Out of Darkness into the Fluorescent Light Stephen R. Grobmyer, MD, - - PowerPoint PPT Presentation

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 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

Eakins, The Gross Clinic (1875)

S.W. Gross. Tumors of the Mammary Gland, 1880.

The Era of Radical Lymph Node Surgery for Breast Cancer

Samuel W. Gross, MD (1837-1889)

“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

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. Accuracy of SLN: 97% Sensitivity of SLN: 91.2% Specificity of SLN: 100% There were no axillary recurrences in SLN only cohort!

Median follow-up 46 months

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 approach1
• High degree of variation in the proficiency and yield
• f 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
• utcome of the operation.

Is Surgeon Associated with Variation in Yield

• f 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%

0% 25% 50% 75% 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

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

Technetium-99m Sulfur Colloid Isosulfan Blue Dye Methylene Blue Dye

• Radioactive material handling

and disposal issues

• Requires gamma probe
• Can be injected intra-
• peratively
• Patient discomfort with pre-op

injection

• Global shortages of

Technetium

• High cost
• Risk of anaphylaxis
• Supply limited at times
• Cannot be seen

transcutaneously

• Visualization difficult in obese

patients

• Not validated using studies of

completion ALND

• Side effects: skin necrosis and

induration; pulmonary edema and CNS reactions

• Cannot be seen

transcutaneously

• Visualization difficult in obese

patients

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

• perating 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) BMI <25 36 39% 25.1-30 30 32.6% 30.1-35 16 17.4% >35.1 10 11% Tumor Type Invasive Ductal 68 74% Invasive lobular 9 10% Mixed 12 13% Ductal Carcinoma in Situ 3 3% Tumor Size Tis 3 3% T1a 5 5% T1b 32 35% T1c 32 35% T2 20 22% Receptor Status Estrogen Receptor Positive 81 88% HER2 Amplified 5 5.4% Triple Negative 10 11%

Results

• 92 female patients
• 1 failed mapping with both

ICG and Tc-99 (1%)

• 1 failed mapping with Tc

(1%)

• No adverse reactions to ICG

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% mapped not mapped 33 14% 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 (range) 2.0 (1-7) 2.0 (1-5) p=0.34

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

(with Operating Microscope)

Grobmyer, Djohan, Valente, Schwarz (Cleveland Clinic) SSO 2108 (Chicago Preserved and Clipped Blue Arm Lympatics

A R M

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

ICG + Radiocolloid Isosulfan Blue Dye

Shilad, Cakmakoglu, Schwarz, Valente, Djohan, Grobmyer. ASO 25(1): 3106, 2018.

Triple Mapping

Triple Mapping Enables LVB

Digital Augmented Reality Loupes Prototype in OR

SLN Mapping Data Using Digital Loupes

A. Fluorescence guided to SLN mapping of breast cancer, and imaged under regular surgical room lighting with fluorescence excitation. B. Fluorescent SLN imaged with adjustable white lighting from our custom light source, and fluorescence excitation. C. Fluorescent SLN imaged with all white light off, and only fluorescence excitation light on.

A PAN-TUMOR FLUORESCENT IMAGING PROBE (ONM-100) THAT DETECTS PRIMARY CANCER AND LYMPH NODE METASTASES

Tumor/Fluorescence-Guided Cancer Surgery: A New Era in Cancer Surgery?

Courtesy of Charles Balch, MD

Solid Tumors Have Acidic pH

• All 256 human

tumors tested were acidic

• Tumor pH~6.8
• Blood pH = 7.4

Tumors require high levels of glucose GLUCOSE Produces lactic acid an metabolic acidosis in tumors

Gatenby et al, Nat. Rev. Cancer, 2006 Webb et al. Nature Reviews 2011 Thompson et al, Science, 2009

Courtesy of Charles Balch, MD

Hypothesis

“A chemical transistor” that is able to digitize an analog biologic signal (pH) will improve the accuracy of cancer staging, surveillance and surgery.

Courtesy of Charles Balch, MD

OncoNano pH Nanoprobe

Summary of Results to Date

• Reacts with primary tumors and/or metastases in all

cancers tested to date:

• Mouse tumors
• Implanted human tumors in mice
• Outbred dogs (N=10)
• Human breast cancer and head and neck cancer (N=15)
• 100% specificity, 100% sensitivity
• No discernable adverse effects or toxicity in any species,

including humans

Courtesy of Charles Balch, MD

Post Excision of Soft Tissue Sarcoma from Dogs

38

Patient 1 Patient 2 Courtesy of Charles Balch, MD

Dye Localizes to Sites of Human Breast Cancer

Courtesy of Charles Balch, MD

OncoNano pH Nanoprobe

• This ultra-sensitive pH fluorescent imaging agent provides

a universal strategy to visualize tumors with broad applicability for surgical therapy and pathological staging

• The FDA has approved a “fast track” IND for a phase 2

trial to be initiated later in 2019

• This paradigm shift in imaging technology has the potential

to transform cancer staging, diagnosis, surgical resection, and monitoring of therapy for almost all solid cancers tested so far

Courtesy of Charles Balch, MD

Out of the Darkness and Into the “Fluorescent” Light

• Axillary surgery continues to evolve for breast

cancer patients

• There is a need to standardize approaches to

SLN surgery

• Use of fluorescence imaging allows accurate

and safe sentinel node surgery and functional lymphatic surgery

• Fluorescent tumor specific contrast agents and

wearable technology have the potential to revolutionize approaches to cancer surgery