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A four node axillary sampling trial on breast cancer patients
ARTICLE IN PRESS The Breast (2006) 15, 203–209
THE BREAST www.elsevier.com/locate/breast
ORIGINAL ARTICLE
A four node axillary sampling trial on breast cancer patients Kanji Tanaka, Daigo Yamamoto, Sayaka Kanematsu, Homa Okugawa, Yasuo Kamiyama Department of Surgery, Kansai Medical University, 10–15, Fumizono, Moriguchi, Osaka 570-8507, Japan Received 13 January 2005; received in revised form 19 April 2005; accepted 28 April 2005
KEYWORDS Four node sampling; Breast cancer
Summary The surgical management of axillary lymph nodes in early breast cancer remains controversial, although several maneuvers have been developed such as axillary node clearance (ANC), four node axillary sampling (4NAS), and sentinel node biopsy. A total of 237 cases of primary breast cancer at stages I and II were studied prospectively to elucidate the correlation between 4NAS and ANC. All calculated values by 4NAS showed high sensitivity, specificity, and overall accuracy as follows in this study: 92.9%, 100% and 98.5% for stage I, and 93.8%, 100% and 98.3% for stage II. Likewise, the false negative (FN) rates were 7.1% for stage I, 6.3% for stage II, 6.7% for T1, 6.4% for T2, 7.4% for N0, 0% for N1, and 6.5% for all cases. These rates were very low, although 7.4% for N0 and 0% for N1 were quite clearly different. This implies that all FN cases were N0, and were caused by micrometastases with normal consistency and size. 4NAS may be as accurate a procedure as ANC in assessing axillary nodal stage. & 2005 Elsevier Ltd. All rights reserved.
Introduction The treatment of breast cancer, especially axillary surgery, has been changing over the last decades toward a minimal procedure to reduce postoperative morbidity and to spare the increasing proportion of patients without axillary metastases.1 Alternative axillary operations have been mainly axillary node clearance (ANC),2 four node axillary Corresponding author. Tel.: +81 6 69921001x3424;
fax: +81 6 69928414. E-mail address: [email protected] (K. Tanaka).
sampling (4NAS),1 and recently sentinel node biopsy (SNB).3–5 SNB is now widely used for the staging of clinically node-negative patients with breast cancer. It is highly accurate in predicting the status of both the axillary and the extra-axillary lymph nodes.4,5 However, 4NAS still seems to be an attractive method for minimally invasive axillary surgery because of no additional prerequisites, its possible usefulness in areas with limited sources, 100% detection rate of axillary lymph nodes, and no anaphylactoid reaction from isosulfan or patent blue dye.6–9
0960-9776/$ - see front matter & 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2005.04.020
ARTICLE IN PRESS 204 The technique of 4NAS was pioneered in the Edinburgh breast unit and relies on the theory that the axillary nodes most likely to be involved are those that are palpable intraoperatively.10–12 4NAS adds little if any morbidity to the treatment of the primary tumor and no additional cost (unlike SNB). The lower axilla is mobilized and four nodes are individually identified. This staging modality has been subjected to randomized trials comparing it with ANC in terms of morbidity, recurrence, and mortality.10–12 These trials have shown that 4NAS (followed by radiotherapy in node-positive patients) is associated with lower overall morbidity and has equivalent recurrence rates and mortality to ANC. In this study, we examined 237 cases of Japanese primary breast cancer according to preoperative staging, tumor size, and nodal status, and tried to assess the accuracy of 4NAS compared with ANC.
Patients and methods Patient backgrounds (Table 1) A total of 237 cases of primary breast cancers at stages I and II, operated on at Kansai Medical University hospital from October 1997 to September 2000, were enrolled to clarify the accuracy of 4NAS. Informed patient consent was obtained prior to all studies. The number of patients at stage I was 65 and there were 172 at stage II. The mean age (mean7S.D.) was 56.3713.1 and 57.9712.0, respectively. There were 30 and 63 grade I tumors, 24 and 88 grade II cases, and 11 and 21 grade III cases. Estrogen receptor (ER) statuses (:+) were 1:1.54 and 1:2.0. Nineteen and 83 cases had simple mastectomy, the Patey method was used in 0 and 15 cases, subcutaneous mastectomy (SCM) in 4 and 15 cases, wide local excision (WLE) in 42 and 59 cases, level I and II lymphadenectomy in 59 and 145 cases, and level III in 6 and 27 cases. The total numbers of excised axillary lymph nodes (mean7S.D.) were 17.775.7 and 18.677.1 for stages I and II, respectively. Patient stage in this study was assessed according to the UICC criteria.13 N0 indicates no regional lymph node metastases and N1 shows positive metastases to movable ipsilateral axillary nodes by preoperative assessment.
Operation (4NAS) technique Operations such as Auchincloss, Patey, SCM, and WLE methods were performed. The indications for
K. Tanaka et al. Table 1
Patients’ backgrounds.
Age (mean7S.D.) Tumor grade (cases)
Estrogen receptor (:+) Operation method (cases)
Lymphadenectomy level Number of lymph nodes (mean7S.D.) Preoperative tumor size (T) status Preoperative lymph node (N) status
Stage I (n ¼ 65)
Stage II (n ¼ 172)
56.3713.1 I: 30 II: 24 III: 11 1:1.54
57.9712.0 I: 63 II: 88 III: 21 1:2.0
Auchincloss 19 Patey 0 SCM 4 WLE 42 I, II 59
Auchincloss 83 Patey 15 SCM 15 WLE 59 I, II 145
III 6 17.775.7
III 27 18.677.1
T1: 65
T1: 6
T2: — N0: 65
T2: 166 N0: 149
N1: —
N1: 23
SCM ¼ subcutaneous mastectomy; WLE ¼ wide local excision.
WLE were as follows: (1) tumor size less than 1 cm in diameter; (2) no evidence of extensive intraductal component with malignant calcification; (3) no evidence of multiple lesions; (4) the patients were able to receive radiotherapy after WLE; and (5) the patient gave informed consent for WLE. Among the modified radical mastectomies (Auchincloss, Patey, and SCM), the operation was carried out according to the patient’s choice. After completion of the primary operation, an axillary fat pad containing the lymphatic tissue was exposed. Axillary lymph nodes were palpated by the surgeon’s fingers and four lymph nodes were lifted without injuring any major nerves such as the intercostobrachial, long thoracic or thoracodorsal nerves. Firmly palpable lymph nodes, with a high potential for metastases, were selected prior to other lymph nodes. Following this sampling procedure, other axillary lymph nodes received back-up clearance to clarify the relationship between the sampled lymph nodes and all lymph nodes. Therefore, this study was designed to compare the sampled lymph nodes and all lymph nodes to show how sampled lymph nodes reflect the metastatic status of the whole axillary lymph nodes. In addition, there was no ‘‘learning curve,’’ because
ARTICLE IN PRESS 4NAS in breast cancer
205
only firmly palpable lymph nodes were selected as samples and then all lymph nodes were examined by multiple sections after surgery.
Mathematical calculation The sensitivity (Sens), specificity (Spec), positive predictive value, negative predictive value, overall accuracy (OA), and false negative (FN) rate in this study were calculated as follows.14 Factors used in the formula above in the 4NAS trial were metastases-positive sample lymph node {meta (+) 4NAS LN}, metastases-negative sample lymph node {meta () 4NAS LN}, metastases-positive axillary lymph node {meta (+) ANC LN}, and metastasesnegative axillary lymph node {meta () ANC LN}. These 4NAS LNs were divided into true positive (TP) {meta (+) 4NAS LN and meta (+) ANC LN} and false positive {meta (+) 4NAS LN and meta () ANC LN}, while meta () 4NAS LN were FN {meta () 4NAS LN and meta (+) ANC LN} and true negative {meta () 4NAS LN and meta () ANC LN}. All the meta (+) 4NAS LN were counted as metastases-positive ANC lymph nodes in this study. Therefore, all the meta (+) 4NAS LNs were counted as TP cases and none were false positive in this trial.
Results Statistical analysis of stages I and II (Table 2) The calculated values for each stage showed that the Sens was 92.9%, Spec 100%, and OA 98.5% for stage I, while Sens was 93.8%, Spec 100%, and OA 98.3% for stage II. The FN rate, which indicated how many metastatic lymph nodes were neglected in 4NAS, was 7.1% (1 out of 14) for stage I and 6.3% (3 out of 48) for stage II in this study and was low. The TP rate was 20.0% (13 out of 65 cases) for stage I and 26.2% (45 out of 172 cases) for stage II. Table 2
Meanwhile, if these values were calculated together including both stage I and II cases, the data showed a high level of Sens of 93.4%, Spec of 100%, OA of 98.3%, and a low FN rate of 6.5%. The most notable event in this series was that all four FN cases showed normal consistency and size on preoperative palpation and were proven to contain only micrometastases by postoperative histological examination.
Statistical analysis according to tumor size Values from the calculation of tumor size (T) revealed that Sens was 93.3%, Spec 100%, and OA 98.6% for T1 and Sens was 93.6%, Spec was 100%, and OA was 98.2% for T2. The FN rate was 6.7% for T1 and 6.4% for T2, which were almost equal and very low for both sizes. Histologically, metastatic lymph nodes increased according to tumor size.
Statistical analysis by N status (Table 3) The N status data indicated a Sens of 92.6%, Spec of 100%, and OA of 98.1% for N0, and Sens, Spec, and OA were 100% for N1. The FN rate for N0 was 7.4% and the highest in this series, while no FN cases were detected for N1. The probability of histologically metastatic lymph nodes was consistent with the preoperative N assessment, i.e., TP was 23.4% for N0 and 34.8% for N1.
The potential for complete removal of positive nodes by the 4NAS procedure alone (Table 4) If the number of positive nodes removed by 4NAS was limited to 0 or 1, there was no possibility of positive nodes being left in the axilla, with the exception of FN incidence. All FN cases, as stated before, included only micrometastasis, and were hard to find by palpation during the operation. In cases with more than two positive nodes detected
Statistical analysis for four node axillary sampling (4NAS) at stages I and II. No. of cases (%)
Stage I (T1N0) Stage II (T1N1, T2N0, T2N1) All
Sens (%) FN
TN
Spec (%)
OA (%)
PPV (%)
NPV (%)
FN rate (%)
TP
FP
Total
13 (20.0) 45 (26.2)
0 (0) 1 (1.5) 51 (78.5) 65 (100.0) 92.9 0 (0) 3 (1.7) 124 (72.1) 172 (100.0) 93.8
100 100
98.5 98.3
100 100
98.1 97.6
7.1 6.3
58 (24.5)
0 (0) 4 (1.7) 175 (73.8) 237 (100)
100
98.3
100
97.8
6.5
93.4
TP ¼ true positive; FP ¼ false positive; FN ¼ false negative; TN ¼ true negative; Sens ¼ sensitivity; Spec ¼ specificity; OA ¼ overall accuracy; PPV ¼ positive predictive value; NPV ¼ negative predictive value.
ARTICLE IN PRESS 206 Table 3
K. Tanaka et al. Statistical analysis for 4NAS in N0 and N1 cases. No. of cases (%)
N0 (T1+T2) N1 (T1+T2)
Table 4 cases.
Sens (%)
TP
FP
FN
TN
50 (23.4) 8 (34.8)
0 (0) 0 (0)
4 (1.8) 160 (74.8) 0 (0) 15 (65.2)
Spec (%)
OA (%)
PPV (%)
NPV (%)
FN rate (%)
100 100
98.1 100
100 100
97.6 100
7.4 0
Total 214 (100.0) 92.6 23 (100.0) 100
The number of positive nodes and potential for their complete removal by 4NAS alone in N0 and N1
Number of positive
NðþÞ ¼ 0 NðþÞ ¼ 1
NðþÞ ¼ 223 NðþÞ ¼ 4o Total
Complete or incomplete removal of positive nodes
Complete removal Complete removal Incomplete removal (False negative) Complete removal Incomplete removal Complete removal Incomplete removal
N0
N1
All
Possibility (%)
Number of cases
Possibility (%)
Number of cases
Possibility (%)
Number of cases
70.6 11.2 0 1.9 2.3 5.1 4.7 4.2 100
151/214 24/214 0/214 4/214 5/214 11/214 10/214 9/214 214
65.3 8.6 0 0 4.3 4.3 0 17.5 100
15/23 2/23 0/23 0/23 1/23 1/23 0/23 4/23 23
70.0 11.0 0 1.7 2.5 5.1 4.2 5.5 100
166/237 26/237 0/237 4/237 6/237 12/237 10/237 13/237 237
by 4NAS, the chance of incomplete removal or possible residual positive nodes in the axilla arose. This shows that no further axillary operation is necessary in 4NAS if the positive nodes removed are limited to o1. On the other hand, an additional procedure is required during or after surgery if more than two positive nodes are involved.
Discussion The surgical management of axillary lymph nodes in early breast cancer remains controversial, although several maneuvers have been developed such as axillary clearance, pectral node biopsy, 4NAS, triple node biopsy, and SNB.12 In 1985, NSABP B04 revealed, after examining 1665 patients, that axillary nodes were not associated with improved survival compared with no axillary surgery with delayed operation in N0 cases.15 Meanwhile, in 2003 the eighth St Gallen (Switzerland) consensus conference accepted that the staging itself was being refined and altered by new techniques such as SNB, i.e., SNB negativity was estimated as N0.16 The important points for conservative axillary surgery in early breast cancer are thought to be the
following factors. First, it should provide the same accurate information about axillary nodes as ANC. Second, it should provide the same survival benefit and local axillary control of disease as ANC. Third, it should provide the same staging and rational basis for adjuvant therapy as ANC. Fourth, it should provide less morbidity after surgery than ANC. The first point of accuracy is chiefly represented by the FN rate. The FN rates in this study were 6.3–7.1% and were relatively low, but higher than for ANC and SNB. This indicated that 4NAS was an accurate procedure in axillary operations. We reviewed the previous ANC and SNB data. Before the comparison, the problem we encountered was that each investigator used a different calculation technique. Therefore, we re-examined all data and presented them in a uniform manner, which we defined in our study. For ANC, we surveyed former investigations and it was noteworthy that they noted a ‘‘skip’’ or isolated metastases in level III and/or Rotter’s nodes in the absence of involvement of level I or II nodes. We estimated these ‘‘skip’’ or isolated metastases as hypothetical FN cases and did calculations. The FN rate for axillary clearance varied from 2.1% to 4.2% (with the exception of the FN rate of 40.5% found by Smith et al.17), with an
ARTICLE IN PRESS 4NAS in breast cancer
207
average of 2.9% (Table 5). This result suggested axillary clearance is not a perfect method in terms of possible FN, if level I and II clearance is thought to be sufficient during the operation, as there is no further suspicion of positive lymph node involvement in level III. SNB studies, in which more than 100 cases were operated on, revealed FN rates ranging between 0% and 6.9% with an average of 3.7% (Table 6). One study by Giuliano et al.18 in 1997 showed a 0% FN rate using blue dye. The multi-center study reported by McMasters et al.19 indicated an FN rate of 4.5% using radiocolloid. From all the results, FN rates were 6.5% for 4NAS, 2.9% for ANC, and 3.7% for SNB, which were relatively low. In some studies, as for the second point of overall survival, relapse-free survival, and axillary recurrence, they may be the same for 4NAS with both mastectomy or breast conservation therapy and ANC after a randomized and long-term followup.10–12 On the other hand, it has not yet been proven for SNB because of its short history. Many trials are still on-going and we will have to wait for the results.20,21 As for morbidity, every axillary surgery seems to have some postoperative complication. The Edinburgh group randomized three operation methods,
Table 5
i.e., 4NAS with or without radiation (+rad and –rad) and ANC, and investigated postoperative morbidity. Forrest et al.11 performed the three procedures above with mastectomy and found that arm morbidity and persistent arm swelling were observed after all three methods, even though they were most frequent after 4NAS +rad, followed by ANC and 4NAS –rad. Of note, severe interference with daily activity was only observed in the 4NAS +rad trial. Chetty12 in 2001 studied the three procedures above with WLE in terms of postoperative complications such as flexion and arm elevation, medial rotation, and lymph edema. His data showed that flexion and arm elevation and medial rotation were most severely damaged after 4NAS +rad in which medial rotation seemed to be irreversible. On the other hand, lymph edema was most common in ANC. Besides the Edinburgh group, Moffat et al.22 reported that arm lymph edema developed in 0–2.8% of patients undergoing axillary sampling procedures, 2.7–9.4% in patients treated by level I and II axillary dissection, 4.8–8% in those with level I, II, and III clearance, and 2–8.3% in patients treated by axillary irradiation alone. However, once axillary surgery was combined with regional nodal radiotherapy, it resulted in a 3- to 7-fold increase in
Calculated values for axillary node clearance (ANC) with skip metastases.
Study
Year
Number of patients
Sens (%)
Spec (%)
OA (%)
PPV (%)
NPV (%)
FN rate (%)
Smith et al.17 Rosen et al.29 Pigott et al.30 Schwartz et al.31 Senofsky et al.32 All
1977 1983 1984 1986 1991
408 1228 146 277 278 2337
91.0 97.1 96.0 96.9 94.8 95.2
100 100 100 100 100 100
92.6 98.8 97.9 98.6 98.2 97.2
100 100 100 100 100 100
71.2 97.9 95.9 97.3 97.3 91.9
40.5 2.1 4.2 2.7 2.7 10.4
Skip metastases were estimated as false negative cases.
Table 6
Each calculated value for sentinel node biopsy (SNB).
Study
Year
Number of patients
Technique
Sens (%)
Spec (%)
OA (%)
PPV (%)
NPV (%)
FN rate (%)
Giuliano et al.18 Giuliano et al.33 Veronesi et al.25 Borgstein et al.34 Krag et al.35 All
1994 1997 1997 1998
114 100 160 104
Dye Dye Radiocolloid Radiocolloid
88.0 100 95.3 94.7
100 100 100 69.4
95.6 100 97.5 74.0
100 100 100 40.9
93.5 100 94.9 98.3
6.9 0 5.3 1.7
1998
405 883
Radiocolloid
88.6 93.3
100 93.9
82.0 89.8
100 88.1
95.7 96.5
4.5 3.7
ARTICLE IN PRESS 208 the incidence of arm lymph edema compared with an axillary operation alone. At this point, the most concern arises regarding sparing unnecessary postoperative irradiation, so as to avoid severe morbidity. On the other hand, a recent paper showed that radiation-associated morbidity to the axilla induced no brachial plexus damage and only mild to moderate lymphedema in 2 out of 76 patients.23 Another paper also reported that postoperative radiation therapy to the axilla or axillary clearance in node-positive cases after axillary sampling was examined in a total of 1242 patients and lymphedema was found in only 5 (0.04%).24 These differences in postradiation morbidity might be explained by inter-institutional heterogeneity. For example, 18 institutions performed a dummy run in the AMAROS trial 10981/ 22023, and inter-institutional heterogeneity in dose prescription, radiation technique and radiation field positioning was found.21 In our study, 11.2% of N0 and 8.6% of N1 cases showed only one involved node and these were completely removed by 4NAS. In these cases, postoperative irradiation was not performed. However, if more than two nodes were involved, as in 16.3% of N0 and 26.1% of N1, there is a risk of incomplete removal of the metastatic nodes by 4NAS alone and these are candidates for postoperative irradiation. Recently, SNB has been the center of attention and there are some publications on the comparison between 4NAS and SNB.25,26 There is growing evidence that SNB is superior to 4NAS for optimal staging in breast cancer, especially in extra-axillary staging.4,5 Even so, 4NAS is more beneficial in some respects. It does not need additional prerequisites such as radioactive colloid, dye, and a gammadetecting probe and might be especially suitable for institutions with limited sources. Anaphylaxis by blue dye is serious problem in SNB. It is reported that the proportion of patients with an anaphylactoid reaction reaches 1–2%; it is sometimes nearlethal and has life-threatening potential.6–9 We experienced three cases with blue hives, severe broncospasm, and hypotension requiring pressor support. Precautions must be taken in SNB practice and the patients should be informed properly before the operation. In addition, Hansen and Giuliano27 pointed out several flaws of 4NAS. They indicated the impossibility of palpating a small micrometastasis by 4NAS. This is why our study failed to detect four FN cases by 4NAS, in which all nodes contained micrometastasis with normal firmness and size. However, it is also true that this does not necessarily prove the superiority of SNB over 4NAS, because SNB also has
K. Tanaka et al. disadvantages and FN cases. As stated earlier, FN in 4NAS is mainly caused by micrometastasis and in SNB for anatomical reasons. They indicated the difficulty of the 4NAS technique, although 4NAS is much easier than SNB in our experience. Another point is ‘‘Why remove four by chance when one will suffice?’’. MacCarter et al.28 in 2001 reported that there was no absolute upper threshold for the number of SNB nodes that should be removed, so it is not always correct to say that ‘‘one will suffice.’’ After examining all the evidence, we conclude that 4NAS could be one of the options for minimally invasive axillary surgery.
References 1. Forrest APM, Stewart HJ, Roberts MM, Steele RJC. Simple mastectomy and axillary node sampling (pectral node biopsy) in the management of primary breast cancer. Ann Surg 1982;196:371–8. 2. Harris JR, Hellman S, Kinne DW. Limited surgery and radiotherapy for early breast cancer. N Engl J Med 1985;21: 1365–8. 3. Cserni G. The reliability of sampling three to six nodes for staging breast cancer. J Clin Pathol 1999;52:681–3. 4. Estourgie SH, Tanis PJ, Nieweg OE, Olmos RAV, Rutgers EJT, Kroon BBR. Should the hunt for internal mammary chain sentinel nodes begin? An evaluation of 150 breast cancer patients. Ann Surg Oncol 2003;10:935–41. 5. Farrus B, Vidal-Sicart S, Velasco M, Zanon G, Fernandez PL, Munoz M, Santamaria G, Albanell J, Biete A. Incidence of internal mammary node metastases after a sentinel lymph node technique in breast cancer and its implication in the radiotherapy plan. Int J Radiat Oncol Biol Phys 2004;60: 715–21. 6. Ingram D, Hewett L, Maddern P. Anaphylaxis to patent blue during sentinel lymph node biopsy. ANZ J Surg 2004;74: 607–8. 7. Wo ¨hrl S, Focke M, Hinterhuber G, Stingl G, Binder M. Nearfatal anaphylaxis to patent blue V. Br J Dermatol 2004; 150:1037–8. 8. Raut CP, Daley MD, Hunt KK, Akins J, Ross MI, Singletary SE, Marshall Jr GD, Meric-Bernstam F, Babiera G, Feig BW, Ames FC, Kuerer HM. Anaphylactoid reactions to isosulfan blue dye during breast cancer lymphatic mapping in patients given preoperative prophylaxis. J Clin Oncol 2004; 22:567–8. 9. Sprung J, Tully MJ, Ziser A. Anaphylactic reactions to isosulfan blue dye during sentinel node lymphadenectomy for breast cancer. Anesth Analog 2003;96:1051–3. 10. Greenall MJ. Why I favour axillary node sampling in the management of breast cancer. Eur J Surg Oncol 1995;21: 2–7. 11. Forrest APM, Everington D, McDonald CC, Steele RJC, Chetty U, Stewart HJ. The Edinburgh randomized trial of axillary sampling or clearance after mastectomy. Br J Surg 1995; 82:1504–8. 12. Chetty U, Jack W, Prescott RJ, Tyler C, Rodger A. Management of the axilla in operable breast cancer treated by breast conservation: a randomized clinical trial. Br J Surg 2000;87:163–9. 13. UICC. TNM classification. 5th ed. UICC, 1997.
ARTICLE IN PRESS 4NAS in breast cancer 14. Motulsky H. Intuitive biostatistics, 1st ed. Oxford: Oxford University Press; 1995. 15. Fisher B, Redmond C, Fisher ER. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med 1985;312:674–81. 16. Goldhirsch A, Wood WC, Geler RD, Coates AS, Thu ¨rkimann B, Senn HJ. J Clin Oncol 2003;21:3357–65. 17. Smith JA, Gamez-Araujo JJ, Gallanger HS. Carcinoma of the breast. Analysis of total lymph node involvement versus level of metastases. Cancer 1977;39:527–32. 18. Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994;230:391–8. 19. McMasters KM, Giuliano AE, Ross MI. Sentinel-lymph-node biopsy for breast cancer—not yet the standard of care. N Engl J Med 1998;339:990–5. 20. Mansel RE, Goyal A. European studies on breast lymphatic mapping. Semin Oncol 2004;31:304–10. 21. Hurkmans CW, Borger JH, Rutgers EJT, van Tienhoven G. Quality assurance of axillary radiotherapy in the EORTC AMAROS trial 10981/22023: the dummy run. Radiother Oncol 2003;68:233–40. 22. Moffat FL, Senofsky GM, Davis K, Clark KC, Robinson DS, Ketcham AS. Axillary node dissection for early breast cancer: some is good, but all is better. J Surg Oncol 1992;51: 8–13. 23. Morgan DAL, Berridge J, Blamey RW. Postoperative radiotherapy following mastectomy for high-risk breast cancer: a randomized trial. Eur J Cancer 2002;38:1107–10. 24. Rampaul RS, Mullinger K, Macmillan RD, Cid J, Holmes S, Morgan DAL, Blamey RW. Incidence of clinically significant lymphedema as a complication following surgery for primary operable breast cancer. Eur J Cancer 2003;39: 2165–7.
209 25. Veronesi U, Paganelli G, Galimberti V. Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 1997;949:1864–7. 26. Macmillan RD, Barbera D, Hadjiminas DJ. Sentinel node biopsy for breast cancer may have little to offer four-nodesamplers: results of a prospective comparison study. Eur J Cancer 2001;37:1076–80. 27. Hansen MH, Giuliano AE. Why remove four by chance when one will suffice? Eur J Cancer 2001;37:1067–9. 28. MacCarter MD, Yeung H, Fey J, Borgan PI, Cody III HS. The breast cancer patient with multiple sentinel nodes: when to stop? Am Coll Surg 2001;192:692–7. 29. Rosen PP, Lesser ML, Kinne DW, Beattie EJ. Discontinuous or ‘‘skip’’ metastases in breast carcinoma. Analysis of 1228 axillary dissection. Ann Surg 1983;197:276–83. 30. Pigott J, Nichols R, Maddox WA, Balch CM. Metastases to the upper levels of the axillary nodes in carcinoma of the breast and its implications for nodal sampling procedures. Surg Gynecol Obstet 1984;158:255–9. 31. Schwartz DF, D’Ugo DM, Rosenberg AL. Extent of axillary dissection preceding irradiation for carcinoma of the breast. Arch Surg 1986;121:1395–8. 32. Senofsky GM, Moffat FL, Davis K. Total axillary lymphadenectomy in the management of breast cancer. Arch Surg 1991;126:1336–42. 33. Giuliano AE, Jones RC, Brennan M, Statman R. Sentinel lymphadenectomy in breast cancer. J Clin Oncol 1997;15: 2345–50. 34. Borgstein PJ, Pijpers R, Comans EF, van Diest PJ, Boom RP, Meijer S. Sentinel lymph node biopsy in breast cancer: guidelines and pitfalls of lymphoscintigraphy and gamma probe detection. J Am Coll Surg 1998;186:274–83. 35. Krag D, Weaver D, Ashikaga T. The sentinel node in breast cancer—a multicenter validation study. N Engl J Med 1998; 339:941–6.
THE BREAST www.elsevier.com/locate/breast
ORIGINAL ARTICLE
A four node axillary sampling trial on breast cancer patients Kanji Tanaka, Daigo Yamamoto, Sayaka Kanematsu, Homa Okugawa, Yasuo Kamiyama Department of Surgery, Kansai Medical University, 10–15, Fumizono, Moriguchi, Osaka 570-8507, Japan Received 13 January 2005; received in revised form 19 April 2005; accepted 28 April 2005
KEYWORDS Four node sampling; Breast cancer
Summary The surgical management of axillary lymph nodes in early breast cancer remains controversial, although several maneuvers have been developed such as axillary node clearance (ANC), four node axillary sampling (4NAS), and sentinel node biopsy. A total of 237 cases of primary breast cancer at stages I and II were studied prospectively to elucidate the correlation between 4NAS and ANC. All calculated values by 4NAS showed high sensitivity, specificity, and overall accuracy as follows in this study: 92.9%, 100% and 98.5% for stage I, and 93.8%, 100% and 98.3% for stage II. Likewise, the false negative (FN) rates were 7.1% for stage I, 6.3% for stage II, 6.7% for T1, 6.4% for T2, 7.4% for N0, 0% for N1, and 6.5% for all cases. These rates were very low, although 7.4% for N0 and 0% for N1 were quite clearly different. This implies that all FN cases were N0, and were caused by micrometastases with normal consistency and size. 4NAS may be as accurate a procedure as ANC in assessing axillary nodal stage. & 2005 Elsevier Ltd. All rights reserved.
Introduction The treatment of breast cancer, especially axillary surgery, has been changing over the last decades toward a minimal procedure to reduce postoperative morbidity and to spare the increasing proportion of patients without axillary metastases.1 Alternative axillary operations have been mainly axillary node clearance (ANC),2 four node axillary Corresponding author. Tel.: +81 6 69921001x3424;
fax: +81 6 69928414. E-mail address: [email protected] (K. Tanaka).
sampling (4NAS),1 and recently sentinel node biopsy (SNB).3–5 SNB is now widely used for the staging of clinically node-negative patients with breast cancer. It is highly accurate in predicting the status of both the axillary and the extra-axillary lymph nodes.4,5 However, 4NAS still seems to be an attractive method for minimally invasive axillary surgery because of no additional prerequisites, its possible usefulness in areas with limited sources, 100% detection rate of axillary lymph nodes, and no anaphylactoid reaction from isosulfan or patent blue dye.6–9
0960-9776/$ - see front matter & 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2005.04.020
ARTICLE IN PRESS 204 The technique of 4NAS was pioneered in the Edinburgh breast unit and relies on the theory that the axillary nodes most likely to be involved are those that are palpable intraoperatively.10–12 4NAS adds little if any morbidity to the treatment of the primary tumor and no additional cost (unlike SNB). The lower axilla is mobilized and four nodes are individually identified. This staging modality has been subjected to randomized trials comparing it with ANC in terms of morbidity, recurrence, and mortality.10–12 These trials have shown that 4NAS (followed by radiotherapy in node-positive patients) is associated with lower overall morbidity and has equivalent recurrence rates and mortality to ANC. In this study, we examined 237 cases of Japanese primary breast cancer according to preoperative staging, tumor size, and nodal status, and tried to assess the accuracy of 4NAS compared with ANC.
Patients and methods Patient backgrounds (Table 1) A total of 237 cases of primary breast cancers at stages I and II, operated on at Kansai Medical University hospital from October 1997 to September 2000, were enrolled to clarify the accuracy of 4NAS. Informed patient consent was obtained prior to all studies. The number of patients at stage I was 65 and there were 172 at stage II. The mean age (mean7S.D.) was 56.3713.1 and 57.9712.0, respectively. There were 30 and 63 grade I tumors, 24 and 88 grade II cases, and 11 and 21 grade III cases. Estrogen receptor (ER) statuses (:+) were 1:1.54 and 1:2.0. Nineteen and 83 cases had simple mastectomy, the Patey method was used in 0 and 15 cases, subcutaneous mastectomy (SCM) in 4 and 15 cases, wide local excision (WLE) in 42 and 59 cases, level I and II lymphadenectomy in 59 and 145 cases, and level III in 6 and 27 cases. The total numbers of excised axillary lymph nodes (mean7S.D.) were 17.775.7 and 18.677.1 for stages I and II, respectively. Patient stage in this study was assessed according to the UICC criteria.13 N0 indicates no regional lymph node metastases and N1 shows positive metastases to movable ipsilateral axillary nodes by preoperative assessment.
Operation (4NAS) technique Operations such as Auchincloss, Patey, SCM, and WLE methods were performed. The indications for
K. Tanaka et al. Table 1
Patients’ backgrounds.
Age (mean7S.D.) Tumor grade (cases)
Estrogen receptor (:+) Operation method (cases)
Lymphadenectomy level Number of lymph nodes (mean7S.D.) Preoperative tumor size (T) status Preoperative lymph node (N) status
Stage I (n ¼ 65)
Stage II (n ¼ 172)
56.3713.1 I: 30 II: 24 III: 11 1:1.54
57.9712.0 I: 63 II: 88 III: 21 1:2.0
Auchincloss 19 Patey 0 SCM 4 WLE 42 I, II 59
Auchincloss 83 Patey 15 SCM 15 WLE 59 I, II 145
III 6 17.775.7
III 27 18.677.1
T1: 65
T1: 6
T2: — N0: 65
T2: 166 N0: 149
N1: —
N1: 23
SCM ¼ subcutaneous mastectomy; WLE ¼ wide local excision.
WLE were as follows: (1) tumor size less than 1 cm in diameter; (2) no evidence of extensive intraductal component with malignant calcification; (3) no evidence of multiple lesions; (4) the patients were able to receive radiotherapy after WLE; and (5) the patient gave informed consent for WLE. Among the modified radical mastectomies (Auchincloss, Patey, and SCM), the operation was carried out according to the patient’s choice. After completion of the primary operation, an axillary fat pad containing the lymphatic tissue was exposed. Axillary lymph nodes were palpated by the surgeon’s fingers and four lymph nodes were lifted without injuring any major nerves such as the intercostobrachial, long thoracic or thoracodorsal nerves. Firmly palpable lymph nodes, with a high potential for metastases, were selected prior to other lymph nodes. Following this sampling procedure, other axillary lymph nodes received back-up clearance to clarify the relationship between the sampled lymph nodes and all lymph nodes. Therefore, this study was designed to compare the sampled lymph nodes and all lymph nodes to show how sampled lymph nodes reflect the metastatic status of the whole axillary lymph nodes. In addition, there was no ‘‘learning curve,’’ because
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205
only firmly palpable lymph nodes were selected as samples and then all lymph nodes were examined by multiple sections after surgery.
Mathematical calculation The sensitivity (Sens), specificity (Spec), positive predictive value, negative predictive value, overall accuracy (OA), and false negative (FN) rate in this study were calculated as follows.14 Factors used in the formula above in the 4NAS trial were metastases-positive sample lymph node {meta (+) 4NAS LN}, metastases-negative sample lymph node {meta () 4NAS LN}, metastases-positive axillary lymph node {meta (+) ANC LN}, and metastasesnegative axillary lymph node {meta () ANC LN}. These 4NAS LNs were divided into true positive (TP) {meta (+) 4NAS LN and meta (+) ANC LN} and false positive {meta (+) 4NAS LN and meta () ANC LN}, while meta () 4NAS LN were FN {meta () 4NAS LN and meta (+) ANC LN} and true negative {meta () 4NAS LN and meta () ANC LN}. All the meta (+) 4NAS LN were counted as metastases-positive ANC lymph nodes in this study. Therefore, all the meta (+) 4NAS LNs were counted as TP cases and none were false positive in this trial.
Results Statistical analysis of stages I and II (Table 2) The calculated values for each stage showed that the Sens was 92.9%, Spec 100%, and OA 98.5% for stage I, while Sens was 93.8%, Spec 100%, and OA 98.3% for stage II. The FN rate, which indicated how many metastatic lymph nodes were neglected in 4NAS, was 7.1% (1 out of 14) for stage I and 6.3% (3 out of 48) for stage II in this study and was low. The TP rate was 20.0% (13 out of 65 cases) for stage I and 26.2% (45 out of 172 cases) for stage II. Table 2
Meanwhile, if these values were calculated together including both stage I and II cases, the data showed a high level of Sens of 93.4%, Spec of 100%, OA of 98.3%, and a low FN rate of 6.5%. The most notable event in this series was that all four FN cases showed normal consistency and size on preoperative palpation and were proven to contain only micrometastases by postoperative histological examination.
Statistical analysis according to tumor size Values from the calculation of tumor size (T) revealed that Sens was 93.3%, Spec 100%, and OA 98.6% for T1 and Sens was 93.6%, Spec was 100%, and OA was 98.2% for T2. The FN rate was 6.7% for T1 and 6.4% for T2, which were almost equal and very low for both sizes. Histologically, metastatic lymph nodes increased according to tumor size.
Statistical analysis by N status (Table 3) The N status data indicated a Sens of 92.6%, Spec of 100%, and OA of 98.1% for N0, and Sens, Spec, and OA were 100% for N1. The FN rate for N0 was 7.4% and the highest in this series, while no FN cases were detected for N1. The probability of histologically metastatic lymph nodes was consistent with the preoperative N assessment, i.e., TP was 23.4% for N0 and 34.8% for N1.
The potential for complete removal of positive nodes by the 4NAS procedure alone (Table 4) If the number of positive nodes removed by 4NAS was limited to 0 or 1, there was no possibility of positive nodes being left in the axilla, with the exception of FN incidence. All FN cases, as stated before, included only micrometastasis, and were hard to find by palpation during the operation. In cases with more than two positive nodes detected
Statistical analysis for four node axillary sampling (4NAS) at stages I and II. No. of cases (%)
Stage I (T1N0) Stage II (T1N1, T2N0, T2N1) All
Sens (%) FN
TN
Spec (%)
OA (%)
PPV (%)
NPV (%)
FN rate (%)
TP
FP
Total
13 (20.0) 45 (26.2)
0 (0) 1 (1.5) 51 (78.5) 65 (100.0) 92.9 0 (0) 3 (1.7) 124 (72.1) 172 (100.0) 93.8
100 100
98.5 98.3
100 100
98.1 97.6
7.1 6.3
58 (24.5)
0 (0) 4 (1.7) 175 (73.8) 237 (100)
100
98.3
100
97.8
6.5
93.4
TP ¼ true positive; FP ¼ false positive; FN ¼ false negative; TN ¼ true negative; Sens ¼ sensitivity; Spec ¼ specificity; OA ¼ overall accuracy; PPV ¼ positive predictive value; NPV ¼ negative predictive value.
ARTICLE IN PRESS 206 Table 3
K. Tanaka et al. Statistical analysis for 4NAS in N0 and N1 cases. No. of cases (%)
N0 (T1+T2) N1 (T1+T2)
Table 4 cases.
Sens (%)
TP
FP
FN
TN
50 (23.4) 8 (34.8)
0 (0) 0 (0)
4 (1.8) 160 (74.8) 0 (0) 15 (65.2)
Spec (%)
OA (%)
PPV (%)
NPV (%)
FN rate (%)
100 100
98.1 100
100 100
97.6 100
7.4 0
Total 214 (100.0) 92.6 23 (100.0) 100
The number of positive nodes and potential for their complete removal by 4NAS alone in N0 and N1
Number of positive
NðþÞ ¼ 0 NðþÞ ¼ 1
NðþÞ ¼ 223 NðþÞ ¼ 4o Total
Complete or incomplete removal of positive nodes
Complete removal Complete removal Incomplete removal (False negative) Complete removal Incomplete removal Complete removal Incomplete removal
N0
N1
All
Possibility (%)
Number of cases
Possibility (%)
Number of cases
Possibility (%)
Number of cases
70.6 11.2 0 1.9 2.3 5.1 4.7 4.2 100
151/214 24/214 0/214 4/214 5/214 11/214 10/214 9/214 214
65.3 8.6 0 0 4.3 4.3 0 17.5 100
15/23 2/23 0/23 0/23 1/23 1/23 0/23 4/23 23
70.0 11.0 0 1.7 2.5 5.1 4.2 5.5 100
166/237 26/237 0/237 4/237 6/237 12/237 10/237 13/237 237
by 4NAS, the chance of incomplete removal or possible residual positive nodes in the axilla arose. This shows that no further axillary operation is necessary in 4NAS if the positive nodes removed are limited to o1. On the other hand, an additional procedure is required during or after surgery if more than two positive nodes are involved.
Discussion The surgical management of axillary lymph nodes in early breast cancer remains controversial, although several maneuvers have been developed such as axillary clearance, pectral node biopsy, 4NAS, triple node biopsy, and SNB.12 In 1985, NSABP B04 revealed, after examining 1665 patients, that axillary nodes were not associated with improved survival compared with no axillary surgery with delayed operation in N0 cases.15 Meanwhile, in 2003 the eighth St Gallen (Switzerland) consensus conference accepted that the staging itself was being refined and altered by new techniques such as SNB, i.e., SNB negativity was estimated as N0.16 The important points for conservative axillary surgery in early breast cancer are thought to be the
following factors. First, it should provide the same accurate information about axillary nodes as ANC. Second, it should provide the same survival benefit and local axillary control of disease as ANC. Third, it should provide the same staging and rational basis for adjuvant therapy as ANC. Fourth, it should provide less morbidity after surgery than ANC. The first point of accuracy is chiefly represented by the FN rate. The FN rates in this study were 6.3–7.1% and were relatively low, but higher than for ANC and SNB. This indicated that 4NAS was an accurate procedure in axillary operations. We reviewed the previous ANC and SNB data. Before the comparison, the problem we encountered was that each investigator used a different calculation technique. Therefore, we re-examined all data and presented them in a uniform manner, which we defined in our study. For ANC, we surveyed former investigations and it was noteworthy that they noted a ‘‘skip’’ or isolated metastases in level III and/or Rotter’s nodes in the absence of involvement of level I or II nodes. We estimated these ‘‘skip’’ or isolated metastases as hypothetical FN cases and did calculations. The FN rate for axillary clearance varied from 2.1% to 4.2% (with the exception of the FN rate of 40.5% found by Smith et al.17), with an
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average of 2.9% (Table 5). This result suggested axillary clearance is not a perfect method in terms of possible FN, if level I and II clearance is thought to be sufficient during the operation, as there is no further suspicion of positive lymph node involvement in level III. SNB studies, in which more than 100 cases were operated on, revealed FN rates ranging between 0% and 6.9% with an average of 3.7% (Table 6). One study by Giuliano et al.18 in 1997 showed a 0% FN rate using blue dye. The multi-center study reported by McMasters et al.19 indicated an FN rate of 4.5% using radiocolloid. From all the results, FN rates were 6.5% for 4NAS, 2.9% for ANC, and 3.7% for SNB, which were relatively low. In some studies, as for the second point of overall survival, relapse-free survival, and axillary recurrence, they may be the same for 4NAS with both mastectomy or breast conservation therapy and ANC after a randomized and long-term followup.10–12 On the other hand, it has not yet been proven for SNB because of its short history. Many trials are still on-going and we will have to wait for the results.20,21 As for morbidity, every axillary surgery seems to have some postoperative complication. The Edinburgh group randomized three operation methods,
Table 5
i.e., 4NAS with or without radiation (+rad and –rad) and ANC, and investigated postoperative morbidity. Forrest et al.11 performed the three procedures above with mastectomy and found that arm morbidity and persistent arm swelling were observed after all three methods, even though they were most frequent after 4NAS +rad, followed by ANC and 4NAS –rad. Of note, severe interference with daily activity was only observed in the 4NAS +rad trial. Chetty12 in 2001 studied the three procedures above with WLE in terms of postoperative complications such as flexion and arm elevation, medial rotation, and lymph edema. His data showed that flexion and arm elevation and medial rotation were most severely damaged after 4NAS +rad in which medial rotation seemed to be irreversible. On the other hand, lymph edema was most common in ANC. Besides the Edinburgh group, Moffat et al.22 reported that arm lymph edema developed in 0–2.8% of patients undergoing axillary sampling procedures, 2.7–9.4% in patients treated by level I and II axillary dissection, 4.8–8% in those with level I, II, and III clearance, and 2–8.3% in patients treated by axillary irradiation alone. However, once axillary surgery was combined with regional nodal radiotherapy, it resulted in a 3- to 7-fold increase in
Calculated values for axillary node clearance (ANC) with skip metastases.
Study
Year
Number of patients
Sens (%)
Spec (%)
OA (%)
PPV (%)
NPV (%)
FN rate (%)
Smith et al.17 Rosen et al.29 Pigott et al.30 Schwartz et al.31 Senofsky et al.32 All
1977 1983 1984 1986 1991
408 1228 146 277 278 2337
91.0 97.1 96.0 96.9 94.8 95.2
100 100 100 100 100 100
92.6 98.8 97.9 98.6 98.2 97.2
100 100 100 100 100 100
71.2 97.9 95.9 97.3 97.3 91.9
40.5 2.1 4.2 2.7 2.7 10.4
Skip metastases were estimated as false negative cases.
Table 6
Each calculated value for sentinel node biopsy (SNB).
Study
Year
Number of patients
Technique
Sens (%)
Spec (%)
OA (%)
PPV (%)
NPV (%)
FN rate (%)
Giuliano et al.18 Giuliano et al.33 Veronesi et al.25 Borgstein et al.34 Krag et al.35 All
1994 1997 1997 1998
114 100 160 104
Dye Dye Radiocolloid Radiocolloid
88.0 100 95.3 94.7
100 100 100 69.4
95.6 100 97.5 74.0
100 100 100 40.9
93.5 100 94.9 98.3
6.9 0 5.3 1.7
1998
405 883
Radiocolloid
88.6 93.3
100 93.9
82.0 89.8
100 88.1
95.7 96.5
4.5 3.7
ARTICLE IN PRESS 208 the incidence of arm lymph edema compared with an axillary operation alone. At this point, the most concern arises regarding sparing unnecessary postoperative irradiation, so as to avoid severe morbidity. On the other hand, a recent paper showed that radiation-associated morbidity to the axilla induced no brachial plexus damage and only mild to moderate lymphedema in 2 out of 76 patients.23 Another paper also reported that postoperative radiation therapy to the axilla or axillary clearance in node-positive cases after axillary sampling was examined in a total of 1242 patients and lymphedema was found in only 5 (0.04%).24 These differences in postradiation morbidity might be explained by inter-institutional heterogeneity. For example, 18 institutions performed a dummy run in the AMAROS trial 10981/ 22023, and inter-institutional heterogeneity in dose prescription, radiation technique and radiation field positioning was found.21 In our study, 11.2% of N0 and 8.6% of N1 cases showed only one involved node and these were completely removed by 4NAS. In these cases, postoperative irradiation was not performed. However, if more than two nodes were involved, as in 16.3% of N0 and 26.1% of N1, there is a risk of incomplete removal of the metastatic nodes by 4NAS alone and these are candidates for postoperative irradiation. Recently, SNB has been the center of attention and there are some publications on the comparison between 4NAS and SNB.25,26 There is growing evidence that SNB is superior to 4NAS for optimal staging in breast cancer, especially in extra-axillary staging.4,5 Even so, 4NAS is more beneficial in some respects. It does not need additional prerequisites such as radioactive colloid, dye, and a gammadetecting probe and might be especially suitable for institutions with limited sources. Anaphylaxis by blue dye is serious problem in SNB. It is reported that the proportion of patients with an anaphylactoid reaction reaches 1–2%; it is sometimes nearlethal and has life-threatening potential.6–9 We experienced three cases with blue hives, severe broncospasm, and hypotension requiring pressor support. Precautions must be taken in SNB practice and the patients should be informed properly before the operation. In addition, Hansen and Giuliano27 pointed out several flaws of 4NAS. They indicated the impossibility of palpating a small micrometastasis by 4NAS. This is why our study failed to detect four FN cases by 4NAS, in which all nodes contained micrometastasis with normal firmness and size. However, it is also true that this does not necessarily prove the superiority of SNB over 4NAS, because SNB also has
K. Tanaka et al. disadvantages and FN cases. As stated earlier, FN in 4NAS is mainly caused by micrometastasis and in SNB for anatomical reasons. They indicated the difficulty of the 4NAS technique, although 4NAS is much easier than SNB in our experience. Another point is ‘‘Why remove four by chance when one will suffice?’’. MacCarter et al.28 in 2001 reported that there was no absolute upper threshold for the number of SNB nodes that should be removed, so it is not always correct to say that ‘‘one will suffice.’’ After examining all the evidence, we conclude that 4NAS could be one of the options for minimally invasive axillary surgery.
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