Sentinel node biopsy (SNB) has become the standard procedure following the excision of primary melanoma tumors with a Breslow's thickness ≥ 1 mm or IV/V Clark's level. To date, there is agreement that this minimal invasive surgery alone has no impact on overall survival. In a randomized study, Morton et al. stated that no survival benefit was associated with SNB compared with observation,1 but despite this finding the authors concluded that SNB should be preferred to observation. On the basis of these conclusions, Rosenberg commented that although SNB provides prognostic information it is an expensive procedure with associated morbidity.2 Ross et al. reported the results of the Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1) that demonstrated a non-significant survival advantage for patients in the SNB group at a median follow-up of 5 years. However, the authors noted that SN-positive patients who underwent immediate lymphadenectomy (selective lymphadenectomy) had a significant (20%) survival advantage compared with those in the observation group who subsequently developed palpable nodal disease,3 similarly to the results (P = 0.04) in World Health Organization's randomized trial.4 These data demonstrate that SN micrometastasis detected only by immunohistochemistry can become macrometastasis when detected by routine histopathology with greater probability of systemic dissemination and worse prognosis,5 in addition to the possibility of 'false positivity' as noted by Thomas.6 Early surgical and medical treatment of nodal disease could favourably alter the natural history of melanoma.
High-dose interferon-alpha (HDI) has been shown to increase recurrence-free survival (RFS) but no clear improvement in terms of overall survival for patients with high-risk disease.7,8 A recent study demonstrated that adjuvant HDI is most beneficial in terms of RFS rather than overall survival for patients with stage IIIA disease, confirming the value of SNB as an important staging procedure.9 HDI is associated with toxicity and pegylated interferon-alpha (PEG-IFN-alpha) is preferred owing to its favorable tolerability and compliance when used at a dose of 4.5–7.5 µg/kg/wk.10 The EORTC 18991 trial demonstrated that PEG-IFN-alpha (6 µg/kg/wk for 8 weeks as induction therapy followed by 3 µg/kg/wk for 12 months as maintenance phase) is an efficacious post-surgical adjuvant therapy for stage III–N1 (microscopic SN involvement). In particular, PEG-IFN-alpha produces favorable 4-year RFS with acceptable and reversible grade 3–4 toxicity,11 comparable to the findings with HDI.9 Further follow-up, however, might prove beneficial in terms of overall survival, especially for the N1 subset of patients. It would be interesting to investigate the RFS, overall survival and toxicity outcomes after maintenance treatment with PEG-IFN-alpha for 5 years at a dose of 3 µg/kg twice a week,10 and to determine the outcome in patients with stage IIIA and IIIB melanoma in the N1 subgroup. In fact, Kirkwood and coauthors observed that the efficacy of HDI seems greater when the metastasis burden is small12 and this approach might cure microscopic residual disease after SNB in some cases. The identification of molecular prognostic factors13 in SN metastasis could predict therapeutic benefit of the high-dose PEG-IFN-alpha and indicate which patients have to be selected for improved therapeutic outcomes, particularly in terms of overall survival.
We agree with the conclusions of Sondak et al. who commented that more and more patients with stage IIIA-B melanoma will be diagnosed worldwide because of the commonly used SNB procedure and we agree on the importance of using high-dose PEG-IFN-alpha for a prolonged period as adjuvant therapy in early advanced disease.14 Moreover, patients with more advanced stage IIIC–N2 melanoma (clinically palpable SN involvement) could be selected for the post-surgical adjuvant combination therapy with high-dose PEG-IFN-alpha and tailored multitarget tyrosine kinase inhibitors (MTKIs).15,16
References
Morton DL et al. (2006) Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355: 1307–1317
Rosenberg SA (2008) Why perform sentinel-lymph-node biopsy in patients with melanoma? Nat Clin Pract Oncol 5: 1
Ross MI and Gershenwald JE (2008) How should we view the results of the Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1)? Ann Surg Oncol 15: 670–673
Cascinelli N et al. (1998). Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 351: 793–796
Kretschmer L et al. (2004) Patients with lymphatic metastasis of cutaneous malignant melanoma benefit from sentinel lymphonodectomy and early excision of their nodal disease. Eur J Cancer 40: 212–218
Thomas JM (2008) Prognostic false-positivity of the sentinel node in melanoma. (2008) Nat Clin Pract Oncol 5: 18–23
Kirkwood JM et al. (1996) Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14: 7–17
Kirkwood JM et al. (2000) High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18: 2444–2458
Anaya DA et al. (2008) Adjuvant high-dose interferon for cutaneous melanoma is most beneficial for patients with early stage III disease. Cancer 112: 2030–2037
Bukowski RM et al. (2002) Treating cancer with PEG Intron: pharmacokinetic profile and dosing guidelines for an improved interferon-alpha-2b formulation. Cancer 95: 389–396
Eggermont AMM et al. (2008) Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet 372: 117–126
Kirkwood JM et al. (2008) Adjuvant therapy with high-dose interferon α2b in patients with high-risk stage IIB/III melanoma. Nat Clin Pract Oncol 5: 2–3
Palmieri G et al. (2007) Issues affecting molecular staging in the management of patients with melanoma. J Cell Mol Med 11 : 1–17
Sondak VK and Flaherty LE (2008) Adjuvant therapy of melanoma: is pegylated interferon alfa-2b what we've been waiting for? Lancet 372: 89–90
Fecher LA et al. (2008) The MAPK pathway in melanoma. Curr Opin Oncol 20: 183–189
Eberle J et al. (2007) Overcoming apoptosis deficiency of melanoma – hope for new therapeutic approaches. Drug Resist Updat 10: 218–234
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Minutilli, E., Trefzer, U., Stockfleth, E. et al. Sentinel node biopsy needs for a suitable therapeutic management of the cutaneous melanoma. Nat Rev Clin Oncol 6, E1 (2009). https://doi.org/10.1038/ncponc1302
Issue Date:
DOI: https://doi.org/10.1038/ncponc1302