Sentinel Lymph Node Biopsy: Current Evidence for its Role in Managing Melanoma

Transcription

1 Sentinel Lymph Node Biopsy: Current Evidence for its Role in Managing Melanoma John A Zitelli MD Adjunct Clinical Associate Professor Dermatology, Otolaryngology, Plastic Surgery University of Pittsburgh Medical Center

2 Why is this topic important today? You play an important role in management! Confusion, uncertainty, controversy about SLNBx Malpractice fears if you don t refer Changing evidence of the benefit of SLNBx To have the evidence to advise your patients truthfully Do you know what type of informed consent your patients get?

3 Four suggested Roles for SLNBx in melanoma 1. To improve survival in patients with intermediate thickness melanomas or high risk thin melanomas by removing nodal deposits before spread systemically or before they are detected clinically

4 Four suggested Roles for SLNBx in melanoma 2. To provide prognostic information as the most important predictor of death from melanoma

5 Four suggested Roles for SLNBx in melanoma 3. To avoid long term complications associated with complete dissection for palpable nodes by removing positive nodes early

6 Four suggested Roles for SLNBx in melanoma 4. To aid in the decision for systemic adjuvant therapy

7 Lets examine the evidence for these 4 roles for SLNBx

8 First, let s review how tumors metastasize Theory #1: Tumor cells follow an orderly progression from the primary site, first into lymphatics and then into vascular system to form distant metastatic deposits. (SLN is first site of metastasis) Theory #2: Tumor cells spread simultaneously through the lymphatic system and the vascular system. (SLN samples tumor cells and antigens flowing from regional lymphatics)

9 So What do Lymph Nodes do? They Sample 4 SLN Melanoma Heart 1. Direct invasion into blood vessels - arteries or veins 2. Enter lymphatics and bypass nodes 3. Enter sentinel node and deposit or pass through 4. Bypass sentinel node and enter other nodes in basin 5. The LN samples local antigens, it is not a filter

10 How do cells metastasize? Dissemination of cancer cells is a very early event Early cancer cells are mostly dormant Dissemination of nodal and distant metastases are simultaneous. The preponderance of evidence refutes the orderly progression theory

11 Let s examine the evidence to support these 4 roles for SLNBx

12 1. Is the Role of SLNBx a Survival Benefit? No Electively removing clinically normal nodes has never provided a survival benefit for any solid tumor MSLT-I showed no survival benefit for performing a SLNBx + CLND MSLT-II (and DeCOG-SLT) showed no survival benefit to remove positive lymph nodes further down the chain in patients with a positive SLNBx.

13 2. Is SLNBx the best prognostic test? The prognostic significance of SLNBx is the most common reason offered to justify the procedure. The 2017 American Society of Clinical Oncology (ASCO)-Society of Surgical Oncology (SSO) guideline for sentinel lymph node biopsy in melanoma states: The recommendation for staging with SLN biopsy in the intermediatethickness population is based on the established prognostic significance of SLN status.. Where did the established prognostic significance come from?

14 The origin of SLNBx as the best prognostic Test MSLT-1 Confusing conclusion: SLN status was the strongest predictor of death from melanoma Risk of death from melanoma Hazard Ratio P-value SLN Status (positive vs negative) 2.4 <0.001 Breslow Thickness (per 1-mm increase) 1.59 <0.001

15 The origin of SLNBx as the best prognostic test? 10 yr melanoma-specific survival (MSS) Risk of death from melanoma HR (-) 85% 15% (+) 62% 38% yr melanoma-specific survival (MSS) Risk of death from melanoma HR 1mm 90% 10% 2mm 84% 16% 3mm 75% 25% 4mm 60% 40%

16 2. Is SLNBx the best prognostic test? Three important studies: 1. Zagarella. SLNB as the most powerful predictor.. cannot be substantiated. 2. Freeman: (Meta-analysis) SLNBx may not provide more accurate prognostic information than Breslow thickness for most melanomas. 3. Stiegel: SLN status does not offer better prognostic information compared to Breslow thickness alone.

17 *Stiegel Cleveland Clinic Data Base patients Does SLNBx give us any more info than Breslow Tx? 5 year Survival % according to Breslow thickness and SLN status* Thickness SLN + Breslow thickness SLN P-value

18 2. Is SLNBx the best prognostic test? No Most melanoma patients are not a candidate for the test: 70% of patients have melanomas less than 1mm thick Many of the remaining 30% of eligible patients choose not to have the test The test fails most patients who have the test: The False negative rate is up to 14%, The False positive rate is 11-34% SLNBx only identifies one third of patients who will die from melanoma Twice as many SLN- patients die as SLN+ patients

19 Better prognostic tools for melanoma patients Web-based models using known clinic-pathologic features Breslow thickness plus other important data LifeMath.net Memorial Sloan Kettering Nomogram AJCCmelanomaprognosis.net Gene Expression Profile GEP predicts metastatic events and death better than SLNBx or any other prognostic tool alone Combined with clinicopathologic factors may be better

20 3. Is the role of SLNBx to avoid the long-term complications associated with CLND? Group 1000 patients Complication rate Number of patients with complications Total number of patients with complications CLND for palpable disease (195 patients) 20% CLND for SLN+ biopsy (160 patients) CLND for false (-) SLN (40 patients) SLN biopsy alone (800 patients) 12.4% 20 20% 8 3.6% 30 58

21 4. Can SLNBx identify patients who benefit from Adjuvant Systemic Therapy? Not yet Most studies have been limited to unresectable, advanced metastatic melanoma, not Stage IIIA SLN+ patients KEYNOTE-006: Pembrolizumab versus ipilimumab for advanced melanoma. This study enrolled only unresectable or advanced melanoma, not stage IIIA. CheckMate 238: Nivolumab versus Ipilimumab in resected stage III or IV Melanoma. This study enrolled only Stage IIIB, IIIC, or IV melanoma. CheckMate 066: Nivolumab in unresectable Stage III or IV melanoma BRAF native melanoma. CheckMate 067: Nivolumab and Ipilimumab in advanced melanoma. This study enrolled only Stage III unresectable or Stage IV melanoma.

22 4. Can SLNBx identify patients who benefit from Adjuvant Systemic Therapy? Not yet 1. Ipilimumab (CTLA-4) alone is approved for Stage IIIA patients with SLN deposits >1mm in diameter {EORTC 18071} Ipi prolonged survival in the entire group of stage III patients There was no apparent survival advantage for Stage IIIA patients with microscopic disease Eggermont (author) Cost for drug alone, first year of 3yr = $700,000. Side effects severe (five deaths [1.1%] due to drug). Ipi is not a cost effective choice for Stage IIIA patients

23 4. Can SLNBx identify patients who benefit from Adjuvant Systemic Therapy? Not yet 2. Dabrafenib (BRAF) + Trametinib (MEK) in Stage III BRAF mutated melanoma: (SLN+ with deposits > 1mm diameter only accounted for 18% pts) {COMBI-AD} Few patients eligible: Only 20% of SLN patients are positive, only 50% of those have BRAF mutations, and only 20% of those have deposits > 1mm, so only 2% of SLN patients would be eligible. The combination drug increased relapse-free survival compared to placebo, but the overall survival effect was not significant in the first interim analysis Cost - $250,000 / year for drugs alone. Mitogen-activated protein kinase inhibitors are not a costeffective choice for Stage IIIA patients

24 4. Can SLNBx identify patients who benefit from Adjuvant Therapy? Not yet To date, there is no systemic adjuvant therapy that prolongs survival in patients with clinically normal nodes, or patients who are SLNBx positive

25 Summary of the evidence for the role of SLNBx 1. Not a procedure that provides a survival benefit 2. Not the best prognostic test 3. Does not reduce the long term complications of complete lymph node dissection 4. Does not select patients for systemic adjuvant therapy - yet

26 The last word: Your role 1. Provide true informed consent. 32% of patients believe it would prevent disease-spread. 2. Offer Clinical trials for systemic adjuvant therapy. Know what is available locally 3. Pay attention to the literature: Watch for adjuvant therapy indicated for patients at high risk for metastasis staged by SLNBx, Class 2b Gene Expression Profile test results, or other prognostic tests.

27 References Slide 9: Fisher B. Biological research in the evolution of cancer surgery: a personal perspective. Cancer Res. 2008;68(24): Slide 10: Eyles J, Puaux AL, Wang X, et al. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J Clin Invest. 2010;120(6): Röcken M. Early tumor dissemination, but late metastasis: insights into tumor dormancy. J Clin Invest. 2010;120(6): Harper KL, Sosa MS, Entenberg D, et al. Mechanism of early dissemination and metastasis in Her2+ mammary cancer. Nature Hosseini R, Lamers GE, Soltani HM, Meijer AH, Spaink HP, Schaaf MJ. Efferocytosis and extrusion of leukocytes determine the progression of early mycobacterial pathogenesis. J Cell Sci. 2016;129(18):

28 References (cont) Slide 12: Cady B. Lymph node metastases. Indicators, but not governors of survival. Arch Surg. 1984;119(9): Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7): Faries MB, Thompson JF, Cochran AJ, et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med. 2017;376(23):

29 References (cont) Slide 16: Zagarella S, Lee S, Heenan P. Sentinel lymph node biopsy status is not the most powerful of prognosis in cutaneous melanoma. Australas J Dermatol. 2017;58(4): Freeman SR, Gibbs BB, Brodland DG, Zitelli JA. Prognostic value of sentinel lymph node biopsy compared with that of Breslowthickness: implications for informed consent in patients with invasive melanoma. Dermatol Surg. 2013;39(12): Stiegel E, Xiong D, Ya J, Funchain P, et al. Prognostic value of sentinel lymph node biopsy according to Breslow thickness for cutaneous melanoma. Accepted for publication to the Journal of the American Academy of Dermatology January 2018.

30 References (cont) Slide 18: Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7): Gerami P, Cook RW, Russell MC, et al. Gene expression profiling for molecular staging of cutaneous melanoma in patients undergoing sentinel lymph node biopsy. J Am Acad Dermatol. 2015;72(5): e783. Slide 19: Gerami P, Cook RW, Russell MC, et al. Gene expression profiling for molecular staging of cutaneous melanoma in patients undergoing sentinel lymph node biopsy. J Am Acad Dermatol. 2015;72(5): e783. Ferris LK, Farberg AS, Middlebrook B, et al. Identification of high-risk cutaneous melanoma tumors is improved when combining the online American Joint Committee on Cancer Individualized Melanoma Patient Outcome Prediction Tool with a 31-gene expression profile-based classification. J Am Acad Dermatol. 2017;76(5): e813.

31 References (cont) Slide 22: Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390(10105): Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. 2017;377(19): Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4): Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017;377(14):

32 References (cont) Slide 23: Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med. 2016;375(19): Slide 24: Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. 2017;377(19): Slide 27: Sadideen H, Saxena S, Dobbs TD, Adams TS. Patient experience of sentinel lymph node biopsy for melanoma. J Plast Reconstr Aesthet Surg. 2017;70(5):