 patients were treated with conservative surgery followed by radiation therapy to the intact breast at our institution prior to December 1989. The cut-off date of December 1989 was chosen so as to have a minimum evaluable follow-up of 5 years on all patients. Of these 1040 patients, 579 underwent axillary lymph node dissection. Axillary dissection was not routinely performed, particularly in the earlier years of the study if the treating physicians did not feel the results of the axillary lymph node dissection would influence decisions regarding systemic therapy (9). Of the 579 patients undergoing axillary lymph node dissection, 167 (29%) were noted to have pathologically involved axillary lymph nodes. Fifty-one of the 167 patients with pathologically involved lymph nodes (30%) had four or more lymph nodes involved at the time of diagnosis and serve as the patient population base for this study. Characteristics for these 51 patients are given in Table 1. All 51 patients underwent lumpectomy followed by axillary lymph node dissection. During this time interval, there was no specific attempt made to obtain nor document the pathologic margin status of the lumpectomy specimen. In most cases, the surgical approach was limited to a Level I and Level II axillary lymph node dissection. The median number of lymph nodes sampled was 16 and the median number of positive lymph nodes was 7 (range 4-21) (see Table 1). The pathologic reports were reviewed in detail to determine the degree of extracapsular extension of tumor. Unfortunately, this pathologic feature was not consistently reported on, particularly in the earlier years of the study. A total of 13 patients were specifically noted to have extracapsular extension of tumor. However, this is likely to be an underestimate (3, 14, 19). Following lumpectomy and axillary lymph node dissection, all patients were treated with radiation therapy using tangential fields directed at the intact breast. Patient contours were routinely obtained and appropriate wedges were used to obtain homogeneous dose distribution throughout the breast. Patients were treated to the whole breast to a total median dose of 48 Gy. In all patients, a boost was used via smaller tangential fields and/or electron beam to the tumor bed to a total median dose of 64
Volume
35, Number
3. I996
Table 1. Patient/tumor characteristics (n = 5 1) Age (years)50 Follow-up (years) 9.29 median (range 5.19-20/22) Clinical stage I 11 III Tumor size Median 2.5 cm (range 1-8 cm) Axillary dissection Lymph nodes sampled Lymph nodes positive 4-7 + lymph nodes 8- 10 f lymph nodes > 10 + lymph nodes Histology Infiltrating ductal Infiltrating lobular Other ER Positive Negative Unknown PR Positive Negative Unknown/not done
71 ‘9
20 77 1
16 median (4-31 range) 7 median (4-21 range) 32 9 10 48 1 2 18 19 14 18 16 17
Gy. Regional nodal irradiation was administered to 50 of the 51 patients (98%), while only 1 patient was treated to the breast alone. The radiation therapy treatment techniques are summarized in Table 2. Forty of the 50 patients (80%) received radiation therapy directed at the supraclavicular fossa, omitting axillary radiation. External beam radiation was administered to the supraclavicular fossa using a separate anterior beam half-blocked at the central axis. The field was angled 10-15” off of the spinal cord and extended medially from the midline and laterally to the medial border of the head of the humerus. The dose was generally prescribed at the central axis to a depth of 3 cm using a 6 MeV beam to a total median dose of 46 Gy. A typical supraclavicular treatment field is demonstrated in Fig. 1. The superior border of the tangential breast field was matched to the supraclavicular field clinically by angling the couch. Ten of the 5 1 patients (20%) received external beam radiation therapy to the supraclavicular fossa and axillary lymph nodes using a treatment technique similar to that described above, modified by extending the lateral border of the supraclavicular field laterally to include the entire humeral head and clear the entire axillary contents (8). The field was similarly treated to a total median dose of 46 Gy specified at a depth of 3 cm. Of these patients, none received a posterior axillary boost. The 10 patients receiving complete axillary radiation were treated in this fashion at the discretion of the treating radiation oncologist, and did not significantly differ from those treated to
Long-term outcome Table 2. Treatment
l
K. MEHTA
characteristics Number/percent
Lumpectomy & axillary lymph node dissection XRT Systemic Therapy Chemotherapy alone Tamoxifen alone Chemotherapy + tamoxifen
5 l/( 100%) 51/(100%) 49/(96%) 27 8 14 Median Dose
Number/percent Radiation Technique XRT to Breast Nodal XRT XRT to SCF XRT to SCF/axilla XRT to IM XRT: radiation ternal mammary.
51/(100%) 50/(98%) 40/(80%) 10/(20%) 35/(70%)
therapy: SCF: supraclavicular
64 Gy 46 Gy 46 Gy 46 Gy fossa; IM: in-
the supraclavicular field alone with respect to the primary tumor size and number of lymph nodes involved. Thirty-five of the 5 1 patients (69%) received radiation therapy to the internal mammary nodes with a separate en face field of photons mixed with 12 MeV electrons.
Fig. 1. Typical
supraclavicular
AND
B. G. HAFFTY
681
This field was also treated to a total median dose of 46 Gy specified at a depth of 3 cm. Although the internal mammary nodes may have been incidentally included in the tangential fields in those patients without a separate internal mammary (IM) field, there was no specific attempt made to document inclusion of the internal mammary nodes via lymph node scintigraphy or computer tomography (CT) -based treatment plans. Adjuvant systemic therapy was administered to 49 of the 5 1 patients (96% ) . Two of the 5 1 patients had refused any systemic therapy offered. Systemic cytotoxic chemotherapy alone was administered to 27 patients; 14 patients received a combination of systemic cytotoxic chemotherapy and hormonal therapy, while 8 patients received hormonal therapy alone. The specific systemic therapeutic regimens used are outlined in Table 3. Of the 41 patients receiving cytotoxic chemotherapy, 8 (20%) received all radiation prior to chemotherapy, 22 (54%) received radiation therapy concomittantly with cytotoxic chemotherapy, 6 (14%) received radiation therapy sandwiched between cycles of cytotoxic chemotherapy, and 5 patients ( 12%) received radiation therapy following completion of all systemic therapy (Table 3 ) . Patients were routinely followed by the radiation oncol-
fossa treatment field.
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I. .I. Radiation Oncology 0 Biology 0 Physics
Volume 35. Number 4, 1996
Table 3. Systemic therapy details Drugs CMF-based (CMF, CMFP, CMFVP) Doxorubicin-based (CAF) Other chemotherapy (S-FU/alkeran) (S-FU/MTX) Tamoxifen alone Sequence RT first followed by chemotherapy Concurrent RT + chemotherapy Sandwich chemotherapy-RT-chemotherapy Chemotherapy followed by RT
DISCUSSION 33 6
1 1 8 8 22 6
5
ogist along with the referring surgeon and medical oncologist. Annual mammography was an integral component of the follow-up program. Diagnostic studies for systemic disease were performed as clinically indicated and at the discretion of the referring physicians and radiation oncologist. Breast failure was defined as histologically confirmed reappearance of tumor in the ipsilateral breast. Regional nodal relapses were defined as failure in the ipsilateral axilla and/or supraclavicular fossa, while distant failure was defined as any clinical and/or radiographic evidence of metastatic disease. RESULTS As of December 1994, with a minimum evaluable follow-up of 5 years and a median follow-up of 9.29 years, the averall 5- and IO-year survival for the 51 patients are 86 and 58%, respectively. The crude survival and recurrence statistics are summarized in Table 4. Five patients experienced an ipsilateral breast tumor recurrence resulting in 5- and IO-year breast relapse-free survival rate of 96 and 82%, respectively. Only 1 of the 5 patients who experienced an ipsilateral breast tumor recurrence was from the group of patients with a delay in radiation of more than 16 weeks. Regional nodal relapses were noted in 2 qut of the 51 patients resulting in a 5- and loyear nodal recurrence-free survival rate of 96%. There were no internal mammary nodal failures in the group of 5 1 patients treated. Both patients experiencing a regional nodal failure were treated with treatment techniques encompassing the surpaclavicular fossa and axilla, and both of these failures were within the radiated port. Of the 40 patients treated to the supraclavicular fossa alone (omitting axillary radiation), none have failed in the dissected, but unirradiated. axilla. A total of 18 patients relapsed with clinical and/or radiographic evidence of metastatic disease resulting in a IO-year distant disease-free survival rate of 65% and, as noted above, a IO-year overall survival rate of 58%. As expected, those patients with more than seven nodes involved had a poorer distant disease-free and overall survival than those patients with four to seven nodes (Figs. 2 and 3).
The majority of patients with operable breast cancer are potential candidates for conservative surgery followed by radiation therapy to the intact breast with or without regional nodal irradiation. Despite a clinically negative axilla, approximately one-third of patients undergoing axillary dissection are found to have pathologically involved lymph nodes and approximately one-third of those patients will have four or more lymph nodes involved at the time of diagnosis (4, 7, 16- 19 ) . Although it is wellestablished and routinely accepted that those patients with histologically negative axillae may be adequately treated with tangential fields alone, considerable controversy exists regarding patients with histologically involved lymph nodes (2, 6-16). The current study was undertaken to review our treatment policies, patterns of failure, and long-term outcome in patients with four or more involved lymph nodes at the time of diagnosis undergoing conservative surgery followed by radiation therapy. Several other series have reviewed treatment strategies and patterns of failure in conservatively treated breast cancer patients (2, 6, 8 - 11, 16). Halverson et al. noted that the incidence of axillary failure was greater in those patients with four or more nodes than for patients with one to three lymph nodes involved. They concluded that there was little support for radiation to the supraclavicular fossa and axilla for patients with less than four nodes, but there were too few patients with four or more lymph nodes involved to make any firm recommendations in this group of patients ( 10). In a review of conservatively treated patients from the Joint Center, Recht et aE. reported a 2.3% actuarial nodal failure rate at 5 years. In that study, 431 patients had node-positive disease, and 108 had four or more positive nodes. The majority of patients in their series with four or more positive nodes (87 out of 108 or 80%) received radiation therapy to the supraclavicular fossa and axillae. Although they did not specifically report on arm edema Table 4. Pattern of failure/patient outcome Patient status
N
Percent
Breast relapse Nodal relapse Distant relapse Alive NED Dead NED Alive w/disease Dead w/disease
5
9.8 3.9
2
18 29 5
35.3
56.9 9.8 3.9 29.4
2
15
Actuarial Actuarial 5-yr survival 10-yr survival Overall survival Breast recurrence-free survival Nodal recurrence-free survival Distant recurrence-free survival Disease-free survival
86%
96% 96% 74% 70%
58% 82% 96% 65% 53%
Long-term
outcome
l
K.
MEHTA
AND
B. G.
683
HAFFTY
Distant Recurrence-Free Survival W)
Fig. 2. Distant disease-free survival by number of positive nodes.
in this study, a previous report from this institution indicated a significant degree of arm edema when axillary radiation was used in patients undergoing extensive lymph node dissection ( 16). They concluded that the radiation therapy to the axilla and supraclavicular fossa should not be routinely used following an adequate axillary lymph node dissection for patients with histologically negative nodes as well as for patients with one to three positive nodes, but made no firm conclusions or treatment recommendations for those patients with four or more involved lymph nodes ( 16). Most practicing radiation oncologists, however, continue to offer some form of regional nodal irradiation for patients with four or more involved lymph nodes. Several studies have demonstrated an acceptable regional nodal control rate with adequate axillary lymph node dissection (3, 6, 8, 10, 11, 14- 16, 19). There is considerable variability and controversy, however, regarding radiation treatment techniques specifically with regard to whether or not the axillary contents should be treated in patients with multiple positive axillary nodes (2, 3, 6-18). In the current study, radiation therapy to the supraclavicular fossa alone (omitting axillary radiation in the majority
of patients) resulted in an excellent regional nodal control rate. All of these patients had four or more nodes involved with the median number of involved nodes of seven. Although extracapsular extension was clearly documented in only 13 patients, it is reasonable to assume that the majority of these patients in fact had extracapsular nodal involvement. Pathological studies by Veronesi et al. ( 19) and Leonard et al. ( 14) have demonstrated extracapsular tumor extension in over 80% of patients with four or more lymph nodes involved at the time of axillary dissection. Studies by Siegel et al. and Leonard et al. also demonstrated a high axillary control rate with axillary dissection, omitting axillary radiation ( 14, 18). Based on these surgical series, as well as the current study, we feel that axillary radiation can safely be omitted even in the presence of extracapsular extension in patients with four or more lymph nodes involved provided an adequate lymph node dissection has been performed. However, a portion of the lower axillary contents would, by necessity, be routinely included in the tangential breast field. We continue to routinely treat the supraclavicular fossa in patients with four or more positive nodes, because this treatment policy has resulted in excellent regional nodal control and minimal added morbidity in patients undergoing breast conservation therapy.
Overal 1 w
oo2
4
6
8
Years
Fig. 3. Overall survival by number of positive nodes.
10
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1. J. Radiation Oncology l Biology 0 Physics
The majority of patients in the current study were treated to the internal mammary nodes via a separate en face field using a mixed beam of photons and electrons. Because internal mammary nodal failures are exceedingly rare, it is difficult to draw any firm conclusions regarding the benefit of internal mammary nodal irradiation (7- 10, 15, 16). Given the increasing tendency to use adriamycinbased systemic therapy and the potential added cardiac morbidity using a separate en face internal mammary field, we no longer routinely treat the internal mammary nodes. While the tangential breast field will incidentally include a portion of the internal mammary lymph nodes, no specific attempt with respect to CT treatment planning was made in the patients treated in this series to treat the internal mammary nodes in the 16 patients treated without a separate IM field. Currently, for those patients in whom internal mammary nodal radiation is felt to be clinically indicated or mandated by a protocol, we would recommend a treatment planning CT scan to design a treatment plan that would minimize the dose to the underlying cardiac and pulmonary structures. A second goal of this current study was to review the long-term outcome with respect to overall survival, disease-free survival, and distant metastases in this group of high risk patients with four or more lymph nodes involved at the time of diagnosis. Given the emerging treatment options with dose-intensive chemotherapy with or without peripheral stem cell or bone marrow transplant support, it is important to establish long-term results in historical control patients treated with conventional therapy. The majority of patients in the current series were treated with
Volume 35. Number 4, 1996 standard cytoxan, methotrexate, 5-fluorouracil ( CMF ) or cytoxan, adriamycin, 5fluorouracil (CAF) -based cytotoxic chemotherapy. Despite a median number of seven lymph nodes involved, these patients experienced a respectable IO-year survival rate of 58%. Although this is a selected group of patients with a median tumor size of 2.5 cm undergoing conservative treatment. these results compare favorably with other series of patients with four or more nodes invoIved and serve as a historical control with which to compare more dose-intenstive treatment strategies. Our overall actuarial lo-year survival rate of 58% is identical to the lo-year survival rate reported by Bonadonna et al. in their randomized trial of patients with four or more nodes receiving sequential adriamycin/CMF chemotherapy ( 1) . Current ongoing clinical trials will hopefully better define the role of dose-intensive chemotherapy with or without bone marrow or stem ceil support. Note that the current study, as well as others reported in the literature, demonstrates a realistic probability of long-term survival in those patients with four or more positive nodes who undergo breast-conserving surgery followed by radiation therapy to the intact breast and regional lymph nodes with conventional adjuvant cytotoxic chemotherapy. We conclude that for patients with early stage operable breast cancer harboring four or more involved axillary lymph nodes, radiation therapy to the intact breast with regional nodal irradiation to the supraclavicular fossa combined with conventional adjuvant systemic therapy results in a high rate of local regional control and a reasonable probability of long-term survival.
REFERENCES 1. Bonadonna, G.; Zambetti, M.; Valagussa, P. Sequential or alternating doxombicin and CMF regiments in breast cancer with more than three positive nodes. JAMA 273:542547; 1995. 2. Dewar, J. A.; Sarrazin, D.; Benhanou, E.; Petit, J. Y.; Benhanou, S.; Arriagada, R.; Fontaine, F.; Castaigne, D.; Contesso, G. Management of the axilla in conservatively treated breast cancer: 592 patients treated at Institut Gustave Roussy. Int. J. Radiat. Oncol. Biol. Phys. 13:475-480; 1987. 3. Donegan, W. L.; Stine, S. B.; Sauter, T. G. Implications of extracapsular nodal metastasis for treatment and prognosis of breast cancer. Cancer 72:778-782; 1993. 4. Fisher, B.; Redmond, C.; Fisher, E. R.; Bauer, M.; Wolmark, N.; Wickerham, D. L.; Deutsch, M.; Montague, E.; Margolese, R.; Foster, R. Ten-year results of a randomzied clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N. Engl. J. Med. 312:674-681; 1985. 5. Fisher, B.; Redmond, C.; Poisson, R.; Margolese, R.; Wolmark. N.; Wickerham, L.; Fisher, E.; Duetsch, M.; Caplan, R.; Pilch, Y.; Glass, A.; Shibata, H.; Lemer, H.; Terz, J.; Sidorovich, L. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N. Engl. J. Med. 320:822-828; 1989. 6. Fowble, B.; Solin, L.; Schultz, D. J.; Goodman, R. L. Fre-
7.
8. 9. 10.
11.
12.
quency, sites of relapse, and outcome of regional node failures following conservative surgery and radiation for early breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 17:703710; 1989. Fowble, B.; Goodman, R. L.; Glick, J. H.; Rosato, E. F. Breast cancer treatment: A comprehensive guide to management. St. Louis, MO; Mosby-Year Book Inc.; 1991:128-129. Haffty, B. G.; Fischer, D.; Fischer, J. J. Regional nodal irradiation in the conservative treatment of breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 19:859-865; 1990. Haffty, B. G.; McKhann, C.; Beinfield, M.; Fischer, D.; Fischer, J. J. Breast conservation therapy without axillary dissection. Arch. Surg. 128:1315-1319; 1993. Halverson, K. J.; Taylor, M. E.; Perez, C. A.; Garcia, D. M.; Myerson, R.; Philpott, G.; Levy, J.; Simpson, J. R.; Tucher, G.; Rush, C. 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. 26:593-599; 1993. Hoskin, P. J.; Rajan, B.; Ebbs, S.; Tait, D.; Milan, S.; Yamold, J. R. Selective avoidance of lymphatic radiotherapy in the conservative management of early breast cancer. Radiother. Oncol. 25:83-88; 1992. Jacobson, J. A.; Danforth, D. N.; Cowan, K. H.; D’ Angelo, T.; Steinberg, S. M.; Pierce, L.; Lippman, M. E.; Lichter, A. S.; Glatstein, E.; Okunieff, P. Ten-year results of a com-
Long-term outcome
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parisonof conservationwith mastectomyin the treatment of stageI and II breastcancer.N. Engl. J. Med. 332:907911; 1995. 13. Larson,D.; Weinstein,M.; Goldberg, I.; Silver, B.; Recht, A.; Cady, B.; Silen, W.; Harris, J. Edemaof the arm as a function of the extent of axillary surgery in patientswith stage I-II carcinomaof the breast treated witih primary radiotherapy. Int. J. Radiat. 0~01. Biol. Phys. 12:15751582; 1986. 14. Leonard,C.; Corkill, M.; Tompkin, J.; Zhen, B.; Waitz, D.; Norton, L.; Kinzie, J. Are axillary recurrencesand overall survival affectedby axillary extranodaltumor extensionin breastcancer: Implications for radiation therapy. J. Clin. Oncol. 13:47-53; 1995. 15. Marks, L. B.; Halperin, E. C.; Prosnitz, L. R.; Ross,M.; Vredenburgh,J.; Rosner,G.; Peters,W.; and the CALGB. Postmastectomy radiotherapyfollowing adjuvantchemotherapy and autologousbone marrow transplantationfor breast cancerpatientswith 210 positive axillary lymph nodes.Int. J. Radiat.Oncol. Biol. Phys. 23:1021-1026; 1992.
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16. Recht, A.; Come, S. E.; Gelman,R. S.; Goldstein, I. M.; Tishler, S.; Gore, S. M.; Abner, A. L.; Vicini, F. A.; Silver, B.; Connolly, J. L.; Schnitt, S. J.; Coleman,C. N.; Harris, J. R. Integration of conservativesurgery, radiotherapy,and chemotherapyfor the treatmentof early stage,node-positive breastcancer:Sequencing,timing andoutcome.J. Clin. Oncol. 9:1662-1667; 1991. 17. Recht, A.; Pierce, S. M.; Abner, A.; Cicini, F.: Osteen, R. T.; Love, S. M.; Silber, B.; Harris,J. R. Regionalnodal failure after conservativesurgeryandradiotherapyfor early stagebreastcarcinoma.J. Clin. Oncol. 9:988-996: 1991. 18. Siegel, B. M.; Mazel, K. A.; Love, S. M. Level I and II axillary dissectionin the treatment of early stagebreast cancer.Arch. Surg. 125:1144-l 147; 1990. 19. Veronesi,U.; Rilke, F.; Luini, A.; Sacchini,V.; Galimberti, V.; Campa,T.; DeiBei, E.; Greco,M.; Magni, A.; Mersow, M.; Quagliuolo,V. Distributionof axillary nodemetastases by level of invasion-An analysisof 539 cases.Cancer 59:682-687; 1987.
Biol.
Phys., Vol. 35, No. 4. pp. 679~-685. 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0360.3016/96 $lS.OO + .OO
PII: SO360-3016( 96)00015-6
ELSEVIER
l
Oncology
Clinical
Original
Contribution
LONG-TERM OUTCOME IN PATIENTS WITH FOUR OR MORE POSITIVE LYMPH NODES TREATED WITH CONSERVATIVE SURGERY AND RADIATION THERAPY KIRAN
MEHTA,
M.D. AND BRUCE G. HAFITY, M.D.
Department of Therapeutic Radiology, Yale University School of Medicine. New Haven, CT 06520 Purpose: The purpose of this study was to review management strategies with respect to systemic therapy, radiation therapy treatment techniques, and patient outcome (local regional control, distant metastases, and overall survival) in patients undergoing conservative surgery and radiation therapy (CS + RT) who had four or more lymph nodes involved at the time of original diagnosis. Methods and Materials: Of 1040 patients undergoing CS + RT at our institution prior to December 1989, 579 patients underwent axillary lymph node dissection. Of those patients undergoing axillary lymph node dissection, 167 had positive nodes and 51 of these patients had four or more positive lymph nodes involved and serve as the patient population base for this study. All patients received radiation therapy to the intact breast using tangential fields with subsequent electron beam boost to the tumor bed to a total median dose of 64 Gy. The majority of patients received regional nodal irradiation as follows: 40 patients received RT to the supraclavicular region without axilla to a median dose of 46 Gy, 10 patients received radiation to the supraclavlcular region and axllla to a median dose of 46 Gy. Thirty of the 51 patients received a separate internal mammary port with a mixed beam of photons and electrons. One patient received radiation to the tangents alone without regional nodal irradiation. Adjuvant systemic therapy was used in 49 of the 51 patients (96% ) with 27 patients receiving chemotherapy alone, 14 patients receiving cytotoxic chemotherapy and tamoxlfen, and 8 patients receiving tamoxifen alone. Results: As of December 1994, with a minimum evaluable follow-up of 5 years and a median follow-up of 9.29 years, there have been 18 distant relapses, 2 nodal relapses, and 5 breast relapses. Actuarial statistics reveal a lo-year distant metastases-free rate of 65%, lo-year nodal recurrence-free rate of 96%, and a loyear breast recurrence-free rate of 82%. All five patients who sustained a breast relapse were successfully salvaged with mastectomy. Both patients with nodal relapses (one supraclavicular and one axillarylsupraclavicular) failed within the irradiated volume. Of the 40 patients treated to the supraclavlcular fossa (omitting complete axillary radiation), none failed in the dissected axllla. With a median follow-up of nearly 10 years, 29 of the 51 patients (57%) remain alive without evidence of disease, 15 (29%) have died with disease, 2 (4%) remain alive with disease, and 5 (10%) have died without evidence of disease. Overall actuarial lo-year survival for these 51 patients is 58%. Conclusions: We conclude that in patients found to have four or more positive lymph nodes at the time of axlllary lymph node dissection, conservative surgery followed by radiation therapy to the intact breast with appropriate adjuvant systemic therapy results in a reasonable long-term survival with a high rate of local regional control. Omission of axillary radiation in this subset of patients appears appropriate because there were no axillary failures among the 41 dissected but unirradiated axillae. Breast cancer, Lymph nodes, Irradiation,
Conservative
INTRODUCTION
surgery, Chemotherapy.
Breast conservation with lumpectomy followed by radiation therapy to the intact breast is now widely accepted as an alternative to mastectomy for the majority of women with operable breast cancer. It has clearly been demonstrated in retrospective series as well as prospective randomized trials that patients with pathologically negative,
as well as patients with pathologically involved, axillary lymph nodes can be treated conservatively and enjoy a survival rate equivalent to their counterparts undergoing modified radical mastectomy (5, 7, 12). Those patients who have a pathologically negative axilla following axillary dissection may be adequately treated with tangential fields directed at the intact breast without regional nodal irradiation. There is considerable controversy and unset-
Reprint requests to: Bruce G. Haffty, M.D., Department of Therapeutic Radiology. Yale University School of Medicine,
P.O. Box 208040, New Haven, CT 06.520-8040. Accepted for publication 29 December 1995.40. 679
680
1. J. Radiation
Oncology
0 Biology
0 Physics
tled issues regarding optimal treatment techiques and outcome in patients with positive nodes undergoing breast conservation therapy ( 2, 6- 16). The purpose of the current study was to review our institution’s treatment policy and outcome in patients with four or more pathologically involved lymph nodes undergoing conservative surgery and radiation therapy. Specifically, we reveiwed our management practices with respect to the integration of systemic therapy and radiation therapy with particular attention to radiation therapy treatment techniques, patterns of failure, and long-term outcome in this group of patients. METHODS
AND
MATERIALS
A total of 1040 patients were treated with conservative surgery followed by radiation therapy to the intact breast at our institution prior to December 1989. The cut-off date of December 1989 was chosen so as to have a minimum evaluable follow-up of 5 years on all patients. Of these 1040 patients, 579 underwent axillary lymph node dissection. Axillary dissection was not routinely performed, particularly in the earlier years of the study if the treating physicians did not feel the results of the axillary lymph node dissection would influence decisions regarding systemic therapy (9). Of the 579 patients undergoing axillary lymph node dissection, 167 (29%) were noted to have pathologically involved axillary lymph nodes. Fifty-one of the 167 patients with pathologically involved lymph nodes (30%) had four or more lymph nodes involved at the time of diagnosis and serve as the patient population base for this study. Characteristics for these 51 patients are given in Table 1. All 51 patients underwent lumpectomy followed by axillary lymph node dissection. During this time interval, there was no specific attempt made to obtain nor document the pathologic margin status of the lumpectomy specimen. In most cases, the surgical approach was limited to a Level I and Level II axillary lymph node dissection. The median number of lymph nodes sampled was 16 and the median number of positive lymph nodes was 7 (range 4-21) (see Table 1). The pathologic reports were reviewed in detail to determine the degree of extracapsular extension of tumor. Unfortunately, this pathologic feature was not consistently reported on, particularly in the earlier years of the study. A total of 13 patients were specifically noted to have extracapsular extension of tumor. However, this is likely to be an underestimate (3, 14, 19). Following lumpectomy and axillary lymph node dissection, all patients were treated with radiation therapy using tangential fields directed at the intact breast. Patient contours were routinely obtained and appropriate wedges were used to obtain homogeneous dose distribution throughout the breast. Patients were treated to the whole breast to a total median dose of 48 Gy. In all patients, a boost was used via smaller tangential fields and/or electron beam to the tumor bed to a total median dose of 64
Volume
35, Number
3. I996
Table 1. Patient/tumor characteristics (n = 5 1) Age (years)
71 ‘9
20 77 1
16 median (4-31 range) 7 median (4-21 range) 32 9 10 48 1 2 18 19 14 18 16 17
Gy. Regional nodal irradiation was administered to 50 of the 51 patients (98%), while only 1 patient was treated to the breast alone. The radiation therapy treatment techniques are summarized in Table 2. Forty of the 50 patients (80%) received radiation therapy directed at the supraclavicular fossa, omitting axillary radiation. External beam radiation was administered to the supraclavicular fossa using a separate anterior beam half-blocked at the central axis. The field was angled 10-15” off of the spinal cord and extended medially from the midline and laterally to the medial border of the head of the humerus. The dose was generally prescribed at the central axis to a depth of 3 cm using a 6 MeV beam to a total median dose of 46 Gy. A typical supraclavicular treatment field is demonstrated in Fig. 1. The superior border of the tangential breast field was matched to the supraclavicular field clinically by angling the couch. Ten of the 5 1 patients (20%) received external beam radiation therapy to the supraclavicular fossa and axillary lymph nodes using a treatment technique similar to that described above, modified by extending the lateral border of the supraclavicular field laterally to include the entire humeral head and clear the entire axillary contents (8). The field was similarly treated to a total median dose of 46 Gy specified at a depth of 3 cm. Of these patients, none received a posterior axillary boost. The 10 patients receiving complete axillary radiation were treated in this fashion at the discretion of the treating radiation oncologist, and did not significantly differ from those treated to
Long-term outcome Table 2. Treatment
l
K. MEHTA
characteristics Number/percent
Lumpectomy & axillary lymph node dissection XRT Systemic Therapy Chemotherapy alone Tamoxifen alone Chemotherapy + tamoxifen
5 l/( 100%) 51/(100%) 49/(96%) 27 8 14 Median Dose
Number/percent Radiation Technique XRT to Breast Nodal XRT XRT to SCF XRT to SCF/axilla XRT to IM XRT: radiation ternal mammary.
51/(100%) 50/(98%) 40/(80%) 10/(20%) 35/(70%)
therapy: SCF: supraclavicular
64 Gy 46 Gy 46 Gy 46 Gy fossa; IM: in-
the supraclavicular field alone with respect to the primary tumor size and number of lymph nodes involved. Thirty-five of the 5 1 patients (69%) received radiation therapy to the internal mammary nodes with a separate en face field of photons mixed with 12 MeV electrons.
Fig. 1. Typical
supraclavicular
AND
B. G. HAFFTY
681
This field was also treated to a total median dose of 46 Gy specified at a depth of 3 cm. Although the internal mammary nodes may have been incidentally included in the tangential fields in those patients without a separate internal mammary (IM) field, there was no specific attempt made to document inclusion of the internal mammary nodes via lymph node scintigraphy or computer tomography (CT) -based treatment plans. Adjuvant systemic therapy was administered to 49 of the 5 1 patients (96% ) . Two of the 5 1 patients had refused any systemic therapy offered. Systemic cytotoxic chemotherapy alone was administered to 27 patients; 14 patients received a combination of systemic cytotoxic chemotherapy and hormonal therapy, while 8 patients received hormonal therapy alone. The specific systemic therapeutic regimens used are outlined in Table 3. Of the 41 patients receiving cytotoxic chemotherapy, 8 (20%) received all radiation prior to chemotherapy, 22 (54%) received radiation therapy concomittantly with cytotoxic chemotherapy, 6 (14%) received radiation therapy sandwiched between cycles of cytotoxic chemotherapy, and 5 patients ( 12%) received radiation therapy following completion of all systemic therapy (Table 3 ) . Patients were routinely followed by the radiation oncol-
fossa treatment field.
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I. .I. Radiation Oncology 0 Biology 0 Physics
Volume 35. Number 4, 1996
Table 3. Systemic therapy details Drugs CMF-based (CMF, CMFP, CMFVP) Doxorubicin-based (CAF) Other chemotherapy (S-FU/alkeran) (S-FU/MTX) Tamoxifen alone Sequence RT first followed by chemotherapy Concurrent RT + chemotherapy Sandwich chemotherapy-RT-chemotherapy Chemotherapy followed by RT
DISCUSSION 33 6
1 1 8 8 22 6
5
ogist along with the referring surgeon and medical oncologist. Annual mammography was an integral component of the follow-up program. Diagnostic studies for systemic disease were performed as clinically indicated and at the discretion of the referring physicians and radiation oncologist. Breast failure was defined as histologically confirmed reappearance of tumor in the ipsilateral breast. Regional nodal relapses were defined as failure in the ipsilateral axilla and/or supraclavicular fossa, while distant failure was defined as any clinical and/or radiographic evidence of metastatic disease. RESULTS As of December 1994, with a minimum evaluable follow-up of 5 years and a median follow-up of 9.29 years, the averall 5- and IO-year survival for the 51 patients are 86 and 58%, respectively. The crude survival and recurrence statistics are summarized in Table 4. Five patients experienced an ipsilateral breast tumor recurrence resulting in 5- and IO-year breast relapse-free survival rate of 96 and 82%, respectively. Only 1 of the 5 patients who experienced an ipsilateral breast tumor recurrence was from the group of patients with a delay in radiation of more than 16 weeks. Regional nodal relapses were noted in 2 qut of the 51 patients resulting in a 5- and loyear nodal recurrence-free survival rate of 96%. There were no internal mammary nodal failures in the group of 5 1 patients treated. Both patients experiencing a regional nodal failure were treated with treatment techniques encompassing the surpaclavicular fossa and axilla, and both of these failures were within the radiated port. Of the 40 patients treated to the supraclavicular fossa alone (omitting axillary radiation), none have failed in the dissected, but unirradiated. axilla. A total of 18 patients relapsed with clinical and/or radiographic evidence of metastatic disease resulting in a IO-year distant disease-free survival rate of 65% and, as noted above, a IO-year overall survival rate of 58%. As expected, those patients with more than seven nodes involved had a poorer distant disease-free and overall survival than those patients with four to seven nodes (Figs. 2 and 3).
The majority of patients with operable breast cancer are potential candidates for conservative surgery followed by radiation therapy to the intact breast with or without regional nodal irradiation. Despite a clinically negative axilla, approximately one-third of patients undergoing axillary dissection are found to have pathologically involved lymph nodes and approximately one-third of those patients will have four or more lymph nodes involved at the time of diagnosis (4, 7, 16- 19 ) . Although it is wellestablished and routinely accepted that those patients with histologically negative axillae may be adequately treated with tangential fields alone, considerable controversy exists regarding patients with histologically involved lymph nodes (2, 6-16). The current study was undertaken to review our treatment policies, patterns of failure, and long-term outcome in patients with four or more involved lymph nodes at the time of diagnosis undergoing conservative surgery followed by radiation therapy. Several other series have reviewed treatment strategies and patterns of failure in conservatively treated breast cancer patients (2, 6, 8 - 11, 16). Halverson et al. noted that the incidence of axillary failure was greater in those patients with four or more nodes than for patients with one to three lymph nodes involved. They concluded that there was little support for radiation to the supraclavicular fossa and axilla for patients with less than four nodes, but there were too few patients with four or more lymph nodes involved to make any firm recommendations in this group of patients ( 10). In a review of conservatively treated patients from the Joint Center, Recht et aE. reported a 2.3% actuarial nodal failure rate at 5 years. In that study, 431 patients had node-positive disease, and 108 had four or more positive nodes. The majority of patients in their series with four or more positive nodes (87 out of 108 or 80%) received radiation therapy to the supraclavicular fossa and axillae. Although they did not specifically report on arm edema Table 4. Pattern of failure/patient outcome Patient status
N
Percent
Breast relapse Nodal relapse Distant relapse Alive NED Dead NED Alive w/disease Dead w/disease
5
9.8 3.9
2
18 29 5
35.3
56.9 9.8 3.9 29.4
2
15
Actuarial Actuarial 5-yr survival 10-yr survival Overall survival Breast recurrence-free survival Nodal recurrence-free survival Distant recurrence-free survival Disease-free survival
86%
96% 96% 74% 70%
58% 82% 96% 65% 53%
Long-term
outcome
l
K.
MEHTA
AND
B. G.
683
HAFFTY
Distant Recurrence-Free Survival W)
Fig. 2. Distant disease-free survival by number of positive nodes.
in this study, a previous report from this institution indicated a significant degree of arm edema when axillary radiation was used in patients undergoing extensive lymph node dissection ( 16). They concluded that the radiation therapy to the axilla and supraclavicular fossa should not be routinely used following an adequate axillary lymph node dissection for patients with histologically negative nodes as well as for patients with one to three positive nodes, but made no firm conclusions or treatment recommendations for those patients with four or more involved lymph nodes ( 16). Most practicing radiation oncologists, however, continue to offer some form of regional nodal irradiation for patients with four or more involved lymph nodes. Several studies have demonstrated an acceptable regional nodal control rate with adequate axillary lymph node dissection (3, 6, 8, 10, 11, 14- 16, 19). There is considerable variability and controversy, however, regarding radiation treatment techniques specifically with regard to whether or not the axillary contents should be treated in patients with multiple positive axillary nodes (2, 3, 6-18). In the current study, radiation therapy to the supraclavicular fossa alone (omitting axillary radiation in the majority
of patients) resulted in an excellent regional nodal control rate. All of these patients had four or more nodes involved with the median number of involved nodes of seven. Although extracapsular extension was clearly documented in only 13 patients, it is reasonable to assume that the majority of these patients in fact had extracapsular nodal involvement. Pathological studies by Veronesi et al. ( 19) and Leonard et al. ( 14) have demonstrated extracapsular tumor extension in over 80% of patients with four or more lymph nodes involved at the time of axillary dissection. Studies by Siegel et al. and Leonard et al. also demonstrated a high axillary control rate with axillary dissection, omitting axillary radiation ( 14, 18). Based on these surgical series, as well as the current study, we feel that axillary radiation can safely be omitted even in the presence of extracapsular extension in patients with four or more lymph nodes involved provided an adequate lymph node dissection has been performed. However, a portion of the lower axillary contents would, by necessity, be routinely included in the tangential breast field. We continue to routinely treat the supraclavicular fossa in patients with four or more positive nodes, because this treatment policy has resulted in excellent regional nodal control and minimal added morbidity in patients undergoing breast conservation therapy.
Overal 1 w
oo2
4
6
8
Years
Fig. 3. Overall survival by number of positive nodes.
10
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1. J. Radiation Oncology l Biology 0 Physics
The majority of patients in the current study were treated to the internal mammary nodes via a separate en face field using a mixed beam of photons and electrons. Because internal mammary nodal failures are exceedingly rare, it is difficult to draw any firm conclusions regarding the benefit of internal mammary nodal irradiation (7- 10, 15, 16). Given the increasing tendency to use adriamycinbased systemic therapy and the potential added cardiac morbidity using a separate en face internal mammary field, we no longer routinely treat the internal mammary nodes. While the tangential breast field will incidentally include a portion of the internal mammary lymph nodes, no specific attempt with respect to CT treatment planning was made in the patients treated in this series to treat the internal mammary nodes in the 16 patients treated without a separate IM field. Currently, for those patients in whom internal mammary nodal radiation is felt to be clinically indicated or mandated by a protocol, we would recommend a treatment planning CT scan to design a treatment plan that would minimize the dose to the underlying cardiac and pulmonary structures. A second goal of this current study was to review the long-term outcome with respect to overall survival, disease-free survival, and distant metastases in this group of high risk patients with four or more lymph nodes involved at the time of diagnosis. Given the emerging treatment options with dose-intensive chemotherapy with or without peripheral stem cell or bone marrow transplant support, it is important to establish long-term results in historical control patients treated with conventional therapy. The majority of patients in the current series were treated with
Volume 35. Number 4, 1996 standard cytoxan, methotrexate, 5-fluorouracil ( CMF ) or cytoxan, adriamycin, 5fluorouracil (CAF) -based cytotoxic chemotherapy. Despite a median number of seven lymph nodes involved, these patients experienced a respectable IO-year survival rate of 58%. Although this is a selected group of patients with a median tumor size of 2.5 cm undergoing conservative treatment. these results compare favorably with other series of patients with four or more nodes invoIved and serve as a historical control with which to compare more dose-intenstive treatment strategies. Our overall actuarial lo-year survival rate of 58% is identical to the lo-year survival rate reported by Bonadonna et al. in their randomized trial of patients with four or more nodes receiving sequential adriamycin/CMF chemotherapy ( 1) . Current ongoing clinical trials will hopefully better define the role of dose-intensive chemotherapy with or without bone marrow or stem ceil support. Note that the current study, as well as others reported in the literature, demonstrates a realistic probability of long-term survival in those patients with four or more positive nodes who undergo breast-conserving surgery followed by radiation therapy to the intact breast and regional lymph nodes with conventional adjuvant cytotoxic chemotherapy. We conclude that for patients with early stage operable breast cancer harboring four or more involved axillary lymph nodes, radiation therapy to the intact breast with regional nodal irradiation to the supraclavicular fossa combined with conventional adjuvant systemic therapy results in a high rate of local regional control and a reasonable probability of long-term survival.
REFERENCES 1. Bonadonna, G.; Zambetti, M.; Valagussa, P. Sequential or alternating doxombicin and CMF regiments in breast cancer with more than three positive nodes. JAMA 273:542547; 1995. 2. Dewar, J. A.; Sarrazin, D.; Benhanou, E.; Petit, J. Y.; Benhanou, S.; Arriagada, R.; Fontaine, F.; Castaigne, D.; Contesso, G. Management of the axilla in conservatively treated breast cancer: 592 patients treated at Institut Gustave Roussy. Int. J. Radiat. Oncol. Biol. Phys. 13:475-480; 1987. 3. Donegan, W. L.; Stine, S. B.; Sauter, T. G. Implications of extracapsular nodal metastasis for treatment and prognosis of breast cancer. Cancer 72:778-782; 1993. 4. Fisher, B.; Redmond, C.; Fisher, E. R.; Bauer, M.; Wolmark, N.; Wickerham, D. L.; Deutsch, M.; Montague, E.; Margolese, R.; Foster, R. Ten-year results of a randomzied clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N. Engl. J. Med. 312:674-681; 1985. 5. Fisher, B.; Redmond, C.; Poisson, R.; Margolese, R.; Wolmark. N.; Wickerham, L.; Fisher, E.; Duetsch, M.; Caplan, R.; Pilch, Y.; Glass, A.; Shibata, H.; Lemer, H.; Terz, J.; Sidorovich, L. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N. Engl. J. Med. 320:822-828; 1989. 6. Fowble, B.; Solin, L.; Schultz, D. J.; Goodman, R. L. Fre-
7.
8. 9. 10.
11.
12.
quency, sites of relapse, and outcome of regional node failures following conservative surgery and radiation for early breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 17:703710; 1989. Fowble, B.; Goodman, R. L.; Glick, J. H.; Rosato, E. F. Breast cancer treatment: A comprehensive guide to management. St. Louis, MO; Mosby-Year Book Inc.; 1991:128-129. Haffty, B. G.; Fischer, D.; Fischer, J. J. Regional nodal irradiation in the conservative treatment of breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 19:859-865; 1990. Haffty, B. G.; McKhann, C.; Beinfield, M.; Fischer, D.; Fischer, J. J. Breast conservation therapy without axillary dissection. Arch. Surg. 128:1315-1319; 1993. Halverson, K. J.; Taylor, M. E.; Perez, C. A.; Garcia, D. M.; Myerson, R.; Philpott, G.; Levy, J.; Simpson, J. R.; Tucher, G.; Rush, C. 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. 26:593-599; 1993. Hoskin, P. J.; Rajan, B.; Ebbs, S.; Tait, D.; Milan, S.; Yamold, J. R. Selective avoidance of lymphatic radiotherapy in the conservative management of early breast cancer. Radiother. Oncol. 25:83-88; 1992. Jacobson, J. A.; Danforth, D. N.; Cowan, K. H.; D’ Angelo, T.; Steinberg, S. M.; Pierce, L.; Lippman, M. E.; Lichter, A. S.; Glatstein, E.; Okunieff, P. Ten-year results of a com-
Long-term outcome
l
K. MEHTA AND B. G. HAFFFY
parisonof conservationwith mastectomyin the treatment of stageI and II breastcancer.N. Engl. J. Med. 332:907911; 1995. 13. Larson,D.; Weinstein,M.; Goldberg, I.; Silver, B.; Recht, A.; Cady, B.; Silen, W.; Harris, J. Edemaof the arm as a function of the extent of axillary surgery in patientswith stage I-II carcinomaof the breast treated witih primary radiotherapy. Int. J. Radiat. 0~01. Biol. Phys. 12:15751582; 1986. 14. Leonard,C.; Corkill, M.; Tompkin, J.; Zhen, B.; Waitz, D.; Norton, L.; Kinzie, J. Are axillary recurrencesand overall survival affectedby axillary extranodaltumor extensionin breastcancer: Implications for radiation therapy. J. Clin. Oncol. 13:47-53; 1995. 15. Marks, L. B.; Halperin, E. C.; Prosnitz, L. R.; Ross,M.; Vredenburgh,J.; Rosner,G.; Peters,W.; and the CALGB. Postmastectomy radiotherapyfollowing adjuvantchemotherapy and autologousbone marrow transplantationfor breast cancerpatientswith 210 positive axillary lymph nodes.Int. J. Radiat.Oncol. Biol. Phys. 23:1021-1026; 1992.
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16. Recht, A.; Come, S. E.; Gelman,R. S.; Goldstein, I. M.; Tishler, S.; Gore, S. M.; Abner, A. L.; Vicini, F. A.; Silver, B.; Connolly, J. L.; Schnitt, S. J.; Coleman,C. N.; Harris, J. R. Integration of conservativesurgery, radiotherapy,and chemotherapyfor the treatmentof early stage,node-positive breastcancer:Sequencing,timing andoutcome.J. Clin. Oncol. 9:1662-1667; 1991. 17. Recht, A.; Pierce, S. M.; Abner, A.; Cicini, F.: Osteen, R. T.; Love, S. M.; Silber, B.; Harris,J. R. Regionalnodal failure after conservativesurgeryandradiotherapyfor early stagebreastcarcinoma.J. Clin. Oncol. 9:988-996: 1991. 18. Siegel, B. M.; Mazel, K. A.; Love, S. M. Level I and II axillary dissectionin the treatment of early stagebreast cancer.Arch. Surg. 125:1144-l 147; 1990. 19. Veronesi,U.; Rilke, F.; Luini, A.; Sacchini,V.; Galimberti, V.; Campa,T.; DeiBei, E.; Greco,M.; Magni, A.; Mersow, M.; Quagliuolo,V. Distributionof axillary nodemetastases by level of invasion-An analysisof 539 cases.Cancer 59:682-687; 1987.