Melanoma in Central Oregon:

Transcription

1 Melanoma Stats ,380 people in the US will get melanoma this year (up from 68,720 in 2013) About 10,130 deaths (up from 8,650 in 2013) Rates higher in males and elderly, but occurs at all ages; one of the most common cancers in persons under 30 Incidence of Melanoma Melanoma in Central Oregon: Incidence, Prevention, Staging and Treatment John T. Vetto MD, FACS Disclosures: Genentech (Spouse Salary) Castle Biosciences (Advisory Board) Division of Surgical Oncology Disclaimer: I Yam What I Yam What I am not: Dermatologist Epidemiologist Medical or Radiation Oncologist What I am: A melanoma surgical oncologist cares deeply about impacting the damage done by melanoma on individuals and society knows enough about the other specialties to be dangerous (and run a multi disciplinary program)

2 Melanoma: Epidemic Proportions Causes? Environmental: UV exposure? Increasing?global warming?thinning ozone layer Hereditary *Cultural* skin sense The Electromagnetic Spectrum Shorter Wavelengths = Higher Energy UVA: once thought to have a minor role in melanoma, but known to be a major contributor to skin damage and cancer. UVA penetrates deeper into the skin and has more energy than UVB UV Radiation is a Class I Carcinogen (WHO) Lifetime Risk of Developing Cutaneous Melanoma in the US Year Lifetime Risk : : : : : : :53 Arch Dermatol. 2010;146:318 Questions Frequently Asked by Dermatologists and PCPs About Melanoma Why are we seeing so much? What type of biopsy is best? How much more excision should be done? Is it really melanoma? How to stage? Should any tests be ordered? Which patients should be referred for SLNBx? What if the nodes feel enlarged or pt gives history of enlarged nodes? How to treat? How to follow up?

3 Bathing costumes 1910 Kathleen Rockwell, Bend Oregon, circa 1905 They don t call it Sunriver for nothin (Owners Pool, 1990s) Risk Factors for Melanoma Environment >3 blistering sunburns before age 20 Tanning bed use, especially as an AYA Outdoor, especially summer, jobs for >3 years as an adolescent Genetics Family history Li Faumeni (p 54), Pancreas (p 16) Skin type (I V; especially types I and II) FAMMM syndrome

4 Prevention: Oregon Tanning Bed Law House Bill 2896 Passed into law March 2013 Prohibits minors (18yo <) from using tanning beds without a medical order 13 states ACA: 10% Federal excise tax Incidence of Melanoma Poor skin sense Tanning Bed Laws

5 St Charles: 72 cases Melanoma in analytic 38 nonanalytic 56% male SEER Stages at Dx: 40% MIS 36% local 15% regional 6% distant 3% unknown Melanoma in Central Oregon: A Perfect Storm China Hat Campground 300 days of sunshine/year High elevation (more UVA and UVB) Mostly Caucasian / Celtic (Bend : 91% White) 18 tanning parlors in Bend / 5 Urgent Care clinics High numbers of lifeguards Poor skin sense Melanoma in Central Oregon: By the Numbers Oregon: 5 th most common cause of cancer and cancer death, men and women Rate in Nation: 1 st in th in 2014 (29.6 /100,000/yr) 4 th highest death rate St Charles Cancer Registry (NCDB, 2015): 34 analytic, 72 total By county: Douglas and Josephine worst Central Oregon: Mixed bag

6 Melanoma: The Patriotic Cancer Red=inflammation Blue=active tumor White=regression What Type of Initial Biopsy is Best? Boards answer : Excisional biopsy with narrow margins Reality: Partial biopsies frequently used by Derm older age provider preferences lesion factors large lesions excision anatomically impractical Low clinical suspicion C.K. Bichakjian. J Am Acad Dermatol. 2011; 65: Questions Frequently Asked by Dermatologists and PCPs About Melanoma Why are we seeing so much? What type of biopsy is best? How much more excision should be done? Is it really melanoma? How to stage? Should any tests be ordered? Which patients should be referred for SLNBx? What if the nodes feel enlarged or pt gives history of enlarged nodes? How to treat? How to follow up? The ABCDEs of Melanoma Diagnosis Asymmetry One half of the lesion is shaped One half of the lesion is shaped differently than the other Border The border of the lesion is irregular, blurred, or ragged Color Inconsistent pigmentation, with Inconsistent pigmentation, with varying shades of brown and black Evolution History of change in the lesion Diameter >6 mm, or a progressive change in size.

7 Questions Frequently Asked by Dermatologists and PCPs About Melanoma Why are we seeing so much? What type of biopsy is best? How much more excision should be done? Is it really melanoma? How to stage? Should any tests be ordered? Which patients should be referred for SLNBx? What if the nodes feel enlarged or pt gives history of enlarged nodes? How to treat? How to follow up? Biopsy Type Shave Higher incidence of + deep and peripheral margins vs. excisional Consider excisional bx if shave= 0.75mm< melanoma present at base Punch Higher incidence of + peripheral margins vs. excisional Higher mean area of subsequent wide excision Excisional must orient longitudinally No impact on SLN accuracy, tumor recurrence, or survival Mills JK. Am J Surg 2013 Implications for SLNBx Partial bx techniques may underestimate depth 13% thin melanomas ( 1.0mm) upstaged Consider excisional biopsy prior to Rx planning for T1a lesions that do not meet SLNBx criteria Mills J. Am J Surg. 2013; 205:

8 Spitzoid Melanomas: Influence of Age Assertion: Even when metastatic, pts with Spitzoid melanomas do better than pts with non Spitzoid ( adult ) melanomas Columbia Univ: Cancer 2007;109:15 Literature review: 82 cases, <17yo, all stage III or IV Ages 0 10: 86% were stage III, 5 yr DFS=88% Ages 11 17: 59% were stage IV, 5 yr DFS=49% NCI Milan: Pediatrics 2005; 115:649 n=33, all stages Ages 0 9: 5 yr DFS=90% Ages 10 14: 5 yr DFS=47% Age Predicts Px in Young Better Than SLN Status Roaten, et al., 2005 J Ped Surg Spitz Nevi Named for Sophie Spitz Epithelial, Spindle cell nevi Occur 6 mo 71yo, mean age 19 Irreg, tan in color Sun exposure hanging bananas nests of cells 25% have Chr 11 duplications DDx=melanoma with Spitz features Spitzoid Melanoma Gross: Often do not have ABCs Usually wild type for BRAF, NRAS Literature variable as to reported outcomes

9 Melanoma in the Young Adult lesions Age Tumor Genetic Analyses Comparative Genomic Hybridization (CGH) For histo indeterminate lesions, before proceeding with morbid adult therapy Looks at copy number differences between normal and tumor genomes Melanomas: gains in 6p, 1q, 7p, 7q, 8q, 17q, 20q losses in 9p, 9q, 10p, 10q, 6q, 11q Multiple abnormalities Spitz nevi: gains in 11p Cons: Expense, time (up to 6 weeks) Fluorescent In Situ Hybridization (FISH) Cheaper, faster,? valid as CGH International Sentinel Lymph Node Working Group Database OHSU Data Prospective, n=27 Pts undergoing sentinel node biopsy only Selective; many Spitz lesions excluded by CGH With increasing age both node + and survival rates decrease Age/mean n Male Female Positive CLNDx Died 1 10 / / (36%) 3 1 (9%) / (23%) 3 2 (15%) Children are not Little Adults Giotto, 13th Century Raphael, 16 th Century

10 Questions Frequently Asked by Dermatologists and PCPs About Melanoma Why are we seeing so much? What type of biopsy is best? How much more excision should be done? Is it really melanoma? How to stage? Should any tests be ordered? Which patients should be referred for SLNBx? What if the nodes feel enlarged or pt gives history of enlarged nodes? How to treat? How to follow up? 7 th Ed. AJCC Key Features of Primary Ulceration: lack of intact dermis overlying the primary tumor Prognosis of Txb=T(x+1)a Mitoses Michigan System (/mm 2 ) Most important px-tic factor for T1 lesions after thickness Balch C. J Clin Oncol 2009;27:6199 Synoptic report ( report card ) Microsatellites -LVI -TILs regression -Desmoplasia -VGP Utility of CGH Case 19 yr old female with a changing mole on back Bx: 5.2mm melanoma, no negative features Rec: PET/CT, brain MRI, 2cm margin, SLNBx Second opinion OHSU Dermpath: Spitzoid melanoma vs. AMN. Sent for CGH UCSF: Micro: Deep penetrating nevus GCH: NO chromosomal abnormalities Pt had a 1cm margin excision, no SLNBx Determining Malignant Potential in Young Patients Dermpath second opinion Chromosomal analyses: FISH or CGH Age Multigene microarrays: need to validate in children If Spitzoid and favorable genetics: 1cm margins, no SLNBx If adult genetics: WE + SLNBx

11 Questions Frequently Asked by Dermatologists and PCPs About Melanoma Why are we seeing so much? What type of biopsy is best? How much more excision should be done? Is it really melanoma? How to stage? Should any tests be ordered? Which patients should be referred for SLNBx? What if the nodes feel enlarged or pt gives history of enlarged nodes? How to treat? How to follow up? Should I do a Work up? Tests NCCN guidelines: Routine imaging and lab tests not recommended Scanning (PET/CT, brain MRI) only for specific signs or symptoms or if DDx includes a met (epidermotropic) Physical examination Satellite, in transit lesions Other primaries If BCCs, SCCs OK to schedule for Mohs Palpable nodes In effect Released Guarded secret Word on street: AJCC 8 th Ed. Melanoma Back to 0.75 Mitotic rate cutoff no longer 1/mm2? Demographics (age and gender) Determining Malignant Potential in an Era of Change Personalized Medicine Gross Demographics Age, gender, etc Structural (micro features/stage) Breslow, ulceration, mitoses, etc. SLN status Exam and imaging Genetic Tumor GEP CGH/FISH Heraclitus Mutational testing (drug targets) Patient P 16, P 53, etc. Hughes KS. Personal communication

12 Questions Frequently Asked by Dermatologists and PCPs About Melanoma Why are we seeing so much? What type of biopsy is best? How much more excision should be done? Is it really melanoma? How to stage? Should any tests be ordered? Which patients should be referred for SLNBx? What if the nodes feel enlarged or pt gives history of enlarged nodes? How to treat? How to follow up? Which Patients Should be Referred for SLNB? T2 T4 (>1mm) (NCCN, SSO, ASCO, AAD) T1? (<1mm) Features Chance for +SLN Criteria <0.75 and T1a <5% NCCN >0.75, or ulceration, or regression >0.75 and >1 mitosis >5% MSKCC 12.5% U Penn Han D. J Clin Oncol. 2013;31:4387 T4 (>4mm) White I. Am J Surg May 2014 Surgical Management Clinical Stage I and II Melanoma Wide Excision (WLE) plus SLNB Evaluate by H&E, IHC, serial sectioning Node negative Node positive Observation metastatic work-up Closed study: MAVIS SOC: CLNDx MSLT-II trial data is pending Adjuvant therapy on/off study Off study: IFN or Ipilimumab On Study: SWOG 1404 WLE of Localized Melanoma Recommended Margins (NCCN) T stage Melanoma Thickness Margin 0 T1 T2 T3 T4 MIS 1 mm mm mm >4 mm 5mm 1 cm 1 2 cm 2 cm 2 cm Based on a consensus of data from 5 RCTs May need to modify on certain anatomic areas (e.g. face). Ott PS, Berman RS. Surg Onc Clin NA 2011;20:39

13 OHSU Prospective SLN Database 28% 21% H&N Trunk (including Shoulder) Upper Extremity 20% 31% Lower Extremity Ellis MC, et al. Am J Surg. 2010;199:663 MSLT 1 Update 10 year MSS for node+ T2 T3 melanomas: SLNB 62% Observation 42% Multivariate analysis: SLN status most important predictor of disease recurrence and death SLNB provides Accurate staging Enhanced regional control Signif improvement MSS if node + SSO, ASCO, NCCN, AAD guidelines Morton DL. NEJM2014; 370: What is the chance of a +SLN? Thickness Chance of a + SLN (nonulceratedulcerated) T1 <1 mm 3-13% T mm 13-24% T mm 24-34% T4 > % Pawlik TM. Contemp Surg 2005;61:175 OHSU Prospective SLN Database 1998-present >1400 patients, clinically node negative, underwent SLNB OHSU-Knight IRB # 1108, part of NSLNWG Linked to OHSU tumor registry for recurrence and survival rates Multivariate regression, log rank, K-M survival 50

14 Who Doesn t Need a Completion Node Dissection? Are some pts with microscopic ds in SLN cured by SLNB alone? 80% of SLN+ cases, SLN is the only +node Rotterdam Criteria: Max diam of the largest met in the SLN <0.1 mm; mm; >1 mm For <0.1mm: 0% positive nodes on CLNDx (NSLN) Same Px as -SLN patients. Can be spared a CLND Validated on EORTC data, but still retrospective van der Ploeg AP, et al. Eur J Cancer. 2010;46:2414 MSLT-II Trial Began 2005 Positive SLN pts randomized to CLNDx vs. observation Pre-op U/S guided bx reduced need by only 1.7% Halstedian Model Primary (T) Nodal (N) Distant (M) Non-Halstedian Model Primary Nodal Distant Melanoma temple Drainage to parotid SLNs Prior WLE? Lymphoscintogram/ SLNB accuracy same or slightly less (0 11% error rate) Neg factors: transverse incisions, flaps, grafts Bottom line: while the SLN can usually still be found after prior WLE, combined WLE and SLNBx strongly preferred Combined minimizes morbidity, cost, pt discomfort Keleman PR. JACS 1999;189: Morris K. Am J Surg 2001; 181:423 6 Leong SP. Ann Surg Onc 2003; 10: Gannon CJ. Cancer 2006; 107:

15 Validation Study #2: Distant Metastasis-Free Survival Rates for Head and Neck Tumors Determined by Ulceration Status, SLNB or GEP 100% Ulceration SLNB GEP 75% 50% 25% n=59 p=0.014 Time (years) Ulc - Ulc + 0 n=65 p= Time (years) SLNB+ 8 SLNB- 10 Sentinel Lymph Node Status: Key in Adults Morton, et al., 2006 NEJM SLN patients die of melanoma twice as often as SLN+ Why? T1a patients usually not staged Comparing 83% to 17% SLN negative patients can fail: In nodes (false negative SLNs [2 9%]) Distant only (no nodal metastatic potential) Node positive patients treated aggressively Node negative patients usually observed Nodal Primary Distant % free of metastasis 0% n=65 p= Time (years) Class 2 8 Class 1 10 SLNBx tells you how, when and if a clinically node negative patient will progress Primary Diller, abstract accepted at Society for Surgical Oncology, March 2015 Courtesy Castle Biosciences Nodal Distant Disease-Free, Distant Metastasis-free and Overall Survival SLNB AND GEP Prognostic Prediction DFS DMFS OS DFS = Disease Free Survival; DMFS = Distant Metastasis-Free Survival; OS = Overall Survival Gerami, JAAD in press 2015 Censor date: May

16 Present and Future roles for GEP SLN for clinically node negative primary? NCCN Guidelines What if the Patient has Enlarged Nodes? Get an ultrasound guided needle biopsy (FNA or core) If positive: pt has at least stage IIIB or C disease (5%). Consider MUP! The patient needs: PET/CT, Brain MRI for staging Node dissection Post operative adjuvant therapy Radiation Immunotherapy (clinical trial) Unresectable and TK mutant: neoadjuvant therapy (BRAF/MEK combo) Questions Frequently Asked by Dermatologists and PCPs About Melanoma Why are we seeing so much? What type of biopsy is best? How much more excision should be done? Is it really melanoma? How to stage? Should any tests be ordered? Which patients should be referred for SLNBx? What if the nodes feel enlarged or pt gives history of enlarged nodes? How to treat? How to follow up? Negative But high risk (IIB, IIC): Do GEP Class 2 Yes SLNBx positive Adjuvant therapy No: Do GEP Class 2 Questions Frequently Asked by Dermatologists and PCPs About Melanoma Why are we seeing so much? What type of biopsy is best? How much more excision should be done? Is it really melanoma? How to stage? Should any tests be ordered? Which patients should be referred for SLNBx? What if the nodes feel enlarged or pt gives history of enlarged nodes? How to treat? How to follow up?

17 In-Transit Melanoma Intralesional Injections T-VEC Talimogene laherparepvec Modified herpes simplex virus Replicate in and lyse tumor cells Promote regional and systemic immunity production of GM CSF to activate APCs in injected lesions Phase II studies overall response rate 26% patients stage IIIC IV Responses in injected and uninjected lesions Andtbacka et al. J Clin Oncol 2015;33: In-Transit Melanoma Regional Therapy ILI/ILP Regional metastases confined to an extremity Not amenable to resection or intralesional injection Deliver high regional doses limiting systemic absorption/toxicity Hyperthermia improves efficacy & toxicity Surgical Management Clinical Stage I and II Melanoma Wide Excision (WLE) plus SLNB Evaluate by H&E, IHC, serial sectioning Node negative Node positive Observation metastatic work-up Closed study: MAVIS SOC: CLNDx MSLT-II trial data is pending Adjuvant therapy on/off study Off study: IFN or Ipilimumab On Study: SWOG 1404 In-Transit Melanoma Treatment Options Surgical excision Intralesional injection Local Therapies Local ablation (out of favor) Topical imiquimod (dermal lesions) Radiation (unresectable) Regional Therapies Isolated limb infusion Isolated limb perfusion Immunotherapy Systemic Therapies Small molecule inhibitors Chemotherapy Gabriel E & Skitzki J. Cancer 2015;7:

18 In-Transit Melanoma Limb Rx and BOD Median survival low BOD 81 mo Median survival low BOD 27 mo Dossett LA et al. Ann Surg Oncol 2016;23: s/p Limb Infusion and Ipilimumab Slide courtesy of Dr. Ariyan MSKCC In-Transit Melanoma Isolated Limb Infusion Described 1990s Minimally invasive, non-oxygenated adaptation of ILP Performed with percutaneously inserted catheters without the need for bypass machine Well tolerated and can be repeated Hyperthermic - 37 Analysis of 7 studies: - overall response rates 40-80% - complete response rates 30-40% Kroon HM et al. Ann Surg Oncol 2016;23:

19 Metastatic Disease M1: distant skin, SQ, or distant L.N. mets M2: lung mets M3: all other visceral mets, elevated LDH Survival by Type of Metastatic Melanoma Balch CM, et al. JCO. 2009; 27:6199 In-Transit Melanoma Outcomes of treatment Gabriel E & Skitzki J. Cancers 2015;7: In-Transit Disease Always repeat staging prior to treatment Low burden of disease excise to negative margins as possible Mod burden of disease intralesional therapy preferred High burden of disease consider referral for ILI/ILP if confined to extremity Ablation/imiquimod/RT palliative

20 Objective Response to Ipilimumab : Can Occur After Initial Progression Screening Wk 20: Regression Wk 12: Progression Wk 36: Still Regressing Saenger YM. Cancer Res. 2008;68:9884 Case 40 yr old female T3b melanoma midline back, WE only 21 months later: Seizure, bilat axillary masses Crani: V600E+ Metastasectomy: Did you get it all? SWOG 9430 Only prospective study N=77 61% non visceral Median f/u=5 yrs OS=21 months 4 yr surv =30% New agents: evolving role Sosman J. Cancer, 2011 Systemic options IL 2 toxic, durable responses, occas CRs DTIC, Temodar Low RRs, cross BBB TKIs, Anti BRAF, anti MEK rapid onset, not durable. Tumor must have target mutation Combination therapy is FDA approved Check point inhibitors, Anti CTLA 4, Anti PD 1 Slower onset. Target not required Combination therapy is FDA approved

21 Questions Frequently Asked by Dermatologists and PCPs About Melanoma Why are we seeing so much? What type of biopsy is best? How much more excision should be done? Is it really melanoma? How to stage? Should any tests be ordered? Which patients should be referred for SLNBx? What if the nodes feel enlarged or pt gives history of enlarged nodes? How to treat? How to follow up? Guidelines for f/u after Rx of Melanoma: At least annual, q 3 12 months No strong evidence for a particular schedule Base on: Stage Hx of other melanomas or atypical lesions FamHx Pt anxiety and awareness (compliance) Teach: monthly self exams Tumor Board Post craniectomy RT Resect axillary masses Stage IV resected NED Adjuvant study: Ipi vs. Nivo On progression: kinase therapy, study DFS: approval of Ipi+Nivo Melanoma Uveal (Ocular) Melanoma Melanoma (Non ocular) ICON 1 Phase 1, Single and Repeated Escalating Intravitreal Doses of ICON 1 in Patients with Uveal Melanoma Who are Planned to Undergo Enucleation Stages 2B, 2C, or 3 MAVIS A Double Blinded, Placebo controlled Phase III of Polyvalent Vaccine in Post resection High risk Melanoma Adjuvant Therapies Stages 3 or 4 resectable S1404 A Phase III Randomized Trial Comparing Either High Dose Interferon or Ipilimumab to Pembrolizumab Post resection High Risk Melanoma Current melanoma disease group trial portfolio IMCgp100 A Phase Ib/II Open label Study of IMCgp100 + Durvalumab or Tremelimumab or Durvalumab + Tremelimumab Compared to IMCgp100 Alone Non Mutation Specific Dynavax A Phase 1b/2, Open label, Dose escalation and Expansion Trial of Intratumoral SD 101 in Combination With Pembrolizumab Stages 3 and 4, unresectable Takara A Phase II, combination therapy of HF10 (HSV 1 virus) with Ipilimumab in unresectable stage IIIB/IIIC or IV melanoma Mutation Specific BRAF V600E/K EA6134 Phase III trial of Dabrafenib + Trametinib followed by Ipilimumab + Nivolumab vs. Ipilimumab + Nivolumab followed by Dabrafenib + Trametinib Key Open for Enrollment In Development Enrollment on Hold

22 OHSU Multidiciplinary Melanoma Team Shared Beliefs Patient selection is key; Platinum Rule Decisions are shared Consider clinical trials at every step of the way Exciting time for melanoma patients and providers Melanoma Summary Incidence rising Avoid extensive re excision prior to Rx planning Partial biopsy OK. Proper orientation if excisional Ultrasound/cores for enlarged nodes SLNB remains central to staging, Px, Rx planning Role for CLND may evolve pending RCTs Search for effective adjuvants continues RT has a role for local control and possibly in immunotherapy New targeted and check point agents for advanced disease may extend survival and resectability Skin follow up important Build a team around the melanoma patient

23 Melanoma in Central Oregon: Resources and Partners St Charles Medical Center Cancer Center Heme Onc Rad Onc Surgery NCDB (Melissa Chalker CTR) Bend Memorial Clinic Dermatology, Mohs surgery (Dr Wisco) Heme Onc Surgery Dermatology Allison Dermatology Bend Dermatology Clinic Deschutes Dermatology Center Central Oregon Dermatology Peters Dermatology Center Shameless Plug: OHSU/Knight Multidisciplinary Melanoma Conference Surgical Oncology Medical Oncology Radiation Oncology Dermatology Nuclear Medicine/Radiology Dermatopathology Surgical Pathology Medical Genetics Clinical Trial staff Data Managers Melanoma in Central Oregon and at OHSU: Bridging the Gap John T. Vetto MD, FACS OHSU Skin Cancer Program OHSU Skin Cancer Program Champions: Sancy Leachman, John Vetto, Matt Taylor, Kristen Masssimino, Pam Cassidy Executive working group (approx 50, meets twice monthly) Tumor board (2 nd and 4 th Thursday, 7am) Clinical trials program Collaborative partnership between 10 laboratories War on Melanoma Registry (approx 12,000) Mole Mapper App Tumor Bank: OHSU, U of Pittsburgh, CalPacific, Northwestwern Community Partners (incl. Bend; Champion Dr Wisko) Operations Team (Knight Cancer Institute) Steering committee (18 internal/external advisors, meets q 6 months)

24 Linking the OHSU Multidisciplinary Skin Cancer Program and Central Oregon Melanoma conference 7 8am 1 st, 2 nd, and 4 th Thursdays of the month 1 st : Melanoma Executive Working Group 2 nd and 4 th Tumor Board and brief Didactic presentations Pam Russell, russellp@ohsu.edu Referrals: Questions: vettoj@ohsu.edu