AJCC 8 Implementation January 1, 2018 Melanoma of the Skin. Suraj Venna

Transcription

1 AJCC 8 Implementation January 1, 2018 Melanoma of the Skin Suraj Venna

2 Personalized Medicine

3 AJCC 8 th Edition This Time It s Personal Traditional AJCC (TNM) population-based analyses of large databases with 1000 s of cases Simple to use Clinically relevant because of overall survival data Very limited with factors that are used to make such predictions (melanoma: depth, MR, ulceration, nodal status) Precision Medicine Core: Personalized Probabilistic Prediction Tool Help to refine a given individuals prognosis Incorporate patient factors (age, sex) and other tumor-related (TILs, growth phase, LVI) as well as molecular biomarkers Provide accurate prognostic information (OS, recurrence) Conditional Survival (p) of an event occurring over time Web-based tools

4 AJCC 8 th Edition, Jan 1, 2018 New International Melanoma Database International melanoma database 10 cancer centers 1/3 cases from Australia 40,000 patients diagnosed with Stages 1 to 3 melanoma First complete database in the Sentinel Node era Most are SSM, NM (applied to DMM,LM,Acral) Data over a 20 year period Expert panel of 36 members Designed for more frequent updates Gershenwald J et al. Melanoma of the Skin. In AJCC Cancer Staging Manual 8 th Ed. 2017

5 Melanomas Not Staged Using the Melanoma of the Skin system These types of melanoma Melanoma of the conjunctiva Are staged according to Conjunctival melanoma Melanoma of the uvea Uveal melanoma Mucosal melanoma arising in head and neck Mucosal melanoma of the head and neck Mucosal melanoma of the urethra, vagina, rectum and anus No AJCC staging system Gershenwald J et al. Melanoma of the Skin. In AJCC Cancer Staging Manual 8 th Ed. 2017

6 AJCC Goals Allow collection of standardized data to support clinical care Staging systems are based (sometimes) limited data, supplemented by expert opinion Classifies extent of disease based mostly on anatomic parameters Primary tumor (T) Regional nodal disease (N) Distant metastases (M) Major challenge to TNM is the rapid evolution in cancer biology/molecular markers

7 Why is it important to Stage Our Patients? Prognosis Management Sentinel lymph node biopsy Adjuvant therapy Treatment Clinical trials Longitudinal follow up Frequency of clinical examination Determining the type of follow up (medonc,surg,derm) Frequency of additional testing

8 Histologic Prognostic Marker Timeline 1977 First Melanoma Staging per AJCC Breslow s Depth <0.76mm mm mm >4mm 2001 AJCC 6 Breslow s Depth 1mm mm mm >4mm 2009 AJCC 7 Breslow s Depth 1mm mm mm >4mm 1. Breslow s Depth 2. Clark s level 1. Breslow s Depth 2. Clark s level 3. Ulceration 1. Breslow s Depth 2. Ulceration 3. Mitotic rate replaced Clark s level

9 T (Tumor) Updates

10 AJCC 7 th Edition T Categories Primary Tumor (T) TX T0 Tis Primary tumor cannot be assessed (for example, curettage Or severely regressed melanoma) No evidence of primary tumor Melanoma in situ T Thickness Classification (mm) Ulceration Status/Mitoses T1 1.0 a: w/o ulceration and mitosis < 1/mm 2 T a: w/o ulceration b: with ulceration T a: w/o ulceration b: with ulceration T4 > 4.0 a: w/o ulceration b: with ulceration b: with ulceration or mitoses 1/mm 2

11 KEY CHANGES AJCC 8 Definition of Primary Tumor (T) All principal T-category tumor thickness ranges are maintained Tumor mitotic rate is removed as staging criterion for T1 tumors New cut-point for T1 tumors is 0.8mm For the first time there is a distinction between the clinical staging and pathologic staging of T1 melanomas Gershenwald J et al. Melanoma of the Skin. In AJCC Cancer Staging Manual 8 th Ed. 2017

12 Melanoma Institute Australia Data: 6270 Patients With permission from Richard Scolyer MD

13 KEY CHANGES AJCC 8 Definition of Primary Tumor (T) T1a melanomas are < 0.8mm and non ulcerated (MR irrelevant) T1b melanomas are 0.8mm to 1.0mm regardless of ulceration < 0.8mm with ulceration (MR irrelevant) Gershenwald J et al. Melanoma of the Skin. In AJCC Cancer Staging Manual 8 th Ed. 2017

14 KEY CHANGES AJCC 8 Definition of Primary Tumor (T) Tumor thickness now recorded to the nearest 0.1mm, not the nearest 0.01mm Convention for rounding decimal values Round down for those ending in 1 to 4 Round up for those ending in 5 to 9 i.e. 0.75mm will now be recorded as 0.8mm i.e. 0.54mm will now be recorded as 0.5mm 0.8mm tumor are melanomas in the range of 0.75 to 0.84 (T1b) 1.0mm tumor are melanomas in the range of 0.95 to 1.04 (T1b) The NEW T1b range is 0.75 to 1.04mm Gershenwald J et al. Melanoma of the Skin. In AJCC Cancer Staging Manual 8 th Ed., p568, 2017

15 AJCC 8: Definition of Primary Tumor (T) Definition of Primary Tumor (T): T Category Thickness Ulceration Status Tis (Melanoma in situ) Not applicable Not applicable T / 1.0 mm Unknown or unspecified T1a < 0.8 mm Without ulceration T1b mm Regardless ulceration status < 0.8 mm With ulceration T / > mm Unknown or unspecified T2a > mm Without ulceration T2b > mm With ulceration T / > mm Unknown or unspecified T3a > mm Without ulceration T3b > mm With ulceration T4 4.1 / > 4.0 mm Unknown of unspecified T4a > 4.0 mm Without ulceration T4b > 4.0 mm With ulceration Gershenwald J et al. Melanoma of the Skin. In AJCC Cancer Staging Manual 8 th Ed. 2017

16 N (Nodal) Updates

17 AJCC 7: N Categories Regional Lymph Nodes (N) NX N0 Patients in whom the regional nodes cannot be assessed (for example, previously removed for another reason) No regional metastases detected STAGE III MELANOMA N1-3 Regional metastases based upon the number of metastatic Nodes and presence or absence of intralymphatic Metastases (in transit or satellite metastases) NOTE: N1-3 and a-c subcategories assigned as shown below: N No. of Classification Metastatic Nodes Nodal Metastatic Mass N1 1 node a: microstastasis 1 b: macrostastasis 2 N2 2-3 nodes a: micrometastasis 1 b: macrometastasis 2 c: in transit met(s)/satellite(s) without metastatic nodes AJCC 8 N1 a,b,c N2 a,b,c N4 N3 4 or more metastatic noses, or matted nodes, Or in transit met(s)/satellite(s) with metastatic node(s) N3 a,b,c

18 AJCC 8: N category New Pathologic Group: Stage IIID T4 ulcerated with at least 4 nodes/matted/nonnodal+2nodes) Microscopic disease redefined as Clinically occult Macroscopic disease redefined as Clinically detected Tumor burden should be collected on all patients with Stage III Gershenwald J et al. Melanoma of the Skin. In AJCC Cancer Staging Manual 8 th Ed. 2017

19 AJCC 8: Non-nodal Locoregional Metastases Microsatellite microscopic cutaneous/subcutaneous metastasis adjacent or deep to a primary melanoma Satellite recurrence within 2cm of the primary In-transit recurrence > 2cm from the primary Presence of microsatellites, satellites, in-transit now categorized as N1c,N2c, or N3c based on the # of involved nodes (0,1, 2 respectively) Gershenwald J et al. Melanoma of the Skin. In AJCC Cancer Staging Manual 8 th Ed. 2017

20 AJCC 8: N Categories N Number of tumor-involved regional lymph node In-transit,sat/microsat NX Regional nodes not assessed. Exception: pathological N No category is not required for T1 melanomas, use cn. N0 No regional metastases detected No N1 1 node or in-transit/sat/microsat, no tumor-involved nodes N1a 1 clinically occult (i.e., detected by SLN biopsy) No N1b 1 clinically detected No N1c No regional lymph node disease Yes N2 2 or 3 nodes or in-transit/sat/microsat with 1 node N2a 2 or 3 clinically occult (i.e., detected by SLN) No N2b 2 or 3, at least one of which was clinically detected No N2c 1 clinically occult or clinically detected Yes N3 4 nodes or in-transit/sat/microsat with 2nodes or matted nodes without or with in-transit/sat/microsat N3a 4 clinically occult (i.e., detected by SLN biopsy) No N3b N3c 4 at least one of which was clinically detected, or presence of any number of matted nodes 2 clinically occult or clinically detected and/or presence of any number of matted nodes Gershenwald J et al. Melanoma of the Skin. In AJCC Cancer Staging Manual 8 th Ed No Yes

21 Survival for N disease 5 year survival ranges from 70% (N1a) to 39% (N3) disease Balch C M et al. JCO 2009;27:

22 Survival spectrum in Stage III AJCC 7 Positive SLN 3 and any thickness non-ulcerated primary (T1a-T4a) AJCC 8 Positive SLN 3 and limited to T1a/b and T2a AJCC 8: New Stage IIID Balch C M et al. JCO 2009;27:

23 M (Metastasis) Updates

24 AJCC 7 : M Categories Distant Metastasis (M) M0 M1a M1b M1c No detectable evidence of Distant metastases Metastases to skin, subcutaneous, or distant lymph nodes Metastases to lung Metastases to all other visceral sites or distant metastases to any site combined with an elevated serum LDH CNS lumped in w/m1c NOTE: Serum LDH is incorporated into the M category as shown below: M Classification Site Serum LDH M1a Distant skin, subcutaneous, or nodal mets Normal M1b Lung metastases Normal M1c All other visceral metastases Normal Any distant metastasis Elevated Elevated LDH defined M1c

25 AJCC 8: M - categories New M1d designation to include CNS metastasis (regardless of other sites) Poor prognosis associated with CNS spread Frequent exclusion criteria from clinical trials Serum LDH to be recorded for all sites (0) for not elevated (1) for elevated Unknown Gershenwald J et al. Melanoma of the Skin. In AJCC Cancer Staging Manual 8 th Ed. 2017

26 AJCC 8: M Categories M Category Anatomic site LDH Level M0 No evidence of distant metastasis Not applicable M1 Evidence of distant metasis See below M1a Skin, soft tissues including muscle,and or nonregional nodes Not recordered or unspecified M1a(0) M1a(1) M1b Lung with or without M1a sites of Not elevated Elevated M1b(0) Not elevated M2b(1) Elevated M1c Non-CNS/Non-pulmonary, visceral sites Not recordered or unspecified M1c(0) Not elevated M1c(1) Elevated M1d CNS with or without M1a, M1b, or M1c sites of disease Not recordered or unspecified M1d(0) M1d(1) Normal Elevated Gershenwald J et al. Melanoma of the Skin. In AJCC Cancer Staging Manual 8 th Ed. 2017

27 Clinical versus Pathologic Staging Clinical staging Initial stage Pathological staging Definitive stage Microstaging of the primary melanoma Microstaging of the primary melanoma Should be used after biopsy of the primary melanoma PLUS additional staging information from WLE and/or SLN and/or CLND Diagnostic biopsies to evaluate possible regional and/or distant metastasis are also included Gershenwald J et al. Melanoma of the Skin. In AJCC Cancer Staging Manual 8 th Ed. 2017

28 Clinical (ctnm) When T is And N is And M is Clinical Stage Tis N0 M0 0 T1a N0 M0 IA T1b N0 M0 IB T2a N0 M0 IB T2b N0 M0 IIA T3a N0 M0 IIA T3b N0 M0 IIB T4a N0 M0 IIB T4b N0 M0 IIC Any T, Tis N1 M0 III Any T Any N M1 IV Example: 0.7mm + ulceration : Stage 1B Gershenwald J et al. Melanoma of the Skin. In AJCC Cancer Staging Manual 8 th Ed. 2017

29 Pathological (ptnm) When T is And N is And M is Pathologic Stage Tis N0 M0 0 T1a N0 M0 IA T1b N0 M0 IA T2a N0 M0 IB T2b N0 M0 IIA T3a N0 M0 IIA T3b N0 M0 IIB T4a N0 M0 IIB T4b N0 M0 IIC Example: WLE (-) and SLN (-) : Stage 1A Gershenwald J et al. Melanoma of the Skin. In AJCC Cancer Staging Manual 8 th Ed. 2017

30 BURDEN of T1 melanomas

31 Proportion of malignant melanomas by thickness: US T1 melanomas account for 70% V. Criscione and M. Weinstock. Journal of Investigative Dermatology , Journal of Investigative Dermatology , DOI: ( /jid )

32 Nearly 30% of deaths from melanoma are patients initially diagnosed with a T1 lesion About 30% of deaths from melanoma are patients initially diagnosed with a T1 melanoma Tumor thickness Percentage No. of cases , , ,702 >4 5 6,894 Total 130,194 Fatal melanomas , , ,474 >4 22 2,041 Total 9,129 ~27% ~3% V. Criscione and M. Weinstock. Journal of Investigative Dermatology ,

33 More People Die from Thin Melanomas ( 1mm) than from Thick Melanomas (>4mm) mm 14%(112) 17.3%(169) 19.3%(219) 22.7%(296) %(126) 15.7%(153) 17.1%(194) 20.8%(272) %(138) 17.1%(167) 18.7%(212) 20.4%(267) >4 11.3%(90) 13.2%(129) 14.5%(165) 14.2%(186) More People Die from Thin Melanomas ( 1mm) than from Thick Melanomas (>4mm) in Queensland,Australia. J of Investigative Dermatology(2015)135,

34 More People Die from Thin Melanomas ( 1mm) than from Thick Melanomas (>4mm) Median (25%, 75%) duration between first melanoma diagnosis and death by thickness of first primary TOTAL 1mm 5 (3 6) 6 (3 9) 7 (3 11) 7 (4 13) 6 (3 10) mm 4 (2 6) 4 (3 7) 4 (2 8) 5 (2 8) 4 (2 7) mm 2 (1 5) 3 (2 5) 3 (2 5.5) 3 (2 6) 3 (2 5) >4 mm 2 (1 3) 2 (1 4) 4 (2 6) 2 (1 3) 2 (1 4) About 3% of patients with T1 melanoma die of their melanoma on average, 7 years after the initial diagnosis More People Die from Thin Melanomas ( 1mm) than from Thick Melanomas (>4mm) in Queensland,Australia. J of Investigative Dermatology(2015)135,

35 NCCN Recommendations for SLN V published Oct 11, 2017 If risk of positive SLN is <5% does not recommend Clinical Stage 1A, T1a lesions <0.8mm, non-ulcerated, not transected and no other adverse features If risk of positive SLN is 5-10%, discuss and consider Clinical Stage 1B, T1b <0.8mm with ulceration or mm +/- ulceration Clinical Stage 1A, T1a <0.8mm with adverse features (MR 2; young age;lvi)

36 Studies with at least 50 patients with T1 melanomas who have undergone SLNB Study N Positive SLNB Factors associated with (+) SLNB N, % Venna et al., (7) Tumor thickness, Age, TILs, Site, Wright et al,[46] (5) Age, Clark, Sex Murali et al,[28] (6.7) Tumor thickness, LVI Wong et al,[50] (3.6) None Ranieri et al,[10] (6.5) Tumor thickness, Clark, MR Kesmodel et al,[22] (5) Tumor thickness, MR Stitzenberg et al,[48] (4) None 2004 Oliveira Filho et al,[54] 77 8(10.4) Tumor thickness, MR, Ulceration, Muller et al,[51] 75 0 (0) None Bedrosian et al,[18] 71 4(5.6) Tumor thickness Jacobs et al, [19] (3.1) None Hershko et al,[52] (8) Tumor thickness, Clark Cecchi et al,[53] (4) Tumor thickness Venna S, Thummala S, Nosrati M, Leong S, Miller J, Sagebiel R, Kashani-Sabet M. Analysis of sentinel lymph node positivity in patients with thin primary melanoma.jaad 2013.

37 Rate of Positive SLN in Thin Melanomas ( 1/mm2) NCCN V published October 11, 2017

38 Effect of Thickness on Rate of Positive SLN in Thin Melanomas ( 1mm) NCCN V published October 11, 2017

39 JAMA Dermatology July 2017 Association Between Patient Age and Lymph Node Positivity in Thin Melanoma. Identify factors associated with positive SLN, T1 melanoma Retrospective cohort using NCDB N=8772 T1 that had undergone SLN biopsy (+) SLN in 333/8772 (3.8%) Multivariate analysis: independently associated with (+) SLN Younger Age (<40) Female Sex Depth >0.76 Mitoses Clark s (III,IV,V) Ulceration LVI Authors: Sinnamon, A; Neuwirth M. Yalamuchi P, Gimotty P, Elder D, Xu X, Kelz R, Roses R, Chu E, Ming M, Fraker M, Karakousis G

40 From: Association Between Patient Age and Lymph Node Positivity in Thin Melanoma JAMA Dermatol. 2017;153(9): doi: /jamadermatol Classification Tree Analysis for SLN non-mitogenic MR info on 88.4% mitogenic Young patients with T1 mitogenic melanomas discuss/consider SLN Date of download: 10/2/2017 Copyright 2017 American Medical Association. All Rights Reserved.

41 From: Association Between Patient Age and Lymph Node Positivity in Thin Melanoma JAMA Dermatol. 2017;153(9): doi: /jamadermatol How do the NCCN recommendations stack up??? OK OK OK?? X OK OK X Date of download: 10/2/2017 Copyright 2017 American Medical Association. All Rights Reserved.

42 From: Association Between Patient Age and Lymph Node Positivity in Thin Melanoma JAMA Dermatol. 2017;153(9): doi: /jamadermatol *T1a tumors 0.50 to 0.75 mm not shown; nodal positivity rate was < 3% for all ages in this group Date of download: 10/2/2017 Copyright 2017 American Medical Association. All Rights Reserved.

43 Five Year Survival in Patients with Nodular and Superficial Spreading Melanomas in the US Population SEER based analysis year OS comparing SSM vs NM We identified 5,011 patients with NM and 22,420 patients with SSM. Statistical tests: Chi-square test to compare proportions, and the Kaplan-Meier method with Z-score to compare 5-year relative survival. Manuscript in preparation: Blair Saunders, BA, Shandiz Shahbazi, BS, Hongkun Wang, PhD,Sekwon Jang, MD, Suraj Venna, MD

44 5-year OS SSM vs NM Relative Survival 100.0% 100% 100.0% 99.8% 99.2% 98.8% 98.3% 100.0% 93.5% 80% 84.4% 77.0% 60% 72.4% 69.0% 40% 20% Total NM (N = 5011) Total SSM (N = 22420) 0%

45 Nodular subtype is an adverse feature even in THIN melanomas 100.0% 100.0% 100.0% 99.9% 99.2% 98.5% 00% 100.0% 94.2% 80% 87.1% 80.5% 76.3% 60% 70.8% 40% 20% 0% T1b NM (N = 546) T1b SSM (N = 2783)

46 T1 Prognostic gap T1b is not an automatic recommendation for SLN When making decision about SLN in T1 patients, we need to consider all the available clinical and pathologic factors

47 Cutaneous melanoma is most unpredictable.two melanomas can have the same diameter, but vary considerably in depth. Alexander Breslow MD, 1970 Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 1970;172:90

48 Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 1970;172:90

49 These criteria are not absolute and one can expect on occasion to find a lesion <0.76mm in maximal thickness which will recur and metastasize. I have seen such lesions at the National Cancer Institute..these small lethal melanomas must represent a very small percent of lesions operated on - Alexander Breslow MD, November 1970 Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 1970;172:90