- Email: [email protected]
Preoperative chemotherapy and sentinel lymphadenectomy for breast cancer
The American Journal of Surgery 182 (2001) 312–315
Preoperative chemotherapy and sentinel lymphadenectomy for breast cancer Lorraine Tafra, M.D.a,*, Kathryn M. Verbanac, Ph.D., M.S.b, Donald R. Lannin, M.D.b a
The Breast Center, Lesly and Pat Sajak Pavilion, Anne Arundel Medical Center, 2002 Medical Pkwy., Annapolis, MD 21401, USA b Department of Surgery, East Carolina University School of Medicine, Greenville, NC 27858, USA Manuscript received June 29, 2001; revised manuscript July 10, 2001 Presented at the Second Annual Meeting of the American Society of Breast Surgeons, La Jolla, California, May 3– 6, 2001.
Abstract Background: Sentinel lymphadenectomy (SL) for breast cancer is becoming the standard of care for selected patients treated by experienced surgeons. One of the few contraindications for performing SL alone is prior chemotherapy (PC). There are, however, no data to support that PC interferes with the ability of the sentinel node to predict the presence of disease in the remaining axillary lymph nodes. The goal of this study was to determine the effect of PC on patients undergoing SL for breast cancer. Methods: A multicenter trial was organized in 1997 to evaluate the diagnostic accuracy of SL in patients with breast cancer. Investigators were recruited after attending a course on the technique of SL. Technetium-99 and isosulfan blue were injected into the peritumor region and a gamma probe was used to aid identification of the sentinel nodes. The only exclusion criteria for entrance into the trial were palpable or suspicious axillary lymph nodes. A total of 968 patients were enrolled in the trial. Twenty-nine patients were treated with PC and compared with 939 patients not receiving PC. Results: The overall, sentinel node identification rate for the PC patients was 93% (27 of 29) compared with 88% (822 of 939) for patients not treated with PC. There were no false negatives in those patients receiving PC compared with a 13% (25 of 193) false negative rate in those patients not receiving PC. The mean tumor size was 1.4 cm for the PC group and 0.6 cm for the remaining patients (P ⬍0.005). The mean number of sentinel nodes found was 2.0 for the non-PC group and 2.5 for the PC group (not significant). As expected, a higher proportion of patients had positive axillary nodes in the PC group (52%, 15 of 29) compared with the remaining patients (21%, 200 of 939). Conclusion: In this small group of patients, PC did not adversely impact the false negative or identification rate. Most patients receiving chemotherapy have larger tumors and a higher chance of harboring metastatic disease but a significant group of these patients (48%) without metastases can potentially be spared an axillary node dissection. © 2001 Excerpta Medica, Inc. All rights reserved. Keywords: Sentinel node biopsy; Breast cancer; Preoperative chemotherapy
Since its introduction, lymphatic mapping and sentinel lymphadenectomy (SL) has quickly gained acceptance as a technique to define lymph drainage patterns in malignancies [1–11] and has become the standard of care for surgeons experienced in the technique [12]. Controversial contraindications to SL, not accompanied by an axillary node dissection, have included factors such as larger tumors, prior breast biopsy, prior radiation therapy, and preoperative chemotherapy (PC). It has been suggested that chemotherapy may interfere with the anatomy and physiology of the lymphatics and render SL inaccurate. No data have shown this * Corresponding author. Tel.: ⫹1-410-897-6702; fax: ⫹1-410-8976705. E-mail address: [email protected]
to be the case. We hypothesize that patients undergoing PC can undergo SL with no adverse affects on its accuracy.
Methods Investigative sites A multicenter trial was conducted from February 1997 through March 2001 and enrolled patients from surgical investigators that participated in a formal lymphatic mapping and SL course. The course included hands-on experience in a porcine model that has previously been described [13]. Institutional review board approval was obtained from all investigative sites and all patients signed informed con-
0002-9610/01/$ – see front matter © 2001 Excerpta Medica, Inc. All rights reserved. PII: S 0 0 0 2 - 9 6 1 0 ( 0 1 ) 0 0 7 1 8 - 8
L. Tafra et al. / The American Journal of Surgery 182 (2001) 312–315
sents. Investigative sites included both private practice and academic centers.
Table 1 Comparison of patient characteristics Study characteristics
Preoperative chemotherapy
No preoperative chemotherapy
Significance
Mean age Mean tumor size Lymphatic invasion present Pathology Infiltrating ductal Infiltrating lobular
48 ⫾ 13 1.4 ⫾ 1.7 cm 14% (4/29)
58 ⫾ 14 0.6 ⫾ 1.3 cm 15% (146/939)
P ⬍0.05 P ⬍0.05 NS
72% (21/29) 3% (1/29)
65% (613/939) 8% (73/939)
NS
Technique of sentinel lymphadenectomy The technique of SL included a peritumoral injection with 2 to 5 mL isosulfan blue (American Regent Laboratories, Inc., Shirley, New York) as well as a peritumoral injection of 1 mCi (37 MBq) of technetium sulfur collid (Tc99; CIS-US, Bedford, Massachusetts). Each investigative site had a choice of using filtered or unfiltered Tc99. Filtered Tc99 was obtained by passing radiocolloid over a 0.2-m filter. Only the timing of isosulfan blue injection was restricted and it was injected immediately prior to surgery. Intraoperative use of the gamma probe was required on all patients to aid in the identification of the sentinel node. A sentinel node was defined as any node that was blue, both blue and hot (with hot defined as an ex vivo count equal to or greater than 10 times a background count), or hot only node, and the location of all sentinel nodes in vivo was recorded. The background count was taken off the lower extremity or abdomen. In most cases the sentinel node was harvested prior to performing the definitive surgery on the breast. A standard level I and II lymph node dissection was performed after sentinel node excision in the majority of patients. Patients Exclusion criteria were clinically suspicious or positive axillary nodes, pregnancy, and extensive cardiac, pulmonary or renal disease. Data collected intraoperatively included the type of gamma probe used (C-track, Carewise, Morgan Hill, California; Neoprobe, Neoprobe Corp., Dublin, Ohio; and Navigator, US Surgical Corp., Bedford, Ohio), technique of diagnosis (including patients undergoing prior lumpectomy, open biopsy, FNA biopsy, or core biopsy), tumor size, time of Tc99 injection, time of sentinel node harvest, and use of filtered versus unfiltered Tc99. Pathology All sentinel nodes were serially sectioned, and every other section was submitted for polymerase chain reaction studies as part of a laboratory protocol. Each section submitted to pathology was analyzed using multiple sections. The majority of hematoxylin and eosin (H&E) negative sentinel nodes were analyzed by immunohistochemistry with a cytokeratin cocktail (Cytokeratin AE1:3; Boehringer Mannheim Corp., Indianapolis, Indiana). Statistics Fisher’s exact test for nominal variables was used to compare identification rates and false negative rates. The identification rate in this trial is defined as the ability to
313
NS ⫽ not significant.
successfully identify a sentinel node. The false negative rate is defined as the number of patients with a negative sentinel node (and a positive nonsentinel node) divided by the patients with positive axillary lymph nodes. A one-way analysis of variance was used to compare the mean number of nodes found and mean ex vivo counts between the two groups. The SPSS 8.0 statistical software was used for the statistical analysis. All reported P values for Fisher’s exact test were two-tailed.
Results A total of 968 patients enrolled in the trial and 29 received PC. Patient characteristics are summarized in Table 1 and show, not unexpectedly, a higher mean size of tumor and younger age in the PC group. Table 2 compares various aspects of performance of SL in the two groups. The filtered Tc99 preparation was used more frequently in the PC group compared with the non-PC group (P ⬍0.004). The injection interval refers to the time between injecting the Tc99 and dissecting the sentinel node. The location of sentinel nodes revealed that 16% (150 of 939) of patients had sentinel nodes at level II not significantly different from 10% (3 of 29) in the PC group. There were no differences in the hottest node counts on the sentinel node between the two groups. Ninety percent (26 of 29) of the PC group underwent a complete lymph node dissection compared with 71% (663 of 939) in the non-PC group. The overall identification rate for the entire group was 88% (849 of 968) and the overall false negative rate was 12% (25 of 208). There was no Table 2 Characteristics of sentinel lymphadenectomy technique Sentinel node biopsy
Prior chemotherapy
No prior chemotherapy
C-Track versus Neoprobe Injection interval Filtered Tc99 versus unfiltered Tc99
71% (17/24) vs. 54% (380/706) vs. NS 29% (7/24) 46% (326/706) 107 min 107 min NS 76% (19/25) vs. 46% (398/860) vs. P ⬍0.004 34% (6/25) 54% (462/860)
Tc99 ⫽ technetium-99; NS ⫽ not significant.
Significance
314
L. Tafra et al. / The American Journal of Surgery 182 (2001) 312–315
Table 3 Impact of preoperative chemotherapy on sentinel lymphadenectomy node biopsy
Identification rate False negative rate Percent positive sentinel nodes Mean number of sentinel nodes
Prior chemotherapy
No prior chemotherapy
Significance
93% (27/29) 0% (0/26) 52% (15/29)
88% (822/939) 13% (25/193) 21% (200/939)
NS NS P ⬍0.0004
2.5 ⫾ 1.9
2.0 ⫾ 1.7
NS
NS ⫽ not significant.
statistically significant difference between the identification rate and false negative rate between the two groups as shown in Table 3.
Comments This multicenter sentinel node trial was organized to systematically determine the factors that may impact on the accuracy of the technique. We have previously shown that prior breast biopsy, injection interval (time of Tc99 injection to SL), tumor size, and probe type does not influence the identification or false negative rate [13,14]. This study of patients treated with SL and receiving PC has revealed no difference in the accuracy of the technique compared with patients not receiving PC. Few studies have investigated the affects of PC on the accuracy of sentinel node biopsy. In a small study the high false negative rate was felt to be attributed to PC [15]. The overall false negative rate was 16% (5 of 31) and 3 of the false negative patients had received chemotherapy preoperatively. The overall identification rate in this study was quite low at 80% suggesting that the low level of experience with the technique could account for the high false negative rate. A recent presentation at the Society of Surgical Oncology in March of 2001 investigated patients from NSABP B-27. This randomized trial was organized to determine the efficacy of preoperative and postoperative docetaxel following preoperative doxorubicin/cyclophosphamide chemotherapy. A retrospective review found that of 1,936 patients, 280 underwent SL followed by a complete lymph node dissection. The technique used varied among these patients and included mapping with radioisotope alone (16%), isosulfan blue dye alone (35%), and both agents (46%.) The overall identification rate was 83% and the false negative rate was 9%. The rates are similar to those of other multicenter series of surgeons just starting to adopt the technique. Although this was a retrospective study without a formal protocol, the large numbers of patients in the study supports the hypothesis that PC does not influence the accuracy of the technique.
In our series, no surgeon participated in a learning trial prior to enrolling patients. We have previously shown a significant learning curve from this data [16]. In the PC groups, 5 of the patients underwent SL by surgeons who had performed 10 or fewer procedures. In 11 of the patients the surgeons had performed fewer than 20 procedures. In spite of this low experience level, no significant affect on accuracy of SL has been seen. The use of filtered Tc99 was used more frequently in the PC group. We have previously shown no difference in the false negative or identification rate when comparing the use of filtered versus unfiltered. Other factors could have potentially influenced the false negative and identification rate to mask an adverse affect of PC on the accuracy of SL. As expected a greater percentage of the patients who received PC had positive sentinel nodes. It is important to realize, however, that not all patients with advanced breast cancers receiving PC have metastatic lymph nodes. In our series, a significant percentage (48%) could have possibly been spared an axillary dissection. It has been suggested that PC is a contraindication for SL because it causes an alteration in the lymphatic anatomy and physiology. This alteration could potentially interfere with lymphotropic agents, such as Tc99, and prevent their transit to the sentinel node. If this were true, a difference in the site of the sentinel nodes (level I, II, III, or internal mammary) as well as the number of sentinel nodes found would be expected in the two groups. Neither of these factors was found to be different (see Table 3). In addition, if PC altered the lymphatic anatomy, it would be expected that the absorption of the Tc99 would be altered and result in either significantly higher or lower sentinel node radioactivity counts as determined by the gamma probes. This also was not found. Together, these data support the hypothesis that PC does not interfere with the lymphatic anatomy. PC, as with any factor that potentially influences the results of SL, must be at first considered a contraindication until proven otherwise. Although the overall number of patients in this series is large, the number of patients treated with PC is too small to reach a definite conclusion. A prospective randomized trial is not necessary to prove that chemotherapy does not influence the results of SL but a validation series is needed. This would require PC patients undergoing SL to also have an axillary lymph node dissection. Until the results of such a study, it is appropriate to communicate with patients for whom PC is being considered that there is a small chance that they do not have metastatic disease to lymph nodes and that SL should be considered prior to the start of PC. It is very encouraging to speculate that even patients with large tumors being treated with PC could potentially be spared an axillary node dissection.
L. Tafra et al. / The American Journal of Surgery 182 (2001) 312–315
References [1] Guenther JM, Krishnamoorthy M, Tan LR. Sentinel lymphadenectomy for breast cancer in a community managed care setting. Cancer J Sci Am 1997;3:336 – 40. [2] Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994;220:391– 8. [3] Veronesi U, Paganelli G, Galimberti V, et al. Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 1997;349:1864 –7. [4] Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127:392–9. [5] Decesare SL, Fiorica JV, Roberts WS, et al. A pilot study utilizing intraoperative lymphoscintigraphy for identification of the sentinel lymph nodes in vulvar cancer. Gynecol Oncol 1997;66:425– 8. [6] Javaheri S, Cruse CW, Stadelmann WK, Reintgen DS. Sentinel node excision for the diagnosis of metastatic neuroendocrine carcinoma of the skin: a case report. Ann Plast Surg 1997;39:299 –302. [7] Levenback C, Burke TW, Morris M, et al. Potential applications of intraoperative lymphatic mapping in vulvar cancer. Gynecol Oncol 1995;59:216 –20.
315
[8] Terada KY, Coel MN, Ko P, Wong JH. Combined use of intraoperative lymphatic mapping and lymphoscintigraphy in the management of squamous cell cancer of the vulva. Gynecol Oncol 1998;70:65–9. [9] Koch WM, Choti MA, Civelek AC, et al. Gamma probe-directed biopsy of the sentinel node in oral squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 1998;124:455–9. [10] Bostick P, Essentinel R, Sarantou T, et al. Intraoperative lymphatic mapping for early-stage melanoma of the head and neck. Am J Surg 1997;174:536 –9. [11] Kelemen PR, Van Herle AJ, Giuliano AE. Sentinel lymphadenectomy in thyroid malignant neoplasms. Arch Surg 1998;133:288 –92. [12] Edwards M, Giuliano A, Reintgen D, Tafra L. Consensus statement on guidelines for performance of sentinel lymph node biopsy for breast cancer. Am Soc Breast Surg Quart 1998;Fall:3. [13] Tafra L, Chua A, Ng P, Aycock D, et al. Filtered vs. unfiltered technetium sulfur colloid (Tc99) in lymphatic mapping in a pig model. Ann Surg Oncol 1997;6:83–7. [14] Tafra L, Lannin D, Swanson M, et al. Multicenter trial of sentinel node biopsy for breast cancer using both technetium sulfur colloid and isosulfan blue dye. Ann Surg 2001;233:51–9. [15] Nason KS, Anderson BO, Byrd DR, et al. Increased false negative sentinel node biopsy rates after preoperative chemotherapy for invasive breast carcinoma. Cancer 2000;89:2187–94.
Preoperative chemotherapy and sentinel lymphadenectomy for breast cancer Lorraine Tafra, M.D.a,*, Kathryn M. Verbanac, Ph.D., M.S.b, Donald R. Lannin, M.D.b a
The Breast Center, Lesly and Pat Sajak Pavilion, Anne Arundel Medical Center, 2002 Medical Pkwy., Annapolis, MD 21401, USA b Department of Surgery, East Carolina University School of Medicine, Greenville, NC 27858, USA Manuscript received June 29, 2001; revised manuscript July 10, 2001 Presented at the Second Annual Meeting of the American Society of Breast Surgeons, La Jolla, California, May 3– 6, 2001.
Abstract Background: Sentinel lymphadenectomy (SL) for breast cancer is becoming the standard of care for selected patients treated by experienced surgeons. One of the few contraindications for performing SL alone is prior chemotherapy (PC). There are, however, no data to support that PC interferes with the ability of the sentinel node to predict the presence of disease in the remaining axillary lymph nodes. The goal of this study was to determine the effect of PC on patients undergoing SL for breast cancer. Methods: A multicenter trial was organized in 1997 to evaluate the diagnostic accuracy of SL in patients with breast cancer. Investigators were recruited after attending a course on the technique of SL. Technetium-99 and isosulfan blue were injected into the peritumor region and a gamma probe was used to aid identification of the sentinel nodes. The only exclusion criteria for entrance into the trial were palpable or suspicious axillary lymph nodes. A total of 968 patients were enrolled in the trial. Twenty-nine patients were treated with PC and compared with 939 patients not receiving PC. Results: The overall, sentinel node identification rate for the PC patients was 93% (27 of 29) compared with 88% (822 of 939) for patients not treated with PC. There were no false negatives in those patients receiving PC compared with a 13% (25 of 193) false negative rate in those patients not receiving PC. The mean tumor size was 1.4 cm for the PC group and 0.6 cm for the remaining patients (P ⬍0.005). The mean number of sentinel nodes found was 2.0 for the non-PC group and 2.5 for the PC group (not significant). As expected, a higher proportion of patients had positive axillary nodes in the PC group (52%, 15 of 29) compared with the remaining patients (21%, 200 of 939). Conclusion: In this small group of patients, PC did not adversely impact the false negative or identification rate. Most patients receiving chemotherapy have larger tumors and a higher chance of harboring metastatic disease but a significant group of these patients (48%) without metastases can potentially be spared an axillary node dissection. © 2001 Excerpta Medica, Inc. All rights reserved. Keywords: Sentinel node biopsy; Breast cancer; Preoperative chemotherapy
Since its introduction, lymphatic mapping and sentinel lymphadenectomy (SL) has quickly gained acceptance as a technique to define lymph drainage patterns in malignancies [1–11] and has become the standard of care for surgeons experienced in the technique [12]. Controversial contraindications to SL, not accompanied by an axillary node dissection, have included factors such as larger tumors, prior breast biopsy, prior radiation therapy, and preoperative chemotherapy (PC). It has been suggested that chemotherapy may interfere with the anatomy and physiology of the lymphatics and render SL inaccurate. No data have shown this * Corresponding author. Tel.: ⫹1-410-897-6702; fax: ⫹1-410-8976705. E-mail address: [email protected]
to be the case. We hypothesize that patients undergoing PC can undergo SL with no adverse affects on its accuracy.
Methods Investigative sites A multicenter trial was conducted from February 1997 through March 2001 and enrolled patients from surgical investigators that participated in a formal lymphatic mapping and SL course. The course included hands-on experience in a porcine model that has previously been described [13]. Institutional review board approval was obtained from all investigative sites and all patients signed informed con-
0002-9610/01/$ – see front matter © 2001 Excerpta Medica, Inc. All rights reserved. PII: S 0 0 0 2 - 9 6 1 0 ( 0 1 ) 0 0 7 1 8 - 8
L. Tafra et al. / The American Journal of Surgery 182 (2001) 312–315
sents. Investigative sites included both private practice and academic centers.
Table 1 Comparison of patient characteristics Study characteristics
Preoperative chemotherapy
No preoperative chemotherapy
Significance
Mean age Mean tumor size Lymphatic invasion present Pathology Infiltrating ductal Infiltrating lobular
48 ⫾ 13 1.4 ⫾ 1.7 cm 14% (4/29)
58 ⫾ 14 0.6 ⫾ 1.3 cm 15% (146/939)
P ⬍0.05 P ⬍0.05 NS
72% (21/29) 3% (1/29)
65% (613/939) 8% (73/939)
NS
Technique of sentinel lymphadenectomy The technique of SL included a peritumoral injection with 2 to 5 mL isosulfan blue (American Regent Laboratories, Inc., Shirley, New York) as well as a peritumoral injection of 1 mCi (37 MBq) of technetium sulfur collid (Tc99; CIS-US, Bedford, Massachusetts). Each investigative site had a choice of using filtered or unfiltered Tc99. Filtered Tc99 was obtained by passing radiocolloid over a 0.2-m filter. Only the timing of isosulfan blue injection was restricted and it was injected immediately prior to surgery. Intraoperative use of the gamma probe was required on all patients to aid in the identification of the sentinel node. A sentinel node was defined as any node that was blue, both blue and hot (with hot defined as an ex vivo count equal to or greater than 10 times a background count), or hot only node, and the location of all sentinel nodes in vivo was recorded. The background count was taken off the lower extremity or abdomen. In most cases the sentinel node was harvested prior to performing the definitive surgery on the breast. A standard level I and II lymph node dissection was performed after sentinel node excision in the majority of patients. Patients Exclusion criteria were clinically suspicious or positive axillary nodes, pregnancy, and extensive cardiac, pulmonary or renal disease. Data collected intraoperatively included the type of gamma probe used (C-track, Carewise, Morgan Hill, California; Neoprobe, Neoprobe Corp., Dublin, Ohio; and Navigator, US Surgical Corp., Bedford, Ohio), technique of diagnosis (including patients undergoing prior lumpectomy, open biopsy, FNA biopsy, or core biopsy), tumor size, time of Tc99 injection, time of sentinel node harvest, and use of filtered versus unfiltered Tc99. Pathology All sentinel nodes were serially sectioned, and every other section was submitted for polymerase chain reaction studies as part of a laboratory protocol. Each section submitted to pathology was analyzed using multiple sections. The majority of hematoxylin and eosin (H&E) negative sentinel nodes were analyzed by immunohistochemistry with a cytokeratin cocktail (Cytokeratin AE1:3; Boehringer Mannheim Corp., Indianapolis, Indiana). Statistics Fisher’s exact test for nominal variables was used to compare identification rates and false negative rates. The identification rate in this trial is defined as the ability to
313
NS ⫽ not significant.
successfully identify a sentinel node. The false negative rate is defined as the number of patients with a negative sentinel node (and a positive nonsentinel node) divided by the patients with positive axillary lymph nodes. A one-way analysis of variance was used to compare the mean number of nodes found and mean ex vivo counts between the two groups. The SPSS 8.0 statistical software was used for the statistical analysis. All reported P values for Fisher’s exact test were two-tailed.
Results A total of 968 patients enrolled in the trial and 29 received PC. Patient characteristics are summarized in Table 1 and show, not unexpectedly, a higher mean size of tumor and younger age in the PC group. Table 2 compares various aspects of performance of SL in the two groups. The filtered Tc99 preparation was used more frequently in the PC group compared with the non-PC group (P ⬍0.004). The injection interval refers to the time between injecting the Tc99 and dissecting the sentinel node. The location of sentinel nodes revealed that 16% (150 of 939) of patients had sentinel nodes at level II not significantly different from 10% (3 of 29) in the PC group. There were no differences in the hottest node counts on the sentinel node between the two groups. Ninety percent (26 of 29) of the PC group underwent a complete lymph node dissection compared with 71% (663 of 939) in the non-PC group. The overall identification rate for the entire group was 88% (849 of 968) and the overall false negative rate was 12% (25 of 208). There was no Table 2 Characteristics of sentinel lymphadenectomy technique Sentinel node biopsy
Prior chemotherapy
No prior chemotherapy
C-Track versus Neoprobe Injection interval Filtered Tc99 versus unfiltered Tc99
71% (17/24) vs. 54% (380/706) vs. NS 29% (7/24) 46% (326/706) 107 min 107 min NS 76% (19/25) vs. 46% (398/860) vs. P ⬍0.004 34% (6/25) 54% (462/860)
Tc99 ⫽ technetium-99; NS ⫽ not significant.
Significance
314
L. Tafra et al. / The American Journal of Surgery 182 (2001) 312–315
Table 3 Impact of preoperative chemotherapy on sentinel lymphadenectomy node biopsy
Identification rate False negative rate Percent positive sentinel nodes Mean number of sentinel nodes
Prior chemotherapy
No prior chemotherapy
Significance
93% (27/29) 0% (0/26) 52% (15/29)
88% (822/939) 13% (25/193) 21% (200/939)
NS NS P ⬍0.0004
2.5 ⫾ 1.9
2.0 ⫾ 1.7
NS
NS ⫽ not significant.
statistically significant difference between the identification rate and false negative rate between the two groups as shown in Table 3.
Comments This multicenter sentinel node trial was organized to systematically determine the factors that may impact on the accuracy of the technique. We have previously shown that prior breast biopsy, injection interval (time of Tc99 injection to SL), tumor size, and probe type does not influence the identification or false negative rate [13,14]. This study of patients treated with SL and receiving PC has revealed no difference in the accuracy of the technique compared with patients not receiving PC. Few studies have investigated the affects of PC on the accuracy of sentinel node biopsy. In a small study the high false negative rate was felt to be attributed to PC [15]. The overall false negative rate was 16% (5 of 31) and 3 of the false negative patients had received chemotherapy preoperatively. The overall identification rate in this study was quite low at 80% suggesting that the low level of experience with the technique could account for the high false negative rate. A recent presentation at the Society of Surgical Oncology in March of 2001 investigated patients from NSABP B-27. This randomized trial was organized to determine the efficacy of preoperative and postoperative docetaxel following preoperative doxorubicin/cyclophosphamide chemotherapy. A retrospective review found that of 1,936 patients, 280 underwent SL followed by a complete lymph node dissection. The technique used varied among these patients and included mapping with radioisotope alone (16%), isosulfan blue dye alone (35%), and both agents (46%.) The overall identification rate was 83% and the false negative rate was 9%. The rates are similar to those of other multicenter series of surgeons just starting to adopt the technique. Although this was a retrospective study without a formal protocol, the large numbers of patients in the study supports the hypothesis that PC does not influence the accuracy of the technique.
In our series, no surgeon participated in a learning trial prior to enrolling patients. We have previously shown a significant learning curve from this data [16]. In the PC groups, 5 of the patients underwent SL by surgeons who had performed 10 or fewer procedures. In 11 of the patients the surgeons had performed fewer than 20 procedures. In spite of this low experience level, no significant affect on accuracy of SL has been seen. The use of filtered Tc99 was used more frequently in the PC group. We have previously shown no difference in the false negative or identification rate when comparing the use of filtered versus unfiltered. Other factors could have potentially influenced the false negative and identification rate to mask an adverse affect of PC on the accuracy of SL. As expected a greater percentage of the patients who received PC had positive sentinel nodes. It is important to realize, however, that not all patients with advanced breast cancers receiving PC have metastatic lymph nodes. In our series, a significant percentage (48%) could have possibly been spared an axillary dissection. It has been suggested that PC is a contraindication for SL because it causes an alteration in the lymphatic anatomy and physiology. This alteration could potentially interfere with lymphotropic agents, such as Tc99, and prevent their transit to the sentinel node. If this were true, a difference in the site of the sentinel nodes (level I, II, III, or internal mammary) as well as the number of sentinel nodes found would be expected in the two groups. Neither of these factors was found to be different (see Table 3). In addition, if PC altered the lymphatic anatomy, it would be expected that the absorption of the Tc99 would be altered and result in either significantly higher or lower sentinel node radioactivity counts as determined by the gamma probes. This also was not found. Together, these data support the hypothesis that PC does not interfere with the lymphatic anatomy. PC, as with any factor that potentially influences the results of SL, must be at first considered a contraindication until proven otherwise. Although the overall number of patients in this series is large, the number of patients treated with PC is too small to reach a definite conclusion. A prospective randomized trial is not necessary to prove that chemotherapy does not influence the results of SL but a validation series is needed. This would require PC patients undergoing SL to also have an axillary lymph node dissection. Until the results of such a study, it is appropriate to communicate with patients for whom PC is being considered that there is a small chance that they do not have metastatic disease to lymph nodes and that SL should be considered prior to the start of PC. It is very encouraging to speculate that even patients with large tumors being treated with PC could potentially be spared an axillary node dissection.
L. Tafra et al. / The American Journal of Surgery 182 (2001) 312–315
References [1] Guenther JM, Krishnamoorthy M, Tan LR. Sentinel lymphadenectomy for breast cancer in a community managed care setting. Cancer J Sci Am 1997;3:336 – 40. [2] Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994;220:391– 8. [3] Veronesi U, Paganelli G, Galimberti V, et al. Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 1997;349:1864 –7. [4] Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127:392–9. [5] Decesare SL, Fiorica JV, Roberts WS, et al. A pilot study utilizing intraoperative lymphoscintigraphy for identification of the sentinel lymph nodes in vulvar cancer. Gynecol Oncol 1997;66:425– 8. [6] Javaheri S, Cruse CW, Stadelmann WK, Reintgen DS. Sentinel node excision for the diagnosis of metastatic neuroendocrine carcinoma of the skin: a case report. Ann Plast Surg 1997;39:299 –302. [7] Levenback C, Burke TW, Morris M, et al. Potential applications of intraoperative lymphatic mapping in vulvar cancer. Gynecol Oncol 1995;59:216 –20.
315
[8] Terada KY, Coel MN, Ko P, Wong JH. Combined use of intraoperative lymphatic mapping and lymphoscintigraphy in the management of squamous cell cancer of the vulva. Gynecol Oncol 1998;70:65–9. [9] Koch WM, Choti MA, Civelek AC, et al. Gamma probe-directed biopsy of the sentinel node in oral squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 1998;124:455–9. [10] Bostick P, Essentinel R, Sarantou T, et al. Intraoperative lymphatic mapping for early-stage melanoma of the head and neck. Am J Surg 1997;174:536 –9. [11] Kelemen PR, Van Herle AJ, Giuliano AE. Sentinel lymphadenectomy in thyroid malignant neoplasms. Arch Surg 1998;133:288 –92. [12] Edwards M, Giuliano A, Reintgen D, Tafra L. Consensus statement on guidelines for performance of sentinel lymph node biopsy for breast cancer. Am Soc Breast Surg Quart 1998;Fall:3. [13] Tafra L, Chua A, Ng P, Aycock D, et al. Filtered vs. unfiltered technetium sulfur colloid (Tc99) in lymphatic mapping in a pig model. Ann Surg Oncol 1997;6:83–7. [14] Tafra L, Lannin D, Swanson M, et al. Multicenter trial of sentinel node biopsy for breast cancer using both technetium sulfur colloid and isosulfan blue dye. Ann Surg 2001;233:51–9. [15] Nason KS, Anderson BO, Byrd DR, et al. Increased false negative sentinel node biopsy rates after preoperative chemotherapy for invasive breast carcinoma. Cancer 2000;89:2187–94.