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Axillary sampling in the definitive treatment of breast cancer by radiation therapy and lumpectomy
In,. J Rodiotion Oncology Rio/. Phys Vol. Primed in the USA All nghts reserved.
9, pp.
036(r3016/83/030339~6$03.00/0 Copyright 8 1983 Pergamon Press Ltd
339-344
??Original Contribution AXILLARY SAMPLING IN THE DEFINITIVE TREATMENT OF BREAST CANCER BY RADIATION THERAPY AND LUMPECTOMY CHRISTOPHERM. ROSE, M.D.,* LESLIE E. BOTNICK, M.D.,* MARK WEINSTEIN, M.D.,? JAY R. HARRIS, M.D.,* CLINTON KOUFMAN, M.D.,? WILLIAM SILEN, M.D.7 AND SAMUEL HELLMAN, M.D.* Harvard Medical School, Boston, MA 02115 Between January, 1967 and July, 1980, 176 women who were referred to the Joint Center for Radiation Therapy (JCRT) for definitive breast irradiation underwent low axillary dissection. A typical operative technique is described. The dissection stops short of the axillary vein although the vein is usually visualized. One hundred thirty-two axillae were thought to be No or N,,. Forty-six axillae were felt to be N,,,. Seventeen percent of the T, No patients had pathologically positive nodes. Twenty-seven percent of the T, No patients had positive nodes. When 5 or less nodes were removed at axillary sampling the incidence of nodal involvement was very low. There were no differences in nodal positivity when comparing upper quadrant to lower or central lesions. Lateral lesions appeared to have higher positivity rates compared with either medial or central lesions. Ninety-four percent of axillae with Nu, lesions were pathologically confirmed. The complication rate for this procedure was low. There were 5 transient non-surgical complications and 1 cellulitis resulting in a frozen shoulder, which required corrective surgery. There were no cases of moderat or severe arm edema. Axillary sampling is compared to axillary dissection as a diagnostic procedure. Axillary sampling may underestimate the true pathologic positive rate, but diagnostic accuracy appears excellent if level 1 and 2 nodes are sampled. Breast cancer, Axillary metastases, Treatment of breast cancer.
INTRODUCTION Radiation therapy without mastectomy is now being employed as a definitive treatment for localized breast cancer. Local control and survival results equivalent to those seen with mastectomy are being achieved.9*‘0(P.40’), ‘3*‘5-‘7Unfortunately, over 60% of those women who present with disease amenable to surgery will eventually succumb to breast cancer regardless of the local or regional treatment.4 Chemotherapy has been used to treat those patients with apparently localized disease who have a high probability of harboring occult metastases. This group of patients with a poor prognosis includes those with histologically positive axillary lymph nodes. Such patients have a 70% chance of developing distant metastases within IO years.‘4,20Randomized studies employing single agent or combination chemotherapy have demonstrated significant improvement in relapse-free survival in patients with histologically positive lymph nodes.2,7While such “adjuvant” treatment appears to increase the likelihood of cure, it is difficult to administer and sometimes toxic.
Other methods need to be developed to identify those patients who might benefit from adjuvant chemotherapy when regional lymph node removal is not included in the local treatment for early stage breast cancer. Clinical examination of the axilla is associated with a 20-35s error rate;s’8 it cannot be used to identify patients being treated by radiation and lumpectomy, who may have a poor prognosis. Complete axillary dissection, on the other hand, may be associated with unacceptable side effects if combined with breast irradiation.‘.6 This paper describes the technique of limited axillary dissection (“axillary sampling”) that has evolved at the Joint Center for Radiation Therapy (JCRT) and reports on the diagnostic accuracy of this test.
*Joint Center for Radiation Therapy, Department of Radiation Therapy. TDepartment of Surgery, Beth Israel Hospital. Reprints requests to: C. M. Rose, 50 Binney Street, Boston, MA 02115.
Parts of this paper were presented at the M.B. Levene Memorial Symposium, Bass River, Massachusetts, September 25, 1981. Accepted for publication 22 September 1982.
339
METHODS AND MATERIALS Between January, 1967 and July, 1980, 176 women who were referred to the JCRT for definitive radiation of their invasive breast cancers underwent axillary sampling. Two women who had bilateral metachronous cancers underwent bilateral axillary sampling.
340
Radiation Oncology 0 Biology 0 Physics
Initially, the surgery was performed to confirm the presence of metastatic tumor deposits in clinically positive axillae and to remove the bulk of disease in order to facilitate radiation therapy. Later, with the emergence of adjuvant chemotherapy, sampling was performed routinely. Since 1978, all pre-menopausal women referred to the JCRT have undergone axillary sampling. Most recently, the identification of subgroups of post-menopausal women who may benefit from cyclophosphamide, methotrexate and 5-fluorouraci131’9 has led to increased use of sampling in post-menopausal patients. The technique of axillary sampling has evolved over the past 10 years and varies somewhat from surgeon to surgeon. In all cases the axillary vein is neither closely approached nor stripped of adjacent lymphatics. No attempt is made to remove level 3 lymph nodes (proximal to the pectoralis minor muscle); only those level 2 nodes beneath the pectoralis minor muscle that are accessible without undue dissection are removed, along with the level 1 nodes distal to the pectoralis minor muscle. The sampling is almost always performed under general anesthesia. The definitive treatment for breast cancer at the JCRT includes an iridium- 192 implant in most patients. Recently we have started to do iridium implants at the time of the sampling in selected patients in whom the diagnosis was made by excisional biopsy prior to referral for definitive treatment several weeks following the local excision of the tumor. The following is a description of a typical procedure: The axilla is shaved just prior to surgery. With the patient standing, the line of incision, approximately 6 cm in length, is marked to lie along a natural skin crease in the mid-axilla such that its most anterior extent is posterior to the anterior axillary line (the lateral border of the pectoralis major muscle) so that the line of incision is not visible with the arm abducted (Fig. 1). The arm may be abducted to 90 degrees on an arm board after the induction of anesthesia. Dissection is
Fig. I
External
landmarks
March 1983, Volume 9, Number 3
made through the subcutaneous tissues to the pectoralis fascia overlying the nerves, vessels, and lymphatics that transverse the axilla. The subcutaneous tissue may be several cm thick in an obese patient; care must be taken not to mistakenly remove this tissue in the belief that it is the “axillary fat pad.“” The pectoral fascia is the condensation of the aponeurosis of the pectoralis major muscle anteriorly and the latissimus dorsi muscle posteriorly. The fascia is opened transversely exposing the axillary fat pad that contains the lymphatic tissue. The two aforementioned muscles are exposed, identifying the anterior and posterior margins of dissection. The sampling is continued just to the deep pectoral fascia, separating the axillary fat pad from it for approximately 3 cm in the caudad and cephalad directions. Dissection then proceeds caudad to cephalad along the chest wall; care is taken not to injure the intercostobrachial, long thoracic and the thoracodorsal nerves. The dissection stops short of the axillary vein, although the vein is sometimes visualized. No attempt is made to clean the axillary vein of lymphatic tissue. (Fig. 2). The dissected tissue is divided between clamps and ligated to prevent the development of a lymphocele. Effort is made to remove all clinically suspicious nodes in order to facilitate subsequent radiotherapy. No routine attempt has been to remove the interpectoral (Rotter’s) nodes; although over the past year, some of the surgeons referring patients to the JCRT have been examining the interpectoral space and biopsying nodes if they appear suspicious. At the end of the procedure, the deep pectoral fascia is closed in separate layers. A soft, fluffy pressure dressing and an arm sling are used for 5-7 days to eliminate the residual space deep to the pectoral fascia. Suction catheters or rubber drains are occasionally employed. If the patient is not having an interstitial iridium implant, she is often allowed to go home on the day after surgery. The axillary specimens are pathologically dissected in
for axillary incision.
Axillary
sampling
??C. M.
341
ROSE et al
Axillarv vein
u
Intercostobrachial’n. I Axillary nodes D
Thoracodorsal
“‘3 Fig. 2. Operative
anatomy
order
to identify the nodes and to determine the nodal The clearing technique is not used. Three or four sections of each node are routinely examined microscopically, but in no cases are the blocks step sectioned. status.
RESULTS One hundred thirty-two axillae were thought initially to be clinically negative (NO) or suspicious (Nla). Fortysix axillae were felt to contain metastases (N 1b). Table 1 presents the incidence of disease in the 132 clinically uninvolved axillae. Seventeen percent of the patients with Tl, NO (2 cm) lesions had pathologically positive nodes. Twenty-seven percent of the patients with T2 (2.1-5.0 cm) lesions had positive nodes. There was a trend toward higher rates of axillary metastases as the size of the primary lesion increased. Table 2 presents the relationship between the number of nodes sampled and incidence of histologically positive axillae in NO and Nla patients. When 1 to 5 nodes were removed, the incidence of pathologic positivity was very low. There was no difference in nodal positivity when comparing upper quadrant to lower quadrant or central lesions (Table 3). There appeared to be a trend toward higher positivity rates with lateral lesions when compared with either medial or central lesions. This trend was present for both Tl and T2 lesions (Table 3). Because there was some correlation between number of nodes Table I. NO and N 1a patients: Incidence of disease as a function of primary size and median number of nodes removed
T, T>
No. of pts.
(%)
No. of nodes
1l/66 II/47 7119
(17) (23) (39)
10 7 7
O-2.0 cm 2.1-3.5 cm 3.6-5.0 cm
T, vs T,: P = 0.10. O-2.0 cm. vs 3.665.0 cm.
.2 > p > .I.
Long thoracic
n.
of axillary sampling.
sampled and nodal positivity rate, the median number of nodes sampled per axilla was analyzed with respect to the size and location of the primary lesion. These data are presented in Table 4. There were slightly more nodes removed for the lateral lesions. Table 5 presents the nodal positivity rate for the clinically positive (N 1b) axillae and compares the present series with two others in the literature. There was pathological confirmation in 91% of samplings when JCRT physicians and referring surgeons felt the nodes to be clinically positive. Complications of axillary sampling were assessed in all patients included in this series (Table 6). The minimum follow-up time was 9 months with the median time being greater than 2$ years. There were a total of 6 complications. Five of the six complications were minor and self-limited as described in Table 7. The sixth complication was axillary phlebitis with reduced mobility of the shoulder. Corrective surgery resulted in good functional recovery. There were no prolonged or severe episodes (greater than 3 cm difference in arm diameter) of arm or hand edema after axillary sampling and breast irradiation. It is our impression that there is an increased incidence of mild breast edema following the combined
Table 2. NO and N la patients: Nodal positivity as a function of no. nodes obtained No. nodes l-5 6-10 II-15 15 Not stated
Tl
T2
All
(%)
2114 4125 3117 2110
2123 7124 6110 318 0/t
4/37 II/49 9127 5/18 O/l
(11) (22) (33) (28)
l8/66 (27%)
291132 (22%)
II/16 (17%) l-5 nodes vs greater
than 5 nodes
p < .05.
342
Radiation Oncology 0 Biology 0 Physics Table 3. NO and Nla group: Incidence
TI T2 All
March 1983, Volume 9, Number 3 of axillary metastases
by quadrant
Upper outer
Lower outer
Upper inner
Lower inner
Central
7135 (20%) IO/34 (29%) 17169 (25%)
217 (29%)
O/l1 (0%)
O/l (0%)
2/12 (17%) 3115 (20%)
318
217
(Z) (33%)
(29%) 2118 (11%)
\‘24/84*7/ (26%)
012 (0%)
o/3
5127
(0%) 12121
*A (lO%)\
(19%) 5127 7/48+/(19%) (14%)
*Outer quadrant vs inner quadrants
touter
quadrant vs inner quadrants
procedure, although quantitation.
its transient
.2>p>.1. + central
nature
.2 > p > . I.
prevents
exact
DISCUSSION We have been employing axillary sampling routinely for the past 3 years in order to identify a cohort of patients with a high risk of developing distant metastases after primary treatment of breast cancer with radiation. The nodal positivity data are consistent with the information provided by the large mastectomy series. We have shown an increased incidence of metastasis in clinically negative or unsuspicious axillae, as the size of the primary lesion increases. Smart et al.*’ and Haagensen’“‘P.400’ have presented similar data clinically for NO, Nla, and N 1b axillae. Shottenfield et a/.*’ have results for clinical NO axillae that-are very similar to our own (Table 8). The present study implies an unequal distribution of axillary metastases in clinically negative axillae from medial and lateral quadrants. Although similar data have been presented by Haagensen for NO and Nl patients combined ‘“(p.40’)there are no data from mastectomy series which address this issue in the clinically negative axilla. There are direct lymphatic connections between the lymphatics of the medial portion of the breast and the level 3 lymph nodes. It is thus theoretically possible that metastases to these nodes only may occur from medial lesions and be undetected by the axillary sampling. If this were the case, the proportion of patients with axillary nodal involvement should be lower than that of similar reports using full axillary dissection.
Table 4. NO and N la patients: Median number of nodes sampled per patient Lateral Tl T2
10.5 (21%) 7.5 (31%)
Medial
+ central
Medial
(li%)
5.5 (0)
(2i%)
(262%)
T3 (2Z%) (% incidence
(Ii%) nodal involvement)
(PO%)
Smith et al.** have analyzed the total lymph node involvement versus level of metastases in patients with positive axillary specimens after radical mastectomy. They have shown level 3 only involvement in 10% of their positive specimens. Rilke et ~1.‘~ have performed a similar analysis of the lymph node involvement in their group of patients from Milan. At most, 6 of the 166 or 4% of their patients have level 3 involvement alone. The false negative rate for clinical examination in several large mastectomy series range from 23-44%, with a mean value of 32%.S,‘I.*I Thus, it would appear as if axillary sampling may be underestimating the true pathological positive rate by about 10%. However, these series are comprised of Columbia Stage A patients and are not broken down by size of primary. This is best seen by comparing our data with the report of Shottenfield et al.,” who perform a size analysis. The final pathologically positive rate for the entire series is critically dependent upon the mixture of Tl and small T2 primaries. It is possible that the discrepancy between our results and those of Butcher’, Handley Thackray,” and Smart et al.” have more to do with the size of the primary lesions than the surgical procedure performed. The present series has a higher true positive rate than has been previously reported. It has been stated that when the axilla is thought to be positive, 5 of the patients may have negative nodes.*’ Perhaps our criteria for calling a Table 5. N I b patients: Present series Tl T2 Total
% incidence Shottenlield
et ai.”
14117 28129 42146 (9 I %)
To-Tz 54175 (71%)
of metastases Smart
et al.”
T,-T, 3581404 (87%)
Table 6. Complications of axillary sampling (at least 6 month interval since completion of radiation) 51178 l/l78 61178
minor complication major complication total complication
= 2.8% = 0.6% = 3.4%
343
Axillary sampling 0 C. M. ROSEet al Table 8. Incidence of axiltary metastases in NO and N I a patients
Table 7. Complications Minor
I
2
3
4
5
Major 6
T,No (O/l ‘I)-treatment completed 1/78--developed venous swelling during radiation-relieved with aspirin, elevation; heat and treatment break of 1 week-no sequela T,No (O/17)-treatment completed 3/77-acute edema of arm and breast with palpable axillary vein during radiation-resolved spontaneously T2No (O/12)-treatment completed 4/78-arm swelling post treatment resolved spontaneously within 3 months T,N, (I 2/ 12)-treatment completed 8/78-5200 rad to axillar (4800 rad anteriorly) iridium implant 1850 rad-Cyclophosphamide, Methotrexate, S-Fluorouracil-Supf. phlebitis post implant resolved on conservative management T,N, (2/S)-treatment completed 12/77-5000 rad (all anterior)-Cyclophosphamide, Methotrexate, S-Fluorouracil-3 months post treatment developed edema + erythema of chest wall with decrease range of shoulder motionresolved within 1 month on Physiotherapy and break in chemotherapy program and discontinuation of methotrexate T,N, (0/3)--completed radiation 9/76developed venous thrombosis and superficial phlebitis of axillary vein during radiation; treated with phenylalamine mustard for 1 year; underwent lysis of right axillary subcutaneous tissue because of decreased mobility of right arm in l/ 78; 4 years post initial treatment she has good range of motion and is pain-free.
node positive are more stringent. If this were true, while the proportion of false positive physical exams would be lower, a greater proportion of involved axillae would be called negative. The overall axillary metastasis rate in NO and N 1 combined groups should be similar to mastectomy series. The present series is compared with the SEER report*’ in Table 9. When compared stage for stage, the incidence of axillary metastasis is very similar. Diagnostic accuracy appears excellent if level 1 and 2 nodes are sampled adequately. The alternative to axillary sampling in the definitive treatment of breast cancer by radiation is a complete axillary dissection. When axillary dissection is combined with post-operative radiation the incidence of moderate or severe arm edema is 10%. Clark et a1.6 describe a 56% incidence of breast lymphedema after axillary dissection and breast irradiation. The alternative would be to not treat the axillary apex with an en face field. Even so, one must always treat a portion of the axillae with the
Shottenfield et ai.”
Present study T,
T2 Total
17%
[661 27% 66 22%
(4-5%)*
18%
[661 30% [tOOI 26%
(12%)’ (9%)*
[ ] number of patients. *( ) % level 2 or 3 nodes. Table 9. NO + N 1a + N 1b patients: metastases
l-1 T? All
Incidence
of axillary
Present series
Smart et al.”
30% (83) 48% (95) 40% (178)
28% (1,597) 46% (2,505) 39% (4,102)
tangential fields and thus breast edema may still be a problem. In those cases where the axillae are more than minimally involved with tumor, one would depend upon chemotherapy to prevent local recurrence. Bonadonna has already reported local and regional recurrences in his mastectomy and chemotherapy group without locoregional irradiation.* With low axillary sampling followed by axillary radiation, complications have been minimal and we have had no axillary recurrences. In our center, diagnostic accuracy appears adequate when 5 or more nodes are obtained, however, the absolute numerical standard will probably vary from institution to institution depending upon the pathologic preparation and examination. In conclusion, axillary sampling is a safe procedure associated with minimal morbidity if the axillary vein is not approached and the dissection is confined to level 1 and low level 2 nodes. The more adequate the low axillary dissection the greater the likelihood of nodal positivity, and accuracy approaches that of axillary dissection. The large majority of patients can be assessed as to the pathological status of the axilla and thus be appropriately placed on adjuvant chemotherapy when it is indicated. The importance of axillary sampling in the total treatment of management of women with breast cancer by radiation will ultimately depend upon whether adjuvant chemotherapy data continue to show benefit.
REFERENCES I. Atkins, H., Hayward, J.L., Klugmen, D.J., Wayte, A.B.: Treatment of Early Breast Cancer: A Report after 10 years of a clinical trial. Brit. Med. J. 2: 423429, 1972. 2. Bonadonna, G., Brusamolino, E., Valagussa, P., Rossi, A.,
Brugnatelli, L., Brambilla, C., Lena, M. D., Tancini, G., Bajetta, E., Musumeci, R., Veronesi, U.: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N. Eng. J. Med. 294: 406-410, 1976.
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Radiation Oncology 0 Biology 0 Physics
3. Bonadonna, G., Valagussa, P.: Dose-response effect of adjuvant chemotherapy. N. Eng. J. Med. 304: 10-I 5, 1981. 4. Brinkley, D., Haybittle, J.L.: The curability of breast cancer. Lancet 1: 95-97, 1975. 5. Butcher, H.R.: Radical mastectomy for mammary carcinoma. Ann. Surg. 170: 883-884, 1969. 6. Clarke, D., Gofinet, D.R., Martinez, A.: Breast lymphedema as a complication of staging axillary dissection in the treatment of breast cancer by irradiation (Abstr.). Int. J. Radiat. Oncol. Biol. Phys. 6: 1417, 1980. 7. Fisher, B., Carbone, P., Economou, S. G., Frelick, R., Glass, A., Lerner, H., Redmond, C., Zelen, M., Band, P., Katrych, D. L., Wolmark, N., Fisher, E.R.: L-phenylalamine mustard (L-PAM) in the management of primary breast cancer. A report of early findings. N. Eng. J. Med. 288: 998-l 006, 1974. 8. Fisher, B., Slack, N.H.: Number of lymph nodes examined and the prognosis of breast carcinoma. Surg. Gynecol. Obstet. 130: 79-87, 1970. 9. Fletcher, G.H., Montague, E., Nelson, A.J.: Combination of Conservative Surgery and Irradiation for Cancer of the Breast. Am. J. Roentgenol. 126: 216-226, 1976. 10. Haagensen, C.D.: Diseases of the Breast. Philadelphia, W.B. Saunders Co. 197 1, pp. 149-I 54,400-40 I. 1I. Handley, R.S.. Thackray, A.C.: Conservative radical mastectomy (Patey’s operation). Ann. Surg. 170: 880-881, 1969. 12. Hellman, S., Harris, J.R., Levene, M.B.: Radiation therapy of early carcinoma of the breast without mastectomy. Cancer 46: 988-994,198O. 13. Levene, M.B., Harris, J.R., Hellman, S.: Primary radiation therapy for operable carcinoma of the breast. Surg. C/in. North Am. 58: 767-776, 1978.
March 1983, Volume 9, Number 3 14. McLaughlin, C.W., Coe, J.D., Adwers, J.R.: A thirty year study of breast cancer in a consecutive series of private patients. Is axillary nodal study a valuable index in prognosis? Am. J. Surg. 136: 250-253, 1978. 15. Montague, E.D., Gutierrez, A.E., Barker, J.L., Tapley, N.D., Fletcher, G.H.: Conservative Surgery and irradiation for the treatment of favorable breast cancer. Cancer 43: 1058-1061.1979. 16. Pierquin, B., Owen, R., Maylin, C., Otmezquire, Y., Raynal, M., Mueller, W., Hannoun, S.: Radiation therapy in the management of primary breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 6: 17-24, 1980. 17. Prosnitz, L., Goldenburg, I.S., Packard, R.A., Levene, M.B., Harris, J., Hellman, S., Wallner, P.E., Brady, L.W., Mansfield, C.W., Kramer, S.: Management of early stage cancer of the breast without mastectomy. Cancer 39: 917923, 1977. 18. Rilke, F., Andreola, S., Carbone, A., Clemente, C., Pilotte, S.: The importance of pathology in prognosis and management of breast cancer. Sem. Oncol. 5: 360-372, 1978. 19. Rossi, A., Bonadonna, G., Valagussa, P., Banfi, A., Veronesi. U.: CMF adjuvant program for breast cancer: 5 year results. Proc. Am. Sot. Clin. Oncol. 21: 404, 1980. 20. Shottenfield, D., Nash, A.G., Robbins, G.F., Beattie. E.J.: Ten year results of the treatment of primary operable breast carcinoma. A summary of 304 patients evaluated by the TNM system. Cancer 38: 1001-1007. 1976. 21. Smart, C.R.. Myers, M.H., Gloeakler, L.A.: Implications from SEER data on breast cancer management. Cancer 41: 787-789. 1978. 22. Smith, J.A., Gomez-Araujo, J., Gallagher, H.S., White, E.C., McBride, C.M.: Carcinoma of the breast. Analysis of total lymph node involvement versus level of metastasis. Cancer 39: 527-532. 1977.
9, pp.
036(r3016/83/030339~6$03.00/0 Copyright 8 1983 Pergamon Press Ltd
339-344
??Original Contribution AXILLARY SAMPLING IN THE DEFINITIVE TREATMENT OF BREAST CANCER BY RADIATION THERAPY AND LUMPECTOMY CHRISTOPHERM. ROSE, M.D.,* LESLIE E. BOTNICK, M.D.,* MARK WEINSTEIN, M.D.,? JAY R. HARRIS, M.D.,* CLINTON KOUFMAN, M.D.,? WILLIAM SILEN, M.D.7 AND SAMUEL HELLMAN, M.D.* Harvard Medical School, Boston, MA 02115 Between January, 1967 and July, 1980, 176 women who were referred to the Joint Center for Radiation Therapy (JCRT) for definitive breast irradiation underwent low axillary dissection. A typical operative technique is described. The dissection stops short of the axillary vein although the vein is usually visualized. One hundred thirty-two axillae were thought to be No or N,,. Forty-six axillae were felt to be N,,,. Seventeen percent of the T, No patients had pathologically positive nodes. Twenty-seven percent of the T, No patients had positive nodes. When 5 or less nodes were removed at axillary sampling the incidence of nodal involvement was very low. There were no differences in nodal positivity when comparing upper quadrant to lower or central lesions. Lateral lesions appeared to have higher positivity rates compared with either medial or central lesions. Ninety-four percent of axillae with Nu, lesions were pathologically confirmed. The complication rate for this procedure was low. There were 5 transient non-surgical complications and 1 cellulitis resulting in a frozen shoulder, which required corrective surgery. There were no cases of moderat or severe arm edema. Axillary sampling is compared to axillary dissection as a diagnostic procedure. Axillary sampling may underestimate the true pathologic positive rate, but diagnostic accuracy appears excellent if level 1 and 2 nodes are sampled. Breast cancer, Axillary metastases, Treatment of breast cancer.
INTRODUCTION Radiation therapy without mastectomy is now being employed as a definitive treatment for localized breast cancer. Local control and survival results equivalent to those seen with mastectomy are being achieved.9*‘0(P.40’), ‘3*‘5-‘7Unfortunately, over 60% of those women who present with disease amenable to surgery will eventually succumb to breast cancer regardless of the local or regional treatment.4 Chemotherapy has been used to treat those patients with apparently localized disease who have a high probability of harboring occult metastases. This group of patients with a poor prognosis includes those with histologically positive axillary lymph nodes. Such patients have a 70% chance of developing distant metastases within IO years.‘4,20Randomized studies employing single agent or combination chemotherapy have demonstrated significant improvement in relapse-free survival in patients with histologically positive lymph nodes.2,7While such “adjuvant” treatment appears to increase the likelihood of cure, it is difficult to administer and sometimes toxic.
Other methods need to be developed to identify those patients who might benefit from adjuvant chemotherapy when regional lymph node removal is not included in the local treatment for early stage breast cancer. Clinical examination of the axilla is associated with a 20-35s error rate;s’8 it cannot be used to identify patients being treated by radiation and lumpectomy, who may have a poor prognosis. Complete axillary dissection, on the other hand, may be associated with unacceptable side effects if combined with breast irradiation.‘.6 This paper describes the technique of limited axillary dissection (“axillary sampling”) that has evolved at the Joint Center for Radiation Therapy (JCRT) and reports on the diagnostic accuracy of this test.
*Joint Center for Radiation Therapy, Department of Radiation Therapy. TDepartment of Surgery, Beth Israel Hospital. Reprints requests to: C. M. Rose, 50 Binney Street, Boston, MA 02115.
Parts of this paper were presented at the M.B. Levene Memorial Symposium, Bass River, Massachusetts, September 25, 1981. Accepted for publication 22 September 1982.
339
METHODS AND MATERIALS Between January, 1967 and July, 1980, 176 women who were referred to the JCRT for definitive radiation of their invasive breast cancers underwent axillary sampling. Two women who had bilateral metachronous cancers underwent bilateral axillary sampling.
340
Radiation Oncology 0 Biology 0 Physics
Initially, the surgery was performed to confirm the presence of metastatic tumor deposits in clinically positive axillae and to remove the bulk of disease in order to facilitate radiation therapy. Later, with the emergence of adjuvant chemotherapy, sampling was performed routinely. Since 1978, all pre-menopausal women referred to the JCRT have undergone axillary sampling. Most recently, the identification of subgroups of post-menopausal women who may benefit from cyclophosphamide, methotrexate and 5-fluorouraci131’9 has led to increased use of sampling in post-menopausal patients. The technique of axillary sampling has evolved over the past 10 years and varies somewhat from surgeon to surgeon. In all cases the axillary vein is neither closely approached nor stripped of adjacent lymphatics. No attempt is made to remove level 3 lymph nodes (proximal to the pectoralis minor muscle); only those level 2 nodes beneath the pectoralis minor muscle that are accessible without undue dissection are removed, along with the level 1 nodes distal to the pectoralis minor muscle. The sampling is almost always performed under general anesthesia. The definitive treatment for breast cancer at the JCRT includes an iridium- 192 implant in most patients. Recently we have started to do iridium implants at the time of the sampling in selected patients in whom the diagnosis was made by excisional biopsy prior to referral for definitive treatment several weeks following the local excision of the tumor. The following is a description of a typical procedure: The axilla is shaved just prior to surgery. With the patient standing, the line of incision, approximately 6 cm in length, is marked to lie along a natural skin crease in the mid-axilla such that its most anterior extent is posterior to the anterior axillary line (the lateral border of the pectoralis major muscle) so that the line of incision is not visible with the arm abducted (Fig. 1). The arm may be abducted to 90 degrees on an arm board after the induction of anesthesia. Dissection is
Fig. I
External
landmarks
March 1983, Volume 9, Number 3
made through the subcutaneous tissues to the pectoralis fascia overlying the nerves, vessels, and lymphatics that transverse the axilla. The subcutaneous tissue may be several cm thick in an obese patient; care must be taken not to mistakenly remove this tissue in the belief that it is the “axillary fat pad.“” The pectoral fascia is the condensation of the aponeurosis of the pectoralis major muscle anteriorly and the latissimus dorsi muscle posteriorly. The fascia is opened transversely exposing the axillary fat pad that contains the lymphatic tissue. The two aforementioned muscles are exposed, identifying the anterior and posterior margins of dissection. The sampling is continued just to the deep pectoral fascia, separating the axillary fat pad from it for approximately 3 cm in the caudad and cephalad directions. Dissection then proceeds caudad to cephalad along the chest wall; care is taken not to injure the intercostobrachial, long thoracic and the thoracodorsal nerves. The dissection stops short of the axillary vein, although the vein is sometimes visualized. No attempt is made to clean the axillary vein of lymphatic tissue. (Fig. 2). The dissected tissue is divided between clamps and ligated to prevent the development of a lymphocele. Effort is made to remove all clinically suspicious nodes in order to facilitate subsequent radiotherapy. No routine attempt has been to remove the interpectoral (Rotter’s) nodes; although over the past year, some of the surgeons referring patients to the JCRT have been examining the interpectoral space and biopsying nodes if they appear suspicious. At the end of the procedure, the deep pectoral fascia is closed in separate layers. A soft, fluffy pressure dressing and an arm sling are used for 5-7 days to eliminate the residual space deep to the pectoral fascia. Suction catheters or rubber drains are occasionally employed. If the patient is not having an interstitial iridium implant, she is often allowed to go home on the day after surgery. The axillary specimens are pathologically dissected in
for axillary incision.
Axillary
sampling
??C. M.
341
ROSE et al
Axillarv vein
u
Intercostobrachial’n. I Axillary nodes D
Thoracodorsal
“‘3 Fig. 2. Operative
anatomy
order
to identify the nodes and to determine the nodal The clearing technique is not used. Three or four sections of each node are routinely examined microscopically, but in no cases are the blocks step sectioned. status.
RESULTS One hundred thirty-two axillae were thought initially to be clinically negative (NO) or suspicious (Nla). Fortysix axillae were felt to contain metastases (N 1b). Table 1 presents the incidence of disease in the 132 clinically uninvolved axillae. Seventeen percent of the patients with Tl, NO (2 cm) lesions had pathologically positive nodes. Twenty-seven percent of the patients with T2 (2.1-5.0 cm) lesions had positive nodes. There was a trend toward higher rates of axillary metastases as the size of the primary lesion increased. Table 2 presents the relationship between the number of nodes sampled and incidence of histologically positive axillae in NO and Nla patients. When 1 to 5 nodes were removed, the incidence of pathologic positivity was very low. There was no difference in nodal positivity when comparing upper quadrant to lower quadrant or central lesions (Table 3). There appeared to be a trend toward higher positivity rates with lateral lesions when compared with either medial or central lesions. This trend was present for both Tl and T2 lesions (Table 3). Because there was some correlation between number of nodes Table I. NO and N 1a patients: Incidence of disease as a function of primary size and median number of nodes removed
T, T>
No. of pts.
(%)
No. of nodes
1l/66 II/47 7119
(17) (23) (39)
10 7 7
O-2.0 cm 2.1-3.5 cm 3.6-5.0 cm
T, vs T,: P = 0.10. O-2.0 cm. vs 3.665.0 cm.
.2 > p > .I.
Long thoracic
n.
of axillary sampling.
sampled and nodal positivity rate, the median number of nodes sampled per axilla was analyzed with respect to the size and location of the primary lesion. These data are presented in Table 4. There were slightly more nodes removed for the lateral lesions. Table 5 presents the nodal positivity rate for the clinically positive (N 1b) axillae and compares the present series with two others in the literature. There was pathological confirmation in 91% of samplings when JCRT physicians and referring surgeons felt the nodes to be clinically positive. Complications of axillary sampling were assessed in all patients included in this series (Table 6). The minimum follow-up time was 9 months with the median time being greater than 2$ years. There were a total of 6 complications. Five of the six complications were minor and self-limited as described in Table 7. The sixth complication was axillary phlebitis with reduced mobility of the shoulder. Corrective surgery resulted in good functional recovery. There were no prolonged or severe episodes (greater than 3 cm difference in arm diameter) of arm or hand edema after axillary sampling and breast irradiation. It is our impression that there is an increased incidence of mild breast edema following the combined
Table 2. NO and N la patients: Nodal positivity as a function of no. nodes obtained No. nodes l-5 6-10 II-15 15 Not stated
Tl
T2
All
(%)
2114 4125 3117 2110
2123 7124 6110 318 0/t
4/37 II/49 9127 5/18 O/l
(11) (22) (33) (28)
l8/66 (27%)
291132 (22%)
II/16 (17%) l-5 nodes vs greater
than 5 nodes
p < .05.
342
Radiation Oncology 0 Biology 0 Physics Table 3. NO and Nla group: Incidence
TI T2 All
March 1983, Volume 9, Number 3 of axillary metastases
by quadrant
Upper outer
Lower outer
Upper inner
Lower inner
Central
7135 (20%) IO/34 (29%) 17169 (25%)
217 (29%)
O/l1 (0%)
O/l (0%)
2/12 (17%) 3115 (20%)
318
217
(Z) (33%)
(29%) 2118 (11%)
\‘24/84*7/ (26%)
012 (0%)
o/3
5127
(0%) 12121
*A (lO%)\
(19%) 5127 7/48+/(19%) (14%)
*Outer quadrant vs inner quadrants
touter
quadrant vs inner quadrants
procedure, although quantitation.
its transient
.2>p>.1. + central
nature
.2 > p > . I.
prevents
exact
DISCUSSION We have been employing axillary sampling routinely for the past 3 years in order to identify a cohort of patients with a high risk of developing distant metastases after primary treatment of breast cancer with radiation. The nodal positivity data are consistent with the information provided by the large mastectomy series. We have shown an increased incidence of metastasis in clinically negative or unsuspicious axillae, as the size of the primary lesion increases. Smart et al.*’ and Haagensen’“‘P.400’ have presented similar data clinically for NO, Nla, and N 1b axillae. Shottenfield et a/.*’ have results for clinical NO axillae that-are very similar to our own (Table 8). The present study implies an unequal distribution of axillary metastases in clinically negative axillae from medial and lateral quadrants. Although similar data have been presented by Haagensen for NO and Nl patients combined ‘“(p.40’)there are no data from mastectomy series which address this issue in the clinically negative axilla. There are direct lymphatic connections between the lymphatics of the medial portion of the breast and the level 3 lymph nodes. It is thus theoretically possible that metastases to these nodes only may occur from medial lesions and be undetected by the axillary sampling. If this were the case, the proportion of patients with axillary nodal involvement should be lower than that of similar reports using full axillary dissection.
Table 4. NO and N la patients: Median number of nodes sampled per patient Lateral Tl T2
10.5 (21%) 7.5 (31%)
Medial
+ central
Medial
(li%)
5.5 (0)
(2i%)
(262%)
T3 (2Z%) (% incidence
(Ii%) nodal involvement)
(PO%)
Smith et al.** have analyzed the total lymph node involvement versus level of metastases in patients with positive axillary specimens after radical mastectomy. They have shown level 3 only involvement in 10% of their positive specimens. Rilke et ~1.‘~ have performed a similar analysis of the lymph node involvement in their group of patients from Milan. At most, 6 of the 166 or 4% of their patients have level 3 involvement alone. The false negative rate for clinical examination in several large mastectomy series range from 23-44%, with a mean value of 32%.S,‘I.*I Thus, it would appear as if axillary sampling may be underestimating the true pathological positive rate by about 10%. However, these series are comprised of Columbia Stage A patients and are not broken down by size of primary. This is best seen by comparing our data with the report of Shottenfield et al.,” who perform a size analysis. The final pathologically positive rate for the entire series is critically dependent upon the mixture of Tl and small T2 primaries. It is possible that the discrepancy between our results and those of Butcher’, Handley Thackray,” and Smart et al.” have more to do with the size of the primary lesions than the surgical procedure performed. The present series has a higher true positive rate than has been previously reported. It has been stated that when the axilla is thought to be positive, 5 of the patients may have negative nodes.*’ Perhaps our criteria for calling a Table 5. N I b patients: Present series Tl T2 Total
% incidence Shottenlield
et ai.”
14117 28129 42146 (9 I %)
To-Tz 54175 (71%)
of metastases Smart
et al.”
T,-T, 3581404 (87%)
Table 6. Complications of axillary sampling (at least 6 month interval since completion of radiation) 51178 l/l78 61178
minor complication major complication total complication
= 2.8% = 0.6% = 3.4%
343
Axillary sampling 0 C. M. ROSEet al Table 8. Incidence of axiltary metastases in NO and N I a patients
Table 7. Complications Minor
I
2
3
4
5
Major 6
T,No (O/l ‘I)-treatment completed 1/78--developed venous swelling during radiation-relieved with aspirin, elevation; heat and treatment break of 1 week-no sequela T,No (O/17)-treatment completed 3/77-acute edema of arm and breast with palpable axillary vein during radiation-resolved spontaneously T2No (O/12)-treatment completed 4/78-arm swelling post treatment resolved spontaneously within 3 months T,N, (I 2/ 12)-treatment completed 8/78-5200 rad to axillar (4800 rad anteriorly) iridium implant 1850 rad-Cyclophosphamide, Methotrexate, S-Fluorouracil-Supf. phlebitis post implant resolved on conservative management T,N, (2/S)-treatment completed 12/77-5000 rad (all anterior)-Cyclophosphamide, Methotrexate, S-Fluorouracil-3 months post treatment developed edema + erythema of chest wall with decrease range of shoulder motionresolved within 1 month on Physiotherapy and break in chemotherapy program and discontinuation of methotrexate T,N, (0/3)--completed radiation 9/76developed venous thrombosis and superficial phlebitis of axillary vein during radiation; treated with phenylalamine mustard for 1 year; underwent lysis of right axillary subcutaneous tissue because of decreased mobility of right arm in l/ 78; 4 years post initial treatment she has good range of motion and is pain-free.
node positive are more stringent. If this were true, while the proportion of false positive physical exams would be lower, a greater proportion of involved axillae would be called negative. The overall axillary metastasis rate in NO and N 1 combined groups should be similar to mastectomy series. The present series is compared with the SEER report*’ in Table 9. When compared stage for stage, the incidence of axillary metastasis is very similar. Diagnostic accuracy appears excellent if level 1 and 2 nodes are sampled adequately. The alternative to axillary sampling in the definitive treatment of breast cancer by radiation is a complete axillary dissection. When axillary dissection is combined with post-operative radiation the incidence of moderate or severe arm edema is 10%. Clark et a1.6 describe a 56% incidence of breast lymphedema after axillary dissection and breast irradiation. The alternative would be to not treat the axillary apex with an en face field. Even so, one must always treat a portion of the axillae with the
Shottenfield et ai.”
Present study T,
T2 Total
17%
[661 27% 66 22%
(4-5%)*
18%
[661 30% [tOOI 26%
(12%)’ (9%)*
[ ] number of patients. *( ) % level 2 or 3 nodes. Table 9. NO + N 1a + N 1b patients: metastases
l-1 T? All
Incidence
of axillary
Present series
Smart et al.”
30% (83) 48% (95) 40% (178)
28% (1,597) 46% (2,505) 39% (4,102)
tangential fields and thus breast edema may still be a problem. In those cases where the axillae are more than minimally involved with tumor, one would depend upon chemotherapy to prevent local recurrence. Bonadonna has already reported local and regional recurrences in his mastectomy and chemotherapy group without locoregional irradiation.* With low axillary sampling followed by axillary radiation, complications have been minimal and we have had no axillary recurrences. In our center, diagnostic accuracy appears adequate when 5 or more nodes are obtained, however, the absolute numerical standard will probably vary from institution to institution depending upon the pathologic preparation and examination. In conclusion, axillary sampling is a safe procedure associated with minimal morbidity if the axillary vein is not approached and the dissection is confined to level 1 and low level 2 nodes. The more adequate the low axillary dissection the greater the likelihood of nodal positivity, and accuracy approaches that of axillary dissection. The large majority of patients can be assessed as to the pathological status of the axilla and thus be appropriately placed on adjuvant chemotherapy when it is indicated. The importance of axillary sampling in the total treatment of management of women with breast cancer by radiation will ultimately depend upon whether adjuvant chemotherapy data continue to show benefit.
REFERENCES I. Atkins, H., Hayward, J.L., Klugmen, D.J., Wayte, A.B.: Treatment of Early Breast Cancer: A Report after 10 years of a clinical trial. Brit. Med. J. 2: 423429, 1972. 2. Bonadonna, G., Brusamolino, E., Valagussa, P., Rossi, A.,
Brugnatelli, L., Brambilla, C., Lena, M. D., Tancini, G., Bajetta, E., Musumeci, R., Veronesi, U.: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N. Eng. J. Med. 294: 406-410, 1976.
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Radiation Oncology 0 Biology 0 Physics
3. Bonadonna, G., Valagussa, P.: Dose-response effect of adjuvant chemotherapy. N. Eng. J. Med. 304: 10-I 5, 1981. 4. Brinkley, D., Haybittle, J.L.: The curability of breast cancer. Lancet 1: 95-97, 1975. 5. Butcher, H.R.: Radical mastectomy for mammary carcinoma. Ann. Surg. 170: 883-884, 1969. 6. Clarke, D., Gofinet, D.R., Martinez, A.: Breast lymphedema as a complication of staging axillary dissection in the treatment of breast cancer by irradiation (Abstr.). Int. J. Radiat. Oncol. Biol. Phys. 6: 1417, 1980. 7. Fisher, B., Carbone, P., Economou, S. G., Frelick, R., Glass, A., Lerner, H., Redmond, C., Zelen, M., Band, P., Katrych, D. L., Wolmark, N., Fisher, E.R.: L-phenylalamine mustard (L-PAM) in the management of primary breast cancer. A report of early findings. N. Eng. J. Med. 288: 998-l 006, 1974. 8. Fisher, B., Slack, N.H.: Number of lymph nodes examined and the prognosis of breast carcinoma. Surg. Gynecol. Obstet. 130: 79-87, 1970. 9. Fletcher, G.H., Montague, E., Nelson, A.J.: Combination of Conservative Surgery and Irradiation for Cancer of the Breast. Am. J. Roentgenol. 126: 216-226, 1976. 10. Haagensen, C.D.: Diseases of the Breast. Philadelphia, W.B. Saunders Co. 197 1, pp. 149-I 54,400-40 I. 1I. Handley, R.S.. Thackray, A.C.: Conservative radical mastectomy (Patey’s operation). Ann. Surg. 170: 880-881, 1969. 12. Hellman, S., Harris, J.R., Levene, M.B.: Radiation therapy of early carcinoma of the breast without mastectomy. Cancer 46: 988-994,198O. 13. Levene, M.B., Harris, J.R., Hellman, S.: Primary radiation therapy for operable carcinoma of the breast. Surg. C/in. North Am. 58: 767-776, 1978.
March 1983, Volume 9, Number 3 14. McLaughlin, C.W., Coe, J.D., Adwers, J.R.: A thirty year study of breast cancer in a consecutive series of private patients. Is axillary nodal study a valuable index in prognosis? Am. J. Surg. 136: 250-253, 1978. 15. Montague, E.D., Gutierrez, A.E., Barker, J.L., Tapley, N.D., Fletcher, G.H.: Conservative Surgery and irradiation for the treatment of favorable breast cancer. Cancer 43: 1058-1061.1979. 16. Pierquin, B., Owen, R., Maylin, C., Otmezquire, Y., Raynal, M., Mueller, W., Hannoun, S.: Radiation therapy in the management of primary breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 6: 17-24, 1980. 17. Prosnitz, L., Goldenburg, I.S., Packard, R.A., Levene, M.B., Harris, J., Hellman, S., Wallner, P.E., Brady, L.W., Mansfield, C.W., Kramer, S.: Management of early stage cancer of the breast without mastectomy. Cancer 39: 917923, 1977. 18. Rilke, F., Andreola, S., Carbone, A., Clemente, C., Pilotte, S.: The importance of pathology in prognosis and management of breast cancer. Sem. Oncol. 5: 360-372, 1978. 19. Rossi, A., Bonadonna, G., Valagussa, P., Banfi, A., Veronesi. U.: CMF adjuvant program for breast cancer: 5 year results. Proc. Am. Sot. Clin. Oncol. 21: 404, 1980. 20. Shottenfield, D., Nash, A.G., Robbins, G.F., Beattie. E.J.: Ten year results of the treatment of primary operable breast carcinoma. A summary of 304 patients evaluated by the TNM system. Cancer 38: 1001-1007. 1976. 21. Smart, C.R.. Myers, M.H., Gloeakler, L.A.: Implications from SEER data on breast cancer management. Cancer 41: 787-789. 1978. 22. Smith, J.A., Gomez-Araujo, J., Gallagher, H.S., White, E.C., McBride, C.M.: Carcinoma of the breast. Analysis of total lymph node involvement versus level of metastasis. Cancer 39: 527-532. 1977.