Axillary Surgery for Breast Cancer: Out of Darkness into the “Fluorescent” Light Stephen R. Grobmyer, MD, FACS Professor of Surgery Zapis Endowed Chair for Breast Cancer Research Co-Leader, Breast Cancer Program Cleveland Clinic Cleveland, Ohio
Disclosures • Travel support - Zeiss Meditech • Medical Advisory Board - Seno Medical • Research Support - Mitaka USA • Research Support - GRAIL • Research Support - Lumicell
There was an Era of Radical Lymph Node Surgery for Breast Cancer “Even if I should be Eakins, The Gross Clinic (1875) deemed too bold in recommending that the axilla be attacked, when it is apparently free from disease, surgeons of extended experience will agree with me…” -Samuel W. Gross, MD S.W. Gross. Tumors of the Mammary Gland , 1880.
The Era of Radical Lymph Node Surgery for Breast Cancer “It is far wiser to attack the axillary tumor… While I am not unmindful of the fact that these radical measures must of necessity increase the mortality, I cannot avoid thinking that the end justifies the means.” -Samuel W. Gross, MD Samuel W. Gross, MD (1837-1889) S.D. Gross. Tumors of the Mammary Gland , 1880.
Halsted Radical Mastectomy • 1882 Halsted performed mastectomy with removal of pectoralis minor and major muscles. • “The contents of the axilla are dissected away with scrupulous care and also with the sharpest possible knife. The axillary vein should be stripped absolutely clean.” W.C. White. Cancer of the Breast , 1930.
Courtesy of E.M. Copeland
Evolution of Less Radical Procedures for Breast Cancer ““ Refuse to submit to a radical mastectomy,” Crile exhorted his patients .” “Simpler procedures which gave equal results with less side effects.” George “Barney” Crile, Jr. (1907-1992)
Sentinel Node Biopsy Has Revolutionized Axillary Management in Breast Cancer Blue Dye Alone Sentinel Node identification rate 78% Accuracy 95.6% False negative rate 0% Giuliano et al. Ann Surg 220: 391, 1994.
Completion ALND Can Safely be Omitted in SLN ( – ) Patients Randomized trial SLN group: only ALND if SLN+ ALND: all had SLN and ALND All patients had partial mastectomy + whole breast radiation. Median follow-up 46 months Accuracy of SLN: 97% Sensitivity of SLN: 91.2% Specificity of SLN: 100% There were no axillary recurrences in SLN only cohort! Veronesi et al. NEJM 349: 546, 2003.
ALND May Be Safely Omitted in Lumpectomy Patients in cN0 patients with 1-2+ SLNs ACOSOG Z0011 Giuliano et al. JAMA 318(10): 918, 2017.
SLN May Be Useful in Patients Following Neoadjuvant Therapy in Patients Presenting with cN1 • Need 2 dyes (blue and radiocolloid) for mapping • Remove > 2 nodes to achieve low false negative rate • Targeted axillary dissection may further reduce false negative rate • Interest in this approach has increased with increasing efficacy of systemic therapy
Sentinel Lymph Node (SN) Biopsy in Breast Cancer Management • No uniform technical approach 1 • High degree of variation in the proficiency and yield of SN biopsy • There is a need to improve the “technical performance and success rates of SN biopsy” 1 1. James, Coffman, Chagpar, Boughey, Klimberg, Morrow, Giuliano, Harlow. Ann Surg Onc 23(11): 3459, 2016. 2. Larson, Valente, Tu, Dalton, Grobmyer. Surgery 164(4): 680, 2018.
Potential for Variation in Results of Process of SLN Biopsy • No single standard for how the procedure is performed • No specific credentials for performing SLN biopsy • No standard for results of the procedure - Number of SLN removed (removing excess nodes can result in increased morbidity) - SLN positive rate (oncologic yield) (failure to remove sentinel nodes can result in understaging) • Potential for individual surgeon variation and hospital variation in the yield and outcome of the operation.
Is Surgeon Associated with Variation in Yield of SLN Procedures? • 15,571 patients; 2478 providers, SEER-Medicare linked to provider files • Mean patient age 73 years • Caucasian 87%; African American 6%; Asian 3%; Other 4% • ER+ 85%; PR+ 74%; HER2+ 8.2%; TNBC 7.9% 75% 50% 25% 0% T1 T2 T3 T4 Larson, Valente, Tu, Dalton, Grobmyer. Surgery 164(4): 680, 2018.
There is Surgeon Associated Variation in Sentinel Lymph Node Procedures • There is surgeon-associated variation in the number of SLN examined by T stage (p<0.001) • There is surgeon associated variation in the rate of sentinel node positivity by T stage (p<0.001) • Suggests need to standardize or improve techniques of SLN biopsy Larson, Valente, Tu, Dalton, Grobmyer. Surgery 164(4): 680, 2018.
There are Limitations to Current Approaches Technetium-99m Sulfur Colloid Isosulfan Blue Dye Methylene Blue Dye • • Radioactive material handling Not validated using studies of • High cost and disposal issues completion ALND • Risk of anaphylaxis • • Requires gamma probe Side effects: skin necrosis and • Supply limited at times • Can be injected intra- induration; pulmonary edema • Cannot be seen operatively and CNS reactions transcutaneously • • Patient discomfort with pre-op Cannot be seen • Visualization difficult in obese injection transcutaneously patients • • Global shortages of Visualization difficult in obese Technetium patients James et al. Ann Surg Onc 23(11): 3459, 2016 Layeeque, Kepple, Henry-Tillman, Adkins, Kass, Colvert, Gibson, Mancino, Korourian, Klimberg. Ann Surg 239 (6): 841, 845 James, Coffman, Chagpar, Boughey, Klimberg, Morrow, Giuliano, Harlow. Ann Surg Onc 23(11): 3459, 2016 Efron, Knudsen, Hirshorn, Copeland. Breast J. 8(6): 396, 2002
Fluorescence Imaging with Indocyanine Green (ICG) Offers Potential Advantages for SN Mapping • ICG safely used in humans for over 50 years • High signal to background ratio • No reported reactions • Inexpensive and widely available • No special handling of dye required • Requires fluorescence camera - which are becoming common in many operating rooms Zeng et al. Mol. Imaging Biol. 2018 June 21
Methods • Pre-op periareolar injection with Tc-99m sulfur colloid • Intra-op periareolar injection with ICG (0.8-1.0cc) - 0.5% ICG solution • SNs were defined as “sentinel” if they were fluorescent and/or met threshold for radioactive positivity • Failed mapping = No uptake of ICG and/or Tc
Methods • Transit time recorded (injection to visualization of SN) • Transcutaneous lymphatic and SN identification using translucent image enhancer (PDE) • Fluorescent SNs removed from axilla first and radioactivity assessed after removal • Once fluorescent nodes removed then any remaining radioactive nodes were removed from axilla • Non-parametric tests of significance. p< 0.05 considered significant
N=92 Percent (%) Median Age 59 years (35-81) Results BMI <25 36 39% • 92 female patients 25.1-30 30 32.6% 30.1-35 16 17.4% >35.1 10 11% Tumor Type • 1 failed mapping with both Invasive Ductal 68 74% Invasive lobular 9 10% ICG and Tc-99 (1%) Mixed 12 13% Ductal Carcinoma in Situ 3 3% Tumor Size • 1 failed mapping with Tc Tis 3 3% T1a 5 5% (1%) T1b 32 35% T1c 32 35% T2 20 22% Receptor Status • No adverse reactions to ICG Estrogen Receptor Positive 81 88% HER2 Amplified 5 5.4% Triple Negative 10 11%
ICG Had Rapid Transit to the Axilla • Median transit time of ICG to axilla: 5 minutes (range 2-29 minutes) • Transit time was significantly longer in obese patients (p=0.025)
Most SNs were Mapped by Both ICG and Tc-99 N % Total SLNs 235 ICG Tc-99 mapped mapped 191 81% not mapped 33 14% mapped not mapped mapped 11 5%
Number of SLNs Identified and Removed was Similar ICG Tc p value Mean # SNs (SD) 2.5 (1.42) 2.2 (1.23) Median # SNs 2.0 (1-7) 2.0 (1-5) p=0.34 (range)
Detection Rate of Pathologically Positive SN was Similar 24 Total Path Positive Axillary SLNs ICG + 24/24 (100%) ICG - 0 (0%) Tc-99 + 23/24 (94%) Tc-99 - 1/24 (6%)
Conclusions • ICG is comparable to Tc-99m for SN mapping (# of nodes and identification of + SNs) • ICG offers numerous advantages over visible dyes and Tc- 99m for mapping (cost, handling, efficiency, safety) • ICG is good option for single agent SN mapping in breast cancer patients
Lymphatico-Venous Bypass: Restoring Lymphatic Following Axillary Node Dissection 1. Reverse Mapping Injection of Isosulfan Blue Dye on proximal arm injection 2. Perform Lymphatic and Venous Preserving ALND with sharp dissection 3. Lymphatico-Venous Bypass A (with Operating Microscope) R M Preserved and Clipped Blue Grobmyer, Djohan, Valente, Schwarz (Cleveland Clinic) Arm Lympatics SSO 2108 (Chicago
Lymphatico-Venous Bypass: Restoring Lymphatic Follow Axillary Node Dissection • Operation under sub 1mm environment • Special Operating Microscope; • 42X Magnification- Super- microsurgery lens • Super-Microsurgery Instrument Set • 12/0 Nylon Suture Djohan, Valente, Grobmyer, Schwarz (Cleveland Clinic)
Triple Mapping to Facilitate LV Bypass in cN1 Patients Having NAC Isosulfan Blue Dye ICG + Radiocolloid Shilad, Cakmakoglu, Schwarz, Valente, Djohan, Grobmyer. ASO 25(1): 3106, 2018.
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