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ORIGINAL ARTICLES |
From the Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
Correspondence: Address correspondence and reprint requests to: Tari A. King, MD, 1275 York Avenue, MRI-1026, New York, NY 10021; Fax: 212-794-5812; E-mail: kingt{at}mskcc.org
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Methods: From January 2001 to November 2002, 1728 breast cancer patients underwent 1832 SLN mapping procedures with the combined technique of intraparenchymal blue dye and intradermal radioisotope. Details of each procedure and all allergic reactions were prospectively recorded. Bilateral synchronous SLN procedures were considered as one dye exposure but as two distinct procedures for determining mapping success. Dye-only success was defined as the proportion of cases in which the SLN was identified by blue dye alone. Overall dye success was defined as the proportion of cases in which the SLN was identified by blue dye with or without isotope.
Results: When stratified by volume of blue dye, there were no significant differences in dye-only successes, overall dye successes, or mapping failures. Allergic reactions were documented in 31 (1.8%) of 1728 patients. Hypotensive reactions occurred in 3 (.2%) of 1728 patients; 2 (.1%) required pressor support. There was a nonsignificant trend toward fewer allergic reactions with smaller volumes of blue dye.
Conclusions: In combined-technique SLN mapping protocols for breast cancer, using smaller volumes of blue dye may represent a means of optimizing the safety of the procedure without compromising its success.
Key Words: Isosulfan blue dye • Sentinel lymph node • Breast cancer • Allergic reactions
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INTRODUCTION |
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In a recent review of patients undergoing SLN biopsy for breast cancer at Memorial Sloan-Kettering Cancer Center (MSKCC), adverse reactions to isosulfan blue dye occurred in 39 (1.6%) of 2392 patients.12 Most reactions (69%) produced urticaria, blue hives, a generalized rash, or pruritus. Hypotensive reactions requiring pressor support occurred in nine patients (.4%). To our knowledge, allergic reactions to 99mTc-labeled colloid during SLN mapping for breast cancer have not been reported.
Several studies have evaluated the optimal dose, timing, technique, and safety of the radioisotope injection,13–18 but the volume of blue dye as it relates to SLN identification rates and patient safety has not been evaluated. This study examined whether the volume of isosulfan blue dye is related to the rate of SLN identification or to the incidence of allergic reactions in SLN mapping for breast cancer.
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METHODS |
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For the purpose of determining SLN identification rates, patients with a history of axillary surgery and/or breast radiotherapy (n = 57), patients treated with neoadjuvant chemotherapy (n = 33), and patients with incomplete data entry regarding the method of SLN identification (n = 23) were excluded from the analysis. Therefore, 1719 SLN procedures were examined for SLN identification rates. Dye-only success was defined as the proportion of cases in which the SLN was identified by blue dye alone. Overall dye success was defined as the proportion of cases in which the SLN was identified by blue dye alone plus those cases in which the SLN was identified by blue dye and isotope.
Our experience with the SLN technique continues to demonstrate that in a single SLN procedure, more than one SLN is typically identified.1,2,4,12 Therefore, any number of, or combination of, blue, hot, and/or blue and hot nodes may be identified in a single procedure, and all, none, or some of these SLNs may harbor metastatic disease. To perform a quantitative analysis of the effect of blue-dye volume on SLN identification rates, the total numbers of blue-only positive SLNs, hot-only positive SLNs, and blue and hot positive SLNs for each procedure were tabulated and compared across volume categories.
For the purpose of determining the incidence of adverse reactions to isosulfan blue dye, bilateral synchronous SLN mapping procedures (n = 81) were counted as one dye exposure, and the volume of blue dye was recorded as the total dye used for the bilateral procedure. Bilateral, staged SLN mapping procedures (n = 23) were counted as two dye exposures. Data entry regarding allergic reactions was complete for all patients; therefore, a total of 1751 dye exposures were evaluated in 1728 patients. Details of all allergic reactions were reviewed and graded according to severity as defined by Montgomery et al.12 A grade 1 reaction was defined as urticaria, pruritus, blue hives, or a generalized rash. A grade 2 reaction involved transient hypotension (systolic blood pressure >70 mm Hg) not requiring pressor support, and a grade 3 reaction was defined as hypotension (systolic blood pressure <70 mm Hg) requiring pressor support.
Patients were stratified by volume of isosulfan blue dye used, based on 1-mL increments. For SLN identification rates, we compared five volume categories ranging from .1 to 1.0 mL (category 1) to 4.1 to 5.0 mL (category 5). For incidence of allergic reaction, patients exposed to more than 5.0 mL of blue dye (range, 5.5–8.0 mL) were included in a sixth volume category (>5.0 mL). All patients receiving >5.0 mL of blue dye had synchronous bilateral SLN mapping procedures.
Continuous variables were compared by using Student’s t-test and Wilcoxon’s rank sum test. The Fisher-Freeman-Halton test was used to compare categorical variables across all volume categories. When a significant difference was noted, individual volume categories were compared by using Fisher’s exact test, and P values were corrected for multiple testing by the stepdown Bonferroni procedure.19 Statistical analysis was performed with SPSS (SPSS Inc., Chicago, IL) and StatXact 5 (Cytel Software Corp., Cambridge, MA).
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RESULTS |
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Of 27 grade 1 reactions, 24 were documented during surgery, and 3 were noted in the recovery room. All grade 1 and 2 reactions (n = 28) resolved with a combination of diphenhydramine and corticosteroids (n = 19) or diphenhydramine alone (n = 9). The single patient with a decrease in SpO2 responded to diphenhydramine, corticosteroids, and increased oxygen delivery via nasal cannula. The two grade 3 reactions resolved with diphenhydramine, corticosteroids, and intraoperative pressor support. In one of these patients, a single 5.5-µg bolus of ephedrine was administered, and this resulted in immediate resolution of the hypotension. In the second patient, a positive SLN led to an axillary node dissection, and six doses of epinephrine were given during surgery over 2.5 hours for a total dose of 50 µg. After surgery, the patient remained hemodynamically stable without further pressor support. No patient required intubation or conversion to general anesthesia solely as a result of the allergic reaction. Three patients with grade 1 reactions, who otherwise would have had outpatient procedures, were admitted to the hospital for overnight observation.
The presence of a sulfa allergy had no effect on the incidence or severity of allergic reaction. Three (2.0%) of 149 patients with a sulfa allergy experienced a grade 1 reaction, and 27 (1.7%) of 1579 patients without a sulfa allergy experienced a grade 1 reaction (not significant). There were no grade 2 or 3 reactions in patients with a sulfa allergy. Among the 31 reactive patients, 13 (42%) reported a history of allergy to various other agents, including penicillin, tetracycline, narcotics, intravenous contrast, nuts, and eggs. A similar proportion, 15 (48%) of 31 reactive patients, received preoperative antibiotics, most commonly cefazolin (13 of 15). A relationship between the severity of reaction to isosulfan blue dye and history of allergy to other agents or to the use of preoperative antibiotics was not observed.
Although this was not statistically significant, there was a trend toward fewer allergic reactions with smaller volumes of blue dye (Fig. 3). The mean volume of dye used for all procedures (n = 1751) was 2.8 mL (range, .5–8.0 mL). The mean volume of dye used in procedures in which a reaction occurred was 3.1 mL (range, 1.0–8.0 mL). The difference in the volume of blue dye used between the reactive and nonreactive groups was not statistically significant (Student’s t-test and Wilcoxon’s rank sum tests). The two grade 3 reactions occurred in patients who received 1.5 and 4.0 mL of blue dye respectively for unilateral SLN biopsy procedures.
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DISCUSSION |
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SLN Identification Rates
After January 2001, we began injecting smaller amounts of blue dye, ranging from .5 to 5.0 mL, for a unilateral SLN biopsy procedure. This analysis demonstrates that dye-only success rates and overall dye success rates were not compromised by using smaller amounts of blue dye (Table 2). As in our previous trend analysis,21 these data continue to demonstrate that the marginal benefit of blue dye, defined as the percentage of cases in which the SLN is identified by blue dye alone, remains low, irrespective of the volume used (Fig. 2; dye-only success, 1.3%–2.7%). Yet the quantitative data demonstrate that of 716 positive SLNs excised, 75 (10.5%) were blue-only positive SLNs. The proportion of blue-only positive SLNs excised ranged from 5.5% to 14.8% across all volume categories (Fig. 1). Therefore, in patients with nodal metastases, the identification of a positive SLN by blue dye is not compromised by using smaller amounts of blue dye.
One may have expected to see a proportional increase in hot-only SLNs excised and in isotope-only identification rates with smaller amounts of blue dye. Among all cases, isotope-only success peaked at 17% in volume category 3, decreasing to 12.5% and 8.1% in volume categories 4 and 5, respectively; however, this did not reach statistical significance (Fig. 2). Quantitatively, there was also no statistically significant difference in the number of hot-only positive SLNs excised across all volume categories, ranging from 17.5% to 29.1% (Fig. 1).
In this series, the volume of blue dye used was often influenced by the patient’s body habitus, the location of the primary breast lesion, and the result of the preoperative lymphoscintigram. Although this is not the case in all practices, many surgeons use smaller volumes of blue dye when the primary tumor is close to the axilla, thereby minimizing the discoloration of the axillary tissue, which may interfere with the identification of a blue sentinel node. Conversely, larger amounts of blue dye may be used in obese patients or when the preoperative lymphoscintigram is negative. Because we did not control for these factors and because the volume of blue dye used was not randomized, this analysis may be somewhat biased, and isotope success rates may be associated with the volume of blue dye used. These limitations do not allow us to define an optimal volume of blue dye to be used for SLN mapping.
Adverse Reactions
The incidence of allergic reactions involving isosulfan blue dye in our series was 1.8%, most of which (87%) were grade 1 reactions: urticaria, blue hives, a generalized rash, or pruritus. This is consistent with the information provided on the package insert for Lymphazurin 1%6 and is similar to the incidence of allergic reactions (1.6%) in our earlier series of 2392 patients who underwent SLN biopsy from 1996 to 2000.12 In this analysis, although there was a trend toward fewer allergic reactions with smaller volumes of blue dye, there was no statistical difference in the overall incidence of allergic reactions when compared across all volume categories, nor was there a statistical difference between the mean volumes of dye used in reactive versus nonreactive patients. Given the small number of events, perhaps our study was underpowered to detect this difference.
Acute transient or prolonged desaturation, as measured by pulse oximetry, is a systemic manifestation of isosulfan blue dye that does not necessarily represent an allergic reaction. In a prospective study designed to assess the effects of isosulfan blue dye on pulse oximetry, 5 mL of blue dye resulted in a maximum SpO2 decrease of 3% in patients undergoing SLN biopsy.22 Pulse oximetry uses spectrophotometric analysis and plethysmography to calculate the oxygen saturation of hemoglobin.23 Isosulfan blue dye, like other vital dyes, interferes with pulse oximetry measurements because isosulfan blue absorbs light at a wavelength of 647 nm and deoxyhemoglobin absorbs light at 660 nm.9 Therefore, if isosulfan blue dye is present in sufficient quantities, as is possible in our patient who received 8.0 mL of dye during a bilateral procedure, it may be interpreted as an increase in the measured amount of unsaturated oxygen, which in turn decreases the reported percent oxygen saturation. If a factitious decrease in SpO2 is confirmed by normal arterial blood gas analysis, this manifestation of isosulfan blue dye can be excluded from future series of allergic reactions.
It is interesting to note that the severity of the allergic reactions to isosulfan blue dye in our experience has been somewhat less than that reported by others. Only 3 (.2%) patients in the current series and 12 (.5%) patients in our earlier series experienced any degree of hypotension, compared with 7 (1.1%) of 639 patients reported by Albo et al.11 All 7 of the patients reported by Albo et al. received 5 mL of isosulfan blue dye, and all 7 required pressor support, whereas only 11 (.3%) of 4120 patients required pressor support in our combined series.
Comparing the grade of reactions between our early and late series and excluding the single patient in the current series with an isolated factitious decrease in SpO2, we found that grade 3 reactions were less frequent in this series: 2 of 30 (6.7%) reactive patients required pressor support, compared with 9 (23.1%) of 39 reactive patients reported previously. This difference did not reach statistical significance. Most of the reactions in both series were grade 1 reactions, representing 69% and 87% of all reactions, whereas grade 2 reactions represented 8.0% and 3.2% of all reactions in the early and late series, respectively. The mean volume of blue dye used for all procedures in the current series was 2.8 mL, compared with a mean of 3.9 mL reported previously.
Considering the decreased severity of reactions in our experience compared with other published reports, as well as the differences between our early and late series, these observations suggest that the incidence of grade 2 and 3 reactions may be decreased by using a smaller volume of blue dye. However, as stated previously in the comparison of all allergic reactions, the limited number of reactions observed makes the statistical analysis difficult, and perhaps the clinical observation is more important in this scenario. A similar observation was suggested by Wayne et al.24 in a retrospective review of the incidence of anaphylactic reactions to isosulfan blue dye in patients undergoing lymphatic mapping for melanoma in which 1 to 3 mL of blue dye was injected intradermally compared with that of patients undergoing lymphatic mapping for breast cancer with a 5-mL intraparenchymal injection. They reported anaphylactic reactions in 7 (1.1%) of 639 breast cancer patients as compared with only 2 (.13%) of 1492 melanoma patients, a finding that was highly statistically significant. Another possibility for the decreasing incidence of grade 2 and 3 reactions in our reported experience is that increased awareness of the potential for a serious reaction may have resulted in earlier recognition and treatment of milder, and perhaps earlier, signs of an allergic reaction, thereby limiting their consequences.
Whether the injection technique (i.e., intradermal vs. intraparenchymal vs. subareolar) is also a factor in the risk of allergic reaction requires further study. An intradermal injection, which can result in tattooing of the skin, is often not an attractive option for breast cancer patients; however, subareolar injection techniques are gaining popularity and may be associated with a lower risk of inadvertent intravenous injection, which may be a factor in the risk of reaction. In this series, all patients underwent an intraparenchymal blue-dye injection; however, we are currently collecting data from cases that used a subareolar injection technique, and we may be able to comment on this variation in future analyses.
In this series, the overall marginal benefit of blue dye (1.9%) was similar to the overall incidence of allergic reactions (1.8%). Therefore, 32 patients were afforded the opportunity of avoiding axillary node dissection and its potential morbidities by the use of isosulfan blue dye, whereas 31 patients experienced an allergic reaction, 27 (87%) of which were mild grade 1 reactions. However, the marginal benefit of blue dye (1.9%) was far greater than the incidence of more serious grade 2 or 3 reactions (0.2%). Further, when stratified by volume of blue dye, our data demonstrate that the incidence of allergic reaction remains less than 2% (the marginal benefit of blue dye) when the volume of blue dye does not exceed 4.0 mL.
In addition to the increased sensitivity gained by using isosulfan blue dye in a combined-technique mapping protocol, isosulfan blue dye also provides an important backup in cases of isotope failure and is of substantial benefit in the training of surgical residents and surgeons new to SLN biopsy. Visualization of a blue lymphatic leading to a blue lymph node requires good exposure and promotes meticulous dissection, both of which contribute to a thorough knowledge of normal and variant axillary anatomy; therefore, we continue to prefer the combined technique of intraparenchymal blue dye and intradermal radioisotope, even in cases in which the preoperative lymphoscintigram demonstrates a hot axillary SLN.
As the indications for SLN biopsy continue to expand, the risk-benefit ratio of using isosulfan blue dye will require continued analysis. For example, should isosulfan blue dye be used when performing SLN biopsy in conjunction with prophylactic mastectomy? In our patient population, occult carcinoma is identified in 9.1% (13 of 143) of patients undergoing prophylactic mastectomy, and the SLN positivity rate is 1.4% (2 of 143) (King T, unpublished data), which is slightly less than the overall risk of an allergic reaction in this series. An additional 1.4% (2 of 143) of patients with occult invasive carcinoma were spared an axillary node dissection, which compares favorably with a 0.2% risk of a serious grade 2 or 3 allergic reaction. Whether the risk-benefit ratio of using isosulfan blue dye for SLN mapping in the prophylactic mastectomy population is favorable will depend on the perceived level of risk of the individual or population choosing prophylactic mastectomy and will likely vary among institutions. Nevertheless, if SLN biopsy with isosulfan blue dye is performed in conjunction with prophylactic mastectomy, using smaller amounts of blue dye to minimize the risk of an allergic reaction should be considered.
This analysis demonstrates that in combined-technique SLN mapping protocols, SLN identification rates are not compromised by using smaller amounts of blue dye, and although this was not statistically significant, there was a trend toward a higher incidence of allergic reactions with larger volumes. Although most allergic reactions to isosulfan blue dye that occur during the course of SLN mapping are grade 1 reactions, serious anaphylactic reactions can occur. As the number of patients undergoing SLN biopsy for breast cancer continues to increase, using smaller volumes of blue dye may represent a means of optimizing the safety of the procedure without compromising its success.
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FOOTNOTES |
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Received for publication October 15, 2003. Accepted for publication January 28, 2004.
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