Arising from: Thomas JM (2008) Prognostic false-positivity of the sentinel node in melanoma. Nat Clin Pract Oncol 5: 18–23 doi: 10.1038/ncponc1014

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