«Aut tace aut loquere meliora silentio» Francesco GIAMMARILE

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2 «Aut tace aut loquere meliora silentio» Francesco GIAMMARILE

3 Presentation Outline Introduction: the GOSTT Concept The EANM Guideline in Melanoma Future trends and concluding remarks I sort of thought your presentation was going to be in powerpoint.

4 The GOSTT concept (radio)guided intraoperative Scintigraphic Tumor Targeting

5 Evolution of oncologic surgery Historical: open and see Passed: open and listen Present: see, open and listen Future: see, open, listen and see with new eyes

6 Sentinel Node in Melanoma Indications Methods Radiopharmaceuticals Instrumentation Clinical evidence

7 Indications SLNB is indicated for patients with thick clinically lymph node-negative melanoma: stage T1b T4b N0 and M0 (not in patients with known dissemination) Thickness Risk of + SLN SLN indications (mm) (%) >4 40 prognosis staging ? no

8 Rationale Classification Significant decrease in survival when thickness (T stage) and number of involved nodes (N stage) increase

9 Contraindications Pregnancy and childhood are not contraindications Preoperative evaluation with FNAB may select patients with a malignant SN to proceed directly to CLND Indication of SLNB Clinically suspected LN + - FNAB SLNB CLND? Survey

10 Injection techniques Tuberculin syringes (virtually no dead space), needle: 25- or 27-gauge Intradermal injection: tangent to the skin surface, to produce a visible wheal in the skin at a distance of cm from the scar or the tumor margin 2-4 sites around the tumor/scar: Head-neck and trunk: 4 injections, roughly equatorially, around the lesion (because the drainage may be both cranial and caudal and across the midline of the body) Extremities: 2 injections, medial and lateral to the lesion Volume: small ( ml) in order not to collapse lymphatics and to avoid rupture of the wheal on the skin surface, which will cause contamination and loss of activity for the drainage visualization No consensus: Radiopharmaceutical type and activity

11 99m Tc labeled colloids Radiopharmaceuticals Size max (nm) Size mean range (nm) Antimony sulphide 80 -> 5-30 Albumin nanocolloid (Nanocoll ) 100 -> 5-80 Sulfide nanocolloid (Lymphoscint ) > Rhenium sulfide nanocolloid (Nanocis ) > Sulphur colloid (filtered) 5,000 (unfilt.) ---> Colloidal tin hydroxide (Hepatate ) > Dextran > Human serum albumin > Nonspecific, particle size-related phagocytosis by macrophages in lymph nodes Tilmanocept Receptor targeting agent (active phagocytosis) : binding to macrophages and dendritic cells in lymph nodes through non-saturable mannose receptors (CD 206)

12 Acquisition modalities Planar/dynamic No Consensus Landmarks SPECT-CT

13 Drainage patterns Drainage Node Field (%) Trunc anterior Trunc posterior Head and neck Base of neck Preauricular Postauricular Occipital - <1 10 <1 Cervical level I Cervical level II < Cervical level III 2 < Cervical level IV < Cervical level V Supraclavicular Axilla Triangular space - 10 <1 5 Paravertebral Costal margin Groin Interval nodes Lymphatic drainage unpredictable

14 Pre-surgical imaging Dynamic imaging: - SLN identified by lymphatic collector passing directly from the melanoma site strongly recommended in the trunk and head-neck regions optional, in other regions (time consuming but se/sp improved) Delayed, static imaging (early and delayed) - A node that appears in a separate node field only on delayed image is also a SLN accurate mapping of the precise lymphatic drainage from the melanoma site is fundamental however, unknown clinical impact on postoperative morbidity, recurrence rate and reduction of operation time Non-visualization of SN: consider more delayed images (up to 24 h) SPECT/CT and/or re-injection of tracer Melanoma sites may drain: to several SLN in a node basin to several nodal basin

15 Interval (in-transit) nodes In-transit (interval) nodes (unexpected locations) about 7% of patients lie along a lymphatic vessel between melanoma site and recognized node field popliteal nodes; triangular intermuscular space (behind the axilla); para-aortic, paravertebral and retroperitoneal; intercostal nodes; internal mammary nodes SN ITN Uren RF et al. Arch Surg. 2000

16 SPECT/CT: Added Values No/poor visualization on planar imaging low activity injection closer to nodes depth attenuation correction Planar images difficult to interpret: deep lymphatic drainage (pelvis, abdomen, or mediastinum) complex anatomy (head and neck) unexpected/unusual drainage patterns exact localization

17 SPECT/CT: Added Values CT component informations

18 SPECT/CT: Added Values

19 SPECT/CT: Added Values JNM 2015 Cutaneous melanoma additional SLNs (20%) better intraoperative search (29%) adjustment in surgical approach (29%) reduction in operative time (40 min) reduction in hospital stay duration

20 SPECT/CT: Added Values Hybrid imaging with SPECT and CT including anatomical information improves the localization of SLNs and reduces misinterpretation of images. SPECT/CT should be performed in head and neck melanoma owing to the complex anatomy. Moreover, SPECT/CT is highly recommended for the groin area and recommended for the axillary area because it facilitates the detection of in-transit nodes and aberrant lymphatic drainage stasis in lymph vessels and consequently facilitates the surgical procedure. Right calcaneum melanoma

21 Surgical techniques Blue Dye vs Probe Center Blue dye only Patient nb Identified SN Metastasis Ist. Naz. Tumori, Milano 74 90% 16% J. Wayne Cancer Inst. CA % 22% Melanoma Unit, Sydney % 21% Total dye % 20.7% Probe and dye California Univ. CA % 18.4% Free Univ. Amsterdam % 21.5% L. Moffitt Cancer Cent. FA % 14% N. Cancer Inst. Amsterdam % 24% Total probe % 19.8%

22 Surgical techniques

23 Clinical aspects False negative = removal of a normal non SLN, in presence of a pathological SLN (NB failure of the method: non detection of SLN in imaging and/or surgical procedures)

24 Clinical aspects Completion lymph node dissection in case of metastatic sentinel node - Not a dogma any more for breast cancer patients (Giuliano et al. JAMA 2011) - Trial in melanoma: No significant difference in 10-yr melanoma-specific survival Significantly greater 10-yr disease-free survival and lower 10-yr loco-regional recurrence rate no evidence for benefit (Kyrgidis et al. Cochrane Database Syst Rev. May 2015)

25 Clinical aspects Prognosis Important prognostic information Identification of patients with nodal metastases who may benefit from complete lymphadenectomy No gain in DFS

26 Clinical aspects Prognosis Yamamoto RF et al. Cancer. 2015

27 Latest technological knowledge Radiopharmaceuticals Instrumentation

28 Perspectives in Imaging Agents for Lymphatic Mapping Tilmanocept Rapid SLN Uptake Anterior view, 10 min PI Coronal SPECT/CT, 2 hrs PI Courtesy S. Schneeaum, Tel Aviv

29 Tilmanocept versus Radiocolloids - Higher specific radioactivity. - Faster clearance from injection site. - Faster migration to draining lymph nodes. - Longer retention in lymph nodes. - Greater scintigraphic contrast. - Lesser migration to higher-tier lymph nodes. - Greater signal-to-background ratio. - Comparable sensitivity but greater specificity in SN identification. - Higher count-rate in tumor-positive lymph nodes? - Higher cost The advantages of this tracer include rapid clearance from the injection depot and low accumulation in second-echelon nodes. This novel radiopharmaceutical might be of particular utility in patients with head and neck melanoma.

30 Perspectives in Imaging Agents for Lymphatic Mapping SPIO Superparamagnetic iron oxide based MRI contrast agents

31 Perspectives in Imaging Agents for Lymphatic Mapping Bimodal (hybrid) agents Simultaneous scintigraphic and optical imaging (near-infrared fluorescence): Fluorescent agent (ICG) Tissue penetration signals Brouwer OR, Ann Surg Oncol (2012) Assembled nanoparticule containing ICG

32 Hybrid radiopharmaceuticals Added value for laparoscopic surgery or in case of complex lymphatic anatomy

33 Potential Aspects for Radioguided Surgery Portable gamma camera No SLN on preoperative imaging Courtesy S Vidal, Barcelona Portable gamma camera: SLN is depicted Increased resolution and sensitivity

34 Potential Aspects for Radioguided Surgery Portable gamma camera Courtesy S Vidal, Barcelona

35 Potential Aspects for Radioguided Surgery Freehand SPECT Courtesy S Vidal, Barcelona

36 Potential Aspects for Radioguided Surgery LightPath Cerenkov luminescence (light) emitted by β + particle (PET imaging agents) FDG (breast cancer)

37 Take home message Standardization: guidelines (imaging) no overall survival benefit has yet been shown for SLN main goals: staging and better local tumor control better selection for complete regional lymph node dissection (CLND) to reduce morbidity

38 The most important thing is not to stop questioning." It is not the answer that enlightens, but the question. "It is impossible to speak in such a way that you cannot be misunderstood." ANY QUESTIONS?